Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues: Total synthesis and structure-cytotoxicity relationships

Article abstract of DOI:10.1021/jo9606113

The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

Full text of DOI:10.1021/jo9606113

5326
J . Org. Chem. 1996, 61, 5326-5351
Ap lyr on in e A, a P oten t An titu m or Su bsta n ce of Ma r in e Or igin ,
Ap lyr on in es B a n d C, a n d Ar tificia l An a logu es: Tota l Syn th esis
a n d Str u ctu r e-Cytotoxicity Rela tion sh ip s
Hideo Kigoshi, Kiyotake Suenaga, Tsuyoshi Mutou, Takeshi Ishigaki, Toshiyuki Atsumi,
Hiroyuki Ishiwata, Akira Sakakura, Takeshi Ogawa, Makoto Ojika, and Kiyoyuki Yamada*
Department of Chemistry, Faculty of Science, Nagoya University, Chikusa, Nagoya 464, J apan
Received April 2, 1996X
The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine
origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the
C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans
aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide
7 followed by J ulia olefination with sulfone 8 gave the C5-C20 segment 9, while the J ulia coupling
reaction between segments 5 and 6 provided the C21-C34 segment 10. J ulia olefination between
segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which
was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of
two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for
the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural
congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis
of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the
structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and
their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side-
chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological
studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and
depolymerized F-actin to G-actin.
The sea hare Aplysia kurodai is known to be a rich
at its terminus and that the hydroxyl groups in 1 are
esterified with two amino acids. Aplyronine A (1) is
structurally related to a family of 22-membered mac-
rolides called scytophycins,4 which includes scytophycin
C. While the N,N,O-trimethylserine group in 1 is known
to play an important role in its cytotoxicity,2a more
detailed studies on the structure-cytotoxicity relation-
ships in 1 are needed. Although 1 exhibits strong
cytotoxicity (IC50 ) 0.48 ng/ mL against HeLa S3 cells)2a,5
and exceedingly potent antitumor activities in vivo (T/
C: 545% against P388 murine leukemia, 556% against
Lewis lung carcinoma, 398% against Ehrlich carcinoma,
255% against colon 26 carcinoma, and 201% against B16
melanoma),2a the scarcity of a natural supply has pre-
vented the further evaluation of this compound as a
potential therapeutic agent. These facts and the novel
polyfunctional 24-membered lactone structures of 1-3
prompted us to attempt to synthesize these natural
source of various unique metabolites.1 In the course of
our search for bioactive compounds from J apanese speci-
mens of this animal, we isolated a strongly cytotoxic
compound called aplyronine A (1) as a minute constituent
and elucidated its gross structure.2a Further, the abso-
lute stereochemistry of 1 was determined on the basis of
NMR spectroscopy and organic synthetic methods.2b-d
Aplyronines B (2) and C (3) were isolated from the sea
hare Aplysia kurodai together with 1, and their gross
structures were deduced by comparison of their spectral
data with those of 1.2a In addition, their stereostructures
were established by synthesis.3c The structural features
of 1 are that 1 is a 24-membered macrolide which
possesses a side chain with an N-formyl enamine group
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Yamamura, S.; Hirata, Y. Tetrahedron 1963, 19, 1485-1496.
Matsuda, H.; Tomiie, Y.; Yamamura, S.; Hirata, Y. J . Chem. Soc.,
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Lett. 1977, 2171-2172. Howard, B. M.; Fenical, W. Phytochemistry
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Kigoshi, H.; Imamura, Y.; Yoshikawa, K.; Yamada, K. Tetrahedron
Lett. 1990, 31, 4911-4914. Ojika, M.; Kigoshi, H.; Yoshikawa, K.;
Nakayama, Y.; Yamada, K. Bull. Chem. Soc. J pn. 1992, 65, 2300-
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5307-5308.
(3) For preliminary communications, see: (a) Kigoshi, H.; Ojika, M.;
Suenaga, K.; Mutou, T.; Hirano, J .; Sakakura, A.; Ogawa, T.; Nisiwaki,
M.; Yamada, K. Tetrahedron Lett. 1994, 35, 1247-1250. (b) Kigoshi,
H.; Ojika, M.; Ishigaki, T.; Suenaga, K.; Mutou, T.; Sakakura, A.;
Ogawa, T.; Yamada, K. J . Am. Chem. Soc. 1994, 116, 7443-7444. (c)
Suenaga, K.; Ishigaki, T.; Sakakura, A.; Kigoshi, H.; Yamada, K.
Tetrahedron Lett. 1995, 36, 5053-5056.
(4) (a) Isolation and structures: Ishibashi, M.; Moore, R. E.; Patter-
son, G. M. L.; Xu, C.; Clardy, J . J . Org. Chem. 1986, 51, 5300-5306.
Carmeli, S.; Moore, R. E.; Patterson, G. M. L. J . Nat. Prod. 1990, 53,
1533-1542. J ung, J . H.; Moore, R. E.; Patterson, G. M. L. Phytochem-
istry 1991, 30, 3615-3616. (b) Synthetic studies: Paterson, I.; Smith,
J . D. J . Org. Chem. 1992, 57, 3261-3264. Paterson, I.; Cumming, J .
G. Tetrahedron Lett. 1992, 33, 2847-2850. Paterson, I.; Yeung, K.-S.
Tetrahedron Lett. 1993, 34, 5347-5350. Paterson, I.; Smith, J . D.
Tetrahedron Lett. 1993, 34, 5351-5354. Paterson, I.; Yeung, K.-S.;
Smaill, J . B. Synlett 1993, 774-776. Paterson, I.; Cumming, J . G.;
Smith, J . D.; Ward, R. A.; Yeung, K.-S. Tetrahedron Lett. 1994, 35,
3405-3408.
(2) (a) Yamada, K.; Ojika, M.; Ishigaki, T.; Yoshida, Y.; Ekimoto,
H.; Arakawa, M. J . Am. Chem. Soc. 1993, 115, 11020-11021. (b) Ojika,
M.; Kigoshi, H.; Ishigaki, T.; Yamada, K. Tetrahedron Lett. 1993, 34,
8501-8504. (c) Ojika, M.; Kigoshi, H.; Ishigaki, T.; Nisiwaki, M.;
Tsukada, I.; Mizuta, K.; Yamada, K. Tetrahedron Lett. 1993, 34, 8505-
8508. (d) Ojika, M.; Kigoshi, H.; Ishigaki, T.; Tsukada, I.; Tsuboi, T.;
Ogawa, T.; Yamada, K. J . Am. Chem. Soc. 1994, 116, 7441-7442.
(5) The IC50 values for the cytotoxicities of aplyronines 1-3 are
different from those2a previously reported. Since the IC50 values in the
present study were shown to be reproducible, these values will be used
hereafter.
S0022-3263(96)00611-1 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5327
Sch em e 1
compounds and their artificial analogues. We report here
the detailed synthesis of aplyronines A (1),3a,b B (2),3c and
C (3),3c and their artificial analogues, and describe the
structure-cytotoxicity relationships in the aplyronines
and artificial analogues, and further describe that the
target biomolecule that interacts with 1 is actin, the
protein in cytoskeleton.
between the C5-C20 segment 9 and the C21-C34
segment 10 and a macrolactonization by the Yamaguchi
method.10
Resu lts a n d Discu ssion
Syn th esis of th e C5-C20 Segm en t. Synthesis of the
C5-C11 segment 4 began with the Evans aldol reaction
between imide 117 and (R)-3-(benzyloxy)-2-methylpropa-
nal11 to afford hydroxy imide 12 (88%) (Scheme 2).
Removal of the chiral auxiliary in 12 with trimethylalu-
minum and N,O-dimethylhydroxylamine hydrochloride12
gave amide 13 in 96% yield. Amide 13 was silylated with
tert-butyldimethylsilyl triflate (TBSOTf) and 2,6-luti-
dine,13 to give silyl ether 14 quantitatively. Reduction
of 14 with diisobutylaluminum hydride (DIBAL) gave
aldehyde 15 (99%), the Horner-Emmons reaction of
which with (i-PrO)2P(O)CH2COOEt gave conjugated ester
16 quantitatively. Ester 16 was reduced with DIBAL to
allylic alcohol 17 quantitatively, which in turn was
transformed into epoxide 18 under Sharpless asymmetric
epoxidation conditions,8 using (+)-diethyl tartrate, to give
one diastereomer in 96% yield. Reductive cleavage of the
oxirane ring in 18 with sodium bis(2-methoxyethoxy)-
aluminum hydride (Red-Al)14 afforded diol 19a (74%),
which possesses anti-syn-anti stereochemistry concerning
the four contiguous stereocenters, along with triol 19b
(15%). The primary hydroxyl group in 19a was protected
by pivaloyl chloride and pyridine, giving ester 20 in 99%
yield. Removal of the benzyl protecting group in 20 by
hydrogenolysis afforded diol 21 in 99% yield. Diol 21 was
converted with Bu3P-PhSSPh15 into sulfide 22 (91%), the
secondary hydroxyl group of which was silylated with
triethylsilyl chloride (TESCl) and imidazole to give silyl
ether 23 quantitatively. Compound 23 was oxidized with
Scheme 1 outlines the synthesis of the aplyronines,
which includes the following key operations: (1) three
of the four contiguous stereocenters, C7-C106 in the C5-
C11 segment 4, C23-C26 in the C21-C27 segment 5,
and C29-C32 in the C28-C34 segment 6, were con-
structed by the Evans aldol reaction7 and the Sharpless
epoxidation;8 (2) the C5-C20 segment 9 was synthesized
by connecting segments 4, 7, and 8 in sequential order;
(3) the C21-C34 segment 10 was prepared by connecting
segments 5 and 6; and (4) a J ulia olefination reaction9
(10) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(11) Meyers, A. I.; Babiak, K. A.; Campbell, A. L.; Comins, D. L.;
Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudspeth, J . P.; Kane,
J . M.; Reider, P. J .; Roland, D. M.; Shimizu, K.; Tomioka, K.; Walkup,
R. D. J . Am. Chem. Soc. 1983, 105, 5015-5024.
(12) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171-4174. Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc.
1988, 110, 2506-2526.
(6) The numbering used in this paper corresponds to that of
aplyronine A (1).
(13) Corey, E. J .; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.
(7) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129.
(14) Finan, J . M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719-2722.
Nicolaou, K. C.; Uenishi, J . J . Chem. Soc., Chem. Commun. 1982,
1292-1293.
(8) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5974-
5976.
(9) J ulia, M.; Paris, J .-M. Tetrahedron Lett. 1973, 4833-4836.
(15) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409-1412.

5328 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
Sch em e 2a
Sch em e 3a
a
(a) p-Toluenesulfonyl chloride (TsCl), pyridine, 0 °C, 2 h; (b)
NaI, CaCO3, acetone, 50 °C, 13.5 h, 99% (2 steps); (c) LiAlH4, THF,
23 °C, 1 h, 100%; (d) t-BuPh2SiCl (TBDPSCl), imidazole, DMF, 0
°C, 1.7 h; (e) MeI, NaH, THF, 0 °C, 1 h, 95% (2 steps); (f) Bu4NF,
THF, 23 °C, 12 h, 100%; (g) TsCl, pyridine, 0 °C, 2.5 h; (h)
PhSO2Me, BuLi, THF, 23 °C, 3.2 h, 77% (2 steps).
Sch em e 4a
a
(a) Bu2BOTf, Et3N, CH2Cl2, 0 °C, then (R)-3-(benzyloxy)-2-
methylpropanal, -78 °C, 3 h f 0 °C, 20 min, 88%; (b) Me3Al,
MeONHMe‚HCl, THF, toluene, CH2Cl2, -10 f 0 °C, 1.6 h, 96%;
(c) t-BuMe2SiOTf (TBSOTf), 2,6-lutidine, CH2Cl2, 0 °C, 1 h, 100%;
(d) DIBAL, THF, hexane, -78 °C,
2 h, 99%; (e) (i-PrO)2-
P(O)CH2COOEt, t-BuOK, THF, -78 °C, 1 h f 0 °C, 1.5 h, 100%;
(f) DIBAL, CH2Cl2, hexane, -78 °C, 1 h, 100%; (g) Ti(O-i-Pr)4, (+)-
diethyl tartrate, t-BuOOH, molecular sieves 4 Å, CH2Cl2, -23 °C,
1 h, 96%; (h) NaAlH2(OCH2CH2OMe)2, DME, 0 °C, 2 h, 74%; (i)
pivaloyl chloride (PivCl), pyridine, 0 °C, 1.5 h, 99%; (j) H2, 10%
Pd-C, EtOH, 23 °C, 3.5 h, 99%; (k) (PhS)2, Bu3P, DMF, 23 °C, 12
h, 91%; (l) Et3SiCl (TESCl), imidazole, DMF, 23 °C, 1.4 h, 100%;
(m) m-CPBA, NaHCO3, CH2Cl2, 23 °C, 1.5 h, 100%.
m-chloroperoxybenzoic acid to the C5-C11 segment 4
quantitatively.
Two small segments, iodide 7 and sulfone 8, were
prepared as follows (Scheme 3).
Iodide 7 was prepared from commercially available (R)-
2,2-dimethyl-1,3-dioxolane-4-methanol (24), which was
converted into alcohol 25.16 Reaction of alcohol 25 with
p-toluenesulfonyl chloride gave tosylate 26, which was
converted into iodide 7 in 99% yield.
Sulfone 8 was synthesized from lactone 29,17 which was
prepared from commercially available (R)-dihydro-5-
(hydroxymethyl)-2(3H)-furanone (28). Reduction of 29
with LiAlH4 gave diol 30 quantitatively. Protection of
the primary hydroxyl group in 30 was effected selectively
with tert-butyldiphenylsilyl chloride, and the secondary
hydroxyl group of the resulting silyl ether 31 was
methylated to afford methyl ether 32 (95% from 30). The
silyl group of 32 was removed with Bu4NF to give alcohol
33 quantitatively. Alcohol 33 was converted into tosylate
34, reaction of which with the carbanion of methyl phenyl
sulfone gave sulfone 8 (77% from 33).
a
(a) 4, LDA, THF, -78 °C, 25 min, then 7, HMPA, 23 °C, 1.5
h; (b) 5% Na-Hg, Na2HPO4, MeOH, 0 °C, 2 h, 76% (2 steps); (c)
H2, 10% Pd-C, NaHCO3, EtOH, 23 °C, 2.5 h, 98%; (d) Dess-
Martin periodinane, pyridine, CH2Cl2, 23 °C, 0.7 h, 91%; (e)
Me2CuLi, Et2O, -78 °C, 1 h; (f) Dess-Martin periodinane,
pyridine, CH2Cl2, 23 °C, 0.7 h, 93% (2 steps); (g) 8, BuLi, THF,
-78 °C, 2 h; (h) 6% Na-Hg, Na2HPO4, MeOH, 0 °C, 2.3 h, 44% (2
steps); (i) AcOH, H2O, THF, 23 °C, 6.6 h, 97%; (j) DMSO, Ac2O,
AcOH, 23 °C, 2 h f 40 °C, 5.5 h, 86%; (k) HCO2H, Et2O, 23 °C, 15
min, 90%; (l) Dess-Martin periodinane, pyridine, CH2Cl2, 23 °C,
1 h, 80%.
Alkylation18 of the carbanion generated from 4 with
iodide 7 in THF-HMPA and subsequent reductive
removal of the sulfonyl group with 5% sodium amalgam
afforded benzyl ether 35 in 76% yield (Scheme 4).
Addition of HMPA as a cosolvent in the alkylation
reaction improved the yield of the alkylation product
remarkably. Hydrogenolysis of 35 with 10% Pd-C as a
catalyst gave alcohol 36 (98%). Although we examined
the J ulia olefination between 4 and aldehyde 27 and
(16) This compound was prepared by a route different from that
employed in the present work: Takatani, M.; Yoshioka, Y.; Tasaka,
A.; Terashita, Z.; Imura, Y.; Nishikawa, K.; Tsushima, S. J . Med. Chem.
1989, 32, 56-64.
(17) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J . Org. Chem. 1988,
53, 4094-4098.
(18) Kondo, K.; Tunemoto, D. Tetrahedron Lett. 1975, 1007-1010.
J ulia, M.; Blasioli, C. Bull. Soc, Chim. Fr. 1976, 1941-1946.

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5329
Sch em e 5a
subsequent catalytic reduction that led to alcohol 36,
alcohol 36 was obtained in low yield (57% overall yield)
and was contaminated with an epimer at C13. Dess-
Martin oxidation19 of alcohol 36 provided aldehyde 37 in
91% yield, whereas under Swern oxidation conditions20
epimerization at C13 occurred to a considerable extent
during the conversion of 36 into 37. Addition of Me2CuLi
to aldehyde 37 gave a diastereomeric mixture of second-
ary alcohols, which was oxidized with the Dess-Martin
periodinane to methyl ketone 38 in 93% yield.
J ulia coupling between 38 and the carbanion generated
from sulfone 8 provided a diastereomeric mixture of
hydroxy sulfones, which was treated with 6% sodium
amalgam to give (E)-olefin 39 (44%), (Z)-olefin 40 (19%),
and a diastereomeric mixture of tertiary alcohol 41 (25%).
(Z)-Olefin 40 could be isomerized to the desired (E)-olefin
39 under equilibrium conditions promoted by PhSH and
AIBN21 in 41% yield, and a diastereomeric mixture of
tertiary alcohol 41 was dehydrated with POCl3 and
pyridine to give (E)-olefin 39 in 43% yield. At this stage,
the TES protecting group at C7 in 39 was changed to a
(methylthio)methyl (MTM) group, because the protecting
group at C7 in 39 must be differentiated from the TES
protecting groups at C23 and C25 in the C21-C34
segment 10 to be coupled with 9 later in the synthesis
(cf. Scheme 8). Thus, the TES group in 39 was hydro-
lyzed selectively under acidic conditions using aqueous
acetic acid in THF to give alcohol 42 in 97% yield.
Protection of the hydroxyl group in 42 was effected by
treatment with DMSO, Ac2O, and AcOH to give MTM
ether 43 (86%) along with ketone 44 (14%). Stereose-
lective reduction of ketone 44 to 42 could not be achieved
with a variety of reagents (NaBH4, LiAlH(O-t-Bu)3, etc.).
The trityl group in 43 was removed with formic acid in
ether22 to afford alcohol 45 (90%). Oxidation of the
hydroxyl group in alcohol 45, which possesses an MTM
group that is liable to be oxidized, was effected with the
Dess-Martin periodinane to give the C5-C20 segment
9 in 80% yield, while Swern oxidation of 45 gave the
desired 9 in poor yield due to instability of the MTM
group under the oxidation conditions.
Syn th esis of th e C21-C34 Segm en t. Synthesis of
the C21-C34 segment was effected by connection of two
segments, the C21-C27 and C28-C34 segments 5 and
6, both of which have the syn-anti-anti relative stereo-
chemistry with regard to the four contiguous stereo-
centers. Both segments were prepared by a synthetic
strategy similar to that for the C5-C11 segment 4. The
synthesis of 5 started with the Evans aldol reaction
between imide ent-11 and 3-(benzyloxy)propanal to give
hydroxy imide 46 in 85% yield as a single diastereomer
(Scheme 5). Transamidation of 46 to amide 47 followed
by protection of the hydroxy group in 47 afforded silyl
ether 48 (99% from 46). The amide group in 48 was
reduced with DIBAL to give aldehyde 49 (98%). The
Horner-Emmons reaction of 49 with (i-PrO)2P(O)CH2-
COOEt provided stereoselectively conjugated ester 50a
(96%) along with conjugated ester 50b (3%). Conjugated
ester 50a was quantitatively converted into allylic alcohol
51 by DIBAL reduction. The Sharpless oxidation of 51
using (-)-diethyl tartrate gave epoxide 52 (99%), treat-
a
(a) Bu2BOTf, Et3N, CH2Cl2, 0 °C, then 3-(benzyloxy)propanal,
-78 °C, 2 h f 0 °C, 2 h, 85%; (b) Me3Al, MeONHMe‚HCl, THF,
toluene, -10 f 0 °C, 1.5 h, 99%; (c) Et3SiCl (TESCl), imidazole,
DMF, 23 °C, 35 min, 100%; (d) DIBAL, THF, hexane, -78 °C, 1.5
h, 98%; (e) (i-PrO)2P(O)CH2COOEt, t-BuOK, THF, -78 °C, 1.5 h
f 0 °C, 1.5 h, 96%; (f) DIBAL, CH2Cl2, hexane, -78 °C, 1.5 h,
100%; (g) Ti(O-i-Pr)4, (-)-diethyl tartrate, t-BuOOH, molecular
sieves 4 Å, CH2Cl2, -23 °C, 2 h, 99%; (h) Me2CuLi, Et2O, -20 °C,
14 h f 0 °C, 2 h, 75%; (i) (PhS)2, Bu3P, DMF, 23 °C, 4 h, 99%; (j)
Et3SiCl (TESCl), imidazole, DMF, 23 °C, 2.5 h, 100%; (m) m-CPBA,
NaHCO3, CH2Cl2, 23 °C, 1 h, 100%.
ment of which with Me2CuLi23 provided diol 53a (75%),
which possesses the syn-anti-anti stereochemistry con-
cerning the four contiguous stereocenters, along with diol
53b (18%). Reaction of diol 53a with Bu3P-PhSSPh15
gave sulfide 54 in 99% yield. Protection of the secondary
hydroxy group in 54 afforded silyl ether 55, the sulfide
group of which was oxidized to give the C21-C27
segment 5 (quantitatively from 54).
Synthesis of the C28-C34 segment 6 was effected
using the same synthetic strategy as for 5. The Evans
aldol reaction of imide 11 with (benzyloxy)acetaldehyde
gave hydroxy imide 5624 (79%), which was converted into
amide 5725 in 99% yield (Scheme 6). The hydroxyl group
of 57 was silylated with tert-butyldimethylsilyl chloride
(TBSCl) to give silyl ether 5825 quantitatively. Silyl ether
58 was transformed into diol 63a by the same sequence
of reactions as described for the preparation of diol 53a
from silyl ether 48. Thus, silyl ether 58 was reduced to
aldehyde 5925 (99%), the Horner-Emmons reaction of
which with (i-PrO)2P(O)CH2COOEt gave conjugated ester
60a (90%) along with conjugated ester 60b (7%). Reduc-
(23) J ohnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 4347-4350.
(24) For the preparation of ent-56, see: Evans, D. A.; Kaldor, S. W.;
J ones, T. K.; Clardy, J .; Stout, T. J . J . Am. Chem. Soc. 1990, 112, 7001-
7031.
(25) Preparation of this compound, which was described in our
preliminary communication,3a was recently reported by Evans and
co-workers: Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J .
Am. Chem. Soc. 1995, 117, 3448-3467.
(19) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
(20) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
(21) Schwarz, M.; Graminski, G. F.; Waters, R. M. J . Org. Chem.
1986, 51, 260-263.
(22) Besodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett.
1986, 27, 579-580.

5330 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
Sch em e 6a
Sch em e 7a
a
(a) 5, BuLi, THF, -78 °C, 30 min, then 6, -78 °C, 3 h; (b) 5%
Na-Hg, Na2HPO4, MeOH, 0 °C, 2 h, 82% (2 steps); (c) Ca, liquid
NH3, THF, i-PrOH, -78 °C, 1 h, 98%; (d) H2, 5% Rh-Al2O3, EtOH,
23 °C, 1.6 h, 91%; (e) (PhS)2, Bu3P, DMF, 23 °C, 14 h, 99%; (f)
m-CPBA, NaHCO3, CH2Cl2, 23 °C, 1 h, 100%; (g) 3,4-(MeO)2-
C6H3CH2OCH2Cl, i-Pr2NEt, CH2Cl2, 23 °C, 16 h, 98%.
dioxabicyclo[3.2.1]octane compound 67. After chromato-
graphic separation, the two minor products 66b and 67
were subjected to equilibration (camphorsulfonic acid,
MeOH, 23 °C) to afford a mixture of 66a , 66b, and 67,
from which the major acetal 66a was obtained. By
repeating this procedure, 66b and 67 could be trans-
formed into 66a (74% from 65a ). The benzyl protecting
group in 66a was removed with sodium in liquid am-
monia to give diol 68, the primary hydroxyl group of
which was silylated with tert-butyldiphenylsilyl chloride
to provide silyl ether 69 (quantitatively from 66a ).
Protection of the secondary hydroxyl group in 69 as a
benzyl ether group followed by desilylation with Bu4NF
afforded alcohol 72 (74% from 69) along with silyl ether
71 (16%), which resulted from migration of the silyl group
in 69. Swern oxidation of 72 provided the C28-C34
segment 6 quantitatively.
J ulia coupling of the carbanion generated from the
C21-C27 segment 5 with the C28-C34 segment 6
afforded hydroxy sulfones, reduction of which gave olefin
73a (82% from 6) along with diastereomeric alcohols 73b
(7%) and 73c (3%) (Scheme 7). Two benzyl protecting
groups in 73a were removed with calcium in liquid
ammonia,26 to furnish diol 74 (98%), hydrogenation of
which provided diol 75 in 91% yield. Reaction of diol 75
with Bu3P-PhSSPh15 afforded sulfide 76 (99%), which
was oxidized with m-chloroperoxybenzoic acid to sulfone
77 quantitatively.
Selection of a protecting group for the C29 hydroxyl
group in 77 was crucial to the synthesis of aplyronines.
Initially, we chose a [(4-methoxybenzyl)oxy]methyl ether
group27 to protect the hydroxyl group in 77, but it turned
out that this protecting group could not be removed at
the later stage of the synthesis without decomposition
of the R,â,γ,δ-unsaturated lactone moiety in the synthetic
intermediates. Thus, we chose a [(3,4-dimethoxybenzyl)-
oxy]methyl ether group28 because it can be removed
under milder conditions using 2,3-dichloro-5,6-dicyano-
p-benzoquinone (DDQ) than those required for removal
of a [(4-methoxybenzyl)oxy]methyl group. [(3,4-Dimethox-
ybenzyl)oxy]methyl chloride28 was prepared from 3,4-
dimethoxybenzyl alcohol by the procedure reported for
a
(a) Bu2BOTf, Et3N, CH2Cl2, 0 °C, then (benzyloxy)acetalde-
hyde, -78 °C, 1 h f 0 °C, 3 h, 79%; (b) Me3Al, MeONHMe‚HCl,
THF, toluene, CH2Cl2, 0 °C, 1.5 h, 99%; (c) t-BuMe2SiCl (TBSCl),
imidazole, DMF, 23 °C, 5.5 h, 100%; (d) DIBAL, THF, hexane, -78
°C, 2 h, 99%; (e) (i-PrO)2P(O)CH2COOEt, t-BuOK, THF, -78 °C,
1.5 h f 0 °C, 1.5 h, 90%; (f) DIBAL, CH2Cl2, hexane, -78 °C, 1 h,
97%; (g) Ti(O-i-Pr)4, (+)-diethyl tartrate, t-BuOOH, molecular
sieves 4 Å, CH2Cl2, -23 °C, 1.5 h, 96%; (h) Me2CuLi, Et2O, -23
°C, 6 h f 4 °C, 16 h, 93%; (i) p-toluenesulfonyl chloride (TsCl),
pyridine, 0 °C, 5 h, 100%; (j) NaCN, DMSO, 50 °C, 2.5 h, 91%; (k)
DIBAL, CH2Cl2, hexane, -78 °C, 1 h, then SiO2, 23 °C, 14.5 h; (l)
CSA, MeOH, reflux, 1.6 h; (m) CSA, MeOH, 23 °C, 14 h, 74% from
65a ; (n) Na, THF, liquid NH3, -78 °C, 30 min, 100%; (o)
t-BuPh2SiCl (TBDPSCl), imidazole, DMF, 0 °C, 1.3 h, 100%; (p)
PhCH2Br (BnBr), NaH, DMF, 0 °C, 15 min f 23 °C, 1 h; (q)
Bu4NF, THF, 23 °C, 13 h, 74% (2 steps); (r) DMSO, (COCl)2,
CH2Cl2, -78 °C, 13 min, then Et3N, 0 °C, 25 min, 100%.
tion of 60a afforded allylic alcohol 61 (97%), which was
transformed into epoxide 62 by Sharpless epoxidation
using (+)-diethyl tartrate in 96% yield as a single
diastereomer. Regioselective oxirane ring opening of 62
with Me2CuLi gave diol 63a in 93% yield, which pos-
sesses the syn-anti-anti stereochemistry with regard to
the four contiguous stereocenters, along with diol 63b
(7%).
Diol 63a was converted with p-toluenesulfonyl chloride
and pyridine into tosylate 64 quantitatively, the reaction
of which with NaCN gave nitrile 65a (91%) and oxetane
65b (7%). Reduction of 65a with DIBAL and subsequent
hydrolysis using silica gel afforded a hemiacetal, acid
treatment of which in MeOH provided a separable
mixture of diastereomeric acetals 66a and 66b and the
(26) Hwu, J . R.; Chua, V.; Schroeder, J . E.; Barrans, R. E., J r.;
Khoudary, K. P.; Wang, N.; Wetzel, J . M. J . Org. Chem. 1986, 51,
4731-4733.
(27) Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762-
763. Kozikowski, A. P.; Wu, J .-P. Tetrahedron Lett. 1987, 28, 5125-
5128.
(28) Gu¨ndel, W.-H.; Kramer, W. Chem. Ber. 1978, 111, 2594-2604.

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5331
Sch em e 8a
urated ester 81 in 89% yield, which was contaminated
with a small amount (about 5%) of (4Z)-isomer. As
described above, the minor geometrical isomers concern-
ing the C4 and C20 double bonds were separated by
HPLC after macrolactonization of seco acid 83. Selective
removal of the two TES groups in 81 gave diol 82, the
ester group of which was hydrolyzed with LiOH in
aqueous methanol to afford seco acid 83 (quantitatively
from 81). The macrolactonization of 83 was accomplished
by the modified Yamaguchi method,10,30 to yield the 24-
membered lactone 84 (40%) and the 26-membered lactone
85 (28%). The 26-membered lactone 85 could be isomer-
ized to the 24-membered lactone 84 under equilibrium
conditions (84/85 ) ca. 2.5/1) in the presence of Ti(O-i-
31
Pr)4 (84: 65% isolation yield).
Silylation of the hydroxyl group in 84 with TBSCl gave
disilyl ether 86a in 98% yield (Scheme 9). The cyclic
acetal moiety of 86a was hydrolyzed under acidic condi-
tions to afford a hemiacetal, which was reduced with
NaBH(OMe)3 in MeOH to give diol 87a in 72% yield.
When the reduction described above was carried out with
NaBH4 in EtOH, reduction took place not only at the
hemiacetal moiety but also at the R,â,γ,δ-unsaturated
lactone system. The primary hydroxyl group of 87a was
protected as a trityl ether group to give trityl ether 88a
(98%), the secondary hydroxyl group of which was acety-
lated to afford acetate 89a quantitatively. Removal of
the trityl group of 89a gave alcohol 90a (84%), the Dess-
Martin oxidation of which afforded aldehyde 91a in 88%
yield. The terminal N-formyl enamine structure was
constructed by reaction32 of 91a with N-methylformamide
in the presence of pyridinium p-toluenesulfonate (PPTS)
to afford enamide 92a in 48% yield. Removal of the
protecting group at C29 in 92a was effected with 2,3-
dichloro-5,6-dicyano-p-benzoquinone33 (DDQ) in CH2Cl2-
t-BuOH-phosphate buffer (pH 6) to give alcohol 93a in
88% yield. The remaining task necessary for the syn-
thesis of aplyronine A was the introduction of two amino
acids into 93a (Scheme 10). The hydroxyl group in 93a
was esterified with N,N-dimethylalanine under Keck
conditions.34 Esterification of alcohol 93a with (S)-N,N-
dimethylalanine gave a >9:1 mixture of the (S)- and (R)-
dimethylalanine esters 94, whereas esterification of 93a
with (R)-N,N-dimethylalanine afforded a 1:1 mixture of
the (S)- and (R)-dimethylalanine esters 94. These find-
ings suggest that (S)-N,N-dimethylalanine differs from
(R)-N,N-dimethylalanine with regard to the rate of the
esterification reaction with alcohol 93a and that the
activated forms of (S)- and (R)-N,N-dimethylalanines are
interconvertible with each other. On the basis of these
findings, the hydroxyl group of 93a was esterified with
N,N-dimethylalanine (S/R ) 3/2) under Keck conditions
to give a diastereomeric mixture of dimethylalanine
esters 94 (S/R ) 4/1) in 94% yield. Further, hydrolysis
a
(a) 10, BuLi, THF, -78 °C, 30 min, then 9, -78 °C, 2 h; (b)
Ac2O, DMAP, pyridine, 23 °C, 3 h; (c) 5% Na-Hg, Na2HPO4,
MeOH, 0 °C, 1.5 h, 88% (3 steps); (d) DIBAL, CH2Cl2, -78 °C, 2
h, 100%; (e) Dess-Martin periodinane, pyridine, CH2Cl2, 23 °C,
35 min, 85%; (f) LDA, (EtO)2P(O)CH2CHdCHCO2Et, THF, -40
°C, 8 min f 0 °C, 15 min, 89%; (g) HF‚pyridine, pyridine, THF,
23 °C, 3 h, 100%; (h) LiOH, MeOH, H2O, 23 °C, 12 h, 100%; (i)
2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, CHCl3, 23° C, 15 h,
40%; (j) Ti(O-i-Pr)4, CH2Cl2, 23 °C, 19 h, 65%.
the preparation of [(4-methoxybenzyl)oxy]methyl chlo-
ride.27 The C29 hydroxyl group of sulfone 77 was
protected with [(3,4-dimethoxybenzyl)oxy]methyl chloride
and i-Pr2NEt to give the C21-C34 segment 10 in 98%
yield.
Con str u ction of th e Ma cr ola cton e Rin g a n d Syn -
th esis of Ap lyr on in e A. With the C5-C20 and C21-
C34 segments 9 and 10 in hand, the stage was set for
the task of connecting these two segments. The J ulia
coupling of 9 and the carbanion generated from 10 gave
a diastereomeric mixture of hydroxy sulfones, acetylation
of which and subsequent reduction gave olefin 78 (88%
from 9) (Scheme 8), which was obtained as an inseparable
9:1 mixture of (20E)- and (20Z)-isomers. The minor
(20Z)-isomer could be separated by HPLC at a later stage
in the synthesis, i.e., after macrolactonization of seco acid
83. The pivaloyl group of olefin 78 was removed by
DIBAL reduction to give alcohol 79 quantitatively, and
the resulting hydroxyl group in 79 was oxidized with the
Dess-Martin periodinane to give aldehyde 80 in 85%
yield. The Horner-Emmons reaction of aldehyde 80 with
(EtO)2P(O)CH2CHdCHCOOEt29 afforded R,â,γ,δ-unsat-
(29) Sato, K.; Mizuno, S.; Hirayama, M. J . Org. Chem. 1967, 32,
177-180.
(30) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1990, 31, 6367-6370.
(31) For titanium(IV) alkoxide-catalyzed transesterification, see:
Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨gger, M. Synthesis 1982, 138-141.
(32) Kiefel, M. J .; Maddock, J .; Pattenden, G. Tetrahedron Lett.
1992, 33, 3227-3230.
(33) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888; 889-892. Aicher, T. D.; Buszek, K. R.; Fang, F. G.;
Forsyth, C. J .; J ung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.;
Spero, D. M.; Yoon, S. K. J . Am. Chem. Soc. 1992, 114, 3162-3164.
(34) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394-2395.

5332 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
Sch em e 9a
Sch em e 10a ,b
a
Synthesis of aplyronines A (1) and B (2): (a) N,N-dimethyla-
lanine (S/R ) 3/2 for 94; S/R ) 8/5 for 97), DCC, CSA, DMAP,
CH2Cl2, 23 °C, 15 h, (94) 94%, (97) 79%; (b) AgNO3, 2,6-lutidine,
H2O, THF, 30 °C, 16 h, (95) 97%, (2) 85%; (c) N,N,O-trimeth-
ylserine (S/R ) 5/2 for 96; S/R ) 1/0 for 99), DCC, CSA, DMAP,
CH2Cl2, 35 °C, 1.5 h, (96) 85%; (99) 84%; (d) HF‚pyridine, pyridine,
b
23 °C, 5 h, (1) 84%, (98) 88%. Synthesis of aplyronine C (3): (a)
N,N-dimethylalanine (S/R ) 1/1), DCC, CSA, DMAP, CH2Cl2, 23
°C, 11.5 h, 78%; (b) AgNO3, 2,6-lutidine, H2O, THF, 30 °C, 18 h,
77%; (d) HF‚pyridine, pyridine, 23 °C, 5 h, 45%.
A (1), we employed the synthetic intermediates of aply-
ronine A (1) for synthesis of aplyronines B (2) and C (3).
In the synthesis of aplyronine B (2), selection of the
protecting group for the C25 hydroxyl in the 24-
membered lactone 84 was important for the manipulation
of hydroxyl groups at C7, C9, and C29 in the later stages
of the synthesis. Initially, the 2,2,2-trichloroethoxycar-
bonyl group was chosen as a protecting group for the C25
hydroxyl, but was found to be labile under NaBH4 or
NaBH(OMe)3 reduction. Next, the hydroxyl group at C25
in 84 was protected as a (methylthio)methyl (MTM)
ether: i.e., 84 was converted into MTM ether 86b (43%)
and ketone 86c (50%) (Scheme 9). Ketone 86c could be
converted stereoselectively into 84 (75%) and the C25
epimer (9%). With the use of MTM ether 86b, aplyronine
B (2) was synthesized by a sequence of reactions similar
to that for the synthesis of aplyronine A (1) from silyl
ether 86a . Thus, MTM ether 86b was transformed into
a
(a) (86a ) TBSCl, imidazole, DMF, 60 °C, 24 h, 98%; (86b)
DMSO, Ac2O, AcOH, 40 °C, 2 h, 43%; (b) HCl, H2O, DME, 23 °C,
5.5 h; (c) NaBH(OMe)3, MeOH, 23 °C, 4.5 h, (87a ) 72% (2 steps),
(87b) 71% (2 steps); (d) TrCl, pyridine, 50 °C, 11.5 h, (88a ) 98%,
(88b) 97%; (e) Ac2O, DMAP, pyridine, 23 °C, 12.5 h, (89a ) 100%,
(89b) 99%; (f) HCO2H, Et2O, 23 °C, 15 min, (90a ) 84%, (90b) 84%;
(g) Dess-Martin periodinane, pyridine, CH2Cl2, 23 °C, 1.5 h, (91a )
88%, (91b) 73%; (h) MeNHCHO, PPTS, hydroquinone, molecular
sieves 3 Å, benzene, reflux, 6.5 h, (92a ) 48%, (92b) 42%; (i) DDQ,
CH2Cl2, t-BuOH, phosphate buffer (pH 6), 23 °C, 110 min, (93a )
88%, (93b) 69%.
35
(36) The subtle differences in the signal intensities in the 1H and
13C NMR spectra which were observed between natural and synthetic
aplyronine A (1) are due to the different diastereomeric ratios of two
amino acid moieties. Natural aplyronine A (1) was obtained as a
diastereomeric mixture with respect to two amino acids,1a and the ratio
(S/R) of each amino acid in natural 1 varied with the animal samples
employed, although compounds with the S configuration were always
predominant (6-3/1 and 2-1.1/1 ratios for N,N-dimethylalanine and
N,N,O-trimethylserine moieties, respectively). The diastereomeric
ratios of the N,N-dimethylalanine part and the N,N,O-trimethylserine
part in natural 1, which were used for comparison purposes, were S/R
) 72/28 and S/R ) 52/48, respectively.
of the MTM group in 94 with AgNO3 gave alcohol 95
in 97% yield. Esterification of alcohol 95 with (S)-N,N,O-
trimethylserine gave a 3:2 mixture of (S)- and (R)-
trimethylserine esters 96, whereas esterification of al-
cohol 95 with (R)-N,N,O-trimethylserine afforded a 1:3
mixture of esters 96. Thus, the hydroxyl group in 95 was
esterified with N,N,O-trimethylserine (S/R ) 5/2) to give
a diastereomeric mixture of trimethylserine esters 96
(S/R ) 4/3, 85%), the two silyl groups of which were
removed to provide aplyronine A (1) in 84% yield.
Synthetic aplyronine A (1) was found to correspond
uniquely to natural aplyronine A (1) in all respects,
(37) To unambiguously identify the carbon backbone of synthetic
and natural 1, synthetic 1 was subjected to the same sequence of
degradation reactions2b that was previously used with natural 1 to
remove two amino acids to afford pentaacetate i ([R]21 -14 (c 0.06,
D
including spectroscopic (UV, IR, H and 13C NMR, MS,
1
CHCl3)), which corresponds to the carbon backbone of 1. The pentaac-
etate i thus obtained was identical to natural i ([R]24 -15 (c 0.16,
D
RD) and chromatographic properties and cytotoxicity,
CHCl3))2b in all respects.
except for the signal intensities due to amino acid
moieties in H and 13C NMR spectra.36,37
1
Syn th esis of Ap lyr on in es B a n d C. Assuming that
the stereochemistry of the carbon backbone of aply-
ronines B (2) and C (3) is identical with that of aplyronine
(35) Corey, E. J .; Bock, M. G. Tetrahedron Lett. 1975, 3269-3270.

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5333
Sch em e 11a
Sch em e 12a
a
(a) HCl, H2O, dioxane, 50 °C, 1.5 h, 63% (b) LiAlH(O-t-Bu)3,
a
THF, 0 °C, 2 h, 60%.
(a) AgNO3, 2,6-lutidine, H2O, THF, 30 °C, 16 h, 98%; (b)
N,N,O-trimethylserine (S/R ) 5/2), DCC, CSA, DMAP, CH2Cl2,
35 °C, 6 h, 84%; (c) HF‚pyridine, pyridine, 23 °C, 4 h, 84%; (d)
DDQ, CH2Cl2, t-BuOH, phosphate buffer (pH 6), 23 °C, 55 min,
(105) 50%; (107) 70%; (e) HF‚pyridine, pyridine, THF, 23 °C, 10
h, 89%.
diol 87b (71%), which was subsequently converted into
alcohol 90b by three steps (81%). Oxidation of 90b gave
aldehyde 91b (73%), which was transformed into enam-
ide 92b (42%). Deprotection of the [(3,4-dimethoxyben-
zyl)oxy]methyl group at C29 in 92b and subsequent
esterification with N,N-dimethylalanine (S/R ) 8/5)
afforded a diastereomeric mixture of N,N-dimethylala-
nine esters 97 (S/R ) 4/1, 55%) (Scheme 10). Desilylation
of 97 followed by esterification with (S)-N,N,O-trimeth-
ylserine gave a diastereomeric mixture of N,N,O-trim-
ethylserine esters 99 (S/R ) 5/6) in 74% yield. Finally,
hydrolysis of the MTM groups in 99 furnished aplyronine
B (2) in 85% yield. Synthetic aplyronine B (2) cor-
responded uniquely to natural aplyronine B (2) by
comparison of their spectroscopic (UV, IR, 1H NMR,
FABMS, and CD) and chromatographic properties.38
Aplyronine C (3) was easily prepared from a synthetic
intermediate 93a of aplyronine A (1) by three steps (27%)
(Scheme 10). The spectral data, including the CD
spectrum, of synthetic aplyronine C (3) were identical
with those of natural 3.39
Thus, the absolute stereochemistry of aplyronine A (1)
has been confirmed, and the absolute stereostructures
of aplyronines B (2) and C (3) have been determined
unambiguously by enantioselective total synthesis.
Syn th esis of th e Ar tificia l An a logu es of Ap lyr o-
n in e A. To investigate the structure-cytotoxicity rela-
tionships of aplyronines, their artificial analogues were
synthesized.
First, two aplyronine derivatives that lack the N-formyl
enamine moiety were prepared from aplyronine A (1).
Acidic hydrolysis of the N-formyl enamine moiety of 1
gave aldehyde 100 (63%), which was reduced to give
alcohol 101 (60%) (Scheme 11).
was transformed into 105 by three steps (35%). An
analogue without either of the amino acid moieties 107
was also prepared from alcohol 102 by sequential removal
of the two protecting groups (62%).
Further, an analogue without the side chain of aply-
ronine A (1), 117, was synthesized from a synthetic
intermediate 9 of 1 (Scheme 13). Alcohol 11840 was
transformed into sulfone 120 (97% from 118) (Scheme
13). Olefin 108 (20E/20Z ) 6/1) was prepared from the
C5-C20 segment 9 and sulfone 120 by four steps (48%
yield from 9). Deprotection of the pivaloyl group in 108
followed by oxidation provided aldehyde 110 (43%), which
was converted into R,â,γ,δ-unsaturated ester 111 in 72%
yield (4E/4Z ) 20/1). Deprotection of the TES group in
111 and subsequent hydrolysis gave seco acid 113 (83%).
Macrocyclization of seco acid 113 afforded stereochemi-
cally pure lactone 114 in 51% yield after chromatographic
purification. Further, lactone 114 was converted into
analogue 117 by three steps (40%).
Str u ctu r e-Cytotoxicity Rela tion sh ip s of Ap ly-
r on in es a n d Ar tificia l An a logu es. The cytotocixities
of aplyronines and artificial analogues against HeLa S3
cells were evaluated in vitro. Aplyronines A (1), B (2),
and C (3) showed cytotoxicities with IC50s of 0.48, 3.11,
and 21.2 ng/mL, respectively.5 Three artificial analogues
of aplyronines, 100, 101, and 105, showed cytotoxicities
with IC50s of 2.02, 1.72, and 1.03 ng/mL, respectively.
Three other analogues, 107, aplyronine A diacetate, and
117, showed cytotoxicities with IC50s of 113, 216, and
2100 ng/mL, respectively. Comparison of the cytotoxici-
ties of 1-3 revealed that the trimethylserine moiety plays
an important role in the strong cytotoxicity of 1. Two
hydroxyl groups in aplyronine A (1) were shown to be
responsible for its strong cytotoxicity through a compari-
son of the cytotoxicity of 1 and its diacetate. Aplyronine
A (1) is ∼4000-fold more cytotoxic than the analogue 117,
which indicates that the side chain of 1 is essential for
the potent cytotoxicity of 1. In contrast, the N-formyl
enamine part and the dimethylalanine part of 1 were
shown to be unimportant for the strong cytotoxicity of 1
by a comparison of 1 and the three analogues 100, 101,
and 105.
Next, the analogue which lacked the dimethylalanine
moiety 105 was synthesized from a synthetic intermedi-
ate 92a of aplyronine A (1) (Scheme 12). Deprotection
of the MTM group of 92a gave alcohol 102 (98%), which
(38) Natural aplyronine B (2) was obtained as a diastereomeric
mixture with respect to two amino acids. The diastereomeric ratios of
the N,N-dimethylalanine moiety and the N,N,O-trimethylserine moiety
in natural 2, which were used for comparison purposes, were S/R )
4/1 and S/R ) 1/1, respectively. The small differences in the signal
intensities in the NMR spectra and the differences in the specific
rotation which were observed between natural and synthetic aplyro-
nine B (2) are due to the different diastereomeric ratios of two amino
acid parts. Natural and synthetic aplyronine B (2) were shown to have
identical absolute stereochemistries with regard to the main chain by
comparison of their CD spectra: both natural and synthetic aplyronine
B (2) showed a negative Cotton effect at 265 nm.
F u r th er Biologica l Stu d ies of Ap lyr on in e A (1).
Additional studies were performed to identify the target
(39) Natural aplyronine C (3) was obtained as a diastereomeric
mixture with respect to N,N-dimethylalanine. The diastereomeric ratio
of the N,N-dimethylalanine moiety in natural aplyronine C (3), which
has been used for comparison purposes, was S/R ) 2/1.
(40) Nambara, T.; Matsuhisa, N. Yakugaku Zasshi 1963, 83, 642-
647.

5334 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
Sch em e 13a
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, materials were obtained
from commercial supplies and used without further purifica-
tion. All solvents were purified by a standard procedure before
use. tert-Butyl hydroperoxide in toluene,42 the Dess-Martin
periodinane,19,43 and copper(I) iodide44 were prepared according
to procedures in the literature. All reactions involving orga-
nometallic reagents were conducted under a nitrogen or argon
atmosphere. Fuji silysia silica gel BW-820 MH and Merck
aluminum oxide 90 (activity II-III) were used for column
chromatography unless otherwise noted. Merck precoated
silica gel 60 F254 plates were used for thin-layer chromatog-
raphy (TLC). Melting points are uncorrected. NMR spectra
were measured at 270, 400, 500, or 600 MHz for 1H and 67.8
MHz for 13C. J values are given in Hz.
Experimental data for compounds 87b-93b, 97-99, 108-
116, 119, and 120 are given in the the supporting information.
Hyd r oxy Im id e 12. To a stirred solution of imide 11 (2.03
g, 8.71 mmol) in CH2Cl2 (17 mL) cooled at 0 °C were added a
1.0 M solution of dibutylboron triflate in CH2Cl2 (9.6 mL, 9.6
mmol) and triethylamine (1.7 mL, 12.0 mmol), successively.
The reaction mixture was stirred at 0 °C for 30 min and cooled
to -78 °C. A solution of (R)-3-(benzyloxy)-2-methylpropanal
(1.55 g, 8.71 mmol) in CH2Cl2 (2.0 mL, 2.0 mL rinse) was
added, and the reaction mixture was stirred at -78 °C for 3 h
and at 0 °C for 20 min. The reaction was quenched by addition
of 0.5 M phosphate buffer (pH 7, 20 mL) and MeOH (30 mL).
After the reaction mixture was cooled to -10 °C, 30% aqueous
hydrogen peroxide (15 mL) in MeOH (30 mL) was added over
10 min, and the resulting solution was stirred at 0 °C for 1 h.
The organic solvents were evaporated, and Et2O (30 mL) was
added to the aqueous mixture. The mixture was cooled to 0
°C, and saturated aqueous Na2S2O3 (30 mL) was added slowly.
The resulting mixture was extracted with Et2O (150 mL, 50
mL). The extracts were combined, washed with 5% aqueous
NaHCO3 (50 mL) and brine (30 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (100 g, hexane-Et2O 5:1 f 3: 1 f
2: 1 f 1: 1 f Et2O) to give 12 (3.16 g, 88%) as a colorless oil:
[R]27D -30.9 (c 1.02, CHCl3); IR (CHCl3) 3470 (br), 1775, 1705,
1455, 1370, 1345, 1235, 1195 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.41-7.25 (m, 10 H), 5.61 (d, J ) 7.3 Hz, 1 H), 4.74 (dq, J )
7.3, 6.9 Hz, 1 H), 4.52 (s, 2 H), 3.96 (dq, J ) 3.3, 6.6 Hz, 1 H),
3.90 (ddd, J ) 2.6, 3.3, 8.3 Hz, 1 H), 3.73 (d, J ) 2.6 Hz, 1 H),
3.62 (dd, J ) 5.1, 9.2 Hz, 1 H), 3.58 (dd, J ) 6.6, 9.2 Hz, 1 H),
1.99 (m, 1 H), 1.23 (d, J ) 6.9 Hz, 3 H), 0.98 (d, J ) 6.9 Hz, 3
H), 0.90 (d, J ) 6.6 Hz, 3 H); MS (FAB) m/ z 434 (M + Na)+;
HRMS (FAB) calcd for C24H29NNaO5 [(M + Na)+] 434.1944,
found 434.1925.
a
(a) 120, BuLi, THF, -78 °C, 2.5 h; (b) Ac2O, DMAP, pyridine,
23 °C, 2 h; (c) (i) 5% Na-Hg, Na2HPO4, MeOH, 0 °C, 20 min; (ii)
Et3SiCl (TESCl), imidazole, DMF, 23 °C, 1 h, 48% (4 steps); (d)
DIBAL, CH2Cl2, -78 °C, 25 min, 92%; (e) Dess-Martin periodi-
nane, pyridine, CH2Cl2, 23 °C, 90 min, 47%; (f) LDA, (EtO)2-
P(O)CH2CHdCHCO2Et, THF, -40 °C, 10 min f 0 °C, 20 min,
72%; (g) HF‚pyridine, pyridine, THF, 23 °C, 20 min; (h) LiOH,
MeOH, H2O, 23 °C, 12.5 h, 83% (2 steps); (i) 2,4,6-trichlorobenzoyl
chloride, DMAP, Et3N, CHCl3, 23° C, 2 h, 51%; (j) AgNO3, 2,6-
lutidine, H2O, THF, 30 °C, 19.5 h, 94%; (k) N,N,O-trimethylserine
(S/R ) 5/2), DCC, CSA, DMAP, CH2Cl2, 35 °C, 45 min, 100%; (l)
HF‚pyridine, pyridine, 23 °C, 2 h, 63%; (m) Et3SiCl (TESCl),
pyridine, 23 °C, 30 min, 97%; (n) m-CPBA, NaHCO3, CH2Cl2, 23
°C, 1 h, 100%.
biomolecules that interact with aplyronine A (1). No
interaction was observed between aplyronine A (1) and
DNA or microtubules. However, in an investigation
performed by Professor H. Karaki, the University of
Tokyo, aplyronine A (1) interacted with actin, the protein
in cytoskeleton: 1 inhibited the polymerization of G-actin
to F-actin and depolymerized F-actin to G-actin by
severing.41
Am id e 13. To a stirred suspension of N,O-dimethylhy-
droxylamine hydrochloride (2.8 g, 29 mmol) in THF (10 mL)
cooled at -10 °C was added a 2.0 M solution of trimethylalu-
minum in toluene (14 mL, 28 mmol) dropwise. The resulting
solution was stirred at 0 °C for 10 min and at room temper-
ature for 30 min. The solution was recooled to -10 °C, and a
solution of hydroxy imide 12 (5.50 g, 13 mmol) in 5:4 THF-
CH2Cl2 (16 mL) was added. The reaction mixture was warmed
to 0 °C, stirred for 1.6 h, and transferred into a rapidly stirred
mixture of CH2Cl2 (40 mL) and 0.5 M aqueous HCl (40 mL) at
0 °C. The resulting two-phase mixture was stirred at 0 °C for
2 h and extracted with CH2Cl2 (300 mL then 2 × 50 mL). The
extracts were combined, washed with brine (50 mL), dried
(Na2SO4), and concentrated. The residue was purified by
column chromatography on silica gel (150 g, hexane-EtOAc
2:1 f 1: 1 f EtOAc) to give 13 (3.8 g, 96%) as a colorless oil
and 4-(S)-methyl-5-(S)-phenyl-2-oxazolidinone (2.3 g, 97%) as
colorless crystals. 13: [R]27D +14.1 (c 1.04, CHCl3); IR (CHCl3)
Con clu sion s
Enantioselective total synthesis of aplyronine A (1) was
carried out by a convergent route (0.39% overall yield
based on the longest linear sequence (47 steps), average
yield for each step 89%), which confirmed the absolute
stereochemistry of 1. The absolute stereostructures of
aplyronines B (2) and C (3), which were isolated only
in very minute amounts from the natural source,
were determined by enantioselective synthesis, which
demonstrates the usefulness of organic synthesis in the
structural elucidation of complex natural products. In
addition, the structure-cytotoxicity relationships of aply-
ronines were determined to a considerable extent by
organic synthesis.
1
3470 (br), 1635, 1480, 1455, 1420, 1390, 1360, 1090 cm-1; H
(42) Hill, J . G.; Rossiter, B. E.; Sharpless, K. B. J . Org. Chem. 1983,
48, 3607-3608.
(43) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(44) House, H. O.; Chu, C.-Y.; Wilkins, J . M.; Umen, M. J . J . Org.
Chem. 1975, 40, 1460-1469.
(41) Saito, S.; Watabe, S.; Ozaki, H.; Kigoshi, H.; Yamada, K.;
Karaki, H. Manuscript in preparation.

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5335
NMR (270 MHz, CDCl3) δ 7.36-7.25 (m, 5 H), 4.55 (d, J )
11.9 Hz, 1 H), 4.50 (d, J ) 11.9 Hz, 1 H), 3.98 (br s, 1 H), 3.72
(dd, J ) 3.1, 8.4 Hz, 1 H), 3.67 (s, 3 H), 3.66 (dd, J ) 4.0, 8.9
Hz, 1 H), 3.57 (dd, J ) 5.8, 8.9 Hz, 1 H), 3.18 (s, 3 H), 3.04 (m,
1 H), 1.89 (m, 1 H), 1.18 (d, J ) 6.9 Hz, 3 H), 1.00 (d, J ) 6.9
Hz, 3 H); MS (FAB) m/ z 318 (M + Na)+; HRMS (FAB) calcd
for C16H25NNaO4 [(M + Na)+] 318.1681, found 318.1678.
Silyl Eth er 14. To a stirred solution of amide 13 (1.66 g,
5.63 mmol) in CH2Cl2 (30 mL) cooled at 0 °C were added 2,6-
lutidine (1.4 mL, 12.0 mmol) and tert-butyldimethylsilyl tri-
flate (2.00 mL, 8.71 mmol). The mixture was stirred at 0 °C
for 1 h and diluted with H2O (30 mL), and the resulting
mixture was extracted with CH2Cl2 (3 × 30 mL). The
combined extracts were washed with brine (30 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (100 g, CH2Cl2) to give
14 (2.30 g, 100%) as a colorless oil: [R]26D +9.18 (c 1.20, CHCl3);
Allylic Alcoh ol 17. To a stirred solution of conjugated
ester 16 (2.44 g, 5.81 mmol) in CH2Cl2 (24 mL) and hexane
(48 mL) cooled to -78 °C was added a 1.0 M solution of
diisobutylaluminum hydride in hexane (23.0 mL, 23.0 mmol)
dropwise. The solution was stirred at -78 °C for 1 h, and the
reaction was quenched by addition of MeOH (3.8 mL). After
the mixture was warmed to room temperature, Et2O (480 mL),
saturated aqueous NaCl (7.7 mL), and anhydrous MgSO4 (19
g) were added. The resulting mixture was stirred for 2 h and
filtered through a pad of Celite, and the residue was washed
with EtOAc (300 mL). The filtrate and the washings were
combined and concentrated. The residual oil was purified by
column chromatography on silica gel (110 g, hexane-Et2O 4:1
f 3: 2) to give 17 (2.29 g, 100%) as a colorless oil: [R]24D +19.7
(c 1.20, CHCl3); IR (CHCl3) 3610, 3440 (br), 1475, 1465, 1460,
1385, 1365, 1260, 1100, 840 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.37-7.25 (m, 5 H), 5.65 (dd, J ) 6.6, 15.5 Hz, 1 H), 5.56
(td, J ) 5.2, 15.5 Hz, 1 H), 4.50 (d, J ) 12.1 Hz, 1 H), 4.44 (d,
J ) 12.1 Hz, 1 H), 4.04 (dd, J ) 5.0, 5.2 Hz, 2 H), 3.56 (dd, J
) 4.8, 9.1 Hz, 1 H), 3.50 (dd, J ) 5.0, 5.0 Hz, 1 H), 3.25 (dd, J
) 7.7, 9.1 Hz, 1 H), 2.38 (m, 1 H), 1.98 (m, 1 H), 1.18 (t, J )
5.0 Hz, 1 H), 0.98 (d, J ) 6.9 Hz, 6 H), 0.88 (s, 9 H), 0.03 (s, 3
H), 0.02 (s, 3 H); MS (FAB) m/ z 401 (M + Na)+; HRMS (FAB)
calcd for C22H38NaO3Si [(M + Na)+] 401.2488, found 401.2469.
Ep oxid e 18. To a stirred mixture of powdered molecular
sieves 4 Å (4.0 g) and titanium tetraisopropoxide (4.4 mL, 15
mmol) in CH2Cl2 (50 mL) cooled at -23 °C was added a 2.0 M
solution of (+)-diethyl tartrate in CH2Cl2 (9.7 mL, 19.4 mmol).
The mixture was stirred at -23 °C for 10 min, and a solution
of allylic alcohol 17 (4.29 g, 11.3 mmol) in CH2Cl2 (12 mL) and
a 3.4 M solution of tert-butyl hydroperoxide in toluene (8.0 mL,
27.2 mmol) were added, successively. The solution was stirred
at -23 °C for 1 h and was diluted with 0.5 M aqueous tartaric
acid (50 mL). The resulting mixture was stirred at -23 °C
for 15 min and at room temperature for 2 h. The mixture was
extracted with EtOAc (250 mL, 80 mL, then 2 × 50 mL). The
combined extracts were washed with brine (50 mL), dried (Na2-
SO4), and concentrated. The residual oil was dissolved in Et2O
(100 mL), and to this solution 1 M aqueous NaOH (40 mL)
was added at 0 °C. After the mixture was stirred at 0 °C for
45 min, the organic layer was separated, and the aqueous layer
was extracted with Et2O (150 mL, 50 mL). The organic layer
and the extracts were combined, washed with brine (20 mL),
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (100 g,
hexane-EtOAc 10:1 f 5: 1 f 3: 1) to give 18 (4.27 g, 96%) as
IR (CHCl3) 1650, 1475, 1465, 1390, 1260, 1080, 1050, 835 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.36-7.26 (m, 5 H), 4.49 (d, J )
11.9 Hz, 1 H), 4.43 (d, J ) 11.9 Hz, 1 H), 3.94 (dd, J ) 2.6, 8.2
Hz, 1 H), 3.59 (dd, J ) 5.3, 9.2 Hz, 1 H), 3.56 (s, 3 H), 3.19
(dd, J ) 7.8, 9.2 Hz, 1 H), 3.14 (m, 1 H), 3.11 (s, 3 H), 1.93 (m,
1 H), 1.11 (d, J ) 6.9 Hz, 3 H), 1.01 (d, J ) 6.9 Hz, 3 H), 0.90
(s, 9 H), 0.06 (s, 6 H); MS (FAB) m/ z 432 (M + Na)+; HRMS
(FAB) calcd for C22H39NNaO4Si [(M + Na)+] 432.2546, found
432.2558.
Ald eh yd e 15. To a stirred solution of silyl ether 14 (2.06
g, 5.03 mmol) in THF (35 mL) cooled at -78 °C was added a
1.0 M solution of diisobutylaluminum hydride in hexane (10.0
mL, 10.0 mmol) dropwise. The solution was stirred at -78
°C for 2 h, and the reaction was quenched by addition of
acetone (0.5 mL). The solution was stirred at -78 °C for 5
min and then transferred into a rapidly stirred mixture of
hexane (80 mL) and 0.5 M aqueous tartaric acid (80 mL) at
room temperature. The resulting two-phase mixture was
stirred at room temperature for 30 min. The layers were
separated, and the aqueous layer was extracted with 1:3 CH2-
Cl2-hexane (4 × 80 mL). The organic layer and the extracts
were combined, washed with brine (50 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (90 g, hexane-Et2O 20:1 f 10:
1) to give 15 (1.75 g, 99%) as a colorless oil: [R]25 +35.0 (c
D
1.20, CHCl3); IR (CHCl3) 2705, 1720, 1470, 1460, 1455, 1360,
1255, 1095, 840 cm-1; 1H NMR (270 MHz, CDCl3) δ 9.69 (d, J
) 1.0 Hz, 1 H), 7.38-7.25 (m, 5 H) ,4.49 (d, J ) 12.2 Hz, 1 H),
4.43 (d, J ) 12.2 Hz, 1 H), 4.21 (dd, J ) 3.9, 6.1 Hz, 1 H), 3.46
(dd, J ) 5.6, 9.2 Hz, 1 H), 3.36 (dd, J ) 5.9, 9.2 Hz, 1 H), 2.50
(ddq, J ) 1.0, 3.9, 6.9 Hz, 1 H), 2.02 (dddq, J ) 5.6, 5.9, 6.1,
6.9 Hz, 1 H), 1.10 (d, J ) 6.9 Hz, 3 H), 0.97 (d, J ) 6.9 Hz, 3
H), 0.86 (s, 9 H), 0.05 (s, 3 H), -0.01 (s, 3 H); MS (FAB) m/ z
373 (M + Na)+; HRMS (FAB) calcd for C20H34NaO3Si [(M +
Na)+] 373.2175, found 373.2155.
a colorless oil: [R]25 -8.58 (c 1.01, CHCl3); IR (CHCl3) 3590,
D
3460 (br), 1475, 1465, 1455, 1380, 1360, 1255, 840 cm-1; H
1
NMR (270 MHz, CDCl3) δ 7.36-7.25 (m, 5 H), 4.52 (d, J )
12.1 Hz, 1 H), 4.46 (d, J ) 12.1 Hz, 1 H), 3.88 (ddd, J ) 2.0,
5.3, 12.2 Hz, 1 H), 3.81 (dd, J ) 2.8, 6.9 Hz, 1 H), 3.63 (ddd, J
) 4.0, 7.6, 12.2 Hz, 1 H), 3.56 (dd, J ) 4.6, 8.9 Hz, 1 H), 3.28
(dd, J ) 7.6, 8.9 Hz, 1 H), 2.95-2.89 (m, 2 H), 1.99 (m, 1 H),
1.66 (dd, J ) 5.3, 7.6 Hz, 1 H), 1.47 (m, 1 H), 0.95 (d, J ) 6.9
Hz, 3 H), 0.93 (d, J ) 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H),
0.06 (s, 3 H); MS (FAB) m/ z 417 (M + Na)+; HRMS (FAB)
calcd for C22H38NaO4Si [(M + Na)+] 417.2438, found 417.2421.
Red u ction of Ep oxid e 18. To a stirred solution of epoxide
18 (4.0 g, 10 mmol) in 1,2-dimethoxyethane (50 mL) cooled at
-23 °C was added a 70% solution of sodium bis(2-methoxy-
ethoxy)aluminum hydride in toluene (6.0 mL, 22 mmol)
dropwise. The mixture was warmed to 0 °C and stirred at 0
°C for 2 h. H2O (3 mL) was added, and the mixture was
warmed to room temperature. To the mixture were added
Et2O (70 mL) and 10% aqueous (+)-tartaric acid (50 mL).
After being stirred at room temperature for 30 min, the
mixture was extracted with EtOAc (150 mL and then 2 × 50
mL). The combined extracts were washed with brine (30 mL),
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (100 g,
hexane-EtOAc 5:1 f 3:1 f 2:1 f 1:1 f EtOAc) to give diol
19a (2.94 g, 74%) and triol 19b (426 mg, 15%) as a colorless
oil, repectively. 19a : [R]20D +14.1 (c 1.20, CHCl3); IR (CHCl3)
Con ju ga ted Ester 16. To a stirred solution of diisopropyl
(ethoxycarbonyl)methylphosphonate (7.8 mL, 32.8 mmol) in
THF (50 mL) cooled to 0 °C was added potassium tert-butoxide
(3.34 g, 29.8 mmol), and the resulting solution was stirred at
room temperature for 1 h. The solution was cooled to -78 °C,
and a solution of aldehyde 15 (2.93 g, 8.36 mmol) in THF (25
mL) was added. After the reaction mixture was stirred at -78
°C for 1 h and at 0 °C for 1.5 h, Et2O (75 mL) and saturated
aqueous NH4Cl (65 mL) were added. The resulting mixture
was stirred at room temperature for 15 min and extracted with
CH2Cl2 (3 × 70 mL). The extracts were combined, washed
with brine (50 mL), dried (Na2SO4), and concentrated. The
residual oil was purified by column chromatography on silica
gel (200 g, hexane-Et2O 20:1 f 9: 1) to give 16 (3.52 g, 100%)
as a colorless oil: [R]25D +26.5 (c 1.11, CHCl3); IR (CHCl3) 1710,
1655, 1475, 1465, 1455, 1370, 1260, 1095, 840 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.37-7.26 (m, 5 H), 6.97 (dd, J ) 15.8,
7.9 Hz, 1 H), 5.77 (dd, J ) 15.8, 1.3 Hz, 1 H), 4.46 (s, 2 H),
4.18 (q, J ) 7.3 Hz, 2 H), 3.62 (dd, J ) 5.3, 5.3 Hz, 1 H), 3.50
(dd, J ) 5.1, 8.9 Hz, 1 H), 3.28 (dd, J ) 7.3, 8.9 Hz, 1 H), 2.53
(m, 1 H), 1.97 (m, 1 H), 1.28 (t, J ) 7.3 Hz, 3 H), 1.04 (d, J )
6.6 Hz, 3 H), 0.98 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 3
H), 0.02 (s, 3 H); MS (FAB) m/ z 443 (M + Na)+; HRMS (FAB)
calcd for C24H40NaO4Si [(M + Na)+] 443.2594, found 443.2581.
1
3440 (br), 1475, 1465, 1455, 1255, 1070, 835 cm-1; H NMR
(270 MHz, CDCl3) δ 7.36-7.26 (m, 5 H), 4.49 (s, 2 H), 3.97 (br
s, 1 H), 3.88 (dd, J ) 2.5, 5.4 Hz, 1 H), 3.86-3.80 (m, 3 H),

5336 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
3.61 (dd, J ) 5.0, 9.2 Hz, 1 H), 3.34 (dd, J ) 7.3, 9.2 Hz, 1 H),
2.99 (dd, J ) 4.3, 5.9 Hz, 1 H), 2.09 (m, 1 H), 1.82-1.76 (m, 2
H), 1.59 (m, 1 H), 1.01 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.82
(d, J ) 6.9 Hz, 3 H), 0.10 (s, 3 H), 0.06 (s, 3 H); MS (FAB) m/ z
419 (M + Na)+; HRMS (FAB) calcd for C22H40NaO4Si [(M +
Silyl Eth er 23. To a stirred solution of sulfide 22 (1.21 g,
2.51 mmol) and imidazole (600 mg, 8.80 mmol) in DMF (5 mL)
at room temperarure was added triethylsilyl chloride (0.63 mL,
3.75 mmol). The resulting solution was stirred at room
temperarure for 1.4 h, and a small amount of ice (ca. 1 g)
and H2O (1 mL) were added. The resulting mixture was
stirred at room temperarure for 30 min and extracted with
Et2O (3 × 10 mL). The combined extracts were washed with
brine (4 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (40
g, hexane-Et2O 40: 1) to give 23 (1.50 g, 100%) as a colorless
oil: [R]21D +17.6 (c 1.00, CHCl3); IR (CHCl3) 1720, 1585, 1480,
Na)+] 419.2594, found 419.2577. 19b: [R]19 -36.8 (c 1.09,
D
CHCl3); IR (CHCl3) 3440 (br), 1455, 1425, 1385, 1365, 1240,
1105, 1070, 975 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.40-7.15
(m, 5 H), 4.54 (d, J ) 12.2 Hz, 1 H), 4.50 (d, J ) 12.2 Hz, 1 H),
4.30 (br s, 1 H), 4.05 (dd, J ) 3.1, 6.4 Hz, 1 H), 3.98-3.78 (m,
4 H), 3.60 (dd, J ) 4.4, 8.9 Hz, 1 H), 3.51 (dd, J ) 8.9, 8.9 Hz,
1 H), 3.38 (br s, 1 H), 2.16-1.82 (m, 2 H), 1.71-1.53 (m, 2 H),
1.01 (d, J ) 7.2 Hz, 3 H), 0.75 (d, J ) 6.9 Hz, 3 H); MS (FAB)
m/ z 305 (M + Na)+; HRMS (FAB) calcd for C16H26NaO4 [(M
+ Na)+] 305.1729, found 305.1729.
1
1470, 1460, 1285, 1255, 1165, 835 cm-1; H NMR (270 MHz,
CDCl3) δ 7.33-7.24 (m, 4 H), 7.16 (m, 1 H), 4.22 (ddd, J ) 5.5,
5.5, 10.8 Hz, 1 H), 4.03 (ddd, J ) 7.3, 7.3, 10.8 Hz, 1 H), 3.73
(ddd, J ) 5.0, 5.0, 6.6 Hz, 1 H), 3.63 (dd, J ) 3.6, 3.6 Hz, 1 H),
2.95 (dd, J ) 5.8, 12.7 Hz, 1 H), 2.77 (dd, J ) 8.6, 12.7 Hz, 1
H), 1.89 (m, 1 H), 1.78 (m, 1 H), 1.71-1.66 (m, 2 H), 1.21 (s, 9
H), 1.05 (d, J ) 6.9 Hz, 3 H), 0.93 (t, J ) 7.9 Hz, 9 H), 0.90 (d,
J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.57 (q, J ) 7.9 Hz, 6 H), 0.02
(s, 3 H), -0.03 (s, 3 H); MS (FAB) m/ z 619 (M + Na)+; HRMS
(FAB) calcd for C32H60NaO4SSi2 [(M + Na)+] 619.3648, found
619.3649.
Ester 20. To a solution of diol 19a (480 mg, 1.21 mmol) in
pyridine (4.8 mL) cooled at 0 °C was added pivaloyl chloride
(0.23 mL, 1.87 mmol) with stirring. The solution was stirred
at 0 °C for 1.5 h and diluted with H2O (10 mL). The resulting
mixture was stirred at room temperature for 30 min and
extracted with Et2O (5 × 10 mL). The combined extracts were
washed with brine (5 mL), dried (Na2SO4), and concentrated.
The residual oil was purified by column chromatography on
silica gel (25 g, hexane-Et2O 10:1 f 5:1 f 3:1) to give 20 (579
C5-C11 Segm en t 4. To a stirred solution of silyl ether
23 (2.66 g, 4.46 mmol) in CH2Cl2 (25 mL) cooled to 0 °C were
added NaHCO3 (2.4 g, 28 mmol) and m-chloroperoxybenzoic
acid (2.3 g, 13 mmol). After 5 min, the mixture was warmed
to room temperature and stirred at room temperature for 1.5
h. Saturated aqueous Na2S2O3 (10 mL) and H2O (20 mL) were
added, and the resulting mixture was stirred at room tem-
perature for 1 h and extracted with Et2O (200 mL, 50 mL).
The combined extracts were washed with saturated aqueous
Na2S2O3 (20 mL) and brine (20 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (100 g, hexane-Et2O 10:1 f 4: 1) to
mg, 99%) as a colorless oil: [R]20 +24.4 (c 1.07, CHCl3); IR
D
(CHCl3) 3460 (br), 1720, 1480, 1470, 1465, 1400, 1290, 1260,
1170, 840 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.36-7.26 (m, 5
H), 4.49 (s, 2 H), 4.31 (ddd, J ) 5.3, 8.6, 11.2 Hz, 1 H), 4.21
(ddd, J ) 4.9, 6.3, 11.2 Hz, 1 H), 3.95 (dd, J ) 2.3, 5.9 Hz, 1
H), 3.61 (m, 1 H), 3.59 (dd, J ) 4.9, 9.1 Hz, 1 H), 3.32 (dd, J
) 7.6, 9.1 Hz, 1 H), 3.17 (d, J ) 3.6 Hz, 1 H), 2.05 (m, 1 H),
1.92 (m, 1 H), 1.71-1.51 (m, 2 H), 1.19 (s, 9 H), 0.99 (d, J )
6.9 Hz, 3 H), 0.88 (s, 9 H), 0.84 (d, J ) 6.9 Hz, 3 H), 0.07 (s, 3
H), 0.05 (s, 3 H); MS (FAB) m/ z 503 (M + Na)+; HRMS (FAB)
calcd for C27H48NaO5Si [(M + Na)+] 503.3169, found 503.3181.
give 4 (2.86 g, 100%) as a colorless oil: [R]20 +9.9 (c 0.989,
D
Diol 21. A mixture of ester 20 (1.31 g, 2.73 mmol) and 10%
Pd on carbon (281 mg) in EtOH (40 mL) was stirred under a
hydrogen atmosphere at room temperature for 3.5 h. The
mixture was filtered through a pad of Celite, and the residue
was washed with EtOAc (200 mL). The filtrate and the
washings were combined and concentrated. The residue was
purified by column chromatography on silica gel (20 g, hex-
ane-EtOAc 4:1 f 2: 1 f 1: 1) to give 21 (1.05 g, 99%) as
colorless crystals: mp 104-105 °C (hexane); [R]24D +6.5 (c 1.07,
CHCl3); IR (CHCl3) 3480 (br), 1720, 1480, 1470, 1465, 1365,
1290, 1255, 1165, 1075, 840 cm-1; 1H NMR (270 MHz, CDCl3)
δ 4.44 (ddd, J ) 4.3, 9.6, 11.2 Hz, 1 H), 4.12 (ddd, J ) 5.6, 5.6,
11.2 Hz, 1 H), 4.08 (dd, J ) 2.0, 5.6 Hz, 1 H), 3.65-3.47 (m, 3
H), 3.36 (d, J ) 3.3 Hz, 1 H), 2.62 (dd, J ) 5.0, 7.6 Hz, 1 H),
2.03-1.89 (m, 2 H), 1.66 (m, 1 H), 1.57 (m, 1 H), 1.20 (s, 9 H),
0.91 (s, 9 H), 0.90 (d, J ) 7.2 Hz, 3 H), 0.85 (d, J ) 6.9 Hz, 3
H), 0.11 (s, 3 H), 0.08 (s, 3 H); MS (CI) m/ z (relative intensity)
391 [(M + H)+, 5], 333 (17), 315 (13), 211 (41), 203 (51), 159
(50), 145 (100). Anal. Calcd for C24H42O5Si: C, 61.49; H,
10.84. Found C, 61.64; H, 10.44.
CHCl3); IR (CHCl3) 1720, 1590, 1480, 1475, 1465, 1305, 1290,
1255, 1155, 1185, 935 cm-1 1H NMR (270 MHz, CDCl3) δ
;
7.92-7.89 (m, 2 H), 7.66-7.55 (m, 3 H), 4.18 (ddd, J ) 6.2,
6.2, 10.9 Hz, 1 H), 4.01 (ddd, J ) 7.1, 7.1, 10.9 Hz, 1 H), 3.73
(ddd, J ) 3.5, 6.5, 6.5 Hz, 1 H), 3.52 (dd, J ) 2.6, 5.0 Hz, 1 H),
3.12 (dd, J ) 2.6, 14.2 Hz, 1 H), 2.87 (dd, J ) 9.2, 14.2 Hz, 1
H), 2.28 (m, 1 H), 1.69-1.65 (m, 2 H), 1.57 (m, 1 H), 1.21 (s, 9
H), 1.12 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 7.6 Hz, 9 H), 0.86 (s,
9 H), 0.84 (d, J ) 7.6 Hz, 3 H), 0.60 (q, J ) 7.6 Hz, 6 H),
0.02 (s, 6 H); MS (FAB) m/ z 651 (M + Na)+. Anal. Calcd for
C32H60O6SSi2: C, 61.10; H, 9.61. Found C, 61.10; H, 9.87.
Iod id e 7. To a stirred solution of alcohol 25 (615 mg, 3.13
mmol) in pyridine (2.0 mL) cooled to 0 °C was added p-
toluenesulfonyl chloride (1.82 g, 9.57 mmol). After 2 h, the
reaction was quenched by addition of ice (0.5 g). The resulting
mixture was stirred at room temperature for 1 h, diluted with
H2O (10 mL), and extracted with Et2O (15 mL, 4 × 10 mL).
The combined extracts were washed with brine (5 mL), dried
(Na2SO4), and concentrated to give crude tosylate 26 (1.2 g)
as a colorless oil, which was used in the next experiment
without purification. To a stirred solution of 26 (1.2 g) in
acetone (6.0 mL) were added CaCO3 (634 mg, 6.33 mmol) and
NaI (1.43 g, 9.54 mmol) at room temperature. The reaction
mixture was warmed to 50 °C and stirred for 13.5 h. After
cooling, H2O (15 mL) was added, and the mixture was
extracted with Et2O (150 mL, 25 mL). The combined extracts
were washed with H2O (10 mL) and brine (10 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (30 g, hexane-Et2O 10:
1 f 5:1) to give 7 (946 mg, 99%) as a colorless oil: [R]21D -6.7
(c 1.06, CHCl3); IR (CHCl3) 1495, 1455, 1180, 1085, 1120, 1085,
1030, 905 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.38-7.27 (m, 5
H), 4.56 (s, 2 H), 3.62 (dd, J ) 4.6, 9.9 Hz, 1 H), 3.53 (dd, J )
5.3, 9.9 Hz, 1 H), 3.43 (s, 3 H), 3.42-3.26 (m, 3 H); MS (EI)
m/ z (relative intensity) 306 (M+, 33), 185 (8), 147 (7), 117 (7),
91 (100); HRMS (EI) calcd for C11H15IO2 (M+) 306.0117, found
306.0118.
Su lfid e 22. To a stirred solution of diol 21 (434 mg, 1.11
mmol) and diphenyl disulfide (510 mg, 2.33 mmol) in DMF
(11 mL) at room temperature was added tributylphosphine
(0.56 mL, 2.25 mmol), and the resulting solution was stirred
at room temperature for 12 h. H2O (5 mL) was added, and
the resulting mixture was concentrated. The residual oil was
purified by column chromatography on silica gel (50 g, hex-
ane-Et2O 40:1 f 20: 1 f 10: 1 f 3: 1) to give 22 (490 mg,
91%) as a colorless oil: [R]20 +29.8 (c 0.888, CHCl3); IR
D
(CHCl3) 3480 (br), 1720, 1585, 1480, 1475, 1460, 1285, 1255,
1165, 835 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.36-7.13 (m, 5
H), 4.35 (ddd, J ) 5.0, 8.9, 11.2 Hz, 1 H), 4.17 (ddd, J ) 5.6,
5.6, 11.2 Hz, 1 H), 3.95 (dd, J ) 2.0, 5.6 Hz, 1 H), 3.51 (dddd,
J ) 3.6, 3.6, 9.2, 9.2 Hz, 1 H), 3.27 (dd, J ) 3.9, 12.5 Hz, 1 H),
3.09 (d, J ) 3.6 Hz, 1 H), 2.63 (dd, J ) 9.6, 12.5 Hz, 1 H),
2.00-1.86 (m, 2 H), 1.67 (m, 1 H), 1.55 (m, 1 H), 1.19 (s, 9 H),
1.07 (d, J ) 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.82 (d, J ) 7.2 Hz, 3
H), 0.07 (s, 3 H), 0.05 (s, 3 H); MS (FAB) m/ z 505 (M + Na)+;
HRMS (FAB) calcd for C26H46NaO4SSi [(M + Na)+] 505.2784,
found 505.2782.
Diol 30. To a stirred solution of lactone 29 (5.97 g, 16.0
mmol) in THF (50 mL) cooled at 0 °C was added a 1.0 M
solution of lithium aluminum hydride in THF (32.0 mL, 32.0

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5337
mmol) dropwise. The solution was stirred at room tempera-
ture for 1 h, and then NaF (4.09 g) and a solution of THF-
H2O (9:1, 100 mL) were added. After being stirred at room
temperature for 20 min, the mixture was filtered through a
pad of Celite. The residue was washed with THF (300 mL),
and the filtrate and the washings were combined and concen-
trated. The residual oil was purified by column chromatog-
raphy on silica gel (300 g, hexane-EtOAc 4:1 f 2: 1 f 1: 1 f
concentrated to give a crude tosylate 34 (5.9 g) as a colorless
oil. Crude 34 was employed in the next experiment without
purification. To a stirred solution of methyl phenyl sulfone
(2.8 g, 18 mmol) in THF (160 mL) cooled at -23 °C was added
a 1.52 M solution of BuLi in hexane (11.5 mL, 17.5 mmol).
The mixture was warmed to room temperature and stirred for
40 min, and the solution of crude 34 (5.9 g) in THF (14 mL)
was added. The mixture was stirred at room temperature for
3.2 h, and the reaction was quenched by addition of aqueous
NH4Cl (20 mL). The mixture was extracted with Et2O (150
mL, 25 mL). The combined extracts were washed with brine
(30 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (150 g,
hexane-Et2O 5: 1 f 3:1 f 2:1 f 1:1) and by medium-pressure
liquid chromatography (Fuji Silysia, Micro Bead Silica Gel
B-(30-70)µ, 139 g, hexane-EtOAc 3.6:1 f 3.3:1 f 3.0:1, 8
mL/min) to give 8 (tR ) 110 min, 3.70 g, 77%) as a colorless
oil: [R]27D +15.5 (c 0.866, CHCl3); IR (CHCl3) 1600, 1490, 1450,
1: 4) to give 30 (6.03 g, 100%) as a colorless oil: [R]28 -6.2 (c
D
1.31, CHCl3); IR (CHCl3) 3580, 3400 (br), 1595, 1490, 1445,
1
1070 cm-1; H NMR (270 MHz, CDCl3) δ 7.45-7.40 (m, 6 H),
7.36-7.21 (m, 9 H), 3.92 (m, 1 H), 3.37-3.54 (m, 2 H), 3.15
(dd, J ) 3.6, 9.2 Hz, 1 H), 3.07 (dd, J ) 7.9, 9.2 Hz, 1 H), 2.75
(br s, 1 H,), 2.35 (br s, 1 H), 1.80 (m, 1 H), 1.45 (ddd, J ) 5.3,
7.9, 14.5 Hz, 1 H), 1.38 (ddd, J ) 4.6, 6.8, 14.5 Hz, 1 H), 0.88
(d, J ) 6.9 Hz, 3 H); MS (FAB) m/ z 399 (M + Na)+; HRMS
(FAB) calcd for C25H28NaO3 [(M + Na)+] 399.1936, found
399.1945.
1
1310, 1150, 1090 cm-1; H NMR (270 MHz, CDCl3) δ 7.91-
Meth yl Eth er 32. To a stirred solution of diol 30 (1.34 g,
3.56 mmol) in DMF (13.5 mL) cooled at 0 °C were added
imidazole (600 mg, 8.81 mmol) and tert-butyldiphenylsilyl
chloride (0.96 mL, 3.69 mmol). After 1.7 h at 0 °C, the reaction
was quenched by addition of H2O (30 mL), and the resulting
solution was stirred at room temperature for 30 min. The
mixture was extracted with Et2O (3 × 30 mL). The combined
extracts were washed with brine (30 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (100 g, hexane-ethyl acetate 20:1 f
10:1 f 5:1) to give a 13:1 mixture of silyl ether 31 and tert-
butyldiphenylsilanol (2.16 g) as a colorless oil. To a stirred
solution of the crude silyl ether (2.16 g) in THF (12 mL) cooled
at 0 °C were added methyl iodide (0.85 mL, 13.6 mmol) and
NaH (442 mg of 60% dispersion in mineral oil, 11.0 mmol),
successively. After 1 h, the reaction was quenched by addition
of ice (1 g) and saturated aqueous NH4Cl (10 mL). The
mixture was extracted with Et2O (3 × 50 mL). The combined
extracts were washed with brine (10 mL), dried (Na2SO4), and
concentrated. The residue was dissolved in Et2O (40 mL),
washed with saturated aqueous Na2S2O3 (5 mL) and brine (5
mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (100 g,
hexane-Et2O 40:1 f 20:1 f 10:1) to give 32 (2.13 g, 95%) as
7.85 (m, 2 H), 7.68-7.51 (m, 3 H), 7.46-7.41 (m, 6 H), 7.32-
7.19 (m, 9 H), 3.29 (s, 3 H), 3.20 (m, 1 H), 3.10-3.00 (m, 4 H),
1.73 (m, 1 H), 1.63-1.45 (m, 2 H), 1.38 (dd, J ) 6.3, 6.3 Hz, 2
H), 0.83 (d, J ) 6.3 Hz, 3 H); MS (FAB) m/ z 551 (M + Na)+;
HRMS (FAB) calcd for C33H36NaO4S [(M + Na)+] 551.2232,
found 551.2224.
Ben zyl Eth er 35. To a stirred solution of the C5-C11
segment 4 (401 mg, 0.64 mmol) in THF (1.5 mL) cooled at -78
°C under a stream of nitrogen was added a 0.6 M solution of
lithium diisopropylamide (1.4 mL, 0.7 mmol) prepared from
diisopropylamine (0.25 mL, 1.8 mmol), a 1.59 M solution of
BuLi in hexane (0.95 mL, 1.5 mmol), and THF (1.8 mL) at
-78 °C. After 25 min, the mixture was warmed to 0 °C.
Hexamethylphosphoric triamide (0.49 mL, 2.8 mmol) was
added, and the mixture was stirred at 0 °C for 5 min.
A
solution of iodide 7 (253 mg, 0.83 mmol) in THF (1.4 mL) was
added at 0 °C, and the resulting mixture was warmed to room
temperature and stirred at room temperature for 1.5 h. The
reaction was quenched by addition of saturated aqueous NH4-
Cl (1 mL), and the mixture was extracted with Et2O (3 × 10
mL). The combined extracts were washed with saturated
aqueous Na2S2O3 (5 mL), saturated aqueous NaHCO3 (5 mL),
and brine (5 mL) successively; dried (Na2SO4); and concen-
trated. The residual oil was purified by column chromatog-
raphy on silica gel (40 g, hexane-Et2O 40:1 f 20:1 f 10:1 f
5:1) to give a diastereomeric mixture of sulfones (462 mg) as
a colorless oil, which was employed in the next experiment
without separation of the diastereomers. To a vigorously
stirred solution of the diastereomeric mixture of sulfones (462
mg) in MeOH (10 mL) cooled at 0 °C were added Na2HPO4
(1.21 g, 8.52 mmol) and 5% sodium amalgam (2.62 g, 5.70
mmol), and the mixture was stirred at 0 °C for 2 h. The
mixture was diluted with saturated aqueous NH4Cl (5 mL),
stirred at room temperature for 1 h, and extracted with Et2O
(3 × 10 mL). The combined extracts were washed with brine
(10 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (12 g,
hexane-Et2O 40:1 f 20:1 f 10:1) to give 35 (316 mg, 76%)
as a colorless oil: [R]23D +18.0 (c 1.09, CHCl3); IR (CHCl3) 1720,
1465, 1290, 1255, 1165, 835 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.36-7.25 (m, 5 H), 4.56 (s, 2 H), 4.23 (ddd, J ) 5.3, 5.3,
10.6 Hz, 1 H), 4.04 (ddd, J ) 7.3, 7.3, 10.6 Hz, 1 H), 3.68 (ddd,
J ) 4.6, 4.6, 6.9 Hz, 1 H), 3.48 (d, J ) 5.0 Hz, 2 H), 3.42 (dd,
J ) 4.0, 4.0 Hz, 1 H), 3.41 (s, 3 H), 3.30 (m, 1 H), 1.79 (m, 1
H), 1.70-1.01 (m, 7 H), 1.19 (s, 9 H), 0.95 (t, J ) 7.9 Hz, 9 H),
0.91-0.87 (m, 6 H), 0.89 (s, 9 H), 0.59 (q, J ) 7.9 Hz, 6 H),
0.04 (s, 6 H); MS (FAB) m/ z 689 (M + Na)+; HRMS (FAB)
calcd for C37H70NaO6Si2 [(M + Na)+] 689.4609, found 689.4614.
Anal. Calcd for C37H70O6Si2: C, 66.61; H, 10.58. Found C,
67.05; H, 11.02.
a colorless oil: [R]29 +5.5 (c 0.920, CHCl3); IR (CHCl3) 1590,
D
1490, 1445, 1425, 1110, 840 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.66-7.61 (m, 4 H), 7.48-7.16 (m, 21 H), 3.50 (dd, J ) 4.6,
9.9 Hz, 1 H), 3.43 (dd, J ) 5.9, 9.9 Hz, 1 H), 3.32 (s, 3 H), 3.29
(m, 1 H), 3.09 (d, J ) 4.6 Hz, 2 H), 1.76 (m, 1 H), 1.59 (ddd, J
) 4.9, 6.9, 14.2 Hz, 1 H), 1.35 (ddd, J ) 6.3, 7.9, 14.2 Hz, 1 H),
1.03 (s, 9 H), 0.93 (d, J ) 6.6 Hz, 3 H); MS (FAB) m/ z 651 (M
+ Na)+; HRMS (FAB) calcd for C42H48NaO3Si [(M + Na)+]
651.3270, found 651.3274.
Alcoh ol 33. To a stirred solution of methyl ether 32 (1.35
g, 2.15 mmol) in THF (20 mL) was added a 1.0 M solution of
Bu4NF in THF (4.3 mL, 4.3 mmol) at room temperature. After
12 h, saturated aqueous NH4Cl (25 mL) was added, and the
mixture was extracted with Et2O (3 × 30 mL). The combined
extracts were washed with brine (8 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (75 g, hexane-Et2O 2:1 f 1:1 f 1:2)
to give 33 (854 mg, 100%) as a colorless oil: [R]19 +13.1 (c
D
0.861, CHCl3); IR (CHCl3) 3630, 3400 (br), 1600, 1490, 1450,
1
1090 cm-1; H NMR (270 MHz, CDCl3) δ 7.49-7.42 (m, 6 H),
7.34-7.19 (m, 9 H), 3.48-3.31 (m, 3 H), 3.41 (s, 3 H), 3.21
(dd, J ) 5.3, 9.9 Hz, 1 H), 3.12 (dd, J ) 4.6, 9.9 Hz, 1 H), 2.48
(dd, J ) 5.3, 7.3 Hz, 1 H), 1.76 (m, 1 H), 1.63-1.50 (m, 2 H),
0.88 (d, J ) 6.9 Hz, 3 H); MS (FAB) m/ z 413 (M + Na)+; HRMS
(FAB) calcd for C26H30NaO3 [(M + Na)+] 413.2093, found
413.2098.
Su lfon e 8. To a stirred solution of alcohol 33 (3.54 g, 9.08
mmol) in pyridine (8.0 mL) cooled at 0 °C was added p-
toluenesulfonyl chloride (3.47 g, 18.2 mmol). After 2.5 h, the
reaction was quenched by addition of ice (2 g) and H2O (10
mL), and the resulting mixture was stirred at room temper-
ature for 1 h. The mixture was extracted with Et2O (150 mL,
25 mL). The combined extracts were washed with 5% aqueous
NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), and
Alcoh ol 36. A mixture of benzyl ether 35 (216 mg, 0.324
mmol), NaHCO3 (33 mg, 0.39 mmol), and 10% Pd on carbon
(106 mg) in EtOH (10 mL) was stirred under a hydrogen
atmosphere at room temperature for 2.5 h. The mixture was
filtered through a pad of Celite, and the residue was washed
with EtOAc (50 mL). The filtrate and the washings were
combined and concentrated. The residual oil was purified by

5338 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
column chromatography on silica gel (10 g, hexane-Et2O 3:1
f 1:1) to give 36 (182 mg, 98%) as a colorless oil: [R]25D +32.9
(c 0.855, CHCl3); IR (CHCl3) 3580 (br), 1720, 1465, 1285, 1255,
J u lia Cou p lin g Rea ction of Meth yl Keton e 38 w ith
Su lfon e 8. To a stirred solution of sulfone 8 (125 mg, 0.237
mmol) in THF (2 mL) cooled at -78 °C was added a 1.56 M
solution of BuLi in hexane (0.15 mL, 0.23 mmol) dropwise.
The mixture was stirred at -78 °C for 30 min, and then a
solution of methyl ketone 38 (70 mg, 0.12 mmol) in THF (1.5
mL) was added dropwise, and the resulting mixture was
stirred at -78 °C for 2 h. The reaction was quenched by
addition of saturated aqueous NH4Cl (2 mL), and the mixture
was extracted with Et2O (30 mL, 10 mL). The combined
extracts were washed with brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (10 g, hexane-Et2O 5:1 f 3: 1 f 2: 1
f 1: 1) to give a diastereomeric mixture of hydroxy sulfones
(124 mg) as a colorless oil along with recovered 8 (48 mg, 38%).
The hydroxy sulfones were employed in the next experiment
without separation of the diastereomers. To a vigorously
stirred solution of the diastereomeric mixture of hydroxy
sulfones (124 mg) in MeOH (5 mL) cooled at 0 °C were added
Na2HPO4 (357 mg, 2.51 mmol) and 6% sodium amalgam (510
mg, 1.33 mmol). The mixture was stirred at 0 °C for 2.3 h,
diluted with saturated aqueous NH4Cl (3 mL), then stirred at
room temperature for 45 min, and extracted with Et2O (30 mL,
10 mL). The combined extracts were washed with brine (5
mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (5 g, hexane-
Et2O 10:1 f 5: 1 f 3: 1 f 1: 1) to give a mixture of olefins (73
mg) and a diastereomeric mixture of tertiary alcohol 41 (27
mg, 25% from 38) as a colorless oil, respectively. Further
purification of olefins by medium-pressure liquid chromatog-
raphy (Fuji Silysia, Micro Bead Silica Gel B-(30-70)µ, 8.2 g,
1
1165, 835 cm-1; H NMR (270 MHz, CDCl3) δ 4.23 (ddd, J )
5.6, 5.6, 10.9 Hz, 1 H), 4.05 (ddd, J ) 7.3, 7.3, 10.9 Hz, 1 H),
3.74-3.66 (m, 2 H), 3.49 (ddd, J ) 5.6, 5.6, 5.6 Hz, 1 H), 3.42
(dd, J ) 3.0, 4.6 Hz, 1 H), 3.40 (s, 3 H), 3.22 (dddd, J ) 3.3,
6.3, 6.3, 6.3 Hz, 1 H), 1.92 (dd, J ) 5.3, 6.9 Hz, 1 H), 1.79 (m,
1 H), 1.70-1.63 (m, 2 H), 1.58-1.41 (m, 4 H), 1.20 (s, 9 H),
1.15 (m, 1 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.92-0.88 (m, 6 H),
0.90 (s, 9 H), 0.60 (q, J ) 7.9 Hz, 6 H), 0.05 (s, 6 H); MS (FAB)
m/ z 599 (M + Na)+; HRMS (FAB) calcd for C30H64NaO6Si2 [(M
+ Na)+] 599.4140, found 599.4117.
Ald eh yd e 37. To a stirred solution of alcohol 36 (1.41 g,
2.45 mmol) in CH2Cl2 (20 mL) were added pyridine (3.0 mL,
37 mmol) and the Dess-Martin periodinane (1.71 g, 4.03
mmol) at room temperature. The mixture was stirred at room
temperature for 0.7 h and was diluted with Et2O (10 mL),
saturated aqueous NaHCO3 (10 mL), and saturated aqueous
Na2S2O3 (10 mL). The resulting mixture was stirred at room
temperature for 1 h, and extracted with Et2O (100 mL, 20 mL).
The combined extracts were washed with saturated aqueous
NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL) succes-
sively; dried (Na2SO4); and concentrated. The residual oil was
purified by column chromatography on silica gel (30 g, hex-
ane-Et2O 20:1 f 10: 1 f 3: 1) to give 37 (1.28 g, 91%) as a
colorless oil: [R]27 -4.6 (c 0.968, CHCl3); IR (CHCl3) 2730,
D
1730 (sh), 1720, 1465, 1285, 1255, 1165, 835 cm-1; H NMR
1
(270 MHz, CDCl3) δ 9.65 (d, J ) 2.3 Hz, 1 H), 4.23 (ddd, J )
5.3, 5.3, 10.6 Hz, 1 H), 4.05 (ddd, J ) 7.3, 7.3, 10.6 Hz, 1 H),
3.68 (ddd, J ) 5.3, 5.3, 5.3 Hz, 1 H), 3.50 (ddd, J ) 2.3, 5.0,
5.0 Hz, 1 H), 3.44 (s, 3 H), 3.42 (m, 1 H), 1.81-1.47 (m, 7 H),
1.19 (s, 9 H), 1.20 (m, 1 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.92-
0.87 (m, 6 H), 0.90 (s, 9 H), 0.60 (q, J ) 7.9 Hz, 6 H), 0.04 (s,
6 H); MS (FAB) m/ z 597 (M + Na)+; HRMS (FAB) calcd for
C30H62NaO6Si2 [(M + Na)+] 597.3683, found 597.3654.
hexane-EtOAc (45:1), 4 mL/min) afforded (E)-olefin 39 (tR
)
60 min, 50 mg, 44% from 38) and (Z)-olefin 40 (tR ) 35 min,
22 mg, 19% from 38) as a colorless oil, respectively. 39: [R]26
D
+25.7 (c 1.55, CHCl3); IR (CHCl3) 1720, 1600, 1445, 1380, 1285,
1250, 1160, 835 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.49-7.44
(m, 6 H), 7.33-7.19 (m, 9 H), 5.30 (dd, J ) 7.3, 7.3 Hz, 1 H),
4.23 (ddd, J ) 5.3, 5.3, 10.6 Hz, 1 H), 4.03 (ddd, J ) 7.3, 7.3,
10.6 Hz, 1 H), 3.69 (ddd, J ) 4.3, 4.3, 7.3 Hz, 1 H), 3.43 (s, 3
H), 3.43-3.30 (m, 3 H), 3.18-3.08 (m, 2 H), 3.11 (s, 3 H), 2.13
(ddd, J ) 5.9, 7.3, 13.2 Hz, 1 H), 1.81-1.74 (m, 2 H), 1.67-
1.17 (m, 9 H), 1.47 (s, 3 H), 1.19 (s, 9 H), 1.15 (m, 1 H), 0.95,
(t, J ) 7.9 Hz, 9 H), 0.89-0.85 (m, 9 H), 0.89 (s, 9 H), 0.60 (q,
J ) 7.9 Hz, 6 H), 0.03 (s, 6 H); MS (FAB) m/ z 981 (M + Na)+;
HRMS (FAB) calcd for C58H94NaO7Si2 [(M + Na)+] 981.6437,
Meth yl Keton e 38. To a suspension of copper(I) iodide (3.3
g, 17 mmol) in Et2O (30 mL) cooled at -23 °C was added a
1.06 M solution of MeLi in Et2O (28 mL, 30 mmol) dropwise.
The mixture was stirred at -23 °C for 30 min and cooled to
-78 °C, and then a solution of aldehyde 37 (1.60 g, 2.79 mmol)
in Et2O (5 mL) was added dropwise. The mixture was stirred
at -78 °C for 1 h, and the reaction was quenched by addition
of a 2:1 mixture of saturated aqueous NH4Cl and concentrated
aqueous NH3 (45 mL). The resulting mixture was warmed to
room temperature, stirred for 1 h, and extracted with Et2O
(100 mL, 20 mL). The combined extracts were washed with
brine (15 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (30
g, hexane-Et2O 10:1 f 5: 1 f 3:1 f 1: 1) to give a diastere-
omeric mixture of secondary alcohols (1.60 g) as a colorless
oil, which was employed in the next experiment without
separation of the diastereomers. To a stirred solution of the
diastereomeric mixture of secondary alcohols (1.60 g) in CH2-
Cl2 (25 mL) were added pyridine (3.0 mL, 37 mmol) and the
Dess-Martin periodinane (1.89 g, 4.46 mmol) at room tem-
perature. The mixture was stirred at room temperature for
0.7 h, and was diluted with Et2O (10 mL), saturated aqueous
NaHCO3 (10 mL), and saturated aqueous Na2S2O3 (10 mL),
and the stirring was continued for 1 h. The mixture was
extracted with Et2O (100 mL, 20 mL), and the combined
extracts were washed with 5% aqueous NaHCO3 (20 mL), H2O
(15 mL), and brine (15 mL) successively; dried (Na2SO4); and
concentrated. The residual oil was purified by column chro-
matography on silica gel (30 g, hexane-Et2O 20:1 f 10: 1 f
found 981.6423. 40: [R]20 +10.6 (c 1.16, CHCl3); IR (CHCl3)
D
1720, 1600, 1450, 1380, 1285, 1250, 1165, 835 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.49-7.44 (m, 6 H), 7.33-7.19 (m, 9 H),
5.35 (dd, J ) 6.6, 6.6 Hz, 1 H), 4.23 (ddd, J ) 5.3, 5.3, 10.6
Hz, 1 H), 4.03 (ddd, J ) 7.3, 7.3, 10.6 Hz, 1 H), 3.93 (dd, J )
7.6, 7.6 Hz, 1 H), 3.69 (ddd, J ) 4.3, 4.3, 6.9 Hz, 1 H), 3.43 (s,
3 H), 3.43-3.31 (m, 2 H), 3.16-3.06 (m, 2 H), 3.13 (s, 3 H),
1.96 (dd, J ) 6.6, 6.6 Hz, 2 H), 1.79 (m, 1 H), 1.68-1.33 (m, 10
H), 1.56 (s, 3 H), 1.19 (s, 9 H), 0.95, (t, J ) 7.9 Hz, 9 H), 0.89-
0.84 (m, 9 H), 0.88 (s, 9 H), 0.59 (q, J ) 7.9 Hz, 6 H), 0.03 (s,
6 H); MS (FAB) m/ z 981 (M + Na)+; HRMS (FAB) calcd for
C58H94NaO7Si2 [(M + Na)+] 981.6437, found 981.6461. 41: IR
(CHCl3) 3575(br), 1720, 1600, 1465, 1450, 1290, 1255, 1165
cm-1; 1H NMR (270 MHz, CDCl3) δ 7.51-7.44 (m, 6 H), 7.34-
7.18 (m, 9 H), 4.24 (ddd, J ) 5.6, 5.6, 10.9 Hz, 1 H), 4.05 (ddd,
J ) 7.3, 7.3, 10.9 Hz, 1 H), 3.70 (m, 1 H), 3.47 (s, 3 H), 3.44
(m, 1 H), 3.42 (s, 3 H), 3.37 (m, 1 H), 3.11 (d, J ) 4.5 Hz, 2 H),
2.88 (m, 1 H), 2.04 (br s, 1 H) [2.12], 1.88-1.00 (m, 15 H), 1.20
(s, 9 H), 1.13 (s, 3 H) [1.05], 0.96 (t, J ) 7.6 Hz, 9 H), 0.93-
0.85 (m, 9 H), 0.90 (s, 9 H), 0.60 (q, J ) 7.6 Hz, 6 H), 0.05 (s,
6 H) (the minor counterparts of doubled signals in the ratio of
3:2 are in brackets); MS (FAB) m/ z 999 (M + Na)+; HRMS
(FAB) calcd for C58H96NaO8Si2 [(M + Na)+] 999.6542, found
999.6557.
5: 1) to give 38 (1.53 g, 93%) as a colorless oil: [R]27 -1.8 (c
D
1.09, CHCl3); IR (CHCl3) 1720, 1465, 1290, 1255, 1170, 835
cm-1 1H NMR (270 MHz, CDCl3) δ 4.23 (ddd, J ) 5.6, 5.6,
;
10.9 Hz, 1 H), 4.05 (ddd, J ) 7.3, 7.3, 10.9 Hz, 1 H), 3.68 (ddd,
J ) 5.6, 5.6, 5.6 Hz, 1 H), 3.47 (dd, J ) 4.6, 7.9 Hz, 1 H), 3.42
(dd, J ) 3.0, 4.6 Hz, 1 H), 3.34 (s, 3 H), 2.15 (s, 3 H), 1.84-
1.43 (m, 7 H), 1.19 (s, 9 H), 1.15 (m, 1 H), 0.97 (t, J ) 7.9 Hz,
9 H), 0.91-0.87 (m, 6 H), 0.90 (s, 9 H), 0.61 (q, J ) 7.9 Hz, 6
H), 0.05 (s, 6 H); MS (FAB) m/ z 611 (M + Na)+. Anal. Calcd
for C31H64O6Si2: C, 63.21; H, 10.95. Found C, 63.11; H, 11.06.
Isom er iza tion of (Z)-Olefin 40. A 0.02 M solution of
benzenethiol in benzene (1.0 mL, 0.020 mmol) was added to
(Z)-olefin 40 (21.2 mg, 0.0221 mmol) at room temperature. To
the solution was added 2,2′-azobis(isobutyronitrile) (1.6 mg,
0.0097 mmol), and the resulting mixture was kept under reflux
for 12.5 h. During the reaction, 2,2′-azobis(isobutyronitrile)
(16.2 mg, 0.099 mmol) and a 0.078 M solution of benzenethiol

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5339
in benzene (1.25 mL, 0.098 mmol) were added in portions. The
mixture was cooled to room temperature and concentrated. The
residual oil was purified twice by column chromatography on
silica gel [(2 g, hexane-EtOAc 47:1 f 23: 1 f 11: 1 f 7: 1)
and (2 g, hexane-Et2O 79:1 f 39:1 f 19:1 f 9: 1)] to give a
mixture of olefins (39/40 ) 5/6) (18.9 mg, 90%) as a colorless
oil.
Deh yd r a tion of Ter tia r y Alcoh ol 41. To a stirred
solution of tertiary alcohol 41 (34.8 mg, 0.036 mmol) in
pyridine (0.5 mL) cooled at 0 °C was added phosphoryl
trichloride (0.1 mL, 1.07 mmol). The solution was stirred at
0 °C for 24 h and diluted with saturated aqueous NaHCO3 (3
mL). The mixture was extracted with Et2O (3 × 5 mL). The
combined extracts were washed with brine (1 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (2 g, hexane-Et2O 12: 1
f 8:1) and medium-pressure liquid chromatography (Fuji
Silysia, silica gel FL60D 6.4 g, hexane-EtOAc 40:1, 3 mL/
min) to give (E)-olefin 39 (tR ) 50 min, 14.0 mg, 43%) and the
mixture of isomeric olefins (10.6 mg, 32%).
(s, 9 H), 1.08 (d, J ) 7.3 Hz, 3 H), 0.87 (s, 9 H), 0.86 (d, J )
6.9 Hz, 3 H), 0.85 (d, J ) 6.9 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3
H); MS (FAB) m/ z 865 (M + Na)+; HRMS (FAB) calcd for
C52H78NaO7Si [(M + Na)+] 865.5414, found 865.5414.
Alcoh ol 45. To a stirred solution of (methylthio)methyl
ether 43 (43.9 mg, 0.0486 mmol) in Et2O (0.6 mL) was added
formic acid (0.4 mL) at room temperature, and the mixture
was stirred at room temperature for 15 min. The mixture was
poured into saturated aqueous NaHCO3 (10 mL) cooled at 0
°C, and the resulting mixture was extracted with Et2O (30 mL,
10 mL). The combined extracts were washed with saturated
aqueous NaHCO3 (5 mL) and brine (5 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (2 g, hexane-Et2O 4:1 f 1: 1 f
1: 2) to give 45 (30.3 mg, 90%) as a colorless oil: [R]26 +34.5
D
(c 1.18, CHCl3); IR (CHCl3) 3580, 3440 (br), 1720, 1465, 1285,
1
1255, 1165, 835 cm-1; H NMR (270 MHz, CDCl3) δ 5.33 (dd,
J ) 6.9, 6.9 Hz, 1 H), 4.65 (d, J ) 11.5 Hz, 1 H), 4.58 (d, J )
11.5 Hz, 1 H), 4.20-4.08 (m, 2 H), 3.71 (ddd, J ) 3.3, 6.6, 11.2
Hz, 1 H), 3.63 (ddd, J ) 3.0, 5.3, 8.2 Hz, 1 H), 3.50 (dd, J )
3.6, 3.6 Hz, 1 H), 3.47-3.30 (m, 3 H), 3.41 (s, 3 H), 3.15 (s, 3
H), 2.17 (s, 3 H), 2.10 (m, 1 H), 1.99 (dd, J ) 5.6, 5.6 Hz, 1 H),
1.96-1.32 (m, 11 H), 1.50 (s, 3 H), 1.21 (s, 9 H), 1.05-0.83 (m,
4 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d, J ) 6.6
Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H); MS (FAB) m/ z 685 (M +
Na)+. Anal. Calcd for C35H70O7SSi: C, 63.40; H, 10.64. Found
C, 63.42; H, 10.69.
Alcoh ol 42. To a stirred solution of (E)-olefin 39 (63 mg,
0.066 mmol) in THF (1.6 mL) was added a 4:1 mixture of acetic
acid and H2O (2 mL), and the mixture was stirred at room
temperarture for 6.6 h. The mixture was poured into satu-
rated aqueous NaHCO3 (25 mL) cooled at 0 °C, and the
mixture was extracted with Et2O (30 mL, 10 mL). The
combined extracts were washed with saturated aqueous
NaHCO3 (5 mL) and brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (10 g, hexane-Et2O 4:1 f 2: 1 f 1: 1)
C5-C20 Segm en t 9. To a stirred solution of alcohol 45
(37.5 mg, 0.0565 mmol) in CH2Cl2 (0.8 mL) were added
pyridine (0.04 mL, 0.5 mmol) and the Dess-Martin periodi-
nane (31.5 mg, 0.0743 mmol) at room temperature. The
mixture was stirred at room temperature for 1 h. The mixture
was diluted with Et2O (4 mL), saturated aqueous NaHCO3 (3
mL), and saturated aqueous Na2S2O3 (3 mL), stirred at room
temperature for 30 min, and extracted with Et2O (3 × 8 mL).
The combined extracts were washed with H2O (2 mL) and
brine (2 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (2 g,
hexane-Et2O 5:1 f 3: 1 f 2: 1 f 1:1) to give 9 (30.0 mg, 80%)
as a colorless oil: [R]19D +67.2 (c 1.22, CHCl3); IR (CHCl3) 2710,
to give 42 (54 mg, 97%) as a colorless oil: [R]27 +19.9 (c 1.23,
D
CHCl3); IR (CHCl3) 3450 (br), 1720, 1600, 1450, 1380, 1285,
1255, 1165, 835 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.48-7.44
(m, 6 H), 7.33-7.20 (m, 9 H), 5.30 (dd, J ) 6.9, 6.9 Hz, 1 H),
4.33 (ddd, J ) 5.0, 8.9, 10.9 Hz, 1 H), 4.20 (ddd, J ) 5.0, 5.9,
10.9 Hz, 1 H), 3.80 (dd, J ) 1.7, 5.0 Hz, 1 H), 3.54 (m, 1 H),
3.42 (s, 3 H), 3.40-3.30 (m, 2 H), 3.16-3.06 (m, 2 H), 3.11 (s,
3 H), 3.02 (br d, J ) 3.6 Hz, 1 H), 2.14 (ddd, J ) 5.6, 6.9, 12.9
Hz, 1 H), 1.92 (m, 1 H), 1.78 (m, 1 H), 1.67-1.17 (m, 10 H),
1.47 (s, 3 H), 1.20 (s, 9 H), 0.89 (s, 9 H), 0.88-0.86 (m, 3 H),
0.86 (d, J ) 6.6 Hz, 3 H), 0.82 (d, J ) 6.9 Hz, 3 H), 0.06 (s, 3
H), 0.04 (s, 3 H); MS (FAB) m/ z 867 (M + Na)+; HRMS (FAB)
calcd for C52H80NaO7Si [(M + Na)+] 867.5571, found 867.5597.
(Meth ylth io)m eth yl Eth er 43 a n d Keton e 44. To a
stirred solution of alcohol 42 (275 mg, 0.326 mmol) in DMSO
(2 mL) was added a 1:5.6 mixture of acetic acid and acetic
anhydride (1.65 mL) at room temperature. The mixture was
stirred at room temperature for 2 h and at 40 °C for 5.5 h.
The reaction mixture was poured into saturated aqueous
NaHCO3 (35 mL) cooled at 0 °C, and the mixture was extracted
with Et2O (50 mL, 20 mL). The combined extracts were
washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (10 g,
hexane-Et2O 7:1 f 5: 1 f 3: 1) to give 43 (254 mg, 86%) and
1
1730 (sh), 1720, 1460, 1290, 1250, 1165, 830 cm-1; H NMR
(270 MHz, CDCl3) δ 9.64 (d, J ) 2.3 Hz, 1 H), 5.33 (dd, J )
6.9, 6.9 Hz, 1 H), 4.65 (d, J ) 11.5 Hz, 1 H), 4.58 (d, J ) 11.5
Hz, 1 H), 4.22-4.07 (m, 2 H), 3.66-3.60 (m, 2 H), 3.50 (dd, J
) 3.6, 3.6 Hz, 1 H), 3.43 (s, 3 H), 3.38 (dd, J ) 6.9, 6.9 Hz, 1
H), 3.15 (s, 3 H), 2.17 (s, 3 H), 2.15 (m, 1 H), 1.98-1.32 (m, 11
H), 1.51 (s, 3 H), 1.20 (s, 9 H), 1.05-0.83 (m, 4 H), 0.93 (d, J
) 6.6 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d, J ) 6.6 Hz, 3 H), 0.06 (s,
3 H), 0.05 (s, 3 H); MS (FAB) m/ z 683 (M + Na)+; HRMS (FAB)
calcd for C35H68NaO7SSi (M + Na)+ 683.4352, found 683.4351.
Hyd r oxy Im id e 46. Experimental procedure was followed
as described for compound 12. 46: [R]29 +8.56 (c 1.15,
D
CHCl3); IR (CHCl3) 3690, 3500 (br), 1780, 1710 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.44-7.27 (m, 10 H), 5.64 (d, J ) 7.3 Hz,
1 H), 4.77 (dq, J ) 6.6, 7.3 Hz, 1 H), 4.53 (s, 2 H), 4.19 (ddt, J
) 2.3, 3.6, 9.2 Hz,1 H), 3.84 (dq, J ) 3.6, 6.9 Hz, 1H), 3.70 (m,
2 H), 3.31 (d, J ) 2.3 Hz, 1H), 1.96-1.71 (m, 2 H), 1.26 (d, J
) 6.9 Hz, 3 H), 0.89 (d, J ) 6.6 Hz, 3 H); MS (FAB) m/ z 420
(M + Na)+, 398 (M + H)+; HRMS (FAB) calcd for C23H28NO5
[(M + H)+] 398.1967, found 398.1979.
44 (46 mg, 14%) as a colorless oil, respectively. 43: [R]26
D
+40.7 (c 1.07, CHCl3); IR (CHCl3) 1720, 1600, 1450, 1290, 1255,
1165, 840 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.48-7.44 (m, 6
H), 7.34-7.20 (m, 9 H), 5.30 (dd, J ) 6.9, 6.9 Hz, 1 H), 4.64 (d,
J ) 11.5 Hz, 1 H), 4.57 (d, J ) 11.5 Hz, 1 H), 4.22-4.07 (m, 2
H), 3.63 (ddd, J ) 3.0, 5.3, 8.3 Hz, 1 H), 3.49 (dd, J ) 3.6, 3.6
Hz, 1 H), 3.42 (s, 3 H), 3.42-3.33 (m, 2 H), 3.16-3.06 (m, 2
H), 3.11 (s, 3 H), 2.15 (s, 3 H), 2.13 (ddd, J ) 5.4, 6.9, 13.2 Hz,
1 H), 1.95 (m, 1 H), 1.86-1.67 (m, 3 H), 1.65-1.11 (m, 7 H),
1.48 (s, 3 H), 1.20 (s, 9 H), 1.04-0.85 (m, 10 H), 0.89 (s, 9 H),
0.05 (s, 3 H), 0.04 (s, 3 H); MS (FAB) m/ z 927 (M + Na)+;
HRMS (FAB) calcd for C54H84NaO7SSi [(M + Na)+] 927.5605,
Am id e 47. Experimental procedure was followed as de-
scribed for compound 13. 47: [R]26D -11.1 (c 1.65, CHCl3); IR
(CHCl3) 3660, 3470 (br), 1635, 1460, 1230, 1090, 995 cm-1; 1H
NMR (270 MHz, CDCl3) δ 7.36-7.25 (m, 5 H), 4.52 (s, 2 H),
4.06 (m, 1 H), 3.91 (s, 1 H), 3.73-3.61 (m, 2 H), 3.66 (s, 3 H),
3.18 (s, 3 H), 2.92 (m, 1 H), 1.91-1.66 (m, 2 H), 1.20 (d, J )
6.9 Hz, 3 H); MS (FAB) m/ z 304 (M + Na)+, 282 (M + H)+;
HRMS (FAB) calcd for C15H23NNaO4 [(M + Na)+] 304.1525,
found 304.1522.
found 927.5610. 44: [R]29 +19.3 (c 1.42, CHCl3); IR (CHCl3)
D
1725, 1600, 1480, 1450, 1285, 1255, 1160, 840 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.50-7.44 (m, 6 H), 7.34-7.19 (m, 9 H),
5.29 (dd, J ) 6.9, 6.9 Hz, 1 H), 4.36-4.11 (m, 2 H), 3.85 (dd,
J ) 4.7, 4.7 Hz, 1 H), 3.42 (s, 3 H), 3.42-3.29 (m, 2 H), 3.16-
3.08 (m, 2 H), 3.10 (s, 3 H), 2.81 (ddd, J ) 6.3, 6.3, 17.0 Hz, 1
H), 2.73 (ddd, J ) 6.3, 6.3, 17.0 Hz, 1 H), 2.67 (dq, J ) 5.3, 6.9
Hz, 1 H), 2.12 (ddd, J ) 5.9, 6.9, 13.2 Hz, 1 H), 1.76 (ddd, J )
6.9, 6.9, 13.2 Hz, 1 H), 1.64-1.31 (m, 8 H), 1.46 (s, 3 H), 1.16
Silyl Eth er 48. Experimental procedure was followed as
described for compound 23. 48: [R]26 -1.94 (c 1.55, CHCl3);
D
IR (CHCl3) 1650, 1460, 1240, 1110, 995, 840 cm-1; H NMR
1
(270 MHz, CDCl3) δ 7.36-7.23 (m, 5 H), 4.50 (d, J ) 12.4 Hz,
1 H), 4.46 (d, J ) 12.4 Hz, 1 H), 4.04 (dt, J ) 7.9, 5.1 Hz, 1 H),
3.63-3.47 (m, 2 H), 3.59 (s, 3 H), 3.14 (s, 3 H), 2.97 (m, 1 H),
1.91-1.75 (m, 2 H), 1.16 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 7.9

5340 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
Hz, 9 H), 0.61 (q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 418 (M +
Na)+, 396 (M + H)+; HRMS (FAB) calcd for C21H38NO4Si [(M
+ H)+] 396.2570, found 396.2569.
to give diol 53a (360 mg, 75%) and diol 53b (85 mg, 18%) as a
colorless oil, respectively. 53a : [R]25 -15.2 (c 1.13, CHCl3);
D
IR (CHCl3) 3400 (br), 1450, 1090, 995 cm-1; 1H NMR (270 MHz,
CDCl3) δ 7.38-7.28 (m, 5 H), 4.80 (d, J ) 2.3 Hz, 1 H), 4.52
(d, J ) 11.9 Hz, 1 H), 4.46 (d, J ) 11.9 Hz, 1 H), 4.15 (ddd, J
) 3.0, 5.0, 7.9 Hz, 1 H), 3.89 (ddd, J ) 3.3, 3.3, 10.9 Hz, 1 H),
3.66 (ddd, J ) 2.3, 4.3, 8.9 Hz, 1 H), 3.58 (ddd, J ) 5.3, 6.6,
10.9 Hz, 1 H), 3.53 (t, J ) 5.6, 2 H), 3.47 (dd, J ) 3.3, 6.6 Hz,
1 H), 2.03 (m, 1 H), 1.91-1.70 (m, 3 H), 1.06 (d, J ) 6.9 Hz, 3
H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.84 (d, J ) 7.3 Hz, 3 H), 0.64 (q,
J ) 7.9 Hz, 6 H); MS (FAB) m/ z 419 (M + Na)+, 397 (M +
H)+. Anal. Calcd for C22H40O4Si: C, 66.62; H, 10.16. Found:
Ald eh yd e 49. Experimental procedure was followed as
described for compound 15. 49: [R]26 -53.8 (c 1.25, CHCl3);
D
IR (CHCl3) 2720, 1725, 1455, 1105, 1010, 805 cm-1; H NMR
1
(270 MHz, CDCl3) δ 9.78 (d, J ) 1.0 Hz, 1 H), 7.38-7.26 (m,
5 H), 4.51 (d, J ) 11.9 Hz, 1 H), 4.45 (d, J ) 11.9 Hz, 1 H),
4.33 (ddd, J ) 3.6, 5.6, 7.3 Hz, 1 H), 3.58-3.46 (m, 2 H), 2.47
(ddq, J ) 1.0, 3.6, 6.9 Hz, 1 H), 1.91-1.70 (m, 2 H), 1.06 (d, J
) 6.9 Hz, 3 H), 0.94 (t, J ) 7.9 Hz, 9 H), 0.58 (q, J ) 7.9 Hz,
6 H); MS (FAB) m/ z 359 (M + Na)+; HRMS (FAB) calcd for
C19H32NaO3Si [(M + Na)+] 359.2018, found 359.2011.
C, 66.47; H, 10.41. 53b: [R]25 +6.08 (c 1.35, CHCl3); IR
D
(CHCl3) 3570, 3400 (br), 1450, 1075, 1000 cm-1; 1H NMR (270
MHz, CDCl3) δ 7.36-7.28 (m, 5 H), 4.49 (s, 2 H), 3.81 (dt, J )
5.9, 5.9 Hz, 1 H), 3.70-3.37 (m, 5 H), 3.29 (br s, 1 H), 2.19 (br
s, 1 H), 1.97-1.62 (m, 4 H), 0.95 (t, J ) 7.9 Hz, 9 H), 0.87 (d,
J ) 6.9 Hz, 3 H), 0.75 (d, J ) 6.9 Hz, 3 H), 0.61 (q, J ) 7.9 Hz,
6 H); MS (FAB) m/ z 419 (M + Na)+, 397 (M + H)+; HRMS
(FAB) calcd for C22H41O4Si [(M + H)+] 397.2774, found
397.2779.
Hor n er -Em m on s Rea ction of Ald eh yd e 49. Experi-
mental procedure was followed as described for compound 16.
This reaction provided 50a (96%) and 50b (3%). 50a : [R]26
D
-43.3 (c 1.03, CHCl3); IR (CHCl3) 1715, 1655, 1460, 1280, 1105,
1010, 835 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.38-7.25 (m, 5
H), 7.04 (dd, J ) 6.9, 15.8 Hz, 1 H), 5.79 (dd, J ) 1.3, 15.8 Hz,
1 H), 4.51 (d, J ) 11.9 Hz, 1 H), 4.45 (d, J ) 11.9 Hz, 1 H),
4.18 (q, J ) 7.3 Hz, 2 H), 3.85 (dt, J ) 8.3, 4.3 Hz, 1 H), 3.52
(dd, J ) 5.9, 6.9 Hz, 2 H), 2.45 (dddq, J ) 1.3, 6.9, 8.3, 6.9 Hz,
1 H), 1.83-1.56 (m, 2 H), 1.28 (t, J ) 7.3 Hz, 3 H), 1.02 (d, J
) 6.9 Hz, 3 H), 0.94 (t, J ) 7.9 Hz, 9 H), 0.59 (q, J ) 7.9 Hz,
6 H); MS (FAB) m/ z 407 (M + H)+; HRMS (FAB) calcd for
Su lfid e 54. Experimental procedure was followed as
described for compound 22. 54: [R]23 -44.3 (c 1.24, CHCl3);
D
IR (CHCl3) 3430 (br), 1585, 1455, 1110, 1090, 1000 cm-1; H
1
NMR (270 MHz, CDCl3) δ 7.37-7.12 (m, 10 H), 4.51 (d, J )
11.5 Hz, 1 H), 4.45 (d, J ) 11.5 Hz, 1 H), 4.33 (d, J ) 2.3 Hz,
1 H), 4.04 (m, 1 H), 3.53 (m, 1 H), 3.52 (t, J ) 6.3 Hz, 2 H),
3.24 (dd, J ) 3.3, 12.9 Hz, 1 H), 2.74 (dd, J ) 9.6, 12.9 Hz, 1
H), 1.95 (m, 1 H), 1.80 (m, 1 H), 1.83 (td, J ) 6.3, 6.3 Hz, 2 H),
1.13 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 7.9 Hz, 9 H), 0.73 (d, J
) 6.9 Hz, 3 H), 0.61 (q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 511
(M + Na)+, 489 (M + H)+; HRMS (FAB) calcd for C28H44NaO3-
SSi [(M + Na)+] 511.2678, found 511.2690.
C23H39O4Si [(M + H)+] 407.2617, found 407.2609. 50b: [R]26
D
+44.8 (c 1.40, CHCl3); IR (CHCl3) 1710, 1640, 1190, 1095, 1015,
1
830 cm-1; H NMR (270 MHz, CDCl3) δ 7.37-7.23 (m, 5 H),
6.16 (dd, J ) 10.2, 11.6 Hz, 1 H), 5.74 (dd, J ) 1.0, 11.6 Hz, 1
H), 4.51 (d, J ) 12.2 Hz, 1 H), 4.47 (d, J ) 12.2 Hz, 1 H), 4.14
(q, J ) 7.3 Hz, 2 H), 3.80 (dt, J ) 6.9, 5.0 Hz, 1 H), 3.58 (dddq,
J ) 1.0, 6.9, 10.2, 6.9 Hz, 1 H), 3.55 (t, J ) 6.6 Hz, 2 H), 1.92-
1.69 (m, 2 H), 1.26 (t, J ) 7.3 Hz, 3 H), 1.00 (d, J ) 6.9 Hz, 3
H), 0.93 (t, J ) 7.9 Hz, 9 H), 0.57 (q, J ) 7.9 Hz, 6 H); MS
(FAB) m/ z 407 (M + H)+; HRMS (FAB) calcd for C23H39O4Si
[(M + H)+] 407.2617, found 407.2641.
Silyl Eth er 55. Experimental procedure was followed as
described for compound 23. 55: [R]21 -11.7 (c 1.11, CHCl3);
D
1
IR (CHCl3) 1580, 1455, 1080, 1005 cm-1; H NMR (270 MHz,
CDCl3) δ 7.36-7.12 (m, 10 H), 4.51 (d, J ) 11.9 Hz, 1 H), 4.45
(d, J ) 11.9 Hz, 1 H), 3.94 (m, 1 H), 3.64 (dd, J ) 2.6, 6.9 Hz,
1 H), 3.45 (t, J ) 6.9 Hz, 2 H), 3.17 (dd, J ) 3.0, 12.5 Hz, 1 H),
2.64 (dd, J ) 10.2, 12.5 Hz, 1 H), 1.96-1.73 (m, 3 H), 1.61
(ddq, J ) 4.0, 6.9, 6.9 Hz, 1 H), 1.09 (d, J ) 6.9 Hz, 3 H), 0.94
(t, J ) 7.6 Hz, 9 H), 0.93 (t, J ) 7.6 Hz, 9 H), 0.77 (d, J ) 6.9
Hz, 3 H), 0.60 (q, J ) 7.9 Hz, 6 H), 0.57 (q, J ) 7.9 Hz, 6 H);
MS (FAB) m/ z 603 (M + H)+; HRMS (FAB) calcd for C34H59O3-
SSi2 [(M + H)+] 603.3723, found 603.3717.
Allylic Alcoh ol 51. Experimental procedure was followed
as described for compound 17. 51: [R]26 -38.4 (c 1.29,
D
CHCl3); IR (CHCl3) 3610, 3440 (br), 1455, 1095, 1005, 835
1
cm-1; H NMR (270 MHz, CDCl3) δ 7.37-7.27 (m, 5 H), 5.74
(dd, J ) 6.6, 15.5 Hz, 1 H), 5.61 (dt, J ) 15.5, 5.3 Hz, 1 H),
4.51 (d, J ) 11.9 Hz, 1 H), 4.45 (d, J ) 11.9 Hz, 1 H), 4.09 (dd,
J ) 5.3, 5.9 Hz, 2 H), 3.75 (dt, J ) 8.2, 4.0 Hz, 1 H), 3.53 (dd,
J ) 5.9, 7.3 Hz, 2 H), 2.31 (ddq, J ) 6.6, 8.2, 6.9 Hz, 1 H),
1.82-1.59 (m, 2 H), 1.24 (t, J ) 5.9 Hz, 1 H), 0.98 (d, J ) 6.9
Hz, 3 H), 0.95 (t, J ) 7.9 Hz, 9 H), 0.59 (q, J ) 7.9 Hz, 6 H);
C21-C27 Segm en t 5. Experimental procedure was fol-
MS (FAB) m/ z 365 (M + H+); HRMS (FAB) calcd for C21H36
-
lowed as described for compound 4. 5: [R]21 +4.56 (c 1.10,
D
NaO3Si [(M + Na)+] 387.2331, found 387.2321.
CHCl3); IR (CHCl3) 1580, 1455, 1300, 1140, 1080, 1005 cm-1
;
Ep oxid e 52. Experimental procedure was followed as
described for compound 18. 52: [R]23D -3.71 (c 0.921, CHCl3);
1H NMR (270 MHz, CDCl3) δ 7.91-7.87 (m, 2 H), 7.66-7.50
(m, 3 H), 7.42-7.23 (m, 5 H), 4.50 (d, J ) 11.9 Hz, 1 H), 4.43
(d, J ) 11.9 Hz, 1 H), 3.91 (dt, J ) 3.6, 6.6 Hz, 1 H), 3.56 (dd,
J ) 1.3, 6.9 Hz, 1 H), 3.40 (t, J ) 6.6 Hz, 2 H), 3.27 (dd, J )
1.0, 14.5 Hz, 1 H), 2.85 (dd, J ) 10.2, 14.5 Hz, 1 H), 2.23 (m,
1 H), 1.79 (dt, J ) 6.6, 6.6 Hz, 2 H), 1.42 (ddq, J ) 3.6, 6.9, 6.9
Hz, 1 H), 1.16 (d, J ) 6.9 Hz, 3 H), 0.93 (t, J ) 7.6 Hz, 9 H),
0.90 (t, J ) 7.6 Hz, 9 H), 0.57 (d, J ) 6.9 Hz, 3 H), 0.60 (q, J
) 7.9 Hz, 6 H), 0.57 (q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 657
(M + Na)+, 635 (M + H)+. Anal. Calcd for C34H58O5SSi2: C,
64.30; H, 9.21. Found: C, 64.32; H, 9.25.
1
IR (CHCl3) 3600, 3470 (br), 1455, 1090, 1005 cm-1; H NMR
(270 MHz, CDCl3) δ 7.38-7.24 (m, 5 H), 4.51 (d, J ) 11.9 Hz,
1 H), 4.46 (d, J ) 11.9 Hz, 1 H), 4.02 (dt, J ) 3.3, 6.3 Hz, 1 H),
3.91 (ddd, J ) 2.3, 5.6, 12.5 Hz, 1 H), 3.61 (ddd, J ) 4.3, 7.3,
12.5 Hz, 1 H), 3.49 (t, J ) 6.6 Hz, 2 H), 2.98-2.92 (m, 2 H),
1.90-1.72 (m, 2 H), 1.74 (dd, J ) 5.6, 7.3 Hz, 1 H), 1.48 (ddq,
J ) 3.3, 6.9, 6.9 Hz, 1 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.88 (d, J
) 6.9 Hz, 3 H), 0.61 (q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 403
(M + Na)+; HRMS (FAB) calcd for C21H36NaO4Si [(M + Na)+]
403.2281, found 403.2282.
Oxir a n e Rin g Op en in g of Ep oxid e 52. To a suspension
of copper(I) iodide (2.56 g, 13.4 mmol) in Et2O (15 mL) cooled
at -23 °C was added a 1.09 M solution of MeLi in Et2O (21
mL, 22.9 mmol) dropwise. After the solution was stirred at
-23 °C for 30 min, a solution of epoxide 52 (461 mg, 1.23 mmol)
in Et2O (5.0 mL) was added. The reaction mixture was stirred
at -23 °C for 2 h and kept at -20 °C for 12 h. After the
mixture was warmed to 0 °C and stirred for 2 h, a 2:1 mixture
of saturated aqueous NH4Cl and 28% aqueous NH3 (27 mL)
was added. The resulting mixture was stirred at room
temperature for 1.5 h, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL).
The organic layer and the extracts were combined, washed
with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (30 g, hexane-Et2O 2:1 f 1: 1 f 1: 2)
Hor n er -Em m on s Rea ction of Ald eh yd e 59. Experi-
mental procedure was followed as described for compound 16.
This reaction provided 60a (90%) and 60b (7%). 60a : [R]24
D
+14.1 (c 1.00, CHCl3); IR (CHCl3) 1705, 1650, 1365, 1255, 1090,
1
1030 cm-1; H NMR (270 MHz, CDCl3) δ 7.36-7.26 (m, 5 H),
6.98 (dd, J ) 7.6, 15.8 Hz, 1 H), 5.81 (dd, J ) 1.3, 15.8 Hz, 1
H), 4.52 (d, J ) 11.9 Hz, 1 H), 4.47 (d, J ) 11.9 Hz, 1 H), 4.18
(q, J ) 7.3 Hz, 2 H), 3.82 (ddd, J ) 4.6, 5.6, 5.6 Hz, 1 H), 3.42
(dd, J ) 5.6, 9.6 Hz, 1 H), 3.36 (dd, J ) 5.6, 9.6 Hz, 1 H), 2.60
(dddq, J ) 1.3, 4.6, 7.6, 6.6 Hz, 1 H), 1.28 (t, J ) 7.3 Hz, 3 H),
1.03 (d, J ) 6.6 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 6 H); MS (FAB)
m/ z 415 (M + Na)+; HRMS (FAB) calcd for C22H36NaO4Si [(M
+ Na)+] 415.2280, found 415.2296. 60b: [R]24 -54.9 (c 1.02,
D
CHCl3); IR (CHCl3) 1710, 1640, 1450, 1415, 1250, 1190, 1095,
1
1030 cm-1; H NMR (270 MHz, CDCl3) δ 7.35-7.25 (m, 5 H),
6.16 (dd, J ) 10.2, 11.5 Hz, 1 H), 5.72 (dd, J ) 0.8, 11.5 Hz, 1
H), 4.53 (d, J ) 12.2 Hz, 1 H), 4.46 (d, J ) 12.2 Hz, 1 H), 4.16

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5341
(q, J ) 7.3 Hz, 2 H), 3.81 (ddd, J ) 4.9, 4.9, 6.3 Hz, 1 H), 3.67
(dddq, J ) 0.8, 4.9, 10.2, 6.6 Hz, 1 H), 3.45 (dd, J ) 4.9, 9.9
Hz, 1 H), 3.39 (dd, J ) 6.3, 9.9 Hz, 1 H), 1.27 (t, J ) 7.3 Hz,
3 H), 1.00 (d, J ) 6.6 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H); MS
(FAB) m/ z 415 (M + Na)+; HRMS (FAB) calcd for C22H36NaO4-
Si [(M + Na)+] 415.2280, found 415.2274.
mmol) at room temperature. The reaction mixture was
warmed to 50 °C and stirred for 2.5 h. After cooling, H2O (20
mL) was added, and the mixture was extracted with Et2O (3
× 50 mL). The combined extracts were washed with H2O (30
mL) and brine (30 mL), dried (Na2SO4), and concentrated. The
residual oil was purified by column chromatography on silica
gel (50 g, hexane-Et2O 10:1 f 7:1 f 5:1 f 3:1 f 2:1) to give
65a (1.05 g, 91%) and oxetane 65b (76 mg, 7%) as a colorless
oil, respectively. 65a : [R]24D +12.2 (c 1.03, CHCl3); IR (CHCl3)
Allylic Alcoh ol 61. Experimental procedure was followed
as described for compound 17. 61: [R]24D +9.7 (c 1.10, CHCl3);
IR (CHCl3) 3605, 3500 (br), 1450, 1360, 1250, 1090, 835 cm-1
;
1
3420 (br), 2230, 1455, 1355, 1250, 1100, 1055 cm-1; H NMR
1H NMR (270 MHz, CDCl3) δ 7.37-7.26 (m, 5 H), 5.70 (dd, J
) 5.6, 15.8 Hz, 1 H), 5.61 (dt, J ) 15.8, 4.9 Hz, 1 H), 4.50 (s,
2 H), 4.08 (dd, J ) 4.9, 5.6 Hz, 2 H), 3.72 (ddd, J ) 5.6, 5.6,
5.6 Hz, 1 H), 3.44 (dd, J ) 5.6, 9.6 Hz, 1 H), 3.36 (dd, J ) 5.6,
9.6 Hz, 1 H), 2.43 (ddq, J ) 5.6, 5.6, 6.9 Hz, 1 H), 1.58 (t, J )
5.6 Hz, 1 H), 0.99 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6
H); MS (FAB) m/ z 373 (M + Na)+; HRMS (FAB) calcd for
C20H34NaO3Si [(M + Na)+] 373.2175, found 373.2168.
(270 MHz, CDCl3) δ 7.39-7.25 (m, 5 H), 4.55 (d, J ) 12.0 Hz,
1 H), 4.48 (d, J ) 12.0 Hz, 1 H), 4.09 (dt, J ) 3.0, 5.9 Hz, 1 H),
4.03 (d, J ) 3.9 Hz, 1 H), 3.53 (d, J ) 5.9 Hz, 2 H), 3.42 (ddd,
J ) 3.9, 3.9, 7.9 Hz, 1 H), 2.50 (dd, J ) 4.6, 16.8 Hz, 1 H), 2.32
(dd, J ) 8.9, 16.8 Hz, 1 H), 2.01 (m, 1 H), 1.90 (m, 1 H), 1.15
(d, J ) 6.9 Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H),
0.11 (s, 3 H), 0.08 (s, 3 H); MS (FAB) m/ z 414 (M + Na)+;
HRMS (FAB) calcd for C22H37NNaO3Si [(M + Na)+] 414.2440,
found 414.2431. 65b: [R]24D -25.5 (c 2.23, CHCl3); IR (CHCl3)
Ep oxid e 62. Experimental procedure was followed as
described for compound 18. 62: [R]23 -26.1 (c 1.09, CHCl3);
D
1
1450, 1355, 1250, 1125, 1060, 1015, 955 cm-1; H NMR (270
IR (CHCl3) 3600, 3500 (br), 1475, 1450, 1250, 1360, 1090 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.37-7.26 (m, 5 H), 4.54 (d, J )
12.2 Hz, 1 H), 4.46 (d, J ) 12.2 Hz, 1 H), 4.05 (dt, J ) 3.0, 5.9
Hz, 1 H), 3.90 (ddd, J ) 2.3, 5.3, 12.5 Hz, 1 H), 3.61 (ddd, J )
4.3, 7.6, 12.5 Hz, 1 H), 3.42 (d, J ) 5.9 Hz, 2 H), 2.98-2.92
(m, 2 H), 1.65 (dd, J ) 5.3, 7.6 Hz, 1 H), 1.60 (ddq, J ) 3.0,
6.9, 6.9 Hz, 1 H), 0.90 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.06
(s, 3 H), 0.06 (s, 3 H); MS (FAB) m/ z 389 (M + Na)+; HRMS
(FAB) calcd for C20H34NaO4Si [(M + Na)+] 389.2124, found
382.2132.
MHz, CDCl3) δ 7.37-7.24 (m, 5 H), 4.56 (d, J ) 12.0 Hz, 1 H),
4.54 (dd, J ) 5.9, 7.9 Hz, 1 H), 4.46 (d, J ) 12.0 Hz, 1 H), 4.18
(dd, J ) 5.9, 6.6 Hz, 1 H), 4.14 (dd, J ) 6.3, 9.9 Hz, 1 H), 4.05
(dt, J ) 2.0, 6.6 Hz, 1 H), 3.38 (d, J ) 6.6 Hz, 2 H), 2.65 (m, 1
H), 2.03 (m, 1 H), 1.20 (d, J ) 6.6 Hz, 3 H), 0.87 (s, 9 H), 0.70
(d, J ) 6.6 Hz, 3 H), 0.06 (s, 3 H), 0.03 (s, 3 H); MS (FAB) m/ z
387 (M + Na)+, 365 (M + H)+; HRMS (FAB) calcd for C21H36
-
NaO3Si [(M + Na)+] 387.2331, found 387.2336.
Cyclic Aceta ls 66a ,b a n d 67. To a stirred solution of
nitrile 65a (464 mg, 1.19 mmol) in CH2Cl2 (15 mL) cooled at
-78 °C was added a 1.0 M solution of diisobutylaluminum
hydride in hexane (5.5 mL, 5.5 mmol). The solution was
stirred at -78 °C for 1 h, and the reaction was quenched by
addition of MeOH (1.0 mL). After the mixture was warmed
to room temperature, 0.5 M aqueous sodium potassium tar-
trate (12 mL) was added. The resulting mixture was stirred
at room temperature for 2 h, and the organic layer was
separated. The aqueous layer was extracted with Et2O (3 ×
30 mL). The organic layer and the extracts were combined,
washed with brine (10 mL), dried (Na2SO4), and concentrated.
The residual oil was dissolved in benzene (25 mL), and silica
gel (12 g) was added. Benzene was completely evaporated
from the mixture. The mixture of the crude products adsorbed
on silica gel was kept at room temperature for 14.5 h and
washed with MeOH. The eluate was concentrated to give a
crude hemiacetal (493 mg) as a colorless oil. To a stirred
solution of the crude hemiacetal (493 mg) in MeOH (12 mL)
was added camphorsulfonic acid (138 mg, 0.59 mmol), and this
mixture was kept under reflux for 1.6 h. After cooling,
triethylamine (0.5 mL) was added, and the resulting mixture
was concentrated. The residual oil was purified by column
chromatography on silica gel (30 g, hexane-Et2O 5:1 f 4:1 f
3:1 f 1:1) to give 66a (134 mg, 38%) and a fraction containing
66b and 67 (196 mg) as a colorless oil, respectively. To a
stirred solution of the fraction containing 66b and 67 (196 mg)
in MeOH (5.0 mL) was added camphorsulfonic acid (81 mg,
0.34 mmol) at room temperature. After the mixture was
stirred at room temperature for 14 h, triethylamine (0.3 mL)
was added, and the resulting mixture was concentrated. The
residual oil was purified by column chromatography on silica
gel (30 g, hexane-Et2O 5:1 f 4:1 f 3:1 f 1:1) to give 66a (85
mg, 24%) and a fraction containing 66b and 67 (106 mg) as
colorless oil, respectively. Further, from the fraction contain-
ing 66b and 67 (106 mg), 66a (43 mg, 12%), 66b (43 mg 12%),
and 67 (7 mg, 2%) were obtained by repeating the procedure
described above. 66a : [R]22D +44.0 (c 1.11, CHCl3); IR (CHCl3)
Oxir a n e Rin g Op en in g of Ep oxid e 62. Experimental
procedure was followed as described for compound 53a . This
reaction provided 63a (93%) and 63b (7%). 63a : mp 32-34
°C (benzene); [R]24D -4.2 (c 1.30, CHCl3); IR (CHCl3) 3450 (br),
1470, 1450, 1250, 1100, 1060 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.39-7.25 (m, 5 H), 4.55 (d, J ) 11.9 Hz, 1 H), 4.48 (d, J )
11.9 Hz, 1 H), 4.38 (d, J ) 4.0 Hz, 1 H), 4.19 (dt, J ) 2.6, 5.6
Hz, 1 H), 3.85 (ddd, J ) 3.3, 5.6, 10.9 Hz, 1 H), 3.61 (ddd, J )
5.6, 5.6, 10.9 Hz, 1 H), 3.57 (m, 1 H), 3.51 (d, J ) 5.6 Hz, 2 H),
3.37 (dd, J ) 5.6, 5.6 Hz, 1 H), 2.05 (ddq, J ) 2.6, 6.9, 6.9 Hz,
1 H), 1.79 (m, 1 H), 1.04 (d, J ) 7.3 Hz, 3 H), 0.90 (d, J ) 6.9
Hz, 3 H), 0.88 (s, 9 H), 0.13 (s, 3 H), 0.09 (s, 3 H); MS (EI) m/ z
(relative intensity) 382 (M+, 13), 325 (100), 215 (55), 173 (70),
145 (82). Anal. Calcd for C21H38O4Si: C, 65.92; H, 10.01.
Found: C, 65.78; H, 9.73. 63b: mp 72-73 °C (hexane); [R]24
D
-10.0 (c 0.974, CHCl3); IR (CHCl3) 3570, 3420 (br), 1475, 1450,
1390, 1360, 1250, 1075 cm-1 1H NMR (270 MHz, CDCl3) δ
;
7.37-7.25 (m, 5 H), 4.51 (s, 2 H), 3.79 (dt, J ) 5.0, 5.0 Hz, 1
H), 3.71 (m, 1 H), 3.49 (d, J ) 5.0 Hz, 2 H), 3.57-3.40 (m, 2
H), 2.79 (d, J ) 4.0 Hz, 1 H), 2.13 (dd, J ) 4.6, 6.3 Hz, 1 H),
2.01 (m, 1 H), 1.68 (m, 1 H), 0.89 (s, 9 H), 0.88 (d, J ) 6.6 Hz,
3 H), 0.78 (d, J ) 6.9 Hz, 3 H), 0.07 (s, 3 H), 0.05 (s, 3 H); MS
(FAB) m/ z 383 (M + H)+; HRMS (FAB) calcd for C21H39O4Si
[(M + H)+] 383.2618, found 383.2626.
Tosyla te 64. To a stirred solution of diol 63a (841 mg, 2.20
mmol) in pyridine (6.0 mL) cooled at 0 °C was added p-
toluenesulfonyl chloride (1.34 g, 7.15 mmol). The mixture was
stirred at 0 °C for 5 h, and the reaction was quenched by
addition of H2O (5 mL). The resulting mixture was stirred at
room temperature for 1 h, diluted with H2O (5 mL), and
extracted with Et2O (3 × 15 mL). The combined extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated.
The residual oil was purified by column chromatography on
silica gel (50 g, hexane-Et2O 10:1 f 5:1 f 2:1) to give 64 (1.18
24
g, 100%) as a colorless oil: [R]D +24.2 (c 1.10, CHCl3); IR
(CHCl3) 3420 (br), 1595, 1470, 1355, 1250, 1090, 955 cm-1; 1H
NMR (270 MHz, CDCl3) δ 7.81-7.75 (m, 2 H), 7.38-7.27 (m,
7 H), 4.53 (d, J ) 12.0 Hz, 1 H), 4.46 (d, J ) 12.0 Hz, 1 H),
4.27 (dd, J ) 4.9, 9.7 Hz, 1 H), 4.06 (dt, J ) 2.8, 6.3 Hz, 1 H),
3.89 (dd, J ) 7.6, 9.7 Hz, 1 H), 3.84 (d, J ) 3.9 Hz, 1 H), 3.49
(d, J ) 6.3 Hz, 2 H), 3.40 (ddd, J ) 3.9, 3.9, 8.2 Hz, 1 H), 2.44
(s, 3 H), 2.00 (m, 1 H), 1.92 (m, 1 H), 0.97 (d, J ) 6.9 Hz, 3 H),
0.87 (d, J ) 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3
H); MS (FAB) m/ z 559 (M + Na)+; HRMS (FAB) calcd for
C28H44NaO4SSi [(M + Na)+] 559.2525, found 559.2547.
Nitr ile 65a . To a stirred solution of tosylate 64 (1.29 g,
2.40 mmol) in DMSO (15 mL) was added NaCN (0.53 g, 10.0
1
3500 (br), 1455, 1385, 1230, 1100, 1030, 990 cm-1; H NMR
(270 MHz, CDCl3) δ 7.37-7.25 (m, 5 H), 4.91 (d, J ) 5.0 Hz,
1 H), 4.61 (d, J ) 11.9 Hz, 1 H), 4.54 (d, J ) 11.9 Hz, 1 H),
4.22 (m, 1 H), 3.59 (dd, J ) 7.3, 7.3 Hz, 1 H), 3.54 (dd, J ) 7.3,
9.6 Hz, 1 H), 3.49 (dd, J ) 4.6, 9.6 Hz, 1 H), 3.31 (s, 3 H), 2.81
(d, J ) 3.6 Hz, 1 H), 2.26 (dddq, J ) 7.3, 7.3, 10.6, 6.6 Hz, 1
H), 2.08 (dd, J ) 7.3, 12.9 Hz, 1 H), 1.74 (ddq, J ) 2.0, 7.3, 7.3
Hz, 1 H), 1.63 (ddd, J ) 5.0, 10.6, 12.9 Hz, 1 H), 1.07 (d, J )
6.6 Hz, 3 H), 0.95 (d, J ) 7.3 Hz, 3 H); MS (FAB) m/ z 317 (M
+ Na)+; HRMS (FAB) calcd for C17H26NaO4 [(M + Na)+]

5342 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
317.1729, found 317.1737. 66b: [R]22D -88.9 (c 0.713, CHCl3);
washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (100 g,
hexane-Et2O 50:1 f 30:1 f 20:1 f 10:1 f 4:1) to give a 4:1
mixture of benzyl ether 70 and silyl ether 71 (2.18 g), which
was dissolved in THF (15 mL). To this solution was added a
1.0 M solution of Bu4NF in THF (7.0 mL, 7.0 mmol) at room
temperature. The reaction mixture was stirred at room
temperature for 13 h, and then saturated aqueous NH4Cl (25
mL) was added. The mixture was extracted with Et2O (3 ×
30 mL). The combined extracts were washed with brine (10
mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (100 g,
hexane-Et2O 20:1 f 10:1 f 2:1 f 1:1 f 1:2) to give 72 (943
mg, 74% from 69) and silyl ether 71 (368 mg 16% from 69) as
a colorless oil, respectively. 72: [R]21D +45.1 (c 0.899, CHCl3);
IR (CHCl3) 3560, 3450 (br), 1550, 1495, 1450, 1380, 1350, 1095,
IR (CHCl3) 3500 (br), 1455, 1385, 1360, 1235, 1100, 1025, 995
1
cm-1; H NMR (270 MHz, CDCl3) δ 7.37-7.25 (m, 5 H), 4.96
(dd, J ) 2.3, 5.6 Hz, 1 H), 4.61 (d, J ) 11.5 Hz, 1 H), 4.53 (d,
J ) 11.5 Hz, 1 H), 4.08 (m, 1 H), 3.61 (dd, J ) 5.6, 7.9 Hz, 1
H), 3.54 (dd, J ) 6.9, 9.6 Hz, 1 H), 3.49 (dd, J ) 5.0, 9.6 Hz,
1 H), 3.30 (s, 3 H), 3.07 (d, J ) 3.6 Hz, 1 H), 2.29 (ddd, J )
5.6, 9.9, 13.2 Hz, 1 H), 2.04 (m, 1 H), 1.80 (m, 1 H), 1.51 (ddd,
J ) 2.3, 5.9, 13.2 Hz, 1 H), 1.08 (d, J ) 6.9 Hz, 3 H), 1.01 (d,
J ) 6.9 Hz, 3 H); MS (FAB) m/ z 317 (M + Na)+; HRMS (FAB)
calcd for C17H26NaO4 [(M + Na)+] 317.1729, found 317.1721.
67: [R]23D -35.4 (c 0.819, CHCl3); IR (CHCl3) 1455, 1365, 1270,
1130, 1085, 1040, 960 cm-1 1H NMR (270 MHz, CDCl3) δ
;
7.38-7.25 (m, 5 H), 5.46 (d, J ) 4.6 Hz, 1 H), 4.62 (d, J ) 12.2
Hz, 1 H), 4.48 (d, J ) 12.2 Hz, 1 H), 4.11 (ddd, J ) 3.6, 4.6,
6.9 Hz, 1 H), 3.78 (d, J ) 1.7 Hz, 1 H), 3.47 (dd, J ) 6.9, 9.6
Hz, 1 H), 3.36 (dd, J ) 4.6, 9.6 Hz, 1 H), 2.37 (dd, J ) 8.6,
13.5 Hz, 1 H), 2.22 (m, 1 H), 1.57-1.42 (m, 2 H), 1.09 (d, J )
6.3 Hz, 3 H), 1.06 (d, J ) 6.6 Hz, 3 H); MS (FAB) m/ z 285 (M
+ Na)+; HRMS (FAB) calcd for C16H22NaO3 [(M + Na)+]
285.1466, found 285.1447.
1
1025 cm-1; H NMR (270 MHz, CDCl3) δ 7.41-7.24 (m, 5 H),
4.93 (d, J ) 4.6 Hz, 1 H), 4.73 (d, J ) 11.5 Hz, 1 H), 4.67 (d,
J ) 11.5 Hz, 1 H), 3.91 (ddd, J ) 3.3, 5.0, 6.6 Hz, 1 H), 3.72
(ddd, J ) 5.0, 6.6, 10.2 Hz, 1 H), 3.61 (ddd, J ) 5.0, 7.6, 10.2
Hz, 1 H), 3.56 (dd, J ) 6.6, 9.6 Hz, 1 H), 3.32 (s, 3 H), 2.26 (m,
1 H), 2.11 (dd, J ) 7.3, 12.5 Hz, 1 H), 2.05 (dd, J ) 5.0, 7.6
Hz, 1 H), 1.73 (m, 1 H), 1.65 (ddd, J ) 4.6, 9.9, 12.5 Hz, 1 H),
1.11 (d, J ) 6.3 Hz, 3 H), 0.95 (d, J ) 6.9 Hz, 3 H); MS (EI)
m/ z (relative intensity) 263 [(M - OCH3)+, 12], 194 (34), 141
(53), 91 (100). Anal. Calcd for C17H26O4: C, 69.36; H, 8.90.
Diol 68. Sodium (291 mg, 12.7 mmol) was added to a
stirred solution of acetal 66a (357 mg, 1.21 mmol) in THF (10
mL) and liquid NH3 (10 mL) cooled at -78 °C. After the
mixture was stirred at -78 °C for 30 min, saturated aqueous
NH4Cl (5 mL) was added. The mixture was allowed to warm
to room temperature, stirred for 1.5 h, and extracted with
EtOAc (3 × 20 mL). The combined extracts were washed with
brine (20 mL), dried (Na2SO4), and concentrated. The residual
solid was purified by column chromatography on silica gel (6
g, hexane-EtOAc 1:1 f EtOAc) to give 68 (247 mg, 100%) as
colorless crystals: mp 46-47 °C (hexane); [R]D20 +83.0 (c 0.888,
CHCl3); IR (CHCl3) 3500 (br), 1455, 1385, 1230, 1100, 1025,
990 cm-1; 1H NMR (270 MHz, CDCl3) δ 4.93 (d, J ) 4.9 Hz, 1
H), 3.94 (m, 1 H), 3.70 (ddd, J ) 3.6, 7.9, 11.2 Hz, 1 H), 3.59
(ddd, J ) 3.6, 8.2, 11.2 Hz, 1 H), 3.56 (dd, J ) 7.6, 7.6 Hz, 1
H), 3.35 (s, 3 H), 3.26 (d, J ) 5.3 Hz, 1 H), 2.27 (dd, J ) 3.6,
8.2 Hz, 1 H), 2.28 (m, 1 H), 2.10 (dd, J ) 6.9, 13.2 Hz, 1 H),
1.80 (ddq, J ) 3.0, 7.6, 7.3 Hz, 1 H), 1.63 (ddd, J ) 5.3, 10.6,
13.2 Hz, 1 H), 1.07 (d, J ) 6.3 Hz, 3 H), 0.99 (d, J ) 7.3 Hz, 3
H); MS (EI) m/ z (relative intensity) 173 [(M - OCH3)+, 100],
155 (96), 137 (23), 115 (40). Anal. Calcd for C10H20O4: C,
58.80; H, 9.87. Found: C, 58.93; H, 9.54.
Found: C, 69.28; H, 9.04. 71: [R]21 -11.1 (c 1.14, CHCl3);
D
IR (CHCl3) 1595, 1450, 1425, 1360, 1110, 1025 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.76-7.67 (m, 4 H), 7.44-7.28 (m, 6 H),
7.22-7.15 (m, 3 H), 6.99-6.93 (m, 2 H), 4.84 (d, J ) 4.6 Hz, 1
H), 4.52 (ddd, J ) 1.6, 5.9, 6.9 Hz, 1 H), 4.04 (d, J ) 11.9 Hz,
1 H), 3.98 (d, J ) 11.9 Hz, 1 H), 3.66 (dd, J ) 6.6, 10.2 Hz, 1
H), 3.33 (dd, J ) 6.9, 9.9 Hz, 1 H), 3.24 (dd, J ) 5.9, 9.9 Hz,
1 H), 3.11 (s, 3 H), 2.22 (m, 1 H), 2.06 (dd, J ) 7.6, 12.5 Hz, 1
H), 1.76 (m, 1 H), 1.60 (ddd, J ) 4.6, 9.6, 12.5 Hz, 1 H), 1.10
(d, J ) 6.6 Hz, 3 H), 1.02 (s, 9 H), 0.97 (d, J ) 6.9 Hz, 3 H);
MS (FAB) m/ z 555 (M + Na)+; HRMS (FAB) calcd for C33H44
-
NaO4Si [(M + Na)+] 555.2907, found 555.2925.
C28-C34 Segm en t 6. To a stirred solution of oxalyl
chloride (0.03 mL, 0.34 mmol) in CH2Cl2 (3.0 mL) cooled at
-78 °C was added a solution of DMSO (0.03 mL, 0.45 mmol)
in CH2Cl2 (0.17 mL) dropwise. The resulting solution was
stirred at -78 °C for 5 min, and a solution of alcohol 72 (66.7
mg, 0.227 mmol) in CH2Cl2 (0.5 mL, 2 × 0.5 mL rinse) was
added dropwise. The mixture was stirred at -78 °C for 18
min and triethylamine (0.16 mL, 1.13 mmol) was added. The
resulting mixture was warmed to 0 °C and stirred for 25 min.
H2O (3 mL) was added, and the solution was stirred at room
temperature for 20 min. The mixture was extracted with a
4:1 mixture of benzene-Et2O (3 × 10 mL). The combined
extracts were washed with brine (3 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (3 g, hexane-Et2O 5:1 f 3:1) to give
Silyl Eth er 69. To a stirred solution of diol 68 (152 mg,
0.744 mmol) in DMF (3.0 mL) cooled at 0 °C were added tert-
butyldiphenylsilyl chloride (0.30 mL, 1.15 mmol) and imidazole
(160 mg, 2.35 mmol). The mixture was stirred at 0 °C for 1.3
h, and the reaction was quenched by addition of ice (1 g) and
H2O (6 mL). The resulting mixture was warmed to room
temperature, stirred for 40 min, and extracted with Et2O (3
× 15 mL). The combined extracts were washed with brine (5
mL), dried (Na2SO4), and concentrated. The residual solid was
purified by column chromatography on silica gel (20 g, hex-
ane-Et2O 7:1 f 4: 1 f 2: 1) to give 69 (329 mg 100%) as
colorless crystals: mp 97-98 °C (pentane); [R]19D +28.4 (c 1.09,
CHCl3); IR (CHCl3) 3500 (br), 1590, 1465, 1430, 1365, 1230,
6 (66.6 mg, 100%) as a colorless oil: [R]19 +26.3 (c 1.13,
D
CHCl3); IR (CHCl3) 2700, 1725, 1600, 1455, 1380, 1095, 1025
1
cm-1; H NMR (270 MHz, CDCl3) δ 9.72 (d, J ) 1.0 Hz, 1 H),
1
1115 cm-1; H NMR (270 MHz, CDCl3) δ 7.70-7.65 (m, 4 H),
7.42-7.26 (m, 5 H), 4.92 (d, J ) 4.9 Hz, 1 H), 4.73 (d, J ) 11.2
Hz, 1 H), 4.61 (d, J ) 11.2 Hz, 1 H), 4.23 (dd, J ) 1.0, 2.9 Hz,
1 H), 3.60 (dd, J ) 6.3, 9.8 Hz, 1 H), 3.31 (s, 3 H), 2.28 (m, 1
H), 2.12 (dd, J ) 7.3, 12.7 Hz, 1 H), 2.10 (m, 1 H), 1.66 (ddd,
J ) 4.9, 9.8, 12.7 Hz, 1 H), 1.11 (d, J ) 6.3 Hz, 3 H), 0.92 (d,
J ) 7.3 Hz, 3 H); MS (FAB) m/ z 315 (M + Na)+; HRMS (FAB)
calcd for C17H24NaO4 [(M + Na)+] 315.1572, found 315.1593.
Olefin 73a . To a stirred solution of the C21-C27 segment
5 (1.33 g, 2.09 mmol) in THF (9.0 mL) cooled at -78 °C was
added a 1.52 M solution of BuLi in hexane (1.35 mL, 2.05
mmol) dropwise. The resulting yellow solution was stirred at
-78 °C for 30 min, and a solution of the C28-C34 segment 6
(314 mg, 1.07 mmol) in THF (1.5 mL, 2 × 1.0 mL rinse) was
added. The mixture was stirred at -78 °C for 3 h, and the
reaction was quenched by addition of saturated aqueous NH4-
Cl (12 mL). The mixture was stirred at room temperature for
10 min and extracted with Et2O (3 × 25 mL). The combined
extracts were washed with brine (7 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
7.47-7.33 (m, 6 H), 4.89 (d, J ) 5.0 Hz, 1 H), 4.14 (dddd, J )
2.0, 3.3, 5.6, 7.3 Hz, 1 H), 3.71 (dd, J ) 7.3, 10.1 Hz, 1 H), 3.62
(dd, J ) 7.1, 7.1 Hz, 1 H), 3.61 (dd, J ) 5.6, 10.1 Hz, 1 H),
3.25 (s, 3 H), 2.77 (d, J ) 3.3 Hz, 1 H), 2.24 (dddq, J ) 7.1,
7.1, 10.7, 6.8 Hz, 1 H), 2.07 (dd, J ) 7.1, 12.7 Hz, 1 H), 1.75
(ddq, J ) 2.0, 7.1, 7.1 Hz, 1 H), 1.63 (ddd, J ) 5.0, 10.7, 12.7
Hz, 1 H), 1.09 (s, 9 H), 1.06 (d, J ) 6.8 Hz, 3 H), 0.89 (d, J )
7.1 Hz, 3 H); MS (EI) m/ z (relative intensity) 410 [(M -
OCH3)+, 5], 393 (5), 353 (55), 255 (55). Anal. Calcd for
C26H38O4Si: C, 70.55; H, 8.65. Found: C, 70.47; H, 8.65.
Alcoh ol 72. To a stirred solution of silyl ether 69 (1.92 g,
4.34 mmol) in DMF (10 mL) cooled at 0 °C were added benzyl
bromide (1.65 mL, 13.9 mmol) and NaH (348 mg of 60%
dispersion in mineral oil, 14.5 mmol), successively. The
mixture was stirred at 0 °C for 15 min and at room temper-
ature for 1 h. The reaction was quenched by addition of ice (3
g) and saturated aqueous NH4Cl (50 mL). The resulting
mixture was stirred at room temperature for 20 min and
extracted with Et2O (3 × 50 mL). The combined extracts were

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5343
matography on silica gel (15 g, hexane-Et2O 20:1 f 10:1 f
5:1 f 3:1 f 1:1) to give a diastereomeric mixture of hydroxy
sulfones (958 mg) as a colorless oil along with recovered 5 (623
mg, 47%). These hydroxy sulfones were used in the next
experiment without separation of the diastereomers. To a
vigorously stirred solution of hydroxy sulfones (958 mg 1.03
mmol) in MeOH (35 mL) cooled at 0 °C were added Na2HPO4
(2.48 g, 17.5 mmol) and 5% sodium amalgam (5.28 g, 11.5
mmol). The mixture was stirred at 0 °C for 2 h, and then
saturated aqueous NH4Cl (50 mL) was added. The resulting
mixture was warmed to room temperature, stirred for 70 min,
and extracted with Et2O (3 × 30 mL). The combined extracts
were washed with brine (7 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified by column chromatog-
raphy on silica gel (40 g, hexane-Et2O 20:1 f 10:1 f 5:1 f
3:1) to give 73a (673 mg, 82% from 6) and two diastereomers
of alcohols (more polar isomer 73b, 53.3 mg, 7%; less polar
isomer 73c, 22.3 mg, 3% from 6) as a colorless oil, respectively.
73a : [R]19D +18.0 (c 1.31, CHCl3); IR (CHCl3) 1450, 1375, 1360,
1235, 1090, 950 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.37-7.19
(m, 10 H), 5.83 (dd, J ) 8.2, 15.8 Hz, 1 H), 5.47 (dd, J ) 7.6,
15.8 Hz, 1 H), 4.90 (d, J ) 4.9 Hz, 1 H), 4.54 (d, J ) 11.9 Hz,
1 H), 4.46 (d, J ) 12.2 Hz, 1 H), 4.41 (d, J ) 12.2 Hz, 1 H),
4.33 (d, J ) 11.9 Hz, 1 H), 4.21 (dd, J ) 2.3, 7.6 Hz, 1 H), 3.99
(dt, J ) 4.0, 6.9 Hz, 1 H), 3.67 (dd, J ) 6.6, 8.9 Hz, 1 H), 3.64
(dd, J ) 1.7, 8.9 Hz, 1 H), 3.42 (t, J ) 6.9 Hz, 2 H), 3.29 (s, 3
H), 2.43 (m, 1 H), 2.23 (m, 1 H), 2.08 (dd, J ) 7.6, 12.5 Hz, 1
H), 1.84 (dt, J ) 6.9, 6.9 Hz, 2 H), 1.70-1.50 (m, 3 H), 1.08 (d,
J ) 6.6 Hz, 3 H), 1.03 (d, J ) 6.9 Hz, 3 H), 0.94-0.90 (m, 3
H), 0.94 (t, J ) 7.9 Hz, 9 H), 0.93 (t, J ) 8.3 Hz, 9 H), 0.83 (d,
J ) 6.9 Hz, 3 H), 0.61 (q, J ) 7.9 Hz, 6 H), 0.58 (q, J ) 8.3 Hz,
6 H); MS (FAB) m/ z 791 (M + Na)+; HRMS (FAB) calcd for
C45H76NaO6Si2 [(M+ Na)+] 791.5079, found 791.5073. 73b:
cm-1
;
1H NMR (270 MHz, CDCl3) δ 5.79 (ddd, J ) 1.0, 7.6,
15.5 Hz, 1 H), 5.48 (ddd, J ) 0.7, 6.3, 15.5 Hz, 1 H), 4.92 (d, J
) 5.0 Hz, 1 H), 4.30 (m, 1 H), 3.99 (ddd, J ) 5.0, 5.0, 6.3 Hz,
1 H), 3.82-3.60 (m, 3 H), 3.57 (dd, J ) 7.9, 7.9 Hz, 1 H), 3.35
(s, 3 H), 3.14 (d, J ) 6.3 Hz, 1 H), 2.39 (m, 1 H), 2.28 (m, 1 H),
2.18 (t, J ) 5.3 Hz, 1 H), 2.08 (dd, J ) 6.9, 12.5 Hz, 1 H),
1.93-1.66 (m, 4 H), 1.60 (ddd, J ) 5.0, 10.6, 12.5 Hz, 1 H),
1.07 (d, J ) 6.3 Hz, 3 H), 1.05 (d, J ) 6.9 Hz, 3 H), 0.97 (t, J
) 7.6 Hz, 18 H), 0.89 (d, J ) 6.9 Hz, 3 H), 0.86 (d, J ) 6.9 Hz,
3 H), 0.64 (q, J ) 7.6 Hz, 6 H), 0.63 (q, J ) 7.6 Hz, 6 H); MS
(FAB) m/ z 611 (M + Na)+, 589 (M + H)+; HRMS (FAB) calcd
for C31H64NaO6Si2 [(M+ Na)+] 611.4140, found 611.4158.
Diol 75. A mixture of diol 74 (218 mg, 0.356 mmol) and
5% Rh on alumina (60 mg) in EtOH (3.0 mL) was stirred under
a hydrogen atmosphere at room temperature for 1.6 h. The
reaction mixture was filtered through a pad of Celite, and the
residue was washed with EtOAc (40 mL). The filtrate and
the washings were combined and concentrated. The residual
oil was purified by column chromatography on silica gel (40
g, hexane-Et2O 3:1 f 1:1 f 1:2) to give 75 (200 mg, 91%) as
a colorless oil: [R]19D +26.6 (c 0.693, CHCl3); IR (CHCl3) 3610,
3500 (br), 1460, 1415, 1360, 1240, 1100, 1025 cm-1; H NMR
1
(270 MHz, CDCl3) δ 4.91 (d, J ) 5.0 Hz, 1 H), 4.00 (ddd, J )
4.7, 4.7, 6.4 Hz, 1 H), 3.88-3.62 (m, 3 H), 3.57 (dd, J ) 6.6,
8.2 Hz, 1 H), 3.54 (dd, J ) 3.0, 6.6 Hz, 1 H), 3.34 (s, 3 H), 2.76
(d, J ) 5.0 Hz, 1 H), 2.28 (m, 1 H), 2.09 (dd, J ) 6.9, 12.9 Hz,
1 H), 2.07 (t, J ) 5.3 Hz, 1 H), 1.94-1.29 (m, 10 H), 1.06 (d, J
) 6.6, 3 H), 0.97 (t, J ) 7.6 Hz, 9 H), 0.96 (t, J ) 7.6 Hz, 9 H),
0.98-0.93 (m, 6 H), 0.87 (d, J ) 6.9 Hz, 3 H), 0.63 (q, J ) 7.6
Hz, 12 H); MS (FAB) m/ z 613 (M + Na)+, 591 (M + H)+, 559
(M - OCH3)+; HRMS (FAB) calcd for C31H66NaO6Si2 [(M+
Na)+] 613.4296, found 613.4292.
Su lfid e 76. Experimental procedure was followed as
[R]18 +26 (c 0.51, CHCl3); IR (CHCl3) 3400 (br), 1455, 1360,
D
described for compound 22. 76: [R]21 +20.7 (c 1.62, CHCl3);
D
1
1240, 1095, 1030 cm-1; H NMR (270 MHz, CDCl3) δ 7.40-
IR (CHCl3) 3500 (br), 1585, 1460, 1360, 1240, 1100, 1025 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.30-7.14 (m, 5 H), 4.91 (d, J )
5.0 Hz, 1 H), 3.92 (ddd, J ) 3.9, 5.6, 5.6 Hz, 1 H), 3.83 (m, 1
H), 3.57 (dd, J ) 6.9, 8.2 Hz, 1 H), 3.52 (dd, J ) 2.6, 6.9 Hz,
1 H), 3.34 (s, 3 H), 2.86 (dd, J ) 7.3, 8.9 Hz, 2 H), 2.73 (d, J )
4.6 Hz, 1 H), 2.28 (m, 1 H), 2.09 (dd, J ) 7.3, 12.9 Hz, 1 H),
1.88-1.78 (m, 2 H), 1.75-1.25 (m, 8 H), 1.05 (d, J ) 6.6 Hz, 3
H), 0.97 (d, J ) 7.2 Hz, 3 H), 0.96 (d, J ) 6.9 Hz, 3 H), 0.93 (t,
J ) 7.9 Hz, 18 H), 0.82 (d, J ) 7.3 Hz, 3 H), 0.61 (q, J ) 7.9
Hz, 6 H), 0.56 (q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 705 (M +
Na)+, 683 (M + H)+, 651 (M - OCH3)+; HRMS (FAB) calcd for
C37H70NaO5SSi2 [(M + Na)+] 705.4380, found 705.4387.
Su lfon e 77. Experimental procedure was followed as
7.22 (m, 10 H), 4.91 (d, J ) 4.6 Hz, 1 H), 4.72 (d, J ) 11.5 Hz,
1 H), 4.65 (d, J ) 11.5 Hz, 1 H), 4.45 (s, 2 H), 4.05 (dt, J ) 2.6,
6.9 Hz, 1 H), 3.79 (m, 1 H), 3.69 (dd, J ) 1.7, 6.9 Hz, 1 H),
3.64 (dd, J ) 2.3, 8.3 Hz, 1 H), 3.58 (br s, 1 H), 3.57 (dd, J )
6.9, 9.6 Hz, 1 H), 3.42 (t, J ) 6.9 Hz, 2 H), 3.31 (s, 3 H), 2.26
(m, 1 H), 2.10 (dd, J ) 7.3, 12.5 Hz, 1 H), 2.01 (m, 1 H), 1.87
(dt, J ) 6.9, 6.9 Hz, 2 H), 1.82-1.45 (m, 5 H), 1.10 (d, J )
6.6Hz, 3 H), 1.05 (d, J ) 7.3 Hz, 3 H), 0.97 (d, J ) 6.9 Hz, 3
H), 0.95 (t, J ) 8.2 Hz, 18 H), 0.80 (d, J ) 6.9 Hz, 3 H), 0.65
(q, J ) 8.2 Hz, 6 H), 0.59 (q, J ) 8.2 Hz, 6 H); MS (FAB) m/ z
809 (M + Na)+, 787 (M + H)+, 755 (M - OCH3)+; HRMS (FAB)
calcd for C45H78NaO7Si2 [(M + Na)+] 809.5185, found 809.5170.
73c: [R]18 +11 (c 0.21, CHCl3); IR (CHCl3) 3550 (br), 1460,
described for compound 4. 77: [R]24 +26.0 (c 0.730, CHCl3);
D
D
1360, 1240, 1070, 1025 cm-1
;
1H NMR (270 MHz, CDCl3) δ
IR (CHCl3) 3500 (br), 1460, 1360, 1310, 1230, 1150, 1085 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.94-7.88 (m, 2 H), 7.69-7.54
(m, 3 H), 4.91 (d, J ) 5.0 Hz, 1 H), 3.80 (ddd, J ) 5.3, 5.3, 5.3
Hz, 1 H), 3.82 (m, 1 H), 3.56 (dd, J ) 6.6, 8.2 Hz, 1 H), 3.42
(dd, J ) 3.0, 6.6 Hz, 1 H), 3.34 (s, 3 H), 3.20-2.98 (m, 2 H),
2.79 (br s, 1 H), 2.28 (m, 1 H), 2.09 (dd, J ) 7.3, 12.9 Hz, 1 H),
1.93-1.82 (m, 2 H), 1.74-1.24 (m, 8 H), 1.06 (d, J ) 6.6, 3 H),
0.96 (d, J ) 7.3 Hz, 3 H), 0.92 (t, J ) 7.9 Hz, 9 H), 0.90 (t, J
) 7.9 Hz, 9 H), 0.85 (d, J ) 7.3 Hz, 3 H), 0.79 (d, J ) 6.9 Hz,
3 H), 0.56 (q, J ) 7.9 Hz, 6 H), 0.52 (q, J ) 7.9 Hz, 6 H); MS
(FAB) m/ z 737 (M + Na)+, 715 (M + H)+, 683 (M - OCH3)+;
HRMS (FAB) calcd for C37H70NaO7SSi2 [(M + Na)+] 737.4278,
found 737.4262.
C21-C34 Segm en t 10. P r ep a r a tion of a Stock Solu -
tion of [(3,4-Dim eth oxyben zyl)oxy]m eth yl Ch lor id e. To
a stirred solution of 3,4-dimethoxybenzyl alcohol (5.4 g, 32
mmol) in 1,2-dimethoxyethane (30 mL) cooled to 0 °C were
added NaH (2.85 g of 60% dispersion in mineral oil, 71 mmol),
NaI (5.5 g, 36 mmol), and (methylthio)methyl chloride (3.0 mL,
36 mmol), successively. The mixture was stirred at 0 °C for
15 min and at room temperature for 13 h. The reaction
mixture was recooled to 0 °C, and the reaction was quenched
by addition of H2O (30 mL). The mixture was extracted with
Et2O (200 mL, 50 mL). The combined extracts were washed
with brine (10 mL), dried (Na2SO4), and concentrated. The
residual oil was purified by column chromatography on silica
gel (100 g, hexane-EtOAc 5:1 f 3:1) to give 3,4-dimethoxy-
benzyl (methylthio)methyl ether (4.9 g, 67%) as a yellow oil.
7.40-7.22 (m, 10 H), 4.92 (d, J ) 5.0 Hz, 1 H), 4.83 (d, J )
11.5 Hz, 1 H), 4.71 (d, J ) 11.5 Hz, 1 H), 4.47 (s, 2 H), 4.01
(dt, J ) 3.3, 6.3 Hz, 1 H), 3.74 (dd, J ) 1.7, 7.6 Hz, 1 H), 3.66
(m, 1 H), 3.61 (dd, J ) 1.7, 7.6 Hz, 1 H), 3.57 (dd, J ) 6.3, 9.9
Hz, 1 H), 3.44 (t, J ) 6.9 Hz, 2 H), 3.30 (s, 3 H), 2.27 (br s, 1
H), 2.22 (m, 1 H), 2.11 (dd, J ) 7.6, 12.2 Hz, 1 H), 2.02 (m, 1
H), 1.92-1.80 (m, 2 H), 1.73 (m, 1 H), 1.65 (ddd, J ) 5.0, 9.6,
12.2 Hz, 1 H), 1.48 (m, 1 H), 1.42 (m, 1 H), 1.28 (m, 1 H), 1.12
(d, J ) 6.3 Hz, 3 H), 0.94 (t, J ) 7.9 Hz, 18 H), 0.97-0.90 (m,
6 H), 0.83 (d, J ) 7.3 Hz, 3 H), 0.61 (q, J ) 7.9 Hz, 6 H), 0.58
(q, J ) 7.9 Hz, 6 H); MS (FAB) m/ z 809 (M + Na)+, 787 (M +
H)+, 755 (M - OCH3)+; HRMS (FAB) calcd for C45H78NaO7Si2
[(M + Na)+] 809.5185, found 809.5184.
Diol 74. Calcium (1.23 mg, 30.7 mmol) was added to a
stirred solution of olefin 73a (780 mg, 1.01 mmol) in THF (15
mL), isopropyl alcohol (4.5 mL), and liquid NH3 (10 mL) cooled
to -78 °C. After the mixture was stirred at -78 °C for 1 h,
NH4Cl (6.9 g) and Fe(NO3)3‚9H2O (1.1 g) were added. The
mixture was stirred at -78 °C for 1 h and allowed to warm to
room temperature. The residue was dissolved in H2O (20 mL),
and the mixture was stirred at room temperature for 1 h and
extracted with EtOAc (3 × 50 mL). The combined extracts
were washed with brine (10 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified by column chromatog-
raphy on silica gel (30 g, hexane-Et2O 3:1 f 1:1) to give 74
(586 mg, 98%) as a colorless oil: [R]19D +32.1 (c 0.878, CHCl3);
IR (CHCl3) 3610, 3470 (br), 1455, 1410, 1380, 1235, 1020, 970

5344 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
To a stirred solution of 3,4-dimethoxybenzyl (methylthio)-
methyl ether (721 mg, 3.16 mmol) in CH2Cl2 (8.0 mL) cooled
at -78 °C was added a solution of sulfuryl chloride (0.26 mL,
3.23 mmol) in CH2Cl2 (6.2 mL). The mixture was stirred at
-78 °C for 45 min and concentrated. The resulting yellow oil
was dissolved in CH2Cl2 (3.0 mL) to give a solution of [(3,4-
dimethoxybenzyl)oxy]methyl chloride (1.05 M solution in CH2-
Cl2).
1255, 1155, 1095, 1030, 970, 830 cm-1
;
1H NMR (400 MHz,
CDCl3) (20E-isomer) δ 6.92-6.89 (m, 2 H), 6.81 (d, J ) 7.8
Hz, 1 H), 5.50 (ddd, J ) 7.3, 7.3, 15.6 Hz, 1 H), 5.33 (dd, J )
6.8, 6.8 Hz, 1 H), 5.22 (dd, J ) 8.3, 15.6 Hz, 1 H), 4.88 (d, J )
4.4 Hz, 1 H), 4.83 (d, J ) 6.3 Hz, 1 H), 4.81 (d, J ) 6.3 Hz, 1
H), 4.64 (d, J ) 11.7 Hz, 1 H), 4.60 (d, J ) 11.2 Hz, 1 H), 4.58
(d, J ) 11.2 Hz, 1 H), 4.56 (d, J ) 11.7 Hz, 1 H), 4.20-4.09
(m, 2 H), 4.03 (m, 1 H), 3.96 (m, 1 H), 3.88 (s, 3 H), 3.87 (s, 3
H), 3.64 (m, 1 H), 3.59-3.48 (m, 4 H), 3.37 (dd, J ) 6.8, 6.8
Hz, 1 H), 3.27 (s, 3 H), 3.22 (s, 3 H), 3.15 (s, 3 H), 2.33-2.05
(m, 5 H), 2.16 (s, 3 H), 1.95 (m, 1 H), 1.86-1.74 (m, 2 H), 1.73-
1.36 (m, 15 H), 1.50 (s, 3 H), 1.20 (s, 9 H), 1.10 (d, J ) 6.4 Hz,
3 H), 1.01-0.93 (m, 17 H), 0.95 (t, J ) 7.8 Hz, 9 H), 0.95 (t, J
) 7.8 Hz, 9 H), 0.89 (s, 9 H), 0.78 (d, J ) 6.8 Hz, 3 H), 0.60 (q,
J ) 7.8 Hz, 6 H), 0.59 (q, J ) 7.8 Hz, 6 H), 0.05 (s, 3 H), 0.05
(s, 3 H); MS (FAB) m/ z 1419 (M + Na)+; HRMS (FAB) calcd
for C76H144NaO14SSi3 [(M + Na)+] 1419.9482, found 1419.9470.
Alcoh ol 79. To a stirred solution of olefin 78 (20E/20Z )
9/1) (80.7 mg, 0.0577 mmol) in CH2Cl2 (4.0 mL) cooled at -78
°C was added a 1.0 M solution of diisobutylaluminum hydride
in hexane (0.23 mL, 0.23 mmol) dropwise. The mixture was
stirred at -78 °C for 2 h and the reaction was quenched by
addition of MeOH (0.5 mL), saturated aqueous sodium potas-
sium tartrate (7.5 mL), and H2O (7.5 mL). The resulting
mixture was warmed to room temperature, stirred at room
temperature for 30 min, and extracted with Et2O (2 × 10 mL).
The combined extracts were washed with brine (5 mL), dried
(Na2SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (10 g, hexane-EtOAc 4:1
f 2: 1) to give 79 (20E/20Z ) 9/1, by 1H NMR) (76.6 mg, 100%)
To a stirred solution of sulfone 77 (157 mg, 0.220 mmol) in
CH2Cl2 (2.0 mL) cooled at 0 °C were added diisopropylethy-
lamine (2.0 mL, 11.5 mmol) and the 1.05 M solution of [(3,4-
dimethoxybenzyl)oxy]methyl chloride in CH2Cl2 (2.7 mL, 2.84
mmol). The mixture was stirred at room temperature for 16
h, and the reaction was quenched by addition of MeOH (10
mL). The resulting mixture was stirred at room temperature
for 2.5 h, and H2O (10 mL) was added. The organic layer was
separated, and the aqueous layer was extracted with hexane
(4 × 15 mL). The oraganic layer and the extracts were
combined, washed with brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on alumina (30 g, hexane-EtOAc 15:1 f 10:1 f
7:1 f 5:1 f 3:1) and subsequently on silica gel (8 g, hexane-
EtOAc 6:1 f 4:1 f 3:1 f 2:1) to give 10 (194 mg, 98%) as a
colorless oil: [R]27 +13.7 (c 1.20, CHCl3); IR (CHCl3) 1595,
D
1515, 1460, 1305, 1260, 1150, 1095, 1030 cm-1; 1H NMR (270
MHz, CDCl3) δ 7.92-7.87 (m, 2 H), 7.68-7.52 (m, 3 H), 6.92-
6.88 (m, 2 H), 6.82 (d, J ) 8.6 Hz, 1 H), 4.88 (d, J ) 4.6 Hz, 1
H), 4.81 (s, 2 H), 4.60 (d, J ) 11.6 Hz, 1 H), 4.55 (d, J ) 11.6
Hz, 1 H), 4.02 (m, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.78 (ddd,
J ) 5.3, 5.3, 5.3 Hz, 1 H), 3.57 (dd, J ) 6.6, 9.9 Hz, 1 H), 3.41
(dd, J ) 2.6, 6.9 Hz, 1 H), 3.25 (s, 3 H), 3.15-2.94 (m, 2 H),
2.23 (m, 1 H), 2.09 (dd, J ) 7.3, 12.2 Hz, 1 H), 1.91-1.78 (m,
2 H), 1.67-1.28 (m, 8 H), 1.10 (d, J ) 6.6, 3 H), 0.95-0.85 (m,
6 H), 0.88 (t, J ) 7.6 Hz, 18 H), 0.75 (d, J ) 7.3 Hz, 3 H), 0.55
(q, J ) 7.6 Hz, 6 H), 0.50 (q, J ) 7.6 Hz, 6 H); MS (FAB) m/ z
917 (M + Na)+. Anal. Calcd for C47H82O10SSi2: C, 63.05; H,
9.23. Found: C, 62.92; H, 9.42.
as a colorless oil: [R]25 +41.6 (c 0.915, CHCl3); IR (CHCl3)
D
3470 (br), 1595, 1515, 1465, 1380, 1255, 1095, 1030, 970, 835
cm-1 1H NMR (400 MHz, CDCl3) (20E-isomer) δ 6.93-6.90
;
(m, 2 H), 6.82 (d, J ) 8.3 Hz, 1 H), 5.50 (ddd, J ) 7.3, 7.3, 15.1
Hz, 1 H), 5.34 (dd, J ) 6.8, 6.8 Hz, 1 H), 5.22 (dd, J ) 8.3,
15.1 Hz, 1 H), 4.88 (d, J ) 4.4 Hz, 1 H), 4.83 (d, J ) 6.8 Hz, 1
H), 4.81 (d, J ) 6.8 Hz, 1 H), 4.69 (d, J ) 11.7 Hz, 1 H), 4.60
(d, J ) 11.2 Hz, 1 H), 4.59 (d, J ) 11.7 Hz, 1 H), 4.56 (d, J )
11.2 Hz, 1 H), 4.04 (dd, J ) 6.8, 6.8 Hz, 1 H), 3.96 (m, 1 H),
3.88 (s, 3 H), 3.87 (s, 3 H), 3.81-3.68 (m, 3 H), 3.61-3.52 (m,
3 H), 3.49 (dd, J ) 3.4, 4.4 Hz, 1 H), 3.38 (dd, J ) 6.4, 6.4 Hz,
1 H), 3.27 (s, 3 H), 3.22 (s, 3 H), 3.16 (s, 3 H), 2.56 (t, J ) 5.4
Hz, 1 H), 2.40-2.05 (m, 5 H), 2.21 (s, 3 H), 1.97 (m, 1 H), 1.84
(m, 1 H), 1.71-1.30 (m, 16 H), 1.50 (s, 3 H), 1.10 (d, J ) 6.8
Hz, 3 H), 1.08-0.86 (m, 17 H), 0.96 (t, J ) 7.8 Hz, 9 H), 0.95
(t, J ) 7.8 Hz, 9 H), 0.89 (s, 9 H), 0.78 (d, J ) 7.3 Hz, 3 H),
0.60 (q, J ) 7.8 Hz, 6 H), 0.59 (q, J ) 7.8 Hz, 6 H), 0.05 (s, 3
H), 0.04 (s, 3 H); MS (FAB) m/ z 1335 (M + Na)+; HRMS (FAB)
calcd for C71H136NaO13SSi3 [(M + Na)+] 1335.8907, found
1335.8910.
Olefin 78. To a stirred solution of the C21-C34 segment
10 (248 mg, 0.277 mmol) in THF (2.0 mL) cooled at -78 °C
was added a 1.59 M solution of BuLi in hexane (0.17 mL, 0.27
mmol) dropwise. The mixture was stirred at -78 °C for 30
min, and a solution of the C5-C20 segment 9 (101 mg, 0.153
mmol) in THF (0.5 mL) was added dropwise. The resulting
mixture was stirred at -78 °C for 2 h. The reaction was
quenched by addition of saturated aqueous NH4Cl (5 mL), and
the mixture was extracted with Et2O (3 × 10 mL). The
combined extracts were washed with brine (5 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified twice
by column chromatography on silica gel [(40 g, hexane-Et2O
4:1 f 2: 1 f 1: 1 f 1: 2) and (30 g, benzene-Et2O 20:1 f 15:
1 f 10: 1 f 5: 1)] to give a diastereomeric mixture of hydroxy
sulfones (207 mg) as a colorless oil along with recovered 10
(121 mg, 49%). The hydroxy sulfones were employed in the
next experiment without separation of the diastereomers. To
a stirred solution of the diastereomeric mixture of hydroxy
sulfones (207 mg) in pyridine (1.2 mL) were added acetic
anhydride (0.6 mL) and 4-(dimethylamino)pyridine (5.4 mg,
0.044 mmol) at room temperature. The mixture was stirred
at room temperature for 3 h and concentrated. The residue
was purified by column chromatography on silica gel (20 g,
hexane-Et2O 2:1 f 1: 1 f 1: 2) to give a diastereomeric
mixture of acetoxy sulfones (198 mg) as a colorless oil. The
acetoxy sulfones were employed in the next experiment
without separation of the diastereomers. To a vigorously
stirred solution of the diastereomeric mixture of acetoxy
sulfones (198 mg) in MeOH (4.0 mL) cooled at 0 °C were added
Na2HPO4 (640 mg, 4.51 mmol) and 5% sodium amalgam (972
mg, 2.12 mmol), and the mixture was stirred at 0 °C for 1.5 h.
The mixture was diluted with saturated aqueous NH4Cl (5
mL), stirred at room temperature for 1 h, and extracted with
Et2O (3 × 10 mL). The combined extracts were washed with
brine (5 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (5 g,
hexane-Et2O 5: 1 f 3: 1 f 1: 1) to give 78 (20E/20Z ) 9/1, by
1H NMR) (187 mg, 88% from 9) as a colorless oil: [R]25D +34.6
(c 0.904, CHCl3); IR (CHCl3) 1720, 1595, 1515, 1460, 1375,
Ald eh yd e 80. Experimental procedure was followed as
described for compound 9. 80 (20E/20Z ) 9/1, by 1H NMR):
[R]25D +26.7 (c 1.22, CHCl3); IR (CHCl3) 2730, 1725, 1595, 1515,
1465, 1380, 1255, 1095, 1030, 970, 835 cm-1 1H NMR (270
;
MHz, CDCl3) (20E-isomer) δ 9.82 (t, J ) 2.3 Hz, 1 H), 6.93-
6.89 (m, 2 H), 6.82 (d, J ) 8.3 Hz, 1 H), 5.51 (ddd, J ) 7.9, 7.9,
15.2 Hz, 1 H), 5.34 (dd, J ) 6.6, 6.6 Hz, 1 H), 5.22 (dd, J )
8.3, 15.2 Hz, 1 H), 4.88 (d, J ) 5.0 Hz, 1 H), 4.82 (s, 2 H), 4.67
(d, J ) 11.5 Hz, 1 H), 4.61 (d, J ) 11.5 Hz, 1 H), 4.60 (d, J )
11.5 Hz, 1 H), 4.55 (d, J ) 11.5 Hz, 1 H), 4.10-3.92 (m, 3 H),
3.88 (s, 3 H), 3.87 (s, 3 H), 3.64-3.47 (m, 4 H), 3.38 (dd, J )
6.6, 6.6 Hz, 1 H), 3.27 (s, 3 H), 3.22 (s, 3 H), 3.16 (s, 3 H),
2.65-2.48 (m, 2 H), 2.39-2.04 (m, 5 H), 2.14 (s, 3 H), 2.00 (m,
1 H), 1.84 (m, 1 H), 1.79-1.30 (m, 15 H), 1.50 (s, 3 H), 1.19-
0.95 (m, 16 H), 1.09 (d, J ) 6.6 Hz, 3 H), 0.96 (t, J ) 7.6 Hz,
9 H), 0.95 (t, J ) 7.6 Hz, 9 H), 0.89 (s, 9 H), 0.78 (d, J ) 6.9
Hz, 3 H), 0.60 (q, J ) 7.6 Hz, 6 H), 0.59 (q, J ) 7.6 Hz, 6 H),
0.05 (s, 6 H); MS (FAB) m/ z 1333 (M + Na)+; HRMS (FAB)
calcd for C71H134NaO13SSi3 [(M + Na)+] 1333.8752, found
1333.8770.
r,â,γ,δ-Un sa tu r a ted Ester 81. To a stirred solution of
triethyl 4-phosphonocrotonate (101 mg, 0.404 mmol) in THF
(3.0 mL) cooled at -40 °C was added a 0.5 M solution of
lithium diisopropylamide (0.70 mL, 0.35 mmol) prepared from
diisopropylamine (0.15 mL, 1.1 mmol), a 1.59 M solution of
BuLi in hexane (0.65 mL, 1.0 mmol), and THF (1.2 mL) at

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5345
-78 °C. The mixture was stirred at -40 °C for 25 min, and a
solution of aldehyde 80 (20E/20Z ) 9/1) (150 mg, 0.115 mmol)
in THF (0.6 mL) was added dropwise. The resulting mixture
was stirred at -40 °C for 8 min and at 0 °C for 15 min. The
mixture was diluted with saturated aqueous NH4Cl (2 mL)
and extracted with Et2O (30 mL, 10 mL). The combined
extracts were washed with brine (4 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (10 g, hexane-Et2O 3: 1 f 1: 1) to
mg, 100%) as a colorless oil: [R]26 -5.1 (c 1.06, CHCl3); IR
D
(CHCl3) 3600-2200 (br), 1690, 1640, 1615, 1595, 1515, 1465,
1380, 1260, 1095, 1025, 970, 835 cm-1 1H NMR (270 MHz,
;
CDCl3) (4E,20E-isomer) δ 7.28 (dd, J ) 9.9, 15.5 Hz, 1 H),
6.95-6.90 (m, 2 H), 6.83 (d, J ) 7.9 Hz, 1 H), 6.28 (dd, J )
9.9, 15.2 Hz, 1 H), 6.18 (ddd, J ) 6.3, 6.3, 15.2 Hz, 1 H), 5.79
(d, J ) 15.5 Hz, 1 H), 5.62 (ddd, J ) 6.9, 6.9, 15.2 Hz, 1 H),
5.42-5.26 (m, 2 H), 4.91 (d, J ) 5.0 Hz, 1 H), 4.86 (d, J ) 6.9
Hz, 1 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.65-4.55 (m, 4 H), 4.10-
3.93 (m, 2 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.68 (dd, J ) 3.3, 3.3
Hz, 1 H), 3.64-3.57 (m, 3 H), 3.43-3.24 (m, 2 H), 3.31 (s, 3
H), 3.24 (s, 3 H), 3.16 (s, 3 H), 2.60-2.04 (m, 7 H), 2.14 (s, 3
H), 1.94-1.74 (m, 3 H), 1.72-1.26 (m, 14 H), 1.49 (s, 3 H),
1.21-0.82 (m, 13 H), 1.10 (d, J ) 6.3 Hz, 3 H), 0.96 (d, J ) 7.3
Hz, 3 H), 0.89 (s, 9 H), 0.83 (d, J ) 6.9 Hz, 3 H), 0.05 (s, 3 H),
0.04 (s, 3 H). Signals of three protons (COOH, 2 × ÃΗ) were
not observed; MS (FAB) m/ z 1173 (M + Na)+; HRMS (FAB)
calcd for C63H110NaO14SSi [(M + Na)+] 1173.7282, found
1173.7270.
1
give 81 (4E/4Z ) 19/1, 20E/20Z ) 9/1, by H NMR) (144 mg,
89%) as a colorless oil: [R]25D +10.7 (c 1.17, CHCl3); IR (CHCl3)
1705, 1645, 1615, 1595, 1515, 1465, 1365, 1260, 1095, 1025,
970, 835 cm-1; 1H NMR (270 MHz, CDCl3) (4E,20E-isomer) δ
7.26 (dd, J ) 9.6, 15.5 Hz, 1 H), 6.92-6.89 (m, 2 H), 6.82 (d,
J ) 7.9 Hz, 1 H), 6.25 (dd, J ) 9.6, 15.2 Hz, 1 H), 6.15 (ddd,
J ) 6.3, 6.3, 15.2 Hz, 1 H), 5.80 (d, J ) 15.5 Hz, 1 H), 5.50
(ddd, J ) 7.3, 7.3, 15.2 Hz, 1 H), 5.34 (dd, J ) 7.3, 7.3 Hz, 1
H), 5.22 (dd, J ) 8.2, 15.2 Hz, 1 H), 4.88 (d, J ) 4.6 Hz, 1 H),
4.82 (s, 2 H), 4.62 (d, J ) 11.6 Hz, 1 H), 4.61 (d, J ) 11.6 Hz,
1 H), 4.56 (d, J ) 11.6 Hz, 1 H), 4.55 (d, J ) 11.6 Hz, 1 H),
4.20 (q, J ) 7.3 Hz, 2 H), 4.03 (m, 1 H), 3.96 (m, 1 H), 3.88 (s,
3 H), 3.87 (s, 3 H), 3.65-3.46 (m, 5 H), 3.38 (dd, J ) 6.6, 6.6
Hz, 1 H), 3.27 (s, 3 H), 3.22 (s, 3 H), 3.16 (s, 3 H), 2.45 (m, 1
H), 2.38-2.04 (m, 6 H), 2.14 (s, 3 H), 1.92-1.76 (m, 2 H), 1.68-
1.26 (m, 15 H), 1.50 (s, 3 H), 1.29 (t, J ) 7.3 Hz, 3 H), 1.18-
0.92 (m, 13 H), 1.09 (d, J ) 6.6 Hz, 3 H), 0.95 (t, J ) 7.6 Hz,
9 H), 0.95 (t, J ) 7.6 Hz, 9 H), 0.89 (s, 9 H), 0.84 (d, J ) 7.3
Hz, 3 H), 0.78 (d, J ) 6.9 Hz, 3 H), 0.60 (q, J ) 7.6 Hz, 6 H),
0.59 (q, J ) 7.6 Hz, 6 H), 0.06 (s, 3 H), 0.05 (s, 3 H); MS (FAB)
Ma cr ola cton iza tion of Seco Acid 83. To a stirred
solution of seco acid 83 (4E/4Z ) 19/1, 20E/20Z ) 9/1) (39.8
mg, 0.0589 mmol) in CHCl3 (150 mL) were added triethy-
lamine (0.2 mL, 1.4 mmol), 4-(dimethylamino)pyridine (359
mg, 2.93 mmol), and 2,4,6-trichlorobenzoyl chloride (0.2 mL,
1.3 mmol), successively at room temperature. The mixture
was stirred at room temperature for 15 h and washed with 1
M aqueous HCl (2 × 4 mL), saturated aqueous NaHCO3 (2 ×
4 mL), H2O (7 mL), and brine (6 mL), successively; dried
(NaSO4); and concentrated. The residue was purified by
column chromatography on silica gel (10 g, hexane-EtOAc 2: 1
f 1:1) and preparative HPLC (Develosil 30-10, 20 × 250 mm,
hexane-EtOAc-MeOH 85:15:1, 5 mL/min) to give the 24-
membered lactone 84 (tR ) 70 min, 15.5 mg, 40%) and the 26-
membered lactone 85 (tR ) 84 min, 10.0 mg, 26%) as a colorless
m/ z 1429 (M + Na)+; HRMS (FAB) calcd for C77H142NaO14
-
SSi3 [(M + Na)+] 1429.9326, found 1429.9310.
Diol 82. A solution of R,â,γ,δ-unsaturated ester 81 (4E/4Z
) 19/1, 20E/20Z ) 9/1) (91.9 mg, 0.0653 mmol) in a 5:3:1
mixture of THF, pyridine, and HF‚pyridine (1 mL) was stirred
at room temperature for 3 h. The mixture was diluted with
EtOAc (5 mL) and cooled to 0 °C, and then saturated aqueous
NaHCO3 (10 mL) was added. The organic layer was separated,
and the aqueous layer was extracted with EtOAc (3 × 10 mL).
The organic layer and the extracts were combined, washed
with brine (5 mL), dried (Na2SO4), and concentrated. The
residual oil was purified by column chromatography on silica
gel (10 g, hexane-EtOAc 2: 1 f 1: 1 f 1: 2 f EtOAc) to give
82 (4E/4Z ) 19/1, 20E/20Z ) 9/1, by 1H NMR) (77.0 mg, 100%)
as a colorless oil: [R]25D +5.1 (c 0.957, CHCl3); IR (CHCl3) 3470
(br), 1700, 1640, 1615, 1595, 1515, 1465, 1365, 1260, 1095,
oil, respectively. 84: [R]22 +56.9 (c 1.01, CHCl3); IR (CHCl3)
D
3490 (br), 1690, 1640, 1615, 1595, 1515, 1465, 1380, 1260,
1095, 1030, 970, 835 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.27
(dd, J ) 9.9, 15.5 Hz, 1 H), 6.90-6.94 (m, 2 H), 6.82 (d, J )
8.9 Hz, 1 H), 6.33-6.18 (m, 2 H), 5.84 (d, J ) 15.5 Hz, 1 H),
5.54 (ddd, J ) 4.4, 9.3, 15.4 Hz, 1 H), 5.37 (d, J ) 11.0 Hz, 1
H), 5.09 (dd, J ) 9.3, 15.4 Hz, 1 H), 5.05 (m, 1 H), 4.89 (d, J
) 5.1 Hz, 1 H), 4.86 (d, J ) 6.9 Hz, 1 H), 4.83 (d, J ) 6.9 Hz,
1 H), 4.62 (d, J ) 11.5 Hz, 1 H), 4.59 (d, J ) 11.5 Hz, 1 H),
4.55 (d, J ) 11.5 Hz, 1 H), 4.53 (d, J ) 11.5 Hz, 1 H), 4.05
(ddd, J ) 0.5, 6.6, 6.6 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H),
3.62 (m, 1 H), 3.56 (dd, J ) 6.6, 9.9 Hz, 1 H), 3.54-3.44 (m, 2
H), 3.37 (dd, J ) 4.5, 10.4 Hz, 1 H), 3.27 (s, 3 H), 3.20 (s, 3 H),
3.17 (s, 3 H), 3.14 (m, 1 H), 2.99 (ddd, J ) 2.3, 4.6, 9.9 Hz, 1
H), 2.45 (ddd, J ) 10.6, 10.6, 14.3 Hz, 1 H), 2.34 (ddd, J ) 4.0,
8.2, 14.5 Hz, 1 H), 2.27-2.05 (m, 4 H), 2.15 (s, 3 H), 1.97 (m,
1 H), 1.89 (m, 1 H), 1.71 (m, 1 H), 1.68-1.39 (m, 10 H), 1.45
(s, 3 H), 1.35 (m, 1 H), 1.30-0.88 (m, 5 H), 1.10 (d, J ) 6.6 Hz,
3 H), 1.01 (d, J ) 6.9 Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3 H), 0.89-
0.87 (m, 3 H), 0.89 (s, 9 H), 0.87 (d, J ) 7.3 Hz, 3 H), 0.83 (d,
J ) 6.9 Hz, 3 H), 0.74 (d, J ) 5.3 Hz, 3 H), 0.04 (s, 3 H),
0.04 (s, 3 H); MS (FAB) m/ z 1155 (M + Na)+. Anal. Calcd
for C63H108O13SSi: C, 66.75; H, 9.60. Found C, 66.71; H, 9.63.
1025, 970, 835 cm-1 1H NMR (400 MHz, CDCl3) (4E,20E-
;
isomer) δ 7.27 (dd, J ) 10.2, 15.1 Hz, 1 H), 6.96-6.90 (m, 2
H), 6.83 (d, J ) 8.3 Hz, 1 H), 6.25 (dd, J ) 10.2, 15.1 Hz, 1 H),
6.17 (ddd, J ) 6.3, 6.3, 15.1 Hz, 1 H), 5.80 (d, J ) 15.1 Hz, 1
H), 5.62 (ddd, J ) 7.3, 7.3, 15.3 Hz, 1 H), 5.41-5.28 (m, 2 H),
4.90 (d, J ) 4.9 Hz, 1 H), 4.86 (d, J ) 6.8 Hz, 1 H), 4.83 (d, J
) 6.8 Hz, 1 H), 4.63-4.56 (m, 4 H), 4.19 (q, J ) 7.3 Hz, 2 H),
4.06 (dd, J ) 6.3, 6.3 Hz, 1 H), 3.97 (m, 1 H), 3.89 (s, 3 H),
3.87 (s, 3 H), 3.66-3.54 (m, 4 H), 3.38 (dd, J ) 6.8, 6.8 Hz, 1
H), 3.31 (m, 1 H), 3.30 (s, 3 H), 3.23 (s, 3 H), 3.16 (s, 3 H), 2.85
(d, J ) 2.4 Hz, 1 H), 2.81 (d, J ) 5.4 Hz, 1 H), 2.54-2.37 (m,
2 H), 2.36-2.06 (m, 5 H), 2.14 (s, 3 H), 1.90-1.79 (m, 3 H),
1.72-1.30 (m, 14 H), 1.50 (s, 3 H), 1.29 (t, J ) 7.3 Hz, 3 H),
1.11-0.88 (m, 13 H), 1.11 (d, J ) 6.3 Hz, 3 H), 0.97 (d, J ) 7.3
Hz, 3 H), 0.89 (s, 9 H), 0.84 (d, J ) 7.3 Hz, 3 H), 0.06 (s, 3 H),
0.05 (s, 3 H); MS (FAB) m/ z 1201 (M + Na)+; HRMS (FAB)
calcd for C65H114NaO14SSi [(M + Na)+] 1201.7596, found
1201.7600.
Seco Acid 83. To a stirred solution of diol 82 (4E/4Z )
19/1, 20E/20Z ) 9/1) (65.9 mg, 0.0589 mmol) in MeOH (4 mL)
was added 5 M aqueous LiOH (0.5 mL) at room temperature,
and the mixture was stirred at room temperature for 12 h.
The mixture was diluted with EtOAc (10 mL), cooled to 0 °C,
and acidified (pH 1) with 1 M aqueous HCl (3 mL). Sodium
chloride (2 g) was added to the mixture and the organic layer
was separated, and the aqueous layer was extracted with
EtOAc (2 × 10 mL). The organic layer and the extracts were
combined, washed with brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (4 g, hexane-EtOAc 1: 1 f EtOAc)
to give 83 (4E/4Z ) 19/1, 20E/20Z ) 9/1, by 1H NMR) (65.1
85: [R]22 +24.1 (c 1.05, CHCl3); IR (CHCl3) 3500 (br), 1685,
D
1640, 1615, 1595, 1515, 1465, 1380, 1255, 1100, 1015, 970, 835
cm-1; 1H NMR (600 MHz, CDCl3) δ 7.28 (dd, J ) 9.9, 15.5 Hz,
1 H), 6.93-6.90 (m, 2 H), 6.82 (d, J ) 8.9 Hz, 1 H), 6.30 (dd,
J ) 9.9, 15.5 Hz, 1 H), 6.22 (ddd, J ) 6.3, 6.3, 15.5 Hz, 1 H),
5.83 (d, J ) 15.5 Hz, 1 H), 5.54 (ddd, J ) 5.6, 8.9, 15.2 Hz, 1
H), 5.28 (dd, J ) 8.2, 15.2 Hz, 1 H), 5.23 (dd, J ) 6.0, 6.9 Hz,
1 H), 4.90 (d, J ) 5.0 Hz, 1 H), 4.90 (m, 1 H), 4.86 (d, J ) 6.9
Hz, 1 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.65 (d, J ) 11.5 Hz, 1 H),
4.60 (d, J ) 11.5 Hz, 1 H), 4.60 (d, J ) 11.5 Hz, 1 H), 4.59 (d,
J ) 11.5 Hz, 1 H), 4.07 (ddd, J ) 0.5, 6.6, 6.6 Hz, 1 H), 3.88 (s,
3 H), 3.87 (s, 3 H), 3.78 (m, 1 H), 3.60-3,55 (m, 2 H), 3.53 (dd,
J ) 7.3, 15.5 Hz, 1 H), 3.46 (m, 1 H), 3.38 (dd, J ) 6.9, 6.9 Hz,
1 H), 3.29 (s, 3 H), 3.21 (s, 3 H), 3.16 (s, 3 H), 2.73 (d, J ) 3.6
Hz, 1 H), 2.51 (m, 1 H), 2.38-2.19 (m, 3 H), 2.19 (s, 3 H), 2.15-
2.01 (m, 3 H), 1.94 (m, 1 H), 1.86 (m, 1 H), 1.78 (m, 1 H), 1.72
(m, 1 H), 1.68-1.10 (m, 13 H), 1.49 (s, 3 H), 1.11 (d, J ) 6.3
Hz, 3 H), 0.98 (m, 1 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.92-0.86
(m, 9 H), 0.89 (s, 9 H), 0.85 (d, J ) 6.6 Hz, 3 H), 0.84 (d, J )

5346 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
6.6 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H); MS (FAB) m/ z 1155
(M + Na)+; HRMS (FAB) calcd for C63H108NaO13SSi [(M +
Na)+] 1155.7178, found 1155.7190.
Hz, 1 H), 4.65 (d, J ) 11.5 Hz, 1 H), 4.60 (d, J ) 11.9 Hz, 1 H),
4.53 (d, J ) 11.5 Hz, 1 H), 4.53 (d, J ) 11.9 Hz, 1 H), 4.04 (br
s, 1 H), 3.89 (s, 3 H), 3.88 (m, 1 H), 3.87 (s, 3 H), 3.72 (ddd, J
) 5.6, 5.6, 11.2 Hz, 1 H), 3.65-3.42 (m, 6 H), 3.38 (dd, J )
4.6, 10.2 Hz, 1 H), 3.20 (s, 3 H), 3.17 (s, 3 H), 3.12 (br s, 1 H),
2.44 (m, 1 H), 2.38-2.16 (m, 3 H), 2.16 (s, 3 H), 2.10-1.75 (m,
6 H), 1.75-0.95 (m, 15 H), 1.45 (s, 3 H), 1.01 (d, J ) 7.3 Hz,
3 H), 0.95 (d, J ) 7.3 Hz, 3 H), 0.93 (d, J ) 6.8 Hz, 3 H), 0.91-
0.88 (m, 6 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.87 (d, J ) 7.3 Hz,
3 H), 0.78 (d, J ) 5.9 Hz, 3 H), 0.11 (s, 3 H), 0.05 (s, 3 H), 0.05
(s, 3 H), 0.04 (s, 3 H); MS (FAB) m/ z 1257 (M + Na)+; HRMS
(FAB) calcd for C68H122NaO13SSi2 [(M + Na)+] 1257.8042, found
1257.8020.
Tr ityl Eth er 88a . To a stirred solution of diol 87a (45.3
mg, 0.0367 mmol) in pyridine (0.4 mL) was added trityl
chloride (40.2 mg, 0.144 mmol) at room temperature. The
solution was stirred at 50 °C for 11.5 h and was cooled to room
temperature. Ice (ca. 1 g) and H2O (1 mL) were added, and
the mixture was stirred at room temperature for 1 h and
extracted with Et2O (2 × 5 mL). The combined extracts were
washed with saturated aqueous NaHCO3 (2 mL) and brine (2
mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (2 g, hexane-
Et2O-triethylamine 80:20:1 f 1: 1: 0 f 1: 2: 0) to give 88a
(52.9 mg, 98%) as a colorless oil: [R]20D +37.7 (c 0.906, CHCl3);
IR (CHCl3) 3480 (br), 1705, 1645, 1615, 1595, 1515, 1465, 1375,
1255, 1030, 970, 835 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.48-
7.39 (m, 6 H), 7.31-7.15 (m, 10 H), 6.89-6.86 (m, 2 H), 6.80
(d, J ) 8.9 Hz, 1 H), 6.27-6.10 (m, 2 H), 5.82 (d, J ) 15.2 Hz,
1 H), 5.55 (ddd, J ) 4.3, 10.2, 14.9 Hz, 1 H), 5.27 (br dd, J )
4.0, 9.2 Hz, 1 H), 5.12-5.06 (m, 2 H), 4.82 (d, J ) 6.9 Hz, 1
H), 4.76 (d, J ) 6.9 Hz, 1 H), 4.64 (d, J ) 11.9 Hz, 1 H), 4.59
(d, J ) 11.9 Hz, 1 H), 4.53 (d, J ) 11.9 Hz, 1 H), 4.52 (d, J )
11.9 Hz, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.84 (m, 1 H), 3.59
(m, 1 H), 3.56-3.34 (m, 6 H), 3.19 (s, 3 H), 3.17 (s, 3 H), 3.18
(m, 1 H), 3.01 (m, 1 H), 2.44 (m, 1 H), 2.37-0.95 (m, 24 H),
2.16 (s, 3 H), 1.45 (s, 3 H), 0.96 (d, J ) 6.9 Hz, 3 H), 0.95-0.84
(m, 12 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.84 (d, J ) 6.6 Hz, 3 H),
0.79 (d, J ) 5.6 Hz, 3 H), 0.13 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 3
H), 0.05 (s, 3 H); MS (FAB) m/ z 1499 (M + Na)+.
Isom er iza t ion of 26-Mem b er ed La ct on e 85 t o 24-
Mem ber ed La cton e 84. To a stirred solution of the 26-
membered lactone 85 (9.6 mg, 0.0085 mmol) in CH2Cl2 (0.4
mL) was added titanium tetraisopropoxide (0.01 mL, 0.034
mmol) at room temperature. The solution was stirred at room
temperature for 19 h and diluted with Et2O (2 mL) and 10%
aqueous (+)-tartaric acid (2 mL). The mixture was stirred at
room temperature for 20 min and extracted with Et2O (25 mL,
8 mL). The combined extracts were washed with brine (3 mL),
dried (NaSO4), and concentrated. The residual oil was purified
by thin-layer chromatography on silica gel (200 × 200 × 0.25
mm, hexane-EtOAc 1:1) to give 84 (6.2 mg, 65%) along with
recovered 85 (1.5 mg, 15%).
Disilyl Eth er 86a . To a stirred solution of the 24-
membered lactone 84 (15.5 mg, 0.0137 mmol) and imidazole
(157 mg, 2.31 mmol) in DMF (0.2 mL) was added tert-
butyldimethylsilyl chloride (149 mg, 0.989 mmol) at room
temperature, and the resulting solution was stirred at 60 °C
for 24 h. The mixture was cooled to room temperature, and
ice (ca. 1 g) and H2O (3 mL) were added. The mixture was
stirred at room temperature for 20 min and extracted with
Et2O (3 × 6 mL). The combined extracts were washed with 1
M aqueous HCl (2 × 2 mL), saturated aqueous NaHCO3 (4
mL), H2O (3 mL), and brine (3 mL), successively, dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (5 g, hexane-EtOAc 5:1
f 2: 1) to give 86a (16.8 mg, 98%) as a colorless oil: [R]22
D
+45.3 (c 1.11, CHCl3); IR (CHCl3) 1705, 1645, 1615, 1595, 1515,
1465, 1375, 1255, 1095, 1030, 970, 835 cm-1 1H NMR (270
;
MHz, CDCl3) δ 7.21 (dd, J ) 9.9, 15.2 Hz, 1 H), 6.94-6.88 (m,
2 H), 6.82 (d, J ) 7.9 Hz, 1 H), 6.28-6.10 (m, 2 H), 5.81 (d, J
) 15.2 Hz, 1 H), 5.55 (ddd, J ) 4.0, 10.2, 15.2 Hz, 1 H), 5.26
(br dd, J ) 4.3, 9.2 Hz, 1 H), 5.12-4.98 (m, 2 H), 4.89 (d, J )
4.6 Hz, 1 H), 4.83 (d, J ) 6.9 Hz, 1 H), 4.81 (d, J ) 6.9 Hz, 1
H), 4.59 (d, J ) 11.6 Hz, 1 H), 4.58 (s, 2 H), 4.52 (d, J ) 11.6
Hz, 1 H), 4.03 (br dd, J ) 6.6, 6.6 Hz, 1 H), 3.88 (s, 3 H), 3.87
(s, 3 H), 3.65-3.43 (m, 5 H), 3.37 (dd, J ) 4.3, 10.2 Hz, 1 H),
3.27 (s, 3 H), 3.19 (s, 3 H), 3.16 (s, 3 H), 2.43 (m, 1 H), 2.37-
0.95 (m, 24 H), 2.16 (s, 3 H), 1.45 (s, 3 H), 1.09 (d, J ) 6.3 Hz,
3 H), 0.93-0.85 (m, 15 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.79 (d,
J ) 5.6 Hz, 3 H), 0.12 (s, 3 H), 0.05 (s, 9 H); MS (FAB) m/ z
1269 (M + Na)+; HRMS (FAB) calcd for C69H122NaO13SSi2 [(M
+ Na)+] 1269.8042, found 1269.8060.
Aceta te 89a . To a stirred solution of trityl ether 88a (18.0
mg, 0.0122 mmol) in pyridine (0.4 mL) were added acetic
anhydride (0.2 mL) and 4-(dimethylamino)pyridine (1.0 mg,
0.0082 mmol) at room temperature. The mixture was stirred
at room temperature for 12.5 h and concentrated. The residual
oil was purified by column chromatography on silica gel (2 g,
hexane-Et2O 2:1 f 1: 1 f 1: 2) to give 89a (18.6 mg, 100%)
as a colorless oil: [R]26D +43.2 (c 1.00, CHCl3); IR (CHCl3) 1725,
1710 (sh), 1645, 1615, 1595, 1515, 1465, 1380, 1255, 1030, 970,
Diol 87a . To a stirred solution of disilyl ether 86a (64.0
mg, 0.0513 mmol) in 1,2-dimethoxyethane (6.0 mL) was added
1 M aqueous HCl (1.5 mL) at room temperature. The solution
was stirred at room temperature for 5.5 h, cooled to 0 °C, and
diluted with Et2O (5 mL) and saturated aqueous NaHCO3 (2
mL). The organic layer was separated, and the aqueous layer
was extracted with Et2O (3 × 5 mL). The organic layer and
the extracts were combined, washed with brine (4 mL), dried
(Na2SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (5 g, hexane-EtOAc 5:1
f 3: 1 f 3: 2) to give a diastereomeric mixture of hemiacetals
(48.0 mg) as a colorless oil along with recovered 86a (9.6 mg,
15%). To a stirred solution of the hemiacetals (48.0 mg) in
MeOH (2 mL) cooled at 0 °C was added sodium trimethoxy-
borohydride (66.6 mg, 0.521 mmol). The solution was stirred
at room temperature for 4.5 h. The reaction was quenched
by addition of acetone (0.2 mL), and the resulting mixture was
stirred at room temperature for 10 min. Saturated aqueous
NH4Cl (2 mL) was added, and the mixture was extracted with
Et2O (3 × 5 mL). The combined extracts were washed with
brine (4 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (10
g, hexane-EtOAc 3: 1 f 1: 1 f 1: 2) to give 87a (45.7 mg, 72%)
1
835 cm-1; H NMR (270 MHz, CDCl3) δ 7.47-7.41 (m, 6 H),
7.33-7.18 (m, 10 H), 6.91-6.87 (m, 2 H), 6.82 (d, J ) 8.6 Hz,
1 H), 6.27-6.12 (m, 2 H), 5.82 (d, J ) 15.2 Hz, 1 H), 5.55 (ddd,
J ) 4.3, 10.6, 14.8 Hz, 1 H), 5.28 (br dd, J ) 4.3, 9.2 Hz, 1 H),
5.12-4.95 (m, 3 H), 4.77 (d, J ) 6.9 Hz, 1 H), 4.67 (d, J ) 6.9
Hz, 1 H), 4.62 (d, J ) 11.5 Hz, 1 H), 4.59 (d, J ) 11.5 Hz, 1 H),
4.52 (d, J ) 11.9 Hz, 1 H), 4.48 (d, J ) 11.9 Hz, 1 H), 3.88 (s,
3 H), 3.86 (s, 3 H), 3.59 (m, 1 H), 3.55-3.33 (m, 5 H), 3.19 (s,
3 H), 3.18 (m, 1 H), 3.17 (s, 3 H), 2.99 (m, 1 H), 2.44 (m, 1 H),
2.37-1.73 (m, 10 H), 2.16 (s, 3 H), 2.00 (s, 3 H), 1.72-0.90 (m,
14 H), 1.45 (s, 3 H), 1.12-0.86 (m, 12 H), 0.95 (d, J ) 6.6 Hz,
3 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 0.79 (d, J ) 5.6 Hz, 3 H), 0.71
(d, J ) 6.9 Hz, 3 H), 0.14 (s, 3 H), 0.08 (s, 3 H), 0.05 (s, 3 H),
0.05 (s, 3 H); MS (FAB) m/ z 1541 (M + Na)+.
Alcoh ol 90a . Experimental procedure was followed as
described for compound 45. 90a : [R]25D +46.9 (c 0.995, CHCl3);
IR (CHCl3) 3500 (br), 1725, 1710, 1645, 1615, 1595, 1515, 1465,
1
1380, 1255, 1030, 970, 835 cm-1; H NMR (270 MHz, CDCl3)
δ 7.22 (dd, J ) 9.9, 15.2 Hz, 1 H), 6.90-6.85 (m, 2 H), 6.82 (d,
J ) 8.6 Hz, 1 H), 6.30-6.10 (m, 2 H), 5.82 (d, J ) 15.2 Hz, 1
H), 5.54 (ddd, J ) 4.3, 10.6, 15.2 Hz, 1 H), 5.26 (br dd, J )
5.0, 9.9 Hz, 1 H), 5.14-5.00 (m, 2 H), 5.00 (dd, J ) 2.3, 9.6
Hz, 1 H), 4.77 (d, J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 1 H),
4.61 (d, J ) 11.9 Hz, 1 H), 4.60 (d, J ) 11.9 Hz, 1 H), 4.53 (d,
J ) 11.9 Hz, 1 H), 4.49 (d, J ) 11.9 Hz, 1 H), 3.89 (s, 3 H),
3.87 (s, 3 H), 3.76 (m, 1 H), 3.69-3.41 (m, 6 H), 3.38 (dd, J )
4.6, 10.2 Hz, 1 H), 3.19 (s, 3 H), 3.17 (s, 3 H), 2.51-2.16 (m, 4
as a colorless oil: [R]20 +31.5 (c 0.971, CHCl3); IR (CHCl3)
D
3440 (br), 1705, 1645, 1615, 1595, 1515, 1465, 1375, 1260,
1030, 970, 835 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J
) 9.9, 15.2 Hz, 1 H), 6.90-6.86 (m, 2 H), 6.82 (d, J ) 8.6 Hz,
1 H), 6.25-6.12 (m, 2 H), 5.83 (d, J ) 15.2 Hz, 1 H), 5.54 (ddd,
J ) 4.3, 10.2, 14.9 Hz, 1 H), 5.25 (br dd, J ) 5.0, 9.2 Hz, 1 H),
5.11-5.02 (m, 2 H), 4.82 (d, J ) 6.9 Hz, 1 H), 4.77 (d, J ) 6.9

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5347
H), 2.16 (s, 3 H), 2.04 (s, 3 H), 2.04-0.85 (m, 40 H), 1.45 (s, 3
H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.79 (d, J ) 5.6 Hz, 3 H), 0.13
(s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H); MS (FAB)
(pH 6, 2 mL), 5% aqueous NaHCO3 (2 mL), H2O (2 mL), and
brine (2 mL), successively, dried (Na2SO4), and concentrated.
The residual oil was purified by thin-layer chromatography
on silica gel (200 × 200 × 0.25 mm, CHCl3-acetone 15:1) to
m/ z 1299 (M + Na)+; HRMS (FAB) calcd for C70H124NaO14
-
SSi2 [(M + Na)+] 1299.8149, found 1299.8130.
give 93a (1.7 mg, 88%) as a colorless amorphous powder: [R]23
D
+23 (c 0.075, CHCl3); IR (CHCl3) 3520 (br), 1730 (sh), 1710,
Ald eh yd e 91a . Experimental procedure was followed as
1
1655, 1465, 1375, 1255, 1080, 1050, 970, 835 cm-1; H NMR
described for compound 9. 91a : [R]22 +49 (c 0.44, CHCl3);
D
(270 MHz, CDCl3) δ 8.29 [8.07] (s, 1 H), 7.21 (m, 1 H), 6.51
[7.18] (d, J ) 14.2 Hz, 1 H), 6.27-6.12 (m, 2 H), 5.82 (d, J )
15.2 Hz, 1 H), 5.55 (ddd, J ) 4.0, 10.2, 15.2 Hz, 1 H), 5.28 (m,
1 H), 5.09-4.96 (m, 3 H), 4.82 [4.81] (dd, J ) 3.0, 9.9 Hz, 1
H), 4.60 (d, J ) 11.6 Hz, 1 H), 4.53 (d, J ) 11.6 Hz, 1 H), 3.60-
3.35 (m, 7 H), 3.19 (s, 3 H), 3.16 (s, 3 H), 3.02 [3.05] (s, 3 H),
2.60-1.77 (m, 10 H), 2.16 (s, 3 H), 2.16 [2.15] (s, 3 H), 1.70-
1.25 (m, 12 H), 1.45 (s, 3 H), 1.12-0.84 (m, 16 H), 1.06 [1.05]
(d, J ) 6.6 Hz, 3 H), 0.89 (s, 9 H), 0.89 (s, 9 H), 0.79 (d, J )
5.6 Hz, 3 H), 0.12 (s, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.03 (s,
3 H) (the minor counterparts of doubled signals in the ratio of
2:1 are in brackets); MS (FAB) m/ z 1158 (M + Na)+; HRMS
(FAB) calcd for C62H113NNaO11SSi2 [(M + Na)+] 1158.7470,
found 1158.7480.
IR (CHCl3) 2725, 1730, 1710 (sh), 1645, 1615, 1595, 1515, 1465,
1
1375, 1250, 1045, 970, 835 cm-1; H NMR (400 MHz, CDCl3)
δ 9.77 (m, 1 H), 7.22 (dd, J ) 9.9, 15.2 Hz, 1 H), 6.89-6.86 (m,
2 H), 6.82 (d, J ) 8.9 Hz, 1 H), 6.25-6.14 (m, 2 H), 5.82 (d, J
) 15.2 Hz, 1 H), 5.54 (ddd, J ) 4.3, 10.2, 15.2 Hz, 1 H), 5.25
(dd, J ) 4.9, 9.6 Hz, 1 H), 5.10-4.98 (m, 3 H), 4.76 (d, J ) 6.9
Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 1 H), 4.60 (d, J ) 11.6 Hz, 1 H),
4.59 (d, J ) 11.6 Hz, 1 H), 4.53 (d, J ) 11.6 Hz, 1 H), 4.49 (d,
J ) 11.6 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.60 (m, 1 H),
3.53-3.35 (m, 5 H), 3.19 (s, 3 H), 3.16 (s, 3 H), 2.49-2.44 (m,
3 H), 2.37-2.16 (m, 4 H), 2.16 (s, 3 H), 2.04 (s, 3 H), 2.04-
1.21 (m, 17 H), 1.45 (s, 3 H), 1.13-0.86 (m, 4 H), 0.97 (d, J )
6.6 Hz, 3 H), 0.97 (d, J ) 6.8 Hz, 3 H), 0.93 (d, J ) 6.8 Hz, 3
H), 0.92 (d, J ) 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.88 (s, 9 H), 0.87
(d, J ) 7.2 Hz, 3 H), 0.78 (d, J ) 5.6 Hz, 3 H), 0.13 (s, 3 H),
0.06 (s, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H); MS (FAB) m/ z 1297
(M + Na)+; HRMS (FAB) calcd for C70H122NaO14SSi2 [(M +
Na)+] 1297.7992, found 1297.7980.
En a m id e 92a . A solution of aldehyde 91a (10.3 mg,
0.00808 mmol), N-methylformamide (0.1 mL, 1.7 mmol),
hydroquinone (1.8 mg, 0.016 mmol), and pyridinium p-tolu-
enesulfonate (3.8 mg, 0.015 mmol) in benzene (6 mL) was
heated to reflux for 6.5 h under a stream of argon with
continuous removal of water and use of molecular sieves 3 Å.
During the reaction, benzene (7 mL) was added to the solution
in portions. The mixture was cooled to room temperature,
diluted with saturated aqueous NaHCO3 (1 mL), and extracted
with EtOAc (10 mL, 5 mL, then 3 mL). The combined extracts
were washed with brine (3 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified twice by column chro-
matography on silica gel [(2 g, hexane-EtOAc 5:1 f 3: 1 f
2: 1 f 1: 1) and (2 g, hexane-acetone 5:1 f 3:1 f 2:1)] to give
92a (5.1 mg, 48%) as a colorless amorphous powder along with
recovered 91a (3.0 mg, 29%). 92a : [R]25D +28 (c 0.42, CHCl3);
IR (CHCl3) 1720 (sh), 1700, 1655, 1515, 1460, 1375, 1255, 1080,
1030, 970, 835 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.27 [8.06]
(s, 1 H), 7.22 (dd, J ) 9.1, 15.1 Hz, 1 H), 6.89-6.86 (m, 2 H),
6.82 (d, J ) 8.3 Hz, 1 H), 6.48 [7.17] (d, J ) 13.9 Hz, 1 H),
6.27-6.12 (m, 2 H), 5.82 (d, J ) 15.1 Hz, 1 H), 5.53 (ddd, J )
4.0, 10.6, 14.8 Hz, 1 H), 5.25 (m, 1 H), 5.10-4.97 (m, 4 H),
4.76 [4.75] (d, J ) 6.9 Hz, 1 H), 4.64 (d, J ) 6.9 Hz, 1 H), 4.61
(d, J ) 11.5 Hz, 1 H), 4.60 (d, J ) 11.5 Hz, 1 H), 4.53 (d, J )
11.5 Hz, 1 H), 4.49 (d, J ) 11.5 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s,
3 H), 3.60 (m, 1 H), 3.55-3.35 (m, 5 H), 3.19 (s, 3 H), 3.16 (s,
3 H), 2.99 [3.02] (s, 3 H), 2.56 (m, 1 H), 2.46 (br d, J ) 10.7
Hz, 1 H), 2.37-2.16 (m, 3 H), 2.16 (s, 3 H), 2.07 [2.06] (s, 3 H),
2.01 (m, 1 H), 1.85-1.17 (m, 16 H), 1.45 (s, 3 H), 1.12-0.85
(m, 4 H), 1.03 [1.02] (d, J ) 6.9 Hz, 3 H), 0.93 (d, J ) 7.3 Hz,
3 H), 0.92 (d, J ) 6.8 Hz, 3 H), 0.89 (s, 18 H), 0.88 (d, J ) 7.3
Hz, 3 H), 0.87 (d, J ) 7.3 Hz, 3 H), 0.78 (d, J ) 5.6 Hz, 3 H),
0.12 (s, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H), 0.03 (s, 3 H) (the
minor counterparts of doubled signals in the ratio of 2:1 are
in brackets); MS (FAB) m/ z 1338 (M + Na)+; HRMS (FAB)
calcd for C72H125NNaO14SSi2 [(M + Na)+] 1338.8258, found
1338.8280.
Dim eth yla la n in e Ester s 94. To a mixture of alcohol 93a
(5.6 mg, 0.0049 mmol), L-N,N-dimethylalanine (7.8 mg, 0.067
mmol), D-N,N-dimethylalanine (5.2 mg, 0.044 mmol), 4-(dim-
ethylamino)pyridine (36.6 mg, 0.300 mmol), and (()-camphor-
sulfonic acid (26.4 mg, 0.114 mmol) was added a 0.20 M
solution of dicyclohexylcarbodiimide in CH2Cl2 (0.55 mL, 0.11
mmol) at room temperature. The mixture was stirred at room
temperature for 15 h, and saturated aqueous NaHCO3 (2.5 mL)
was added. The mixture was stirred at room temperature for
1 h and extracted with EtOAc (5 × 3 mL). The combined
extracts were washed with brine (3 mL), dried (Na2SO4), and
concentrated. The residue was dissolved in Et2O (1 mL) and
filtered through a small plug of cotton, and the residue was
washed with Et2O (4 mL). The filtrate and the washings were
combined and concentrated. The residue was purified by
column chromatography on silica gel (2 g, CH2Cl2-acetone 5: 1
f 3:1 f 1: 1) to give a diastereomeric mixture of dimethyla-
lanine esters 94 (S/ R ) 4/1) (5.7 mg, 94%) as a colorless
amorphous powder: [R]30 +11 (c 0.065, MeOH); IR (CHCl3)
D
1725, 1700, 1655, 1465, 1375, 1250, 1080, 1035, 970, 835 cm-1
;
1H NMR (500 MHz, acetone-d6) δ 8.37 [8.11]a (s, 1 H), 7.25
(dd, J ) 10.2, 15.2 Hz, 1 H), 6.85 [7.16]a (d, J ) 14.5 Hz, 1 H),
6.41 (dd, J ) 10.2, 15.2 Hz, 1 H), 6.32 (m, 1 H), 5.93 (d, J )
15.2 Hz, 1 H), 5.57 (ddd, J ) 4.3, 10.2, 14.8 Hz, 1 H), 5.31 (m,
1 H), 5.16 (dd, J ) 3.4, 9.6 Hz, 1 H), 5.11-4.99 (m, 3 H), 4.82
(dd, J ) 1.6, 9.9 Hz, 1 H), 4.68 (d, J ) 11.9 Hz, 1 H), 4.63 (d,
J ) 11.9 Hz, 1 H), 3.72-3.66 (m, 2 H), 3.55 (m, 1 H), 3.50
(ddd, J ) 6.0, 6.0, 9.6 Hz, 1 H), 3.44 (dd, J ) 5.6, 10.0 Hz, 1
H), 3.21 (m, 1 H), 3.13 (s, 3 H), 3.13 (s, 3 H), 2.97 [3.09]a (s, 3
H), 2.64 (m, 1 H), 2.49 (br d, J ) 13.5 Hz, 1 H), 2.42-2.26 (m,
3 H), 2.35 [2.32]b (s, 6 H), 2.19 (s, 3 H), 2.18-1.92 (m, 2 H),
1.86 (m, 1 H), 1.78-1.06 (m, 15 H), 1.46 (s, 3 H), 1.27 [1.22]b
(d, J ) 7.1 Hz, 3 H), 1.03-0.95 (m, 18 H), 0.93 (s, 9 H), 0.92
(s, 9 H), 0.81 (d, J ) 6.4 Hz, 3 H), 0.17 (s, 3 H), 0.11 (s, 3 H),
0.10 (s, 3 H), 0.09 (s, 3 H) (signals of three protons (CH3COO)
were overlapped with the solvent signals; the minor counter-
parts of doubled signals in the ratios of 2:1 (superscript a) and
4:1 (superscript b) are in brackets); MS (FAB) m/ z 1235 (M +
H)+; HRMS (FAB) calcd for C67H123N2O12SSi2 [(M + H)+]
1235.8336, found 1235.8300.
Alcoh ol 95. To a stirred solution of dimethylalanine esters
94 (S/R ) 4/1) (3.8 mg, 0.0031 mmol) in THF (0.28 mL) and
H2O (0.07 mL) were added 2,6-lutidine (0.05 mL, 0.43 mmol)
and silver nitrate (67.5 mg, 0.397 mmol) at room temperature.
The mixture was stirred at 30 °C for 16 h in the dark and was
filtered through a pad of Celite, and the residue was washed
with EtOAc (10 mL). The filtrate and the washings were
combined, washed with H2O (2 mL) and brine (2 mL), and
concentrated. The residual oil was purified by column chro-
matography on silica gel (2 g, hexane-EtOAc-MeOH 10:2:1
f 4:2:1) to give alcohol 95 (S/R ) 4/1) (3.5 mg, 97%) as a
Alcoh ol 93a . To a stirred solution of enamide 92a (2.3 mg,
0.0017 mmol) in CH2Cl2 (0.36 mL), tert-butyl alcohol (0.02 mL),
and 1 M phosphate buffer (pH 6, 0.02 mL) cooled at 0 °C was
added 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (0.5 mg,
0.0022 mmol). The mixture was warmed to room temperature
and stirred at room temperature for 35 min. To the mixture
cooled at 0 °C was added DDQ (0.7 mg, 0.0031 mmol), and
the mixture was stirred at room temperature for 40 min.
Further, the mixture was cooled to 0 °C and DDQ (0.5 mg,
0.0022 mmol) was added. After the mixture was stirred at
room temperature for 35 min, 1 M phosphate buffer (pH 6, 2
mL) was added. The mixture was stirred at room temperature
for 40 min and extracted with Et2O (10 mL, 3 × 3 mL). The
combined extracts were washed with 1 M phosphate buffer
colorless amorphous powder: [R]28 +10 (c 0.04, MeOH); IR
D
(CHCl3) 3450 (br), 1725 (sh), 1705, 1655, 1480, 1375, 1250,
1
1080, 1035, 970, 835 cm-1; H NMR (500 MHz, acetone-d6) δ
8.37 [8.12]a (s, 1 H), 7.25 (dd, J ) 11.0, 15.0 Hz, 1 H), 6.86

5348 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
(br), 1730, 1690 (sh), 1655, 1455, 1370, 1240, 1095, 970 cm-1
[7.16]a (d, J ) 15.0 Hz, 1 H), 6.43-6.33 (m, 2 H), 5.90 (d, J )
15.0 Hz, 1 H), 5.57 (ddd, J ) 4.8, 10.2, 14.4 Hz, 1 H), 5.31 (m,
1 H), 5.19 (dd, J ) 5.0, 9.3 Hz, 1 H), 5.12-4.99 (m, 3 H), 4.82
(dd, J ) 2.1, 10.4 Hz, 1 H), 3.83 (dd, J ) 2.4, 5.5 Hz, 1 H),
3.67 (br s, 1 H), 3.67 (m, 1 H), 3.55 (m, 1 H), 3.49 (m, 1 H),
3.43 (dd, J ) 5.2, 10.2 Hz, 1 H), 3.23 (m, 1 H), 3.13 (s, 3 H),
3.12 (s, 3 H), 2.97 [3.09]a (s, 3 H), 2.63 (m, 1 H), 2.50 (br d, J
) 13.5 Hz, 1 H), 2.42-2.26 (m, 3 H), 2.35 [2.32]b (s, 6 H), 2.18-
1.83 (m, 3 H), 1.80-1.08 (m, 15 H), 1.45 (s, 3 H), 1.27 [1.24]b
(d, J ) 7.1 Hz, 3 H), 1.02-0.85 (m, 18 H), 0.93 (s, 9 H), 0.92
(s, 9 H), 0.81 (d, J ) 6.6 Hz, 3 H), 0.16 (s, 3 H), 0.10 (s, 3 H),
0.10 (s, 6 H) (signals of three protons (CH3COO) were
overlapped with the solvent signals; the minor counterparts
of doubled signals in the ratios of 2:1 (superscript a) and 4:1
(superscript b) are in brackets); MS (FAB) m/ z 1175 (M + H)+;
HRMS (FAB) calcd for C65H119N2O12Si2 [(M + H)+] 1175.8302,
found 1175.8290.
;
1H NMR (500 MHz, acetone-d6) δ 8.36 [8.10]a (s, 1 H), 7.23
[7.24]c (dd, J ) 10.8, 15.3 Hz, 1 H), 6.84 [7.16]a (d, J ) 14.4
Hz, 1 H), 6.43 [6.46]c (dd, J ) 10.8, 15.2 Hz, 1 H), 6.29 (m, 1
H), 5.98 (d, J ) 15.3 Hz, 1 H), 5.61 (ddd, J ) 4.0, 10.5, 15.3
Hz, 1 H), 5.47 (br d, J ) 10.7 Hz, 1 H), 5.18 (m, 1 H), 5.05
[5.11]a (dd, J ) 9.4, 14.4 Hz, 1 H), 5.03 (m, 1 H), 4.95 (dd, J )
9.3, 15.3 Hz, 1 H), 4.80 [4.81]a (dd, J ) 2.7, 10.0 Hz, 1 H), 4.75
[4.72]c (br d, J ) 10.0 Hz, 1 H), 3.69 [3.68]c (dd, J ) 7.6, 9.3
Hz, 1 H), 3.60 (dd, J ) 5.5, 9.3 Hz, 1 H), 3.57 (d, J ) 5.0 Hz,
1 H), 3.52 (m, 1 H), 3.50 (br s, 1 H), 3.47 (m, 1 H), 3.37 [3.38]c
(dd, J ) 5.5, 7.6 Hz, 1 H), 3.34 [3.31]c (s, 3 H), 3.30 (m, 1 H),
3.20 (m, 1 H), 3.13 (s, 3 H), 3.11 (s, 3 H), 3.06 (m, 1 H), 2.97
[3.09]a (s, 3 H), 2.66 (m, 1 H), 2.51-2.38 (m, 2 H), 2.37 [2.38]c
(s, 6 H), 2.34 [2.32]b (s, 6 H), 2.27 (m, 1 H), 2.18-1.85 (m, 4
H), 1.76-1.46 (m, 9 H), 1.51 [1.52]c (s, 3 H), 1.43-1.08 (m, 6
H), 1.26 [1.21]b (d, J ) 7.1 Hz, 3 H), 1.03-0.96 (m, 15 H), 0.91-
0.87 (m, 3 H), 0.76 [0.74]c (d, J ) 5.5 Hz, 3 H) (signals of three
protons (CH3COO) were overlapped with the solvent signals;
the minor counterparts of doubled signals in the ratios of 2:1
(superscript a), 4:1 (superscript b), and 4:3 (superscript c) are
in brackets); 13C NMR (67.8 MHz, acetone-d6) δ 172.7, 170.7,
170.4 [170.6]c, 167.5, 162.9 [161.7]a, 145.1, 141.1, 135.4 [135.5]c,
133.4, 132.9, 131.7 [131.8]c, 131.1 [126.3]a, 130.7 [130.6]c, 121.7
[121.8]c, 110.0 [112.1]a, 86.8 [86.7]c, 82.4, 78.0, 77.4, 77.0, 76.6,
72.8, 72.8, 72.5, 68.0 [67.8]c, 63.5 [62.9]b, 59.0 [59.0]c, 55.5, 55.4,
42.6 [42.7]c, 41.9, 41.6, 41.0, 39.1 [39.3]c, 38.2, 38.1 [38.5]c, 38.1,
37.6 [37.8]a, 34.8, 33.3, 32.6 [32.6]c, 30.6, 27.3 [33.0]a, 25.3, 22.6,
21.0, 20.3, 19.9, 17.9, 16.4, 15.9 [15.2]b, 11.7 [11.5]c, 10.7, 10.3,
10.0 [10.0]a (signals due to two carbons were overlapped with
the solvent signals; the minor counterparts of doubled signals
in the ratios of 2:1 (superscript a), 4:1 (superscript b), and 4:3
(superscript c) are in brackets); MS (FAB) m/ z 1076 (M + H)+;
HRMS (FAB) calcd for C59H102N3O14 [(M + H)+] 1076.7362,
found 1076.7400.
Tr im eth ylser in e Ester s 96. To a mixture of alcohol 95
(S/R ) 4/1) (3.5 mg, 0.0030 mmol), L-N,N,O-trimethylserine
(4.9 mg, 0.033 mmol), D-N,N,O-trimethylserine (2.0 mg, 0.013
mmol), 4-(dimethylamino)pyridine (14.5 mg, 0.119 mmol), and
(()-camphorsulfonic acid (11.4 mg, 0.049 mmol) was added a
0.090 M solution of dicyclohexylcarbodiimide in CH2Cl2 (0.52
mL, 0.047 mmol) at room temperature. The mixture was
stirred at 35 °C for 1.5 h, cooled to room temperature, and
diluted with saturated aqueous NaHCO3 (2 mL). The mixture
was stirred at room temperature for 20 min and extracted with
EtOAc (5 × 2 mL). The combined extracts were washed with
brine (2 mL), dried (Na2SO4), and concentrated. The residue
was dissolved in Et2O (1 mL) and filtered through a small plug
of cotton, and the residue was washed with Et2O (4 mL). The
filtrate and the washings were combined and concentrated.
The residue was purified by column chromatography on silica
gel (2 g, hexane-EtOAc-MeOH 10:10:1 f 4:4:1) to give a
diastereomeric mixture of trimethylserine esters 96 (S/R ) 4/3
as to the trimethylserine part, S/R ) 4/1 as to the dimethy-
lalanine part) (3.3 mg, 85%) as a colorless amorphous pow-
(Meth ylth io)m eth yl Eth er 86b a n d Keton e 86c. To a
stirred solution of the 24-membered lactone 84 (17 mg, 0.015
mmol) in DMSO (0.24 mL) was added a 1:5.6 mixture of acetic
acid and acetic anhydride (0.20 mL) at room temperature. The
mixture was stirred at 40 °C for 2 h and poured into saturated
aqueous NaHCO3 (4 mL) cooled at 0 °C. The mixture was
extracted with Et2O (10 mL, 5 mL). The combined extracts
were washed with H2O (2 mL) and brine (2 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (2 g, hexane-EtOAc 2:1
f 1: 1) and preparative HPLC (Develosil 30-10, 20 × 250 mm,
der: [R]28 -2.0 (c 0.020, MeOH); IR (CHCl3) 1730, 1700 (sh),
D
1655, 1460, 1375, 1250, 1095, 970, 835 cm-1
;
1H NMR (500
MHz, acetone-d6) δ 8.37 [8.11]a (s, 1 H), 7.21 [7.22]c (dd, J )
11.0, 15.3 Hz, 1 H), 6.86 [7.16]a (d, J ) 14.2 Hz, 1 H), 6.42
[6.43]c (dd, J ) 11.0, 15.3 Hz, 1 H), 6.25 (m, 1 H), 5.93 [5.94]c
(d, J ) 15.3 Hz, 1 H), 5.56 (ddd, J ) 4.0, 10.8, 14.4 Hz, 1 H),
5.31 (br d, J ) 10.7 Hz, 1 H), 5.17 (m, 1 H), 5.12-4.98 (m, 3
H), 4.85 (m, 1 H), 4.81 (br d, J ) 10.1 Hz, 1 H), 3.70 [3.69]c
(dd, J ) 7.6, 9.2 Hz, 1 H), 3.62 (m, 1 H), 3.61 [3.59]c (dd, J )
5.5, 9.2 Hz, 1 H), 3.54 (m, 1 H), 3.51-3.42 (m, 2 H), 3.38 (dd,
J ) 5.5, 7.6 Hz, 1 H), 3.34 [3.31]c (s, 3 H), 3.20 (m, 1 H), 3.11
(s, 3 H), 3.11 (s, 3 H), 2.96 [3.08]a (s, 3 H), 2.67 (m, 1 H), 2.56-
2.43 (m, 3 H), 2.37 (s, 6 H), 2.33 [2.30]b (s, 6 H), 2.18-1.87 (m,
3 H), 1.85 (m, 1 H), 1.73-1.47 (m, 9 H), 1.48 [1.51]c (s, 3 H),
1.43-1.08 (m, 6 H), 1.25 [1.20]b (d, J ) 7.1 Hz, 3 H), 1.02-
0.95 (m, 18 H), 0.92 (s, 9 H), 0.91 (s, 9 H), 0.79 [0.79]c (d, J )
6.4 Hz, 3 H), 0.15 (s, 3 H), 0.09 (s, 3 H), 0.09 (s, 6 H) (signals
of three protons (CH3COO) were overlapped with the solvent
signals; the minor counterparts of doubled signals in the ratios
of 2:1 (superscript a), 4:1 (superscript b), and 4:3 (superscript
c) are in brackets); MS (FAB) m/ z 1304 (M + H)+; HRMS
(FAB) calcd for C71H130N3O14Si2 [(M + H)+] 1304.9092, found
1304.9080.
hexane-EtOAc-MeOH 80:20:1, 5 mL/min) to give 86b (tR
)
35 min, 7.7 mg, 43%) and 86c (tR ) 50 min, 8.4 mg, 50%) as a
colorless oil, respectively. 86b: [R]26D +61.2 (c 0.745, CHCl3);
IR (CHCl3) 1705, 1645, 1515, 1465, 1260, 1140, 1095, 1030,
970, 835 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J ) 10.2,
15.6 Hz, 1 H), 6.93-6.89 (m, 2 H), 6.83 (d, J ) 7.8 Hz, 1 H),
6.26-6.15 (m, 2 H), 5.82 (d, J ) 15.6 Hz, 1 H), 5.57 (ddd, J )
3.9, 10.2, 14.6 Hz, 1 H), 5.42 (br d, J ) 11.2 Hz, 1 H), 5.06-
4.98 (m, 2 H), 4.89 (d, J ) 4.3 Hz, 1 H), 4.84 (d, J ) 6.8 Hz, 1
H), 4.82 (d, J ) 6.8 Hz, 1 H), 4.69 (d, J ) 10.7 Hz, 1 H), 4.59
(d, J ) 11.7 Hz, 1 H), 4.58 (s, 2 H), 4.53 (d, J ) 10.7 Hz, 1 H),
4.52 (d, J ) 11.7 Hz, 1 H), 4.03 (br dd, J ) 6.3, 6.3 Hz, 1 H),
3.88 (s, 3 H), 3.87 (s, 3 H), 3.64-3.45 (m, 4 H), 3.37 (dd, J )
4.3, 10.7 Hz, 1 H), 3.27 (s, 3 H), 3.18 (s, 3 H), 3.16 (s, 3 H),
3.04 (dd, J ) 2.9, 7.8 Hz, 1 H), 2.46-1.00 (m, 25 H), 2.22 (s, 3
H), 2.16 (s, 3 H), 1.44 (s, 3 H), 1.10 (d, J ) 6.4 Hz, 3 H), 1.01
(d, J ) 6.8 Hz, 3 H), 0.93-0.86 (m, 12 H), 0.88 (s, 9 H), 0.79
(d, J ) 5.4 Hz, 3 H), 0.04 (s, 3 H), 0.04 (s, 3 H); MS (FAB) m/ z
1215 (M + Na)+; HRMS (FAB) calcd for C65H112NaO13S2Si [(M
Ap lyr on in e A (1). A solution of trimethylserine esters 96
(S/R ) 4/3 as to the trimethylserine part, S/R ) 4/1 as to the
dimethylalanine part) (3.3 mg, 0.0025 mmol) in a 3:5 mixture
of pyridine and HF‚pyridine (0.3 mL) was stirred at room
temperature for 5 h. The mixture was diluted with EtOAc (2
mL) and poured into saturated aqueous NaHCO3 (8 mL) cooled
at 0 °C, and the resulting mixture was extracted with EtOAc
(4 × 8 mL). The combined extracts were washed with brine
(4 mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (2 g, hexane-
EtOAc-MeOH 3: 3: 1 f 2: 2: 1 f 1: 1: 1) to give aplyronine A
(1) (S/R ) 4/3 as to the trimethylserine part, S/R ) 4/1 as to
the dimethylalanine part) (2.3 mg, 84%) as a colorless amor-
phous powder: [R]28D +34 (c 0.038, MeOH) [natural [R]28D +33
(c 0.036, MeOH)]; UV (MeCN) λmax 256 nm (ꢀ 31 000) [natural
UV (MeCN) λmax 256 nm (ꢀ 30 000)]; IR (CHCl3) 3690, 3500
+ Na)+] 1215.7213, found 1215.7210. 86c: [R]26 +67.3 (c
D
0.910, CHCl3); IR (CHCl3) 1715, 1705 (sh), 1645, 1515, 1465,
1260, 1135, 1095, 1030, 970, 835 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.22 (dd, J ) 10.2, 15.1 Hz, 1 H), 6.93-6.89 (m, 2
H), 6.83 (d, J ) 7.8 Hz, 1 H), 6.25-6.15 (m, 2 H), 5.80 (d, J )
15.1 Hz, 1 H), 5.51 (ddd, J ) 3.9, 10.2, 14.6 Hz, 1 H), 5.32 (m,
1 H), 5.06-4.98 (m, 2 H), 4.88 (d, J ) 4.9 Hz, 1 H), 4.83 (d, J
) 6.8 Hz, 1 H), 4.80 (d, J ) 6.8 Hz, 1 H), 4.59 (d, J ) 11.7 Hz,
1 H), 4.58 (d, J ) 12.2 Hz, 1 H), 4.55 (d, J ) 11.7 Hz, 1 H),
4.52 (d, J ) 12.2 Hz, 1 H), 4.04 (br dd, J ) 6.3, 6.3 Hz, 1 H),
3.89 (s, 3 H), 3.88 (s, 3 H), 3.60 (m, 1 H), 3.54 (dd, J ) 6.4, 9.8

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5349
Hz, 1 H), 3.52-3.43 (m, 2 H), 3.37 (dd, J ) 4.4, 10.3 Hz, 1 H),
3.26 (s, 3 H), 3.16 (s, 3 H), 3.15 (s, 3 H), 2.89 (dq, J ) 6.8, 6.8
Hz, 1 H), 2.64 (ddq, J ) 6.8, 6.8, 6.8 Hz, 1 H), 2.39-1.06 (m,
23 H), 2.15 (s, 3 H), 1.43 (s, 3 H), 1.09 (d, J ) 6.8 Hz, 3 H),
1.09 (d, J ) 6.8 Hz, 3 H), 1.08 (d, J ) 6.8 Hz, 3 H), 0.91 (d, J
) 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.87 (d, J ) 6.8 Hz, 3 H), 0.86 (d,
J ) 6.8 Hz, 3 H), 0.76 (d, J ) 5.9 Hz, 3 H), 0.04 (s, 3 H), 0.04
(s, 3 H); MS (FAB) m/ z 1153 (M + Na)+; HRMS (FAB) calcd
for C63H106NaO13SSi [(M + Na)+] 1153.7021, found 1153.7020.
Red u ction of Keton e 86c. To a stirred solution of ketone
86c (11.5 mg, 0.0102 mmol) in MeOH cooled at -23 °C was
added sodium borohydride (3.5 mg, 0.092 mmol). The solution
was stirred at -23 °C for 3 h, and the reaction was quenched
by addition of acetone (0.1 mL). The mixture was stirred at
-23 °C for 30 min, diluted with saturated aqueous NH4Cl (2
mL), and extracted with Et2O (10 mL, 5 mL). The combined
extracts were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residual oil was purified by medium-
pressure liquid chromatography (Fuji Silysia, silica gel FL60D,
Hz, 3 H), 0.78 (d, J ) 6.6 Hz, 3 H) (signals of three protons
(CH3COO) were overlapped with the solvent signals; the minor
counterparts of doubled signals in the ratios of 2:1 (superscript
a), 4:1 (superscript b), and 5:6 (superscript c) are in brackets);
MS (FAB) m/ z 1076 (M + H)+; HRMS (FAB) calcd for
C59H102N3O14 [(M + H)+] 1076.7362, found 1076.7370.
Ap lyr on in e C (3). A solution of alcohol 95 (S/R ) 2/1) (1.37
mg, 0.00116 mmol) in a 3:5 mixture of pyridine and HF‚-
pyridine (0.5 mL) was stirred at room temperature for 5 h.
The mixture was poured into saturated aqueous NaHCO3 (5
mL) cooled to 0 °C and extracted with EtOAc (5 × 5 mL). The
combined extracts were washed with brine (2 mL), dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (2 g, hexane-EtOAc-
MeOH 5: 5: 1 f 3: 3: 1 f 1: 1: 1) and preparative HPLC
(Develosil ODS-HG-5, 10 × 250 mm, MeCN-0.02 M aqueous
NH4OAc, 3 mL/min, tR ) 12 min) and column chromatography
on alumina (0.5 g, EtOAc f EtOAc-MeOH 95:5) to give
aplyronine C (3) (S/R ) 2/1) (0.50 mg, 45%) as a colorless
6.4 g, hexane-EtOAc 3:2 f 1: 1, 2 mL/min) to give 84 (tR
)
amorphous powder: [R]27D +19 (c 0.042, MeOH) [natural [R]29
D
25 min, 8.7 mg, 75%) along with the C25-epimer (tR ) 49 min,
+21 (c 0.041, MeOH)]; CD (c 0.0033, MeOH) λext 277 nm (∆ꢀ
-0.90) [natural CD (c 0.0033, MeOH) λext 277 nm (∆ꢀ -1.0)];
UV (MeCN) λmax 259 nm (ꢀ 33 000) [natural UV (MeCN) λmax
260 nm (ꢀ 30 000)]; IR (CHCl3) 3620, 3480 (br), 1730, 1725
1.1 mg, 9%) as a colorless oil, respectively. C25-ep im er : [R]29
D
+48 (c 0.20, CHCl3); IR (CHCl3) 3480 (br), 1705, 1640, 1515,
1465, 1260, 1095, 1030, 970, 835 cm-1 1H NMR (270 MHz,
;
1
CDCl3) δ 7.21 (dd, J ) 10.3, 15.2 Hz, 1 H), 6.93-6.88 (m, 2
H), 6.83 (d, J ) 7.9 Hz, 1 H), 6.25-6.14 (m, 2 H), 5.81 (d, J )
15.2 Hz, 1 H), 5.55 (ddd, J ) 4.3, 10.2, 14.8 Hz, 1 H), 5.17 (m,
1 H), 5.12-5.00 (m, 2 H), 4.89 (d, J ) 5.0 Hz, 1 H), 4.81 (s, 2
H), 4.59 (d, J ) 11.5 Hz, 1 H), 4.57 (s, 2 H), 4.53 (d, J ) 11.5
Hz, 1 H), 4.01 (m, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.64-3.43
(m, 4 H), 3.43-3.34 (m, 2 H), 3.28 (s, 3 H), 3.19 (s, 3 H), 3.17
(s, 3 H), 2.45-0.96 (m, 26 H), 2.16 (s, 3 H), 1.44 (s, 3 H), 1.10
(d, J ) 6.3 Hz, 3 H), 0.99 (d, J ) 6.9 Hz, 3 H), 0.93 (d, J ) 6.9
Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.87 (d, J )
7.6 Hz, 3 H), 0.85 (d, J ) 6.9 Hz, 3 H), 0.78 (d, J ) 5.3 Hz, 3
H), 0.04 (s, 6 H); MS (FAB) m/ z 1155 (M + Na)+; HRMS (FAB)
calcd for C63H108NaO13SSi [(M + Na)+] 1155.7178, found
1155.7210.
(sh), 1690, 1655, 1460, 1375, 1240, 1090, 1080, 970 cm-1; H
NMR (600 MHz, acetone-d6) δ 8.37 [8.10] (s, 1 H), 7.26 (dd, J
) 10.3, 15.4 Hz, 1 H), 6.85 [7.15] (d, J ) 14.4 Hz, 1 H), 6.42
(ddd, J ) 5.1, 9.2, 15.4 Hz, 1 H), 6.37 (dd, J ) 10.3, 15.4 Hz,
1 H), 5.93 (d, J ) 15.4 Hz, 1 H), 5.62 (ddd, J ) 4.4, 10.6, 15.0
Hz, 1 H), 5.47 (br d, J ) 11.4 Hz, 1 H), 5.22 (br dd, J ) 4.8,
10.6 Hz, 1 H), 5.05 [5.11] (dd, J ) 9.5, 14.3 Hz, 1 H), 5.03-
4.99 (m, 2 H), 4.80 (br d, J ) 9.9 Hz, 1 H), 3.80 (br d, J ) 4.0
Hz, 1 H), 3.66 (m, 1 H), 3.60 (br d, J ) 5.1 Hz, 1 H), 3.50-3.46
(m, 2 H), 3.40 (m, 1 H), 3.37 (br d, J ) 5.1 Hz, 1 H), 3.18 (m,
1 H), 3.12 (s, 3 H), 3.11 (s, 3 H), 3.05 (m, 1 H), 2.97 [3.09] (s,
3 H), 2.66 (m, 1 H), 2.44 (m, 1 H), 2.34-2.22 (m, 2 H), 2.33
[2.31] (s, 6 H), 2.14 (m, 1 H), 2.08-1.91 (m, 2 H), 2.03 [2.02]
(s, 3 H), 1.79 (m, 1 H), 1.73-1.70 (m, 2 H), 1.67-1.50 (m, 7
H), 1.45 (s, 3 H), 1.35 (m, 1 H), 1.31-1.13 (m, 5 H), 1.25 [1.20]
(d, J ) 7.0 Hz, 3 H), 1.01 (d, J ) 6.8 Hz, 3 H), 1.00 (d, J ) 7.0
Hz, 3 H), 1.00 (d, J ) 7.0 Hz, 3 H), 0.99 (d, J ) 7.0 Hz, 3 H),
0.98 (d, J ) 6.5 Hz, 3 H), 0.89 [0.90] (d, J ) 7.0 Hz, 3 H), 0.78
(d, J ) 6.5 Hz, 3 H) (the minor counterparts of doubled signals
in the ratio of 2:1 are in brackets); MS (FAB) m/ z 969 (M +
Na)+, 947 (M + H)+; HRMS (FAB) calcd for C53H91N2O12 [(M
+ H)+] 947.6572, found 947.6600.
Ap lyr on in e B (2). To a stirred solution of N,N,O-trimeth-
ylserine esters 99 (S/R ) 5/6 as to the trimethylserine part,
S/R ) 4/1 as to the dimethylalanine part) (1.3 mg, 0.0011
mmol) in THF (0.2 mL) and H2O (0.05 mL) were added 2,6-
lutidine (0.05 mL, 0.43 mmol) and silver nitrate (68 mg, 0.40
mmol) at room temperature, and the mixture was stirred at
30 °C for 16 h in the dark. The mixture was filtered through
a pad of Celite, and the residue was washed with EtOAc (15
mL). The filtrate and the washings were combined, washed
with saturated aqueous NaHCO3 (2 mL), H2O (2 mL), and
brine (2 mL), and concentrated. The residual oil was purified
by column chromatography on silica gel (0.5 g, hexane-
EtOAc-MeOH 5:5:1 f 2:2:1) to give aplyronine B (2) (S/R )
5/6 as to the trimethylserine part, S/R ) 4/1 as to the
dimethylalanine part) (1.0 mg, 85%) as a colorless amorphous
powder: [R]24 -5.1 (c 0.051, MeOH) [natural [R]24 +3.7 (c
Ald eh yd e 100. To a stirred solution of aplyronine A (1)
(S/R ) 1.1/1 as to the trimethylserine part, S/R ) 4/1 as to
the dimethylalanine part) (2.3 mg, 0.0021 mmol) in dioxane
(0.6 mL) was added 2 M aqueous HCl (0.2 mL) at room
temperature, and the resulting solution was stirred at 50 °C
for 1.5 h. The mixture was cooled to room temperature and
poured into saturated aqueous NaHCO3 (4 mL) cooled at 0 °C,
and the resulting mixture was extracted with CHCl3 (4 × 4
mL). The combined extracts were washed with H2O (2 mL),
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (2 g, hexane-
EtOAc-MeOH 5:5:1 f 3: 3: 1 f 2: 2: 1) and preparative HPLC
(Develosil 60-5, 10 × 250 mm, hexane-1,2-dichloroethane-
MeOH-H2O-triethylamine 50:45:4.5:0.25:0.25, 3.0 mL/min)
to give 100 (S/R ) 1.1/1 as to the trimethylserine part, S/R )
4/1 as to the dimethylalanine part) (tR ) 41 min, 1.4 mg, 63%)
as a colorless amorphous powder: [R]28D +54 (c 0.065, MeOH);
UV (MeCN) λmax 261 nm (ꢀ 33 000); IR (CHCl3) 3480 (br), 2720,
D
D
0.19, MeOH)]; CD (c 0.0041, MeOH) λext 265 nm (∆ꢀ -3.7)
[natural CD (c 0.0039, MeOH) λext 265 nm (∆ꢀ -3.3)]; UV
(MeCN) λmax 258 nm (ꢀ 29 000) [natural UV (MeCN) λmax 258
nm (ꢀ 30 200)]; IR (CHCl3) 3470 (br), 1725, 1695, 1655, 1460,
1375, 1240, 1090, 975 cm-1; 1H NMR (600 MHz, acetone-d6) δ
8.37 [8.11]a (s, 1 H), 7.27 (dd, J ) 10.3, 15.4 Hz, 1 H), 6.85
[7.16]a (d, J ) 14.3 Hz, 1 H), 6.51-6.43 (m, 2 H), 5.94 (d, J )
15.4 Hz, 1 H), 5.62 (ddd, J ) 4.0, 10.6, 15.0 Hz, 1 H), 5.49 (br
d, J ) 11.0 Hz, 1 H), 5.25 (m, 1 H), 5.05 [5.10]a (dd, J ) 9.5,
14.3 Hz, 1 H), 5.03 (m, 1 H), 4.98 (dd, J ) 9.9, 15.0 Hz, 1 H),
4.93 (dd, J ) 1.8, 9.2 Hz, 1 H), 4.80 [4.80]a (dd, J ) 2.6, 10.3
Hz, 1 H), 3.79 (dd, J ) 4.8, 8.4 Hz, 1 H), 3.68 (dd, J ) 7.3, 9.2
Hz, 1 H), 3.67 (br s, 1 H), 3.62-3.57 (m, 2 H), 3.53-3.46 (m,
2 H), 3.41 [3.40]c (dd, J ) 6.6, 6.6 Hz, 1 H), 3.29 [3.28]c (s, 3
H), 3.18 [3.23]b (m, 1 H), 3.12 (s, 3 H), 3.11 (s, 3 H), 3.06 (m,
1 H), 2.97 [3.09]a (s, 3 H), 2.65 (m, 1 H), 2.45 (m, 1 H), 2.36
[2.37]c (s, 6 H), 2.35-2.23 (m, 2 H), 2.33 [2.31]b (s, 6 H), 2.15
(m, 1 H), 2.09-1.91 (m, 3 H), 1.87-1.78 (m, 2 H), 1.73 (m, 1
H), 1.67-1.48 (m, 6 H), 1.45-1.08 (m, 6 H), 1.44 (s, 3 H), 1.26
[1.20]b (d, J ) 7.3 Hz, 3 H), 1.00 (d, J ) 7.0 Hz, 3 H), 1.00 (d,
J ) 7.0 Hz, 3 H), 0.98 (d, J ) 7.0 Hz, 3 H), 0.90 [0.91]c (d, J )
7.0 Hz, 3 H), 0.90 (d, J ) 7.0 Hz, 3 H), 0.88 [0.94]c (d, J ) 6.6
1730, 1700 (sh), 1645, 1620, 1460, 1375, 1240, 1095, 970 cm-1
;
1H NMR (500 MHz, acetone-d6) δ 9.75 (dd, J ) 1.4, 2.3 Hz, 1
H), 7.23 (dd, J ) 10.5, 15.1 Hz, 1 H), 6.45 [6.46]a (dd, J ) 10.5,
15.0 Hz, 1 H), 6.29 [6.31]a (ddd, J ) 5.0, 9.6, 15.0 Hz, 1 H),
5.99 (d, J ) 15.1 Hz, 1 H), 5.62 (ddd, J ) 4.1, 11.0, 15.1 Hz, 1
H), 5.48 (br d, J ) 11.0 Hz, 1 H), 5.18 (m, 1 H), 5.01 (ddd, J )
1.8, 6.9, 6.9 Hz, 1 H), 4.97 (dd, J ) 9.6, 15.1 Hz, 1 H), 4.80
(dd, J ) 2.8, 9.6 Hz, 1 H), 4.74 (br t, J ) 12.0 Hz, 1 H), 3.69
[3.68]a (dd, J ) 7.8, 9.4 Hz, 1 H), 3.65-3.40 (m, 3 H), 3.60 (dd,
J ) 5.7, 9.4 Hz, 1 H), 3.48 (ddd, J ) 4.1, 9.6, 10.9 Hz, 1 H),
3.38 [3.39]a (dd, J ) 5.7, 7.8 Hz, 1 H), 3.34 [3.31]a (s, 3 H),
3.33 (m, 1 H), 3.20 [3.23]b (q, J ) 6.9 Hz, 1 H), 3.12 (s, 3 H),

5350 J . Org. Chem., Vol. 61, No. 16, 1996
Kigoshi et al.
3.10 (s, 3 H), 3.07 (m, 1 H), 2.61 (m, 1 H), 2.57 (m, 1 H), 2.52-
2.40 (m, 2 H), 2.37 [2.38]a (s, 6 H), 2.33 [2.31]b (s, 6 H), 2.40-
2.22 (m, 2 H), 2.16 (m, 1 H), 2.03 [2.01]b (s, 3 H), 2.10-1.98
(m, 2 H), 1.92 (m, 1 H), 1.78 (m, 1 H), 1.72-1.46 (m, 8 H),
1.51 [1.52]a (s, 3 H), 1.42 (m, 1 H), 1.36-1.08 (m, 5 H), 1.27
[1.21]b (d, J ) 6.9 Hz, 3 H), 1.04-0.98 (m, 12 H), 0.94 (d, J )
6.9 Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3 H), 0.76 [0.75]a (d, J ) 6.0
Hz, 3 H) (the minor counterparts of doubled signals in the
ratios of 1.1:1 (superscript a) and 4:1 (superscript b) are in
brackets); MS (FAB) m/ z 1035 (M + H)+; HRMS (FAB) calcd
for C57H99N2O14 [(M + H)+] 1035.7097, found 1035.7080.
Alcoh ol 101. To a stirred solution of aldehyde 100 (S/R )
1.1/1 as to the trimethylserine part, S/R ) 4/1 as to the
dimethylalanine part) (1.0 mg) in THF (0.05 mL) cooled at 0
°C was added a 0.5 M solution of lithium tri-tert-butoxyalu-
minum hydride [LiAlH(O-t-Bu)3] (0.005 mL, 0.0025 mmol).
After the mixture was stirred at 0 °C for 30 min, a 0.5 M
solution of LiAlH(O-t-Bu)3 (0.005 mL, 0.0025 mmol) was added,
and the mixture was stirred at 0 °C for 50 min. Further, a
0.5 M solution of LiAlH(O-t-Bu)3 (0.005 mL, 0.0025 mmol) was
added, and the mixture was stirred at 0 °C for 40 min. After
the reaction was quenched by addition of H2O (0.03 mL), the
mixture was filtered through a pad of Celite, and the residue
was washed with THF (10 mL). The filtrate and the washings
were combined and concentrated. The residual oil was purified
by column chromatography on silica gel (1 g, hexane-EtOAc-
MeOH 5:5:1 f 3: 3: 1 f 1: 1: 1) and preparative HPLC
(Develosil 60-5, 10 × 250 mm, 1,2-dichloroethane-MeOH-
H2O-triethylamine 95:4.5:0.25:0.25, 3.0 mL/min) to give 101
(S/R ) 1.1/1 as to the trimethylserine part, S/R ) 4/1 as to
the dimethylalanine part) (tR ) 29 min, 0.6 mg, 60%) as a
colorless oil: [R]26D +42 (c 0.056, MeOH); UV (MeCN) λmax 260
nm (ꢀ 21 000); IR (CHCl3) 3630, 3500 (br), 1730, 1700 (sh),
1460, 1255, 1100, 1030, 970 cm-1; 1H NMR (270 MHz, acetone-
d6) δ 8.37 [8.11]a (s, 1 H), 7.21 [7.21]b (dd, J ) 10.9, 15.5 Hz,
1 H), 6.97-6.84 (m, 3 H), 6.84 [7.17]a (d, J ) 14.2 Hz, 1 H),
6.48-6.15 (m, 2 H), 5.91 (d, J ) 15.5 Hz, 1 H), 5.55 (m, 1 H),
5.30 (m, 1 H), 5.22-4.96 (m, 4 H), 4.85 (m, 1 H), 4.74 (d, J )
6.9 Hz, 1 H), 4.64 (d, J ) 6.9 Hz, 1 H), 4.60 (d, J ) 11.5 Hz, 1
H), 4.46 (d, J ) 11.5 Hz, 1 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.76-
3.27 (m, 8 H), 3.34 [3.31]b (s, 3 H), 3.11 (s, 6 H), 2.95 [3.07]a (s,
3 H), 2.75-1.10 (m, 23 H), 2.37 (s, 6 H), 1.48 (s, 3 H), 1.01 (d,
J ) 6.6 Hz, 3 H), 1.01-0.88 (m, 9 H), 0.97 (d, J ) 6.3 Hz, 3
H), 0.96 (d, J ) 6.9 Hz, 3 H), 0.92 (s, 9 H), 0.91 (s, 9 H), 0.79
(d, J ) 6.3 Hz, 3 H), 0.15 (s, 3 H), 0.09 (s, 9 H) (signals of
three protons (CH3COO) were overlapped with the solvent
signals; the minor counterparts of doubled signals in the ratios
of 2:1 (superscript a) and 4:3 (superscript b) are in brackets);
MS (FAB) m/ z 1407 (M + Na)+; HRMS (FAB) calcd for
C76H132N2NaO16Si2 [(M + Na)+] 1407.9014, found 1407.8980.
Diol 104. Experimental procedure was followed as de-
scribed for aplyronine A (1). 104 (S/R ) 4/3): [R]26 +23 (c
D
0.075, CHCl3); IR (CHCl3) 3630, 3500 (br), 1730, 1690, 1655,
1
1515, 1460, 1375, 1240, 1025, 970 cm-1; H NMR (400 MHz,
acetone-d6) δ 8.36 [8.09]a (s, 1 H), 7.21 [7.22]b (dd, J ) 10.7,
15.1 Hz, 1 H), 6.96-6.85 (m, 3 H), 6.83 [7.16]a (d, J ) 14.2 Hz,
1 H), 6.44 (m, 1 H), 6.29 (m, 1 H), 5.97 (d, J ) 15.1 Hz, 1 H),
5.57 (m, 1 H), 5.43 (br d, J ) 11.2 Hz, 1 H), 5.17 (m, 1 H), 5.08
[5.13]a (dd, J ) 4.9, 14.2 Hz, 1 H), 5.01-4.89 (m, 2 H), 4.74 (d,
J ) 6.8 Hz, 1 H), 4.71 (m, 1 H), 4.65 (d, J ) 6.8 Hz, 1 H), 4.61
(d, J ) 11.5 Hz, 1 H), 4.44 (d, J ) 11.5 Hz, 1 H), 3.79 (s, 3 H),
3.78 (s, 3 H), 3.68 [3.67]b (dd, J ) 7.9, 9.3 Hz, 1 H), 3.58 (dd,
J ) 5.4, 9.3 Hz, 1 H), 3.54-3.28 (m, 7 H), 3.33 [3.30]b (s, 3 H),
3.11 (s, 3 H), 3.09 (s, 3 H), 3.05 (m, 1 H), 2.95 [3.07]a (s, 3 H),
2.76-1.06 (m, 23 H), 2.35 [2.37]b (s, 6 H), 1.49 (br s, 3 H), 1.02-
0.95 (m, 12 H), 0.90 (d, J ) 6.8 Hz, 3 H), 0.86 (d, J ) 6.8 Hz,
3 H), 0.75-0.71 (m, 3 H) (signals of three protons (CH3COO)
were overlapped with the solvent signals; the minor counter-
parts of doubled signals in the ratios of 2:1 (superscript a) and
4:3 (superscript b) are in brackets); MS (FAB) m/ z 1179 (M +
Na)+; HRMS (FAB) calcd for C64H104N2NaO16 [(M + Na)+]
1179.7284, found 1179.7260.
1
1645, 1605, 1460, 1375, 1245, 1100, 970 cm-1; H NMR (500
MHz, acetone-d6) δ 7.23 (dd, J ) 11.0, 15.3 Hz, 1 H), 6.45
[6.46]a (dd, J ) 11.0, 15.0 Hz, 1 H), 6.29 [6.30]a (ddd, J ) 5.0,
10.0, 15.0 Hz, 1 H), 5.98 (d, J ) 15.3 Hz, 1 H), 5.62 (ddd, J )
4.3, 10.7, 15.0 Hz, 1 H), 5.49 (br d, J ) 10.7 Hz, 1 H), 5.18 (m,
1 H), 4.98 (dd, J ) 6.1, 6.1 Hz, 1 H), 4.97 (dd, J ) 8.2, 15.0
Hz, 1 H), 4.79 (dd, J ) 2.8, 10.1 Hz, 1 H), 4.74 (br t, J ) 11.5
Hz, 1 H), 3.70 [3.69]a (dd, J ) 7.6, 9.2 Hz, 1 H), 3.67 (m, 1 H),
3.60 (dd, J ) 5.5, 9.2 Hz, 1 H), 3.56 (d, J ) 5.2 Hz, 1 H), 3.56-
3.41 (m, 5 H), 3.37 [3.38]a (dd, J ) 5.5, 7.6 Hz, 1 H), 3.34 [3.31]a
(s, 3 H), 3.19 [3.22]b (q, J ) 7.0 Hz, 1 H), 3.12 (s, 3 H), 3.10 (s,
3 H), 3.08 (m, 1 H), 2.46-2.20 (m, 4 H), 2.37 [2.38]a (s, 6 H),
2.33 [2.31]b (s, 6 H), 2.20-2.14 (m, 1 H), 2.09-1.90 (m, 3 H),
2.00 [1.98]b (s, 3 H), 1.76-1.50 (m, 11 H), 1.51 [1.51]a (s, 3 H),
1.41 (m, 1 H), 1.30-1.13 (m, 6 H), 1.25 [1.21]b (d, J ) 7.3 Hz,
3 H), 1.03-0.98 (m, 12 H), 0.92 (d, J ) 7.0 Hz, 3 H), 0.89 (d,
J ) 7.0 Hz, 3 H), 0.76 [0.75]a (d, J ) 5.8 Hz, 3 H) (the minor
counterparts of doubled signals in the ratios of 1.1:1 (super-
script a) and 4:1 (superscript b) are in brackets); MS (FAB)
m/ z 1037 (M + H)+; HRMS (FAB) calcd for C57H101N2O14 [(M
+ H)+] 1037.7253, found 1037.7230.
An a logu e 105. To a stirred solution of diol 104 (S/R ) 4/3)
(1.4 mg, 0.0012 mmol) in CH2Cl2 (0.36 mL), tert-butyl alcohol
(0.02 mL), and 1 M phosphate buffer (pH 6, 0.02 mL) cooled
at 0 °C was added 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) (0.7 mg, 0.0031 mmol). The mixture was warmed to
room temperature, and the stirring was continued for 20 min.
To the mixture cooled at 0 °C was added DDQ (0.5 mg, 0.0022
mmol), and the resulting mixture was stirred at room tem-
perature for 20 min. Again, the mixture was cooled to 0 °C
and DDQ (0.6 mg, 0.0026 mmol) was added. After the mixture
was stirred at room temperature for 15 min, 1 M phosphate
buffer (pH 6, 1 mL) was added. The mixture was stirred at
room temperature for 2 h and extracted with Et2O (10 mL, 2
× 5 mL). The combined extracts were washed with 1 M
phosphate buffer (pH 6, 2 mL), saturated aqueous NaHCO3
(2 mL), H2O (2 mL), and brine (2 mL), successively, dried (Na2-
SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (0.5 g, CH2Cl2-acetone
5:1 f 3:1 f 2:1 f 1:1), preparative HPLC (Develosil ODS-
HG-5, 10 × 250 mm, MeCN-0.02 M aqueous NH4OAc 65:35,
2 mL/min), and column chromatography on alumina (0.1 g,
EtOAc f EtOAc-MeOH 9: 1) to give 105 (S/R ) 4/3) (0.6 mg,
50%) as a colorless amorphous powder along with recovered
Alcoh ol 102. Experimental procedure was followed as
described for compound 95. 102 : [R]26 +21 (c 0.12, CHCl3);
D
IR (CHCl3) 3480 (br), 1715, 1695, 1655, 1515, 1465, 1375, 1255,
1080, 970 cm-1; 1H NMR (270 MHz, CDCl3) δ 8.27 [8.06] (s, 1
H), 7.22 (dd, J ) 9.6, 15.5 Hz, 1 H), 6.89-6.85 (m, 2 H), 6.82
(d, J ) 8.3 Hz, 1 H), 6.48 [7.17] (d, J ) 13.9 Hz, 1 H), 6.28-
6.13 (m, 2 H), 5.79 (d, J ) 15.5 Hz, 1 H), 5.50 (ddd, J ) 4.3,
9.9, 14.5 Hz,1 H), 5.23 (m, 1 H), 5.18-4.97 (m, 4 H), 4.76 [4.76]
(d, J ) 7.3 Hz, 1 H), 4.64 (d, J ) 7.3 Hz, 1 H), 4.56 (d, J )
11.5 Hz, 1 H), 4.49 (d, J ) 11.5 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s,
3 H), 3.79 (m, 1 H), 3.60 (m, 1 H), 3.53-3.38 (m, 5 H), 3.20 (s,
3 H), 3.16 (s, 3 H), 2.99 [3.02] (s, 3 H), 2.80-2.00 (m, 9 H),
2.07 [2.07] (s, 3 H), 1.83-1.10 (m, 14 H), 1.46 (s, 3 H), 1.03
[1.02] (d, J ) 6.9 Hz, 3 H), 0.96-0.83 (m, 15 H), 0.90 (s, 9 H),
0.89 (s, 9 H), 0.79 (d, J ) 6.3 Hz, 3 H), 0.12 (s, 3 H), 0.08 (s, 3
H), 0.07 (s, 3 H), 0.03 (s, 3 H) (the minor counterparts of
doubled signals in the ratio of 2:1 are in brackets); MS (FAB)
104 (0.4 mg, 30%). 105: [R]27 +29 (c 0.059, MeOH); UV
D
(MeCN) λmax 256 nm (ꢀ 27 000); IR (CHCl3) 3680, 3510 (br),
1
1715, 1695, 1660, 1480, 1250, 1075, 970 cm-1; H NMR (600
MHz, acetone-d6) δ 8.36 [8.09]a (s, 1 H), 7.21 [7.21]b (dd, J )
10.6, 15.4 Hz, 1 H), 6.84 [7.15]a (d, J ) 13.9 Hz, 1 H), 6.44
[6.45]b (dd, J ) 10.6, 16.1 Hz, 1 H), 6.29 (m, 1 H), 5.98 [5.98]b
(d, J ) 15.4 Hz, 1 H), 5.61 (ddd, J ) 4.0, 10.6, 15.0 Hz, 1 H),
5.47 (br d, J ) 11.4 Hz, 1 H), 5.17 (m, 1 H), 5.07 [5.13]a (dd, J
) 9.5, 13.9 Hz, 1 H), 4.94 (dd, J ) 9.2, 15.0 Hz, 1 H), 4.87
[4.88]a (dd, J ) 2.6, 10.1 Hz, 1 H), 4.71 (m, 1 H), 3.68 [3.67]b
(dd, J ) 7.7, 9.5 Hz, 1 H), 3.58 (dd, J ) 5.5, 9.5 Hz, 1 H), 3.53-
3.44 (m, 5 H), 3.35 [3.37]b (dd, J ) 5.5, 7.7 Hz, 1 H), 3.33 [3.29]b
(s, 3 H), 3.30 (m, 1 H), 3.11 (s, 3 H), 3.09 (s, 3 H), 3.05-2.99
(m, 2 H), 2.96 [3.07]a (s, 3 H), 2.63 (m, 1 H), 2.48-2.38 (m, 2
m/ z 1278 (M + Na)+; HRMS (FAB) calcd for C70H121NNaO14
-
Si2 [(M + Na)+] 1278.8224, found 1278.8200.
Tr im eth ylser in e Ester s 103. Experimental procedure
was followed as described for compound 96. 103 (S/R ) 4/3):
[R]26 +8 (c 0.11, CHCl3); IR (CHCl3) 1725, 1700, 1655, 1515,
D

Synthesis of Aplyronines A, B, and C
J . Org. Chem., Vol. 61, No. 16, 1996 5351
H), 2.35 [2.37]b (s, 6 H), 2.29 (m, 1 H), 2.17-1.86 (m, 4 H),
2.09 [2.08]a (s, 3 H), 1.75 (m, 1 H), 1.70-1.47 (m, 8 H), 1.50
[1.49]b (s, 3 H), 1.44-1.04 (m, 6 H), 1.02 (d, J ) 6.6 Hz, 3 H),
1.01 (d, J ) 7.0 Hz, 3 H), 0.99 [0.97]b (d, J ) 7.0 Hz, 3 H), 0.94
[0.94]a (d, J ) 6.6 Hz, 3 H), 0.88 [0.88]a (d, J ) 7.0 Hz, 3 H),
0.85 [0.85]a (d, J ) 7.0 Hz, 3 H), 0.74 [0.73]b (d, J ) 6.2 Hz, 3
H) (the minor counterparts of doubled signals in the ratios of
2:1 (superscript a) and 4:3 (superscript b) are in brackets); MS
(FAB) m/ z 977 (M + H)+; HRMS (FAB) calcd for C54H93N2O13
[(M + H)+] 977.6677, found 977.6696.
J ) 9.2, 15.0 Hz, 1 H), 4.87 [4.88] (dd, J ) 2.9, 11.9 Hz, 1 H),
3.78 (br d, J ) 4.4 Hz, 1 H), 3.66 (m, 1 H), 3.51-3.45 (m, 4 H),
3.38 (m, 1 H), 3.36 (br d, J ) 5.5 Hz, 1 H), 3.11 (s, 3 H), 3.10
(s, 3 H), 3.04-2.97 (m, 2 H), 2.96 [3.08] (s, 3 H), 2.63 (m, 1 H),
2.44 (m, 1 H), 2.30 (m, 1 H), 2.23 (m, 1 H), 2.14-1.98 (m, 2
H), 2.09 [2.08] (s, 3 H), 1.93 (m, 1 H), 1.81-1.50 (m, 10 H),
1.44-1.00 (m, 6 H), 1.42 (s, 3 H), 1.02 (d, J ) 6.6 Hz, 3 H),
0.99 (d, J ) 7.0 Hz, 3 H), 0.96 (d, J ) 7.0 Hz, 3 H), 0.95 (d, J
) 7.0 Hz, 3 H), 0.88 [0.88] (d, J ) 7.0 Hz, 3 H), 0.85 (d, J )
7.0 Hz, 3 H), 0.77 (d, J ) 6.6 Hz, 3 H) (the minor counterparts
of doubled signals in the ratio of 2:1 are in brackets); MS (FAB)
m/ z 870 (M + Na)+; HRMS (FAB) calcd for C48H81NNaO11 [(M
+ Na)+] 870.5707, found 870.5696.
Tr iol 106. A solution of alcohol 102 (1.4 mg, 0.0011 mmol)
in a 8:3:5 mixture of THF, pyridine, and HF‚pyridine (0.4 mL)
was stirred at room temperature for 10 h. The mixture was
poured into saturated aqueous NaHCO3 (6 mL) cooled at 0 °C,
and the resulting mixture was extracted with EtOAc (20 mL,
2 × 15 mL). The combined extracts were washed with brine
(4 mL), dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (0.2 g, CH2-
Cl2-acetone 5: 1 f 3: 1 f 2: 1 f 1: 1) to give 106 (1.0 mg,
An a logu e 117. A solution of ester 116 (S/R ) 2/1) (1.5 mg,
0.0020 mmol) in a 7:10 mixture of pyridine and HF‚pyridine
(0.3 mL) was stirred at room temperature for 2 h. The mixture
was poured into saturated aqueous NaHCO3 (10 mL) cooled
at 0 °C, and the mixture was extracted with EtOAc (5 × 10
mL). The combined extracts were washed with brine (5 mL),
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (1 g, hexane-
EtOAc-MeOH 10: 10: 1 f 5: 5: 1 f 3: 3: 1) to give 117 (S/R
89%) as a colorless oil: [R]27 +9 (c 0.091, CHCl3); IR (CHCl3)
D
3690, 3500 (br), 1730, 1695, 1655, 1520, 1465, 1375, 1245, 975
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.28 [8.08] (s, 1 H), 7.28
(dd, J ) 9.8, 15.1 Hz, 1 H), 6.90-6.86 (m, 2 H), 6.82 (d, J )
7.8 Hz, 1 H), 6.48 [7.17] (d, J ) 14.2 Hz, 1 H), 6.24 (dd, J )
9.8, 14.6 Hz, 1 H), 6.17 (ddd, J ) 5.4, 8.8, 14.6 Hz, 1 H), 5.84
(d, J ) 15.1 Hz, 1 H), 5.52 (m, 1 H), 5.36 (br d, J ) 10.7 Hz,
1 H), 5.18-4.98 (m, 4 H), 4.78 [4.77] (d, J ) 6.8 Hz, 1 H), 4.66
[4.66] (d, J ) 6.8 Hz, 1 H), 4.63 (d, J ) 11.7 Hz, 1 H), 4.47 (d,
J ) 11.7 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.73 (m, 1 H),
3.63 (m, 1 H), 3.52-3.41 (m, 5 H), 3.33 (m, 1 H), 3.20 (s, 3 H),
3.18 (s, 3 H), 3.02 [3.05] (s, 3 H), 2.97 (m, 1 H), 2.63-2.32 (m,
5 H), 2.19-1.94 (m, 3 H), 2.08 [2.07] (s, 3 H), 1.78-1.05 (m,
15 H), 1.46 (s, 3 H), 1.05 (d, J ) 6.8 Hz, 3 H), 1.04-0.98 (m,
6 H), 0.91 (d, J ) 6.8 Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H), 0.81
(d, J ) 6.8 Hz, 3 H), 0.73 (d, J ) 5.9 Hz, 3 H) (the minor
counterparts of doubled signals in the ratio of 2:1 are in
brackets); MS (FAB) m/ z 1050 (M + Na)+; HRMS (FAB) calcd
for C58H93NNaO14 [(M + Na)+] 1050.6490, found 1050.6490.
An a logu e 107. To a stirred solution of diol 106 (1.4 mg,
0.0014 mmol) in CH2Cl2 (0.36 mL), tert-butyl alcohol (0.02 mL),
and 1 M phosphate buffer (pH 6, 0.02 mL) cooled at 0 °C was
added 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (0.7 mg,
0.0031 mmol). The mixture was warmed to room temperature,
and the stirring was continued for 20 min. To the mixture
cooled at 0 °C was added DDQ (0.5 mg, 0.0022 mmol), and
the resulting mixture was stirred at room temperature for 20
min. Again, the mixture was cooled to 0 °C, and DDQ (0.5
mg, 0.0022 mmol) was added. After the mixture was stirred
at room temperature for 1 h, 1 M phosphate buffer (pH 6, 1
mL) was added. The mixture was stirred at room temperature
for 1 h and extracted with Et2O (20 mL, 2 × 10 mL). The
combined extracts were washed with 1 M phosphate buffer
(pH 6, 4 mL), saturated aqueous NaHCO3 (4 mL), H2O (4 mL),
and brine (4 mL), successively; dried (Na2SO4); and concen-
trated. The residual oil was purified by column chromatog-
raphy on silica gel (0.2 g, CH2Cl2-acetone 5:1 f 3:1 f 2:1 f
1:1) and preparative HPLC (Develosil ODS-HG-5, 10 × 250
mm, MeOH-H2O 70:30, 2 mL/min) to give 107 (tR ) 44min,
) 2/1) (0.8 mg, 63%) as a colorless oil: [R]27 +61 (c 0.054,
D
MeOH); UV (MeCN) λmax 258 nm (ꢀ 25 000); IR (CHCl3) 3620,
3520 (br), 1740 (sh), 1715, 1650, 1620, 1465, 1270, 1095, 975
cm-1 1H NMR (500 MHz, acetone-d6) δ 7.20 (dd, J ) 11.0,
;
15.3 Hz, 1 H), 6.40 [6.41] (dd, J ) 11.0, 14.7 Hz, 1 H), 6.22 (m,
1 H), 5.88 (d, J ) 15.3 Hz, 1 H), 5.61 (ddd, J ) 4.6, 9.8, 15.3
Hz, 1 H), 5.24 (m, 1 H), 5.07 (br dd, J ) 8.9, 15.3 Hz, 1 H),
4.81 (m, 1 H), 4.47 (m, 1 H), 4.05 (m, 1 H), 3.71-3.29 (m, 5
H), 3.68 (m, 1 H), 3.59 (m, 1 H), 3.32 [3.30] (s, 3 H), 3.12 [3.12]
(s, 3 H), 3.12 [3.12] (s, 3 H), 2.46-2.27 (m, 4 H), 2.37 [2.37] (s,
6 H), 2.09-0.80 (m, 20 H), 1.52 [1.52] (s, 3 H) (the minor
counterparts of doubled signals in the ratio 2:1 are in brackets);
MS (FAB) m/ z 622 (M + H)+; HRMS (FAB) calcd for C35H60
NO8 [(M + H)+] 622.4319, found 622.4312.
-
Ack n ow led gm en t. We are grateful to Dr. Yasuhiko
Kakui and Ms. Mutsuko Kimura, Nippon Kayaku Co.
Ltd. for evaluating the cytotoxicities of natural and
synthetic compounds. This work was supported in part
by Grants-in-Aid for Scientific Research (no. 04403009)
and for Scientific Research on Priority Areas (Asym-
metric Synthesis of Chiral Molecules, Natural Su-
pramolecules) from the Ministry of Education, Science,
and Culture, J apan, the Fujisawa Foundation, the
Shorai Foundation for Science and Technology, the
Kowa Life Science Foundation, the Naito Foundation,
and Ono Pharmaceutical Co. T.I. and T.O. gratefully
acknowledge J SPS for a predoctoral fellowship. Finally,
we thank Mr. Takaya Tsuboi and Ms. J unko Hirano for
their technical assistance.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1
natural and synthetic 1-3; H NMR spectra of 6-9, 12-18,
19a ,b, 20, 22, 23, 30, 32, 33, 35-44, 46-49, 50a ,b, 51, 52,
53a ,b, 54, 55, 60a ,b, 61, 62, 63b, 64, 65a ,b, 66a ,b, 67, 71,
73a -c, 74-83, 85, 86a -93a , 86b-93b, 86c, 94-111, 113-
117, 119, 120, and, C-25ep im er ; and experimental data for
87b-93b, 97-99, 108-116, 119 and 120 (124 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
0.8 mg, 70%) as a colorless amorphous powder: [R]27 +36 (c
D
0.11, MeOH); UV (MeCN) λmax 260 nm (ꢀ 29 000); IR (CHCl3)
3500 (br), 1710 (sh), 1690, 1655, 1460, 1375, 1255, 970 cm-1
;
1H NMR (600 MHz, acetone-d6) δ 8.36 [8.09] (s, 1 H), 7.25 (dd,
J ) 10.3, 15.0 Hz, 1 H), 6.84 [7.15] (d, J ) 14.3 Hz, 1 H), 6.41
(ddd, J ) 4.8, 8.7, 15.4 Hz, 1 H), 6.36 (dd, J ) 10.3, 15.4 Hz,
1 H), 5.92 (d, J ) 15.0 Hz, 1 H), 5.61 (ddd, J ) 4.0, 10.6, 15.0
Hz, 1 H), 5.47 (br d, J ) 11.0 Hz, 1 H), 5.20 (br dd, J ) 3.7,
9.9 Hz, 1 H), 5.07 [5.13] (dd, J ) 9.5, 14.3 Hz, 1 H), 4.98 (dd,
J O9606113