Total synthesis of an antitumor agent, mucocin, based on the "chiron approach"

Article abstract of DOI:10.1021/jo020211h

The total synthesis of a powerful antitumor acetogenin, mucocin (1), was achieved through a palladium-catalyzed cross-coupling reaction of the THP-THF fragment 2 and a terminal butenolide 3. The key process for construction of the fragment 2 was chelation-controlled addition of ethynylmagnesium chloride to disilyl aldehyde 23a and condensation of the alkyllithium prepared therefrom with THP aldehyde 4 in the presence of CeCl₃. Synthesis of the lactone 3 relied on a novel approach by taking advantage of a radical cyclization of acyclic selenocarbonate 6. The three building blocks 4, 5a, and 6 were prepared stereoselectivly from D-galactose (7), 2,5-anhydro-D-mannitol (8), and L-rhamnose (9), respectively. A new and efficient method for desymmetrization of the C₂-symmetrical compound 8 is also described.

Full text of DOI:10.1021/jo020211h

Tota l Syn th esis of a n An titu m or Agen t, Mu cocin , Ba sed on th e
“Ch ir on Ap p r oa ch ”
Shunya Takahashi* and Tadashi Nakata
RIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama 351-0198, J apan
shunyat@riken.go.jp
Received March 26, 2002
The total synthesis of a powerful antitumor acetogenin, mucocin (1), was achieved through a
palladium-catalyzed cross-coupling reaction of the THP-THF fragment 2 and a terminal butenolide
3. The key process for construction of the fragment 2 was chelation-controlled addition of
ethynylmagnesium chloride to disilyl aldehyde 23a and condensation of the alkyllithium prepared
therefrom with THP aldehyde 4 in the presence of CeCl3. Synthesis of the lactone 3 relied on a
novel approach by taking advantage of a radical cyclization of acyclic selenocarbonate 6. The three
building blocks 4, 5a , and 6 were prepared stereoselectivly from D-galactose (7), 2,5-anhydro-D-
mannitol (8), and L-rhamnose (9), respectively. A new and efficient method for desymmetrization
of the C2-symmetrical compound 8 is also described.
In tr od u ction
ring has been discovered (Figure 1).4-6 Mucocin (1), which
was isolated from the leaves of Rollinia mucosa (J acq.)
Baill. (Annonaceae) by McLaughlin et al., is the first
annonaceous acetogenin to be reported that bears a THP
ring along with a THF ring.7 This novel type of acetogenin
was found to be quite active in the BST assay8 (IC50 1.3
µg/mL) and showed remarkable inhibitory activities
against A-549 (lung cancer) and PACA-2 (pancreatic
cancer) solid tumor lines with a potency of more than
10000 times that of adriamycin. The powerful antitumor
activity and the unique structure of 1 have consequently
made it an attractive target similar to other classical
THF acetogenins9 for synthetic chemists.10 Here, we
describe the stereocontrolled total synthesis of 1 utilizing
the “chiron” approach11 which involved a highly stereo-
selective addition of organometallic reagents to sugar-
Annonaceous acetogenins are a family of polyketide-
derived fatty acid natural products isolated from the
tropical and subtropical plant family, Annonaceae, and
are characterized by a long alkyl chain with a terminal
γ-lactone subunit, one to three tetrahydrofuran (THF)
rings, and some carbinol chiral centers along it.1 Many
of these compounds exhibit a broad spectrum of biological
activities such as cytotoxic, antitumor, insecticidal, fun-
gicidal, anthelmintic, immunosuppressive, and antifeed-
ant effects. As the mode of action, a blockage of the
mitochondrial NADH-ubiquinone oxidoreductase in com-
plex I, which is a membrane bound and essential enzyme
for ATP production, is discussed.2 Furthermore, these
natural products were also shown to inhibit a ubiquinone-
linked NADH oxidase found in the plasma membrane of
specific tumor cell-lines, including some which show
multidrug resistance.3 Such consideration suggests that
these natural products are expected to be new candidates
for anticancer agents.
(4) For muconin, see: Shi, G.; Kozlowski, J . F.; Schwedler, J . T.;
Wood, K. V.; MacDougal, J . M.; McLaughlin, J . L. J . Org. Chem. 1996,
61, 7988-7989.
(5) For jimenezin, see: (a) Chavez, D.; Acevedo, L. A.; Mata, R. J .
Nat. Prod. 1998, 61, 419-421. (b) Takahashi, S.; Maeda, K.; Hirota,
S.; Nakata, T. Org. Lett. 1999, 1, 2025-2028.
(6) For pyranicin and pyragonicin, see: Alali, F. Q.; Rogers, L.;
Zhang, Y.; McLaughlin, J . L. Tetrahedron 1998, 54, 5833-5844.
(7) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao,
G.-X.; He, K.; MacDougal, J . M.; McLaughlin, J . L. J . Am. Chem. Soc.
1995, 117, 10409-10410.
Recently, a new skeletal type of acetogenins bearing a
hydroxylated or an unsubstituted tetrahydropyran (THP)
* To whom correspondence should be addressed. Tel: +81-48-
467-9377. Fax: +81-48-462-4666.
(1) Zafro-Polo, M. C.; Gonzalez, M. C.; Estornell, E.; Sahpaz, S.;
Cortes, D. Phytochemistry 1996, 42, 253-271. Zeng, L.; Ye, Q.;
Oberlies, N. H.; Shi, G.; Gu, Z. -M.; He, K.; McLaughlin, J . L. Nat.
Prod. Rep. 1996, 13, 275-306. Zafro-Polo, M. C.; Figadere, B.; Gallardo,
T.; Tormo, J . R.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. Alali,
F. Q.; Liu, X.-X.; McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504-540
and references therein.
(2) (a) Degli Esposti, M. Biochim. Biophys. Acta 1998, 1364, 222-
235. (b) Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura,
H.; McLaughlin, J . L. Biochim. Biophys. Acta 1998, 1365, 443-452.
(c) Degli Esposti, M.; Ghelli, A.; Ratta, M.; Cortes, D. Biochem. J . 1994,
301, 161-167. (d) Friedrich, T.; Van Heek, P.; Leif, H.; Ohnishi, T.;
Forche, E.; Kunze, B.; J ansen, R.; Trowitzsch-Kienast, W.; Ho¨fle, G.;
Reichenbach, H.; Weiss, H. Eur. J . Biochem. 1994, 219, 691-698.
(3) (a) Morre´, J . D.; De Cabo, R.; Farley, C.; Oberlies, N. H.;
McLaughlin, J . L. Life Sci. 1995, 56, 343-348. (b) Oberlies, N. H.; Croy,
V. L.; Harrision, M. L.; McLaughlin, J . L. Cancer Lett. 1997, 115, 73-
79. (c) Oberlies, N. H.; Chang, C.-J .; McLaughlin, J . L. J . Med. Chem.
1997, 40, 2102-2106.
(8) McLaughlin, J . L. In Methods in Plant Biochemistry; Hostett-
mann, K., Ed.; Academic Press: London, 1991; Vol. 6, pp 1-35.
(9) For recent total synthesis of THF acetogenins, see: (a) Hu, T.-
S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J . Org. Chem. 2001, 66, 853-861. (b)
Maezaki, N.; Kojima, N.; Sakamoto, A.; Iwata, C.; Tanaka, T. Org. Lett.
2001, 3, 429-432. (c) Dixon, D. J .; Ley, S. V.; Reynolds, D. J . Angew.
Chem., Int. Ed. 2000, 39, 3622-3626. (d) Emde, U.; Koert, U. Eur. J .
Org. Chem. 2000, 1889-1904. (e) Hu, T.-S.; Wu, Y.-L.; Wu, Y. Org.
Lett. 2000, 2, 887-889. (f) Yu, Q.; Wu, Y.; Ding, H.; Wu, Y.-L. J . Chem.
Soc., Perkin Trans. 1 1999, 1183-1188. (g) Sinha, S. C.; Sinha, S. C.;
Keinan, E. J . Org. Chem. 1999, 64, 7067-7073. (h) Yu, Q.; Yao, Z.-J .;
Chen, X.-G.; Wu, Y.-L. J . Org. Chem. 1999, 64, 2440-2445. (i) Sinha,
A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Org. Chem. 1999, 64, 2381-
2386. (j) Marshall, J . A.; J iang, H. J . Org. Chem. 1999, 64, 971- 975.
(k) Wang, Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron: Asymmetry 1999,
10, 667- 670. (l) Wang, Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron Lett.
1999, 40, 977-980. (m) Emde, U.; Koert, U. Tetrahedron Lett. 1999,
40, 5979-5982. (n) Hu, T.-S.; Yu, Q.; Lin, Q.; Wu, Y.-L.; Wu, Y. Org.
Lett. 1999, 1, 399-401 and references therein.
10.1021/jo020211h CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/09/2002
J . Org. Chem. 2002, 67, 5739-5752
5739

Takahashi and Nakata
SCHEME 1
three types of carbohydrates (7-9) was expected to be
quite useful for synthesizing 1 in enantiometrically pure
form.
F IGURE 1.
Syn th esis of th e THP F r a gm en t (4). A character-
istic structural feature of 1 should be the presence of the
3-hydroxy-2,6-cis THP ring system with a long side chain
at the C-2 position. For construction of such a ring
system, we planned to utilize a C-glycosidation method15
on a glycopyranolactone developed by Kishi et al. 2,3,4-
Tri-O-benzyl-D-galactopyranose 1016 was silylated [1.0
equiv of chloro tert-butyldiphenylsilane (TBDPSCl), imi-
dazole, DMF], and the resulting hemiacetal 11 was
oxidized under Swern’s conditions (DMSO, (COCl)2, CH2-
Cl2, -70 °C then Et3N, -70 to 0 °C) to give lactone 12a
in good yield (Scheme 2). Reaction of 12a with decylmag-
nesium bromide in ether at -78 °C followed by reduction
with triethylsilane in the presence of BF3‚Et2O proceeded
stereoselectively, giving C-glycoside 13a in 82% yield. In
derived carbonyl compounds.12 In contrast to our sub-
strate control approach, Keinan and Sinha et al.13 and
Koert et al.14 disclosed total synthesis of 1 based on the
reagent control.
Resu lts a n d Discu ssion
Our synthetic strategy directed toward 1 was based
on a convergent process which involves a Pd-catalyzed
cross-coupling reaction of the THP-THF segment 2 and
vinyl iodide 3 as illustrated in Scheme 1. The central core
2 can be further disconnected to THP aldehyde 4 and
ethynyl THF 5. Each compound would be synthesized
from D-galactose (7) and 2,5-anhydro-D-mannitol (8),
respectively. On the other hand, the C1-C2 bond cleavage
of γ-lactone 3 leads to olefin 6, which might be obtained
via stereoselective alkylation at the C-1 position of
L-rhamnose (9). The “chiron” approach starting from
1
the H NMR spectra of 13a , the signal corresponding to
the proton of H-2 was observed at 3.18 ppm as triplets
of doublet (J 2,3 ) 8.8 Hz). The large coupling constant
value of this proton indicates the compound having 2,6-
cis substituents on a six-membered ring. In this reaction
the corresponding R-isomer could not be isolated. The
high â-stereoselectivity would be explained by axial
attack of hydride to the intermediary oxonium ion (Figure
2).15 Debenzylation of 13a with 10% Pd/C under a
hydrogen atmosphere was accompanied by a little desi-
lylation and provided the desired triol 15 in 52% yield
along with tetraol 14 (36%). The latter was converted into
the former by resilylation. As loss of the TBDPS group
(10) (a) Crimmins, M. T.; Rafferty, S. W. Tetrahedron Lett. 1996,
37, 5649-5652. (b) Evans, P. A.; Roseman, J . D. Tetrahedron Lett.
1997, 38, 5249-5252. (c) Evans, P. A.; Murthy, V. S. Tetrahedron Lett.
1998, 39, 9627-9628. (d) Evans, P. A.; Murthy, V. S.Tetrahedron Lett.
1999, 40, 1253-1256. (e) Takahashi, S., Fujisawa, K., Sakairi, N.,
Nakata, T. Heterocycles 2000, 53, 1361-1370. (f) Hoppen, S.; Emde,
U.; Friedrich, T.; Grubert, L.; Koert, U. Angew. Chem., Int. Ed. 2000,
39, 2099-2102.
(11) Hanessian, S. In Total Synthesis of Natural Products ‘Chiron’
Approach; Pergamon Press: Oxford, 1983.
(12) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 723-
726 and 727-730.
(13) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha,
S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120, 11279-11284.
(14) Baurle, S.; Hoppen, S.; Koert, U. Angew. Chem., Int. Ed. 1999,
38, 1263-1266; Hoppen, S.; Baurle, S.; Koert, U. Chem. Eur. J . 2000,
6, 2382-2396.
(15) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976-4978.
(16) Eby, R.; Sondheimer, S. J .; Schuerch, C. Carbohydr. Res. 1979,
73, 273-276.
5740 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (a) TBDPSCl (1.3 equiv), imidazole,
DMF, rt, 89%; (b) (COCl)2, DMSO, CH2Cl2, -70 °C and then Et3N,
-70 to 0 °C, quant.; (c) decylmagnesium bromide, Et2O, -78 °C;
(d) Et3SiH, BF3‚Et2O, CH2Cl2, -40 to -20 °C, 82% for 13a , 80%
for 13b; (e) 10% Pd/C, H2, EtOAc-MeOH, rt, 52% for 15 and 36%
for 14 from 13a ; (f) TBDPSCl (1.0 equiv), imidazole, DMF, rt, 85%
in two steps from 13b; (g) HC(OMe)3, CSA, CH2Cl2, rt, and then
Ac2O, 135 °C, 66%; (h) 10% Pd/C, H2, EtOAc, rt; (i) NaOMe, MeOH,
rt; (j) MOMCl, i-Pr2NEt, CH2Cl2, 0 °C to room temperature; (k)
TBAF, THF, rt, 93% from 16 in four steps.
a
Reagents and conditions: (a) PivCl, pyridine, 0 °C to room
temperature; (b) TBDMSCl, imidazole, DMF, rt, 69% from 8 for
19a ; TBDPSOTf, 2,6-lutidine, CH2Cl2, rt, 64% from 8 for 19b;
BnBr, NaH, n-Bu4NI, DMF, 0 °C, 39% from 8 for 19c; (c) LAH,
Et2O, 0 °C, 71% for 22; (d) TrCl (1.1 equiv), 2,6-di-tert-butyl-4-
methylpyridine or 2,6-lutidine, CH2Cl2, -20 °C to room temper-
ature, 51-68% based on the SM consumed; (e) TrCl, pyridine, rt,
and then TBDMSCl, imidazole, rt, 92%; (f) Et2AlCl (2.3 equiv),
hexane, -78 to 0 °C, 83%; (g) (COCl)2, DMSO, CH2Cl2, -70 °C
and then Et3N, -70 to 0 °C, quant.
controlled elongation by a two-carbon unit at the side
chain of the 2-formyl-5-(1-trityloxymethyl)THF derivative
23 as a key step.19 The compound was prepared from a
commercially available 2,5-anhydro-D-mannitol (8) through
a unique desymmetrization as shown in Scheme 3.
Compound 8 was treated with pivaloyl chloride (2.1 mol
equiv) in pyridine, and the resulting diol 18 was subjected
to silylation [chloro tert-butyldimethylsilane (TBDMSCl),
imidazole, DMF] to afford fully protected compound 19a
in 69% yield. We expected the bulky silyl protecting
groups introduced at the oxygen functions would prevent
unfavorable chelation of C-3, -4 oxygen moieties with a
metal in the stereocontrolled ethynylation.21 Upon treat-
ment with lithium aluminum hydride (LAH), 19a gave
diol 22 in 71% yield. Monotritylation of 22 was achieved
with trityl chloride (1.1 mol equiv) in the presence of 2,6-
F IGURE 2.
was found to be not suitable for large-scale preparation
of 15, a more practical route starting from the benzyl
analogue 12b17 was developed. As expected, C-glycosi-
dation of 12b under the same conditions also gave only
the â-isomer 13b in 80% yield. Hydrogenation and
silylation of 13b provided 15 in 85% yield. Regioselective
deoxygenation of 15 was achieved by Ando’s protocol.18
Thus, 15 was treated with trimethyl orthoformate in the
presence of d-camphorsulfonic acid, and the resulting
ortho esters were, without purification, heated in acetic
anhydride at 135 °C, giving allyl acetate 16 in 66% yield.
This compound was converted into alcohol 17 in 93%
overall yield by the following sequence: (1) hydrogenation
of a double bond, (2) deacetylation with sodium methox-
ide, (3) methoxymethylation with methoxymethyl (MOM)
chloride and N,N-diisopropylethylamine, (4) desilylation
with tetrabutylammonium fluoride (TBAF). Swern oxida-
tion of 17 gave the building block 4 in almost quantitative
yield.
(19) Reaction of 5b 20 with lithium trimethylsilylacetylide or eth-
ynylmagnesium chloride in ethereal solvent resulted in a 1:1 to 1:3
mixture of the corresponding ethynyl alcohols. The selectivity was not
improved even if in the presence of additives such as zinc, copper, and
lithium salt. Recently, the paper has appeared dealing with the similar
results.9c On the other hand, Koert et al. reported that reaction of 5b
with alkyl Grignard reagents in the presence of CuBr gave R-chelation-
controlled products in high diastereoselectivity (∼90% de).20
Syn th esis of th e THF F r a gm en t (5a ). The central
core of 1 consists of a threo-trans-THF ring system. Our
synthetic approach to the core system included stereo-
(17) This compound was prepared from a commercially available
methyl R-D-galactopyranoside in three steps with 55% overall yield,
see ref 15.
(20) Koert, U.; Stein, M.; Wagner, H. Liebigs Ann. 1995, 1415-1426.
(21) Takahashi, S.; Kuzuhara, H.; J . Chem. Soc., Perkin Trans. 1
1997, 607-612.
(18) Ando, M.; Ohhara, H.; Takase, K. Chem. Lett. 1986, 879-882.
J . Org. Chem, Vol. 67, No. 16, 2002 5741

Takahashi and Nakata
TABLE 1. Nu cleop h ilic Ad d ition to th e Ald eh yd es 23a -c
entry
compd
conditionsa
ratio (24/25)
yield (%)
1
23a
23a
23a
23a
23b
23b
23b
23c
23c
23c
HCtCMgCl, THF-Et2O, 0 °C
HCtCMgCl, ZnCl2, CH2Cl2-Et2O-THF, -78 °C
HCtCMgCl, ZnCl2, Et2O-THF, -78 °C
TMSCtCLi, THF, 0 °C
HCtCMgCl, THF-Et2O, 0 °C
HCtCMgCl, ZnCl2, Et2O-THF, -78 °C
TMSCtCLi, THF, 0 °C
HCtCMgCl, THF-Et2O, 0 °C
HCtCMgCl, ZnCl2, Et2O-THF, -78 °C
TMSCtCLi, THF, 0 °C
78/22
93/7
72
2
70
3
89/11
66/34
36/64
58/42
29/71
25/75
66/34
42/58
63
4
47b
69
5
6
47
7
53b
83
8
9
40
10
70b
a
b
6.0-10 mol equiv of organometallic reagent and ZnCl2 (3.0 mol equiv) were employed. After workup, the crude product was treated
with K2CO3 in methanol before purification.
lutidine or 2,6-di-tert-butyl-4-methylpyridine to furnish
monotrityl alcohol 20a (68%, based upon 22 consumed).
In contrast to the monotritylation, selective detritylation
gave a quite promising result as follows. Successive
treatment of 8 with trityl chloride and TBDMSCl in one-
pot manner gave fully protected THF 21 in 92% yield.
Deprotection of 21 using diethylaluminum chloride22 (2.3
mol equiv) in hexane at -78 to 0 °C proceeded cleanly,
giving 20a in 83% yield. Production of the corresponding
diol 22 was revealed to be a trace amount by judging TLC
analyses. It should be noted that this reaction is strongly
solvent dependent. For example, deprotection reaction in
CH2Cl2 resulted in a mixture of 20a and 22. Precipitation
of the monoaluminum alkoxide complex derived from 21
may cause the selectivity. In this way, desymmetrization
of 8 was efficiently established [75% yield from 8 via 21
(2 steps) vs 35% yield in four steps for the previous route].
The alcohol 20a was transformed into aldehyde 23a using
the Swern oxidation in a quantitative yield. To examine
the effect of hydroxy protecting groups in the ethynyla-
tion, the TBDPS and benzyl analogues 23b and 23c were
also prepared through 19b,c and 20b,c from 8 in the
same way.
entries and moderately good. The best result was ob-
tained by using 23a and ethynylmagnesium chloride in
the presence of ZnCl2 in dichloromethane-ether-THF
to give a 93:7 mixture of the desired â-alcohol 24a and
its epimer 25a in 70% yield. These isomers could be easily
separated by chromatography on silica gel, and their
stereochemistry was determined by the modified Mosh-
er’s method23 of the corresponding MTPA esters.24 The
stereoselective formation of compound 24a (entry 2,3)
would be explained by the formation of cyclic chelate
involving the aldehyde carbonyl and the ring oxygen as
shown in Figure 3A.25 On the other hand, addition of
ZnCl2 did not improve the selectivity in the case of 23b,c
(entries 6 and 9). Therefore, we estimated that the
addition to 23b or 23c (entry 5,7,8, and 10) proceeded in
accordance with Cram’s rule through a transition state
corresponding to the Felkin-Anh model (Figure 3B)26
rather than the chelate-controlled addition. However, the
possibility of competing â-chelation also cannot be ruled
out as several examples were reported in the literature.27
SCHEME 4a
F IGURE 3.
The alcohol 24a thus obtained was converted into the
corresponding MOM ether 5a 28 and employed to the next
coupling reaction.
(23) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.
(24) Differences in the chemical shifts (∆S-R values in δ (500 MHz,
CDCl3)) between (R)- and (S)-MTPA esters of 24a are as follows; H-2
(+0.06), H-3 (+0.01), H-4 (-0.01), H-5 (+0.02), H-1′ (-0.07), H-3′
(-0.07), H2-1′′ (+0.06, +0.02). In addition, the stereochemistry of 24b,c
and 25b,c was determined by the correlation with 24a ,25a and 5a .
a
Reagents and conditions: (a) See Table 1; (b) MOMCl,
i-Pr2NEt, CH2Cl2, 0 °C to room temperature, 90%.
(25) Wolfrom, M. L.; Hanessian, S. J . Org. Chem. 1962, 27, 1800-
1804.
(26) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205-
2208. Anh, N. T.; Eisenstein, O. E. Nouv. J . Chem. 1977, 1, 61. Anh,
N. T. Top. Curr. Chem. 1980, 88, 145.
(27) For example, Izumi, M.; Tsuruta, O.; Hashimoto, H. Carbohydr.
Res. 1996, 280, 287- 302. Giuliano, R. M.; Villani, F. J ., J r.; J . Org.
Chem. 1995, 60, 202-211.
(28) When 24a was employed to the coupling reaction with 4, the
silyl migration occurred.
Having three types of aldehyde 23a -c, we investigated
stereoselective ethynylation (Scheme 4). As shown in
Table 1, the ratio of produced Cram and anti-Cram
compounds varied in a wide range depending on the kind
of the protecting group and the reagent employed,
whereas chemical yields were in a narrow range in all
(22) Koster, H.; Sinha, N. D. Tetrahedron Lett. 1982, 23, 2641-2644.
5742 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
Syn th esis of th e C10-C34 Segm en t (2). As we could
secure two components (4 and 5a ) needed for synthesis
of 2, the condensation reaction was examined (Scheme
5). Initial attempts to react 4 with a lithium or magne-
sium reagent derived from 5a resulted in low-moderate
yield of the coupled product 26 as an inseparable mixture
F IGURE 4.
29
(Table 2). In contrast, addition of anhydrous CeCl3 to
the solution of the lithium acetylide prior to addition of
4 gave 26 in good yield (78%). 1H NMR analyses,23
however, revealed that the major isomer was an un-
desired â-alcohol (86% de).30 In these cases, it would be
reasonable to assume a transition state as shown in
Figure 4. After further experimentation, the correspond-
ing saturated isomers (28 and 29) obtained after hydro-
genation were found to be readily separated by column
chromatography on silica gel. Furthermore, highly ste-
reoselective production of compound 28 was realized by
Our attention was next turned to deoxygenation of the
THF ring with two oxygen functionality, which could
provide a clue for preparing novel analogues of 1.33 Prior
to the deoxygenation, the 19-hydroxyl group in 28 was
protected as MOM ether (Scheme 6). Cleavage of the silyl
SCHEME 6a
SCHEME 5a
a
Reagents and conditions: (a) See Table 2; (b) 5% PtO2, H2,
EtOAc, rt; (c) TPAP, NMO, MS4A, CH2Cl2, rt, 97% from 26 in two
steps; (d) L-Selectride, THF, -78 °C, 94% (28/29 ) 24/1).
a
Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, 0 °C
to room temperature; (b) TBAF, THF, rt, 92% from 28 in two steps;
(c) MsCl, Et3N, CH2Cl2, 0 °C to room temperature; (d) Zn, NaI,
DMF, 140 °C; (e) 10% Pd/C, H2, EtOAc, rt; (f) aq AcOH, 50 °C,
74% from 31 in four steps; (g) (COCl)2, DMSO, CH2Cl2, -70 °C
and then Et3N, -70 to 0 °C, quant.; (h) Ph3P, CBr4, Et3N, CH2Cl2,
0 °C, 78% from 35 in two steps; (i) EtMgBr (2.1 equiv), THF, -5
°C, 97%.
TABLE 2. Cou p lin g Rea ction betw een 4 a n d 5a
entry
conditionsa
ratio (R/â)b
yield (%)
1
2
3
4
n-BuLi, LiI, Et2O, -78 °C
EtMgBr, Et2O, -78 °C
n-BuLi, Et2O, -12 to 0 °C
n-BuLi, CeCl3, THF, -78 °C
40/60
25/75
20/80
7/93
23
66
59
78
a
1.6-2.0 mol equiv of organometallic reagent was employed.
protecting groups in 30 with TBAF yielded diol 31 in 92%
yield from 28. Treatment of 31 with methanesulfonyl
chloride-triethylamine afforded dimesylate 32, which
The ratio was determined by 1H NMR analyses (400 MHz).
b
using a simple two-step oxidation-reduction sequence of
the mixture. Thus, the mixture of reduction products
(28/29 ) ca. 7/93) was oxidized by n-tetrapropylammo-
nium perruthenate in the presence of N-methylmorpho-
line N-oxide,31 and then the corresponding ketone 27 was
reduced with L-Selectride in THF at -78 °C to afford the
desired R-alcohol 28 in high yield (88% from 26) and its
isomer 29 (3%).32 This simple procedure made possible
the efficient installation of the C-19 stereochemistry.
(30) Differences in the chemical shifts (∆S-R values of major isomer
in δ (400 MHz, CDCl3))between (R)- and (S)-MTPA esters of 26 are as
follows; H2-1 (+0.01, +0.02), H-2 (+0.00), H-3 (+0.02), H-4 (+0.02),
H-5 (+0.03), H-6 (+0.01), H-9 (+0.01), H-10 (- 0.06), H2-11 (-0.15,
-0.06), H2-12 (-0.02, -0.06), H-13 (-0.09), H-14 (-0.09), H2-15 (-0.26,
-0.05).
(29) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
25, 4233-4236. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura,
Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49,
3904-3912.
(31) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627.
(32) Reduction of 27 with Zn(BH4)2 in ether at -10 °C gave 29
predominantly (28/29 ) 6/94, total 98% yield).
J . Org. Chem, Vol. 67, No. 16, 2002 5743

Takahashi and Nakata
TABLE 3. Nu cleop h ilic Ad d ition to th e Hem ia ceta l 40
was subjected to a reductive elimination by using sodium
iodide-zinc powder34 in DMF at 130 °C to furnish olefin
33. Hydrogenation followed by detritylation of 34 under
acidic conditions produced alcohol 35 in 74% overall yield
in four steps. After Swern oxidation of 35, the resulting
ratio
yield
entry
conditionsa
{42(45)/43(46)} (%)
1
2
3
41, n-BuLi, Et2O, -78 °C to rt
41, n-BuLi, toluene, -78 °C to rt
41, n-BuLi, hexane-Et2O (3:1),
-78 °C to rt
20/80
33/67
14/86
73
66
78
35
aldehyde 36 reacted with (MeO)2P(O)C(N2)COCH3 in
the presence of potassium carbonate to give terminal
acetylene 2 in 63% yield. On the other hand, a two-step
sequence36 via dibromoolefin 37 afforded a somewhat
higher overall yield (76% from 35) than that in the
foregoing procedure. Thus, 36 was treated with triph-
enylphosphine-carbon tetrabromide in the presence of
triethtylamine to give 37 in 78% yield. The olefination
in the absence of triethylamine resulted in a mixture of
demethoxymethylated products. Upon treatment with 2.1
equiv of n-butyllithium, 37 led to 2 in 60% yield, while
the use of ethylmagnesium bromide (2.1 equiv) as a base
gave 97% yield of 2.
Syn th esis of th e C1-C9 Segm en t (3). As a γ-hydroxy
butenolide unit such as the right-half segment 3 is a key
building block for synthesis of annonaceous acetogenins,
several methods for the preparation of such subunit have
been devised. However, the synthetic examples reported
so far have mainly relied on aldol addition of γ-alkyloxy
esters with a chiral aldehyde or alkylation with an optical
active terminal epoxide or a chiral γ-lactone.37 Our new
synthetic approach to 3 was based on a radical cycliza-
tion38 of acyclic selenocarbonate 6.39 Synthesis began with
methanolysis of phenyl 5-O-acetyl-2,3-O-isopropylidene-
1-thio-L-rhamnofuranoside 38, which was synthesized
from L-rhamnose (9) in three steps.40 The 2,3-O-isopro-
pylidene group was expected to function as not only a
foothold for 1,2-asymmetric induction but also the equiva-
lent of olefin needed in the later radical cyclization. After
protection of the hydroxy group in 39 as a methoxyphe-
nylmethyl (MPM) ether, the furanoside was treated with
N-bromosuccinimide to afford 40 in 85% yield (Scheme
7). Stereoselective introduction of the C4-side chain into
40 was examined under several conditions (Table 3).
Reaction of 40 with the lithium reagent obtained from
4141 in ether gave the desired alcohol 4342 and its epimer
42 in 58 and 15% yield, respectively. Furthermore, the
use of a mixed solvent system (hexane-ether ) 3:1) was
effective; 67% yield of 43 was attained along with 42
4
5
6
41, n-BuLi, LiI, Et2O, -78 °C to rt
41, n-BuLi, MgBr2, Et2O, -78 °C to rt
41, n-BuLi, CeCl3, Et2O-HMPA,
-78 °C to rt
41, n-BuLi, Et2O-HMPA, -78 °C to rt
41, EtMgBr, Et2O, -78 °C to rt
44, hexane-Et2O (5:4), -78 °C to rt
29/71
45/55
24/76
79
21
41
7
8
9
6/94
81/19
18/82
42
79
65
a
3.0-4.0 mol equiv of silyl ether and organometallic reagent
(2.9-3.8 mol equiv) were employed.
(11%). Addition of HMPA markedly improved the ste-
reoselectivity (42/43 ) 6/94), but was not so practical due
to the low yield (42%). On the other hand, reverse
diastereofacial selectivity (42/43 ) 81/19) was observed
when the corresponding magnesium derivative was
employed. The minor alcohol 42 could be taken back to
the desired isomer 43 in 72% overall yield by a two-step
sequence (1. MnO2 oxidation, 2. NaBH4-CeCl3‚7H2O).
The difference in these stereoselectivities would be
explained by two types of chelation as shown in Figure
5. According to this explanation, the use of more hindered
alkyllithium was expected to increase the selectivity.
However, reaction with the alkyllithium derived from
4443 gave a similar result (45/46 ) 18/82, 65% yield).44
F IGURE 5.
For further transformation, the two hydroxy groups in
43 were protected as MOM ether (90%), and the resulting
triple bond in 47 was hydrogenated over 5% Rh/Al2O3,
giving 48 in 95% yield. Exposure of this to mild acidic
conditions led to removal of the acetonide group, giving
49 in 73% yield along with triol 50 (23%). The latter was
taken back to the former by monosilylation (89%). Deoxy-
genation of 49 via the corresponding ortho ester afforded
Z-olefin 51 in 87% yield. After debenzylation of 51 with
DDQ,45 the resulting alcohol 52 was transformed into
selenocarbonate 6 according to Corey’s procedure38 (1.
(CCl3O)2CO,46 pyridine; 2.PhSeH, Et3N). Radical cycliza-
(33) Several THF acetogenins carrying a hydroxyl group on the THF
ring have been recently isolated, see: (a) mucoxin;4 (b) goniotriocin:
Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J . L. J . Nat. Prod. 1999,
62, 31-34.
(34) Tipson, R. S.; Cohen, A.; Carbohydr. Res. 1965, 1, 338-340.
(35) Muller, S.; Liepold, B.; Roth, G. J .; Bestmann, H. J . Synlett
1996, 521-522.
(36) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(37) For example, see: (a) Hoye, T. R.; Hanson, P. R. Tetrahedron
Lett. 1993, 34, 5043-5046. (b) Yao, Z.-J .; Wu, Y.-L. Tetrahedron Lett.
1994, 35, 157-160. (c) Koert, U. Tetrahedron Lett. 1994, 35, 2517-
2520. (d) Hoye, T. R.; Humpal, P. E.; J imenez, J . I. Mayer, M. J .; Tan,
L.; Ye, Z. Tetrahedron Lett. 1994, 35, 7517-7520. (e) Hanessian, S.;
Grillo, T. A. J . Org. Chem. 1998, 63, 1049-1057. (f) Schaus, S. E.;
Branalt, J .; J acobsen, E. N.; J . Org. Chem. 1998, 63, 4876-4877, and
references therein.
(42) Differences in the chemical shifts (∆S-R values in δ (500 MHz,
CDCl3)) between (R)- and (S)-MTPA esters of 43 are as follows; H2-1
(+0.05), H2-2 (+0.04), H-5 (-0.03), H-6 (-0.10), H-7 (-0.14), H-8
(-0.17), H-9 (-0.05), H-10 (-0.01), Me2-C (-0.04, -0.08).
(38) Singh, A. K.; Bakshi, R. K.; Corey, E. J . J . Am. Chem. Soc. 1987,
109, 6187-6189.
(43) McGarvey, G. J .; Stepanian, M. W. Tetrahedron Lett. 1996, 37,
5461-5464.
(39) A similar radical approach was also reported by Evans and
Murthy; see ref 10c.
(44) The structure was determined by transformation of 46 into the
corresponding MOM ether 48.
(40) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J . Am. Chem.
Soc. 1983, 105, 2430-2434.
(41) Nicolaou, K. C.; Petasis, N. A.; Li, W. S.; Ladduwahetty, T.;
Randall, J . L.; Webber, S. E.; Hernandez, P. E. J . Org. Chem. 1983,
48, 5400-5403.
(45) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888.
(46) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26,
894-895.
5744 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
SCHEME 7a
a
Reagents and conditions: (a) NaOMe, MeOH, rt, quant.; (b) MPMCl, NaH, n-Bu4NI, DMF, 0 °C, and then N-bromosuccinimide, aq
THF, 0 °C, 85% in two steps; (c) see Table 3; (d) MnO2, CH2Cl2, rt, and then NaBH4, CeCl3‚7H2O, MeOH, 0 °C, 72%; (e) MOMCl, i-Pr2NEt,
CH2Cl2, 0 °C, 90%; (f) 5% Rh/Al2O3, H2, EtOAc, rt, 95%; (g) aq AcOH, rt, 73% for 49 and 23% for 50; (h) TBDPSCl, imidazole, DMF, 0 °C,
89%; (i) HC(OMe)3, CSA, CH2Cl2, rt, and then Ac2O, 135 °C, 87% in two steps; (j) DDQ, aq CH2Cl2, 0 °C, 89%; (k) triphosgene, pyridine,
CH2Cl2, 0 °C, and then PhSeH, Et3N, 78% in two steps; (l) Bu3SnH, AIBN, toluene, 100 °C, 86% for 53 and 4% for 54; (m) TBAF, AcOH,
THF, rt, and then DBU, CH3CN, -10 °C, 60% in two steps; (n) (COCl)2, DMSO, CH2Cl2, -70 °C and then Et3N, -70 to 0 °C, 88%; (o)
CHI3, CrCl2, THF, 0 °C to room temperature, 84%.
was employed to the next step. The TBDPS group in 53
was removed by TBAF in the presence of acetic acid, and
then the resulting alcohol was treated briefly with DBU
in acetonitrile at -10 °C, affording butenolide 55 in 60%
yield from 53. Partial epimerization at C-5 was observed
when the elimination reaction was conducted in THF at
room temperature. After Swern oxidation of 55, the
aldehyde was subjected to a vinyl iodide formation48 with
chromous chloride and iodoform, affording the right-half
segment 3 as a 4.5:1 mixture of E/ Z isomers in 74% yield.
Tot a l Syn t h esis of Mu cocin (1). The complete
carbon skeleton of 1 was assembled by joining 2 and 3
in the presence of (PPh3)2PdCl2 and CuI in triethyl-
amine49 to give a labile enyne 56 in 79% yield. This
underwent regioselective reduction with Wilkinson’s
catalyst in benzene-ethanol to give fully protected mu-
F IGURE 6.
cocin 57 in 70% yield (Scheme 8). Finally, all of the MOM
groups in 57 were cleaved by BF3‚Et2O in methyl sulfide50
tion of 6 with tributyltin hydride (Bu3SnH) in toluene at
to give mucocin (1), whose spectral properties were
100 °C proceeded nicely to give 3,4-trans-γ-lactone 53 and
indistinguishable from those of the natural product.
3,4-cis-isomer 54 in 86 and 3% yield, respectively. These
relative stereochemistry were established by the NMR
analyses together with the difference NOE experiments.
The 3,4-trans stereoselection in the radical cyclization
(47) J ohnson, F.; Malhotra, S. K. J . Am. Chem. Soc. 1965, 87, 5492-
5493. Malhotra, S. K.; J ohnson, F. J . Am. Chem. Soc. 1965, 87, 5493-
5495.
would result from reaction of the acyl radical through a
transition state (A) rather than B because of an allylic
strain47 (Figure 6). Although both isomers could be a key
intermediate for preparation of 3, the major isomer 53
(48) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408-7410.
(49) Hoye, T. R.; Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801-1802.
(50) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J .
Org. Chem. 1995, 60, 4419-4427.
J . Org. Chem, Vol. 67, No. 16, 2002 5745

Takahashi and Nakata
SCHEME 8a
a
Reagents and conditions: (a) (Ph3P)2PdCl2, CuI, Et3N, rt, 78%; (b) (Ph3P)3RhCl, H2, benzene-EtOH (6:1), rt, 70%; (c) BF3‚Et2O,
Me2S, -10 to 0 °C, 77%.
Analytical sample was prepared by chromatography on silica
gel with CHCl3-MeOH (10:1) as the eluent.
In conclusion, total synthesis of mucocin (1) based on
a substrate control was achieved in 30 steps with 3.4%
overall yield from methyl R-D-galactopyranoside; the
chiral centers C-20 (S) and C-23 (R) of 1 were derived
from 7, C-12 (R) and C-15 (S) from 8, and C-36 (S) from
9, respectively, while the stereochemistry at C-4 (R), C-16
(S), C-19 (S), and C-24 (S) were mainly constructed by a
1,2-asymmetric induction derived from the preexisting
chirality in the substrate. The strategy described herein
should be applicable to preparation of pharmacologicaliy
important analogues of 1.
14: [R]27D -0.72° (c 0.14, MeOH); IR (KBr) 3400, 3332, 2918,
2850, 1093, 1080, 1046, 989 cm-1; 1H NMR (400 MHz, MeOH-
d4) δ 0.89 (3H, t, J ) 6.8 Hz), 1.03-1.45 (16H, m), 1.58 (1H,
m), 1.83 (1H, m), 3.04 (1H, brt, J ) 8.8 Hz), 3.32-3.43 (3H,
m), 3.65 (1H, dd, J ) 12, 5.9 Hz), 3.69(1H, dd, J ) 12, 6.8 Hz),
3.85 (1H, brd, J ) 2.0 Hz); 13C NMR (100 MHz, MeOH-d4) δ
14.4, 23.7, 26.6, 30.4, 30.7, 30.8, 32.8, 33.0, 62.7, 70.8, 72.8,
76.5, 80.1, 81.5. Anal. Found: C, 62.91; H, 10.44. Calcd for
C
16H32O5: C, 63.13; H, 10.60.
(2R ,3R ,4S ,5R ,6S )-2-(1-t er t -Bu t yld ip h e n ylsilyl)oxy-
m eth yl-3,4,5-tr ih yd r oxy-6-d ecyltetr a h yd r op yr a n (15). To
a stirred solution of 14 (6.75 g) and imidazole (4.53 g, 66.6
mmol) in DMF (100 mL) was added chloro tert-butyldiphenyl-
silane (5.77 mL, 22.2 mmol), and then the mixture was stirred
at room temperature for 18 h. After addition of ice-water, the
resulting mixture was directly concentrated, diluted with CH2-
Cl2 (100 mL), washed successively with water, cold dil HCl
solution, sat. NaHCO3 solution, water, and brine, dried, and
concentrated. Chromatography on silica gel with toluene-ethyl
acetate (1:1) and then CHCl3-MeOH (20:1) as the eluent
Exp er im en ta l Section
(2R,3R,4S,5R,6S)-3,4,5-Tr ib en zyloxy-2-(1-b en zyloxy-
m eth yl)-6-d ecyltetr a h yd r op yr a n (13b). To a stirred solu-
tion of 12b (1.19 g, 2.21 mmol) in ether (21 mL) was added
dropwise a solution of decylmagnesium bromide (1.0 M solu-
tion in ether, 2.65 mL) at -78 °C, and the mixture was stirred
at the same temperature for 2.5 h. Saturated aqueous NH4Cl
was added at -78 °C with vigorously stirring, and then the
resulting mixture was extracted with ether (20 mL × 2). The
extracts were washed successively with water, brine, dried,
and concentrated to give a syrup (1.60 g), which was dissolved
in CH2Cl2 (27 mL). To the stirred solution was added dropwise
BF3‚Et2O (0.28 mL, 2.21 mmol) and triethylsilane (1.76 mL,
11.1 mL) at -40 °C, and then the mixture was stirred at -30
to -40 °C for 3.5 h. Saturated aqueous NaHCO3 was added,
and the resulting mixture was stirred at -30 °C f rt for 1 h,
extracted with CH2Cl2 (30 mL × 2). The extracts were washed
with water, brine, dried, and concentrated. Chromatography
on silica gel with hexane-ether (8:1) as the eluent yielded 13b
yielded 15 (10.4 g, 85% in 2 steps): [R]27 -0.58° (c 1.72,
D
CHCl3); IR (neat) 3400, 3080, 2930, 1430, 1118, 1080, 703 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J ) 6.8 Hz), 1.06
(9H, s), 1.21-1.40 (15H,m), 1.42-1.62 (2H, m), 1.81-1.91 (1H,
m), 3.10 (1H, td, J ) 8.8, 8.8, 2.0 Hz), 3.43 (1H, brt, J ) 5.2
Hz), 3.47 (1H, dd, J ) 9.3, 2.9 Hz), 3.52 (1H, dd, J ) 9.3, 8.7
Hz), 3.40-3.75 (2H, brs), 3.85-3.95 (2H, m), 4.08 (1H, brd, J
) 2.5 Hz), 4.16-4.38 (1H, brs), 7.36-7.43 (6H, m), 7.69-7.73
(4H, m); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.1, 22.7, 25.6,
26.8, 29.3, 29.6, 29.7, 29.8, 31.9, 64.1, 70.4, 72.0, 75.8, 77.5,
79.9, 127.7, 129.8, 132.9, 133.1, 135.5, 135.6; HRMS calcd for
C
32H51O5Si [M + H]+ 543.3506, found 543.3512. Anal. Found:
(1.17 g, 80%): [R]27 -5.9° (c 0.36, CHCl3); IR (neat) 3064,
C, 70.76; H, 9.56. Calcd for C32H50O5Si: C, 70.80; H, 9.28.
D
3031, 2924, 1454, 1117, 1101, 733 cm-1; H NMR (400 MHz,
1
(2S,5R,6S)-2-(1-ter t-Bu t yld ip h en ylsilyl)oxym et h yl-5-
a cetoxy-6-d ecyl-3,4-d ih yd r op yr a n (16). To a stirred mix-
ture of 15 (129 mg, 0.24 mmol) and trimethyl orthoformate
(0.26 mL, 2.38 mmol) in CH2Cl2 (1.0 mL) was added d-
camphorsulfonic acid (3.1 mg, 0.01 mmol). The mixture was
stirred at room temperature for 3 h, and then diluted with
ether (10 mL), washed with sat. NaHCO3 solution, water,
brine, dried, and concentrated to give a 4:1 mixture of the
corresponding ortho esters (151 mg): 1H NMR (500 MHz,
CDCl3) δ 0.87 (3H, t, J ) 6.8 Hz), 1.06 (9H, s), 1.21-1.43 (16H,
m), 1.58 (1H, m), 1.77 (1H, m), 2.15 (0.8H, d, J ) 3.9 Hz), 2.21
(0.2H, d, J ) 3.9 Hz), 3.03 (0.2H, m), 3.05 (0.8H, ddd, J ) 9.3,
8.8, 2.4 Hz), 3.30-3.35 (1H, m), 3.33 (2.4H, s), 3.38 (0.6H, s),
3.72 (0.2H, ddd, J ) 6.9, 6.3, 2.0 Hz), 3.79 (0.8H, ddd, J ) 7.4,
6.8, 2.0 Hz), 3.85-3.93 (2H, m), 4.01 (0.2H, dd, J ) 7.4, 5.4
Hz), 4.19 (0.8H, dd, J ) 7.4, 5.4 Hz), 4.22 (0.2H, dd, J ) 5.8,
2.0 Hz), 4.38 (0.8H, dd, J ) 5.3, 2.0 Hz), 5.73 (0.2H, s), 5.80
(0.8H, s), 5.94 (1H, dt, J ) 10, 1.5, 1.5 Hz), 7.35-7.42 (6H,
m), 7.67-7.70 (4H, m), which was heated in acetic anhydride
(1.5 mL) at 130 °C with stirring for 7 h, concentered and
coevaporated with xylene (× 5). Chromatography on silica gel
CDCl3) δ 0.92 (3H, t, J ) 6.8 Hz), 1.22-1.38 (15H, m), 1.46-
1.63 (2H, m), 1.87 (1H, m), 3.23 (1H, ddd, J ) 8.8, 8.8, 2.4
Hz), 3.54 (1H, t, J ) 6.4 Hz), 3.58-3.64 (3H, m), 3.70 (1H, t,
J ) 9.3 Hz), 4.01 (1H, brd, J ) 2.4 Hz), 4.46, 4.52 (2H, each d,
J ) 11.7 Hz), 4.68, 4.98 (2H, each d, J ) 11.7 Hz), 4.71, 4.79
(2H, each d, J ) 11.7 Hz), 7.29-7.53 (20H, m); 13C NMR (100
MHz, CDCl3) δ 14.1, 22.7, 25.7, 29.3, 29.6, 31.9, 69.1, 72.2,
73.5, 73.7, 74.4, 75.5, 77.3, 79.3, 79.8, 84.9, 127.5, 127.6, 127.7,
127.8, 128.1, 128.2, 128.3, 128.4, 138.0, 138.4, 138.5, 138.8.
Anal. Found: C, 79.40; H, 8.77. Calcd for C44H56O5: C, 79.48;
H, 8.49.
(2R,3R,4S,5R,6S)-2-Hyd r oxym eth yl-3,4,5-tr ih yd r oxy-6-
d ecyltetr a h yd r op yr a n (14). A mixture of 13b (15.0 g, 22.6
mmol) and 10% Pd/C (1.25 g) in methanol-ethyl acetate (1:1,
70 mL) was vigorously stirred at room temperature for 4 d
under hydrogen atmosphere, filtered through a pad of Celite.
The Celite pad was washed thoroughly with methanol. The
filtrate and washings were combined, concentrated, and then
coevaporated with toluene-pyridine to give 14 (6.75 g), which
was employed to the next step without further purification.
5746 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
with hexane-ethyl acetate (10:1) as the eluent yielded 16 (86.1
mg, 66%): [R]26D -90.2° (c 0.26, CHCl3); IR (neat) 3075, 2930,
Hz), 4.61, 4.72 (2H, each d, J ) 6.8 Hz), 9.63 (1H, brs); 13C
NMR (100 MHz, CDCl3) δ 14.1, 22.6, 25.2, 25.7, 29.3, 29.5,
29.6, 29.7, 31.8, 31.9, 55.6, 75.0, 80.7, 81.0, 95.4, 201.7; HRMS
calcd for C18H35O4 [M + H]+ 315.2535, found 315.2519.
1
1743, 1428, 1235, 1118, 1030, 700 cm-1; H NMR (400 MHz,
CDCl3) δ 0.88 (3H, t, J ) 6.8 Hz), 1.06 (9H, s), 1.21-1.34 (16H,
m), 1.43 (1H, m), 1.57 (1H, m), 2.08 (3H, s), 3.43 (1H, ddd, J
) 8.7, 8.7, 2.2 Hz), 3.60 (1H, dd, J ) 10, 6.3 Hz), 3.73 (1H, dd,
J ) 10, 5.9 Hz), 4.22 (1H, m), 5.09 (1H, m), 5.74 (1H, ddd, J )
10, 2.0, 2.0 Hz), 5.94 (1H, dt, J ) 10, 1.5, 1.5 Hz), 7.35-7.42
(6H, m), 7.67-7.70 (4H, m); 13C NMR (100 MHz, CDCl3) δ 14.1,
19.3, 21.2, 22.7, 25.2, 26.8, 29.3, 29.6, 31.9, 32.5, 66.3, 69.8,
75.6, 75.8, 119.4, 126.5, 127.6, 129.6, 130.6, 133.5, 133.6, 134.3,
135.6, 170.6. Anal. Found: C, 74.15; H, 9.23. Calcd for
(2R,3R,4R,5R)-3,4-Di-ter t-bu tyld im eth ylsilyloxy-2,5-d i-
(1-tr ityloxym eth yl)tetr a h yd r ofu r a n (21). To a stirred solu-
tion of 8 (1.64 g, 10.0 mmol) in pyridine (12 mL) was added
chloro triphenylmethane (5.85 g, 21 mmol) at room tempera-
ture, and then the mixture was stirred rt for 5 h. More chloro
triphenylmethane (0.59 g, 2.1 mmol) was added, and stirring
was continued for 3 h. The reaction mixture was diluted with
pyridine (12 mL). To this solution was added chloro tert-
butyldimethylsilane (6.78 g, 45 mmol) and imidazole (4.08 g,
60 mmol) at room temperature, and then the mixture was
stirred at rt for 3 h. After addition of ice-water, the mixture
was extracted with ether (30 mL × 3). The extracts were
washed successively with water, cold dil HCl solution, sat.
NaHCO3 solution, water and brine, dried, and concentrated.
Chromatography on silica gel with hexane-ethyl acetate (40:
C
34H50O4Si: C, 74.13; H, 9.15.
(2S,5R,6S)-2-H yd r oxym et h yl-5-m et h oxym et h yloxy-6-
d ecyltetr a h yd r op yr a n (17). A mixture of 16 (6.84 g, 12.4
mmol) and 10% Pd/C (0.67 g) in ethyl acetate-methanol (2:1,
30 mL) was vigorously stirred at room temperature for 8 h
under hydrogen atmosphere and filtered through a pad of
Celite. The Celite pad was washed thoroughly with ethyl
acetate. The filtrate and washings were combined, concen-
trated, and coevaporated with toluene to give a syrup (7.30
g), which was dissolved in methanol-CH2Cl2 (1:1, 50 mL).
Sodium methoxide (0.13 g, 2.4 mmol) was added to the
solution, and the mixture was stirred at room temperature for
4 d, made neutral with Dowex 50W X-8 (H+) resin. The
mixture was filtered and the filtrate evaporated, coevaporated
with toluene to give a syrup (7.02 g), which was dissolved in
CH2Cl2 (85 mL). To this solution were added N,N-diisopropyl-
ethylamine (17.3 mL, 99.3 mmol) and chloromethyl methyl
ether (4.72 mL, 62.1 mmol) at 0 °C, and then the mixture was
stirred at 0 °C to rt for 2 d. After addition of ice-water, the
resulting mixture was extracted with ether (30 mL × 2). The
extracts were washed successively with water, cold dil HCl
solution, sat. NaHCO3 solution, water and brine, dried, and
concentrated to give a syrup (7.03 g). To a stirred solution of
the syrup (7.03 g) in THF (40 mL) was added dropwise 1.0 M
solution of TBAF in THF (14 mL, 14 mmol) at room temper-
ature, and the mixture was stirred at room temperature for
18 h, concentrated. The residue was diluted with CH2Cl2. The
solution was washed with water, brine, dried, and concen-
trated. The residue was purified by chromatography on silica
gel with hexane-ethyl acetate (10:1f4:1) as the eluent to yield
1) as the eluent yielded 21 (8.11 g, 92%); [R]23 +1.8° (c 0.56,
D
CHCl3); IR (neat) 3060, 3033, 3023, 2929, 1597, 1491, 1471,
1448, 1251, 1088, 836 cm-1 1H NMR (400 MHz, CDCl3) δ
;
-0.08 (3H, s), -0.04 (3H, s), 0.72 (9H, s), 3.15 (1H, dd, J )
9.3, 5.8 Hz), 3.33 (1H, dd, J ) 9.3, 6.3 Hz), 4.01 (1H, brs), 4.13
(1H, brt, J ) 6.0 Hz), 7.20-7.28 (8H, m), 7.46-7.48 (7H, m);
13C NMR (100 MHz, CDCl3) δ -4.7, 17.7, 25.7, 64.8, 80.6, 86.0,
86.7, 126.9, 127.7, 128.9, 144.1. Anal. Found: C, 76.50; H, 7.91.
Calcd for C56H68O5Si2: C, 76.67; H, 7.81.
(2R,3R,4R,5R)-3,4-Di-ter t-bu tyld im eth ylsilyloxy-5-(h y-
dr oxym eth yl)-2-(1-tr ityloxym eth yl) tetr ah ydr ofu r an (20a)
fr om 21. To a stirred solution of 21 (268 mg, 0.31 mmol) in
hexane (4 mL) was added dropwise a solution of diethylalu-
minum chloride (0.7 mL, 1.0 M solution in hexane) at -78 °C,
and then the yellow color suspension was stirred at -78 °C
for 1 h and -78 f 0 °C for 3 h. After addition of sat. NaHCO3
solution at 0 °C, the resulting mixture was stirred vigorously
at 0 °C for 1 h and then extracted with dichloromethane (10
mL × 2). The extracts were washed successively with water
and brine, dried, and concentrated. Chromatography on silica
gel with hexane-ethyl acetate (6:1 f 4:1) as the eluent yielded
20a (160 mg, 83%): [R]26 +13.1° (c 1.10, CHCl3); IR (neat)
D
3469, 3060, 2954, 2930, 1471, 1449, 1252, 1092, 837 cm-1; 1H
NMR (300 MHz, CDCl3) δ -0.02 (3H, s), -0.01 (3H, s), 0.06
(3H, s), 0.09 (3H, s), 0.73 (9H, s), 0.88 (9H, s), 1.53 (1H, t, J )
1.0 Hz), 2.49 (1H, dd, J ) 5.9, 5.5 Hz), 3.11 (1H, dd, J ) 9.7,
6.0 Hz), 3.37 (1H, dd, J ) 9.7, 7.0 Hz), 3.71 (2H, m), 3.97 (2H,
m), 4.06 (1H, brs), 4.19 (1H, t, J ) 6.3 Hz), 7.20-7.29 (8H,
m), 7.42-7.47 (7H, m); 13C NMR (75 MHz, CDCl3) δ -4.8, -4.7,
-4.6, 17.7, 17.8, 25.6, 25.7, 62.9, 64.0, 80.2, 80.5, 86.5, 86.8,
87.5, 126.9, 127.7, 128.7, 144.0. Anal. Found: C, 69.70; H, 8.62.
Calcd for C37H54O5Si2: C, 69.99; H, 8.57.
17 (3.64 g, 93% from 16): [R]26 -42.3° (c 2.23, CHCl3); IR
D
(neat) 3450, 2930, 1430, 1110, 1040 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.87 (3H, t, J ) 6.8 Hz), 1.19-1.63 (23H, m), 1.82
(1H, m), 2.02 (1H, dd, J ) 8.5, 3.9 Hz), 2.22 (1H, m), 3.17 (1H,
ddd, J ) 8.8, 8.8, 2.3 Hz), 3.22 (1H, ddd, J ) 9.3, 9.3, 3.9 Hz),
3.37 (3H, s), 3.43 (1H, m), 3.49 (1H, m), 3.58 (1H, m), 4.60,
4.72 (2H, each d, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
14.1, 22.7, 25.4, 26.6, 29.3, 29.6, 29.7, 29.8, 31.9, 32.1, 55.6,
65.8, 75.8, 80.4, 95.4. Anal. Found: C, 67.99; H, 11.59. Calcd
for C18H36O4: C, 68.31; H, 11.47.
(2S ,3R ,4R ,5R )-3,4-Di-t er t -b u t yld im e t h ylsilyloxy-2-
for m yl-5-(1-tr ityloxym eth yl)tetr a h yd r ofu r a n (23a ). To a
stirred solution of oxalyl chloride (0.15 mL, 1.70 mmol) in CH2-
Cl2 (4 mL) was added dropwise a solution of DMSO (0.27 mL,
3.43 mmol) in CH2Cl2 (0.3 mL) at -70 °C under Ar, and the
mixture was stirred for 30 min at -70 °C. At -70 °C a solution
of 20a (240 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added
dropwise, and the mixture was stirred at the same tempera-
ture for 1 h. Triethylamine (0.52 mL, 3.73 mmol) was added,
and the resulting mixture was gradually warmed to 0 °C with
stirring and poured into ice-water. The mixture was extracted
with ether (10 mL × 3). The extracts were washed with cold
HCl solution, sat. NaHCO3 solution, water, and brine, dried,
and concentrated to give 23a (240 mg, quantitative), which
was employed to the next step without further purification.
(2S,5R,6S)-2-F or m yl-5-m eth oxym eth yloxy-6-d ecyltet-
r a h yd r op yr a n (4). To a stirred solution of oxalyl chloride
(0.07 mL, 0.79 mmol) in CH2Cl2 (1.5 mL) was added dropwise
a solution of DMSO (0.12 mL, 1.58 mmol) in CH2Cl2 (0.5 mL)
at -70 °C under Ar, and the mixture was stirred for 25 min
at -70 °C. At -70 °C, a solution of 17 (50.0 mg, 0.16 mmol) in
CH2Cl2 (0.5 mL) was added dropwise, and the mixture was
stirred at the same temperature for 30 min. Triethylamine
(0.33 mL, 2.37 mmol) was added, and the resulting mixture
was gradually warmed to 0 °C with stirring and poured into
ice-water. The mixture was extracted with ether (15 mL ×
2). The extracts were washed with cold HCl solution, sat.
NaHCO3 solution, water and brine, dried, and concentrated
to give 4 (49.6 mg, quantitative), which was employed to the
next step without further purification. [R]27 -79.8° (c 0.38,
[R]26 +2.6° (c 0.43, CHCl3); IR (neat) 3060, 2954, 2930, 2885,
D
D
CHCl3); IR (neat) 2940, 1742, 1470, 1110, 1043, 922 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.87 (3H, t, J ) 6.8 Hz), 1.22-1.40
(17H, m), 1.41-1.58 (2H, m), 1.82-1.96 (2H, m), 2.26-2.34
(1H, m), 3.22 (1H, ddd, J ) 8.8, 8.8, 2.4 Hz), 3.24 (1H, ddd, J
) 9.4, 9.4, 4.4 Hz), 3.37 (3H, s), 3.74 (1H, dd, J ) 11.2, 2.4
2858, 1733, 1598, 1471, 1449, 1253, 1109, 1089, 835 cm-1; 1H
NMR (400 MHz, CDCl3) δ -0.02 (3H, s), 0.01 (3H, s), 0.07 (3H,
s), 0.11 (3H, s), 0.72 (9H, s), 0.87 (9H, s), 3.16 (1H, dd, J )
9.3, 6.3 Hz), 3.47 (1H, dd, J ) 9.3, 7.3 Hz), 4.02 (1H, d, J )
1.0 Hz), 4.03 (1H, brs), 4.10 (1H, brs), 4.35 (1H, t, J ) 6.8 Hz),
J . Org. Chem, Vol. 67, No. 16, 2002 5747

Takahashi and Nakata
7.20-7.29 (8H, m), 7.42-7.47 (7H, m), 9.63 (1H, d, J ) 1.5
Hz); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.8, 17.7, 17.8, 25.6,
64.5, 78.3, 82.1, 86.8, 88.5, 90.8, 126.9, 127.7, 128.7, 144.0,
203.2; HRMS calcd for C37H52O5Si2Na [M + Na]+ 655.3251,
found 655.3240.
(2R,3R,4R,5R,6S,9RS,10S,13R,14S)-3,4-Bis(ter t-bu tyld i-
m eth ylsilyloxy)-2,5:10,14-d ioxid o-6,13-bis(m eth oxym eth -
oxy)-1-tr ityloxytetr a cos-7-yn -9-ol (26). To a stirred mixture
of 5a (6.03 g, 8.57 mmol) in THF (100 mL) was added dropwise
a 1.58 M solution of n-BuLi (5.06 mL, 8.00 mmol) in hexane
at -78 °C, and the mixture was stirred at -78 °C for 1 h. To
the resulting solution was added anhydrous cerium chloride
(1.97 g,. 8.00 mmol), and then stirring was continued for 1 h
at -78 °C. A solution of 4 (1.58 g, 5.00 mmol) in THF (10 mL)
was added dropwise at -78 °C, and the mixture was stirred
at -78 °C for 2 h and then at -78∼ -23 °C for 3 h. After being
quenched with sat. NH4Cl solution at -23 °C, the resulting
suspension was stirred at -23 °C to rt for 0.5 h. Ether (100
mL) was added, and then the organic layer was separated. The
aqueous layer was treated with cold oxalic acid and extracted
with ether (100 mL × 2). The organic layers were combined,
washed with sat. NaHCO3 solution, water, and brine, dried,
and concentrated. The residue was subjected to chromatograpy
on silica gel with hexane-ethyl acetate (7:1 f 5:1 f 4:1) as
the eluent, giving 26 (3.95 g, 78%) as an unseparable mixture
of alcohols. Starting acetylene compound 5a (2.82 g, 47%) was
also recovered.
(2R ,3R ,4R ,5R )-3,4-Di-t er t -b u t yld im e t h ylsilyloxy-2-
[(1S)-(1-h ydr oxy)eth yn yl]-5-(1-tr ityloxym eth yl)tetr ah ydr o-
fu r a n (24a ) a n d (2R,3R,4R,5R)-3,4-Di-ter t-bu tyld im eth yl-
silyloxy-2-[(1R)-(1-h ydr oxy)eth yn yl]-5-(1-tr ityloxym eth yl)-
tetr a h yd r ofu r a n (25a ). To a stirred solution of 23a (320 mg,
0.51 mmol) in CH2Cl2 (8.3 mL) was added dropwise a 1.0 M
etheral solution of ZnCl2 (1.52 mL, 1.52 mmol) at -70 °C under
Ar, and the mixture was stirred for 1 h at -70 °C. To this
stirred solution was added dropwise a solution of ethynylmag-
nesium chloride (0.5 M solution in THF, 6.08 mL, 3.04 mmol)
at -70 °C, and the mixture was stirred at the same temper-
ature for 6 h and at -70∼20 °C for 12 h. Saturated aqueous
NH4Cl was added at 0 °C with vigorously stirring, and then
the resulting mixture was extracted with ether (20 mL × 3).
The extracts were washed successively with water and brine,
dried, and concentrated. Chromatography on silica gel with
hexane-ethyl acetate (30:1 f 4:1) as the eluent yielded 24a
(215 mg, 65%) and 25a (17 mg, 5%).
26: IR (neat) 3450, 3060, 2930, 1473, 1449, 1254, 1100,
1035, 839 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.10 (3H, s), 0.12
(3H, s), 0.20 (3H, s), 0.21 (3H, s), 0.81 (9H, s), 0.96 (3H, t, J )
6.4 Hz), 0.99 (9H, s), 1.33-1.99 (21H, m), 2.31 (1H, m), 2.51
(0.93H, d, J ) 6.8 Hz), 2.72 (0.04H, d, J ) 6.9 Hz), 3.22-3.43
(3H, m), 3.40-3.55 (2H, m), 3.43 (3H, s), 3.47 (3H, s), 4.07 (1H,
brd, J ) 9.3 Hz), 4.19 (1H, s), 4.22 (1H, brt, J ) 7.8 Hz), 4.30
(1H, s), 4.49 (1H, brdd, J ) 5.9, 2.4 Hz), 4.65-4.80 (4H, m),
4.97 (1H, d, J ) 6.3 Hz), 7.20-7.28 (8H, m), 7.41-7.43 (7H,
m); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.9, -4.8, -4.7, -4.5,
14.1, 17.6, 17.7, 22.6, 24.9, 25.4, 25.6, 29.3, 29.4, 29.5, 29.6,
29.7, 31.9, 32.0, 53.3, 55.3, 55.4, 64.5, 64.6, 66.0, 75.3, 78.6,
79.6, 80.1, 80.5, 80.6, 80.9, 82.6, 84.6, 84.8, 86.7, 87.3, 88.9,
94.2, 94.3, 95.2, 96.1, 126.8, 127.6, 128.7, 144.0. HRMS calcd
for C59H92O10Si2Na [M + Na]+ 1039.6127, found 1039.6146.
Anal. Found: C, 69.37; H, 9.16. Calcd for C59H92O10Si2: C,
69.64; H, 9.11.
24a : [R]24D +2.9° (c 1.34, CHCl3); IR (neat) 3448, 3312, 3060,
1
2929, 1471, 1449, 1252, 1086, 836 cm-1; H NMR (400 MHz,
CDCl3) δ 0.00 (3H, s), 0.01 (3H, s), 0.10 (3H, s), 0.11 (3H, s),
0.72 (9H, s), 0.89 (9H, s), 2.47 (1H, d, J ) 2.0 Hz), 2.90 (1H, d,
J ) 3.4 Hz), 3.11 (1H, dd, J ) 9.8, 7.3 Hz), 3.41 (1H, dd, J )
9.8, 6.8 Hz), 3.95 (1H, brd, J ) 7.3 Hz), 4.07 (1H, brs), 4.10
(1H, brs), 4.22 (1H, t, J ) 6.8 Hz), 4.54 (1H, ddd, J ) 7.3, 3.4,
2.0 Hz), 7.20-7.29 (8H, m), 7.42-7.45 (7H, m); 13C NMR (75
MHz, CDCl3) δ -4.9, -4.8, -4.7, -4.6, 17.7, 17.8, 25.6, 25.7,
62.6, 64.2, 73.8, 80.1, 80.3, 82.1, 86.8, 87.5, 90.4, 126.9, 127.8,
128.7, 143.9. Anal. Found: C, 71.05; H, 8.41. Calcd for
C
39H54O5Si2: C, 71.08; H, 8.26.
25a : [R]24D +9.0° (c 1.07, CHCl3); IR (neat) 3414, 3310, 3060,
1
2930, 1471, 1449, 1254, 1114, 1069, 837 cm-1; H NMR (400
MHz, CDCl3) δ 0.00 (3H, s), 0.03 (3H, s), 0.15 (3H, s), 0.16
(3H, s), 0.71 (9H, s), 0.92 (9H, s), 2.47 (1H, d, J ) 2.00 Hz),
3.11 (1H, dd, J ) 9.8, 7.4 Hz), 3.43 (1H, dd, J ) 9.8, 7.3 Hz),
3.88 (1H, brd, J ) 6.4 Hz), 4.08 (1H, brd, J ) 3.9 Hz), 4.09
(1H, brs), 4.30 (1H, dd, J ) 7.4, 7.3 Hz), 4.33 (1H, brs), 4.53
(1H, ddd, J ) 6.4, 3.9, 2.0 Hz),7.20-7.29 (8H, m), 7.42-7.44
(7H, m); 13C NMR (75 MHz, CDCl3) δ -4.9, -4.7, -4.6, 17.6,
17.9, 25.6, 25.7, 62.9, 63.9, 74.2, 79.5, 80.0, 83.0, 86.9, 87.8,
90.1, 127.0, 127.8, 128.7, 143.9. Anal. Found: C, 71.10; H, 8.31.
Calcd for C39H54O5Si2: C, 71.08; H, 8.26.
(2R ,3R ,4R ,5R ,6S ,10S ,13R ,14S )-3,4-Bis(t er t -b u t yld i-
m eth ylsilyloxy)-2,5:10,14-d ioxid o-6,13-bis(m eth oxym eth -
oxy)-1-tr ityloxytetr a cos-9-on e (27). A suspension of PtO2
(11 mg) in ethyl acetate (1.0 mL) was vigorously stirred at
room temperature for 10 min under hydrogen atmosphere.
Then, a solution of 26 (46.0 mg, 45 µmol) in ethyl acetate (0.2
mL) was added to a stirred above suspension, and the mixture
was vigorously stirred at room temperature for 7 h under
hydrogen atmosphere and filtered through a pad of Celite. The
Celite pad was washed thoroughly with ethyl acetate. The
filtrate and washings were combined and concentrated to give
a syrupy oil (45.2 mg), which was dissolved in CH2Cl2 (0.5 mL).
To a stirried solution were added TPAP (15.6 mg, 44 mmol),
NMO (7.7 mg, 66 mmol), and 4 Å molecular sieves (30 mg) at
room temperature, and the mixture was stirried at room
temperature for 1.2 h. After being quenched with i-PrOH (0.1
mL), the reaction mixture was diluted with CH2Cl2 and then
poured into a colomn of silica gel (hexane:ethyl acetate )
10:1). Elution with hexane-ethyl acetate (10:1) gave ketone
(2R,3R,4R,5R)-3,4-Di-ter t-bu tyldim eth ylsilyloxy-2-[(1S)-
(1-m eth oxym eth yloxy)eth yn yl]-5-(1-tr ityloxym eth yl)tet-
r a h yd r ofu r a n (5a ). To a stirred mixture of 24a (3.46 g, 5.25
mmol) and N,N-diisopropylethylamine (7.30 mL, 41.9 mmol)
in CH2Cl2 (50 mL) was added dropwise chloromethyl methyl
ether (2.00 mL, 26.2 mmol) at 0 °C, and then the mixture was
stirred at 0 °C to room temperature for 1 d. After addition
water, the mixture was extracted with ether (30 mL × 2). The
extracts were washed successively with water, cold dil HCl
solution, sat. NaHCO3 solution, water, and brine, dried, and
concentrated. Chromatography on silica gel with hexane-ethyl
acetate (20:1 f 10:1 f 1:1) as the eluent yielded 5a (3.32 g,
27 (44.5 mg, 97%): [R]25 -38.0° (c 0.75, CHCl3); IR (neat)
D
3034, 2930, 1719, 1471, 1449, 1260, 1100, 1035, 839 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.05 (3H, s), 0.08 (3H, s), 0.11 (6H,
s), 0.78 (9H, s), 0.91 (9H, s), 1.11-2.03 (21H, m), 2.27 (1H,
m), 2.81 (2H, brt, J ) 7.0 Hz), 3.15-3.38 (4H, m), 3.41 (3H,
s), 3.44 (3H, s), 3.76 (1H, m), 3.84 (1H, ddd, J ) 7.3, 7.3, 1.8
Hz), 4.05 (1H, brs), 4.12 (1H, brs), 4.14 (1H, m), 4.63, 4.72,
4.75, 4.80 (4H, each d, J ) 6.8 Hz), 7.24-7.32 (8H, m), 7.45-
7.47 (7H, m); 13C NMR (75 MHz, CDCl3) δ -4.8, -4.6, -0.03,
0.09, 14.1, 17.6, 17.8, 22.7, 24.8, 25.3, 25.6, 25.7, 27.4, 29.3,
29.6, 29.7, 29.8, 29.9, 31.9, 32.0, 34.2, 55.5, 55.8, 64.3, 75.2,
76.3, 80.6, 80.7, 80.9, 82.2, 85.9, 86.7, 89.4, 95.3, 97.0, 126.8,
127.6, 128.7, 144.0, 210.1; HRMS calcd for C59H94O10Si2Na [M
90%): mp 66-68 °C (hexane-ether), [R]28 +28.6° (c 1.01,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 0.01 (3H, s), 0.02 (3H,
s), 0.12 (3H, s), 0.13 (3H, s), 0.73 (9H, s), 0.91 (9H, s), 2.44
(1H, d, J ) 2.0 Hz), 3.17 (1H, dd, J ) 9.3, 8.3 Hz), 3.36 (1H,
dd, J ) 9.3, 5.9 Hz), 3.41 (3H, s), 3.99 (1H, d, J ) 9.3 Hz),
4.12 (1H, brs), 4.14 (1H, dd, J ) 7.8, 5.9 Hz), 4.24 (1H, brs),
4.58 (1H, dd, J ) 9.3, 2.0 Hz), 4.69, 4.91 (2H, each d, J ) 6.3
Hz), 7.20-7.28 (8H, m), 7.41-7.44 (7H, m); 13C NMR (75 MHz,
CDCl3) δ -4.9, -4.8, -4.7, -4.6, 17.7, 17.8, 25.6, 25.7, 55.4,
64.4, 66.0, 75.0, 80.1, 80.6, 80.7, 86.7, 87.5, 89.0, 94.4, 126.9,
127.7, 128.7, 144.0. Anal. Found: C, 70.04; H, 8.38. Calcd for
C41H58O6Si2: C, 70.04; H, 8.32.
5748 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
+ Na]+ 1041.6283, found 1041.6287. Anal. Found: C, 69.48;
J ) 6.5 Hz), 1.20-1.84 (31H, m), 2.21 (1H, m), 3.09 (1H, ddd,
J ) 8.8, 8.3, 2.4 Hz), 3.15 (1H, dd, J ) 9.7, 6.8 Hz), 3.19 (1H,
m), 3.30 (1H, dd, J ) 9.7, 6.4 Hz), 3.33 (1H, m), 3.36 (3H, s),
3.37 (3H, s), 3.40 (3H, s), 3.47 (1H, m), 3.75 (1H, m), 3.83 (1H,
1H, dd, J ) 6.8, 2.4 Hz), 4.00 (1H, brs), 4.05-4.11 (2H, m),
4.59 (1H, d, J ) 6.8 Hz), 4.64-4.78 (5H, m), 7.22-7.33 (9H,
m), 7.44-7.46 (6H, m); 13C NMR (100 MHz, CDCl3) δ -4.7,
-4.5, 14.1, 17.7, 17.8, 22.7, 25.5, 25.6, 25.7, 26.2, 26.8, 27.9,
29.4, 29.6, 29.7, 29.8, 30.0, 31.9, 32.2, 55.5, 55.7, 55.8, 64.4,
75.8, 77.2, 79.3, 79.6, 80.6, 80.9, 81.0, 85.7, 86.7, 89.1, 95.3,
96.9, 97.0, 126.9, 127.7, 128.8, 144.1; HRMS calcd for C61H100O11-
Si2Na [M + Na]+ 1087.6702, found 1087.6697. Anal. Found:
C, 68.84; H, 9.58. Calcd for C61H100O11Si2: C, 68.75; H, 9.46.
H, 9.21. Calcd for C59H94O10Si2: C, 69.50; H, 9.29.
(2R,3R,4R,5R,6S,9S,10S,13R,14S)-3,4-Bis(ter t-bu t yld i-
m eth ylsilyloxy)-2,5:10,14-d ioxid o-6,13-bis(m eth oxym eth -
oxy)-1-tr ityloxytetr acos-9-ol (28) an d (2R,3R,4R,5R,6S,9R,
10S,13R,14S)-3,4-Bis(ter t-b u t yld im et h ylsilyloxy)-2,5:10,
14-dioxido-6,13-bis(m eth oxym eth oxy)-1-tr ityloxytetr acos-
9-ol (29). To a stirred solution of ketone 27 (63.8 mg, 62 µmol)
in THF (2.0 mL) was added L-Selectride (1.0 M solution in
THF; 0.13 mL, 0.13 mmol) at -78 °C, and then the mixture
was stirred at the same temperature for 2 h. After addition of
sat. NH4Cl solution followed by MgSO4, the resulting mixture
was stirred at -78 °C to rt for 1.5 h and then filtered through
a pad of Celite. The Celite pad was washed thoroughly with
ethyl acetate. The filtrate and washings were combined and
concentrated. The residue was subjected to chromatograpy on
silica gel with hexane-ethyl acetate (10:1 f 4:1) as the eluent,
giving a mixture of 28 and 29 (28/29 ) ca. 24/1 by 1H NMR
analyses), which were separated into each isomer {28 (58.0
mg, 91%) and 29 (2.0 mg, 3%)} by chromatograpy on silica gel
with hexane-ethyl acetate (8:1) as the eluent.
(2R ,3S ,4S ,5S ,6S ,9S ,10S ,13R ,14S )-2,5:10,14-Dioxid o-
6,9,13-tr is(m eth oxym eth oxy)-1-tr ityloxytetr a cos-3,4-d i-
ol (31). To a stirred solution of 30 (64.0 mg, 60 µmol) in THF
(1.0 mL) was added dropwise 1.0 M solution of TBAF in THF
(0.15 mL, 0.15 mmol) at room temperature, and the mixture
was stirred at room temperature for 5.5 h and diluted with
ethyl acetate (5 mL). The solution was washed with sat. NH4-
Cl solution, water, and brine, dried, and concentrated. The
residue was purified by chromatography on silica gel with
hexane-ethyl acetate (2:1f 1:1f 1:2) as the eluent to yield
28: [R]27D -31.5° (c 0.18, CHCl3); IR (neat) 3580, 3060, 2930,
1
1477, 1450, 1254, 1100, 1038, 839 cm-1; H NMR (400 MHz,
31 (47.8 mg, 92% form 28); [R]26 -10.6° (c 0.11, CHCl3); IR
D
CDCl3) δ 0.01 (6H, s), 0.03 (3H, s), 0.07 (3H, s), 0.74 (9H, s),
0.86-0.88 (12H, brs), 1.20-1.43 (22H, m), 1.45-1.78 (3H, m),
1.81 (1H, brt), 2.18 (1H, m), 2.56 (1H, d, J ) 3.0 Hz), 3.10-
3.15 (3H, m), 3.18 (1H, ddd, J ) 9.3, 9.3, 3.9 Hz), 3.31 (1H,
dd, J ) 9.3, 6.3 Hz), 3.37 (3H, s), 3.39 (3H, s), 3.40 (1H, m),
3.76 (1H, ddd, J ) 7.4, 7.4, 3.9 Hz), 3.84 (1H, dd, J ) 6.8, 2.0
Hz), 4.01 (1H, brs), 4.08-4.10 (2H, brs), 4.60 (1H, d, J ) 6.8
Hz), 4.70-4.73 (2H, m), 4.78 (1H, d, J ) 6.8 Hz), 7.20-7.28
(8H, m), 7.41-7.44 (7H, m); 13C NMR (100 MHz, CDCl3) δ
-4.9, -4.7, 14.0, 17.5, 17.7, 22.5, 25.2, 25.5, 25.6, 26.5, 27.4,
28.4, 29.2, 29.5, 29.6, 31.8, 31.9, 55.3, 55.6, 64.2, 73.2, 75.5,
76.6, 80.2, 80.5, 80.9, 85.7, 86.5, 89.0, 95.1, 96.9, 126.7, 126.9,
127.4, 127.5, 127.7, 128.4, 128.6, 128.9, 143.9. HRMS calcd
for C59H96O10Si2Na [M + Na]+ 1043.6440, found 1043.6431.
Anal. Found: C, 69.42; H, 9.49. Calcd for C59H96O10Si2: C,
69.37; H, 9.47.
(neat) 3442, 2926, 1448, 1150, 1101, 1033, 918 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.83 (3H, t, J ) 6.5 Hz), 1.20-1.84 (31H,
m), 2.21 (1H, m), 3.10 (1H, ddd, J ) 8.1, 8.1, 1.5 Hz), 3.15-
3.27 (3H, m), 3.35 (1H, m), 3.36 (3H, s), 3.38 (3H, s), 3.41 (3H,
s), 3.50 (1H, m), 3.76 (1H, m), 3.99-4.15 (4H, m), 4.59 (1H, d,
J ) 6.8 Hz), 4.66-4.78 (5H, m), 7.22-7.33 (9H, m), 7.44-7.46
(6H, m); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 25.5, 26.3,
26.5, 29.3, 29.6, 29.7, 30.0, 31.9, 32.1, 55.5, 55.8, 56.1, 64.9,
75.7, 77.7, 78.9, 79.4, 79.6, 79.8, 80.9, 83.5, 86.1, 87.5, 95.3,
96.4, 97.3, 127.2, 127.9, 128.7, 143.2; HRMS calcd for C49H72O11-
Na [M + Na]+ 859.4972, found 859.4995. Anal. Found: C,
70.09; H, 8.43. Calcd for C49H72O11: C, 70.31; H, 8.67.
(2R,3R,4R,5R,6S,9S,10S,13R,14S)-2,5:10,14-Dioxid o-3,4-
bis(m eth a n esu lfon yloxy)-6,9,13-tr is(m eth oxym eth oxy)-
1-tr ityloxytetr a cosa n e (32). To a stirred mixture of 31 (47.8
mg, 57.0 µmol) and triethylamine (0.06 mL, 0.40 mmol) in CH2-
Cl2 (1.0 mL) was added dropwise methanesulfonyl chloride (13
µL, 0.17 mmol) at 0 °C, and then the mixture was stirred at 0
°C to room temperature for 12 h. After addition water, the
mixture was extracted with CH2Cl2 (5 mL × 3). The extracts
were washed successively with water, cold dil HCl solution,
sat. NaHCO3 solution, water, and brine, dried, and concen-
trated to give 32 (55.3 mg, 98%), which was employed to the
next step without further purification. Analytical sample was
prepared by chromatography on silica gel with hexane-ethyl
acetate (2:1 f 1:1) as the eluent.
29: [R]27D -23.4° (c 1.13, CHCl3); IR (neat) 3478, 3060, 2930,
1
1477, 1450, 1254, 1100, 1038, 839 cm-1; H NMR (400 MHz,
CDCl3) δ 0.01 (6H, s), 0.03 (3H, s), 0.07 (3H, s), 0.75 (9H, s),
0.87-0.89 (12H, brs), 1.22-1.55 (22H, m), 1.62-1.93 (4H, m),
2.22 (1H, m), 2.32 (1H, d, J ) 3.9 Hz), 3.12-3.24 (4H, m), 3.31
(1H, dd, J ) 9.3, 6.3 Hz), 3.37 (3H, s), 3.41 (3H, s), 3.59 (1H,
m), 3.79 (1H, m), 3.85 (1H, dd, J ) 6.8, 2.0 Hz), 4.00 (1H, brs),
4.09 (1H, brs), 4.10 (1H, brt, J ) 6.3 Hz), 4.60, 4.72 (2H, each
d, J ) 6.8 Hz), 4.73, 4.79 (2H, each d, J ) 6.8 Hz), 7.20-7.29
(8H, m), 7.41-7.44 (7H, m); 13C NMR (100 MHz, CDCl3) δ
-4.8, -4.5, 14.1, 17.7, 17.8, 22.7, 24.5, 25.4, 25.6, 25.7, 28.4,
28.5, 29.3, 29.6, 29.7, 29.8, 31.9, 32.1, 55.5, 55.9, 64.2, 73.4,
75.8, 79.6, 80.6, 80.7, 80.9, 85.8, 86.7, 89.1, 95.3, 97.1, 126.9,
127.7, 128.7, 144.0. HRMS calcd for C59H96O10Si2Na [M + Na]+
1043.6440, found 1043.6453. Anal. Found: C, 69.26; H, 9.53.
Calcd for C59H96O10Si2: C, 69.37; H, 9.47.
(2R ,3R,4R,5R,6S,9S,10S,13R,14S)-3,4-Bis(ter t-b u t yld i-
m eth ylsilyloxy)-2,5:10,14-dioxido-6,9,13-tr is(m eth oxym eth -
oxy)-1-tr ityloxytetr a cosa n e (30). To a stirred mixture of 28
(63 mg, 62.3 µmol) and N,N-diisopropylethylamine (0.22 mL,
1.24 mmol) in CH2Cl2 (0.5 mL) was added dropwise chloro-
methyl methyl ether (50 µL, 0.62 mmol) at 0 °C, and then the
mixture was stirred at 0 °C for 2 h and room temperature for
16 h. After addition of water, the mixture was extracted with
ether (3 mL ×3). The extracts were washed successively with
water, cold dil HCl solution, sat. NaHCO3 solution, water, and
brine, dried, and concentrated to give 30 (64 mg, 97%), which
was employed to the next step without further purification.
Analytical sample was prepared by chromatography on silica
gel with hexane-ethyl acetate (10:1) as the eluent.
32: [R]D -4.1° (c 0.22, CHCl3). IR (neat) 2926, 1366, 1179,
1
1151, 1101, 1033, 960, 918 cm-1; H NMR (500 MHz, CDCl3)
δ 0.88 (3H, t, J ) 6.7 Hz), 1.20-1.91 (29H, m), 2.18 (1H, m),
2.96 (3H, s), 3.05-3.52 (6H, m), 3.11 (3H, s), 3.35 (3H, s), 3.36
(3H, s), 3.42 (3H, s), 3.83 (1H, m), 4.32-4.38 (2H, m), 4.59 (1H,
d, J ) 6.8 Hz), 4.65 (1H, d, J ) 6.8 Hz), 4.70-4.75 (3H, m),
4.78 (1H, d, J ) 6.8 Hz), 5.33-5.38 (2H, m), 7.22-7.33 (9H,
m), 7.44-7.46 (6H, m); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7,
25.5, 26.2, 26.4, 27.2, 29.3, 29.5, 29.6, 29.7, 30.0, 31.9, 32.1,
38.2, 38.3, 42.9, 55.5, 55.8, 56.1, 62.8, 75.8, 79.3, 80.9, 81.6,
83.5, 83.6, 83.7, 83.9, 87.2, 95.3, 97.1, 97.2, 127.2, 127.9, 128.7,
143.4; HRMS calcd for C51H76O15S2Na [M + Na]+ 1015.4523,
found 1015.4525.
(2S,5S,6S,9S,10S,13R,14S)-2,5:10,14-Dioxid o-6,9,13-tr is-
(m eth oxym eth oxy)-1-tr ityloxytetr a cos-3-en e (33). A mix-
ture of 32 (55.3 mg, 56.0 µmol), NaI (66.7 mg, 0.445 mmol),
and Zn powder (54.5 mg, 0.834 mmol) in DMF (1.0 mL) was
heated at 140-145 °C with stirring for 13 h. Additional NaI
(66.7 mg, 0.445 mmol) and Zn powder (54.5 mg, 0.834 mmol)
were added, and stirring was continued for 5 h. More ad-
ditional NaI (71.0 mg, mmol) and Zn powder (60.0 mg, mmol)
were added, and stirring was further continued for 7 h. After
30: [R]D -30.8° (c 0.21, CHCl3). IR (neat) 2927, 1252, 1150,
1101, 1034, 919 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.01 (3H,s),
0.02 (6H,s), 0.06 (3H,s), 0.75 (9H,s), 0.86 (9H, s), 0.87 (3H, t,
J . Org. Chem, Vol. 67, No. 16, 2002 5749

Takahashi and Nakata
being cooled to room temperature, the reaction mixture was
diluted with water (3 mL) and then extracted with CH2Cl2 (5
mL × 3). The extracts were washed with water and brine,
dried, and concentrated to give 33 (45.0 mg, quantitative yield),
which was employed to the next step without further purifica-
tion. Analytical sample was prepared by chromatography on
silica gel with hexane-ethyl acetate (10:1 f 6:1 f 4:1) as the
eluent.
mL) was added dropwise a solution of DMSO (0.13 mL, 1.24
mmol) in CH2Cl2 (0.5 mL) at -70 °C under Ar, and the mixture
was stirred for 30 min at -70 °C. At -70 °C a solution of 35
(70.0 mg, 0.12 mmol) in CH2Cl2 (0.6 mL) was added dropwise,
and the mixture was stirred at the same temperature for 1 h.
Triethylamine (0.26 mL, 1.86 mmol) was added, and the
resulting mixture was gradually warmed to 0 °C with stirring
and poured into ice-water. The mixture was extracted with
ether (10 mL × 3). The extracts were washed with cold HCl
solution, sat. NaHCO3 solution, water, and brine, dried, and
concentrated to give aldehyde 36 (69.0 mg): IR (neat) 2920,
33: [R]D -128.8° (c 0.16, CHCl3). IR (neat) 3059, 2926, 1491,
1449, 1150, 1102, 1035, 918 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.87 (3H, t, J ) 6.7 Hz), 1.20-1.81 (27H, m), 2.22 (1H, m),
3.06-3.12 (2H, m), 3.16-3.23 (2H, m), 3.33 (1H, m), 3.36 (3H,
s), 3.37 (3H, s), 3.39 (3H, s), 3.50 (1H, m), 3.61 (1H, m), 4.59
(1H, d, J ) 6.4 Hz), 4.66-4.77 (5H, m), 4.96-5.00 (2H, m),
5.89, 5.95 (2H, each brd, J ) 6.3 Hz), 7.19-7.30 (9H, m), 7.43-
7.46 (6H, d, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1,
22.7, 25.5, 26.3, 26.5, 26.9, 29.3, 29.6, 29.7, 30.1, 31.9, 32.1,
55.5, 55.7, 55.8, 66.5, 75.8, 79.2, 79.3, 79.9, 80.9, 85.4, 86.4,
88.1, 95.3, 96.9, 97.0, 126.6, 126.9, 127.7, 128.0, 128.7, 129.8,
144.1; HRMS calcd for C49H70O9Na [M + Na]+ 825.4918, found
825.4929. Anal. Found: C, 73.10; H, 9.10. Calcd for C49H70O9:
C, 73.28; H, 8.79.
1
1738, 1465, 1150, 1103, 1038, 918 cm-1; H NMR (400 MHz,
CDCl3) δ 0.86 (3H, t, J ) 6.8 Hz), 1.20-2.02 (29H, m), 2.22
(1H, m), 3.08 (1H, ddd, J ) 9.2, 9.2, 2.4 Hz), 3.19 (1H, ddd, J
) 9.3, 9.3, 3.9 Hz), 3.32 (1H, m), 3.35 (3H, s), 3.37 (3H, s),
3.39 (3H, s), 3.47 (1H, m), 3.52 (1H, m), 4.10 (1H, m), 4.31
(1H, ddd, J ) 8.3, 7.8, 1.9 Hz), 4.59 (1H, d, J ) 6.7 Hz), 4.66-
4.75 (4H, m), 4.79 (1H, d, J ) 6.7 Hz), 9.65 (1H, d, J ) 1.9
Hz). This compound was employed to the next step without
further purification. To a stirried solution of CBr4 (82.2 mg,
0.25 mmol) in CH2Cl2 (1.0 mL) was added triphenylphosphine
(130 mg, 0.50 mmol) in CH2Cl2 (0.3 mL) at 0 °C. After 5 min,
triethylamine (0.14 mL, 0.99 mmol) was added. After 3 min,
a solution of the aldehyde 36 (69.0 mg) in CH2Cl2 (0.6 mL)
was added dropwise at 0 °C. The mixture was stirred at 0 °C
for 20 h, poured into sat. NaHCO3 solution, and then extracted
with CH2Cl2 (10 mL × 3). The extracts were washed with
water and brine, dried, and concentrated. The residue was
purified by chromatography on silica gel with hexane-ethyl
acetate (10:1) as the eluent to give 37 (69.0 mg, 78% from 35
in two steps): 1H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J )
6.8 Hz), 1.21-1.84 (H, m), 1.95-2.05 (1H, m), 2.18-2.28 (2H,
m), 3.10 (1H, ddd, J ) 9.3, 8.8, 2.2 Hz), 3.20 (1H, ddd, J ) 9.6,
8.8, 4.2 Hz), 3.30-3.51 (2H, m), 3.36 (3H, s), 3.38 (3H, s), 3.39
(3H, s), 4.04 (1H, m), 4.54-4.82 (7H, m), 6.50 (1H, d, J ) 7.3
Hz). To a stirred solution of 37 (27.5 mg, 0.04 mmol) in THF
(0.4 mL) was added a 1.0 M solution of ethylmagnesium
bromide in THF (0.08 mL, 0.08 mmol) dropwise at -5 °C, and
then the mixture was stirred at the same temperature for 0.5
h. After addition of sat. NH4Cl solution, the resulting mixture
was extracted with ether (5 mL × 3). The extracts were washed
with water and brine, dried, and concentrated. The residue
was purified by chromatography on silica gel with hexane-
ethyl acetate (10:1 f 4:1) as the eluent to give 2 (20.7 mg,
97%): [R]24D -67.8° (c 0.46, CHCl3); IR (neat) 3260, 2930, 1150,
1100, 1038, 918 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.87 (3H,
t, J ) 6.6 Hz), 1.20-1.82 (26H, m), 1.94-2.27 (4H, m), 2.40
(1H, d, J ) 2.0 Hz), 3.09 (1H, ddd, J ) 9.3, 8.8, 2.4 Hz), 3.19
(1H, ddd, J ) 9.8, 8.8, 3.9 Hz), 3.31-3.42 (2H, m), 3.36 (3H,
s), 3.37 (3H, s), 3.38 (3H, s), 3.45-3.52 (2H, m), 4.16 (1H, brq,
J ) 7.0 Hz), 4.57-4.78 (6H, m); 13C NMR (100 MHz, CDCl3) δ
14.1, 22.7, 25.5, 26.3, 26.7, 27.0, 27.3, 29.3, 29.6, 29.7, 30.1,
31.9, 32.1, 33.3, 55.5, 55.8, 68.1, 72.6, 75.8, 79.1, 79.3, 79.4,
80.9, 81.0, 83.8, 95.3, 96.8, 97.0; HRMS calcd for C31H56O8Na
[M + Na]+ 579.3873, found 579.3846. Anal. Found: C, 66.84;
H, 10.27. Calcd for C31H56O8: C, 66.87; H, 10.14.
(2S,5S,6S,9S,10S,13R,14S)-2,5:10,14-Dioxid o-6,9,13-tr is-
(m eth oxym eth oxy)-1-tr ityloxytetr a cosa n e (34). A mixture
of 33 (45.0 mg, 56 µmol) and 10% Pd/C (22 mg) in ethanol (0.8
mL) was vigorously stirred at room temperature for 18 h under
hydrogen atmosphere and filtered through a pad of Celite. The
Celite pad was washed thoroughly with ethyl acetate. The
filtrate and washings were combined and concentrated to give
34 (44.6 mg), which was employed to the next step without
further purification. Analytical sample was prepared by chro-
matography on silica gel with hexane-ethyl acetate (4:1) as
the eluent.
34: [R]23D -55.7° (c 0.30, CHCl3). IR (neat) 2925, 1449, 1150,
1101, 1038, 919 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.87 (3H,
t, J ) 6.7 Hz), 1.20-2.05 (29H, m), 2.22 (1H, m), 2.99 (1H, dd,
J ) 9.3, 4.8 Hz), 3.09 (1H, ddd, J ) 9.7, 8.9, 2.4 Hz), 3.15 (1H,
dd, J ) 9.3, 5.3 Hz), 3.19 (1H, ddd, J ) 9.8, 9.3, 3.8 Hz), 3.30-
3.35 (1H, m), 3.36 (3H, s), 3.37 (3H, s), 3.41 (3H, s), 3.45-3.53
(2H, m), 4.01 (1H, m), 4.21 (1H, m), 4.59 (1H, d, J ) 6.8 Hz),
4.65-4.78 (4H, m), 4.90 (1H, d, J ) 6.8 Hz), 7.19-7.30 (9H,
m), 7.45-7.47 (6H, d, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3)
δ 14.1, 22.6, 25.6, 26.4, 26.7, 27.1, 28.4, 28.8, 29.4, 29.6, 29.7,
29.8, 30.1, 30.3, 31.9, 32.1, 55.5, 55.7, 55.8, 66.5, 75.8, 78.1,
79.3, 79.5, 79.7, 80.9, 81.7, 86.3, 95.3, 96.8, 97.0, 126.9, 127.7,
128.8, 144.2; HRMS calcd for C49H72O9Na [M + Na]+ 827.5074,
found 827.5064. Anal. Found: C, 73.01; H, 9.14. Calcd for
C49H72O9: C, 73.10; H, 9.01.
(2S,5S,6S,9S,10S,13R,14S)-2,5:10,14-Dioxid o-6,9,13-tr is-
(m eth oxym eth oxy)tetr a cos-1-ol (35). A solution of 34 (44.6
mg) in 90% AcOH (1.1 mL) was heated at 50 °C with stirring
for 3 h, concentrated, and coevaporated with toluene. The
residue was purified by chromatography on silica gel with
toluene-ethyl acetate (1:1 f 1:2 f 1:3) as the eluent to give
alcohol 35 (23.5 mg, 74% from 31 in four steps): [R]27D -51.7°
(c 0.33, CHCl3); IR (neat) 3470, 2920, 1150, 1110, 1038, 918
(5S,6S,7R,8S,9S)-6,7-Isopr opyliden edioxy-9-p-m eth oxy-
ben zyloxy-3-d ecyn e-5,8-d iol (42) a n d (5R,6S,7R,8S,9S)-
6,7-Isopr opyliden edioxy-9-p-m eth oxyben zyloxy-3-decyn e-
5,8-d iol (43). To a stirred mixture of 41 (194 mg, 0.63 mmol)
in hexane-ether (3:1, 0.8 mL) was added dropwise a 1.50 M
solution of n-BuLi in hexane (0.41 mL, 0.62 mmol) at -78 °C,
and the mixture was stirred at -78 °C for 1 h. A solution of
40 (68.0 mg, 0.21 mmol) in ether (0.2 mL) was added dropwise
at -60 °C, and the mixture was gradually warmed to 5 °C for
17 h with stirring. After being quenched with sat. NH4Cl
solution at 0 °C, the resulting mixture was extracted with
ether (10 mL × 2). The extracts were washed with water and
brine, dried, and concentrated. The residue was subjected to
chromatograpy on silica gel with hexane-ether (1:1 f 1:2) as
the eluent, giving desired alcohol 43 (89.0 mg, 67%) and 42
(15.0 mg, 11%).
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.86 (3H, t, J ) 6.7 Hz),
1.20-2.04 (29H, m), 2.22 (1H, m), 3.09 (1H, ddd, J ) 9.1, 9.1,
2.1 Hz), 3.20 (1H, ddd, J ) 9.8, 9.8, 4.3 Hz), 3.33 (1H, m), 3.37
(3H, s), 3.38 (3H, s), 3.40 (3H, s), 3.45-3.53 (3H, m), 3.65 (1H,
m), 3.99 (1H, dd, J ) 7.9, 6.4 Hz), 4.10 (1H, m), 4.59 (1H, d, J
) 6.7 Hz), 4.66-4.75 (4H, m), 4.79 (1H, d, J ) 6.7 Hz); 13C
NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.5, 26.3, 26.5, 27.0, 27.4,
28.9, 29.3, 29.6, 29.7, 30.1, 31.9, 32.1, 55.5, 55.7, 55.8, 64.7,
75.8, 79.1, 79.4, 79.8, 80.9, 81.5, 95.3, 96.8, 96.9; HRMS calcd
for C30H58O9Na [M + Na]+ 585.3979, found 585.3972. Anal.
Found: C, 63.85; H, 10.51. Calcd for C30H58O9: C, 64.03; H,
10.39.
(3S,6S,7S,10S,11S,14R,15S)-3,6:11,15-Dioxid o-7,10,14-
tr is(m eth oxym eth oxy)p en ta cos-1-yn e (2). To a stirred
solution of oxalyl chloride (54 µL, 0.62 mmol) in CH2Cl2 (1.5
5750 J . Org. Chem., Vol. 67, No. 16, 2002

Total Synthesis of an Antitumor Agent, Mucocin
42: [R]27D +8.0° (c 0.20, CHCl3); IR (neat) 3400, 3070, 2940,
temperature for 1 h and poured into ice-water. The resulting
mixture was extracted with ethyl acetate (3 mL × 3). The
extracts were washed with cold HCl solution, water, sat.
NaHCO3 solution, water, and brine, dried, concentrated.
Chromatography on silica gel with hexane-ethyl acetate (2:1
f 3:2) as the eluent yielded an unstable enyne 56 (32.1 mg,
79%) as a stereoisomeric mixture (E/ Z ) 27/1). Starting iodide
3 (11.3 mg) was also recovered. 56: IR (neat) 2930, 1760, 1460,
1150, 1105, 1038, 920 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.86
(3H, t, J ) 8.7 Hz), 1.18-1.82 (30H, m), 1.40 (3H, d, J ) 6.8
Hz), 1.85-2.25 (6H, m), 2.47 (2H, brd, J ) 5.4 Hz), 3.07 (1H,
ddd, J ) 8.8, 8.8, 2.0 Hz), 3.18 (1H, ddd, J ) 9.5, 9.5, 3.8 Hz),
3.28-3.40 (2H, m), 3.32, 3.35, 3.36, 3.37 (12H, each s), 3.47
(2H, m), 3.81 (1H, m), 4.13 (1H, dd, J ) 7.4, 5.9 Hz), 4.57-
4.78 (8H, m), 5.00 (1H, qd, J ) 6.8, 1.5 Hz), 5.46 (0.97H, brdd,
J ) 16.1, 1.5 Hz), 5.80-5.88 (0.06H, m), 6.07 (0.97H, ddd, J )
16.1, 7.3, 6.9 Hz), 7.14-7.16 (1H, m), 13C NMR (100 MHz,
CDCl3) δ 14.1, 19.0, 22.6, 24.3, 25.5, 26.3, 26.7, 26.9, 27.5, 29.3,
29.57, 29.62, 29.69, 30.0, 30.1, 31.9, 32.0, 32.8, 33.5, 33.6, 55.4,
55.6, 55.7, 55.8, 68.7, 68.8, 75.1, 75.3, 75.8, 77.5, 79.2, 79.4,
79.5, 80.8, 80.9, 83.1, 87.6, 95.3, 95.6, 96.8, 96.9, 109.2, 109.6,
130.4, 144.3, 151.5, 173.8; HRMS calcd for C45H76O12Na [M +
Na]+ 831.5234, found 831.5253.
1
1615, 1515, 1250, 1113, 1038, 703 cm-1; H NMR (400 MHz,
CDCl3) δ 1.04 (9H, s), 1.27 (3H, d, J ) 5.8 Hz), 1.34 (3H, s),
1.49 (3H, s), 2.47 (2H, dt, J ) 7.3, 7.3, 2.0 Hz), 2.81 (1H, d, J
) 7.8 Hz), 3.52 (1H, dq, J ) 7.8, 5.8 Hz), 3.68 (1H, d, J ) 7.3
Hz), 3.76 (2H, t, J ) 7.3 Hz), 3.79 (3H, s), 4.02 (1H, brt, J )
7.8, 7.8, 1.5 Hz), 4.12 (1H, dd, J ) 6.8, 5.4 Hz); 4.37, 4.55 (2H,
each d, J ) 11.7 Hz), 4.47 (1H, dd, J ) 6.8, 2.0 Hz), 4.58 (1H,
m), 6.86 (2H, m), 7.22 (2H, d, J ) 8.8 Hz), 7.35-7.42 (6H, m),
7.66 (4H, dd, J ) 7.3, 1.0 Hz); 13C NMR (100 MHz, CDCl3) δ
16.4, 19.1, 22.9, 24.9, 26.7, 26.8, 55.2, 61.9, 62.2, 70.6, 70.9,
75.3, 75.4, 79.1, 79.8, 83.6, 108.0, 113.8, 127.7, 129.4, 129.6,
130.3, 133.5, 135.5, 135.7, 159.2. Anal. Found: C, 70.05; H,
7.69. Calcd for C37H48O7Si: C, 70.22; H, 7.64.
43: [R]26D +12.9° (c 0.16, CHCl3); IR (neat) 3440, 3075, 2940,
1
1615, 1515, 1477, 1250, 1113, 1038, 703 cm-1; H NMR (400
MHz, CDCl3) δ 1.04 (9H, s), 1.27 (3H, d, J ) 5.8 Hz), 1.35,
1.51 (6H, each s), 2.47 (2H, dt, J ) 7.3, 7.3, 2.0 Hz), 2.65 (1H,
d, J ) 7.3 Hz), 2.75 (1H, d, J ) 5.4 Hz), 3.49 (1H, dq, J ) 7.8,
5.8 Hz), 3.72 (1H, dt, J ) 8.3, 8.3, 1.4 Hz), 3.75 (2H, t, J ) 7.3
Hz), 3.79 (3H, s), 4.15 (1H, dd, J ) 7.3, 5.9 Hz), 4.35, 4.52
(2H, each d, J ) 11.2 Hz), 4.47 (1H, dd, J ) 7.3, 2.0 Hz), 4.62
(1H, brt), 6.85 (2H, m), 7.22 (2H, d, J ) 8.8 Hz), 7.35-7.44
(6H, m), 7.66 (4H, dd, J ) 7.8, 1.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 16.4, 19.1, 22.9, 24.5, 26.6, 26.7, 55.2, 61.6, 62.2, 70.6,
71.4, 75.0, 75.6, 76.6, 79.3, 79.9, 83.5, 108.3, 113.7, 127.6, 129.3,
129.6, 130.3, 133.5, 135.5, 159.1. Anal. Found: C, 69.93; H,
7.70. Calcd for C37H48O7Si: C, 70.22; H, 7.64.
(2′R,3R,4R,5S)-3-(6′-ter t-Bu tyldiph en ylsilyloxy-2′-(m eth -
oxym eth oxy)h exyl)-5-m eth yl-tetr a h yd r ofu r a n -2-on e (53)
a n d (2′R,3S,4R,5S)-3-(6′-ter t-Bu t yld ip h en ylsilyloxy-2′-
(m et h oxym et h oxy)h exyl)-5-m et h ylt et r a h yd r ofu r a n -2-
on e (54). To a stirred solution of 6 (2.22 g, 3.11 mmol) in
toluene (130 mL) was added dropwise a mixture of tributyltin
hydride (1.67 mL, 6.22 mmol) and 2,2′-azobisisobutyronitrile
in toluene (50 mL) over 30 min at 100-110 °C, and the mixture
was stirred at the same temperature for 1.5 h and concen-
trated. Chromatography on silica gel with hexane-ethyl
acetate (9:1 f 5:1 f 3:1) as the eluent yielded trans-lactone
53 (1.49 g, 86%) and cis-lactone 54 (63.0 mg, 4%).
4,16,19,23-Tetr a(m eth oxym eth oxy)m u cocin (57). A mix-
ture of 56 (22.4 mg, 28 µmol) and tris(triphenylphosphine)-
rhodium chloride (8.1 mg, 8.7 µmol) in benzene-ethanol (6:1,
0.7 mL) was stirred at room temperature for 4.5 h under
hydrogen atmosphere and concentrated. Again, the residue
was diluted with benzene-ethanol (6:1, 0.7 mL), and more tris-
(triphenylphosphine)rhodium chloride (8.1 mg, 8.7 µmol) was
added. The resulting mixture was stirred at room temperature
for 2 h under hydrogen atmosphere, concentrated, and then
passed through a column of silica gel {hexane-ethyl acetate
(2:1 f 1:1) } to give a syrup, which was purified by preparative
TLC {hexane-ethyl acetate (1:1) } to give 57 (15.9 mg, 70%):
[R]22D -34.6° (c 0.10, CHCl3), IR (neat) 2927, 1759, 1457, 1318,
1212, 1150, 1101, 1035, 918 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.87 (3H, t, J ) 6.3 Hz), 1.20-1.81 (41H, m), 1.41 (3H, d, J
) 6.8 Hz), 1.90-2.05 (2H, m), 2.22 (1H, m), 2.49 (2H, brd, J )
5.4 Hz), 3.08 (1H, ddd, J ) 8.8, 8.8, 2.2 Hz), 3.19 (1H, ddd, J
) 9.3, 9.3, 3.9 Hz), 3.32 (1H, m), 3.34, 3.37, 3.38, 3.39 (12H,
each s), 3.47 (2H, m), 3.78-3.90 (2H, m), 3.97 (1H, qd, J )
8.3, 6.8 Hz), 4.46-4.76 (8H, m), 5.01 (1H, qd, J ) 6.8, 1.5 Hz),
7.16 (1H, m); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.1, 22.7,
25.2, 25.5, 26.3, 26.4, 26.7, 26.9, 28.6, 29.3, 29.6, 29.7, 29.8,
30.0, 30.1, 31.9, 32.0, 32.2, 34.4, 35.8, 55.5, 55.6, 55.7, 75.6,
75.8, 77.5, 79.15, 79.2, 79.3, 79.5, 79.9, 80.9, 95.3, 95.6, 96.8,
96.9, 130.6, 151.3, 173.9; HRMS calcd for C45H82O12Na [M +
Na]+ 837.5704, found 837.5692. Anal. Found: C, 66.65; H,
10.27. Calcd for C45H82O12: C, 66.31; H, 10.14.
53: [R]26D -28.3° (c 1.42, CHCl3); IR (neat) 3070, 2930, 1778,
1430, 1150, 1110, 1045, 703 cm-1; 1H NMR (500 MHz, CDCl3)
δ 1.04 (9H, s), 1.46 (3H, d, J ) 6.4 Hz), 1.43-1.60 (6H, m),
1.74 (1H, ddd, J ) 13.1, 8.6, 4.6 Hz), 2.09 (1H, ddd, J ) 13.1,
4.9, 3.4 Hz), 2.84 (1H, ddd, J ) 6.4, 4.6, 3.4 Hz), 3.36 (3H, s),
3.37 (3H, s), 3.66 (2H, t, J ) 6.4 Hz), 3.77 (1H, m), 3.82 (1H,
dd, J ) 7.3, 6.1 Hz), 4.34 (1H, dd, J ) 6.4, 6.1 Hz), 4.64 (2H,
s), 4.66, 4.70 (2H, each d, J ) 7.0 Hz), 7.36-7.42 (6H, m), 7.65-
7.67 (4H, m); 13C NMR (100 MHz, CDCl3) δ 19.0, 21.0, 26.6,
32.4, 33.7, 34.0, 43.9, 55.4, 55.5, 63.5, 75.1, 79.4, 85.2, 95.6,
96.4, 127.4, 129.3, 133.7, 135.3, 175.8; HRMS calcd for
Mu cocin (1). To a stirred solution of 57 (6.6 mg, 8.1 µmol)
in methyl sulfide (0.7 mL) was added BF3‚Et2O (40 µL, 0.30
mmol) at -10 °C, and the mixture was stirred at -10 to 0 °C
for 1 h. After addition of sat. NaHCO3 solution, the resulting
mixture was extracted with EtOAc (4 mL × 3). The extracts
were washed with water, brine, dried, and concentrated.
Chromatography on silica gel with ethyl acetate-hexane
(1:1) f ethyl acetate as the eluent yielded 7 (4.0 mg, 77%):
C
31H46O7SiNa [M + Na]+ 581.2911, found 581.2912. Anal.
Found: C, 66.57; H, 8.33. Calcd for C31H46O7Si: C, 66.63; H,
8.30.
54: [R]26D -12.0° (c 0.44, CHCl3); IR (neat) 3070, 2930, 1775,
1430, 1150, 1110, 1030, 703 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.05 (9H, s), 1.34 (3H, d, J ) 6.8 Hz), 1.46-1.60 (6H, m),
1.79 (1H, ddd, J ) 14.6, 8.3, 6.3 Hz), 1.94 (1H, ddd, J ) 14.6,
6.8, 3.9 Hz), 2.91 (1H, ddd, J ) 6.8, 6.3, 5.9 Hz), 3.35 (3H, s),
3.38 (3H, s), 3.66 (2H, t, J ) 6.4 Hz), 3.82 (1H, m), 4.02 (1H,
d, J ) 5.9 Hz), 4.60 (1H, brq, J ) 6.9 Hz), 4.64-4.71 (4H, m),
7.35-7.42 (6H, m), 7.65-7.67 (4H, m); 13C NMR (100 MHz,
CDCl3) δ 18.1, 19.2, 21.4, 26.8, 28.6, 32.6, 34.8, 39.1, 55.6, 55.9,
63.7, 76.2, 80.0, 80.2, 96.0, 96.2, 127.6, 129.5, 134.0, 135.5,
177.4; HRMS calcd for C31H46O7SiNa [M + Na]+ 581.2911,
found 581.2902. Anal. Found: C, 66.47; H, 8.16. Calcd for
31H46O7Si: C, 66.63; H, 8.30.
{8(E,Z)}-4,16,19,23-Tetr a (m eth oxym eth oxy)m u cocin -8-
en e-10-yn e (56). To a stirried solution of 2 (28.0 mg, 50 mmol)
and 3 (32.0 mg, 84 mmol) in Et3N (1 mL) were added (Ph3P)2-
PdCl2 (3.5 mg, 5 mmol) and CuI (3.0 mg, 16 mmol) at room
temperature, and the reaction mixture was stirred at room
mp 59-60 °C (hexane-ether), [R]24 -13.9° (c 0.11, CH2Cl2);
D
IR (CHCl3) 3421, 2925, 1747, 1456, 1079 cm-1; H NMR (500
1
MHz, CDCl3) δ 0.88 (3H, t, J ) 6.8 Hz), 1.20-1.78 (41H, m),
1.43 (3H, d, J ) 6.8 Hz), 1.82 (1H, m), 1.95-2.05 (2H, m), 2.11
(1H, m), 2.27 (1H, brs), 2.40 (1H, brdd, J ) 15.1, 8.3 Hz), 2.52
(1H, brd, J ) 15.1 Hz), 2.72 (1H, brs), 2.85 (1H, brs), 3.05 (1H,
ddd, J ) 8.8, 8.8, 2.4 Hz), 3.15 (1H, brt, J ) 6.3 Hz), 3.27 (1H,
ddd, J ) 9.3, 9.3, 4.9 Hz), 3.42 (1H, brt, J ) 7.3 Hz), 3.46 (1H,
m), 3.79 (1H, ddd, J ) 7.3, 7.3, 7.3 Hz), 3.82-3.90 (2H, m),
5.05 (1H, qd, J ) 6.8, 1.5 Hz), 7.18 (1H, m); 13C NMR (100
MHz, CDCl3) δ 14.1, 19.1, 22.7, 25.5, 26.2, 26.9, 28.3, 28.7,
28.8, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 32.0, 32.4, 32.6, 33.3,
35.6, 37.4, 69.9, 70.6, 73.5, 73.8, 78.0, 79.3, 80.1, 81.9, 82.0,
C
J . Org. Chem, Vol. 67, No. 16, 2002 5751

Takahashi and Nakata
131.2, 151.8, 174.6; HRMS calcd for C37H67O8 [M + H]+
to Dr. H. Koshino (RIKEN) for measurement of 2D-
NMR spectra, Ms. K. Harata (RIKEN) for mass spectral
measurements, and Dr. T. Chihara and his collaborators
in RIKEN for the elemental analyses.
639.4836, found 639.4833.
Ack n ow led gm en t. This work was supported by
Grant-in-Aid for Encouragement of Young Scientists
from the Ministry of Education, Science and Culture in
J apan and a Special Grant for Promotion of Research
from the Institute of Physical and Chemical Research
(RIKEN). We would like to thank Prof. J . L. McLaughlin
(Purdue University) for providing spectra of mucocin
and its related compounds. We also express our thanks
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 3, 4, 6, 32, and 56, general procedures, and
experimental details for compounds 3, 6, 11-15, 18-20, 22,
23b,c-25b,c, 39, 40, 45-52, and 55. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020211H
5752 J . Org. Chem., Vol. 67, No. 16, 2002