Asymmetric total synthesis of halicholactone

Article abstract of DOI:10.1021/jo001036c

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisatlylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)₃ complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons - Smith reaction. The use of RCM (ring-closing metathesis) methodology (4 → 35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.

Full text of DOI:10.1021/jo001036c

J . Org. Chem. 2001, 66, 81-88
81
Asym m etr ic Tota l Syn th esis of Ha lich ola cton e
Yasutaka Baba,† Goutam Saha,† Syusuke Nakao,† Chuzo Iwata,† Tetsuaki Tanaka,*,†
Toshiro Ibuka,‡,| Hirofumi Ohishi,‡ and Yoshiji Takemoto*,‡
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, J apan,
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita,
Osaka 565-0871, J apan, and Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara,
Takatsuki, Osaka 569-1094, J apan
takemoto@pharm.kyoto-u.ac.jp
Received J uly 10, 2000
The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bis-
allylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic
rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of
(diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was
successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The
use of RCM (ring-closing metathesis) methodology (4 f 35) was pivotal for the formation of a nine-
membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and
stereoselective, other oxylipins could be synthesized by the protocol described herein.
In tr od u ction
from a common intermediate. For this purpose, we
employed the modified Simmons-Smith reaction6 for the
regio- and stereoselective cyclopropanation and the RCM
(ring-closing metathesis) methodology7,8 for the formation
of an unsaturated or saturated lactone fragment. By this
flexible approach, various oxylipins could be synthesized
stereoselectively. As an example of this approach, the
Marine metabolites containing a trans-disubstituted
cyclopropane subunit and saturated and unsaturated
lactones of various ring sizes, which are called oxylipins,
are a growing class of natural products. Among these
compounds, halicholactone 11 and constanolactones 22 are
derived from eicosanoid with a C20 carbon chain, while
solandelactones 33 is thought to have originated from
docosanoid possessing a C22 carbon chain. These com-
pounds possess important and interesting biological
activities such as the inhibition of lipoxygenase and
farnesyl protein transferase. From these biological activi-
ties and unusual structural features, oxylipins have
attracted the wide attention of a number of synthetic
organic chemists. Whereas there have already been
several reports concerning the total synthesis of related
eicosanoids,4 the stereoselective construction of the ste-
reogenic centers of C9 to C12 still remained to be solved
in the synthesis of halicholactone.5 In planning our
approach, we hoped to develop a general and stereocon-
trolled route that will be sufficiently practical to facilitate
the synthesis of these compounds and their analogues
† Osaka University.
‡ Kyoto University.
present paper9 describes the asymmetric total synthesis
§ Osaka University of Pharmaceutical Sciences.
| Deceased J anuary 20, 2000.
(1) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett.
1989, 30, 4543-4546. (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stouk,
T. J .; Clardy, J . Tetrahedron Lett. 1991, 32, 2427-2430.
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2995-2998. (b) Nagle, D. G.; Gerwick, W. H. J . Org. Chem. 1994, 59,
7227-7237.
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2970-2971. (b) White, J . D.; J ennies, M. S. J . Am. Chem. Soc. 1995,
117, 6224-6233. (c) Nagasawa, T.; Onoguchi, Y.; Matsumoto, T.;
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Commun. 1995, 139-140. (b) Critcher, D. J .; Connolly, S.; Wills, M.
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S.; Wills, M. J . Org. Chem. 1997, 62, 6638-6657. (d) Mohapatr, D. K.;
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Chem., Int. Ed. Engl. 1997, 36, 2036-2055. (c) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413-4450. (d) Armstrong, S. K. J . Chem.
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1523-1533.(f) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-
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2000, 65, 482-493. (f) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.;
Schanz, H.-J .; Nolan, S. P. J . Org. Chem. 2000, 65, 2204-2207.
10.1021/jo001036c CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/09/2000

82 J . Org. Chem., Vol. 66, No. 1, 2001
Baba et al.
Sch em e 1. Retr osyn th etic An a lysis of
Ha lich ola cton e 1
Sch em e 2a
of halicholactone, isolated from the marine sponge Hali-
chondoria okadai by the Yamada group as lipoxygenase
inhibitors in 1989.1a
Resu lts a n d Discu ssion
a
Reagents and conditions: (a) TBSOTf, pyridine, 0 °C, 100%;
Retr osyn th etic An a lysis. Recognizing the impor-
tance of developing a flexible synthesis of 1, our synthetic
approach to a nine-membered unsaturated lactone in-
volves a Z-selective RCM reaction (Scheme 1). Thus,
disconnection of the C5-C6 double bond revealed the bis-
terminal olefin 4 as a potential key intermediate. This
compound could be synthesized from the alcohol 5 by
epoxidation with inversion of configuration at C8 followed
by vinylation and esterification with 5-hexenoic acid. We
envisioned the regio- and stereoselective introduction of
the desired cyclopropane ring into the C9-C11 olefin of
the bis-allylic alcohol 6 via modified Simmons-Smith
cyclopropanation to give 5. The key steps proposed for
the conversion of 8 to 6 include a regioselective introduc-
tion of the phenylsulfenyl groups and stereoselective
[2,3]-sigmatropic rearrangement10 for the incorporation
of the C12 stereocenter via sulfide 7. We planned to
synthesize the triol complex 8 using iron-tricarbonyl
chemistry,11 that is, a catalytic asymmetric alkylation of
achiral dialdehyde Fe(CO)3 complex 912 and subsequent
stereoselective dihydroxylation with OsO4.13
(b) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C, 99%; (c) DIBAL-H,
CH2Cl2, -78 °C, 97%; (d) (i) OsO4, Py, -20 °C; (ii) saturated
aqueous NaHSO3, 94%; (e) PivCL, Py, CH2Cl2, 0 °C to room
temperature, 97%; (f) TBSOTf, pyridine, 0 °C, 56% (89% based on
the consumed 8); (g) (ClCH2CO)2O, DMAP, CH2Cl2, 16a : 89%,
16b: 81%; (h) TMSSPh, Sc(OTf)3, CH2Cl2, -78 °C to room
temperature (62%); (i) Me2AlSPh, CH2Cl2, - 78 °C, 69%.
to give the corresponding R,â-unsaturated ester 12 (99%).
DIBAL-mediated reduction of 12, and sequential dihy-
droxylation of the resulting allylic alcohol 13 with OsO4
provided triol complex 8 (91%) as an inseparable dia-
stereoisomeric mixture with good stereoselectivity (R: â
ratio ∼9:1, detected from 500 MHz 1H NMR).13 The
protection of the primary hydroxyl group of 8 with PivCl
and TBSOTf gave 14a and 14b, respectively. Further-
more, the diols 14a and 14b were converted into the bis-
chloroacetoxy compounds 16a and 16b, respectively. At
this stage, the diastereoisomers contaminated in 16a and
16b were separated by silica gel column chromatography.
Confirmation of the relative stereochemical outcome of
the asymmetric alkylation and dihydroxylation was
provided by X-ray crystallographic analysis of 16b (see
Figure S1 in Supporting Information). We next examined
regio- and stereoselective introduction of a phenylsulfanyl
group in at least two synthetic intermediates by substitu-
tion with retention of configuration at C3.14 The diol 14b
was treated with TMSSPh/Sc(OTf)3 or CH(SPh)3/TsOH
in CH2Cl2 at room temperature, but the undesired
product 15 was obtained as the sole product. These
results indicate that the C15-hydroxyl group adjacent to
the Fe(CO)3 moiety tends to react faster than the C9-
hydroxyl group of the 1,2-diol moiety in the Lewis acid-
Syn th esis of th e P h en yl Su lfid e F e(CO)3 Com p lex
7. The sequence leading to the required compound 7 is
shown in Scheme 2. The known chiral aldehyde Fe(CO)3
complex 1012 was initially converted to the tert-butyldi-
methylsilyloxy (TBS) ether 11 (TBSOTf, pyridine, 100%)
which was then condensed with triethylphosphonoacetate
(9) For our preliminary communication of asymmetric total synthe-
sis of halicholactone, see: Takemoto, Y.; Baba, Y.; Saha, G.; Nakao,
S.; Iwata, C.; Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653-
3656.
(10) (a) Tang, R.; Mislow, K. J . Am. Chem. Soc. 1970, 92, 2100-
2104. (b) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-
155. (c) Bruckner, R. Comprehensive Organic Synthesis; Trost, B. M.;
Freming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 873-908. (d)
J ones-Hertzog, D. K.; J orgensen, W. L. J . Org. Chem. 1995, 60, 6682-
6683.
(11) For recent reviews of iron-tricarbonyl complexes, see: (a) Gre´e,
R. Synthesis 1989, 341-355. (b) Harrington, P. J . Transition Metals
in Total Synthesis; J ohn Wiley & Sons: New York, 1990. (c) Pearson,
A. J . Iron Compounds in Organic Synthesis; Academic Press: London,
1994. (d) Iwata, C.; Takemoto, Y. Chem. Commun. 1996, 2497-2504.
(e) Donaldson, W. A. Aldrich. Acta 1997, 30, 17-24. (f) Cox, L. R.; Ley,
S. V. Chem. Soc. Rev. 1998, 27, 301-314. (g) Kno¨lker, H.-J . Chem.
Soc. Rev. 1999, 28, 151-157.
(12) (a) Takemoto, Y.; Baba, Y.; Noguchi, I.; Iwata, C. Tetrahedron
Lett. 1996, 37, 3345-3346. (b) Takemoto, Y.; Baba, Y.; Honda, A.;
Nakao, S.; Noguchi, I.; Iwata, C.; Tanaka, T.; Ibuka, T. Tetrahedron
1998, 54, 15567-15580.
(13) The similar dihydroxyration of Fe(CO)3 complexes has been
reported: Gigou, A.; Lellouche, J .-P.; Beaucourt, J .-P.; Toupet, L.;
Gre´e, R. Angew. Chem., Int. Ed. Engl. 1989, 28, 755-757.
(14) (a) Uemura, M.; Minami, T.; Yamashita, Y.; Hiyoshi, K.;
Hayashi, Y. Tetrahedron Lett. 1987, 28, 641-644. (b) Roush, W. R.;
Wada, C. K. Tetrahedron Lett. 1994, 35, 7347-7350.

Asymmetric Total Synthesis of Halicholactone
J . Org. Chem., Vol. 66, No. 1, 2001 83
Sch em e 3a
Sch em e 4a
a
Reagents and conditions: (a) MeLi, Et2O, 0 °C, 90%; (b)
Pb(OAc)4, Na2CO3, CH2Cl2, -40 °C; tetraallyltin, Sc(OTf)3, CH3CN,
68% (28a :298b ) 1:1); (c) DIAD, AcOH, PPh3, THF; NaH, MeOH,
60% (70% based on the consumed 28a ); (d) C5H9CO2H, DCC,
DMAP, CH2Cl2, 82%; (e) (Cy3P)2RuCl2dCHPh, Ti(Oi-Pr)4, CH2Cl2,
(6mM) reflux (19%).
diastereomeric face-selectivity of the C9-C11 double
bond for the cyclopropanation of 6 could be controlled by
the hydroxyl or ether group at C8.16 To investigate the
hypothesis, several alcohols 20 and 26 and acetonides 22,
24-25 were prepared from 6 for the following cyclopro-
panation. In fact, the modified Simmons-Smith reaction
of 22 with Et2Zn (2.5 equiv) and CH2I2 (3 equiv) in CH2-
Cl2 at 0 °C gave rise to the bis-cyclopropanes 23 along
with mono-cyclopropane. Furthermore, neither the aceto-
nides 24 and 25 nor alcohol 26 afforded the corresponding
cyclopropyl compounds. Fortunately, we found that the
same reaction of 21 provided the desired mono-cyclopro-
panated product 5 in 68% yield as a single product (11%
recovery of 21). These results suggest that the C8-
hydroxyl group of 21 plays an important role in promot-
ing the regio- and stereoselective cyclopropanation, while
the isopropylidene acetal group of 22, 24, and 25 is
ineffective for the delivery of a methylene unit to the C9-
C11 double bond. In addition, by comparing the results
of the SEM ether 5 and the TBS ether 26, it was revealed
that the bulky protecting group (TBS group) of the C12-
hydroxyl group impeded the desired cyclopropanation due
to steric hindrance.
Syn th esis of Ha lich ola cton e 1. The final task in the
enantioselective synthesis of halicholactone 1 was the
formation of a nine-membered lactone possessing a (Z)-
olefin by the RCM reaction. Two alternative routes to 1
are presented in Schemes 4 and 5. The first elaboration
began with the synthesis of allylic alcohol 28b. The
requisite alcohol 28b was synthesized from 5 by the
following sequence: removal of the pivaloyl group with
MeLi (90%), cleavage of a 1,2-diol with Pb(OAc)4, and
introduction of an allyl group (68%, 28a /28b ) 1/1).17 The
stereochemistry of the C8 chiral center of 28a and 28b
was deduced from the modified MTPA ester method.18
Thus, esterification of 28b with both (R)- and (S)-R-
methoxy-R-(trifluoromethyl)phenylacetic acid (MTPA)
a
Reagents and conditions: (a) CAN K2CO3, MeCN, -30 °C,
97%; (b) m-CPBA, CH2Cl2, -78 °C, 95%; (c) P(OMe)3, MeOH, 75
°C, 88%; (d) SEMCl, i-Pr2NEt, n-Bu4Nl, CH2Cl2, 100%; (e) DIBAL-
H, CH2Cl2, -78 °C, 91%; (f) PivCl, Py-CH2Cl2, 0 °C to room
temperature, 64% (85% based on the consumed 20); (g) Et2Zn,
CH2I2, CH2Cl2, -20 °C, 69% (77% based on the consumed 21).
mediated nucleophilic substitution reaction. Then, the
reaction of 16a , bearing a more reactive leaving group,
with Me2AlSPh15 at -78 °C was conducted to give the
desired phenyl sulfide 7 in 69% yield as the single isomer.
A key requirement for the success of this reaction is that
an equimolar amount of the trimethylaluminum and
thiophenol should be premixed prior to the addition of
16a and the resulting mixture is kept at -78 °C;
otherwise, bis-phenyl sulfide was produced as a major
product. The relative stereochemistry of C9 and C15 in
the sulfides 7 and 15 was elucidated from the reported
examples and the well-known reaction mechanism.11,14
Furthermore, the elucidation was unambiguously con-
firmed by chemical transformation of 7 into halicholac-
tone 1.
Syn th esis of th e Cyclop r op a n e 5. The synthesis of
the cyclopropyl alcohol 5 by Simmons-Smith reaction is
outlined in Scheme 3. After decomplexation of 7 with
ceric(IV) ammonium nitrate (CAN), successive treatment
of the resulting sulfide 17 with m-CPBA and P(OMe)3 in
refluxing MeOH furnished the desired allylic alcohol 6
stereoselectively in 81% overall yield from 7 via sulfoxide
18. The S stereochemistry of the C12 chiral center and
the E geometry of the C9-C11 double bond were tenta-
tively assigned on the assumption that the [2,3]sigma-
tropic rearrangement proceeded via the well-precedented
chairlike transition state.10c This assumption was sub-
sequently confirmed by the total synthesis of halicholac-
tone 1. At this stage, we presumed that the group-
selectivity of the two olefins (C9dC11 vs C13dC14) and
(16) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307-1370. (b) Charette, A. B.; Marcoux, J .-F. Synlett 1995, 1197-
1207. (c) Barrett, A. G. M.; Doubleday: W. W.; Hamprecht, D.; Kasdorf,
K.; Tustin, G. J .; White, A. J . P.; Williams, D. J . Chem. Commun. 1997,
1693-1700. (d) Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997,
62, 584-594. (e) Sugimura, T.; Yoshikawa, M.; Mizuguchi, M.; Tai, A.
Chem. Lett. 1999, 831-832.
(17) Hachiya, I.; Kobayashi S. J . Org. Chem. 1993, 58, 6958-6960.
(18) (a) Ohtani, I.; Kusumi, J .; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096. (b) Yoshida, W. Y.; Bryan, P. J .;
Baker, B. J .; McClintock, J . B. J . Org. Chem. 1995, 60, 780-782.
(15) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Bull. Chem. Soc.
J pn. 1981, 54, 274-278.

84 J . Org. Chem., Vol. 66, No. 1, 2001
Baba et al.
TBAF21 (64%) and protection of the resulting diol 32,
providing the diacetate 33 (88%). The diacetate 4 was
prepared from 33 via 34 by a two-step sequence [i. acid-
catalyzed deprotection of the ethoxyethyl group (71%),
ii. DCC-mediated esterification (82%)]. After many ex-
periments on the RCM reaction of 4, it was revealed that
the reaction of 4 with the catalyst A in the presence of a
Sch em e 5a
8a
catalytic amount of Ti(Oi-Pr)4 under highly diluted
conditions (0.1 mM in CH2Cl2) gave rise to the desired
Z-isomer 35 in 72% yield along with the corresponding
dimer (11%). When the reaction was performed under
more than 1.0 mM concentration of 4, almost the same
amount of the dimer as that of the desired product 35
was produced (20-30% yield). The RCM reaction pro-
ceeded with exclusive (Z)-selectivity and the (E)-isomer
of 35 could not be detected under any reaction conditions.
Finally, the total synthesis of halicholactone 1 was
completed by methanolysis of two acetyl groups (61%).
The obtained product 1 was identical (1H NMR, 13C NMR,
IR, mass, and [R]D) in all respects to the reported data of
the natural halicholactone 1.1
a
Reagents and conditions: (a) ethyl vinyl ether, PPTS, CH2Cl2,
90%; (b) TBAF, MS 4A, 85 °C, DMPU, 64%; (c) Ac2O, Et3N, DMAP,
CH2Cl2, 88%; (d) PPTS, t-BuOH, 69% (71% bsed on the consumed
33); (e) 5-hexenoic acid, DCC, DMAP, CH2Cl2, 82%; (f) catalyst A,
Ti(Oi-Pr)4, CH2Cl2 (0.1 mM), reflux, 72%; (g) K2CO3, MeOH, 61%.
Con clu sion
In conclusion, we have achieved the asymmetric total
synthesis of halicholactone 1 from the chiral (diene)Fe-
(CO)3 complex 10. The Lewis acid-mediated regio- and
stereoselective nucleophilic substitution of the ester Fe-
(CO)3 complex (16a f 7) is the keystone of the strategy
for the stereospecific construction of the bis-allylic triol
derivative. The salient features of the synthesis are the
use of the modified Simmons-Smith reaction for the
regio- and stereoselective cyclopropanation (21 f 5) as
well as the ring-closing metathesis for the formation of
a nine-membered lactone (4 f 35). The highly stereose-
lective strategy described herein may be relevant to the
synthesis of other oxylipins possessing six- to eight-
membered saturated and unsaturated lactone fragments.
F igu r e 1. ∆δ ) δS - δR for (R)- and (S)-MPTA esters of 28b.
demonstrated positive chemical shift differences (∆δ )
δS - δR) for the protons on C9 through C15 (Figure 1),
while the protons on C5 through C7 showed negative
differences, which is consistent with C8 bearing an R
configuration. Although this manipulation gave the
undesired product 28a along with 28b, 28a was easily
converted into 28b in 70% yield via the standard Mit-
sunobu protocol.19 The subsequent assembly of the alco-
hol 28b and 5-hexenoic acid was easily performed by the
DCC-condensation procedure, giving rise to the ester 29
in 82% yield. The ring-closing metathesis (RCM)7,8 of the
resulting product 29 with Grubbs catalyst A20 afforded
the desired lactone 30 only in a disappointingly low yield
(19%) together with the recovered starting material (45%
yield) and the corresponding dimer (8% yield). We did
not optimize this reaction, because we encountered a
serious problem in the following reaction. Namely, re-
moval of the protecting groups (TBS and SEM groups)
of the obtained product 30 resulted only in decomposed
products due to the instability of the cyclopropane and
lactone units to the reaction conditions. We expected that
the problem could be overcome by replacement of the
protecting group of 30 from the TBS and SEM groups to
an acetyl group, and we next examined another route as
shown in Scheme 5. Treatment of alcohol 28b with ethyl
vinyl ether in the presence of PPTS (90%) was followed
by removal of the TBS and SEM groups of 31 with
Exp er im en ta l Section
(2S,5R,6R,2E,4E)-Tr ica r b on ylir on [(η4-2-5)-6-ter t-b u -
tyld im eth ylsilyloxyu n d eca -2,4-d ien a l] (11). To a stirred
solution of 109 (1.36 g, 4.22 mmol) in pyridine (15 mL) was
added TBSOTf (2.7 mL, 11.8 mmol) at 0 °C under a nitrogen
atmosphere. After 1.5 h, brine was added to the reaction
mixture, and the resulting mixture was extracted with AcOEt.
The extract was washed with brine, dried over MgSO4, and
then concentrated in vacuo, and pyridine was removed azeo-
tropically with toluene. The residue was purified by column
chromatography (SiO2, hexane/AcOEt ) 6/1) to gave 11 (1.83
g, 100%) as a yellow oil: Rf 0.55 (hexane/AcOEt ) 4:1); [R]28
D
+120.6 (c ) 1.11, CHCl3); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.10
(s, 3H), 0.89 (s, 12H), 1.25-1.34 (m, 6H), 1.36 (dd, 1H, J )
3.7, 7.9 Hz), 1.55-1.67 (m, 3H), 3.53 (m, 1H), 5.40 (dd, 1H, J
) 4.9, 8.5 Hz), 5.79 (dd, 1H, J ) 4.9, 7.9 Hz), 9.32 (d, 1H, J )
3.7 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.2, -3.8, 14.0, 18.1,
22.6, 24.3, 25.8 (3C), 31.6, 39.2, 55.1, 68.8, 74.3, 81.9, 87.5,
195.9, 208.5; IR (KBr) 2958, 2858, 2060, 1984, 1686 cm-1; MS
(EI) m/z (%) 408 (M+-CO, 0.2), 352 (M+ - 3CO, 52), 75 (100).
Anal. Calcd for C20H32FeO5Si: C, 55.04; H, 7.39. Found: C,
55.08; H, 7.32.
(4S,7R,8R,2E,4E,6E)-Tr ica r bon ylir on [eth yl (η4-4-7)-8-
ter t-bu tyld im eth ylsilyloxytr id eca -2,4,6-tr ien oa te] (12).
To a stirred suspension of NaH (washed with hexane, 148 mg,
6.17 mmol) and dry THF (5.5 mL) was added diethoxy-
phosphonoethyl acetate (1.2 mL, 6.17 mmol) at 0 °C under a
(19) Mitsunobu, O. Synthesis 1981, 1-28.
(20) (a) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs,
R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 100-110. (c)
Belderrain, T. R.; Grubbs, R. H. Organometallics 1997, 16, 4001-4003.
(21) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149-
7152.

Asymmetric Total Synthesis of Halicholactone
J . Org. Chem., Vol. 66, No. 1, 2001 85
nitrogen atmosphere. After 10 min, 11 (2.06 g, 4.72 mmol) in
dry THF (10 mL) was added to the reaction mixture, and the
resulting mixture was stirred for 20 min at 0 °C under a
nitrogen atmosphere. The reaction mixture was quenched with
ice-water and extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and then concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
hexane/AcOEt ) 40/1) to give 12 (2.38 g, 99%) as a yellow oil:
Rf 0.48 (hexane/AcOEt ) 10/1); [R]28D +164.6 (c ) 1.01, CHCl3);
1H NMR (CDCl3) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.89 (s, 12H),
1.28 (t, 3H, J ) 7.3 Hz), 1.32-1.54 (m, 7H), 1.60 (m, 2H), 1.75
(m, 1H), 3.44 (m, 1H), 4.17 (q, 2H, J ) 7.3 Hz), 5.22 (dd, 1H,
J ) 4.9, 8.5 Hz), 5.38 (dd, 1H, J ) 4.9, 7.3 Hz), 5.89 (d, 1H, J
) 15.3 Hz), 6.80 (dd, 1H, J ) 10.4, 15.3 Hz); 13C NMR (CDCl3,
67.8 MHz) δ -4.2, -3.7, 14.0, 14.2, 18.1, 22.6, 24.5, 25.9 (3C),
31.7, 39.2, 56.9, 60.3, 67.3, 74.7, 83.7, 85.1, 119.1, 148.2, 166.5,
210.4; IR (KBr) 2931, 2050, 1986, 1974, 1711, 1630 cm-1; MS
(EI) m/z (%) 422 (M+ - 2CO, 67), 290 (100). Anal. Calcd for
dry CH2Cl2 (2.7 mL) was added pivaloyl chloride (PivCl) (0.33
mL, 2.68 mmol) at 0 °C under a nitrogen atmosphere over a
period of 30 min. The reaction mixture was stirred for 1 h at
0 °C and at room temperature for 4 h. After brine was added
to the reaction mixture, and the resulting mixture was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 5/1) to give 14a (1.35 g, 97%) as a yellow oil: Rf 0.46 (hexane/
AcOEt ) 2/1); [R]30D +28.7 (c ) 0.87, CHCl3); 1H NMR (CDCl3)
δ 0.07 (s, 3H), 0.09 (s, 3H), 0.85-0.90 (m, 3H), 0.87 (s, 9H),
1.20 (s, 9H), 1.20-1.46 (m, 8H), 1.57 (ddd, 2H, J ) 2.4, 7.3,
14.6 Hz), 2.46 (br s, 1H), 2.51 (br s, 1H), 3.40-3.45 (m, 2H),
3.81 (br s, 1H), 4.14 (dd, 1H, J ) 6.1, 11.6 Hz), 4.19 (dd, 1H,
J ) 6.1, 11.6 Hz), 5.19 (dd, 1H, J ) 4.9, 8.5 Hz), 5.34 (dd, 1H,
J ) 4.9, 8.5 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.2, -3.7,
14.0, 18.1, 22.6, 24.4, 25.8 (3C), 27.8 (3C), 31.6, 38.8, 39.2, 60.8,
65.3, 67.2, 72.8 (2C), 74.7, 84.3, 84.6, 179.3, 210.0; IR (KBr)
3454, 2046, 1979, 1716 cm-1; MS (FAB) m/z 605 (M + Na)+.
Anal. Calcd for C27H46FeO8Si: C, 55.66; H, 7.95. Found: C,
55.72; H, 7.83.
C
24H38FeO6Si: C, 56.91; H, 7.56. Found: C, 57.11; H, 7.44.
(4S,7R,8R,2E,4E,6E)-Tr ica r b on ylir on [(η4-4-7)-8-ter t-
b u t yld im et h ylsilyloxyt r id eca -2,4,6-t r ien ol] (13). To a
stirred solution of 12 (2.38 g, 4.70 mmol) in dry CH2Cl2 (50
mL) was added DIBAL-H (0.95 M in toluene, 15 mL, 15.3
mmol) at -78 °C under a nitrogen atmosphere. After 15 min,
a saturated potassium sodium tartrate solution (18 mL) was
added to the reaction mixture at -78 °C, and the resulting
mixture was stirred at room temperature. The mixture was
extracted with AcOEt, and the extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 5/1) to give 13 (2.12 g, 97%) as a yellow oil: Rf 0.20 (hexane/
(2R,3S,4S,7R,8R,4E,6E)-Tr icar bon ylir on [(η4-4-7)-8-ter t-
bu tyld im eth ylsilyloxy-2,3-bis(ch lor oa cetoxy)tr id eca -4,6-
d ien yl] 2,2-Dim eth ylp r op a n oa te (16a ). To a stirred solution
of 14a (1.35 g, 2.32 mmol) in dry CH2Cl2 (20 mL) were added
4-(dimethylamino)pyridine (DMAP) (1.42 g, 11.6 mmol) and
chloracetic anhydride (1.79 g, 10.4 mmol) at 0 °C under a
nitrogen atmosphere. The reaction mixture was stirred for 1
h at 0 °C and at room temperature for 2 h. After brine was
added to the reaction mixture, and the resulting mixture was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 15/1) to give 16a (1.52 g, 89%) as a yellow oil: Rf 0.54 (CH2-
AcOEt ) 5/1); [R]23 +4.8 (c ) 0.96, CHCl3); 1H NMR (CDCl3)
D
δ 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 12H), 1.26-1.40 (m, 7H),
1.41-1.50 (m, 3H), 1.88 (t, 1H, J ) 9.2 Hz), 3.41 (ddd, 1H, J
) 4.9, 5.5, 8.5 Hz), 4.08 (m, 2H), 5.14 (dd, 1H, J ) 4.9, 8.5
Hz), 5.19 (dd, 1H, J ) 4.9, 7.9 Hz), 5.68 (dd, 1H, J ) 10.4,
15.3 Hz), 5.86 (dt, 1H, J ) 15.3, 5.5 Hz); 13C NMR (CDCl3,
67.8 MHz) δ -4.2, -3.7, 14.0, 18.1, 22.6, 24.6, 25.9 (3C), 31.7,
39.3, 61.0, 63.3, 66.3, 75.0, 82.3, 83.5, 130.2, 132.8, 211.6; IR
(KBr) 3437, 2044, 1979, 1616 cm-1; MS (EI) m/z (%) 409 (M+
+ 1 - 2CO, 0.5), 381 (M+ + 1 - 3CO, 1.2), 324 (1.3), 75 (100).
Anal. Calcd for C22H36FeO5Si: C, 56.89; H, 7.81. Found: C,
56.80; H, 7.74.
Cl2/hexane ) 2/1); [R]28 +12.1 (c ) 0.75, CHCl3); 1H NMR
D
(CDCl3) δ 0.04 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 0.88-0.90
(m, 3H), 0.98 (t, 1H, J ) 8.5 Hz), 1.16 (s, 9H), 1.18-1.42 (m,
7H), 1.54-1.58 (m, 2H), 3.45 (ddd, 1H, J ) 4.5, 4.9, 7.9 Hz),
4.07-4.15 (m, 1H), 4.11 (s, 4H), 4.20 (dd, 1H, J ) 7.9, 10.9
Hz), 4.95 (dd, 1H, J ) 2.4, 9.1 Hz), 5.17-5.22 (m, 2H), 5.48
(dd, 1H, J ) 4.8, 8.5 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.2,
-3.7, 13.9, 18.1, 22.6, 24.1, 25.8 (3C), 27.1 (3C), 31.7, 38.7,
39.0, 40.5, 40.8, 52.8, 60.0, 68.1, 74.3 (2C), 74.9, 83.6, 85.8,
(2R,3S,4S,7R,8R,4E,6E)-Tr icar bon ylir on [(η4-4-7)-8-ter t-
bu t yld im et h ylsilyloxyt r id eca -4,6-d ien yl-1,2,3-t r iol] (8).
To a stirred solution of 13 (2.12 g, 4.56 mmol) in pyridine (23
mL) was added OsO4 (1.19 g, 4.68 mmol) in pyridine (4.0 mL)
at -20 °C under an argon atmosphere. After 25 min, a
saturated NaHSO3 solution (45 mL) was added to the reaction
mixture and the resulting mixture was stirred for 12 h at room
temperature. The mixture was filtered through a pad of Celite,
and the residue was washed thoroughly with AcOEt (200 mL).
After the combined filtrates were concentrated to half volume,
it was poured into a saturated ammonium chloride, and the
resulting mixture was extracted with AcOEt. The extract was
washed with brine, dried over MgSO4, and then concentrated
in vacuo, and pyridine was removed azeotropically with
toluene. The residue was purified by column chromatography
(SiO2, hexane/AcOEt ) 2/3) to give the triol 8 (2.13 g, 94%) as
166.3, 166.8, 179.3, 210.0; IR (KBr) 2051, 1984, 1737 cm-1
MS (FAB) m/z 757 (M + Na)+. Anal. Calcd for C31H48Cl2FeO10
Si: C, 50.59; H, 6.57. Found: C, 50.54; H, 6.38.
;
-
(2R,3S,4S,7R,8R,4E,6E)-Tr icar bon ylir on [(η4-4-7)-8-ter t-
bu tyld im eth ylsilyloxy-2-ch lor oa cetoxy-3-p h en ylth iotr i-
d eca -4,6-d ien yl] 2,2-Dim eth ylp r op a n oa te (7). To a stirred
solution of 16a (242 mg, 0.330 mmol) in dry CH2Cl2 (3.3 mL)
was added Me2AlSPh (0.58 M in CH2Cl2-hexane, 2.9 mL, 1.65
mmol) at -78 °C under a nitrogen atmosphere. After 3 h, a
saturated NaHCO3 solution was added to the reaction mixture,
and the resulting mixture was extracted with AcOEt. The
extract was washed with brine, dried over MgSO4, and then
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, hexane/AcOEt ) 30/1) to give 7 (171
mg, 69%) as a yellow oil: Rf 0.51 (hexane/AcOEt ) 15/1 × 2);
[R]28 +2.9 (c ) 1.06, CHCl3); 1H NMR (CDCl3) δ 0.07 (s, 3H),
D
a yellow oil: Rf 0.23 (hexane/AcOEt ) 1/1); [R]30 +20.4 (c )
0.10 (s, 3H), 0.87-0.90 (m, 3H), 0.90 (s, 9H), 1.08 (t, 1H, J )
9.1 Hz), 1.17 (s, 9H), 1.21-1.43 (m, 7H), 1.54 (s br, 2H), 3.08
(dd, 1H, J ) 2.4, 10.4 Hz), 3.38-3.42 (m, 1H), 4.08 (s, 2H),
4.37 (dd, 1H, J ) 6.7, 11.5 Hz), 4.52 (dd, 1H, J ) 5.5, 11.6
Hz), 4.69 (dd, 1H, J ) 4.9, 8.5 Hz), 5.05 (dd, 1H, J ) 4.9, 8.6
Hz), 5.29 (ddd, 1H, J ) 2.4, 7.3, 9.8 Hz), 7.34-7.40 (m, 3H),
7.48-7.50 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) δ -4.2, -3.6,
14.0, 18.2, 22.6, 24.6, 25.9 (3C), 27.0 (3C), 31.5, 38.7, 39.1, 40.6,
55.1, 59.1, 62.4, 67.6, 74.7, 75.9, 83.0, 84.3, 128.8, 129.3 (2C),
132.7, 134.8 (2C), 166.4, 177.8, 210.3; IR (KBr) 2046, 1980,
1735 cm-1; MS (FAB) m/z 773 (M + Na)+. Anal. Calcd for
D
1.28, CHCl3); 1H NMR (CDCl3) δ 0.07 (s, 3H), 0.10 (s, 3H), 0.88
(s, 12H), 1.26-1.42 (m, 8H), 1.55-1.59 (m, 2H), 2.01 (br s, 1H),
2.49 (br s, 1H), 2.57 (br s, 1H), 3.43 (m, 1H), 3.53 (m, 1H),
3.70 (m, 1H), 3.78 (m, 2H), 5.21(dd, 1H, J ) 4.9, 8.5 Hz), 5.33
(dd, 1H, J ) 4.9, 7.9 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.2,
-3.7, 14.0, 18.1, 22.6, 24.8, 25.9 (3C), 31.7, 39.2, 61.4, 65.2,
67.2, 74.1, 74.7, 74.8, 83.2, 84.7, 211.4; IR (KBr) 3363, 2046,
1977, 1969 cm-1; MS (EI) m/z (%) 499 (M+ + 1, 0.07), 443 (M+
+ 1 - 2CO, 0.2), 415 (M+ + 1 - 3CO, 0.5), 75 (100). Anal.
Calcd for C22H38FeO7Si: C, 53.01; H, 7.68. Found: C, 53.11;
H, 7.57.
C
35H51ClFeO8SSi: C, 55.95; H, 6.84. Found: C, 56.02; H, 6.85.
(2R ,3S ,4S ,7R ,8R ,4E ,6E )-Tr ica r b on ylir on [(η4-4-7)-8-
ter t-bu tyld im eth ylsilyloxy-2,3-d ih yd r oxytr id eca -4,6-d i-
en yl] 2,2-Dim eth ylp r op a n oa te (14a ). To a stirred solution
of 8 (1.14 g, 2.68 mmol) in a mixture of pyridine (2.7 mL) and
(2R,3R,8R,4E,6E)-8-ter t-Bu tyld im eth ylsilyloxy-2-ch lo-
r oa cetoxy-3-p h en ylth iotr id eca -4,6-d ien yl 2,2-Dim eth yl-
p r op a n oa te (17). To a vigorous stirred suspension of 7 (159
mg, 0.212 mmol), potassium carbonate (146 mg, 1.05 mmol),

86 J . Org. Chem., Vol. 66, No. 1, 2001
Baba et al.
and CH3CN (2.5 mL) was added a solution of ceric(IV)
ammonium nitrate (CAN) (285 mg, 0.520 mmol) in dry CH3-
CN (4.5 mL) at -30 °C under a nitrogen atmosphere. After
30 mim, a saturated NaHCO3 solution was added to the
reaction mixture, and the resulting mixture was extracted with
AcOEt. The extract was washed with brine, dried over MgSO4,
and then concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexane/AcOEt ) 5/1) to give
18.2, 22.6, 24.7, 25.9 (3C), 27.1 (3C), 31.7, 38.1, 38.8, 40.7, 64.4,
65.2, 72.3, 73.2, 74.5, 91.4, 124.6, 127.1, 135.3, 137.6, 166.2,
177.9; IR (KBr) 1737 cm-1; MS (FAB) m/z 671 (M + Na)+. Anal.
Calcd for C32H61ClO7Si2: C, 59.18; H, 9.46. Found: C, 59.07;
H, 9.36.
(2R,5R,8R,3E,6E)-8-ter t-Bu t yld im et h ylsilyloxy-2-h y-
d r oxy-5-(2-tr im eth ylsilyl)eth oxym eth oxytr id eca -3,6-d i-
en yl 2,2-Dim eth ylp r op a n oa te (21). To a stirred solution of
19 (1.00 g, 1.50 mmol) in dry CH2Cl2 (13 mL) was added
DIBAL-H (1.0 M in toluene, 9.2 mL, 9.24 mmol) at -78 °C
under a nitrogen atmosphere. After 15 min, a saturated
potassium sodium tartrate solution (9.5 mL) was added to the
reaction mixture at -78 °C, and the resulting mixture was
stirred at room temperature. The mixture was extracted with
AcOEt, and the extract was washed with brine, dried over
MgSO4, and then concentrated in vacuo. The residue was
purified by column chromatography (SiO2, hexane/AcOEt )
2/1) to give diol 20 (684 mg, 84%) as a colorless oil. To a stirred
solution of 20 (684 mg, 1.40 mmol) in a mixture of pyridine
(1.4 mL) and dry CH2Cl2 (1.4 mL) was added PivCl (0.18 mL,
1.47 mmol) at 0 °C. The reaction mixture was stirred for 30
min at 0 °C and at room temperature for 12 h. After brine
was added to the reaction mixture, the resulting mixture was
extracted with AcOEt. The extracts were washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 5/1 to 4/1 to 1/1) to give 21 (517 mg, 64%) and 20 (138 mg,
17 (125 mg, 97%) as a colorless oil: Rf 0.40 (hexane/AcOEt )
1
20/1 × 2); [R]28 +18.2 (c ) 1.06, CHCl3); H NMR (CDCl3) δ
D
0.00 (s, 3H), 0.03 (s, 3H), 0.86-0.92 (m, 3H), 0.88 (s, 9H), 1.14-
1.56 (m, 8H), 1.17 (s, 9H), 3.86 (t, 1H, J ) 8.8 Hz), 4.01 (d,
2H, J ) 2.4 Hz), 4.08 (dt, 1H, J ) 6.1, 12.2 Hz), 4.13 (dd, 1H,
J ) 7.3, 12.2 Hz), 4.44 (dd, 1H, J ) 3.0, 12.2 Hz), 5.32 (ddd,
1H, J ) 3.0, 7.3, 10.0 Hz), 5.43 (dd, 1H, J ) 6.1, 14.6 Hz),
5.58 (dd, 1H, J ) 6.1, 14.6 Hz), 5.94 (dd, 1H, J ) 10.9, 15.2
Hz), 6.04 (dd, 1H, J ) 10.9, 15.2 Hz), 7.27-7.31 (m, 3H), 7.39-
7.41 (m, 2H); 13C NMR (CDCl3, 67.8 MHz) δ -4.8, -3.4, 14.0,
18.2, 22.5, 24.8, 25.8 (3C), 27.1 (3C), 31.7, 38.1, 38.7, 40.6, 52.8,
63.3, 72.7, 74.4, 126.2, 127.4, 128.0, 128.9, 132.6 (2C), 133.8,
133.9 (2C), 138.9, 166.6, 177.9. IR (KBr) 1766 cm-1; MS (FAB)-
m/z 633 (M + Na)+. Anal. Calcd for C32H51ClFeO5SSi: C, 62.86;
H, 8.40. Found: C, 62.73; H, 8.15.
(2R,5S,8R,3E,6E)-8-ter t-Bu tyld im eth ylsilyloxy-2-ch lo-
r oa cetoxy-5-h yd r oxytr id eca -3,6-d ien yl 2,2-Dim eth ylp r o-
p a n oa te (6). To a stirred solution of 17 (165 mg, 0.270 mmol)
in dry CH2Cl2 (2.2 mL) was added m-CPBA (90%, 517 mg,
0.270 mmol) at -78 °C. After 30 mim, a saturated NaHCO3
solution was added to the reaction mixture, and the resulting
mixture was extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and then concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
hexane/AcOEt ) 5/1) to give sulfoxide 18 (161 mg, 95%) as a
colorless oil. To a stirred solution of 18 (161 mg, 0.257 mmol)
in MeOH (2.5 mL) was added trimethyl phosphite (75.7 µL,
0.642 mmol) under a nitrogen atmosphere, and the reaction
mixture was stirred at 65 °C for 1.5 h. The reaction mixture
was concentrated in vacuo. The residue was purified by column
chromatography (SiO2, hexane/AcOEt ) 8/1) to give 6 (133 mg,
20%). 21: a colorless oil; Rf 0.48 (hexane/AcOEt ) 2/1); [R]25
D
-11.1 (c ) 1.45, CHCl3); 1H NMR (CDCl3) δ 0.003 (s, 3H), 0.015
(s, 9H), 0.03 (s, 3H), 0.85-0.90 (m, 3H), 0.87 (s, 9H), 0.92 (t,
2H, J ) 8.5 Hz), 1.18-1.50 (m, 8H), 1.21 (s, 9H), 2.12 (d, 1H,
J ) 4.2 Hz), 3.56-3.67 (m, 2H), 4.01 (dd, 1H, J ) 6.7, 11.6
Hz), 4.09 (dt, 1H, J ) 14.6, 6.1 Hz), 4.15 (dd, 1H, J ) 3.6, 11.6
Hz), 4.37-4.41 (m, 1H), 4.57 (t, 1H, J ) 6.1 Hz), 4.64 (d, 1H,
J ) 6.7 Hz), 4.67 (d, 1H, J ) 6.7 Hz), 5.46 (dd, 1H, J ) 7.3,
15.2 Hz), 5.66 (dd, 1H, J ) 6.1, 15.2 Hz), 5.70 (dd, 1H, J )
5.5, 15.8 Hz), 5.79 (dd, 1H, J ) 5.5, 15.2 Hz); 13C NMR (CDCl3,
75.5 MHz) δ -4.8, -4.2, -1.4 (3C), 14.0, 18.0, 18.2, 22.6, 24.9,
25.9 (3C), 27.2 (3C), 31.7, 38.2, 38.8, 65.1, 67.8, 70.4, 72.8, 75.2,
91.4, 127.6, 130.0, 132.3, 137.2, 178.6; IR (KBr) 3467, 1733
cm-1; MS (FAB) m/z 595 (M + Na)+. Anal. Calcd for C30H60O6-
Si2: C, 62.88; H, 10.55. Found: C, 62.57; H, 10.36.
88%) as a colorless oil: Rf 0.46 (hexane/AcOEt ) 2/1); [R]26
D
+16.7 (c ) 0.92, CHCl3); 1H NMR (CDCl3) δ 0.003 (s, 3H), 0.031
(s, 3H), 0.85-0.90 (m, 3H), 0.88 (s, 9H), 1.18 (s, 9H), 1.20-
1.47 (m, 8H), 1.66-1.70 (m, 1H), 4.05 (s, 2H), 4.06-4.11 (m,
2H), 4.27 (dd, 1H, J ) 3.0, 11.6 Hz), 4.65 (t, 1H, J ) 4.8 Hz),
5.57 (dd, 1H, J ) 6.7, 15.2 Hz), 5.62 (ddd, 1H, J ) 3.0, 7.3, 9.3
Hz), 5.67 (dd, 1H, J ) 1.2, 7.9 Hz), 5.70 (dt, 1H, J ) 1.2, 7.9
Hz), 5.90 (dd, 1H, J ) 5.5, 15.2 Hz); 13C NMR (CDCl3, 67.8
MHz) δ -4.8, -4.3, 14.0, 18.2, 22.6, 24.8, 25.8 (3C), 27.1 (3C),
31.7, 38.0, 38.8, 40.7, 63.4, 71.9, 72.5, 73.2, 123.5, 129.4, 135.9,
137.0, 166.3, 177.9; IR (KBr) 3523, 1736 cm-1; MS (FAB) m/z
541 (M + Na)+; HRMS (FAB) Calcd for C26H47ClNaO6Si (M +
Na)+: 541.2728. Found: 541.2723.
(2R)-2-Hyd r oxy-2-{(1R,2R)-2-[(1R,4R,2E)-4-ter t-bu tyld i-
m eth ylsilyloxy-1-(2-tr im eth ylsilyl)eth oxym eth oxyn on -2-
en yl]cyclop r op yl}eth yl 2,2-Dim eth ylp r op a n oa te (5). To
a stirred solution of 21 (186 mg, 0.324 mmol) in dry CH2Cl2
(3.5 mL) was added diethyl zinc (1.0 M in hexane, 0.81 mL,
0.812 mmol) at -20 °C under an argon atmosphere. After 10
min, diiodomethane (78.2 µL, 0.972 mmol) was added dropwise
to the mixture. After 10 min, the solution turned to cloudy
and stirring was continued for 8 h. After a saturated NH4Cl
solution was added to the mixture, and the resulting mixture
was extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 10/1) to give 21 (21 mg, 11%) and 5 (131 mg, 69%). 5: a
(2R,5S,8R,3E,6E)-8-ter t-Bu tyld im eth ylsilyloxy-2-ch lo-
r oa cetoxy-5-(2-tr im eth ylsilyl)eth oxym eth oxytr id eca -3,6-
d ien yl 2,2-Dim eth ylp r op a n oa te (19). To a stirred solution
of 6 (809 mg, 1.56 mmol) in dry CH2Cl2 (10 mL) were added
tetrabutylammonium iodide (28.8 mg, 0.078 mmol), diisopro-
pylethylamine (1.1 mL, 6.24 mmol), and 2-(trimethylsilyl)-
ethoxymethyl chloride (0.83 mL, 4.67 mmol) at 0 °C under a
nitrogen atmosphere. The reaction mixture was stirred at 0
°C for 1 h and at room temperature for 10 h. After brine was
added to the reaction mixture, and the resulting mixture was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 20/1) to give 19 (1.01 g, 100%) as a colorless oil: Rf 0.60
colorless oil; Rf 0.62 (hexane/AcOEt ) 4/1× 3); [R]26 -44.4 (c
D
) 1.11, CHCl3); 1H NMR (CDCl3) δ 0.017 (s, 9H), 0.04 (s, 6H),
0.63-0.66 (m, 1H), 0.68-0.76 (m, 1H), 0.85-0.94 (m, 6H), 0.88
(s, 9H), 0.99-1.03 (m, 1H), 1.19-1.34 (m, 6H), 1.21 (s, 9H),
1.40-1.46 (m, 2H), 2.04-2.05 (m, 1H), 3.38 (s br, 1H), 3.49
(ddd, 1H, J ) 6.1, 10.4, 14.0 Hz), 3.63 (t, 1H, J ) 7.3 Hz), 3.72
(ddd, 1H, J ) 6.1, 10.4, 14.0 Hz), 4.05 (dd, 1H, J ) 7.3, 11.6
Hz), 4.10 (ddd, 1H, J ) 5.6, 6.1, 11.6 Hz), 4.22 (dd, 1H, J )
3.0, 11.6 Hz), 4.63 (s, 2H), 5.44 (dd, 1H, J ) 7.3, 15.2 Hz),
5.63 (dd, 1H, J ) 6.1, 15.2 Hz);13C NMR (CDCl3, 75.5 MHz) δ
-4.8, -4.3, -1.4 (3C), 7.8, 14.0, 18.1, 18.21, 18.27, 20.2, 22.6,
24.9, 25.9 (3C), 27.2 (3C), 31.7, 38.3, 38.8, 65.0, 68.5, 72.5, 72.6,
77.6, 91.5, 127.5, 137.4, 178.8; IR (KBr) 3491, 1732 cm-1; MS
(EI) m/z (%) 529 (M+ - t-Bu, 23), 439 (M+ - OSEM, 41), 73
(100); HRMS (EI) Calcd for C27H53O6Si2 (M+ - t-Bu): 529.3380.
Found: 529.3376.
(hexane/AcOEt ) 2/1); [R]24 +8.7 (c ) 1.14, CHCl3); 1H NMR
D
(CDCl3) δ 0.001 (s, 3H), 0.016 (s, 9H), 0.032 (s, 3H), 0.86-
0.88 (m, 3H), 0.88 (s, 9H), 0.92 (t, 2H, J ) 8.5 Hz), 1.15-1.58
(m, 8H), 1.18 (s, 9H), 3.57-3.66 (m, 2H), 4.04 (s, 2H), 4.04-
4.12 (m, 2H), 4.28 (dd, 1H, J ) 3.6, 12.2 Hz), 4.58 (t, 1H, J )
6.7 Hz), 4.62 (d, 1H, J ) 7.3 Hz), 4.64 (d, 1H, J ) 6.7 Hz),
5.44 (dd, 1H, J ) 7.3, 15.2 Hz), 5.62 (ddd, 1H, J ) 3.6, 7.3, 9.1
Hz), 5.64-5.69 (m, 2H), 5.83 (dd, 1H, J ) 6.1, 15.2 Hz); 13C
NMR (CDCl3, 75.5 MHz) δ -4.8, -4.3, -1.4 (3C), 14.0, 18.0,
(2R)-2-{(1R,2R)-2-[(1R,4R,2E)-4-ter t-Bu tyldim eth ylsilyl-
oxy-1-(2-tr im eth ylsilyl)eth oxym eth oxyn on -2-en yl]cyclo-
p r op yl}eth a n e-1,2-d iol (27). To a stirred solution of 5 (107

Asymmetric Total Synthesis of Halicholactone
J . Org. Chem., Vol. 66, No. 1, 2001 87
mg, 0.183 mmol) in dry Et2O (1.5 mL) was added MeLi (1.0 M
in Et2O, 0.92 mL, 0.915 mmol) at 0 °C under a nitrogen
atmosphere. After 1 h, water was added to the reaction
mixture, and the resulting mixture was extracted with AcOEt.
The extract was washed with brine, dried over MgSO4, and
then concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexane/AcOEt ) 3/1) to give
27 (83.0 mg, 90%) as a colorless oil: Rf 0.31 (hexane/AcOEt )
2/1); [R]26D -58.2 (c ) 0.25, CHCl3); 1H NMR (CDCl3) δ -0.005
(s, 3H), 0.016 (s, 9H), 0.04 (s, 3H), 0.61-0.68 (m, 2H), 0.86-
0.96 (m, 6H), 0.89 (s, 9H), 0.97-1.03 (m, 1H), 1.26-1.53 (m,
8H), 2.04 (m, 1H), 2.26 (m, 1H), 3.12 (s br, 1H), 3.46-3.51 (m,
1H), 3.53-3.60 (m, 1H), 3.62-3.68 (m, 1H), 3.70-3.75 (m, 2H),
4.10 (dt, 1H, J ) 5.4, 5.4 Hz), 4.62 (s, 2H), 5.39 (dd, 1H, J )
7.9, 15.8 Hz), 5.63 (dd, 1H, J ) 5.5, 15.2 Hz); 13C NMR (CDCl3,
75.5 MHz) δ -4.8, -4.4, -1.5 (3C), 8.1, 14.0, 18.08, 18.14, 18.2,
20.6, 22.6, 24.8, 25.8 (3C), 31.7, 38.3, 65.0, 66.6, 72.4, 75.5,
77.5, 91.4, 126.7, 137.9; IR (KBr) 3367 cm-1; MS (FAB) m/z
525 (M + Na)+; HRMS (FAB) Calcd for C26H54NaO5Si2 (M +
Na)+: 525.3408. Found: 525.3398.
warmed to room temperature and then stirred for at room
temperature for 16 h. Solvent was removed in vacuo, the
residue was diluted with AcOEt, washed with a saturated
NaHCO3 solution and brine, dried over MgSO4, and then
concentrated in vacuo. After the residue was diluted with
MeOH, NaH (60% in oil, 97.5 mg, 2.43 mmol) was added to
the mixture. The resulting mixture was stirred for 30 min at
room temperature. After water was added to the reaction
mixture, MeOH was removed in vacuo, and the residue was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 10/1 to 5/1) to give 28b (30.2 mg, 60%) and 28a (7.7 mg,
15%).
(1S )-1-{(1R ,2R )-2-[(1R ,4R ,2E )-4-t er t -Bu t yld im e t h yl-
silyloxy-1-(2-tr im eth ylsilyl)eth oxym eth oxyn on -2-en yl]-
cyclop r op yl}bu t-3-en yl Eth oxyeth yl Eth er (31). To a
stirred solution of 28b (84.3 mg, 0.164 mmol) in dry CH2Cl2
(1.5 mL) were added ethyl vinyl ether (37.3 µL, 0.493 mmol)
and PPTS (10.3 mg, 0.0410 mmol) at room temperature. After
15 h, a saturated NaHCO3 solution was added to the reaction
mixture, and the resulting mixture was extracted with AcOEt.
The extract was washed with brine, dried over MgSO4, and
then concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexane/AcOEt ) 15/1) to give
(1R )-1-{(1R ,2R )-2-[(1R ,4R ,2E )-4-t er t -Bu t yld im e t h yl-
silyloxy-1-(2-tr im eth ylsilyl)eth oxym eth oxyn on -2-en yl]-
cyclop r op yl}bu t-3-en -1-ol (28a ) a n d (1S)-1-{(1R,2R)-2-
[(1R,4R,2E)-4-ter t-Bu tyld im eth ylsilyloxy-1-(2-tr im eth yl-
silyl)eth oxym eth oxyn on -2-en yl]cyclop r op yl}bu t-3-en -1-
ol (28b). To a stirred suspension of 27 (377 mg, 0.750 mmol),
Na2CO3 (95.4 mg, 0.900 mmol), and dry CH2Cl2 (5.0 mL) was
added lead acetate (90%, 406 mg, 0.825 mmol) at -40 °C. The
reaction mixture was stirred from -40 °C to 0 °C for 1.5 h
and at room temperature for 30 min and then filtered through
a pad of SiO2. The filtrate was concentrated in vacuo to give
aldehyde (288 mg). The crude aldehyde was diluted with dry
CH3CN (5.0 mL), and tetraallyltin (44.2 µL, 0.184 mmol) and
Sc(OTf)3 (4.5 mg, 9.20 µmol) were added to the mixture. The
resulting mixture was stirred for 1 h at room temperature.
After brine was added to the reaction mixture, the resulting
mixture was extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and then concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
hexane/AcOEt ) 10/1) to give 28b (107 mg, 34%) and 28a (106
mg, 34%). 28b: a colorless oil; Rf 0.40 (hexane/AcOEt ) 5/1);
31 (86.0 mg, 90%) as a colorless oil: Rf 0.88 (hexane/AcOEt )
1
7/1); [R]24 -54.4 (c ) 0.92, CHCl3); H NMR (CDCl3) δ 0.02
D
(s, 9H), 0.038 (s, 3H), 0.041 (s, 3H), 0.39 (ddd, 1/2H, J ) 4.9,
4.9, 8.5 Hz), 0.50-0.58 (m, 1+1/2H), 0.76-0.97 (m, 6H), 0.89
(s, 9H), 1.01-1.08 (m, 1H), 1.17 (q, 3H, J ) 7.3 Hz), 1.12-
1.31 (m, 6H), 1.25 (d, 3H, J ) 5.5 Hz), 1.35-1.45 (m, 2H),
2.29-2.34 (m, 2H), 3.16 (m, 1H), 3.43-3.75 (m, 5H), 4.10 (m,
1H), 4.62-4.64 (m, 2H), 4.77 (q, 1/2H, J ) 5.5 Hz), 4.79 (q,
1/2H, J ) 5.5 Hz), 5.00-5.09 (m, 2H), 5.47 (dd, 1H, J ) 7.3,
15.3 Hz), 5.65 (dd, 1H, J ) 6.7, 15.3 Hz), 5.82-5.95 (m, 1H);
13C NMR (CDCl3, 75.5 MHz) δ -4.8, -4.33, -4.28, -1.4 (3C),
6.6, 7.7, 14.0, 15.1, 18.1, 18.2, 19.3, 19.8, 20.2, 20.4, 21.3, 21.9,
22.6, 24.9, 25.0, 25.9, 31.8, 38.3, 39.4, 40.4, 59.0, 59.2, 64.9,
72.5, 72.7, 77.6, 77.8, 77.9, 91.4, 91.5, 97.8, 116.4, 116.8, 127.5,
127.8, 134.9, 135.4, 136.8, 137.4; IR (KBr) 2931, 1641, 1096,
1030 cm-1; MS (FAB) m/z 607 (M + Na)+; HRMS (FAB) Calcd
for C32H64NaO5Si2 (M + Na)+: 607.4190. Found: 607.4190.
(1R,4R,2E)-1-{(1R,2R)-2-[(1S)-1-Eth oxyeth oxybu t-3-en yl]-
cyclop r op yl}n on -2-en e-1,4-d iol (32). To a solution of 31
(83.0 mg, 0.142 mmol) in THF was added TBAF (1.0 M in THF,
1.0 mL, 1.06 mmol), and THF was removed in vacuo. To the
residue were added powdered molecular sieves 4A (100 mg)
and DMPU (1.0 mL), and the resulting mixture was stirred
for 18 h at 85 °C. The reaction mixture was directly purified
by column chromatography (SiO2, hexane/AcOEt ) 1/1) to give
32 (30.8 mg, 64%) as a colorless oil: Rf 0.49 (hexane/AcOEt )
[R]26 -52.3 (c ) 1.08, CHCl3); 1H NMR (CDCl3) δ 0.019 (s,
D
9H), 0.02 (s, 3H), 0.04 (s, 3H), 0.54 (ddd, 1H, J ) 4.3, 4.9, 8.5
Hz), 0.60 (ddd, 1H, J ) 4.9, 4.9, 8.5 Hz), 0.76-0.90 (m, 5H,
C16-H), 0.89 (s, 9H), 0.92-0.97 (m, 1H), 1.02 (m, 1H), 1.26
(m, 6H), 1.42-1.46 (m, 2H), 1.70 (s, 1H), 2.28 (ddd, 1H, J )
6.7, 7.9, 13.4 Hz), 2.37 (m, 1H), 3.07 (dt, 1H, J ) 7.9, 12.8
Hz), 3.52 (ddd, 1H, J ) 6.7, 10.4, 14.0 Hz), 3.67-3.75 (m, 2H),
4.10 (q, 1H, J ) 6.1 Hz), 4.64 (d, 1H, J ) 6.7 Hz), 4.67 (d, 1H,
J ) 7.3 Hz), 5.09-5.14 (m, 2H), 5.47 (dd, 1H, J ) 7.3, 15.3
Hz), 5.65 (dd, 1H, J ) 5.5, 15.3 Hz), 5.87 (m, 1H);13C NMR
(CDCl3, 75.5 MHz) δ -4.8, -4.3, -1.5 (3C), 8.2, 14.0, 18.1, 18.2,
21.3, 21.8, 22.6, 24.9, 25.9 (3C), 31.7, 38.3, 41.4, 65.0, 72.6,
74.1, 77.9, 91.4, 117.5, 127.2, 134.7, 137.4; IR (KBr) 3439, 1641
cm-1; MS (FAB) m/z 519 (M + Li)+; HRMS (FAB) Calcd for
1/1); [R]24 -2.8 (c ) 1.48, CHCl3); 1H NMR (CDCl3) δ 0.42
D
(ddd, 1/2H, J ) 5.5, 5.5, 8.5 Hz), 0.49 (ddd, 1/2H, J ) 4.9, 4.9,
8.5 Hz), 0.55-0.60 (m, 1H), 0.89 (t, 3H, J ) 5.5 Hz), 0.94 (m,
1H), 1.07-1.13 (m, 1H), 1.17 (q, 3H, J ) 7.3 Hz), 1.26-1.34
(m, 6H), 1.29 (d, 3H, J ) 5.5 Hz), 1.34-1.53 (m, 2H), 1.71 (br
s, 1H), 2.12 (br s, 1H), 2.32-2.38 (m, 2H), 3.05 (dt, 1/2H, J )
5.5, 13.4 Hz), 3.12 (dt, 1/2H, J ) 6.4, 14.0 Hz), 3.46-3.61 (m,
2H), 3.70 (m, 1/2H), 3.84 (m, 1/2H), 4.10 (dt, 1H, J ) 6.1, 6.1
Hz), 4.77 (q, 1/2H, J ) 5.5 Hz), 4.90 (q, 1/2H, J ) 5.5 Hz),
C
28H56LiO4Si2 (M + Li)+: 519.3877. Found: 519.3863; 28a : a
colorless oil; Rf 0.30 (hexane/AcOEt ) 5/1); [R]26 -63.1 (c )
D
1
0.67, CHCl3); H NMR (CDCl3) δ: 0.019 (s, 9H), 0.02 (s, 3H),
0.04 (s, 3H), 0.61-0.68 (m, 2H), 0.86-0.91 (m, 6H), 0.89 (s,
9H), 0.92 (m, 1H), 1.26 (m, 6H), 1.43 (m, 2H), 1.60 (s, 1H),
2.26 (ddd, 1H, J ) 6.7, 7.9, 13.4 Hz), 2.39 (m, 1H), 3.08 (m,
1H), 3.46-3.57 (m, 2H), 3.73 (m, 1H), 4.12 (m, 1H), 4.63 (s,
2H), 5.11-5.15 (m, 2H), 5.48 (dd, 1H, J ) 7.9, 15.9 Hz), 5.63
(dd, 1H, J ) 5.5, 15.9 Hz), 5.85 (m, 1H); 13C NMR (CDCl3, 75.5
MHz) δ -4.8, -4.3, -1.4 (3C), 8.7, 14.0, 18.1, 18.2, 21.1, 22.1,
22.6, 24.9, 25.9 (3C), 31.8, 38.4, 41.8, 64.9, 72.5, 74.0, 78.1,
91.3, 118.0, 127.6, 134.7, 137.2; IR (KBr) 3439, 1641 cm-1; MS
(FAB) m/z 519 (M + Li)+; HRMS (FAB) Calcd for C28H56LiO4-
Si2 (M + Li)+: 519.3877. Found: 519.3892.
Con ver sion of 28a in to 28b by Mitsu n obu P r otocol. To
a solution of 28a (50.6 mg, 0.0987 mmol) in dry THF (1.0 mL)
were added PPh3 (70.0 mg, 0.266 mmol) and AcOH (15.2 µL,
0.266 mmol) at room temperature. The mixture was cooled to
0 °C, and DIAD (62.2 µL, 0.316 mmol) was added to the
reaction mixture. After 10 min, the resulting mixture was
5.03-5.10 (m, 2H), 5.65-5.80 (m, 2H), 5.82-5.93 (m, 1H); 13
C
NMR (CDCl3, 75.5 MHz) δ 7.0, 7.6, 14.0, 15.2, 15.4, 19.7, 19.8,
20.2, 22.5, 23.9, 24.0, 25.08, 25.13, 31.7, 37.1, 37.2, 39.6, 40.4,
58.9, 59.2, 72.1, 72.3, 73.7, 74.4, 77.9, 79.3, 97.7, 98.3, 116.6,
117.0, 131.4, 131.6, 134.0 134.1, 134.6, 135.1; IR (KBr) 3401,
2931, 1641, 1096, 1032 cm-1; MS (FAB) m/z 363 (M + Na)+;
HRMS (FAB) Calcd for C20H36NaO4 (M+Na)+: 363.2511.
Found: 363.2515.
(1R,4R,2E)-4-Acetoxy-1-{(1R,2R)-2-[(1S)-1-eth oxyeth ox-
ybu t-3-en yl]cyclop r op yl}n on -2-en yl Aceta te (33). To a
stirred solution of 32 (30.0 mg, 0.0881 mmol) in dry CH2Cl2
(1.0 mL) were added Et3N (49.1 µL, 0.352 mmol) and DMAP
(0.5 mg, 4.41 µmol) at room temperature. After the addition
of Ac2O (25.1 µL, 0.264 mmol) to the mixture at 0 °C, the
mixture was stirred for 20 min at 0 °C and at room temper-

88 J . Org. Chem., Vol. 66, No. 1, 2001
Baba et al.
ature for 2.5 h and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt
) 4/1) to give 33 (31.4 mg, 84%) as a colorless oil: Rf 0.65
(hexane/AcOEt ) 2/1); [R]24D +10.0 (c ) 1.53, CHCl3); 1H NMR
(CDCl3) δ 0.39 (ddd, 1/2H, J ) 4.9, 4.9, 8.5 Hz), 0.52-0.62 (m,
1+1/2H), 0.88 (t, 3H, J ) 6.7 Hz), 0.93 (m, 1H), 1.12 (m, 1H),
1.17 (q, 3H, J ) 7.3 Hz), 1.26-1.30 (m, 9H), 1.52-1.63 (m,
2H), 2.04 (s, 3H), 2.06 (s, 3H), 2.30-2.38 (m, 2H), 3.15 (dt,
1/2H, J ) 6.7, 14.0 Hz), 3.15 (dt, 1/2H, J ) 6.7, 12.8 Hz), 3.44-
3.61 (m, 2H), 4.75 (q, 1/2H, J ) 5.5 Hz), 4.85-4.92 (m, 1+1/
2H), 5.05 (m, 2H), 5.25 (m, 1H), 5.62-5.70 (m. 2H), 5.71-5.92
(m, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 6.9, 8.1, 13.9, 15.28,
15.33, 20.0, 20.1, 20.7, 21.2 (2C), 22.4, 24.7, 31.42, 31.44, 34.2,
39.4, 40.4, 58.7, 59.3, 73.7, 73.8, 76.0, 76.2, 76.6, 77.4, 97.7,
97.9, 116.7, 117.2, 129.2, 129.6, 131.0, 131.4, 134.4, 135.0,
170.1, 170.2; IR (KBr) 2935, 1740, 1641, 1236 cm-1; MS (FAB)-
m/z 447 (M + Na)+; HRMS (FAB) Calcd for C24H40NaO6 (M +
Na)+: 447.2723. Found: 447.2738.
µL, 6.22 µmol) in dry CH2Cl2 (203 mL) was refluxed for 1.5 h
under an argon atmosphere. After a solution of the catalyst A
(5.1 mg, 6.22 µmol) in dry CH2Cl2 (4.0 mL) was added to the
mixture, the whole was refluxed for 43 h. The mixture was
filtered through a short pad of SiO2. The solvent of the
combined filtrate was removed in vacuo. The residue was
purified by column chromatography (SiO2, hexane/AcOEt )
7/1) to give 35 (6.3 mg, 72%) and dimer (2.0 mg, 11%). 35: a
colorless oil; Rf 0.58 (hexane/AcOEt ) 3/1); [R]25 -56.3 (c )
D
0.28, CHCl3); 1H NMR (C6D6) δ 0.34 (ddd, 1H, J ) 4.9, 4.9, 8.5
Hz), 0.65 (ddd, 1H, J ) 4.9, 4.9, 8.5 Hz), 0.76 (m, 1H), 0.85 (t,
3H, J ) 6.7 Hz), 1.21 (m, 1H), 1.11-1.36 (m, 6H), 1.53 (m,
2H), 1.61 (m, 2H), 1.69 (s, 3H), 1.70 (s, 3H), 1.77 (m, 1H), 1.82
(m, 1H), 2.09 (m, 2H), 2.30 (m, 1H), 2.38 (m, 1H), 4.32 (ddd,
1H, J ) 1.2, 7.9, 7.9 Hz), 4.96 (dd, 1H, J ) 4.3, 8.5 Hz), 5.41
(dt, 1H, J ) 6.1, 6.1 Hz), 5.34-5.39 (m, 2H), 5.79-5.87 (m,
2H); 13C NMR (CDCl3, 75.5 MHz) δ 8.9, 14.0, 20.0, 20.6, 21.3
(2C), 22.4, 24.7, 25.3, 26.5, 31.5, 33.5, 33.8, 34.3, 73.7, 75.73,
75.75, 124.6, 129.7, 131.0, 134.7, 170.2, 170.3, 174.0; IR (KBr)
2927, 1740, 1240 cm-1; MS (EI) m/z (%) 421 (M+ + 1, 0.6), 361
(0.8), 318 (1.4), 300 (1.6), 251 (75), 209 (44), 191 (29), 99 (100);
HRMS (FAB) Calcd for C24H37O6 (M + H)+: 421.2590. Found:
421.2567. Dimer of 27: a colorless oil; Rf 0.30 (hexane/AcOEt
) 3/1); 1H NMR (C6D6) δ 0.31 (m, 2H), 0.64 (m, 2H), 0.85-
0.94 (m, 10H), 1.19-1.28 (m, 12H), 1.53 (m, 4H), 1.63 (m, 4H),
1.72 (m, 12H), 1.77-1.82 (m, 4H), 1.96 (m, 4H), 2.30 (m, 4H),
4.50 (m, 2H), 4.97 (m, 2H), 5.26-5.39 (m, 2H), 5.40-5.45 (m,
4H), 5.75-5.85 (m, 4H); IR (KBr) 2931, 1735, 1240 cm-1; MS
(FAB) m/z 841 (M + H)+; HRMS (FAB) Calcd for C48H73O12
(M + H)+: 841.5102. Found: 841.5104.
(1R,4R,2E)-4-Acetoxy-1-{(1R,2R)-2-[(1S)-1-h yd r oxybu t-
3-en yl]cyclop r op yl}n on -2-en yl Aceta te (34). To a stirred
solution of 33 (10.3 mg, 0.0532 mmol) in tert-BuOH (0.25 mL)
was added PPTS (3.1 mg, 0.0122 mmol) at room temperature.
After 5 h, a saturated NaHCO3 solution was added to the
reaction mixture, and the resulting mixture was extracted with
AcOEt. The extract was washed with brine, dried over MgSO4,
and then concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexane/AcOEt ) 4/1) to give
33 (0.3 mg, 3%) and 34 (5.9 mg, 69%). 34: a colorless oil; Rf
0.31 (hexane/AcOEt ) 2/1); [R]24 +20.4 (c ) 0.67, CHCl3); 1H
D
NMR (CDCl3) δ 0.55 (ddd, 1H, J ) 5.5, 5.5, 8.5 Hz), 0.68 (ddd,
1H, J ) 4.2, 5.5, 8.5 Hz), 0.85 (m, 1H), 0.88 (t, 3H, J ) 6.7
Hz), 1.10 (dddd, 1H, J ) 4.2, 4.2, 8.5, 8.5 Hz), 1.25-1.32 (m,
6H), 1.52-1.56 (m, 2H), 1.73 (s, 1H), 2.05 (s, 3H), 2.07 (s, 3H),
2.27 (m, 1H), 2.36 (m, 1H), 3.08 (dt, 1H, J ) 7.3, 12.2 Hz),
4.76 (dd, 1H, J ) 6.1, 8.5 Hz), 5.11 (m, 1H), 5.16 (m, 2H), 5.66
(dd, 1H, J ) 6.1, 15.3 Hz), 5.71 (dd, 1H, J ) 5.5, 15.3 Hz),
5.86 (m, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 8.8, 14.0, 20.5,
21.2 (2C), 22.5, 22.7, 24.7, 31.4, 34.1, 41.6, 73.6, 74.3, 76.6,
117.8, 130.1, 131.1, 134.6, 170.3, 170.6; IR (KBr) 3446, 2953,
1738, 1641, 1240 cm-1; MS (FAB) m/z 375 (M + Na)+; HRMS
(FAB) Calcd for C20H32NaO5 (M + Na)+: 375.2148. Found:
375.2141.
Ha lich ola cton e (1). To a stirred solution of 35 (4.8 mg,
0.0114 mmol) in MeOH (0.3 mL) was added K2CO3 (6.3 mg,
0.0457 mmol) at room temperature. After being stirred for 30
min, the mixture was filtered, and then the filtrate was
concentrated in vacuo. The residue was purified by PTLC
(hexane/AcOEt ) 1/3) to give 11 (2.3 mg, 62%) as a colorless
oil: Rf 0.30 (hexane/AcOEt ) 1/3); [R]24 -79.3 (c ) 0.20,
D
CHCl3); 1H NMR (C6D6) δ 0.27 (ddd, 1H, J ) 4.9, 4.9, 8.5 Hz),
0.45 (ddd, 1H, J ) 4.9, 4.9, 8.5 Hz), 0.86 (m, 1H), 0.89 (t, 3H,
J ) 6.7 Hz), 1.03 (m, 1H), 1.20-1.49 (m, 8H), 1.50 (m, 2H),
1.55 (m, 2H), 1.77 (m, 1H), 1.91 (ddd, 1H, J ) 1.2, 7.2, 13.4
Hz), 2.07 (m, 2H), 2.34 (m, 1H), 2.39 (m, 1H), 3.53 (dd, 1H, J
) 4.3, 6.7 Hz), 3.92 (m, 1H), 4.33 (ddd, 1H, J ) 1.2, 8.5, 12.2
Hz), 5.34-5.44 (m, 2H), 5.63-5.70 (m, 2H); 13C NMR (CDCl3,
125.7 MHz) δ 8.2, 14.0, 19.5, 22.6, 23.4, 25.1, 25.3, 26.5, 31.8,
33.6, 33.9, 37.3, 72.3, 74.1, 76.1, 124.7, 131.7, 134.1, 134.7,
(1S)-1-{(1R,2R)-2-[(1R,4R,2E)-1,4-Bis(a cet oxy)n on -2-
en yl]cyclop r op yl}bu t-3-en yl Hex-5-en oa te (4). To a stirred
solution of 34 (13.2 mg, 0.0374 mmol) in dry CH2Cl2 (0.7 mL)
was added 5-hexenoic acid (13.3 µL, 0.112 mmol), DMAP (14.6
mg, 0.120 mmol), and DCC (23.1 mg, 0.112 mmol) at room
temperature. After being stirred for 15 h, the mixture was
filtered through a pad of SiO2, and the filtrate was concen-
trated in vacuo. The residue was purified by PTLC (hexane/
174.0; IR (KBr) 3392, 1734 cm-1; MS (EI) m/z (%) 318 (M+
-
H2O, 0.5), 265 (1.2), 247 (1.7), 238 (4), 209 (31), 82 (100); MS
(FAB) m/z: 319 (M - OH)+; HRMS (FAB) Calcd for C20H31O3
(M - OH)+: 319.2273. Found: 319.2269.
AcOEt ) 2/1) to give 4 (13.8 mg, 82%) as a colorless oil: Rf
1
0.68 (hexane/AcOEt ) 2/1); [R]25 -4.1 (c ) 0.45, CHCl3); H
Ack n ow led gm en t. This article is dedicated to the
Memory of Professor Toshiro Ibuka. This work was
supported in part by The J apan Health Sciences Foun-
dation, Suzuken Memorial Foundation and Grant-in-
Aid for Scientific Research (C) from the Ministry of
Education, Science, Sports, and Culture, J apan.
D
NMR (C6D6) δ 0.33 (ddd, 1H, J ) 4.9, 4.9, 8.5 Hz), 0.61 (ddd,
1H, J ) 4.9, 4.9, 8.5 Hz), 0.82 (m, 1H), 0.85 (t, 3H, J ) 6.7
Hz), 1.14-1.31 (m, 6H), 1.35 (dddd, 1H, J ) 4.9, 4.9, 8.5, 8.5
Hz), 1.50 (m, 1H), 1.60 (m, 1H), 1.70 (s, 3H), 1.71 (s, 3H), 1.74
(m, 2H), 2.00 (q, 2H, J ) 7.3 Hz), 2.21-2.33 (m, 4H), 4.51 (dt,
1H, J ) 6.7, 6.7 Hz), 4.93-5.06 (m, 5H), 5.42 (dt, 1H, J ) 6.1,
6.1 Hz), 5.66-5.76 (m, 2H), 5.76-5.78 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 8.8, 13.9, 20.0, 20.3, 21.2 (2C), 22.5, 24.1,
24.7, 31.5, 33.1, 33.7, 34.3, 39.0, 73.7, 75.2, 75.8, 115.4, 117.8,
129.3, 131.3, 133.4, 137.6, 170.2 (2C), 173.0; IR (KBr) 2929,
1738, 1643 cm-1; MS (FAB) m/z 449 (M + H)+; HRMS (FAB)
Calcd for C26H41O6 (M + H)+: 449.2903. Found: 449.2929.
12,15-Bis(a cetoxy)h a lich ola cton e (35). The solution of
4 (9.3 mg, 0.0207 mmol) and freshly distilled Ti(Oi-Pr)4 (1.9
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for 14b, 16b, 15, 23, 29, 30, MTPA-esters of 28b, X-ray
crystallographic data for 16b, and proton and carbon NMR
data for 1, 4, 5, 6, 27, 28a , 28b, 31, 32, 33, 34, 35. This
material is available free of charge via Internet at
http://pubs.acs.org.
J O001036C