Enantioselective synthesis of (+)-isobretonin A

Article abstract of DOI:10.1021/jo960134o

An enantioselective synthesis of (±)-isobretonin A is described. The chiral glycerol moiety was enantioselectively prepared by reduction of an optically active β-keto sulfoxide. The all-trans trienic part of the molecule was stereoselectively synthesized via reductive elimination of a 1,6-dibenzoate 2,4-diene with sodium amalgam.

Full text of DOI:10.1021/jo960134o

J . Org. Chem. 1996, 61, 4369-4373
4369
En a n tioselective Syn th esis of (+)-Isobr eton in A
Guy Solladie´,* Marc Adamy, and Franc¸oise Colobert
Laboratoire de Ste´re´ochimie associe´ au CNRS, Ecole Europe´enne de Chimie, Polyme`res et Mate´riaux
(ECPM), Universite´ Louis Pasteur, 1 rue Blaise Pascal, 67008 Strasbourg, France
Received J anuary 22, 1996X
An enantioselective synthesis of (+)-isobretonin A is described. The chiral glycerol moiety was
enantioselectively prepared by reduction of an optically active â-keto sulfoxide. The all-trans trienic
part of the molecule was stereoselectively synthesized via reductive elimination of a 1,6-dibenzoate
2,4-diene with sodium amalgam.
Sch em e 1
(+)-Isobretonin A is a unique chiral glycerol derivative.
The chirality is due to the presence of two different
substituents on the primary hydroxylic groups: an all-E
4,6,8-dodecatrienic ether and a 4-hydroxybenzoate.
This molecule was isolated from an unidentified sponge
belonging to the class Demospongiae of Brittany waters.1
The basic structure was elucidated in 1987 and its
absolute configuration, (S)-(+), was recently determined
by total synthesis2 of a mixture of the all-E and E,Z,E
isomers.
We report in this paper the first enantio- and stereo-
selective synthesis of (+)-isobretonin A. As shown in the
retrosynthetic Scheme 1, this approach is based on the
asymmetric reduction of â-keto sulfoxide 3 to prepare the
enantiomerically pure glycerol derivative 1 and on the
reductive elimination of 1,6 dibenzoate 2,4-diene 4 to
obtain all-E trienic bromide 2.
â-Keto sulfoxide (-)-(S)-3 was prepared by condensa-
tion of the p-methoxybenzyl ether of methyl glycolate 5,
readily available from bromoacetic acid in 85% yield, and
the carbanion of (-)-(S)-methyl p-tolyl sulfoxide.3 Fol-
lowing our previous results,4 the reduction of â-keto
sulfoxide 3 with DIBAL yielded [2R,S(S)]-â-hydroxy
sulfoxide 6 in 61% overall yield from ester 5 (Scheme 2).
The R configuration of the hydroxylic carbon was ex-
pected from the reaction mechanism already published4d
and also from the numerous examples we already pub-
lished.5 The large nonequivalence (∆ν ) 66 Hz) of the
7 was submitted to a Pummerer rearrangement with
acetic anhydride-sodium acetate and the intermediate
8 reduced with lithium aluminum hydride in ether,
affording in high yield glycerol derivative (+)-(S)-1.
The synthesis of the trienic part is based on our
previous work:6 we have shown that 1,6-dibenzoate 2,4-
dienes could be very efficiently transformed into all-trans
triene via a reductive elimination reaction induced by
sodium amalgam. Condensation of the Grignard deriva-
tive of diacetylene on butyraldehyde gave 9 in 72% yield
(Scheme 3). The compound 9 was lithiated with n-BuLi
and added to protected hydroxybutyraldehyde (made
from butanediol via monoprotection and oxidation) giving
the diacetylenic diol 10 in 89%, as a mixture of diaste-
reoisomers. The triple bonds in diol 10 were reduced
with activated Zn-Cu in MeOH/H2O,7 affording the
corresponding (Z,Z)-dienic diol in 85% yield, which was
converted into the corresponding dibenzoate 4 in quan-
titative yield. The Z,Z configuration of the double bonds
1
two diastereotopic protons R to the sulfoxide group in H
NMR is characteristic of the relative 2(R),S(S) config-
uration.4a,b The final comparison with natural isobreto-
nin will indeed confirm the absolute configuration as-
signment. The diastereoselectivity for the reduction was
higher than 98%; only one diastereoisomer was observed
1
in the H and 13C NMR spectra of the crude reduction
mixture.
After the hydroxylic group was protected with tert-
butyldiphenylsilyl chloride, the resulting TBDPS ether
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) Guella, G.; Mancini, I.; Pietra, F. Helv. Chim. Acta 1989, 72,
1121.
(2) Mancini, I.; Guella, G.; Pietra, F. Helv. Chim. Acta 1991, 74,
941.
(3) Solladie´, G.; Hutt, J .; Girardin, A. Synthesis 1987, 173.
(4) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435. (b) Solladie´, G.; Demailly, G.; Greck, C. I. J . Org. Chem. 1985,
50, 1552. (c) Solladie´, G.; Frechou, C.; Demailly, G.; Greck, C. J . Org.
Chem. 1986, 51, 1912. (d) Solladie´-Cavallo, A.; Suffert, J .; Adib, A.;
Solladie´, G. Tetrahedron Lett. 1990, 31, 6649.
1
was confirmed at this stage by H NMR.
Application of the reductive elimination reaction with
sodium amalgam to compound 4 gave the triene 11 as a
(5) (a) Solladie´, G.; Rubio, A.; Carren˜o, M. C.; Garcia-Ruano, J . L.
Tetrahedron: Asymmetry 1990, 1, 187. (b) Solladie´, G.; Hamdouchi,
C.; Ziani-Cherif, C. Tetrahedron: Asymmetry 1991, 2, 801. (c) Solladie´,
G.; Almario, A.; Colobert, F. Synlett 1992, 167. (d) Solladie´, G.; Lohse,
O. J . Org. Chem. 1993, 58, 4555. (e) Solladie´, G.; Almario, A.;
Dominguez, C. Pure Appl. Chem. 1994, 66, 2159.
(6) (a) Solladie´, G.; Stone, G. B.; Rubio, A. Tetrahedron Lett. 1993,
34, 1803. (b) Solladie´, G.; Stone, G. B.; Andre`s, J . M.; Urbano, A.
Tetrahedron Lett. 1993, 34, 2835.
(7) Boland, W.; Schro¨er, N.; Sieler, C.; Feigel, N. Helv. Chim. Acta
1987, 70, 1025.
S0022-3263(96)00134-X CCC: $12.00 © 1996 American Chemical Society

4370 J . Org. Chem., Vol. 61, No. 13, 1996
Solladie´ et al.
Sch em e 2
oil, [R]D +5 (c 1.5, MeOH), identical in all respects with
the natural product, [R]D +5.4 (c 0.16, MeOH).2
In conclusion, this short and efficient synthesis of (+)-
isobretonin A demonstrated the powerful combination in
total synthesis of chiral sulfoxides to create the chiral
centers and of the reductive elimination of dienic diben-
zoates to create the polyenic parts.
Exp er im en ta l Section
Meth yl (p-Meth oxyben zyloxy)glycola te, 5. To a stirred
solution of bromoacetic acid (7.25 g, 52 mmol) in anhydrous
THF (150 mL) was added sodium hydride (3.13 g, 130 mmol).
The solution was stirred at room temperature until the
evolution of hydrogen stopped. A solution of p-methoxybenzyl
alcohol (7.25 g, 52.5 mmol) in anhydrous THF (150 mL) was
then added at 0 °C, and the resulting mixture was stirred at
25 °C until the evolution of hydrogen stopped. Tetrabutyl-
ammonium bromide (1 g, 3 mmol) was added, and the resulting
mixture was heated at reflux temperature for 4 h. After the
resulting mixture was cooled to 0 °C, the solution was
hydrolyzed with ethanol (15 mL) and concentrated. The
resulting oil was diluted with diethyl ether (50 mL), and the
organic layer was extracted with aqueous NaHCO3 (3 × 50
mL). The aqueous layer was acidified to pH ) 1 with 10%
sulfuric acid, extracted with diethyl ether (3 × 100 mL), dried
(MgSO4), and evaporated. The resulting oil was dissolved in
methanol (200 mL) and heated at 60 °C for 4 h in the presence
of p-toluenesulfonic acid (50 mg, 0.26 mmol). After the solution
was cooled at 25 °C, the solvent was then evaporated and the
crude product was purified by chromatography on silica gel
(EtOAc-hexane, 1:9) giving ester 5 as a yellow oil (9.04 g,
82%): 1H NMR (200 MHz, CDCl3) δ 3.76 (s, 3H), 3.80 (s, 3H),
4.07 (s, 2H), 4.56 (s, 2H), 6.88-7.28 (AA′BB′, J ) 10 Hz, ∆ν )
80 Hz, 4H); 13C NMR (50 MHz, CDCl3) δ 51.5, 55.0, 66.7, 72.7,
113.7, 129.3, 126.6, 159.4, 178.7. Anal. Calcd for C11H14O4:
C, 62.84; H, 6.71. Found: C, 62.64; H, 6.65.
Sch em e 3
(-)-(S)-3-(p -Met h oxyb en zyloxy)-1-(p -t olylsu lfin yl)-2-
p r op a n on e, 3. To a stirred solution of diisopropylamine (1.9
mL, 1.4 mmol) in THF (20 mL) under argon was added
dropwise at -15 °C a 1.5 M solution of n-butyllithium in
hexane (9.1 mL, 13.6 mmol). After 30 min of stirring, the
mixture was allowed to reach 0 °C and a solution of (-)-(S)-
methyl p-tolyl sulfoxide (2.0 g, 13.0 mmol) in THF (20 mL)
was added. After 30 min of stirring, the resulting solution
was added to a solution of ester 5 (1.28 g, 6.1 mmol) in THF
(20 mL) at 0 °C. The reaction mixture was allowed to reach
room temperature and stirred for 2 h. The reaction was finally
quenched with saturated ammonium chloride (50 mL), 5%
sulfuric acid was added untill pH ) 2, and the solution was
extracted with dichloromethane (3 × 55 mL), dried (MgSO4),
and evaporated. Crude product 3 was used in the next step
without further purification, the excess of methyl p-tolyl
sulfoxide being difficult to separate by chromatography.
However, an analytical sample of â-keto sulfoxide 3 was
obtained by crystallization in diethyl ether: [R]D -141 (c 1.3,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 2.67 (s, 3H), 3.77 (s, 3H),
3.86 (AB, J AB ) 13.6 Hz, ∆ν ) 32.7 Hz, 2H), 3.98 (s, 2H), 4.43,
(s, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 7.21 (d, J ) 8.6 Hz, 2H), 7.28
(d, J ) 8 Hz, 2H), 7.49 (d, J ) 8.1 Hz, 2H): 13C NMR (50 MHz,
CDCl3) δ 21.6, 55.4, 66.0, 73.3, 75.9, 114.0, 124.2, 128.9, 129.9,
130.2, 139.7, 142.3, 159.7, 199.9. Anal. Calcd for C18H20O4S:
C, 65.03; H, 6.07. Found: C, 65.00; H, 6.05.
(-)-[2(R),S(S)]-3-(p -Met h oxyb en zyloxy)-1-(p -t olylsu l-
fin yl)-2-p r op a n ol, 6. To a solution of â-keto sulfoxide 3 in
anhydrous THF (40 mL) under argon at -78 °C was quickly
added a 1 M solution of DIBAL in toluene (7 mL, 7 mmol).
After the solution was stirred for 30 min at -78 °C, the
reaction was quenched with saturated ammonium chloride (30
mL) and the pH was ajusted to 4-5 with 5% H2SO4. The
solution was extracted with dichloromethane (3 × 20 mL),
dried (MgSO4), and evaporated. The crude product was
purified by chromatography (EtOAc-hexane, 3:1) on silica gel
to give 6 (1.24 g, 61%): [R]D -151 (c 1.2, CHCl3); 1H NMR
(200MHz, CDCl3) δ 2.41 (s, 3H), 2.74-3.03 (AB part of ABX,
unique product in 76% yield. The E,E,E geometry of the
double bonds of alcohol 12 was established by H NMR
1
in the presence of Pr(fod)3. The absence of any other
isomer was confirmed by 13C NMR showing only one set
of six vinylic carbons. Finally, the primary alcohol was
transformed into bromide 13 in 86% yield.
Ether (+)-(S)-14 was obtained, in 78% yield, via a
Williamson reaction between alcohol 1 and bromide 13
(Scheme 4). After the MPM group was removed in 84%
yield, esterification of the alcohol 15 with 4-hydroxyben-
zoic chloride followed by deprotection of the TBDPS group
afforded in 83% yield (+)-isobretonin A as a colorless

Enantioselective Synthesis of (+)-Isobretonin A
J . Org. Chem., Vol. 61, No. 13, 1996 4371
Sch em e 4
J AB ) 14 Hz, J AX ) 9.5 Hz, J BX ) 2.4 Hz, ∆ν ) 66 Hz, 2H),
3.36-3.54 (m, 2H), 3.80 (s, 3H), 4.39-4.44 (X part of ABX,
1H and m, 2H), 6.85 (d, J ) 9 Hz, 2H), 7.19 (d, J ) 9 Hz, 2H),
7.33 (d, J ) 8 Hz, 2H), 7.51 (d, J ) 8 Hz, 2H); 13C NMR (50
MHz, CDCl3) δ 21.5, 55.4, 59.4, 66.1, 72.9, 73.2, 113.9, 124.1,
129.5, 129.8, 130.2, 139.9, 141, 7,159.4. Anal. Calcd for
C18H22O4S: C, 65.64; H, 6.63, Found: C, 65.46; H 6.58.
(-)-[2(R),S(S)]-2-(ter t-Bu tyld ip h en ylsiloxy)-3-(p-m eth -
oxyben zyloxy)-1-(p-tolyl su lfin yl)-p r op a n e, 7. To a solu-
tion of compound 6 (1.15 g, 3.4 mmol) in dimethylformamide
(15 mL) under argon at room temperature was added imida-
zole (623 mg, 9 mmol). After the solution was stirred for 10
min, tert-butyldiphenylsilyl chloride (1.5 g, 5 mmol) was added,
the solution was stirred for 12 h, the reaction was quenched
with saturated ammonium chloride (30 mL), and the solution
was extracted with ethyl acetate (2 × 30 mL) and dichlo-
romethane (2 × 30 mL), dried (MgSO4), filtered, and concen-
trated. The crude product was purified by chromatography
on silica gel (EtOAc-hexane, 1:3) to give 7 (1.9 g, 98%): [R]D
-75 (c 1.5, CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.10 (s, 9H),
7.72 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 19.7, 21.1, 21.3,
27.1, 55.4, 71.6, 72.9, 73.8, 74.1, 81.6, 85.3, 113.8, 127.7, 128.6,
129.5, 129.8, 130.1, 130.2, 130.3, 132.9, 133.2, 133.7, 133.8,
134.0, 136.1, 136.1, 136.4, 137.8, 138.2, 159.2, 169.6. Anal.
Calcd for C36H42O5SSi: C, 70.32; H 6.89. Found: C, 70.26; H,
6.96.
(+)-(S )-2-(t er t -Bu t yld ip h e n ylsiloxy)-3-(p -m e t h oxy-
ben zyloxy)-1-p r op a n ol, 1. To a solution of 8 (1.0 g, 1.7
mmol) in diethyl ether (15 mL) under argon was added
dropwise at -78 °C a 1 M solution of LiAlH4 in diethyl ether
(5.1 mL, 5.1 mmol). After the solution was stirred for 2 h at
0 °C, the reaction was quenched with saturated ammonium
chloride (15 mL) and the pH of the solution adjusted to 2-3
with 5% H2SO4. The solution was extracted with ethyl acetate
(3 × 15 mL), dried (MgSO4), and evaporated. The crude
product was purified by chromatography on silica gel (EtOAc-
hexane, 3:1) to give 1 as a yellow oil (628 mg, 81%): [R]D +6
1
(c 1.5, MeOH); +8 (c 1.5, CHCl3); H NMR (200 MHz, CDCl3)
δ 1.14 (s, 9H), 3.5-3.6 (m, 2H), 3.63-3.76 (AB part of ABX,
J AB ) 11.4 Hz, J AX ) 3.9 Hz, J BX ) 5.3 Hz, ∆ν ) 20 Hz, 2H),
3.80 (s, 3H), 3.85-3.93 (m, 1H), 4.60 (s, 2H), 6.89 (d, J ) 9
Hz, 2H), 7.28 (d, J ) 9 Hz, 2H), 7.36-7.45 (m, 6H), 7.73-7.78
(m, 4H); 13C NMR (50 MHz, CDCl3) δ 20.7, 25.4, 55.3, 63.1,
64.6, 66.1, 76.4, 114.0, 128.0, 128.7, 130.4, 132.6, 133.4, 135.3,
159.2. Anal. Calcd for C27H34O4Si: C, 71.96; H, 7.61.
Found: C, 71.85; H, 7.53.
2.40 (s, 3H), 2.86-3.07 (AB part of ABX, J AX ) 8.5 Hz, J BX
)
4 Hz, J AB ) 13 Hz, ∆ν ) 22 Hz, 2H), 3.19-3.39 (AB part of
ABX, J AX ) 4.5 Hz, J BX ) 4 Hz, J AB ) 10 Hz, ∆ν ) 25 Hz, 2H),
3.78 (s, 3H), 4.05-4.14 (AB, J AB ) 11.3 Hz, ∆ν ) 31.6 Hz, 2H),
4.38-4.45 (X part of both ABX, 1H), 6.78 (d, J ) 9 Hz, 2H),
7.03 (d, J ) 9 Hz, 2H), 7.29-7.47 (m, 10H), 7.73-7.78 (m, 4H);
13C NMR (50 MHz, CDCl3) δ 19.7, 21.4, 27.1, 55.2, 64.1, 67.7,
72.7 73.0, 113.4, 123.9, 127.6, 127.9, 129.3, 129.7, 130.0, 130.1,
132.7, 134.2, 135.9, 136.2, 141.1, 141.7, 159.2. Anal. Calcd
for C34H40O4SSi: C, 71.29; H, 7.05. Found: C, 71.40; H, 7.12.
(2R)-1-Acetoxy-2-(ter t-bu tyldiph en ylsilyloxy)-3-(p-m eth -
oxyben zyloxy)-1-(p-tolylth io)p r op a n e, 8. To a solution of
7 (1.45 g, 2.6 mmol) in acetic anhydride (80 mL) was added
sodium acetate (2.4 g, 2.9 mmol) under argon. After the
solution was heated at 130 °C for 11 h, acetic anhydride was
evaporated, the residue was dissolved in diethyl ether, and
the solution was filtered through Celite and concentrated. The
crude product was purified by chromatography on silica gel
(CH2Cl2-hexane, 1:1) to give 8 as a yellow oil (1.46 g, mixture
of diastereomers, 94%): 1H NMR (200 MHz, CDCl3) δ 1.02 and
1.09 (s, 9H), 1.78 and 1.86 (s, 3H), 2.30 (s, 3H), 3.37-3.73 (m,
AB part of ABX for the two diastereomers, 2H), 3.78 and 3.80
(s, 3H), 4.01-4.3 (X part of ABX, 1H and AB, J AB ) 8.8 Hz,
∆ν ) 25.7 Hz, 2H), 6.18 and 6.24 (d, J ) 7 Hz and 2 Hz,
respectively, 1H), 6.78 and 6.82 (d, J ) 6 Hz and 6 Hz,
respectively, 2H), 6.98-7.09 (m, 4H), 7.20-7.42 (m, 8H), 7.60-
1,3-Octa d iyn -5-ol, 9. To a solution of potassium hydroxide
(51g, 0.9 mol) in a 82/18 DMSO/H2O mixture (100 mL) was
dropwise added at room temperature 1,4-dichloro-2-butyne (25
g, 0.20 mol). At the end of the addition, the mixture was
heated at 95 °C for 1.5 h. Butadiyne was added to two flasks
of THF (10 mL) respectively cooled at -60 and -78 °C. A total
of 8.20 g of butadiyne was isolated in the THF solution. A 1
M solution of EtMgBr in diethyl ether (131.2 mL, 131.2 mmol)
was added dropwise. This cloudy solution was stirred at room
temperature for 1.5 h and then cooled to -78 °C. Butyralde-
hyde (8.91 mL, 98.4 mmol) in dry THF (20 mL) was added
slowly over a period of 20 min. The reaction mixture was
allowed to reach 0 °C and stirred for 50 min. Workup was
carried out by quenching the reaction with saturated NH4Cl
(150 mL). The aqueous layer was then extracted three times
with diethyl ether. The combined organic layers were washed
with saturated NH4Cl (150 mL) and NaCl (150 mL), dried over
MgSO4, filtered and concentrated. The crude product was then
purified by column chromatography (EtOAc-hexane, 1:5) to
give 9 (22.28 g, 72%): 1H NMR (200 MHz, CDCl3) δ 0.95 (t, J

4372 J . Org. Chem., Vol. 61, No. 13, 1996
Solladie´ et al.
) 7.5 Hz, 3H), 1.17-1.77 (m, 4H), 1.92 (d, J ) 6 Hz, 1H), 2.19
(s, 1H), 4.42 (q, J ) 6 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ
13.7, 18.4, 31.0, 39.5, 62.5, 68.5, 68.7, 76.5. Anal. Calcd for
C8H10O: C, 78.65; H, 8.26. Found: C, 78.61; H, 8.20.
1-(ter t-Bu tyld im eth ylsiloxy)-4,9-d ih yd r oxyd od eca -5,7-
d iyn e, 10. To a solution of 9 (1.1 g, 8.8 mmol) in anhydrous
THF (60 mL) under argon at -78 °C was added dropwise a
1.5 M solution of n-butyllithium in hexane (11.7 mL, 17.5
mmol) producing a strong green coloration. After the solution
was stirred for 1 h at 0 °C, a solution of 4-(tert-butyldimeth-
ylsiloxy)butyraldehyde (1.5g, 7.3 mmol) in THF (60 mL) was
added at -78 °C. After the solution was stirred for 50 min at
-78 °C and for 50 min at 0 °C, the reaction was quenched
with saturated ammonium chloride (60 mL) and the pH was
adjusted to 4-5 with 5% H2SO4. The solution was extracted
with ethyl acetate (3 × 60 mL), dried, and evaporated. The
crude product was purified by chromatography (EtOAc-
hexane, 1:2) to give 10 (2.5 g, 89%, mixture of diastereomers):
1H NMR (200 MHz, CDCl3) δ 0.08 (s, 6H), 0.90 (s, 9H), 0.94 (t
, J ) 7 Hz, 3H), 1.42-1.88 (m, 10H), 3.60-3.83 (m, 2H), 4.42-
4.58 (m, 2H); 13C NMR (50 MHz, CDCl3) δ -5.4, 13.7, 18.4,
18.4, 26.0, 28.4, 34.9, 39.6, 62.2, 62.3, 63.1, 65.9, 80.5. Anal
Calcd for C18H32O3Si: C, 66.62; H, 9.95: Found: C, 66.56; H,
9.87.
(5Z,7Z)-1-(t er t -Bu t yld im e t h ylsiloxy)-4,9-d ib e n zoyl-
d od eca d ien e, 4. (1) P r ep a r a tion for a ctiva ted Zn . For
1.6 g of diene (5.4 mmol), Zn (19.3 g, 0.3 mol) was stirred in
water (75 mL) for 15 min under argon. A flux of argon was
maintained for the entire preparation. Copper acetate (1.9 g,
10.4 mmol) was first added, and the mixture was stirred for
15 min. Then silver nitrate (1.9 g, 11.2 mmol) was added and
stirring was continued for 0.5 h. The reaction mixture was
then filtered and washed with water (50 mL), methanol (50
mL), acetone (50 mL), and diethyl ether (50 mL) to give
activated Zn.
was filtered. The organic layer was dried and evaporated. The
crude product was purified by chromatography on silica gel
(hexane) to give 11 (324.5 mg, 76%): 1H NMR (200 MHz,
CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H and t, J ) 7.5 Hz overlapped,
3H), 1.37 (sexet., J )7.5 Hz, 2H), 1.62 (tt, J ) 7.7 Hz, J ) 6.4
Hz, 2H), 2.05 (q, J ) 7.5 Hz, 2H), 2.13 (q, J ) 7.7 Hz, 2H), 3.6
(t, J ) 6.4 Hz, 2H), 5.59-5.71 (m, 2H), 6.01-6.06 (m, 4H); 13
C
NMR (50 MHz, CDCl3) δ -5.2, 13.8, 18.4, 22.6, 26.0, 29.2, 32.5,
35.0, 62.6, 130.7, 130.8, 130.85, 131.1, 133.8, 134.4. Anal.
Calcd for C18H34OSi: C, 73.40; H, 11.65. Found: C, 73.32; H,
11.60.
(4E,6E, 8E)-Dod eca tr ien e-1-ol, 12. To a solution of sily-
lated alcohol 11 (300 mg, 1 mmol) in THF (30 mL) at 0 °C
under argon was added a 1 M TBAF solution in THF (1.5 mL,
1.5 mmol). The reaction mixture was allowed to reach room
temperature and stirred for 12 h, the reaction was then
quenched with 2 g of silica gel, and the solution was evapo-
rated. The crude product was then dissolved in 1 mL of
dichloromethane and purified by chromatography on silica gel
(EtOAc-hexane, 1:4) to give alcohol 12 (149 mg, 81%): 1H
NMR (200 MHz, CDCl3) δ 0.88 (t, J ) 7.5 Hz, 3H), 1.39 (sextet,
J ) 7.5 Hz, 2H), 1.62 (tt, J ) 6.5 Hz, J ) 7.5 Hz, 2H), 2.05 (q,
J ) 7 Hz, 2H), 2.15 (q, J ) 7.5 Hz, 2H), 2.44 (bs, 1H), 3.59 (t,
J ) 6.5 Hz, 2H), 5.55-5.75 (m, 2H), 5.09-6.15 (m, 4H); 13C
NMR (50 MHz, CDCl3) δ 13.8, 22.6, 29.2, 32.3, 35.0, 62.2,
130.6, 130.6, 131.1, 131.3, 133.3, 134.6. Anal. Calcd for
C12H20O: C, 79.95; H, 11.19 . Found: C, 79.87; H, 11.08.
(4E,6E,8E)-1-Br om od od eca tr ien e, 13. To a solution of
alcohol 12 (140 mg, 0.8 mmol) and CBr4 (387 mg, 1.2 mmol)
in CH2Cl2 (10 mL) was added over a period of 4 h a solution of
PPh3 (203.78 mg, 0.8 mmol). The mixture was then stirred
for 12 h. The solution was then evaporated, and the crude
product was purified by chromatography on silica gel (hexane)
to give bromo derivative 13 (161 mg, 86%): 1H NMR (200 MHz,
CDCl3) δ 0.92 (t, J ) 7 Hz, 3H), 1.37 (sextet, J ) 7 Hz, 2H),
1.83 (tt, J ) 6.5 Hz, J ) 7 Hz, 2H), 2.07 (q, J ) 7 Hz, 2H),
2.14 (q, J ) 7 Hz, 2H), 3.39 (t, J ) 6.5 Hz, 2H), 5.55-5.75 (m,
2H), 5.9-6.15 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 13.6, 22.4,
29.0, 32.1, 34.8, 66.4, 131.2, 131.2, 131.9, 133.8, 135.2. Anal.
Calcd for C12H19Br: C, 59.27; H, 7.88. Found: C, 59.15; H,
7.80.
(+)-(S)-(4E,6E,8E)- 2-(ter t-Bu tyld iph en ylsiloxy)-1-d od e-
ca tr ien oxy-3-(p-m eth oxyben zyloxy)p r op a n e, 14. To a
solution of compound 1 (172 mg, 0.4 mmol) in THF (10 mL) at
0 °C was added NaH (10 mg, 0.4 mmol). After the solution
was stirred at room temperature for 1 h, a catalytic amount
of tetrabutylammonium bromide (12 mg, 0.04 mmol) was
added, immediately followed by the addition of a solution of
bromide 13 (95 mg, 0.4 mmol) in THF (10 mL). The mixture
was heated at 60 °C for 2 h, the reaction was quenched with
saturated NH4Cl (20 mL), and the solution was extracted with
ethyl acetate (3 × 20 mL), dried (MgSO4), and evaporated. The
crude product was purified by chromatography on silica gel
(EtOAc-hexane, 1:9) to give 14 (182 mg, 78%): [R]D +3 (c 1.3,
MeOH); +4 (c 1.2, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.88
(t, J ) 7 Hz, 3H), 1.14 (s, 9H), 1.40 (sextet, J ) 7 Hz, 2H),
1.62 (q, J ) 7 Hz, 2H), 2.05 (q, J ) 7 Hz, 2H), 2.17 (q, J ) 7
Hz, 2H), 3.43 (t, J ) 7 Hz, 2H), 3.48-3.54 (m, 2H), 3.56-3.74
(AB part of ABX, J AB ) 11.4 Hz, J AX ) 3.7 Hz, J BX ) 5.6 Hz,
∆ν ) 22 Hz, 2H), 3.79 (s, 3H), 3.8-3.92 (X part of ABX, 1H),
4.58 (s, 2H), 5.55-5.75 (m, 2H), 5.82-6.12 (m, 4H), 6.87 (d, J
) 9 Hz, 2H), 7.27 (d, J ) 9 Hz, 2H), 7.39-7.43 (m, 6H), 7.73-
7.78 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 13.8, 20.8, 22.6,
25.4, 29.2, 32.4, 34.9, 55.4, 62.5, 63.1, 65.1, 65.8, 76.2, 114.1,
127.9, 128.7, 130.3, 130.6, 130.6, 131.2, 131.4, 132.6, 133.2,
133.3, 134.7, 135.3. Anal. Calcd for C39H52O4Si: C, 76.42; H,
8.56. Found: C, 76.37; H, 8.50.
(2) To a solution of compound 10 (1.7 g, 5.3 mmol) in a 1/1
methanol/water mixture (75 mL) was added Zn activated by
copper acetate (19.3 g, 295 mmol). After being stirred for 12
h, the solution was filtered through celite and the slurry was
carefully extracted with ethyl acetate. The solution was
partially evaporated, and the resulting aqueous layer was
extracted with ethyl acetate (3 × 50 mL), dried, and evapo-
rated. The crude product was purified by chromatography on
silica gel (EtOAc-hexane, 1:2) to give the corresponding
dienediol (1.5 g, 85%, mixture of diastereomers): 1H NMR (200
MHz, CDCl3) δ 0.07 (s, 6H), 0.90-0.96 (s, 9H and t, J ) 7 Hz
overlapped, 3H), 1.17-1.66 (m, 10H), 3.6-3.75 (m, 2H), 4.56-
4.68 (m, 2H), 5.43-5.57 (m, 2H), 6.28-6.37 (m, 2H); 13C NMR
(50 MHz, CDCl3) δ -5.3, 14.1, 18.4, 19.6, 26.0, 30.0, 35.0, 39.6,
63.4, 67.3, 67.4, 123.8, 124.3, 135.6, 135.9. Anal. Calcd for
C18H36O3Si: C, 65.80; H, 11.06. Found: C, 65.69; H, 10.99.
(3) To a solution of the preceding diol (1 g, 3 mmol) in
pyridine (60 mL) under argon at room temperature was added
dropwise benzoyl chloride (950 mg, 6.8 mmol). After the
solution was stirred for 12 h, diethyl ether (60 mL) was added.
The solution was washed successively with saturated NaHCO3
(60 mL) and brine (60 mL). The organic layer was then dried,
filtered, and concentrated. The crude product was purified by
chromatography on silica gel (EtOAc-hexane, 1:5) to give
dibenzoate
4
(1.63 g, quantitative yield, mixture of
diastereomers): 1H NMR (200 MHz, CDCl3) δ 0.01 and 0.04
(s, 6H), 0.85 and 0.88 (s, 9H), 0.92 and 0.94 (t, J ) 7.1 Hz,
3H), 1.17-2 (m, 8H), 3.62 and 3.64 (t, J ) 6 Hz, 2H), 5.6 (bt,
J ) 8 Hz, 2H), 5.95 (bq, J ) 8 Hz, 2H), 6.61 and 6.64 (bd, J )
8 Hz, 2H), 7.37-7.59 (m, 6H), 7.99-8.05 (m, 4H); 13C NMR
(50 MHz, CDCl3) δ -5.2, 14.0, 18.5, 26.1, 28.5, 31.4, 37.1, 65.0,
70.4, 125.9, 126.2, 126.4, 129.7, 130.61, 130.7, 131.6, 132.9,
165.9. Anal. Calcd for C32H44O5Si: C, 71.60; H, 8.22.
Found: C, 71.53; H, 8.20.
(+)-(R)-2-(ter t-Bu tyld ip h en ylsiloxy)-3-(4E,6E,8E-d od e-
ca t r ien oxy)-p r op a n -1-ol, 15. To a stirred CH2Cl2 (2 mL)
solution of 14 (180 mg, 0.3 mmol) containing a small amount
of water (100 µL) was added DDQ (66 mg, 0.3 mmol) at room
temperature. After 1 h, saturated NaHCO3 (2 mL) was added
and the mixture extracted with CH2Cl2 (3 × 5 mL). The
extract was washed with saturated NaHCO3 (10 mL) and brine
and then dried over MgSO4. The solvent was evaporated, and
the residue was chromatographed on a silica gel column
(4E ,6E ,8E )-1-(t er t -Bu t yld im e t h ylsiloxy)d od e ca t r i-
en e, 11. To a solution of 4 (0.8 g, 1.5 mmol) in a 3/1 mixture
of anhydrous THF/methanol (90 mL) under argon at room
temperature was added Na2HPO4 (1.5 g, 11 mmol). The
temperature was lowered to -20 °C, and a 6% Na(Hg)
amalgam was added (6 g, 15.6 mmol). The mixture was stirred
for 4 h. Diethyl ether (200 mL) was added, and the mixture

Enantioselective Synthesis of (+)-Isobretonin A
J . Org. Chem., Vol. 61, No. 13, 1996 4373
(EtOAc-hexane, 1:5) to give 15 (120 mg, 84%): [R]D +4 (c 1.2,
MeOH); +6 (c 1.2, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.89
(t, J ) 7 Hz, 3H), 1.14 (s, 9H), 1.39 (sextet, J ) 7 Hz, 2H),
1.64 (q, J ) 7 Hz, 3H), 2.09 (q, J ) 7 Hz, 2H), 2.13 (q, J ) 7
Hz, 2H), 3.39-3.55 (m, 4H), 3.56-3.75 (AB part of ABX, J AB
) 11.5 Hz, J AX ) 3.7 Hz, J BX ) 5.6 Hz, ∆ν ) 21.9 Hz, 2H),
3.8-3.92 (X part of ABX, 1H), 5.57-5.76 (m, 2H), 5.94-6.15
(m, 4H), 7.39-7.46 (m, 6H), 7.74-7.79 (m, 4H); 13C NMR (50
MHz, CDCl3) δ 13.7, 20.8, 22.6, 26.6, 29.2, 32.35, 35.0, 62.5,
63.1, 65.8, 76.2, 127.9, 130.3, 130.6, 131.2, 131.4, 132.6, 133.2,
134.7, 135.2, 135.3. Anal. Calcd for C31H44O3Si: C, 75.56, H,
9.01. Found: C, 75.50; H, 8.92.
(+)-(S )-(4E ,6E ,8E )-1-((p -t er t -Bu t yld ip h e n ylsiloxy)-
b e n zoyl)-2-(t er t -b u t yld ip h e n ylsiloxy)-3-d od e ca t r ie n -
oxyp r op a n e, 16. To a solution of 15 (116 mg, 0.2 mmol) in
dry pyridine (10 mL), (p-tert-butyldiphenylsiloxy)benzoyl chlo-
ride (200 mg, 0.5 mmol) was added and the resulting mixture
stirred under argon for 12 h. Workup was carried out by
adding diethyl ether (10 mL) to the reaction mixture. The
resulting solution was washed with saturated NaHCO3 (20
mL) and brine (20 mL), dried over MgSO4, and evaporated.
The crude product was purified by chromatography on silica
gel (EtOAc-hexane, 1:9) to give 16 (202 mg, quantitative): [R]D
+2 (c 1.9, MeOH); +3 (c 1.9, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 0.88 (t, J ) 7.3 Hz, 3H), 1.15 (s, 18H), 1.41 (sextet,
J ) 7.3 Hz, 2H), 1.64 (q, J ) 7 Hz, 2H), 2.04 (q, J ) 7.3 Hz,
2H), 2.16 (q, J ) 7.3 Hz, 3H), 3.41 (t, J ) 6.5 Hz, 2H), 3.54
(AB part of ABX, J AB ) 10 Hz, J BX ) 6 Hz, J AX ) 4 Hz, ∆ν)
11 Hz, 2H), 4.13 (X part of both ABX, 1H), 4.35 (AB part of
ABX, J AB ) 11 Hz, J AX ) 5 Hz, J BX ) 5 Hz, ∆ν ) 12 Hz, 2H),
5.52-5.70 (m, 2H), 5.94-6.02 (m, 4H), 6.87 (d, J ) 9 Hz, 2H),
7.37-7.46 (m, 12H), 7.74-7.79 (m, 8H), 7.94 (d, J ) 9 Hz, 2H);
13C NMR (50 MHz, CDCl3) δ 13.81, 20.8, 22.5, 26.6, 29.2, 29.5,
34.9, 65.9, 69.1, 70.9, 71.5, 115.2, 122.0, 127.5, 128.0, 129.4,
129.9, 130.3, 130.8, 131.0, 132.1, 132.8, 134.1, 134.9, 160.2,
166.2. Anal. Calcd for C54H66O5Si2: C, 76.19; H, 7.82.
Found: C, 76.11; H, 7.85.
(+)-Isobr eton in A. To a solution of 16 (190 mg, 0.2 mmol)
in THF (20 mL) at 0 °C under argon was added a 1 M solution
of TBAF in THF (0.5 mL, 0.5 mmol). The reaction mixture
was allowed to reach room temperature and was stirred for
12 h, the reaction was then quenched with 2 g of silica gel
and the solution was evaporated. The mixture was then
dissolved in 1 mL of CH2Cl2 and purified by column chroma-
tography on silica gel (EtOAc-hexane, 1:3) to give isobretonin
A (68.38 mg, 83%): [R]D +5 (c 1.5, MeOH); +8 (c 1.5, CHCl3);
1H NMR (200 MHz, CDCl3) δ 0.88 (t, J ) 7.3 Hz, 3H), 1.40
(sextet, J ) 7.3 Hz, 2H), 1.62 (pentet, J ) 7.0 Hz, 2H), 2.04
(q, J ) 7.3 Hz, 2H), 2.13 (q, J ) 7.3 Hz, 2H), 3.44 (t, J ) 6.5
Hz, 2H), 3.54 (AB part of ABX, J AX ) 4 Hz, J BX ) 6 Hz, J AB
)
10 Hz, ∆ν ) 13 Hz, 2H), 4.13 (X part of both ABX, 1H), 4.37
(AB part of ABX, J AX ) 5 Hz, J BX ) 5 Hz, J AB ) 11 Hz, 2H),
5.55-5.71 (m, 2H), 5.94-6.06 (m, 4H), 6.87 (d, J ) 9 Hz, 2H),
7.94 (d, J ) 9 Hz, 2H); 13C NMR (50 MHz, CDCl3) 13.9, 22.5,
29.2, 29.5, 34.9, 65.9, 69.1, 70.9, 71.5, 115.2, 122.0, 129.3, 130.6,
130.8, 131.4, 132.0, 132.2, 134.0, 160.2, 166.2. Anal. Calcd
for C22H30O5: C, 70.56; H, 8.08. Found: C, 70.50; H, 7.98.
J O960134O