Enantioselective synthesis of (-)-curcumanolide A using enzymatic transesterification of meso-spirodiol

Article abstract of DOI:10.1021/jo962150r

meso-Spirodiol 12 and spirodiacetate 13 were stereoselectively prepared using π-face selective Grignard addition to norbornanone 7. Asymmetric transesterification of meso-diol and hydrolysis of meso-diacetate were studied using lipases. Pseudomonas fluorescens lipase-catalyzed transesterification of meso-diol 12 afforded the monoacetate (-)-21 of high enantiomeric excess (> 99% ee). The formal synthesis of (-)-curcumanolide A has been achieved from the optically active (-)-21.

Full text of DOI:10.1021/jo962150r

3
824
J . Org. Chem. 1997, 62, 3824-3830
En a n tioselective Syn th esis of (-)-Cu r cu m a n olid e A Usin g
En zym a tic Tr a n sester ifica tion of m eso-Sp ir od iol
Toshiaki Fujita, Masakazu Tanaka,* Yoshihiko Norimine, and Hiroshi Suemune*
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-82, J apan
Kiyoshi Sakai
Kyushu Women’s University, J iyugaoka 1-1, Yahata-nishi, Kitakyushu 807, J apan
Received November 18, 1996X
meso-Spirodiol 12 and spirodiacetate 13 were stereoselectively prepared using π-face selective
Grignard addition to norbornanone 7. Asymmetric transesterification of meso-diol and hydrolysis
of meso-diacetate were studied using lipases. Pseudomonas fluorescens lipase-catalyzed transes-
terification of meso-diol 12 afforded the monoacetate (-)-21 of high enantiomeric excess (>99%
ee). The formal synthesis of (-)-curcumanolide A has been achieved from the optically active (-)-
2
1.
In tr od u ction
reduction of aldehyde, and acetylation of the hydroxy
functions (three-step, 59%). Compound 9 was thought
to be a good substrate for the preliminary study of enzy-
matic hydrolysis for the synthesis of curcumanolide A.
Stereoselective preparation of 7-substituted norbornene
1
Curcumanolide A (1) is a natural product, isolated
from the crude drug zedoary and other Curcuma species,
and possesses the unique structure of three contiguous
chiral centers and a spirolactone moiety. In 1992, Kato
et al. reported the racemic synthesis of curcumanolide A
1
0 was achieved by π-face selective Grignard addition to
6
2
norbornanone. By the treatment with Grignard reagent
prepared from 2-(2-bromoethyl)-1,3-dioxolane in THF at
starting from homogeranyl cyanide in 3% overall yield.
When we started our study of the enantioselective
synthesis of curcumanolide A, no report concerning the
enantioselective synthesis or the absolute configuration
of curcumanolide A has been made. Therefore, we
envisioned being able to synthesize both enantiomers of
this target molecule starting from the meso-compound.
While we were studying the synthesis of curcumanolide
A, Honda et al. reported the enantiospecific first synthesis
of this molecule starting from (-)-carvone and deter-
0
9
°C, norbornanone 7 was converted into adduct 10 in
7% yield. The π-face selectivity of adduct 10 was
1
determined to be 25 to 1, because the H NMR spectrum
showed the olefin signals at δ 5.99 (t, J ) 2.1 Hz) and δ
6
.13 (t, J ) 2.1 Hz) in the ratio of 25 to 1. By the
treatment with J ones reagent at 0 °C, a spontaneous
three-step sequence [(i) deacetalization; (ii) oxidation; (iii)
lactonization] occurred in one pot, and the adduct 10 was
converted into lactone 11 in 88% yield. Ozonolysis of 11
mined the absolute configuration of (-)-curcumanolide
A as 5R,6S,9S.3 In this paper, we describe the formal
at -78 °C, followed by reduction with NaBH
meso-spirodiol 12 in 64% yield, and subsequent acetyla-
tion with Ac O-pyridine gave meso-spirodiacetate 13 in
7% yield. The stereochemistry of meso-diol 12 was
4
, afforded
synthesis of (-)-curcumanolide A by way of π-face selec-
tive Grignard addition to norbornanone 7 and lipase-
catalyzed asymmetric transesterification of meso-spirodi-
ol.
2
9
1
determined to be 5s,6R,9S based on the NOESY H NMR
spectrum. The NOEs were observed between the meth-
ylene proton signals δ 3.73 (m, 4H) at the hydroxymethyl
function and the â-methylene proton signals δ 2.21 (t, J
) 8.2 Hz, 2H) at the lactone function. This meant that
the carbonyl function of norbornanone 7 was reacted with
Grignard reagent from the olefin site through remote
electronic effect. This result was in accord with Mehta’s
report.6
Resu lts a n d Discu ssion
Retr osyn th etic An alysis. Curcumanolide A (1) would
be prepared from Kato’s intermediate diol 2.2 Compound
2
would be prepared from chiral monoacetates (3a or 3b),
and the monoacetates might be prepared from meso-
diacetate 4 by enzymatic hydrolysis or meso-diol 5 by
enzymatic transesterification. The ozonolysis of olefin
in the norbornene skeleton was thought to be a good
method for the preparation of meso-compounds (4 and
meso-Diacetate 15a was also prepared from the adduct
1
H
0. By deprotection of the acetal function with AcOH-
O-THF at 50 °C, reduction of aldehyde with NaBH
2
4
,
5
) in a stereoselective manner. 7-Substituted norbornene
and protection of alcohol with MOMCl, the adduct 10 was
converted into MOM-protected norbornene 14 in 43%
yield. Compound 14 was converted into meso-diacetate
derivative 6 would be prepared from norbornanone 7 by
π-face selective Grignard addition through remote elec-
tronic perturbation of the ketone by the alkene.
1
5a by ozonolysis of olefin, reduction with NaBH
4
, and
Syn th esis of Su bstr a tes for En zym a tic Rea ction .
acetylation with Ac O-pyridine in 31% yield.
2
meso-Spirodiacetate 9 was first prepared from norbor-
nanone 7,4 by protection of the carbonyl function as
En zym a tic Rea ction of m eso-Com p ou n d s. Pre-
liminary enzymatic hydrolysis of meso-spirodiacetate 9
was studied using three kinds of lipases, such as Rhizo-
5
ethylene acetal (89%), followed by ozonolysis of olefin,
X
Abstract published in Advance ACS Abstracts, May 15, 1997.
(
1) (a) Shiobara,Y.; Asakawa, Y.; Kodama, K.; Yasuda, K.; Takemoto,
(4) Gassman, P. G.; Marshall, J . L. Org. Synth. 1968, 48, 25 and
T. Phytochemistry 1985, 24, 2629. (b) Gao, J .-F.; Ohkura, T.; Harimaya,
K.; Higuchi, M.; Kawamata, T.; Ying, W.-X.; Iitaka, Y. Chem. Pharm.
Bull. 1986, 34, 5122.
68.
(5) (a) Gassman, P. G.; Macmillan, J . G. J . Am. Chem. Soc. 1969,
91, 5527. (b) Gassman, P. G.; Schaffhausen, J . G. J . Org. Chem. 1978,
43, 3214.
(
2) Hirukawa, T.; Oguchi, M.; Yoshikawa, N.; Kato, T. Chem. Lett.
992, 2343.
3) Honda, T.; Ishige, H. J . Chem. Soc., Perkin Trans. 1 1994, 3567.
1
(6) Ganguly, B.; Chandrasekhar, J .; Khan, F. A.; Mehta, G. J . Org.
Chem. 1993, 58, 1734.
(
S0022-3263(96)02150-0 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Synthesis of (-)-Curcumanolide A
J . Org. Chem., Vol. 62, No. 12, 1997 3825
Sch em e 1. Retr osyn th etic An a lysis of (-)-Cu r cu m a n olid e A
Sch em e 2a
Ta ble 1. En zym a tic Hyd r olysis of m eso-Dia ceta te 9
monoacetate
reaction
time (h)
recovery
(%)
entry
enzyme
% yield
% ee
1
2
3
RDL
PFL
PPL
16
120
48
91
51
72
>99
82
33
-
40
20
The enantiomeric excess (% ee) of the hydrolyzed
1
products was determined by H NMR spectra after
conversion into the corresponding Mosher’s esters[(+)-
R-methoxy-R-(trifluoromethyl)phenylacetic acid (MT-
PA)].11 The H NMR spectra of (+)-MTPA ester derived
from (()-16 showed the methoxy proton signals at δ 3.53
1
(m, 1.5 H) and 3.56 (m, 1.5 H), while the corresponding
signal from (-)-16 hydrolyzed by RDL was observed at
δ 3.53 (m, 3 H) only. The specific rotations of all the
monoalcohols obtained showed a minus sign. We previ-
ously reported the asymmetric hydrolyses of meso-1,3-
a
Reagents: (i) ethylene glycol, p-TsOH; (ii) O3 and then NaBH4;
(
(
iii) Ac2O, pyridine; (iv) 2-(2-bromoethyl)-1,3-dioxolane, Mg, THF;
v) J ones reagent; (vi) AcOH-THF-H2O, 50 °C; (vii) NaBH4; (viii)
MOMCl; (ix) PFL.
7
bis(acetoxymethyl)cyclopentane derivatives using RDL.
In the case of meso-spirodiacetate 9, hydrolysis using
RDL also afforded the monoalcohol of high enantiomeric
excess in good yield (91% yield, >99% ee). Hydrolysis
by PFL afforded the monoalcohol of moderate enantio-
meric excess (82% ee), and hydrolysis by PPL afforded
the monoalcohol of low enantiomeric excess (33% ee). The
absolute configuration of (-)-16 was unambiguously
determined by chemical correlation as shown in Scheme
3. (1S,2R)-2-(Ethoxycarbonyl)cyclopentanol 17 was con-
verted to the 2-(acetoxymethyl)cyclopentanol 18 by Li-
7
,8
pus delemar lipase (RDL), Pseudomonas fluorescens
lipase (PFL), and porcine pancreatic lipase (PPL).9,10 The
enzymatic hydrolysis was performed in 0.1 M phosphate
buffer (pH 7.0) at 30 °C and was terminated when a spot
of the diol appeared on the TLC plate. The results of
the hydrolyses are summarized in Table 1.
(
7) (a) Suemune, H.; Okano, K.; Akita, H.; Sakai, K. Chem. Pharm.
Bull. 1987, 35, 1741. (b) Tanaka, M.; Yoshioka, M.; Sakai, K.
Tetrahedron: Asymm. 1993, 4, 981. (c) Tanaka, M.; Norimine, Y.;
Fujita, T.; Suemune, H.; Sakai, K. J . Org. Chem. 1996, 61, 6952.
AlH
4
reduction and acetylation of primary alcohol with
(
8) (a) Derewenda, U.; Swenson, L.; Green, R.; Wei, Y.; Kobos, P.
M.; J oerger, R.; Haas, M. J .; Derewenda, Z. S. J . Lipid Res. 1994, 35,
24. (b) Derewenda, U.; Swenson, L.; Green, R.; Wei, Y.; Dodson, G.
G.; Yamaguchi, S.; Haas, M. J .; Derewenda, Z. S. Nat. Struct. Biol.
994, 1, 36. (c) Derewenda, U.; Swenson, L.; Green, R.; Wei, Y.;
Yamaguchi, S.; J oerger, R.; Haas, M. J .; Derewenda, Z. S. Protein Eng.
994, 7, 551.
9) (a) Xie, Z.-F. Tetrahedron: Asymm. 1991, 2, 733. (b) Suemune,
Ac O in 55% yield. Oxidation of the secondary alcohol
2
with PCC (66%), followed by protection of the carbonyl
function with ethylene glycol, afforded the ethylene acetal
(20, 72%). The specific rotation of ethylene acetal 20
showed -13.4°. The monoalcohol (-)-16 was also con-
verted into the ethylene acetal 20 in 23% yield by
oxidation with PCC and subsequent decarbonylation with
5
1
1
(
H. Yakugaku Zasshi 1992, 112, 432. (c) Wong, C.-H.; Whitesides, G.
M. Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
d) Hirose, Y. Faruaw 1996, 32, 1075.
3 3
RhCl(PPh ) in refluxing benzene. The specific rotation
(
(
10) (a) Tanaka, M.; Yoshioka, M.; Sakai, K. J . Chem. Soc., Chem.
Commun. 1992, 1454. (b) P. fluorescens lipase (PFL) has been reclas-
sified as P. cepacia lipase (PCL). However, we use the former name
for the sake of uniformity with previous results.
(11) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512.

3
826 J . Org. Chem., Vol. 62, No. 12, 1997
Fujita et al.
Sch em e 3a
7
box-type model and the result of absolute configuration
of (-)-16 in the preliminary experiment.
For the improvement of enantiomeric excess, the
lipase-catalyzed transesterification of meso-spirodiol 12
was examined using three kinds lipases aforementioned.
It was anticipated that the transesterification of meso-
diol 12 would afford monoacetate (-)-21, which was an
enantiomer of hydrolyzed product (+)-21, because the
transesterification of meso-diol and the hydrolysis of
meso-diacetate using the same lipase are complementary.
Among the lipases used, PFL-catalyzed transesterifica-
tion of 12 in vinyl acetate proceeded smoothly to afford
the monoacetate (-)-21 of 94% ee in 48% yield. Further-
more, the same reaction by PFL in n-octane-vinyl
acetate (3:1) afforded the enantiomerically pure monoac-
etate (-)-21 in 56% yield (Scheme 4).
a
Reagents: (i) LiAlH4; (ii) Ac2O, pyridine; (iii) PCC; (iv) PPTS,
ethylene glycol; (v) RhCl(PPh3)3, benzene.
F or m a l Syn th esis of (-)-Cu r cu m a n olid e A. The
product obtained by transesterification was an enanti-
omer of (+)-21; therefore, the absolute configuration of
Ta ble 2. En zym a tic Hyd r olysis of m eso-Dia ceta te 13
(-)-21 was assumed to be 5S,6R,9S. Consequently, it
was necessary for the acetoxymethyl function at C6-
position in (-)-21 to be converted into the methyl function
for the synthesis of (-)-curcumanolide A. The conversion
of stereochemistry in (-)-21 with a (9S)-hydroxymethyl
group into 23 with a (6R)-hydroxymethyl group was
achieved in 88% yield by the protection of alcohol with
TBDMSCl and subsequent solvolysis of the acetyl func-
monoacetate
reaction
time (h)
recovery
(%)
entry
enzyme
% yield
% ee
1
2
3
RDL
PFL
PPL
214
215
121
63
49
65
86
75
23
22
29
14
tion with K
2 3
CO in MeOH. By substitution of alcohol
with iodide, and subsequent reduction with zinc in AcOH,
the alcohol 23 was converted to the lactone 25 in 63%
yield. The isopropenyl function of curcumanolide A was
thought to be introduced by the oxidation of alcohol to
carboxylic acid, methylation, and dehydration. Protec-
tion of the lactone moiety was needed to introduce the
isopropenyl function; therefore, the lactone 25 was
converted into the diol 28 in 90% yield by the reduction
of lactone with super hydride, the protection of primary
of this material showed -16.9°. Based on the comparison
of specific rotation, the absolute configuration of (-)-16
was determined to be 1S,3R. The result was in ac-
cordance with our RDL model.7 These results encour-
aged us to study the synthesis of (-)-curcumanolide A
using enzymatic hydrolysis.
Asymmetric hydrolysis of meso-diacetate 15a was first
attempted using three kinds of lipases. However, no
hydrolysis proceeded for a few days. This suggests that
the cis-oriented bulky MOM-oxypropyl substituent pre-
vented lipases from approaching both of the acetyl
functions. In the case of using RDL as a catalyst,
prolongation of the reaction time (20 days) afforded a
small amount of monoacetate 15b of low enantiomeric
excess (32% ee).
alcohol with Ac
Oxidation of the primary alcohol with J ones reagent,
followed by esterification with CH , afforded the meth-
yl ester 29 in low yield. The isolated yield of 29 was
2
O-pyridine, and deprotection of TBDMS.
2
N
2
12
improved to 56% by the adoption of PtO
2
2
-O oxidation.
The ester 29 was converted into the triol 30 by methy-
lation with MeLi in 47% yield. Oxidation of 30 with PDC
in DMF afforded the lactone 31 in 79% yield. The
spectroscopic data of 31 were identical with the reported
2
4
Therefore, hydrolysis of meso-spirodiacetate 13 was
next tried. The results are summarized in Table 2. The
specific rotations of all the hydrolyzed products indicated
a plus sign. The enantiomeric excess of the hydrolyzed
products was determined by 1H NMR spectra of the
values. The specific rotation of 31 showed [R]
D
-21.48,
which is the same as that of Honda’s reported [R]
D
-21.39.3 This means that (-)-21 has the absolute
configuration of 5S,6R,9S, and the stereochemistry of (+)-
21 is 5R,6S,9R, which are in accord with the RDL box-
type model and our assumptions. Thus, the formal
synthesis of (-)-curcumanolide A has been completed.
1
corresponding (+)-MTPA esters. The H NMR spectra
of (+)-MTPA ester derived from racemic (()-21 showed
the methoxy proton signals at δ 3.55 (br s) and 3.51 (br
1
s) in the ratio of 1 to 1, while the H NMR spectra of
Con clu sion
(
+)-MTPA ester derived from the enzymatic hydrolyzed
product (+)-21 showed the corresponding signals at δ 3.55
br s) and 3.51 (br s) in a different ratio. Unfortunately,
meso-Spirodiol 12 and spirodiacetate 13 were prepared
stereoselectively from norbornanone. Enzymatic hy-
drolysis of 13 in aqueous solution and transesterification
of 12 in organic solvent proceeded in enantioselective
manner to afford the optically active monoacetates. The
monoacetate (-)-21 obtained by PFL-catalyzed transes-
terification was used for the formal synthesis of (-)-
curcumanolide A. The strategy described here would be
(
the hydrolysis of 13 by lipases required prolonged reac-
tion time (121-215 h), and the enantiomeric excess of
the products was not satisfactory. The maximum enan-
tiomeric excess of (+)-21 (86% ee) was obtained in the
case of using RDL. Hydrolysis by PFL afforded the
monoacetate of moderate enantiomeric excess (75% ee)
and hydrolysis by PPL afforded the monoacetate of low
enantiomeric excess (23% ee). The absolute configuration
of (+)-21 was assumed to be 5R,6S,9R, based on our RDL
(12) (a) Heyns, K.; Blazejewicz, L. Tetrahedron 1960, 9, 67. (b)
Maurer, P. J .; Takahara, H.; Rapoport, H. J . Am. Chem. Soc. 1984,
106, 1095.

Enantioselective Synthesis of (-)-Curcumanolide A
J . Org. Chem., Vol. 62, No. 12, 1997 3827
Sch em e 4a
a
Reagents: (i) PFL, n-octane-vinyl acetate (3:1); (ii) TBDMSCl, imidazole, DMF; (iii) K2CO3, MeOH; (iv) I2, PPh3; (v) Zn, AcOH; (vi)
LiEt3BH; (vii) Ac2O, pyridine; (viii) TBAF, THF; (ix) PtO2, O2 and then CH2N2; (x) MeLi, THF; (xi) PDC, DMF.
useful for the enantioselective synthesis of natural
products having a spiro skeleton and/or a five-membered
ring.
4
°C until the color of solution become slightly blue. NaBH (400
mg, 10.6 mmol) was added portionwise to the reaction mixture.
The reaction mixture was gradually warmed to 0 °C, and then
acetone (5 mL) was added to destroy the excess reagent. The
mixture was evaporated in vacuo to leave an oily residue,
which was dissolved in pyridine (20 mL) and Ac
and the whole was stirred overnight. The reaction mixture
was diluted with 5% aqueous NaHCO , extracted with EtOAc,
2
O (10 mL),
Exp er im en ta l Section
1H NMR spectra were determined at 270 MHz unless
3
2 4
and then dried over Na SO . Removal of the solvent in vacuo
otherwise noted. For O
7,800 V, O flow rate; 0.5 mL/min) was used. Et
distilled from Na/benzophenone before use. Benzene and CH
Cl were distilled from P . Vinyl acetate (monomer) was
3
oxidation, an Ishii ozone generator
gave an oily residue, which was purified by column chroma-
tography on silica gel. The fraction eluted with 20% EtOAc
in hexane afforded 9 (1.42 g, 59%) as a colorless oil: IR (neat)
(
2
2
O was
2
-
2
2 5
O
-
1 1
1
4
730 cm ; H NMR (CDCl
3
) δ 4.09 (dd, J ) 6.9, 11.0 Hz, 2H),
purchased from Tokyo Kasei Corp., PPL (Type II) was pur-
.04 (dd, J ) 7.2, 11.0 Hz, 2H), 3.97 (dd, J ) 5.7, 9.2 Hz, 2H),
chased from Sigma Corp., RDL (EC 3.1.1.3) was purchased
from Seikagaku Kogyo Corp. (J apan), and PFL (Amano PS)10
3.94 (dd, J ) 5.7, 9.2 Hz, 2H), 2.39 (m, 2H), 2.04 (s, 6H), 1.87
m, 2H), 1.47 (m, 2H); 13C NMR (25 MHz, CDCl
) δ 170.9,
16.9, 66.3, 65.1, 63.7, 46.3, 24.9, 21.0; EIMS m/z 272 (M , 5),
230 (4), 213 (41), 153 (100); FAB(+)HRMS calcd for C13
(
1
3
was given courtesy of Amano Pharmaceutical Corp. (J apan),
+
and all were used as received. Norbornanone 7 was prepared
4
20 6
H O
according to Marshall’s methods, and compound 17 was given
+
(
M ) 272.1260, found 272.1266.
syn -[2-(1,3-Dioxola n -2-yl)eth yl]bicyclo[2.2.1]h ep t-2-en -
a n ti-7-ol (10). A solution of 2-(2-bromoethyl)-1,3-dioxolane
7.04 g, 38.9 mmmol) in THF (15 mL) was added dropwise to
from Takeda Pharmaceutical Corp. (J apan).
2
-Nor bor n en -7-on e Eth ylen e Aceta l (8).5 A mixture of
norbornanone 7 (600 mg, 5.56 mmol), p-toluenesulfonic acid
150 mg, 0.88 mmol), and ethylene glycol (500 mg, 8.1 mmol)
in benzene (40 mL) was refluxed for 4 h. After being cooled
to room temperature, the mixture was diluted with 5%
(
(
the stirred mixture of Mg (1.03 g, 42.4 mmol) in THF (45 mL),
and the mixture was sonicated for 1 h at room temperature.
Then, the mixture was cooled to 0 °C, and a solution of 7 (2.12
g, 19.6 mmol) in THF (10 mL) was added dropwisely. After
being stirred for 2 h, the reaction mixture was quenched with
aqueous NaHCO
3
, extracted with EtOAc, and dried over
MgSO . Removal of the solvent in vacuo gave an oily residue,
4
which was purified by column chromatography on silica gel.
The fraction eluted with 5% EtOAc in hexane afforded 8 (755
mg, 90%) as a colorless oil: IR (neat) 3075, 2950, 1310, 1200
saturated aqueous NH
Et O and then dried over MgSO
2
4
Cl, and the solution was extracted with
. After removal of the solvent,
4
the residue was purified by column chromatography on silica
gel (10% EtOAc in hexane) to give 10 (4.01 g , 97%) as colorless
-
1
1
cm ; H NMR (100 MHz, CDCl
3
) δ 6.18 (t, J ) 2.2 Hz, 2H),
3
2
3
6
.92 (dd, J ) 4.4, 10.0 Hz, 2H), 3.83 (dd, J ) 4.4, 10.0 Hz,
-1 1
crystals: mp 64-65 ˚C; IR (Nujol) 3460 cm ; H NMR (CDCl
δ 5.99 (t, J ) 2.1 Hz, 2H), 4.86 (t, J ) 4.3 Hz, 1H), 4.04-4.82
m, 4H), 2.56 (br s, 1H), 2.42 (m, 2H), 1.99 (dm, J ) 11.0 Hz,
3
)
H), 2.53 (m, 2H), 1.90 (dm, J ) 10.5 Hz, 2H), 0.97 (dd, J )
.4, 10.5 Hz, 2H); 13C NMR (25 MHz, CDCl
) δ 134.2, 125.3,
3
(
2
+
4.9, 64.5, 45.5, 22.8; EIMS m/z 152 (M , 100), 79 (68).
13
H), 1.70-1.90 (m, 4H), 0.96 (dd, J ) 3.6, 11.0 Hz, 2H);
NMR (68 MHz, CDCl ) δ 135.2, 104.6, 91.9, 64.9, 48.6, 30.0,
26.2, 23.3; EIMS m/z 210 (M , 25), 191 (9), 149 (100); FAB-
C
cis-2,2-(Eth ylen edioxy)cyclopen tan e-1,3-dim eth an ol Di-
3
+
a ceta te (9). Ozone gas was bubbled into a solution of 8 (1.34
g, 8.82 mmol) in MeOH (15 mL) and CH Cl (12 mL) at -78
+
2
2
18 3
(+)HRMS calcd for C12H O (M ) 210.1256, found 210.1249.

3
828 J . Org. Chem., Vol. 62, No. 12, 1997
Fujita et al.
a n ti-2′-Oxa -3′-oxosp ir o[b icyclo[2.2.1]h ep t -2-en e-7,1′-
2H), 1.65 (m, 2H), 0.97 (dd, J ) 3.4, 11.3 Hz, 2H); EIMS m/z
+
cyclop en ta n e] (11). J ones reagent was added dropwise to
the stirred solution of 10 (1.07 g, 5.09 mmol) in acetone (50
mL) at room temperature until the solution showed a red color.
The reaction was quenched with 2-propanol, and then acetone
was evaporated. The solution was diluted with water, ex-
212 (M , 0.5), 180 (28), 150 (100); FAB(+)HRMS calcd for
+
C
12
H
20
O
3
(M ) 212.1412, found 212.1440.
(
1s,2R ,5S )-2,5-Bis(a c e t oxym e t h yl)-[1-[3-(m e t h oxy-
m eth oxy)p r op yl]]cyclop en ta n ol (15a ). Compound 15a
was prepared from compound 14 in a similar manner to that
described for the preparation of 9. colorless oil: IR (neat) 3450
2 4
tracted with Et O, and then dried over MgSO . After removal
of the solvent, the residue was purified by column chroma-
tography on silica gel (10% EtOAc in hexane) to give 11 (737
mg , 88%) as colorless crystals: mp 55-56 ˚C; IR (Nujol) 1760
-1 1
(
6
5
3
3
br), 1730 cm ; H NMR (CDCl ) δ 4.96 (s, 2H), 4.13 (dd, J )
.3, 11.2 Hz, 2H), 4.02 (dd, J ) 7.9, 11.2 Hz, 2H), 3.55 (t, J )
.9 Hz, 2H), 3.67 (s, 3H), 2.49 (br s, 1H), 2.27 (m, 2H), 2.06 (s,
H), 2.02 (m, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.48 (m, 2H);
-
1
1
cm ; H NMR (CDCl
3
) δ 6.04 (t, J ) 2.1 Hz, 2H), 2.63 (m,
2
(
(
H), 2.50 (t, J ) 8.4 Hz, 2H), 2.21 (t, J ) 8.4 Hz, 2H), 2.02
+
FAB(+)HRMS calcd for C16
29 7
H O (M + H) 333.1913, found
1
3
dm, J ) 11.6, 2H), 1.08 (dd, J ) 3.6, 11.6 Hz, 2H); C NMR
3
33.1905.
68 MHz, CDCl ) δ 176.8, 134.2, 100.2, 48.3, 29.3, 25.4, 23.3;
3
En zym a tic Hyd r olysis of Meso Com p ou n d s. Gen er a l
Meth od s. A suspension of substrate (100 mg) and enzyme
10 mg) in acetone (0.1 mL) and 0.1 M phosphate buffer (10
+
+
EIMS m/z 165 (M + H, 11), 164 (M , 100), 108 (23), 79 (34);
+
FAB(+)HRMS calcd for C10
65.0911.
5s,6R,9S)-6,9-Bis(h yd r oxym et h yl)-1-oxa -2-oxosp ir o-
4.4]n on a n e (12). Ozone gas was bubbled into a solution of
1 (632 mg, 3.85 mmol) in MeOH (15 mL) and CH Cl (10 mL)
at -78 °C until the color of solution become slightly blue.
NaBH (500 mg, 13.5 mmol) was added portionwise to the
13 2
H O (M + H) 165.0915, found
(
1
mL, pH 7.0) was stirred at 30 °C, and the reaction was
monitored by TLC. When a spot of the diol appeared on TLC,
hydrolysis was terminated by extracting the mixture with
EtOAc. The EtOAc extract was dried over MgSO and then
4
concentrated in vacuo to leave an oily residue, which was
(
[
1
2
2
4
purified by column chromatography on silica gel.
reaction mixture. The reaction mixture was gradually warmed
to 0 °C, and then acetone (5 mL) was added for destroying the
excess reagent. The mixture was evaporated in vacuo to leave
an oily residue, which was purified by column chromatography
on silica gel. The fraction eluted with EtOAc afforded 12 (492
2
-(Ace t oxym e t h yl)-5-(h yd r oxym e t h yl)-[1-[3-(m e t h -
oxym eth oxy)p r op yl]]cyclop en ta n ol (15b): colorless oil;
25
-1
1
[
R]
D
-3.08 (c 0.51, CHCl
3
); IR (neat) 3440, 1730 cm ; H
NMR (CDCl
3
) δ 4.63 (s, 2H), 4.17 (dd, J ) 6.6, 10.9 Hz, 1H),
4
1
3
2
.07 (dd, J ) 7.9, 10.9 Hz, 1H), 3.76 (dd, J ) 8.6, 10.8 Hz,
-
1 1
mg, 64%) as a colorless oil: IR (neat) 3400 (br), 1760 cm ; H
NMR (CDCl ) δ 3.73 (m, 4H), 2.66 (t, J ) 8.2 Hz, 2H), 2.51
m, 2H), 2.21 (t, J ) 8.2 Hz, 2H), 1.95 (m, 2H), 1.50 (br, 2H),
H), 3.66 (dd, J ) 6.1, 10.8 Hz, 1H), 3.56 (t, J ) 5.9 Hz, 2H),
3
.37 (s, 3H), 2.80 (br s, 1H), 2.26 (m, 2H), 2.06 (s, 3H), 1.55-
(
1
4
.05 (m, 7H), 1.35 (m, 2H); FAB(+)HRMS calcd for C14
27 6
H O
1
3
.40 (m, 2H); C NMR (68 MHz, CDCl
3
) δ 177.7, 95.0, 62.3,
+
(
M + H) 291.1807, found 291.1815.
+
9.5, 29.9, 23.3, 22.0; EIMS m/z 200 (M , 3), 183 (14), 182 (100);
1
+
MTP A Ester of 15b. The 270 MHz H NMR spectrum of
+)-MTPA ester derived from the monoacetate (()-15b showed
the methoxy proton signals at δ 3.53 (m) and 3.55 (m) in the
ratio of 1 to 1, while the corresponding signal from (-)-15b
hydrolyzed by RDL was observed at δ 3.53 (m) and 3.55 (m)
in the ratio of 66 to 34.
FAB(+)HRMS calcd for C10
01.1145.
5s,6R,9S)-6,9-Bis(acetoxym eth yl)-1-oxa-2-oxospir o[4.4]-
n on a n e (13). A mixture of 12 (200 mg, 1.00 mmol), DMAP
10 mg), and A O (3 mL) in pyridine (5 mL) was stirred
overnight at room temperature. The mixture was diluted with
% aqueous NaHCO , extracted with EtOAc, and dried over
Na SO . Removal of the solvent in vacuo gave an oily residue,
17 4
H O (M + H) 201.1127, found
(
2
(
(
2
(
1S,3R)-1-(Acet oxym et h yl)-2,2-(et h ylen ed ioxy)-3-(h y-
5
3
2
5
d r oxym eth yl)cyclop en ta n e (16): colorless oil; [R]
D
-4.57
2
4
-
1 1
(
3
c 1.18, CHCl ); IR (neat) 3450, 1730 cm ; H NMR (CDCl ) δ
3
3
which was purified by column chromatography on silica gel.
The fraction eluted with 50% EtOAc in hexane afforded 13
.93-4.13 (m, 6H), 3.60-3.73 (m, 2H), 2.22-2.41 (m, 3H), 2.05
13
-
1
(s, 3H), 1.45-1.95 (m, 4H); C NMR (25 MHz, CDCl ) δ 171.0,
3
(
275 mg, 97%) as a colorless oil: IR (neat) 1760, 1730 cm ;
1
118.4, 66.2, 64.9, 63.7, 61.9, 48.9, 46.6, 25.6, 23.6, 21.0; EIMS
H NMR (CDCl
8.6, 11.6 Hz, 2H), 2.65 (m, 2H), 2.60 (t, J ) 8.5 Hz, 2H),
.12 (t, J ) 8.5 Hz, 2H), 2.04 (s, 6H), 1.95 (m, 2H), 1.32 (m,
3
) δ 4.24 (dd, J ) 5.7, 11.6 Hz, 2H), 4.01 (dd, J
+
m/z 230 (M , 8), 212 (8), 171 (100); FAB(+)HRMS calcd for
)
+
C
11
H
18
O
5
(M ) 230.1154, found 230.1169.
2
2
2
1
1
3
MTP A Ester of 16. The 270 MHz H NMR spectrum of
(+)-MTPA ester derived from the monoacetate (()-16 showed
the methoxy proton signals at δ 3.53 (m, 1.5 H) and 3.56 (m,
H); C NMR (68 MHz, CDCl
3
) δ 176.1, 170.9, 93.0, 63.1, 45.8,
+
9.3, 22.6, 21.2, 20.8; FAB(+)HRMS calcd for C14
21 6
H O (M +
H) 285.1338, found 285.1338.
1
.5 H), while the corresponding signal from (-)-16 hydrolyzed
by RDL was observed at δ 3.53 (m, 3 H) only.
5R,6S,9R)-6-(Acetoxym eth yl)-9-(h ydr oxym eth yl)-1-oxa-
-oxosp ir o[4.4]n on a n e (21): colorless oil, 63% yield by PFL,
syn -7-[3-(Meth oxym eth oxy)p r op yl]bicyclo[2.2.1]h ep t-
-en -a n ti-7-ol (14). A solution of 10 (548 mg, 2.61 mmol) in
2
(
AcOH-THF-H
After being cooled to room temperature, the solution was
diluted with 5% aqueous NaHCO , extracted with EtOAc, and
then dried over MgSO After removal of the solvent, the
residue was dissolved in MeOH (10 mL), and NaBH (150 mg,
.10 mmol) was added. After being stirred for 2 h, the solution
2
O (30 mL, 4:1:1) was stirred at 50 °C for 2 h.
2
8
2
1
6% ee; [R]
D
+4.98 (c 1.05, CHCl
3
); IR (neat) 3450, 1770, 1730
) δ 4.22 (dd, J ) 5.6, 11.5 Hz, 1H), 4.01
3
-
1 1
cm ; H NMR (CDCl
3
4
.
(
dd, J ) 8.6, 11.5 Hz, 1H), 3.70 (m, 2H), 2.50-2.80 (m, 3H),
4
2
7
1
6
2
.45 (m, 1H), 2.25 (ddd, J ) 6.3, 10.2, 13.2, 1H) 2.09 (ddd, J )
4
.3, 10.2, 13.2, 1H), 2.04 (s, 3H), 1.94 (m, 2H), 1.72 (br, 1H),
was diluted with acetone, and then the solution was evapo-
rated. The residue was diluted with brine, and the mixture
.32 (m, 2H); 13C NMR (25 MHz, CDCl
) δ 176.8, 171.0, 93.9,
3
3.3, 62.2, 49.1, 46.1, 29.5, 23.2, 22.7, 21.6, 20.8; EIMS m/z
was extracted with EtOAc and then dried over MgSO
4
.
+
42 (M , 2), 224 (6), 182 (45), 164 (100); FAB(+)HRMS calcd
for C H O (M + H) 243.1232, found 243.1237.
Removal of the solvent afforded crude diol as colorless crys-
+
1
tals: IR (Nujol) 3300 (br); H NMR (CDCl
3
) δ 6.00 (t, J ) 2.0
12 19
5
Hz, 2H), 3.65 (t, J ) 5.9 Hz, 2H), 2.46 (m, 2H), 2.00-2.40 (br,
P F L-Ca ta lyzed Tr a n sester ifica tion of Diol 12. A sus-
pension of diol 12 (116 mg, 0.58 mmol) and PFL (20 mg) in
n-octane-vinyl acetate (3:1, 10 mL) was stirred at room
temperature for 8 h. PFL was filtered off, and the filtrate was
concentrated in vacuo to leave an oily residue, which was
purified by column chromatography on silica gel. The fraction
eluted with 60% EtOAc in hexane afforded (-)-21 (79 mg, 56%)
2
(
H), 1.98 (dm, J ) 11.3, 2H), 1.81 (m, 2H), 1.60 (m, 2H), 0.99
dd, J ) 3.5, 11.3 Hz, 2H).
A solution of crude diol (ca. 330 mg), N,N-diisopropylamine
(295 mg, 2.30 mmol), and MOMCl (0.17 mL, 2.20 mmol) in
CH
solution was diluted with water, extracted with EtOAc, and
dried over MgSO . After removal of the solvent, the residue
2 2
Cl (10 mL) was stirred at room temperature for 3 h. The
as a colorless oil: >99% ee; [R]20
-6.41 (c 1.01, CHCl
).
D
3
4
1
was purified by column chromatography on silica gel (10%
MTP A Ester of 21. The 270 MHz H NMR spectrum of
(+)-MTPA ester derived from the monoacetate (()-21 showed
the methoxy proton signals at δ 3.55 (br s) and 3.51 (br s) in
the ratio of 1 to 1, while the corresponding signal from (+)-21
hydrolyzed by RDL was observed at δ 3.51 (br s) and 3.55 (br
EtOAc in hexane) to give 14 (239 mg, 43%) as a colorless oil:
-
1
1
IR (neat) 3460 (br) cm ; H NMR (CDCl
Hz, 2H), 4.62 (s, 2H), 3.52 (t, J ) 6.1, 2H), 3.36 (s, 3H), 2.43
m, 2H), 2.30 (br s, 1H), 1.98 (dm, J ) 11.3 Hz, 2H), 1.79 (m,
3
) δ 5.99 (t, J ) 2.1
(

Enantioselective Synthesis of (-)-Curcumanolide A
J . Org. Chem., Vol. 62, No. 12, 1997 3829
s) in the ratio of 93 to 7, and the corresponding signal from
28.1, 25.8, 22.9, 21.7, 18.2, 13.5, -5.5, -5.6; FAB(+)HRMS
+
(
-)-21 transesterified by PFL was observed at δ 3.55 (br s, 3
calcd for C16
H
31
O
3
Si
1
(M + H) 299.2042, found 299.2039.
H), only.
(1R,2S,5S)-2-[(ter t-Bu tyldim eth ylsiloxy)m eth yl]-5-m eth -
yl-1-(3-h yd r oxyp r op yl)cyclop en ta n ol (26). Super hydride
(
5R,6R,9S)-6-(Acet oxym et h yl)-9-[(ter t-bu t yld im et h yl-
(1.0 M, 15 mL, 15 mmol) was added dropwise to the stirred
siloxy)m eth yl]-1-oxa -2-oxosp ir o[4.4]n on a n e (22). A mix-
ture of (-)-21 (635 mg, 2.62 mmol), imidazole (535 mg, 7.86
mmol), and TBDMSCl (1.18 g, 7.83 mmol) in DMF (20 mL)
was stirred at room temperature for 6 h. The solution was
solution of 25 (492 mg, 1.65 mmol) in THF (30 mL) at room
temperature, and the solution was stirred for 2 h. The solution
was diluted with brine, neutralized with 10% aqueous HCl,
extracted with EtOAc, and then dried over MgSO . After
4
removal of the solvent, the oily residue was purified by column
chromatography on silica gel (30% EtOAc in hexane) to give
diluted with saturated aqueous NH
EtOAc. The EtOAc extract was washed with brine and dried
over MgSO . Removal of the solvent afforded an oily residue,
which was purified by column chromatography on silica gel
4
Cl and extracted with
4
2
6
2
6 (487 mg, 98%) as a colorless oil: [R]
D
+10.24 (c 1.31,
-
1
1
CHCl
3
); IR (neat) 3300 (br) cm ; H NMR (CDCl ) δ 3.64-
3
(
20% EtOAc in hexane) to give 22 (867 mg, 93%) as a colorless
2
5
-1
3.70 (m, 4H), 2.60 (br, 1H), 1.50-2.23 (m, 7H), 1.18-1.32 (m,
oil: [R]
D
-10.7 (c 0.97, CHCl
3
); IR (neat) 1775, 1740 cm ;
) δ 4.19 (dd, J ) 5.9, 11.5 Hz, 1H), 4.01 (dd, J
13
1
4H), 0.96 (d, J ) 6.9 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H);
NMR (125 MHz, CDCl
C
H NMR (CDCl
3
3
) δ 81.9, 64.2, 64.1, 52.3, 45.5, 29.3,
)
8.2, 11.5 Hz, 1H), 3.69 (dd, J ) 4.8, 10.9 Hz, 1H), 3.62 (dd,
2
C
7.6, 27.3, 25.9, 23.3, 18.1, 14.8, -5.5; FAB(+)HRMS calcd for
J ) 6.6, 10.9 Hz, 1H), 2.45-2.73 (m, 3H), 2.27-2.45 (m, 2H),
+
16
H
35
O
3
Si
1
(M + H) 303.2355, found 303.2351.
2
0
1
2
.07 (m, 1H), 2.04 (s, 3H), 1.89 (m, 2H), 1.22-1.55 (m, 2H),
3
.88 (s, 9H), 0.05 (s, 6H); 1 C NMR (125 MHz, CDCl
70.9, 94.1, 63.3, 61.9, 49.1, 46.3, 29.6, 25.8, 23.6, 22.7, 22.2,
(1R,2S,5S)-1-(3-Acetoxyp r op yl)-2-[(ter t-bu tyld im eth yl-
3
) δ 176.7,
siloxy)m eth yl]-5-m eth ylcyclop en ta n ol (27). Compound 27
was prepared from compound 26 in a similar manner to that
described for the preparation of 13: 97% yield; colorless oil;
+
0.8, 18.2, -5.5, -5.6; FAB(+)HRMS calcd for C18
H) 357.2097, found 357.2097.
5R,6R,9S)-9-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-6-(h y-
d r oxym eth yl)-1-oxa -2-oxosp ir o[4.4]n on a n e (23). A mix-
ture of 22 (850 mg, 2.38 mmol) and K CO (165 mg, 1.19 mmol)
in MeOH (20 mL) was stirred at room temperature for 2 h.
The reaction mixture was diluted with saturated aqueous NH
Cl and extracted with EtOAc, and then the EtOAc extract was
dried over MgSO After removal of the solvent, the oily
residue was purified by column chromatography on silica gel
33 5 1
H O Si (M
+
2
4
-1
[
R]
D
+9.18 (c 1.01, CHCl
H NMR (CDCl ) δ 4.08 (t, J ) 6.8 Hz, 2H), 3.70 (dd, J ) 6.3,
0.2 Hz, 1H), 3.65 (dd, J ) 9.4, 10.2 Hz, 1H), 2.80 (br, 1H),
.05 (s, 3H), 1.45-2.25 (m, 6H), 1.20 (m, 2H), 0.95 (d, J ) 6.9
3
); IR (neat) 3450 (br), 1740 cm ;
(
1
3
1
2
2
3
Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H); FAB(+)HRMS calcd for
4
-
+
C
18
H
37
O
4
Si
1
(M + H) 345.2461, found 345.2439.
(
1R,2S,5S)-1-(3-Acet oxyp r op yl)-2-(h yd r oxym et h yl)-5-
4
.
m eth ylcyclop en ta n ol (28). Tetrabutylammonium fluoride
1 M, 0.2 mL, 0.2 mmol) was added dropwise to the stirred
(
(
25% EtOAc in hexane) to give 23 (713 mg, 95%) as a colorless
solution of 27 (34.6 mg, 0.10 mmol) in THF (2 mL) at room
temperature, and the solution was stirred for 1 h. The solution
2
5
-1
oil: [R]
D
-7.60 (c 0.99, CHCl
3
); IR (neat) 3450, 1770 cm ;
) δ 3.68 (m, 4H), 2.63 (m, 2H), 2.13-2.48 (m,
1
H NMR (CDCl
3
was diluted with saturated aqueous NH
4
Cl, extracted with
4
H), 1.89 (m, 2H), 1.30-1.60 (m, 3H), 0.88 (s, 9H), 0.05 (s, 6H);
EtOAc, and dried over MgSO Removal of the solvent in
4
.
1
3
C NMR (125 MHz, CDCl
3
) δ 177.2, 94.9, 62.3, 62.1, 49.7, 49.5,
vacuo gave an oily residue, which was purified by column
chromatography on silica gel. The fraction eluted with 50%
EtOAc in hexane afforded 28 (23 mg, 99%) as a colorless oil:
2
9.8, 25.8, 23.6, 23.2, 22.5, 18.2, -5.5, -5.6; FAB(+)HRMS
+
calcd for C16
5S,6S,9S)-9-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-6-(io-
d om eth yl)-1-oxa -2-oxosp ir o[4.4]n on a n e (24). A mixture
of I (1.53 g, 6.03 mmol) and PPh (1.58 g, 6.02 mmol) in CH
Cl (30 mL) was stirred at 0 °C for 2 h. Then, a solution of 23
948 mg, 3.01 mmol) and pyridine (500 mg, 6.33 mmol) in CH
Cl (30 mL) was added dropwise to the stirred solution, and
the whole was stirred for 3 h. The solution was diluted with
saturated aqueous Na , and extracted with Et O. The
etheral extract was washed with water, and dried over MgSO
31 4 1
H O Si (M + H) 315.1991, found 315.1990.
(
22
-1
[
R]
D
+7.13 (c 1.06, CHCl
H NMR (CDCl ) δ 4.10 (t, J ) 6.6 Hz, 2H), 3.70 (m, 2H), 2.07
s, 3H), 1.50-2.25 (m, 10H), 1.26 (m, 2H), 0.94 (d, J ) 6.9 Hz,
3
); IR (neat) 3400 (br), 1740 cm ;
1
3
2
3
2
-
(
3
4
2
13
H); C NMR (125 MHz, CDCl
3
) δ 171.3, 82.3, 65.3, 63.9, 52.4,
(
2
-
5.6, 29.2, 26.8, 23.7, 23.4, 21.0, 14.6; FAB(+)HRMS calcd for
2
+
C
12
H
23
O
4
(M + H) 231.1596, found 231.1615.
1R,2R,5S)-1-(3-Acetoxyp r op yl)-2-(m eth oxyca r bon yl)-
gas was bubbled to the
(200 mg, 0.88 mmol) in H O (30
mL) for 1 h. Then, compound 28 (280 mg, 1.22 mmol) was
added and O gas was bubbled at 60 °C for 10 h. PtO was
filtered off, and the filtrate was extracted with EtOAc. The
EtOAc extract was dried over MgSO and concentrated in
vacuo to leave an oily residue. The residue was dissolved in
Et O (20 mL). The solution was treated with ethereal CH
(
2
S
2
O
3
2
5
-m eth ylcyclop en ta n ol (29).
H
2
4
.
stirred suspension of PtO
2
2
After removal of the solvent, the oily residue was purified by
column chromatography on silica gel (5% EtOAc in hexane)
2
2
2
5
to give 24 (1.21 g, 95%) as a yellowish oil: [R]
D
-5.72 (c 1.02,
-
1 1
CHCl
3
); IR (neat) 1770 cm ; H NMR (CDCl
3
) δ 3.69 (dd, J )
4
4
)
.3, 11.2 Hz, 1H), 3.59 (dd, J ) 7.3, 11.2 Hz, 1H), 3.25 (dd, J
4.3, 9.4 Hz, 1H), 2.99 (dd, J ) 9.4, 10.7 Hz, 1H), 2.69 (ddd,
J ) 8.9, 8.9, 17.8 Hz, 1H), 2.64 (m, 1H), 2.52 (ddd, J ) 4.6,
.9, 17.8 Hz, 1H), 1.75-2.45 (m, 5H), 1.25-1.55 (m, 2H), 0.88
2
2 2
N
solution at 0 °C until the color of solution maintained yellow,
and the whole was left at room temperature for 2 h. After
removal of the solvent, the residue was purified by column
9
(
1
3
s, 9H), 0.04 (s, 6H); C NMR (125 MHz, CDCl
3
) δ 176.4, 93.7,
6
2.2, 50.7, 49.4, 29.5, 27.8, 25.8, 21.6, 21.5, 18.2, 3.2, -5.5,
chromatography on silica gel (15% EtOAc in hexane) to give
+
-
5.6; FAB(+)HRMS calcd for C16
H
30
O
3
Si
1
I
1
(M + H) 425.1011,
23
2
9 (175 mg, 56%) as a colorless oil: [R]
D
-29.67 (c 0.81,
found 425.1009.
-1 1
CHCl
3
); IR (neat) 3450, 1740 cm ; H NMR (CDCl
3
) δ 4.04 (t,
(
5R,6S,9S)-9-[(ter t-Bu tyldim eth ylsiloxy)m eth yl]-6-m eth -
J ) 6.6 Hz, 2H), 3.71 (s, 3H), 2.82 (t, J ) 9.2 Hz, 1H), 2.17 (br
yl-1-oxa -2-oxosp ir o[4.4]n on a n e (25). A suspension of 24
s, 1H), 2.05 (s, 3H), 2.00 (m, 3H), 1.72 (m, 2H), 1.35-1.59 (m,
(
(
1.25 g, 2.95 mmol) and zinc dust (960 mg, 14.7 mmol) in AcOH
20 mL) was stirred at room temperature for 20 min and then
4H), 0.97 (d, J ) 6.6 Hz, 3H); FAB(+)HRMS calcd for C13
H
23
O
5
+
(M + H) 259.1545, found 259.1542.
at 80 °C for 30 min. Zinc dust was filtered off, and the filtrate
was diluted with saturated aqueous NaHCO and extracted
with EtOAc. The EtOAc extract was washed with brine and
dried over MgSO . Removal of the solvent in vacuo gave an
oily residue, which was purified by column chromatography
on silica gel. The fraction eluted with 5% EtOAc in hexane
(1R,2S,5S)-2-(2-Hydr oxyisopr opyl)-1-(3-h ydr oxypr opyl)-
5-m eth ylcyclop en ta n ol (30). An ethereal solution of MeLi
(1.5 M, 3.6 mL) was added to the stirred solution of 29 (174
mg, 0.67 mmol) in THF (15 mL) at 0 °C, and the solution was
stirred for 2 h. The solution was diluted with saturated
3
4
4 4
aqueous NH Cl, extracted with EtOAc, and dried over MgSO .
2
6
afforded 25 (581 mg, 66%) as a colorless oil: [R]
D
-2.76 (c
) δ 3.67 (dd,
J ) 5.0, 11.2 Hz, 1H), 3.60 (dd, J ) 7.4, 11.2 Hz, 1H), 2.67
ddd, J ) 8.6, 10.0, 18.0 Hz, 1H), 2.49 (ddd, J ) 5.0, 10.0, 18.0
Hz, 1H), 2.16-2.38 (m, 3H), 1.76-2.05 (m, 3H), 1.10-1.46 (m,
H), 0.93 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13
NMR (125 MHz, CDCl ) δ 177.2, 95.4, 62.7, 48.8, 42.6, 29.8,
After removal of the solvent, the oily residue was purified by
column chromatography on silica gel (45% EtOAc in hexane)
-1 1
1
3 3
.02, CHCl ); IR (neat) 1770 cm ; H NMR (CDCl
2
3
to leave 30 (69 mg, 47%) as a colorless oil: [R]
D
+3.51 (c 1.20,
3
-
1 1
(
CHCl
3
); IR (neat) 3350 (br) cm ; H NMR (CDCl ) δ 3.65 (t, J
) 5.6 Hz, 2H), 2.30-3.20 (br, 2H), 1.33 (s, 3H), 1.27 (s, 3H),
2
C
0.98 (d, J ) 6.6 Hz, 3H), 1.00-2.15 (m, 11H); FAB(+)HRMS
+
3
calcd for C12
H
25
O
3
(M + H) 217.1804, found 217.1808.

3
830 J . Org. Chem., Vol. 62, No. 12, 1997
5R,6S,9S)-9-(2-H yd r oxyisop r op yl)-6-m et h yl-1-oxa -2-
Fujita et al.
(
Synthetic Organic Chemistry, J apan. We are grateful
for stipend given to Y.N. by the J apan Society for the
Promotion of Science. We thank Amano Pharmaceuti-
cal Co., Ltd., for kindly providing lipases. We also thank
Dr. Ryuichi Isobe, Mr. Yoshitsugu Tanaka, and Ms.
Yasuko Soeda for the measurement of MS and NMR
spectra.
oxosp ir o[4.4]n on a n e (31). A mixture of 30 (68 mg, 0.31
mmol), PDC (500 mg, 1.33 mmol), and molecular sieves 3A
(
20 mg) in DMF (2 mL) was stirred overnight at room
temperature. The mixture was diluted with brine, extracted
with EtOAc, and dried over MgSO . Removal of the solvent
4
in vacuo afforded an oily residue, which was purified by column
chromatography on silica gel. The fraction eluted with 15%
2
4
EtOAc in hexane gave 31 (52 mg, 79%) as a colorless oil: [R]
D
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of all new compounds, partial H NMR spectra
-
21.48 (c 0.82, CHCl
3
), [lit. [R]
D
-21.39 (c 0.6, CHCl
3
)]; IR
) δ 2.97 (ddd, J ) 9.6,
1
-
1
1
(
neat) 3460, 1760 cm ; H NMR (CDCl
3
of MTPA esters for the determination of ee, 13C NMR spectra
of compounds 8-13, 16, 21-26, 28, and 31, GC data of 11
and 31, experimental section for the determination of absolute
configuration of (-)-16 (43 pages). This material is contained
in libraries on microfiche, immediately follows this article
in the microfilm version of the journal, and can be ordered
from the ACS; see any current masthead page for ordering
information.
1
1
2
1
1
0.6, 13.5 Hz, 1H), 2.47-2.70 (m, 2H), 2.15-2.30 (m, 2H),
.63-1.93 (m, 4H), 1.31 (s, 3H), 1.22 (s, 3H), 1.15-1.30 (m,
H), 0.91 (d, J ) 6.6 Hz, 3H); 1 C NMR (68 MHz, CDCl
3
3
) δ
77.3, 95.0, 71.6, 53.9, 43.9, 31.5, 29.7, 29.6, 26.5, 20.6, 20.0,
+
2.7; FAB(+)HRMS calcd for C12
21 3
H O (M + H) 213.1491,
found 213.1499.
Ack n ow led gm en t. This work was partly supported
by the Yamanouchi Pharmaceutical Co. Award in
J O962150R