A Catalytic Asymmetric Synthesis of 11-Deoxy-PGF1α Using ALB, a Heterobimetallic Multifunctional Asymmetric Complex

Article abstract of DOI:10.1021/jo9723319

A catalytic asymmetric synthesis of 11-deoxy-PGF_1α has been achieved using a cascade Michaelaldol reaction as a key step. This cascade reaction was efficiently promoted by a catalytic use of AlLibis[(S)-binaphthoxide] complex (ALB) to give the three-component coupling product at room temperature in 92percent ee and in 84percent yield. The three-component coupling product was then converted to (+)-ll-deoxy-PGF_1α through several steps, including an oxidative decarboxylation, an aldol reaction, and a Wharton reaction. Moreover, the racemic enone, 20 was transformed into 21, the three-component coupling product, a potential intermediate for PGF_1α in 97percent ee and in 75percent yield through catalytic kinetic resolution.

Full text of DOI:10.1021/jo9723319

3666
J . Org. Chem. 1998, 63, 3666-3672
A Ca ta lytic Asym m etr ic Syn th esis of 11-Deoxy-P GF 1r Usin g ALB, a
Heter obim eta llic Mu ltifu n ction a l Asym m etr ic Com p lex
Ken-ichi Yamada, Takayoshi Arai,† Hiroaki Sasai,† and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113, J apan
Received December 31, 1997
A catalytic asymmetric synthesis of 11-deoxy-PGF1R has been achieved using a cascade Michael-
aldol reaction as a key step. This cascade reaction was efficiently promoted by a catalytic use of
AlLibis[(S)-binaphthoxide] complex (ALB) to give the three-component coupling product at room
temperature in 92% ee and in 84% yield. The three-component coupling product was then converted
to (+)-11-deoxy-PGF1R through several steps, including an oxidative decarboxylation, an aldol
reaction, and a Wharton reaction. Moreover, the racemic enone, 20 was transformed into 21, the
three-component coupling product, a potential intermediate for PGF1R, in 97% ee and in 75% yield
through catalytic kinetic resolution.
Sch em e 1
We have developed a variety of heterobimetallic asym-
metric complexes that efficiently promote many catalytic
asymmetric reactions, such as nitro-aldol reactions,1,2
Michael reactions,1 hydrophosphonylations,1 epoxide open-
ing reactions with thiols,3 epoxidations of R,â-unsaturated
ketones,4 and aldol reactions with unmodified ketones.5
These heterobimetallic asymmetric complexes are mul-
tifunctional asymmetric catalysts, showing both Brønsted
basicity and Lewis acidity to make a variety of useful
catalytic asymmetric reactions possible. Among the
many heterobimetallic complexes, AlLibis(binaphthoxide)
complex (ALB) shows one of the most interesting chemi-
cal reactivities. That is, this catalyst enables a cascade
Michael-aldol reaction,6 which gives rise to the three-
component coupling product in high enantiomeric excess
even at room temperature. Other complexes, such as the
LaNa3tris(binaphthoxide) complex (LSB), the alkali metal-
free lanthanum complex, or GaNabis(binaphthoxide), are
also quite useful for catalytic asymmetric Michael reac-
tions.1 These complexes, however, do not promote cas-
cade Michael-aldol reactions effectively and, thus, only
give rise to highly optically active Michael adducts as
major products. These results suggest that only inter-
mediates of the aluminum enolate type, generated during
the ALB-catalyzed Michael reactions, can react with
aldehydes much faster than the competing protonation
step can take place. We decided to demonstrate the
usefulness of the above-mentioned cascade catalytic
asymmetric Michael-aldol reactions by applying them
to catalytic asymmetric syntheses of biologically signifi-
cant compounds. As the first step of these planned
synthetic projects, the development of a catalytic asym-
metric synthesis of 11-deoxy-PGF1R (1)7 was undertaken.
In this paper, we want to report a catalytic asymmetric
synthesis of 1 using a cascade Michael-aldol reaction as
a key step as well as an efficient synthesis of 21 through
catalytic kinetic resolution.
A retrosynthetic analysis for the catalytic asymmetric
synthesis of 11-deoxy-PGF1R (1) is described in Scheme
1. The rationale for adopting methyl-substituted diben-
zyl malonate (4) as a Michael donor is as follows.
Although a cascade catalytic asymmetric Michael-aldol
reaction using dialkyl malonate proceeds, unfortunately,
it results in only a modest chemical yield of the desired
three-component coupling product. On the other hand,
the use of methyl-substituted dialkyl malonate instead
of dialkyl malonate gives rise, generally, to an excellent
yield of the three-component coupling product. We
thought that the three-component coupling product 2
could be converted to 1.
† Current address: The Institute of Scientific and Industrial Re-
search, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047,
J apan.
(1) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236 and references cited therein.
According to the retrosynthetic analysis shown above,
we first examined a cascade catalytic asymmetric
(2) Takaoka, E.; Yoshikawa, N.; Yamada, Y. M. A.; Sasai, H.;
Shibasaki, M. Heterocycles 1997, 46, 157.
(3) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J . Am. Chem.
Soc. 1997, 119, 4783.
(4) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M.
Ibid. 1997, 119, 2329.
(5) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871.
(6) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki,
M. Ibid. 1996, 35, 104.
(7) For previously reported total syntheses of (()-11-deoxy-PGF1R
,
see; (a) Caton, M. P. L.; Coffee, E. C. J .; Watkins, G. L. Tetrahedron
Lett. 1972, 773. (b) Alvarez, F. S.; Wren, D.; Prince, A. J . Am. Chem.
Soc. 1972, 94, 7823. (c) Alvarez, F. S.; Wren, D. Tetrahedron Lett.
1973, 569. (d) Burton, T. S.; Caton, M. P. L.; Coffee, E. C. J .; Parker,
T.; Stuttle, K. A. J .; Watkins, G. L. J . Chem. Soc., Perkin Trans. 1
1976, 2550. For the only synthesis of optically pure (+)-11-deoxy-
PGF1R from natural PGs, see: (e) Lincoln, F. H.; Schneider, W. P.; Pike,
J . E. J . Org. Chem. 1973, 38, 951.
S0022-3263(97)02331-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/08/1998

Catalytic Asymmetric Synthesis of 11-Deoxy-PGF1R
J . Org. Chem., Vol. 63, No. 11, 1998 3667
Sch em e 2
Michael-aldol reaction. Prior to this research project,
only benzaldehyde and hydrocinnamaldehyde had been
utilized for the catalytic asymmetric three-component
coupling reactions. So, the first challenging point in the
present synthesis was to determine whether or not the
aldehyde 58 could be used for the catalytic asymmetric
three-component coupling reaction. We were very pleased
to find that AlLibis[(S)-binaphthoxide] (ALB) (10 mol %)
can catalyze the tandem Michael-aldol reaction of cy-
clopentenone (3) with dibenzyl methylmalonate (4) (1.2
equiv)9 and the aldehyde 5 (1.5 equiv) at room temper-
ature to give the desired three-component coupling
product 2 in 86% yield as a mixture of two diastereomers
presence of MS 4A, ALB II (5 mol %), which was prepared
from ALB (5 mol %) and sodium tert-butoxide (4.5 mol
%), very efficiently catalyzed the tandem Michael-aldol
reaction to give 2 in 84% yield and in 92% ee. The three-
component coupling product 2 was then converted to 8
through mesylation followed by elimination12 in 87%
yield.13 Recrystallization of 8 from ether-hexane (two
times) afforded optically pure 8 in 57% yield. The
intermediates 6 and 7, shown in Scheme 2, are proposed
for the highly efficient cascade reaction. The coordination
of the enone to the aluminum should not only result in
an activation of the enone but also fix the position of the
enone so that high facial selectivity in the Michael
addition could be achieved. The relatively large elec-
tronegativity of aluminum (1.5) would allow the inter-
mediary aluminum enolate to react with the aldehyde
faster than protonation of the enolate can take place.
Hydrosilylation of optically pure 8 catalyzed by chlo-
rotris(triphenylphosphine)rhodium at 80 °C14 followed by
treatment with aqueous hydrogen fluoride (46%) in
acetonitrile at room temperature for 5 h gave the trans
ketone 9 (Scheme 3). The cis isomer that was obtained
as a mixture of diastereomers (cis:trans ) 1:4) in a
shorter reaction time (30 min) completely epimerized to
trans-9 in acidic conditions (catalytic CSA, 1,2-dichloro-
ethane, reflux; or 46% aqueous hydrogen fluoride, aceto-
nitrile, room temperature). The stereochemistry of trans-9
was unequivocally determined by converting it to 11-
deoxy-PGF1R. Reduction of the ketone 9 with L-Selectride
in THF-CH2Cl2 at -78 °C furnished the R-alcohol 10
exclusively. The stereochemistry of 10 was determined
by comparing the chemical shift of the carbinolic proton
of 10 with that of the â-isomer.15 The alcohol 10 then
underwent a protection with tert-butyldimethylsilyl tri-
fluoromethanesulfonate and 2,6-lutidine (CH2Cl2, -78
°C), giving 11 in 73% overall yield from 8.
1
(6:1-17:1 by H NMR). Barton deoxygenation of these
diastereomers gave trans ketone 9 without a trace of cis
ketone.10 Thus, the relative stereochemistry of both side
chains appeared to be perfectly controlled, and the
stereochemistry of the secondary hydroxyl group was
moderately controlled, giving a mixture of two diaster-
eomers. The optical purity of 2 was determined to be
91% ee at the stage of the (E)-enone 8 (Scheme 2). The
absolute configuration was unequivocally determined by
converting 2 to 11-deoxy-PGF1R. It might be noteworthy
that such a high enantioselectivity could be achieved even
at room temperature. After several attempts, we suc-
ceeded in reducing the amount of ALB catalyst by using
an improved, so-called second generation catalyst (ALB
II)1,11 and by simultaneously adding MS 4A. In the
(8) Suzuki, M.; Kawagishi, T.; Yanagisawa, A.; Suzuki, T.; Okamura,
N.; Noyori, R. Bull. Chem. Soc. J pn. 1988, 61, 1299.
(9) As expected, the use of dibenzyl malonate instead of dibenzyl
methylmalonate (4) as a Michael donor gave the three-component
coupling products in only 9% yield.
(10) Acylation of 2 (ca. 17:1 mixture of diastereomers) with TCDI
gave a mixture of diastereomers of i (ca. 12:1), whose reduction under
radical conditions furnished 9 (as shown below). No cis isomer was
detected by 1H NMR.
With the optically pure 11 in large quantities, the next
synthetic task was an effective construction of the
ω-chain. Toward this end, 11 was efficiently transformed
(12) Posner, G. H.; Gurria, G. M.; Babiak, K. A. J . Org. Chem. 1977,
42, 3173.
(13) The (Z)-isomer was also isolated as a minor product (<10%).
(14) Ojima, I.; Kogure, T. Organometallics 1982, 1, 1390.
(15) The chemical shift of the carbinolic proton of 10 was δ 4.2 and
that of the epimer was δ 3.9. Carbinolic proton signals in R-alcohols
in this type of substituted cyclopentanes appear consistently at lower
field, relative to those in the â-alcohols (see ref 7c).
(11) Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M. J . Am. Chem.
Soc. 1998, 120, 442.

3668 J . Org. Chem., Vol. 63, No. 11, 1998
Yamada et al.
Sch em e 3a
Sch em e 4a
a
Key: (a) (1) (PH3P)3RhCl, Et3SiH; (2) aqueous HF, CH3CN;
(b) L-Selectride, THF-CH2Cl2; (c) TBDMSOTf, 2,6-lutidine, CH2Cl2;
(d) (1) H2 10% Pd-C, CH3OH; (2) Pb(OAc)4, pyridine, benzene;
(3) K2CO3, CH3OH; (e) (1) TICl4, i-PrNEt2; hexanal (13), CH2Cl2;
(2) MsCl, Et3N; DBU, CH2Cl2.
a
KEY: (a) La-(S)-3-(hydroxymethyl)binaphthol complex, TBHP,
MS4A, toluene; (b) N2H4·HCl, Et3N, (dimethylamino)ethanol; (c)
(1) NaBH4, CeCl3, CH3OH; (2) Ac2O, DMAP, pyridine; (d) PdCl2-
(CH3CN)2, THF; (e) K2CO3, CH3OH; (f) (1) HF-pyridine, THF; (2)
aq NaOH, THF.
into the methyl ketone 12. Hydrogenolysis of 11 gave
the dicarboxylic acid, which underwent oxidative decar-
boxylation16 by treatment with lead tetraacetate in the
presence of pyridine in benzene to furnish the diacetate.
Reaction of the diacetate with potassium carbonate in
methanol gave rise to the methyl ketone 12 in 75%
overall yield. Aldol reaction of 12 with hexanal (13)
through the lithium enolate generated by lithium hex-
amethyldisilazide, followed by elimination, furnished the
enone 14 in 66% yield. This transformation was found
to be improved using the titanium enolate,17 giving the
enone 14 in 85% overall yield.
chloride20 in methanol at 0 °C, giving a mixture of
diastereomers of the allylic alcohols 17. The ratio of the
allylic alcohols was determined to be 2 (R-alcohol):1(â-
alcohol) by 1H NMR analysis after converting the mixture
of the allylic alcohols to the allylic acetates 18 (92% from
14). The allylic acetates 18 were treated with a catalytic
amount of bis(acetonitrile)dichloropalladium(II) (4 mol
%) in THF at room temperature for 4.5 h.21 Under these
conditions, the desired product 19 was obtained as an
equilibrium mixture with 18 in a ratio of 3 (19):1 (18).
Deacetylation of the allylic acetates 19 and 18 gave the
allylic alcohols 16 and 17 in 86% combined yield from
18. Re-acetylation of recovered 17 gave 18 as a mixture
of diastereomers in a ratio of 2:1 (R:â). Consequently,
the ratio of diastereomers of 16 should be 2:1 (R:â). 16
was then transformed into 11-deoxy-PGFR (1) by sequen-
tial deprotection (61% overall yield based on 16r). The
optical purity of 1 thus obtained as well as the absolute
configuration were unequivocally confirmed by converting
16 to known optically pure 11-deoxy-PGE1.7e, 22
Furthermore, we examined the possibility of synthesiz-
ing optically active PGF1R (22) using a catalytic kinetic
resolution as a key step. Thus, the racemic enone 2023
underwent a cascade catalytic asymmetric Michael-aldol
reaction under the conditions shown in Scheme 5. The
desired three-component coupling product 21, a potential
intermediate for PGF1R, was obtained in 75% yield (based
on malonate 4) and in 97% ee24 as a mixture of two
diastereomers (12:1 by 1H NMR). Not only almost perfect
Final conversion of 14 to 11-deoxy-PGF1R (1) was
achieved in two ways. As shown in Scheme 4, the first
route to 1 utilized a Wharton reaction.18 We first applied
a catalytic asymmetric epoxidation4 recently developed
in our group to the enone 14. Treatment with a catalyst,
generated from La(O-i-Pr)319 and (S)-3-(hydroxymethyl)-
binaphthol, and tert-butyl hydroperoxide afforded the
desired R-epoxide 15r and the â-epoxide 15â in a ratio
of 17:3 (89%). Under standard epoxidation conditions
with dimethyldioxirane, no stereoselectivity was ob-
served, and 15r and 15â were produced in a ratio of 1:1.
The mixture of the epoxides was then subjected to
Wharton reaction conditions (hydrazine monohydrochlo-
ride and triethylamine in (dimethylamino)ethanol) to give
the desired allylic alcohols 16r and 16â (ca. 17:3) as a
mixture with some byproducts in 32% combined yield.
In an attempt to improve the transformation of 14 to 16r,
we found another approach. That is, the second route
to 1 involved the allylic acetate 18. Thus, the enone 14
was reduced with sodium borohydride and cerium(III)
(16) Tufariello, J . J .; Kissel, W. J . Tetrahedron Lett. 1966, 6145.
(17) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047. (b) Evans, D. A.; Urpi, F.; Somers, T. C.;
Clark, J . S.; Bilodeau, M. T. Ibid. 1990, 112, 8215.
(18) (a) Castedo, L.; Mascan˜as, J . L.; Mourin˜o, A. Tetrahedron Lett.
1987, 28, 2099. (b) Wharton, P. S.; Bohlen, D. H. J . Org. Chem. 1961,
26, 3615.
(20) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226.
(21) Grieco, P. A.; Takigawa, T.; Bongers, S. L.; Tanaka, H. Ibid.
1980, 102, 7588.
(22) (a) Abraham, N. A. Tetrahedron Lett. 1974, 1393. (b) Sih, C.
J .; Salomon, R. G.; Price, P.; Sood, R.; Peruzzotti, G. J . Am. Chem.
Soc. 1975, 97, 857.
(23) (a) Kru¨ger, G.; Harde, C.; Bohlmann, F. Terahedron Lett. 1985,
26, 6027. (b) Paquette, L. A.; Earle, M. J .; Smith, G. F. Org. Synth.
1996, 73, 36.
(19) Purchased from Kojundo Chemical Co., Ltd., 5-1-28, Chiyoda,
Sakato, Saitama 350-02, J apan (Fax: +81-492-84-1351).

Catalytic Asymmetric Synthesis of 11-Deoxy-PGF1R
J . Org. Chem., Vol. 63, No. 11, 1998 3669
MS 4A (100 mg) was added a 0.1 M (S)-ALB THF solution
(0.50 mL, 0.050 mmol), a THF solution of sodium tert-butoxide
(0.49 M, 0.092 mL), 2-cyclopenten-1-one (3) (0.084 mL, 1.0
mmol), methyl 6-formylhexanoate (5) (0.24 mL, 1.5 mmol), and
dibenzyl methylmalonate (4) (0.32 mL, 1.2 mmol) at room
temperature. The reaction mixture was stirred for 90 h at
the same temperature before filtration (Celite). The residual
MS 4A was successively washed with EtOAc, and the filtrate
was washed with 1 N HCl, saturated aqueous NaHCO3, and
brine, then dried (Na2SO4) and concentrated. Purification of
the resulting residue by flash column chromatography (SiO2,
35% EtOAc-hexane) gave â-hydroxy ketones 2 (0.45 g, 84%
based on enone 3, a mixture of two diastereomers) as a pale
Sch em e 5
yellow oil: IR (neat) ν 3513, 1732 cm-1 1H NMR (CDCl3) δ
;
1.47 (s, 3H), 1.21-1.75 (m, 9H), 2.32 (t, 2H, J ) 7.3 Hz), 2.02-
2.39 (m, 5H), 2.94 (m, 0.15H), 3.02 (dt, 0.85H, J ) 8.0, 6.6
Hz), 3.66 (s, 3H), 3.60-3.66 (m, 1H), 5.00-5.16 (m, 4H), 7.22-
7.33 (m, 10H); 13C NMR (CDCl3) δ 18.5, 22.9, 24.8, 25.9, 28.9,
33.9, 34.2, 38.5, 43.4, 51.4, 55.4, 57.1, 67.3, 72.8, 128.2, 128.3,
128.4, 128.5, 128.6, 134.9, 135.0, 171.2, 171.3, 174.2, 218.6;
FABMS: m/z 539 (M+), 521 (M+ - O); HRMS m/z calcd for
C
31H37O7 (M+ - OH) 521.2539, found 521.2515.
Meth yl (E)-7-[(S)-2-[1,1-Bis(ben zyloxyca r bon yl)eth yl]-
5-oxocyclop en tylid en e]h ep ta n oa te (8). To â-hydroxy ke-
tone 2 (3.5 g, 6.5 mmol) in 70 mL of toluene was added
triethylamine (4.5 mL, 30 mmol) and then methanesulfonyl
chloride (1.3 mL, 17 mmol) at 0 °C. After the reaction mixture
was warmed to room temperature and stirred for 25 min,
activated alumina (38 g) was added in several portions. The
reaction mixture was stirred for 26 h before filtration (Celite).
The residual alumina was successively washed with EtOAc,
and the filtrate was washed with 1 N HCl, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), and concentrated. Pu-
rification of the resulting residue by flash column chromatog-
raphy (SiO2, 15% EtOAc-hexane) gave enone 8 (2.9 g, 87%)
in 91% ee as a white-to-yellow solid. Recrystallization of 8
from ether-hexane two times gave 8 (57%) in >99% ee: mp
78 °C; IR (KBr) ν 1725, 1647 cm-1; 1H NMR (CDCl3) δ 1.40 (s,
3H), 1.24-1.63 (m, 6H), 2.27 (t, J ) 7.5 Hz, 2H), 2.02-2.30
(m, 6H), 3.66 (s, 3H), 3.75 (d, J ) 7.3 Hz, 1H), 5.04 (d, J ) 12
Hz, 1H), 5.06 (s, 2H), 5.15 (d, J ) 12 Hz, 1H), 6.60 (dd, J )
5.5, 9.5 Hz, 1H), 7.21-7.32 (m, 10H); 13C NMR (CDCl3) δ 18.7,
23.7, 24.6, 28.3, 28.7, 29.7, 33.8, 35.3, 42.5, 51.4, 58.6, 67.2,
67.3, 127.9, 128.1, 128.3, 128.4, 128.5, 135.0, 137.7, 140.5,
170.8, 173.9, 206.9; MS m/z 521 (M+ + 1), 520 (M+); [R]28D +106
(c ) 0.490, CHCl3). Anal. Calcd for C31H36O7: C, 71.52; H,
6.97. Found: C, 71.59; H, 7.10. The enantiomeric excess of 8
was determined by chiral stationary-phase HPLC analysis
(DAICEL Chiralpak AD, 10% i-PrOH-hexane, flow rate: 1.0
mL/min, retention time: 23 min (S)-isomer and 29 min (R)-
isomer, detection at 254 nm).
kinetic resolution but also relatively high yield was
achieved. This is the first example of a catalytic kinetic
resolution using heterobimetallic multifunctional com-
plexes. The three-component coupling product 21 should
be a useful intermediate for synthesizing a variety of
biologically significant compounds including PGF1R
.
In conclusion, we have achieved a catalytic asymmetric
synthesis of 11-deoxy-PGF1R (1) using a cascade catalytic
asymmetric Michael-aldol reaction as a key step and
succeeded in demonstrating the usefulness of this cascade
reaction.25 Moreover, we have shown a new potential of
heterobimetallic multifunctional catalysts to act as pro-
moter in catalytic kinetic resolutions.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
measured with CDCl3 as a solvent. Chemical shifts are
reported in ppm on the δ scale relative to residual CHCl3 (δ )
7.26 for 1H NMR and δ ) 77.0 for 13C NMR) as an internal
reference. The THF solution of ALB was prepared according
to the reported procedure.6 MS 4A was dried at 180 °C under
reduced pressure for 6 h prior to use. All solvents used in the
reactions were dried prior to use. All reagents were purified
by standard methods. All experiments were performed under
an anhydrous argon atmosphere, unless otherwise mentioned,
and monitored with analytical TLC (Merck Art. 5715, silica
gel 60 F254 plates).
Meth yl 7-[(1R,5S)-2-[1,1-Bis(ben zyloxyca r bon yl)eth yl]-
5-oxocyclop en tyl]h ep ta n oa te (9). To a mixture of enone
8 (1.6 g, 3.1 mmol) and chlorotris(triphenylphosphine)rhodium
(I) (57 mg, 0.062 mmol) was added triethylsilane (2.5 mL, 15
mmol) slowly at 80 °C. After being stirred for 15 min at the
same temperature, the reaction mixture was directly filtered
(SiO2, 10% EtOAc-hexane) to give a crude mixture (2.0 g).
The mixture was dissolved in acetonitrile (29 mL), and 46%
aqueous hydrogen fluoride (1.3 mL) was added to the solution.
After being stirred for 6 h at room temperature, the reaction
mixture was quenched by addition of saturated aqueous
NaHCO3. The organic layer was separated and washed with
brine, and the aqueous layer was extracted with EtOAc (50
mL × 2). The organic layer was dried (Na2SO4) and concen-
trated. The residue was purified by flash column chromatog-
raphy (SiO2, 25% EtOAc-hexane) to give trans ketone 9 (1.4
Meth yl (R)-7-[(1S,2S)-2-[1,1-Bis(ben zyloxyca r bon yl)-
eth yl]-5-oxocyclop en tyl]-7-h yd r oxyh ep ta n oa te (2r) a n d
Meth yl (S)-7-[(1S,2S)-2-[1,1-Bis(ben zyloxycar bon yl)eth yl]-
5-oxocyclop en tyl]-7-h yd r oxyh ep ta n oa te (2b). To dried
(24) The optical purity of 21 was determined after converting it to
R-alcohol ii, shown below, by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AD, 5% i-PrOH-hexane, flow rate: 1.0 mL/
min, retention time: 25 min ii and 29 min its enantiomer, detection
at 254 nm).
g, 86%) as a colorless oil: IR (neat) ν 1735 cm-1 1H NMR
;
(CDCl3) δ 1.45 (s, 3H), 1.14-1.76 (m, 10H), 2.06-2.22 (m, 7H),
2.27 (t, 2H, J ) 7.6 Hz), 2.76 (dt, 1H, J ) 6.9, 6.9 Hz), 3.66 (s,
3H), 5.02-5.30 (m, 4H), 7.22-7.33 (m, 10H); 13C NMR (CDCl3)
δ 18.0, 22.6, 24.8, 25.9, 28.9, 29.4, 31.0, 34.0, 36.9, 45.0, 50.4,
51.4, 56.9, 67.1, 67.2, 128.1, 128.3, 128.5, 135.1, 170.9, 171.0,
174.1, 220.0; MS m/z 523 (M+), 491 (M+ - OMe); HRMS m/z
(25) For a very recent catalytic asymmetric Michael-aldol reaction,
see: Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.

3670 J . Org. Chem., Vol. 63, No. 11, 1998
Yamada et al.
calcd for C31H38O7 522.2618, found 522.2623; [R]25 -3.8 (c )
EtOAc three times. The combined organic layers were dried
(Na2SO4) and concentrated. The resulting residue was purified
by flash column chromatography (SiO2, 5% EtOAc-hexane)
to give methyl ketone 12 (0.19 g, 75%) as a colorless oil: IR
D
0.588, CHCl3).
Meth yl 7-[(1R,2S,5S)-2-[1,1-Bis(ben zyloxycar bon yl)eth -
yl]-5-h yd r oxycyclop en tyl]h ep ta n oa te (10). To ketone 9
(31 mg, 0.060 mmol) in CH2Cl2 (3.0 mL) was added a THF
solution of L-Selectride (1.0 M, 0.072 mL) at -78 °C. The
reaction mixture was stirred for 40 min at the same temper-
ature before THF solution of L-Selectride (1.0 M, 0.030 mL)
was again added. After being stirred for 30 min at the same
temperature, the reaction mixture was quenched by addition
of 3% aqueous H2O2 and diluted with Et2O. The organic layer
was separated and washed with saturated aqueous Na2S2O4
and brine, dried (Na2SO4), and concentrated. The resulting
residue was purified by flash column chromatography (SiO2,
20% EtOAc-hexane) to give R-alcohol 10 (28 mg, 88%) as a
pale yellow oil: IR (neat) ν 3661, 1727 cm-1; 1H NMR (CDCl3)
δ 1.43 (s, 3H), 1.06-1.63 (m, 14H), 1.67-1.73 (m, 1H), 2.06
(ddt, 1H, J ) 9.5, 14, 8.5 Hz), 2.28 (t, 2H, J ) 7.5 Hz), 2.60
(dt, 1H, J ) 5.8, 9.5 Hz), 3.66 (s, 3H), 4.19 (dt, 1H, J ) 4.0,
3.7 Hz), 5.05 (d, 1H, J ) 13 Hz), 5.09 (s, 2H), 5.10 (d, 1H, J )
13 Hz), 7.24-7.31 (m, 10H); 13C NMR (CDCl3) δ 17.3, 24.8,
26.5, 28.0, 28.8, 29.0, 29.5, 33.6, 34.0, 45.9, 46.1, 51.4, 56.7,
66.8, 66.9, 74.0, 128.0, 128.2, 128.4, 135.3, 135.4, 171.4, 171.7,
174.2; MS m/z 525 (M+); [R]27D +21.6 (c ) 0.614, CHCl3). Anal.
Calcd for C31H36O7: C, 70.97; H, 7.68. Found: C, 70.68; H,
7.71.
1
(neat) ν 1741, 1710 cm-1; H NMR (CDCl3) δ 0.03 (s, s, 3H),
0.04 (s, 3H), 0.88 (s, 9H), 1.20-1.73 (m, 13H), 1.99-2.16 (m,
2H), 2.16 (s, 3H), 2.29 (t, 2H, J ) 7.5 Hz), 2.77 (dt, 1H, J )
5.6, 9.1 Hz), 3.66 (s, 3H), 4.19 (br, 1H); 13C NMR (CDCl3) δ
-5.1, -4.4, 18.0, 24.9, 25.7, 26.7, 28.1, 28.7, 29.1, 29.5, 29.6,
34.0, 34.5, 48.4, 51.3, 55.2, 74.8, 174.2, 211.9; MS m/z 385 (M+),
369 (M+ - CH3), 353 (M+ - OCH3), 327 (M+ - CO2CH3);
HRMS m/z calcd for C21H40O4Si 384.2696, found 384.2688;
[R]26 +69.8 (c ) 0.634, CHCl3).
D
Meth yl (8R,9S,12S,E)-9-(ter t-Bu tyld im eth ylsiloxy)-13-
oxo-14-p r osten -1-oa te (14). A CH2Cl2 solution of TiCl4 (1.0
M, 0.56 mL) was added dropwise to methyl ketone 12 (180
mg, 0.47 mmol) in CH2Cl2 (1.8 mL) at -78 °C. After 2 min,
N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) was added
dropwise, and the solution was stirred at -78 °C for 1.5 h.
After the dropwise addition of a solution of hexanal (55 mg,
0.55 mmol) in CH2Cl2 (2.3 mL), stirring was continued at -78
°C for 1.5 h. The reaction mixture was quenched by addition
of saturated aqueous NH4Cl and warmed to room temperature.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The
resulting residue was purified by flash column chromatogra-
phy (SiO2, 18% EtOAc-hexane) to give a mixture of products.
The mixture was dissolved in CH2Cl2 (4.7 mL), and triethyl-
amine (0.33 mL, 2.4 mmol) was added to the solution. Meth-
anesulfonyl chloride (0.091 mL, 1.2 mmol) was added dropwise
to the mixture, and the mixture was allowed to warm to room
temperature. After 15 min, 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.35 mL, 2.4 mmol) was added, and the reaction mixture was
stirred for 70 min at room temperature before being quenched
with saturated aqueous NaHCO3. The organic layer was
separated, and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with 1 N HCl,
saturated aqueous NaHCO3, and brine and then dried (Na2SO4)
and concentrated. The resulting residue was purified by flash
column chromatography (SiO2, 10% EtOAc-hexane) to give
enone 14 (190 mg, 85%) as an oil: IR (neat) ν 1742, 1692, 1666,
1627 cm-1; 1H NMR (CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88-
0.91 (m, 12H), 1.16-1.77 (m, 19H), 2.04-2.13 (m, 2H), 2.21
(ddt, 2H, J ) 1.5, 7.0, 8.2 Hz), 2.28 (t, 2H, J ) 7.6 Hz), 2.99
(dt, 1H, J ) 6.1, 10.1 Hz), 3.65 (s, 3H), 4.20-4.23 (br, 1H),
6.14 (dt, 1H, J ) 15.6, 1.5 Hz), 6.84 (dt, 1H, J ) 15.6, 7.0 Hz);
13C NMR (CDCl3) δ -5.0, -4.4, 13.9, 18.0, 22.4, 24.9, 25.8, 27.6,
27.8, 28.2, 28.7, 29.1, 29.6, 31.3, 32.4, 34.0, 34.7, 48.8, 51.3,
51.8, 75.1, 130.3, 147.5, 174.2, 203.6; MS m/z 466 (M+), 451
(M+ - CH3), 435 (M+ - OCH3), 410 (M+ - t-Bu); HRMS m/z
calcd for C21H40O4Si 466.3478, found 466.3478; [R]24D +62.9 (c
) 0.476, CHCl3).
Meth yl 7-[(1R,2S,5S)-2-[1,1-Bis(ben zyloxycar bon yl)eth -
yl]-5-(ter t-bu tyld im eth ylsiloxy)cyclop en tyl]h ep ta n oa te
(11). To a mixture of alcohol 10 (3.5 g, 6.6 mmol) and 2,6-
lutidine (1.5 mL, 13 mmol) in CH2Cl2 (6.6 mL) was added tert-
butyldimethylsilyl trifluoromethanesulfonate (2.3 mL, 9.9
mmol) at -78 °C. After being stirred for 30 min at the same
temperature, the reaction mixture was quenched by addition
of saturated aqueous NH4Cl and diluted with Et2O. The
mixture was allowed to warm to room temperature, and the
organic layer was separated. The aqueous layer was extracted
with EtOAc. The combined organic layers were washed with
brine, and then dried (Na2SO4) and concentrated. The result-
ing residue was purified by flash column chromatography
(SiO2, 5% EtOAc-hexane) to give TBDMS ether 11 (4.0 g, 96%)
1
as a colorless oil: IR (neat) ν 1732 cm-1; H NMR (CDCl3) δ
0.00 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 1.42 (s, 3H), 0.87-1.68
(m, 14H), 1.95-2.08 (m, 1H), 2.27 (t, 2H, J ) 7.6 Hz), 2.54-
2.63 (m, 1H), 3.66 (s, 3H), 4.13-4.16 (br, 1H), 5.01-5.14 (m,
4H), 7.22-7.32 (m, 10H); 13C NMR (CDCl3) δ -5.1, -4.3, 17.3,
18.0, 25.0, 25.8, 26.4, 28.2, 29.1, 29.3, 29.7, 34.0, 34.1, 46.4,
51.4, 56.9, 66.7, 66.8, 74.5, 128.0, 128.1, 128.4, 135.4, 135.5,
171.6, 171.9, 174.2; MS m/z 638 (M+); HRMS m/z calcd for
C
37H54O7Si 638.3638, found 638.3662; [R]25D +29.2 (c ) 0.646,
CHCl3).
Meth yl 7-[(1R,2S,5S)-2-Acetyl-5-(ter t-bu tyld im eth ylsil-
oxy)cyclop en tyl]h ep ta n oa te (12). A mixture of dibenzyl
ester 11 (0.41 g, 0.64 mmol) and 10% Pd-C (69 mg, 10 mol%)
in methanol (6.4 mL) was stirred in a hydrogen atmosphere
for 11 h at room temperature. The catalyst was removed by
filtration (Celite) and washed successively with methanol. The
filtrate was concentrated to give a crude residue (0.36 g), which
was then dissolved in benzene (0.92 mL). To the solution were
added pyridine (0.13 mL, 1.6 mmol) and lead tetraacetate (0.63
g, 13 mmol). The mixture was gently warmed until the
evolution of carbon dioxide commenced. After the carbon
dioxide evolution had ceased, the mixture was gently re-
warmed. The rewarming was repeated three times before the
reaction mixture was heated to reflux. After 12 h, the reaction
mixture was diluted with Et2O and cooled to room tempera-
ture. The reaction mixture was then filtered (Celite) to remove
salt. The salt was successively washed with Et2O. The filtrate
was washed with 1 N HCl, saturated aqueous NaHCO3, and
brine and then dried (Na2SO4) and concentrated to give a crude
residue. The residue was dissolved in methanol (6.0 mL), and
potassium carbonate (0.18 g, 1.3 mmol) was added to the
solution. The mixture was stirred for 30 min at room tem-
perature, and subsequently the pH value was adjusted to 7
with 1 N HCl and saturated aqueous NaHCO3. Methanol was
removed in vacuo, and the aqueous layer was extracted with
Met h yl (8R,9S,12S,14R,15S)-9-(ter t-Bu t yld im et h ylsi-
loxy)-14,15-ep oxy-13-oxo-1-p r osta n oa te (15r) a n d Meth yl
(8R,9S,12S,14S,15R)-9-(ter t-Bu t yld im et h ylsiloxy)-14,15-
ep oxy-13-oxo-1-p r osta n oa te (15â). To dried MS 4A were
added a solution of (S)-3-(hydroxymethyl)binaphthol (20 mg,
64 µmol) in THF (0.64 mL) and a THF solution of lanthan-
um(III) isopropoxide (0.2 M , 0.23 mL). The suspension was
stirred for 1 h at room temperature before THF was removed
in vacuo. To the resulting residue was added a solution of
the enone 14 (43 mg, 93 µmol) in toluene (1.0 mL) and a
toluene solution of tert-butyl hydroperoxide (4 M , 60 µL) at 0
°C. After being stirred for 27 h at 0 °C, the reaction mixture
was quenched by addition of saturated aqueous NH4Cl. The
insoluble material and aqueous layer were removed by filtra-
tion (Celite, Na2SO4) and successively washed with EtOAc. The
filtrate and the washing were combined and concentrated. The
resulting residue was purified by flash column chromatogra-
phy (SiO2, 5% EtOAc-hexane) to give epoxy ketones 15 (40
1
mg, 89%, R:â ) 85:15 by H NMR analysis): IR (neat) ν 1741,
1702, 1252 cm-1; 1H NMR (CDCl3) δ 0.03 (s, 3H), 0.04 (s, 3H),
0.87-1.69 (m, 20H), 1.72-1.80 (m, 1H), 2.00-2.22 (m, 2H),
2.29 (t, 2H, J ) 7.6 Hz), 2.76 (dt, 0.15H, J ) 5.5, 10.7 Hz),

Catalytic Asymmetric Synthesis of 11-Deoxy-PGF1R
J . Org. Chem., Vol. 63, No. 11, 1998 3671
2.91 (dt, 0.85H, J ) 5.8, 10.1 Hz), 2.99-3.04 (m, 1H), 3.26-
3.27 (brd, 1H), 3.66 (s, 3H), 4.19-4.21 (br, 1H); 13C NMR
(CDCl3) δ -5.0, -4.4, 13.9, 18.0, 22.5, 24.9, 25.4, 25.5, 25.8,
27.0, 27.4, 28.3, 28.7, 29.1, 29.5, 31.4, 31.8, 34.0, 34.5, 34.9,
47.3, 49.1, 49.5, 49.9, 51.4, 58.1, 58.5, 59.3, 74.8, 75.1, 174.2,
211.0; MS m/z 482 (M+), 467 (M+ - CH3), 451 (M+ - OCH3),
425 (M+ - t-Bu); HRMS m/z calcd for C27H50O5Si 482.3428,
found 482.3432.
Met h yl (8R,9S,12S,13S,E)-13-Acet oxy-9-(ter t-b u t yld i-
m et h ylsiloxy)-14-p r ost en -1-oa t e (18r) a n d Met h yl
(8R,9S,12S,13R,E)-13-Acetoxy-9-(ter t-bu tyldim eth ylsiloxy)-
14-p r osten -1-oa te (18â). To the enone 14 (99 mg, 0.21 mmol)
and cerium(III) chloride heptahydrate (79 mg, 0.21 mmol) in
methanol (0.53 mL) was added sodium borohydride (12 mg,
0.32 mmol) at 0 °C. The reaction mixture was stirred for 15
min at the same temperature and quenched by addition of
saturated aqueous NH4Cl. Methanol was removed in vacuo,
and the aqueous layer was extracted with EtOAc. The organic
layer was washed with brine, dried (Na2SO4), and concentrated
to give a mixture of R-alcohol 17r and â-alcohol 17â (95 mg,
96%) as a colorless oil.
the desired allylic alcohols 16 (34 mg, 38%) as a more polar
product, 13-hydroxy isomers 17 (4.1 mg, 4.5%) as a less polar
product, and mixed products (40 mg, 44%). The mixed
products were separated by flash column chromatography
(SiO2, 15% EtOAc-hexane) to give 16 (13 mg, 14%), 17 (6.4
mg, 7.1%), and mixed products (20 mg, 22%). The mixed
products were separated again by flash column chromatogra-
phy (SiO2, 15% EtOAc-hexane) to give 16 (5.7 mg, 6.3%), 17
(5.1 mg, 5.6%), and mixed products (8.6 mg, 9.5%). 16: IR
(neat) ν 3372, 1743 cm-1; 1H NMR (CDCl3) δ 0.02 (s, 3H), 0.03
(s, 3H), 0.86-0.90 (m, 12H), 1.14-1.64 (m, 21H), 1.72-1.80
(m, 1H), 1.92-2.00 (m, 1H), 2.26 (t, 2H, J ) 7.6 Hz), 2.26-
2.33 (m, 1H), 3.66 (s, 3H), 4.02-4.07 (m, 1H), 4.15-4.17 (br,
1H), 5.39-5.50 (m, 2H); 13C NMR (CDCl3) δ -5.1, -4.3, 14.0,
18.0, 22.6, 24.9, 25.1, 25.2, 25.8, 27.1, 27.2, 28.1, 28.2, 29.1,
29.2, 29.6, 29.7, 29.8, 29.9, 31.7, 31.8, 34.1, 34.3, 37.3, 45.6,
45.8, 51.4, 52.2, 73.0, 73.3, 74.2, 132.6, 136.1, 136.6, 174.3; MS
m/z 468 (M+), 450 (M+ - H2O), 437 (M+ - OCH3), 411 (M+
-
t-Bu); HRMS m/z calcd for C27H50O5Si 468.3635, found 468.3637.
(+)-11-Deoxy-P GF 1r (1). To a solution of allylic alcohols
16 (31 mg, 66 µmol) in THF (0.33 mL) was added HF-pyridine
(66 mg) in THF (0.33 mL) at 0 °C. After being stirred for 46
h at room temperature, the reaction mixture was diluted with
EtOAc, washed with saturated aqueous NaHCO3, saturated
aqueous CuSO4, water, and brine, dried (Na2SO4), and con-
centrated. The resulting residue was purified by preparative
TLC (Si2O, 40% EtOAc-hexane) and flash column chroma-
tography (SiO2, 35% EtOAc-hexane) to give less polar 15-epi-
11-deoxy-PGF1R methyl ester (7.5 mg, 34%) and more polar
11-deoxy-PGF1R methyl ester (11 mg, 45%): IR (neat) ν 3394,
1740 cm-1; 1H NMR (CDCl3) δ 0.89 (t, 3H, J ) 6.9 Hz), 1.25-
1.67 (m, 21H), 1.90-2.05 (m, 2H), 2.30 (t, 2H, J ) 7.5 Hz),
2.27-2.35 (m, 1H), 3.66 (s, 3H), 4.03-4.07 (m, 1H), 4.22-4.50
(br, 1H), 5.41-5.49 (m, 2H); 13C NMR (CDCl3) δ 14.0, 22.6,
24.8, 25.2, 27.0, 28.1, 29.0, 29.6, 30.0, 31.7, 33.8, 34.0, 37.4,
45.8, 51.5, 51.6, 73.2, 73.9, 133.1, 135.7, 174.3; MS m/z 354
(M+), 336 (M+ - H2O), 318 (M+ - 2H2O); HRMS m/z calcd for
The mixture of the alcohols 17 (95 mg, 0.20 mmol) was
dissolved in pyridine (2.1 mL). To the solution were added
acetic anhydride (0.20 mL, 2.1 mmol) and 4-(dimethylamino)-
pyridine (3 mg, 0.02 mmol) at room temperature. The reaction
mixture was stirred for 1.5 h at the same temperature, and
water (10 mL) was added. The aqueous layer was extracted
with EtOAc (5 mL × 3). The combined organic layers were
washed with 1 N HCl, saturated aqueous NaHCO3, and brine,
dried (Na2SO4), and concentrated. The residue was purified
by flash column chromatography (SiO2, 5% EtOAc-hexane)
to give acetates 18 (99 mg, 96%, R:â ) 2:1 by 1H NMR analysis)
1
as a colorless oil: IR (neat) ν 1741 cm-1; H NMR (CDCl3) δ
0.02 (s, 3H), 0.03 (s, 3H), 0.86-0.89 (m, 12H), 1.14-1.65 (m,
19H), 2.03 (s, 3H), 1.8-2.05 (m, 4H), 2.30 (brt, 2H), 3.66 (s,
3H), 4.12-4.16 (br, 1H), 5.16 (dd, 0.34H, J ) 7.0, 7.3 Hz), 5.23
(dd, 0.66H, J ) 4.6, 7.0 Hz), 5.33-5.40 (m, 1H), 5.63-5.71 (m,
1H); 13C NMR (CDCl3) δ -5.1, -4.3, 14.0, 18.0, 21.3, 21.4, 22.4,
23.8, 24.5, 25.0, 25.8, 28.1, 28.2, 28.6, 29.2, 29.6, 29.7, 31.3,
32.2, 32.4, 34.0, 34.1, 34.3, 45.3, 46.0, 47.3, 48.2, 51.3, 74.5,
76.3, 78.1, 126.2, 127.6, 134.0, 135.6, 170.3, 170.4, 174.2; MS
m/z 510 (M+), 495 (M+ - CH3), 453 (M+ - t-Bu); HRMS m/z
calcd for C29H54O5Si 510.3740, found 510.3740.
C
21H38O4 354.2770, found 354.2767; [R]24 +38 (c ) 0.510,
D
CHCl3).
To a solution of more polar 11-deoxy-PGF1R methyl ester
(10.5 mg, 30 µmol) in wet THF (1.0 mL, containing 0.33 mL of
water) was added 0.1 N NaOH (0.69 mL). After being stirred
for 17 h at room temperature, the reaction mixture was
quenched by addition of 0.1 N HCl (0.69 mL), and then THF
was removed in vacuo. The residue was diluted with water
and extracted with EtOAc. The organic layer was washed with
brine, dried (Na2SO4), and concentrated. The resulting residue
was purified by preparative TLC (Si2O, 1:15 CH3OH-CH2Cl2)
to give (+)-11-deoxy-PGF1R (1) (9.1 mg, 90%): IR (neat) ν 3361,
1715 cm-1; 1H NMR (CDCl3) δ 0.89 (t, 3H, J ) 6.9 Hz), 1.24-
1.67 (m, 21H), 1.90-2.05 (m, 2H), 2.51-2.35 (m, 1H), 2.33 (t,
2H, J ) 7.3 Hz), 4.07 (dt, 1H, J ) 6.3, 6.3 Hz), 4.24 (br, 1H),
5.41-5.50 (m, 2H); 13C NMR (CDCl3) δ 14.0, 22.6, 24.5, 25.2,
26.5, 27.6, 28.5, 29.1, 29.9, 31.7, 33.7, 33.8, 37.3, 45.6, 51.4,
9-O-(ter t-Bu tyld im eth ylsilyl)-11-d eoxy-P GF 1r Meth yl
Ester (16r) a n d 9-O-(ter t-Bu tyld im eth ylsilyl)-15-epi-11-
d eoxy-P GF 1r Meth yl Ester (16â). Meth od A. To a solution
of the epoxy ketones 15 (16 mg, 34 µmol) and triethylamine
(19 µL, 0.14 mmol) in (dimethylamino)ethanol (34 µL) was
added hydrazine monohydrochloride (7 mg, 0.1 mmol) at 0 °C.
After being stirred for 24 h at the same temperature, the
reaction mixture was diluted with Et2O, washed with 5%
aqueous citric acid, saturated aqueous NaHCO3, and brine,
dried, and concentrated. The resulting residue was purified
by flash column chromatography (SiO2, 10% EtOAc-hexane)
to give a mixture including mainly allylic alcohols 16 (5.1 mg,
32%).
Meth od B. The acetates 18 (98 mg, 0.19 mmol) were
dissolved in THF (1.9 mL), and bis(acetonitrile)dichloropalla-
dium(II) (2 mg, 4 mol %) was added to the solution. The
reaction mixture was stirred for 4.5 h at room temperature,
and water (5 mL) was added. The aqueous layer was extracted
with EtOAc (5 mL × 3). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to give
a crude mixture of acetates 19 and 18 (0.10 g, the ratio of 19
and 18 was determined to be 3:1 by 1H NMR analysis) as a
colorless oil.
73.1, 73.9, 132.7, 135.6, 178.2; MS m/z 340 (M+), 322 (M+
-
H2O), 304 (M+ - 2H2O) ; HRMS m/z calcd for C20H36O4
340.2614, found 340.2614; [R]22 +38 (c ) 0.46, CHCl3).
D
Meth yl (R)-7-[(1R,2S,3R)-2-[1,1-Bis(ben zyloxyca r bon -
yl)eth yl]-3-(ter t-bu tyld im eth ylsiloxy)-5-oxocyclop en tyl]-
7-h yd r oxyh ep ta n oa te (21r) a n d Meth yl (S)-7-[(1R,2S,3R)-
2-[1,1-b i s (b e n z y lo x y c a r b o n y l)e t h y l]-3-(t er t -b u t y l-
d im e t h ylsiloxy)-5-oxocyclop e n t yl]-7-h yd r oxyh e p t a n -
oa te (21â). To dried MS 4A (200 mg) were added a 0.1 M
(S)-ALB THF solution (1.0 mL, 0.10 mmol), a THF solution of
sodium tert-butoxide (0.44 M, 0.21 mL), (()-4-(tert-butyl-
dimethylsiloxy)-2-cyclopenten-1-one (20) (0.45 mL, 2.0 mmol),
methyl 6-formylhexanoate (5) (0.24 mL, 1.5 mmol), and
dibenzyl methylmalonate (4) (0.26 mL, 1.0 mmol) at room
temperature. After being stirred for 40 h at the same
temperature, the reaction mixture was quenched by the
addition of saturated aqueous NH4Cl. The insoluble material
and aqueous layer were removed by filtration (Celite, Na2SO4)
and successively washed with EtOAc. The filtrate and the
washing were combined and then washed with water and
brine. The organic layer was dried (Na2SO4) and concentrated.
The mixture of the acetates 19 and 18 (0.10 g) was dissolved
in methanol (1.9 mL), and potassium carbonate (32 mg, 0.23
mmol) was added to the solution. The reaction mixture was
stirred for 13 h at room temperature and neutralized by
addition of 1 N HCl and saturated aqueous NaHCO3. The
aqueous layer was extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The residue was purified by flash
column chromatography (SiO2, 15% EtOAc-hexane) to give

3672 J . Org. Chem., Vol. 63, No. 11, 1998
Yamada et al.
The resulting residue was purified by flash column chroma-
tography (SiO2, 20% acetone-hexane) to give pure â-hydroxy
ketones 21 (0.50 g, 75% based on malonate 4, a mixture of
(M+ - TBDMSO - H2O); HRMS m/z calcd for C33H43O9Si (M+
- t-Bu) 611.2676, found 611.2657. Anal. Calcd for C37H52
-
O9Si: C, 66.44; H, 7.84. Found: C, 66.21; H, 7.85.
two diastereomers): IR (neat) ν 3457, 1737 cm-1 1H NMR
;
(CDCl3) δ 0.06 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 1.44 (s, 3H),
1.19-1.67 (m, 8H), 2.15 (d, 1H, J ) 21 Hz), 2.29 (t, 2H, J )
7.6 Hz), 2.32 (br, 1H), 2.45 (dd, 1H, J ) 5.8, 10 Hz), 2.78 (br,
0.93H), 2.84 (br, 0.07H), 3.66 (s, 3H), 3.75 (s, 1H), 3.75-3.77
(br, 1H), 4.41 (d, 1H, J ) 5.8 Hz), 5.01-5.16 (m, 4H), 7.20-
7.33 (m, 10H); 13C NMR (CDCl3) δ -4.9, -4.8, 17.6, 19.3, 24.9,
25.6, 25.7, 29.0, 34.0, 49.4, 51.3, 55.8, 56.7, 57.1, 67.4, 67.5,
70.8, 74.9, 128.1, 128.2, 128.3, 128.5, 134.8, 170.4, 170.7, 174.1,
217.2; MS m/z 611 (M+ - t-Bu), 593 (M+ - t-Bu - H2O), 519
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
1, 2, 9, 11, 12, 14-16, and 18 (9 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.
J O9723319