A systematic study of the hydride reduction of cyclopropyl ketones with structurally simplified substrates. Highly stereoselective reductions of trans-substituted cyclopropyl ketones via the bisected s-cis conformation

Article abstract of DOI:10.1021/jo030019v

The stereoselective hydride reduction of the cis- and trans-substituted cyclopropyl ketones was systematically investigated using a series of structurally simplified substrates, trans-[tertbutyldiphenylsilyloxymethyl]cyclopropyl ketones 1a-e and trans-(benzyloxymethyl)cyclopropyl methyl ketone (2), and the corresponding cis congeners 3a,b,e and 4. The results showed that, not only in the reduction of the cis-substituted cyclopropyl ketones but also in that of the trans-substituted ketones, high stereoselectivity can be realized when the substrate has a bulky substituent on the cyclopropane ring, even though it is attached to the position trans to the acyl moiety. Ab initio calculations based on the density functional theory (DFT) of cyclopropyl ketones showed that (1) the bisected s-cis and s-trans conformers were the only two minimum energy conformers, while the s-cis conformer was more stable than the s-trans and (2) a bulky alkyl group in the acyl moiety and a cis substituent on the cyclopropane ring made the bisected s-cis conformer much more stable. On the basis of these calculations and experimental results, it is likely that the more stable the bisected s-cis conformer of the substrate, the more stereoselective the hydride reduction. Thus, the stereochemistry can be explained by hydride attack on the bisected s-cis conformation of the substrate from the less-hindered face. The predictability of the stereochemical results is predicated on the bisected s-cis transition-state model, which is very important from the viewpoint of synthetic organic chemistry.

Full text of DOI:10.1021/jo030019v

A System a tic Stu d y of th e Hyd r id e Red u ction of Cyclop r op yl
Keton es w ith Str u ctu r a lly Sim p lified Su bstr a tes. High ly
Ster eoselective Red u ction s of Tr a n s-Su bstitu ted Cyclop r op yl
Keton es via th e Bisected s-Cis Con for m a tion
Yuji Kazuta,† Hiroshi Abe,† Tamotsu Yamamoto,‡ Akira Matsuda,† and Satoshi Shuto*,†
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, J apan, and Institute for Life Science Research, Asahi Kasei Co., Ltd., Ohito-cho,
Shizuoka 410-2321, J apan
shu@pharm.hokudai.ac.jp
Received J anuary 13, 2003
The stereoselective hydride reduction of the cis- and trans-substituted cyclopropyl ketones was
systematically investigated using a series of structurally simplified substrates, trans-[tert-
butyldiphenylsilyloxymethyl]cyclopropyl ketones 1a -e and trans-(benzyloxymethyl)cyclopropyl
methyl ketone (2), and the corresponding cis congeners 3a ,b,e and 4. The results showed that, not
only in the reduction of the cis-substituted cyclopropyl ketones but also in that of the trans-
substituted ketones, high stereoselectivity can be realized when the substrate has a bulky
substituent on the cyclopropane ring, even though it is attached to the position trans to the acyl
moiety. Ab initio calculations based on the density functional theory (DFT) of cyclopropyl ketones
showed that (1) the bisected s-cis and s-trans conformers were the only two minimum energy
conformers, while the s-cis conformer was more stable than the s-trans and (2) a bulky alkyl group
in the acyl moiety and a cis substituent on the cyclopropane ring made the bisected s-cis conformer
much more stable. On the basis of these calculations and experimental results, it is likely that the
more stable the bisected s-cis conformer of the substrate, the more stereoselective the hydride
reduction. Thus, the stereochemistry can be explained by hydride attack on the bisected s-cis
conformation of the substrate from the less-hindered face. The predictability of the stereochemical
results is predicated on the bisected s-cis transition-state model, which is very important from the
viewpoint of synthetic organic chemistry.
In tr od u ction
devoted to developing efficient methods for preparing
cyclopropane derivatives.1-6
Cyclopropanes are important as key fragments in
many natural products and as synthetic key intermedi-
ates due to the ease of their ring-opening.1-4 The cyclo-
propane ring is also very useful for restricting the
conformation of biologically active compounds to improve
the activity.5 Therefore, considerable effort has been
We recently devised a new method for restricting the
conformation of cyclopropane derivatives based on the
fact that adjacent substituents on the ring exert signifi-
cant mutual steric repulsion because of their eclipsed
conformation to each other, which has been successfully
used in the design of NMDA (N-methyl-D-aspartic acid)
receptor antagonists.6 In the course of these continuous
studies, we have needed a highly stereoselective method
for the reduction of cyclopropyl ketones.
* To whom correspondence and reprint requests should be ad-
dressed. Phone: +81-11-706-3228. Fax: +81-11-706-498.
† Hokkaido University.
‡ Asahi Kasei Co., Ltd.
It is known that cyclopropanes adjacent to an unsatur-
ated bond, such as vinylcyclopropanes, cyclopropyl ke-
tones, or cyclopropanecarbaldehydes, preferentially exist
in the bisected s-trans and s-cis conformations, as shown
(1) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-Y.; Yip, Y.-C. Tanko, J .;
Hudlicky, T. Chem. Rev. 1989, 89, 165-198. (b) Stammer, C. H.
Tetrahedron 1990, 46, 2231-2254. (c) Small Ring Compounds in
Organic Synthesis VI. Topics in Current Chemistry 207; De Meijero,
A., Ed.; Springer: Berlin, 1999.
(2) Reviews on asymmetric cyclopropanations: (a) Singh, V. K.;
DattaGupta, A.; Sekar, G. Synthesis 1997, 137-149. (b) Doyle, M. P.;
Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946.
(4) Examples of synthesis of chiral cyclopropanes from chiral syn-
thons: (a) Yamanoi, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29, 1181-
1184. (b) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1989, 30, 3803-
3804. (c) Pirrung, M. C.; Dunlap, S. E.; Trinks, V. P. Helv. Chim. Acta
1989, 72, 1301-1310. (d) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya,
A.; Taguchi, T. J . Org. Chem. 1994, 59, 97-103. (e) Critcher, D. J .;
Connolly, S.; Wills, M. J . Org. Chem. 1997, 62, 6638-6657. (f)
Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.;
Ibuka, T. Tetrahedron Lett. 2000, 41, 3653-3656.
(3) Examples of synthesis of chiral cyclopropanes via chemical or
enzymatic optical resolutions: (a) Laumen, K.; Schneider, M. Tetra-
hedron Lett. 1985, 26, 2073-2076. (b) Ader, U.; Breitgoff, D.; Klein,
P.; Laumen, K. E. J . Org. Chem. 1989, 30, 1793-1796. (c) Grandjean,
D.; Chuche, P. P. J . Tetrahedron 1991, 47, 1215-1230. (d) Silva, C.
B.-D.; Benkouider, A.; Pale, P. Tetrahedron Lett. 2000, 41, 3077-3081.
(e) Zhang, X.; Hodgetts, K.; Rachwal, S.; Zhao, H.; Wasley, J . W. F.;
Craven, K.; Brodbeck, R.; Kieltyka, A.; Hoffman, D.; Bacolod, M. D.;
Girard, B.; Tran, J .; Thurkauf, A. J . Med. Chem. 2000, 43, 3923-3932.
(5) Kazuta, Y.; Matsuda, A.; Shuto, S. J . Org. Chem. 2002, 67, 1669-
1677, and references therein.
10.1021/jo030019v CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003
J . Org. Chem. 2003, 68, 3511-3521
3511

Kazuta et al.
F IGURE 1. s-Cis- and s-trans-bisected conformations of R,â-
unsaturated cyclopropanes.
in Figure 1, due to the characteristic stereoelectronic
effects of the cyclopropane ring.1a,7,8 We recently found
that a C-cyclopropylnitrone was also stable in the bi-
sected conformation.6e,f Several groups including ours
have reported that reduction of cyclopropyl ketones by
nucleophilic hydride reagents is possible to proceed
stereoselectively, which has been considered to occur via
the stereoelectronically stable bisected conformation.8
These reactions are very useful for the stereoselective
synthesis of cyclopropane derivatives having a stereo-
genic carbon center at the position adjacent to the
cyclopropane ring. However, only limited examples of
such stereoselective reductions of cyclopropyl ketones are
known, and these are summarized in Tables 1 and 2.8,9
The cyclopropyl ketones having a substituent at the
position cis to the acyl group on the cyclopropane ring,
i.e., the cis-substituted cyclopropyl ketones I, are often
stereoselectively reduced to form the corresponding anti-
alcohols as the major product (Table 1).8 On the other
hand, the hydride reduction of cyclopropyl ketones with-
F IGURE 2. Conceivable reaction pathways of the hydride
reductions of cyclopropyl ketones.
out a substituent attached to the position cis to the acyl
group on the cyclopropane ring, i.e., the trans-substituted
cyclopropyl ketones II, usually occur with low to moder-
ate stereoselectivity,8b,10 except for an example using a
trans-(phosphorylfluoromethyl)cyclopropyl ketone,8f and
the stereochemical results do not seem readily predict-
able.11 The previous examples of the trans-substituted
cyclopropyl ketones are summarized in Table 2.
(6) (a) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Matsuda, A.
Tetrahedron Lett. 1996, 37, 641-644. (b) Shuto, S.; Ono, S.; Hase, Y.;
Ueno, Y.; Noguchi, T.; Yoshii, K.; Matsuda, A. J . Med. Chem. 1996,
39, 4844-4852. (c) Shuto, S.; Ono, S.; Imoto, H.; Yoshii, K.; Matsuda,
A. J . Med. Chem. 1998, 41, 3507-3514. (d) Noguchi, T.; Ishii, K.; Imoto,
H.; Otubo, Y.; Shuto, S.; Ono, S.; Matsuda, A.; Yoshii, K. Synapse 1999,
31, 87-96. (e) Kazuta, Y.; Shuto, S.; Matsuda, A. Tetrahedron Lett.
2000, 41, 5373-5377. (f) Kazuta, Y.; Shuto, S.; Abe, H.; Matsuda, A.
J . Chem. Soc., Perkin Trans.
1 2001, 599-604. (g) Uchino, S.;
Our consideration on the hydride reduction of the
cyclopropyl ketones is summarized in Figure 2. As
described above, cyclopropyl ketones are conformationally
stable in their bisected s-cis and s-trans conformations:7
theoretical calculations7f and experimental7b,c studies
indicate that the s-cis conformation seems to be favored
over the s-trans. The preference for the s-cis conformer,
as shown in Figure 2A, can be understood because in the
s-trans conformer the alkyl group (R1) in the acyl moiety
is oriented toward the cyclopropyl moiety leading to
increased steric repulsion for the cis substituent (R3). In
the s-cis conformation, the substituent (R3) attached to
the position cis to the acyl moiety would effectively hinder
one side of the carbonyl to result in the stereoselective
hydride attack from the less hindered side (Figure 2A).
On the other hand, as shown in Figure 2B, in the s-cis
conformation of the trans-substituted cyclopropyl ke-
tones, the steric repulsion due to the alkyl group (R1)
would be less, because of the absence of the cis substitu-
ent on the cyclopropane ring, than in that of the corre-
sponding cis-substituted ketones. Accordingly, the s-cis
and the s-trans conformers might be similarly stable in
the trans-cyclopropyl ketones, which may be why their
Watanabe, W.; Nakamura, T.; Shuto, S.; Kazuta, Y.; Matsuda, A.;
Nakazima-Iijima, S.; Kohsaka, S.; Kudo, Y.; Mishina, M. FEBS Lett.
2001, 69, 2007-2015. (h) Kazuta, Y.; Tsujita, R.; Ogawa, K.; Hokono-
hara, T.; Yamashita, K.; Morino, K.; Matsuda, A.; Shuto, S. Bioorg.
Med. Chem. 2002, 10, 1777-1791. (i) Kazuta, Y.; Tsujita, R.; Uchino,
S.; Kamiyama, N.; Mochizuki, D.; Yamashita, K.; Ohmori, Y.; Ya-
mashita, A.: Yamamoto, T.; Uchino, S.; Kohsaka, S.; Matsuda, A.;
Shuto, S. J . Chem. Soc., Perkin Trans. 1 2002, 1199-1212. (j) Ono, S.;
Ogawa, K.; Yamashita, K.; Yamamoto, T.; Kazuta, Y.; Matsuda, A.;
Shuto, S. Chem. Pharm. Bull. 50, 966-968. (k) Kazuta, Y.; Tsujita,
R.; Yamashita, K.; Uchino, S.; Kohsaka, S.; Matsuda, A.; Shuto, S.
Bioorg. Med. Chem. 2002, 10, 3829-3848.
(7) (a) Gerasimos, J . K.; Nelsom, J . J . Am. Chem. Soc. 1965, 87,
2864-2870. (b) Pierre, J . L.; Arnaud, P. Bull. Soc. Chim. Fr. 1966,
1690-1693. (c) Bartell, L. S.; Guillory, J . P.; Parks, A. T. J . Phys. Chem.
1965, 69, 3043-3048. (d) Bartell, L. S.; Guillory, J . P. J . Phys. Chem.
1965, 43, 647-654. (e) Bordner, J .; J ones, L. A.; J ohnson, R. L. Cryst.
Struct. Comm. 1972, 1, 389-391. (f) Tocanne, J .-F. Tetrahedron 1972,
28, 389-416. (g) Lute, C. N. A.; Stam, C. H. Rec. Trav. Chim. Pays-
Bas (Rec. J . R. Neth. Chem. Soc.) 1976, 95, 130-132. (h) Roques, R.;
Crasnier, F.; Declercq, J . P.; Germain, G.; Cousse, H.; Mouzin, G. Acta
Crystallogr. 1982, B38, 1375-1377. (i) Crasnier, F.; Labarre, J . F.;
Cousse, H.; D’Hinterland, L. D.; Mouzin, G. Tetrahedron 1975, 31,
825-829.
(8) (a) Descotes, G.; Menet, A.; Collonges, F. Tetrahedron 1973, 29,
2931-2935. (b) Meyers, A. I.; Romine, J . L.; Fleming, S. A. J . Am.
Chem. Soc. 1988, 110, 7245-7247. (c) Lalutens, M.; Delanghe, P. H.
M. J . Org. Chem. 1995, 60, 2474-2487. (d) Ono, S.; Shuto, S.; Matsuda,
A. Tetrahedron Lett. 1996, 37, 221-224. (e) Shuto, S.; Ono, S.; Hase,
Y.; Kamiyama, N.; Takada, H.; Yamashita, K.; Matsuda, A. J . Org.
Chem. 1996, 61, 915-923. (f) Yokomatsu, T.; Yamagishi, T.; Suemune,
K.; Abe, H.; Kihara, T.; Soeda, S.; Shimeno, H.; Shibuya, S. Tetrahedron
2000, 56, 7099-7108.
(10) Mohapatra, D. K.; Datta, A. J . Org. Chem. 1998, 63, 642-646.
(11) Stereocontrol in carbon-nucleophile additions to trans-cyclo-
propyl carbonyls is also known to be exceedingly difficult, see: Critcher,
D. J .; Connolly, S.; Wills, M. J . Org. Chem. 1997, 62, 6638-6657.
(9) Examples of stereochemical reversal in the reduction of cyclo-
propyl ketones when an electrophilic reducing agent DIBAL-H was
used: see ref 8d,e,f.
3512 J . Org. Chem., Vol. 68, No. 9, 2003

Stereoselective Reductions of trans-Cyclopropyl Ketones
TABLE 1. Hyd r id e Red u ction s of th e Cis-Su bstitu ted Cyclop r op yl Keton es Rep or ted P r eviou sly
substrate
R1
Me
R2
R3
conditions
yield (%)
syn/ anti
ref
I
I
I
I
I
I
I
CHdCH2
CO2Me
TMS
Bu3Sn
CONEt2
CONEt2
Me
H
LiAlH4 (0.5 equiv), 35 °C
80
99
48
88
70
91
57
1:16
only anti
1:15
1:15
1:4
8a
8b
8c
8c
8d
8d
8f
a
Me
CO2Me
NaBH4/CeCl3
n-Pr
c-hexyl
Et
Et
Me
H
LiAlH4 (1.1-1.5 equiv), 0 °C
LiAlH4 (1.1-1.5 equiv), 0 °C
NaBH4 (0.9 equiv), -20 °C
L-Selectride (2.5 equiv), -78 °C
K-Selectride (1.1 equiv), -78 °C
n-Bu
Ph
Ph
1:49
1:99
CF2PO3Et2
a
The detailed reaction conditions were not reported in ref 8b.
TABLE 2. Hyd r id e Red u ction of th e Tr a n s-Su bstitu ted Cyclop r op yl Keton es Rep or ted P r eviou sly
substrate
R1
R2
TMS
n-Bu
n-Bu
CH2OTBS
CF2PO3Et2
conditions
yield (%)
syn/ anti
ref
II
II
II
II
II
c-hexyl
c-hexyl
i-Pr
allyl
Me
LiAlH4(1.1-1.5 equiv), 0 °C
LiAlH4 (1.1-1.5 equiv), 0 °C
LiAlH4 (1.1-1.5 equiv), 0 °C
K-Selectride (2 equiv), -78 °C
K-Selectride (1.1 equiv), -78 °C
60
92
62
92
77
1:2.5
1:1
1:1
1:9
1:33
8c
8c
8c
9
8f
hydride reductions are less stereoselective. However,
when the alkyl group (R1) in the acyl moiety is rather
bulky, steric repulsion for the protons at the position cis
to the acyl moiety in the s-trans conformation should
increase to restrict the conformation to the s-cis form, as
shown in Figure 2C, which may allow the reduction to
proceed stereoselectively. We speculated that if the
substituent (R2) on the cyclopropane ring was signifi-
cantly bulky, despite being trans to the acyl moiety, the
hydride access to the stable bisected s-cis conformer from
one side of the carbonyl could be sterically hampered due
to the bulky R2 substituent, as shown in Figure 2C. If
this indeed occurs, the stereoselective hydride reduction
of the trans-substituted cyclopropyl ketones can be real-
ized, particularly by employing a bulky hydride reagent.
Based on these considerations, to develop a versatile
stereoselective method for the reduction of cyclopropyl
ketones, especially the trans-substituted cyclopropyl
ketones, we performed a systematic study of the hydride
reduction of cyclopropyl ketones, using the structurally
simplified trans-substituted substrates 1 and 2 as well
as their diastereomeric cis-substituted congeners 3 and
4 (Figure 3). Conformational analysis of the substrates
was also studied to clarify the mode of the nucleophilic
hydride reduction of the cyclopropyl ketones. In this
paper, we describe the results of these studies.
F IGURE 3. Structurally simplified cyclopropyl ketones as the
reaction substrates.
Therefore, we designed structurally simplified cyclopropyl
ketones as the reaction substrates, namely trans-[tert-
butyldiphenylsilyl (TBDPS) oxymethyl]cyclopropyl ke-
tones 1a-e and trans-(benzyloxymethyl)cyclopropyl meth-
yl ketone (2) (Figure 3) to investigate the above-
mentioned hypothesis and also to realize the highly
stereoselective hydride reduction of the trans-substituted
cyclopropyl ketones. The hydride reduction of the corre-
sponding cis substrates, 3a ,b,e and 4 (Figure 3), was
likewise planned to compare the results with those of the
trans substrates. Use of these simplified substrates would
make the experimental stereochemical results readily
understood. We decided to use these substrates in an
optically active form since the stereochemistries of the
Resu lts a n d Discu ssion
Design a n d Syn th esis of th e Str u ctu r a lly Sim p li-
fied Su bstr a tes. The cyclopropyl ketones used in the
previous studies as the substrates bore sterically and
stereoelectronically different functional groups affecting
the stereochemical outcome, which might make the
reaction mechanism somewhat difficult to understand.
J . Org. Chem, Vol. 68, No. 9, 2003 3513

Kazuta et al.
SCHEME 1
F IGURE 4. X-ray crystallographic structure of 3a .
SCHEME 4
SCHEME 2
propyl ketones 1a -e having the trans-silyloxymethyl
substituent (Scheme 1). The trans-1,2-bis(hydroxymeth-
yl)cyclopropane derivative 75 was converted to aldehyde
12, from which the trans-methyl ketone 2 having a
benzyloxymethyl substituent was prepared via successive
Grignard addition and oxidation (Scheme 2). The cis-
silyloxymethylcyclopropyl ketone substrates 3a ,b,e were
prepared from aldehyde 135 by the successive Grignard
addition/oxidation procedure (Scheme 3). The cis-benzy-
loxymethyl-substituted cyclopropyl methyl ketone 4 was
synthesized from en t-13, which was readily prepared
from S-epichlorohydrin,5 as shown in Scheme 4.
SCHEME 3
Figure 4 shows the X-ray crystallographic structure of
the O-TBDPS-protected cis-cyclopropyl methyl ketone 3a ,
which demonstrates that it exists in the bisected s-cis-
conformation in the solid state.13
Con for m a tion An a lysis by DF T Ca lcu la tion s. We
wanted to know whether the bisected s-trans and/or s-cis
conformations would predominate in the substrates.
Therefore, we examined the conformations of the model
compounds of the substrates, i.e., cyclopropyl methyl
ketone (i), the corresponding ethyl ketone (ii), cis-
methylcyclopropyl methyl ketone (iii), and trans-meth-
ylcyclopropyl methyl ketone (iv), the structures of which
are shown in Figure 5, by ab initio calculations based on
the density functional theory (DFT) using the Gaussian
98 program.14 The final optimizations were carried out
at RB3LYP/6-31G(d). As a result, only two minimum
energy conformers, which were in the s-cis- and s-trans-
bisected conformations, were obtained for the each cy-
clopropyl ketone. The structures of the minimum energy
resulting secondary alcoholic products should be easily
determined by employing the modified Mosher method.12
Syntheses of the substrates are shown in Schemes 1-4.
We recently developed the versatile chiral cyclopropane
intermediates 6 and its enantiomer en t-6, which were
readily synthesized from (R)- or (S)-epichlorohydrin [(R)-
5 or (S)-5], respectively, and were effectively used for the
synthesis of conformationally restricted analogues of
histamine.5 After conversion of the intermediate 6 into
the trans-silyloxymethyl-substituted cyclopropanecarbal-
dehyde 8, Grignard additions to it gave a mixture of the
syn- and anti-alcohol products, 9a -e and 10a -e, PDC
oxidations of which produced the corresponding cyclo-
(12) The stereochemistries of the reduction products were deter-
mined by the modified Mosher’s method (Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J . Am. Chem. Soc. 1991, 113, 4092-4096);
see the Supporting Information.
(13) NOE experiments of the trans-ketone 1a in CDCl3 did not
suggest a stable conformation in solution, and crystals of the trans-
substituted ketones 1a -e and 2 suitable for X-ray crystallographic
analysis were not obtained.
3514 J . Org. Chem., Vol. 68, No. 9, 2003

Stereoselective Reductions of trans-Cyclopropyl Ketones
SCHEME 5
F IGURE 5. Model cyclopropyl ketones for ab initio calcula-
tions.
make the s-cis-bisected conformer much more stable, as
we expected. It may also be important that a substituent
on the cyclopropane ring is able to stabilize the s-cis
conformer even though it is attached to the position trans
to the acyl moiety, based on the results of i and iv.
Hyd r id e Red u ction of th e Cis-Su bstitu ted Cyclo-
p r op yl Keton es. Hydride reductions of the cis-substi-
tuted substrates 3a ,b,e and 4 were examined (Scheme
5). The reactions were performed with LiAlH4 or K-
Selectride (2.0 equiv) as the reducing reagent at -78 °C
in CH2Cl2 (entries 1, 2, and 4-8) or THF (entry 3), and
the results are summarized in Table 3.12 All of the
reductions of the cyclopropyl ketones 3a ,b,e having an
O-TBDPS protecting group occurred highly stereoselec-
tively to give the corresponding anti products (entries
1-7). However, when K-Selectride was used for the
reduction of the ethyl or isobutyl ketones 3b or 3e, the
reaction rate was quite slow and the yield was insuf-
ficient (entries 5 and 7). The reduction of the O-benzyl-
protected methyl ketone 4 with K-Selectride also pro-
ceeded stereoselectively to give the anti product (entry
8); however, the stereoselectivity was somewhat de-
creased compared with that with the corresponding bulky
O-silyl-protected methyl ketone 3a (entry 2). These
results with the structurally simplified cis-substituted
substrates were similar to those of the previously re-
ported hydride reductions of the cyclopropyl ketones
having a cis substituent as summarized in Table 1.
F IGURE 6. Minimum energy s-cis and s-transconformers
obtained by the ab initio calculations of the model cyclopropyl
ketones i (A), ii (B), iii (C), and vi (D).
s-cis and trans conformers are shown in Figure 6. While
the s-cis conformer was more stable than the correspond-
ing s-trans conformer in all the four model ketones, the
relative stability was rather different: the energy dif-
ferences were 2.17 kcal/mol (i), 3.71 kcal/mol (ii), 4.59
kcal/mol (iii), and 3.07 kcal/mol (iv), respectively. These
calculations showed that a bulky alkyl group in the acyl
moiety plus a cis substituent on the cyclopropane ring
Hyd r id e Red u ction of th e Tr a n s-Su bstitu ted Cy-
clop r op yl Keton es. The hydride reductions of the trans-
substituted cyclopropyl ketones 1a -e and 2, lacking the
cis substituent on the cyclopropane ring, were next
investigated, as shown in Scheme 6. The reactions were
carried out with 2.0 equiv of a hydride reagent at -78
°C in CH2Cl2 (entries 1-4 and 6-14) or THF (entry 5),
and the results are summarized in Table 4.12 If the
hydride attack on the substrate in the bisected s-cis
conformation from its less hindered side indeed occurs,
as shown in Figure 2C, the corresponding anti product
should be selectively produced. First, the reaction was
examined with the methyl ketone 1a having an O-TBDPS
protecting group by using several hydride reagents, i.e.,
LiBH4, DIBAL-H, N-Selectride, K-Selectride, and KS-
Selectride (entries 1-6). The reactions with LiBH4,
DIBAL-H, N-Selectride, or K-Selectride gave a diaster-
eomeric mixture of the reduction products, i.e., the syn-
alcohol 9a and the anti-alcohol 10a , in high yield (entries
(14) Gaussian 98, Revision A.6: Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J r., J . A.; Stratmann, R. E.; Burant,
J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc.,
Pittsburgh, PA, 1998.
J . Org. Chem, Vol. 68, No. 9, 2003 3515

Kazuta et al.
TABLE 3. Hyd r id e Red u ction of th e Cis-Su bstitu ted Cyclop r op yl Keton es 3a ,b,e a n d 4a
entry
substrate
R1
Pg
reagent
time (h)
product
yield (%)
syn/antib
1
2
3c
4
5
6
7
8
3a
3a
3a
3b
3b
3e
3e
4
Me
Me
Me
Et
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
Bn
LiAlH4
1
1
1
24
12
24
30
1
14a , 15a
15a
15a
14b, 15b
15b
15e
90
99
99
1:31
K-Selectride
K-Selectride
LiAlH4
K-Selectride
LiAlH4
only anti
only anti
1:35
only anti
only anti
only anti
1:9.5
90 (8)d
51 (44)d
84 (8)d
15 (85)d
97
Et
i-Bu
i-Bu
Me
K-Selectride
K-Selectride
15e
19, 20e
a
b
Reaction was performed with 2.0 equiv of a hydride reagent in CH2Cl2 at -78 °C. Determined by 1H NMR. c Reaction was performed
in THF. Number in parentheses is yield of the substrate recovered. e The mixture of 19 and 20 was successively treated with H2/Pd-C
in MeOH and TBDPSCl/imidazole in DMF to give a mixture of 14a and 15a , which confirmed the structure of the major product 20 as
the anti-alcohol.
d
TABLE 4. Hyd r id e Red u ction of th e Tr a n s-Su bstitu ted Cyclop r op yl Keton es 1a -e a n d 2a
entry
substrate
R1
Pg
reagent
time (h)
products
yield (%)
syn/antib
1
2
3
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1e
2
Me
Me
Me
Me
Me
Me
Et
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
Bn
LiBH4
DIBAL-H
5
9a , 10a
9a , 10a
9a , 10a
9a , 10a
9a , 10a
10a
9b, 10b
10b
9c, 10c
23
90
87
85
93
1:1.4
1:2.2
1:3.5
1:3.4
1:3.6
only anti
1:4.3
only anti
1:4.6
-
0.5
0.5
1
0.5
8
1
8
8
8
1
5
1
5
N-Selectride
K-Selectride
K-Selectride
KS-Selectride
K-Selectride
KS-Selectride
K-Selectride
KS-Selectride
K-Selectride
K-Selectride
K-Selectride
KS-Selectride
4
5c
6
91
88 (3)d
98
7
8
9
10
11
12
13
14
Et
8 (90)d
89
allyl
allyl
i-Pr
i-Bu
Me
Me
69e
9d , 10d
9e, 10e
21, 22f
21, 22f
92
1:19
81 (13)d
92
1:49
1:1.6
1:2.3
2
Bn
80 (7)d
a
b
Reaction was performed with 2.0 equiv of a hydride reagent in CH2Cl2 at -78 °C. Determined by 1H NMR. c Reaction was performed
in THF. Number in parentheses is yield of the substrate recovered. e The yield of enone 23. f The mixture of 21 and 22 was successively
d
treated with H2/Pd-C in MeOH and TBDPSCl/imidazole in DMF to give a mixture of 9a and 10a , which confirmed the structure of the
major product 22 as the anti-alcohol.
SCHEME 6
slowly and a trace of the substrate was recovered,
probably due to the significant bulkiness of the reagent.
The reduction of the corresponding ethyl ketone 1b by
KS-Selectride hardly occurred to give the anti product
in only 8% yield along with 90% yield of the recovered
substrate (entry 8). Similarly the reduction of the allyl
ketone 1c by KS-Selectride did not proceed and the endo
double bond of the substrate migrated to give the
corresponding enone 23 in 69% yield (entry 10). However,
K-Selectride rather effectively reduced the ethyl ketone
1b and the allyl ketone 1c to give the corresponding anti-
alcohols 10b and 10c as the major products (entries 7
and 9). The K-Selectride reductions of the isopropyl
ketone 1d and the isobutyl ketone 1e occurred with high
stereoselectivity to give the expected anti products 10d
and 10e (entries 11 and 12, syn/ anti ) 1:19 and 1:49,
respectively). On the other hand, when the O-silyl-
protecting group of the substrate was replaced with an
O-benzyl group, i.e., substrate 3, the stereoselectivity was
significantly lowered (entries 13 and 14). Thus, we proved
that highly stereoselective reduction of the trans-
substituted ketones occurs when the substrate has a
bulky O-silyl protecting group.
1-5). Although reduction by LiBH4 was almost nonste-
reoselective (entry 1), reductions with DIBAL-H, N-
Selectride, and K-Selectride produced the expected anti
product 10a with some stereoselectivity (entries 2-5,
syn/ anti ) 1:2.2-1.3:5). When KS-Selectride was used,
the reduction of 1a proceeded with high stereoselectivity
to give the anti-alcohol 10a as the sole product in high
yield (entry 6). The reduction by KS-Selectride proceeded
Discu ssion
This is the first study to investigate experimentally
stereoselectivity in the hydride reduction of the cis- and
trans-substituted cyclopropyl ketones in a systematic
manner. The conformations of the substrates, which are
very important to understand the mechanism of the
3516 J . Org. Chem., Vol. 68, No. 9, 2003

Stereoselective Reductions of trans-Cyclopropyl Ketones
electron ionization (EI) or the fast atom bombardment (FAB)
or electrospray ionization (ESI) method. Thin-layer chroma-
tography was performed on Merck coated plate 60F254. Silica
gel chromatography (gravity) was performed with Merck silica
gel 5715 or 9385 (neutral). Reactions were carried out under
an argon atmosphere otherwise noted.
reactions, were also analyzed. Therefore, the results
obtained from this study can be useful for discussing and
understanding the reaction pathways.
The experimental results showed that: (1) the cis-
substituted cyclopropyl ketones are reduced with high
stereoselectivity to give the corresponding anti products
and (2) the trans-substituted ketones give the corre-
sponding anti products also with high stereoselectivity
when the substrate has a bulky O-silyl protecting group
even though it is attached to the position trans to the
acyl moiety. The DFT calculations of the model cyclopro-
pyl ketones suggested that: (1) the bisected s-cis and
s-trans conformers are the only two minimum energy
conformers, while the s-cis conformer is more stable than
the s-trans; (2) a bulky alkyl group in the acyl moiety
and a cis substituent on the cyclopropane ring make the
s-cis-bisected conformer much more stable; and (3) a trans
substituent also stabilizes the s-cis-bisected conformer,
while the effect is smaller than that by the corresponding
cis substituent. On the basis of these experimental and
calculated results, it is likely that the more stable the
bisected s-cis conformer in the substrate, the more
stereoselective the hydride reduction, as we hypothesized.
Accordingly, the stereoselective hydride reduction of
cyclopropyl ketones would be explained by the hydride
attack on the less hindered side of the bisected s-cis
conformation.15
On the other hand, the stereochemistry of reduction
of cyclopropyl ketones by nucleophilic hydride agents is
also in accord with that predicted by the Felkin-Anh
model as previously described by Reiser in an excellent
review on the Felkin-Anh model.16 However, the present
experimental and theoretical studies employing structur-
ally simplified substrates as well as the previous studies
showing the significant stability of the bisected confor-
mations7 suggest that the reductions are likely to proceed
via the bisected conformation-like transition state ef-
fectively stabilized by the characteristic stereoelectronic
feature of the cyclopropane ring.15 Further studies are
needed to confirm the reaction mechanism.
(1R,2R)-2-Ben zyloxym eth yl-1-h ydr oxym eth ylcyclopr o-
p a n e (11). After a mixture of 7 (2.38 g, 7.00 mmol) and NaH
(60% in paraffin liquid, 336 mg, 8.40 mmol) in THF (10 mL)
was stirred at 0 °C for 1 h, BnBr (1.67 mL, 14.0 mmol) was
added, and the resulting mixture was further stirred at room
temperature for 2 days. After addition of MeOH, the mixture
was partitioned between AcOEt and H2O, and the organic
layer was washed with brine, dried (Na2SO4), and evaporated
to give a residual oil. A mixture of the oil and TBAF (1.0 M in
THF, 10.5 mL, 10.5 mmol) in THF (10 mL) was stirred at room
temperature for 3 h, and the resulting mixture was partitioned
between AcOEt and H2O. The organic layer was washed with
brine, dried (Na2SO4), evaporated, and purified by column
chromatography (silica gel; AcOEt/hexane 1:9) to give 11 (737
mg, 55%) as a colorless liquid: [R]23 -15.24 (c 1.930, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.44 (2 H, m), 0.97-1.04 (2 H,
m), 2.19 (1 H, br s), 3.26 (1 H, dd, J ) 7.0, 10.0 Hz), 3.38 (1 H,
m), 3.41 (1 H, dd, J ) 6.0, 10.0 Hz), 3.49 (1 H, m), 4.52 (2 H,
s), 7.26-7.36 (5 H, m); 13C NMR (125 MHz, CDCl3) δ 8.0, 16.7,
19.8, 66.2, 72.6, 73.5, 127.6, 127.7, 128.4, 138.3; LR-MS (EI)
m/z 215 ((M + Na))+, 100.0). Anal. Calcd for C12H16O2: C,
74.97; H, 8.39. Found: C, 74.87; H, 8.37.
(1R,2R)-2-Ben zyloxym eth yl-1-for m ylcyclopr opan e (12).
To a solution of oxalyl chloride (0.52 mL, 6.0 mmol) in CH2Cl2
(5 mL) was added slowly a solution of DMSO (0.85 mL, 24
mmol) in CH2Cl2 (10 mL) at -78 °C over 30 min. To the
resulting mixture was added dropwise a solution of 11 (577
mg, 3.00 mmol) in CH2Cl2 (5 mL) at -78 °C, the mixture was
stirred at the same temperature for 1 h, and then Et3N (3.37
mL, 24.0 mmol) was added. The mixture was further stirred
at the same temperature for 30 min, and then saturated NH4-
Cl and CH2Cl2 was added. The organic layer separated was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; AcOEt/hexane 1:15) to
give 12 as a colorless liquid (503 mg, 88%): [R]23 +43.37 (c
D
0.520, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.07 (1 H, m),
1.32 (1 H, m), 1.79-1.86 (2 H, m), 3.41 (1 H, dd, J ) 6.0, 10.5
Hz), 3.49 (1 H, dd, J ) 5.5, 10.5 Hz), 4.52 (2 H, s), 7.26-7.36
(5 H, m), 9.10 (1 H, d, J ) 4.9 Hz); 13C NMR (125 MHz, CDCl3)
δ 12.4, 21.5, 28.0, 70.9, 72.8, 127.6, 127.7, 128.4, 137.9, 200.2;
LR-MS (ESI) m/z 213 ((M + Na)+, 5.0). Anal. Calcd for
In summary, this study shows that the highly stereo-
selective reduction of the trans-substituted cyclopropyl
ketones can be realized when the substrate has a bulky
substituent on the cyclopropane ring, even though it is
attached to the position trans to the acyl moiety. The
stereochemistry can be explained by the hydride attack
on the bisected s-cis conformation of the substrate from
the less-hindered face. The predictability of the stereo-
chemical results based on the bisected s-cis transition-
state model is very important from the viewpoint of
synthetic organic chemistry.
C
12H14O2: C, 75.76; H, 7.42. Found: C, 75.57; H, 7.54.
(1S,2R)-1-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-2-h y-
d r oxym eth ylcyclop r op a n e (16). A mixture of en t-135 (1.02
g, 3.00 mmol) and NaBH4 (226 mg, 6.00 mmol) in THF (10
mL) was stirred at room temperature for 1 h, and then the
mixture was neutralized with AcOH. The solvent was evapo-
rated, and the residue was partitioned between AcOEt and
H2O. The organic layer was washed with brine, dried (Na2-
SO4), evaporated, and purified by column chromatography
(silica gel; AcOEt/hexane 1:9) to give 16 as a colorless oil (1.00
g, 98%): [R]24 -12.04 (c 1.280, CHCl3); LR-MS (EI) m/z 283
D
((M - t-Bu)+, 3.5%). Anal. Calcd for C21H28O2Si: C, 74.07; H,
8.29. Found: C, 73.76; H, 8.34. The 1H NMR spectrum of 16
was in accord with that of the enantiomer of 16 reported
previously.5
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were recorded
at 400, 500 MHz (1H) and at 125 MHz (13C) and are reported
in ppm downfield from Me4Si. Mass spectra were obtained by
(1S,2R)-2-Ben zyloxym eth yl-1-h yd r oxym eth ylcyclop r o-
p a n e (17). Compound 17 was prepared from 16 (681 mg, 2.00
mmol) as described for 11. After purification by column
chromatography (silica gel; AcOEt/hexane 1:9), 17 was ob-
(15) The conformation of the transition state and the intermediate
can be strongly influenced by conformational effects which stabilize
the ground state conformation, for examples see: (a) Pothier, N.;
Goldstein, S.; Deslongchamps, P. Helv. Chim Acta 1992, 75, 604-620.
(b) Romero, J . A. C.; Tabacco, S. A.; Woerpel, K. A. J . Am. Chem. Soc.
2000, 122, 168-189. (c) Abe, H.; Shuto, S.; Matsuda, A. J . Am. Chem.
Soc. 2001, 123, 11870-11882. (d) Tamura, A.; Abe, H.; Matsuda, A.
Shuto, S. Angew. Chem., Int. Ed. 2003, 42, 1021-1023.
tained as a colorless liquid (246 mg, 64%): [R]23 -83.56 (c
D
1.450, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.21 (1 H, m),
0.81 (1 H, m), 1.28-1.40 (2 H, m), 3.13-3,20 (3 H, m), 3.92 (1
H, dd, J ) 5.4, 10.6 Hz), 3.94 (1 H, m), 4.51 (1 H, d, J ) 11.7
Hz), 4.58 (1 H, d, J ) 11.7 Hz), 7.28-7.37 (5 H, m); 13C NMR
(125 MHz, CDCl3) δ 8.6, 14.7, 18.4, 63.0, 70.7, 73.1, 127.9,
(16) Mengel, A.; Reiser O. Chem. Rev. 1999, 99, 1191-1223.
J . Org. Chem, Vol. 68, No. 9, 2003 3517

Kazuta et al.
127.9, 128.5, 137.4; LR-MS (EI) m/z 215 ((M + Na)+, 100.0).
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.66;
H, 8.23.
t, J ) 7.5 Hz), 0.99 (1 H, m), 1.05 (9 H, s), 1.46 (1 H, br s),
1.62 (2 H, m), 2.87 (1 H, m), 3.44 (1 H, dd, J ) 6.7, 10.7 Hz),
3.68 (1 H, dd, J ) 6.6, 10.7 Hz), 7.36-7.43 (6 H, m), 7.65-
7.67 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.30, 10.05, 18.94,
19.19, 23.27, 26.84, 30.13, 66.45, 77.15, 127.60, 129.57, 133.88,
135.59; LR-MS (ESI) m/z 391 ((M + Na)+, 100.0). Anal. Calcd
for C23H32O2Si: C, 75.95; H, 8.75. Found: C, 75.70; H, 8.54.
(1S,2R)-2-Ben zyloxym eth yl-1-for m ylcyclopr opan e (18).
Compound 18 was prepared from 17 (192 mg, 1.00 mmol) as
described for 12. After purification by column chromatography
(silica gel; AcOEt/hexane 1:15), 18 was obtained as a colorless
liquid (132 mg, 69%): [R]23D +26.01 (c 1.020, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.24 (1 H, m), 1.33 (1 H, m), 1.85 (1 H,
m), 2.04 (1 H, m), 3.43 (1 H, dd, J ) 8.6, J ) 10.4 Hz), 3.81 (1
H, dd, J ) 5.7, J ) 10.4 Hz), 4.45 (1 H, d, J ) 11.8 Hz), 4.49
(1 H, d, J ) 11.8 Hz), 7.26-7.36 (5 H, m), 9.47 (1 H, d, J ) 4.5
Hz); 13C NMR (125 MHz, CDCl3) δ 12.4, 23.7, 26.8, 67.9, 73.0,
127.7, 127.8, 128.4, 138.0, 200.4; LR-MS (ESI) m/z 213 ((M +
Na)+, 100.0). Anal. Calcd for C12H14O2: C, 75.76; H, 7.42.
Found: C, 76.12; H, 7.56.
10b: [R]22 -10.52 (c 1.330, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.43 (2 H, m), 0.75 (1 H, m), 0.96 (3 H, t, J ) 7.5
Hz), 1.01 (1 H, m), 1.05 (9 H, s), 1.51 (1 H, br s), 1.59 (2 H, m),
2.88 (1 H, m), 3.35 (1 H, dd, J ) 7.4, 10.7 Hz), 3.73 (1 H, dd,
J ) 5.6, 10.7 Hz), 7.37-7.44 (6 H, m), 7.66-7.68 (4 H, m); 13
C
NMR (125 MHz, CDCl3) δ 7.8, 10.0, 18.6, 19.2, 23.7, 26.9, 29.7,
66.8, 76.8, 127.6, 129.6, 133.9, 135.6; LR-MS (ESI) m/z 391
((M + Na)+, 100.0). Anal. Calcd for C23H32O2Si: C, 74.95; H,
8.75. Found: C, 74.78; H, 8.99.
(1R,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-
1-h yd r oxy-3-bu ten yl]cyclop r op a n e (9c) a n d (1R,2R)-2-
[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-1-h yd r oxy-3-
bu ten yl]cyclop r op a n e (10c). From the mixture of 9c and
10c (130 mg), 9c (66 mg) and 10c (56 mg) were obtained in a
pure form, after column chromatography (silica gel; AcOEt/
hexane 1:19). 9c: [R]25D -17.88 (c 1.560, CHCl3); 1H NMR (500
MHz, CDCl3) δ 0.44 (1 H, m), 0.54 (1 H, m), 0.84 (1 H, m),
0.96 (1 H, m), 1.05 (9 H, s), 1.62 (1 H, br s), 2.32 (1 H, m), 2.42
(1 H, m), 3.01 (1 H, m), 3.46 (1 H, dd, J ) 6.5, 10.7 Hz), 3.66
(1 H, dd, J ) 5.6, 10.7 Hz), 5.11 (2 H, m), 5.89 (1 H, m), 7.36-
7.44 (6 H, m), 7.65-7.68 (4 H, m); 13C NMR (125 MHz, CDCl3)
δ 7.8, 18.7, 19.2, 22.9, 26.9, 41.9, 66.2, 75.0, 117.6, 127.6, 129.6,
133.9, 134.9, 135.6; LR-MS (EI) m/z 323 ((M - t-Bu)+, 2.5).
Anal. Calcd for C24H32O2Si: C, 75.74; H, 8.47. Found: C, 75.52;
Gen er a l P r oced u r e for th e Gr ign a r d Rea ction of
Ald eh yd e 8, 12, 13, or 18. A mixture of an aldehyde (1.0
mmol) and a Grignard reagent (2.0 equiv) in THF (10 mL) was
stirred at room temperature for 5 h, and then MeOH was
added. The mixture was evaporated, and the residue was
partitioned between AcOEt and H2O. The organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; AcOEt/hexane 1:9) to
give a syn/ anti mixture of the corresponding Grignard addition
products. A part of the mixtures obtained from O-TBDPS
aldehydes 8 and 13 was separated by column chromatography
(silica gel; AcOEt/hexane 1:19) to give the syn and the anti
product in a pure form, respectively. However, the mixture
obtained form O-benzyl aldehydes 12 and 18 could not be
separated into the pure diastereomers. The syn/ anti mixture
was used for the next PDC oxidation.
H, 8.54. 10c: [R]24 -12.66 (c 1.090, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 0.43 (2 H, m), 0.77 (1 H, m), 1.04 (1 H, m),
1.05 (9 H, s), 1.59 (1 H, br s), 2.29 (1 H, m), 2.37 (1 H, m), 3.05
(1 H, m), 3.41 (1 H, dd, J ) 6.9, 10.6 Hz), 3.70 (1 H, dd, J )
5.7, 10.6 Hz), 5.08-5.14 (2 H, m), 5.18 (1 H, m), 7.36-7.43 (6
H, m), 7.66-7.68 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.6,
18.8, 19.2, 23.2, 26.9, 41.4, 66.7, 74.4, 117.0, 127.6, 129.6, 133.9,
134.9, 135.6; LR-MS (EI) m/z 323 ((M - t-Bu)+, 7.0). Anal.
Calcd for C24H32O2Si: C, 75.74; H, 8.47. Found: C, 75.65; H,
8.52.
Gen er a l P r oced u r e for th e P DC Oxid a tion . A mixture
of the syn/ anti mixture of the Grignard reaction products (1.0
mmol), PDC (752 mg, 2.0 mmol), and molecular sieves 5A (200
mg) in CH2Cl2 (20 mL) was stirred at room temperature for 5
h, and the resulting mixture was filtered through a pad of
Florisil and Celite. The filtrate was evaporated, and the
residue was purified by column chromatography (silica gel;
AcOEt/hexane 1:19-1:9) to give the corresponding ketone.
(1R,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-
1-h yd r oxyeth yl]cyclop r op a n e (9a ) a n d (1R,2R)-2-[(ter t-
Bu t yld ip h en ylsilyloxy)m et h yl]-1-[(S)-1-h yd r oxyet h yl)-
cyclop r op a n e (10a ). From the mixture of 9a and 10a (380
mg), 9a (213 mg), and 10a (157 mg) were obtained in a pure
form, after column chromatography (silica gel; AcOEt/hexane
(1R,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-
1-h ydr oxy-2-m eth ylpr opyl]cyclopr opan e (9d) an d (1R,2R)-
2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-1-h yd r oxy-
2-m eth ylp r op yl]cyclop r op a n e (10d ). From the mixture of
9d and 10d (120 mg), 9d (59 mg) and 10d (52 mg) were
obtained in a pure form, after column chromatography (silica
1:19). 9a : [R]18 -11.77 (c 1.220, CHCl3); 1H NMR (500 MHz,
D
gel; AcOEt/hexane 1:19). 9d : [R]26 -22.28 (c 1.850, CHCl3);
CDCl3) δ 0.40 (1 H, m), 0.57 (1 H, m), 0.81 (1 H, m), 0.94 (1 H,
m), 1.05 (9 H, s), 1.27 (3 H, d, J ) 6.2 Hz), 1.45 (1 H, br s),
D
1H NMR (500 MHz, CDCl3) δ 0.39 (1 H, m), 0.43 (1 H, m),
0.86 (1 H, m), 0.99 (3 H, d, J ) 6.8 Hz), 1.00 (3 H, d, J ) 6.8
Hz), 1.01 (1 H, m), 1.04 (9 H, s), 1.40 (1 H, br s), 1.81 (1 H, m),
2.66 (1 H, dd, J ) 6.0, 8.8 Hz), 3.48 (1 H, dd, J ) 6.6, 10.7
Hz), 3.68 (1 H, dd, J ) 5.6, 10.7 Hz), 7.36-7.44 (6 H, m), 7.65-
7.67 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.0, 18.4, 18.7,
19.2, 19.7, 21.3, 26.8, 34.5, 66.4, 80.9, 127.6, 129.6, 133.8, 133.8,
135.6, 135.6; LR-MS (EI) m/z 364 ((M - H2O)+, 4.0). Anal.
3.17 (1 H, dq, J ) 4.4 Hz, J 1′, ) 6.2 Hz), 3.41 (1 H, dd, J )
2′
6.6, 10.5 Hz), 3.68 (1 H, dd, J ) 5.5, 10.5 Hz), 7.36-7.46 (6 H,
m), 7.66-7.67 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 8.12,
18.64, 19.26, 22.63, 25.02, 26.88, 66.40, 71.97, 127.53, 129.51,
133.75, 133.77, 135.49; LR-MS (EI) m/z 297 ((M - t-Bu)+,
19.0%). Anal. Calcd for C22H30O2Si: C, 74.53; H, 8.53. Found:
C, 74.46; H, 8.41. 10a : [R]19D -9.00 (c 0.660, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 0.39 (2 H, m), 0.76 (1 H, m), 1.01 (1 H,
m), 1.05 (9 H, s), 1.23 (3 H, d, J ) 6.2 Hz), 1.54 (1 H, br s),
3.15 (1 H, dq, J ) 6.2, 7.8 Hz), 3.37 (1 H, dd, J ) 6.2, 10.6
Hz), 3.71 (1 H, dd, J ) 5.6, 10.6 Hz), 7.37-7.44 (6 H, m), 7.66-
7.68 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.4, 19.3, 19.4,
22.2, 25.4, 26.9, 66.7, 71.7, 127.6, 129.5, 133.7, 135.5; LR-MS
(EI) m/z 297 ((M - t-Bu)+, 6.0). Anal. Calcd for C22H30O2Si:
C, 74.53; H, 8.53. Found: C, 74.47; H, 8.51.
Calcd for C24H34O2Si: C, 75.34; H, 8.96. Found: C, 75.25; H,
1
9.10. 10d : [R]24 -8.03 (c 1.170, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 0.47 (2 H, m), 0.77 (1 H, m), 0.96 (3 H, d, J ) 6.8
Hz), 0.97 (3 H, d, J ) 6.8 Hz), 1.00 (1 H, m), 1.05 (9 H, s), 1.47
(1 H, br s), 1.78 (2 H, m), 2.67 (1 H, dd, J ′ ) 5.9, 8.5 Hz), 3.30
(1 H, dd, J ) 7.6, 10.6 Hz), 3.77 (1 H, dd, J ) 5.4, 10.6 Hz),
7.35-7.44 (6 H, m), 7.66-7.68 (4 H, m); 13C NMR (125 MHz,
CDCl3) δ 8.7, 18.2, 18.4, 18.6, 19.2, 21.9, 27.0, 34.2, 66.9, 80.5,
127.7, 129.6, 133.9, 135.6; LR-MS (EI) m/z 364 ((M - H2O)+,
2.0). Anal. Calcd for C24H34O2Si: C, 75.34; H, 8.96. Found: C,
75.21; H, 9.01.
(1R,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-
1-h yd r oxyp r op yl]cyclop r op a n e (9b) a n d (1R,2R)-2-[(ter t-
Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-1-h yd r oxyp r op yl]-
cyclop r op a n e (10b). From the mixture of 9b and 10b (290
mg), 9b (150 mg) and 10b (129 mg) were obtained in a pure
form, after column chromatography (silica gel; AcOEt/hexane
(1R,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-
1-h yd r oxy-3-m eth ylbu tyl]cyclop r op a n e (9e) a n d (1R,2R)-
2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-1-h yd r oxy-
3-m eth ylbu tyl]cyclop r op a n e (10e). From the mixture of 9e
and 10e (197 mg), 9e (122 mg) and 10e (61 mg) were obtained
1:19). 9b: [R]21 -16.50 (c 1.350, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.39 (1 H, m), 0.45 (1 H, m), 0.81 (1 H, m), 0.98 (3 H,
3518 J . Org. Chem., Vol. 68, No. 9, 2003

Stereoselective Reductions of trans-Cyclopropyl Ketones
in a pure form, after column chromatography (silica gel;
2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-1-h yd r oxy-
3-m eth ylbu tyl]cyclop r op a n e (15e). From the mixture 14e
and 15e (190 mg), 14e (136 mg) and 15e (46 mg) were obtained
in a pure form, after column chromatography (silica gel;
AcOEt/hexane 1:19). 9e: [R]24 -8.15 (c 1.260, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 0.39 (1 H, m), 0.46 (1 H, m), 0.78 (1
H, m), 0.88 (3 H, d, J ) 6.6 Hz), 0.91 (3 H, d, J ) 6.6 Hz), 0.96
(1 H, m), 1.05 (9 H, s), 1.40 (1 H, br s), 1.43 (1 H, m), 1.54 (1
H, m), 1.86 (1 H, m), 3.00 (1 H, m), 3.40 (1 H, dd, J ) 6.9, 10.6
Hz), 3.68 (1 H, dd, J ) 5.4, 10.6 Hz), 7.36-7.44 (6 H, m), 7.65-
7.68 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.5, 18.9, 19.2,
22.2, 23.3, 24.3, 24.5, 26.8, 46.6, 66.5, 73.8, 127.6, 129.6, 133.9,
135.6; LR-MS (FAB) m/z 419 ((M - t-Bu)+, 10.0). Anal. Calcd
for C25H36O2Si: C, 75.70; H, 9.15. Found: C, 75.58; H, 9.21.
AcOEt/hexane 1:19). 14e: [R]17 -3.46 (c 1.350, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 0.22 (1 H, m), 0.69 (1 H, m), 0.87 (3
H, d, J ) 6.6 Hz), 0.92 (3 H, d, J ) 6.6 Hz), 1.02 (1 H, m), 1.06
(9 H, s), 1.19 (1 H, m), 1.55-1.58 (2 H, m), 1.64 (1 H, br s),
1.83 (1 H, m, H-3′), 3.40 (1 H, m), 3.58 (1 H, dd, J ) 8.5, 11.2
Hz), 3.80 (1 H, dd, J ) 6.2, 11.2 Hz), 7.36-7.44 (6 H, m), 7.66-
7.70 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 7.47, 18.62, 19.16,
21.48, 23.82, 23.92, 24.52, 26.86, 46.84, 64.20, 70.05, 127.60,
127.63, 129.60, 129.61, 133.78, 133.79, 135.53, 135.60; LR-MS
(FAB) m/z 397 ((M + H)+, 2.0). Anal. Calcd for C25H36O2Si: C,
10e: [R]24 -19.08 (c 1.280, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.42 (2 H, m), 0.75 (1 H, m), 0.89 (3 H, d, J ) 6.6
Hz), 0.97 (3 H, d, J ) 6.6 Hz), 1.04 (1 H, m), 1.07 (9 H, s), 1.34
(1 H, m), 1.45 (1 H, br s), 1.52 (1 H, m), 1.82 (1 H, m), 3.02 (1
H, m), 3.34 (1 H, dd, J ) 7.2, 10.7 Hz), 3.77 (1 H, dd, J ) 5.6,
10.7 Hz), 7.37-7.44 (6 H, m), 7.65-7.68 (4 H, m); 13C NMR
(125 MHz, CDCl3) δ 7.7, 18.9, 19.2, 22.2, 23.5, 24.5, 24.6, 26.9,
46.2, 66.8, 73.5, 127.6, 129.6, 133.9, 135.6; LR-MS (FAB) m/z
419 ((M - t-Bu)+, 3.0%). Anal. Calcd for C25H36O2Si: C, 75.70;
H, 9.15. Found: C, 75.55; H, 9.14.
75.70; H, 9.15. Found: C, 75.60; H, 9.03. 15e: [R]20 +16.97
D
1
(c 1.080, CHCl3); H NMR (500 MHz, CDCl3) δ 0.11 (1 H, m),
0.69 (1 H, m), 0.94 (6 H, d, J 4′, ) 6.6 Hz), 1.06 (9 H, s), 1.12
3′
(2 H, m), 1.18 (1 H, m), 1.44 (1 H, m), 1.67 (1 H, m), 1.91 (1 H,
m), 3.35 (1 H, dd, J ) 11.4, 11.4 Hz), 3.39 (1 H, m), 3.83 (1 H,
br s), 4.10 (1 H, dd, J ) 5.2, 11.4 Hz), 7.37-7.46 (6 H, m),
7.67-7.74 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 8.4, 16.5,
19.1, 22.5, 23.4, 24.0, 24.6, 26.8, 65.5, 70.6, 127.8, 127.8, 129.8,
129.9, 133.0, 133.0, 135.5, 135.7; LR-MS (FAB) m/z 397 ((M +
H)+, 5.0). Anal. Calcd for C25H36O2Si: C, 75.70; H, 9.15.
Found: C, 75.68; H, 9.30.
(1S,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-
1-h yd r oxyeth yl]cyclop r op a n e (14a ) a n d (1S,2R)-2-[(ter t-
Bu t yld ip h en ylsilyloxy)m et h yl]-1-[(R)-1-h yd r oxyet h yl]-
cyclop r op a n e (15a ). From the mixture of 14a and 15a (160
mg), 14a (105 mg) and 15a (52 mg) were obtained in a pure
form, after column chromatography (silica gel; AcOEt/hexane
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(1-
eth a n oyl)cyclop r op a n e (1a ). Compound 1a was obtained
in 89% yield from 8 as an oil: [R]19 -55.15 (c 1.490, CHCl3);
1:19). 14a : [R]20 +5.04 (c 1.010, CHCl3); 1H NMR (500 MHz,
D
D
1H NMR (500 MHz, CDCl3) δ 0.88 (1 H, m, H-3a), 1.05 (9 H,
s, -C(CH3)3), 1.20 (1 H, m, H-3b), 1.67 (1 H, m, H-2), 1.85 (1
H, m, H-1), 2.19 (3 H, s, H-2′), 3.51 (1 H, dd, H-1′′a, J ) 6.0,
J ) 11.0 Hz), 3.77 (1 H, dd, H-1′′b, J ) 4.8, 11.0 Hz), 7.37-
CDCl3) δ 0.21 (1 H, m), 0.69 (1 H, m), 1.03 (1 H, m), 1.06 (9 H,
s), 1.24 (1 H, m), 1.39 (3 H, d, J ) 6.2 Hz), 3.52 (1 H, dd, J )
8.8, 11.2 Hz), 3.53 (1 H, m), 3.85 (1 H, dd, J ) 6.9, J ) 11.2
Hz), 7.37-7.44 (6 H, m), 7.65-7.70 (4 H, m); 13C NMR (125
MHz, CDCl3) δ 7.68, 18.50, 19.17, 23.74, 24.57, 26.82, 64.22,
68.48, 127.63, 127.66, 129.63, 133.70, 133.74, 135.54, 135.60;
LR-MS (ESI) m/z 297 ((M - t-Bu)+, 1.5). Anal. Calcd for
1
7.45 (6 H, m, aromatic), 7.64-7.66 (4 H, m, aromatic), the H
NMR assignments indicated were in agreement with the
COSY spectra; NOE (400 MHz, CD2Cl2, 32 °C) H-2 f H-3b
(4.0%), H-2f H-2′ (1.0%), H-2f H-1′′a (1.9%), H-2 f H-1′′b
(2.4%), H-3b f H-2 (6.2%), H-3b f H-3a (23.0%), H-2′ f H-1
(1.6%), H-2′ f H-2 (0.5%), H-2′ f H-3b (0.3%); NOE (400 MHz,
CD2Cl2, -78 °C) H-2 f H-3b (3.7%), H-2 f H-1′′a (1.4%), H-2
f H-1′′b (2.0%), H-3b f H-2 (5.9%), H-3b f H-3a (12.9%),
H-2′ f H-1 (1.5%), H-2′ f H-2 (0.3%);13C NMR (125 MHz,
CDCl3) δ 14.6, 19.2, 26.4, 26.8, 26.9, 30.4, 64.7, 127.7, 129.7,
129.7, 133.5, 133.6, 135.6, 208.0. LR-MS (EI) m/z 295 ((M -
t-Bu)+, 100.0). Anal. Calcd for C22H28O2Si: C, 74.95; H, 8.01.
Found: C, 74.99; H, 8.04.
C
22H30O2Si: C, 74.53; H, 8.53. Found: C, 74.64; H, 8.62. 15a :
1
[R]19 +12.66 (c 0.820, CHCl3); H NMR (500 MHz, CDCl3) δ
D
0.10 (1 H, m), 0.68 (1 H, m), 1.06 (9 H, s), 1.13-1.26 (2 H, m),
1.37 (3 H, d, J ) 6.1 Hz), 3.35 (1 H, dd, J ) 11.0, 11.4 Hz),
3.51 (1 H, m), 3.99 (1 H, br s), 4.10 (1 H, dd, J ) 5.0, 11.4 Hz),
7.35-7.46 (6 H, m), 7.68-7.74 (4 H, m); 13C NMR (125 MHz,
CDCl3) δ 8.2, 17.5, 19.0, 21.9, 24.8, 26.8, 63.7, 68.9, 127.8,
127.8, 129.8, 129.9, 132.9, 132.9, 135.5, 135.6; LR-MS (ESI)
m/z 297 ((M - t-Bu)+, 1.0). Anal. Calcd for C22H30O2Si: C,
74.53; H, 8.53. Found: C, 74.42; H, 8.45.
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(1-
p r op a n oyl)cyclop r op a n e (1b). Compound 1b was obtained
(1S,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-
1-h ydr oxypr opyl]cyclopr opan e (14b) an d (1S,2R)-2-[(ter t-
Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(R)-1-h yd r oxyp r op yl]-
cyclop r op a n e (15b). From the mixture of 14b and 15b (160
mg), 14b (114 mg) and 15b (40 mg) were obtained in a pure
form, after column chromatography (silica gel; AcOEt/hexane
in 79% from 8 yield as an oil: [R]20 -77.96 (c 1.020, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.85 (1 H, m), 1.04 (9 H, s), 1.07
(3 H, t, J ) 7.4 Hz), 1.18 (1 H, m), 1.66 (1 H, m), 1.84 (1 H, m),
2.46-2.57 (2 H, m), 3.50 (1 H, dd, J ) 6.1, 11.0 Hz), 3.77 (1 H,
dd, J ) 4.8, 11.0 Hz), 7.37-7.44 (6 H, m), 7.64-7.66 (4 H, m);
13C NMR (125 MHz, CDCl3) δ 8.0, 14.3, 19.2, 25.3, 26.1, 26.8,
36.7, 64.8, 127.7, 129.7, 129.7, 133.6, 133.6, 135.6, 135.6, 210.6;
LR-MS (FAB) m/z 367 ((M + H)+, 8.0). Anal. Calcd for
1:19). 14b: [R]20 +2.60 (c 1.370, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.22 (1 H, m), 0.69 (1 H, m), 0.99 (3 H, t, J ) 7.4
Hz), 1.05 (9 H, s), 1.06 (1 H, m), 1.24 (1 H, m), 1.54-1.66 (2
H, m), 1.83 (1 H, m), 3.27 (1 H, m), 3.55 (1 H, dd, J ) 8.6, 11.2
Hz), 3.85 (1 H, dd, J ) 6.0, 11.2 Hz), 7.37-7.44 (6 H, m), 7.65-
7.71 (4 H, m);13C NMR (125 MHz, CDCl3) δ 7.31, 10.05, 18.65,
19.14, 23.02, 26.80, 30.60, 64.26, 73.20 (C-1′), 127.62, 127.65,
129.61, 133.73, 133.76, 135.53, 135.59; LR-MS (FAB) m/z 369
((M + H)+, 4.0). Anal. Calcd for C23H32O2Si: C, 74.95; H, 8.75.
Found: C, 74.70; H, 8.77. 15b: [R]21D +12.64 (c 1.130, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.13 (1 H, m), 0.72 (1 H, m),
1.02 (3 H, t, J ) 7.5 Hz), 1.06 (9 H, s), 1.10-1.26 (2 H, m),
1.68 (1 H, m), 1.77 (1 H, m), 3.26 (1 H, m), 3.35 (1 H, dd, J )
11.2, 11.2 Hz), 3.91 (1 H, br s), 4.10 (1 H, dd, J ) 5.0, 11.2
Hz), 7.39-7.46 (6 H, m), 7.68-7.74 (4 H, m); 13C NMR (125
MHz, CDCl3) δ 8.5, 10.3, 16.5, 19.1, 23.1, 26.8, 29.7, 65.5, 74.0,
127.8, 127.8, 129.8, 129.9, 133.0, 133.0, 135.5, 135.7; LR-MS
(FAB) m/z 369 ((M + H)+, 7.0). Anal. Calcd for C23H32O2Si: C,
74.95; H, 8.75. Found: C, 74.64; H, 8.79.
C
23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.30; H, 8.21.
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(3-
bu ten oyl)cyclop r op a n e (1c). Compound 2c was obtained in
48% yield from 8 as an oil: [R]22 -63.92 (c 0.400, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 0.90 (1 H, m), 1.04 (9 H, s), 1.22 (1
H, m), 1.70 (1 H, m), 1.91 (1 H, m), 3.25 (2 H, dd, J ) 1.1, 6.9
Hz), 3.51 (1 H, dd, J ) 6.0, 11.0 Hz), 3.77 (1 H, dd, J ) 4.6,
11.0 Hz), 5.16 (2 H, m), 5.94 (1 H, m), 7.35-7.45 (6 H, m),
7.64-7.65 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 14.7, 19.2,
25.3, 26.8, 27.1, 48.5, 64.5, 118.6,127.7, 129.7, 129.7, 130.7,
133.5, 133.5, 135.5, 135.6, 207.7; LR-MS (ESI) m/z 401 ((M +
Na)+
, 100.0). Anal. Calcd for C24H30O2Si: C, 76.14; H, 7.99.
Found: C, 75.94; H, 8.12.
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(2-
m eth yl-1-p r op a n oyl)cyclop r op a n e (1d ). Compound 1d was
obtained in 82% yield from 8 as an oil: [R]22D -62.38 (c 1.360,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.85 (1 H, m), 1.04 (9 H,
(1S,2R)-2-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-[(S)-
1-h ydr oxy-3-m eth ylbu tyl]cyclopr opan e (14e) an d (1S,2R)-
J . Org. Chem, Vol. 68, No. 9, 2003 3519

Kazuta et al.
s), 1.12 (3 H, d, J ) 6.9 Hz), 1.15 (3 H, t, J ) 6.9 Hz), 1.18 (1
H, m), 1.63 (1 H, m), 1.94 (1 H, m), 2.70 (1 H, m), 3.49 (1 H,
dd, J ) 6.3, 11.0 Hz), 3.79 (1 H, dd, J ) 5.6, 11.0 Hz), 7.37-
7.45 (6 H, m), 7.64-7.66 (4 H, m);1 3C NMR (125 MHz, CDCl3)
δ 14.3, 18.1, 18.3, 19.2, 24.0, 26.8, 26.9, 41.7, 64.9, 127.7, 129.7,
129.7, 133.5, 133.6, 135.5, 135.6, 213.6; LR-MS (ESI) m/z 403
((M + Na)+, 100.0). Anal. Calcd for C24H32O2Si: C, 75.74; H,
8.47. Found: C, 75.71; H, 8.59.
4.53 (1 H, s, J ) 12.0 Hz), 7.26-7.36 (5 H, m); 13C NMR (125
MHz, CDCl3) δ 15.1, 24.1, 26.9, 30.3, 71.6, 72.6, 127.6, 127.7,
128.4, 138.1, 207.5; LR-MS (FAB) m/z 205 ((M + H)+), 53.0).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.11;
H, 7.89.
(1S,2R)-2-Ben zyloxym eth yl-1-eth an oylcyclopr opan e (4).
Compound 18 (192 mg, 1.0 mmol) was successively treated by
the above general procedures of the Grignard reaction with
MeMgBr and the PDC oxidation to give 4 (159 mg, 78%) as a
colorless oil: [R]18D +85.51 (c 1.110, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.00 (1 H, m), 1.21 (1 H, m), 1.74 (1 H, m), 2.16 (1 H,
m), 2.31 (3 H, s), 3.30 (1 H, dd, J ) 10.2, 10.2 Hz), 3.74 (1 H,
dd, J ) 5.2, 10.2 Hz), 4.40 (2 H, s), 7.25-7.34 (5 H, m); 13C
NMR (125 MHz, CDCl3) δ 12.1, 23.8, 25.3, 31.8, 67.6, 73.0,
127.6, 127.8, 128.3, 138.3, 206.3; LR-MS (FAB) m/z 205 ((M +
H)+, 64.0). Anal. Calcd for C13H16O2: C, 76.44; H, 7.90.
Found: C, 76.21; H, 7.96.
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(3-
m eth yl-1-bu th a n oyl)cyclop r op a n e (1e). Compound 1e was
obtained in 74% from 8 as an oil: [R]21 -66.54 (c 1.120,
D
CHCl3);1H NMR (500 MHz, CDCl3) δ 0.84 (1 H, m, H-3a), 0.92
(3 H, d, H-4′a, J 4′a,3′ ) 6.6 Hz), 0.93 (3 H, d, H-4′b, J 4′b,3′ ) 6.6
Hz), 1.04 (9 H, s, -C(CH3)3), 1.19 (1 H, m, H-3b), 1.65 (1 H,
m, H-2), 1.85 (1 H, m, H-1), 2.16 (1 H, m, H-3′), 2.36 (2 H, m,
H-2′), 3.48 (1 H, dd, H-1′′a, J 1′′a,2 ) 6.2 Hz, J 1′′a,1′′b ) 11.0 Hz),
3.78 (1 H, dd, H-1′′b, J 1′′b,2 ) 4.6 Hz, J 1′′b,1′′a ) 11.0 Hz), 7.37-
1
7.45 (6 H, m, aromatic), 7.62-7.65 (4 H, m, aromatic), the H
Gen er a l P r oced u r e for th e Hyd r id e Red u ction of
Keton es 1, 2, 3, or 4 (Ta bles 3 a n d 4). To a solution of a
ketone 1, 2, 3, or 4 (0.10 mmol) in CH2Cl2 (2 mL) was added
a solution of a hydride reagent (LiAlH4, 1.0 M in THF; LiBH4,
2.0 M in THF; DIBAL-H, 1.0 M in n-hexane; N-Selectride, 1.0
M in THF; K-sElectride, 1.0 M in THF; KS-Selectride, 1.0 M
in THF), and the mixture was stirred at -78 °C for 0.5-30 h.
The resulting mixture was evaporated, and the residue was
partitioned between AcOEt and H2O. The organic layer was
washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (silica gel;
AcOEt/hexane 1:9) to give a syn/ anti mixture of the product,
NMR assignments indicated were in agreement with the
COSY spectra; NOE (400 MHz, CD2Cl2, -78 °C) H-2 f H-3b
(3.3%), H-2 f H-1′′a (1.2%), H-2 f H-1′′b (1.9%), H-3b f H-2
(2.2%), H-3b f H-3a (18.9%), H-2′a f H-1 (1.3%), H-2′a f
H-2′b (22.8%), H-2′′b f H-1 (2.0%), H-2′′b f H-2 a (22.8%);
13C NMR (125 MHz, CDCl3) δ 14.3, 19.2, 22.6, 22.7, 24.9, 26.0,
26.8, 26.8, 52.9, 64.8, 127.7, 129.7, 129.7, 133.6, 133.6, 135.6,
135.6, 210.0; LR-MS (ESI) m/z 417 ((M + Na)+, 100.0). Anal.
Calcd for C25H34O2Si: C, 76.09; H, 8.68. Found: C, 75.98; H,
8.80.
(1S,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl])-1-(1-
eth a n oyl)cyclop r op a n e (3a ). Compound 3a was obtained
in 84% yield from 13 as white crystals: mp (hexane/AcOEt)
1
the ratio of which was determined by H NMR analysis. The
results are summarized in Tables 3 and 4.
73-74 °C; [R]20 +35.42 (c 1.030, CHCl3); 1H NMR (500 MHz,
D
(1S,2R)-2-Ben zyloxym eth yl-1-[(S)-1-h yd r oxyeth yl]cy-
clop r op a n e (19) a n d (1S,2R)-2-Ben zyloxym eth yl-1-[(R)-
1-h yd r oxyeth yl]cyclop r op a n e (20). The K-Selectride re-
duction of 4 gave a mixture of 19 and 20 (Table 3, entry 7),
the structures of which were confirmed after its conversion
into the corresponding O-TBDPS-protected derivatives 14a
and 15a as described below: 1H NMR (500 MHz, CDCl3) for
major product 20, δ 0.18 (1 H, m), 0.80 (1 H, m), 1.09 (1 H,
m), 1.28 (1 H, m), 1.30 (3 H, d, H-2′, J ) 6.2 Hz), 3.18 (1 H,
dd, J ) 10.3, 10.8 Hz), 3.33 (1 H, m), 3.69 (1 H, br s), 3.96 (1
H, dd, J ) 5.5, 10.3 Hz), 4.53 (1 H, d, J ) 11.6 Hz), 4.57 (1 H,
d, J ) 11.6 Hz), 7.26-7.35 (5 H, m), for minor product 19, δ
0.32 (1 H, m), 0.80 (1 H, m), 1.04 (1 H, m), 1.28 (1 H, m), 1.31
(3 H, d, J ) 6.2 Hz), 3.33 (1 H, dd, J ) 8.6, 10.4 Hz), 3.46 (1
H, m), 3.62 (1 H, dd, J ) 6.7, 10.4 Hz), 4.47 (1 H, d, J ) 11.6
Hz), 4.55 (1 H, d, J ) 11.6 Hz), 7.26-7.35 (5 H, m); HR-MS
(EI) calcd for C13H18O2 206.2808, found 206.2797 (M+).
(1R,2R)-2-Ben zyloxym eth yl-1-[(R)-1-h yd r oxyeth yl]cy-
clop r op a n e (21) a n d (1R,2R)-2-Ben zyloxym eth yl-1-[(S)-
1-h yd r oxyeth yl]cyclop r op a n e (22). The K-Selectride or KS-
Selectride reduction of 2 gave a mixture of 21 and 22 (Table
4, entries 12 and 13), the structures of which were confirmed
after its conversion into the corresponding O-TBDPS-protected
derivatives 9a and 10 as described below: 1H NMR (500 MHz,
CDCl3) for major product 22, δ 0.46 (2 H, m), 0.83 (1 H, m),
1.09 (1 H, m), 1.25 (3 H, d, J ) 6.2 Hz), 3.12 (1 H, m), 3.18 (1
H, dd, J ) 7.6, 10.0 Hz), 3.44 (1 H, dd, J ) 6.2, 10.0 Hz), 4.52
(2 H, s), 7.26-7.36 (5 H, m), for minor product 21, δ 0.46 (1
H, m), 0.58 (1 H, m), 0.83 (1 H, m), 1.03 (1 H, m), 1.27 (3 H, d,
J ) 6.3 Hz), 3.23 (1 H, m), 3.33 (2 H, m), 4.53 (2 H, s), 7.26-
7.36 (5 H, m); HR-MS (EI) calcd for C13H18O2 206.2808, found
206.2804 (M+).
CDCl3) δ 0.90 (1 H, m), 1.04 (9 H, s), 1.13 (1 H, m), 1.68 (1 H,
m), 2.16 (1 H, m), 2.35 (3 H, s), 3.51 (1 H, dd, J ) 9.7, 11.1
Hz), 3.87 (1 H, dd, J ) 5.1, 11.1 Hz), 7.36-7.44 (6 H, m), 7.61-
7.68 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 11.7, 19.2, 25.5,
26.6, 26.8, 31.8, 61.5, 127.6, 129.6, 133.7, 134.0, 135.5, 206.2;
LR-MS (EI) m/z 295 ((M - t-Bu)+, 80.0). Anal. Calcd for
C
22H28O2Si: C, 74.95; H, 8.01. Found: C, 74.74; H, 8.06.
(1S,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(1-
p r op a n oyl)cyclop r op a n e (3b). Compound 3b was obtained
in 72% yield from 13 as white crystals: mp (hexane/AcOEt)
72-74 °C; [R]20 +33.26 (c 1.010, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.89 (1 H, m), 1.01 (9 H, s), 1.11 (3 H, t, J ) 7.5 Hz),
1.13 (1 H, m), 1.65 (1 H, m), 2.13 (1 H, m), 2.60-2.77 (2 H,
m), 3.53 (1 H, dd, J ) 9.7, 11.2 Hz), 3.87 (1 H, dd, J ) 5.0,
11.2 Hz), 7.36-7.42 (6 H, m), 7.60-7.68 (4 H, m); 13C NMR
(125 MHz, CDCl3) δ 8.0, 11.4, 19.2, 25.5, 26.3, 26.8, 37.2, 61.5,
127.6, 127.6, 129.5, 133.8, 134.1, 135.5, 208.8; LR-MS (FAB)
m/z 367 ((M + H)+, 25.0). Anal. Calcd for C23H30O2Si: C, 75.36;
H, 8.25. Found: C, 75.36; H, 8.38.
(1S,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(3-
m eth yl-1-bu th a n oyl)cyclop r op a n e (3e). Compound 3e was
obtained from 13 in 79% yield as an oil: [R]25D +33.59 (c 1.380,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.89 (1 H, m), 0.94 (3 H,
d, J ) 6.6 Hz), 0.96 (3 H, d, J ) 6.6 Hz), 1.02 (9 H, s), 1.10 (1
H, m), 1.62 (1 H, m), 2.10 (1 H, m), 2.20 (1 H, m), 2.53 (2 H, d,
J ) 6.8 Hz), 3.59 (1 H, dd, J ) 9.4, 11.2 Hz), 3.85 (1 H, dd, J
) 5.3, 11.2 Hz), 7.36-7.43 (6 H, m), 7.61-7.68 (4 H, m); 13C
NMR (125 MHz, CDCl3) δ 11.7, 19.2, 22.7, 22.8, 24.6, 25.1,
26.5, 26.8, 53.7, 61.4, 127.6, 129.5, 129.5, 133.8, 134.1, 135.5,
135.5, 208.3; LR-MS (FAB) m/z 395 ((M + H)+, 26.0). Anal.
Calcd for C25H34O2Si: C, 76.09; H, 8.68. Found: C, 76.00; H,
8.58.
(1R,2R)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-1-(2-
bu ten oyl)cyclop r op a n e (23). Compound 23 was obtained in
69% yield as an oil by the treatment of 1c with KS-Selectride
(Table 4, entry 9), after column chromatography (silica gel;
AcOEt/hexane 1:19): 1H NMR (500 MHz, CDCl3) δ 0.91 (1 H,
m), 1.04 (9 H, s), 1.26 (1 H, m), 1.70 (1 H, m), 1.91 (3 H, dd, J ′
) 1.6, 6.8 Hz), 2.06 (1 H, m), 3.56 (1 H, dd, J ) 6.0, 11.0 Hz),
3.79 (1 H, dd, J ) 4.8, 11.0 Hz), 6.20 (1 H, dq, J ) 1.6, 5.6
Hz), 6.87 (1 H, dq, J ) 5.6, 6.8 Hz), 7.37-7.45 (6 H, m), 7.64-
(1R,2R)-2-Ben zyloxym eth yl-1-eth an oylcyclopr opan e (2).
Compound 12 (192 mg, 1.0 mmol) was successively treated by
the above general procedures for the Grignard reaction with
MeMgBr and the PDC oxidation to give 2 (173 mg, 85%) as a
colorless oil: [R]20 -115.38 (c 2.130, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 0.89 (1 H, m), 1.25 (1 H, m), 1.76 (1 H, m),
1.90 (1 H, m), 2.23 (3 H, s), 3.32 (1 H, dd, J ) 6.8, 10.5 Hz),
3.49 (1 H, dd, J ) 5.6, 10.5 Hz), 4.50 (1 H, s, J ) 12.0 Hz),
3520 J . Org. Chem., Vol. 68, No. 9, 2003

Stereoselective Reductions of trans-Cyclopropyl Ketones
7.66 (4 H, m); 13C NMR (125 MHz, CDCl3) δ 14.5, 18.3, 19.3,
23.8, 26.9, 27.0, 64.8, 127.7, 129.7, 129.7, 132.3, 133.6, 135.6,
135.6, 142.1, 207.7; HR-MS (FAB) calcd for C24H31O2Si 379.2093,
found 379.2107 ((M + H)+).
in calculations. The intensities were corrected for the Lorentz,
polarization, and the extinction effect, but not for the absorp-
tion. The structure was solved by the direct method and refined
by full-matrix least squares technique using maXus (version
4.3) as the computer program. The non-hydrogen atoms were
refined anisotropically. The hydrogen atoms were included by
calculation, but these positions were not refined. The R values
were 0.038.
Ca lcu la tion s. All ab initio and DFT (density functional
theory) calculations were performed using the Gaussian 98
program14 on an SGI O2 workstation. The preoptimized
geometries by RHF/6-31G(d) were taken to be the input
geometries for final optimization by RB3LYP/6-31G(d). Finally,
single-point energies were calculated by RB3LYP/6-31G(d).
Con ver sion of 19/20 Mixtu r e in to 14a /15a Mixtu r e. A
mixture of 19 and 20 (17 mg, 80 µmol) and 10% Pd-charcoal
(5 mg) in MeOH (1 mL) was stirred under atmospheric
pressure hydrogen gas at room temperature for 1 h, and then
the catalyst was filtered off. The filtrate was evaporated, and
a mixture of the residue, TBDPSCl (21 µL, 0.80 µmol), and
imidazole (5 mg, 0.80 µmol) in DMF (1 mL) was stirred at room
temperature for 5 h. After addition of MeOH, the resulting
mixture was partitioned between AcOEt and H2O, and the
organic layer separated was washed with brine, dried (Na2-
SO4), evaporated. The residue was purified by column chro-
matography (silica gel; AcOEt/hexane 1:9) to give a mixture
of 14a and 15a (26 mg, 90%) as an oil.
Con ver sion of 21/22 Mixtu r e in to 9a /10a Mixtu r e. A
mixture of 21 and 22 (20 mg, 100 µmol) was converted into a
mixture of 9a and 10a (29 mg, 85%) as described above for
the mixture of 19a and 20a .
X-r a y cr ysta llogr a p h ic d a ta of 3a : C22H28O2Si, M )
352.55, monoclinic, P21, a ) 10.289 (3) Å, b ) 9.002 (2) Å, c )
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) from the J apan Society for Promo-
tion of Science. We are grateful to Ms. H. Matsumoto,
A. Maeda, and S. Oka (Center for Instrumental Analy-
sis, Hokkaido University) for technical assistance with
NMR, MS, and elemental analyses and to Daiso Co.,
Ltd. for the gift of chiral epichlorohydrins.
12.155 (2) Å, â ) 113.39(2)°, V ) 1033.4(4) Å3, Z ) 2, Dcalc
)
1.133 Mg cm-3. Cell parameters were determined and refined
from 26 reflections in the range 26.5° < θ < 30.0°. A colorless
crystal (0.40 × 0.30 × 0.25 mm) was mounted on a Mac Science
MXC18 diffractometer with graphite-monochromated Cu KR
radiation (λ ) 1.541 78 Å). Data collection using the ω/2θ scan
technique gave 1744 reflections at room temperature, 1644
unique, of which 1612 with I > 3.00σ(I) reflections were used
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for determination of the stereochemistry of the syn and
anti products by the modified Mosher method. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O030019V
J . Org. Chem, Vol. 68, No. 9, 2003 3521