Asymmetric reduction of β-ketoesters and chiral β-iminoesters: Impact of a α-quaternary stereocenter

Article abstract of DOI:10.1002/chir.20909

Diastereomeric reduction of nonactivated, hindered β-keto and chiral β-iminoesters are described. The influence of a α-stereocontrolled center on the efficiency and stereoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize β-hydroxy- and β-aminoesters in good yields. In the case of chiral β-iminoesters, influence of matched/mismatched diastereomeric pairs has been assessed. Copyright

Full text of DOI:10.1002/chir.20909

CHIRALITY 23:265–271 (2011)
Asymmetric Reduction of b-Ketoesters and Chiral b-Iminoesters:
Impact of a a-Quaternary Stereocenter
HADIA ALMAHLI,1,2 FREDERIC HENDRA,1,3 CLAIRE TROUFFLARD,3,4 CHRISTIAN CAVE,1,3 DELPHINE JOSEPH,1,3
´
´
´
AND SANDRINE DELARUE-COCHIN1,3
*
1Universite´ Paris-Sud, Equipe de Synth`ese Organique et Pharmacochimie, UMR CNRS 8076 BioCIS,
F-92296 Chaˆtenay-Malabry, France
2Faculty of Pharmacy, Department of Pharmacognosy, Aleppo University, Aleppo, Syria
3IPSIT ‘‘Institut Paris-Sud d’Innovation The´rapeutique’’, F-92296 Chaˆtenay-Malabry, France
4De´partement RMN, Universite´ Paris-Sud, UMR CNRS 8076 BioCIS, F-92296 Chaˆtenay-Malabry, France
ABSTRACT
Diastereomeric reduction of nonactivated, hindered b-keto and chiral b-imi-
noesters are described. The influence of a a-stereocontrolled center on the efficiency and ste-
reoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize b-
hydroxy- and b-aminoesters in good yields. In the case of chiral b-iminoesters, influence of
matched/mismatched diastereomeric pairs has been assessed. Chirality 23:265–271,
C
VV
2011.
2010 Wiley-Liss, Inc.
KEY WORDS: asymmetric synthesis; diastereoselectivity; b-aminoesters; b-hydroxyesters
were recorded on Bruker Vector 22 spectrophotometer. 1H and 13C spec-
INTRODUCTION
tra were recorded, respectively, at 300 and 75 MHz on a Bruker Avance
Chiral b-hydroxy, b-aminoesters, and acids are syntheti-
cally valuable building blocks for the construction of natural
products and pharmaceuticals.1–3 An access to such com-
pounds can be envisioned by an atom economic method,
such as the stereoselective reduction of b-keto and b-imi-
noesters, respectively: this strategy proved to be efficient in
the synthesis of RWJ-53308, a GP IIb/IIIa antagonist.4
Although widely studied, this strategy appears restricted to
nonhindered or activated derivatives. Indeed, only few exam-
ples describe the asymmetric reduction of sterically hindered
derivatives possessing a quaternary carbon atom on the a-
position. In these cases, reduction is usually performed by
asymmetric catalytic hydrogenation using ruthenium and
rhodium chiral complexes5–13 or chiral reducing agents,
such as diisopinocamphenylchloroborane.14 In addition, the
reduction of b-ketoesters, bearing a pre-existing a-quater-
nary chiral center is scarcely reported15–18 and, to the best of
our knowledge, only one example showed the reduction of
chiral b-iminoesters by hydride transfer.19 Due to the wide
occurrence of these chiral b-hydroxyester and b-aminoester
fragments in more complex synthetic or natural targets,
there is still a steady demand for the development of practi-
cal methodology exempt from external chiral reductant.
In this preliminary study, we report the diastereoselective
reduction of nonactivated hindered b-keto and chiral b-imi-
noesters, bearing a a-quaternary stereocontrolled center, by
boro- and lithio-hydride derivatives.
20
300. CDCl3 was used as internal reference. Specific rotations [a]D
were measured on a PolAAr32 polarimeter with sodium (589 nm) lamp
at 208C in a 1 dm-cell. Diastereomeric excesses (de) were evaluated by
1H NMR spectroscopy. Positive EI-MS and APCI-MS spectra were
recorded respectively on a Bruker Esquire LC.
(2S)-5-Benzyl 1-ethyl 2-methyl-2-(1-((1R)-1-
phenylethylimino)ethyl)pentanedioate 10b.
To a solution of (R)-1-phenylethylamine (1.2 equiv) and freshly dis-
tilled triethylamine (6 equiv) in anhydrous CH2Cl2 (C 5 0.1 M), was
added dropwise, at 08C and under inert atmosphere, TiCl4 (0.5 equiv)
then compound 1b (1 equiv). After stirring the mixture at reflux for 24
h, Et2O was added. The reactive medium was filtered over celite and the
filtrate was concentrated to give, without purification, the desired prod-
uct 10b as yellow oil. RMN 1H: 7.40–7.05 (10 Harom, m), 5.15 1 5.13
(CH2, s), 4.19 1 4.16 (CH2, q, J5 7.2), 2.95 (CH, m), 2.20 (CH2, m), 2.15
(CH3, s). 1.80 (CH2, m), 1.27 1 1.28 (CH3, t, J 5 7.2), 1.15 (CH3, d, J 5
6.4), 1.00 (CH3, s); RMN 13C: 176.4 1 176.2 1 173.1 1 172.9 (COO),
160.1 (C5N), 145.7 1 143.8 (Cq), 126.6–128.4 (CH), 72.0 1 72.2 (CH2),
60.3 1 60.2 (CH2), 52.3 (CH), 50.7 1 50.1 (Cq), 31.2 1 30.6 (CH2), 28.1
(CH2), 25.75 (CH3), 22.4 1 22.8 (CH3), 18.2 (CH3), 15.4 1 15.3 (CH3);
IR (cm21): 3000, 1750, 1680, 1460, 1300.
Method A: Reduction with NaBH4. To a solution of b-
ketoester 2a/b-iminoester 1a (1 equiv) in anhydrous THF (C 5 1 M),
was added MeOH (1 equiv) and NaBH4 (1 equiv), at 2788C and under
inert atmosphere. After stirring the mixture at 2788C during 9 h, water
was added, THF was evaporated and the aqueous layer was extracted
three times with CH2Cl2. The resulting organic layers were combined,
washed with brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by column chromatography (cyclohexane/AcOEt:
7/3) to yield the desired hydroxyester 3a and lacton 4/aminoester 5a.
EXPERIMENTAL
Commercial reagents were used without purification. b-Iminoester
1a-b and b-ketoester 2a-c were synthesized according classical proce-
20–22
dures.
Prior to use, THF was freshly distilled from sodium-benzo-
phenone and toluene from CaH2. All anhydrous reactions were carried
out under argon atmosphere. Analytical thin layer chromatography was
performed on Merck 60F-254 precoated silica (0.2 mm) on glass and
was revealed by UV-light or K¨agi-Misher reagent. All flash chromatogra-
phy separations were performed with Merck Kieselgel (40–63 lm). Melt-
ing points were recorded on an Electrothermal digital apparatus and
were uncorrected. Infrared (IR) spectra were obtained as neat films and
*Correspondence to: Sandrine Delarue-Cochin, Faculte´ de Pharmacie de
Chaˆtenay-Malabry, Universite´ Paris Sud, UMR CNRS 8076, Equipe de Syn-
the`se Organique et Pharmacochimie, 5 rue J.-B. Cle´ment, 92296 Chaˆtenay-
Malabry cedex, France. E-mail: Sandrine.delarue-cochin@u-psud.fr
Received for publication 28 October 2009; Accepted 22 June 2010
DOI: 10.1002/chir.20909
Published online 13 October 2010 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2010 Wiley-Liss, Inc.

266
ALMAHLI ET AL.
(1) (2S)-5-Tert-Butyl 1-ethyl 2-((1R)-1-hydroxyethyl)-
Method B: Luche reduction. To a solution of b-ketoester
2a-b (1 equiv) in anhydrous MeOH (C 5 1 M) was added CeCl3.7H2O
(1.3 equiv) at room temperature. After stirring the mixture for 1 h at
room temperature, a suspension of NaBH4 (1 equiv) in anhydrous
MeOH (C 5 2 M) was added dropwise, at 2788C and under inert atmos-
phere. After stirring the mixture at 2788C during 3 h, water was added,
MeOH was evaporated and the aqueous layer was extracted three times
with CH2Cl2. The resulting organic layers were combined, washed with
brine, dried over Na2SO4, filtered and concentrated. The residue was
purified by column chromatography (cyclohexane/AcOEt: 7/3) to yield
the desired hydroxyester 3a-b and lacton 4.
2-methylpentanedioate 3a
1
Rf 5 0.13 cyclohexane/ACOEt: 7/3; H NMR: 4.1914.16 (CH2, q, J 5
7.2), 3.90 (CH, m), 2.73 (bs, OH), 2.20 (CH2, m), 1.79 (CH2, m),
1.4011.30 (C(CH3)3, s), 1.2711.28 (CH3, t, J 5 7.2), 1.05 (CH3, d, J 5
6.4), 1.01 (CH3, s); 13C NMR: 176.41176.21173.11172.9 (COO),
80.3180.2 (Cq), 71.4171.3 (CH), 60.3160.2 (CH2), 50.7150.1 (Cq),
31.2130.6 (CH2), 28.1 (CH2), 24.7123.4 (CH3), 15.4115.3 (CH3),
16.8116.6 (CH3), 24.7123.4 (CH3); [a]D205 16 (c 1.0 in DCM, de 31%)
IR (cm21): 3510, 1750, 1460, 1300. ESI-MS: m/z 5 571 ([2M1Na]1,
100%), 513 (26%), 497 (42%), 378 (38%), 297 ([M1Na]1, 69%).
Method C: Reduction with NaHB(O2CiPr)3. NaBH4 (3
equiv) was slowly added to isobutyric acid (20 equiv) at 08C and under
inert atmosphere. After stirring the mixture for 30 min at room tempera-
ture, anhydrous toluene was added and the resulting solution of NaH-
B(O2CiPr)3 in toluene (C 5 1 M) was cooled to 08C. A solution of b-
ketoester 2a-c/b-iminoester 1a-b or 10b (1 equiv) in anhydrous toluene
(C 5 0.2 M) was then added at 08C. After stirring the mixture for 5 h at
08C, with regular addition of NaBH4 (1 equiv every hour), water was
added, then a solution of NaOH 3 M until pH>10. The reactive medium
was extracted three times with AcOEt. The resulting organic layers
were combined, washed with brine, dried over Na2SO4, filtered and con-
centrated. The residue was purified by column chromatography (cyclo-
hexane/AcOEt: 7/3) to yield the desired hydroxyester 3a-c and lacton
4/ b-aminoester 5a-b.
(2) (2S)-5-Benzyl 1-ethyl 2-((1R)-1-hydroxyethyl)-
2-methylpentanedioate 3b
1
Rf 5 0.15 (cyclohexane/AcOEt: 8.5/1.5); H NMR: 7.40–7.05 (5 Harom,
m), 5.1515.13 (CH2, s), 4.1914.16 (CH2, q, J 5 7.2), 3.90 (CH, m), 2.73
(bs, OH), 2.20 (CH2, m), 1.80 (CH2, m), 1.2711.28 (CH3, t, J 5 7.2), 1.15
(CH3, d, J 5 6,4), 1.05 (CH3, s); 13C NMR: 176,41176.21173.11172.9
(COO), 145.71143.8 (Cq), 126.6–128.4 (CH), 72.0172.2 (CH2), 71.4171.3
(CH), 60.3160.2 (CH2), 50.7150.1 (Cq), 31.2130.6 (CH2), 28.1 (CH2),
22.4122.8 (CH3), 16.8116.6 (CH3), 15.4115.3 (CH3); [a]D205 25 (c 1.1 in
DCM, de 67%); IR (cm21): 3410, 1750, 1714, 1460, 1300. ESI-MS: m/z 5
639 ([2M1Na]1, 30%), 531 (34%), 331 ([M1Na]1, 100%), 223 (42%).
(2S)-1-Ethyl 5-methyl 2-((1R)-1-hydroxyethyl)-2-
methylpentanedioate 3c
Method D: Reduction with Zn(BH4)2. To a solution of b-
ketoester 2a/b-iminoester 1a-b or 10b (1 equiv) in anhydrous THF (C
5 0.4 M) was added, at 0 8C and under inert atmosphere, a freshly pre-
pared solution of Zn(BH4)2 in THF (3 equiv). After stirring the mixture
for 1 h at 08C then for 2 h at room temperature, water was added, THF
was evaporated and the aqueous layer was extracted three times with
Et2O. The resulting organic layers were combined, washed with brine,
dried over Na2SO4, filtered and concentrated. The residue was purified
by column chromatography (cyclohexane/AcOEt: 7/3) to yield the
desired hydroxyester 3a and lacton 4/b-aminoester 5a-b.
1H NMR: 4.1914.16 (CH2, q, J 5 7.2), 3.90 (CH, m), 3.6213.64 (CH3,
s), 2.71 (bs, OH), 2.20 (CH2, m), 1.80 (CH2, m), 1.2711.28 (CH3, t,
J
5 7.2), 1.06 (CH3, d, J 5
6,4), 1.00 (CH3, s); 13C NMR:
176,41176.21173.11172.9 (COO), 72.0172.1 (CH), 60.3160.2 (CH2),
51.0 (CH3), 50.7150.1 (Cq), 31.2130.6 (CH2), 29.2 (CH3), 28.1 (CH2),
22.4122.8 (CH3), 15.4115.3 (CH3); IR (cm21): 3510, 1750, 1460, 1300.
(An inseparable mixture of hydroxyester 3c and lacton 4 was systemati-
cally obtained.)
(1) (2R,3S)-Ethyl 2,3-dimethyl-6-oxo-tetrahydro-2H-
Method E: Reduction with L-Selectride. To a solution of
b-ketoester 2a/b-iminoester 1b-10b (1 equiv) in anhydrous THF (C 5
0.5 M) was added, at 2788C and under inert atmosphere, L-Selectride (5
equiv). After stirring the mixture for 5 h at room temperature, a saturated
solution of NH4Cl was added, THF was evaporated and the aqueous layer
was extracted three times with CH2Cl2. The resulting organic layers were
combined, washed with brine, dried over Na2SO4, filtered and concen-
trated. The residue was purified by column chromatography (cyclo-
hexane/AcOEt: 7/3) to yield the desired hydroxyester 3a and lacton 4/
b-aminoester 5b.
pyran-3-carboxylate 4
1H NMR: 4.19 (CH2, q, J 5 7.2), 4.78 (CH, m), 2.6712.53 (CH2, m),
2.3511.78 (CH2, m), 1.4011.30 (C(CH3)3, s), 1.32 (CH3, d, J 5 6.4), 1.27
(CH3, t, J 5 7.2), 1.21 (CH3, s); 13C NMR: 174.51170.9 (COO), 78.8
(CH), 61.4 (CH2), 44.3 (Cq), 29.8 (CH2), 26.7 (CH2), 16.5 (CH3), 16.3
(CH3), 14.1 (CH3); [a]D 5 115 (c 0.8 in DCM, de 100%). IR (cm21):
20
1746, 1460, 1300. ESI-MS: m/z 5 423 ([2M1Na]1, 100%), 320 (21%), 223
[M1Na]1, 44%).
(2) (2S)-5-tert-Butyl 1-ethyl 2-methyl-2-((1S)-1-((1S)-1-
phenylethylamino)-ethyl)pentanedioate 5a
Method F: Reduction with LiAlH(OtBu)3. To a solution
of b-ketoester 2a/b-iminoester 1b-10b (1 equiv) in anhydrous THF (C
5 0.5 M) was added, at 2788C and under inert atmosphere, LiAl-
H(OtBu)3 (1.2 equiv). After stirring the mixture for 3 h at 2788C then
3h at 08C, NaOH 2 M was added, THF was evaporated and the aqueous
layer was extracted three times with CH2Cl2. The resulting organic
layers were combined, washed with brine, dried over Na2SO4, filtered
and concentrated. The residue was purified by column chromatography
(cyclohexane/AcOEt: 7/3) to yield the desired compound hydroxyester
3a and lacton 4/ b-aminoester 5b.
Rf 5 0.43 (cyclohexane/ AcOEt: 8/2); 1H NMR: 7.93–7.90 (5 Harom,
m), 4.1914.16 (CH2, q, J 5 7.2), 3.74 (CH, m), 2.95 (CH, m), 3.18–3.00
(CH2, m), 2.73 (NH, bs), 2.27–2.05 (CH2, m), 1.32 (CH3, s), 1.2511.23
(CH3, t, J5 7.2, H1), 1.15 (CH3, d, J 5 6.4), 1.05 (CH3, d, J 5 6,4); 13C
NMR: 171,51171.41170.81170.6 (COO), 145.71143.8 (C), 126.6–128.4
(CH), 82.1182.4 (Cq), 61.7161.5 (CH2), 56.5156.2 (CH), 52.3(CH), 52.0
(Cq), 30.8130.2 (CH2), 28.1 (CH3), 27.5 (CH2), 22.8122.4 (CH3), 18.5
(CH3), 16.8116.6 (CH3), 15.4115.3 (CH3); [a]D205 212 (c 0.25 in DCM,
de 38%); IR (cm21): 3000, 1750, 1460, 1300. APCI-MS: m/z 5 402 (32%),
378 ([M1H]1, 100%).
Method G: Reduction with NaBH4/ZnCl2. To a solution
of b-iminoester 1b (1 equiv) in anhydrous THF (C 5 1 M) was added,
at 08C and under inert atmosphere, a solution of ZnCl2 (3 equiv) in anhy-
drous THF (C 5 10 M). After stirring the mixture for 1 h at 08C, NaBH4
(6 equiv) was added. After stirring the mixture for 1 h at 08C than for 2
h at room temperature, a saturated solution of NH4Cl was added, THF
was evaporated and the aqueous layer was extracted three times with
Et2O. The resulting organic layers were combined, washed with brine,
dried over Na2SO4, filtered and concentrated. The residue was purified
by column chromatography (cyclohexane/AcOEt: 7/3) to yield the
desired b-aminoester 5b.
(2) (2S)-5-Benzyl 1-ethyl 2-methyl-2-((1S)-1-((1S)-1-
phenylethylamino)ethyl) pentanedioate 5b
1
Rf 5 0.5 (cyclohexane/AcOEt: 85:15); H NMR: 7.40–7.05 (10 Harom,
m), 5.1515.13 (CH2, s), 4.1914.16 (CH2, q, J 5 7.2), 3.70 (CH, m), 2.95
(CH, m), 2.73 (NH, bs), 2.20 (CH2, m), 1.80 (CH2, m), 1.2711.28 (CH3,
t, J 5 7.2), 1.15 (CH3, d, J 5 6.4), 1.05 (CH3, d, J 5 6,4) , 1.00 (CH3, s);
13C NMR: 176.41176.21173.11172.9 (COO), 145.71143.8 (Cq), 126.6–
128.4 (CH), 72.00172.2 (CH), 60.3160.2 (CH2), 56.5156.2 (CH2), 52.3
(CH), 50.7150.1 (Cq), 31.2130.6 (CH2), 28.1 (CH2), 22.4122.8 (CH3),
Chirality DOI 10.1002/chir

ASYMMETRIC REDUCTION OF ꢀ-KETOESTERS AND ꢀ-IMINOESTERS
267
Scheme 1. Synthesis of the iminoesters 1a-1c, ketoesters 2a-2c, and hydroxyesters 3a-3c.
18.2 (CH3), 16.8116.6 (CH3), 15.4115.3 (CH3); [a]D205 215 (c 0.2 in
RESULTS AND DISCUSSION
DCM, de 38%). IR (cm21): 3000, 1750, 1460, 1300. APCI-MS: m/z 5 412
([M1H]1, 100%).
The (S)-b-iminoesters 1a-c and the (S)-b-ketoesters 2a-c
have been synthesized by asymmetric Michael reaction
according the literature procedure (Scheme 1). Good yields
(40–85%) and excellent enantiomeric excesses (85–95%)
were obtained.20–22
(2) (2S)-5-Benzyl 1-ethyl 2-methyl-2-((1S)-1-
((1R)-1-phenylethylamino)ethyl) pentanedioate 50b
1
We first carried out the reduction of b-ketoesters 2a-c
using a variety of reducing agents (Scheme 1, Table 1). So-
dium borohydride was used alone or in Luche reaction con-
dition.23 Sodium tris(isobutyroxy)borohydride,24,25 zinc boro-
hydride,26,27 L-Selectride,28,29 and lithium tri-tert-butoxyalu-
minium hydride30,31 have also been assessed. The reaction
was monitored by TLC and diastereomeric excesses (de)
Rf 5 0.5 (cyclohexane/AcOEt: 85:15); H NMR: 7.40–7.05 (10 Harom,
m), 5.1515.13 (CH2, s), 4.1914.16 (CH2, q, J 5 7.2), 3.70 (CH, m), 2.95
(CH, m), 2.75 (NH, bs), 2.20 (CH2, m), 1.80 (CH2, m), 1.2711.28 (CH3,
t, J 5 7.2), 1.15 (CH3, d, J 5 6.4), 1.05 (CH3, d, J 5 6,4) , 1.00 (CH3, s);
13C NMR: 176,41176.21173.11172.9 (COO), 145.71143.8 (Cq), 126.6–
128.4 (CH), 72.00172.2 (CH), 60.3160.2 (CH2), 56.5156.2 (CH2), 52,3
(CH), 50.7150.1 (Cq), 31.2130.6 (CH2), 28.1 (CH2), 22.4122.8 (CH3),
20
18.2 (CH3), 16.8116.6 (CH3), 15.4115.3 (CH3); [a]D 5 24.5 (c 0.2 in
1
were measured by H NMR experiments. All reduction reac-
DCM, de 45%). IR (cm21): 3000, 1750, 1460, 1300. APCI-MS: m/z 5 412
([M1H]1, 100%).
tions were first attempted at 2788C. If no reaction occurred
at this low temperature, the reaction mixture was gradually
warmed to 2108C, then to 08C and in final to ambient tem-
perature until complete starting ketone consumption. The
optimized reaction conditions have been summarized in
Table 1.
The desired b-hydroxyesters 3a-c were purified by flash
chromatography on silica gel. However, in the case of the
hydroxyesters 3b and 3c, partial annulation occurred during
purification leading the lactone 4 (Scheme 1). Lactonisation
proceeded predominantly in the case of the methyl hydrox-
yester 3c. The steric hindrance of the tert- butyl ester group of
3a circumvented the side reaction of lactonisation. Moreover,
both the reduction product and the lactonisation byproduct
present the same diastereomeric excess, excluding a kinetic
control of the cyclisation whatever the diastereomeric alcohol.
(2) (2S,3S)-Ethyl 2,3-dimethyl-6-oxopiperidine-
3-carboxylate 6
A solution of b-aminoester 5a-b (1 equiv) and catalytic amount of Pd/
C in anhydrous MeOH (C 5 0.1 M) was stirred at room temperature for
2 h under an hydrogen atmosphere. The reactive medium was then fil-
tered over celite and the filtrate was concentrated to yield the desired
lactam 6 as yellow oil (69% yield). Rf 5 0.5 (cyclohexane/AcOEt: 8.5/
1.5); 1H NMR: 7.07 (NH), 4.11 (CH2, q, J 57.2), 3.39 (CH, m), 2.43
(CH2,dd, J1 57, J2519), 2.14 (CH2, dd, J1 5 8, J2 5 15), 1.26 (CH3, s),
1.21 (CH3, t, J 57.2), 1.16 (CH3, d, J 56.4); 13C NMR: 174.11171.5
(COO), 60.7 (CH2), 54.8 (CH), 43.5 (Cq), 28.0 (CH2), 27.3 (CH2), 22.0
(CH3), 17.4 (CH3), 14.0 (CH3); [a]D205 214 (c 3.0 in DCM, de 67%). IR
(cm21): 1750, 1672, 1460, 1300. APCI-MS: m/z 5 399 ([2M1H]1, 95%),
200 ([2M1H]1, 100%).
TABLE 1. Diastereoselective reduction of b-ketoesters 2a-c
Yields (%)a
3a-c
Entry
Starting material
Method
Reductive agent and reaction conditions
4
De (%)b
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2b
2c
A
B
C
D
E
F
B
C
C
NaBH4 1 equiv, MeOH 1 equiv THF, 2788C, 9 h
NaBH4 1 equiv/CeCl3 1.3 equiv MeOH, 2788C, 3 h
NaHB(O2CiPr)3 3 equiv toluene, 08C, 7 h
Zn(BH4)2 3 equiv THF 08C, 1 h then 248C, 3 h
L-Selectride 5 equiv THF 248C, 5 h
LiAlH(OtBu)3 1.2 equiv THF 2788C 3 h then 08C, 3 h
NaBH4 1 equiv/CeCl3 1.3 equiv MeOH, 2788C, 3 h
NaHB(O2CiPr)3 3 equiv toluene, 08C, 7 h
65
43
84
44
72
79
41
79
20
–
–
–
24
–
7
11
31
20
17
15
10
23
11
–
6
62
NaHB(O2CiPr)3 3 equiv toluene, 08C, 7 h
aIsolated yields after column chromatography.
bDetermined by 1H NMR.
Chirality DOI 10.1002/chir

268
ALMAHLI ET AL.
chiral centers in the major lacton diastereomer 4. Moreover,
whatever the reaction conditions and the reductive agents
used, the same major diastereomer 4 was observed. As a
result, absolute configuration of the major hydroxyesters 3a-
c were shown to be a (2S, 10R) configuration. The stereo-
chemical outcome of the reduction of ketoester could find an
explanation on the basis of both a cyclic Cram chelated with
Zn(II) or borate intermediate and a nonchelated Felkin-Anh
one (Fig. 1).31
The Cram chelated model led to the major syn diaste-
reomer, the Felkin Anh nonchelated one to the minor anti
diastereomer. Chelated intermediate was slightly preferred
to nonchelated intermediate, giving a mixture of the syn and
anti hydroxyesters. This lack of facial diastereoselectivity
might be due to the quaternary carbon atom in the a-position
which allowed insufficient side differentiation and/or made
such complexation more difficult. Our results confirmed the
previous work of Alvarez-Ibarra et al.,16 which concluded that
the diastereoselectivity was highly dependant of ketoester’s
structure, reducing agent, solvent and additive.
Fig. 1. Chelated versus nonchelated intermediates for ketoesters 2a-c.
Due to the inadequacy of asymmetric induction by the a-
quaternary carbon atom, we studied the influence of an addi-
tionnal chiral center borne by an imino group instead of the
carbonyl moiety.
Use of sodium borohydride gave the desired hydroxyester
3a in good chemical yield but without notable stereoselectiv-
ity (Entry 1), suggesting the poor influence of the stereocon-
trolled quaternary center on the diastereoselectivity in those
conditions. Addition of a chelating agent, such as cerium chlo-
ride did not improve diastereoselectivity or chemical yield
(Entry 2). Likewise, hindered reductive agents, such as L-
selectride and lithium tri-tert-butoxyaluminium hydride did not
allow an enhancement of diastereoselectivity (Entries 5 and
6). From this study, better diastereoselectivities were obtained
using zinc borohydride or NaHB(O2CiPr)3 (Entries 3, 4, 8,
and 9). In this last case, the hindered isobutyrate hydride has
a slight impact on diastereoselectivity, de rising up to 31%. On
the other hand, the reduction by ZnBH4 resulted in an
increasing amount of the nondesired lactone (Entry 4).
The same reducing agents were evaluated on the chiral b-
iminoesters 1a-b (Scheme 2, Table 2). Similarly, the reduc-
tion of the iminoester 1a by sodium borohydride gave the
corresponding amino compound with very poor diastereose-
lectivity (Entry 1). Zn(BH4)2 (Entries 3 and 5), NaHB(O2-
CiPr)3 (Entries 2 and 4), L-selectride (Entry 7) and lithium
tri-tert-butoxyaluminium hydride (Entry 8) reduced iminoes-
ters 1a-c less efficiently than ketoesters 2a-c in terms of
chemical yields. However, the presence of the chiral imine
part caused a global improvement of diastereoselectivity,
comparatively to the corresponding ketoesters. We can also
note that a ZnCl2/NaBH4 mixture33,34 instead of freshly pre-
pared Zn(BH4)2 did not modified neither diastereoselectivity
nor chemical yield (Entries 5 and 6).
Applied to a diastereomerically pure major lacton 4, one
1
and two dimensional H NMR experiments showed a spatial
To evaluate the matched/mismatched diastereomeric pairs
effect on the asymmetric induction, the diastereomeric imi-
noester 10b was prepared in 67% yield according to a method
dedicated to hindered imines synthesis (Scheme 2).35 Never-
correlation between the hydrogen of the tertiary chiral center
and the ester moiety (Scheme 1). These NMR spectroscopy
analyses ascertained the relative configuration of the vicinal
Scheme 2. Reduction of iminoesters 1a-1b and 10b and access to the lactam derivative 6. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com]
Chirality DOI 10.1002/chir

ASYMMETRIC REDUCTION OF ꢀ-KETOESTERS AND ꢀ-IMINOESTERS
269
TABLE 2. Diastereoselective reduction of b-iminoesters 1a-b and 10b
Entry
Starting material
Method
Reductive agent and reaction conditions
Yield (%)a
De (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
A
C
D
C
D
G
E
F
C
D
E
F
NaBH4 1 equiv, MeOH 1 equiv THF, 2788C, 9 h
NaHB(O2CiPr)3 3 equiv THF toluene, 08C, 7 h
Zn(BH4)2 3 equiv THF 08C 1 h then 248C 2 h
NaHB(O2CiPr)3 3 equiv Toluene, 08C, 5 h
Zn(BH4)2 3 equiv THF 08C 1 h then 248C 2 h
NaBH4 6 equiv/ ZnCl2 3 equiv THF, 08C 1 h then 248C 2 h
L-Selectride 5 equiv THF 248C, 5 h
75
82
56
23
49
55
43
34
47
45
46
53
10
50
45
45
32
31
27
18
45
17
67
68
1b
1b
1b
1b
1b
10b
10b
10b
10b
LiAlH(OtBu)3 1.2 equiv THF 2788C 3 h then 08C, 3 h
NaHB(O2CiPr)3 3 equiv Toluene, 08C, 4 h
10
11
12
Zn(BH4)2 3 equiv THF 08C 1 h then 248C 2:30 h
L-Selectridec 5 equiv THF 248C, 5 h
LiAlH(OtBu)3 1.2 equiv THF 2788C 3 h then 08C, 3 h
aIsolated yields after column chromatography.
bDetermined by 1H NMR.
c5 equiv were required to total starting material consumption.
theless, attempts to synthesize the bulky tert-butylester ana-
logue 10a remained fruitless. The reduction of the diastereo-
meric imine 10b led to the diastereomer 50b whose newly cre-
ated stereogenic center possessed the same configuration as
for 5b (Entries 9–12 versus entries 4–7). According
the reducing agents used, the diastereoselective excess was
found to be highly dependent of the chiral imine configuration.
After hydrogenolysis step and subsequent cyclisation of a
diastereomerically enriched aminoester 5b fraction (de 56%),
the corresponding lactam 6 was analyzed by one and two
COSY correlations along with a ‘‘W’’ long range coupling
between the equatorial hydrogen atom borne by the (C3)
carbon atom and the hydrogen atom borne by the tertiary
(C4) chiral center ascertained the absolute configuration
(2S, 10S) of the major aminoester diastereomer 5a-b but also
for 50b, giving the same lactam 6.
By opposition to the ketoester derivatives, the reduction of
the iminoesters provided inversion of the diastereoselectivity
and the anti aminoesters became the major diastereomers.
Consequently, chelated intermediates formation appeared far
less efficient for iminoesters 1a-b than for ketoesters 2a-c.
1
dimensional H NMR experiments (Scheme 2). NOESY and
Scheme 3. Matched and mismatched effect on Non Chelated Felkin Anh Intermediate 1b and 10b.
Chirality DOI 10.1002/chir

270
ALMAHLI ET AL.
8. Daley CJA, Bergens SH. The first complete identification of a diastereo-
meric catalyst-substrate (alkoxide) species in an enantioselective ketone
hydrogenation mechanistic investigations. J Am Chem Soc 2002;124:
3680–3691.
This is in contradiction with previous results described in
the literature but nevertheless for less hindered imino and
enaminoesters.34,36 In our case, the stereochemical outcome
of the reduction reaction affording the major anti diaste-
reomer 5a-b could be explained assuming a predominantly
non chelated Felkin Anh model: the presence of both hin-
dered methylbenzyl moiety on the imino group and the qua-
ternary carbon atom in the a-position prevents the formation
of the cyclic chelated intermediate. Furthermore, with bul-
kier reducing agents, we observed a matched pair effect in
the (R,S)-diastereomer 10b (Entries 7 and 8 versus 11 and
12) which became a mismatched effect with chelating reduc-
ing agent (Entry 5 versus 10) (Scheme 3). So, the action of
L-selectride or lithium tri-tert-butoxyaluminium hydride applied
to 10b allowed the access to aminoester 5b with the best
diastereomeric excesses up to 68%. In the situation of the bul-
kiest reducing agents, the supplementary R-stereocenter borne
by the imino group efficiently overrides the influence of the
S-stereocenter in the substrate: starting from 10b, the selectivity
is dramatically increased in favor of 50b (matched case), while
with the diastereomer 1b, the Felkin and the anti-Felkin
products are formed in near equivalent ratio (mismatched
case). As depicted in Scheme 3, only the seemingly equivalent
steric hindrance of the methyl and the alkyl chain could explain
the matched and mismatched conformations.
9. Hu A, Ngo HL, Lin W. Chiral, porous, hybrid solids for highly enantiose-
lective heterogeneous asymmetric hydrogenation of b-keto esters.
Angew Chem Int Ed 2003;42:6000–6003.
10. Kesanli B, Lin W. Mesoporous silica anchored Ru catalysts for highly
enantioselective hydrogenation of b-ketoesters. Chem Commun 2004;
2284–2285.
11. Makino K, Fujii T, Hamada Y. Rhodium-catalyzes asymmetric hydro-
genation through dynamic kinteic resolution: asymmetric synthesis of
anti-b-hydroxy-a-amino acids esters. Tetrahedron: Asymmetry 2006;17:
481–485.
12. Sawamura M, Kuwano R, Shirai J, Ito Y. Asymmetric hydrosilylation of
keto esters catalyzed by a rhodium complex with trans-chelating chiral
diphosphine EtTRAP. Synlett 1995;347–348.
13. Evans DA, Michal FE, Tedrow JS, Campos KR. Application of chiral
mixed phosphorous/sulfur ligands to enantioselective rhodium-catalyzed
dehydroamino acid hydrogenation and ketone hydrosilylation processes.
J Am Chem Soc 2003;125:3534–3543.
14. Brown HC, Chandrasekharan J, Ramachandran PV. Chiral synthesis via
organoboranes. 14. Selective reductions. 41. Diisopynocamphenylchloro-
borane, an exceptionally efficient chiral reducing agent. J Am Chem Soc
1988;110:1539–1546.
15. Kitazume T, Kobayashi T, Yamamoto T, Yamazaki T. A highly stereocon-
trolled synthetic approach to versatile monofluorinated molecules. J Org
Chem 1987;52:3218–3223.
16. Alvarez-Ibarra C, Csaky AG, Quiroga ML, Ramirez D. Diastereoselective
reduction of a-acyl-N-[bis(methylthio)methylene]alaninates and phenyla-
laninates. Synthesis of a,a-disubstituted b-hydroxy- a-aminoesters. Tetra-
hedron 1997;53:2189–2198.
CONCLUSION
In conclusion, we have studied the influence of a a-quater-
nary chiral carbon atom on the reduction of b-keto and b-imi-
noesters. This work constitutes the first experimental study
of reduction of b-iminoesters bearing a a-quaternary stereo-
controlled center. We have shown that diastereoselectivity
could be inverted starting from b-iminoesters instead of
b-ketoesters, with modest to good diastereoselectivity. Start-
ing from chiral b-iminoesters, we showed that matched/mis-
matched effect using an additional stereogenic center was
highly dependant of the nature of the reductant. Investiga-
tions of this matched/mismatched effect with bulkier chiral
amines on asymmetric induction are ongoing.
17. Nemoto T, Harada T, Matsumoto T, Hamada Y. Pd-Catalyzed enantiose-
lective synthesis of quaternary a-amino acid derivatives using a phenylal-
anine derived P-chirogenic diaminophosphine oxide. Tetrahedron Lett
2007;48:6304–6307.
18. Dietz FR, Gro¨ger H. Novel catalytic synthetic route to protected a-methyl
threonine and the first asymmetric acetyl migration in a Steglich rear-
rangement reaction. Synlett 2008;663–666.
19. Santoro S, Poulsen TB, Jorgensen KA. Enantioselective organocatalytic
subtitutions of a -cyanoacetates on imidoyl chlorides – synthesis of opti-
cally active ketimines. Chem Commun 2007;5155–5157.
20. Gassama A, d’Angelo J, Cave´ C, Mahuteau J, Riche C. Regioselective
annulation of 1,5-diketones: access to functionalized Hagemann’s esters.
Eur J Org Chem 2000;3165–3169.
21. Nour M, Tan K, Jankowski R, Cave´ C. Easy access to optically active
Hagemann’s esters. Tetrahedron: Asymmetry 2001;12:765–769.
ACKNOWLEDGMENTS
22. Hendra F. Ph.D. Dissertation, Re´activite´ d’e´naminoesters chiraux acycliques
vis-a`-vis de la re´action de Michael: application a` la synthe`se de nouveaux
pre´curseurs d’amino et d’hydroxyacides optiquement actifs. Universite´ de
Bourgogne, Dijon, France, 2005.
The authors are grateful to the Syrian government for fi-
nancial support of Hadia Almahli and to Miche`le Danet for
performing mass spectra analyses.
23. Gemal AL, Luche J-L. Lanthanoids in organic synthesis. 6. Reduction of
a-enones by sodium borohydride in the presence of lanthanoid chlorides:
synthetic and mechanistic aspects. J Am Chem Soc 1981;103:5454–5459.
LITERATURE CITED
1. Hasegawa J, Nagashima N. Production of chiral b-hydroxy acids and its
application in organic syntheses. In: Patel RN, editor. Stereoselective bio-
catalysis, New-York: Marecl Dekker; 2000. p 343–363.
24. Xu D, Prasad K, Repic O, Blacklock TJ. A practical synthesis of enantio-
pure ethyl cis-2-amino-1-cyclohexanecarboxylate via asymmetric reduc-
tive amination methodology. Tetrahedron: Asymmetry 1997;8:1445–1451.
2. Cardillo G, Tomasini C. Asymmetric synthesis of b-amino acids and a-
substituted b-amino acids. Chem Soc Rev 1996;25:117–128.
25. Wright K, de Castries A, Sarciaux M, Formaggio F, Toniolo C, Toffoletti
A, Wakselman M, Mazaleyrat J-P. Synthesis and spectroscopic
characterization of enantiopure protected trans-amino-1-oxyl-2,2,6,6-tetra-
methyl piperidine-3-carboxylic acid (trans-b-TOAC) Tetrahedron Lett 2005;46:
5573–5576.
3. Gellman SH. Foldamers: a manifesto. Acc Chem Res 1998;31:173–181.
4. Zhong HM, Cohen JH, Abdel-Magid AF, Kenney BD, Maryanoff CA,
Shah RD, Villani FJ Jr, Zhang F, Zhang X. An efficient stereoselective
synthesis of methyl-(S)-3-amino-3-(3-pyridyl)propanoate. Tetrahedron Lett
1999;40:7721–7725.
26. Narasimhan S, Madhavan S, Ganeshwar Prasad K. Facile reductions of
carboxylic acids to alcohol by zinc borohydride. J Org Chem 1995;60:
5314–5315.
5. Burk MJ, Harper TGP, Kalberg CS. Highly enantioselective hydrogena-
tion of b-keto esters under mild conditions. J Am Chem Soc 1995;117:
4423–4424.
27. Cimarelli C, Palmieri G. Asymmetric reduction of enantiopures imines
with zinc borohydride: stereoselective synthesis of chiral amines. Tetra-
hedron: Asymmetry 2000;11:2555–2563.
6. Yamano T, Taya N, Kawada M, Huang T, Imamoto T. Enantioselective
hydrogenation of b-ketoesters catalyzed by P-chiral bis(dialkylphosphi-
no)ethanes-Ru(II). Tetrahedron Lett 1999;40:2577–2580.
28. Kuwano R, Ito Y. Catalytic asymmetric allylation of prochiral nucleophiles
a-acetamido-b-ketoesters. J Am Chem Soc 1999;121:3236–3237.
7. Blanc D, Ratovelomanana-Vidal V, Gillet J-P, Geneˆt J-P. Asymmetric syn-
thesis of fluorinated b-hydroxy esters via ruthenium-mediated hydrogen-
ation. J Organomet Chem 2000;603:128–130.
29. Ooi T, Miki T, Taniguchi M, Shiraishi M, Takeuchi M, Maruoka K.
Highly enantioselective construction of quaternary stereocenters on b-
Chirality DOI 10.1002/chir

ASYMMETRIC REDUCTION OF ꢀ-KETOESTERS AND ꢀ-IMINOESTERS
271
keto esters by phase-transfer catalytic asymmetric alkylation and Michael
reaction. Angew Chem Int Ed 2003;42:3796–3798.
33. Fustero S, Pina B, de la Torre MG, Navarro A, de Arellano CR, Simon A.
First highly diastereoselective synthesis of syn a-methyl b-fluoroalkyl
b-amino esters. Org Lett 1999;1:977–980.
30. Boireau G, Deberly A. Highly diastereoselective reduction of (-)
menthylphenylglyoxalate and (-) menthylpyruvate using
hindered lithiumtrialkoxyaluminohydrides. Tetrahedron: Asymmetry
1991;2:771–774.
a
new
34. Ohkura H, Handa M, Katagiri T, Uneyama K. Diastereoselective synthe-
sis of S-tert-butyl-b-(trifluoromethyl)isocysteine. J Org Chem 2002;67:
2692–2695.
31. Cawley JJ, Petrocine DV. A study of the lithium aluminium hydride
reduction of a series of nonenolizable ketones. J Org Chem 1976;41:
2608–2611.
35. Moss N, Gauthier J, Ferland J-M. The enantioselective synthesis of neo-
pentylamine derivatives. Synlett 1995;142–144.
36. Cimarelli C, Palmieri G. Stereoselective reduction of enantiopure b-enam-
32. Mengel A, Reiser O. Around and beyond Cram’s rule. Chem Rev 1999;
99:1191–1223.
ino esters by hydride:
b-amino esters. J Org Chem 1996;61:5557–5563.
a convenient synthesis of both enantiopure
Chirality DOI 10.1002/chir