The asymmetric Michael-type alkylation of chiral β-enamino esters: Critical role of a benzyl ester group in the racemization of adducts

Article abstract of DOI:10.1016/j.tetasy.2005.10.034

In contrast with keto diester (R)-10a bearing a methyl ester group at the quaternary carbon center, the benzyl ester analogue (R)-10a partially racemized during workup, thereby revealing that the nature of the ester group at the quaternary carbon center h

Full text of DOI:10.1016/j.tetasy.2005.10.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3853–3857
The asymmetric Michael-type alkylation of chiral
b-enamino esters: critical role of a benzyl ester group
in the racemization of adducts
a
b
a
a
´ ´
Mathieu Pizzonero, Frederic Hendra, Sandrine Delarue-Cochin,
Marie-Elise Tran Huu-Dau,c Franc¸oise Dumas,a, Christian Cave,
*
´
Mohammed Nourb,ꢀ and Jean dꢁAngeloa
a
ˆ
BioCIS, UMR 8076, Centre d’Etude Pharmaceutique, Universite´ Paris-Sud, 5 rue J-B.Cle´ment, 92296 Chatenay-Malabry, France
b
ˆ
Unite´ de Mole´cules d’Inte´ret Biologique, UFR Pharmacie, B.P. 879000, 21079 Dijon, France
cInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Received 20 September 2005; accepted 26 October 2005
Abstract—In contrast with keto diester (R)-10a bearing a methyl ester group at the quaternary carbon center, the benzyl ester
analogue (R)-10a partially racemized during workup, thereby revealing that the nature of the ester group at the quaternary carbon
center has a critical role in the rate of racemization of such Michael adducts.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Me
N
Ph
H
Me
NH
Ph
H
O
Owing to the widespread presence of quaternary carbon
centers (QCCs) in natural products (e.g., terpenes,
steroids, alkaloids), their stereocontrolled elaboration
remains a central challenge of contemporary organic
synthesis. In this respect, the asymmetric Michael reac-
tion involving chiral imines under neutral conditions,
which we disclosed in 1985, has emerged as a simple
and efficient tool for the stereoselective construction of
QCCs.1 Basically, condensation of chiral imines 2,
derived from racemic 2-substituted ketones 1 and enantio-
pure 1-phenylethylamine, to electron-deficient alkenes 4
furnished after hydrolytic workup 2,2-ketones 5 in fair
yields and with high degrees of regio- and stereoselectiv-
ity. It has been established that the nucleophilic partners
involved in this reaction are, in fact the more substituted
secondary enamines 3, in tautomeric equilibrium with
imines 2 (Scheme 1).2
R
R
R
2
1
3
O
EWG
R
4
EWG
3
2
then H3O+
5
Scheme 1.
A great variety of substrates have been successfully used
in this Michael reaction, without alteration of its
remarkable features. The utilization of b-keto ester 1
(R = CO2R0) is of peculiar interest, giving facile access
to highly functionalized chiral synthons, exemplified
by 6 (note that with such substrates, the imine/enamine
tautomeric equilibrium is completely displaced toward
the enamino ester form 3, R = CO2R0).3 However,
because of the significant acidity of the b-keto ester
moiety (pKa ca. 11), subsequent racemization of the
adducts, involving a transient retro-Michael process
may now occur. For instance, after careful distillation
under a reduced pressure, the ee of adduct 6 (originally
P95%) was significantly lowered, reflecting a partial
*
Corresponding author. Tel.: +33 (0)1 46 83 55 63; fax: + 33 (0)1 46
83 57 52; e-mail: francoise.dumas@cep.u-psud.fr
Present address: Laboratoire de Pharmacochimie des Substances
ꢀ
´
´
Naturelles, Universite de la Nouvelle-Caledonie, BP 4477, 98847
Noume´a, New Calendonia.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.034

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M. Pizzonero et al. / Tetrahedron: Asymmetry 16 (2005) 3853–3857
thermal racemization. The presence of a conjugate
aromatic nucleus in the starting b-keto ester notably
enhances its acidity, the interfering retro-Michael
process is now highly favored: adduct 7 of 87% ee
completely racemized within a few weeks, when kept
in the solid state at room temperature (Scheme 2).4
a
H
Ph
Me
RO2C
O
C
N
H
9a,b
RO
O
8a,b
a: R = Me
b: R = Bn
b
RO2C
H
O
c
O
O
MeO2C
CO2Me
CO2Me
CO2Me
O
RO2C
O
O
11b
10a,b
6
7
Scheme 3. Reagents and conditions: (a) (R)-1-phenylethylamine,
Scheme 2.
˚
mixture of basic Al2O3, SiO2, and 5 A molecular sieves (2:1:9),
cyclohexane, 20 ꢁC, 3 days; (b) methyl acrylate, MgBr2, Et2O–THF,
24 h, 20 ꢁC, then 20% aqueous AcOH, 70%; (c) NaBH4, CeCl3Æ7H2O,
MeOH, ꢀ78 ꢁC, then CSA, refluxing toluene, 75%.
Herein, we report that in contrast with adduct (R)-10a,
the benzyl ester analogue (R)-10b partially racemized dur-
ing workup, thereby revealing that the nature of the ester
group at the quaternary carbon center has also a critical
role in the rate of racemization of Michael adducts.
the erosion of selectivity observed with adduct (R)-10b
(Scheme 4).
Me
H
Ph
N
H
2. Results and discussion
O
O
O
a
b
OR
O
OR
Although keto diesters of type 6 constitute particularly
attractive chiral building blocks for the synthesis of
a variety of complex molecules, the critical problem of
discriminating the two ester groups should be resolved.
A conventional solution to this problem would be the
utilization of a benzyl ester group, selectively cleavable
by hydrogenolysis. In this respect, we recently envi-
sioned that Michael adduct (R)-10b to be a key chiral
intermediate in the synthesis of (ꢀ)-cephalotaxine.5
However, although the addition of benzyl enamino ester
(R)-9b to methyl acrylate furnished the desired adduct
(R)-10b with a satisfactory chemical yield of 70%, its
ee, determined by chiral HPLC, was only 55%.
12a,b
13a,b
O
a: R = Me
b: R = Bn
OR
SO2Ph
14a,b
Scheme 4. Reagents and conditions: (a) (S)-1-phenylethylamine,
mixture of basic Al2O3, SiO2, and 5 A molecular sieves (2:1:9),
cyclohexane, 20 ꢁC, 3 days; (b) phenyl vinyl sulfone, refluxing THF,
5 days, then 20% aqueous AcOH, 63% (15a), 80% (15b).
˚
The argument that the decrease in enantioselectivity
observed in the case of adduct (R)-10b does not reflect
a kinetic control, but very likely a subsequent partial
racemization during workup, was strengthened by calcu-
lating the enthalpies of formation of transition states
corresponding to the Re- and Si-approaches in the addi-
tion of enamino ester 9b with methyl acrylate.
The assumption that partial racemization of 10b might
take place during HPLC analysis4 was discarded by con-
verting 10b into ꢂnon-racemizableꢁ bicyclic lactone 11b of
pure cis ring junction by stereoselective reduction of the
keto group followed by lactonization of the resulting
hydroxy-diester. The ee of 11b established by chiral
HPLC was 60%, a value very close to that of progenitor
10b. Since the ee of Michael adduct (R)-10a, the methyl
analogue of (R)-10b, was found to be P95%,5 it is
manifested that the decrease of enantioselectivity
observed in the case of adduct (R)-10b is due to the pres-
ence of the benzyl ester group at the quaternary carbon
center (Scheme 3).
All the RHF AM16 transition structures were located
using the procedures implemented in MOPAC (Version
5.0).7 All variables were optimized by minimizing the
sum of the squared scalar gradients (NLLSQ and SIG-
MA).8,9 Force calculations were carried out to ensure
that the transition structures located had one imagi-
nary frequency. Final values of the gradient norms
However, considering that the addition of acyclic methyl
enamino ester (S)-13a and benzyl analogue (S)-13b
(both of pure Z geometry, secured by the intramolecular
hydrogen bonding) to phenyl vinyl sulfone has furnished
the corresponding adducts (S)-14a and (S)-14b with
similar ees (98% and 94%, respectively, both determined
by chiral HPLC), it is clear that in conjunction with the
presence of the benzyl ester group at the quaternary
carbon center, other structural factors (particularly the
nature of the electron-withdrawing group harbored by
the starting Michael acceptor) are responsible for
˚
were <1 kcal/A and each transition structure had
one negative eigenvalue in the Hessian matrix as
required. The (S)-cis configuration of the methyl
acrylate was chosen for the calculations, since it was
energetically favored over the (S)-trans one.2b
In analogy with computational studies performed earlier
with a related enaminone and methyl acrylate,2c these
calculations revealed a syn-approach of the reactants,
with the endo-arrangement of the ester part of the

M. Pizzonero et al. / Tetrahedron: Asymmetry 16 (2005) 3853–3857
3855
Figure 1. AM1 optimized transition state geometries for diastereomeric approaches of 9 + methyl acrylate; forming C–C and C–H bonds which are
˚
symbolized by dotted lines (distances in A).
between enamino ester (R)-9b and methyl acrylate, suf-
fered from a notable decrease of enantioselectivity
(55%), compared to the typical values obtained in this
series (P95%). This erosion of selectivity, which
involves an interfering retro-Michael process taking
place during workup, was attributed to the presence in
this adduct of the benzyl ester group at the quaternary
carbon center, an assumption strengthened by calculat-
ing the enthalpies of formation of the corresponding
diastereomeric transition states. However, since adduct
(S)-14a and benzyl analogue (S)-14b exhibited similar
ees (98% and 94%, respectively), additional structural
factors should be evoked to rationalize the unusually
facile racemization of (R)-10b.
Table 1. Enthalpies of formation of transition states for addition of
9 + methyl acrylate (kcal/mol)
Benzyl dihedral angle
Re-approach
Si-approach
90ꢁ
180ꢁ
ꢀ90ꢁ
ꢀ79.6a
ꢀ79.1
ꢀ79.3
ꢀ77.0
ꢀ76.8
ꢀ77.3a
a Lowest energy transition states selected in the present study.
acrylate partner (the carbomethoxy group facing the
nitrogen atom of enamino ester 9b), a transition state
structure geometry, which suggests the implication of a
six-membered ꢂaza-ene-synthesis-likeꢁ pericyclic process,
in which the NH proton of the enamino ester is trans-
ferred to the a-vinylic center of methyl acrylate, in a
nearly concerted fashion with the creation of the C–C
bond.2a When methyl acrylate approaches the Re p-face,
the chiral auxiliary moiety adopts a conformation where
the phenyl dihedral angle is about 75ꢁ. Conversely, when
methyl acrylate approaches the Si p-face, in order to
minimize the steric effects the phenyl group is pushed
away from its most stable position (ca. 75ꢁ, a dihedral
angle value encountered in the Re-approach and in the
crystal structure of a related enamino ester),10 resulting
in a dihedral angle of 165ꢁ. Triads of sub-conformers
corresponding to the rotation of the benzyl group
around CH2–O bond (dihedral angles: 90ꢁ, 180ꢁ, and
ꢀ90ꢁ) were also generated. The AM1 optimized transi-
tion state geometries are shown in Figure 1; the enthal-
pies of formation of all the possible transition states are
given in Table 1. The energy difference between the two
more stable competing Re and Si transition states
(DDH = 2.3 kcal/mol) predicts a p-facial discrimination
in favor of the Re-approach with a selectivity of ca.
40:1 (95% ee), a value which is in excellent agreement
with the experimental selectivities obtained by using a
variety of b-enamino esters as nucleophilic partners in
the present asymmetric Michael reaction.1,2
4. Experimental
4.1. General
Diethyl ether and tetrahydrofuran (THF) were distilled
over Na-benzophenone ketyl. Crude products were puri-
fied by column chromatography on silica gel of 60–120
mesh. IR were recorded on a Bruker VECTOR 22 spec-
1
trometer. The H NMR and 13C NMR spectra were
recorded in CDCl3 solution on a Bruker AC 200 or Bru-
ker Avance 300 spectrometer (200 and 50 MHz, or 300 and
75 MHz, for 1H and 13C, respectively). Optical rotations
were measured at 589 nm in a 1 dm-cell on a Optical
Activity Limited AA-10R. For unambiguous assign-
ment of enantiomers in chiral HPLC, comparisons were
made in all cases with the corresponding racemates. Ele-
mental analyses were performed by the Service de Micro-
analyse, Centre dꢁEtudes Pharmaceutiques, Chatenay-
Malabry, France, with a Perkin–Elmer 2400 analyzer.
4.2. General procedure for the preparation of enamino
esters 9, 13a, and 13b
To a mixture of 2 g of basic aluminum oxide, 1 g of silica
˚
3. Conclusion
gel (230–400 mesh) and 9 g of powdered 5 A molecular
sieves was added a solution of 30 mmol of keto ester
and 35 mmol of enantiopure 1-phenylethylamine in
20 mL of cyclohexane. The resulting slurry was stirred
In conclusion, we have demonstrated that adduct
(R)-10b, resulting from the asymmetric Michael addition

3856
M. Pizzonero et al. / Tetrahedron: Asymmetry 16 (2005) 3853–3857
at 20 ꢁC under nitrogen for 3 days and filtered through a
pad of Celite. The organic layers were concentrated in
vacuo and the excess chiral amine removed by distilla-
tion (0.05 Torr, oil bath 50 ꢁC). The residual enamino
ester was engaged in the next stage without further
purification.
4.2.3.
(S)-2-(2-Benzenesulfonylethyl)-3-methyl-3-oxo-
butyric acid methyl ester 14a. A stirred solution of
enamine 13a (10 mmol) and phenyl vinyl sulfone
(14 mmol) in 50 mL of THF was refluxed under nitrogen
for 5 days. The same workup procedure used to prepare
10 (Section 4.2.1) was applied. Chromatography over
silica gel (ethyl acetate –cyclohexane 1:2) gave 14a as
an oil; yield 63%; [a]D = ꢀ26.0 (c 0.88, CHCl3); IR
4.2.1. (R)-3-(1-Carbobenzyloxy-2-oxocyclopentyl)-propa-
noic acid methyl ester 10. To a stirred solution of mag-
nesium bromide in Et2O [prepared by dropwise addition
of 28.5 mmol of 1,2-dibromoethane to 27 mmol of mag-
nesium in Et2O (40 mL)] were added enamino ester 9
(26 mmol) in Et2O (50 mL) and methyl acrylate
(34 mmol) in THF (10 mL). The resulting mixture was
stirred for 1 day at 20 ꢁC, after which 100 mL of 20%
aqueous acetic acid was added. The mixture was stirred
for an additional 1 day at 20 ꢁC. The solvents were
removed under reduced pressure and 1 M hydrochloric
acid (20 mL) then added. The mixture was extracted
with Et2O (4 · 100 mL) and the combined organic layers
washed with brine, dried over MgSO4, and concen-
trated. Chromatography of the residue over silica gel
(ethyl acetate–cyclohexane 1:4) afforded keto ester 10
as an oil; yield 70%; [a]D = ꢀ1.4 (c 2.82, AcOEt);11 IR
(neat, cmꢀ1): 1735, 1715; H NMR (CDCl3, 300 MHz)
1
d: 7.91 (m, 2H), 7.64 (m, 3H), 3.71 (s, 3H), 3.10 (m,
2H), 2.16 (m, 2H), 2.11 (s, 3H), 1.34 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d: 204.0 (C); 172.0 (C), 138.4 (C),
133.8 (CH), 129.2 (2CH), 127.9 (2CH), 58.0 (C), 52.7
(CH3), 51.7 (CH2), 27.6 (CH2), 25.9 (CH3), 19.2 (CH3).
Anal. Calcd for C14H18O5S: C, 56.36; H, 6.08. Found:
C, 56.66; H, 6.19. HPLC analysis (Daicel Chiralcel AD,
eluent: 4% isopropanol in hexane): two peaks in the ca
100:1 ratio, minor isomer tR 54.2 min, major isomer tR
56.3 min.
4.2.4.
(S)-2-(2-Benzenesulfonylethyl)-3-methyl-3-oxo-
butyric acid benzyl ester 14b. The same procedure used
to prepared 14a (Section 4.2.3) was applied. 14b: oil;
yield 80%; [a]D = ꢀ16.4 (c 1.64, CHCl3), IR (neat,
cmꢀ1): 1738; 1717; 1H NMR (CDCl3, 300 MHz) d:
7.84 (m, 2H), 7.64 (s, 1H), 7.53 (m, 2H), 7.32 (m, 5H),
5.13 (s, 2H), 3.03 (m, 2H), 2.17 (m, 2H), 2.02 (s, 3H),
1.32 (s, 3H). 13C NMR (CDCl3, 75 MHz) d: 203.9 (C),
171.3 (C), 138.5 (C), 134.7 (C), 133.8 (CH), 129.3
(2CH), 128.6 (2CH), 128.6 (CH), 128.4 (2CH), 127.9
(2CH), 67.4 (CH2), 58.1 (C), 51.7 (CH2), 27.6 (CH2),
25.9 (CH3), 19.3 (CH3). Anal. Calcd for C20H22O5S:
C, 64.15; H, 5.92. Found: C, 64.22; H, 6.02. HPLC anal-
ysis (Daicel Chiralcel AD, eluent: 4% isopropanol in
hexane): two peaks in the 32:1 ratio, minor isomer tR
39.9 min, major isomer tR 44.1 min.
1
(neat, cmꢀ1): 1729; H NMR (CDCl3, 200 MHz) d: 7.4–
7.3 (m, 5H), 5.17 (d, J = 12.4 Hz, 1H), 5.13 (d,
J = 12.4 Hz, 1H), 3.66 (s, 3H), 2.54–1.86 (m, 10H);
13C NMR (CDCl3, 50 MHz) d: 214.0 (C), 173.3 (C),
170.8 (C), 135.4 (C), 128.6 (2CH), 128.3 (CH), 127.9
(2CH), 67.0 (CH2), 59.3 (C), 51.6 (CH3), 37.8 (CH2),
33.6 (CH2), 29.5 (CH2), 28.4 (CH2), 19.5 (CH2). Anal.
Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C,
67.01; H, 6.61. HPLC analysis (Daicel Chiralcel OD,
eluent: 20% AcOEt in cyclohexane): two peaks in the
3.4:1 ratio, major isomer tR 9.9 min, minor isomer tR
11.8 min.
4.2.2. (1aS,4aR)-2-Oxo-hexahydro-cyclopenta(b)pyran-
4a-carboxylic acid benzyl ester 11. To a solution of
4.9 mmol of keto ester 10 in 30 mL of methanol was
added 7.9 mmol of cerium chloride heptahydrate. The
mixture was stirred for 1 h at 20 ꢁC and then cooled to
ꢀ78 ꢁC. Sodium borohydride (4.9 mmol) was added
over a period of 45 min. The mixture was poured into
1 M hydrochloric acid (10 mL) and extracted with ethyl
acetate (50 mL). The organic layers were washed with a
satured aqueous solution of sodium hydrogencarbonate
(10 mL), dried over MgSO4, and concentrated. A solu-
tion of camphorsulfonic acid (150 mg) in 90 mL of tolu-
ene was added, the resulting mixture refluxed for 15 h,
and the solvent removed under vacuo. Chromatography
of the residue over silica gel (ethyl acetate–cyclohexane
1:2) afforded lactone ester 11 as an oil; yield 75%; IR
(neat, cmꢀ1): 1723; 1H NMR (CDCl3, 200 MHz) d:
7.41–7.30 (m, 5H), 5.47 (m, 2H), 5.33 (dd, J = 5.9,
3.4 Hz, 1H), 2.53–1.64 (m, 10H); 13C NMR (CDCl3,
50 MHz) d: 174.2 (C), 171.9 (C), 135.1 (C), 128.3
(2CH), 127.9 (CH), 127.6 (2CH), 84.1 (CH), 66.7
(CH2), 51.3 (C), 36.2 (CH2), 33.3 (CH2), 28.0 (CH2),
27.9 (CH2), 22.3 (CH2). HPLC analysis (Daicel Chiral-
cel OD, eluent: 20% AcOEt in cyclohexane): two peaks
in the 4:1 ratio, minor isomer tR 11.9 min, major isomer
tR 13.0 min.
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