Asymmetric synthesis of β-amino acids through application of chiral sulfoxide

Article abstract of DOI:10.1016/S0957-4166(01)00185-9

This paper describes asymmetric synthesis of β-aminophenylpropionic acid through application of a homochiral sulfoxide auxiliary. High kinetically controlled (3R,2S,R^S)-diastereoselectivity (-60°C) is achieved during addition of the lithium enolate of tert-butyl (+)-(R)-p-toluenesulfinylacetate to substituted N-(benzylidene)toluene-4-sulfonamides 2a-2d. The reductive cleavage of adduct 3a with sodium amalgam yielded tert-butyl 3-(toluene-4-sulfonamido)-3-phenylpropionate 5a, which was subjected to ester hydrolysis and subsequent detosylation with sodium in liquid ammonia to yield (S)-β-aminophenylpropionic acid in good yield and high 91% e.e.

Full text of DOI:10.1016/S0957-4166(01)00185-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1095–1099
Asymmetric synthesis of b-amino acids through application of
chiral sulfoxide
A. V. Sivakumar, G. S. Babu and Sujata V. Bhat*
Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400 076, India
Received 16 April 2001
Abstract—This paper describes asymmetric synthesis of b-aminophenylpropionic acid through application of a homochiral
sulfoxide auxiliary. High kinetically controlled (3R,2S,RS)-diastereoselectivity (−60°C) is achieved during addition of the lithium
enolate of tert-butyl (+)-(R)-p-toluenesulfinylacetate to substituted N-(benzylidene)toluene-4-sulfonamides 2a–2d. The reductive
cleavage of adduct 3a with sodium amalgam yielded tert-butyl 3-(toluene-4-sulfonamido)-3-phenylpropionate 5a, which was
subjected to ester hydrolysis and subsequent detosylation with sodium in liquid ammonia to yield (S)-b-aminophenylpropionic
acid in good yield and high 91% e.e. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Application of the chiral sulfoxide group as a chiral
auxiliary provides unique synthetic benefits associated
with its manifold reactivity. The use of chiral sulfoxide
stabilized carbanions for asymmetric carbonꢀcarbon
bond formation via alkylation, or addition to carbonyl
and activated CꢁC double bonds has been extensively
studied over the past two decades.9 In contrast, there
are few reports on chiral sulfoxide anion addition to
imines. One example of this type of reaction is the
asymmetric synthesis of a-arylglycinols via the addition
of lithium p-tolylsulfoxide to N-(PMP) arylaldimines,
followed by ‘non-oxidative’ Pummerer rearrangement.10
This led us to examine the condensation of tert-butyl
(+)-(R)-p-toluenesulfinylacetate to various sulfonyl-
imines. We report herein our efforts towards the syn-
thesis of chiral b-amino-b-phenylpropionic acid deriva-
tives.
Peptides containing b-amino acids have recently
attracted considerable interest due to their interesting
structural and important pharmacological properties.
In particular, most b-amino acids themselves exhibit
powerful antibacterial properties and are key con-
stituents of many naturally occurring peptides, terp-
enes, alkaloids, macrolide and b-lactam antibiotics.1,2
Moreover, there has been a recent surge of research
activity in the taxol related terpenoids containing the
(2R,3S)-b-amino-a-hydroxyphenylpropionic acid side
chain, which is known to be crucial to their anti-cancer
activity.3
In view of the potential biological applications of b-
amino acids, their synthesis in enantiomerically pure
form is necessary and considerable effort has been
expended to design stereocontrolled methods for their
synthesis. However, only few reports describe satisfac-
tory methods for the asymmetric synthesis of b-amino
acids. They include the Michael addition of chiral
amines to cinnamate esters,4,5 the addition of methyl
acetate lithium enolates to chiral sulfinimines,6 the bio-
catalytic reduction of b-amino-a-keto-phenylpropion-
ates7 and the biocatalytic preparation of enantiomeri-
cally pure b-aryl-b-alanines via resolution of their
racemic N-phenylacetyl derivatives by penicillin acylase
(EC 3.5.1.11) from Escherichia coli ATCC 9631.8
2. Results and discussion
An elegant synthesis of b-amino acids has been
achieved by the condensation of tert-butyl (+)-(R)-p-
toluenesulfinylacetate with N-sulfonylimines at −60°C
in the presence of LDA in THF. The requisite tert-
butyl (+)-(R)-p-toluenesulfinylacetate 1 was synthesized
by nucleophilic displacement of (S)-aryl-menthyl-sulfi-
nate using Anderson’s method.11
The sulfonylimines 2a–2d were synthesized in good
yields from direct condensation of aromatic aldehyde
and p-toluene-sulfonamide in the presence of acidic
,
amberlite IR-120 resin and 4 A molecular sieve in
* Corresponding author. E-mail: svbhat@chem.iitb.ernet.in
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00185-9

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A. V. Si6akumar et al. / Tetrahedron: Asymmetry 12 (2001) 1095–1099
toluene at 120°C with azeotropic removal of water.12
Addition of the lithium enolate of tert-butyl (+)-(R)-p-
toluenesulfinylacetate (1.97 mmol scale) generated with
1.2 equivalents of LDA at −60°C to the imines 2a–2d
(2.16 mmol) in THF under kinetic conditions afforded
the syn (3R,2S,RS)-adducts 3a–3d, with the minor anti
(3S,2S,RS)-diastereoisomer 4a–4d. Total yields for the
reaction ranged from 68 to 95% (Scheme 1).
and the imine 2a was repeated at −20°C. As expected,
this reaction yielded 3a and the anti diastereoisomer 4a
in a 7:3 ratio (82% combined yield). The latter com-
pound was isolated by column chromatography over
silica. The stereochemistry of compound 4a was
1
assigned by the H NMR coupling constant of the Ha
and Hb protons (Ja,b=10 Hz).
Formation of the syn isomer, (3R,2S,RS)-3a, as the
major diastereoisomer can be rationalized by the Zim-
merman–Traxler transition state model,13,14 which
involves attack of the stable lithium (Z)-enolate of
tert-butyl (+)-(R)-p-toluenesulfinylacetate on the Si
face of the N-sulfonylimine leading to a cyclic transi-
tion state wherein Li+ chelation between sulfoxide and
enolate oxygens and sulfonylimine nitrogen forms
The structure and stereochemistry of the adducts 3a–3d
1
were assigned based on H NMR spectral data. The
coupling constant (J) of the Ha and Hb protons of the
adducts 3a–3d ranges from 5.12 to 5.49 Hz, which
indicated the syn stereochemistry of the (3R,2S,RS)-
1
configuration. The specific rotation [h]2D0 and H NMR
coupling constant values of the adducts 3a–3d are given
in Table 1. The diastereomeric excess (d.e.) of com-
pounds 3a–3d was evaluated by chiral HPLC
(Chiracel® OD analytical column) with hexane/propan-
2-ol (ratio 4:1) as the mobile phase.
a
six-membered chair conformation (Fig. 1a).
Attack on the Re face of the N-sulfonylimine leads
to the anti (3S,2S,RS)-diastereoisomer (Fig. 1b).
Here the 1,3-diaxial repulsions of R/tert-BuO and p-
tol-SO/p-tol-SO2 disfavor formation of the anti
diastereoisomer.
To improve the yield of the anti diastereoisomer 4a the
reaction of tert-butyl (+)-(R)-p-toluenesulfinylacetate
Scheme 1. Synthesis of enantioselective (S)-b-amino-b-phenylpropionic acid from tert-butyl (+)-(R)-p-toluenesulfinylacetate and
N-(benzylidine)toluene-4-sulfonamides 2a–2d. Keys: (i) LDA, THF, −60°C; (ii) Na/Hg, Na2HPO4, 0°C to rt; (iii) KOH, ethanol,
60°C; (iv) Na/liq. NH3, 3 h reflux.
Table 1. 1H NMR coupling constants, yields and specific rotations of compounds 3a–3d
S. No.
R
Yield (%)
D.e. (%)a
[h]2D0 (c 1.00, acetone)
l Ha
l Hb
Ja,b (Hz)
3a
3b
3c
3d
C6H5
95
79
68
81
91.52
88.45
92.72
88.78
80.99
63.49
96.49
3.57
3.53
3.56
3.51
4.70
4.64
4.71
4.65
5.12
5.13
5.49
5.13
4-MeO-C6H4
3,4-di MeO-C6H3
4-Cl-C6H4
120.99
a D.e. was measured by chiral HPLC (Chiracel® OD analytical column).

A. V. Si6akumar et al. / Tetrahedron: Asymmetry 12 (2001) 1095–1099
1097
reaction flask and the mixture was stirred at 120°C for
12 h, with azeotropic removal of water. After the
reaction was complete (based upon the theoretical
amount of water removal, and monitoring reaction by
TLC), the mixture was allowed to cool at room temper-
ature and filtered. The solvent was removed in vacuo
and the product was purified by crystallization from
n-hexane. Imines 2a–2d are solids, recrystallized from
ethyl acetate, hexane solvents. Quantitative yields were
obtained.
Figure 1. Chelated cyclic transition state for the formation of
diastereoisomer 3a–3d with configuration (3R,2S,RS) and 4a–
4d with configuration (3S,2S,RS).
4.3. General method for condensation of the lithium
enolate of tert-butyl (+)-(R)-p-toluene sulfinylacetate
with N-(benzylidene)toluene-4-sulfonamides
Compound 3a was subjected to reductive cleavage of
the sulfoxide moiety by treatment with Na/Hg in dry
methanol to give 5a in 95% yield {[h]2D0=−14.0 (c=1.0,
acetone)}. Basic hydrolysis of 5a yielded acid 6a which
on subsequent detosylation with Na in liquid ammonia,
followed by purification over ion exchange chromatog-
raphy gave (S)-b-amino-b-phenylpropionic acid 7a with
an e.e. of 91% {[h]2D0=−6.9 (c 1.0, H2O), lit.15 [h]D25=
−7.5 1 (c 1.0, H2O)}.
A solution of tert-butyl (+)-(R)-p-toluenesulfinylacetate
(0.5 g, 1.97 mmol) in dry THF (2 mL) was added
dropwise with stirring to a solution of LDA (2.36
mmol) in THF (10 mL) at −60°C. After 15 min, a
solution of the N-(benzylidene)toluene-4-sulfonamide
(2.16 mmol) 2a–2d in THF (3 mL) was added to the
reaction mixture and stirring was continued for a fur-
ther 15 min. The reaction was quenched with saturated
aqueous NH4Cl, and the solvent was removed in vacuo.
The residue was extracted with ethyl acetate. The
organic layer was dried over Na2SO4 and the solvent
was evaporated in vacuo to give a white residue, which
was further purified by column chromatography over
silica gel (100–200 mesh). Elution with petroleum ether/
ethyl acetate (7:3) yielded the adducts 3a–3d,
respectively.
3. Conclusion
In summary, we have developed an efficient method for
the enantioselective synthesis of b-amino-b-phenylpro-
pionic acid. High kinetically controlled (3R,2S,Rs)-
diastereoselectivity was observed during addition of the
lithium enolate of tert-butyl (+)-(R)-p-toluenesulfinyl-
acetate to substituted N-sulfonylimines 2a–2d. The final
compound 7a was obtained with 91% e.e.
4.3.1. Compound 3a. White solid, mp 172–174°C;
1
[h]2D0=+81.0 (c 1.00, acetone); H NMR (CDCl3, 300
MHz): l 1.27 (s, 6H), 1.60 (s, 3H), 2.31 (s, 3H), 2.43 (s,
3H), 3.57 (d, J=5.12 Hz, 1H), 4.70 (dd, J=5.12, 8.4
Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.05 Hz,
2H), 7.15–7.02 (m, 5H), 7.36 (d, J=8.40 Hz, 2H), 7.46
(d, J=8.05 Hz, 2H), 7.58 (d, J=8.05 Hz, 2H). IR
(KBr): 3230, 2934, 1736, 1710, 1341, 1163 cm−1. Anal.
calcd for C27H31NO5S2: C, 63.13; H, 6.08; N, 2.72.
Found: C, 62.89; H, 6.04; N, 2.46%.
4. Experimental
4.1. General methods
All solvents were purified by standard procedures. IR
spectra were run on a Perkin–Elmer model 681 spec-
trometer. H NMR spectra were recorded on a Varian
1
4.3.2. Compound 4a. White solid, mp 193–195°C;
1
[h]2D0=+121.0 (c 1.00, acetone); H NMR (CDCl3, 500
(300 MHz) spectrometer in CDCl3 and D2O with TMS
as internal standard. Chemical shifts (l) are reported in
parts per million (ppm) of the applied field and cou-
pling constants (J) are expressed in Hertz (Hz). Optical
rotations were measured using a Jasco DIP-370 digital
polarimeter. Microanalyses were performed using a
Carlo Erba Model 1106 elemental analyzer. Melting
points are uncorrected and were obtained on a capillary
apparatus. Silica gel (100–200 mesh) used for column
chromatography was activated by heating at 120°C for
4 h.
MHz): l 1.08 (s, 9H), 2.34 (s, 3H), 2.46 (s, 3H), 3.89 (d,
J=10 Hz, 1H), 4.98 (dd, J=10, 6 Hz, 1H), 6.44 (d,
J=6 Hz, 1H), 7.03 (d, J=8 Hz, 2H), 7.07–7.13 (m,
5H), 7.34 (d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.53
(d, J=8 Hz, 2H). IR (KBr): 3236, 2934, 1716, 1611,
1347, 1150 cm−1. Anal. calcd for C27H31NO5S2: C,
63.13; H, 6.08; N, 2.72. Found: C, 63.10; H, 6.06; N,
2.70%.
4.3.3. Compound 3b. White solid, mp 154–156°C;
1
[h]2D0=+63.50 (c 1.00, acetone); H NMR (CDCl3, 300
4.2. General procedure for the preparation of N-(benz-
ylidene)toluene-4-sulfonamides 2a–2d
MHz): l 1.29 (s, 9H), 2.32 (s, 3H), 2.44 (s, 3H), 3.53 (d,
J=5.12 Hz, 1H), 3.71 (s, 3H), 4.63–4.66 (m, 1H), 6.48
(d, J=8.79 Hz, 1H), 6.81 (d, J=8.42 Hz, 2H), 7.06 (d,
J=8.05 Hz, 2H), 7.35 (d, J=7.68 Hz, 2H), 7.46 (d,
J=8.05 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H). IR (KBr):
3361, 3262, 2933, 1723, 1618, 1308, 1163 cm−1. Anal.
calcd for C28H33NO6S2: C, 61.85; H, 6.12; N, 2.57.
Found: C, 61.84; H, 6.14; N, 2.55%.
A solution of the aldehyde (17 mmol) in toluene (70
mL) was placed in a round bottomed flask equipped
with a Dean Stark assembly. p-Toluenesulfonamide
(3.25 g, 19 mmol), amberlite H+ resin IR-120 (2 g) and
,
powdered molecular sieves (4 A, 2 g) were added to the

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A. V. Si6akumar et al. / Tetrahedron: Asymmetry 12 (2001) 1095–1099
4.3.4. Compound 3c. White solid, mp 158–160°C; [h]2D0=
reaction mixture was extracted with ether (5×20 mL).
The aqueous portion was evaporated to dryness in
vacuo. The hydrochloride of b-amino-b-phenylpropi-
onic acid was obtained contaminated with other inor-
ganic impurities. The hydrochloride was dissolved in
water and filtered through a column of strong acidic
ion-exchange resin (5 g, amberlite IR-120, H+ form)
using first water (100 mL) and then 1N ammonia (200
mL) as eluents. Evaporation of the ammonia gave free
amino acid 7a (100 mg, 77%); mp 215–217°C [Lit.16 for
(S)-7a, mp 216°C], [h]2D0=−6.9 (c=1.00, H2O). [Lit.15
1
+96.50 (c 1.00, acetone); H NMR (CDCl3, 300 MHz):
l 1.30 (s, 9H), 2.31 (s, 3H), 2.44 (s, 3H), 3.56 (d,
J=5.49 Hz, 1H), 3.6 (s, 3H), 3.8 (s, 3H), 4.7 (m, 1H),
6.35–6.48 (m, 3H), 6.59 (d, J=8.24 Hz, 1H), 7.04 (d,
J=8.05 Hz, 2H), 7.36 (d, J=8.05 Hz, 2H), 7.44 (d,
J=8.24 Hz, 2H), 7.60 (d, J=8.24 Hz, 2H). IR (KBr):
3247, 2927, 1729, 1611, 1341, 1268, 1156 cm−1. Anal.
calcd for C29H35NO7S2: C, 60.71; H, 6.14; N, 2.44.
Found: C, 60.68; H, 6.12; N, 2.40%.
1
4.3.5. Compound 3d. White solid, mp 120–122°C;
for (S)-7a, [h]2D5=7.5 1]; H NMR (D2O, 300 MHz): l
1
[h]2D0=+121.0 (c 1.00, acetone); H NMR (CDCl3, 300
2.88 (dd, J 16, 7 Hz, 1H, 1/2CH2), 2.98 (dd, J 16, 8 Hz,
1H, 1/2CH2), 4.69–4.85 (m, 1H), 7.48–7.61 (m, 5H). IR
(KBr): 2612, 2205, 1625, 1580 cm−1.
MHz): l 1.28 (s, 9H), 2.35 (s, 3H), 2.44 (s, 3H), 3.51 (d,
J=5.12 Hz, 1H), 4.65 (m, 1H), 6.60 (d, J=8.42 Hz,
1H), 6.85 (d, J=8.42 Hz, 2H), 7.03–7.05 (m, 4H), 7.36
(d, J=8.06 Hz, 2H), 7.46 (d, J=8.06 Hz, 2H), 7.58 (d,
J=8.42 Hz, 2H). IR (KBr): 3357, 3259, 2922, 1722,
1596, 1341, 1164 cm−1. Anal. calcd for C27H30NO5S2Cl:
C, 59.16; H, 5.51; N, 2.55. Found: C, 58.94; H, 5.48; N,
2.34%.
Acknowledgements
We thank DST for the financial support and RSIC, IIT
Mumbai and TIFR for spectral data.
4.4. Preparation of tert-butyl 3-(4-toluenesulfonamido)-
3-phenylpropanoate 5a
To a mixture of adduct 3a (500 mg, 0.974 mmol) and
anhydrous disodium hydrogen phosphate (550 mg, 3.89
mmol) in dry methanol (30 mL) at 0°C was added
pulverized sodium amalgam (2 g). The solution was
stirred for 20 min at 0°C and the mixture was allowed
to warm to room temperature. Stirring was continued
for another 0.5 h and the reaction mixture was poured
into water and extracted with ethyl acetate. The organic
extract was dried over Na2SO4. The solvent was evapo-
rated in vacuo and the residue was purified by chro-
matography over silica gel (100–200 mesh), elution with
ethyl acetate/petroleum ether (1:9), yielded tert-butyl
3-(4-tolenesulfonamido)-3-phenylpropanoate 5a as a
white crystalline solid (348 mg, 95%), mp 104–106°C;
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[h]2D0=−14.0 (c 1.00, acetone); H NMR (CDCl3, 300
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