A practical and efficient preparation of (S)-2-benzylsuccinic acid: A key acid synthon of KAD-1229

Article abstract of DOI:10.1081/SCC-200025625

This report describes a practical and an efficient synthesis of (S)-2-benzyl-succinic acid, which was employed as a key intermediate for hypoglycemic KAD-1229 by means of asymmetric alkylation of N-acylsultam. The condensation of D-(-)-camphorsultam with 3-phenylpropionyl chloride gave N-acylsultam 1. N-acylsultam 1 reacted with 1.1 equimolar amount of sodium amide base to form chiral enolate, followed by alkylation with tert-butyl bromoacetate to afford 2. Cleavage of ester and saponification with H ₂O₂-LiOH provided the desired compound 5 with excellent yield and high optical purity.

Full text of DOI:10.1081/SCC-200025625

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A Practical and
Efficient Preparation of
(S)‐2‐Benzylsuccinic Acid: A
Key Acid Synthon of KAD‐1229
Jian‐Chao Liu a , Yu‐She Yang a & Ru‐Yun Ji a
a State Key Laboratory of Drug Research , Shanghai
Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences ,
Shanghai, 201203, P.R. China
Published online: 10 Jan 2011.
To cite this article: Jian‐Chao Liu , Yu‐She Yang & Ru‐Yun Ji (2004) A Practical and
Efficient Preparation of (S)‐2‐Benzylsuccinic Acid: A Key Acid Synthon of KAD‐1229,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:14, 2633-2640, DOI: 10.1081/SCC-200025625
To link to this article: http://dx.doi.org/10.1081/SCC-200025625
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2633–2640, 2004
A Practical and Efficient Preparation of (S)-
2-Benzylsuccinic Acid: A Key Acid Synthon
of KAD-1229
*
Jian-Chao Liu, Yu-She Yang, and Ru-Yun Ji
State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai, P.R. China
ABSTRACT
This report describes a practical and an efficient synthesis of (S)-2-benzyl-
succinic acid, which was employed as a key intermediate for hypogly-
cemic KAD-1229 by means of asymmetric alkylation of N-acylsultam.
The condensation of D-(2)-camphorsultam with 3-phenylpropionyl
chloride gave N-acylsultam 1. N-acylsultam 1 reacted with 1.1 equimolar
amount of sodium amide base to form chiral enolate, followed by alkyl-
ation with tert-butyl bromoacetate to afford 2. Cleavage of ester and
*
Correspondence: Yu-She Yang, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, Shanghai 201203, P.R. China; Fax: 86-21-50806786; E-mail:
ysyang@mail.shcnc.ac.cn.
2633
DOI: 10.1080/SCC-200025625
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2634
Liu, Yang, and Ji
saponification with H2O2–LiOH provided the desired compound 5 with
excellent yield and high optical purity.
Key Words: KAD-1229; (S)-2-Benzylsuccinic acid; Camphorsultam.
INTRODUCTION
KAD-1229 (Fig. 1) is a novel hypoglycemic agent with a chemical structure
different from that of the sulfonylureas, which has a rapid-onset but short-lasting
hypoglycemic effect compared with sulfonylureas. KAD-1229 inhibits the
ATP-sensitive potassium channels in pancreatic b-cell and stimulates insulin
secretion like sulfonylureas.[1] The stereochemistry of the asymmetric carbon
in the propionyl group is very important for the activity of the compound and
the (S)-absolute configuration is necessary for the insulin secretory effect.
Recently, KAD-1229 has been in phase III clinical trials in Japan and
in phase II clinical trials in Europe and in the USA for the treatment of type
2 diabetes and expected to be launched in near future. Two different
procedures were used to obtain KAD-1229 from (S)-2-benzylsuccinic acid
(Schs. 1 and 2).[2] The preparation of (S)-2-benzylsuccinic acid has been
reported previously by means of catalytic asymmetric hydrogenation.[3] We
report here a practical and an efficient synthetic strategy for the preparation
of (S)-2-benzylsuccinic acid by using Oppolzer’s camphorsultam as chiral
auxiliary with 68% overall yield and high optical purity.
RESULTS AND DISCUSSION
Stobbe condensation of benzaldehyde with diethyl succinate and saponi-
fication led to benzylidenesuccinic acid. Asymmetric hydrogenation for
the preparation of benzylsuccinic acid according to the literatures
required a chiral diphosphine complex of rhodium or ruthenium such as
Ru2Cl4((þ)-BINAP)2(NEt3), RuHCl ((þ)-BINAP)2, and Rh(COD)Cl2(MOD-
Figure 1. Structure of KAD-1229.

Synthesis of (S)-2-Benzylsuccinic Acid
2635
Scheme 1.
DIOP).[3] The highest ee was noted about 90% in the productions, however
these chiral catalysts are unstable and expensive.
We considered Oppolzer’s camphorsultam served as efficient, versatile,
and practical chiral auxiliary. A highly p-face-selective alkylation of
enolates followed by nondestructive removal of the auxiliary afforded a
highly optically active carboxylic acid. The products could be purified by
crystallization. Recycling of the auxiliary after removal is often practical.
The process for the preparation of (S)-2-benzylsuccinic acid (Sch. 3) starts
from D-(2)-camphorsultam, readily available in 85% yield from the
Scheme 2.

2636
Liu, Yang, and Ji
Scheme 3. Reagents and conditions: (a) NaH, tol., r.t., 91% or CH3CN, refluxing,
10 hr, 89%; (b) NaHMDS, tert-butyl bromoacetate, HMPA, THF, 278–08C, 16 hr,
92%; (c) TFA, CH2Cl2, 87–100%; (d) LiOH, aqueous THF, 30% H2O2, 93%.
natural D-camphor.[4] Treatment of D-(2)-camphorsultam with an excess of
3-phenylpropionyl chloride in the presence of NaH in toluene at room temp-
erature gave 1 in 91% yield.[5] An alternative procedure was performed by
refluxing D-(2)-camphorsultam with 1.1–1.5 equimolar 3-phenylpropionyl
chloride in CH3CN for 8–10 hr.[6] The crude product was then easily purified
by recrystallization from EtOH/H2O in 89% yield. Acylsultam 1 reacted with
the organic base in THF to form chiral enolate in dry ice/ethanol bath, fol-
lowed by alkylation with tert-butyl bromoacetate to give 2. We next examined
the effects of the organic base. The reaction was performed using n-BuLi as
base and gave the desired alkylated production in about 30–40% yield.
Under the same conditions, the reaction using lithium diisopropylamine
(LDA) or sodium hexamethyldisilazide (NaHMDS) gave the product 2 in
60% and 92% yield recrystallized from methanol, respectively. Alkylation
process employing these bases has exhibited high diastereoselectivity and dia-
stereomeric purity of crude product 2, determined to be more than 93%.
However, the reaction using NaHMDS as base proceeded smoothly in high
yield. The ester 2 was cleaved by using TFA in dichloromethane, giving the
free acid 3 in 87% yield.[7] Nondestructive cleavage of compound 3 by hydro-
peroxide-assisted saponification (LiOH, aq. THF, r.t.) gave sultam (96%
recovery yield) and 5 in 93% yield. Finally, the order of cleavages of ester
and chiral auxiliary did not affect the yield and the purity of product 5. The

Synthesis of (S)-2-Benzylsuccinic Acid
2637
overall yield of four step reaction was 68% and the optical purity was more
than 99% (calculated on the basis of the maximum optical rotation
[a]2D0 ¼ 227.0 (c 2.0, EtOAc) for the pure S-enantiomer).[8]
In conclusion, an efficient and practical preparation of (S)-2-benzylsucci-
nic acid has been developed. The absolute stereochemistry was controlled by
use of D-(2)-camphorsultam chiral auxiliary.
EXPERIMENTAL SECTION
¨
Melting points were measured with BUCHI melting point apparatus
and were uncorrected. Mass spectra were taken using Finnigan MAT-95
1
spectrometer. H-NMR spectra were recorded on Varian Mercury 400 NMR
spectrometer in CDCl3 unless otherwise stated, and chemical shifts were
reported in d (TMS as internal standard). Elemental analyses were performed
on Vario EL instrument. Optical rotations were taken with Perkin–Elmer 241
Polarimeter at the sodium D line. THF was freshly distilled from sodium
metal/benzophenone ketyl. All other reagents and solvents were used as
received without further purification.
N-(3-Phenylpropionyl)(2R)-bornane-10,2-sultam
Method A: To a solution of 1(S)-(2)-2,10-bornane sultam (2.20 g,
10.22 mmol) in CH3CN (10 mL) under nitrogen, 3-phenylpropionyl chloride
(1.90 mL, 12.78 mmol) was added and the solution was heated to reflux for
10 hr. After the solution was cooled to ambient temperature, the CH3CN
was removed in vacuo. The residue was diluted with EtOAc and the organic
phase was washed with saturated Na2CO3 and saturated NaCl, dried over
MgSO4, filtered, and concentrated at reduced pressure. The crude product
was recrystallized from methanol (or EtOAc/hexane) to afford 1 as a white
solid (3.16 g, 89%).
Method B: A suspension of 60% sodium hydride (0.60 g, 15.00 mmol) in
toluene (25 mL) was treated with a solution of (1S,2R)-(2)-10,2-bornane sultam
(2.15 g, 10.00 mmol) in dry THF (15 mL). The mixture was stirred for 1 hr.
3-Phenylpropionyl chloride (2.23 mL, 15.00 mmol) in THF (5 mL) was added
over 20 min and the mixture was stirred for 16 hr. Saturated aqueous ammo-
nium chloride (15 mL) was added and the mixture was poured into ether
(50 mL); the separated aqueous layer was washed with ether (25 mL ꢀ 2).
The combined organic extracts were washed with portions (10 mL ꢀ 3) of
water and brine and dried (MgSO4). Evaporation of the solvent gave a
white solid which was re-crystallized from methanol to afford 1 (3.15 g,

2638
Liu, Yang, and Ji
1
91%): m.p. 146–1488C, [a]D20 ¼ 285.6 (c 1.0, CHCl3); H-NMR (CDCl3,
400 MHz) d:=0.95 (3H, s), 1.08 (3H, s), 1.34–1.42 (2H, m), 1.85–1.90 (3H,
m), 2.05–2.07 (2H, d), 2.97–3.07 (4H, m), 3.40–3.50 (2H, m), 3.84–3.88
(1H, t), 7.17–7.30 (5H, m); MS (70 eV) m/z (%): 347 (Mþ, 72), 133 (41),
105 (100), 91 (81). Calculated for C19H25NO3S: %C 65.68, %H 7.25, %N
4.03. Found: %C 65.80, %H 7.06, %N 4.00.
N-[2-(S)-tert-Butoxycarbonylmethyl-3-phenylpropionyl]-
(2R)-bornane-10,2-sultam(2)
A cooled solution of compound 1 (1.74 g, 5.00 mmol) in THF (15 mL) at
2788C (all under nitrogen) was treated with NaHMDS (5.50 mL, 1 M solution
in THF) over 5 min dropwise. The mixture was stirred at 2788C for 0.5 hr, the
solution of tert-butyl bromoacetate (2.20 mL, 15.00 mmol) and HMPA
(2.62 mL, 15.00 mmol) in THF (5 mL) was added dropwise over 10 min.
The mixture was allowed to be warmed to r.t. over 16 hr and then was
stirred at 258C for 4 hr. Saturated aqueous NH4Cl (20 mL) was added to
stop reaction and the mixture was extracted with ether. The combined
organic layer was washed with brine and dried (MgSO4). Evaporation of the
solvent gave crude product which crystallized from methanol to give 2 as crys-
tals (2.13 g, 92%): m.p. 128–1298C, [a]2D0 ¼ 258.2 (c 1.0, MeOH); 1H-NMR
(CDCl3, 400 MHz) d: 0.95 (3H, s), 1.09 (3H, s), 1.37 (9H, s), 1.40–1.48 (2H,
m), 1.85–2.16 (3H, m), 2.31–2.69 (2H, m), 2.99–3.08 (4H, m), 3.30–3.63
(3H, m), 3.85–3.94 (1H, m), 7.20–7.29 (5H, m); MS (70 eV) m/z (%): 461
(Mþ, 8), 347 (52), 133 (38), 105 (100). Calculated for C25H35NO5S: %C
65.05, %H 7.64, %N 3.03. Found: %C 64.91, %H 7.53, %N 2.99.
N-[2-(S)-Carbonylmethyl-3-phenylpropionyl]-(2R)-bornane-
10,2-sultam
2 (1.20 g, 2.60 mmol) was dissolved in CH2Cl2 (10 mL) and=cooled to
08C. Trifluoroacetic acid (5 mL) was added and the mixture was stirred over-
night at room temperature. The volatiles were removed at reduced pressure
and the residue was dissolved in ethyl acetate (15 mL). The organic phase
was washed with 5% NaHCO3 and brine, dried and evaporated to give 3
(0.94 g, 87%) with sufficient purity to be employed in subsequent steps:
m.p. 202–2048C, [a]2D0 ¼ 299.1 (c 1.0, MeOH); 1H-NMR (CDCl3,
400 MHz) d: 0.96 (3H, s), 1.17 (3H, s), 1.32–1.44 (2H, m), 1.85–1.92 (3H,
m), 2.00–2.09 (2H, m), 2.36–2.49 (2H, m), 2.80–2.87 (1H, m), 3.37–3.63
(4H, m), 3.91–3.94 (1H, m), 7.19–7.31 (5H, m); MS (70 eV) m/z (%): 405

Synthesis of (S)-2-Benzylsuccinic Acid
2639
(Mþ, 12), 347 (56), 105 (100). Calculated for C21H27NO5S: %C 62.20, %H
6.71, %N 3.45. Found: %C 62.32, %H 6.65, %N 3.38.
(S)-3-(tert-Butoxycarbonyl)-2-benzylpropanoic Acid (4)
2 (1.00 g, 2.17 mmol) was dissolved in THF (9 mL), the solution of 1N
LiOH (8.67 mL, 4 equimolar) and 30% H2O2 (1.77 mL, 8 equimolar) were
added sequentially at 08C. After 1 hr, the mixture was warmed to room temp-
erature and stirred for overnight. The mixture was diluted with water and
extracted with CH2Cl2. The aqueous phase was acidified to pH ¼ 1–2 with
1 N HCl, saturated with NaCl and extracted with EtOAc. Drying (MgSO4)
of the organic phase and evaporation of the solvent afforded 4 with sufficient
purity to be employed in subsequent steps: (0.48 g, 84%): m.p. 119–1208C;
1H-NMR (CDCl3, 400 MHz) d: 1.41 (9H, s), 2.32–2.37 (1H, dd, J ¼ 2.3,
8.4 Hz), 2.52–2.59 (1H, m), 2.73–2.79 (1H, m), 3.07–3.13 (2H, m), 7.19–
7.33 (5H, m); MS m/z (%, ESI): 287.0 (M þ Na)þ, 263.1 (M 2 H)2.
(S)-2-Benzylsuccinic Acid (5)
.
Method A: Aqueous (30%) H2O2 (1.60 mL, 16.00 mmol) and LiOH H2O
(0.34 g, 8.00 mmol) were added at 08C to a solution of 3 (0.81 g, 2.00 mmol) in
THF/H2O (16 mL, 1 : 1). The mixture was stirred at 08C for 1 hr and then at r.t.
for 12 hr. Dilution with water, extraction with CH2Cl2, drying (MgSO4) of the
organic phase, and evaporation furnished with camphor. The aqueous phase
was acidified to pH ¼ 1–2 with 1 N HCl, saturated with NaCl, and extracted
with EtOAc. The combined organic layer was dried (MgSO4) and concen-
trated at reduced pressure. Crystallization with EtOAc afforded 5 (0.39 g,
93%).
Method B: 4 (0.44 g, 1.66 mmol) was dissolved in CH2Cl2 (5 mL) and
cooled to 08C. The trifluoroacetic acid (2.5 mL) was added and the mixture
was stirred overnight at room temperature. The volatiles were removed
at reduced pressure and the residue was dissolved in ethyl acetate (15 mL).
The organic phase was washed with 5% NaHCO3 and brine, dried
(MgSO4), and concentrated at reduced pressure afforded 5 with a mostly quan-
titative yield (0.34 g): m.p. 163–1648C, [a]2D0 ¼ 227.0 (c 2.0, EtOAc) (Lit.[8]
1
164.58C, [a]2D0 ¼ 227.0 (c 2.0, EtOAc)); H-NMR (CD3OD, 400 MHz) d:
2.25 (1H, dd, J ¼ 16.8, 4.4 Hz), 2.47 (1H, dd, J ¼ 16.8, 9.2 Hz), 2.72 (1H,
dd, J ¼ 12.4, 5.6 Hz), 2.90–2.97 (2H, m), 7.09–7.20 (5H, m); MS m/z (%,
ESI): 231.0 (M þ Na)þ, 207.1 (M 2 H)2. Calculated for C11H12O4: %C
63.45, %H 5.81. Found: %C 63.69, %H 5.76.

2640
Liu, Yang, and Ji
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Received in Japan January 19, 2004