sequent recrystallisation of the residue afforded a further (0.121
g) of the title compound (S)-12. The combined yield of (S)-12
was (0.737 g, 82%); mp 60–61 ЊC; [α]D24 Ϫ16.02 (c 0.83, CHCl3)
(Found: C, 72.2; H, 6.0. C18H18O4 requires C, 72.5; H, 6.1%);
νmax(film)/cmϪ1 3031br s (O–H), 1734s (CHC᎐O), 1713s (CH -
a short plug of Celite. The Celite pad was washed with ethyl
acetate and the filtrate concentrated in vacuo to yield acid (S)-
14 as a colourless oil (0.076 g, 100%), m/z (APCIϪ) 278 (100%,
M Ϫ Hϩ), which was used in the next step without further
purification or characterisation.
᎐
2
C᎐O); δH (lit.8) 7.37–7.12 (10H, m, Ph), 5.11 (2H, s, PhCH2O),
To (S)-14 was added 1-hydroxybenzotriazole (0.055 g, 0.406
mmol), dimethylaminopyridine (0.036 g, 0.298 mmol) and
3ؒHCl (0.077 g, 0.325 mmol) followed by THF (1 mL). The
stirred reaction mixture was cooled to Ϫ22 ЊC and a solution of
dicyclohexylcarbodiimide (0.059 g, 0.285 mmol) in THF (1 mL)
was added dropwise via syringe. The stirred reaction mixture
was maintained at Ϫ22 ЊC for 1 h and was then slowly warmed
to room temperature over 5 h. The reaction mixture was diluted
with ethyl acetate (100 mL), successively washed with aqueous
hydrochloric acid (0.1 , 2 × 50 mL), saturated sodium hydro-
gen carbonate (50 mL) and brine (50 mL), dried (magnesium
sulfate), filtered and finally concentrated in vacuo to afford a
solid yellow residue. Purification by silica gel chromatography
[petroleum ether–diethyl ether (1:1)] afforded (S)-15 as a
colourless oil which crystallised on standing (0.060 g, 85%); mp
80–81 ЊC; [α]D23 ϩ75.3 (c 1.00, CHCl3) (Found: C, 68.8; H, 7.4; N,
5.4. C15H19NO3 requires C, 70.0; H, 7.3; N, 5.4%); νmax(KBr)/
᎐
3.22–3.04 (2H, m, CHCO and PhCH2), 2.79 (1H, dd, J 14.0 and
8.2, PhCH2), 2.74 (1H, dd, J 17.3 and 9.2, CH2CO2), 2.46 (1H,
dd, J 17.3 and 4.7, CH2CO2); δC (50 MHz) 178.1 (CH C᎐O),
᎐
2
174.0 (CHC᎐O), 137.9 and 135.7 (Ph:Cipso), 129.1, 128.7, 128.6,
᎐
128.2 and 126.8 (Ph:C), 66.7 (PhCH2O), 42.9 (CHCO), 37.6
(PhCH2) and 34.9 (CH2CO); m/z (APCIϪ) 297 (100%,
M Ϫ Hϩ), 207 (50%, C11H11O4), 189 (33%).
(S)-Benzylsuccinnic acid (S)-139
To a solution of (S)-12 (0.050 g, 0.168 mmol) in degassed
methanol (3 mL) in a round-bottom flask was cautiously added
palladium on carbon (0.010 g, 20%). The flask was fitted with
a balloon filled with hydrogen. The heterogeneous solution
was vigorously stirred for 2 h at room temperature before the
balloon was removed and the reaction mixture filtered through
a short plug of Celite. The Celite pad was washed with ethyl
acetate and the filtrate concentrated in vacuo to yield a colour-
less oil which crystallised on standing. Recrystallisation of this
material from distilled water afforded the title compound (S)-13
as colourless crystals (0.034 g, 97%); mp 157–159 ЊC; lit.9 mp
153–154 ЊC; [α]D22 Ϫ26.96 (c 0.675, EtOAc); lit.9 [α]D21 Ϫ28.9 (c
0.665, EtOAc); δH (300 MHz, d6-DMSO) 12.24 (2H, s, COOH
and COOH), 7.31–7.17 (5H, m, Ph), 2.94–2.85 (2H, m, CHCO
and PhCH2), 2.73 (1H, dd, J 15.4 and 10.0, PhCH2), 2.42 (1H,
dd, J 16.6 and 8.1, CH2CO2), 2.24 (1H, dd, J 16.6 and 3.5,
CH2CO2).
cmϪ1 1724s (C᎐O); δH (300 MHz) 7.34–7.17 (5H, m, Ph), 3.22–
᎐
3.09 (2H, m, CHCO and PhCH2), 2.92 (1H, dd, J 13.2 and 7.8,
PhCH2), 2.69 (1H, dd, J 18.0 and 8.6, CH2CO2), 2.46 (1H, dd,
J 18.0 and 4.6, CH2CO2), 1.28 [9H, s, C(CH3)3]; δC (50 MHz)
175.6 and 172.8 (C᎐O), 136.7 (Ph:Cipso), 129.4 and 129.1
᎐
(Ph:Cortho and Cmeta), 127.4 (Ph:Cpara), 87.2 [C(CH3)3], 38.4
(CHCO), 36.1 (PhCH2), 30.4 (CH2CO), 27.2 [C(CH3)3]; m/z
(CI, NH3) 279 (68%, MNH4ϩ), 262 (16%, MHϩ), 223 (100%),
206 (20%), 91 (10%).
tert-Butyl (1S,2R,2ЈS)-2-[2Ј-(N-tert-butoxycarbamoylmethyl)-
3Ј-phenylpropionylamino]cyclohexane-1-carboxylate 16
Benzyl (2S)-2-(N-tert-butoxycarbamoylmethyl)-3-phenyl-
propionate (S)-4
To a solution of (S)-4 (0.100 g, 0.271 mmol) in degassed
methanol (3 mL) in a round-bottom flask was cautiously added
palladium on carbon (0.020 g, 20%). The flask was fitted with
a balloon filled with hydrogen. The heterogeneous solution
was vigorously stirred for 1 h at room temperature before the
balloon was removed and the reaction mixture filtered through
a short plug of Celite. The Celite pad was washed with ethyl
acetate and the filtrate concentrated in vacuo to yield acid
(S)-14 as a colourless oil (0.076 g, 100%).
(S)-14 was dissolved in THF (0.5 mL) and cooled to Ϫ22 ЊC
with stirring. A solution of ethyl chloroformate (0.0294 g, 0.271
mmol) in THF (0.5 mL) was then added to the crude acid via
syringe, followed by a solution of triethylamine (0.0300 g, 0.297
mmol) in THF (0.5 mL) dropwise via pipette. The reaction mix-
ture was stirred at Ϫ22 ЊC for 30 min before a mixture of 3ؒHCl
(0.072 g, 0.306 mmol) and triethylamine (0.035 g, 0.347 mmol)
in THF (0.5 mL) were added via pipette. The reaction was
maintained at Ϫ22 ЊC for 1 h and then was slowly warmed to
room temperature overnight. The reaction mixture was diluted
with ethyl acetate (100 mL), successively washed with aqueous
hydrochloric acid (0.1 , 2 × 50 mL), saturated sodium hydro-
gen carbonate (50 mL) and brine (50 mL), dried (magnesium
sulfate), filtered and finally concentrated in vacuo to afford a
yellow oil. Purification by silica gel chromatography [petroleum
ether–diethyl ether (1:1)] afforded the title compound 16 as
colourless oil which crystallised on standing (0.100 g, 80%); mp
64–65 ЊC; [α]D22 ϩ3.52 (c 0.625, CHCl3); νmax(KBr)/cmϪ1 3266br
To a stirred mixture of (S)-12 (0.500 g, 1.678 mmol), dicyclo-
hexylcarbodiimide (0.375 g, 1.846 mmol) and 1-hydroxy-
benzotriazole (0.340 g, 2.517 mmol) at room temperature was
rapidly added DMF (3 mL) via syringe. The reaction mixture
was stirred for 1 h before dimethylaminopyridine (0.410 g, 3.356
mmol) and O-tert-butylhydroxylamine hydrochloride (0.253 g,
2.01 mmol) were added solid and in one portion. Stirring was
maintained for a further 16 h before the reaction mixture was
diluted with ethyl acetate (50 mL), washed with aqueous hydro-
chloric acid (0.1 , 2 × 50 mL) and then brine (50 mL), dried
(magnesium sulfate), filtered and finally concentrated in vacuo
to afford a solid yellow residue. Purification by silica gel chro-
matography [petroleum ether–diethyl ether (7:1)] afforded the
title compound (S)-4 as a colourless oil (0.518 g, 84%); [α]D22
ϩ2.26 (c 0.53, CHCl3); νmax(film)/cmϪ1 3196br s (N–H), 1733s
(CHC᎐O), 1663s (CH C᎐O); δ (300 MHz, d6-DMSO) 10.36
᎐
᎐
2
H
(1H, s, NH), 7.37–7.11 (10H, m, Ph), 5.00 (2H, app s,
PhCH2O), 3.13–3.06 (1H, m, CHCO), 2.90–2.77 (2H, m,
PhCH2), 2.37 (1H, dd, J 15.2 and 8.8, CH2CO2), 2.21 (1H, dd,
J 15.2 and 5.6, CH2CO2), 1.11 [9H, s, C(CH3)3]; δC (50 MHz)
174.9 (CHC᎐O), 170.5 (CH C᎐O), 138.2 and 135.8 (Ph:Cipso),
᎐
᎐
2
129.3, 128.7, 128.4 and 126.9 (Ph:C), 66.7 (PhCH2O), 43.2
(CHCO), 37.9 (PhCH2) and 34.2 (CH2CO), 26.1 [C(CH3)3]; m/z
(APCIϩ) 392 (28%, MNaϩ), 370 (100%, MHϩ), 314 (98%,
MHϩ Ϫ C4H8) [Found (CI, NH3): MHϩ, 370.20280. C22H28-
N1O4 MHϩ requires, 370.20183].
(N–H), 1729s, 1676s and 1648s (C᎐O); δ (500 MHz, d6-
᎐
H
(2S)-2-Benzyl-N-tert-butoxysuccinimide (S)-15
DMSO, 90 ЊC) 9.83 (1 H, br s, NHO), 7.28–7.13 (6H, m, Ph and
NH), 4.07 (1H, tt, J 7.9 and 4.0, CHN), 3.02–2.95 (1H, m,
CHCON), 2.91 (1H, dd, J 13.6 and 7.0, PhCH2), 2.59 (1H, dd,
J 13.6 and 7.2, PhCH2), 2.48 (1H, dt, J 7.8 and 4.0, CHCO2),
2.39 (1H, dd, J 15.2 and 8.4, CH2CON), 2.06 (1H, dd, J 15.2
and 5.2, CH2CON), 1.87–1.80, 1.74–1.68 and 1.62–1.31 [8H,
m, (CH2)4], 1.37 [9H, s, COOC(CH3)3], 1.15 [9H, s, CON-
To a solution of (S)-4 (0.100 g, 0.271 mmol) in degassed
methanol (5 mL) in a round-bottom flask was cautiously added
palladium on carbon (0.020 g, 20%). The flask was fitted with
a balloon filled with hydrogen. The heterogeneous solution
was vigorously stirred for 1 h at room temperature before the
balloon was removed and the reaction mixture filtered through
J. Chem. Soc., Perkin Trans. 1, 1998
2633