The preparation of enantiomerically enriched γ-amino acids (GABAS) using palladium catalysed allylic substitution

Article abstract of DOI:10.1016/S0957-4166(98)00383-8

Enantioselective palladium catalysed allylic substitution reactions have been employed as the asymmetryproducing step in the synthesis of enantiomerically enriched γ-amino acids.

Full text of DOI:10.1016/S0957-4166(98)00383-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3723–3730
The preparation of enantiomerically enriched γ-amino acids
(GABAs) using palladium catalysed allylic substitution
Christopher J. Martin,a David J. Rawson c and Jonathan M. J. Williams a,b,∗
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
bDepartment of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
cDiscovery Chemistry, Pfizer Central Research, Sandwich, Kent, CT13 9NJ, UK
Received 10 September 1998; accepted 17 September 1998
Abstract
Enantioselective palladium catalysed allylic substitution reactions have been employed as the asymmetry-
producing step in the synthesis of enantiomerically enriched γ-amino acids. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Highly enantioselective palladium catalysed allylic substitution reactions have been achieved by many
research groups.1 The ligand 1 has been used by ourselves2 and others3 to effect an efficient enantio-
selective reaction, such as the conversion of the standard allyl acetate 2 into the substitution product 3.
It therefore comes as no surprise that we have been able to apply the reaction to related nucleophiles,
and thereby generate the substitution products 4–7 with high enantioselectivity (for products 4–6,
two diastereomers were formed with little control of selectivity, 8–27% de, probably representing a
thermodynamic ratio).
∗
Corresponding author. E-mail: j.m.j.williams@bath.ac.uk
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00383-8

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This research group has previously demonstrated that substrates of the type exemplified by allylic
acetates 8–11 are synthetically useful, since they are easy to prepare from commercially available β-
phenylcinnamaldehyde, and are therefore more accessible for a wider range of substrates than for those
compounds (such as substrate 2) which proceed via symmetrical allylpalladium complexes.4 We were
pleased to find that using methyl cyanoacetate as the incoming nucleophile, we were able to record high
yields and enantioselectivities in the allylic substitution reaction to generate the substitution products
12–15 (again with little control of diastereoselectivity). The enantioselectivities were determined by
chiral HPLC (Chiralcel OD, hexane:isopropanol, 99:1).
Previous results from these laboratories have demonstrated how α- and β-amino acids can be prepared
using enantioselective palladium catalysed allylic substitution reactions as the key step.5 Herein, we
demonstrate how the cyano ester products 12 and 14 can be converted into γ-amino acids.
2. Results and discussion
The parent compound, GABA, is an important inhibitor neurotransmitter with several roles in the
mammalian central nervous system, and virtually all central neurones appear to be under the inhibitory
control of GABA.6 The importance of chirality in GABA analogues has been described with respect to
interaction with GABA receptors.7

C. J. Martin et al. / Tetrahedron: Asymmetry 9 (1998) 3723–3730
3725
The following simple sequence was employed to convert the substitution products into the correspond-
ing γ-amino acids. The cyanoesters 12 and 14 underwent a Krapcho decarboxylation reaction to afford
the corresponding nitriles 16 and 17. Reduction of the nitrile afforded the amines 18 and 19 which were
protected to give the carbamates 20 and 21. Oxidative cleavage of the alkene affords the carboxylic acids
20 and 21, which were deprotected to afford the γ-amino acids 22 and 23.
3. Experimental
General experimental details, including the purification of solvents and the spectrometers employed
have been detailed elsewhere.2b The preparation of ligand 1 and acetates 8–11 has also been previously
reported.2b,4
3.1. General procedure for the palladium catalysed allylic alkylation of acetate 2 with various nucleo-
philes
The preparation of compounds 4–7 is typified by the formation of compound 6.
A solution of sodiomethyl cyanoacetate (0.21 ml, 1.2 mmol) in dry THF (2 ml) was added slowly to a
solution of rac-(E)-1,3-diphenyl-3-acetoxy-1-propene 2 (200 mg, 0.8 mmol), [(η3-C3H5)PdCl]2 (7.3 mg,
20 µmol) and (4S)-4,5-dihydro-4-isopropyl-2-[2-(diphenylphosphino)phenyl]-1,3-oxazole 1 (30 mg, 80
µmol) in dry THF (3 ml) under an inert atmosphere and stirred for 16 h at ambient temperature. The
reaction was diluted with dichloromethane (50 ml) and washed with a saturated aqueous ammonium
chloride solution (50 ml). The organic layer was separated, dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash chromatography (ethyl acetate:light petroleum, 1:20) to yield
compound 6 as a pale yellow oil (168 mg, 73%). (Found: M+, 291.1260. C19H17NO2 requires M+,
291.1259.) [α]D 18.57 (c 16.8; CHCl3). νmax (neat) cm−1 2250 (CN), 1747 (C_O), 1599 (C_C) and
20

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C. J. Martin et al. / Tetrahedron: Asymmetry 9 (1998) 3723–3730
1262 (C–O). δH (250 MHz; CDCl3) for both diastereomers 7.41–7.24 (10H, m, Ar–H), 6.61–6.44 (2H,
m, Ph(H)C_CH), 4.22 (1H, m, Ph–CH), 3.94 and 3.89 (1H, 2×d, J=7.5, CHCO2Me), 3.70 and 3.68 (3H,
2×s, OCH3). δC (63 MHz; CDCl3) 165.6 and 165.3 (C_O), 139.1, 134.3, 129.2, 129.05, 129.0, 128.8,
128.6, 128.5, 128.3, 128.1, 127.9, 127.8, 127.6, 126.7, 126.5 and 126.4 (arom. C and C_C), 115.2 (CN),
53.2 (OCH3), 49.8 and 49.5 (CHPh), 45.3 and 44.9 (CHCN).
Compound 4 as a colourless oil (90%). (Found: M+, 322.1574. C21H22O3 requires M+, 322.1569.)
[α]D −17.2 (c 0.23; CHCl3). νmax (neat) cm−1 1743 (CO2Et), 1717 (C_O), 1649 (C_C) and 1153
20
(C–O). δH (250 MHz; CDCl3) 7.31–7.18 (10H, m, Ar–H), 6.47 (1H, d, J=9.2, Ph(H)C_CH), minor
diastereomer), 6.41 (1H, d, J=9.2, Ph(H)C_CH, major diastereomer), 6.29 (1H, dd, J=12.6 and 8,
Ph(H)C_CH, major diastereomer), 6.24 (1H, dd, J=12.6, 8, Ph(H)C_CH, minor diastereomer), 4.30
(1H, d, J=8, CH3COCH, minor diastereomer), 4.26 (1H, d, J=8, CH3COCH, major diastereomer),
4.22–4.05 (3H, m, PhCH and OCH2, both diastereomers), 2.29 (3H, s, CH3CO) and 1.28–1.18 (3H,
m, OCH2CH3, both diastereomers). δC (100.6 MHz; CDCl3) 201.7 and 201.4 (C_O), 167.9 and 167.6
(CO2Et), 140.2, 136.8, 131.8, 131.5, 129.5, 129.3, 128.9, 128.8, 128.5, 128.0, 127.9, 127.6, 127.5, 127.2,
126.4 and 126.3 (arom. C and C_C), 65.6 and 65.2 (CHCO2Et), 61.6 and 61.4 (OCH2), 48.9 and 48.7
(Ph-CH), 30.1 and 30.0 (CH3O), 14.3 and 14.2 (CH2CH3).
Compound 5 as a white solid (76%). Mp 134–135°C. (Found: M+, 390.1297. C24H22O3S requires
20
M+, 390.1290.) [α]D −58.9 (c 0.48; CHCl3). νmax (Nujol) cm−1 1722 (C_O), 1598 (C_C), 1307 and
1144 (SO2). δH (250 MHz; CDCl3) 7.49–7.06 (15H, m, Ar–H), 6.41 (1H, d, J=15.7, Ph(H)C_CH), 6.09
(1H, dd, J=15.2 and 4.0, Ph(H)C_CH), 4.72 (1H, d, J=10.4, CH3COCH, minor diastereomer), 4.67 (1H,
d, J=10.4, CH3COCH, major diastereomer), 4.33 (1H, t, J=9.5, PhCH) and 2.41 (3H, s, CH3CO). δC
(63 MHz; CDCl3) 199.9 and 199.8 (C_O), 139.3, 136.5, 134.4, 134.0, 133.3, 132.9, 132.6, 129.7, 129.2,
128.8, 128.7, 128.6, 128.4, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 126.4 and 126.3 (arom.
C and C_C), 79.7 and 79.3 (CHCO), 48.8 and 48.7 ((Ph–CH), 32.4 and 31.5 (CH3O).
Compound 7 as a colourless oil (93%). (Found: M+, 276.1501. C18H18N3 requires M+, 276.1501.)
[α]D 20.0 (c 2.76; CHCl3). νmax (neat) cm−1 2360 (CN) and 1648 (C_C). δH (250 MHz; CDCl3)
20
7.45–7.22 (10H, m, Ar–H), 6.68 (1H, d, J=15.7, PhCH_CH), 6.45 (1H, dd, J=15.6 and 7.4, PhCH_CH)
and 4.12–4.03 (2H, m, NCCHCN and PhCH). δC (63 MHz; CDCl3) 136.5, 135.8, 134.6, 129.4, 129.1,
128.9, 128.7, 128.6, 128.4, 127.9, 126.8 and 123.9 (arom. C and C_C), 111.7 (CN), 49.7 (PhCH) and
30.2 (NCCHCN).
3.2. General procedure for the palladium catalysed allylic alkylation of acetates 8–11
The preparation of compounds 12–15 is typified by the preparation of compound 13.
Methyl cyanoacetate (0.19 ml, 2.1 mmol) was added slowly to a slurry of sodium hydride (51 mg, 2.1
mmol) in dry THF (2 ml) and DMF (1 ml) at 0°C whilst under a nitrogen atmosphere. The resultant anion
was added to a solution of 1,1-diphenylpent-1-enyl-3-acetate 9 (200 mg, 0.7 mmol), [(η3-C3H5)PdCl]2
(7 mg, 19 µmol) and (4S)-4,5-dihydro-4-isopropyl-2-[2-(diphenylphosphino)phenyl]-1,3-oxazole 1 (28
mg, 75 µmol) in dry THF (1 ml) and DMF (0.5 ml) which had been stirred under an inert atmosphere
for 15 min at ambient temperature. The reaction was monitored by TLC for the disappearance of acetate.
Once all the acetate had been converted to product (36–48 h) the reaction was quenched with ammonium
chloride solution. The aqueous phase was extracted with dichloromethane (3×30 ml), the combined
organic phases were dried over MgSO4 and concentrated in vacuo to give the crude product which was
purified by flash chromatography (ethyl acetate:light petroleum, 1:10) to yield the desired product 13, as
a yellow solid. Mp 97–98°C. (Found: M+, 319.1572. C21H21NO2 requires M+, 319.1572.) [α]D −10.3
20
(c 0.348; CHCl3). νmax (Nujol) cm−1 2252 (CN) and 1748 (C_O). δH (250 MHz; CDCl3) 7.43–7.12

C. J. Martin et al. / Tetrahedron: Asymmetry 9 (1998) 3723–3730
3727
(10H, m, Ar–H), 5.97 and 5.90 (1H, d, J=10.7, Ph2C_CH), 3.72 and 3.67 (3H, s, OCH3), 3.56 and 3.50
(1H, d, J=4.6, CHCO2Me), 2.98–2.86 (1H, m, CHCH2), 1.72–1.59 (2H, m, CH2CH3) and 0.98–0.90
(3H, m, CH2CH3). δC (100.6 MHz; CDCl3) 166.0 and 165.9 (C_O), 146.1, 146.07, 139.2, 129.5, 129.4,
128.5, 128.3, 128.3, 128.3, 127.8, 127.8, 127.6, 127.5, 127.5, 127.3, 126.8 and 126.1 (arom. C and C_C),
115.5 and 115.2 (CN), 60.3 (OCH3), 43.2, 42.8, 41.4 and 41.2 (CHCO2Me and CHCH2), 27.0 and 25.6
(CH2CH3) and 11.7 and 11.5 (CH2CH3).
Compound 12 as a viscous pale yellow solid (78%). Mp 69–70°C. (Found: M+, 305.1416. C20H19NO2
requires M+, 305.1416.) [α]D −67.4 (c 0.392; CHCl3). νmax (Nujol) cm−1 2252 (CN) and 1748 (C_O).
20
δH (250 MHz; CDCl3) 7.43–7.12 (10H, m, Ar–H), 6.02 and 5.96 (1H, d, J=10.5, Ph2C_CH), 3.80 and
3.79 (3H, s, OCH3), 3.45 (1H, d, J=6.0, CHCO2Me), 3.17–3.06 (1H, m, CHCH3) and 1.26 (3H, t, J=7.0,
CHCH3). δC (100.6 MHz; CDCl3) 171.1 (C_O), 146.7, 141.3, 138.7, 138.3, 129.4, 129.3, 129.27, 129.2,
129.0, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.5, 124.6 and 123.4 (arom. C and C_C), 115.1
and 115.0 (CN), 60.4 (OCH3), 45.3 (CHCO2Me), 45.1 (CHCH3) and 44.8 and 44.7 (CHCH3).
Compound 14 as a yellow solid (74%). Mp 115–116°C. (Found: M+, 367.1572. C25H21NO2 requires
M+, 367.1572.) [α]D −121.9 (c 0.476; CHCl3). νmax (Nujol) cm−1 2252 (CN) and 1748 (C_O). δH
20
(250 MHz; CDCl3) 7.39–7.05 (15H, m, Ar–H), 6.50 and 6.43 (1H, d, J=10.6, Ph2C_CH), 4.24–4.10
(1H, m, PhCH), 3.80 (1H, m, CHCO2Me) and 3.63 (3H, s, OCH3). δC (63 MHz; CDCl3) 165.2 and
165.0 (C_O), 146.2, 145.2, 141.1, 141.3, 129.4, 129.4, 129.1, 128.4, 128.3, 128.2, 127.9, 127.9, 127.8,
127.7, 127.7, 127.7, 127.5, 127.47, 125.2 and 123.9 (arom. C and C_C), 115.3 and 115.2 (CN), 53.3 and
53.2 (OCH3), 45.7, 45.4, 45.3 and 44.9 (CHCO2Me and CHPh).
Compound 15 as a pale yellow oil (81%). (Found: M+, 401.1183. C25H20ClNO2 requires M+,
401.1182.) [α]D −139.33 (c 3.0; CHCl3). νmax (neat) cm−1 2252 (CN) and 1748 (C_O). δH (250
20
MHz; CDCl3) 7.39–6.99 (14H, m, Ar–H), 6.45 and 6.38 (1H, d, J=10.5, Ph2C_CH), 4.22–4.07 (1H, m,
CHC6H4Cl), 3.81–3.75 (1H, m, CHCO2Me) and 3.66 and 3.64 (3H, s, OCH3). δC (100.6 MHz; CDCl3)
165.7 (C_O), 144.8, 141.5, 139.2, 139.0, 129.4, 129.2, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8, 127.8,
127.7, 127.6, 127.4, 127.36 and 127.0 (arom. C and C_C), 115.4 and 115.2 (CN), 53.4 and 53.2 (OCH3),
44.4 and 44.0 (CHCO2Me) and 35.1 and 35.0 (CHC6H4Cl).
3.3. Procedure for the Krapcho decarboxylation of 12 and 148
A solution of compound 14 (90 mg, 0.24 mmol), sodium chloride (50 mg, 0.8 mmol) and water (20
mg, 1 mmol) in DMSO (5 ml) was heated under reflux for 4 h. The reaction was cooled to ambient
temperature before being diluted with ethyl acetate (50 ml). The organic phase was washed with water
(3×20 ml) and brine (3×20 ml) before being dried over MgSO4 and concentrated in vacuo. The crude
product was purified by flash chromatography (ethyl acetate:light petroleum, 1:6) to yield the desired
product 17 as a pale yellow solid (80%). Mp 81–82°C. (Found: M+, 309.1517. C23H19N requires M+,
309.1517.) [α]D −91.3 (c 0.46; CHCl3). νmax (Nujol) cm−1 2252 (CN) and 1599 (C_C). δH (250
20
MHz; CDCl3) 7.42–7.15 (15H, m, Ar–H), 6.29 (1H, d, J=10.4, Ph2C_CH), 3.81 (1H, m, PhCH) and
2.71 (2H, d, J=6.9). δC (100.6 MHz; CDCl3) 144.3, 141.5, 141.4, 129.6, 129.1, 128.5, 128.2, 127.7,
127.6, 127.4 and 127.0 (arom. C and C_C), 118.1 (CN), 41.5 (PhCH) and 25.3 (CH2CN).
Compound 16 as a pale yellow oil (74%). (Found: M+, 247.1361. C18H17N requires M+, 247.1361.)
20
[α]D −18.0 (c 0.60; CHCl3). νmax (neat) cm−1 2252 (CN) and 1599 (C_C). δH (250 MHz; CDCl3)
7.43–7.16 (10H, m, Ar–H), 5.91 (1H, d, J=10.1, Ph2C_CH), 2.78–2.67 (1H, m, CHCH3), 2.32 (2H, d,
J=6.3, CH2CN) and 1.18 (3H, d, J=6.7, CHCH3). δC (100.6 MHz; CDCl3) 143.4, 141.5, 139.5, 130.5,
129.7, 129.4, 129.2, 128.9, 128.8, 128.7, 128.5, 128.2, 128.0, 127.9, 127.7, 127.5, 127.4 and 127.2 (arom.
C and C_C), 118.3 (CN), 34.1 (CHCH3), 25.0 (CH2CN) and 21.0 (CHCH3).

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3.4. Procedure for the reduction with lithium aluminium hydride of 16 and 17
A solution of compound 17 (550 mg, 1.77 mmol) in dry diethyl ether (3 ml) was added slowly to a
stirring slurry of lithium aluminium hydride (202 mg, 0.64 mmol) in diethyl ether (5 ml) at 0°C whilst
under a nitrogen atmosphere. The resultant solution was heated under reflux for 2 h before being cooled
to 0°C. The reaction was quenched by the careful addition of ‘wet’ diethyl ether (20 ml). A 10% solution
of sulfuric acid (10 ml) was added slowly to the white slurry and the mixture was stirred until all the
precipitate had dissolved (15 min). The aqueous phase was extracted with ethyl acetate (3×50 ml) and
the combined organics were dried over MgSO4 before being reduced in vacuo. The crude product was
purified by flash chromatography to yield the desired amine 19 as a white solid. Mp 75–76°C. (Found:
M+, 313.1830. C23H23N requires M+, 313.1830.) [α]D −89.7 (c 0.584; CHCl3). νmax (Nujol) cm−1
20
3405 (NH2) and 1599 (C_C). δH (250 MHz; CDCl3) 8.19 (2H, br. s, NH2), 7.39–7.05 (15H, Ar–H), 6.17
(1H, d, J=10.4, Ph2C_CH), 3.38 (1H, m, PhCH), 2.93–2.84 (1H, m, CHH0NH2), 2.72–2.61 (CHH0NH2)
and 2.19–2.09 (2H, m, CHCH2). δC (100.6 MHz; CDCl3) 142.9, 142.8, 141.6, 139.4, 130.2, 129.6, 128.9,
128.5, 128.2, 127.4, 127.2, 127.1 and 126.8 (arom. C and C_C), 43.2 (PhCH), 38.5 (CH2NH2) and 34.5
(CHCH2).
Compound 18 as a colourless oil (70%). (Found: M+, 251.1674. C18H21N requires M+, 251.1674.)
20
[α]D −86.0 (c 1.60; CHCl3). νmax (neat) cm−1 3405 (NH2) and 1599 (C_C). δH (250 MHz; CDCl3)
7.38–7.12 (10H, m, Ar–H), 5.82 (1H, d, J=10.3, Ph2C_CH), 5.29 (2H, br. s, NH2), 2.81–2.62 (2H, m,
CH2NH2), 2.37–2.30 (1H, m, CHCH3), 1.61 (2H, q, J=7.6, CHCH2) and 1.02 (3H, d, J=6.6, CHCH3).
δC (100.6 MHz; CDCl3) 142.0, 141.5, 140.1, 124.1, 129.8, 129.8, 129.6, 129.3, 129.2, 128.7, 128.6,
128.4, 128.1, 127.9, 127.3, 127.1 and 126.7 (arom. C and C_C), 39.4 (CH2NH2), 38.3 (CHCH2), 30.8
(CHCH3) and 21.4 (CHCH3).
3.5. Procedure for N-protection with benzyl chloroformate of compounds 18 and 19
Triethylamine (0.25 ml, 1.74 mmol) was added to a stirring solution of amine 19 (500 mg, 1.59 mmol)
and DMAP (10 mg, 82 µmol) in dichloromethane (10 ml). The resultant solution was stirred for 10 min
at ambient temperature before the dropwise addition of benzyl chloroformate (0.25 ml, 1.74 mmol). The
reaction was then heated under reflux for 2 h, cooled to ambient temperature and concentrated in vacuo.
The crude product was purified by flash chromatography (ethyl acetate:light petroleum, 1:6) to yield the
desired product 21 as a pale yellow oil (70%). (Found: (M+NH4)+, 465.2542. C31H33N2O2 requires M+,
465.2542.) [α]D −82.6 (c 0.344; CHCl3). νmax (neat) cm−1 3424 and 3340 (NH), 1713 (C_O) and
20
1028 (C–O). δH (250 MHz; CDCl3) 7.41–7.09 (20H, m, Ar–H), 6.21 (1H, d, J=10.5, Ph2C_CH), 5.04
(2H, s, CH2Ph), 4.51 (1H, br. s, NH), 3.50–3.40 (1H, m, CHPh), 3.25–3.01 (2H, m, CH2NHCbz) and
1.93 (2H, q, J=7.2, CHCH2). δC (100.6 MHz; CDCl3) 156.2 (C_O), 144.3, 142.0, 142.0, 139.8, 136.6,
131.7, 131.0, 129.7, 128.7, 128.5, 128.4, 128.1, 128.04, 128.0, 127.3, 127.2 and 126.4 (arom. C and
C_C), 66.5 (CH2Ph), 43.0 (CHPh), 39.4 (CH2NHCbz) and 37.1 (CHCH2).
Compound 20 as a colourless oil (81%). (Found: MH+, 386.2120. C26H27NO2 requires MH+,
20
386.2137.) [α]D −41.0 (c 0.80; CHCl3). νmax (neat) cm−1 3424 and 3340 (NH), 1713 (C_O) and 1028
(C–O). δH (250 MHz; CDCl3) 7.39–7.14 (15H, m, Ar–H), 5.84 (1H, d, J=10.3, Ph2C_CH), 5.09 (2H, s,
CH2Ph), 4.48 (1H, br. s, NHCbz), 3.25–3.15 (1H, m, CHH0NHCbz), 3.07–2.99 (1H, m, CHH0NHCbz),
2.42–2.30 (1H, m, CHCH3), 1.59–1.46 (2H, m, CHCH2) and 1.05 (3H, d, J=6.6, CHCH3). δC (100.6
MHz; CDCl3) 156.2 (C_O), 142.2, 141.3, 140.2, 136.8, 134.6, 129.6, 128.7, 128.5, 128.4, 128.2, 128.0,
128.0, 127.1 and 127.1 (arom. C and C_C), 66.5 (CH2Ph), 39.4 (CH2NHCbz), 37.5 (CHCH2), 31.6
(CHCH3) and 21.4 (CHCH3).

C. J. Martin et al. / Tetrahedron: Asymmetry 9 (1998) 3723–3730
3729
3.6. Procedure for the oxidative cleavage with chromium trioxide of compounds 20 and 21
A solution of chromium trioxide (1.27 g, 12.7 mmol) in glacial acetic acid (7 ml) was added slowly to a
stirring solution of compound 21 (570 mg, 1.27 mmol) in glacial acetic acid (3 ml). The resultant solution
was stirred for 16 h at ambient temperature before being poured onto water (50 ml). The aqueous phase
was extracted with dichloromethane (6×20 ml) and the combined organics were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane:light
petroleum, 3:1, then dichloromethane:methanol, 9:1) to yield the desired acid 23 as a colourless oil.
(Found: M+, 313.1314. C18H19NO4 requires M+, 313.1314.) [α]D −15.84 (c 0.404; CHCl3). νmax
20
(neat) cm−1 3354 (CO2H and NH), 1785 (CO2H), 1717 (C_O). δH (250 MHz; CDCl3) 7.60–7.20 (10H,
m, Ar–H), 5.34–5.20 (3H, m, CHPh and CH2Ph), 3.96–3.87 (1H, m, CHCHH0), 3.62–3.51 (1H, m,
CHCHH0) and 2.42 (2H, t, J=6.7, CH2NHCbz). δC (100.6 MHz; CDCl3) 197.5 (CO2H), 153.8 (C_O),
133.4, 130.2, 129.3, 128.9, 128.7, 128.6, 128.6, 128.5, 128.4, 128.2 and 127.8 (arom. C), 67.9 (CH2Ph),
52.7 (CHPh), 36.9 (CHCH2) and 35.2 (CH2NHCbz).
Compound 22 as a colourless oil (75%). (Found: M+, 251.1157. C13H17NO4 requires M+, 251.1157.)
20
[α]D −16.55 (c 0.29; CHCl3). νmax (neat) cm−1 3369 (CO2H and NH), 1754 (CO2H), 1722 (C_O). δH
(400 MHz; CDCl3) 7.57–7.16 (5H, m, Ar–H), 5.31 (2H, s, CH2Ph), 3.85–3.79 (1H, m, CHH0NHCbz),
3.66–3.59 (1H, m, CHH0NHCbz), 2.56 (1H, m, CHCH3), 2.23–2.15 (1H, m, CHCHH0), 1.66–1.61 (1H,
m, CHCHH0) and 1.22 (3H, d, J=7.0, CHCH3). δC (100.6 MHz; CDCl3) 176.4 (CO2H), 151.7 (C_O),
128.9, 128.8, 128.5, 128.3, 128.2 and 128.0 (arom. C), 68.0 (CH2Ph), 44.3 (CH2NHCbz), 38.5 (CHCH3),
26.5 (CHCH2) and 15.3 (CHCH3).
3.7. Procedure for N-deprotection of compounds 22 and 23
A solution of compound 23 (200 mg, 0.64 mmol) and 10% palladium on carbon powder (20 mg) in
anhydrous methanol (5 ml) was stirred for 24 h under an atmosphere of hydrogen. The reaction mixture
was filtered through Celite®, the Celite® pad was washed with methanol (5×10 ml) and the filtrate was
concentratred in vacuo. The resultant oil was dissolved in dichloromethane (20 ml) and the organic phase
was extracted with water. The aqeuous phase was then reduced in vacuo to yield the product 25 as a
white solid (65%). Mp 152–153°C. (Found: M−H+, 178.0868. C10H13NO2 requires M−H+, 178.0868.)
20
[α]D 9.7 (c 0.62; H2O). νmax (KBr) cm−1 3288 (CO2H and NH2) and 1692 (CO2H). δH (250 MHz;
D2O) 7.91–7.34 (5H, m, Ar–H), 4.80 (D2O peak obscuring CHPh), 3.61–3.37 (2H, m, CH2NH2) and
2.69–2.44 (2H, m, CHCH2). δC (100.6 MHz; D2O) 179.7 (CO2H), 141.4, 131.8, 129.3, 128.8, 125.6 and
125.2 (arom. C), 79.1 (CHPh), 39.1 (CH2NH2) and 38.2 (CHCH2).
Compound 24 as a white solid (63%). Mp 192–193°C. (Found: M+, 117.0790. C5H11NO2 requires M+,
117.0790.) [α]D 3.5 (c 0.4; H2O). Lit. [α]D −6.7 (c 2.8; H2O).9 νmax (KBr) cm−1 3290 (CO2H and
NH2) and 1698 (CO2H). δH (400 MHz; D2O) 3.42–3.36 (2H, m, CH2NH2), 2.63–2.57 (1H, m, CHCH3),
2.40 (1H, m, CHCHH0), 1.87–1.78 (1H, m, CHCHH0) and 1.20 (3H, d, J=6.9, CHCH3). δC (100.6 MHz;
D2O) 184.9 (CO2H), 40.3 (CH2NH2), 36.6 (CHCH3), 29.3 (CHCH2) and 15.6 (CHCH3).
20
24
Acknowledgements
We thank Pfizer Limited, the EPSRC and the DTI for funding through the LINK asymmetric synthesis
scheme (studentship to C.J.M.).

3730
C. J. Martin et al. / Tetrahedron: Asymmetry 9 (1998) 3723–3730
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