Deracemisation of α-amino acids - (R)- and (S)-phenylalanine from the same enantiomer of a homochiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(98)00304-8

Chiral auxiliary (3S)-N,N'-bis-(p-methoxybenzyl)-3-isopropylpiperazine- 2,5-dione 1 was employed for the synthesis of both enantiomers of phenylalanine using a regioselective deprotonation/stereoselective reprotonation strategy. Modification of this approach enables the efficient deracemisation of (±)-phenylalanine.

Full text of DOI:10.1016/S0957-4166(98)00304-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2795–2798
Deracemisation of α-amino acids — (R)- and (S)-phenylalanine
from the same enantiomer of a homochiral auxiliary
Steven D. Bull, Stephen G. Davies,∗ Simon W. Epstein and Jacqueline V. A. Ouzman
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
Received 15 July 1998; accepted 30 July 1998
Abstract
Chiral auxiliary (3S)-N,N0-bis-(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione 1 was employed for the
synthesis of both enantiomers of phenylalanine using a regioselective deprotonation/stereoselective reprotonation
strategy. Modification of this approach enables the efficient deracemisation of (ꢀ)-phenylalanine. © 1998 Elsevier
Science Ltd. All rights reserved.
A large number of chiral auxiliaries have been developed for the asymmetric synthesis of homochiral
α-amino acids.1 The majority of these auxiliaries rely on stereoselective alkylation of a chiral glycine
enolate equivalent where subsequent cleavage of the major diastereoisomeric product affords the desired
homochiral α-amino acid.2 Although this methodology is ideally suited for the preparation of homochiral
α-amino acids of known absolute configuration, situations often arise where both enantiomers of a given
α-amino acid are required.3 Although both enantiomers of an α-amino acid can be prepared separately
via duplicate syntheses using the same auxiliary of opposite absolute configuration, this approach is
inherently wasteful. An alternative approach involves the possibility of preparing both enantiomers from
a single homochiral auxiliary via a stereodivergent strategy. We now report that homochiral auxiliary
(3S)-N,N0-bis-(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione 1 can be used for the preparation of
both enantiomers of phenylalanine using an epimerisation strategy which relies on the stereoselective
reprotonation of enolate 5.4
We have recently reported that diketopiperazine (DKP) 1 can be used for the asymmetric synthesis of
homochiral α-amino acids in multigram quantities.5 In a typical transformation, deprotonation of DKP
1 with LHMDS at −78°C followed by alkylation with benzyl bromide afforded trans-benzylated DKP
2 ([α]D23=+58.6, c 1.0, CHCl3) in 98% d.e. Homochiral DKP 2 was obtained by recrystallisation of the
crude reaction mixture (ethyl acetate) and deprotected by successive treatment with ceric ammonium
nitrate (CAN) and 6 M HCl to afford homochiral (R)-phenylalanine 3 ([α]D23=+35.0, c 2.0, H2O)6 in
81% yield (Scheme 1). The uniformly high diastereoselectivity observed for alkylation of enolate 4 is
∗
Corresponding author. E-mail: steve.davies@ox.ac.uk
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00304-8

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believed to be a result of its conformation whereby the stereochemical information of the isopropyl
bearing stereogenic centre at C3 controls the conformation of both p-methoxybenzyl protecting groups
(Fig. 1).
Scheme 1.
Molecular modelling studies7 and X-ray crystal structure analysis suggested that (3S,6R)-benzylated
DKP 2 adopted a similar conformation to DKP 1. It was proposed that the β-branched C3 isopropyl
group of 2 should provide sufficient steric bias to enable regioselective deprotonation of the DKP ring
proton at C6 to form enolate 5. Subsequent reprotonation of this enolate 5 with a suitably hindered proton
source should occur trans to both the C3-isopropyl and the N1-p-methoxybenzyl group to afford (3S,6S)-
benzylated DKP 6 in high d.e.8 Deprotection of DKP 6 under standard conditions would then afford
(S)-phenylalanine ent-3 directly from auxiliary 1 (Fig. 2).
Fig. 1.
Fig. 2.

S. D. Bull et al. / Tetrahedron: Asymmetry 9 (1998) 2795–2798
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trans-(3S,6R)-6-Benzyl DKP 2 in THF at −78°C was treated with 2 equiv. of n-butyllithium and
the reaction mixture quenched via addition of a solution of 2,6-di-t-butylphenol in THF at −78°C, to
afford cis-(3S,6S)-benzylated 6 in 92% d.e. Subsequent purification of the crude reaction mixture by
chromatography [petrol:ethyl acetate (50:50)], afforded pure DKP 6 ([α]D23=−235.5, c 1.0, CHCl3) in
93% yield. No evidence could be obtained for a competing deprotonation pathway at the C3 centre since
treatment of DKP 2 in THF at −78°C with 2.5 equiv. of n-BuLi, followed by quenching with MeOD,
afforded DKP 6 with no deuterium incorporation at the C3 centre.9 The enantiomeric purity of DKP 6
1
was confirmed by comparison of its H NMR spectra with that of an authentic sample of racemic (ꢀ)-
6 in the presence of the chiral solvating agent (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol.10 Since the
epimerisation protocol had clearly demonstrated the stereoselective conversion of trans-DKP 2 to cis-
DKP 6 we were interested in determining whether this approach could be applied to the deracemisation
of α-amino acids.11 A 50:50 mixture of the epimeric DKPs 2 and 6 was prepared de novo from racemic
phenylalanine and (S)-valine in 74% yield,12 and the resulting mixture treated with 3.0 equiv. of n-BuLi at
−78°C, followed by reprotonation with 2,6-di-t-butylphenol according to the general protocol described,
to afford DKP 6 (93% d.e.). Purification by chromatography afforded homochiral diastereomerically pure
DKP 6 in 87% isolated yield (Scheme 2).13
Scheme 2.
Subsequent oxidative debenzylation of DKP 6 with ceric ammonium nitrate gave the parent cis-
(3S,6S)-DKP 8 ([α]D23=−69.5, c 1.0, H2O) which was identical to the homochiral material prepared
de novo by thermal cyclisation of dipeptide H2N–(S)-Phe-(S)-Val–OMe, clearly demonstrating that no
racemisation had occurred during deprotonation of DKP 2 with n-BuLi. cis-(3S,6S)-DKP-8 was easily
deprotected using 6 M HCl to give homochiral (S)-phenylalanine ent-3 ([α]D23=−34.7, c 2.0, H2O)5 in
70% yield.
In conclusion, the epimerisation protocol described for DKP 2 clearly demonstrates that both enantio-
mers of phenylalanine 3 and ent-3 can be prepared from homochiral (S)-auxiliary 1, and this approach

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S. D. Bull et al. / Tetrahedron: Asymmetry 9 (1998) 2795–2798
may be employed for the deracemisation of phenylalanine to (S)-phenylalanine. We are currently
investigating the scope of this enolate reprotonation strategy for the deracemisation of other racemic
α-amino acids and its use for the enantiospecific conversion of L- into D-α-amino acids (and vice versa).
Acknowledgements
We thank Oxford Asymmetry International and Zeneca Pharmaceuticals for financial support, and the
DTI and EPSRC for a LINK award.
References
1. R. M. Williams, Synthesis of Optically Active α-Amino Acids, Pergamon Press, Oxford, 1989; R. O. Duthaler, Tetrahedron,
1994, 50, 1540.
2. Some of the more popular methods are: (a) Seebach’s imidazolidinone — D. Seebach, A. R. Sting, M. Hoffmann,
Angew. Chem. Int. Ed. Engl., 1996, 35, 2708; (b) Williams’ oxazinone — R. M. Williams, M. N. Im, J. Am. Chem.
Soc., 1991, 113, 9276; (c) Evans’ oxazolidinone — D. A. Evans, A. E. Weber, J. Am. Chem. Soc., 1986, 108, 6757; (d)
Oppolzers’ sultam — W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett., 1989, 30, 6009; (e) Myers’ pseudoephedrine
auxiliary — A. G. Myers, J. L. Gleason, T. Yoon, J. Am. Chem. Soc., 1995, 117, 8488.
3. (S)-Penicillamine, for example, is used for the treatment of heavy metal poisoning while (R)-penicillamine causes atrophy
and blindness; G. M. Coppola, K. M. Schuster, Asymmetric Synthesis — Construction of Chiral Molecules using Amino
Acids, Wiley, New York, 1987.
4. For an excellent review on the enantiospecific reprotonation of prochiral enolates see: C. Fehr, Angew. Chem. Int. Ed.
Engl., 1996, 35, 2566.
5. S. D. Bull, S. G. Davies, S. W. Epstein, J. V. A. Ouzman, Chem. Commun, 1998, 659.
6. The α-amino acids had identical specific rotations to authentic samples of homochiral phenylalanine and valine purchased
from Aldrich chemical company.
ꢁ
ꢁ
7. Molecular modelling calculations were carried out using the MOPAC™ (Chem 3D™) suite of Molecular Mechanics
programs using PM3 parameters.
8. Juaristi and Seebach have employed a similar enolate reprotonation strategy to epimerise alanine derived imidazolidinone
auxiliaries containing two stereogenic centres, although no d.e. values were reported for these transformations; E. Juaristi,
J. L. Anzorena, A. Boog, D. Madrigal, D. Seebach, E. V. García-Baez, O. García-Barradas, B. Gordillo, A. Kramer, I.
Steiner, S. Zürcher, J. Org. Chem., 1995, 60, 6408.
9. Quenching enolate 5 with MeOD afforded deuterated cis-DKP (6D)-6 in 87% d.e. The use of 2.5 equiv. of n-BuLi resulted
in deuterium incorporation at both C6 and one of the four p-methoxy benzylic protons. Partial incorporation of deuterium
at the C3 position of DKP 6 could only be achieved when 5 equiv. of n-BuLi and prolonged reaction times were employed.
10. Addition of 3 equiv. of this chiral solvating agent clearly resolved the benzylic hydrogens of racemic (ꢀ)-6 in CDCl3 at δ
5.17 and 5.38: W. H. Pirkle, P. E. Adams, J. Org. Chem., 1980, 45, 4117.
11. An alternative approach to the deracemisation of α-amino acids has been reported involving a stereospecific reprotonation
approach using pantolactone as a chiral auxiliary, M. Calmes, J. Daunis, N. Mai, F. Natt, Tetrahedron Lett., 1996, 37, 379;
M. Calmes, J. Daunis, N. Mai, Tetrahedron: Asymmetry, 1997, 8, 1641.
12. Synthesis of the epimeric mixture of DKPs 2 and 6 from racemic phenylalanine may be achieved via p-methoxybenzylation
of the parent DKPs cyclo-(SR)-Phe-(S)-Val which are derived in a similar yield either via condensation of the Leuch’s
anhydride of (S)-valine with (ꢀ)-phenylalanine methyl ester according to the procedure described by S. D. Bull, S. G.
Davies, W. O. Moss, Tetrahedron: Asymmetry, 1998, 9, 321; or via DCC coupling of Z-(S)-valine and (ꢀ)-phenylalanine
methyl ester according to the method described by J. E. Rose, P. D. Leeson, D. Gani, J. Chem. Soc., Perkin. Trans. 1, 1995,
157.
13. The high diastereoselectivity observed for reprotonation of enolate 5 is under kinetic control, since thermodynamic
equilibration of trans-2 or cis-6 via treatment with sodium methoxide in methanol afforded a 60:40 ratio of trans-2:cis-6.