Direct diastereoselective synthesis of (±)-cis- and (±)-trans-4-methylpipecolic acid and derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00138-1

(±)-cis- or (±)-trans-4-Methylpipecolic acid and ester derivatives can be obtained directly by addition of electrophiles to α-lithiated N-Boc 4-methylpiperidine.

Full text of DOI:10.1016/S0040-4039(01)00138-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2119–2120
Direct diastereoselective synthesis of ( )-cis- and
( )-trans-4-methylpipecolic acid and derivatives
Janine Cossy* and Damien Belotti
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 17 November 2000; accepted 21 January 2001
Abstract—( )-cis- or ( )-trans-4-Methylpipecolic acid and ester derivatives can be obtained directly by addition of electrophiles
to a-lithiated N-Boc 4-methylpiperidine. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis of modified unnatural amino acids is still
of great interest and of constant inspiration.1 In partic-
ular much attention has been directed toward the
diastereoselective synthesis of enantiomerically enriched
4-substituted pipecolic acids as they are constituents of
biologically active compounds.2 Access to the cis iso-
mers is much easier than to the trans isomers as the
former are the most conformationally stable.3 One syn-
thesis of alkyl ( )-trans-4-methylpipecolate was
reported in five to six steps from 4-methylpyridine with
an overall yield of 14%.3
carboxylation of 4-methylpiperidine was envisaged.
Although, alkyl chloroformates as electrophiles were
reported to give very low yields of a-aminoesters,7 we
report here that ( )-cis- and ( )-trans-4-methylpipecolic
acid derivatives can be obtained diastereoselectively in a
two-step sequence, in modest yield, from N-Boc 4-
methylpiperidine by a lithiation–carboxylation sequence
with CO2 or alkyl chloroformates, followed by N-Boc
deprotection.
N-Boc 4-methylpiperidine 1 was deprotonated with sec-
BuLi (1.5 equiv., Et2O, −90°C, 4–5 h) in the presence of
TMEDA (1.5 equiv.). After the addition of the alkyl
chloroformate (1.6 equiv.) or CO2 at −90°C, the reac-
tion mixture was allowed to slowly reach rt and stirred
for 12 h to produce the desired carboxylic ester deriva-
tives of type 2 in a modest yield (35–60%) (see Table 1).
After deprotection of 2 with HCl in EtOAc, the 4-
methylpipecolic acid 3 (R=H) or the ester derivatives
were obtained in quantitative yield. The use of CO2 as
the electrophile produced exclusively the cis isomer.
When the acylation was achieved with methyl or ethyl
chloroformate, a mixture of ( )-cis and ( )-trans N-Boc
4-methylpipecolic esters was obtained in respective
ratios of 35/65 and 30/70 in favor of the trans
It has been reported than the N-tert-butoxycarbonyl
group (N-Boc) is an effective directing group for the
a-lithiation of piperidines4 and that the more thermody-
namically stable isomer is the trans N-Boc 4-substituted
pipecolic acid derivatives.5 As alkyl ( )-trans-4-
methylpipecolate was needed to synthesize argatroban,6
Table 1. cis/trans Ratio of 4-methylpipecolic acid and
derivatives
Electrophile
cis/trans
Yield (%)a
CO2
100/0
35/65
30/70
5/95
60
58
60
35
ClCO2CH3
ClCO2C2H5
ClCO2CH2Ph
Keywords: piperidine; pipecolic acid; electrophile; 4-methylpipecolic
acid.
* Corresponding author.
a Yield for 50% conversion of the starting material which was recov-
ered after chromatography on silica gel.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00138-1

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J. Cossy, D. Belotti / Tetrahedron Letters 42 (2001) 2119–2120
Scheme 1. a-Lithiated N-Boc piperidines.
diastereomer. Benzyl chloroformate, afforded mainly
the trans diastereomer (cis/trans=5/95) possibly
because of the increased steric bulk of this reagent. The
results are summarized in Table 1.
Agami, C.; Bihan, D; Morgentin, R.; Puchotkadouri, C.
Synlett 1997, 799–800; (j) Mahra, G. M.; Marshall, G. R.
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Schoenfelder, A.; Didier, B.; Mann, A; Wermuth, C.-G. J.
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Schneider, M.-R.; Mann, A. Synlett 1998, 1337–1338; (m)
Keenan, T. P.; Yaeger, D.; Holt, D. A. Tetrahedron:
Asymmetry 1999, 10, 4331–4341; (n) Couty, F. Amino
Acids 1999, 16, 297–320.
We would expect the lithiated intermediates a and b to
be favored as the N-Boc is in the equatorial orientation
and well situated to coordinate with the a-lithiated
anion.4,8 As the reaction proceeds with an excess of
alkyl chloroformate, equilibration between the cis and
trans 4-methylpipecolic acid or derivatives should not
occur. Furthermore, as it was assumed previously, the
electrophilic substitution of equatorial a-lithiated pipe-
ridines is achieved with retention.4 It would seem there-
fore that both equatorial and axial a-lithiated
piperidines are formed under these conditions (Scheme
1). When a non-bulky acylating reagent is used as CO2,
an equatorial electrophilic substitution is preferred
leading to the cis-2,4-disubstituted N-Boc piperidines.
To minimize steric interactions with the N-Boc group,
axial electrophilic substitution is preferred with steri-
cally hindered acylating reagent such as benzyl
chloroformate.
3. Caddy, D. E.; Utley, J. H. P. J. Chem. Soc., Perkin Trans.
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5. (a) Johnson, F. Chem. Rev. 1968, 68, 375–413; (b) Beak,
P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578–2580 and
references cited therein.
6. (a) Bush, L. R. Cadiosvasc. Drug Rev. 1991, 9, 247–263;
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Although the yield of 4-methylpipecolic acid and their
derivatives by using the carboxylation of a-lithiated
piperidines is modest (30–60%), the method is direct
(two steps) and efficient compared to the other routes.3
Applications of this methodology to the synthesis of
biologically active compounds such as argatroban9 will
be reported in due course.
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