Asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid

Article abstract of DOI:10.1016/S0040-4039(00)00460-3

An asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid was accomplished in eight steps and 31% overall yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00460-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3551–3553
Asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid
Clinton A. Brooks and Daniel L. Comins ∗
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 20 January 2000; revised 18 February 2000; accepted 22 February 2000
Abstract
An asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid was accomplished in eight steps and 31% overall
yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; pyridinium salts; dihydropyridones; amino acids.
Pipecolic acid derivatives are useful synthetic intermediates for the preparation of medicinally impor-
tant compounds such as peptides,1 immunosuppressants,2 enzyme inhibitors3,4 or NMDA antagonists.5
The naturally occurring (2S,4R)-4-hydroxypipecolic acid (1) is found as a constituent of certain cyclo-
peptide antibiotics6 and has been used as a building block in a synthesis of palinavir (2), a potent HIV
protease inhibitor.7 Several racemic and a few enantioselective preparations of 1 have been reported.8
Syntheses of enantiopure (2S,4R)-1 have been carried out by resolution or by using starting materials
from the chiral pool. Herein we report the first chiral auxiliary mediated asymmetric synthesis of 1.
Addition of vinylmagnesium bromide to chiral 1-acylpyridinium salt 3, formed in situ from 4-
methoxy-3-(triisopropylsilyl)pyridine9 and the chloroformate of (−)-TCC,10 provided the crude dihydro-
pyridone 4 in high yield and 85% de (Scheme 1). Recrystallization of the crude product from methanol,
and purification of the concentrated mother liquor by radial PLC (SiO2, EtOAc/hexanes), gave a 78%
yield of diastereomerically pure 4 as a white solid, mp 133–134°C. Reaction with sodium methoxide
followed by aqueous acid provided dihydropyridone 5 in 89% yield with 94% recovery of the chiral
auxiliary, (−)-TCC. N-Acylation of 5 with n-BuLi and benzyl chloroformate gave a near quantitative
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00460-3
tetl 16740

3552
yield of enantiopure carbamate 6. Although conjugate reduction of dihydropyridone 6 could be carried
out with L-Selectride,11 the use of zinc and acetic acid was found to be more convenient and provided
25
the piperidone 7 [α] −30.8 (c 1.67, CHCl3), in higher yield. Oxidative cleavage of the vinyl group
D
23
D
with ozone and subsequent esterification of the crude acid gave ester 8 [α] −17.9 (c 0.24, CHCl3), in
59% yield for the two steps. Stereoselective reduction of the C-4 keto group with K-Selectride afforded
23
D
the piperidinol 912 [α] +81 (c 0.105, CHCl3). Catalytic hydrogenation of 9 gave the desired (2S,4R)-
4-hydroxypipecolic acid (1) in 98% yield as a white solid. An analytically pure sample was obtained
23
D
by recrystallization from hot methanol: mp 273–274°C [lit.8 mp 273–275°C], [α] −20.7 (c 0.30,
25
D
H2O) [lit.8 [α] −21.0 (c 1.03, H2O)]. The spectral properties of our (−)-1 are in agreement with
reported data. The naturally occurring 1 was constructed enantioselectivity in eight steps and 31% overall
yield.13,14 The general approach should be amenable to the preparation of other substituted pipecolic
acids as either antipode.
Scheme 1.
Acknowledgements
We express appreciation to the National Institutes of Health (Grant GM 34442) for partial support of
this work. C.B. also thanks the Burroughs Wellcome Fund for a graduate fellowship. NMR and mass
spectra were obtained at NCSU instrumentation laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National Science Foundation.
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14. NMR data: Compound 6, 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.2, 1H), 7.38 (m, 5H), 5.79 (m, 1H), 5.36–5.06 (m,
6H), 2.89 (dd, J=16.4 and 6.8 Hz, 1H), 2.53 (d, J=16.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 192.2, 152.5, 141.5, 135.0,
132.8, 128.8, 128.4, 117.5, 107.6, 69.2, 54.8, 39.9. Compound 7, 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 5H), 5.77 (m,
1H), 5.19 (m, 5H), 4.21 (m, 1H), 3.38 (m, 1H), 2.78–2.26 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 206.8, 155.3, 136.4,
136.1, 128.6, 128.3, 128.0, 117.9, 67.7, 53.4, 43.4, 40.4, 39.2. Compound 8, 1H NMR (300 MHz, CDCl3) δ 7.45–7.15 (m,
10H), 5.30–4.90 (m, 5H), 4.12 (m, 1H), 3.68 (m, 1H), 3.00–2.65 (m, 2H), 2.50 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
205.2, 170.8, 155.8, 136.2, 135.2, 128.9, 128.8, 128.5, 128.4, 128.2, 68.2, 67.7, 54.8, 41.3, 40.5, 39.8.