An alternative stereoselective synthesis of trans-(2R,3R)-3-hydroxypipecolic acid

Article abstract of DOI:10.1016/S0040-4039(01)00984-4

The enantioselective synthesis of trans-(2R,3R)-3-hydroxypipecolic acid 1b is presented, starting from O-protected methyl mandelate as chiral source. The synthesis involved a regioselective intramolecular nucleophilic substitution of an azido epoxide as t

Full text of DOI:10.1016/S0040-4039(01)00984-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5223–5225
An alternative stereoselective synthesis of
trans-(2R,3R)-3-hydroxypipecolic acid
Mansour Haddad* and Marc Larcheveˆque
Laboratoire de Synthe`se Organique associe´ au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75005 Paris, France
Received 5 April 2001; accepted 1 June 2001
Abstract—The enantioselective synthesis of trans-(2R,3R)-3-hydroxypipecolic acid 1b is presented, starting from O-protected
methyl mandelate as chiral source. The synthesis involved a regioselective intramolecular nucleophilic substitution of an azido
epoxide as the key step . © 2001 Elsevier Science Ltd. All rights reserved.
3-Hydroxypipecolic acid, a six-membered cyclic a-
amino acid, is an interesting target molecule since it
may be seen as a conformationally constrained serine
derivative or a hydroxylated homoproline,1 and may
affect the physiological and pathological processes.2
Moreover, this piperidine unit is found in a number of
biologically important products. For example, the cis-
isomer 1a forms part of the structure of tetrazomine, an
antitumor antibiotic,3 while the trans-isomer 1b is a
precursor of (−)-swainsonine 2, which has showed a
triphenylphosphine) or after reduction of the azide
function failed. This was probably due to steric hin-
drance as indicated in Scheme 1.
In view of these results, we decided to modify slightly
our strategy. For this purpose, compound 5 was treated
in the following way (Scheme 2). The alcohol protec-
tions were removed by acidic treatment, and the triol
thus obtained was transformed into the acetonide 7.
After activation of the remaining primary alcohol with
methanesulfonyl chloride, the latter underwent nucle-
ophilic displacement when submitted to an excess of
sodium azide in dimethylformamide to give the azido
potent and specific a-D-mannosidase inhibitory activ-
ity,4 and it is also found in the structure of Febrifugine
3, a potential anti-malarial agent.5
From a synthetical point of view, only few enantioselec-
tive synthesis of 1b or its enantiomer have been
reported.1,3–6 In this paper, we describe a new route to
trans-3-hydroxypipecolic acid 1b.
compound 8. Acid-promoted hydrolytic removal of the
isopropylidene unit, followed by epoxidation under
conditions described by Sharpless8 gave the azido epox-
ide 9 in good yield.
Our synthesis started from the intermediate 4, which
has been prepared earlier in our laboratory7 from O-
protected methyl mandelate (two steps in 74% overall
yield). In a first approach, 4 was hydrogenated using
PtO2 as a catalyst to give 5 (90% yield). The latter was
then transformed into the selectively activated alcohol
6. However, all attempts to cyclise 6 directly (with
The use of epoxide 9 was chosen because it eliminates
the need for selective activation of only one hydroxyl
group. As expected, when
9 was treated with
triphenylphosphine in the presence of water,9 we
observed, after reduction of the azide function, an
intramolecular nucleophilic displacement which took
place at the benzylic position, to afford the disubsti-
tuted piperidine 10.10 However, the yield was rather low
due probably to the formation of very polar by-prod-
* Corresponding author. E-mail: mhaddad@ext.jussieu.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00984-4

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M. Haddad, M. Larche6eˆque / Tetrahedron Letters 42 (2001) 5223–5225
with trifluoroacetic anhydride, selective deprotection of
the hydroxyl group with K2CO3 in THF, and protec-
tion as the acetate, yielding 11 (Scheme 3). Oxidation
and deprotection finally gave the target compound
1b,13 with spectral data identical to those already
described.
In conclusion, we have developed a new practical
access to trans-3-hydroxypipecolic acid. The latter is
obtained with a high stereoselectivity, starting from
methyl (R)-(−)-mandelate, a commercially available
material.
Scheme 1.
References
1. Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi,
G.; Fava, G. G.; Ferrari, M. B.; Casiraghi, G. Tetra-
hedron: Asymmetry 1997, 17, 2975–2987.
2. Sugisaki, C. H.; Carroll, P. J.; Correia, C. R. D. Tetra-
hedron Lett. 1998, 39, 3413–3416.
3. Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron
Lett. 1998, 39, 3659–3662.
4. Ferreira, F.; Greck, C.; Geneˆt, J. P. Bull. Soc. Chim. Fr.
1997, 134, 615–621.
5. Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033–
7036 references cited therein.
6. (a) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetra-
hedron Lett. 1999, 40, 3843–3846; (b) Agami, C.; Couty,
F.; Mathieu, H. Tetrahedron Lett. 1996, 37, 4001–4002.
7. Haddad, M.; Imogai, H.; Larcheveˆque, M. J. Org. Chem.
1998, 63, 5680–5683.
8. Kolb, H. C.; Sharpless, B. Tetrahedron 1992, 48, 10515–
10530.
9. Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr.
1985, 5, 815–819.
Scheme 2. (a) MeOH/HCl, rt, 90%; (b) CuSO4, acetone,
PPTS, 92%; (c) MsCl, NEt3, DMAP; then NaN3, DMF,
60°C, 82%; (d) THF/10% HCl (2/1), reflux (12 h); then
MeC(OMe)3, Me3SiCl (CH2Cl2/0°C) and K2CO3, MeOH,
76%.
10. (2S,3R)-2-Phenylpiperidin-3-ol 10: [h]2D2=−23 (c 1.5,
MeOH); mp 143–144°C dec. 1H NMR (400 MHz,
CDCl3): l 1.35–1.50 (1H, m), 1.65–1.85 (2H, m), 2.08–
2.18 (1H, m), 2.2–2.4 (2H, m), 2.66 (1H, dt, J=3.6 and
11.5 Hz), 2.97–3.07 (1H, m), 3.34 (1H, d, J=9 Hz), 3.6
(1H, ddd, J=4.4, 9 and 10.6 Hz), 7.15–7.45 (5H, m).
13C NMR (50 MHz, CDCl3): l 24.9, 33.0, 46.5, 69.0,
ucts resulting from the opening of the epoxide by
triphenyl phosphine, and attempts to increase it by
modifying the experimental conditions (amount of
triphenylphosphine or water, the use of LiClO4 as
catalyst11) were unsuccessful. The next steps for the
transformation of 10 into 1b were accomplished in the
following way:12 complete protection by treatment
Scheme 3. (a) P(Ph)3 (1.5 equiv.), H2O (2 equiv.), THF, 48 h, 38%; (b) 1. (CF3CO)2O, NEt3; 2. K2CO3 (2 equiv.), THF; 3.
(CH3CO)2O, NEt3, 80%; (c) 1. RuCl3·H2O, NaIO4; . 2. K2CO3, MeOH, 60%.

M. Haddad, M. Larche6eˆque / Tetrahedron Letters 42 (2001) 5223–5225
5225
72.3, 128.1, 128.7, 140.6; MS (CI, NH3) m/z 178 (MH+,
100%).
11. Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. J. Org.
Chem. 1991, 56, 7043–7048.
12. Haddad, M.; Larcheveˆque, M. Tetrahedron: Asymmetry
1999, 10, 4231–4237.
13. Spectral data for 1b: [h]2D2=−13 (c 0.45, 10% HCl), lit.4
[h]2D2=−14 (c 0.4, 10% HCl); mp 232°C dec. 1H NMR
(400 MHz, D2O): l 1.54 (2H, m), 1.81 (2H, m), 2.93 (1H,
m), 3.18 (1H, m), 3.45 (1H, d, J=7 Hz), 3.98 (1H, m).
13C NMR (50 MHz, D2O): l 18.3, 28.1, 42.4, 61.9, 65.9,
172.0; MS (CI, NH3) m/z 146 (MH+).
.