An efficient stereoselective and stereodivergent synthesis of (2R,3R)- and (2R,3S)-3-hydroxypipecolic acids

Article abstract of DOI:10.1016/S0040-4039(00)01207-7

Asymmetric syntheses of (2R,3R) and (2R,3S)-3-hydroxypipecolic acids are reported featuring a key diastereoselective addition of Buchi's Grignard reagent to the chiral serinal L-5. Based on conformational analysis, a stereocontrolled reduction of piperidi

Full text of DOI:10.1016/S0040-4039(00)01207-7

Tetrahedron Letters 41 (2000) 7033±7036
An ecient stereoselective and stereodivergent synthesis of
(2R,3R)- and (2R,3S)-3-hydroxypipecolic acids
Angelique Jourdant and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 5 May 2000; accepted 13 July 2000
Abstract
Asymmetric syntheses of (2R,3R) and (2R,3S)-3-hydroxypipecolic acids are reported featuring a key
diastereoselective addition of Buchi's Grignard reagent to the chiral serinal l-5. Based on conformational
analysis, a stereocontrolled reduction of piperidin-3-one (15) to cis 2,3-disubstituted piperidine (16) is also
described. # 2000 Elsevier Science Ltd. All rights reserved.
Chiral, non-racemic piperidines are common structural units found in many biologically and
medicinally important natural and non-natural products. It is thus not surprising that many new
asymmetric synthetic methods have been developed.1 Among them, chiral auxiliary based
approaches developed by the groups of Husson,2 Meyers,3 and Comins,4 respectively, are notable
examples. Interestingly, the synthesis of 3-hydroxy-piperidine derivatives,5 such as, 3-hydroxy-
pipecolic acid (1 and 2),6 (+)-prosophylline (3),7 Febrifugine (4)8 etc. (Fig. 1) are less developed
and their asymmetric syntheses have been accomplished only very recently. Our group9 and
Pedrosa et al.10 have recently synthesized a new serinal: l-(N,N-dibenzylamino)serine (TBDMS)
aldehyde (5). The predictable and high diastereofacial selectivity of nucleophilic addition to the
aldehyde function constitutes the main advantage of this synthon.11 As part of a program
directed at synthesizing alkaloids using the enantiopure l-5 and d-5 as chiral building blocks, we
report in this letter an ecient synthesis of both (2R,3R) and (2R,3S)-3-hydroxypipecolic acids
(1 and 2) from l-5.
Figure 1.
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01207-7

7034
Swern oxidation of serinol l-6 gave the aldehyde l-5 which, without puri®cation, was reacted
with Buchi's Grignard reagent12 to give the amino diol 8 in excellent yield and diastereoselectivity
(anti:syn=15:1). The major stereomer was assumed to be anti according to Felkin±Anh model13
and this is corroborated by the obtention of ®nal compound. Catalytic hydrogenation (3N HCl,
tBuOH±THF, Pd/C, H2) followed by N-protection as tert-butoxycarbamate gave piperidine 9 in
80% overall yield. A series of four reactions, namely, hydrogenolysis of the N-benzyl function,
hydrolysis of the acetal, imine formation and reduction of the imine took place under these
hydrogenolysis conditions. It was found that the reaction consistently gave high yields of the
t
desired compound 9 when the hydrogenation was carried out in a mixture of BuOH±THF
instead of MeOH. Selective oxidation of the primary alcohol under various conditions14 failed to
give the desired b-hydroxy carbonyl compound. Consequently, a straightforward three-step
sequence was applied to convert the diol into the primary alcohol 12. Jones' oxidation of 12
followed by simultaneous removal of MOM ether and N-Boc functions under acidic conditions
gave then (2R,3R)-3-hydroxypipecolic acid (1)15 whose physical and spectroscopic data are in full
agreement with those reported in the literature (Scheme 1).
Alternatively, the secondary hydroxyl group of compound 8 was protected as its MOM ether
immediately after its formation to give the fully protected amino diol 13. Hydrogenolysis of 13 in
MeOH (3N HCl, 10% Pd/C) gave directly the piperidine 14 as its hydrochloride salt in 50% yield
(Scheme 2). Partial deprotection of TBDMS and MOM ethers under these acidic conditions were
nevertheless unavoidable.
Scheme 1. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, ^78ꢀC, then Et3N; (b) 2-(2-bromethyl)-1,3-dioxolane
(7), Mg, THF, 86% then 5; (c) (i) H2, 10% Pd/C, 3N HCl, THF:tBuOH (1:1); (ii) Boc2O, H2O, dioxane, 1N NaOH,
80%; (d) TBDPSCl, DMF, imidazole; (e) MOMCl, Hunig's base, CH2Cl2, re¯ux, 90%; (f) HF (48%), pyridine, THF,
85%; (g) CrO3/H2SO4, 2.67 M, acetone, 0ꢀC; (h) 6N HCl, 80ꢀC, 2 h, 75%
Scheme 2. Reagents and conditions: (a) MOMCl, Hunig's base, CH2Cl2, rt, 90%; (b) Pd/C, MeOH, 3N HCl, 50%

7035
1
Analysis of H NMR spectrum of piperidine 9 indicated that it adopted in solution a trans
diaxial conformation exclusively as evidenced by the coupling constant (JH2 H3=1.5 Hz).
Computational studies (Macromodel, version 5.5, force ®eld MM2) also showed that the trans
diaxial conformer was more stable than the trans diequatorial one. Such a conformational
preference is understandable assuming the partial double bond character of the C±N carbamate
bond which causes the A1,3 strain in the trans diequatorial conformation.16 This conformational
analysis led us to develop a synthesis of (2R,3S)-3-hydroxypipecolic acid based on the assumption
that reduction of ketone 15 might be highly stereoselective to give cis 2,3-disubstituted piperidine
16. Indeed, reduction of ketone 15 with sodium borohydride a€orded a single diastereomer whose
1H and 13C spectra are in accord with the assigned con®guration and are di€erent from that of
10. Following the same route described for the synthesis of 1, compound 16 was converted to
(2R,3S)-3-hydroxypipecolic acid (2) in 52% overall yield (Scheme 3).
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, ^78ꢀC, then Et3N, 96%; (b) NaBH4, MeOH, 0ꢀC,
88%; (c) MOMCl, Hunig's base, CH2Cl2, re¯ux, 89%; (d) HF (48%), pyridine, THF, 75%; (e) CrO3/H2SO4, 2.67 M,
acetone, 0ꢀC; (f) 6N HCl, 80ꢀC, 2 h, 78%
The high diastereoselectivity observed in the reduction of 15 can be rationalized on the basis of
Felkin's torsional strain model which disfavors the equatorial attack of hydride.13,17 The presence
of the N-Boc function in the six-membered ring should ¯atten the molecule and decrease the
1,3-diaxial steric interactions, further increasing the axial selectivity (Fig. 2).
Figure 2.
In summary, we have described a highly stereoselective and stereodivergent synthesis of both
the (2R,3R) and (2R,3S)-3-hydroxypipecolic acids from the common serinal (l-5) with 39 and
29% overall yield, respectively. Since its antipode d-5 is easily available, the chemistry developed
here can be applied to the synthesis of other two diasteromeric hydroxypipecolic acids.

7036
Acknowledgements
A doctoral fellowship from MRES to A. Jourdant is gratefully acknowledged. We thank Dr. T.
Laõb for a helpful discussion.
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