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Synthesis 2009(21): 3611-3616  
DOI: 10.1055/s-0029-1216979
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Short and Convenient Synthesis of Enantiopure cis- and trans-4-Hydroxypipecolic Acid

Ernesto G. Occhiato*a, Dina Scarpia, Antonio Guarnaa, Silvia Tabassob, Annamaria Deagostinob, Cristina Prandi*b
a Dipartimento di Chimica Organica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
e-Mail: ernesto.occhiato@unifi.it;
b Dipartimento di Chimica Generale e Chimica Organica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
e-Mail: cristina.prandi@unito.it;
Further Information

Publication History

Received 26 June 2009
Publication Date:
28 August 2009 (online)

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Abstract

The synthesis of (2S,4R)- and (2R,4R)-4-hydroxypipecolic acid has been realized from commercial ethyl (R)-4-cyano-3-hydroxybutanoate through palladium-catalyzed methoxycarbonylation of a 4-hydroxy-substituted lactam-derived vinyl phosphate followed by the stereocontrolled reduction of the enamine double bond. The stereoselective hydrogenation of the suitably 4-hydroxy-protected enantiomer afforded the cis-(2S,4R)-4-hydroxypipecolic acid product, obtained in 66% overall yield over seven steps. The trans-product (42% overall yield over 8 steps) was instead obtained by hydride conjugate addition to the same α,β-unsaturated ester.

Key word

amino acids - carbonylations - coupling - lactams - palladium

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15

Purification is not necessary, but a much cleaner lactam is obtained if the protected nitrile is purified by chromatography.

18

Elimination of ROH to give an α,β,γ,δ-unsaturated ester has been sometime observed by us in the presence of acids, even when compound 10 was stored in fridge and traces of acids were present. The same elimination occurs with phosphate 9.

21

Compounds trans-12a, trans-12b, and trans-12c ¹³ are easily differentiated from the corresponding cis-compounds by ¹H NMR analysis. In trans-compounds, the H2 is shifted downfield [trans-12a: δ = 5.02 and 4.86 (two rotamers); trans-12b: δ = 5.06 and 4.91 (two rotamers); trans-12c: δ = 4.98 and 4.83 (two rotamers)] and H6axial is upfield shifted (˜3.00 ppm in trans-12a,b,c) compared to the corresponding protons in the cis-isomers: H2 resonates at cis-12a: δ = 4.80 and 4.64, cis-12b: δ = 4.77 and 4.62, cis-12c: δ = 4.78 and 4.63; H6axial resonates for cis-12a-c at ca. δ = 3.45. The same applies to the corresponding alcohols: in trans-compound 13 H2 resonates at δ = 5.04 and 4.90 (two rotamers) and H6axial at ca. δ = 3.0. In the corresponding cis-isomer,¹³ H2 resonates at δ = 4.85 and 4.70 (two rotamers) and H6axial is shifted downfield to δ = 3.4.

23

Compound 14 was recovered only in traces after chromatography as it probably decomposed in part. Compound 14 has a diagnostic downfield shifted H4 proton to δ = 4.97, in accordance with the value (δ = 4.90-5.00) reported for the analogous N-tosyl and N-Cbz compounds (see ref. 22). 14: ¹H NMR (200 MHz, CDCl3): δ = 4.97 (m, 1 H), 4.90-4.70 (br m, 1 H), 4.30-4.00 (br m, 1 H), 3.74 (s, 3 H), 3.35-3.15 (br m, 1 H), 2.55-2.40 (m, 1 H), 2.40-2.37 (m, 1 H), 2.14-2.05 (m, 1 H), 1.98-1.85 (m, 1 H).