Enantioselective Synthesis of (2R,4S)- and (2S,4R)-4-Hydroxypipecolic Acid from d-Glucoheptono-1,4-lactone

Abstract

Enantiomerically pure (2R,4S)-4-hydroxypipecolic acid [(+)-1] was synthesized from d-glucoheptono-1,4-lactone (2) via the 3,5-dideoxy-d-xylo-heptono-1,4-lactone (7). The latter was readily prepared by benzoylation of 2, followed by β-elimination and diastereoselective hydrogenation of the resulting furanones (4). Compound 7 was converted into the 6,7-O-cyclohexylidene derivative 11, which on treatment with tosyl chloride for long periods afforded the 2-chloro derivative 14, the precursor of the azide 15. Hydrogenolysis of 15 and protection of the amine gave the N-benzyloxycarbonyl derivative 19, having the required configuration for the stereocenters at C-2 and C-4. Removal of the cyclohexylidene group by hydrolysis and subsequent oxidative degradation of the resulting glycol system afforded the hexurono-6,3-lactone 21 as a key intermediate. Chemoselective reduction of the aldehyde function of 21 led to the alcohol 23, which was derivatized as the mesylate 24. Releasing of the amino group by hydrogenation, and dissolution of resulting 25 in aqueous alkali, promoted the intramolecular nucleophilic displacement of the mesylate to give (+)-1. Its enantiomer [(−)-1] was prepared by a similar sequence starting from 2.

Asymmetric Synthesis of the Four Stereoisomers of 4-Hydroxypipecolic Acid

“…Structures of 4-Hydroxypipecolic acids 1 and 4-oxopipecolic acid (2) Only a few syntheses of enantiomerically enriched 4-hydroxypipecolic acids (1) have been described. 8 These include the transformation of 4-oxopipecolic acid (2), 9 a constituent of the virginiamycins family of cyclopeptides, 10 cyclization of chiral N-acyliminium ions 11 and other procedures which start from D-glucoheptono-1,4lactone, 12 glycidol, 13 or a chiral 1-acylpyridinium salt. 14 Unfortunately many of these methods suffer from limitations which include classical resolutions, 15 inefficient separation of diastereoisomers, expensive reagents and/or lengthy synthetic procedures.…”

Synthesis of a Serine-Based Neuraminic Acid C-Glycoside

“…Lactone 7 could be opened by using acetic acid and water as reaction media, affording the unprotected serine-based neuraminic acid C -glycoside. , Attempts to protect the resulting free amino acid with FmocCl , only afforded the N -Fmoc protected, lactonization product.…”

Synthesis of 3,4-Di-O-benzyl-1-O-methyl-L-galactitol, a key precursor of the C33-C37 fragment of calyculins

“…The structure of the minor product of methanolysis was established as methyl 6-O-methyl-b-D-galactofuranoside (8), on the basis of its spectral data. Thus, the small J 1,2 value (1.6 Hz) indicates a trans relationship for H-1 and H-2, and hence a b-furanoside ring 14 .…”

“…In this case a D-lyxose derivative 6b , previously synthesized by van Boom 7 , was employed as starting material, and the pentitol derivative 1 was an advanced intermediate in the sequence (Scheme 1). In connection with our project on the enantiospecific synthesis of naturally occurring hydroxy amino acids from carbohydrates 8,9 we wish to report here the synthesis of a conveniently protected L-galactitol derivative 3, an analog of 1 having one more carbon atom, as key intermediate for the synthesis of 2a. In our strategy we started from inexpensive and readily available D-galactose, and all the steps to 3 were high yielding.…”