Asymmetric Synthesis of d-Proline, d-Pipecolic Acid, (2R,3S,4R)-3,4-Dihydroxyproline, and 1,4-Dideoxy-1,4-imino-d-talitol from a Common Precursor

Abstract

Methodology involving stereoselective aza-Michael addition and ring-closing metathesis as key steps has been developed for the preparation of (2R)-pipecolic acid, (2R)-proline, (2R,3S,4R)-3,4-dihydroxyproline, and the known glycosidase inhibiting azasugar 1,4-dideoxy-1,4-imino-D-talitol from a common starting material namely (R)-cyclohexylideneglyceraldehyde in good overall yields.Naturally occurring azacyclic α-amino acids, such as proline and pipecolic acid, are privileged structures, for example, as a part structure of natural products in either enantiomeric form, 1 in the synthesis of designed peptides, 2 in asymmetric organocatalysis, 3 as building blocks in organic synthesis 4 for the preparation 5 of compounds of type 1 (Figure 1) and catalysts of type 2, etc. Similarly, several hydroxylated proline derivatives of type 3 belonging to the family of azasugars possess useful levels of glycosidase inhibitory activity. 6 As a result numerous methodologies have emerged for the synthesis of these two classes of compounds involving the use of chiral catalysts, chiral-pool material, chiral auxiliaries, etc. 7,8 Although superb catalytic methods are known, and applicable, in principle, for the synthesis of either enantiomer of these important targets, methods involving the simple conversion of readily available materials remain important. Additionally, incorporation of elements of diversity in any such approach would be of further advantage. Herein, we describe a unified approach to Rconfigured two homologous azacyclic amino acids from a common precursor. Figure 1 Azacyclic structures of importanceOur synthesis (Scheme 1) started from the known 9 (R)-cyclohexylideneglyceraldehyde (4), which was easily converted into the α,β-unsaturated ester 5. 10 We envisaged that conjugate addition of a suitable nitrogen nucleophile to 5 may prove to be diastereoselctive in view of ample analogous precedence 11 and also our earlier success in a related system. 12 Thus, addition of allylamine to this unsaturated ester in the presence of borax 13 under our developed conditions 12 provided a mixture of two possible isomeric products, syn-and anti-β-amino esters 6 in a combined yield of 88% with a diastereomeric ratio of 82:18 (by 1 H NMR). The mixture of diastereomers was then reduced with lithium aluminum hydride to obtain the corresponding mixture of primary alcohols 7 which could also not be separated. However, N-protection of this mixture of β-amino alcohols with benzyl chloroformate neatly provided a separable mixture of the corresponding carbamates 8 and 9 in very good yield and in a diastereomeric ratio of ~4:1.Scheme 1 Synthesis of the β-amino alcohols 8 and 9The major product 8 was assigned syn-stereochemistry based on precedence and corroborated by the synthetic work described herein. We surmised that compound 8 could be utilized as a building block in asymmetric synthesis of the projected amino acids if a successful conversion of the primary alcohol function to an olefinic unit N N H HO OH OH OH 1, n = 1, 2 2, n = 1, 2 3 (...

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…245) [634], iminosugars [635], a benzpyrroloazepine derivative [636], and swainsonine [637]; (2) an α,β-unsaturated five-membered ring lactam for total synthesis of lundurines A and B (e.g. 246) [638]; (3) five-and six-membered ring lactams that contain fluorinated alkene groups [639]; (4) five-and six-membered ring unsaturated lactams for total syntheses of indolizidinone and quinolizidinone derivatives [640]; (5) five-and six-membered ring amines for preparation of cyclic α-amino acid derivatives [641]; (6) tetrahydropyridines [642,643], including those employed in total syntheses of meloscine analogs (e.g. 247) [644], cryptopleurine [645], leuconoxine, leuconodine B, melodinine E (in a diastereoselective RCM) (e.g.…”