Diastereoselective Synthesis of Piperidine Imino Sugars Using Aldol Additions of Metalated Bislactim Ethers to Threose and Erythrose Acetonides

Abstract

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the gamma-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, high trans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-L-altronojirimycin, 1-deoxy-D-gulonojirimycin, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin and 1-deoxy-D-talonojirimycin.

Asymmetric Diels–Alder cycloadditions of d-erythrose 1,3-butadienes to achiral t-butyl 2H-azirine 3-carboxylate

“…[1][2][3][4][5] However, the use of its 1,3-butadiene derivatives 1 is not common. The lack of interest in these dienes, namely as counterparts in Diels-Alder cycloadditions (DA), is probably due to the poor facial selectivity associated with DA thermal processes, although exceptions are known.…”

Access to pyrrolidine imino sugars via tin(ii)-mediated aldol reactions of bislactim ethers: synthesis of 2,5-dideoxy-2,5-imino-d-glucitol

“…6c We have recently described a general strategy for the synthesis of piperidine imino sugars, by using an aldol reaction between metalated bislactim ethers and threose or erythrose acetonides in the key-step. 7 In this paper, we introduce an extension of this methodology to the synthesis of pyrrolidine imino sugars. In adapting the synthetic plan we recognized that amino esters 2 might be valuable intermediates since the target pyrrolidines would originate by cyclization via Departamento de Química Fundamental, Facultade de Ciencias, Universidade da Coruña, Campus da Zapateira s/n, 15071 A Coruña, Spain.…”

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars

“…Substitution in 117 afforded 118, which after reduction and protecting group removal gave galacto-DNJ 17 (Scheme 22). [71] Scheme 18. Chemoenzymatic synthesis of DNJ 3 by Clapés and co-workers.…”