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

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 γ-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.