Synthesis of pyrrolidine homoazasugars and 3,4-dihydroxy-5-hydroxymethylprolines using aldol additions of metalated bislactim ethers to 2,4-O-ethylidene-D-erythroses.

A strategy for the synthesis of 2,5-dideoxy-2,5-iminohexitols and 2,5-dideoxy-2,5-iminoglyconic acids is described by using diastereoselective aldol additions of metalated bislactim ethers to 2,4-O-ethylidene-d-erythroses and intramolecular N-alkylation as key steps. The nature of the metal fragment of the azaenolate and the beta-alkoxy protecting group for the erythrose moiety were varied to modulate the level and the direction of the asymmetric induction in the aldol addition. The contrasting stereochemical results of the tin(II)-mediated aldol reactions have been rationalized with the aid of density functional theory calculations (B3LYP/cc-pVDZ-PP). DFT calculations indicate that boat-shaped transition structures that allow the formation of a stabilizing hydrogen bond can account for the unusual anti,syn-stereoselectivity of the aldol addition to beta-protected 2,4-O-ethylidene-erythroses. In the addition to the "unprotected" 2,4-O-ethylidene-erythrose, the preference for chair-shaped transition structures in which the erythrose moiety is involved in a six-membered chelate ring is consistent with the experimentally observed syn,anti-stereochemical outcome. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of glycosidase inhibitors 2,5-dideoxy-2,5-iminogalactitol and 2,5-dideoxy-2,5-imino-d-glucitol (DGADP and DGDP) and 3,4-dihydroxy-5-hydroxymethylprolines (2,5-dideoxy-2,5-imino-l-gulonic acid and 2,5-dideoxy-2,5-imino-l-galactonic acid) that may be useful for glycosidase and glycuronidase inhibition.

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

2,5-Dideoxy-2,5-imino-D-glucitol (DGDP) has been synthesized via the tin(II)-mediated anti-selective aldol reaction of bislactim ether 5 and a 3-O-silylated 2,4-ethylidene-D-erythrose derivative 6. In accordance with density functional theory calculations (at the B3LYP/cc-pVDZ-PP level), pericyclic transition structures with a boat-like conformation and a stabilizing hydrogen bond can account for the unexpected stereoselectivity.

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 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.