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

Abstract

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.

Chemical Biology: What is Its Role in Drug Discovery?

“…Ducatti has reported the use of polysaccharides from red seaweed in the synthesis of useful carbohydrate building blocks . Others have described the synthesis of tetrafluorinated ribose and fructose (Linclau et al, 2009), 6-deoxy-6-fluorohexoses (Caravano et al, 2009), difluorinated carbasugar phosphates (Anderl et al, 2009), and pyrrolidine homoazasugars (Blanco et al, 2009). The synthesis of unnatural inositol phosphates, 4-C-methyl-Ins(1,4,5)P 3 and 4-C-methyl-Ins(1,3,4,5)P 4 has been reported (Swarbrick et al, 2009).…”