A temperature‐dependent relay of chirality is based on the inversion of the nitrogen lone pair in cyclic azasugars. Elimination from the conformation preferred at a given temperature leads to a cyclic imine, and in a subsequent nucleophilic attack the stereochemical information is relayed.

The hydroxylated pyrrolidine scaffold provides valuable sources not only of glycomimetics 1 but also of hydroxyproline derivatives. 2 With the aim of creating biodivergently targeted libraries, we have exemplified a multicomponent reaction (MCR) giving novel bisamide pyrrolidines accessed through a chlorination-elimination strategy. 3 Previous studies have shown such imines to be efficient scaffolds for reaction with organometallic reagents. 3 We demonstrate here that they are also highly effective components in MCRs that may be applied to library construction.The mechanism proceeds via intermediates that are common to the Ugi reaction, 4 a widely used reaction in library construction. 5 However, the use of cyclic imine components in MCRs is rare: in 1989 Joullié demonstrated the role of a single cyanophenoxy dihydropyrrole. 6,7 It is all the more surprising that such a "Joullié-Ugi" process has not been applied to hydroxylated cyclic scaffolds as this would yield a ready route to compounds that could be considered as either azasugars or dihydroxyprolyl peptides. The motif thus formed would therefore potentially be effective in both carbohydrate processing (e.g., glycosidase) and/or peptide-processing (e.g., prolyl peptidase) inhibitors. 1,2,8 Several important syntheses of dihydroxyproline modules have been reported; 9 many highlight the difficulty, length, 10 relatively low yields, 11 and long reaction times 11 of prolyl amide coupling. Improved access to coupled hydroxyprolines is desirable. We hereby report that entry to the Joullié-Ugi reaction through elimination followed by facile deprotection has allowed access to one of the most wide-ranging azasugar/dihydroxyprolyl libraries, 12 which in turn has yielded potent inhibitors of two disease-associated targets, one based on inhibition of carbohydrate processing and one on peptide processing.Erythritol 3 and threitol 4 imines, formed from treatment of N-chloramine precursors 1 and 2 (Scheme 1) with DBU established the unoptimized viability of reaction with N-acetyl glycine v and benzyl isocyanide D (Scheme 1), giving reasonable yields of elaborated bisamide (68 and 64% yield over two steps from 1 and 2, respectively); excellent diastereoselectivity (de > 98%) was observed for erythritol 6vD. 13 Deprotection with TFA proceeded smoothly in 90% for erythritol 8vD and 62% for the 2,3-trans threitol species 9vD. Conditions for ready parallel handling were then established: isocyanides were removed in vacuo and acids were removed by base wash, and final treatment with TFA afforded pure deprotected product without recourse to chromatography.Carboxylic acids i-ix and isocyanides A-H (Scheme 1) were selected for a library. 12 These included hydrophobic groups since they have been shown to enhance the activity of inhibitors of glycosidases, glucosylceramide synthase, and prolyl-processing enzymes. 8,14 Test arrays probed efficiency. Reaction of 1 with N-acetyl glycine v and isocyanides A-H gave single diastereoisomers in total yields of 43-77%. 15 1 plus acids...

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