Syntheses of Enantiopure 3,4-Diamino-1-Substituted Pyrrolidines

Abstract

A convenient and general route to enantiopure 3,4-diamino-1-substituted pyrrolidines has been devised. 1-Alkyl, 1-alkanoyl, 1-cycloalkyl and 1-aryl-3,4-diaminopyrrolidines of the (3R,4R)-configurations have all been prepared, the cycloalkyl and (mono)aryl being novel derivatives. A previous difficulty in the synthesis of such compounds is the observation that dimesylates undergo two-fold displacement with sodium azide in very poor yields (<10%), if at all. However, use of lithium azide permits satisfactory yields of the diazides 5 and hence the corresponding diamines 6 and their derivatives, and avoids the generation and use of hydrazoic acid, as previously required in a Mitsunobu procedure.Enantiopure trans-vicinal diamino compounds have attracted much interest, such C 2 -symmetric diamines occupying a central role in catalytic asymmetric synthesis. 1 Whereas cyclohexane-1,2-diamine and its derivatives are well described and in enantiopure forms have found extensive use as catalysts in asymmetric synthesis, 2 1,2-diamines on a five-membered ring are much less wellknown, including 3,4-diaminopyrrolidine and its derivatives. Many amino-substituted pyrrolidines possess significant pharmacological properties, 3 including antibacterial activity, 4a and antagonistic activity toward the melanin-concentrating hormone receptor. 4b They have also found use in catalytic asymmetric synthesis. 5 3-Aminopyrrolidines have served as templates for the introduction of essential pharmacophoric groups, 6 and present a relatively conformationally rigid framework suitable for incorporation into anti-filarial agents. 7 trans-3,4-Diaminopyrrolidines have found use in the assembly of numerous systems of specific molecular recognition 8 and as catalysts in enantioselective alkylations, 9 functions that make use of their C 2 symmetry. trans-3,4-Diaminopyrrolidines are also well-suited to development in the context of combinatorial chemistry 10 and have formed the basis of some C-nucleosides. 11 Substituted 3,4-diaminopyrrolidines occupy a niche that is difficult to replace, since a wide variety of 1-substituents may be introduced without losing the essential C 2 symmetry of the molecule. A suitable 1-substituent would also permit attachment to polymeric resins or beads. Despite these applications and advantages, the literature on enantiopure 1-substituted 3,4-diaminopyrrolidines and their related 3,4-disubstituted derivatives is limited, and a general route has not yet been demonstrated. A particular limitation has been observed in attempted two-fold displacements of the corresponding pyrrolidine-trans-3,4-dimesylates with sodium azide; for example, 3,4-diazido-1-dodecylpyrrolidine could be obtained in no more than 10% yield by the use of sodium azide, either in DMF, HMPA, or under twophase conditions using phase-transfer catalysis. 12 An alternative procedure involves the generation of the highly toxic and explosive hydrazoic acid and its use under Mitsunobu conditions (e.g. with diethylacetylene dicarboxylate and triphenylphosphine), 10...

Chiral Tertiary Diamines in Asymmetric Synthesis

“…New breakthroughs may come from some of these new diamines or improvements of some of the already existing and studied structures. Indeed, diamines having a bridgehead structure, − based on aziridine, azetidine, pyrrolidine, − or piperidine core, , derived from cyclobutane, cyclopentane, , or cyclohexane diamines, − derived from metallocene − or other structures, − have already been reported in the literature, but they have not yet been used as tertiary diamines. Considering the restriction we made describing only those having tertiary nitrogen atoms, one can easily obtain a glimpse of the huge potential of diamines in the broad sense of the term when added to all other substitution possibilities.…”