Enantioselective Synthesis of Cyclic Amides and Amines through Mo-Catalyzed Asymmetric Ring-Closing Metathesis

Abstract

First, an efficient method for the synthesis of optically enriched N-fused bicyclic structures is reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-, 5,7-, and 5,8-bicyclic amides can be synthesized in up to >98% ee. The effects of catalyst structure, olefin substitution, positioning of Lewis basic functional groups and ring size are examined and discussed in detail. In the second phase of investigations, a catalytic asymmetric method for highly enantioselective (up to 97% ee) synthesis of small- and medium-ring unsaturated cyclic amines is reported; optically enriched products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereoselective functionalizations of olefins within the optically enriched amine products have been carried out. Both catalytic asymmetric methods include transformations that lead to the formation of trisubstituted as well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high optical purity; such products are not easily accessed by alternative protocols and can be used in enantioselective total syntheses of biologically active molecules.

Catalytic Enantioselective Olefin Metathesis and Natural Product Synthesis

“…In 2005, the first examples of enantioselective olefin metathesis involving substrates that bear Lewis basic amines were reported [3]. Catalytic activity of number of chiral Mo-based diolates (such as 2, Scheme 12.1) were probed; enantioselective ring-closing metathesis (RCM) reactions deliver various azacyclic structures in up to 99/1 enantiomeric ratio (er).…”

Olefin Metathesis of Amine‐Containing Systems: Beyond the Current Consensus

“…[76] Enantioenriched piperidine derivatives were synthesized from trienes 119 and 122 by treatment with chiral molybdenum catalysts 121 in benzene. [77] Under these conditions, tertiary amines and neopentylic unprotected secondary amines readily underwent asymmetric RCM in good yields and enantioselectivities (Scheme 44).…”

“…[85,86] This feature has also been exploited to perform RCM reaction of catechol-protected secondary amines. [77] Alternative approaches to classical RCM reaction have been reported by the group of Takeda; [87] various saturated nitrogen heterocycles such as 139 have been obtained in modest to good yields by titanocene(II)-promoted cyclization of thioacetals 138 (Scheme 52).…”

Asymmetric catalysts for stereocontrolled olefin metathesis reactions

“…As this additional concept of enhanced sterics around the nitrogen is structurally limited and the enantioinduction moderate (71% ee), the use of different N-protecting groups was focused. 38 In this regard the Cbz-group in 66, which usually can be removed with ease, proved to be suitable. 4 efficiently promoted the ARCM in 98% yield and 95% ee with a catalyst loading of 5 mol%.…”