Enantioselective Synthesis of Angularly Substituted 1-Azabicylic Rings: Coupled Dynamic Kinetic Epimerization and Chirality Transfer

Abstract

A new strategy for enantioselective synthesis of azacyclic molecules in which dynamic kinetic equilibration of diastereomeric iminium ions precedes a stereochemistry-determining sigmatropic rearrangement is reported. The method is illustrated by the synthesis in high enantiomeric purity (generally 95–99% ee) of a variety of 1-azabicyclic molecules containing angular allyl or 3-substituted 2-propenyl side chains adjacent to nitrogen and up to three stereogenic centers. In these products, the size of the carbocyclic ring is varied widely (5–12 membered), however useful yields are obtained in forming 1-azabicyclic products containing only fused pyrrolidine and piperidine rings. Chi-rality transfer from substituents at carbons 1 and 2 of the 3-butenylamine fragment of the starting material is investigated, with methyl and phenyl substituents at the allylic position shown to provide exquisite stereocontrol (generally 98–99% chirality transfer). An attractive feature of the method is the ability to carry out the key transformation in the absence of solvent. Illustrated also is the high yielding conversion of four such products to a new family of bicyclic β-amino acids of high enantiomeric purity.

Recent Advances in the Synthesis of Hydrogenated Azocine-Containing­ Molecules

“…Azocine derivative 350 was obtained in 16% yield via cationic aza-Cope rearrangement of aminoketal 349 (Scheme 104 ). 111…”

Asymmetric Synthesis of β-Amino Amides by Catalytic Enantioconvergent 2-Aza-Cope Rearrangement

“…9 Chiral acid catalyzed aza-allylations of simple aldehydes have been reported from the laboratories of Rueping and Wulff, and this body of work provided the mechanistic framework for our experimental plan. 8 Our initial investigations were guided by our recent successes using α -keto ester (±)- 1 in stereoconvergent reactions.…”

“…While catalytic asymmetric sigmatropic rearrangements are well-established, examples of enantioselective 2-aza-Cope rearrangements are comparatively rare, and the 2-aza-Cope reaction as a DKR process has only been demonstrated utilizing stereochemically defined aminoallyl reagents . Chiral acid catalyzed aza-allylations of simple aldehydes have been reported from the laboratories of Rueping and Wulff, and this body of work provided the mechanistic framework for our experimental plan .…”

Silver-Assisted, Iridium-Catalyzed Allylation of Bis[(pinacolato)boryl]methane Allows the Synthesis of Enantioenriched Homoallylic Organoboronic Esters

“…Furthermore, compound 17 underwent an efficient C–B to C–N conversion when treated with LiNHOMe, and yielded homoallylamine 24 after Boc protection in the same pot. Notably, compound 24 was a key intermediate used in the preparation of bicyclic piperidines such as 25 , and had been previously made in four steps from methyl cinnamyl carbonate (vs two steps from tert -butyl cinnamyl carbonate in our sequence). Lastly, we subjected 17 to a direct hydroboration–oxidation sequence to give diol 26 , which has been employed in the synthesis of chiral pyrolidines such as 27 …”