Synthesis of Enantiopure Bicyclic α,α-Disubstituted Spirolactams via Asymmetric Birch Reductive Alkylation

Abstract

The synthesis of enantiopure bicyclic alpha,alpha-disubstituted spirolactams is described using a diastereoselective Birch reductive alkylation as the key step. Hydrogenation of the resultant alkylated cyclohexadienes followed by intramolecular cyclization provides access to enantiopure 8-azaspiro[5.6]dodecan-7-ones.

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

“…24 Synthetic approaches detailed in that particular review include intermolecular Diels-Alder strategies, 25,26 alkylation-cyclization approaches [27][28][29] and an asymmetric Birch reductive alkylation. 30 Importantly, those approaches often involved targeting spirocyclic lactam fragments as precursors to spirocyclic imines. This review represents our recent efforts in the development of synthetic approaches towards cyclic imine toxins, which focus on providing direct access to spirocyclic imine fragments using N-acyl iminium chemistry, with serendipitous discoveries and new methodology developed along the way.…”

Stereodivergent Synthesis and Configurational Assignment of the C1–C15 Segment of Amphirionin-5

“…The synthesis of allylic alcohol 10 started with the known imide 14 . The chiral auxiliary of 14 was reductively removed with LiBH 4 in THF/MeOH to provide primary alcohol 15 in 92% yield (Scheme ). Parikh–Doering oxidation of 15 afforded the corresponding aldehyde 12 , which was subjected to Julia–Kocienski olefination using the known phenyltetrazolyl sulfone 13 and KHMDS in DME at −55 °C to produce ( E )-alkene 16 in 64% yield for the two steps as a single stereoisomer ( E / Z > 20:1).…”

“…Purification of the residue by column chromatography (silica gel, 20% to 40% to 50% EtOAc/hexanes) gave alcohol 15 (4.50 g, 92%) as a colorless oil. The spectroscopic data of 15 were compared to those of the earlier known compound and found to be identical.…”

Spiroimine shellfish poisoning (SSP) and the spirolide family of shellfish toxins: Isolation, structure, biological activity and synthesis

“…Studies on the unusual 6,7-spiroimine moiety of the spirolides are in progress in the Zakarian 94 and Brimble groups. [95][96][97][98][99] For synthesis of related marine toxins containing a spiroimine unit see the 2007 review. 33 The successful synthesis of the 6,7-spiroimine unit of the spirolides would be a major advance for the chemical and pharmacological evaluation of the toxicity of these and related compounds.…”