Radical Cyclizations in the Synthesis of 3‐Methyl‐cis‐octahydroindol‐5‐ones

Abstract

Three approaches to the stereoselective synthesis of 3‐methyl‐cis‐octahydroindoles through a 5‐endo‐trig radical cyclization are described. First, starting from an N‐vinyl‐α‐chloroacetamide, the cyclization was followed by lactam methylenation and hydrogenation. Second, starting from an alkyne‐tethered enamide, the cyclization was promoted by Bu3SnH, and this was followed by protonolysis of the vinylstannane and hydrogenation of the exocyclic alkene. Third, through a 2,2‐dichloropropanamide cyclization onto an alkenyl bond, and hydrogenation of the resulting endocyclic double bond; this represents the most efficient sequence to form the target compounds. 1,5‐Enyne cyclizations through a 5‐endo‐trig process are reported. Here, a remote functional group (ketal or ketone), allowed the diastereoselectivity of the octahydroindole ring formation to be reversed through steric control of the facial selectivity in the hydrogen radical delivery step.

Total Synthesis of (−)-Himalensine A

“…Despite enone 17 possessing the necessary functionality for a ketone/alkyne cycloisomerization, we found successful C–C bond formation was only possible via a reductive radical cyclization approach, , the first of its kind to construct a morphan core. The substrate required for this reaction was synthesized by treatment of enone 17 with TIPSOTf to give TIPS protected product 18 in high yield.…”

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

“…The Diels-Alder reaction can also be used for the preparation of functionalized γ-lactams in a single step [55]. Radical 5-exo or 5-endo cyclizations of substituted N-allyl or N-vinyl α-halo amides VIII [56][57][58][59][60][61] or X [62][63][64][65][66] using atom transfer and other chain reactions, as well as non-chain methods [67][68][69][70][71][72][73] have been used to approach diverse γ-lactam-containing skeletons of the general structure IX or XI, respectively (Scheme 1A).…”