A Convergent and Enantioselective Synthesis of (+)-Amurensinine via Selective C−H and C−C Bond Insertion Reactions

Abstract

A convergent and enantioselective synthesis of the natural product amurensinine is described. The synthetic strategy takes advantage of mild and selective C-H and C-C bond insertion reactions, in addition to the palladium-catalyzed aerobic oxidative kinetic resolution recently developed in these laboratories.The development of mild and selective C-H and C-C bond insertion reactions for complex molecule synthesis has the potential to enable strategic disconnections that would be inconceivable using traditional methods. 1 Because of the sheer abundance of C-H and C-C bonds in most organic molecules and the general shortage of methods to perform selective reactions on these bonds, the application of C-H and C-C activation reactions in the context of natural product synthesis has been limited. Despite these challenges, the number of examples continues to rise. 2 In this communication, we present a convergent and enantioselective synthesis of the natural product amurensinine (1) that employs mild and selective C-H and C-C bond insertion reactions as key strategic maneuvers.Amurensinine (1) is a member of the isopavine family of alkaloids, which are exemplified by a characteristic tetracyclic tetrahydroisoquinoline core structure consisting of a doubly benzannulated azabicyclo[3.2.2]nonane (Figure 1). 3,4 The isopavines exhibit important biological properties for the treatment of neurological disorders, such as Parkinson's and Alzheimer's disease. 5 To date, there has been only one reported enantioselective synthesis of amurensinine (1), which was based on a chiral auxiliary approach. 6Our retrosynthetic strategy for the preparation of amurensinine ((+)-1) commences with the disconnection of the bridging amine functionality, exposing hydroxyester 6 as a synthetic intermediate (Scheme 1). We reasoned that this chiral benzylic alcohol could be produced enantioselectively by application of the palladium-catalyzed oxidative kinetic resolution methodology, recently developed in our group. 7,8 Alcohol (±)-6 could be accessed from ketoester (±)-7, which contains the benzosuberane core carbocycle, an ideal retron for an efficient and mild C-C bond insertion reaction involving the acylalkylation of arynes, previously reported by our laboratories. 9,10 Thus, aryne 8 and β-ketoester 9 were revealed as substrates for the C-C bond insertion reaction. The former may be generated in situ from otrimethylsilyl triflate 10 ,11 and the latter by a position-selective Rh-catalyzed C-H bond insertion reaction of diazo compound 11. 12 stoltz@caltech.edu. Supporting Information Available. Experimental details are available free of charge via the Internet at http://pubs.acs.org. We began our efforts toward amurensinine ((+)-1) with the preparation of β-ketoester 9 (Scheme 2). Functionalization of (3,4-dimethoxyphenyl)acetic acid (12) by standard methods produced diazo compound 11, which was subjected to Rh 2 (OAc) 4 -catalyzed dediazotization. 13 Despite the possibility for intramolecular insertion into a number of C-H bonds at sp 3 a...

PdII‐Catalyzed Monoselective ortho Halogenation of CH Bonds Assisted by Counter Cations: A Complementary Method to Directed ortho Lithiation

“…[1,2] Recently, progress has been made in Pd-catalyzed C À H activation reactions in terms of substrate scope and practicality. [3,4] However, two major obstacles prevent the broad synthetic application of CÀH-functionalization reactions.…”

Palladium‐Catalyzed Enantioselective Oxidation of Chiral Secondary Alcohols: Access to Both Enantiomeric Series

“…Recently, we reported an enantioselective total synthesis of (+)-amurensinine ((+)-3) that employs an oxidative kinetic resolution as a key step to produce an enantioenriched intermediate (i.e., (−)-14) en route to the antipode of the natural product. [21] In order to access the naturally occurring enantiomer (i.e., (−)-3), we applied diamine 11 to the resolution of (±)-14. In the event, use of a dibromide complex provided enantioenriched alcohol (+)-14 in high yield and excellent enantiomeric excess (s = 27, Scheme 2).…”

O ressurgimento da química de benzino com sililaril triflatos no contexto das reações de inserção em ligações sigma

“…17 Em conformidade, tal reação publicada por Stoltz e colaboradores encontrou aplicação na síntese da (+)-amurensinina 18 (Esquema 10).…”

“…18 Pouco tempo depois do trabalho pioneiro de Stoltz e colaboradores ter sido publicado (Esquema 9), Yoshida, Kunai e colaboradores reportaram uma reação similar de inserção de sililaril triflatos em compostos β-dicarbonílicos na presença do sistema KF/éter 18-coroa-6, resultando na formação de compostos aromáticos orto-substituídos.…”