Asymmetric Synthesis of Nortropanes via Rh-Catalyzed Allylic Arylation

Abstract

Tropane derivatives are extensively used in medicine, but catalytic asymmetric methods for their synthesis are underexplored. Here, we report Rh-catalyzed asymmetric Suzuki-Miyaura-type cross-coupling reactions between a racemic N-Boc-nortropane-derived allylic chloride and (hetero)aryl boronic esters. The reaction proceeds via an unexpected kinetic resolution, and the resolved enantiopure allyl chloride can undergo highly enantiospecific reactions with N-, O-, and S-containing nucleophiles. The method was applied in a highly stereoselective formal synthesis of YZJ-1139(1), a potential insomnia treatment that recently completed Phase II clinical trials. Our report represents an asymmetric catalytic method for the synthesis of YZJ-1139(1) and related compounds.

Scheme 1. Tropane Derivatives and Works on Rh-Catalyzed Cross-Coupling Reactions of Cyclic Compounds

Scheme 2. Mechanistic Investigations and the Proposed Mechanism^,

Rh-catalyzed Suzuki–Miyaura coupling reaction with (+)-1a and 2a. Rh-catalyzed Suzuki–Miyaura coupling reaction with (+)-1a and biphep as ligand. Rh-catalyzed Suzuki–Miyaura coupling reaction with (+)-1a and rac-Segphos as ligand. Proposed mechanism. Equilibration between two Rh-σ complexes.

Scheme 3. Scope of the Reaction

Rh[(cod)OH]₂ (2.5 mol %), L1 (6 mol %), (±)-1a (0.2 mmol, 1.0 equiv), 2 (3.0 equiv), CsOH (50 wt % aq.; 2.0 equiv), THF (0.2 M), 65 °C, 1 h. All yields presented are isolated yields. Enantiomeric excess determined by supercritical fluid chromatography (SFC) analysis on a chiral nonracemic stationary phase. Single diastereomer (>20:1) obtained unless stated. 4 h. Dioxane instead of THF, 80 °C overnight. 3j: 18:1 d.r., 3r: 17:1 d.r., 3s: 19:1 d.r. 2 h.

Scheme 4. Scale-Up of the Cross-Coupling Reaction with 2p and Transformation of the Coupling Product and Enantioenriched Substrate^,

Reaction at 1 g scale with 2-furanylboronic pinacol ester 2p. Formal synthesis of YZJ-1139(1). Enantiospecific transformation of enantiopure allyl chloride (+)-1a.