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. 2022 Aug 5;12(15):8995-9002.
doi: 10.1021/acscatal.2c02259. Epub 2022 Jul 12.

Asymmetric Synthesis of Nortropanes via Rh-Catalyzed Allylic Arylation

Yan Zhang  1 , F Wieland Goetzke  1 , Kirsten E Christensen  1 , Stephen P Fletcher  1
Affiliations

Asymmetric Synthesis of Nortropanes via Rh-Catalyzed Allylic Arylation

Yan Zhang et al. ACS Catal. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Oxford University Innovation has filed a patent application(PCT/GB2016/051612) with S.P.F. named as an inventor. Y.Z., F.W.G. and K.E.C. declare no competing financial interests.

Figures

Scheme 1
Scheme 1. Tropane Derivatives and Works on Rh-Catalyzed Cross-Coupling Reactions of Cyclic Compounds
Scheme 2
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
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
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.
See this image and copyright information in PMC

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