Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization Approach

Abstract

Optically pure hinckdentine A was synthesized on a 300 mg scale via an asymmetric catalysis-based strategy. The key steps to the first asymmetric synthesis involved (i) enantioselective dearomative cyclization of an achiral N-acyl indole that allowed for the efficient construction of the key polycyclic indoline intermediate with a crucial tetrasubstituted stereogenic carbon center, (ii) Beckmann fragmentation-mediated ring expansion, (iii) rearrangement-based introduction of an anilinic nitrogen atom, (iv) regioselective tribromination, and (v) final closure of the cyclic amidine moiety.

Heteroannulation of Arynes with α‐Amino Imides: Synthesis of 2,2‐Disubstituted Indolin‐3‐ones and Application to the Enantioselective Total Synthesis of (+)‐Hinckdentine A

“…[3][4][5] After screening different reagents and conditions,w ea chieved the synthesis of the C8,C10-dibrominated compound 27 in 75 %yield by performing the bromination of 26 in DMF at 0 8 8Cu sing NBS (2.7 equiv) as the brominating reagent. [3][4][5] After screening different reagents and conditions,w ea chieved the synthesis of the C8,C10-dibrominated compound 27 in 75 %yield by performing the bromination of 26 in DMF at 0 8 8Cu sing NBS (2.7 equiv) as the brominating reagent.…”

“…[2] Total synthesis of the racemic 8-desbromo analogue and the natural product itself have been achieved by the groups of McWhorter [3] and Kawasaki, [4] respectively.A ne legant enantioselective synthesis of (+ +)-hinckdentine A, featuring akey asymmetric dearomative cyclization of functionalized N-acyl tetrahydrocarbazole,h as recently been accomplished by Kitamura, Fukuyama, and coworkers. [5] As ac ontinuation of our research program dealing with the total synthesis of indoline-based polycyclic natural products, [6] we became interested in (+ +)-hinckdentine A( 1). Our retrosynthetic analysis is outlined in Scheme 1a.W e planned to construct the pentacyclic ring system of 1 from the amino ester 2 through as equence of amidine formation, lactamization, and bromination reactions.Compound 2 could be prepared from 2,2-disubstituted indolin-3-one 3,which was envisaged to be prepared by aformal [3+ +2] heteroannulation between benzyne generated in situ from ortho-(trimethylsilyl)phenyl triflate (4a) [7] and suitably functionalized a,adisubstituted a-amino acid derivative 5.…”

Construction of the Benzomesembrine Skeleton: Palladium(0)‐Catalyzed Intermolecular Arylative Dearomatization of α‐Naphthols and Subsequent Aza‐Michael Reaction

“…[1] Recent developments on the dearomatization of phenol derivatives exhibit great potential in the construction of cyclic enones bearing aq uaternary carbon stereogenic center,s tructures which are common in biologically active natural products. [4][5][6][7][8] Inspired by this intramolecular substrate design, several groups,i ncluding those of Tang, [9] Luan, [10] and You, [11] have made additional contributions in this field. [4][5][6][7][8] Inspired by this intramolecular substrate design, several groups,i ncluding those of Tang, [9] Luan, [10] and You, [11] have made additional contributions in this field.…”

Construction of the Benzomesembrine Skeleton: Palladium(0)‐Catalyzed Intermolecular Arylative Dearomatization of α‐Naphthols and Subsequent Aza‐Michael Reaction

“…[2,3] Pioneering studies on palladium-catalyzed arylative dearomatization of phenols have been achieved by Buchwald and co-workers. [4][5][6][7][8] Inspired by this intramolecular substrate design, several groups,i ncluding those of Tang, [9] Luan, [10] and You, [11] have made additional contributions in this field. However,intermolecular palladium-catalyzed arylative dearomatization of phenol derivatives are much more challenging compared with intramolecular ones because of the more competitive Friedel-Crafts-type reaction and O-arylation pathway.…”