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Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent Interactions for Organocatalytic Bromination.

ABSTRACT: Hinckdentine A, a marine-sponge-derived tribrominated indole alkaloid bearing a unique indolo[1,2-c]quinazoline skeleton, was completed in 12 steps featuring the construction of the Nα-quaternary carbon center by asymmetric azo-ene cyclization. A novel organocatalyst was developed to promote high-yielding tribromination, which represents a challenging process encountered in previous syntheses. Density functional theory calculations scrutinized viable substrates and deciphered the origin of the enhancement of C8 electrophilic bromination with a bifunctional organocatalyst. Moreover, the application of organocatalyst-enabled bromination on various substrates was demonstrated to highlight future late functionalizations of biologically intriguing targets.

SUBMITTER: Ruan Z

PROVIDER: S-EPMC9088303 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent Interactions for Organocatalytic Bromination.

Ruan Zhuwei Z Wang Min M Yang Chen C Zhu Lili L Su Zhishan Z Hong Ran R

JACS Au 20220415 4

Hinckdentine A, a marine-sponge-derived tribrominated indole alkaloid bearing a unique indolo[1,2-<i>c</i>]quinazoline skeleton, was completed in 12 steps featuring the construction of the Nα-quaternary carbon center by asymmetric azo-ene cyclization. A novel organocatalyst was developed to promote high-yielding tribromination, which represents a challenging process encountered in previous syntheses. Density functional theory calculations scrutinized viable substrates and deciphered the origin o ...[more]

PMID: 35557764

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Project description:The use of more than one catalyst in one-pot reaction conditions has become a rapidly evolving protocol in the development of asymmetric catalysis. The lack of molecular insights on the mechanism and enantioselectivity in dual-catalytic reactions motivated the present study focusing on an important catalytic asymmetric Heck-Matsuda cross-coupling. A comprehensive density functional theory (M06 and B3LYP-D3) investigation of the coupling between a spirocyclic cyclopentene and 4-fluorophenyl diazonium species under a dual-catalytic condition involving Pd2(dba)3 (dba = trans, trans-dibenzylideneacetone) and chiral 2,2'-binaphthyl diamine (BINAM)-derived phosphoric acids (BDPA, 2,2'-binaphthyl diamine-derived phosphoric acids) is presented. Among various mechanistic possibilities examined, the pathway with explicit inclusion of the base (in situ generated sodium bicarbonate/sodium biphosphate) is found to be energetically more preferred over the analogous base-free routes. The chiral phosphate generated by the action of sodium carbonate on BDPA is found to remain associated with the reaction site as a counterion. The initial oxidative addition of Pd(0) to the aryl diazonium bond gives rise to a Pd-aryl intermediate, which then goes through the enantiocontrolling migratory insertion to the cyclic alkene, leading to an arylated cycloalkene intermediate. Insights on how a series of noncovalent interactions, such as C-H···O, C-H···N, C-H···F, C-H···π, lp···π, O-H···π, and C-F···π, in the enantiocontrolling transition state (TS) render the migration of the Pd-aryl to the si prochiral face of the cyclic alkene more preferred over that to the re face are utilized for modulating the enantioselectivity. Aided by molecular insights on the enantiocontrolling transition states, we predicted improved enantioselectivity from 37% to 89% by changes in the N-aryl substituents of the catalyst. Subsequent experiments in our laboratory offered very good agreement with the predicted enantioselectivities.

Dataset Information

Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent Interactions for Organocatalytic Bromination.

Publications

Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent Interactions for Organocatalytic Bromination.

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