분자 내 피셔 인돌화 반응을 이용한 천연 알칼로이드의 전합성 연구

Abstract

Aryl hydrazides are effective surrogates of aryl hydrazines, undergoing various reactions including the Fischer indole synthesis to afford the corresponding indoles, when treated with enolizable aldehydes and ketones in the presence of an acid. Unlike aryl hydrazines, the aryl hydrazides are readily accessed from aryl halides via the Pd(0) or Cu(I)-catalyzed coupling reaction with N-Boc hydrazine. We have also reported that N-Cbz-aryl hydrazide can proceed in a Fischer indolization reaction to give N-Cbz-indole without the elimination of N-Cbz group. Prompted by our recent interest on the synthesis of 3,4-fused tricyclic indole alkaloids, we set out to study the intramolecular Fischer indole synthesis of the aryl hydrazide that are linked to carbonyl functions by various tether groups as a new synthetic means to the construction of tricyclic indole system. We found that aryl hydrazide with carbonyl function tethered at the C(4) position of the aromatic ring undergoes intramolecular Fischer indolization to afford novel indolophanes. In addition, strategic insertion of a double or triple bond in the tether allowed for an aromatic Claisen rearrangement or alkynehydroarylation to proceed in a tandem fashion, providing 3,4-fused tri- or tetracyclic indole system. Recently, we found that the aryl hydrazides with a ketone or aldehyde containing side chains linked to the meta-position of the aromatic ring undergo acid promoted intramolecular Fischer indole synthesis to generate 3,4-fused tricyclic indoles. The preparative utility of this conceptually new synthetic approach, which does not require cumbersome prefunctionalization of the indole ring, was demonstrated by its application to a concise synthesis of (-)-aurantioclavine. Further applications of this method to structurally more complex polycyclic indole natural products with 3,4-fused tricyclic indole core are now under study.|아릴 하이드라자이드는 산 조건 하에서 키톤 또는 알데히드와 피셔 인돌화 반응을 통해 다양한 종류의 인돌 화합물 합성에 매우 유용하다. 합성적으로 접근성이 떨어지는 아릴 하이드라진과는 달리, 아릴 하이드라자이드는 Pd(0) 또는 Cu(I)을 이용한 아릴 할라이드와 N-Boc 하이드라진의 짝지음 반응을 통해 쉽게 합성할 수 있다. N-Boc-아릴 하이드라자이드뿐만 아니라, N-Cbz-아릴 하이드라자이드도 피셔 인돌화 반응을 통해 N-Cbz-인돌을 합성할 수 있음을 보여주었다. 많은 연구진들은 3,4-융합된 삼중고리인돌 알칼로이드의 합성에 관심을 갖고 있다. 삼중고리 인돌 구조의 효율적인 합성을 위해, 카보닐 작용기가 연결되어 있는 아릴 하이드라자이드의 분자내 피셔 인돌화 반응을 기획하였다. 방향족 고리의 4번 위치에 카보닐 작용기가 연결되어 있는 아릴 하이드라자이드의 분자내 피셔 인돌화 반응을 통해 여러 가지 융합된 인돌 고리를 합성할 수 있었다. 또한 탄소 체인에 이중결합 또는 삼중결합을 도입하면, 분자내 피셔 인돌화 반응과 방향족 클레이젠 재배열 반응 또는 알카인-수소아릴화반응의 연쇄반응 통해 3,4-융합된 삼중고리인돌, 사중고리 인돌을 합성할 수 있었다. 최근에는, 방향족 고리의 3번 위치에 키톤 또는 알데히드가 연결된 아릴 하이드라자이드의 분자내 피셔 인돌화 반응을 통한 3,4-융합된 삼중고리 인돌 합성을 발표하였다. (-)aurantionclavine의 효율적인 합성을 통해, 새로운 합성법의 가능성을 보여주었다. 앞으로 복잡한 구조의 3,4-융합된 삼중고리 인돌을 포함한 천연물 합성에 응용 될 것으로 기대한다.; Aryl hydrazides are effective surrogates of aryl hydrazines, undergoing various reactions including the Fischer indole synthesis to afford the corresponding indoles, when treated with enolizable aldehydes and ketones in the presence of an acid. Unlike aryl hydrazines, the aryl hydrazides are readily accessed from aryl halides via the Pd(0) or Cu(I)-catalyzed coupling reaction with N-Boc hydrazine. We have also reported that N-Cbz-aryl hydrazide can proceed in a Fischer indolization reaction to give N-Cbz-indole without the elimination of N-Cbz group. Prompted by our recent interest on the synthesis of 3,4-fused tricyclic indole alkaloids, we set out to study the intramolecular Fischer indole synthesis of the aryl hydrazide that are linked to carbonyl functions by various tether groups as a new synthetic means to the construction of tricyclic indole system. We found that aryl hydrazide with carbonyl function tethered at the C(4) position of the aromatic ring undergoes intramolecular Fischer indolization to afford novel indolophanes. In addition, strategic insertion of a double or triple bond in the tether allowed for an aromatic Claisen rearrangement or alkynehydroarylation to proceed in a tandem fashion, providing 3,4-fused tri- or tetracyclic indole system. Recently, we found that the aryl hydrazides with a ketone or aldehyde containing side chains linked to the meta-position of the aromatic ring undergo acid promoted intramolecular Fischer indole synthesis to generate 3,4-fused tricyclic indoles. The preparative utility of this conceptually new synthetic approach, which does not require cumbersome prefunctionalization of the indole ring, was demonstrated by its application to a concise synthesis of (-)-aurantioclavine. Further applications of this method to structurally more complex polycyclic indole natural products with 3,4-fused tricyclic indole core are now under study.