Intramolecular Diels-Alder reactions of 2-pyrones for the total synthesis of natural products

Abstract

디엘스-알더 반응은 가장 강력한 탄소-탄소 결합 형성 화학 반응 중 하나이며, conjugate 되어 있는 1,3-diene과 알켄 dienophile 사이에서 반응이 진행되어 cyclohexene 유도체를 생성합니다. 이로 인해, 많은 디엘스-알더 반응은 합성하기 어렵거나 흥미로운 생리활성을 띄는 천연물 합성을 위해 개발되고 성공적으로 적용이 되었다. 본 연구실에서는 이 디엘스-알더 반응을 다양한 천연물 합성과 그 천연물의 핵심 구조와 작용기들을 빠르게 만들기 위하여 3,5-dibromo-2-pyrone과 그 유도체를 새로운 1,3-diene으로 이용하여 개발하였다.

다양한 천연물 합성을 위한 노력의 일환으로, 최근 분자내 디엘스-알더 반응을 이용하여 천연물인 (+)-fusoxysporone-1, (-)-neocosmosin A, (+)-aplykurodinone-1 and (-)-cyanthiwigin F의 새로운 합성 방법을 계획하였다. 3,5-dibromo-2-pyrone의 3번 탄소 위치에 적절한 치환기가 달려 있는 적절한 dienophile을 도입하기 위해, 위치 선택적인 Sonogashira 커플링과 수은을 촉매로 이용한 hydration 반응을 이용하였다. 브롬화 알카인이 길게 달려있는 2-파이론의 분자내 디엘스-알더 반응은 (-)-neocosmosin A를 합성할 수 있는 거대 락톤 구조를 얻을 수 있었다. 그리고 분자내 수소 결합 이론을 기반으로 한 분자내 디엘스-알더 반응은 (+)-aplykurodinon-1의 합성에 도달할 수 있었다. 이러한 반응들을 적용하여 (+)-fusoxysporone-1과 (-)-cyanthowigin F의 합성을 연구하였다.

| Diels-Alder reaction is one of the most powerful carbon-carbon bond forming chemical reactions, taking place between conjugated 1,3-diene and alkene dienophile to generate a substituted cyclohexene derivative. As such, many Diels-Alder reactions have been elaborated and successfully applied to the synthesis of the natural products with challenging chemical structures and/or intriguing biological activities. Our group has been developed 3,5-dibromo-2-pyrone and its derivatives as new 1,3-dienes for the rapid generation of core structures and functional groups embedded and thus needed for the synthesis of various natural products.

As a part of the on-going efforts in our group, we recently designed new synthetic routes to (+)-fusoxysporone-1, (-)-neocosmosin A, (+)-aplykurodinone-1 and (-)-cyanthiwigin F by utilizing intramolecular Diels-Alder reactions (IMDA). Regioselective Sonogashira coupling and mercury-mediated hydration reactions allowed strategic incorporation of the dienophiles with the appropriate functional groups onto the C3 position of 3,5-dibromo-2-pyrone. IMDA of 2-pyrone with bromo-alkyne connected with a long tether proceeded quite nicely to afford macrolactone skeleton which was readily converted into (-)-neocosmosina A. Incorporation of internal hydrogen bonding concept allowed highly efficient π-facial selective IMDA reaction en route to the formal synthesis of (+)-aplykurodinone-1. Further applications of this method to (+)-fusoxysporone-1 and (-)-cyanthiwigin F are under progress.; Diels-Alder reaction is one of the most powerful carbon-carbon bond forming chemical reactions, taking place between conjugated 1,3-diene and alkene dienophile to generate a substituted cyclohexene derivative. As such, many Diels-Alder reactions have been elaborated and successfully applied to the synthesis of the natural products with challenging chemical structures and/or intriguing biological activities. Our group has been developed 3,5-dibromo-2-pyrone and its derivatives as new 1,3-dienes for the rapid generation of core structures and functional groups embedded and thus needed for the synthesis of various natural products.

As a part of the on-going efforts in our group, we recently designed new synthetic routes to (+)-fusoxysporone-1, (-)-neocosmosin A, (+)-aplykurodinone-1 and (-)-cyanthiwigin F by utilizing intramolecular Diels-Alder reactions (IMDA). Regioselective Sonogashira coupling and mercury-mediated hydration reactions allowed strategic incorporation of the dienophiles with the appropriate functional groups onto the C3 position of 3,5-dibromo-2-pyrone. IMDA of 2-pyrone with bromo-alkyne connected with a long tether proceeded quite nicely to afford macrolactone skeleton which was readily converted into (-)-neocosmosina A. Incorporation of internal hydrogen bonding concept allowed highly efficient π-facial selective IMDA reaction en route to the formal synthesis of (+)-aplykurodinone-1. Further applications of this method to (+)-fusoxysporone-1 and (-)-cyanthiwigin F are under progress.