Calyciphylline A-型虎皮楠生物碱himalensine A的全合成研究进展

Recent progress in the total synthesis of calyciphylline A-type Daphniphyllum alkaloid himalensine A

虎皮楠生物碱自从1909年被首次分离报道至今,已有300多个已知家族成员.它们具有广泛的生物活性以及复杂多变的多环骨架结构,其独特的氮杂笼状稠环结构以及骨架中包含季碳中心的多个手性中心使得其合成极具挑战性.在虎皮楠生物碱的众多家族中,含有20多个成员的calyciphylline A-型虎皮楠生物碱是具有代表性的家族之一,而himalensine A则是calyciphylline A-型虎皮楠生物碱的代表性成员之一.该分子被岳建民课题组分离报道以来受到了众多合成化学家的关注,迄今已有多篇合成研究与全合成工作报道.本文主要介绍关于calyciphylline A-型虎皮楠生物碱himalensine A近期的全合成研究进展.这些工作为虎皮楠生物碱的全合成研究贡献了宝贵的经验,并展示了许多开拓性的思路.

The evergreen plants of the genus Daphniphyllum are found mainly in the Asia-Pacific region and have played important roles in Traditional Chinese Medicine. Their leaves, barks and fruits have long been used to treat a variety of ailments including asthma, rheumatism, inflammation and fever. Since the isolation of daphnimacrine by the Yagi group in 1909,more than 330 structurally fascinating natural products, known as the Daphniphyllum alkaloids, have been isolated and structurally identified over the years. Owing to their unusual and disparate structural backbones, these alkaloids are highly attractive to synthetic chemists, spanning all around the world. Based on their distinct skeletons, these natural compounds can be categorized into 13-35 subfamilies. Among which, calyciphylline A-type is a particularly notable major subfamily that consists of approximately 20 members. These alkaloids show extensive physiological activities, such as anti-HIVand cytotoxicity and so on. Calyciphylline A-type alkaloids possess a characteristic structural backbone consisting of four fused rings [6-6-5-7] with one or more quaternary stereocenters. In 2016, a unique member of this family, namely himalensine A,was isolated from Nepalese Daphniphyllum himalense by Yue group. While its bioactivity remains unexplored,himalensine A possesses an unprecedented skeleton in the calyciphylline A-type alkaloids, which is the first natural C19 Daphniphyllum alkaloid isolated so far. Congested pentacyclic ring skeleton that includes a unique 2-azabicyclo[3.3.1]nonane motif, six stereogenic centers, and an all-carbon quaternary center, makes himalensine A a formidable synthetic challenge.Since its isolation, three impressive total syntheses of himalensine A have been reported by Dixon, Xu and Gao groups,respectively. In 2017, the first enantioselective total synthesis of(-)-himalensine A was disclosed by Dixon and his coworkers. The total synthesis was elegantly accomplished in 22 linear steps. Enantioselective prototropic shift/furan DielsAlder(IMDAF) cascade reaction to construct the ACD tricycle system and a reductive radical cyclization to build the B ring are notable highlights of Dixon’s synthesis. Other notable highlights include a molecular oxygen mediated γ-CH oxidation and a Stetter cyclization to access the critical cyclopentenone ring to achieve the full core of the natural product.Finally, a highly chemoselective lactam reduction delivered the target natural product. In 2019, Xu and co-workers accomplished an efficient total synthesis of(-)-himalensine A in 14 steps. Key features of this strategy include a Cucatalyzed nitrile hydration and Michael addition to construct C ring, a Heck reaction to construct the challenging 2-azabicyclo[3.3.1]nonane motif, and a Meinwald rearrangement reaction to deliver the necessary carbonyl group, which significantly improved the overall synthetic efficiency. Concurrently, Gao and his co-workers reported the total synthesis of himalensine A in a new fashion. They developed a 1,3-dipolar nitrone [3+2] cycloaddition reaction to construct A ring. The Pd-catalyzed enolate alkenylation was employed to fabricate B ring, followed by the construction of the seven-membered ring via a ring closing metathesis reaction. Finally, a Lewis acid-promoted Nazarov cyclization successfully furnished the cyclopentanone F ring. Besides these total synthetic approaches, several other interesting synthetic studies along with noteworthy synthetic strategies reported by the Bonjoch, Stockdill and Hudlicky groups, have showcased valuable and pioneering strategies and methods for the synthesis of himalensine A and its related Daphniphyllum alkaloids. This review covers the efforts toward the synthesis of himalensine A spanning the period from 2017 to 2020. The innovative strategies and methods demonstrated in these impressive efforts are inspiring to the synthesis of various types of Daphniphyllum alkaloids and many other natural products.