The sarpagine alkaloids are one of the largest groups of monoterpenoid indol alkaloids. They were mainly isolated from the plant family Apocynaceae. The sarpagine alkaloids are a natural product group possessing a wide range of biological activities, and have thus attracted attention from the scientific community. Unfortunately the scarcity of the natural products themselves, and the lack of synthetic analogues of comparable complexity have so far hampered further biological investigations. Therefore our idea was to not only aim at solving the problem of material supply for a single family congener, but to accomplish a joint synthetic sequence that enables access to a large number of sarpagines and non-natural derivatives through a shared late-stage synthetic intermediate. The structure of sarpagine alkaloids consists of a pentacyclic skeleton containing an indole (rings A and B) annulated to an 10-aza-tricyclo[5.3.1.05,10]undecan system (rings C-E). This 10-aza-tricyclo[5.3.1.05,10]undecan system embodies a quinuclidine moiety including rings D and E with four stereogenic centers three of which are consecutive. Furthermore, piperidine rings C and D form a nitrogen-bridged eight-membered carbocyclic ring. This work describes the total synthesis of three members of the sarpagine alkaloid family and fifteen non-natural congeners through an improved synthetic sequence, which was designed for gram-scale production of material suited for structure–activity relationship (SAR) studies. Our synthesis starts with the known building blocks 1 and 2, chiral Aggarwal’s ketene equivalent and hydroxypyridinium salt respectively. In a dipolar [5+2] cycloaddition two of the required stereogenic centers are established. Further key transformations include an intramolecular palladium catalyzed enolate coupling as well as a ring enlargement reaction. Final step is a Fischer indol synthesis that leads to the desired sarpagine alkaloids and derivatives. Installation if the indol moiety in the very last step – in contrast to previous syntheses that rely on indole based building blocks in very early stages of their syntheses – enables the synthesis of a collection of sarpagines and non-natural derivatives in one step from one common intermediate 3.

Total syntheses of sarpagine alkaloids and non-natural derivatives

2019 Fall National Meeting

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