Oligomerization is a strategy widely used by nature to construct vast families of secondary metabolites with prodigious functional diversity. Formed through the action of enzymatic catalysis, almost every class of natural products, including terpenoids, polyketides, and alkaloids, contain highly complex and unique oligomeric backbone structures which are intimately associated with their biological activities. In the laboratory setting, however, the use of asymmetric catalysis to achieve the controlled oligomerization of complex natural products remains an unrealized goal. This presentation will discuss the development of an iterative approach using a chiral copper catalyst to enable the rapid construction of several oligomeric polypyrroloindoline natural products, including hodgkinsine, hodgkinsine B, quadrigemine H, and isopsychotridines B and C. Exploiting the modular design of the catalyst system, we show it is possible to access any possible stereoisomer in this class of alkaloids, as demonstrated by the synthesis of putatively unnatural quadrigemine H-type isomers. Ultimately this strategy represents a new paradigm for total synthesis that enables rapid access to compounds of potential medicinal value.

Catalyst-controlled oligomerization for the synthesis of polypyrroloindoline natural products

253rd National Meeting (2017)

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