From retro(bio)synthesis to total synthesis: Programmable synthesis and site-selective modification of (+)-Neopeltolide

Nature synthesizes a remarkable diversity of polyketide natural products, many of which play critical roles in human health. Their complex structures and biological activities arise from a modular biosynthetic process that sequentially incorporates simple building blocks. Inspired by this logic, iterative synthetic strategies have emerged as a general approach to access polyketides with repeating motifs such as polyols, polyenes, and polydeoxypropionates. However, a greater challenge lies in constructing topologically complex, polycyclic polyketides rich in sp^3-hybridized carbons. Nature achieves this architectural complexity through controlled cyclizations of modular backbones, often followed by post-synthetic modifications. Embedding modular scaffolds within polycyclic frameworks obscures the underlying iterative logic, complicating retrosynthetic analysis and modular design. Overcoming this challenge is key to extending iterative strategies toward a generalized approach for synthesizing biologically relevant polycyclic polyketides.

In this talk, I will introduce Retromol, a retro(bio)synthetic algorithm that deconstructs modular natural products—including polyketides, non-ribosomal peptides, and hybrids—into sequences of building blocks. I will demonstrate how these primary sequences can be translated into forward iterative syntheses of the encoded linear backbones, which undergo programmed cyclizations to form complex polycyclic structures. As a case study, I will highlight the synthesis of the cytotoxic and antifungal natural product (+)-neopeltolide, showcasing how this strategy enables precise site-selective modifications, complete stereochemical control, and flexible access to structurally related analogs.