Synthesis of (−)-Melodinine K: A Case Study of Efficiency in Natural Product Synthesis

Efficiency is a key organizing principle
in modern natural product
synthesis. Practical criteria include time, cost, and effort expended
to synthesize the target, which tracks with step-count and scale.
The execution of a natural product synthesis, that is, the sum and
identity of each reaction employed therein, falls along a continuum
of chemical (abiotic) synthesis on one extreme, followed by the hybrid
chemoenzymatic approach, and ultimately biological (biosynthesis)
on the other, acknowledging the first synthesis belongs
to Nature. Starting materials also span a continuum of structural
complexity approaching the target with constituent elements on one
extreme, followed by petroleum-derived and “chiral pool”
building blocks, and complex natural products (i.e., semisynthesis)
on the other. Herein, we detail our approach toward realizing the
first synthesis of (−)-melodinine K, a complex bis-indole alkaloid.
The total syntheses of monomers (−)-tabersonine and (−)-16-methoxytabersonine
employing our domino Michael/Mannich annulation is described. Isolation
of (−)-tabersonine from Voacanga africana and
strategic biotransformation with tabersonine 16-hydroxylase for site-specific
C–H oxidation enabled a scalable route. The Polonovski–Potier
reaction was employed in biomimetic fragment coupling. Subsequent
manipulations delivered the target. We conclude with a discussion
of efficiency in natural products synthesis and how chemical and biological
technologies define the synthetic frontier.