Synergy of synthesis, computation and NMR reveals correct baulamycin structures

Abstract

Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory-combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared-enabled us rapidly to pinpoint and synthesize the correct structures.

Towards the generalized iterative synthesis of small molecules

“…86 Amination followed by amide formation furnished the core of (+)-kalkitoxin in an overall 52% yield. This same approach has been used to synthesize baulamycin A, 87 tatanan A, 88 fluorohexestrol, 89 and C30 botryococcene 90 and many other targets. 91 More broadly, the versatility of this homologation method, which tolerates a diversity of structural variation in its building blocks, opens the door for divergent synthesis.…”

Stereocontrolled Synthesis as an Enabling Tool for the Configurational Assignment of Marine Polyketide Natural Products

“…As illustrated with leiodermatolide, the DP4 parameter introduced by Smith and Goodman successfully allowed for the corroboration of the macrocyclic stereochemistry in leiodermatolide. More recently, the Aggarwal group demonstrated just how powerful a synergistic combination of computational methods and synthesis is in their landmark stereochemical elucidation of the baulamycins . In this final example, we demonstrate that it is through combination of synthesis and computational NMR methods that we were able to successfully tackle a seemingly intractable number of stereoisomers presented by the natural product hemicalide.…”

Stereochemical revision of xylogranatin F by GIAO and DU8+ NMR calculations

“…NMR calculations have become an increasingly useful and widely employed tool in both structural determination and revision of complicated molecules, especially in the context of natural products isolation and multistep synthesis (for reviews, see previous studies [1][2][3][4] ; for several notable examples using NMR calculations for structural revision, see previous works [5][6][7][8][9][10][11] ). Utilization of modern quantum chemical computations has the advantage of magnifying and quantifying subtle differences among similar structures (eg, diastereomers).…”