THE TOTAL SYNTHESIS OF DOLABRIFEROL C VIA ONE-POT ENANTIOSELECTIVE BISALDOL REACTIONS
Date
2019-06-28
Authors
Journal Title
Journal ISSN
Volume Title
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ORCID
0000-0002-9733-508X
Type
Thesis
Degree Level
Doctoral
Abstract
Dolabriferol C is a member of a small family of marine natural products known as non-contiguous polypropionates that are esters of a polypropionate carboxylic acid with a polypropionate alcohol. The origin of these so-called ‘natural products’ is uncertain, but they are often hypothesized to arise from a retro-Claisen fragmentation of a hemiacetal formed from a 5-hydroxy-1,3-dione embedded in a contiguous polypropionate chain. To test that conjecture, these putative precursors have been targeted for total synthesis to allow exploration of their properties, especially the tendency to rearrange into the non-contiguous ‘natural products’. In previous work, the Ward group produced experimental evidence for the proposed origin of non-contiguous polypropionates baconipyrone A, baconipyrone C, and dolabriferol by total synthesis from their putative contiguous precursors via a retro-Claisen approach.
Towards the synthesis of the putative contiguous precursor of dolabriferol C, a new strategy was contemplated and examined the potential of bisenolates of meso 1,5-diketones, previously unknown entities. The research presented herein describes the development and application of one-pot sequential enantiotopic group selective (SEGS) aldol reactions as a powerful strategy for highly convergent polypropionate synthesis. Both (E,E)- and (Z,Z)- meso bisenol borinates were prepared stereoselectively from meso 1,5-diketones, and were successfully used in enantioselective desymmetrization and SEGS bisaldol reactions to synthesize several meso, racemic, and enantiopure polypropionate motifs with high diastereoselectivities.
The putative contiguous precursor was prepared via a highly stereoselective bisaldol reaction of a meso 1,5-diketone with two different chiral aldehydes that generates the full carbon skeleton of the precursor and sets the absolute configuration of eight stereocenters in a one-pot process. Brief exposure of the putative precursor to neutral alumina cleanly produced dolabriferol C via a remarkably chemoselective retro-Claisen reaction thereby establishing this natural product as a plausible isolation artifact. This is the first total synthesis of dolabriferol C (and the putative contiguous precursor) and was achieved in 7 steps with 13.6% overall yield from the known enantiopure aldehyde. Using this strategy, an improved synthesis of dolabriferol was also achieved in 5 steps with 34% overall yield from the known enantiopure aldehyde.
Description
Keywords
Total Synthesis, One-pot Stereoselective Aldol Reactions, Polypropionates, Enantioselective Synthesis of Dolabriferol C, Meso Bisenolates, Meso 1,5-Diketones, Enantioselective Desymmetrization, Kinetic Resolution, Enantiotopic Group Selectivity, Asymmetric Synthesis, Organic Synthesis.
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Chemistry
Program
Chemistry