Progress Toward an Enantioselective Total Synthesis of Ineleganolide

Citation

Roizen, Jennifer Lyn (2010) Progress Toward an Enantioselective Total Synthesis of Ineleganolide. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z93F4MMN. https://resolver.caltech.edu/CaltechTHESIS:11172009-113840501

Abstract

Investigations toward an enantioselective total synthesis of ineleganolide (1) are disclosed. These studies have driven the development of a novel asymmetric ketone alkylation to form C(α)-tetrasubstituted carbonyl compounds. Products of these alkylations have been converted to α-hydroxy ketones, acids, and esters, completing an asymmetric formal synthesis of (–)-quinic acid.

Additionally, one of these products, a chloroalkene, has been advanced in the synthesis of the [6–7–5–5]-fused core of ineleganolide. The chloroalkene can be converted through a mild oxidative bromination, Wittig olefination, and Luche reduction sequence to rapidly access the enantioenriched cyclopentenol fragment of ineleganolide. Two of these alcohols can be coupled with a cyclohexenone-derived carboxylic acid to append the six-membered ring fragment. These flexible vinylogous β-ketoesters can be advanced to a rigid [5–5–3]-fused cyclopropane.

At the outset of this work, we envisioned the advancement of a [5–5]-fused cyclopropane through a tandem Wolff/Cope rearrangement to access the [6–7–5–5]-fused core of ineleganolide. Synthetic studies toward this rearrangement are described. Additionally, we explore a translactonization/Cope rearrangement and a cyclopropanation/Cope/epoxidation cascade sequence to access the [6–7–5–5]-fused scaffold. In the course of these efforts, a rich body of chemistry has been developed exploring translactonizations in cis-substituted cyclopentane diols, including the translactonization/Cope cascade.

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