Progress Toward an Enantioselective Total Synthesis of Ineleganolide
Jennifer Lyn Roizen, Roizen, Jennifer Lyn (Creator)
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.
Thesis, Dissertation, English, 2010