# Development of a Stereoselective Synthesis of Isomers of (+)-Disorazole Z1’s Lateral Chain

## TL;DR

This paper describes a new method to synthesize a complex chiral lateral chain found in the natural product (+)-Disorazole Z1.

## Contribution

The study introduces stereoselective synthetic routes for a chiral lateral chain with orthogonal protection strategies.

## Key findings

- Two consecutive aldol steps with a lactone intermediate produced natural and non-natural lateral chain precursors with high stereoselectivity.
- X-ray crystallography confirmed the stereochemistry of the synthesized compounds.
- Fine adjustments in transesterification helped retain a sensitive protecting group and avoid relactonization.

## Abstract

(+)-Disorazole Z1
(1) bears two lateral
chains, each
including a chiral quaternary carbon center with an ester moiety and
a methyl group surrounded by two chiral secondary alcohols. Herein,
we present different routes to synthesize the lateral chain, unveiling
details of their development. The strategies, which include two consecutive
aldol steps with a lactone intermediate, led to natural 2 and non-natural 3 lateral chain precursors with very
good stereoselectivity. The stereochemistry was confirmed by X-ray
crystallography. The results show an alternative lactonization procedure
as well as the impact of detailed fine adjustments of the transesterification
of a δ-lactone ring on retaining a sensitive triethylsilyl protecting
group and avoiding relactonization. Furthermore, the influence of
polysubstituted lactones on the stereoselectivity of the subsequent
aldol reaction is shown. Vicinal hydroxy groups around the chiral
quaternary center were protected in a sequence that allows orthogonal
deprotection if a lateral chain should be incorporated in a more complicated
structure. This work was crucial for our total synthesis of (+)-disorazole
Z1 and could also be helpful for syntheses of other chiral acyclic
α-quaternary-β,β′-hydroxy esters.