Stereochemical control of skeletal diversity

Abstract

[reaction: see text]. Substrates having appendages that pre-encode skeletal information (sigma-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (sigma-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity.

Figure 1

Previously, the sequential use of complexity-generating reactions, the Ugi 4CC–IMDA, was shown to produce complex molecules efficiently. Here we show that the orientation of a single substituent R₃, denoted as a σ-element, leads to products having different skeletal arrays.

Figure 2

Racemic tricycle 1 was acylated with 4-pentenoyl-(R,R)-pseudoephedrine, yielding diastereomers that were purified using silica gel chromatography. Following saponification, the resolved acids (+)-4 and (−)-4 were used in subsequent experiments.

Figure 3

Two examples of N–Me pentenamides illustrating the role of stereochemistry in determining the direction followed in ring-closing vs ring-opening/ring-closing reactions.

Figure 4

Six examples of NH pentenamides illustrating the role of a single stereogenic center in determining the direction followed in ring-closing vs ring-opening/ring-closing reactions.

Figure 5

Two examples of pentenoate esters illustrating the independence of amino alcohol orientation in determining the direction followed in ring-closing vs ring-opening/ring-closing reactions.