Stereochemical and skeletal diversity arising from amino propargylic alcohols

Abstract

An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargylic alcohols is quantified using principal moment-of-inertia (PMI) shape analysis.

Figure 1

Stereochemical and skeletal diversity.

Scheme 1. Synthesis of Diastereoisomeric Amino Propargylic Alcohols

ee was determined by SFC analysis. dr was determined by ¹H NMR analysis of the inseparable mixture of the two diastereomers.

Scheme 2. Skeletal Diversty through Functional Group Pairing Reactions

Ratio endo/exo = 10:1.5 was determined by ¹H NMR. Single stereoisomer. Intramolecular enyne metathesis product 13a was also obtained as minor product in 38% yield.

Figure 2

Skeletal diversity from anti-amino propargylic alcohol 1b. Note: ^asingle stereoisomer.

Figure 3

Molecular shape analysis. (A) PMI plot depicting relationships between compounds 1a and 5a−14a shown in Scheme 2. Substrate−product relationships are indicated with matched colors between product markers and circles around substrate markers. (B) PMI plot showing shape differences between diastereomeric pairs a (◼) and b (+) for compounds 1 and 6−13. Distances between pairs are listed in decreasing order, and the three most distant pairs are noted by arrows. (C) PMI plot comparing virtual library based on the Scheme 2 (see text) with subsets of molecules of different origins: commercial compounds (CC), natural products (NP).