Steroid diversification by multicomponent reactions.

Daniel G Rivera,Leslie Reguera,Javier A Ramírez,Cecilia I Attorresi

doi:10.3762/bjoc.15.121

Abstract

Reports on structural diversification of steroids by means of multicomponent reactions (MCRs) have significantly increased over the last decade. This review covers the most relevant strategies dealing with the use of steroidal substrates in MCRs, including the synthesis of steroidal heterocycles and macrocycles as well as the conjugation of steroids to amino acids, peptides and carbohydrates. We demonstrate that steroids are available with almost all types of MCR reactive functionalities, e.g., carbonyl, carboxylic acid, alkyne, amine, isocyanide, boronic acid, etc., and that steroids are suitable starting materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and supramolecular chemistry applications.

Highlights

The utilization of multicomponent reactions (MCRs) [1] for the derivatization of biomolecules has continuously grown over the last years
The review is divided in different aspects of steroid chemistry, such as modification of the side chain and the steroidal nucleus, the assembly of nitrogen-heterocycles fused to the steroid-ring system, the steroid conjugation and macrocyclization, all relying on MCRs
We have demonstrated that MCRs are powerful tools for the derivatization of steroids, including the formation of steroidal heterocycles and macrocycles and the conjugation to other biomolecular components

Summary

Introduction

The utilization of multicomponent reactions (MCRs) [1] for the derivatization of biomolecules has continuously grown over the last years. Rings B and C can be naturally functionalized with a varied set of groups including hydroxy, carbonyl and olefins, which along with those present in rings A and D and the side chain are the basis of steroid biological functions. Such oxygenated and alkene groups represent the entrance door for subsequent synthetic modifications, including the incorporation of MCR reactive functionalities. The review is divided in different aspects of steroid chemistry, such as modification of the side chain and the steroidal nucleus, the assembly of nitrogen-heterocycles fused to the steroid-ring system, the steroid conjugation and macrocyclization, all relying on MCRs

Modification of the steroidal nucleus and the side chain

Steroids as amine and carboxylic acid components

Steroids as the isocyanide component

Synthesis of steroid-fused heterocycles

Conjugation of steroids to carbohydrates and peptides

Multicomponent synthesis of steroidal macrocycles and cages

Conclusion