A Planning Strategy for Diversity‐Oriented Synthesis

TLDR

Diversity‑oriented synthesis (DOS) differs from target‑oriented synthesis and medicinal or combinatorial chemistry by broadly populating chemical space with small molecules of diverse structures, whereas target‑oriented synthesis has been advanced through retrosynthetic analysis. The study aims to develop efficient three‑ to five‑step pathways that generate collections of small molecules with skeletal and stereochemical diversity and defined coordinates in chemical space, and that can subsequently be functionalized site‑ and stereoselectively with diverse appendages. The authors employ forward‑synthetic analysis, a parallel‑logic approach built on retrosynthetic foundations, to design diverse skeletons and stereochemistries that allow appendages to be positioned in multiple orientations around the molecules. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.

Abstract

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.