Traceless Solid-Phase Organic Synthesis

Abstract

Traceless solid-phase synthesis represents an ultimate sophisticated synthetic strategy on insoluble supports. Compounds synthesized on solid supports can be released without a trace of the linker that was used to tether the intermediates during the synthesis. Thus, the target products are composed only of the components (atoms, functional groups) inherent to the target core structure. A wide variety of synthetic strategies have been developed to prepare products in a traceless manner, and this review is dedicated to all aspects of traceless solid-phase organic synthesis. Importantly, the synthesis does not need to be carried out on a linker designed for traceless synthesis; most of the synthetic approaches described herein were developed using standard, commercially available linkers (originally devised for solid-phase peptide synthesis). The type of structure prepared in a traceless fashion is not restricted. The individual synthetic approaches are divided into eight sections, each devoted to a different methodology for traceless synthesis. Each section consists of a brief outline of the synthetic strategy followed by a description of individual reported syntheses.

Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

“…Analysis of the top-selling 200 small-molecule pharmaceuticals indicates that automated SPS-flow synthesis could potentially be applied to a wide range of pharmaceutical molecules. For the small molecules that lack an obvious handle for covalent attachment to a solid support, simultaneous advances in linker strategies 42 and traceless SPS 43,44 can substantially expand the scope of molecules that are amenable to this strategy. The desire for process intensification (for example, to decrease overall reaction time); the need to tolerate solid reagents; the development of more economic solid-supports with diverse functional anchors; the combination of reagent preparation, synthesis and downstream purification and formulation into a single, compact unit; the realization of large-scale production 45 ; and parallel assembly of two SPS-flow column reactors or a solution-based continuous-flow system with a SPS-flow column reactor for convergent synthesis can further enhance the value and extensively expand the scope of this strategy.…”

Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application

“…Notably, secondary amine was used instead of traditional primary amine. This is an example of traceless synthesis [90]. Scheme 72.…”

“…This method of cleavage is known as multifunctional (multidirectional) cleavage [88] and utilizes a safety-catch linker [89]. A description of this methodology is included in a recently published review [90].…”

“…2020, 21, x FOR PEER REVIEW 21 of 52 safety-catch linker [89]. A description of this methodology is included in a recently published review [90].…”

Diketomorpholines: Synthetic Accessibility and Utilization

“…DKMs are accessible through various polymer-supported methods. 17 Cyclization of resin-bound bromides 19 ( Scheme 5 ) was induced by treatment with TFA, initially leading to cleavage from the Wang resin, followed by ring closure to DKMs (R 1 = H or alkyl, R 2 = alkyl). 18 A resin which consisted of polyethylene glycol attached to cross-linked polystyrene through an ether linkage was employed for DKM synthesis.…”