Price-Focused Analysis of Commercially Available Building Blocks for Combinatorial Library Synthesis

Abstract

Combinatorial libraries are synthesized by combining smaller reagents (building blocks), the price of which is an important component of the total costs associated with the synthetic exercise. A significant portion of commercially available reagents are too expensive for large scale work. In this study, 13 commonly used reagent classes in combinatorial library synthesis (primary and secondary amines, carboxylic acids, alcohols, ketones, aldehydes, boronic acids, acyl halides, sulfonyl chlorides, isocyanates, isothiocyanates, azides and chloroformates) were analyzed with respect to the cost, physicochemical properties (molecular weight and calculated logP), chemical diversity, and 3D-likeness using a large data set. The results define the chemical space accessible under a constraint of limited financial resources.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…Novelty and commercial accessibility are yet other factors that are considered to be very important. [229,230] Analysis of the reagent classes that are most popularw ith medicinal chemists reflectsr esults obtainedf rom studies on the most frequently used reactions. In particular, amines (especially secondary amines), carboxylic acids, and boronic acids or their derivativesw ere ranked most highlyo nd esirability;f ollowed by arylation and alkylation agents;a ldehydes,a lcohols, and aromatic amines;a nd, finally,s ulfonyl halides, ketones, and isocyanates.…”

A Scalable Metal‐, Azide‐, and Halogen‐Free Method for the Preparation of Triazoles

“…Replacement of the azide with a primary amine nucleophile, the most common commercially available nitrogen containing substrate, is of great interest to the synthetic community. [9] In 1986, Sakai et al reported the synthesis of substituted 1,2,3-triazoles 11 through the reaction of an a,a-dichloroketone 10, tosylhydrazide and a primary amine (Figure 1 b). [10] The scope of this transformation was explored by Westermann and co-workers [11] and demonstrated on scale by Hanselmann et al, [12] providing a novel process to form this heterocyclic core.…”

Synthesis of Aldehydes by Organocatalytic Formylation Reactions of Boronic Acids with Glyoxylic Acid

“…With more than four thousand commercially available aryl boronic acids,t hey have become one of the most versatile building blocks in organic synthesis. [1] Notably,recent significant advances in borylation methods has made aryl boronic acids,particularly those that are heavily functionalized, more readily accessible. [2] Theunique reactivity of substances in this family has led to am yriad of carbon-carbon and carbonheteroatom bond-forming processes,which are either difficult to carry out or show poor functional-group tolerance,and/or low efficiencywhen their halide counterparts are employed as substrates.These reactions,which include the introduction of oxygen, [3] nitrogen, [4] and halogen, [5] as well as alkyl, alkynyl, alkenyl, and alkyl moieties, [6] are generally accomplished using transition-metal complexes (Scheme 1a).…”