A Synthesis Strategy Yielding Skeletally Diverse Small Molecules Combinatorially

Abstract

The efficient synthesis of small molecules having many molecular skeletons is an unsolved problem in diversity-oriented synthesis (DOS). We describe the development and application of a synthesis strategy that uses common reaction conditions to transform a collection of similar substrates into a collection of products having distinct molecular skeletons. The substrates have different appendages that pre-encode skeletal information, called sigma-elements. This approach is analogous to the natural process of protein folding in which different primary sequences of amino acids are transformed into macromolecules having distinct three-dimensional structures under common folding conditions. Like sigma-elements, the amino acid sequences pre-encode structural information. An advantage of using folding processes to generate skeletal diversity in DOS is that skeletal information can be pre-encoded into substrates in a combinatorial fashion, similar to the way protein structural information is pre-encoded combinatorially in polypeptide sequences, thus making it possible to generate skeletal diversity in an efficient manner. This efficiency was realized in the context of a fully encoded, split-pool synthesis of approximately 1260 compounds potentially representing all possible combinations of building block, stereochemical, and skeletal diversity elements.

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

“…A successful DOS must address the four principal types of structural diversity mentioned previously 1,4,18,44,46 . Th e most challenging facet of DOS, and of central importance to its success, is the ability to effi ciently incorporate skeletal diversity into a compound collection 1,3,9,10,19,47,48 . Th e effi cient generation of multiple molecular scaffolds is regarded as one of the most eff ective methods of increasing the overall structural diversity of a collection of molecules and has been reported to increase the odds of addressing a broad range of biological targets (relative to a single-scaff old library) 3,9,10,14,15,18,19,49 .…”

“…A collection of substrates that contain appendages with suitable ' preencoded ' skeletal information (so-called σ elements) into products have distinct molecular skeletons using a common set of conditions ( Fig. 3 ) 1,3,10,48,50 . In practice, such methods are usually based around intramolecular reactions that ' pair ' strategically positioned functional groups in the substrates, resulting in compounds with diverse skeletons 3,10,30 .…”

Biology-inspired synthesis of compound libraries

“…One example for such a reaction cascade is the introduction of terminal olefins with different chain lengths and subsequent ring closing metathesis. Other reactions used include for instance ring expansion and aldol reactions [13,14]. Another synthetic approach towards skeletal diversity as an example for implementing structural diversity in compound libraries is illustrated in Figure 4 [15].…”

Facile Synthesis of Enantiomerically Pure 2‐ and 2,3‐Disubstituted Furans Catalysed by Mixed Lewis Acids: An Easy Route to 3‐Iodofurans and 3‐(Hydroxymethyl)furans

“…They can also be utilized as building synthons in diversity-oriented-synthesis (DOS). [22] Work towards this end is currently underway in our laboratory.…”