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Synthesis of Small Molecules with High Scaffold Diversity: Exploitation of Metathesis Cascades in Combination with Inter‐ and Intramolecular Diels–Alder Reactions
Author(s) -
O'LearySteele Catherine,
Pedersen Palle J.,
James Thomas,
LanyonHogg Thomas,
Leach Stuart,
Hayes Jerome,
Nelson Adam
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201000707
Subject(s) - intramolecular force , metathesis , scaffold , salt metathesis reaction , chemistry , chemical space , cascade , grubbs' catalyst , combinatorial chemistry , linker , drug discovery , organic chemistry , polymerization , computer science , biochemistry , chromatography , database , polymer , operating system
Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter‐ and intramolecular Diels–Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to “reprogram” the molecular scaffolds. In many cases, the metathesis products were 1,3‐dienes, which were potential substrates for either inter‐ or intramolecular Diels–Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a “safety‐catch” linker that we have developed. It was demonstrated that, in certain cases, Diels–Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.