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Synthesis of Novel Migrastatin and Dorrigocin A Analogues from D ‐Glucal
Author(s) -
Anquetin Guillaume,
Rawe Sarah L.,
McMahon Kevin,
Murphy Evelyn P.,
Murphy Paul V.
Publication year - 2008
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.200701033
Subject(s) - glucal , chemistry , stereochemistry , glycal , alkene , steric effects , derivative (finance) , enantioselective synthesis , salt metathesis reaction , allylic rearrangement , combinatorial chemistry , metathesis , stereoselectivity , organic chemistry , catalysis , financial economics , economics , polymer , polymerization
The synthesis of a range of analogues of the migrastatin macrolide core has been achieved from tri‐ O ‐acetyl‐ D ‐glucal in order to facilitate structure–activity studies. Efficient macrolactone formation was achieved in the presence of a reactive olefin, by increasing steric hindrance in the olefin environment. Acyclic analogues of migrastatin, structurally related to dorrigocin A, have also been prepared from D ‐glucal. The dorrigocin A analogues were prepared using the combination of the cross metathesis of ethyl 6‐heptenoate with a glycal derivative and a subsequent allylic rearrangement–alkene isomerisation reaction (Perlin reaction). A synthetic route is thus provided that will enable dorrigocin A analogues to be prepared in parallel to migrastatin analogues in the search for novel anti‐cancer and anti‐arthritic therapeutics. Biological evaluation of one migrastatin and one dorrigocin A sugar derived analogue show that they inhibit proliferation and serum‐induced migration of tumour and synovial cells at higher concentrations than evodiamine. Dorrigocin A analogues displayed similar potency to analogues of the migrastatin core.