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Synthesis of (±)‐Spongiolactone Enabling Discovery of a More Potent Derivative
Author(s) -
Harvey Natalie L.,
Krysiak Joanna,
Chamni Supakarn,
Cho Sung Wook,
Sieber Stephan A.,
Romo Daniel
Publication year - 2015
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.201405980
Subject(s) - chemistry , stereocenter , aldol reaction , stereochemistry , natural product , pharmacophore , cyclohexanone , stereoselectivity , cancer cell lines , total synthesis , combinatorial chemistry , k562 cells , enantioselective synthesis , catalysis , cancer cell , cell , organic chemistry , biochemistry , cancer , biology , genetics
Abstract An eleven‐step synthesis of (±)‐spongiolactone from 1,3‐cyclohexanedione is reported that relies on a diastereoselective, nucleophile‐catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β‐lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure–activity studies that revealed a regio‐ and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.