Enantioselective synthesis of the protein phosphatase inhibitor (-)-motuporin.
A highly convergent asymmetric synthesis of the protein phosphatase inhibitor motuporin 1a is described. Synthesis and coupling of the individual peptide fragments [34 + 35 --> 51] followed by macrocyclization afforded the fully protected motuporin precursor 33, which is converted to the natural product by dehydration and ester hydrolysis. Six of the eight stereogenic centers associated with the natural product were introduced using asymmetric crotylsilane bond construction methodology. Our approach features an efficient Pd(0)-catalyzed cross-coupling reaction between a configurationally well-defined vinyl zinc intermediate 22 and an (E)-vinyl iodide 7, which afforded compound 43, resulting in the construction of the trisubstituted (E,E)-diene system of the motuporin side chain. Improved reaction conditions for macrocyclization in the formation of 33 are also detailed.
Hu
Tao
T
Department of Chemistry, Metcalf Center for Science and Engineering, 590 Commonwealth Avenue, Boston University, Boston, Massachusetts 02215, USA.
Panek
James S
JS
D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C093605:motuporin; D010749:Phosphoprotein Phosphatases