Asymmetric synthesis of the aminocyclitol pactamycin, a universal translocation inhibitor.
An asymmetric total synthesis of the aminocyclopentitol pactamycin is described. The title compound is delivered in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to nonstrategic downstream manipulations. This synthesis is immediately accommodating to the preparation of structural analogs.
Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-3290, United States.
Robert J
RJ
Sharpe
Justin T
JT
Malinowski
Jeffrey S
JS
Johnson
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D010142:Pactamycin / Q000138:chemical synthesis*; D010422:Pentanones / Q000737:chemistry; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000903:Antibiotics, Antineoplastic; D010422:Pentanones; D011500:Protein Synthesis Inhibitors; D010142:Pactamycin; C008790:acetylacetone