Total synthesis of the hydroxyketone kurasoin A using asymmetric phase-transfer alkylation.
The total synthesis of the farnesyltransferase inhibitor kurasoin A has been achieved using a novel asymmetric phase-transfer-catalyzed glycolate alkylation reaction. 2,5-Dimethoxyacetophenone 7 with cinchonidinium catalyst 9(10 mol %) and hydroxide base with pivaloyl benzyl bromide 8 provided S-alkylation product 10 in high yield (80-99%) and excellent enantioselectivity. Baeyer-Villiger oxidation, Weinreb amide formation, and benzyl Grignard addition to the TES-ether 17 gave the protected target. Lithium hydroxide and peroxide generated kurasoin A ([alpha](D) +8.4 degrees ) without isomerization.
Andrus
Merritt B
MB
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, Utah 84602-5700, USA. mbandrus@chem.byu.edu
Hicken
Erik J
EJ
Stephens
Jeffrey C
JC
Bedke
D Karl
DK
D000478:Alkylation; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006900:Hydroxylation; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007659:Ketones / Q000737:chemistry*; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007211:Indoles; D007659:Ketones; D010636:Phenols; C102430:kurasoin A; C102431:kurasoin B; D051231:Farnesyltranstransferase