Stereocontrolled Total Synthesis of (±)-FR901483

The total synthesis of potent immunosuppressant FR901483 (1) is reported.The remarkable feature of our convergent synthesis is the p-methoxybenzyl and methylamino groups are stereoselectively incorporated within the tri-cyclic core skeleton.The skeleton itself is constructed by an intramolecular aldol reaction on a symmetrical keto-aldehyde (14), which is readily derived by an eight-step sequence from nitromethane and methyl acrylate.MeO 2 C CO 2 Me CO 2 Me NO 2 MeNO 2 CO 2 Me + 9 cat.DBU MeCN, 0 °C H 2 , Ra-Ni MeOH, 60 °C MeO 2 C CO 2 Me NH O NaH cat.MeOH benzene, 90 °C 76% (3 steps) NH O CO 2 Me OH NH O O aq.NaOH MeOH, 100 °C; conc.HCl (neutralization) 1) cat.CSA, HC(OMe) 3 , MeOH 2) NaH, allyl bromide, THF/DMF 3) cat.CSA, acetone/H 2 O, 70 °C 75% (4 steps)