Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin

Described is the first catalytic, asymmetric synthesis of (-)-podophyllotox in and its C-2-epimer, (-)picropodophyllin. Asymmetry is achieved via the e nzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediat ed ester hydrolysis. A second key feature of the synthesis is the strategic ally late introduction of the highly oxygenated natural ring E through an a rylcopper species. The successful implementation of this approach augers we ll for the introduction of other functionalized rings E for future SAR work . The synthesis begins from piperonal, which is fashioned into isobenzofura n (IBF) precursor 14 in three steps (bromination, acetalization, and haloge n-metal exchange/hydroxymethylation). Interestingly, treatment of 14 with H OAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate(15) and maleate-IBF Diels-Alder add ucts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimeth yl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained . On the other hand, the desired meso diester 16 is obtained pure and in ne arly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH4) of 16 provides meso diol 19, which is then treated with Ac2O, BzCl, and PhC H2COCl to provide the corresponding meso diesters, 20-22. Screening of thes e meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL . Even on 10-20 g scales, asymmetry is efficiently introduced here, yieldin g the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corr ected yield, 95% ee). Protecting group manipulation and oxidation (Swern) p rovide aldehyde 27b, which undergoes efficient retro-Michael ring opening t o produce dihydronaphthalene 30, in which the C-3 and C-4 stereocenters are properly set. Following several unsuccessful approaches to the intramolecu lar delivery of ring E (via Claisen rearrangement, Heck-type cyclization, o r radical cyclization), a highly diastereoselective, intermolecular conjuga te addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenyl magnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yiel d, only the required alpha-stereochemistry at C-1 is observed). The conjuga te addition product is converted to (-)-picropodophyllin in two steps (lact onization, SEM deprotection) or to (-)-podophyllotoxin, in three steps, thr ough the introduction of a C-2-epimerization step, under Kende conditions, prior to the final conjugate addition.