Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (-)-norsecurinine, and phyllanthine

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronors ecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originat ed from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile w ith SmI2 afforded the 6-azabicyclo-[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine, (8) with the;required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based am ide oxidation methodology developed in these laboratories as a key step, pr oviding tricycle 33. Annulation of the D-ring onto alpha-hydroxyketone 33 w ith the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8 ). In the securinine series, the D-ring was incorporated using,an intramole cular Wadsworth-Horner-Emmons olefination of phenylselenylated alpha-hydrox yketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenol ide 50 to give (-)-norsecurinine (6). The A-ring df phyllanthine (2) was fo rmed from hydroxyketone 14 using a stereoselective Yb(OTf)(3)-promoted hete ro-Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, a ffording adduct 35. Conjugate reduction and stereoselective equatorial keto ne reduction of vinylogous amide 35 provided tricyclic intermediate 36, whi ch could then be elaborated in a few steps to stable hydroxyenone 53 via al pha-selenophenylenone intermediate 52. The D-ring was then constructed, aga in using an intramolecular Wadsworth- Horner-Emmons olefination reaction to give phyllanthine (2).