Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization

Abstract

Taxol (1) is a clinically used antineoplastic diterpenoid. The tetracyclic ring system comprises a 6/8/6-membered carbocycle (ABC-ring) and a fused oxetane ring (D-ring) embedded with a bridgehead double bond and decorated with multiple oxygen functionalities. Here, we report a convergent total synthesis of this exceedingly complex natural product. The C-ring fragment was designed to possess a bromocyclohexenone and an extra tetrahydrofuran ring to control the reactivity and selectivity, as well as to minimize functional group manipulations en route to 1. The α-alkoxyacyl telluride of the A-ring served as a radical precursor, and intermolecular radical coupling with the C-ring realized the installation of the C2- and C3-stereocenters and reductive removal of the bromide. After the C8-quaternary stereocenter was constructed by exploiting the three-dimensional shape of the intermediate, the C11-vinyl triflate of A-ring and the C8-methyl ketone of C-ring were utilized for Pd(0)-catalyzed cyclization of the central eight-membered B-ring with the bridgehead olefin. Adjustment of the oxidation level and attachment of the oxetane D-ring completed the total synthesis of 1 (28 steps, as the longest linear sequence). The fragment design principle and implementation of the powerful radical coupling reaction described in the present synthesis provide valuable information for planning and executing syntheses of diverse densely oxygenated terpenoids.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

“…Considering that attachment of a sterically hindered group on C15 might alter this selectivity, thus favoring the desired C8À C17 bond formation, C15 brominesubstituted dienone 27 was quickly prepared using a similar procedure to that for the synthesis of 25 to test this strategy. [18] Initially, standard radical cyclization conditions (AIBN, n Bu 3 SnH, PhH, 80 °C) were examined under nitrogen atmosphere (Table 1, entry 1). Much to our delight, the desired cyclization product 28 could indeed be obtained, albeit in a very low yield (< 5%).…”