Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by SmI₂-Mediated Cyclization

Abstract

A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described. SmI2-mediated reductive cyclization of an allylic benzoate possessing an aldehyde function, synthesized from tri-O-acetyl-d-glucal and 1,3-cyclohexanedione, smoothly afforded the highly strained 6-8-6 tricarbocyclic structure in 66% yield.

Two-Phase Synthesis of Taxol

“…A relatively concise totally synthetic approach to 1 has been widely viewed as impossible, with one textbook (published in 2007) declaring that "…even an academic-type synthesis of 1 poses a major challenge, unlikely to be solved by a preparation under 30 or 40 steps in length". 9 This prediction had so far proven true, as ten distinct syntheses have been disclosed (from 1994 to 2015), [19][20][21][22][23][24][25][26][27][28][29][30][31] involving the effort of more than 150 chemists, to arrive at syntheses traversing through 36 to 59 isolated intermediates. Of those, seven have reported totally synthetic approaches and three have described formal syntheses that intercept known intermediates.…”

“…The difference between both the wondrous efficiency and diversity of taxanes accessed through Nature's enzymatic machinery (biosynthesis) 32 and the most valiant efforts of human chemists in the laboratory is rather striking. From a strategic perspective, three of these syntheses used naturally-occurring terpene starting materials, 19,20,23,24,27 six of them fused two chemically synthesized six-membered ring systems to form the central eight-membered ring, 21,22,25,[27][28][29][30][31] and one built out by double annulation onto an already-constructed eight-membered ring. 26 Although these approaches follow the canonical rules of retrosynthetic analysis and establish the feasibility of accessing specifically 1, none of them enabled divergency in their 2 retrosynthetic design that could be developed into a blueprint for future analogue exploration.…”

Transgenesis as a Tool for the Efficient Production of Selected Secondary Metabolites from Plant in Vitro Cultures

“…As this drug is widely used in cancer therapy in humans, there is great interest in increasing its productivity from natural sources. Although paclitaxel can be chemically synthesized [71], this process is not commercially profitable, and its best sources are in vitro and ex vitro plant cultures. A number of previous works have attempted to optimize the process of obtaining taxanes by genetic transformation.…”

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

“…[38] Thus, exposure of 14 to NBS in the presence of benzoyl peroxide furnished an allylic bromide which could be smoothly converted into the silyl ether 15 by solvolysis with AgOTf and TMSOH (79 % yield, one-pot). The free tertiary alcohol (15), which served as a bystander to two CÀH oxidations, could now be eliminated using the Burgess reagent and the crude olefin was subjected to a strategic reduction using DIBALH to set the proper stereochemistry of 16 at C13 (81 % yield, one pot). In preparation for installation of the challenging C9 oxygen atom, the triol was protected as the tri-MOM ether and the allylic silyl ether was selectively oxidized directly using IBX (85 % yield, one-pot) to afford 17.…”

“…The spectacular clinical success of taxanes combined with their stunning complexity has motivated and inspired scores of chemists over the past several decades. [1][2][3] Indeed, Taxol (1, Figure 1) can be treated as ab arometer to measure progress and advances in the science of chemical synthesis.This iconic natural product has been prepared on ten separate occasions (seven total syntheses [4][5][6][7][8][9][10][11][12] and three formal syntheses [13][14][15][16] ), thus elegantly demonstrating the feasibility of its reconstitution by purely chemical means.Notwithstanding the beauty of these landmark accomplishments,t hey are eight to nine orders of magnitude less efficient than biological production. To be sure,m ere milligrams were produced all together by total synthesis,w hereas metric tons of Taxol are accessed every year through ap lant cell culture process developed by Bristol-Myers Squibb and Phyton Biotech, Inc.…”