Scalable enantioselective total synthesis of taxanes

Abstract

Taxanes are a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel) — a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which possesses a suitable functional handle to access more oxidised members of its family. This route enabled a gram-scale preparation of the ”parent” taxane, taxadiene, representing the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The taxane family’s characteristic 6-8-6 tricyclic system containing a bridgehead alkene is forged via a vicinal difunctionalisation/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed via substrate control. This study lays a critical foundation for a planned access to minimally oxidised taxane analogs and a scalable laboratory preparation of Taxol itself.

Indium(III)‐Promoted Organocatalytic Enantioselective α‐Alkylation of Aldehydes with Benzylic and Benzhydrylic Alcohols

“…By careful chromatographic separation it was possible to obtain a sample with dr = 1.2:1 and the relative configuration of the diastereoisomers were consequently assigned for the ester and aldehyde moieties. For most of the isolated products, similar evidence was obtained by 1 H NMR spectroscopy; the relative configuration of the major diastereoisomer obtained in the addition of aldehydes to hindered benzhydrylic substrates was assigned as anti. The relative configurations of the esters were correlated to the corresponding aldehydes.…”

“…[1] In the past decade, organocatalytic [2] methods have emerged as complementary to organometallic-based techniques for catalysed transformations. In particular, enamine, [3] iminium, [4] and SOMO catalysis, [5] as well as photocatalysis [6] have contributed to the enhanced synthetic utility and versatility of carbonyl compounds.…”

Carbon-atom wires: 1-D systems with tunable properties

“…This includes carbon wires connecting metal leads, graphene, and nanotubes as device prototypes. [37][38][39][40][41][42][43][44][45][46][47] Here we review the present state of research on carbonatom wires based on both experimental and theoretical results, with particular focus on the structure-dependent properties. The review is organized as follows.…”

Scaffold Diversity Synthesis with Branching Cascades Strategy

“…Although, recently, many successful "scale-up" TOS endeavors [11][12][13] have been reported, yet, TOS remains an impractical method when it comes to providing a large number of molecules for screening purposes. Synthesis of compound libraries that are either natural-product-derived/inspired molecules [14] or based on "privileged scaffolds" [15] are endeavors to fill up the natural-product-like chemical space.…”