The Chemical Synthesis of C‐Ring Aryl Taxoids

Abstract

Abstract:We designed and targeted for synthesis the C-ring aryl taxoids 2a-c in order to develop methods for the construction of the taxoid skeleton and to test their cytotoxicity against tumor cells. Compound 2 a was synthesized by a convergent route from hydrazone 5 and aldehyde 4. Key steps included a Shapiro reaction to join 5 and 4, a McMurry coupling to construct the %membered ring, a carbonate opening to introduce the 2-ben- Keywordsantitumor agents -carbocyclesdrug research taxol zoate group, and an allylic oxidation followed by side-chain attachment. A similar sequence led to compound 2c, whereas attempts to attain 2 b were thwarted by the lability of the benzyl group during the carbonate opening. The biological activity of 2a and 2 c against tumor cells was considerably less than that of taxol.

Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance

“…Subsequent steps in this highly convergent synthesis included two other important carbon-carbon bond forming processes, namely the Shapiro reaction (rarely used in total synthesis) and the McMurry coupling reaction, the latter employed as the key process to form Taxol®’s most strained and challenging domain, ring B. In addition to the total synthesis of the targeted molecule, the Taxol® campaign led to a number of synthetic technology discoveries 56 and new biological insights. 56,57 These include: (a) the regioselective opening of cyclic carbonates to hydroxy esters; (b) the design, synthesis, and biological investigation of several water-soluble taxoids and other Taxol® prodrugs and analogues; 57a (c) a fascinating self-assembling designed Taxol® that formed helices in aqueous solution; 57c and (d) a number of Taxol®-based fluorescent probes for tubulin imaging studies.…”

“…In addition to the total synthesis of the targeted molecule, the Taxol® campaign led to a number of synthetic technology discoveries 56 and new biological insights. 56,57 These include: (a) the regioselective opening of cyclic carbonates to hydroxy esters; (b) the design, synthesis, and biological investigation of several water-soluble taxoids and other Taxol® prodrugs and analogues; 57a (c) a fascinating self-assembling designed Taxol® that formed helices in aqueous solution; 57c and (d) a number of Taxol®-based fluorescent probes for tubulin imaging studies. 58 The availability of such molecules through chemical synthesis enabled conformational and tubulin binding investigations and led to insights into nanostructures with remarkable physical and biological properties.…”

Reagents for Carbonyl Methylenation in Organic Synthesis

“…However, aldehydes and ketones can be methylenated in the presence of the less reactive esters or amides [76], whilst another side-reaction which can occur, olefin metathesis, requires refluxing in THF for extended periods [77]. However, aldehydes and ketones can be methylenated in the presence of the less reactive esters or amides [76], whilst another side-reaction which can occur, olefin metathesis, requires refluxing in THF for extended periods [77].…”

The McMurry Coupling and Related Reactions

“…By assuming that the product stereochemistry is controlled by steric interactions in the ring being formed, some prediction of the reaction diastereoselectivity could be made [220]. Various natural products have also been synthesized, namely sarcophytol B [221], crassin [222], periplanone C [223], and taxol [224][225][226][227][228], the latter being perhaps the most famous natural product to have been prepared with the aid of low-valent titanium compounds. The TiCl 4 -Mg(Hg) system was found to be very efficient, at 0 C in THF, for the intra-and intermolecular pinacol coupling of aliphatic and aromatic aldehydes and ketones; reaction of a cyclic ketone with an excess of acetone gave the unsymmetrical diol [229].…”