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Organic Chemistry Highlights

Total Synthesis

Monday, April 4, 2022
Douglass F. Taber
University of Delaware

The Li Synthesis of Paclitaxel (TaxolŽ)

Paclitaxel (TaxolŽ) (3) is a critical tool for cancer chemotherapy. Chuang-Chuang Li of the Southern University of Science and Technology developed a convergent approach to 3, based on the reductive cyclization of 1 to 2 (J. Am. Chem. Soc. 2021, 143, 17862. DOI: 10.1021/jacs.1c09637).

The construction of 1 goes back to the work of P. W. Hickmott of the University of Salford (J. Chem. Soc. (C) 1968, 2599. DOI: 10.1039/J39680002599). Acylation of the morpholine enamine 4 with acryloyl chloride followed by hydrolysis and ketalization led to 5. Based on other literature precedent, exposure of the derived hydrazone to I2 led to 6, that was hydrolyzed and protected as the thioketal 7.

The preparation of the other half of 1 began with the commercial ketone 8, prepared in enantiomerically-pure form by reduction of the 1,3-diketone. Benzylation followed by Vilsmeier reaction and reduction led to the alcohol 9. Reduction of the derived mesylate followed by oxidative cleavage delivered the aldehyde 10. Rubottom oxidation of the silyl enol ether proceeded with high diastereoselectivity, to give, after protection, the bromide 12, that was formylated and deprotected to give 1.

Despite the literature precedent for the reductive cyclization of similar but less substituted keto aldehydes, the conversion of 1 to 2 was particularly challenging. Eventually, it was found that adding Sm metal to the medium led to efficient conversion. The diol 2 was not stable, so it was protected, leading to the crystalline 13.

Hydrolysis, selective acetylation and oxidation of 13 led to the monoketone, that was epimerized to the more stable 14. Debenzylation, silylation and oxidation then gave the triketone 15. Selective tosylhydrazone formation, reduction and protection set the stage for Kabalka reduction, leading to the requisite trans-fused alkene 16. Singlet oxygenation followed by a modification of the literature endgame then completed the synthesis of paclitaxel 3.

Silicon-based lifeforms? Maybe not, but silicon-based pharmaceuticals may not be far off. Ruotian Jiang and Zhenlei Song of Sichuan University showed that sila-mesembranol (20), prepared by combining the prochiral silane 17 with the propargyl ester 18 to give 19, retained the anti-anxiolytic activity of the Sceletium alkaloid (Org. Chem. Front. 2021, 8, 5941. DOI: 10.1039/D1QO00682G).

D. F. Taber, Org. Chem. Highlights 2022, April 4.