A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization

Abstract

A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups

“…Following a similar approach to synthesize a C,D-spiro taxane in our lab, 7 the allylation of 4-OH could only be realized in the presence of (PPh 3 ) 4 Pd and ally-tert-butylcarbonate, since it was found difficult to occur by using similar conditions as methylation (Scheme 5). However, from compound 8, the reaction occurred exclusively at the 3′-N amide (data not shown).…”

“…Hence, based on the literature protocol, intermediate 6 was synthesized from 1a for the follow-up studies. After the protection of the 20-OH with a triethylsilyl (TES) group, the elimination of the iodo atom in compound 7 was realized by using the LiCl/NaHCO 3 system in DMF, to give the desired product in high yield (91%) (Scheme ) according to the similar synthetic strategy developed in our lab . The selection of the protective group at C20 was important, since the elimination could not occur if 20-OH was masked with other groups, such as p -toluenesulfonyl or methylthiomethyl.…”

Design, synthesis and SAR study of 3rd-generation taxoids bearing 3-CH3, 3-CF3O and 3-CHF2O groups at the C2-benzoate position

“…These limitations are, at least in part, due to multi-drug resistance (MDR) caused by overexpression of ABC cassette efflux pumps, overexpression of β-III tubulin isoform, point mutations in the microtubule binding site and cancer stem cells [8][9][10]. In order to address these issues, a number of new taxoids [11][12][13][14][15][16][17], new formulations [18][19][20][21][22] and new combination therapies [23][24][25][26][27][28] are currently in different stages of preclinical and clinical development [1,17]. Nevertheless, it is critical to keep developing next-generation taxoid anticancer agents with superior pharmacological properties and potency against various types of cancers, in particular drug-resistant and metastatic cancers, as well as cancer stem cells (CSCs), which are responsible for tumor recurrence and metastasis, causing major problems in cancer therapy [1,2].…”

Novel taxane derivatives from Taxus wallichiana with high anticancer potency on tumor cells

“…It is well known, paclitaxel, as a microtubule‐stabilizing drug, which cause cells to arrest in G 2 ‐M phase of cell cycle by inducing tubulin polymerization. And this is the mechanism of paclitaxel targeting cancer cells . Meanwhile, in view of the results of Cell proliferation and viability experiment, we, therefore, concluded that these four compounds, as novel natural products with paclitaxel‐like microtubule‐stabilizing activity, represents their major importance in the clinical treatment of cancer.…”