A one-step synthesis of a deuterated paclitaxel analogue: 10-Deacetoxy-(10α-2H)paclitaxel

Dutta, Debasree; Hadd, Harry E.; Velde, David G. Vander; Georg, Gunda I.

doi:10.1016/s0960-894x(99)00609-5

Cited by 5 publications

(4 citation statements)

References 3 publications

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“…It was envisioned that perhaps the β-acetoxy group might be more readily cleaved using these conditions given the structural similarities to the diterpene taxol. 23 Thus, the reaction of 7 with acetic acid under modified Mitsunobu conditions 25 afforded acetate 10a in 80% yield. To confirm the inversion of stereochemistry at C-2, the 1 H NMR spectrum of 10a was compared to 1.…”

Section: Resultsmentioning

confidence: 98%

“…To circumvent this problem, we sought to prepare the C-2 epimer of 1 . It was envisioned that perhaps the β-acetoxy group might be more readily cleaved using these conditions given the structural similarities to the diterpene taxol . Thus, the reaction of 7 with acetic acid under modified Mitsunobu conditions afforded acetate 10a in 80% yield.…”

Section: Resultsmentioning

confidence: 99%

“…The treatment of imidazole 8 with 2,2′-azobis(2-methylpropionitrile) (AIBN) and tributyltin hydride in toluene afforded an epimeric mixture of 9a and 9b in 13 and 28% yield, respectively. Other attempts to remove the 2-acetoxy group in 1 using either samarium iodide 23 or Zn and acetic acid were unsuccessful. 24 To circumvent this problem, we sought to prepare the C-2 epimer of 1.…”

Section: Resultsmentioning

confidence: 99%

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Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Semisynthesis of Salvinicins A and B and Other Chemical Transformations of Salvinorin A

et al. 2005

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Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for κ opioid receptors. One approach to better understanding the mode of binding of 1 at κ receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with δ opioid antagonist activity. Keywords salvinorin A; salvinicin A; salvinicin B; neoclerodane diterpenes; and Salvia divinorumExtracts of the opium poppy, Papaver somniferum, have been used for centuries to relieve pain and to induce sleep. 1 Among the most important constituents in opium are the alkaloids morphine and codeine. Many of the agonists and antagonists derived from these alkaloids are essential for the practice of modern medicine. While many potent agonists are effective analgesics, they have undesirable side effects, such as tolerance, dependence, and respiratory depression. 2Recently, opioid receptors have been implicated in the actions of salvinorin A (1), the major active ingredient of Salvia divinorum Epling & Játiva (Lamiaceae), a hallucinogenic plant that has been used historically in the traditional practices of the Mazatecs in Oaxaca, This finding is unique because 1 represents the only known lipid-like small molecule that † This work was presented in part at the American Society of Pharmacognosy 46 th Annual Meeting, July 23 -July 27, 2005.*To whom correspondence should be addressed, S327 PHAR, MNPC, 115 S. Grand Ave. Iowa City, Iowa 52242-1112, Telephone: (319) Fax: (319) selectively and potently activates a peptidergic G-protein coupled receptor (GPCR). 7, 8 Diterpene 1 was found to be a high efficacy agonist for κ opioid receptors (κOR). 6, 9 Thus, 1 provides a truly unique template for the development of novel agents to attenuate pain with a potential for reduced abuse liability.Recently, we 10, 11 and others 12-15 have described the isolation and synthesis of several novel neoclerodane diterpenes with opioid receptor activity. Among these compounds were salvinicin A (2) and salvinicin B (3). 11 Diterpene 2 was identified as a partial κOR agonist, whereas, 3 was found to be the first neoclerodane diterpene with μ antagonist activity. There is a growing body of information as to why 1 and related analogues have activity at opioid receptors. 10, 11, 13-17 However, there are few synthetic methods described for related analogues of 1. Based on previous reports, 10, 11, 13,14 the C-2 position and furan ring appear to be important sites for the op...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Semisynthesis of Salvinicins A and B and Other Chemical Transformations of Salvinorin A

et al. 2005

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“…100 The modulation of multi-drug resistance in tumour cells by taxinine derivatives has been examined. 101 The synthesis of 7-deoxy-6-hydroxypaclitaxel 102 and 10-deacetoxypaclitaxel 103 have been reported. The structures of some rearrangement products of taxanes under various mineral and Lewis acid catalysed conditions have been elucidated.…”

Section: Taxanesmentioning

confidence: 99%