Synthesis of [3″‐³H]taxol and [13‐³H]taxol¹

Abstract

SUMMARY7-Triethylsilylbaccatin Ill (1 1) was coupled with cis-1 -benroyC3-triethylsiloxy-4-(3'-bromophenyl)azetidin-Z-one. Hydrolysis of the silyl groups gave 3"-bromotaxol which was reduced with tritium gas to give[3"-3H]taxol with specific activity of 19.3 Ci mrnol. Reduction of 7-triethylsilyl-13-oxobaccatin Ill with [3H]borane-tetrahydrofuran complex gave 7-triethylsilyl[l3-3H]baccatin Ill (17). Coupling of 17 with cis-3-triethylsiloxy-4-phenyl-(3R,4S)-azetidin-2-one and hydrolysis gave [13-3H]taxol with specific activity of 1.66 Ci/mmol. Key words: taxol, tritium INTRODUCTIONSince the discovery in 1971 of the diterpenoid taxol2, with its anticancer activity and unusual ability to stabilize the assembly of microt~bules3~~, there has been a need for radiolabeled taxol to facilitate pharmacological studies. Although taxol has been labeled by tritium exchange4 and by introducing a 7-[3H]acetyl groups, until recently taxol's complex structure has precluded site-specific labeling. Recent developments in taxol chemistry have provided methods for specifically labeling taxol both in the side chain and in the baccatin 111 ring system. Several research groups have reported the semi-synthesis of taxol based on coupling a side-chain synthon with suitably protected baccatin 111.6-10 We found that an adaptation of the methods of Holton8~9and Ojima'o was the most effective for the semimicro scale required for synthesis of radiolabeled taxol at high specific activity. RESULTS AND DISCUSSIONThe key intermediate for the preparation of side-chain labeled taxol, bromolactam 8 , was prepared by adapting the procedure of Holton.8 The synthetic scheme is shown in Chart 1. Benzenimine 3 was prepared in 73% yield from the addition of p-anisidine to 3-bromobenzaldehyde. lmine 3 was treated with acetoxyacetyl chloride and triethylamine to give azetidinone 4 in 45% yield. The methoxyphenyl group was cleaved from 4 with ceric ammonium nitrate (CAN) to give ester 5 in 70% yield, and the ester group was hydrolyzed with potassium hydroxide to provide hydroxyazetidinone 6 in 57% yield.Because the coupling reaction with baccatin Ill favors the desired stereochemistry depending on reaction conditions and protecting groupg, 6 was not resolved. Several

Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

“…CoA esters of ␣-phenylala- nine, phenylisoserine, and N-Bz phenylisoserine were similarly prepared, except that the latter two amino acids required t-Boc protection of the C-2 hydroxyl before conversion to the mixed anhydride. [ 3 H]Baccatin III was prepared by modification of an established procedure (13).…”

Lipase-catalyzed resolution of 4-aryl-substituted β-lactams: effect of substitution on the 4-aryl ring

“…Racemic 3-acetoxy-4-(3-bromophenyl)-1-(4-methoxyphenyl)azetidin-2-one (6)-18. 36 With the procedure described above 18 was prepared as a yellow solid, mp 150 -1528C. 1 3.3.20.…”

Synthesis of deuterium‐labelled paclitaxel and its hydroxyl metabolite

“…[10][11][12][13][14][15][16] The chiral side chain of taxol contains phenylisoserine ester and b-lactam. For our synthesis, the [ 2 H 5 ]benzoyl group was introduced of (7) 0 -O-(t-butyldimethylsilyl)-6, 7-dehydropaclitaxel (9).…”

“…The preparation of the stable labelled versions of the title compounds with M15 was requested. Although 3 H-paclitaxel and 14 C-paclitaxel have been prepared for pharmacological studies, 10,11 the synthesis of its stable labelled internal standards has not been disclosed in detail. 12 In this paper, the synthetic routes to [ 2 H 5 ]paclitaxel and its 6a-hydroxyl metabolite are described in detail.…”