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A Short and Convenient Way to Produce the Taxole A-Ring Utilizing the Shapiro Reaction

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A Short and Convenient Way to Produce the Taxole A-Ring Utilizing the Shapiro Reaction TETRAHEDRON Pergamon Tetrahedron 58 22002) 2175±2181 A short and convenient way to produce the Taxole A-ring utilizing the Shapiro reaction Olli P. ToÈrmaÈkangas,a Reijo J. Toivola,b Esko K. Karvinenc and Ari M. P. Koskinena,p aLaboratory of Organic Chemistry, Helsinki University of Technology, P.O. Box 6100, FIN-02015 Espoo, HUT, Finland bDepartment of Chemistry, University of Oulu, P.O. Box 3000, FIN-90014 Oulu, Finland cNeste Chemicals Oy, Technology Center, P.O. Box 310, FIN-06101 Porvoo, Finland Received 22 October 2001; accepted 24 January 2002 AbstractÐThe Shapiro reaction was utilized in an ef®cient route to a Taxole A-ring building block. Commercially available 2-methyl-1,3- cyclohexanedione was converted in three simple steps to various arenesulfonylhydrazones and then to the target molecule with the Shapiro reaction. Remarkable differences were observed in the reactivity and stability of different hydrazones and their dianions in the Shapiro reaction. This pathway is the shortest one reported to give the target molecule in good overall yield. The use of different electrophiles in the ®nal Shapiro reaction step allows alternative ways to prepare the target alcohol. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction Our retrosynthetic strategy for Taxole is shown in Scheme 1. We have earlier reported our entries to the side Synthetic preparation of Taxol 1 is still under intensive chain 26 and the C-ring precursor 4.7 Compound 5 has been investigation due to its extremely low availability from utilized successfully as an A-ring precursor in the total nature 2bark of Paci®c yew tree Taxus brevifolia) and synthesis of Taxole by Nicolaou et al.8 growing shortage in treatment against a number of mam- malian cancers.1 Semisynthesis of Taxole from 10- The Shapiro reaction is an ef®cient way to create a new C±C deacetylbaccatin III, readily available from the needles of bond to the carbonyl carbon of ketones simultaneously Taxus baccata, has provided some amelioration against lack introducing a vinylic moiety into the product. In the Shapiro of Taxol.2 Several different strategies to Taxole A-ring reaction the ketone derived hydrazone is converted to a fragments have been developed utilizing Diels±Alder dianion using an alkyl lithium base and then decomposed reaction,3 modi®cation of cyclohexanones4 and ene- directly to the vinyl anion.9 The vinyl anion can also be reaction5 as the most common methods. alkylated to introduce a substituent to the neighboring AcO O OH X NHBz OHC CO R MeO2C BzHN O Ph 2 O OHC OH Ph O O O OH HO OBz OAc 2 3 4 1 O RO 5 Scheme 1. Retrosynthetic analysis of Taxole and the role of A-ring building block. Keywords: Shapiro reaction; Taxol; shortest synthetic pathway. p Corresponding author. Tel.: 1358-9-451-2526; fax: 1358-9-451-2538; e-mail: ari.koskinen@hut.® 0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0040-4020202)00089-3 2176 O. P. ToÈrmaÈkangas et al. / Tetrahedron 58 42002) 2175±2181 carbon atom. The lithiated vinyl anion reacts readily with distilled 2103±1048C; 13 mmHg) in order to obtain suf®- electrophiles allowing an easy entry to the ®nal product. The cient purity. Dimethylation of cyclohexane-1,3-dione use of intramolecular electrophiles allows preparation of directly to 7 was also attempted but the yield was rather cyclic products with high stereoselectivity.10 low 240%) and more side products were observed. In this paper we report the shortest and simplest synthesis of Selective monoketalization of pure 2,2-dimethyl-1,3-cyclo- a Taxole A-ring fragment utilizing the Shapiro reaction as hexadione 7 was achieved by treatment with 2,2-dimethyl- the key step. The route involves only four steps and 1,3-propanediol and 1 mol% of p-TsOH in CH2Cl2 with proceeds with high yields. azeotropic removal of water.12 Traces of two side products were observed but no diketalized dione. 2. Results and discussion In the beginning of this work, we wanted to study the reactivity of different electrophiles in the Shapiro reaction. The synthesis plan for the A-ring precursor 10 is shown in The aim was to use tosyl 12a and trisylhydrazone 12b Scheme 2. We have earlier reported the ®rst two steps in a 2Scheme 3) as model compounds. Ketone 8 was ®rst complementary and longer route to the Taxole A-ring converted 2LDA/CH3I) to the methylated ketone 11 in block.4d Herein we optimized those steps and the product, 66% yield. However, preparation of the arylsulfonylhydra- monoketal 8, was used as the starting material in the zones from ketone 11 proved to be impossible or extremely preparation of the hydrazones 9a±c. The Shapiro reaction slow. No product was observed in the case of 12b and only of 9a±c and related hydrazones 12a±b was investigated traces of product was formed in the case of 12a even after carefully. 24 h. The steric hindrance caused by the methyl groups in the a-position obviously retards the reaction. With HCl as Methylation of commercially available 2-methyl-1,3-cyclo- acid catalyst, only deketalization of 11 was observed. hexanedione 6 was carried out with K2CO3/CH3Iin acetone.11 The product mixture contained 85% of the We decided to use sterically less hindered hydrazones 9a±c desired 7 and 15% of 3-methoxy-2-methyl-cyclohex-2- 2of ketone 8) as model compounds 2Scheme 2) in order to enone as the side product 2ratios based on GC analysis). uncover the limitations in the Shapiro reaction. Addition- The crystalline side product was ®ltered off and recycled ally, the use of hydrazones 9a±c instead of hydrazones to the enol form of the starting material 6 by treatment with 12a±b provides one step shorter reaction pathway. All 2 M HCl in CH2Cl2. Diketone 7 was isolated in 99% purity stable hydrazones 9a±c were prepared in excellent yields. when CH2Cl2 was used as the solvent in the extraction. If Typically hydrazones are prepared under concentrated toluene was used instead of CH2Cl2 the product had to be conditions so that all starting material and reagent hardly O O O abO O O O 67(69%) 8 (94%) c R' O O d H O R S N N HO O O O R' 10 (62% from 9a) 9a R=CH3, R'=H (92%) b R=R'=CH3 (79%) c R=R'=CH(CH3) (94%) Scheme 2. Synthesis of Taxole A-ring block via tosylhydrazone 9a. Reagents and conditions: 2a) K2CO3,CH3I, acetone, rfx, 8 h; 2b) CH2Cl2, Me2C2CH2OH)2, p-TsOH£H2O, CH2Cl2, rfx, 7 h; 2c) EtOH 2THF in 9b), hydrazide, 1408C 16 min, then rt 6 h; 2d) THF, 2508C, n-BuLi, 30 min, CH3I, 30 min, n-BuLi, from 2508C to rt, 25 min, paraformaldehyde, 30 min. R' O O H O a O b RSN N 8 O O O R' 11 12 a R=CH3, R'=H b R=R'=CH(CH3)2 Scheme 3. Reagents and conditions: 2a) LDA, THF, 2788C, CH3I, 08C then rt; 2b) hydrazide, EtOH, 2HCl). O. P. ToÈrmaÈkangas et al. / Tetrahedron 58 42002) 2175±2181 2177 dissolve in the solvent.13 Also a small excess of hydrazine 2508C gives dianion 15 which can be observed as a slightly 2105±110 mol%) is usually required to run the reaction to orange color. When this dianion is heated to room completion. If the ketone used is sterically hindered, temperature it slowly decomposes to vinyl anion 16. The addition of a catalytic amount of HCl, re¯uxing the reaction decomposition can be easily observed as the formation of 14 mixture and longer reaction time are sometimes needed. small bubbles when N2 is liberated. An electrophile must be Here, under optimized reaction conditions to prepare 9a±c, added immediately when the gas formation has ceased the reaction mixture is ®rst heated up to 130 to 1408C until especially if THF is used as the solvent in order to avoid complete dissolution is achieved and then allowed to react at possible protonation of vinyl anion 16 by THF. room temperature 2too high reaction temperatures caused partial decomposition of the product even at 1508C). The The strength of the used alkyl lithium base in the use of acid catalyst was not necessary. Absolute EtOH was Shapiro reaction is also crucial.15 Stronger bases like found to be the best solvent in the preparation of tosyl- t-BuLi are sometimes required in the deprotonation. In hydrazone 9a and trisylhydrazone 9c allowing a our case the formation of dianion 15 from 14 can be carried spontaneous crystallization of the hydrazones from the out easily with n-BuLi. However, t-BuLi gave similar reaction mixture. The preparation of 9a was carried out results. also in THF and MeOH successfully but in lower yields. Additionally, the reaction was slightly slower and the We initially studied the Shapiro reaction with trisylhydra- hydrazone did not crystallize out from the reaction mixture. zone 9c which was treated with t-BuLi at 2788C in THF and Mesitylhydrazone 9b was prepared only in THF. formation of the ®rst dianion 13c was observed as a red Differences in the stabilities of hydrazones 9a±c during color 2Scheme 4). The dianion of trisylhydrazone was storage were also observed. Tosylhydrazone 9a seems to found to be too labile even at 2788C and decomposition be very stable and can be stored at 148C for a few years was observed. Methylation of the dianion was carried out at under argon. Trisylhydrazone 9c decomposed partly under 2788C as well as the preparation of the second dianion 15c, similar conditions giving yellowish color in a few months.
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