(2S)-1-(2-[(2S,3R,6S)-6-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-3-methyl-2-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】15042

【品名】(2S)-1-(2-[(2S,3R,6S)-6-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-3-methyl-2-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylic acid

【CA登记号】

【分子式】C₂₈H₄₆INO₇Si

【分子量】663.66575

【元素组成】C 50.67% H 6.99% I 19.12% N 2.11% O 16.88% Si 4.23%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

A total synthesis of rapamycin has been described: The condensation of the iodo-compound (I) with dithiane (II) by means of tert-butyllithium in THF followed by elimination of the acetal group with trichloroacetic acid gives the aldehyde (III), which is condensed with the dithiane (IV) by means of tert-butyllithium in THF, and the resulting compound methylated with NaH and methyl iodide to afford the acetal (V) as a diastereomeric mixture (in the newly formed methoxy group) that was resolved by flash chromatography. The sequential reaction of (V) first with p-toluenesulfonic acid to hydrolyze the acetal group, and then with CBr4 in THF/HMPT and finally with butyllithium in THF gives the terminal acetylene derivative (VI). Elimination of the dithiane and PMB groups, and reaction with tributyl tin hydride affords the trans-vinylene alcohol (VII), which is esterified with piperidine carboxylic acid (VIII) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) and DMAP in dichloromethane yielding the condensation ester (IX). Finally, this compound is submitted to an intramolecular Stille cyclization with the tris(2-furyl)phosphine palladium dichloride complex in DMF/THF, which after desilylation with tetrabutylammonium fluoride (TBAF) and HF.pyridine afforded rapamycin.

参考文献中间体

合成目标

【1】 McCauley, J.A.; Leahy, J.W.; Smith, A.B.; Leazer, J.L.; Maleczka, R.E.; Condon, S.M.; Total synthesis of rapamycin and demethoxyrapamycin. J Am Chem Soc 1995, 117, 19, 5407.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	15035	([(1S,2R,4S)-4-[(2R,3R)-4-iodo-3-(4-methoxybenzyl)-2-methylbutyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1S,2R,4S)-4-[(2R,3R)-4-iodo-3-(4-methoxybenzyl)-2-methylbutyl]-2-methoxycyclohexyl triisopropylsilyl ether	C₂₉H₅₁IO₃Si	详情	详情
(II)	15036	tert-butyl[[(1R,2E,4R)-1-(dimethoxymethyl)-4-(1,3-dithian-2-yl)-2-methyl-2-pentenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2E,4R)-1-(dimethoxymethyl)-4-(1,3-dithian-2-yl)-2-methyl-2-pentenyl ether	C₁₉H₃₈O₃S₂Si	详情	详情
(III)	15037	(2R,3E,5R)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[2-((2S,3R)-2-(4-methoxybenzyl)-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-3-methyl-3-hexenal	C₄₆H₈₂O₅S₂Si₂	详情	详情
(IV)	15038	(2S,4R)-4-(1,3-dithian-2-yl)-1-methoxy-2-methylpentyl methyl ether; 2-[(1R,3S)-4,4-dimethoxy-1,3-dimethylbutyl]-1,3-dithiane	C₁₂H₂₄O₂S₂	详情	详情
(V)	15039	tert-butyl(dimethyl)silyl (1R,2E,4R)-1-[(R)-[2-[(1R,3S)-4,4-dimethoxy-1,3-dimethylbutyl]-1,3-dithian-2-yl](methoxy)methyl]-4-[2-((2R,3R)-2-(4-methoxybenzyl)-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-2-methyl-2-pentenyl ether; tert-butyl([(1R,2E,4R)-1-[(R)-[2-[(1R,3S)-4,4-dimethoxy-1,3-dimethylbutyl]-1,3-dithian-2-yl](methoxy)methyl]-4-[2-((2R,3R)-2-(4-methoxybenzyl)-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-2-methyl-2-pentenyl]oxy)dimethylsilane	C₅₉H₁₀₈O₇S₄Si₂	详情	详情
(VI)	15040	tert-butyl([(1R,2E,4R)-1-[(R)-[2-[(1R,3S)-1,3-dimethyl-4-pentynyl]-1,3-dithian-2-yl](methoxy)methyl]-4-[2-((2S,3R)-2-(4-methoxybenzyl)-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-2-methyl-2-pentenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1R,2E,4R)-1-[(R)-[2-[(1R,3S)-1,3-dimethyl-4-pentynyl]-1,3-dithian-2-yl](methoxy)methyl]-4-[2-((2S,3R)-2-(4-methoxybenzyl)-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-2-methyl-2-pentenyl ether	C₅₈H₁₀₂O₅S₄Si₂	详情	详情
(VII)	15041	(2R,3S,6R,7E,9R,10R,12R,14S,15E)-9-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-10-methoxy-1-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,6,8,12,14-pentamethyl-16-(tributylstannyl)-7,15-hexadecadiene-5,11-dione	C₅₆H₁₁₀O₇Si₂Sn	详情	详情
(VIII)	15042	(2S)-1-(2-[(2S,3R,6S)-6-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-3-methyl-2-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylic acid	C₂₈H₄₆INO₇Si	详情	详情
(IX)	15043	(1S,4R,5E,7R,8R,10R,12S,13E)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-1-((1R)-2-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethyl)-4,6,10,12-tetramethyl-3,9-dioxo-14-(tributylstannyl)-5,13-tetradecadienyl (2S)-1-(2-[(2S,3R,6S)-6-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-3-methyl-2-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylate	C₈₄H₁₅₄INO₁₃Si₃Sn	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The intermediate piperidine carboxylic acid (VIII) was obtained as follows: The acetylene orthoester (X) was submitted sequentially to hydrolysis with acetic acid, silylation with TBS-Cl, reduction with DIBAL and Swern oxidation to give the acetylenic aldehyde (XI), which was condensed with 1-acetylpiperidine-2-carboxylic acid (XII), and the resulting compound was esterified with diazomethane, submitted to a Dess-Martin oxidation yielding a tricarbonyl compound that, without isolation was desilylated with HF yielding the cyclic hemiketal (XIII). This hemiketal was silylated with TES-triflate and submitted to hydrostannylation with tributyl tin hydride and AIBN, and tin - iodine exchange with I2/LiI in pyridine at 130 C to afford the desired (E,E)-divinylene iodide fragment (VIII). The syntheses of the starting fragments (I), (II), (IV), (X) and (XII) has already been reported (see Smith, A.B. et al. Tetrahedron Lett 1994, 35(28): 4907 and Smith, A.B. et al. Tetrahedron Lett 1994, 35(28): 4911).

参考文献中间体

合成目标

【1】 McCauley, J.A.; Leahy, J.W.; Smith, A.B.; Leazer, J.L.; Maleczka, R.E.; Condon, S.M.; Total synthesis of rapamycin and demethoxyrapamycin. J Am Chem Soc 1995, 117, 19, 5407.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	15042	(2S)-1-(2-[(2S,3R,6S)-6-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-3-methyl-2-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylic acid	C₂₈H₄₆INO₇Si	详情	详情
(X)	15044	[(E,5S)-5-methoxy-4-methyl-6-[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]-3-hexen-1-ynyl](trimethyl)silane; methyl (1S,2E)-2-methyl-5-(trimethylsilyl)-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2-penten-4-ynyl ether	C₂₁H₃₆O₄Si	详情	详情
(XI)	15045	(2R,5S,7S,8E)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-methoxy-2,8-dimethyl-11-(trimethylsilyl)-8-undecen-10-ynal	C₂₃H₄₄O₃Si₂	详情	详情
(XII)	15046	(2S)-1-acetylhexahydro-2-pyridinecarboxylic acid	C₈H₁₃NO₃	详情	详情
(XIII)	15047	methyl (2S)-1-(2-[(2R,3R,6S)-2-hydroxy-6-[(2S,3E)-2-methoxy-3-methyl-3-hexen-5-ynyl]-3-methyltetrahydro-2H-pyran-2-yl]-2-oxoacetyl)-2-piperidinecarboxylate	C₂₃H₃₃NO₇	详情	详情

Extended Information