tert-butyl(dimethyl)[2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]silane; tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether -Drug Synthesis Database

【结构式】

【分子编号】61305

【品名】tert-butyl(dimethyl)[2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]silane; tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether

【CA登记号】

【分子式】C₂₃H₄₆O₂Si₂

【分子量】410.78804

【元素组成】C 67.25% H 11.29% O 7.79% Si 13.67%

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：(XX)

The synthesis of the dihydropyran intermediate (XX) has been performed as follows: The reduction of the known aldehyde (XIV) with NaBH4 in methanol, followed by reaction with Tbdms-Cl and imidazole in DMF gives the silyl ether (XV), which is selectively deprotected with DDQ in dichloromethane and treated with TsCl and TEA to yield the tosylate (XVI). The reaction of (XVI) with NaCN in hot DMSO, followed by reaction with MeLi in ethyl ether affords the methyl ketone (XVII), which is treated with KHMDS and Ph-NTf2 in THF to provide the enol triflate (XVIII). Finally, this compound is treated with Tms-CH2-MgCl , Pd(PPh3)4 and LiCl in ethyl ether to furnish the target dihydropyran intermediate (XX).

参考文献中间体

合成目标

【1】 Mulzer, J.; Hanbauer, M.; Total synthesis of the antitumor agent (-)-laulimalide. Tetrahedron Lett 2002, 43, 18, 3381.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	61207	2-((2R,6S)-6-{(2R)-3-[(4-methoxybenzyl)oxy]-2-methylpropyl}-5,6-dihydro-2H-pyran-2-yl)acetaldehyde		C₁₉H₂₆O₄	详情	详情
(XV)	61208	tert-butyl(dimethyl)silyl 2-((2R,6S)-6-{(2R)-3-[(4-methoxybenzyl)oxy]-2-methylpropyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether; tert-butyl[2-((2R,6S)-6-{(2R)-3-[(4-methoxybenzyl)oxy]-2-methylpropyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]dimethylsilane		C₂₅H₄₂O₄Si	详情	详情
(XVI)	61301	(2R)-3-[(2S,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl 4-methylbenzenesulfonate		C₂₄H₄₀O₅SSi	详情	详情
(XVII)	61302	(4R)-5-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-4-methyl-2-pentanone		C₁₉H₃₆O₃Si	详情	详情
(XVIII)	61303	1-{(2R)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}vinyl trifluoromethanesulfonate		C₂₀H₃₅F₃O₅SSi	详情	详情
(XIX)	61304	Trimethylsilylmethylmagnesium Chloride; (Trimethylsilyl)methylmagnesium chloride Solution; Chloro[(trimethylsilyl)methyl]magnesium; (TRIMETHYLSILYLMETHYL)MAGNESIUM CHLORIDE; (TRIMETHYLSILYL)METHYLMAGNESIUM CHL. SOL	13170-43-9	C₄H₁₁ClMgSi	详情	详情
(XX)	61305	tert-butyl(dimethyl)[2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]silane; tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether		C₂₃H₄₆O₂Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XX)

Synthesis of the target compound: The condensation of the 1,3-dioxane intermediate (XIII) with the target dihydropyran intermediate (XX) by means of TiCl4 and TEA in dichloromethane gives the adduct (XXI), whose OH group is oxidized by means of DMP to yield the ketone (XXII). Elimination of the chiral auxiliary of (XXII) by means of K2CO3 in methanol, followed by protection with Mom-Cl and DIEA in DMF affords the fully protected compound (XXIII). Both Tbdms and Tbdps protecting groups of (XXIII) were exchanged for Tes groups by cleavage with TBAF, followed by reaction with Tes-Cl and pyridine to provide compound (XXIV). Selective Swern oxidation of the primary silyl ether group of (XXIV) gives aldehyde (XXV), which is condensed with phosphonate (XXVI) by means of KHMDS in THF to yield the trimethylsilylethyl ester (XXVII). The desilylation of (XXVII) by means of TBAF in THF affords the hydroxyacid (XXVIII), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride to provide the macrolactone (XXIX). Finally, this compound is deprotected by a treatment with Me2BBr and submitted to a selective Sharpless epoxidation to afford the target Laulimalide

参考文献中间体

合成目标

【1】 Mulzer, J.; Hanbauer, M.; Total synthesis of the antitumor agent (-)-laulimalide. Tetrahedron Lett 2002, 43, 18, 3381.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	61155	tert-butyl(diphenyl)silyl (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl ether; (5S,6S)-6-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-2,4,7-trioxa-8-siladecane	C₃₇H₅₂O₆Si	详情	详情
(XX)	61305	tert-butyl(dimethyl)[2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]silane; tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether	C₂₃H₄₆O₂Si₂	详情	详情
(XXI)	61306	4-({(1S,2E,5S,6S,7E)-1-(2-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-propenyl)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienyl}oxy)-2-pentanol	C₅₇H₉₀O₈Si₂	详情	详情
(XXII)	61307	4-({(1S,2E,5S,6S,7E)-1-(2-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-propenyl)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienyl}oxy)-2-pentanone	C₅₇H₈₈O₈Si₂	详情	详情
(XXIII)	61308	tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-{[tert-butyl(diphenyl)silyl]oxy}-6,11-bis(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether; (5S,6E,9S)-5-(2-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-propenyl)-9-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-12,12-dimethyl-11,11-diphenyl-2,4,10-trioxa-11-sila-6-tridecene	C₅₄H₈₄O₈Si₂	详情	详情
(XXIV)	61309	(5S,6E,9S)-11,11-diethyl-9-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-{2-[(2S)-2-methyl-3-((2R,6R)-6-{2-[(triethylsilyl)oxy]ethyl}-3,6-dihydro-2H-pyran-2-yl)propyl]-2-propenyl}-2,4,10-trioxa-11-sila-6-tridecene; 2-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-6,11-bis(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-[(triethylsilyl)oxy]-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)ethyl triethylsilyl ether	C₄₄H₈₀O₈Si₂	详情	详情
(XXV)	61310	2-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-6,11-bis(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-[(triethylsilyl)oxy]-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)acetaldehyde	C₃₈H₆₄O₈Si	详情	详情
(XXVI)	61311	2-(trimethylsilyl)ethyl 2-(diphenoxyphosphoryl)acetate	C₁₉H₂₅O₅PSi	详情	详情
(XXVII)	61312	2-(trimethylsilyl)ethyl (E)-4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-6,11-bis(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-[(triethylsilyl)oxy]-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate	C₄₅H₇₈O₉Si₂	详情	详情
(XXVIII)	61313	(E)-4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-6,11-bis(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid	C₃₄H₅₂O₉	详情	详情
(XXIX)	61314	(1R,7S,11S,15S,17R)-11-(methoxymethoxy)-7-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one	C₃₄H₅₀O₈	详情	详情

Extended Information