(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 -Drug Synthesis Database

【结构式】

【分子编号】61309

【品名】(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

【CA登记号】

【分子式】C₄₄H₈₀O₈Si₂

【分子量】793.2854

【元素组成】C 66.62% H 10.16% O 16.13% Si 7.08%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号：(XXIV)

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