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【结 构 式】

【药物名称】(-)-Laulimalide, Fijianolide B, Laulimalide

【化学名称】(1R,3S,7S,8S,10S,12S,18R)-7-Hydroxy-12-[1(S)-hydroxy-3-[4-methyl-3,6-dihydro-2H-pyran-2(S)-yl]-2(E)-propenyl]-3-methyl-5-methylene-9,13,22-trioxatricyclo[16.3.1.0(8,10)]docosa-15,19-dien-14-one

【CA登记号】115268-43-4, 114995-73-2 (deleted CAS)

【 分 子 式 】C30H42O7

【 分 子 量 】514.66504

【开发单位】University of Hawaii (Originator), Kosan (Bulk Supplier)

【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23

合成路线1

The synthesis of the dihydropyranyl acetaldehyde intermediate (XVII) has been obtained as follows: The reduction of the pentanedioic acid monoethyl ester (I) with BH3 gives the hydroxyester (II), which is oxidized with DMP to yield the aldehyde (III). The reaction of (III) with the chiral borane (IV) affords the 5-hydroxyoctenoic ester (V), which is treated with dimethylamine to provide the corresponding amide (VI). The reaction of (VI) with propenal diethylacetal (VII) gives ether (VIII), which is submitted to a ring closing metathesis reaction catalyzed by a Ru catalyst to yield the dihydropyran derivative (IX). The reaction of (IX) with tert-butyldimethylsilyloxy ethylene (X) catalyzed by LiClO4 affords the dihydropyranyl acetaldehyde (XI), which is reduced with NaBH4 and protected with Tes-Cl to provide the butyramide (XII). The reaction of (XII) with MeLi gives the pentanone (XIII), which is treated with Ph-NTf2 and KHMDS to yield the enol triflate (XIV). The reaction of (XIV) with Tms-CH2-MgCl affords the methylene derivative (XV), which is selectively desilylated with K2CO3 to provide the dihdyropyranyl ethanol compound (XVI). Finally, this compound is oxidized with DMP to obtain the target dihydropyranyl acetaldehyde intermediate (XVII).

参考文献 中间体
【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 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
(I) 61124 (3R)-3-methyl-5-oxo-5-propoxypentanoic acid C9H16O4 详情 详情
(II) 61125 propyl (3R)-5-hydroxy-3-methylpentanoate C9H18O3 详情 详情
(III) 61126 propyl (3R)-3-methyl-5-oxopentanoate C9H16O3 详情 详情
(IV) 61128 　 C4H8 详情 详情
(V) 61127 propyl (3R,5S)-5-hydroxy-3-methyl-7-octenoate C12H22O3 详情 详情
(VI) 61129 (3R,5S)-5-hydroxy-N,N,3-trimethyl-7-octenamide C11H21NO2 详情 详情
(VII) 61131 1-propoxy-2-propenyl propyl ether; 3,3-dipropoxy-1-propene C9H18O2 详情 详情
(VIII) 61130 (3R,5S)-N,N,3-trimethyl-5-[(1-propoxy-2-propenyl)oxy]-7-octenamide C17H31NO3 详情 详情
(IX) 61132 (3R)-N,N,3-trimethyl-4-[(2S)-6-propoxy-3,6-dihydro-2H-pyran-2-yl]butanamide C15H27NO3 详情 详情
(X) 61133 tert-butyl(dimethyl)(vinyloxy)silane; tert-butyl(dimethyl)silyl vinyl ether C8H18OSi 详情 详情
(XI) 61134 (3R)-N,N,3-trimethyl-4-[(2S,6R)-6-(2-oxoethyl)-3,6-dihydro-2H-pyran-2-yl]butanamide C14H23NO3 详情 详情
(XII) 61135 (3R)-N,N,3-trimethyl-4-((2S,6R)-6-{2-[(triethylsilyl)oxy]ethyl}-3,6-dihydro-2H-pyran-2-yl)butanamide C20H39NO3Si 详情 详情
(XIII) 61136 (4R)-4-methyl-5-((2S,6R)-6-{2-[(triethylsilyl)oxy]ethyl}-3,6-dihydro-2H-pyran-2-yl)-2-pentanone C19H36O3Si 详情 详情
(XIV) 61137 1-[(2R)-2-methyl-3-((2S,6R)-6-{2-[(triethylsilyl)oxy]ethyl}-3,6-dihydro-2H-pyran-2-yl)propyl]vinyl trifluoromethanesulfonate C20H35F3O5SSi 详情 详情
(XV) 61138 2-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl triethylsilyl ether; trimethyl{2-[(2S)-2-methyl-3-((2S,6R)-6-{2-[(triethylsilyl)oxy]ethyl}-3,6-dihydro-2H-pyran-2-yl)propyl]-2-propenyl}silane C23H46O2Si2 详情 详情
(XVI) 61139 2-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-1-ethanol C17H32O2Si 详情 详情
(XVII) 61140 2-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)acetaldehyde C17H30O2Si 详情 详情

合成路线2

The synthesis of the phosphonate intermediate (XXXVII) has been performed as follows: The reaction of the 2-hexynoic ester (XVIII) with Tbdps-Cl gives the silyl ether (XIX), which is reduced with DIBAL to yield the propargyl alcohol (XX). The protection of (XX) by reaction with dihydropyran affords the tetrahydropyranyl ether (XXI), which is selectively deprotected by means of DDQ to provide the acetylenic alcohol (XXII). The oxidation of (XXII) by means of SO3/pyridine, and NaClO2, followed by methylation with diazomethane gives the acetylenic ester (XXIII), which is condensed with phosphonate (XXIV) by means of BuLi to yield the chiral phosphonate (XXV). The condensation of (XXV) with 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XXVI) affords the ketonic adduct (XXVII), which is reduced with NaBH4 and CeCl3 to provide the secondary alcohol (XXVIII). The reaction of (XXVIII) with Mom-Cl gives the corresponding Mom-ether (XXIX), whose tetrahydropyranyl group is hydrolyzed by means of HCl to yield the primary alcohol (XXX). The selective monoreduction of the acetylenic triple bond of (XXX) by means of Red-Al affords the octadienyl alcohol (XXXI), which is oxidized with DMP to the expected aldehyde (XXXII). The reaction of (XXXII) with (R,R)-pentane-2,4-diol (XXXIII) affords the propylene ketal (XXXIV), which is desilylated by means of TBAF to provide the secondary alcohol (XXXV). The condensation of (XXXV) with the phosphonoacetic acid (XXXVI) furnishes the corresponding ester (XXXVII).

参考文献 中间体
【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 61141 propyl (5S)-5-hydroxy-6-[(4-methoxybenzyl)oxy]-2-hexynoate C17H22O5 详情 详情
(XIX) 61142 propyl (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexynoate C33H40O5Si 详情 详情
(XX) 61143 (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexyn-1-ol C30H36O4Si 详情 详情
(XXI) 61144 tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether C35H44O5Si 详情 详情
(XXII) 61145 (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexyn-1-ol C27H36O4Si 详情 详情
(XXIII) 61146 methyl (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynoate C28H36O5Si 详情 详情
(XXIV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(XXV) 61147 dimethyl (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynylphosphonate C30H41O7PSi 详情 详情
(XXVI) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情
(XXVII) 61149 (E,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-one C35H44O5Si 详情 详情
(XXVIII) 61150 (E,3S,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-ol C35H46O5Si 详情 详情
(XXIX) 61151 (5S,6S)-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-6-[4-(tetrahydro-2H-pyran-2-yloxy)-2-butynyl]-2,4,7-trioxa-8-siladecane; tert-butyl(diphenyl)silyl (1S)-1-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether C37H50O6Si 详情 详情
(XXX) 61152 (5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7-octen-2-yn-1-ol C32H42O5Si 详情 详情
(XXXI) 61153 (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadien-1-ol C32H44O5Si 详情 详情
(XXXII) 61154 (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C32H42O5Si 详情 详情
(XXXIII) 57935 (2S,4S)-2,4-pentanediol C5H12O2 详情 详情
(XXXIV) 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
(XXXV) 61156 (1E,3S,4S,6E)-7-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-3-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-heptadien-4-ol C21H34O6 详情 详情
(XXXVI) 61157 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid C6H7F6O5P 详情 详情
(XXXVII) 61158 (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 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate C27H39F6O10P 详情 详情

合成路线3

The condensation of the dihydropyranyl acetaldehyde intermediate (XVII) with the phosphonate (XXXVII) by means of KHMDS gives the open chain adduct (XXXVIII), which is cyclized by means of EtAlCl2 in dichloromethane to yield the macrolactone (XXXIX). The oxidation of the secondary OH group of (XXXIX) by means of DMP affords the ketone (XL), which is treated with TsOH in chloroform to provide the alcohol (XLI). The deprotection of the Mom-protecting group by means of Me2BBr in dichloromethane gives the dihydroxylated macrolactone (XLII), which is finally epoxidized by means of (+)-DIPT, t-BuOOH and Ti(i-PrO)4 to yield the target Laulimalide.

参考文献 中间体
【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 61140 2-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)acetaldehyde C17H30O2Si 详情 详情
(XXXVII) 61158 (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 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate C27H39F6O10P 详情 详情
(XXXVIII) 61159 (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 (Z)-4-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-buten C40H64O8Si 详情 详情
(XXXIX) 61160 (1R,7S,11S,15S,17S)-11-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}-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 C36H54O8 详情 详情
(XL) 61161 (1R,7S,11S,15S,17S)-7-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-11-{[(1R)-1-methyl-2-oxopropyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one C36H52O8 详情 详情
(XLI) 61162 +(1R,7S,11S,15S,17S)-11-hydroxy-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 C32H46O7 详情 详情
(XLII) 61163 (1R,7S,11S,15S,17S)-11-hydroxy-7-{(1S,2E)-1-hydroxy-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 C30H42O6 详情 详情

合成路线4

The butenoic ester intermediate (VIII) has been obtained as follows: The condensation of the known aldehyde (I) with phosphonate (II) by means of KHMDS in THF gives the unsaturated ester (III), which is selectively hydrolyzed at its benzoate group by means of K2CO3 in methanol to yield the ethanol derivative (IV). The oxidation of (IV) by means of DMP affords the acetaldehyde (V), which is condensed with the phosphorane (VI) by means of DBU and LiCl in acetonitrile to provide the methyl ketone (VII) (1). Finally, this compound is methylated by means of Me2Zn and Ni(acac)2 in ethyl ether to give the target butenoic ester intermediate (VIII)

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.
【2】 Paterson, I.; et al.; Synthesis of the macrocyclic core of laulimalide. Org Lett 2001, 3, 2, 213.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 61164 2-[(2S,6R)-6-(2-oxoethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl benzoate C16H18O4 详情 详情
(II) 41856 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 88738-78-7 C7H9F6O5P 详情 详情
(III) 61165 2-{(2S,6R)-6-[(Z)-4-methoxy-4-oxo-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}ethyl benzoate C19H22O5 详情 详情
(IV) 61166 methyl (Z)-4-[(2R,6S)-6-(2-hydroxyethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate C12H18O4 详情 详情
(V) 59559 Dimethyl acetonylphosphonate; Acetylmethylphosphonic acid dimethyl ester; Dimethyl (2-oxopropyl)phosphonate 4202-14-6 C5H11O4P 详情 详情
(VI) 61167 methyl (Z)-4-[(2R,6S)-6-(2-oxoethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate C12H16O4 详情 详情
(VII) 61168 methyl (Z)-4-{(2R,6S)-6-[(E)-4-oxo-2-pentenyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate C15H20O4 详情 详情
(VIII) 61169 methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate C16H24O4 详情 详情

合成路线5

The intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) has been obtained as follows: The cyclization of 2-(Tbdms-O)acetaldehyde (IX) with 1-methoxy-3-methylbutadiene (X) by means of a chiral Cr catalyst gives the chiral dihydropyran derivative (XI), which is desilylated and demethoxylated by means of triethylsilane, BF3/Et2O and HCl to yield the dihydropyran methanol derivative (XII). Finally, this compound is oxidized to the target intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) by means of oxalyl chloride , DMSO and TEA

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 61170 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde 102191-92-4 C8H18O2Si 详情 详情
(X) 61171 (1E)-1-methoxy-3-methyl-1,3-butadiene; methyl (1E)-3-methyl-1,3-butadienyl ether C6H10O 详情 详情
(XI) 61172 tert-butyl(dimethyl)silyl [(2S,6R)-6-methoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl]methyl ether; tert-butyl{[(2S,6R)-6-methoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl]methoxy}dimethylsilane C14H28O3Si 详情 详情
(XII) 61173 [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methanol C7H12O2 详情 详情
(XIII) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情

合成路线6

The intermediate octadienal derivative (XXXI) has been obtained as follows: The selective monosilylation of 3(R),4-dihydroxybutyric acid methyl ester (XIV) by means of Tbdms-Cl and imidazole in dichloromethane gives the terminal silyl ether (XV), which is treated with PmbOC(=NH)CCl3 and TfOH in ethyl ether to yield the fully protected compound (XVI). The reduction of the ester group of (XVI) by means of LiAlH4 in THF affords the butanol derivative (XVII), which is subjected to Dess-Martin oxidation to furnish the corresponding aldehyde (XVIII). The condensation of (XVIII) with phosphonate (XIX) by means of DIEA and LiCl in acetonitrile provides the hexenoic ester (XX), which is reduced with DIBAL to the corresponding unsaturated alcohol (XXI). The reaction of (XXI) with Tbdps-Cl and imidazole gives the silyl ether (XXII), which is selectively monodesilylated by means of TsOH in ethanol to yield the alcohol (XXIII). The Swern oxidation of (XXIII) affords the corresponding aldehyde (XXIV), which is methylated with MeMgCl to provide the secondary alcohol (XXV). The Swern oxidation of (XXXV) yields the methyl ketone (XXVI), which is condensed with the intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) by means of (cHex)2BCl and TEA, followed by a treatment with MsCl and TEA to afford the octadienone (XXVII). The reduction of (XXVII) by means of Zn(BH4)2 in ethyl ether provides the octadienol (XXVIII), which is silylated with Tbdms-OTf and lutidine to give the silyl ether (XXIX). The selective monodeprotection of (XXIX) by means of TBAF in AcOH yields the octadienol (XXX), which is oxidized with DMP to afford the intermediate octadienal derivative (XXXI)

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情
(XIV) 11807 methyl (3S)-3,4-dihydroxybutanoate C5H10O4 详情 详情
(XV) 61174 methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutanoate C11H24O4Si 详情 详情
(XVI) 61175 methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanoate C19H32O5Si 详情 详情
(XVII) 61176 (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-1-butanol C18H32O4Si 详情 详情
(XVIII) 61177 (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanal C18H30O4Si 详情 详情
(XX) 61178 methyl (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexenoate C21H34O5Si 详情 详情
(XXI) 61179 (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexen-1-ol C20H34O4Si 详情 详情
(XXII) 61180 (E,9R)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenyl ether C36H52O4Si2 详情 详情
(XXIII) 61181 (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexen-1-ol C30H38O4Si 详情 详情
(XXIV) 61182 (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenal C30H36O4Si 详情 详情
(XXV) 61183 (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-ol C31H40O4Si 详情 详情
(XXVI) 61184 (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-one C31H38O4Si 详情 详情
(XXVII) 61185 (1E,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-one C38H46O5Si 详情 详情
(XXVIII) 61186 (1E,3S,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-ol C38H48O5Si 详情 详情
(XXIX) 61187 (E,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-10-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (1S,2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-4-hexenyl ether C44H62O5Si2 详情 详情
(XXX) 61188 (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadien-1-ol C28H44O5Si 详情 详情
(XXXI) 61189 (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C28H42O5Si 详情 详情

合成路线7

Synthesis of the target compound: The condensation of the butenoic ester intermediate (VIII) with the intermediate octadienal derivative (XXXI) by means of (+)-Ipc2BCl , TEA and H2O2 in ethyl ether gives the linear adduct (XXXII), which is silylated with Tbdms-OTf and lutidine to yield the fully protected intermediate (XXXIII). The reduction of the ester group of (XXXIII) with DIBAL gives the alcohol (XXXIV), which is oxidized with DMP and NaClO2 to yield the carboxylic acid (XXXV). The selective deprotection of the Pmb ether of (XXXV) by means of DDQ in dichloromethane affords the hydroxyacid (XXXVI), which is submitted to cyclization by means of DEAD and PPh3 in benzene to provide the macrolactone (XXXVII). The methylenation of the ketonic group of (XXXVII) by reaction with Zn, PbI2, TiCl4 and CH2I2 in THF gives the exomethylene derivative (XXXVIII), which is desilylated by treatment with HF and pyridine in THF to yield the immediate precursor (XXXIX). Finally, this compound is selectively epoxidized by reaction with (+)-DIPT, tBuOOH and Ti(OiPr)4 in dichloromethane to afford the target Laulimalide

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 61169 methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate C16H24O4 详情 详情
(XXXI) 61189 (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C28H42O5Si 详情 详情
(XXXII) 61190 methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate C44H66O9Si 详情 详情
(XXXIII) 61191 methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate C50H80O9Si2 详情 详情
(XXXIV) 61192 (2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-1-{(2R,6R)-6-[(Z)-4-hydroxy-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7,12-tridecadien-4-one C49H80O8Si2 详情 详情
(XXXV) 61193 (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid C49H78O9Si2 详情 详情
(XXXVI) 61194 (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-hydroxy-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid C41H70O8Si2 详情 详情
(XXXVII) 61195 (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-triene-5,13-dione C41H68O7Si2 详情 详情
(XXXVIII) 61196 (1R,7S,11S,15S,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-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 C42H70O6Si2 详情 详情
(XXXIX) 61197 (1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-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 C30H42O6 详情 详情

合成路线8

The synthesis of the 1,3-dioxane intermediate (XIII) has been performed as follows: The reaction of 2(S)-hydroxycyclopentanone (I) with Tbdps-Cl and imidazole in DMF gives the silyl ether (II), which is condensed with the phosphonate (III) by means of BuLi in THF to yield the new phosphonate (IV) after silylation with Tes-Cl and LDA. The Horner-Wadsworth-Emmons olefination of carbaldehyde (V) with phosphonate (IV) by means of LiCl and TEA in THF affords the silylated ketone (VI), which is reduced with NaBH4/CeCl3 and protected with Mom-Cl and DIEA to provide the dihydropyran derivative (VII). The cleavage of the Tes protecting group by means of TsOH, followed by oxidation of the resulting alcohol with SO3/pyridine in DMSO/dichloromethane gives the aldehyde (VIII). A new olefination reaction of aldehyde (VIII) with phosphorane (IX) by means of NaH in THF yields the methoxyamide (X), which is reduced with DIBAL in THF to afford the unsaturated aldehyde (XI). Finally, this aldehyde is treated with (2R,4R)-pentanediol (XII) and montmorillonite K-10 in hot toluene to provide the target 1,3-dioxane intermediate (XIII).

参考文献 中间体
【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
(I) 61198 (2S)-2-hydroxycyclopentanone C5H8O2 详情 详情
(II) 61199 (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}cyclopentanone C21H26O2Si 详情 详情
(III) 61200 dipropyl methylphosphonate C7H17O3P 详情 详情
(IV) 61201 dipropyl (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-oxo-5-[(triethylsilyl)oxy]pentylphosphonate C33H55O6PSi2 详情 详情
(V) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情
(VI) 61202 (E,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-[(triethylsilyl)oxy]-1-hexen-3-one C34H50O4Si2 详情 详情
(VII) 61203 (5S,6S)-6-{[tert-butyl(diphenyl)silyl]oxy}-10,10-diethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-2,4,9-trioxa-10-siladodecane; tert-butyl(diphenyl)silyl (1S,2S,3E)-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-{2-[(triethylsilyl)oxy]ethyl}-3-butenyl ether C36H56O5Si2 详情 详情
(VIII) 61204 (3S,4S,5E)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-(methoxymethoxy)-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-5-hexenal C30H40O5Si 详情 详情
(IX) 61205 dipropyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate C10H22NO5P 详情 详情
(X) 61206 (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-6-(methoxymethoxy)-N-methyl-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienamide C34H47NO6Si 详情 详情
(XI) 61154 (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C32H42O5Si 详情 详情
(XII) 57935 (2S,4S)-2,4-pentanediol C5H12O2 详情 详情
(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

合成路线9

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
【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10

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
【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
(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

合成路线11

Synthesis of the acetylenic dihydropyran intermediate (VII): The reaction of the chiral oxazolinone (I) with allylmagnesium bromide (II) by means of CuBr, BF3/Et2O and Mg(OMe)2, followed by ozonolysis with O3 in dichloromethane gives the aldehyde (III), which is condensed with the enol ether (IV) by means of a chiral Cr catalist to yield the dihydropyranone(V). The reduction of (V) with NaBH4 and CeCl3, followed by acylation with Ac2O affords the acetoxydihydropyran derivative (VI). Which is finally condensed with the allenic tributyl tin compound (VII) and trimethylsilylmethyl magnesium chloride in THF to provide the target acetylenic dihydropyran intermediate (VIII).

参考文献 中间体
【1】 Williams, D.R.; et al.; Synthesis of (-)-laulimalide: An agent for microtubule stabilization. Tetrahedron Lett 2002, 43, 27, 4841.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62935 (4R)-3-[(E)-2-butenoyl]-4-phenyl-1,3-oxazolidin-2-one C13H13NO3 详情 详情
(II) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(III) 62936 Methyl (3R)-3-methyl-5-oxopentanoate C7H12O3 详情 详情
(IV) 62937 {[(E)-3-methoxy-1-methylene-2-propenyl]oxy}(trimethyl)silane; (E)-3-methoxy-1-methylene-2-propenyl trimethylsilyl ether C8H16O2Si 详情 详情
(V) 62938 methyl (3R)-3-methyl-4-[(2R)-4-oxo-3,4-dihydro-2H-pyran-2-yl]butanoate C11H16O4 详情 详情
(VI) 62939 methyl (3R)-4-[(2R,4S)-4-(acetyloxy)-3,4-dihydro-2H-pyran-2-yl]-3-methylbutanoate C13H20O5 详情 详情
(VII) 62940 2-[1,1'-biphenyl]-4-ylethyl 2-(tributylstannyl)-2,3-butadienyl ether; 4-(2-{[2-(tributylstannyl)-2,3-butadienyl]oxy}ethyl)-1,1'-biphenyl C30H44OSn 详情 详情
(VIII) 62941 2-[1,1'-biphenyl]-4-ylethyl 4-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynyl ether; 4-(2-{[4-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynyl]oxy}ethyl)-1,1'-biphenyl C33H44O2Si 详情 详情

合成路线12

Synthesis of the aldehydic epoxide intermediate (XIV): The reaction of the protected diol (IX) with propanedithiol and BF3/Et2O, followed by reation with p-MeO-C6H4CH(OMe)2 and TsOH, reductive cleavage with DIBAL, and final oxidation with TPAP gives the chiral aldeyde (X). The condensation of (X) with the organozinc derivative (XI) in dichloromethane gives the secondary alcohol (XII), which is silylated by means of TBDMS-OTf and DIEA and submitted to a ring closing metathesis reaction catalyzed by a Ru catalyst yielding the dihydropyran derivative (XIII). Finally this compound is desilylated and epoxidized by means of PPTS ant tBu-OOH in the presence of (+)-DET, and oxidized with DMP to afford the target the aldehydic epoxide intermediate (XIV).

参考文献 中间体
【1】 Williams, D.R.; et al.; Synthesis of (-)-laulimalide: An agent for microtubule stabilization. Tetrahedron Lett 2002, 43, 27, 4841.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62942 tert-butyl(dimethyl)silyl (E)-4-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-2-butenyl ether; tert-butyl({(E)-4-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-2-butenyl}oxy)dimethylsilane C17H34O3Si 详情 详情
(X) 62943 (2S,4E)-2-(2-[1,1'-biphenyl]-4-ylethoxy)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-hexenal C26H36O3Si 详情 详情
(XI) 62944 [(1E,3S)-3-(allyloxy)-5-methyl-1,5-hexadienyl](methyl)zinc C11H18OZn 详情 详情
(XII) 62945 (2E,5S,6S,7E,9S)-9-(allyloxy)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-11-methyl-2,7,11-dodecatrien-6-ol C36H52O4Si 详情 详情
(XIII) 62946 (1S,2S,4E)-2-(2-[1,1'-biphenyl]-4-ylethoxy)-6-{[tert-butyl(dimethyl)silyl]oxy}-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-4-hexenyl tert-butyl(dimethyl)silyl ether; 4-{2-[((1S,3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-1-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-3-pentenyl)oxy]ethyl}-1,1'-biphenyl C40H62O4Si2 详情 详情
(XIV) 62947 (2S)-3-{(2S,3S,4E)-2-(2-[1,1'-biphenyl]-4-ylethoxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-pentenyl}-2-oxiranecarbaldehyde C34H46O5Si 详情 详情

合成路线13

Synthesis of the target Laulimalide: The condensation of the acetylenic dihydropyran intermediate (VIII) with the aldehydic epoxide intermediate (XIV) by means of BF3/Et2O, followed by silylation with TBDMS-OTf and DIEA gives the epoxide adduct (XV). The selective deprotection of (XV) with DDQ followed by oxidation with MnO2 and NaClO2 to yields the hydroxyacid (XVI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and DMAP to afford the acetylenic macrolactone (XVII). The selective monoreduction ossf the triple bond of (XVII) by means of H2 over Lindlar catalyst in the presence of 1- hexane and quinoline provides the silylated precursor (XVIII), which is finally deprotected by means od TBAF as usual to furnish the target Laulimalide.

参考文献 中间体
【1】 Williams, D.R.; et al.; Synthesis of (-)-laulimalide: An agent for microtubule stabilization. Tetrahedron Lett 2002, 43, 27, 4841.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 62941 2-[1,1'-biphenyl]-4-ylethyl 4-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynyl ether; 4-(2-{[4-((2R,6R)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynyl]oxy}ethyl)-1,1'-biphenyl C33H44O2Si 详情 详情
(XIV) 62947 (2S)-3-{(2S,3S,4E)-2-(2-[1,1'-biphenyl]-4-ylethoxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-pentenyl}-2-oxiranecarbaldehyde C34H46O5Si 详情 详情
(XVI) 62948 4-((2R,6R)-6-{(2S)-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-((2R,3S)-3-{(2S,3S,4E)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-5-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-pentenyl}oxiranyl)ethyl]-2-methyl-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl C42H70O8Si2 详情 详情
(XVII) 62949 7-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-12-[1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-2-propenyl]-3-methyl-5-methylidene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docos-19-en-15-yn-14-one C42H68O7Si2 详情 详情
(XVIII) 62950 7-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-12-[1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-2-propenyl]-3-methyl-5-methylidene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docosa-15,19-dien-14-one C42H70O7Si2 详情 详情

合成路线14

The intermediate carbaldehyde (VI) and Weinreb amide (IX) have been obtained as follows. The reaction of tetrahydropyranyl glycidol (I) with methyl phenylsulfone (II) by means of BuLi in THF gives the secondary alcohol (III), which is protected with Pmb-Cl and NaH in DMF to yield the diether (IV). Selective cleavage of the THP group of (IV) by means of CSA in methanol affords the primary alcohol (V), which is oxidized with (COCl)2 and DMSO in dichloromethane to provide the aldehyde (VI). Further oxidation of (VI) by means of NaClO2 in t-butanol gives the carboxylic acid (VII), which is finally condensed with N,O-dimethylhydroxylamine (VIII) by means of iso-butyl chloroformate in dichloromethane to yield the intermediate Weinreb amide (IX).

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63105 2-[(2R)oxiranyloxy]tetrahydro-2H-pyran; (2R)oxiranyl tetrahydro-2H-pyran-2-yl ether C7H12O3 详情 详情
(II) 23622 methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane 3112-85-4 C7H8O2S 详情 详情
(III) 63106 (2S)-4-(phenylsulfonyl)-1-(tetrahydro-2H-pyran-2-yloxy)-2-butanol C15H22O5S 详情 详情
(IV) 63107 2-{[(2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butyl]oxy}tetrahydro-2H-pyran; (3S)-3-[(4-methoxybenzyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)butyl phenyl sulfone C23H30O6S 详情 详情
(V) 63108 (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)-1-butanol C18H22O5S 详情 详情
(VI) 63109 (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanal C18H20O5S 详情 详情
(VII) 63110 (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanoic acid C18H20O6S 详情 详情
(VIII) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(IX) 63111 (2S)-N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methyl-4-(phenylsulfonyl)butanamide C20H25NO6S 详情 详情

合成路线15

The intermediate phenyl sulfone (XXIII) has been obtained as follows. The reaction of tetrahydropyranyl glycidol (I) with isopropenyl bromide (X) by means of CuCN in THF gives the secondary alcohol (XI), which is treated with allyl bromide (XII) and KH in THF to yield the allyl ether (XIII). A ring closing metathesis reaction with (XIII) catalyzed by a Ru catalyst yields the protected dihydropyran derivative (XIV), which is treated with CSA in methanol to afford the carbinol (XV). The oxidation of (XV) with (COCl)2 and DMSO in dichloromethane provides the carbaldehyde (XVI), which is treated with CBr4 and PPh3 in dichloromethane to give the dibromovinyl derivative (XVII). The condensation of (XVII) with the intermediate aldehyde (VI) by means of BuLi in THF yields the propargyl alcohol derivative (XVIII), which is oxidized with DMP to the corresponding acetylenic ketone (XIX). Alternatively, acetylenic ketone (XIX) can also be obtained by condensation of dibromovinyl derivative (XVII) with the intermediate Weinreb amide (IX) by means of BuLi in THF. The enantioselective reduction of ketone (XIX) with L-Selectride in THF affords the chiral propargyl alcohol (XX), which is reduced with Red-Al and treated with TFA to provide the trans-allylic alcohol (XXI). The reaction of the diol (XXI) with Pmp-CH(OEt)2 and CSA gives the acetal (XXII), which is finally reduced with DIBAL in dichloromethane to yield the intermediate Pmb-protected phenyl sulfone (XXIII).

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63105 2-[(2R)oxiranyloxy]tetrahydro-2H-pyran; (2R)oxiranyl tetrahydro-2H-pyran-2-yl ether C7H12O3 详情 详情
(VI) 63109 (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanal C18H20O5S 详情 详情
(IX) 63111 (2S)-N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methyl-4-(phenylsulfonyl)butanamide C20H25NO6S 详情 详情
(X) 42375 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide 557-93-7 C3H5Br 详情 详情
(XI) 63112 (2S)-4-methyl-1-(tetrahydro-2H-pyran-2-yloxy)-4-penten-2-ol C11H20O3 详情 详情
(XII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XIII) 63113 allyl (1S)-3-methyl-1-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-butenyl ether; 2-{[(2S)-2-(allyloxy)-4-methyl-4-pentenyl]oxy}tetrahydro-2H-pyran C14H24O3 详情 详情
(XIV) 63114 2-{[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methoxy}tetrahydro-2H-pyran; [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methyl tetrahydro-2H-pyran-2-yl ether C12H20O3 详情 详情
(XV) 61173 [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methanol C7H12O2 详情 详情
(XVI) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情
(XVII) 63115 (2S)-2-(2,2-dibromovinyl)-4-methyl-3,6-dihydro-2H-pyran C8H10Br2O 详情 详情
(XVIII) 63116 (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol C26H30O6S 详情 详情
(XIX) 63117 (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-one C26H28O6S 详情 详情
(XX) 63118 (3S,4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol C26H30O6S 详情 详情
(XXI) 63119 (E,3S,4S)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexene-3,4-diol C18H24O5S 详情 详情
(XXII) 63120 2-((4S,5S)-2-(4-methoxyphenyl)-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-1,3-dioxolan-4-yl)ethyl phenyl sulfone; (2S)-2-((E)-2-{(4S,5S)-2-(4-methoxyphenyl)-5-[2-(phenylsulfonyl)ethyl]-1,3-dioxolan-4-yl}ethenyl)-4-methyl-3,6-dihydro-2H-pyran C26H30O6S 详情 详情
(XXIII) 63121 (3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol C26H32O6S 详情 详情

合成路线16

The reaction of the chiral diol (XXIV) first with MsCl and TEA, and then with NaCN gives the chiral butyronitrile (XXV), which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (XXVI). The reaction of (XXVI) with allyl tributyl tin (XXVII), (S)-BINOL and Ti(OiPr)4 affords the secondary alcohol (XXVIII), which is condensed with acetal (XXIX) by means of PPTS to provide the diene (XXX). A ring closing metathesis reaction in (XXX) by means of a Ru catalyst gives the dihydropyran derivative (XXXI). Alternatively, the reaction of (XXVIII) with propenoyl chloride (XXXII) by means of TEA gives the diene (XXXIII), which is submitted to a ring closing metathesis reaction as before to yield the dihydropyranone (XXXIV). The reduction of (XXXIV) with DIBAL, followed by treatment with CSA and ethanol affords the dihydropyran derivative (XXXV). The reaction of both acetals (XXXI) or (XXXV) with CH2=CH-O-Tbdms (XXXVI) in the presence of Montmorillonite as Lewis acid, followed by a treatment with NaBH4 provides the dihydropyran (XXXVII) as a single isomer.

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 63122 (2R)-3-(benzyloxy)-2-methyl-1-propanol C11H16O2 详情 详情
(XXV) 63123 (3R)-4-(benzyloxy)-3-methylbutanenitrile C12H15NO 详情 详情
(XXVI) 63124 (3R)-4-(benzyloxy)-3-methylbutanal C12H16O2 详情 详情
(XXVII) 61128 　 C4H8 详情 详情
(XXVIII) 63125 (4S,6R)-7-(benzyloxy)-6-methyl-1-hepten-4-ol C15H22O2 详情 详情
(XXIX) 63126 3,3-diethoxy-1-propene; 1-ethoxy-2-propenyl ethyl ether C7H14O2 详情 详情
(XXX) 63127 1-[({(2R,4S)-4-[(1-ethoxy-2-propenyl)oxy]-2-methyl-6-heptenyl}oxy)methyl]benzene; benzyl (2R,4S)-4-[(1-ethoxy-2-propenyl)oxy]-2-methyl-6-heptenyl ether C20H30O3 详情 详情
(XXXI) 63128 (2S,6R)-2-[(2R)-3-(benzyloxy)-2-methylpropyl]-6-ethoxy-3,6-dihydro-2H-pyran; benzyl (2R)-3-[(2S,6R)-6-ethoxy-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl ether C18H26O3 详情 详情
(XXXII) 11577 Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride 814-68-6 C3H3ClO 详情 详情
(XXXIII) 63130 (1S)-1-[(2R)-3-(benzyloxy)-2-methylpropyl]-3-butenyl acrylate C18H24O3 详情 详情
(XXXIV) 63131 (6S)-6-[(2R)-3-(benzyloxy)-2-methylpropyl]-5,6-dihydro-2H-pyran-2-one C16H20O3 详情 详情
(XXXV) 63132 (2S,6S)-2-[(2R)-3-(benzyloxy)-2-methylpropyl]-6-ethoxy-3,6-dihydro-2H-pyran; benzyl (2R)-3-[(2S,6S)-6-ethoxy-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl ether C18H26O3 详情 详情
(XXXVI) 61133 tert-butyl(dimethyl)(vinyloxy)silane; tert-butyl(dimethyl)silyl vinyl ether C8H18OSi 详情 详情
(XXXVII) 63129 benzyl (2R)-3-[(2S,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl ether; (2-{(2R,6S)-6-[(2R)-3-(benzyloxy)-2-methylpropyl]-5,6-dihydro-2H-pyran-2-yl}ethoxy)(tert-butyl)dimethylsilane C24H40O3Si 详情 详情

合成路线17

The cleavage of the benzyl ether of (XXXVII) by means of Li/NH3, followed by treatment with I2 and PPh3 gives the iodide derivative (XXXVIII), which is condensed with tetrahydrofuranone (XXXIX) (obtained by reaction of epoxide (XL) with methyl 2-(phenylsulfonyl)acetate (XLI) and NaH) by means of NaH to afford the adduct (XLII). The reductive cleavage of the tetrahydrofuranone (XLII) by means of Red-Al provides the diol (XLIII), which is treated with Ph-COCl and Na/Hg to give the methylene derivative (XLIV). The reaction of (XLIV) with Mom-Cl and DIEA yields the Mom-ether compound (XLV), which is selectively deprotected by means of DDQ to afford the primary alcohol (XLVI). The oxidation of (XLVI) with oxalyl chloride provides the carbaldehyde (XLVII).

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXVII) 63129 benzyl (2R)-3-[(2S,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl ether; (2-{(2R,6S)-6-[(2R)-3-(benzyloxy)-2-methylpropyl]-5,6-dihydro-2H-pyran-2-yl}ethoxy)(tert-butyl)dimethylsilane C24H40O3Si 详情 详情
(XXXVIII) 63133 tert-butyl(2-{(2R,6S)-6-[(2R)-3-iodo-2-methylpropyl]-5,6-dihydro-2H-pyran-2-yl}ethoxy)dimethylsilane; tert-butyl(dimethyl)silyl 2-{(2R,6S)-6-[(2R)-3-iodo-2-methylpropyl]-5,6-dihydro-2H-pyran-2-yl}ethyl ether C17H33IO2Si 详情 详情
(XXXIX) 63134 (5S)-5-{[(4-methoxybenzyl)oxy]methyl}-3-(phenylsulfonyl)dihydro-2(3H)-furanone C19H20O6S 详情 详情
(XL) 63135 4-methoxybenzyl (2R)oxiranylmethyl ether; (2R)-2-{[(4-methoxybenzyl)oxy]methyl}oxirane C11H14O3 详情 详情
(XLI) 63136 methyl 2-(phenylsulfonyl)acetate C9H10O4S 详情 详情
(XLII) 63137 (5S)-3-{(2R)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-5-{[(4-methoxybenzyl)oxy]methyl}-3-(phenylsulfonyl)dihydro-2(3H)-furanone C36H52O8SSi 详情 详情
(XLIII) 63138 (4S)-2-{(2R)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-5-[(4-methoxybenzyl)oxy]-2-(phenylsulfonyl)-1,4-pentanediol C36H56O8SSi 详情 详情
(XLIV) 63139 (2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-[(4-methoxybenzyl)oxy]-4-penten-2-ol C30H50O5Si 详情 详情
(XLV) 63140 tert-butyl(dimethyl)silyl 2-((2R,6R)-6-{(2S)-4-[(2S)-3-[(4-methoxybenzyl)oxy]-2-(methoxymethoxy)propyl]-2-methyl-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethyl ether; tert-butyl[2-((2R,6R)-6-{(2S)-4-[(2S)-3-[(4-methoxybenzyl)oxy]-2-(methoxymethoxy)propyl]-2-methyl-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)ethoxy]dimethylsilane C32H54O6Si 详情 详情
(XLVI) 63141 (2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-(methoxymethoxy)-4-penten-1-ol C24H46O5Si 详情 详情
(XLVII) 63142 (2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-(methoxymethoxy)-4-pentenal C24H44O5Si 详情 详情

合成路线18

The condensation of carbaldehyde (XLVII) with the intermediate Pmb-protected phenyl sulfone (XXIII) by means of BuLi, Ac2O and Na/Hg gives the linear adduct (XLVIII), which is protected at its free OH group by means of DHP and PPTS, and selectively deprotected with TBAF yielding the primary alcohol (XLIX). The oxidation of (XLIX) with DMP affords the acetaldehyde derivative (L), which is condensed with CBr4 and PPh3 to provide the dibromovinyl derivative (LI). The condensation of (LI) with methyl chloroformate (LII) by means of BuLi gives the acetylenic ester (LIII), which is treated with CSA to eliminate the THP protecting group and yield the hydroxy ester (LIV). The hydrolysis of the ester (LIV) with LiOH in THF/water affords the hydroxyacid (LV).

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIII) 63121 (3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol C26H32O6S 详情 详情
(XLVII) 63142 (2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-(methoxymethoxy)-4-pentenal C24H44O5Si 详情 详情
(XLVIII) 63143 (1E,3S,4S,6E,8S)-10-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-3-[(4-methoxybenzyl)oxy]-8-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6,10-undecatrien-4-ol C44H70O8Si 详情 详情
(XLIX) 63144 2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-1-ethanol C43H64O9 详情 详情
(L) 63145 2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}acetaldehyde C43H62O9 详情 详情
(LI) 63146 (1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl tetrahydro-2H-pyran-2-yl ether 2-{[(1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl]oxy}tetrahydro-2H-pyran C44H62Br2O8 详情 详情
(LII) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(LIII) 63147 methyl 4-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate C46H64O10 详情 详情
(LIV) 63148 methyl 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(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-butynoate C41H56O9 详情 详情
(LV) 63149 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(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-butynoic acid C40H54O9 详情 详情

合成路线19

The cyclization of the hydroxyacid (LV) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF/benzene gives the acetylenic macrolactone (LVI), which is reduced with Lindlar catalyst and 1-hexene in ethyl acetate to yield the cis-macrolactone (LVII). The Mom-protecting group of (LVII) is selectively removed by means of PPTS in tert-butanol to afford the allylic alcohol (LVIII), which is submitted to a Sharpless epoxidation with t-BuOOH, (+)-DET and Ti(OiPr)4 in dichloromethane providing the epoxide (LIX). Finally, the Pmb-protecting group of (LIX) is removed by means of DDQ in dichloromethane to furnish the target Laulimalide.

参考文献 中间体
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LV) 63149 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(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-butynoic acid C40H54O9 详情 详情
(LVI) 63150 15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-11-{[(methyloxy)methyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-9,19-dien-3-yn-5-one C40H52O8 详情 详情
(LVII) 63151 15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-11-{[(methyloxy)methyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one C40H54O8 详情 详情
(LVIII) 63152 11-hydroxy-15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one C38H50O7 详情 详情
(LIX) 63153 7-hydroxy-3-methyl-12-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-5-methylidene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docosa-15,19-dien-14-one C38H50O8 详情 详情

合成路线20

The acetylenic ester intermediate (XVI) has been obtained as follows. The reaction of acetaldehyde (I) with acetyl bromide (II) by means of a chiral Al catalyst gives lactone (III), which is condensed with N,O-dimethylhydroxylamine (IV) to yield the Weinreb amide (V). The reduction of (V) with iBu2AlH affords the chiral butyraldehyde (VI), which is condensed with acetyl bromide (II) and DIEA to provide the lactone (VII). The reaction of (VII) with methylmagnesium bromide gives the chiral pentanoic acid (VIII), which is reduced with BH3/Me2S and reoxidated with PCC to yield the aldehyde (IX). The condensation of (IX) with acetyl bromide (II) and DIEA affords the lactone (X), which is treated with the lithium salt (XI) to provide the dihydropyranone (XII). The reduction of (XII) with NaBH4 and CeCl3, followed by reaction with Ac2O and TEA gives the acetoxy derivative (XIII), which is desilylated with TBAF and oxidized with PDC to yield the methyl ketone (XIV). Finally, the condensation of (XIV) with the allenic tributyl tin derivative (XV) by means of Bu3Sn-OTf in dichloromethane affords the target acetylenic ester intermediate (XVI).

参考文献 中间体
【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(II) 63866 acetyl bromide C2H3BrO 详情 详情
(III) 63867 (4R)-4-methyl-2-oxetanone C4H6O2 详情 详情
(IV) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(V) 63868 (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-N-methylbutanamide C22H31NO3Si 详情 详情
(VI) 63871 (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}butanal C20H26O2Si 详情 详情
(VII) 63870 (4R)-4-((2R)-2-{[tert-butyl(diphenyl)silyl]oxy}propyl)-2-oxetanone C22H28O3Si 详情 详情
(VIII) 63869 (3S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-methylhexanoic acid C23H32O3Si 详情 详情
(IX) 63872 (3S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-methylhexanal C23H32O2Si 详情 详情
(X) 63873 (4S)-4-((2R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpentyl)-2-oxetanone C25H34O3Si 详情 详情
(XI) 63874 　 C7H13LiN2 详情 详情
(XII) 63875 (2R)-2-((2R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpentyl)-2,3-dihydro-4H-pyran-4-one C27H36O3Si 详情 详情
(XIII) 63879 　 C27H37AcO3Si 详情 详情
(XIV) 63878 (2R,4S)-2-[(2R)-2-methyl-4-oxopentyl]-3,4-dihydro-2H-pyran-4-yl acetate C13H20O4 详情 详情
(XV) 63877 tert-butyl 2-(tributylstannyl)-2,3-butadienoate C20H38O2Sn 详情 详情
(XVI) 63876 tert-butyl 4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate C19H28O4 详情 详情

合成路线21

The chiral unsaturated aldehyde intermediate (XXV) has been obtained as follows. The reaction of the chiral lactone (XVII) first with N,O-dimethylhydroxylamine and then with PmbO-(C=NH)CCl3 gives the Weinreb amide (XVIII), which is reduced with Bu2AlH to yield the butyraldehyde (XIX). The condensation of (XIX) with phosphorane (XX) affords the unsaturated ester (XXI), which is reduced with Bu2AlH to provide the unsaturated alcohol (XXII). The reaction of (XXII) with TrCl and lutidine gives the trityl ether (XXIII), which is desilylated by means of TBAF to yield the primary alcohol (XXIV). Finally, this compound is oxidized with DMP to afford the desired unsaturated aldehyde intermediate (XXV).

参考文献 中间体
【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63307 1,1,1-trichloro-3-(4-methoxyphenyl)-2-propanimine C10H10Cl3NO 详情 详情
(XVII) 63880 4-{[tert-butyl(diphenyl)silyl]oxy}-2-oxetanone C19H22O3Si 详情 详情
(XVIII) 63881 (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-3-[(4-methoxybenzyl)oxy]-N-methylbutanamide C30H39NO5Si 详情 详情
(XIX) 63882 (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanal C28H34O4Si 详情 详情
(XX) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XXI) 63884 ethyl (E,5S)-6-{[tert-butyl(diphenyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexenoate C32H40O5Si 详情 详情
(XXII) 63885 (E,5S)-6-{[tert-butyl(diphenyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexen-1-ol C30H38O4Si 详情 详情
(XXIII) 63883 tert-butyl(diphenyl)silyl (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenyl]oxy}diphenylsilane C49H52O4Si 详情 详情
(XXIV) 63886 (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexen-1-ol C33H34O4 详情 详情
(XXV) 63887 (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal C33H32O4 详情 详情

合成路线22

Synthesis of the target Laulimalide. The condensation of the tin derivative (XXVI) with the chiral isopropenyl boron derivative (XXVII) gives the secondary alcohol (XXVIII), which is alkylated with allyl bromide (XXIX) and KHMDS to yield the allyl ether (XXX). The ring closing metathesis reaction in (XXX) by means of Schrock catalyst affords the dihydropyranyl stannane (XXXI), which is treated with N-iodosuccinimide to provide the iodovinyl compound (XXXII). The reaction of (XXXII) with BuLi and MgBr2 gives the vinylmagnesium derivative (XXXIII), which is condensed with the unsaturated aldehyde intermediate (XXV) to yield the olefinic alcohol (XXXIV). The reaction of (XXXIV) with Tbdms-Cl and imidazole affords the silyl ether (XXXV), which is selectively deprotected with formic acid, and oxidated with DMP to provide the chiral unsaturated aldehyde (XXXVI).

参考文献 中间体
【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 63887 (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal C33H32O4 详情 详情
(XXVI) 63888 (E)-3-(tributylstannyl)-2-propenal C15H30OSn 详情 详情
(XXVII) 63889 　 C5H11B 详情 详情
(XXVIII) 63890 (1E)-5-methyl-1-(tributylstannyl)-1,5-hexadien-3-ol C19H38OSn 详情 详情
(XXIX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXX) 63891 [(1E)-3-(allyloxy)-5-methyl-1,5-hexadienyl](tributyl)stannane; allyl 3-methyl-1-[(E)-2-(tributylstannyl)ethenyl]-3-butenyl ether C22H42OSn 详情 详情
(XXXI) 63894 tributyl{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}stannane C20H38OSn 详情 详情
(XXXII) 63893 (2S)-2-[(E)-2-iodoethenyl]-4-methyl-3,6-dihydro-2H-pyran C8H11IO 详情 详情
(XXXIII) 63892 bromo{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}magnesium C8H11BrMgO 详情 详情
(XXXIV) 63895 (1E,3S,4S,6E)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(trityloxy)-1,6-octadien-3-ol C41H44O5 详情 详情
(XXXV) 63896 tert-butyl(dimethyl)silyl (1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl]oxy}dimethylsilane C47H58O5Si 详情 详情
(XXXVI) 63897 (2E,5S,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C28H42O5Si 详情 详情

合成路线23

The diastereoselective condensation of the unsaturated aldehyde intermediate (XXXVI) with the acetylenic ester intermediate (XVI) by means of a chiral boron catalyst and TEA gives the aldol adduct (XXXVII), which is treated with Tbdms-Cl and imidazole to yield the silyl ether (XXXVIII). The stepwise deprotection of (XXXVIII) first with DDQ and then with Tms-OTf affords the acetylenic hydroxyacid (XXXIX), which is cyclized by means of 2,4,6-trichlorobenzoyl chloride and DIEA to provide the macrolactone (XL). The triple bond hydrogenation under Lindlar conditions (H2, Pd/CaCO3) gives the expected Z-alkene derivative (XLI). The reaction of the ketone group of (XLI) with CH2I2, Zn, PbCl2 and TiCl4 yields the methylenated compound (XLII), which is treated with HF and pyridine to eliminate the silyl protecting groups and afford the precursor (XLIII). Finally, compound (XLIII) is diastereoselectively epoxidated under Sharpless conditions (t-BuOOH, (+)-DIPT, and Ti(OiPr)4) to provide the target Laulimalide.

参考文献 中间体
【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63902 (1R,3S,7S,8S,10S,12S,18R)-7-hydroxy-12-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-3-methyl-5-methylene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docosa-15,19-dien-14-one C30H42O7 详情 详情
(XVI) 63876 tert-butyl 4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate C19H28O4 详情 详情
(XXXVI) 63897 (2E,5S,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C28H42O5Si 详情 详情
(XXXVII) 63898 tert-butyl 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate C47H70O9Si 详情 详情
(XXXVIII) 63900 tert-butyl 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate C53H84O9Si2 详情 详情
(XXXIX) 63899 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-hydroxy-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid C41H68O8Si2 详情 详情
(XL) 63901 (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-9,19-dien-3-yne-5,13-dione C41H66O7Si2 详情 详情
(XLI) 61195 (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-triene-5,13-dione C41H68O7Si2 详情 详情
(XLII) 61196 (1R,7S,11S,15S,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-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 C42H70O6Si2 详情 详情
(XLIII) 61197 (1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-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 C30H42O6 详情 详情
Extended Information