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【结 构 式】

【药物名称】Phomoidride B, CP-263114

【化学名称】(-)-2-[14-[4(E)-Hexenoyl]-18-[6(E)-octenyl]-3,7,9-trioxo-2,8,15-trioxapentacyclo[10.3.3.0(1,11).0(4,16).0(6,10)]octadeca-6(10),16-dien-4-yl]acetic acid
　　　　　　(-)-(5R*,7aR*,9R*,11S*,11aS*,12S*)-12-[6(E)-Octenyl]-1,3,6-trioxo-9-[1-oxo-4(E)-hexenyl]-1,4,9,10,11,11a-hexahydro-11,5,7a-[2]propen[1]yl[3]ylidene-3H,7aH-furo[3,4-d]pyrano[2,3-b]oxocin-5(6H)-acetic acid

【CA登记号】186700-09-4

【 分 子 式 】C31H36O9

【 分 子 量 】552.62717

【开发单位】Pfizer (Originator)

【药理作用】Farnesyl Transferase Inhibitors, Squalene Synthase Inhibitors

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1

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 35688 (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane C13H27IOSi 详情 详情
(XVII) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情

合成路线2

The cyclization of (XVII) by means of Me2AlCl in dichloromethane gives the tricyclic ketone (XVIII), which is desilylated with TBAF in THF yielding the ethanol (XIX). The oxidation of (XIX) with Dess Martin periodinane (DMP) in dichloromethane affords the corresponding aldehyde (XX), which is condensed with the lithium 1,3-dithiane (XXI) in THF to give the secondary alcohol (XXII). The silylation of this alcohol with Tes-OTf and NaH in THF yields the silyl ether (XXIII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXIV). The reaction of (XXIV) with Pdo and CO in methanol gives the methyl ester (XXV), which is treated with PhI(OCOCF3)2 and methanol to afford the gem-dimethoxy compound (XXVI).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情
(XVIII) 35690 　 C42H68O5Si 详情 详情
(XIX) 35691 　 C33H48O5 详情 详情
(XX) 35692 　 C33H46O5 详情 详情
(XXI) 35693 [2-[(E)-3-pentenyl]-1,3-dithian-2-yl]lithium C9H15LiS2 详情 详情
(XXII) 35694 　 C42H62O5S2 详情 详情
(XXIII) 35695 　 C48H76O5S2Si 详情 详情
(XXIV) 35696 　 C49H75F3O7S3Si 详情 详情
(XXV) 35697 　 C50H78O6S2Si 详情 详情
(XXVI) 35698 　 C49H78O8Si 详情 详情

合成路线3

The reduction of the ester group of (XXVI) with DIBAL in toluene gives the carbinol (XXVII), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxy-carbonitrile (XXVIII). The sulfonation of the primary OH group of (XXVIII) with Ms-Cl affords the mesylate (XXIX), which is treated with K2CO3 in methanol providing the intermediate epoxide (XXX). The reaction of (XXX) with oxalic acid in ethanol/water affords the maleic anhydride derivative (XXXI), which by a selective hydrolysis with aqueous AcOH gives the alpha hydroxy ketone (XXXII). The silylation of the OH group of (XXXII) with Tbdms-OTf and lutidine in dichloromethane yields the silyl ether (XXXIII).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVI) 35698 　 C49H78O8Si 详情 详情
(XXVII) 35699 　 C48H78O7Si 详情 详情
(XXVIII) 35700 　 C49H79NO8Si 详情 详情
(XXIX) 35701 　 C52H85NO8SSi 详情 详情
(XXX) 35702 　 C49H77NO7Si 详情 详情
(XXXI) 35703 　 C49H74O9Si 详情 详情
(XXXII) 35704 　 C41H54O8 详情 详情
(XXXIII) 35705 　 C47H68O8Si 详情 详情

合成路线4

The cleavage of the 4-methoxybenzyl group of (XXXIII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXIV), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXV). The cyclization of (XXXV) with AcOH affords the tetracyclic compound (XXXVI), which is silylated at the carbinol group with Tes-OTf and lutidine giving the silyl ether (XXXVII). The oxidation of (XXXVII) with DMP in refluxing benzene affords the carbinol (XXXVIII) (1), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XXXIX). The oxidation of the hydroxymethyl group of (XXXIX) with DMP in dichloromethane yields corresponding aldehyde (XL), which is silylated at the remaining OH group with Tbdms-OTf and lutidine in dichloromethane to afford the silyl ether (XLI). The oxidation of the aldehyde group of (XLI) with NaClO2 in tert-butanol/water gives the carboxylic acid (XLII).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIII) 35705 　 C47H68O8Si 详情 详情
(XXXIV) 35706 　 C39H60O8Si 详情 详情
(XXXV) 35707 　 C39H58O8Si 详情 详情
(XXXVI) 35708 　 C36H54O8Si 详情 详情
(XXXVII) 35709 　 C42H68O8Si2 详情 详情
(XXXVIII) 35710 　 C42H68O9Si2 详情 详情
(XXXIX) 35711 　 C30H38O8 详情 详情
(XL) 35712 　 C30H36O8 详情 详情
(XLI) 35713 　 C36H50O8Si 详情 详情
(XLII) 35714 　 C36H50O9Si 详情 详情

合成路线5

The reaction of (XLII) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLIII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLIV). The rearrangement of (XLIV) with Ag2O in DMF/water affords the acetic acid derivative (XLV), which is condensed with indoline (XLVI) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (XLVII). The desilylation of (XLVII) with TFA/water in dichloromethane gives the secondary alcohol (XLVIII), which is oxidized with DMP in dichloromethane to yield the corresponding ketonic compound (XLIX). The dehydrogenation of the indoline group of (XLIX) with chloranil in refluxing toluene affords the corresponding indole derivative (L).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLII) 35714 　 C36H50O9Si 详情 详情
(XLIII) 35715 　 C39H56O9SSi 详情 详情
(XLIV) 35716 　 C37H50N2O8Si 详情 详情
(XLV) 35717 　 C37H52O9Si 详情 详情
(XLVI) 19652 indoline 496-15-1 C8H9N 详情 详情
(XLVII) 35718 (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione C45H59NO8Si 详情 详情
(XLVIII) 35719 (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione C39H45NO8 详情 详情
(XLIX) 35720 (9S,12S,13S,15R)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione C39H43NO8 详情 详情
(L) 35721 (9S,12S,13S,15R)-15-[(E)-4-hexenoyl]-9-[2-(1H-indol-1-yl)-2-oxoethyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione C39H41NO8 详情 详情

合成路线6

Compound (L) is treated with LiOH and NaH2PO4 in THF/water to provide the dihydroxylated acetic acid derivative (LI), which is finally cyclized to the target compound by means of methanesulfonic acid in chloroform.

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(L) 35721 (9S,12S,13S,15R)-15-[(E)-4-hexenoyl]-9-[2-(1H-indol-1-yl)-2-oxoethyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione C39H41NO8 详情 详情
(LI) 35722 2-[(14S,15S)-11-hydroxy-15-[(2R,6E)-2-hydroxy-3-oxo-6-octenyl]-14-[(E)-6-octenyl]-3,5,9-trioxo-4,10-dioxatetracyclo[9.4.0.0(2,6).0(8,12)]pentadeca-2(6),12-dien-8-yl]acetic acid C31H38O10 详情 详情

合成路线7

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情

合成路线8

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
【2】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 19241 (2S)oxiranylmethanol 60456-23-7 C3H6O2 详情 详情
(XVII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XVIII) 40293 tert-butyl(dimethyl)silyl (1R)-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-(trimethylsilyl)-3-butynyl ether; (5R)-2,2,3,3,8,8,9,9-octamethyl-5-[3-(trimethylsilyl)-2-propynyl]-4,7-dioxa-3,8-disiladecane C20H44O2Si3 详情 详情
(XIX) 40294 tert-butyl(dimethyl)silyl (2R,4E)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-pentenyl ether; (5R)-5-[(E)-3-iodo-2-propenyl]-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane C17H37IO2Si2 详情 详情
(XX) 40295 (E,7R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-4-octen-3-one C46H78O6Si2 详情 详情
(XXI) 40296 　 C15H23AlCl2O 详情 详情
(XXII) 40297 　 C46H78O6Si2 详情 详情
(XXIII) 40298 　 C34H50O6 详情 详情
(XXIV) 35692 　 C33H46O5 详情 详情
(XXV) 35693 [2-[(E)-3-pentenyl]-1,3-dithian-2-yl]lithium C9H15LiS2 详情 详情
(XXVI) 35694 　 C42H62O5S2 详情 详情
(XXVII) 35695 　 C48H76O5S2Si 详情 详情
(XXVIII) 35696 　 C49H75F3O7S3Si 详情 详情

合成路线9

The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al(CN) in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords mesylate (XXXIII), which is treated with K2CO3 in MeOH providing intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid affords the maleic anhydride derivative (XXXV).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
【2】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15713 Oxalic acid 144-62-7 C2H2O4 详情 详情
(XXVIII) 35696 　 C49H75F3O7S3Si 详情 详情
(XXIX) 35697 　 C50H78O6S2Si 详情 详情
(XXX) 35698 　 C49H78O8Si 详情 详情
(XXXI) 35699 　 C48H78O7Si 详情 详情
(XXXII) 35700 　 C49H79NO8Si 详情 详情
(XXXIII) 40299 　 C51H83NO8SSi 详情 详情
(XXXIV) 35702 　 C49H77NO7Si 详情 详情
(XXXV) 35703 　 C49H74O9Si 详情 详情

合成路线10

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in dichloromethane yields corresponding aldehyde (XLIV).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
【2】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
【3】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXV) 35703 　 C49H74O9Si 详情 详情
(XXXVI) 35704 　 C41H54O8 详情 详情
(XXXVII) 35705 　 C47H68O8Si 详情 详情
(XXXVIII) 35706 　 C39H60O8Si 详情 详情
(XXXIX) 35707 　 C39H58O8Si 详情 详情
(XL) 40300 (8S,14R,15R)-15-((2S,6E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-oxo-6-octenyl)-11-hydroxy-8-(hydroxymethyl)-14-[(E)-6-octenyl]-4,10-dioxatetracyclo[9.4.0.0(2,6).0(8,12)]pentadeca-2(6),12-diene-3,5-dione C36H54O8Si 详情 详情
(XLI) 40301 (8R,14R,15R)-15-((2S,6E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-oxo-6-octenyl)-11-hydroxy-14-[(E)-6-octenyl]-8-[[(triethylsilyl)oxy]methyl]-4,10-dioxatetracyclo[9.4.0.0(2,6).0(8,12)]pentadeca-2(6),12-diene-3,5-dione C42H68O8Si2 详情 详情
(XLII) 35710 　 C42H68O9Si2 详情 详情
(XLIII) 35711 　 C30H38O8 详情 详情
(XLIV) 35712 　 C30H36O8 详情 详情

合成路线11

The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLIV) 35712 　 C30H36O8 详情 详情
(XLV) 35713 　 C36H50O8Si 详情 详情
(XLVI) 35714 　 C36H50O9Si 详情 详情
(XLVII) 35715 　 C39H56O9SSi 详情 详情
(XLVIII) 35716 　 C37H50N2O8Si 详情 详情
(XLIX) 35717 　 C37H52O9Si 详情 详情
(L) 19652 indoline 496-15-1 C8H9N 详情 详情
(LI) 35718 (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione C45H59NO8Si 详情 详情
(LII) 35719 (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione C39H45NO8 详情 详情

合成路线12

The oxidation of (LII) with DMP in dichloromethane yields the corresponding ketonic compound (LIII), which is dehydrogenated at the indoline group with chloranil in refluxing toluene affording the corresponding indole derivative (LIV). Compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the dihydroxylated acetic acid derivative (LV), which is finally cyclized to the target compound by means of methanesulfonic acid in chloroform.

参考文献 中间体
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677.
【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LII) 35719 (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione C39H45NO8 详情 详情
(LIII) 35720 (9S,12S,13S,15R)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione C39H43NO8 详情 详情
(LIV) 35721 (9S,12S,13S,15R)-15-[(E)-4-hexenoyl]-9-[2-(1H-indol-1-yl)-2-oxoethyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione C39H41NO8 详情 详情
(LV) 35722 2-[(14S,15S)-11-hydroxy-15-[(2R,6E)-2-hydroxy-3-oxo-6-octenyl]-14-[(E)-6-octenyl]-3,5,9-trioxo-4,10-dioxatetracyclo[9.4.0.0(2,6).0(8,12)]pentadeca-2(6),12-dien-8-yl]acetic acid C31H38O10 详情 详情

合成路线13

The condensation of 4-(ethylsulfanyl)-2-butynoic acid methyl ester (I) with the vinyl copper derivative (III) by means of DBU in THF gives the addition product (IV), which is treated with methyl chloroformate and LHMDS in THF yielding the malonic ester (V): The condensation of (V) with the chiral oxazolidinone (VI) by means of Cs2CO3 in acetonitrile affords the addition compound (VII), which is further condensed with the aldehyde (VIII) by means of Bu2B-OTf and TEA in dichloromethane giving the adduct (IX). The cyclization of (IX) by means of ZnCl2 and pyridine in dichloromethane yields the bicyclic compound (X), which is treated with allyl thioglycolate (XI) and LHMDS in ether producing the opening of the thiazolidinone ring. The resulting thiocarboxylic ester (XII) is submitted to cyclization by means of DBU in THF furnishing the tricyclic compound (XIII), which is selectively dehydrated and decarboxylated with Pd(OAc)2/PPh3 and pyr/Ac2O giving the tricyclic thiophenone (XIV). The oxidation of (XIV) with TBDMS-Cl, DBU and AgNO3 in hot DMSO affords the tricyclic thiophenedione (XV).

参考文献 中间体
【1】 Waizumi, N.; et al.; Total synthesis of (-)-CP-263,114 (phomoidride B). J Am Chem Soc 2000, 122, 32, 7825.
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) 40302 methyl 4-(propylsulfanyl)-2-butynoate C8H12O2S 详情 详情
(II) 40303 methyl 4-(propylsulfanyl)-2,3-butadienoate C8H12O2S 详情 详情
(III) 40304 (1E,8E)-1,8-decadienylcopper C10H17Cu 详情 详情
(IV) 40305 methyl (4E,11E)-3-[(E)-(propylsulfanyl)methylidene]-4,11-tridecadienoate C18H30O2S 详情 详情
(V) 40306 dimethyl 2-[(2E,9E)-1-[(Z)-(propylsulfanyl)methylidene]-2,9-undecadienyl]malonate C20H32O4S 详情 详情
(VI) 40307 (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one C13H13NO3 详情 详情
(VII) 40308 dimethyl 2-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2-[(2E,9E)-1-[(E)-(propylsulfanyl)methylidene]-2,9-undecadienyl]malonate C33H45NO7S 详情 详情
(VIII) 40309 (E)-4-[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2-butenal C13H22O3 详情 详情
(IX) 40310 dimethyl 2-[(2S,4E)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-6-[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]-3-oxo-4-hexenyl]-2-[(2E,9E)-1-[(E)-(propylsulfanyl)methylidene]-2,9-undecadienyl]malonate C46H65NO10S 详情 详情
(X) 40311 dimethyl (4S,6R,7R,8R,10R)-4-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-7-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-8-[(E)-6-octenyl]-5-oxo-10-(propylsulfanyl)bicyclo[4.3.1]dec-1(9)-ene-2,2-dicarboxylate C46H65NO10S 详情 详情
(XI) 40312 allyl 2-sulfanylacetate C5H8O2S 详情 详情
(XII) 40313 dimethyl (4S,6R,7R,8R,10R)-4-([[2-(allyloxy)-2-oxoethyl]sulfanyl]carbonyl)-7-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-8-[(E)-6-octenyl]-5-oxo-10-(propylsulfanyl)bicyclo[4.3.1]dec-1(9)-ene-2,2-dicarboxylate C41H62O10S2 详情 详情
(XIII) 40314 3-allyl 8,8-dimethyl (1R,2R,3S,11R,12R,13R)-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2-hydroxy-11-[(E)-6-octenyl]-5-oxo-13-(propylsulfanyl)-4-thiatricyclo[7.3.1.0(2,6)]tridec-9-ene-3,8,8-tricarboxylate C41H62O10S2 详情 详情
(XIV) 40315 dimethyl (1R,11R,12R,13R)-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-11-[(E)-6-octenyl]-5-oxo-13-(propylsulfanyl)-4-thiatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8,8-dicarboxylate C37H56O7S2 详情 详情
(XV) 40316 dimethyl (1R,11R,12R,13R)-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-11-[(E)-6-octenyl]-3,5-dioxo-13-(propylsulfanyl)-4-thiatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8,8-dicarboxylate C37H54O8S2 详情 详情

合成路线14

The successive treatment of (XV) with LiOH and Ba(OH)2 caused selective hydrolyses of the thiomaleic group and the less hindered methyl ester, yielding finally monocarboxylic acid (XVI). The conventional Arndt-Eister (oxalyl chloride, diazomethane and silver benzoate/tert-butanol) was used to convert acid (XVI) into the homologated ester (XVII). Careful oxidation of the sulfanyl group of (XVII) with MCPBA followed by a treatment with trifluoroacetic anhydride yields the ketone (XVIII), which is hydrolyzed and cyclized by means of 80% AcOH affording the cyclic acetal (XIX). Finally, this compound is oxidized with Jones reagent and the tert-butyl ester is deprotected with formic acid to provide the target compound.

参考文献 中间体
【1】 Waizumi, N.; et al.; Total synthesis of (-)-CP-263,114 (phomoidride B). J Am Chem Soc 2000, 122, 32, 7825.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 40316 dimethyl (1R,11R,12R,13R)-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-11-[(E)-6-octenyl]-3,5-dioxo-13-(propylsulfanyl)-4-thiatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8,8-dicarboxylate C37H54O8S2 详情 详情
(XVI) 40317 (1R,8R,11R,12R,13R)-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-8-(methoxycarbonyl)-11-[(E)-6-octenyl]-3,5-dioxo-13-(propylsulfanyl)-4-oxatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8-carboxylic acid C36H52O9S 详情 详情
(XVII) 40318 methyl (1R,8S,11R,12R,13R)-8-[2-(tert-butoxy)-2-oxoethyl]-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-11-[(E)-6-octenyl]-3,5-dioxo-13-(propylsulfanyl)-4-oxatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8-carboxylate C41H62O9S 详情 详情
(XVIII) 40319 methyl (1R,8S,11R,12R)-8-[2-(tert-butoxy)-2-oxoethyl]-12-[[(4S,5S)-5-butyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-11-[(E)-6-octenyl]-3,5,13-trioxo-4-oxatricyclo[7.3.1.0(2,6)]trideca-2(6),9-diene-8-carboxylate C38H54O10 详情 详情
(XIX) 40320 tert-butyl 2-[(2R,12R,13S,14R,15S)-14-butyl-15-(hydroxymethyl)-12-[(E)-6-octenyl]-4,6,18-trioxo-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-dien-9-yl]acetate C34H46O9 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)