Phomoidride A, CP-225917, -Drug Synthesis Database

【结构式】

【药物名称】Phomoidride A, CP-225917

【化学名称】(+)-2-[11-Hydroxy-5-[2-hydroxy-3-oxo-6(E)-octenyl]-6-[6(E)-octenyl]-1,3,13-trioxo-3,4,5,6,9,10-hexahydro-1H-11,9-(epoxymethano)-4,8-methanocyclonona[c]furan-9-yl]acetic acid

【CA登记号】

【分子式】C₃₁H₃₈O₁₀

【分子量】570.64251

【开发单位】Pfizer (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, 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	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	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), 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	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

Finally, compound (L) is treated with LiOH and NaH2PO4 in THF/water to provide the target compound.

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

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 PmbCl 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.; 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.
【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
(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 the mesylate (XXXIII), which is treated with K2CO3 in MeOH providing the intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid in EtOH/H2O affords the maleic anhydride derivative (XXXV).

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.
【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
	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 CH2Cl2/H2O 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 CH2Cl2/H2O giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in CH2Cl2 yields corresponding aldehyde (XLIV).

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.
【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.; 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	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 CH2Cl2 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). Finally, compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the target compound.

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.

中间体序号	中间体编号	品名	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

Extended Information