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【结 构 式】

【药物名称】Salicylihalamide A

【化学名称】N-[3-[5(R),14-Dihydroxy-6(S)-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3(S)-yl]-1(E)-propenyl]-2(Z),4(Z)-heptadienamide

【CA登记号】198481-99-1

【 分 子 式 】C26H33NO5

【 分 子 量 】439.55661

【开发单位】US Department of Health & Human Services (Originator)

【药理作用】ONCOLYTIC DRUGS

合成路线1

The reaction of the chiral epoxide (I) with 4-methoxybenzaldehyde (II) by means of NaAl(OMe)3H in THF gives the 1,3-dioxane (III), which is opened by reduction with DIBAL in dichloromethane to yield the chiral benzyl ether (IV). The oxidation of the primary alcohol of (IV) with DMP in dichloromethane affords the corresponding aldehyde (V), which is condensed with the boronate (VI) and S,S-diisopropyl tartrate in toluene to provide the unsaturated alcohol (VII).The protection of (VII) with Tbdps-Cl and imidazole yields the fully protected triol (VIII), which is oxidized at the terminal double bond with 9-BBN in THF to give the primary alcohol (IX). The oxidation of (IX) with DMP in dichloromethane affords the aldehyde (X), which is condensed with methylenetriphenylphosphorane (XI) in THF to provide the terminal olefin (XII). Elimination of the Pmb protecting group of (XII) with DDQ in dichloromethane gives the alcohol (XIII), which is esterified with 2-allyl-6-methoxybenzoic acid (XIV)(obtained by allylation of 2-methoxybenzoic acid (XV) with allyl bromide (XVI), BuLi and MgBr2) by means of DEAD and PPh3 yielding the ester (XVII). The cyclization of (XVII) by means of a metathesis reaction catalyzed by a ruthenium catalyst in refluxing dichloromethane affords the bicyclic lactone (XVIII), which is treated with BBr3 in dichloromethane to provide the dihydroxylated lactone (XIX).

1 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.
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) 47480 [(2R,3R)-3-[3-(benzyloxy)propyl]oxiranyl]methanol C13H18O3 详情 详情
(II) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(III) 47481 (4R)-4-[3-(benzyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxane; benzyl 3-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propyl ether C21H26O4 详情 详情
(IV) 47482 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]-1-hexanol C21H28O4 详情 详情
(V) 47483 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]hexanal C21H26O4 详情 详情
(VI) 47484 dimethyl (E)-2-butenylboronate C6H13BO2 详情 详情
(VII) 47485 (3S,4R,6R)-9-(benzyloxy)-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonen-4-ol C25H34O4 详情 详情
(VIII) 47486 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-3-butenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-8-nonenyl ether C41H52O4Si 详情 详情
(IX) 47487 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonanol C41H54O5Si 详情 详情
(X) 47488 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methylnonanal C41H52O5Si 详情 详情
(XI) 27301 methylene(triphenyl)phosphorane C19H17P 详情 详情
(XII) 47489 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-4-pentenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-9-decenyl ether C42H54O4Si 详情 详情
(XIII) 47490 (4R,6R,7S)-1-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-7-methyl-9-decen-4-ol C34H46O3Si 详情 详情
(XIV) 13926 2-Methoxybenzoic acid; o-Methoxybenzoic Acid 579-75-9 C8H8O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 47491 2-allyl-6-methoxybenzoic acid C11H12O3 详情 详情
(XVII) 47492 (1S,3R,4S)-1-[3-(benzyloxy)propyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate C45H56O5Si 详情 详情
(XVIII) 47493 (3S,5R,6S)-3-[3-(benzyloxy)propyl]-5-[[tert-butyl(diphenyl)silyl]oxy]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C43H52O5Si 详情 详情
(XIX) 47494 (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C35H44O5Si 详情 详情

合成路线2

The oxidation of the primary alcohol of (XIX) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XX), which is condensed with (Z,Z)-2,4-heptadienamide (XXI) by means of Tms-OTf in dichloroethane to yield the N,N-acylated aminal (XXII). This compound undergoes elimination when treated with NaH in hot trifluoromethylbenzene affording enamide (XXIII) as a mixture of (Z) and (E) isomers, which is treated with TBAF in THF undergoing elimination of the Tips protecting group only and providing the monosilylated compound (XXIV). Removal of the remaining silyl group requires more drastic conditions (TBAF in THF/HMPA) that cause isomerization of the enamide double bond yielding a mixture of the target compound Salicylhalamide A along with its isomer Salicylhalamide B that are separated by HPLC chromatography. The intermediate (Z,Z)-2,4-heptadienamide (XXI) has been obtained as follows: The oxidation of (Z)-2-penten-1-ol (XXV) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XXVI), which is condensed with phosphonate (XXVII) by means of KH in THF to yield methyl (Z,Z)-2,4-heptadienoate (XXVIII). The hydrolysis of (XXVIII) with Ba(OH)2 in methanol/water affords (Z,Z)-2,4-heptadienoic acid (XXIX), which is finally treated with ethyl chloroformate and ammonia to provide the target amide (XXI).

1 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 47502 (2Z,4Z)-N-((E)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide C51H71NO5Si2 详情 详情
(XXIIIb) 47503 (2Z,4Z)-N-((Z)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide C51H71NO5Si2 详情 详情
(XXIVa) 47504 (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide C42H51NO5Si 详情 详情
(XXIVb) 47505 (2Z,4Z)-N-[(Z)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide C42H51NO5Si 详情 详情
(XIX) 47494 (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C35H44O5Si 详情 详情
(XX) 47500   C44H62O5Si2 详情 详情
(XXI) 47499 (2Z,4Z)-2,4-heptadienamide C7H11NO 详情 详情
(XXII) 47501 (2Z,4Z)-N-[3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-[(2Z,4Z)-2,4-heptadienoylamino]propyl]-2,4-heptadienamide C58H82N2O6Si2 详情 详情
(XXV) 47495 cis-2-pentenol; (Z)-2-penten-1-ol 1576-95-0 C5H10O 详情 详情
(XXVI) 47496 (Z)-2-pentenal C5H8O 详情 详情
(XXVII) 41856 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 88738-78-7 C7H9F6O5P 详情 详情
(XXVIII) 47497 methyl (2Z,4Z)-2,4-heptadienoate C8H12O2 详情 详情
(XXIX) 47498 (2Z,4Z)-2,4-heptadienoic acid C7H10O2 详情 详情

合成路线3

The chiral tetrahydropyran intermediate (XI) has been obtained as follows. The reaction of (-)-pseudoephedrine propionamide (I) with the allyl bromide (II) by the Myers' method gives pentenamide (III), which is reduced with LiNH2BH3 in THF to yield 2(S)-methyl-4-penten-1-ol (IV). Swern oxidation of (IV) affords the corresponding aldehyde (V), which is submitted to an asymmetric aldol condensation with the silyl enol ether (VI) catalyzed by Cu(OTf)2, (S)-Tol-BINAP and (Bu4N)Ph3SiF2 in THF to provide the adduct (VII). The methanolysis of (VII) with Me-OH in refluxing toluene gives the beta-keto ester (VIII), which is treated with Et2BOMe, NaBH4 and HF to yield the chiral hydroxy lactone (IX). The reduction of (IX) with DIBAL in THF affords the lactol (X), which is finally methylated with Ts-OH in refluxing methanol to provide the target tetrahydropyran intermediate (XI).

1 Bauer, M.; Maier, M.E.; Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction. Org Lett 2002, 4, 13, 2205.
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) 56935 N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylpropanamide C13H19NO2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 56936 (2S)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-dimethyl-4-pentenamide C16H23NO2 详情 详情
(IV) 56937 (2S)-2-methyl-4-penten-1-ol C6H12O 详情 详情
(V) 26241 (2S)-2-methyl-4-pentenal C6H10O 详情 详情
(VI) 53651 [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether n/a C10H18O3Si 详情 详情
(VII) 56938 6-[(2R,3S)-2-hydroxy-3-methyl-5-hexenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one C13H20O4 详情 详情
(VIII) 56939 methyl (5R,6S)-5-hydroxy-6-methyl-3-oxo-8-nonenoate C11H18O4 详情 详情
(IX) 56940 (4S,6R)-4-hydroxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2-one C10H16O3 详情 详情
(X) 56941 (4S,6R)-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2,4-diol C10H18O3 详情 详情
(XI) 56942 (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol C11H20O3 详情 详情

合成路线4

The Stille coupling of the benzodioxanone (XII) with allyltributyltin (XIII) by means of trifurylphosphine (TFP) and Pd2(dba)3 gives the 6-allylsalicylic acid (XIV), which is esterified with the intermediate (XI) by means of DEAD and PPH3 in ethyl ether to yield the ester (XV). Hydrolysis of the lactol group of (XV) with Ac-OH affords the carbaldehyde (XVI), which is condensed with the phosphorane (XVII) to provide the unsaturated ester (XVIII). The silylation of the free OH groups of (XVIII) with Tbdms-OTf and lutidine gives the protected compound (XIX), which is submitted to a rig closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to yield the macrolactone (XX). The selective hydrolysis of the methyl ester group of (XX) by treatment with (Bu3Sn)2O in refluxing toluene affords the unsaturated carboxylic acid (XXI), which is treated with DPPA in refluxing benzene to provide the corresponding isocyanate (XXII). The reaction of the isocyanate group of (XXII) with (1Z,3Z)-hexadienyl cuprate, prepared in situ by reaction of Et-Li, CuBr/Me2S and acetylene, gives the silylated heptadienamide (XXIII), along with some pentanamide and nonatrienamide derivatives that are separated by chromatography. Finally, compound (XXIII) is desilylated by means of HF and pyridine in THF to provide the target salicylhalamide A.

1 Bauer, M.; Maier, M.E.; Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction. Org Lett 2002, 4, 13, 2205.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 56942 (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol C11H20O3 详情 详情
(XII) 56943 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl trifluoromethanesulfonate C11H9F3O6S 详情 详情
(XIII) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(XIV) 56944 2-allyl-6-hydroxybenzoic acid C10H10O3 详情 详情
(XV) 56945 (4R,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-yl 2-allyl-6-hydroxybenzoate C21H28O5 详情 详情
(XVI) 56946 (1R,3R,4S)-3-hydroxy-4-methyl-1-(2-oxoethyl)-6-heptenyl 2-allyl-6-hydroxybenzoate C20H26O5 详情 详情
(XVII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane;Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVIII) 56947 (1S,3R,4S)-3-hydroxy-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-hydroxybenzoate C23H30O6 详情 详情
(XIX) 56948 (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-{[tert-butyl(dimethyl)silyl]oxy}benzoate C35H58O6Si2 详情 详情
(XX) 56949 methyl (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoate C33H54O6Si2 详情 详情
(XXI) 56950 (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid C32H52O6Si2 详情 详情
(XXII) 56951 (3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-3-isocyanato-2-propenyl]-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C32H51NO5Si2 详情 详情
(XXIII) 56952 (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide C38H61NO5Si2 详情 详情

合成路线5

The stereoselective allylation of aldehyde (I) by means of allylmagnesium bromide (II) catalyzed by (-)-Ipc2BOMe gives the alcohol (III), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (IV). The oxidation of the terminal double bond of (IV) by means of OsO4, NMO and NaIO4 affords the carbaldehyde (V), which is diastereoselectively condensed with the chiral bornanesultam (VI) by means of TiCl4 and DIEA in dichloromethane to provide the adduct (VII). The protection of the OH group of (VII) with Mom-Cl, NaI and DIEA in refluxing DME gives the Mom-ether (VIII). The reductive cleavage of the chiral auxiliary by means of LiEt3BH in THF yields the carbinol (IX), which is treated with Ts-Cl, TEA and DMAP in dichloromethane to afford the tosylate (X). The reductive cleavage of the tosyl group of (X) by means of LiEt3BH in THF provides the chiral methylated compound (XI), which is desilylated by means of TBAF in THF to give the corresponding alcohol (XII). The reaction of (XII) with benzoic acid (XIII) by means of DEAD and PPh3 in refluxing ethyl ether yields the benzoate ester (XIV), which is submitted to a ring closing metathesis (RCA) reaction by means of a Ru catalyst to afford the macrolactone (XV). The selective monodeprotection of (XV) by means of DDQ in dichloromethane/water provides the ethanol derivative (XVI), which is oxidized by means of DMP in dichloromethane to give the carbaldehyde (XVII). The homologation of (XVII) by means of a Horner-Wadsworth-Emmons reaction with phosphonate (XVIII) by means of NaH in THF yields the unsaturated allyl ester (XIX), which is treated with BBr3 in dichloromethane to eliminate the methoxy and methoxymethoxy protecting group, yielding the dihydroxy compound (XX).

1 Xie, X.-S.; De Brabander, J.K.; Wang, R.; Liao, X.; Wu, Y.; Total synthesis and initial structure-function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds. J Am Chem Soc 2002, 124, 13, 3245.
2 Smith, A.B. III; et al.; Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement. J Am Chem Soc 2001, 123, 44, 10942.
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) 42455 3-[(4-methoxybenzyl)oxy]propanal C11H14O3 详情 详情
(II) 10336 (3aR,4S,6R,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-ol C27H28O5 详情 详情
(III) 58187 (3S)-1-[(4-methoxybenzyl)oxy]-5-hexen-3-ol C14H20O3 详情 详情
(IV) 58188 tert-butyl(dimethyl)silyl (1S)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-butenyl ether; tert-butyl[((1S)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-butenyl)oxy]dimethylsilane C20H34O3Si 详情 详情
(V) 58189 (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]pentanal C19H32O4Si 详情 详情
(VI) 58190 (1R)-10,10-dimethyl-4-(4-pentenoyl)-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C15H23NO3S 详情 详情
(VII) 58191 (1R)-4-((2S)-2-{(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxy-5-[(4-methoxybenzyl)oxy]pentyl}-4-pentenoyl)-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C34H55NO7SSi 详情 详情
(VIII) 58192 (1R)-4-{(2S)-2-[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-pentenoyl}-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C36H59NO8SSi 详情 详情
(IX) 58193 (2R)-2-[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-penten-1-ol C26H46O6Si 详情 详情
(X) 58194 (2R)-2-[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-pentenyl 4-methylbenzenesulfonate C33H52O8SSi 详情 详情
(XI) 58195 (5R,7R)-7-{2-[(4-methoxybenzyl)oxy]ethyl}-9,9,10,10-tetramethyl-5-[(1S)-1-methyl-3-butenyl]-2,4,8-trioxa-9-silaundecane; tert-butyl(dimethyl)silyl (1R,3R,4S)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-(methoxymethoxy)-4-methyl-6-heptenyl ether C26H46O5Si 详情 详情
(XII) 58196 (3R,5R,6S)-1-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)-6-methyl-8-nonen-3-ol C20H32O5 详情 详情
(XIII) 47491 2-allyl-6-methoxybenzoic acid C11H12O3 详情 详情
(XIV) 58197 (1S,3R,4S)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-(methoxymethoxy)-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate C31H42O7 详情 详情
(XV) 58198   C29H36O7 详情 详情
(XVI) 58199   C21H28O6 详情 详情
(XVII) 58200   C21H26O6 详情 详情
(XVIII) 58201 allyl 2-(diethoxyphosphoryl)acetate; Allyl p,p-diethylphosphonoacetate; Phosphonoacetic acid p,p-diethyl allyl ester C9H17O5P 详情 详情
(XIX) 58202   C26H32O7 详情 详情
(XX) 58203   C23H26O6 详情 详情

合成路线6

The reaction of the dihydroxy compound (XX) with Tbdms-Cl and imidazole gives the disilylated compound (XXI), which is deallylated by means of Pd(PPh3)4 to yield the 2-butenoic acid derivative (XXII). The reaction of (XXII) with the phosphoryl azide (XXIII) by means of TEA in benzene affords the butenoyl azide (XXIV), which is converted into the isocyanate (XXV) by heating in refluxing benzene. The reaction of (XXV) with 1,3-hexadienyl bromide (XXVI) by means of t-BuLi in THF provides the 2,4-heptadienoyl amide (XXVII), which is finally desilylated by means of HF and pyridine in THF to obtain the target Salicylihalamide A.

1 Xie, X.-S.; De Brabander, J.K.; Wang, R.; Liao, X.; Wu, Y.; Total synthesis and initial structure-function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds. J Am Chem Soc 2002, 124, 13, 3245.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 58203   C23H26O6 详情 详情
(XXI) 58204   C35H54O6Si2 详情 详情
(XXII) 58205 (E)-4-((2S,4R,5S)-4,14-bis{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-16-oxooxa-7,8,11,13-cyclohexadecatetraen-2-yl)-2-butenoic acid C32H54O6Si2 详情 详情
(XXIII) 58206   C12H10N3O3P 详情 详情
(XXIV) 58207 (E)-4-((2S,4R,5S)-4,14-bis{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-16-oxooxa-7,8,11,13-cyclohexadecatetraen-2-yl)-2-butenoyl azide C32H53N3O5Si2 详情 详情
(XXV) 58208 (13S,14R,16S)-4,14-bis{[tert-butyl(dimethyl)silyl]oxy}-16-[(E)-3-isocyanato-2-propenyl]-13-methyloxa-4,6,9,10-cyclohexadecatetraen-2-one C32H53NO5Si2 详情 详情
(XXVI) 58209 (1Z,3Z)-1-bromo-1,3-hexadiene C6H9Br 详情 详情
(XXVII) 58210 (2Z,4Z)-N-[(E)-3-((2S,4R,5S)-4,14-bis{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-16-oxooxa-7,8,11,13-cyclohexadecatetraen-2-yl)-1-propenyl]-2,4-heptadienamide C38H63NO5Si2 详情 详情

合成路线7

The condensation of aldehyde (I) with boronate (II) in toluene gives the chiral alcohol (III), which is treated with Tbdms-OTf and TEA to yield the silyl ether (IV). The hydroxylation of the terminal double bond of (IV) by means of 9-BBN in refluxing THF affords the primary alcohol (V), which is oxidized by means of the Swern oxidant to provide the aldehyde (VI). The homologation of (VI) with methyltriphenylphosphonium iodide (VII) and NaHMDS gives the unsaturated compound (VIII), which is deprotected at the ketonide group by means of TFA in dichloromethane to afford the diol (IX). The dehydration of (IX) by means of tosylimidazole (X) and NaH in THF provides the epoxide (XI), which is condensed with the Grignard reagent (XIII) (obtained by reaction of the tributyltin derivative (XII) with MgBr2) to give the secondary alcohol (XIV). The reaction of 2-allyl-6-methoxybenzamide (XV) with I2 in THF/water gives the lactone (XVI), which is treated with Zn and AcOH to yield 2-allyl-6-methoxybenzoic acid (XVII). The esterification of acid (XVII) with alcohol (XIV) by means of DEAD and PPH3 affords the corresponding ester (XVIII), which is submitted to a ring closing metathesis reaction by means of a Ru catalyst to provide the macrolactone (XIX). The cleavage of the Pmb protecting group of (XIX) by means of DDQ gives the primary alcohol (XX), which is oxidized to the aldehyde (XXI) by means of DMP oxidant.

1 Smith, A.B.; Zheng, J.Y.; Total synthesis of (-)-salicylihalamide A and related congeners. Tetrahedron 2002, 58, 33, 6455.
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) 61703 2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]acetaldehyde C9H16O3 详情 详情
(II) 61704 diisopropyl (4S,5S)-2-[(E)-2-butenyl]-1,3,2-dioxaborolane-4,5-dicarboxylate C14H23BO6 详情 详情
(III) 61705 (2R,3S)-1-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-4-penten-2-ol C13H24O3 详情 详情
(IV) 61706 tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl)oxy]dimethylsilane C19H38O3Si 详情 详情
(V) 61707 (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-1-pentanol C19H40O4Si 详情 详情
(VI) 61708 (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methylpentanal C19H38O4Si 详情 详情
(VII) 13484 Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 2065-66-9 C19H18IP 详情 详情
(VIII) 61709 tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl)oxy]dimethylsilane C20H40O3Si 详情 详情
(IX) 61710 (2S,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-7-octene-1,2-diol C15H32O3Si 详情 详情
(X) 47846 1-[(4-methylphenyl)sulfonyl]-1H-imidazole 2232-08-8 C10H10N2O2S 详情 详情
(XI) 61711 tert-butyl(dimethyl)({(1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl}oxy)silane; tert-butyl(dimethyl)silyl (1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl ether C15H30O2Si 详情 详情
(XII) 61712 tributyl{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}stannane; 4-methoxybenzyl (E)-3-(tributylstannyl)-2-propenyl ether C23H40O2Sn 详情 详情
(XIII) 61713 bromo{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}magnesium C11H13BrMgO2 详情 详情
(XIV) 61716 (2E,5R,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-1-[(4-methoxybenzyl)oxy]-8-methyl-2,10-undecadien-5-ol C26H44O4Si 详情 详情
(XV) 61714 2-allyl-6-methoxy-N,N-dipropylbenzamide C17H25NO2 详情 详情
(XVI) 61715 3-(iodomethyl)-8-methoxy-3,4-dihydro-1H-isochromen-1-one C11H11IO3 详情 详情
(XVII) 47491 2-allyl-6-methoxybenzoic acid C11H12O3 详情 详情
(XVIII) 61717 (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate C37H54O6Si 详情 详情
(XIX) 61718 (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-3-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C35H50O6Si 详情 详情
(XX) 61719 (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-4-hydroxy-2-butenyl]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C27H42O5Si 详情 详情
(XXI) 61720 (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal C27H40O5Si 详情 详情

合成路线8

The demethylation of (XXI) by means of BBr3 gives the hydroxyaldehyde (XXII), which is oxidized to the corresponding carboxylic acid (XXIII) by means of NaClO2. The protection of the phenolic OH group of (XXIII) by means of Tbdms-OTf and TEA yields the silyl ether (XXIV), which is submitted to a Curtius rearrangement by means of isobutyl chloroformate, NaN3 and 2-(trimethylsilyl)ethanol, affording the carbamate (XXV). The acylation of carbamate (XXV) with heptadienoyl chloride (XXVI) and NaHMDS provides the advanced intermediate (XXVII), which is finally deprotected by successive treatments with TBAF and with HF/pyridine to provide the target Salicylhalamide A.

1 Smith, A.B.; Zheng, J.Y.; Total synthesis of (-)-salicylihalamide A and related congeners. Tetrahedron 2002, 58, 33, 6455.
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) 56950 (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid C32H52O6Si2 详情 详情
(XXI) 61720 (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal C27H40O5Si 详情 详情
(XXII) 61721 (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal C26H38O5Si 详情 详情
(XXIII) 61722 (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid C26H38O6Si 详情 详情
(XXV) 61723 2-(trimethylsilyl)ethyl (E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenylcarbamate C37H65NO6Si3 详情 详情
(XXVI) 61725 (2Z,4Z)-2,4-heptadienoyl chloride C7H9ClO 详情 详情
(XXVII) 61724 2-(trimethylsilyl)ethyl (E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl[(2Z,4Z)-2,4-heptadienoyl]carbamate C44H73NO7Si3 详情 详情
Extended Information