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【结 构 式】

【药物名称】(+)-Resiniferatoxin, Resiniferatoxin, RTX-107, RTX

【化学名称】4-Hydroxy-3-methoxybenzeneacetic acid (2S,3aR,3bS,6aR,9aR,9bR,10R,11aR)-2-benzyl-6a-hydroxy-8,10-dimethyl-11a-(1-methylethenyl)-7-oxo-3a,3b,6,6a,9a,10,11,11a-octahydro-7H-2,9b-epoxyazuleno[5,4-e]-1,3-benzodioxol-5-ylmethyl ester

【CA登记号】57444-62-9, 136849-17-7 (tritium-labeled)

【 分 子 式 】C37H40O9

【 分 子 量 】628.72595

【开发单位】National Institutes of Health (Originator), Afferon (Licensee), Icos (Licensee)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Neuropathic Pain, Treatment of, RENAL-UROLOGIC DRUGS, Urologic Drugs, Vanilloid VR1 Receptor Agonists

合成路线1

The total synthesis of (+)-resiniferatoxin started with the asymmetric Sharpless epoxidation of 1,4-pentadien-3-ol (I) to afford the epoxy-alcohol (II), which was further protected as the benzyl ether (III). Epoxide ring opening in (III) with the lithium acetylide (IV) in the presence of BF3 at -78 ºC yielded the acetylenic alcohol (V), which was subsequently cyclized to lactone (VI) under acidic conditions. Methylation of the lithium enolate of lactone (VI) gave rise to the trans- lactone (VII) as the major diastereoisomer. Addition of the lithiated derivative of O-(tert-butyldimethylsilyl)furfuryl alcohol (VIII) to the lactone (VII) produced the furyl ketone (IX). After protection of the hydroxyl group of (IX) as the corresponding acetate ester (X), reduction of its ketone function with NaBH4 furnished alcohol (XI). Oxidation of the furan nucleus of (XI) with m-CPBA produced the intermediate diketone (XII) which spontaneously cyclized to the pyranone (XIII). Acetylation of the hydroxyl group of (XIII) gave the (acetyloxy)pyranone (XIV).

1 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647.
2 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976.
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) 11471 1,4-Pentadien-3-ol 922-65-6 C5H8O 详情 详情
(II) 11501 (1R)-1-[(2S)Oxiranyl]-2-propen-1-ol C5H8O2 详情 详情
(III) 11502 (2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether C12H14O2 详情 详情
(IV) 55241 (2-ethoxyethynyl)lithium C4H5LiO 详情 详情
(V) 55242 (3R,4S)-3-(benzyloxy)-7-ethoxy-1-hepten-6-yn-4-ol C16H20O3 详情 详情
(VI) 11503 (5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone C14H16O3 详情 详情
(VII) 11504 (3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone C15H18O3 详情 详情
(VIII) 55243 tert-butyl(2-furylmethoxy)dimethylsilane; tert-butyl(dimethyl)silyl 2-furylmethyl ether C11H20O2Si 详情 详情
(IX) 55244 (2R,4S,5R)-5-(benzyloxy)-1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-4-hydroxy-2-methyl-6-hepten-1-one C26H38O5Si 详情 详情
(X) 55245 (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-2-methyl-3-oxopropyl}-3-butenyl acetate C28H40O6Si 详情 详情
(XI) 55246 (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-3-hydroxy-2-methylpropyl}-3-butenyl acetate C28H42O6Si 详情 详情
(XII) 55247 (1S,3R,6Z)-1-[(1R)-1-(benzyloxy)-2-propenyl]-9-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-3-methyl-5,8-dioxo-6-nonenyl acetate C28H42O7Si 详情 详情
(XIII) 55248 (1S,2R)-2-(benzyloxy)-1-{(2R)-2-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl]propyl}-3-butenyl acetate C28H42O7Si 详情 详情
(XIV) 55249 6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate C30H44O8Si 详情 详情

合成路线2

Treatment of pyranone (XIV) with DBU in boiling acetonitrile generated the pyrilium intermediate (XV) which underwent intramolecular cycloaddition to the desired endo cycloadduct (XVI). Catalytic double bond hydrogenation of enone (XVI) provided the saturated ketone (XVII). Wittig reaction of (XVII) with methylene triphenylphosphorane, followed by reacetylation with acetyl chloride furnished the exocyclic methylene derivative (XVIII). Allylic oxidation of (XVIII) by means of SeO2 and t-BuOOH, and further MnO2 oxidation of the resultant alcohol led to the methylene ketone (XIX). This was then subjected to conjugate addition of vinyl cuprate to provide ketone (XX). Diastereoselective addition of the lithium acetylide (XXI) to ketone (XX) followed by quenching with N-methyl-N-(trimethylsilyl)trifluoroacetamide furnished the silyl ether (XXII) along with some unsilylated carbinol, which was converted to (XXII) by independent silylation with chlorotrimethylsilane and imidazole. The tricyclic system (XXIII) was then obtained by zirconocene-mediated cyclization of (XXII), followed by selective acetate hydrolysis with 90 % AcOH.

1 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647.
2 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976.
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) 55249 6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate C30H44O8Si 详情 详情
(XV) 55250 2-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-pyraniumolate C28H40O6Si 详情 详情
(XVI) 55251 (1R,2R,4S,5R,6S,8S)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-9-en-4-yl acetate C28H40O6Si 详情 详情
(XVII) 55252 (1R,2R,4S,5R,6S,8R)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate C28H42O6Si 详情 详情
(XVIII) 55253 (1R,2R,4S,5R,6S,8R)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-methylene-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate C29H44O5Si 详情 详情
(XIX) 55254 (1R,2R,4S,5R,6S,8S)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-methylene-10-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate C29H42O6Si 详情 详情
(XX) 55255 (1R,2R,4S,5R,6S,8S,11S)-11-allyl-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-10-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate C31H46O6Si 详情 详情
(XXI) 52731 (2-phenylethynyl)lithium C8H5Li 详情 详情
(XXII) 55256 (1R,2R,4S,5R,6S,8S,10R,11S)-11-allyl-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-10-(2-phenylethynyl)-10-[(trimethylsilyl)oxy]-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate C42H60O6Si2 详情 详情
(XXIII) 55257 (1R,2S,4S,6R,8S,10S,11R,12S,14R)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,14-dimethyl-5-[(Z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-ol C40H60O5Si2 详情 详情

合成路线3

Oxidation of alcohol (XXIII) employing tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide provided ketone (XXIV). Addition of isopropenylmagnesium bromide to ketone (XXIV) occurred by the beta-face giving rise to carbinol (XXV). Subsequent ozonolysis of (XXV) produced the oxidative cleavage of both double bonds to yield diketone (XXVI). Hydrogenolysis of the O-benzyl protecting group of (XXVI) followed by reaction of the resultant diol with triphosgene furnished the cyclic carbonate (XXVII). The C20 tert-butyldimethylsilyl group of (XXVII) was selectively removed by treatment with HF to afford alcohol (XXVIII), which was further converted into alkyl iodide (XXIX) via the corresponding triflate, and then displacement with tetrabutylammonium iodide. Reductive elimination of the iodo ether moiety of (XXIX) with activated zinc afforded the exocyclic olefin (XXX).

1 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647.
2 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976.
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) 55257 (1R,2S,4S,6R,8S,10S,11R,12S,14R)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,14-dimethyl-5-[(Z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-ol C40H60O5Si2 详情 详情
(XXIV) 55258 (1R,2S,4S,6R,8S,10S,11R,14R)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,14-dimethyl-5-[(Z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-one C40H58O5Si2 详情 详情
(XXV) 55259 (1R,2S,4S,6R,8S,10S,11R,12R,14R)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-12-isopropenyl-4,14-dimethyl-5-[(Z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-ol C43H64O5Si2 详情 详情
(XXVI) 55260 (1R,2S,4S,6R,8S,10S,11R,12S,14R)-12-acetyl-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-12-hydroxy-4,14-dimethyl-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-5-one C35H56O7Si2 详情 详情
(XXVII) 55261 (1R,2R,4S,8R,9S,11S,13R,15S,17S)-4-acetyl-11-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,15-dimethyl-13-[(trimethylsilyl)oxy]-5,7,18-trioxapentacyclo[9.6.1.0~1,9~.0~4,8~.0~13,17~]octadecane-6,14-dione C29H48O8Si2 详情 详情
(XXVIII) 55262 (1R,2R,4S,8R,9S,11S,13R,15S,17S)-4-acetyl-11-(hydroxymethyl)-2,15-dimethyl-13-[(trimethylsilyl)oxy]-5,7,18-trioxapentacyclo[9.6.1.0~1,9~.0~4,8~.0~13,17~]octadecane-6,14-dione C23H34O8Si 详情 详情
(XXIX) 55263 (1R,2R,4S,8R,9S,11S,13R,15S,17S)-4-acetyl-11-(iodomethyl)-2,15-dimethyl-13-[(trimethylsilyl)oxy]-5,7,18-trioxapentacyclo[9.6.1.0~1,9~.0~4,8~.0~13,17~]octadecane-6,14-dione C23H33IO7Si 详情 详情
(XXX) 55264 (3aR,3bS,6aR,8S,9aS,9bR,10R,11aS)-11a-acetyl-9b-hydroxy-8,10-dimethyl-5-methylene-6a-[(trimethylsilyl)oxy]dodecahydroazuleno[5,4-e][1,3]benzodioxole-2,7(3aH)-dione C23H34O7Si 详情 详情

合成路线4

Allylic oxidation of olefin (XXX) with SeO2 and t-BuOOH led to the formation of the desired C7 alcohol (XXXI) along with the C5 regioisomer (XXXII). Chlorination of the allylic alcohol (XXXI) with SOCl2, followed by nucleophilic displacement by benzoate gave the C-20 benzoate (XXXIII). Selective hydrolysis of the cyclic carbonate of (XXXIII) with 0.5 M NaOH furnished the glycol derivative (XXXIV). Coupling of (XXXIV) with the mixed anhydride (XXXV) produced only the C14 phenylacetate ester (XXXVI). This underwent further cyclization with the free hydroxyl groups to the orthoester compound (XXXVII) under mild acidic conditions. The isopropenyl group was regenerated by a Peterson olefination of the C15 ketone of (XXXVII) to provide (XXXVIII). The benzoyl group was then reintroduced in (XXXVIII) at C20 yielding (XXXIX).

1 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647.
2 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX) 55264 (3aR,3bS,6aR,8S,9aS,9bR,10R,11aS)-11a-acetyl-9b-hydroxy-8,10-dimethyl-5-methylene-6a-[(trimethylsilyl)oxy]dodecahydroazuleno[5,4-e][1,3]benzodioxole-2,7(3aH)-dione C23H34O7Si 详情 详情
(XXXI) 55265 (3aR,3bS,4R,6aR,8S,9aS,9bR,10R,11aS)-11a-acetyl-4,9b-dihydroxy-8,10-dimethyl-5-methylene-6a-[(trimethylsilyl)oxy]dodecahydroazuleno[5,4-e][1,3]benzodioxole-2,7(3aH)-dione C23H34O8Si 详情 详情
(XXXII) 55266 (3aR,3bS,6R,6aS,8S,9aS,9bR,10R,11aS)-11a-acetyl-6,9b-dihydroxy-8,10-dimethyl-5-methylene-6a-[(trimethylsilyl)oxy]dodecahydroazuleno[5,4-e][1,3]benzodioxole-2,7(3aH)-dione C23H34O8Si 详情 详情
(XXXIII) 55267 {(3aR,3bS,6aR,8S,9aS,9bR,10R,11aS)-11a-acetyl-9b-hydroxy-8,10-dimethyl-2,7-dioxo-6a-[(trimethylsilyl)oxy]-3a,3b,6,6a,7,8,9,9a,9b,10,11,11a-dodecahydroazuleno[5,4-e][1,3]benzodioxol-5-yl}methyl benzoate C30H38O9Si 详情 详情
(XXXIV) 55268 {(2S,3aR,6aS,7R,8S,10R,10aR,10bS)-8-acetyl-7,8,10a-trihydroxy-2,10-dimethyl-3-oxo-3a-[(trimethylsilyl)oxy]-1,2,3,3a,4,6a,7,8,9,10,10a,10b-dodecahydrobenzo[e]azulen-5-yl}methyl benzoate C29H40O8Si 详情 详情
(XXXV) 55269 phenylacetic 2,4,6-trichloro-1-benzenecarboxylic anhydride C15H9Cl3O3 详情 详情
(XXXVI) 55270 {(2S,3aR,6aS,7R,8S,10R,10aR,10bS)-8-acetyl-8,10a-dihydroxy-2,10-dimethyl-3-oxo-7-[(2-phenylacetyl)oxy]-3a-[(trimethylsilyl)oxy]-1,2,3,3a,4,6a,7,8,9,10,10a,10b-dodecahydrobenzo[e]azulen-5-yl}methyl benzoate C37H46O9Si 详情 详情
(XXXVII) 55271 {(1R,2S,4S,6R,10S,11R,13S,15S,17R)-15-acetyl-13-benzyl-4,17-dimethyl-5-oxo-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadec-8-en-8-yl}methyl benzoate C37H44O8Si 详情 详情
(XXXVIII) 55272 (1R,2S,4S,6R,10S,11R,13S,15R,17R)-13-benzyl-8-(hydroxymethyl)-15-isopropenyl-4,17-dimethyl-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadec-8-en-5-one C31H42O6Si 详情 详情
(XXXIX) 55273 {(1R,2S,4S,6R,10S,11R,13S,15R,17R)-13-benzyl-15-isopropenyl-4,17-dimethyl-5-oxo-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadec-8-en-8-yl}methyl benzoate C38H46O7Si 详情 详情

合成路线5

Bromination at the alpha-position of ketone (XXXIX) to (XLI) was effected via formation of the corresponding silyl enol ether (XL), followed by treatment with N-bromosuccinimide. Dehydrohalogenation of the resultant bromo ketone (XLI) by means of lithium carbonate and lithium bromide in hot DMF afforded enone (XLII). Sequential removal of the O-silyl and benzoate protecting groups of (XLII) provided diol (XLIII). The C20 alcohol of (XLIII) was then esterified with the mixed anhydride (XLIV) to furnish the (4-O-acetyl)homovanillic ester (XLV). Finally, a soultion of pyrrolidine in CH2Cl2 was employed for the cleavage of the O-acetyl protecting group of (XLV).

1 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647.
2 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIX) 55273 {(1R,2S,4S,6R,10S,11R,13S,15R,17R)-13-benzyl-15-isopropenyl-4,17-dimethyl-5-oxo-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadec-8-en-8-yl}methyl benzoate C38H46O7Si 详情 详情
(XL) 55274 {(1R,2S,6R,10S,11R,13S,15R,17R)-13-benzyl-15-isopropenyl-4,17-dimethyl-5,6-bis[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadeca-4,8-dien-8-yl}methyl benzoate C41H54O7Si2 详情 详情
(XLI) 55275 {(1R,2S,6R,10S,11R,13S,15R,17R)-13-benzyl-4-bromo-15-isopropenyl-4,17-dimethyl-5-oxo-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadec-8-en-8-yl}methyl benzoate C38H45BrO7Si 详情 详情
(XLII) 55276 {(1R,2S,6R,10S,11R,13S,15R,17R)-13-benzyl-15-isopropenyl-4,17-dimethyl-5-oxo-6-[(trimethylsilyl)oxy]-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadeca-3,8-dien-8-yl}methyl benzoate C38H44O7Si 详情 详情
(XLIII) 55277 (1R,2R,6R,10S,11R,13S,15R,17R)-13-benzyl-6-hydroxy-8-(hydroxymethyl)-15-isopropenyl-4,17-dimethyl-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadeca-3,8-dien-5-one C28H32O6 详情 详情
(XLIV) 55278 [4-(acetyloxy)-3-methoxyphenyl]acetic 2,4,6-trichloro-1-benzenecarboxylic anhydride C18H13Cl3O6 详情 详情
(XLV) 55279 [(1R,2R,6R,10S,11R,13S,15R,17R)-13-benzyl-6-hydroxy-15-isopropenyl-4,17-dimethyl-5-oxo-12,14,18-trioxapentacyclo[11.4.1.0~1,10~.0~2,6~.0~11,15~]octadeca-3,8-dien-8-yl]methyl 2-[4-(acetyloxy)-3-methoxyphenyl]acetate C39H42O10 详情 详情
Extended Information