Calphostin C, UCN-1028C, -Drug Synthesis Database

【结构式】

【药物名称】Calphostin C, UCN-1028C

【化学名称】12-[2(R)-(Benzoyloxy)propyl]-4,9-dihydroxy-1-[2(R)-(4-hydroxyphenoxycarbonyloxy)propyl]-2,6,7,11-tetramethoxy-3,10-dihydroperylene-3,10-dione

【CA登记号】121263-19-2

【分子式】C₄₄H₃₈O₁₄

【分子量】790.78506

【开发单位】Kyowa Hakko (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS, Protein Kinase C (PKC) Inhibitors

合成路线1 合成路线2

合成路线1

The bromination of 3,5-dimethoxybenzyl alcohol (I) with NBS gives 2-bromo-3,5-dimethoxybenzyl alcohol (II), which is treated with I2 and triphenylphosphine to yield the benzyl iodide (III). The reaction of (III) with triethyl phosphite affords the phosphonate (IV), which is condensed with the silylated aldehyde (V) by means of lithium hexamethyldisylazide (LiHMDS) giving the silylated pentenol (VI). The reaction of (VI) with chromium hexacarbonyl and BuLi provides the organochromium derivative (VII), which is cyclized with tert-butyl isocyanide and TBAF to afford the naphthalene (VIII). The benzoylation of the OH group of (VIII) with benzoyl chloride gives the benzoate (IX), which is oxidized with dichlorodicyanobenzoquinone (DDQ) to yield the naphthoquinone (X). The oxidative cyclization of (X) with O2 and TFA affords the pentacyclic quinone as a mixture of isomers that was thermally equilibrated to a 3:1 mixture of the desired isomer (XI) (the undesired isomer was recycled).The methylation of (XI) with methyl iodide and TBAF gives the fully methylated perylenequinone (XII).

参考文献中间体

【1】 Merlic, C.A.; et al.; Total synthesis of the calphostins: Application of fischer carbene complexes and thermodynamic control of atropisomers. J Org Chem 2001, 66, 4, 1297.
【2】 Merlic, C.A.; et al.; Carbene complexes in the synthesis of complex natural products: Total synthesis of the calphostins. J Am Chem Soc 2000, 122, 13, 3224.

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)	35424	(3,5-dimethoxyphenyl)methanol	705-76-0	C₉H₁₂O₃	详情	详情
(II)	35425	(2-bromo-3,5-dimethoxyphenyl)methanol		C₉H₁₁BrO₃	详情	详情
(III)	35426	2-bromo-1-(iodomethyl)-3,5-dimethoxybenzene; 2-bromo-3-(iodomethyl)-5-methoxyphenyl methyl ether		C₉H₁₀BrIO₂	详情	详情
(IV)	35427	diethyl 2-bromo-3,5-dimethoxybenzylphosphonate		C₁₃H₂₀BrO₅P	详情	详情
(V)	35428	(2R)-2-methyl-3-(triisopropylsilyl)propanal		C₁₃H₂₈OSi	详情	详情
(VI)	35429	(1R,2E)-4-(2-bromo-3,5-dimethoxyphenyl)-1-methyl-2-butenyl triisopropylsilyl ether; [[(1R,2E)-4-(2-bromo-3,5-dimethoxyphenyl)-1-methyl-2-butenyl]oxy](triisopropyl)silane		C₂₂H₃₇BrO₃Si	详情	详情
(VII)	35430			C₂₉H₄₅CrO₉Si	详情	详情
(VIII)	35431	(2R)-1-[3-(tert-butylamino)-4,5,7-trimethoxy-2-naphthyl]-2-propanol		C₂₀H₂₉NO₄	详情	详情
(IX)	35432	(1R)-1-methyl-2-(4,5,7-trimethoxy-3-neopentyl-2-naphthyl)ethyl benzoate		C₂₈H₃₄O₅	详情	详情
(X)	35433	(1R)-2-(5,7-dimethoxy-3,4-dioxo-3,4-dihydro-2-naphthalenyl)-1-methylethyl benzoate		C₂₂H₂₀O₆	详情	详情
(XI)	35434	(1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,11-dihydroxy-4,6,7,9-tetramethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate		C₄₄H₃₈O₁₂	详情	详情
(XII)	35434	(1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,11-dihydroxy-4,6,7,9-tetramethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate		C₄₄H₃₈O₁₂	详情	详情

合成路线2

Compound (XII) is selectively debenzoylated with sodium methoxide in methanol yielding the monobenzoyl ester (XIII). The acylation of (XIII) with phosgene, triethylamine and monoacetyl hydroquinone (XIV) affords the carbonate ester (XV), which is selectively demethylated with MgI2 and deacetylated with NaHCO3 to afford the target Calpostin C.

参考文献中间体

【1】 Merlic, C.A.; et al.; Total synthesis of the calphostins: Application of fischer carbene complexes and thermodynamic control of atropisomers. J Org Chem 2001, 66, 4, 1297.
【2】 Merlic, C.A.; et al.; Carbene complexes in the synthesis of complex natural products: Total synthesis of the calphostins. J Am Chem Soc 2000, 122, 13, 3224.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	35435	(1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate	C₄₆H₄₂O₁₂	详情	详情
(XIII)	35436	(1R)-2-[12-[(2R)-2-hydroxypropyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate	C₃₉H₃₈O₁₁	详情	详情
(XIV)	35437	4-hydroxyphenyl acetate	C₈H₈O₃	详情	详情
(XV)	35438	(1R)-2-[12-[(2R)-2-([[4-(acetoxy)phenoxy]carbonyl]oxy)propyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate	C₄₈H₄₄O₁₅	详情	详情

Extended Information