FK-228, NSC-630176, FR-901228, -Drug Synthesis Database

【结构式】

【药物名称】FK-228, NSC-630176, FR-901228

【化学名称】(1S,4S,10S,21R)-7-[(Z)-Ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16(E)-ene-3,6,9,19,22-pentone
　　　　　　N-[3(S)-Hydroxy-7-sulfanyl-4(E)-heptenoyl]-D-valyl-D-cysteinyl-2-amino-2(Z)-butenoyl-L-valine (4-1)-lactone cyclic (1-2)-disulfide

【CA登记号】128517-07-7

【分子式】C₂₄H₃₆N₄O₆S₂

【分子量】540.70572

【开发单位】Fujisawa (Originator), Gloucester Pharmaceuticals (Licensee), National Cancer Institute (Codevelopment)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Lung Cancer Therapy, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Antimitotic Drugs, Apoptosis Inducers, Histone Deacetylase (HDAC) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

(i) The formation of a 16-membered depsipeptide: For the first step, L-valine methyl ester (I) was coupled to N-Fmoc-L-threonine using the BOP reagent [(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate], removing the N-Fmoc group with Et2NH and coupling to N-Fmoc-(S-triphenylmethyl)-D-cysteine to yield the tripeptide (II). The tetrapeptide (III) was prepared by deprotection of the tripeptide (II) and BOP-mediated peptide coupling of the resulting amine with N-Fmoc-D-valine. The secondary hydroxyl group was activated as the tosylate and eliminated by treatment with DABCO to produce the internal alkene. After removal of the Fmoc protecting group by addition of Et2NH to the reaction mixture, the 16-membered depsipeptide (IV) was formed.

参考文献中间体

【1】 Li, K.W.; Simon, J.A.; Xing, W.; Wu, J.; Total synthesis of the antitumor depsipeptide FR901228. J Am Chem Soc 1996, 118, 30, 7237.
【2】 Wang, H.-C. R.; FR901228. Drugs Fut 1999, 24, 11, 1184.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16613	methyl (2S)-2-amino-3-methylbutanoate	C₆H₁₃NO₂	详情	详情
(II)	29877	methyl (5S,8S,11S)-1-(9H-fluoren-9-yl)-8-[(1R)-1-hydroxyethyl]-11-isopropyl-3,6,9-trioxo-5-[(tritylsulfanyl)methyl]-2-oxa-4,7,10-triazadodecan-12-oate	C₄₇H₄₉N₃O₇S	详情	详情
(III)	29878	methyl (5R,8S,11S,14S)-1-(9H-fluoren-9-yl)-5,14-diisopropyl-11-((1R)-1-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-3,6,9,12-tetraoxo-8-[(tritylsulfanyl)methyl]-2-oxa-4,7,10,13-tetraazapentadecan-15-oate	C₅₉H₆₄N₄O₁₀S₂	详情	详情
(IV)	29879	methyl (2S)-2-[((Z)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(tritylsulfanyl)propanoyl]amino]-2-butenoyl)amino]-3-methylbutanoate	C₃₇H₄₆N₄O₅S	详情	详情

合成路线2

(ii) The asymmetric construction of the hydroxymercaptoheptenoic acid: For construction of the hydroxymercaptoheptenoic acid (VIII), cesium triphenylmethylthiolate anion was added to methyl 2,4-pentadienoate (V), which resulted in a beta,gamma-unsaturated methyl ester that was converted to an alpha,beta-unsaturated ester after exposure to Cs2CO3. DIBAL reduction to the primary alcohol followed by Swern oxidation yielded the alpha,beta-unsaturated aldehyde (VI). In the presence of the ligand derived from (R)-(-)-binaphthyl amino alcohol, Ti(IV)-catalyzed addition of O-benzyl, O-TMS ketene acetal to the alpha,beta-unsaturated aldehyde (VI) resulted in the aldol product (VII). Hydrolysis of the benzyl ester with LiOH in aqueous methanol formed the beta-hydroxymercaptoheptenoic acid (VIII).

参考文献中间体

【1】 Li, K.W.; Simon, J.A.; Xing, W.; Wu, J.; Total synthesis of the antitumor depsipeptide FR901228. J Am Chem Soc 1996, 118, 30, 7237.
【2】 Wang, H.-C. R.; FR901228. Drugs Fut 1999, 24, 11, 1184.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	29882	[[1-(benzyloxy)vinyl]oxy](trimethyl)silane; benzyl 1-[(trimethylsilyl)oxy]vinyl ether	C₁₂H₁₈O₂Si	详情	详情
(V)	29880	methyl (2E)-2,4-pentadienoate	C₆H₈O₂	详情	详情
(VI)	29881	(E)-5-(tritylsulfanyl)-2-pentenoic acid	C₂₄H₂₂O₂S	详情	详情
(VII)	29883	benzyl (3R,4E)-3-hydroxy-7-(tritylsulfanyl)-4-heptenoate	C₃₃H₃₂O₃S	详情	详情
(VIII)	29884	(3R,4E)-3-hydroxy-7-(tritylsulfanyl)-4-heptenoic acid	C₂₆H₂₆O₃S	详情	详情

合成路线3

(iii) An intramolecular oxidative coupling of the thiols to form a 15-membered disulfide-containing ring: To complete the synthesis of FR901228, the beta-hydroxymercaptoheptenoic acid (VIII) was coupled to the 16-membered cyclic depsipeptide (IV) using the BOP reagent, followed by LiOH-mediated hydrolysis, resulting in the free acid product (IX). Cyclization of the hydroxy acid (IX) with TsOH, DEAD and PPh3 and oxidation of the bis(S-triphenylmethyl)lactone (X) with iodine in methanol solution yielded the depsipeptide FR901228.

参考文献中间体

【1】 Wang, H.-C. R.; FR901228. Drugs Fut 1999, 24, 11, 1184.
【2】 Li, K.W.; Simon, J.A.; Xing, W.; Wu, J.; Total synthesis of the antitumor depsipeptide FR901228. J Am Chem Soc 1996, 118, 30, 7237.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	29879	methyl (2S)-2-[((Z)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(tritylsulfanyl)propanoyl]amino]-2-butenoyl)amino]-3-methylbutanoate	C₃₇H₄₆N₄O₅S	详情	详情
(VIII)	29884	(3R,4E)-3-hydroxy-7-(tritylsulfanyl)-4-heptenoic acid	C₂₆H₂₆O₃S	详情	详情
(IX)	29885	(E,7R,11R,14S,20S)-17-[(Z)ethylidene]-7-hydroxy-11,20-diisopropyl-9,12,15,18-tetraoxo-1,1,1-triphenyl-14-[(tritylsulfanyl)methyl]-2-thia-10,13,16,19-tetraaza-5-henicosen-21-oic acid	C₆₂H₆₈N₄O₇S₂	详情	详情
(X)	29886	(3S,9S,12R,16S)-6-[(Z)ethylidene]-3,12-diisopropyl-16-[(E)-4-(tritylsulfanyl)-1-butenyl]-9-[(tritylsulfanyl)methyl]-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentone	C₆₂H₆₆N₄O₆S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)