Epoxomicin, BU-4061T, -Drug Synthesis Database

【结构式】

【药物名称】Epoxomicin, BU-4061T

【化学名称】2-[Acetyl-(N-methyl)isoleucyl-isoleucyl-threonyl-leucyl]-2(R)-methyloxyrane

【CA登记号】134381-21-8

【分子式】C₂₈H₅₀N₄O₇

【分子量】554.7333

【开发单位】Bristol-Myers Squibb (Originator), Yale University (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Bone Diseases, Treatment of, Bone Formation Stimulants, METABOLIC DRUGS, ONCOLYTIC DRUGS, Treatment of Osteoporosis, Antiinflammatory Drugs, Proteasome Inhibitor

合成路线1 合成路线2

合成路线1

Coupling of threonine benzyl ester (I) to Fmoc-Ile-OH (A) with HBTU, HOBt and DIEA in dichloromethane followed by protection of the hydroxyl group with TBDPS-Cl and imidazole in THF affords protected dipeptide (II). Removal of the Fmoc group of (II) with piperidine/DMF followed by coupling of Fmoc-N-Me-Ile-OH (B) with HBTU, HOBt and DIEA gives fully protected tripeptide (III), which is treated with piperidine/DMF for Fmoc removal and acetylated by means of Ac2O, DIEA in dichloromethane to furnish (IV). Debenzylation of (IV) by hydrogenolysis over Pd/C provides intermediate (V). Addition of 2-bromopropene (VII) and t-BuLi to the Boc-leucine Weinreb amide (VI) in Et2O yields alpha',beta'-unsaturated ketone (VIII), which is oxidized by treatment with H2O2 and DIEA in H2O/benzonitrile/MeOH to afford a mixture of epoxides from which (IX) is separated by column chromatography. Boc deprotection and coupling of peptide (V) with intermediate (IX) by means of TFA, HATU, HOAt, DIEA in dichloromethane, furnishes TBDPS-protected derivative (X), which is finally deprotected by treatment with TBAF in THF.

参考文献中间体

【1】 Sin, N.; et al.; Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999, 9, 15, 2283.

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)	64559	(2S,3S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methylpentanoic acid		C₂₁H₂₃NO₄	详情	详情
(B)	64679	(2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-methylpentanoic acid		C₂₂H₂₅NO₄	详情	详情
(I)	43023	benzyl (2S,3R)-2-amino-3-hydroxybutanoate		C₁₁H₁₅NO₃	详情	详情
(II)	43022	benzyl (2S,3R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-[((2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylpentanoyl)amino]butanoate		C₄₈H₅₄N₂O₆Si	详情	详情
(III)	43024	benzyl (5S,8S,11S)-11-((1R)-1-[[tert-butyl(diphenyl)silyl]oxy]ethyl)-1-(9H-fluoren-9-yl)-4-methyl-5,8-bis[(1S)-1-methylpropyl]-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate		C₅₅H₆₇N₃O₇Si	详情	详情
(IV)	43025	benzyl (2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butanoate		C₄₂H₅₉N₃O₆Si	详情	详情
(V)	43026	(2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butyric acid		C₃₅H₅₃N₃O₆Si	详情	详情
(VI)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(VII)	42375	2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide	557-93-7	C₃H₅Br	详情	详情
(VIII)	43027	tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate		C₁₄H₂₅NO₃	详情	详情
(IX)	43028	tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(X)	43029	(2S,3S)-2-[acetyl(methyl)amino]-N-((1S,2S)-1-[[((1S,2R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-[[((1R)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl)amino]carbonyl]propyl)amino]carbonyl]-2-methylbutyl)-3-methylpentanamide		C₄₄H₆₈N₄O₇Si	详情	详情

合成路线2

Alternatively, a solid phase procedure can be followed: Fmoc-Thr(O-TBDMS)-OH (XI) is anchored on 2-chlorotrityl chloride resin by means of DIEA in CH2Cl2 to yield (XII), which then follows a standard solid-phase peptide synthesis (SPPS) protocol to be converted into (XIII). Peptide (XIV) is obtained by treatment of resin (XIII) with HOAc, trifluoroethanol/dichloromethane and is then coupled with intermediate (IX) to afford (XV) in the conditions described above. Finally, the TBDMS group is removed by means of TBAF in THF.

参考文献中间体

【1】 Sin, N.; et al.; Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999, 9, 15, 2283.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI),(XII)	43030	(2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid	C₂₅H₃₃NO₅Si	详情	详情
(XIII),(XIV)	43031	(2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(dimethyl)silyl]oxy]butyric acid	C₂₅H₄₉N₃O₆Si	详情	详情
(IX)	43028	tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate	C₁₄H₂₅NO₄	详情	详情
(XV)	43032	(2S,3S)-2-[acetyl(methyl)amino]-N-((1S,2S)-1-[[((1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-[[((1R)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl)amino]carbonyl]propyl)amino]carbonyl]-2-methylbutyl)-3-methylpentanamide	C₃₄H₆₄N₄O₇Si	详情	详情

Extended Information