【结 构 式】 |
【分子编号】61823 【品名】benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli 【CA登记号】 |
【 分 子 式 】C49H57N5O14 【 分 子 量 】940.01688 【元素组成】C 62.61% H 6.11% N 7.45% O 23.83% |
合成路线1
该中间体在本合成路线中的序号:(XV)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with 2-mercaptobenzothiazole (II) by means of DIAD and PPh3 in THF gives the thioether (III), which is reduced with NaBH4 and CaCl2 in THF to yield the alcohol (IV). The cyclization of (IV) with 2,2-dimethoxypropane (V) by means of TsOH in dichloromethane affords the oxazolidine (VI), which is oxidized at the thioether group by means of Mo7O24(NH4)6 and H2O2 in ethanol to provide the sulfone (VII). The condensation of (VII) with 7-iodoisatin (VIII) employing LiHMDS and DMPU in THF gives the adduct (IX), which is condensed with the boronic ester (X) -obtained by reaction of the tyrosine derivative (XI) with bis(pinacolato)diboron, KOH and Pd(dppf)Cl2 in hot DMSO- by means of K2CO3 and Pd(dppf)Cl2 in aqueous DME to yield the coupled product (XII). The hydrolysis of the ester group of (XII) with LiOH, followed by condensation with asparagine benzyl ester (XIII) by means of HOAT, EDC and NMM in dichloromethane affords the amide (XIV). This is oxidized at its exocyclic double bond by means of OsO4 and pyridine in THF/methanol to provide the diol (XV).
【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
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) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
(II) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
(III) | 61814 | methyl (2R)-3-(1,3-benzothiazol-2-ylsulfanyl)-2-{[(benzyloxy)carbonyl]amino}propanoate | C19H18N2O4S2 | 详情 | 详情 | |
(IV) | 61815 | benzyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-(hydroxymethyl)ethylcarbamate | C18H18N2O3S2 | 详情 | 详情 | |
(V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(VI) | 61816 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfanyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O3S2 | 详情 | 详情 | |
(VII) | 61817 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O5S2 | 详情 | 详情 | |
(VIII) | 61824 | 7-iodo-1H-indole-2,3-dione | C8H4INO2 | 详情 | 详情 | |
(IX) | 61818 | benzyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H21IN2O4 | 详情 | 详情 | |
(X) | 61820 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C23H36BNO8 | 详情 | 详情 | |
(XI) | 61819 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-iodo-4-(methoxymethoxy)phenyl]propanoate | C17H24INO6 | 详情 | 详情 | |
(XII) | 61821 | benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C39H45N3O10 | 详情 | 详情 | |
(XIII) | 61825 | benzyl (2S)-2,4-diamino-4-oxobutanoate | C11H14N2O3 | 详情 | 详情 | |
(XIV) | 61822 | benzyl (4S)-4-({7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C49H55N5O12 | 详情 | 详情 | |
(XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XV)The reaction of (XV) with TFA promotes the cleavage of the oxazolidine ring and the Boc and Mom protecting groups yielding the amino tetrahydroxy derivative (XVI), which is condensed with 3-methyl-2-oxopentanoic acid (XVII) by means of HOAt and EDC in THF to afford the corresponding amide (XVIII). The hydrogenolysis of (XVIII) with H2 over Pd/C in ethanol promotes the cleavage of the benzyloxy and benzyloxycarbonyl groups which provides the requisite aminoacid (XIX), suitable for macrocyclization. This is performed by means of EDC and HOAt in DMF/dichloromethane to provide the macrocyclic compound (XX). Finally, this compound is treated with Tes-OTf and lutidine in DMF/dichloromethane to obtain the fully silylated, already reported, macrocyclic intermediate (XXI). (see Scheme nos. 27460201c and 27460201d, intermediate (XXV).
【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
/XVI) | 61826 | benzyl (2S)-4-amino-2-[((2S)-2-amino-3-{3-[(3S)-3-((1R,2R)-2-{[(benzyloxy)carbonyl]amino}-1,3-dihydroxypropyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl]-4-hydroxyphenyl}propanoyl)amino]-4-oxobutanoate | C39H41N5O11 | 详情 | 详情 | |
(XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 | |
(XVIII) | 61827 | benzyl (2S)-4-amino-2-({(2S)-3-{3-[(3S)-3-((1R,2R)-2-{[(benzyloxy)carbonyl]amino}-1,3-dihydroxypropyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl]-4-hydroxyphenyl}-2-[(3-methyl-2-oxopentanoyl)amino]propanoyl}amino)-4-oxobutanoate | C45H49N5O13 | 详情 | 详情 | |
(XIX) | 61828 | (2S)-4-amino-2-({(2S)-3-(3-{(3S)-3-[(1R,2R)-2-amino-1,3-dihydroxypropyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl}-4-hydroxyphenyl)-2-[(3-methyl-2-oxopentanoyl)amino]propanoyl}amino)-4-oxobutanoic acid | C30H37N5O11 | 详情 | 详情 | |
(XX) | 53359 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C30H35N5O10 | 详情 | 详情 |
(XXI) | 53360 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C54H91N5O10Si4 | 详情 | 详情 |