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【结 构 式】 
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【分子编号】52438 【品名】3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid 【CA登记号】 |
【 分 子 式 】C27H25NO4 【 分 子 量 】427.49984 【元素组成】C 75.86% H 5.89% N 3.28% O 14.97% |
合成路线1
该中间体在本合成路线中的序号：(XI)The synthesis of the intermediate (S,S)-3-(Fmoc-amino)-2-methyl-5-phenyl-4-pentenoic acid (XI) has been performed as follows: The Horner-Wadsworth-Emmons condensation of cinnamaldehyde (I) with phosphonate (II) by means of NaH in THF gives (E,E)-5-phenyl-2,4-pentadienoic acid ethyl ester (III), which is condensed with (S)-N-benzyl-N-(alpha-methylbenzyl)amine (IV) by means of BuLi in THF to yield the chiral adduct (V). The reaction of (V) with LDA affords the corresponding lithium enolate, which is methylated with methyl iodide in THF to afford the enantioselectively methylated compound (VI). The hydrogenation of (VI) with H2 over Pd(OH)2 in methanol/water/HOAc provides (S,S)-3-amino-2-methyl-5-phenylpentanoic acid methyl ester (VII), which is treated with Boc2O and NaHCO3 in dioxane/water to give the N-protected ester (VIII). The reaction of (VIII) with NBS in CCl4, followed by treatment with DBU at 60 C, yields the pentenoic ester derivative (IX), which is treated first with LiOH and then with TFA to provide (S,S)-3-amino-2-methyl-5-phenyl-4-pentanoic acid (X). Finally, this compound is N-protected by reaction with Fmoc-Cl and K2CO3 in dioxane/water to furnish the target pentenoic acid intermediate (XI).
| 【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696. |
| 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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 52431 | methyl 5-phenyl-2,4-pentadienoate | C12H12O2 | 详情 | 详情 | |
| (IV) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (V) | 52432 | methyl 5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C27H29NO2 | 详情 | 详情 | |
| (VI) | 52433 | methyl 2-methyl-5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C28H31NO2 | 详情 | 详情 | |
| (VII) | 52434 | methyl 3-amino-2-methyl-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 52435 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenylpentanoate | C18H27NO4 | 详情 | 详情 | |
| (IX) | 52436 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (X) | 52437 | 3-amino-2-methyl-5-phenyl-4-pentenoic acid | C12H15NO2 | 详情 | 详情 | |
| (XI) | 52438 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid | C27H25NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The deprotection of Wang-RESIN-coupled N-Fmoc-D-aspartic acid alpha-methyl ester (XII) with piperidine in DMF gives the free RESIN-coupled aspartic acid monoester (XIII), which is condensed with N-Fmoc-sarcosine (XIV) by means of PyBOP in DMF to yield the dipeptide (XV). Deprotection with piperidine affords (XVI), and coupling with PyBOP was repeated with the L-glutamate (XVII) to afford tripeptide (XVIII); with deprotected (XIX) and the intermediate amino acid (XI) to provide tetrapeptide (XX); and with deprotected (XXI) and -Fmoc-L-phenylalanine (XXII) to furnish finally the protected RESIN-bounded pentapeptide (XXIII).
| 【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 52438 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid | C27H25NO4 | 详情 | 详情 | |
| (XII) | 52439 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-4-(methyloxy)-4-oxobutanoic acid | C20H19NO6 | 详情 | 详情 | |
| (XIII) | 52440 | 3-amino-4-(methyloxy)-4-oxobutanoic acid | C5H9NO4 | 详情 | 详情 | |
| (XIV) | 52441 | 2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetic acid | C18H17NO4 | 详情 | 详情 | |
| (XV) | 52442 | 3-({2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid | C23H24N2O7 | 详情 | 详情 | |
| (XVI) | 52443 | 3-{[2-(methylamino)acetyl]amino}-4-(methyloxy)-4-oxobutanoic acid | C8H14N2O5 | 详情 | 详情 | |
| (XVII) | 52444 | 4-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-5-(methyloxy)-5-oxopentanoic acid | C21H21NO6 | 详情 | 详情 | |
| (XVIII) | 52445 | 1-(9H-fluoren-9-yl)-9-methyl-5,13-bis[(methyloxy)carbonyl]-3,8,11-trioxo-2-oxa-4,9,12-triazapentadecan-15-oic acid | C29H33N3O10 | 详情 | 详情 | |
| (XIX) | 52446 | 3-({2-[[4-amino-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid | C14H23N3O8 | 详情 | 详情 | |
| (XX) | 52447 | 1-(9H-fluoren-9-yl)-6,13-dimethyl-9,17-bis[(methyloxy)carbonyl]-3,7,12,15-tetraoxo-5-(2-phenylethenyl)-2-oxa-4,8,13,16-tetraazanonadecan-19-oic acid | C41H46N4O11 | 详情 | 详情 | |
| (XXI) | 52448 | 3-({2-[[4-[(3-amino-2-methyl-5-phenyl-4-pentenoyl)amino]-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid | C26H36N4O9 | 详情 | 详情 | |
| (XXII) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XXIII) | 52449 | 1-(9H-fluoren-9-yl)-9,16-dimethyl-12,20-bis[(methyloxy)carbonyl]-3,6,10,15,18-pentaoxo-8-(2-phenylethenyl)-5-(phenylmethyl)-2-oxa-4,7,11,16,19-pentaazadocosan-22-oic acid | C50H55N5O12 | 详情 | 详情 |