(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid -Drug Synthesis Database

【结构式】

【分子编号】50782

【品名】(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid

【CA登记号】

【分子式】C₁₆H₂₃NO₅

【分子量】309.36236

【元素组成】C 62.12% H 7.49% N 4.53% O 25.86%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IX)

Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).

参考文献中间体

合成目标

【1】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31.
【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837.
【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669.

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)	50775	(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	44205	(2-ethoxy-2-oxoethyl)lithium		C₄H₇LiO₂	详情	详情
(III)	50776	ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate		C₁₅H₂₇NO₅	详情	详情
(IV)	50777	tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(V)	50778	ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₉NO₅	详情	详情
(VI)	50779	2,2,2-trichloro-1-ethanol		C₂H₃Cl₃O	详情	详情
(VII)	50780	2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₆Cl₃NO₅	详情	详情
(VIII)	50781	2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate		C₁₀H₁₈Cl₃NO₃	详情	详情
(IX)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(X)	50783	2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate		C₂₁H₃₁Cl₃N₂O₅	详情	详情
(XI)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid		C₁₂H₂₃NO₄	详情	详情
(XII)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(XIII)	50787	2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₉H₆₆Cl₃N₃O₈Si	详情	详情
(XIV)	50784	2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₂H₆₀Cl₃N₃O₈Si	详情	详情
(XV)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(XVI)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XVII)	50785	2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate		C₄₆H₇₁Cl₃N₄O₁₀Si	详情	详情
(XVIII)	50786	(5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid		C₄₄H₇₀N₄O₁₀Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The modified tyrosine building block (II) was prepared by alkylation of N-Cbz-L-tyrosine (I) at both the phenolic OH and the NH groups employing dimethyl sulfate under phase-transfer conditions. N-Boc-L-Threonine benzyl ether (III) was converted to the corresponding (triethylsilyl)ethoxymethyl ester, and the O-benzyl group was subsequently removed by catalytic hydrogenolysis to afford (IV). Coupling between the tyrosine (II) and threonine (IV) derivatives using DCC and DMAP gave rise to the protected didepsipeptide (V). The SEM protecting group was then cleaved by means of HF in acetonitrile, yielding intermediate (VI)

参考文献中间体

合成目标

【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.
【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid	C₁₇H₁₇NO₅	详情	详情
(II)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid	C₁₉H₂₁NO₅	详情	详情
(III)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₆H₂₃NO₅	详情	详情
(IV)	50746	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate	C₁₅H₃₁NO₆Si	详情	详情
(V)	62532	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate	C₃₄H₅₀N₂O₁₀Si	详情	详情
(VI)	52709	(2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid	C₂₈H₃₆N₂O₉	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

For the synthesis of the other peptidic moiety (L), removal of the N-Boc group from the isostatine derivative (XLI) by means of trifluoroacetic acid gave amino ester (XLII), which was coupled with N-Boc-L-threonine benzyl ether (III) to afford dipeptide (XLIII). Boc group removal in (XLIII) with HCl provided peptide (XLIV), which was coupled with N-Boc-N-methyl-D-leucine (XXVII) to yield tripeptide (XLV). Saponification of the methyl ester group of (XLV) with NaOH provided acid (XLVI). Sequential protection of the alcohol hydroxyl of (XLVI) as the tert-butyldimethylsilyl ether, and esterification of the carboxyl group with trichloroethanol led to the fully protected tripeptide (XLVII). The benzyl ether group of (XLVII) was then removed by catalytic hydrogenolysis to furnish alcohol (XLVIII)

参考文献中间体

合成目标

【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₆H₂₃NO₅	详情	详情
(XXVII)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid	C₁₂H₂₃NO₄	详情	详情
(XLI)	62534	methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate	C₁₄H₂₇NO₅	详情	详情
(XLII)	62550	methyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate	C₉H₁₉NO₃	详情	详情
(XLIII)	62551	methyl (3S,4R,5S)-4-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-3-hydroxy-5-methylheptanoate	C₂₅H₄₀N₂O₇	详情	详情
(XLIV)	62552	methyl (3S,4R,5S)-4-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-3-hydroxy-5-methylheptanoate	C₂₀H₃₂N₂O₅	详情	详情
(XLV)	62553	methyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₂H₅₃N₃O₈	详情	详情
(XLVI)	62554	(6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oic acid	C₃₁H₅₁N₃O₈	详情	详情
(XLVII)	50787	2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₉H₆₆Cl₃N₃O₈Si	详情	详情
(XLVIII)	50784	2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate	C₃₂H₆₀Cl₃N₃O₈Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Coupling between N-Boc-O-benzyl-L-threonine (VII) and L-leucine benzyl ester (VIII) by means of DCC/HOBt gives the protected dipeptide (IX). Subsequent N-Boc group cleavage in (IX) upon treatment with formic acid yields (X). Further coupling of dipeptide (X) with N-Boc-L-phenylalanine (XI), followed by formic acid deprotection, leads to the benzyl-protected tripeptide (XII).

参考文献中间体

合成目标

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(VIII)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(IX)	65160	benzyl (2S)-2-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-4-methylpentanoate		C₂₉H₄₀N₂O₆	详情	详情
(X)	65158	benzyl (2S)-2-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₂₄H₃₂N₂O₄	详情	详情
(XI)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XII)	65159	benzyl (2S)-2-{[(2S,3R)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₃₃H₄₁N₃O₅	详情	详情

Extended Information