Tamandarin B, -Drug Synthesis Database

【结构式】

【药物名称】Tamandarin B

【化学名称】(3S,6S,10S,11R,14R,15R,18S,21S)-14-[N-[2(S)-Hydroxypropionyl]-L-prolyl-D-(N-methyl)leucylamino]-10-hydroxy-3-isobutyl-6,11-diisopropyl-18-(4-methoxybenzyl)-15,19-dimethyl-7,16-dioxa-1,4,12,19-tetraazabicyclo[19.3.0]tetracosane-2,5,8,13,17,20-hexaone
　　　　　　N-[2(S)-Hydroxypropionyl]-L-prolyl-N-methyl-D-leucyl-L-threonyl-(3S,4R)-4-amino-3-hydroxy-5-methylhexanoyl-2(S)-hydroxy-3-methylbutyryl-L-leucyl-L-prolyl-N,O-dimethyl-L-tyrosine O-1.3-C-1.8-lactone

【CA登记号】

【分子式】C₅₃H₈₃N₇O₁₄

【分子量】1042.29096

【开发单位】Universidade Federal Fluminense (Originator), University of California, San Diego (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).

参考文献中间体

【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469.
【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373.

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)	21056	(R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid	640-68-6	C₅H₁₁NO₂	详情	详情
(II)	49332	(2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid		C₁₃H₁₇NO₄	详情	详情
(III)	49323	2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₁₉H₁₆F₅NO₄	详情	详情
(IV)	49324			C₃H₅LiO₂	详情	详情
(V)	49325	methyl (4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxohexanoate		C₁₆H₂₁NO₅	详情	详情
(VI)	49326	methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylhexanoate		C₁₆H₂₃NO₅	详情	详情
(VII)	49327	methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate		C₂₅H₄₃NO₅Si	详情	详情
(VIII)	49328	(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoic acid		C₂₄H₄₁NO₅Si	详情	详情
(IX)	37828	L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid	72-18-4	C₅H₁₁NO₂	详情	详情
(X)	37829	(2S)-2-hydroxy-3-methylbutyric acid		C₅H₁₀O₃	详情	详情
(XI)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XII)	37830	allyl (2S)-2-hydroxy-3-methylbutanoate		C₈H₁₄O₃	详情	详情
(XIII)	49329	(1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate		C₃₂H₅₃NO₇Si	详情	详情
(XIV)	49330	(2S)-2-([(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoyl]oxy)-3-methylbutyric acid		C₂₉H₄₉NO₇Si	详情	详情
(XV)	49331	(1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate		C₃₅H₄₈F₅NO₇Si	详情	详情

合成路线2

The hydrogenolysis of the benzyloxycarbonyl protecting group of tetrapeptide (XVI) with H2 over Pd/C gives peptide (XVII) with a free amino group, which is condensed with the activated ester intermediate (XV) by means of DIEA and DMAP to yield the fully protected linear precursor (XVIII). The mild cleavage of the SEM ester by means of MgBr2 affords the carboxylic acid (XIX), which is hydrogenolyzed with H2 over Pd/C to provide linear peptide (XX) with a terminal amino group. The cyclization of (XX) promoted by HATU gives the protected macrocyclic peptide (XXI).

参考文献中间体

【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469.
【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	49331	(1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate	C₃₅H₄₈F₅NO₇Si	详情	详情
(XVI)	37834	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butanoate	C₄₅H₆₈N₄O₁₂Si	详情	详情
(XVII)	37835	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-[[(2S)-2-[([(2S)-1-[(2S)-2-amino-4-methylpentanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butanoate	C₃₇H₆₂N₄O₁₀Si	详情	详情
(XVIII)	49333	[2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[[(2S)-2-[[((2S)-1-[(2S,5S,9S,10R)-2-isobutyl-5,10-diisopropyl-4,7,12-trioxo-14-phenyl-9-[(triisopropylsilyl)oxy]-6,13-dioxa-3,11-diazatetradec-1-anoyl]pyrrolidinyl)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]butanoate	C₆₆H₁₀₉N₅O₁₆Si₂	详情	详情
(XIX)	49334	(2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[[(2S)-2-[[((2S)-1-[(2S,5S,9S,10R)-2-isobutyl-5,10-diisopropyl-4,7,12-trioxo-14-phenyl-9-[(triisopropylsilyl)oxy]-6,13-dioxa-3,11-diazatetradec-1-anoyl]pyrrolidinyl)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]butyric acid	C₆₀H₉₅N₅O₁₅Si	详情	详情
(XX)	49335	(2S,3R)-3-[[(2S)-2-[[((2S)-1-[(2S,5S,9S)-9-[(1R)-1-amino-2-methylpropyl]-2-isobutyl-5,11,11-triisopropyl-12-methyl-4,7-dioxo-6,10-dioxa-3-aza-11-silatridec-1-anoyl]pyrrolidinyl)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butyric acid	C₅₂H₈₉N₅O₁₃Si	详情	详情
(XXI)	49336	tert-butyl (3S,6R,7S,10R,11S,15S,18S,23aS)-18-isobutyl-10,15-diisopropyl-3-(4-methoxybenzyl)-2,6-dimethyl-1,4,8,13,16,19-hexaoxo-11-[(triisopropylsilyl)oxy]icosahydro-15H-pyrrolo[1,2-g][1,13,4,7,10,17]dioxatetraazacyclohenicosin-7-ylcarbamate	C₅₂H₈₇N₅O₁₂Si	详情	详情

合成路线3

The two remaining protecting groups of (XXI) are simultaneously removed by treatment with HCl in ethyl acetate to give the free cyclopeptide (XXII). Finally, this compound is condensed with (S)-lactoyl-S-prolyl-S-(N-methyl)leucine (XXIII) by means of DEPBT and DIEA to yield the target cyclopeptide (-)-tamandarin B.

参考文献中间体

【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469.
【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	49337	(3S,6R,7S,10R,11S,15S,18S,23aS)-7-amino-11-hydroxy-18-isobutyl-10,15-diisopropyl-3-(4-methoxybenzyl)-2,6-dimethyltetradecahydro-15H-pyrrolo[1,2-g][1,13,4,7,10,17]dioxatetraazacyclohenicosine-1,4,8,13,16,19-hexone	C₃₈H₅₉N₅O₁₀	详情	详情
(XXI)	49336	tert-butyl (3S,6R,7S,10R,11S,15S,18S,23aS)-18-isobutyl-10,15-diisopropyl-3-(4-methoxybenzyl)-2,6-dimethyl-1,4,8,13,16,19-hexaoxo-11-[(triisopropylsilyl)oxy]icosahydro-15H-pyrrolo[1,2-g][1,13,4,7,10,17]dioxatetraazacyclohenicosin-7-ylcarbamate	C₅₂H₈₇N₅O₁₂Si	详情	详情
(XXIII)	37840	(2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid	C₁₅H₂₆N₂O₅	详情	详情

Extended Information