Tamandarin A, -Drug Synthesis Database

【结构式】

【药物名称】Tamandarin A

【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-isopropyl-18-(4-methoxybenzyl)-15,19-dimethyl-11-[1(S)-methylpropyl]-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,5S)-4-amino-3-hydroxy-5-methylheptanoyl-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】250211-78-0

【分子式】C₅₄H₈₅N₇O₁₄

【分子量】1056.31805

【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4

合成路线1

Protection of D-alloisoleucine (I) with Cbz-succinimide afforded benzyl carbamate (II). Activation of the carboxyl group of (II) as the pentafluorophenyl ester (III), followed by condensation with the lithium enolate of methyl acetate, gave beta-ketoester (IV). Stereoselective reduction of (IV) with KBH4 produced alcohol (V) as the major diastereomer. The hydroxyl group of (V) was protected as the triisopropylsilyl ether (VI), and then hydrolysis of the ester group of (VI) yielded carboxylic acid (VII).

参考文献中间体

【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.

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)	32739	L-2-Amino-3-methylpentanoic acid; L-isoleucine	73-32-5	C₆H₁₃NO₂	详情	详情
(II)	23508	(2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid	3160-59-6	C₁₄H₁₉NO₄	详情	详情
(III)	37824	2,3,4,5,6-pentafluorophenyl (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoate		C₂₀H₁₈F₅NO₄	详情	详情
(IV)	23510	methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate		C₁₇H₂₃NO₅	详情	详情
(V)	37825	methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate		C₁₇H₂₅NO₅	详情	详情
(VI)	37826	methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate		C₂₆H₄₅NO₅Si	详情	详情
(VII)	37827	(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid		C₂₅H₄₃NO₅Si	详情	详情

合成路线2

(S)-2-Hydroxyisovaleric acid (IX) was obtained from L-valine (VIII) by diazotization in the presence of sulfuric acid. After protection as the allyl ester (X), coupling with isostatine derivative (VII) using DCC and DMAP afforded (XI). Then, removal of the allyl group of (XI) by means of Pd(PPh3)4 gave acid (XIII), which was activated as the pentafluorophenyl ester (XIII).

参考文献中间体

【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(VII)	37827	(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid		C₂₅H₄₃NO₅Si	详情	详情
(VIII)	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
(IX)	37829	(2S)-2-hydroxy-3-methylbutyric acid		C₅H₁₀O₃	详情	详情
(X)	37830	allyl (2S)-2-hydroxy-3-methylbutanoate		C₈H₁₄O₃	详情	详情
(XI)	37831	(1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate		C₃₃H₅₅NO₇Si	详情	详情
(XII)	37832	(2S)-2-([(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoyl]oxy)-3-methylbutyric acid		C₃₀H₅₁NO₇Si	详情	详情
(XIII)	37833	(1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate		C₃₆H₅₀F₅NO₇Si	详情	详情

合成路线3

Hydrogenolysis of the Cbz group from the fully protected tetrapeptide (XIV) gave the free amine (XV). This was coupled with the activated ester (XIII) to provide the linear precursor (XVI). Selective cleavage of the silylethoxymethyl ester of (XVI) with MgBr2.Et2O, followed by hydrogenolysis of the Cbz group furnished (XVII). Subsequent macrocyclization of (XVII) using HATU afforded the cyclic depsipeptide (XVIII).

参考文献中间体

【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	37833	(1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate	C₃₆H₅₀F₅NO₇Si	详情	详情
(XIV)	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
(XV)	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
(XVI)	37836		C₆₇H₁₁₁N₅O₁₆Si₂	详情	详情
(XVII)	37837		C₅₃H₉₁N₅O₁₃Si	详情	详情
(XVIII)	37838		C₅₃H₈₉N₅O₁₂Si	详情	详情

合成路线4

Treatment of (XVIII) with HCl in EtOAc cleaved both Boc and triisopropylsilyl protecting groups to yield (XIX). This was finally coupled with the preformed side chain (XX) using BOP to afford the title compound.

参考文献中间体

【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVIII)	37838		C₅₃H₈₉N₅O₁₂Si	详情	详情
(XIX)	37839		C₃₉H₆₁N₅O₁₀	详情	详情
(XX)	37840	(2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid	C₁₅H₂₆N₂O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)