(2R)-2-(acetamido)-3-sulfanylpropionic acid -Drug Synthesis Database

【结构式】

【分子编号】43592

【品名】(2R)-2-(acetamido)-3-sulfanylpropionic acid

【CA登记号】

【分子式】C₅H₉NO₃S

【分子量】163.1974

【元素组成】C 36.8% H 5.56% N 8.58% O 29.41% S 19.65%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XII)

Treatment of cis-oxazolidine derivative (I) with isobutyraldehyde (II), LDA and LiBr in THF yields aldol product (III), which is then converted into (IV) by first aminal cleavage by means of MeOH and TfOH, followed by silylation with Tbdms-Cl and imidazole in DMF. Reaction of (IV) with formaldehyde and TsOH in benzene gives oxazolidine system (V), which is then first reduced with LiBH4 in THF/MeOH and then oxidized by means of DMSO, oxalyl chloride and Et3N in CH2Cl2 to provide aldehyde (VI). Mukaiyama aldol coupling of (VI) and (VII) in CH2Cl2 with MgI2 as catalyst, followed by treatment with K2CO3 in MeOH, yields aldol product (VIII), which is then converted into hydroxy lactam (IX) by the sequence: i) N-benzyl cleavage by hydrogenolysis over Pd/C in EtOH in the presence of DIEA; ii) ring closure by heating in MeOH; and iii) desilylation by treatment with HF in acetonitrile. Conversion of alcohol (IX) into dihydroxy acid (X) is achieved by a first oxidation with DMSO, oxalyl chloride and Et3N in CH2Cl2, followed by reaction with NaClO2, NaH2PO4 in t-BuOH and 2-Me-butene and final N/O methylene bridge removal with 1,3-propanedithiol (A) catalyzed by HCl and TFA. Compound (X) undergoes beta-lactonization to omuralide (XI) by means of BOPCl and Et3N in CH2Cl2 and finally (XI) is coupled to N-acetyl-L-cysteine (XII) in CH2Cl2 in the presence of Et3N.

参考文献中间体

合成目标

【1】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	29729	1,3-propanedithiol; 3-sulfanylpropylhydrosulfide	109-80-8	C₃H₈S₂	详情	详情
(I)	43582	methyl (2R,4S)-3-benzyl-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate		C₁₆H₂₃NO₃	详情	详情
(II)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(III)	43583	methyl (2R,4R)-3-benzyl-2-(tert-butyl)-4-(1-hydroxy-2-methylpropyl)-1,3-oxazolidine-4-carboxylate		C₂₀H₃₁NO₄	详情	详情
(IV)	43584	methyl (2R,3S)-2-(benzylamino)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-hydroxy-4-methylpentanoate		C₂₁H₃₇NO₄Si	详情	详情
(V)	43585	methyl (4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carboxylate		C₂₂H₃₇NO₄Si	详情	详情
(VI)	43586	(4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carbaldehyde		C₂₁H₃₅NO₃Si	详情	详情
(VII)	43587	(E)-1-methoxy-1-propenyl trimethylsilyl ether; [[(E)-1-methoxy-1-propenyl]oxy](trimethyl)silane	34880-70-1	C₇H₁₆O₂Si	详情	详情
(VIII)	43588	methyl (2R,3S)-3-[(4S,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidin-4-yl]-3-hydroxy-2-methylpropanoate		C₂₅H₄₃NO₅Si	详情	详情
(IX)	43589	(1S,6R,7S,7aS)-7-hydroxy-7a-(hydroxymethyl)-1-isopropyl-6-methyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one		C₁₁H₁₉NO₄	详情	详情
(X)	43590	(2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₅	详情	详情
(XI)	43591	(1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione		C₁₀H₁₅NO₄	详情	详情
(XII)	43592	(2R)-2-(acetamido)-3-sulfanylpropionic acid		C₅H₉NO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The alkylation of N-acetyl-L-cysteine (I) with farnesyl bromide (II) in methanolic ammonia provided the corresponding farnesyl thioether (III). After activation of the S-alkylated acid (III) as the mixed anhydride (IV) using isobutyl chloroformate and N-methylmorpholine, reaction with diazomethane yielded the diazomethyl ketone (V). This was then converted into the title chloromethyl ketone by treatment with HCl in ethyl acetate.

参考文献中间体

合成目标

【1】 Narla, R.K.; Uckun, F.M.; Perrey, D.A.; Cysteine chloromethyl and diazomethyl ketone derivatives with potent anti-leukemic activity. Bioorg Med Chem Lett 2000, 10, 6, 547.
【2】 Narla, R.K.; Uckun, F.M.; Perry, D.A. (Parker Hughes Institute); Alkyl ketones as potent anti-cancer agents. WO 0000469 .

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)	43592	(2R)-2-(acetamido)-3-sulfanylpropionic acid		C₅H₉NO₃S	详情	详情
(II)	27414	(2E,6E)-1-bromo-3,7,11-trimethyl-2,6,10-dodecatriene		C₁₅H₂₅Br	详情	详情
(III)	44902	(2R)-2-(acetamido)-3-[[(2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]sulfanyl]propionic acid	135304-07-3	C₂₀H₃₃NO₃S	详情	详情
(IV)	44903			C₂₅H₄₁NO₅S	详情	详情
(V)	44904			C₂₁H₃₃N₃O₂S	详情	详情

Extended Information