(E)-3-iodo-2-methyl-2-propenal -Drug Synthesis Database

【结构式】

【分子编号】37952

【品名】(E)-3-iodo-2-methyl-2-propenal

【CA登记号】

【分子式】C₄H₅IO

【分子量】195.98757

【元素组成】C 24.51% H 2.57% I 64.75% O 8.16%

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：(I)

Synthesis of intermediates: Iodinated pivalate (X): The condensation of 3-iodo-2-methyl-2-propenal (I) with the silylated enol ether (II) by means of Zr(O-tBu)4 and 3,3'-I2-BINOL in toluene gives the iodopentenoic acid (III), which is treated with Tips-Cl and imidazole to yield the silyl ether (IV). The reduction of (IV) by means of DIBAL in dichloromethane affords the 5-iodopenten-1-ol (V), which is oxidized by means of (COCl)2 in DMSO/dichloromethane to provide the aldehyde (VI). The Wittig condensation of (VI) with phosphorane (VII) in refluxing THF leads to the heptadienoic ester (VIII), which is reduced with DIBAL in dichloromethane giving the primary alcohol (IX). Finally this alcohol is esterified pivaloyl chloride and pyridine to affords the target iodinated pivalate (X).

参考文献中间体

合成目标

【1】 Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K.; Convergent total synthesis of khafrefungin and its inhibitory activity of fungal sphigolipid syntheses. J Org Chem 2001, 66, 16, 5580.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	37952	(E)-3-iodo-2-methyl-2-propenal	C₄H₅IO	详情	详情
(II)	60333	phenyl 1-[(trimethylsilyl)oxy]-1-propenyl ether; trimethyl{[1-(phenyloxy)-1-propenyl]oxy}silane	C₁₂H₁₈O₂Si	详情	详情
(III)	60334	phenyl 3-hydroxy-5-iodo-2,4-dimethyl-4-pentenoate	C₁₃H₁₅IO₃	详情	详情
(IV)	60335	phenyl 5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-pentenoate	C₂₂H₃₅IO₃Si	详情	详情
(V)	60336	5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-penten-1-ol	C₁₆H₃₃IO₂Si	详情	详情
(VI)	60337	5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-pentenal	C₁₆H₃₁IO₂Si	详情	详情
(VII)	47172	propyl 2-(triphenylphosphoranylidene)propanoate	C₂₄H₂₅O₂P	详情	详情
(VIII)	60338	propyl 7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadienoate	C₂₂H₄₁IO₃Si	详情	详情
(IX)	60339	7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadien-1-ol	C₁₉H₃₇IO₂Si	详情	详情
(X)	60340	7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadienyl 2,2-dimethylpropanoate	C₂₄H₄₅IO₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Asymmetric allylation of 3-iodomethacrolein (VII) with (+)-allyldiisopinocampheyl borane at -100 C provided the enantiopure alcohol (IX). Subsequent coupling of (IX) with the diastereomeric mixture of (6R,7S) and (6S,7R)-acids (X) using DCC and DMAP afforded a mixture of diastereomeric esters from which the required (6R,7S)-isomer (XI) was isolated by flash chromatography. Ring closure by means of olefin methatesis in the presence of a ruthenium initiator gave a separable mixture of E (XII) and Z (XIII) macrolactones. Subsequent desilylation of the desired Z isomer (XIII) with HF.Pyr in THF provided the macrocyclic diol (XIV). Introduction of the thiazole unit in (XIV) was carried out by Stille coupling of vinyl iodide (XIV) with thiazolyl stannane (VI) in the presence of Pd catalyst to provide (XV). Finally, epoxidation of (XV) with methylperoxycarboximidic acid, generated in situ from hydrogen peroxide and acetonitrile, furnished the title compound.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction. Angew Chem. Int Ed Engl 1998, 37, 1-2, 84.
【2】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and related side-chain modified analogues via a stille coupling based strategy. Bioorg Med Chem 1999, 7, 5, 665.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	37951	[4-(tributylstannyl)-1,3-thiazol-2-yl]methanol	C₁₆H₃₁NOSSn	详情	详情
(VII)	37952	(E)-3-iodo-2-methyl-2-propenal	C₄H₅IO	详情	详情
(VIII)	37953	allyl[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl][(5S,6S)-4,4,6-trimethylbicyclo[3.1.1]hept-1-yl]borane	C₂₃H₃₉B	详情	详情
(IX)	37954	(1E,3S)-1-iodo-2-methyl-1,5-hexadien-3-ol	C₇H₁₁IO	详情	详情
(X)	37955	(3S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₃H₄₄O₅Si	详情	详情
(XI)	37956	(1S)-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate	C₃₀H₅₃IO₅Si	详情	详情
(XII)	37957	(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione	C₂₈H₄₉IO₅Si	详情	详情
(XIII)	37958	(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione	C₂₈H₄₉IO₅Si	详情	详情
(XIV)	37959	(4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione	C₂₂H₃₅IO₅	详情	详情
(XV)	37960	(4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione	C₂₆H₃₉NO₆S	详情	详情

Extended Information