(2S)-2-methyl-6-heptenal -Drug Synthesis Database

【结构式】

【分子编号】27185

【品名】(2S)-2-methyl-6-heptenal

【CA登记号】

【分子式】C₈H₁₄O

【分子量】126.19856

【元素组成】C 76.14% H 11.18% O 12.68%

与该中间体有关的原料药合成路线共 7 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5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(X)

C7-C12 fragment.- The selective monoepoxidation of 1,7-octadiene (I) with m-chloroperbenzoic acid (MCPBA) gives the epoxide (II), which is oxidized with periodic acid to the aldehyde (III). Further oxidation of (III) by means of NaClO2 yields 6-heptenoic acid (IV), which is condensed with the lithium salt of the chiral oxazolidinone (V) by means of pivaloyl chloride affording the chiral imide (VI). The methylation of (VI) with methyl iodide and sodium hexamethyldisylazide (NaHMDS) in THF provides the methylated chiral imide (VII) as a single enantiomer. The hydrolysis of (VII) with H2O2 and LiOH gives the corresponding free acid (VIII), which is reduced with LiAlH4 to the primery alcohol (IX). Finally, (IX) is treated with Swern oxidant to afford the desired taret aldehyde (X).

参考文献中间体

合成目标

【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.

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)	27177	1,7-octadiene	3710-30-3	C₈H₁₄	详情	详情
(II)	27178	2-(5-hexenyl)oxirane	19600-63-6	C₈H₁₄O	详情	详情
(III)	27179	6-heptenal		C₇H₁₂O	详情	详情
(IV)	27180	6-heptenoic acid	1119-60-4	C₇H₁₂O₂	详情	详情
(V)	10793	[(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium		C₁₀H₁₀LiNO₂	详情	详情
(VI)	27181	(4S)-4-benzyl-3-(6-heptenoyl)-1,3-oxazolidin-2-one		C₁₇H₂₁NO₃	详情	详情
(VII)	27182	(4S)-4-benzyl-3-[(2S)-2-methyl-6-heptenoyl]-1,3-oxazolidin-2-one		C₁₈H₂₃NO₃	详情	详情
(VIII)	27183	(2S)-2-methyl-6-heptenoic acid		C₈H₁₄O₂	详情	详情
(IX)	27184	(2S)-2-methyl-6-hepten-1-ol		C₈H₁₆O	详情	详情
(X)	27185	(2S)-2-methyl-6-heptenal		C₈H₁₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The synthesis of intermediate tridecenoic acid (VII) has been performed as follows: The condensation of previously reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no. 22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV). The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V), which is selectively monodesilylated with CSA to provide the primary alcohol (VI). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).

参考文献中间体

合成目标

【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	27176	2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone	C₁₂H₂₂O₃	详情	详情
(II)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(III)	44434	(4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one	C₂₀H₃₆O₄	详情	详情
(IV)	44435	(3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one	C₁₇H₃₂O₄	详情	详情
(V)	44436	(5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one	C₃₅H₇₄O₄Si₃	详情	详情
(VI)	44437	(5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one	C₂₉H₆₀O₄Si₂	详情	详情
(VII)	44438	(3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₉H₅₈O₅Si₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	44448	2,2-dimethyl-3-oxopentanal	C₇H₁₂O₂	详情	详情
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(III)	44450	(5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one	C₁₀H₁₈O₂	详情	详情
(IV)	44451	(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one	C₁₆H₃₂O₂Si	详情	详情
(V)	44452	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal	C₁₅H₃₀O₃Si	详情	详情
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(VII)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₃H₄₄O₅Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XXVI)

The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).

参考文献中间体

合成目标

【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
【2】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	27170	chloro(3-methyl-2-butenyl)magnesium		C₅H₉ClMg	详情	详情
(XVII)	15966	propionaldehyde	123-38-6	C₃H₆O	详情	详情
(XVIII)	27171	4,4-dimethyl-5-hexen-3-ol		C₈H₁₆O	详情	详情
(XIX)	27172	(3R)-4,4-dimethyl-5-hexen-3-ol		C₈H₁₆O	详情	详情
(XX)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(XXI)	27173	(1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate		C₁₀H₁₇BrO₂	详情	详情
(XXII)	27174	(4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one		C₁₀H₁₈O₂	详情	详情
(XXIII)	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(XXIV)	27175	(3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol		C₁₂H₂₄O₃	详情	详情
(XXV)	27176	2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone		C₁₂H₂₂O₃	详情	详情
(XXVI)	27185	(2S)-2-methyl-6-heptenal		C₈H₁₄O	详情	详情
(XXVII)	44434	(4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one		C₂₀H₃₆O₄	详情	详情
(XXVIII)	44435	(3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one		C₁₇H₃₂O₄	详情	详情
(XXIX)	44436	(5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one		C₃₅H₇₄O₄Si₃	详情	详情
(XXX)	44437	(5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one		C₂₉H₆₀O₄Si₂	详情	详情
(XXX)	44438	(3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid		C₂₉H₅₈O₅Si₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XXXVII)

The reaction of 2,2-dimethyl-3-oxopentanal (XXXI) with (+)-diisopinocampheyl(allyl)borane (XXXII) in ethyl ether gives the chiral beta-hydroxy ketone (XXXIII), which is protected with Tbdms-OTf to yield the silyl ether (XXXIV). The ozonolysis of the double bond of (XXXIV) affords the aldehyde (XXXV), which is oxidized with NaClO2 to the carboxylic acid (XXXVI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (XII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	44438	(3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₉H₅₈O₅Si₂	详情	详情
(XXXI)	44448	2,2-dimethyl-3-oxopentanal	C₇H₁₂O₂	详情	详情
(XXXII)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(XXXIII)	44450	(5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one	C₁₀H₁₈O₂	详情	详情
(XXXIV)	44451	(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one	C₁₆H₃₂O₂Si	详情	详情
(XXXV)	44452	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal	C₁₅H₃₀O₃Si	详情	详情
(XXXVI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XXXVII)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

The condensation of already reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no. 22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV). The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V), which is selectively monodesilylated with CSA to provide the primary alcohol (VI). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).

参考文献中间体

合成目标

【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	27176	2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone	C₁₂H₂₂O₃	详情	详情
(II)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(III)	44434	(4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one	C₂₀H₃₆O₄	详情	详情
(IV)	44435	(3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one	C₁₇H₃₂O₄	详情	详情
(V)	44436	(5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one	C₃₅H₇₄O₄Si₃	详情	详情
(VI)	44437	(5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one	C₂₉H₆₀O₄Si₂	详情	详情
(VII)	44438	(3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₉H₅₈O₅Si₂	详情	详情

合成路线7

该中间体在本合成路线中的序号：(VII)

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	44448	2,2-dimethyl-3-oxopentanal	C₇H₁₂O₂	详情	详情
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(III)	44450	(5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one	C₁₀H₁₈O₂	详情	详情
(IV)	44451	(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one	C₁₆H₃₂O₂Si	详情	详情
(V)	44452	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal	C₁₅H₃₀O₃Si	详情	详情
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(VII)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₃H₄₄O₅Si	详情	详情

Extended Information