(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one -Drug Synthesis Database

【结构式】

【分子编号】48315

【品名】(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one

【CA登记号】

【分子式】C₃₁H₅₁NO₄Si₂

【分子量】557.92128

【元素组成】C 66.74% H 9.21% N 2.51% O 11.47% Si 10.07%

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：(XX)

Displacement of the nosylate group of (XVI) with rubidium acetate in the presence of crown ether furnished the desired acetate ester (XVIII) accompanied by the elimination byproduct (XVII). Alcohol (XIX), obtained by basic hydrolysis of the acetate ester (XVIII), was protected as the silyl ether (XX) using triethylsilyl triflate. Hydrogenation of the lactam double bond of (XX) over PtO2 gave the saturated lactam (XXI). The azido group was introduced by reaction of the lithium enolate of lactam (XXI) with trisyl azide to afford a diastereomeric mixture from which the desired azide (XXII) was isolated by column chromatography. Simultaneous reduction of the lactam and azide functional groups of (XXII) with concomitant removal of the triethylsilyl protecting group was accomplished by treatment of (XXII) with LiAlH4. The resulting amine (XXIII) was then acylated with benzyl chloroformate to give carbamate (XXIV).

参考文献中间体

合成目标

【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVI)	48311	(1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate	C₃₁H₄₀N₂O₈SSi	详情	详情
(XVII)	48312	(1S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodeca-2,6-dien-4-one	C₂₅H₃₅NO₃Si	详情	详情
(XVIII)	48313	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate	C₂₇H₃₉NO₅Si	详情	详情
(XIX)	48314	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one	C₂₅H₃₇NO₄Si	详情	详情
(XX)	48315	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one	C₃₁H₅₁NO₄Si₂	详情	详情
(XXI)	48316	(1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one	C₃₁H₅₃NO₄Si₂	详情	详情
(XXII)	48317	(1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one	C₃₁H₅₂N₄O₄Si₂	详情	详情
(XXIII)	48318	(1S,3S,6S,7S,8R,9S)-3-amino-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodecan-7-ol	C₂₅H₄₂N₂O₃Si	详情	详情
(XXIV)	48319	benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate	C₃₃H₄₈N₂O₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The condensation of acetonide (I) with 2-aminoacetaldehyde dimethylacetal (II) by means of Ac2O and TEA gives the acetylated enamine (III), which is cyclocondensed with the silylated butadiene (IV) in hot benzonitrile to yield the cycloadduct (V). The cyclization of (V) by means of tBu-OK in ethyl acetate/THF, followed by desilylation with TFA, affords the tricyclic lactam (VI), which is reduced with NaBH(OAc)3 to provide the dihydroxy compound (VII). The silylation of both OH groups of (VII) by means of Tbdms-Cl, followed by selective desilylation of the equatorial silyl ether with TBAF, gives the corresponding alcohol (VIII), which is submitted to a Swern oxidation to yield the ketone (IX). The condensation of (IX) with 4-methoxybenzyl bromide (X) by means of tBu-OK and Red-Al affords the hydroxylated adduct (XI); however, the resulting alcohol presents an unnatural equatorial configuration that is inverted by its esterification with 4-nitrophenylsulfonyl chloride to furnish (XII), followed by acetoxylation of (XII) with rubidium acetate and 18-crown-6, to provide the desired axial acetoxy compound (XIII). The hydrolysis of (XIII) with KOH in methanol gives the corresponding alcohol (XIV), which is silylated with Tes-Otf to yield the bis silyl ether (XV). The reduction of the double bond of (XV) with H2 over PtO2 affords the saturated compound (XVI), which is treated with triethylsilylazide and LDA to provide at the azido compound (XVII). The reduction of lactam and azido groups by means of LiAlH4, followed by protection of the resulting amino group with benzyloxycarbonyl chloride and Na2CO3, gives the benzyl carbamate (XVIII).

参考文献中间体

合成目标

【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125.

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)	46538	2,2-dimethyl-1,3-dioxan-5-one		C₆H₁₀O₃	详情	详情
(II)	34158	aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine	22483-09-6	C₄H₁₁NO₂	详情	详情
(III)	48300	N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide		C₁₂H₂₁NO₅	详情	详情
(IV)	48301	triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether		C₁₃H₂₆OSi	详情	详情
(V)	48303	N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide		C₂₂H₄₁NO₅Si	详情	详情
(VI)	48305	(1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione		C₁₁H₁₃NO₃	详情	详情
(VII)	48306	(1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one		C₁₁H₁₅NO₃	详情	详情
(VIII)	48307	(1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one		C₁₇H₂₉NO₃Si	详情	详情
(IX)	48308	(1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione		C₁₇H₂₇NO₃Si	详情	详情
(X)	27490	1-(bromomethyl)-4-methoxybenzene		C₈H₉BrO	详情	详情
(XI)	48310	(1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one		C₂₅H₃₇NO₄Si	详情	详情
(XII)	48311	(1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate		C₃₁H₄₀N₂O₈SSi	详情	详情
(XIII)	48313	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate		C₂₇H₃₉NO₅Si	详情	详情
(XIV)	48314	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one		C₂₅H₃₇NO₄Si	详情	详情
(XV)	48315	(1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one		C₃₁H₅₁NO₄Si₂	详情	详情
(XVI)	48316	(1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one		C₃₁H₅₃NO₄Si₂	详情	详情
(XVII)	48317	(1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one		C₃₁H₅₂N₄O₄Si₂	详情	详情
(XVIII)	48319	benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate		C₃₃H₄₈N₂O₅Si	详情	详情

Extended Information