(1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione -Drug Synthesis Database

【结构式】

【分子编号】48305

【品名】(1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione

【CA登记号】

【分子式】C₁₁H₁₃NO₃

【分子量】207.22916

【元素组成】C 63.76% H 6.32% N 6.76% O 23.16%

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：(VIII)

The condensation of 2,2-dimethyl-1,3-dioxan-5-one (I) with aminoacetaldehyde dimethyl acetal (II) followed by acetylation with Ac2O/Et3N afforded the amido dioxin (III). Retro Diels-Alder reaction of dioxin (III) in warm benzonitrile generated the amidoacrolein (V), which was trapped in situ with the silyloxydiene (IV) to yield the cycloadduct (VI). Aldol cyclization between the acetamide and aldehyde functionalities of (VI) in the presence of t-BuOK produced the spiro lactam (VII). Subsequent aldol condensation between the acetal and silyl enolate functions of (VII) under acidic conditions furnished the tricyclic hydroxy ketone (VIII). Reduction of the keto group of (VIII) with NaBH(OAc)3 produced the C-4 axial alcohol (IX). Silylation of both hydroxyl groups of (IX) followed by selective cleavage of the C-2 silyl ether provided the C-4 mono silylated derivative (X). The free C-2 hydroxyl group of (X) was then oxidized to the corresponding ketone (XI) under Swern conditions. The potassium enolate of (XI) was stereoselectively alkylated with p-methoxybenzyl bromide (XII) to yield (XIII). Reduction of the keto group of (XIII) with Red-Al gave rise to the alcohol (XIV) in the undesired equatorial configuration. Inversion of the C-2 stereogenic center of (XIV) was achieved via formation of the sulfonate ester (XVI) with 4-nitrobenzenesulfonyl chloride (XV).

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)	48302	N-(2,2-dimethoxyethyl)-N-(1-formylvinyl)acetamide		C₉H₁₅NO₄	详情	详情
(VI)	48303	N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide		C₂₂H₄₁NO₅Si	详情	详情
(VII)	48304	1-(2,2-dimethoxyethyl)-8-[(triisopropylsilyl)oxy]-1-azaspiro[4.5]deca-3,7-dien-2-one		C₂₂H₃₉NO₄Si	详情	详情
(VIII)	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
(IX)	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
(X)	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
(XI)	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
(XII)	27490	1-(bromomethyl)-4-methoxybenzene		C₈H₉BrO	详情	详情
(XIII)	48309	(1S,6S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione		C₂₅H₃₅NO₄Si	详情	详情
(XIV)	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
(XV)	15809	4-nitrobenzenesulfonyl chloride	98-74-8	C₆H₄ClNO₄S	详情	详情
(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

合成路线2

该中间体在本合成路线中的序号：(VI)

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