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【结 构 式】

【分子编号】40273

【品名】(1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate

【CA登记号】

【 分 子 式 】C39H79NO5SSi2

【 分 子 量 】730.297

【元素组成】C 64.14% H 10.9% N 1.92% O 10.95% S 4.39% Si 7.69%
与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(XLI)

The O-silylated 4-hydroxy-delta-caprolactam (XXXIV) was reduced with borane and the resulting piperidine was protected as the N-Boc derivative (XXXV). Lithiation employing sec-butyllithium and TMEDA, followed by addition of aldehyde (XXXIII) produced an inseparable 3:1 mixture of the alcohol epimers (XXXVIIa-b) and the trans-oxazolidinone (XXXVI). Acylation of the mixture with m-(trifluoromethyl)benzoyl chloride afforded a diastereomeric mixture of (trifluoromethyl)benzoates (XXXVIIIa-b), separable by column chromatography. Deprotection of the Boc group from the syn-isomer of (XXXVIII) by means of trimethylsilyl triflate and lutidine gave the free amine (XXXIX). Subsequent cyclization of (XXXIX) with AgNO3 afforded the desired cis-quinolizidine (XL) with very high diastereoselectivity. Reductive cleavage of the (trifluoromethyl)benzoyl group of (XL), followed by treatment of the free alcohol with methanesulfonyl chloride provided mesylate (XLI).

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17346 Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde 60656-87-3 C9H10O2 详情 详情
(XXXVIIa) 40267 tert-butyl (2S,3R,6R)-6-[(1S,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C43H85NO5Si2 详情 详情
(XXXVIIb) 40268 tert-butyl (2S,3R,6R)-6-[(1R,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C43H85NO5Si2 详情 详情
(XXXVIIIa) 40269 tert-butyl (2S,3R,6R)-2-methyl-6-[(1S,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C51H88F3NO6Si2 详情 详情
(XXXVIIb) 40270 tert-butyl (2S,3R,6R)-2-methyl-6-[(1R,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C51H88F3NO6Si2 详情 详情
(XXXIII) 40265 (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienal C23H44O2Si 详情 详情
(XXXIV) 40278 (5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]-2-piperidinone C15H31NO2Si 详情 详情
(XXXV) 40279 tert-butyl (2S,3R)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C20H41NO3Si 详情 详情
(XXXVI) 40266 (1R,5S,6R,8aR)-5-methyl-6-[(triisopropylsilyl)oxy]-1-[(6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadienyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one C39H75NO4Si2 详情 详情
(XXXIX) 40271 (1R,7S)-1-[(2R,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl 3-(trifluoromethyl)benzoate C46H80F3NO4Si2 详情 详情
(XL) 40272 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl 3-(trifluoromethyl)benzoate C46H80F3NO4Si2 详情 详情
(XLI) 40273 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate C39H79NO5SSi2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XLI)

During the reduction of mesylate (XLI) with LiAlH4, one of the triisopropylsilyl groups was selectively removed to afford alcohol (XLII). In contrast, when the same process was applied to the anti-isomer of (XXXVIII), the desired quinolizidine (XLI) was obtained along with a high amount of rearranged product. Acetylation of alcohol (XLII) and subsequent desilylation with aqueous HF gave the allylic alcohol (XLIII). Dehydration to the desired diene (XLV) was achieved by way of the allyl sulfide (XLIV), prepared by treatment of alcohol (XLIII) with N-phenylthiophthalimide and tributylphosphine. Subsequent oxidation of (XLIV) with oxone and thermal syn elimination of the intermediate sulfoxide furnished the title diene.

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLI) 40273 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate C39H79NO5SSi2 详情 详情
(XLII) 40274 (3R,4S,6S,9aS)-4-methyl-6-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-3-ol C29H57NO2Si 详情 详情
(XLIII) 40275 (3R,4S,6S,9aS)-6-[(E,3S)-3-hydroxy-1-decenyl]-4-methyloctahydro-2H-quinolizin-3-yl acetate C22H39NO3 详情 详情
(XLIV) 40276 (3R,4S,6S,9aS)-4-methyl-6-[(E)-3-(phenylsulfanyl)-1-decenyl]octahydro-2H-quinolizin-3-yl acetate C28H43NO2S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XLI)

The O-silylated 4-hydroxy-delta-caprolactam (XXXIV) was reduced with borane and the resulting piperidine was protected as the N-Boc derivative (XXXV). Lithiation employing sec-butyllithium and TMEDA, followed by addition of aldehyde (XXXIII) produ-ced an inseparable 3:1 mixture of the alcohol epimers (XXXVIIa-b) and the trans-oxazolidinone (XXXVI). Acylation of the mixture with m-(trifluoromethyl)benzoyl chloride afforded a diastereomeric mixture of (trifluoromethyl)benzoates (XXXVIIIa-b), separable by column chromatography. Deprotection of the Boc group from the syn-isomer of (XXXVIII) by means of trimethylsilyl triflate and lutidine gave the free amine (XXXIX). Subsequent cyclization of (XXXIX) with AgNO3 afforded the desired cis-quinolizidine (XL) with very high diastereoselectivity. Reductive cleavage of the (trifluoromethyl)benzoyl group of (XL), followed by treatment of the free alcohol with methanesulfonyl chloride provided mesylate (XLI).

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13746 3-(Trifluoromethyl)benzoyl chloride 2251-65-2 C8H4ClF3O 详情 详情
(XXXVIIa) 40267 tert-butyl (2S,3R,6R)-6-[(1S,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C43H85NO5Si2 详情 详情
(XXXVIIb) 40268 tert-butyl (2S,3R,6R)-6-[(1R,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C43H85NO5Si2 详情 详情
(XXXVIIIa) 40269 tert-butyl (2S,3R,6R)-2-methyl-6-[(1S,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C51H88F3NO6Si2 详情 详情
(XXXVIIb) 40270 tert-butyl (2S,3R,6R)-2-methyl-6-[(1R,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C51H88F3NO6Si2 详情 详情
(XXXIII) 40265 (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienal C23H44O2Si 详情 详情
(XXXIV) 40278 (5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]-2-piperidinone C15H31NO2Si 详情 详情
(XXXV) 40279 tert-butyl (2S,3R)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate C20H41NO3Si 详情 详情
(XXXVI) 40266 (1R,5S,6R,8aR)-5-methyl-6-[(triisopropylsilyl)oxy]-1-[(6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadienyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one C39H75NO4Si2 详情 详情
(XXXIX) 40271 (1R,7S)-1-[(2R,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl 3-(trifluoromethyl)benzoate C46H80F3NO4Si2 详情 详情
(XL) 40272 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl 3-(trifluoromethyl)benzoate C46H80F3NO4Si2 详情 详情
(XLI) 40273 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate C39H79NO5SSi2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XLI)

During the reduction of mesylate (XLI) with LiAlH4, one of the triisopropylsilyl groups was selectively removed to afford alcohol (XLII). In contrast, when the same process was applied to the anti-isomer of (XXXVIII), the desired quinolizidine (XLI) was obtained along with a high amount of rearranged product. Acetylation of alcohol (XLII) and subsequent desilylation with aqueous HF gave the allylic alcohol (XLIII). Dehydration to the desired diene (XLV) was achieved by way of the allyl sulfide (XLIV), prepared by treatment of alcohol (XLIII) with N-phenylthiophthalimide and tributylphosphine. Subsequent oxidation of (XLIV) with oxone and thermal syn elimination of the intermediate sulfoxide gave diene (XLV). Finally, the title compound was obtained by basic hydrolysis of the acetate ester of (XLV) with K2CO3 in MeOH.

参考文献 中间体
合成目标
【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLI) 40273 (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate C39H79NO5SSi2 详情 详情
(XLII) 40274 (3R,4S,6S,9aS)-4-methyl-6-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-3-ol C29H57NO2Si 详情 详情
(XLIII) 40275 (3R,4S,6S,9aS)-6-[(E,3S)-3-hydroxy-1-decenyl]-4-methyloctahydro-2H-quinolizin-3-yl acetate C22H39NO3 详情 详情
(XLIV) 40276 (3R,4S,6S,9aS)-4-methyl-6-[(E)-3-(phenylsulfanyl)-1-decenyl]octahydro-2H-quinolizin-3-yl acetate C28H43NO2S 详情 详情
(XLV) 40277 (3R,4S,6S,9aS)-6-[(1E,3E)-1,3-decadienyl]-4-methyloctahydro-2H-quinolizin-3-yl acetate C22H37NO2 详情 详情
Extended Information