(2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol -Drug Synthesis Database

【结构式】

【分子编号】57298

【品名】(2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol

【CA登记号】

【分子式】C₂₁H₄₀O₇

【分子量】404.5444

【元素组成】C 62.35% H 9.97% O 27.68%

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：(XXIV)

The desilylation of (XX) by means of HF in pyridine gives the hydroxyketone (XXI), which is reduced with Me4NBH(OAc)3 and HOAc in acetonitrile to yield the chiral dihydroxy compound (XXII). The methylation of both OH groups of (XXII) by means of methyl iodide and NaH in DMF affords the fully methylated intermediate (XXIII), which is finally debenzylated in the usual way to provide the target chiral trihydroxyalkyl-tetrahydropyran intermediate (XXIV).

参考文献中间体

合成目标

【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XX)	57294	(3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-5-nonen-1-one	C₄₆H₆₆O₇Si	详情	详情
(XXI)	57295	(3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-[(2S,3S,5R,6S)-3-hydroxy-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-nonen-1-one	C₄₀H₅₂O₇	详情	详情
(XXII)	57296	(2R,3S,5R,6S)-2-{(1S,3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-hydroxy-3,5-dimethyl-5-nonenyl}-6-methoxy-5-methyltetrahydro-2H-pyran-3-ol	C₄₀H₅₄O₇	详情	详情
(XXIII)	57297	(2R,3S,5R,6S)-2-{(1S,3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-methoxy-3,5-dimethyl-5-nonenyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; benzyl (2S,3S,4E,7S,9S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-9-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-9-methoxy-5,7-dimethyl-4-nonenyl ether	C₄₂H₅₈O₇	详情	详情
(XXIV)	57298	(2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol	C₂₁H₄₀O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Synthesis of the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI): The reaction of the chiral trihydroxy compound (XI) with 2,4-dimethyl-3-pentanone dimethyl acetal (XII) by means of TsOH in THF gives the ketal (XIII), which is treated with TsCl, TEA and DMAP in dichloromethane to yield the silyl ether (XIV). The condensation of (XIV) with ethynyl lithium (XV) in DMSO affords the propargyl derivative (XVI). The reduction of (XVI) with H2 over Lindlar catalyst in hexane containing quinoline provides the allyl derivative (XVII), which is condensed with propane-1,3-dithiol and BF3/Et2O in dichloromethane to give the chiral hydroxy dithiane (XVIII). The cleavage of the ketal group of (XVIII) by means of TsOH in methanol, followed by reaction of the intermediate diol with TsCl and pyridine yields the primary monotosylate (XIX), which is treated with Tbdms-OTf and lutidine in dichloromethane to afford the bis silyl ether (XX). Finally, this compound is iodinated by means of NaI, Cu and AgNO3 in hot acetonitrile/methanol to provide the desired intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI).

参考文献中间体

合成目标

【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663.
【2】 Smith, A.B. III; et al.; Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic. Tetrahedron Lett 1994, 35, 25, 4271.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	57298	(2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol	C₂₁H₄₀O₇	详情	详情
(XII)	57336	3,3-dimethoxy-2,4-dimethylpentane; 1-isopropyl-1-methoxy-2-methylpropyl methyl ether	C₉H₂₀O₂	详情	详情
(XIII)	57337	(2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octen-1-ol	C₂₈H₅₂O₇	详情	详情
(XIV)	57338	(2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octenyl 4-methylbenzenesulfonate	C₃₅H₅₈O₉S	详情	详情
(XV)	17461	ethynyllithium	C₂HLi	详情	详情
(XVI)	57339	(2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5-decen-9-ynyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-decen-9-ynyl methyl ether	C₃₀H₅₂O₆	详情	详情
(XVII)	57340	(2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5,9-decadienyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5,9-decadienyl methyl ether	C₃₀H₅₄O₆	详情	详情
(XVIII)	57341	(2R,4S,5R,6S,8S,10E,12R)-12-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-2-(1,3-dithian-2-yl)-4,6-dimethoxy-8,10-dimethyl-10,14-pentadecadien-5-ol	C₃₂H₅₈O₅S₂	详情	详情
(XIX)	57342	(2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-13-(1,3-dithian-2-yl)-2,10-dihydroxy-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate	C₃₂H₅₂O₇S₃	详情	详情
(XX)	57343	(2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-13-(1,3-dithian-2-yl)-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate	C₄₄H₈₀O₇S₃Si₂	详情	详情
(XXI)	57344	(1S,2R,3E,6S,8S,9R,10S,12R)-2-allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-1-(iodomethyl)-8,10,13,13-tetramethoxy-4,6,12-trimethyl-3-tridecenyl tert-butyl(dimethyl)silyl ether; (5S,6R,7E,10S,12S,13R)-6-allyl-5-(iodomethyl)-12-methoxy-2,2,3,3,8,10,15,15,16,16-decamethyl-13-[(1S,3R)-1,4,4-trimethoxy-3-methylbutyl]-4,14-dioxa-3,15-disila-7-heptadecene	C₃₆H₇₃IO₆Si₂	详情	详情

Extended Information