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【结 构 式】 
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【分子编号】42372 【品名】1,3-dithiane 【CA登记号】505-23-7 |
【 分 子 式 】C4H8S2 【 分 子 量 】120.23952 【元素组成】C 39.96% H 6.71% S 53.34% |
合成路线1
该中间体在本合成路线中的序号：(IV)Synthesis of the intermediate butyraldehyde (X): The Sharpless asymmetric epoxidation of 2(E)-buten-1-ol by means of t-Bu-OOH and D-(-9-diisopropyl tartrate gives the epoxy alcohol (II), which is treated with Tbdps-Cl, TEA and DMAP to yield the silyl ether (III) The condensation of (III) with 1,3-dithiane (IV) by means of BuLi in THF/HMPA affords the cyclic thioketal (V), which is deprotected by means of TBAF in THF, affording the diol (VI). The reaction of (VI) with 4-methoxybenzaldehyde dimethylacetal (VII) by means of TsOH in DMF provides the benzylidene ketal (VIII), which is submitted to a selective opening by means of DIBAL in dichloromethane to give the secondary benzyl ether (IX). Finally this compound is oxidized with SO3/Pyridine and TEA in DMSO/dichloromethane to obtain the target intermediate, the chiral butyraldehyde (X).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 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) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (II) | 57330 | [(2R,3R)-3-methyloxiranyl]methanol | C4H8O2 | 详情 | 详情 | |
| (III) | 14956 | tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether | C20H26O2Si | 详情 | 详情 | |
| (IV) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (V) | 57331 | (2S,3S)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-(1,3-dithian-2-yl)-2-butanol | C24H34O2S2Si | 详情 | 详情 | |
| (VI) | 57332 | (2S,3S)-3-(1,3-dithian-2-yl)-1,2-butanediol | C8H16O2S2 | 详情 | 详情 | |
| (VII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VIII) | 57333 | (4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-2-(4-methoxyphenyl)-1,3-dioxolane; 4-{(4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-1,3-dioxolan-2-yl}phenyl methyl ether | C16H22O3S2 | 详情 | 详情 | |
| (IX) | 57334 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]-1-butanol | C16H24O3S2 | 详情 | 详情 | |
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Bis-tetrahydropyran intermediate (XXIV). The asymmetric addition of Ipc2B-crotyl to 5-benzyloxypentanal (XI) gives the secondary alcohol (XII), which is protected with Boc2O and NaHMDS in THF yielding the carbamate (XIII). The reaction of (XIII) with IBr in toluene affords the iodinated cyclic carbonate (XIV), which is converted into the epoxide (XV) by reaction with K2CO3 in methanol/water. The reaction of the epoxide (XV) with 1,3-dithiane (XVI) by means of BuLi in THF/HMPA provides the dihydroxy compound (XVII), which is converted into the acetonide (XIX) by reaction with 2,2-dimethoxypropane (XVIII) and PPTS . The condensation of (XIX) with the tetrahydropyran-2-carbaldehyde intermediate (X) by means of BuLi in ethyl ether/HMPA gives the bis acetonide derivative (XX) (1), which is deprotected by means of CSA, cyclized by means of Hg(ClO4)2 and acylated with Piv-Cl and pyridine to yield the bis tetrahydropyranyl intermediate (XXI). The silylation of the OH group of (XXI) by means of Tbdms-OTf, followed by debenzylation by means of HCOONH4 and Pd/C affords the butanol derivative (XXII), which is successively silylated, first with Tbdps-Cl /imidazole and then with Tes-OTf and lutidine to provide the fully silylated compound (XXIII). Finally, the elimination of the pivaloyl group of (XXIII) by means of DIBAL in THF, followed by reaction with I2, PPh3 and imidazole in toluene gives the iodomethyl bis tetrahydropyran intermediate (XXIV) (2).
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 【1】 Smith, A.B. III; Zhuang, L.; Brook, C.S.; Boldi, A.M.; McBriar, M.D.; Moser, W.H.; Murase, N.; Nakayama, K.; Verhoest, P.R.; Lin, Q.; Spongistatin synthetic studies. 1. Construction of a C(29-48) subtarget. Tetrahedron Lett 1997, 38, 50, 8667. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 64603 | (4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde | C18H24O5 | 详情 | 详情 | |
| (XI) | 64604 | 5-(benzyloxy)pentanal | C12H16O2 | 详情 | 详情 | |
| (XII) | 64605 | (3R,4R)-8-(benzyloxy)-3-methyl-1-octen-4-ol | C16H24O2 | 详情 | 详情 | |
| (XIII) | 64606 | (1R,2R)-1-[4-(benzyloxy)butyl]-2-methyl-3-butenyl tert-butyl carbonate | C21H32O4 | 详情 | 详情 | |
| (XIV) | 64607 | (4R,5R)-4-[4-(benzyloxy)butyl]-6-(iodomethyl)-5-methyl-1,3-dioxan-2-one | C17H23IO4 | 详情 | 详情 | |
| (XV) | 64608 | (1R)-5-(benzyloxy)-1-{(1R)-1-[(2S)oxiranyl]ethyl}pentyl methyl carbonate | C18H26O5 | 详情 | 详情 | |
| (XVI) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (XVII) | 64609 | (2S,3S,4R)-8-(benzyloxy)-1-(1,3-dithian-2-yl)-3-methyl-2,4-octanediol | C20H32O3S2 | 详情 | 详情 | |
| (XVIII) | 64610 | 1,3-dimethoxy-2,2-dimethylpropane; 3-methoxy-2,2-dimethylpropyl methyl ether | C7H16O2 | 详情 | 详情 | |
| (XIX) | 64611 | (4R,5R,6S)-4-[4-(benzyloxy)butyl]-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxane; benzyl 4-[(4R,5R,6S)-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]butyl ether | C23H36O3S2 | 详情 | 详情 | |
| (XX) | 64612 | (S)-[(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl][2-({(4S,5R,6R)-6-[4-(benzyloxy)butyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}methyl)-1,3-dithian-2-yl]methanol | C41H60O8S2 | 详情 | 详情 | |
| (XXI) | 64613 | {(2R,3S,4R,5R,6R)-4-(benzyloxy)-6-[(S)-{(2R,4S,5R,6R)-6-[4-(benzyloxy)butyl]-4-hydroxy-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl}(hydroxy)methyl]-3-hydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl pivalate | C38H56O10 | 详情 | 详情 | |
| (XXII) | 64614 | {(2R,3S,4R,5R,6R)-6-[(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-hydroxybutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl](hydroxy)methyl]-3,4-dihydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C30H58O10Si | 详情 | 详情 | |
| (XXIII) | 64615 | {(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C64H118O10Si5 | 详情 | 详情 | |
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (VII): The condensation of epoxide (I) with vinyl lithium (II) by means of CuCN gives the allylic alcohol (III), which is epoxidated to epoxide (IV). The silylation of (IV) with TBDPSCl and imidazole yields the silyl ether (V), which is condensed with 1,3-dithiane (VI) by means of n-BuLi and protected with TBDPSCl as before to afford the desired intermediate (VII).
| 【1】 Guo, J.; et al.; Total synthesis of altohyrtin A (spongistatin 1): Part 1. Angew Chem. Int Ed Engl 1998, 37, 1-2, 187. |
| 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) | 42367 | benzyl 2-[(2S)oxiranyl]ethyl ether; (2S)-2-[2-(benzyloxy)ethyl]oxirane | C11H14O2 | 详情 | 详情 | |
| (II) | 42368 | vinyllithium | 917-57-7 | C2H3Li | 详情 | 详情 |
| (III) | 42369 | (3R)-1-(benzyloxy)-5-hexen-3-ol | C13H18O2 | 详情 | 详情 | |
| (IV) | 42370 | (2S)-4-(benzyloxy)-1-[(2S)oxiranyl]-2-butanol | C13H18O3 | 详情 | 详情 | |
| (V) | 42371 | benzyl (3S)-3-[[tert-butyl(diphenyl)silyl]oxy]-4-[(2S)oxiranyl]butyl ether; ([(1S)-3-(benzyloxy)-1-[(2S)oxiranylmethyl]propyl]oxy)(tert-butyl)diphenylsilane | C29H36O3Si | 详情 | 详情 | |
| (VI) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (VII) | 42373 | benzyl (3S,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-(1,3-dithian-2-yl)hexyl ether; (5S,7S)-5-[2-(benzyloxy)ethyl]-7-(1,3-dithian-2-ylmethyl)-2,2,10,10-tetramethyl-3,3,9,9-tetraphenyl-4,8-dioxa-3,9-disilaundecane | C49H62O3S2Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (XXXIII): The silylation of epoxide (XXI) with TBDMSCl gives the silyl ether (XXII), which is condensed with 1,3-dithiane (VI) by means of n-BuLi to yield the alcohol (XXIII). Epoxidation of (XXIII) with TBAF and NaH affords the epoxide (XXIV), which is condensed with vinyl lithium and CuCN to provide the allyl alcohol (XXV). The methylation of (XXV) with MeI and NaH in THF gives the methyl ether (XXVI). The silylation of epoxide (XXI) with TBDPSCl gives the silyl ether (XXVII), which is condensed with vinyl lithium (II) by means of CuCN in THF, yielding the allyl alcohol (XXVIII). The reaction of (XXVIII) with Boc-ON, n-BuLi and IBr affords the cyclic carbonate (XXIX), which is treated with K2CO3 in MeOH and silylated with TBDPSCl to provide the protected epoxide (XXX). The condensation of epoxide (XXX) with allyl ether (XXVI) by means of NaOtBu and n-BuLi in THF furnished the adduct (XXXI), which is cyclized by means of TBAF and converted into the acetylenic tetrahydropyran (XXXII). Finally, the iodination and reprotection of (XXXII) with Bu3SnH, AIBN, NIS, Mpm-OCH2Cl and DIEA gives the desired intermediate (XXXIII).
| 【1】 Guo, J.; et al.; Total synthesis of altohyrtin A (spongistatin 1): Part 1. Angew Chem. Int Ed Engl 1998, 37, 1-2, 187. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 42368 | vinyllithium | 917-57-7 | C2H3Li | 详情 | 详情 |
| (VI) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (XXI) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XXII) | 42374 | tert-butyl(dimethyl)[(2R)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2R)oxiranylmethyl ether | C9H20O2Si | 详情 | 详情 | |
| (XXIII) | 42387 | (2R)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-(1,3-dithian-2-yl)-2-propanol | C13H28O2S2Si | 详情 | 详情 | |
| (XXIV) | 42388 | (2R)-2-(1,3-dithian-2-ylmethyl)oxirane | C7H12OS2 | 详情 | 详情 | |
| (XXV) | 42389 | (2S)-1-(1,3-dithian-2-yl)-4-penten-2-ol | C9H16OS2 | 详情 | 详情 | |
| (XXVI) | 42390 | (1S)-1-(1,3-dithian-2-ylmethyl)-3-butenyl methyl ether; 2-[(2S)-2-methoxy-4-pentenyl]-1,3-dithiane | C10H18OS2 | 详情 | 详情 | |
| (XXVII) | 26421 | tert-butyl[(2R)oxiranylmethoxy]diphenylsilane; tert-butyl(diphenyl)silyl (2R)oxiranylmethyl ether | C19H24O2Si | 详情 | 详情 | |
| (XXVIII) | 26422 | (2R)-1-[[tert-butyl(diphenyl)silyl]oxy]-4-penten-2-ol | C21H28O2Si | 详情 | 详情 | |
| (XXIX) | 42391 | (4R,6S)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-6-(iodomethyl)-1,3-dioxan-2-one | C22H27IO4Si | 详情 | 详情 | |
| (XXX) | 42392 | tert-butyl(diphenyl)silyl (1R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-[(2S)oxiranylmethyl]ethyl ether; (5R)-2,2,9,9-tetramethyl-5-[(2S)oxiranylmethyl]-3,3,8,8-tetraphenyl-4,7-dioxa-3,8-disiladecane | C37H46O3Si2 | 详情 | 详情 | |
| (XXXI) | 42393 | (2S,4R)-4,5-bis[[tert-butyl(diphenyl)silyl]oxy]-1-[2-[(2S)-2-methoxy-4-pentenyl]-1,3-dithian-2-yl]-2-pentanol | C47H64O4S2Si2 | 详情 | 详情 | |
| (XXXII) | 42394 | tert-butyl(diphenyl)silyl [(2R,4S,6R)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-methoxy-6-[(2S)-2-methoxy-4-pentynyl]tetrahydro-2H-pyran-2-yl]methyl ether; tert-butyl([(2R,4S,6R)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-methoxy-6-[(2S)-2-methoxy-4-pentynyl]tetrahydro-2H-pyran-2-yl]methoxy)diphenylsilane | C45H58O5Si2 | 详情 | 详情 | |
| (XXXIII) | 42395 | tert-butyl(dimethyl)silyl (2R,4S,6R)-2-[(2S,4E)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2H-pyran-4-yl ether; tert-butyl[[(2R,4S,6R)-2-[(2S,4E)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2H-pyran-4-yl]oxy]dimethylsilane | C28H47IO7Si | 详情 | 详情 |