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【结 构 式】 
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【分子编号】16299 【品名】Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 【CA登记号】54655-07-1 |
【 分 子 式 】C5H9LiSi 【 分 子 量 】104.15296 【元素组成】C 57.66% H 8.71% Li 6.66% Si 26.97% |
合成路线1
该中间体在本合成路线中的序号：(V)The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).
| 【1】 Zablocki, J.A.; Rico, J.G.; Garland, R.B.; et al.; Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 1995, 38, 13, 2378-94. |
| 【2】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17739 | N,N,N',N'-tetramethylguanidine; 1,1,3,3-Tetramethylguanidine | 80-70-6 | C5H13N3 | 详情 | 详情 | |
| (III) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
| (IV) | 16298 | 4-oxo-2-azetanyl benzoate; 4-Benzoyloxy-2-azetidinone | 28562-58-5 | C10H9NO3 | 详情 | 详情 |
| (V) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (VI) | 16300 | 4-[2-(trimethylsilyl)ethynyl]-2-azetanone | C8H13NOSi | 详情 | 详情 | |
| (VII) | 16301 | 3-amino-5-(trimethylsilyl)-4-pentynoic acid | C8H15NO2Si | 详情 | 详情 | |
| (VIII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (IX) | 16303 | (3S)-3-[[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoic acid | C17H23NO4Si | 详情 | 详情 | |
| (X) | 16304 | ethyl (3S)-3-[(tert-butoxycarbonyl)[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoate | C24H35NO6Si | 详情 | 详情 | |
| (XI) | 17740 | ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-pentynoate | C12H19NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLVIII)The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).
| 【1】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 46994 | (2S)-1-(tetrahydro-2H-pyran-2-yloxy)-5-(trimethylsilyl)-4-pentyn-2-ol | C13H24O3Si | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XLVI) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XLVII) | 46993 | (2S)oxiranylmethyl tetrahydro-2H-pyran-2-yl ether; 2-[(2S)oxiranylmethoxy]tetrahydro-2H-pyran | C8H14O3 | 详情 | 详情 | |
| (XLVIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (L) | 46995 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynyl tetrahydro-2H-pyran-2-yl ether; [(4S)-4-(methoxymethoxy)-5-(tetrahydro-2H-pyran-2-yloxy)-1-pentynyl](trimethyl)silane | C15H28O4Si | 详情 | 详情 | |
| (LI) | 46996 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentyn-1-ol | C10H20O3Si | 详情 | 详情 | |
| (LII) | 46997 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynal | C10H18O3Si | 详情 | 详情 | |
| (LIII) | 46998 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-ol | C11H22O3Si | 详情 | 详情 | |
| (LIV) | 46999 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-one | C11H20O3Si | 详情 | 详情 | |
| (LV) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (LVI) | 47001 | 4-[(E,3S)-3-(methoxymethoxy)-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; methoxymethyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C16H25NO2SSi | 详情 | 详情 | |
| (LVII) | 47002 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl methoxymethyl ether; 4-[(1E,3S,5Z)-6-iodo-3-(methoxymethoxy)-2-methyl-1,5-hexadienyl]-2-methyl-1,3-thiazole | C13H18INO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Addition of lithium trimethylsilylacetylide (II) to quinuclidin-3-one (I) in THF at -70 C afforded the O-silylated ethynyl quinuclidinol (III). Subsequent palladium-catalyzed coupling of (III) with 4,4'-dibromobenzophenone (IV) gave adduct (V). Finally, the Meyer-Schuster rearrangement of (V) in concentrated H2SO4 furnished the title unsaturated ketone.
| 【1】 Brown, G.R.; Stokes, E.S.E.; Hollinshead, D.M.; et al.; Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: Optimization from lipid profiles. J Med Chem 1999, 42, 7, 1306. |
| 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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (III) | 34446 | 3-ethynyl-3-[(trimethylsilyl)oxy]quinuclidine; 3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl trimethylsilyl ether | C12H21NOSi | 详情 | 详情 | |
| (IV) | 34447 | bis(4-bromophenyl)methanone | 3988-03-2 | C13H8Br2O | 详情 | 详情 |
| (V) | 34448 | (4-bromophenyl)[4-(2-[3-[(trimethylsilyl)oxy]-1-azabicyclo[2.2.2]oct-3-yl]ethynyl)phenyl]methanone | C25H28BrNO2Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The cyclization of tetrahydropyran (I) with 2-butylacrolein (II) by means of K2CO3 at 110 C gives the spirodipyran (III), which is epoxidated with dimethyldioxirane in dichloromethane yielding the epoxide (IV). The rearrangement of (IV) by means of camphorsulfonic acid (CSA) affording the carbaldehyde (V), which is condensed with lithium trimethylsilylacetylene (VI) affording carbinol (VII) with incorrect stereochemistry. The oxidation of (VII) with DMP in dichloromethane providing the ketone (VIII), which is reduced with L-Selectride to the carbinol (IX) with the correct stereochemistry. The treatment of (IX) with K2CO3 in MeOH eliminates the trimethylsilyl group giving the acetylene (X), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding (XI). The selective desilylation of (XI) with HF·pyr in THF affords the primary alcohol (XII), which is oxidated with DMP in dichloromethane affording the aldehyde (VIII). The Wittig condensation of (XIII) with phosphorane (XIV) in hot chlorobenzene furnishes the aldehyde (XV).
| 【1】 Guzzupe, A.N.; et al.; Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B. J Org Chem 2001, 66, 7, 2382. |
| 【2】 Cuzzupe, A.N.; et al.; Total synthesis of (-)-reveromycin B. Org Lett 2000, 2, 2, 191. |
| 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) | 41537 | tert-butyl(dimethyl)[2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethoxy]silane; tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethyl ether | C15H30O2Si | 详情 | 详情 | |
| (II) | 41538 | (Z)-2-butyl-2-butenal | C8H14O | 详情 | 详情 | |
| (III) | 41539 | tert-butyl(dimethyl)silyl 2-[(2R,3S,6S)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethyl ether; tert-butyl[2-[(2R,3S,6S)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethoxy]dimethylsilane | C22H42O3Si | 详情 | 详情 | |
| (IV) | 41540 | C22H42O4Si | 详情 | 详情 | ||
| (V) | 41541 | (2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]decane-2-carbaldehyde | n/a | C22H42O4Si | 详情 | 详情 |
| (VI) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (VII) | 41542 | (1R)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol | n/a | C27H52O4Si2 | 详情 | 详情 |
| (VIII) | 41543 | 1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-one | n/a | C27H50O4Si2 | 详情 | 详情 |
| (IX) | 41544 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol | n/a | C27H52O4Si2 | 详情 | 详情 |
| (X) | 41545 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propyn-1-ol | n/a | C24H44O4Si | 详情 | 详情 |
| (XI) | 41546 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl tert-butyl(dimethyl)silyl ether; tert-butyl([(1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl]oxy)dimethylsilane | n/a | C30H58O4Si2 | 详情 | 详情 |
| (XII) | 41547 | 2-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-1-ethanol | n/a | C24H44O4Si | 详情 | 详情 |
| (XIII) | 41548 | 2-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]acetaldehyde | n/a | C24H42O4Si | 详情 | 详情 |
| (XIV) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XV) | 41549 | (E)-4-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2-methyl-2-butenal | n/a | C27H46O4Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions of (V) provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXIII)The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).
| 【1】 Hatakeyama, S.; et al.; Synthesis and biological characterization of 1alpha,24,25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (24-hydroxylated ED-71). Steroids 2001, 66, 3-5, 267. |
| 【2】 Watanabe, H.; Hatakeyama, S.; Kawase, A. (Chugai Pharmaceutical Co. Ltd.); 24-Hydroxyvitamin D derivs.. EP 1061070; WO 9943645 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46307 | benzyl [(2R,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2R,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XV) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XVI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XVIII) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XIX) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XX) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XXI) | 46313 | 3-([(1R)-1-[(1R)-1,2-dihydroxyethyl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl]oxy)propyl pivalate | C19H34O7 | 详情 | 详情 | |
| (XXII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XXIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXIV) | 46315 | (4R,5R)-4-(3-hydroxypropoxy)-1-octen-7-yne-3,5-diol | C11H18O4 | 详情 | 详情 | |
| (XXV) | 46316 | (5R,6R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-butynyl)-2,2,3,3,12,12,13,13-octamethyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane; tert-butyl(dimethyl)silyl 3-[[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propenyl)-4-pentynyl]oxy]propyl ether | C29H60O4Si3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(A)Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |