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【结 构 式】 
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【分子编号】35896 【品名】bromo(3-butenyl)magnesium 【CA登记号】7103-09-5 |
【 分 子 式 】C4H7BrMg 【 分 子 量 】159.30858 【元素组成】C 30.16% H 4.43% Br 50.16% Mg 15.26% |
合成路线1
该中间体在本合成路线中的序号：(LII)The silylation of hydroxyester (XLVIII) with Tips-Cl and imidazole in THF gives the fully protected compound (XLIX), which is reduced with DIBAL in dichloromethane to the carbinol (L).The epoxidation of the double bond of (L) with MCPBA in dichloromethane yields the epoxide (LI), which is condensed with the Grignard reagent (LII) by means of CuI in ethyl ether/THF affording the diol (LIII). Esterification of the primary OH group of (LIII) with pivaloyl chloride gives the ester (LIV), which is desilylated with TBAF in THF providing the diol (LV). The cyclic ketalization of (LV) catalyzed by PdCl2 and benzoquinone yields the cyclic ketal (LVI), which is debenzylated as usual affording the primary alcohol (LVII). The oxidation of (LVII) with TPAP and NMO in dichloromethane gives the aldehyde (LVIII), which is condensed with diazophosphonate (XXVII) by means of K2CO3 in methanol yielding the ethynyl derivative (LIX), with simultaneous hydrolysis of the pivaloyl ester. The reaction of (LIX) with tributyltin hydride and PdCl2 in dichloromethane affords the vinyl stannane derivative (LX). Finally, the hydroxymethyl group of (LX) is oxidized with TPAP, NMO and NaClO2 to the corresponding carboxylic group of the desired tributylstannane intermediate (XXXII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVII) | 35884 | diethyl 1-diazo-2-oxopropylphosphonate | C7H13N2O4P | 详情 | 详情 | |
| (XXXII) | 35904 | (4S,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid | C24H44O4Sn | 详情 | 详情 | |
| (XLVIII) | 35892 | ethyl (E,4R,5R)-6-(benzyloxy)-5-hydroxy-4-methyl-2-hexenoate | C16H22O4 | 详情 | 详情 | |
| (XLIX) | 35893 | ethyl (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexenoate | C25H42O4Si | 详情 | 详情 | |
| (L) | 35894 | (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexen-1-ol | C23H40O3Si | 详情 | 详情 | |
| (LI) | 35895 | ((2S,3R)-3-[(1R,2R)-3-(benzyloxy)-1-methyl-2-[(triisopropylsilyl)oxy]propyl]oxiranyl)methanol | C23H40O4Si | 详情 | 详情 | |
| (LII) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (LIII) | 35897 | (2S,3S,4R,5R)-6-(benzyloxy)-2-(3-butenyl)-4-methyl-5-[(triisopropylsilyl)oxy]-1,3-hexanediol | C27H48O4Si | 详情 | 详情 | |
| (LIV) | 35898 | (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1-hydroxy-2-methyl-3-[(triisopropylsilyl)oxy]butyl]-5-hexenyl pivalate | C32H56O5Si | 详情 | 详情 | |
| (LV) | 35899 | (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1,3-dihydroxy-2-methylbutyl]-5-hexenyl pivalate | C23H36O5 | 详情 | 详情 | |
| (LVI) | 35900 | [(4S,6S)-3-[(benzyloxy)methyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C23H34O5 | 详情 | 详情 | |
| (LVII) | 35901 | [(4S,6S)-3-(hydroxymethyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C16H28O5 | 详情 | 详情 | |
| (LVIII) | 35902 | [(4S,6S)-3-formyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C16H26O5 | 详情 | 详情 | |
| (LIX) | 35903 | [(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C12H18O3 | 详情 | 详情 | |
| (LX) | 32448 | [(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C24H46O3Sn | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Methyl (R)-7-(3-hydroxy-5-oxo-1-cyclopent-1-yl)heptanoate (I) was protected as the silyl ether (II) using tert-butyldimethylsilyl triflate and 2,6-lutidine. Conjugate addition to (II) of the organocuprate reagent derived from butenylmagnesium bromide (III) and CuBr produced adduct (IV). Reduction of the keto group of (IV) with NaBH4, followed by silylation of the resulting alcohol (V), furnished the bis-silyl ether (VI). Subsequent olefin oxidative cleavage by means of potassium osmate and sodium periodate gave rise to aldehyde (VII). To this was added 2-lithiobenzothiophene (VIII) to yield carbinol (IX). Desilylation of (IX) to triol (X) was then achieved by using HF in pyridine. The methyl ester group of (X) was finally hydrolyzed with LiOH to give the title carboxylic acid.
| 【1】 deLong, M.A.; Soper, D.L.; De, B.; Wos, J.A. (The Procter & Gamble Co.); C16 unsaturated FP-selective prostaglandins analogs. WO 0051980 . |
| 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) | 46438 | methyl 7-[(3R)-3-hydroxy-5-oxo-1-cyclopenten-1-yl]heptanoate | 41138-61-8 | C13H20O4 | 详情 | 详情 |
| (II) | 46439 | methyl 7-((3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-oxo-1-cyclopenten-1-yl)heptanoate | C19H34O4Si | 详情 | 详情 | |
| (III) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (IV) | 46440 | methyl 7-((1R,2R,3R)-2-(3-butenyl)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-oxocyclopentyl)heptanoate | C23H42O4Si | 详情 | 详情 | |
| (V) | 46441 | methyl 7-((1R,2R,3R,5S)-2-(3-butenyl)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxycyclopentyl)heptanoate | C23H44O4Si | 详情 | 详情 | |
| (VI) | 46442 | methyl 7-((1R,2R,3R,5S)-2-(3-butenyl)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)heptanoate | C29H58O4Si2 | 详情 | 详情 | |
| (VII) | 46443 | methyl 7-[(1R,2R,3R,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-(3-oxopropyl)cyclopentyl]heptanoate | C28H56O5Si2 | 详情 | 详情 | |
| (VIII) | 46444 | 1-benzothiophen-2-yllithium | C8H5LiS | 详情 | 详情 | |
| (IX) | 46445 | methyl 7-((1R,2R,3R,5S)-2-[3-(1-benzothiophen-2-yl)-3-hydroxypropyl]-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)heptanoate | C36H62O5SSi2 | 详情 | 详情 | |
| (X) | 46446 | methyl 7-[(1R,2R,3R,5S)-2-[3-(1-benzothiophen-2-yl)-3-hydroxypropyl]-3,5-dihydroxycyclopentyl]heptanoate | C24H34O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXV)A further procedure for the preparation of the key intermediate (XIII) utilized the chiral starting material (S)-4-benzyloxy-1,2-butanediol (XIX), easily accessible from (S)-malic acid. Inversion of the configuration of (XIX) was accomplished via formation of dimesylate (XX), followed by displacement with potassium acetate in refluxing Ac2O. The resultant diacetate (XXI) was hydrolyzed to the required (R)-diol (XXII) by treatment with K2CO3 in MeOH. Conversion of (XXII) into epoxide (XXIV) was performed through the benzylidene ketal (XXIII), following the reported procedure for the corresponding (S)-enantiomer. Copper(I)-catalyzed addition of 3-butenylmagnesium bromide (XXV) to epoxide (XXIV) furnished alcohol (XXVI), which was further protected as the benzyl ether (XXVII). Hydroboration of olefin (XXVII) with in situ generated disiamylborane, followed by oxidative work-up gave rise to the primary alcohol (XXVIII). This was oxidized with pyridinium dichromate to the carboxylic acid (XXIX), which was further esterified by means of methanolic HCl to afford ester (XXX). Then, catalytic hydrogenolysis of the di(benzyloxy) ester (XXX) yielded the target intermediate dihydroxyester (XIII).
| 【1】 Brookes, M.H.; et al.; Syntheses of alpha-(R)- and alpha-(S)-lipoic acid from (S)-malic acid. J Chem Soc - Perkins Trans I 1988, 1, 9. |
| 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) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XIX) | 58043 | (2S)-4-(benzyloxy)-1,2-butanediol | C11H16O3 | 详情 | 详情 | |
| (XX) | 58044 | (2S)-4-(benzyloxy)-2-[(methylsulfonyl)oxy]butyl methanesulfonate | C13H20O7S2 | 详情 | 详情 | |
| (XXI) | 58045 | (2R)-2-(acetyloxy)-4-(benzyloxy)butyl acetate | C15H20O5 | 详情 | 详情 | |
| (XXII) | 58052 | (2R)-4-(benzyloxy)-1,2-butanediol | C11H16O3 | 详情 | 详情 | |
| (XXIII) | 58046 | (4R)-4-[2-(benzyloxy)ethyl]-2-phenyl-1,3-dioxolane; benzyl 2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]ethyl ether | C18H20O3 | 详情 | 详情 | |
| (XXIV) | 42367 | benzyl 2-[(2S)oxiranyl]ethyl ether; (2S)-2-[2-(benzyloxy)ethyl]oxirane | C11H14O2 | 详情 | 详情 | |
| (XXV) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (XXVI) | 58047 | (3S)-1-(benzyloxy)-7-octen-3-ol | C15H22O2 | 详情 | 详情 | |
| (XXVII) | 58048 | 1-({[(3S)-3-(benzyloxy)-7-octenyl]oxy}methyl)benzene; benzyl (1S)-1-[2-(benzyloxy)ethyl]-5-hexenyl ether | C22H28O2 | 详情 | 详情 | |
| (XXVIII) | 58049 | (6S)-6,8-bis(benzyloxy)-1-octanol | C22H30O3 | 详情 | 详情 | |
| (XXIX) | 58050 | (6S)-6,8-bis(benzyloxy)octanoic acid | C22H28O4 | 详情 | 详情 | |
| (XXX) | 58051 | methyl (6S)-6,8-bis(benzyloxy)octanoate | C23H30O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIX)The C1-C6 building block (V) (segment A) can be obtained as follows. Protection of (–)-pantolactone (X) as the tetrahydropyranyl ether (XI) using dihydropyran and pyridinium tosylate, followed by reduction of the lactone ring with DIBAL in cold toluene, gives the lactol (XII). Subsequent Wittig reaction of the cyclic hemiacetal (XII) with methylene triphenylphosphorane affords the hydroxy olefin (XIII), which is protected as the benzyl ether (XIV) by treatment with benzyl bromide and potassium tert-butoxide. Hydroboration of olefin (XIV) followed by quenching with alkaline H2O2 provides the primary alcohol (XV) as the major isomer, which is converted to the acetonide (XVI) by treatment with 2,2-dimethoxypropane and p-toluenesulfonic acid. After catalytic hydrogenolysis of the benzyl ether (XVI), the deprotected alcohol (XVII) is oxidized to aldehyde (XVIII) under Swern conditions. Then, addition of 3-butenylmagnesium bromide (XIX) to the aldehyde (XVIII) provides alcohol (XX), which is oxidized to the target ketone (V) by treatment with N-methylmorpholine N-oxide and a catalytic amount of tetrapropylammonium perruthenate (3). Scheme 2.
| 【3】 Klar, U., Rohr, B., Kuczynski,F., Schwede, W., Berger, M., Skuballa, W., Buchmann, B. Efficient chiral pool synthesis of the C1-C6 fragment of epothilone. Synthesis 2005, (2): 301-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 65648 | C14H24O3 | 详情 | 详情 | ||
| (X) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (XI) | 65653 | C11H19O4 | 详情 | 详情 | ||
| (XII) | 65654 | C11H21O4 | 详情 | 详情 | ||
| (XIII) | 65655 | C12H23O3 | 详情 | 详情 | ||
| (XIV) | 65656 | C19H28O3 | 详情 | 详情 | ||
| (XV) | 65657 | C19H31O4 | 详情 | 详情 | ||
| (XVI) | 65658 | C17H26O3 | 详情 | 详情 | ||
| (XVII) | 65659 | C10H20O3 | 详情 | 详情 | ||
| (XVIII) | 65660 | C10H18O3 | 详情 | 详情 | ||
| (XIX) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (XX) | 65661 | C14H26O3 | 详情 | 详情 |