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【结 构 式】 
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【分子编号】65488 【品名】complex of (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal with Fe(CO)3 【CA登记号】 |
【 分 子 式 】C15H22O.Fe(CO)3 【 分 子 量 】358.215 【元素组成】C 60.35% H 6.19% O 17.86% Fe 15.59% |
合成路线1
该中间体在本合成路线中的序号：(XII)Alitretinoin esters (IIa) and (IIb) can be prepared by a variety of methods. Horner-Emmons reaction of either the ionylideneacetaldehyde (V) (3, 4) or its tricarbonyl iron complex (XII) (5) with diethyl 3-(ethoxycarbonyl)-2-methylprop-2-enylphosphonate (XIII), optionally followed by decomplexation using CuCl2 in EtOH, provides alitretinoin ethyl ester (IIa). Alternatively, Wittig reaction of aldehyde (V) with iodomethylenetriphenylphosphorane, followed by in situ elimination of HI using an excess of sodium hexamethyldisilazide, and then addition of lithium butyl(tributylstannyl)cyanocuprate to the obtained terminal acetylene, leads to the unstable vinyl stannane (XIV). Subsequent Stille coupling of crude stannane (XIV) with the vinyl triflate (XV) (derived from ethyl acetoacetate) furnishes the target 9-cis-retinoate (IIa) (6). In a different route, the addition of lithium butyl(tributylstannyl)-cyanocuprate (generated from Bu3SnH, BuLi and CuCN) to (Z)-3-methyl-2-penten-4-yn-1-ol (XVI) and MnO2 oxidation of the allyl alcohol function results in the stannyl dienal (XVII). Subsequent Horner-Emmons reaction of aldehyde (XVII) with phosphonate (XIII) followed by iododestannylation of the obtained adduct furnishes the tetraenyl iodide (XVIII). 2,2,6-Trimethylcyclohexanone (XIX) is reacted with hydrazine hydrate and Et3N in boiling EtOH to produce the corresponding hydrazone, which is converted to vinyl iodide upon treatment with iodine and DBN. Metalation of the vinyl iodide with t-BuLi followed by trapping with trimethyl borate generates an unstable intermediate, assumed to be the boronic ester (XX). Then, Suzuki coupling between the in situ-generated boronate (XX) and freshly prepared tetraenyl iodide (XVIII) provides the target cis-retinoate (IIa) in satisfactory yields (7, 8). Two related synthetic strategies, useful for introducing tritium labeling onto the cyclohexenyl ring of (II), are based on the catalytic hydrogenation of the conjugated cyclohexadiene compound (XXIa) or its nonconjugated analogue (XXIb) in the presence of Rh(PPh3)3Cl (9). Compound (IIb), along with some labeled derivatives, can be prepared by the following route. Condensation of 2,2,6-trimethylcyclohexanone (XIX) with the bromomagnesium acetylide of (Z)-3-methyl-2-penten-4-yn-1-ol (XVI) affords the propargylic alcohol adduct (XXII). After reduction of the triple bond of (XXII) with LiAlH4, oxidation of the primary alcohol group using MnO2 in dry CH2Cl2 yields the hydroxy dienal (XXIII). Wittig olefination of aldehyde (XXIII) with (methoxycarbonylmethylene)triphenylphosphorane followed by smooth dehydration of the tertiary alcohol with 80% formic acid in hexane then leads to the tetraenoate ester (XXIV). After reduction of ester (XXIV) with DIBALH and reoxidation of the obtained alcohol to aldehyde with MnO2, the addition of methylmagnesium bromide results in the secondary alcohol (XXV). The deuterium and tritium analogues of (XXV) can be similarly obtained by using the corresponding labeled Grignard reagents. Subsequent oxidation of (XXV) with MnO2 followed by condensation of the resulting methyl ketone with methyl diethylphosphonoacetate leads to the 9-cis-methylretinoate (IIb) (10, 11). Scheme 2.
| 【3】 Boehm, M.F., McClurg, M.R., Pathirana, C. et al. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994, 37(3): 408-14. |
| 【4】 Bennani, Y.L. An efficient and stereoselective synthesis of 9-cis-retinoic acid. J Org Chem 1996, 61(10): 3542-4. |
| 【5】 Wada, A., Hiraishi, S., Takamura, N., Date, T., Aoe, K., Ito, M. A novel method for a stereoselective synthesis of trisubstituted olefin using tricarbonyliron complex: A highly stereoselective synthesis of (all-E)- and (9Z)-retinoic acids. J Org Chem 1997, 62(13): 4343-8. |
| 【6】 Wada, A., Fukunaga, K., Ito, M., Mizuguchi, Y., Nakagawa, K., Okano, T. Preparation and biological activity of 13-substituted retinoic acids. Bioorg Med Chem 2004, 12(14): 3931-42. |
| 【7】 Pazos, Y., de Lera, A.R. Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction. Tetrahedron Lett 1999, 40(47): 8287-90. |
| 【8】 Pazos, Y., Iglesias, B., de Lera, A.R. The Suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues. J Org Chem 2001, 66(25): 8483-9. |
| 【9】 Bennani, Y.L., Boehm, M.F. Synthesis of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid. J Org Chem 1995, 60(5): 1195-200. |
| 【10】 Tadikonda, P.K., Lacy, J.M., Rigdon, M.G., DeLuca, H.F. Synthesis of 9-cis-retinoic acid and C-20-[3H3C]-9-cis-retinoic acid with high specific activity. J Label Comp Radiopharm 1997, 34(1): 1-10. |
| 【11】 DeLuca, H.F., Tadikonda, P.K. (Wisconsin Alumni Res. Found.). Method of synthesis of retinoic acid. US 5808120. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Iia) | 65476 | 9-cis-Retinoic acid ethyl ester; Ethyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate | C22H32O2 | 详情 | 详情 | |
| (IIb) | 65477 | 9-cis-Retinoic acid methyl ester; Methyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate | C21H30O2 | 详情 | 详情 | |
| (V) | 65481 | (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal | 1209-68-3 | C15H22O | 详情 | 详情 |
| (XII) | 65488 | complex of (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal with Fe(CO)3 | C15H22O.Fe(CO)3 | 详情 | 详情 | |
| (XIII) | 44704 | ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate | 41891-54-7 | C11H21O5P | 详情 | 详情 |
| (XIV) | 65489 | C28H50Sn | 详情 | 详情 | ||
| (XV) | 65490 | C7H9F3O5S | 详情 | 详情 | ||
| (XVI) | 65491 | (Z)-3-methylpent-2-en-4-yn-1-ol | 105-29-3 | C6H8O | 详情 | 详情 |
| (XVII) | 65492 | C18H34OSn | 详情 | 详情 | ||
| (XVIII) | 65493 | C13H17IO2 | 详情 | 详情 | ||
| (XIX) | 65494 | 2,2,6-Trimethylcyclohexanone | C9H15O | 详情 | 详情 | |
| (XX) | 65495 | C11H21BO2 | 详情 | 详情 | ||
| (XXI) | 65496 | C22H30O2 | 详情 | 详情 | ||
| (XXII) | 65497 | C15H24O2 | 详情 | 详情 | ||
| (XXIII) | 65498 | C15H24O2 | 详情 | 详情 | ||
| (XXIV) | 65499 | C18H26O2 | 详情 | 详情 | ||
| (XXV) | 65500 | C18H28O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The aldehyde intermediates (V) and (XII) are produced starting from β-ionone (XXVI) by several different methods. The lithium enolate of ketone (XXVI) is acylated with diethyl chlorophosphate to produce an enol phosphate intermediate, which undergoes regioselective β-elimination in the presence of LDA to furnish acetylene (XXVII). Deprotonation of (XXVII) with butyl lithium followed by treatment with phenyl cyanate gives nitrile (XXVIII), which undergoes conjugate addition of dimethyl cuprate in cold THF to afford the cis-trienenitrile (XXIX). Subsequent reduction of nitrile (XXIX) using DIBALH in hexane at –78 °C provides the target aldehyde (V) as the major isomer (4). Alternatively, Reformatsky reaction of β-ionone (XXVI) with the organo zinc reagent derived from ethyl bromoacetate followed by acidic dehydration produces a mixture of cis- and trans-ionylideneacetates (XXX), which, after saponification to the corresponding carboxylic acids, are separated by fractional crystallization from acetonitrile. The desired cis-isomer (XXXI) is then esterified by treatment with iodomethane and potassium carbonate under nonisomerizing conditions to furnish the cis-methyl ester (XXXIIa) (14). Reduction of ester (XXXIIa) with LiAlH4 in cold THF followed by re-oxidation of the resulting alcohol with MnO2 in CH2Cl2 affords aldehyde (V) (3, 14). The analogous tritium-labeled intermediate is similarly obtained utilizing [3H]-LiAlH4 in the reduction step (3). The tricarbonyliron complex of β-ionone (XXXIII) can be conveniently prepared by treatment of (XXVI) with dodecacarbonyltriiron(0) in boiling benzene. Condensation of (XXXIII) with the lithium enolate of ethyl acetate in cold THF gives the hydroxy ester adduct (XXXIV), which is dehydrated by means of SOCl2 in pyridine to produce the (9Z)-conjugated ester (XXXV) as the major isomer. Reduction of ester (XXXV) with DIBALH in Et2O at –45 °C yields the trienol derivative (XXXVI), which is converted to aldehyde (XII) without decomplexation by mild oxidation of the corresponding bromomagnesium alkoxide with azodicarbonyldipiperidine under Mukaiyama’s conditions. Alternatively, decomplexation of (XXXV) with CuCl2 provides the ethyl ester (XXXIIb), which is reduced to aldehyde (V) following known procedures (5). Scheme 3.
| 【3】 Boehm, M.F., McClurg, M.R., Pathirana, C. et al. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994, 37(3): 408-14. |
| 【4】 Bennani, Y.L. An efficient and stereoselective synthesis of 9-cis-retinoic acid. J Org Chem 1996, 61(10): 3542-4. |
| 【5】 Wada, A., Hiraishi, S., Takamura, N., Date, T., Aoe, K., Ito, M. A novel method for a stereoselective synthesis of trisubstituted olefin using tricarbonyliron complex: A highly stereoselective synthesis of (all-E)- and (9Z)-retinoic acids. J Org Chem 1997, 62(13): 4343-8. |
| 【14】 Robeson, C.D., Cawley, J.D., Weisler, L., Stern, M.H., Eddinger, C.C., Chechak, A.J. Chemistry of vitamin A. XXIV. The synthesis of geometric isomers of vitamin A via methyl beta-methylglutaconate. J Am Chem Soc 1955, 77(15): 4111. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIIa) | 65506 | C16H24O2 | 详情 | 详情 | ||
| (XXXIIb) | 65507 | C17H26O2 | 详情 | 详情 | ||
| (V) | 65481 | (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal | 1209-68-3 | C15H22O | 详情 | 详情 |
| (XII) | 65488 | complex of (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal with Fe(CO)3 | C15H22O.Fe(CO)3 | 详情 | 详情 | |
| (XXVI) | 39584 | (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one | 14901-07-6 | C13H20O | 详情 | 详情 |
| (XXVII) | 65501 | 73395-75-2 | C13H18 | 详情 | 详情 | |
| (XXVIII) | 65502 | C14H17N | 详情 | 详情 | ||
| (XXIX) | 65503 | C15H21N | 详情 | 详情 | ||
| (XXX) | 65504 | (2E,4E)-3-Methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)penta-2,4-dienoic acid ethyl ester | 5452-61-9 | C17H26O2 | 详情 | 详情 |
| (XXXI) | 65505 | C15H22O2 | 详情 | 详情 | ||
| (XXXIII) | 65508 | C13H20O.Fe(CO)3 | 详情 | 详情 | ||
| (XXXIV) | 65509 | C17H28O3.Fe(CO)3 | 详情 | 详情 | ||
| (XXXV) | 65510 | C17H26O2.Fe(CO)3 | 详情 | 详情 | ||
| (XXXVI) | 65511 | C15H24O.Fe(CO)3 | 详情 | 详情 |