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【结 构 式】 
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【分子编号】22422 【品名】5,7-dihydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one 【CA登记号】 |
【 分 子 式 】C11H12O4 【 分 子 量 】208.21388 【元素组成】C 63.45% H 5.81% O 30.74% |
合成路线1
该中间体在本合成路线中的序号：(XXI)3) Synthesis of ent-Calanolide A, (-)-calanolide A: The Clemensen reduction of 5,7-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one (XXI) with Zn/HCl in methanol gives 5,7-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran (XXII), which is condensed with methyl 2-hexynoate (XXIII) using the palladium catalyst Pd2dba3 to yield dihydrobenzodipyran (XXIV). The regio- and enantioselective allylic alkylation of (XXIV) with 2-methyl-2(E)-butenyl carbonate (XXV) catalyzed by Pd2dba3 using a chiral ligand affords the chiral dihydrobenzodipyran ether (XXVI), which is dehydrogenated with dichlorodicyanobenzoquinone (DDQ) in dioxane to (XXVII). The chemoselective hydroboration of (XXVII) with 9-BBN and H2O2 gives the alcohol (XXVIII) with high diastereomeric selectivity. The Dess-Martin oxidation of (XXVIII) yields the expected aldehyde (XXIX), which is cyclized to (10S,11R,12R)-benzotripyran (XXX) (ent-calanolide B). Finally, this compound is converted into ent-calanolide A by inversion of the C-12 hydroxy group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol. The authors indicate that Calanolide A can be synthesized in the same way by simply using the mirror image of the chiral ligand in the addition of carbonate (XXV) to dihydrobenzodipyran (XXIV).
| 【1】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【2】 Toste, F.D.; Trost, B.M.; A catalytic enantioselective approach to chromans. J Am Chem Soc 1998, 120, 35, 9074. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 22422 | 5,7-dihydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C11H12O4 | 详情 | 详情 | |
| (XXII) | 22423 | 2,2-dimethyl-5,7-chromanediol | C11H14O3 | 详情 | 详情 | |
| (XXIII) | 19609 | methyl 2-hexynoate | 18937-79-6 | C7H10O2 | 详情 | 详情 |
| (XXIV) | 22425 | 5-hydroxy-2,2-dimethyl-10-propyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-8-one | C17H20O4 | 详情 | 详情 | |
| (XXV) | 22426 | methyl (E)-2-methyl-2-butenyl carbonate | C7H12O3 | 详情 | 详情 | |
| (XXVI) | 22427 | 5-[[(1S)-1,2-dimethyl-2-propenyl]oxy]-2,2-dimethyl-10-propyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-8-one | C22H28O4 | 详情 | 详情 | |
| (XXVII) | 22428 | 5-[[(1S)-1,2-dimethyl-2-propenyl]oxy]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C22H26O4 | 详情 | 详情 | |
| (XXVIII) | 22429 | 5-[[(1S,2R)-3-hydroxy-1,2-dimethylpropyl]oxy]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C22H28O5 | 详情 | 详情 | |
| (XXIX) | 22430 | (2S,3S)-3-[(2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromen-5-yl)oxy]-2-methylbutanal | C22H26O5 | 详情 | 详情 | |
| (XXX) | 22431 | (10S,11R,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Friedel Crafts' condensation of phloroglucinol (I) with 3,3-dimethylacrylic acid (II) in the presence of boron trifluoride etherate gave the dihydroxy chromanone (III). Selective alkylation of the 7-hydroxyl group of (III) with iodomethane in the presence of K2CO3 furnished the methyl ether (IV). The carbonyl group of (IV) was subsequently reduced with NaBH4 in refluxing THF under basic conditions to produce chroman (V). The lactone ring of (VII) was then formed by a Pechmann reaction of (V) using ethyl acetoacetate (VI) and boron trifluoride to afford the tricyclic compound (VII). Dehydrogenation of (VII) employing DDQ in refluxing dioxan gave (VIII). The target 3'R,4'R-dihydroxylated derivative (IX) was obtained by Sharpless asymmetric dihydroxylation of (VIII) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst. Diol (IX) was finally esterified with (-)-S-camphanoyl chloride (X) to afford the title diester.
| 【1】 Takeuchi, Y.; McPhail, A.T.; Cosentino, L.M.; Lee, K.-H.; Xie, L.; Anti-AIDS agents.42. Synthesis and anti-HIV activity of disubstituted (3'R, 4'R)-3',4'-Di-O-(S)-camphanoyl-(+)-cis-khellactone analogues. J Med Chem 2001, 44, 5, 664. |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 22422 | 5,7-dihydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C11H12O4 | 详情 | 详情 | |
| (IV) | 47784 | 5-hydroxy-7-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one | C12H14O4 | 详情 | 详情 | |
| (V) | 47785 | 7-methoxy-2,2-dimethyl-5-chromanol | C12H16O3 | 详情 | 详情 | |
| (VI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VII) | 47786 | 5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O4 | 详情 | 详情 | |
| (VIII) | 47787 | 5-methoxy-4,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one | C16H16O4 | 详情 | 详情 | |
| (IX) | 47788 | (9R,10R)-9,10-dihydroxy-5-methoxy-4,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C16H18O6 | 详情 | 详情 | |
| (X) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |