Synthesis of N-Acylated 1,5-Benzodiazepines: Differentiation between Two Possible Acylation Sites via Hydrogen Bonding

Temperature-dependent regioselectivity between amino and hydroxyl groups mediated by hydrogen bonding was observed in the reaction of acetic anhydride with 2-(2,3-dimethoxyphenyl)- 4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1), obtaining 1-acetyl-2-(2,3-dimethoxyphenyl)- 4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1a), when these were reacted at room temperature, and 4-(2-acetoxyphenyl)-1-acetyl-2-(2,3-dimethoxyphenyl)-2,3-dihydro-1H-1,5- benzodiazepine (1b), when they were refluxed (148 - 150 °C). Acylation of the less hindered analog 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2) via crotonyl chloride (a bulky acylating agent compared with acetic anhydride) afforded by refluxing only 1-crotonyl-4- (2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2a). All compounds were characterized spectroscopically, and the molecular structures of compounds 1a and 2a were determined by X-ray diffraction analysis.

Alkene Metathesis: Synthesis of Kainic Acid, Pladienolide B and Amphidinolide Y

As alkene metathesis has developed into one of the tools of organic synthesis, many practical questions have arisen. In the course of a synthesis (Organic Lett. 2007, 9, 1635) of the important neuropharmacological tool (-)-kainic acid 7, Tohru Fukuyama of the University of Tokyo prepared the key intermediate 1 by chiral auxiliary mediated coupling of crotonyl chloride with acetadehyde. Dibal reduction gave the hemiaminal, which underwent reductive amination with glycine methyl ester, leading to the alkene 2. Alkene metathesis of the derived ester 3 to form the unsaturated lactone 4 was then examined in detail. It was found that 0.5 mol % of the second generation Hoveyda catalyst was sufficient to cyclize 3 to 4 in 92% yield. With 0.8 mol %, the yield was 99%. The key to the efficacy of this cyclization was the use of 1,2-dichloroethane at reflux as the reaction solvent. The macrolide pladienolide D 14 induces in vivo tumor regression in several human cancer xenograft models. This activity was important enough that a team at Esai Co., Ltd in Tsukuba headed by Yoshihiko Kotake undertook the total synthesis (Angew. Chem. Int. Ed. 2007, 46, 4350). Their approach used two alkene metathesis steps. To prepare the substrate for the macrolide construction, the alcohol 8 and the acid 9, each prepared by chiral auxiliary control, were coupled to give the ester 10. An extensive investigation led to alkene metathesis conditions that were satisfactory, the use of the second generation Hoveyda catalyst in refluxing toluene. A significant competing side reaction was the migration of the monosubstituted alkene of 10 to make the alkenyl ether. The second alkene metathesis step was the coupling of 12 with 13. The most effective catalyst in this case was the second generation Grubbs. Note that the free alcohol 13 participated successfully in the cross-coupling. According to the authors, this is one of just a few examples of successful cross coupling of an alkene adjacent to a quaternary center. The stereocontrolled construction of trisubstituted alkenes by metathesis is a particular challenge.

2,2-Dimethylsuccinic acid derivatives in isoprenoid synthesis: a 2,2-dimethylvinyl anion equivalent in the synthesis of ar-atlantone, ar-turmerone, and prenylated aromatic compounds

The anion of methyl 2,2-dimethylsuccinate was alkylated with benzylic bromides to give the corresponding 3-substituted-2,2-dimethylsuccinates. Hydrolysis to the dicarboxylic acids, followed by bisdecarboxylation with lead tetraacetate, afforded 1-aryl-3-methyl-2-butenes, which are model prenylated aromatic compounds. Acylation of methyl 2,2-dimethylsuccinate with E-3-(4′-methylphenyl) crotonyl chloride gave the substituted succinate 9. Hydrolysis of the ester groups and acid-catalyzed decarboxylation of the resulting β-ketoacid produced the keto acid 10, which was decarboxylated by the Kochi method, furnishing ar-atlantone. Hydrogenation of 10 yielded 12, which on similar decarboxylation afforded ar-turmerone.