Bifunctional Cinchona Alkaloid Thiourea Catalyzed Highly Efficient, Enantioselective Aza‐Henry Reaction of Cyclic Trifluoromethyl Ketimines: Synthesis of Anti‐HIV Drug DPC 083

Abstract

Biologisch interessante chirale Trifluormethyldihydrochinazolinon‐Gerüste werden durch die Titelreaktion mit nur 1 Mol‐% Katalysator in hohen Ausbeuten (bis 97 %) und mit hohen Enantioselektivitäten (bis 98 % ee) aufgebaut. Eine effiziente Synthese des potenziellen Anti‐HIV‐Wirkstoffs DPC 083 nutzte diese hoch enantioselektive Aza‐Henry‐Reaktion als Schlüsselschritt.

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β‐Amino Esters and Anti‐HIV Drug DPC 083

“…Among them, catalyst (d, S, S)-Bd exhibited the best catalytic activity and chiral induction ability (entry 8). Solvent screening revealed that THF remains to be the solvent of choice, and other solvents such as chloroform, dichloromethane, toluene, and 1,4-dioxane diminish the yield and/or enantioselectivity (entries [11][12][13][14]. The catalyst loading can be reduced to as low as 1 mol % without a significant decrease in the product yield and enantioselectivity, although a prolonged time was required (entries 15 and 16).…”

“…The optical rotation data of DPC 083 (10) are entirely consistent with those described in the literature. [13] Thus, the determination of the stereochemistry of 10 was used as the basis for the assignment of absolute configuration reported in Table 1 and Scheme 1.…”

Synthesis of Condensed Heterocycles, Containing Partially Saturated Pyrimidine Nuclei, from Aromatic Pyrimidine Derivatives

“…) . Moreover, as already mentioned above, N1‐protected 4‐arylquinazolin‐2(1 H )‐ones are inert in aza‐Henry , Mannich and decarboxylative Mannich reactions. At the same time the investigations on the behavior of 4‐arylsubstituted quinazolin‐2(1 H )‐ones under Strecker reaction conditions showed that upon carrying out this reaction in CH 2 Cl 2 in the presence of 73a (10 mol %) as a catalyst the corresponding adducts were obtained with good yields and moderate ee values.…”

“…A highly efficient hydrogen bond‐mediated enantioselective addition of nitroalkanes to 4‐trifluoromethylquinazolin‐2(1 H )‐ones 58 (aza‐Henry reaction) has been achieved in toluene at room temperature in the presence of 1 mol% thiourea‐containing quinine derivative as a catalyst (Scheme ). Dihydroquinazolin‐2(1 H )‐ones 59 were obtained in 72–97% yields with good to excellent enantioselectivity (82–98% ee ) unaffected by the electronic nature of the substituents on the aromatic rings of the cyclic ketimine.…”

Palladium‐Catalyzed Asymmetric Arylation of Trifluoromethylated/Perfluoroalkylated 2‐Quinazolinones with High Enantioselectivity

“…Dihydroquinazolinones containing at rifluoromethylg roup at the 4-position are known to be biologically active. [8] Literature reports for their asymmetric synthesis are focused on enantioselective additiont o4 -trifluoromethyl-2quinazolinone derivatives, [9][10][11][12][13] and successfully employed nucleophiles include ketone enolates, [9] nitroalkanes, [10] cyanide, [11] indoles, [12] and isocyanoacetates. [13] To the best of our knowledge, there is no report on the catalytic asymmetric arylation of 2-quinazolinone derivatives with arylboron reagents.…”