Core-structure-inspired asymmetric addition reactions: enantioselective synthesis of dihydrobenzoxazinone- and dihydroquinazolinone-based anti-HIV agents

Abstract

Dihydrobenzoxazinones and dihydroquinazolinones are the core units present in many anti-HIV agents, such as Efavirenz, DPC 961, DPC 963, and DPC 083. All these molecules contain a trifluoromethyl moiety at the quaternary stereogenic carbon center with S configuration. The enantioselective addition of carbon nucleophiles to ketones or cyclic ketimines could serve as a key step to access these molecules. This tutorial review provides an overview of significant advances in the synthesis of dihydrobenzoxazinone- and dihydroquinazolinone-based anti-HIV agents and relative analogues, with an emphasis on asymmetric addition reactions for the establishment of the CF3-containing quaternary carbon centers.

Basenfreie katalytische asymmetrische C‐C‐Kupplung mit terminalen Inamiden als effizienter Zugang zu multifunktionellen Trifluormethylalkoholen

“…Ergebnisse wurden mit einer Serie an funktionalisierten Analoga erhalten (Nr. [5][6][7][8][9][10][11][12]. Der Wert der b-Hydroxyinamide für Synthesen beruht auf der hohen Dichte an funktionellen Gruppen, die in einem relativ kleinen chiralen Baustein vereint sind.…”

“…[1] Im Unterschied zum allgemeinen Fortschritt bei asymmetrischen Alkinadditionen an Aldehyde, [2] Ketone [3] und Imine, [4] verbleiben Umsetzung von Tr ifluormethylketonen weiterhin eine Herausforderung, [5] die anfangs das Einsetzen von stç-chiometrischen Mengen an Lithium-oder Zink-Aminalkoxiden erforderte.…”

“…Die Bedeutung der trifluormethylsubstituierten Propargylalkohol-Gruppe,z um Beispiel im Anti-HIV-Arzneimittel Efavirenz, hat die Entwicklung mehrerer Methoden, die dieses Motiv in racemischer Form herstellen, stimuliert. [1] Im Unterschied zum allgemeinen Fortschritt bei asymmetrischen Alkinadditionen an Aldehyde, [2] Ketone [3] und Imine, [4] verbleiben Umsetzung von Tr ifluormethylketonen weiterhin eine Herausforderung, [5] die anfangs das Einsetzen von stçchiometrischen Mengen an Lithium-oder Zink-Aminalkoxiden erforderte. [6] Shibasaki und Mitarbeiter zeigten zuerst die Mçglichkeit der asymmetrischen Katalyse auf,u mC F 3 -substituierte Propargylalkohole mit bis zu 52 % ee zu erhalten.…”

Catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols via direct aldol reaction of α-N3amide

“…10 While various effective catalytic alkynylations to CF 3 ketones were documented, most of these methods utilized preformed lithium, magnesium, or zinc alkynylide as the activated nucleophile in the presence of a catalytic amount of chiral promoter. 11 Thus far, only a limited number of studies, including the first example reported by our group in 2007, 12 have addressed the direct alkynylation to trifluoromethyl ketones, 13,14 which avoids the preformation of metal alkynylide and generates the active nucleophile in situ with a catalytic Brønsted base.…”

Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base‐Free Catalytic Asymmetric C−C Bond Formation with Terminal Ynamides

“…gylic alcohol moiety,f or example,i nt he anti-HIV drug Efavirenz, has stimulated the development of several methods that furnish this motif in racemic form. [1] In contrast to the general advance with asymmetric alkynylations of aldehydes, [2] ketones, [3] and imines, [4] trifluoromethyl ketones have remained challenging substrates, [5] and initially required the use of stoichiometric amounts of lithium or zinc aminoalkoxides. [6] Shibasaki and co-workers first demonstrated the feasibility of asymmetric catalysis,a nd generated CF 3 -substituted propargylic alcohols in up to 52 % ee.…”