A straightforward synthesis of optically active trifluoromethyl dihydropyranones and spirocyclic oxindole-dihydropyranones has been realized by the chiral N-heterocyclic carbenes-catalyzed cy-A C H T U N G T R E N N U N G clization of a,b-unsaturated b-methylacyl chlorides with activated trifluoromethyl ketones or isatin derivatives.Keywords: asymmetric catalysis; cyclization; dihy-A C H T U N G T R E N N U N G dropyranones; N-heterocyclic carbenes; organocatalysis; vinylketenes Since Staudingers discovery of ketenes and the cycloaddition of ketene with imines to form b-lactams in early 1900s, [1] the cycloaddition reactions of ketene have become one of the powerful methodologies for construction of cyclic compounds.[2] In last decades, the catalytic enantioselective [2 + 2] or [2 + 4] cycloaddition of ketenes with aldehydes, [3] imines, [4] azo compounds, [5] nitro compounds, [6] oxadienes, [7] and azadienes [8] had been well established. In 2008 and later, we, [9] independently with Smith et al., [10] have demonstrated that N-heterocyclic carbenes (NHCs) [11] were efficient catalysts for the formal cycloaddition reactions of ketenes. The enolates I generated by the addition of NHC to ketenes are considered as the key intermediate for these reaction [Scheme 1, reaction (a)]. We conjecture that vinyl enolates II will be generated if vinylketenes are employed instead of ketenes, thus opening a new possibility of NHC-catalyzed reaction of vinylketenes [Scheme 1, reaction (b)].A literature survey revealed that Peters et al. reported a pioneering asymmetric Cinchona alkaloidscatalyzed cyclization of unsaturated acyl halides with aldehydes (Scheme 2). [12] In this paper, we wish to report an N-heterocyclic carbene-catalyzed cyclization of unsaturated acyl chlorides with activated ketones, which did not work when Cinchona alkaloids were used as the catalysts.[13]5,6-Dihydropyran-2-ones (a,b-unsaturated d-lactones) are widely present in a number of natural and unnatural compounds which possess potent biological Scheme 1. NHC-catalyzed cycloadditions of ketenes and vinylketenes.Scheme 2. Cinchona alkaloids-catalyzed annulation of unsaturated acyl chlorides by Peters et al.
HIV-1 reverse transcriptase (RT) is the primary target for anti-AIDS chemotherapy. Nonnucleoside RT inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 RT. The binding and unbinding processes of alpha-APA, an NNRTI, have been studied using nanosecond conventional molecular dynamics and steered molecular dynamics simulations. The simulation results show that the unbinding process of alpha-APA consists of three phases based on the position of alpha-APA in relation to the entrance of the binding pocket. When alpha-APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and alpha-APA dominate the binding; however, the hydrophilic interactions (both direct and water-bridged hydrogen bonds) also contribute to the stabilizing forces. Whereas Tyr-181 makes significant hydrophobic interactions with alpha-APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of alpha-APA. These two residues have very flexible side chains and appear to act as two "flexible clamps" discouraging alpha-APA to dissociate from the binding pocket. At the pocket entrance, two relatively inflexible residues, Val-179 and Leu-100, gauge the openness of the entrance and form the bottleneck of the inhibitor-unbinding pathway. Two special water molecules at the pocket entrance appear to play important roles in inhibitor recognition of binding and unbinding. These water molecules form water bridges between the polar groups of the inhibitor and the residues around the entrance, and between the polar groups of the inhibitor themselves. The water-bridged interactions not only induce the inhibitor to adopt an energetically favorable conformation so the inhibitor can pass through the pocket entrance, but also stabilize the binding of the inhibitor in the pocket to prevent the inhibitor's dissociation. The complementary steered molecular dynamics and conventional molecular dynamics simulation results strongly support the hypothesis that NNRTIs inhibit HIV-1 RT polymerization activity by enlarging the DNA-binding cleft and restricting the flexibility and mobility of the p66 thumb subdomain that are believed to be essential during DNA translocation and polymerization.
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