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The feasibility of using chiral Lewis acids as catalysts to promotethe inverse-electron-demand Diels-Alder reactions of 1-azadieneswith vinyl ethers has been demonstrated. Two catalyst systems wereidentified for this reaction, both relying on the presence of acoordinating 2-pyridylsulfonyl or 8-quinolylsulfonyl group at theimine nitrogen of the 1-azadiene. The combination of a 8-quinolylsulfonylmoiety and nickel(II)/DBFOX-Ph proved to be highly efficient,allowing the synthesis of substituted piperidine derivatives ingood yields, excellent ENDO selectivity,and enantio-selectivities typically in the range of 77to 92% ee.

The different behavior of N-tosyl imines and N-(2-pyridyl)sulfonyl imines in Cu (II)-catalyzed AFCR is described. DFT theoretical calculations on the mode of coordination of the copper atom to both types of substrates allow understanding this different reactivity.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.