Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,ß-Unsaturated Esters and Amides.

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,ß-unsaturated esters.

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,ß-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis.

To improve the field of catalysis, there is a substantial and growing need for novel high-performance catalysts providing new reactivity. To date, however, the set of reactions that can be reliably performed to prepare chiral compounds in largely one enantiomeric form using chiral catalysts still represents a small fraction of the toolkit of known transformations. In this context, chiral Brønsted bases have played an expanding role in catalyzing enantioselective reactions between various carbon- and heteroatom-centered acids and a host of electrophilic reagents. This Account describes our recent efforts developing and applying a new family of chiral Brønsted bases incorporating an H-bond donor moiety and a strongly basic iminophosphorane, which we have named BIMPs (Bifunctional IMinoPhosphoranes), as efficient catalysts for reactions currently out of reach of more widespread tertiary amine centered bifunctional catalysts. The iminophosphorane Brønsted base is easily generated by the Staudinger reaction of a chiral organoazide and commercially available phosphine, which allows easy modification of the catalyst structure and fine-tuning of the iminophosphorane pKBH+. We have demonstrated that BIMP catalysts can efficiently promote the enantioselective addition of nitromethane to low reactivity N-diphenylphosphinoyl (DPP)-protected imines of ketones (ketimines) to access valuable chiral diamine and α-quaternary amino acid building blocks, and later extended this methodology to phosphite nucleophiles. Subsequently, the reaction scope was expanded to include the Michael addition of high pKa alkyl thiols to α-substituted acrylate esters, ß-substituted α,ß-unsaturated esters, and alkenyl benzimidazoles as well as the challenging direct aldol addition of aryl ketones to α-fluorinated ketones. Finally, BIMP catalysts were shown to be used in key steps in the synthesis of complex alkaloid natural products (-)-nakadomarin A and (-)-himalensine A, as well as in polymer synthesis. In most cases, the predictable nature of the BIMP promoted reactions was demonstrated by multigram scale-up while employing low catalyst loadings (down to 0.05 mol%). Furthermore, it was shown that BIMP catalysts can be easily immobilized onto a solid support in one-step for increased catalyst recycling and flow chemistry applications. Alongside our own work, this Account also includes elegant work by Johnson and co-workers utilizing the BIMP catalyst system, when alternative catalysts proved suboptimal.

Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population.

The autoimmune and gene etiology are implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is important for negative regulation of T-cell activation, and CTLA4 gene has been identified as a risk factor for some autoimmune diseases. However, none studies have been performed about the association between PCOS and the CTLA4 gene before. Here, we aimed to investigate the association of CTLA4 with PCOS in the Chinese Han population though a case-control association analysis of 606 individuals. The tagging variants rs733618 and rs231775 in the CTLA4 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis method. Further analysis found the rs733618 was significantly different between case and control groups in either genotypic or allelic distribution (P = .01 and .009, respectively) while rs231775 not. Moreover, rs733618 was significantly associated with higher body mass index in the dominant model (P = .003) and with higher waist/hip ratio in the recessive model (P = .02). Interestingly, rs733618 was only found to have significant association with homeostatic model assessment for insulin resistance (HOMA-IR) in both dominant and recessive model (P = .009 and .0065, respectively). This is the first study to investigate the association of CTLA4 gene with PCOS. The CTLA4 gene is suggested to correlated with PCOS, and influence PCOS through regulating obesity and the HOMA-IR in a novel way.

[Analysis of antibiotic resistance and genotypes on extended spectrum ß-lactamase and AmpC ß-lactamase producing strains isolated from Uygur and Han newborns].

OBJECTIVE: This study aimed to investigate drug resistance and genotypes of the extended spectrum ß-lactamase (ESBLs) and AmpC ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolated from Uygur and Han newborns in Urumqi. METHODS: Disk diffusion test (Kirby-Bauer) was used for detecting drug resistance of 299 strains to twenty two kinds of antibiotics. Resistance genes of the ESBLs and AmpC ß-lactamase-producing strains were amplified by multiplex PCR and subtypes were confirmed by DNA sequence analysis. Total 148 strains were selected with random number table and sequenced, which included TEM-, SHV-, CTX-M-1-, or CTX-M-9-positive ESBLs-producing strains and DHA-, or CIT-positive AmpC ß-lactamase-producing strains. Antibiotic resistant rates were analyzed by Whonet 5.4 and statistic analysis was performed by chi-square (χ(2)) test with PEMS 3.1. RESULTS: The antibiotic resistant rates between Uygur and Han newborns significantly differ in ESBLs-producing Klebsiella pneumoniae to Sulfamethoxazole-Trimethoprim (80.0% (40/50) and 56.0% (28/50), χ(2) = 6.6176, P = 0.0101), in ESBLs-producing Escherichia coli to Sulbactam and Cefoperazone (54.2% (32/59) and 94.0% (47/50), χ(2) = 21.4512, P = 0.0000), and in AmpC ß-lactamase-producing Klebsiella pneumoniae to Sulbactam and Cefoperazone (100.0% (20/20) and 72.2% (26/36), χ(2) = 6.7633, P = 0.0093) and to Amikacin (65.0% (13/20) and 25.0% (9/36), χ(2) = 8.6246, P = 0.0033). Although SHV gene of ESBLs-producing Escherichia coli was detected from Uygur newborns at only 3.4% (2/59) and not detectable from Han newborns, TEM, CTX-M-1, and CTX-M-9 group genes were all detected over 38.0% (19/50). Among the detected strains, the subtypes of TEM and CTX-M-1 were mainly TEM-1 and CTX-M-15, respectively; whereas the subtypes of SHV and CTX-M-9 included SHV-1, 2, 11, 12, 27, 61, 99 and CTX-M-9, 14, 24, 27, 65, respectively. The strains of Escherichia coli and Klebsiella pneumoniae carrying two or more kinds of ESBLs genotypes were 56.7% (42/74) - 90.0% (63/70). Two species carrying the AmpC gene in two kinds of newborns were only grouped in the subtypes of DHA-1 and CMY-44, and other subtypes were not detected at all. Moreover, TEM-positive ESBLs-producing Escherichia coli were detected from Uygur newborns at the higher rate than that from Han newborns (71.2% (42/59) and 50.0% (25/50), χ(2) = 5.1291, P = 0.0235), while there was no difference in other genotypes detected between two kinds of newborns (χ(2) < 3.7780, P > 0.05). CONCLUSION: There were significant differences in antibiotic resistance and genotype distribution of Klebsiella pneumoniae and Escherichia coli between two nationality newborns, and these two bacteria detected in this study carried multi-resistance genes and showed high resistant to ß-lactamase antibiotics.