Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp3-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD)2 or in situ reduction of Ni(II) salts. However, Ni(COD)2 is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.This Account chronicles the development of air-stable Ni(0) precursors as replacements for Ni(COD)2 or in situ reduction. Based on Schrauzer's seminal discovery of Ni(COD)(DQ) as an air-stable zerovalent organonickel complex, our research laboratories at Scripps Research and Bristol Myers Squibb have developed a class of precatalysts based on the Ni(COD)(EDD) (EDD = electron-deficient diene) framework, relying on the steric and electronic properties of the supporting diene to render the metal center stable to air, moisture, and even silica gel but reactive to ligand substitution and redox changes.The stable Ni(0) complexes can be accessed through ligand exchange with Ni(COD)2, through reduction of Ni(acac)2 using DIBAL-H, or electrochemically via cathodic reduction of Ni(acac)2 to Ni(COD)2, followed by addition of an EDD ligand in one pot. As a toolkit, the complexes demonstrate reactivity that is equivalent or enhanced compared to Ni(COD)2, catalyzing C-C and C-N cross-couplings, Miyaura borylations, C-H activations, and other transformations. Since the initial report on Ni(COD)(DQ), its reactivity in C(sp2)-CN activation, metallophotoredox, and electric field-induced cross-coupling have also been demonstrated.By incorporating the precatalyst toolkit into reaction discovery campaigns, our laboratories have been able to perform C(sp3)-S(alkyl) couplings and metallonitrenoid carboamination, both of which represent challenging transformations that were inaccessible with traditional phosphine, nitrogen, or electron-deficient olefin ligands. Computational and experimental studies demonstrate how the quinone ligands are hemilabile, adopting η1(O)-bound geometries to relieve steric strain or stabilize transition states and intermediates; redox-active, able to transiently oxidize the metal center; and electron-withdrawing or -donating, depending on metal oxidation state and coordination geometry. These studies show how the ligands enable key steps in catalysis beyond imparting air-stability.Since our report documenting the catalytic activity of Ni(COD)(DQ), many other laboratories have also observed unique reactivity with this precatalyst. Ni(COD)(DQ) was found to offer superior reactivity to Ni(COD)2 in C-N cross coupling to form N,N-diaryl sulfonamides and in preparation of biaryls from aryl halides and benzene through a Ni-mediated, base-assisted homolytic aromatic substitution.

Ligand-Promoted Iron-Catalyzed Nitrene Transfer for the Synthesis of Hydrazines and Triazanes through N-Amidation of Arylamines.

Herein, we report that bulky alkylphosphines such as PtBu3 can switch the roles from actor to spectator ligands to promote the FeCl2 -catalyzed N-amidation reaction of arylamines with dioxazolones, giving hydrazides in high efficiency and chemoselectivity. Mechanistic studies indicated that the phosphine ligands could facilitate the decarboxylation of dioxazolones on the Fe center, and the hydrogen bonding interactions between the arylamines and the ligands on Fe nitrenoid intermediates might play a role in modulating the delicate interplay between the phosphine ligand, arylamine, and acyl nitrene N, favoring N-N coupling over N-P coupling. The new ligand-promoted N-amidation protocols offer a convenient way to access various challenging triazane compounds via double or sequential N-amidation of primary arylamines.

Clinical and whole exome sequencing findings in children from Yunnan Yi minority ethnic group with retinitis pigmentosa: two case reports.

BACKGROUND: Retinitis pigmentosa is a group of rare hereditary retinal dystrophy diseases that lead to difficulty seeing at night, progressive loss of peripheral field vision (tunnel vision), and eventual loss of central vision. However, a genetic cause cannot be determined in approximately 60% of cases. CASE PRESENTATION: Two non-consanguineous Yi minority ethnic group families who have a 6.4-year-old boy and a 0.5-year-old boy, respectively, were recruited for genetic diagnosis. Here, we used whole-exome sequencing to detect mutations in the genes of the probands of the retinitis pigmentosa families, and Sanger sequencing to confirm the causal mutations identified by whole exome sequencing. In addition, we report two cases with retinitis pigmentosa caused by RDH12 (c.524C > T) and PRPF4 (c.1273G > A) pathogenic mutations. CONCLUSIONS: These results might extend the mutation spectrum of known retinitis pigmentosa genes and give these two Yi minority ethnic group families from Yunnan more precise genetic counseling and more specific prognoses.

Directed, nickel-catalyzed 1,2-alkylsulfenylation of alkenyl carbonyl compounds.

We report a regioselective, nickel-catalyzed syn-1,2-carbosulfenylation of non-conjugated alkenyl carbonyl compounds with alkyl/arylzinc nucleophiles and tailored N-S electrophiles. This method allows the simultaneous installation of a variety of C(sp3) and S(Ar) (or Se(Ar)) groups onto unactivated alkenes, which complements previously developed 1,2-carbosulfenylation methodology in which only C(sp2) nucleophiles are compatible. A bidentate directing auxiliary controls regioselectivity, promotes high syn-stereoselectivity with a variety of E- and Z-internal alkenes, and enables the use of an array of electrophilic sulfenyl (and seleno) electrophiles. Among compatible electrophiles, those with N-alkyl-benzamide leaving groups were found to be especially effective, as determined through comprehensive structure-reactivity mapping.

Next generation sequencing of RB1gene for the molecular diagnosis of ethnic minority with retinoblastoma in Yunnan.

BACKGROUND: Retinoblastoma is a rare intraocular malignancy and typically initiated by inactivating biallelic mutations of RB1 gene. Each year, ~ 8000 children worldwide are diagnosed for retinoblastoma. In high-income countries, patient survival is over 95% while low-income countries is ~ 30%.If disease is diagnosed early and treated in centers specializing in retinoblastoma, the survival might exceed 95% and many eyes could be safely treated and support a lifetime of good vision. In China, approximate 1100 newly diagnosed cases are expected annually and 28 hospitals covering 25 provinces established centers classified by expertise and resources for better treatment options and follow-up. Comparing with other province of eastern China, Yunnan province is remote geographically. This might result that healthcare staff have low awareness of the role of genetic testing in management and screening in families. METHODS: The patients with retinoblastoma were selected in Yunnan. DNA from blood was used for targeted gene sequencing. Then, an in-house bioinformatics pipeline was done to detect both single nucleotide variants and small insertions/deletions. The pathogenic mutations were identified and further confirmed by conventional methods and cosegregation in families. RESULTS: Using our approach, targeted next generation sequencing was used to detect the mutation of these 12 probands. Bioinformatic predictions showed that nine mutations were found in our study and four were novel pathogenic variants in these nine mutations. CONCLUSIONS: It's the first report to describe RB1 mutations in Yunnan children with retinoblastoma. This study would improve role of genetic testing for management and family screening.

Clinical and whole-exome sequencing findings in two siblings from Hani ethnic minority with congenital glycosylation disorders.

BACKGROUND: PMM2-CDG, is the most common N-linked glycosylation disorder and subtype among all CDG syndromes, which are a series of genetic disorders involving the synthesis and attachment of glycoproteins and glycolipid glycans. The mutations of PMM2-CDG might lead to the loss of PMM2, which is responsible for the conversion of mannose 6- phosphate into mannose 1-phosphate. Most patients with PMM2-CDG have central nervous system involvement, abnormal coagulation, and hepatopathy. The neurological symptoms of PMM2-CDG are intellectual disability (ID), cerebellar ataxia, and peripheral neuropathy. Now, over 100 new CDG cases have been reported. However, each type of CDG is very rare, and CDGs are problematic to diagnose. In addition, few CDGs have been reported in the Chinese population. CASE PRESENTATION: Here we present a Hani ethnic minority family including two siblings with congenital glycosylation disorders. Whole-exome sequencing revealed compound heterozygous for one novel mutation (c.241-242 del variant) and previously reported mutation (c.395 T > C) in gene of PMM2. Two mutations were found in proband and her sibling by whole-exome sequencing. The mutations were identified in this family by Sanger sequencing and no mutations were detected in the normal control. CONCLUSIONS: This is the first report to describe mutations in two siblings of Hani ethnic minority which is one of five ethnic groups found only in Yunnan with a population of more than 1 million.

Characteristics of olfactory ensheathing cells and microarray analysis in Tupaia belangeri (Wagner, 1841).

Tree shrews are most closely related to the primates and so possess a number of advantages in experimental studies; they have been used as an animal model in bacterial and virus infection, cancer, endocrine system disease, and certain nervous system diseases. Their olfactory ensheathing cells (OECs) are able to release several cytokines to promote neuronal survival, regeneration and remyelination. The present study used western blot analysis to identify antibody specificity in protein extracts from whole tree shrew brains to identify the specificity of p75 nerve growth factor receptor (NGFR) derived from rabbits (75 kDa). OECs were cultured and isolated, then stained and identified using the antibodies for p75NGFR. To investigate the capacity of OECs to express cytokines and growth factors, microarray technology was used, and the analysis revealed that OECs were able to express 9,821 genes. Of these genes, 44 genes were from the neurotrophic factor family, which may indicate their potential in transplantation in vivo. The present study considered the function of OECs as revealed by other studies, and may contribute to future research.

A novel variant in MITF in a child from Yunnan-Guizhou Plateau with autosomal dominant inheritance of nonsyndromic hearing loss: A case report.

Deafness and hearing loss may have functional, economic, social and emotional impacts on humans, including the ability of an individual to communicate with others, feelings of isolation and frustration, and health sector costs. The World Health Organization reported that there are 32 million children worldwide with hearing loss. In order to investigate genetic mutations in children of 26 nationalities with hearing loss in Yunnan, Sanger sequencing was employed to screen for mutations in four of the most common pathological genes, including gap junction protein ß2 and 3, solute carrier family 26 member 4 and mitochondrial DNA. Whole exome sequencing was used to detect the mutation in the proband of a family in which these four genes were normal. Subsequently, the mutation was identified by Sanger sequencing. The present study reports a novel mutation, c.718C>G; p. (Arg240Gly) in the melanogenesis associated transcription factor gene, in Han people with hearing loss. The results of the present study may provide parents and children an accurate diagnosis, which may allow physicians to how to rehabilitate children's hearing.

[Two New Abietane Type Diterpenes from Pinecones of Pinus griffithii].

Objective: To study the chemical constituents from the pinecones of Pinus griffithii. Methods: The constituents were separated and purified with chromatographic methods,and spectroscopic analysis were employed for structural elucidation. Results: Two new abietane type diterpenes and seven known compounds were isolated from the pinecones of Pinus griffithii,and were identified as 15-hydroxy-7α-methoxy-abiet-8,11,13-trien-18-oic acid( 1),7α,13-dihydroxy-podocarpane-8,11,13-trien-18-oic acid( 2),7,12,13,15-tetrahydroxy-abiet-8( 14)-en-18-oic acid( 3),7ß,15-dihydroxy-abiet-8,11,13-trien-18-oic acid( 4),18-norabiet-8,11,13-trien-4,7,15-triol( 5),15-hydroxy-abiet-8,11,13-trien-18-oic acid( 6),7α-hydroxy-15-methoxy-abiet-8,11,13-trien-18-oic acid( 7),7α-hydroxypodocarpen-8( 14)-en-13-one-18-oic acid( 8), oleanolic acid( 9). Conclusion: Compounds 1,2 are the new abietane type diterpene,and all compounds are isolated from this plant for first time.

[Chemical Constituents from Pueraria alopecuroides Ratten].

OBJECTIVE: To study the chemical constituents from the ratten of Pueraria alopecuroide. METHODS: Column chromatography techniques were used for compounds separation. And their structures were elucidated by physico-chemical properties and means of spectral analysis. RESULTS: Five flavonoids were isolated from Pueraria alopecuroide and their structures were identified as: (3R)-2', 3'-dihydroxy-6,7,4'-trimethoxyisoflavane(1), (3R)-8,2'-dihydroxy-7,4'-dimethoxyisoflavane(2), (3S)-vestitol(3), (3R)-(-)-7,2'-dihydroxy-3',4'-dimethoxyisoflavane(4), and 5,7,4'-trihydroxy-2',3'-dimethoxyisoflavanone(5). CONCLUSION: Compounds 1 5 are isolated from this plant for the first time and compound 1 is a new compound.