Chiral phosphoric acid-catalyzed Mannich reactions of latent nucleophiles with acyl imines

Chiral phosphoric acids were used to activate the acyl imine to facilitate a highly enantioselective addition of an enecarbamate to afford the 1,3-diamine Mannich adduct. An extensive catalyst screen found that the sterically hindered 9-phenanthryl binaphthyl phosphoric acid was the optimal catalyst for the parent reaction yielding the product in 98% yield and a 96:04 e.r. In order to further optimize the reaction, a series of mechanistic studies were performed, including NMR and ReactIR experiments to understand the reaction in situ. These experiments led to the discovery of a hemiaminal ether intermediate. It was ultimately proposed that the carbonyl moiety present in the enecarbamate does a nucleophilic addition onto the activated acyl imine to yield the chiral hemiaminal ether which then undergoes rearrangement to form the expected product. After additional mechanistic studies, it was observed that the initial formation of the intermediate is the enantiodetermining step and that stereoselective intramolecular rearrangement occurs to form the 1,3-diamine Mannich product. Upon gaining insight from these experiments, optimal conditions were achieved using the parent reaction to yield the Mannich product in a 98% yield and 98:02 e.r. After reaction optimization, the substrate scope was then investigated. Emphasis was placed on the protecting groups of the acyl imines. Following a 2-dimensional screen of catalyst vs protecting group, an optimal catalyst was found for each protecting group. Additionally, other enecarbamates and imines were attempted affording a total of 32 examples with high enantioselectivity and yields. Reductions were then performed on the Mannich product to gain access to the appropriate chiral 1,3-diamine. This methodology represents a new route to make chiral 1,3-diamines through the formation of a chiral hemiaminal ether. This reactivity has been expanded to include syntheses of other diamines such as 1,2-diamines. Preliminary results show that when using glycinate derivatives with acyl imines, the formation of a hemiaminal ether is observed which then undergoes rearrangement to form the chiral 1,2-diamine directly

Investigation of NRXN1 deletions: Clinical and molecular characterization

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray‐based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P  = 6.08 × 10 −7 ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1 . © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97220/1/35780_ftp.pd

High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients

Use of Motor Abundance in Young and Older Adults during Dual-Task Treadmill Walking

Contains fulltext : 110120.pdf (publisher's version ) (Open Access)Motor abundance allows individuals to perform any task reliably while being variable in movement's particulars. The study investigated age-related differences in this feature when young adults (YA) and older adults (OA) performed challenging tasks, namely treadmill walking alone and while performing a cognitive task. A goal function for treadmill walking was first defined, i.e., maintain constant speed at each step, which led to a goal equivalent manifold (GEM) containing all combinations of step time and step length that equally satisfied the function. Given the GEM, amounts of goal-equivalent and non-goal-equivalent variability were afterwards determined and used to define an index providing information about the set of effective motor solutions relative to the GEM. The set was limited in OA compared to YA in treadmill walking alone, indicating that OA made less flexible use of motor abundance than YA. However, this differentiation between YA and OA disappeared when concurrently performing the cognitive task. It is proposed that OA might have benefited from cognitive compensation

The IPBES Conceptual Framework - connecting nature and people

The first public product of the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) is its Conceptual Framework. This conceptual and analytical tool, presented here in detail, will underpin all IPBES functions and provide structure and comparability to the syntheses that IPBES will produce at different spatial scales, on different themes, and in different regions. Salient innovative aspects of the IPBES Conceptual Framework are its transparent and participatory construction process and its explicit consideration of diverse scientific disciplines, stakeholders, and knowledge systems, including indigenous and local knowledge. Because the focus on co-construction of integrative knowledge is shared by an increasing number of initiatives worldwide, this framework should be useful beyond IPBES, for the wider research and knowledge-policy communities working on the links between nature and people, such as natural, social and engineering scientists, policy-makers at different levels, and decision-makers in different sectors of society

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Carbon-Heteroatom Cross-Coupling via an Electronically Excited Nickel (II) Complex

While carbon-heteroatom cross coupling reactions have been extensively studied, many methods are specific andlimited to a set of substrates or functional groups. Reported here is a method that allows for C-O, C-N and C-S cross coupling reactions under one general methodology. We propose that an energy transfer pathway, in which an iridium photosensitizer produces an excited nickel (II) complex, is responsible for the key reductive elimination step that couples aryl halides to 1° and 2° alcohols, anilines, thiophenols, carbamates and sulfonamides.</div

Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone (GPX) is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide (p-QM) using a chiral phosphoric acid (CPA) catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering (PT), were performed in order to probe the mode of asymmetric inductio

Halide Non-Innocence and Direct Photo-Reduction of Ni(II) Enables Coupling of Aryl Chlorides in Dual Catalytic, Carbon-Heteroatom Bond Forming Reactions

Recent mechanistic studies of dual photoredox/Ni-catalyzed, light-driven cross-coupling reactions have found that the photocatalyst (PC) operates through either reductive quenching or energy transfer cycles. To date, reports invoking oxidative quenching cycles are comparatively rare and direct observation of such a quenching event has not been reported. However, when PCs with highly reducing excited states are used (e.g. Ir(ppy)3), photo-reduction of Ni(II) to Ni(I) is thermodynamically feasible. Recently, a unified reaction system using Ir(ppy)3 was developed for forming C–O, C–N, and C–S bonds under the same conditions, a prospect that is challenging with PCs that can photo-oxidize these nucleophiles. Herein, in a detailed mechanistic study of this system, we observe oxidative quenching of the PC (Ir(ppy)3 or a phenoxazine) via nanosecond transient absorption spectroscopy. Speciation studies support that a mixture of Ni-bipyridine complexes form under the reaction conditions, and the rate constant for photoreduction increases when more than one ligand is bound. Oxidative addition of an aryl iodide was observed indirectly via oxidation of the resulting iodide by Ir(IV)(ppy)3. Intriguingly, persistence of the Ir(IV)/Ni(I) ion pair formed in the oxidative quenching step was found to be necessary to simulate the observed kinetics. Both bromide and iodide anions were found to reduce the oxidized form of the PC back to its neutral state. These mechanistic insights inspired the addition of a chloride salt additive, which was found to alter Ni speciation, leading to a 36-fold increase in the initial turnover frequency, enabling the coupling of aryl chlorides

Asymmetric synthesis of griffipavixanthone employing a chiral phosphoric acid-catalyzed cycloaddition

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide using a chiral phosphoric acid catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering, were performed in order to probe the mode of asymmetric induction.We thank the National Institutes of Health (NIH) (R35 GM-118173 to J.A.P., Jr.) and Boston University (BU) for financial support. S.E.S. and R.A.E. acknowledge the NIH for support (R01 GM-078240). K.D.R. is supported by a postdoctoral fellowship (PF-16-235-01-CDD) from the American Cancer Society. NMR (CHE-0619339) and MS (CHE-0443618) facilities at BU are supported by the National Science Foundation (NSF). We also thank the NSF (CHE-1665367 to D.F.C.) for funding. Work at the BU-CMD is supported by the NIH (R24 GM-111625). We acknowledge Prof. Richard Johnson and Dr. Sharon Song (UNH) for their computational investigations in the synthesis of (+/-)-1. We also thank Prof. Benjamin List (MPI) for kindly providing catalysts for our initial screen. (R35 GM-118173 - National Institutes of Health (NIH); Boston University (BU); R24 GM-111625 - NIH; R01 GM-078240 - NIH; PF-16-235-01-CDD - American Cancer Society; CHE-0619339 - National Science Foundation (NSF); CHE-0443618 - National Science Foundation (NSF); CHE-1665367 - NSF)Accepted manuscrip