Generation and reactivity of C(1)-ammonium enolates using isothiourea catalysis

Funding: UK EPSRC (EP/M508214/1, C.M.). Royal Society for a Wolfson Research Merit Award (A.D.S.).C(1)-ammonium enolates are powerful, catalytically generated synthetic intermediates applied in the enantioselective α-functionalization of carboxylic acid derivatives. This review describes the recent developments in the generation and application of C(1)-ammonium enolates from various precursors (carboxylic acids, anhydrides, acyl imidazoles, aryl esters, α-diazoketones, alkyl halides) using isothiourea Lewis base organocatalysts. Their synthetic utility in intra- and intermolecular enantioselective C-C and C-X bond forming processes on reaction with various electrophiles will be showcased utilizing two distinct catalyst turnover approaches.Publisher PDFPeer reviewe

Alkali metal and stoichiometric effects in intermolecular hydroamination catalysed by lithium, sodium and potassium magnesiates

Main group bimetallic complexes, while being increasingly used in stoichiometric deprotonation and metal–halogen exchange reactions, have not yet made a significant impact in catalytic applications. This paper explores the ability of alkali metal magnesiates to catalyse the intermolecular hydroamination of alkynes and alkenes using sytrene and diphenylacetylene as principle setting model substrates. By systematically studying the role of the alkali–metal and the formulation of the heterobimetallic precatalyst, this study establishes higher order potassium magnesiate [(PMDETA)2K2Mg(CH2SiMe3)4] (7) as a highly effective system capable of catalysing hydroamination of styrene and diphenylacetylene with several amines while operating at room temperature. This high reactivity contrasts with the complete lack of catalytic ability of neutral Mg(CH2SiMe3)2, even when harsher reaction conditions are employed (24 h, 80 °C). A pronounced alkali metal effect is also uncovered proving that the alkali metal (Li, Na, or K) is not a mere spectating counterion. Through stoichiometric reactions, and structural and spectroscopic (DOSY NMR) investigations we shed some light on the potential reaction pathway as well as the constitution of key intermediates. This work suggests that the enhanced catalytic activity of 7 can be rationalised in terms of the superior nucleophilic power of the formally dianionic magnesiate {Mg(NR2)4}2− generated in situ during the hydroamination process, along with the ability of potassium to engage in π-interactions with the unsaturated organic substrate, enhancing its susceptibility towards a nucleophilic attack by the amide anion

List of Referees

List of Referees: CIT Vol. 6 (1998), No 1–

Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

Funding: We thank the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850, AstraZeneca and EPSRC [EP/M506631/1 (J.N.A.)], Syngenta and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis [CRITICAT, EP/L016419/1 (W.C.H.)], and EPSRC [EP/M508214/1 (C.M.)] for funding. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. We thank the EPSRC UK National Mass Spectrometry Facility at Swansea University.The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides, in up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).Publisher PDFPeer reviewe

A cascade Suzuki-Miyaura/Diels-Alder protocol : exploring the bifunctional utility of vinyl Bpin

Funding: Industrial CASE studentship awarded from EPSRC and GlaxoSmithKline. The authors thank the EPSRC, GlaxoSmithKline, and the University of St Andrews for studentship funding (DLC), and the University of St Andrews and the EPSRC UK National Mass Spectrometry Facility at Swansea University for analyses.Cascade reactions are an important strategy in reaction design, allowing streamlining of chemical synthesis. Here we report a cascade Suzuki-Miyaura/Diels-Alder reaction, employing vinyl Bpin as a bifunctional reagent in two distinct roles: as an organoboron nucleophile for cross- coupling and as a Diels-Alder dienophile. Merging these two reactions enables a rapid and operationally simple synthesis of functionalized carbocycles in good yield. The effect of the organoboron subtype on Diels- Alder regioselectivity was investigated and post-synthetic modifications were carried out on a model substrate. The potential for a complementary Heck/Diels-Alder process was also assessed.PostprintPeer reviewe

The importance of 1,5-oxygen-chalcogen interactions in enantioselective isochalcogenourea catalysis

Syngenta (Case Award to DJP) and a Philip Leverhulme Prize for funding (SLC, AE). RKM and PHW are grateful to the American Chemical Society Petroleum Research Fund and National Science Foundation (NSF-MRI: CHE-1429616).The importance of 1,5-O···chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch = O, S, Se) is investigated. Conformational analyses of N-acyl isochalcogenouronium species and comparison with kinetic data demonstrate the significance of 1,5-O···Ch interactions in enantioselective catalysis. Importantly, the selenium analogue demonstrates enhanced rate and selectivity profiles across a range of reaction processes including nitronate conjugate addition and formal [4+2] cycloadditions. A gram-scale synthesis of the most active selenium analogue was developed using a previously unreported seleno-Hugerschoff reaction, allowing the challenging kinetic resolutions of tertiary alcohols to be performed at 500 ppm catalyst loading. Density Functional Theory (DFT) and natural bond orbital (NBO) calculations support the role of orbital delocalization (occurring by intramolecular chalcogen bonding) in determining the conformation, equilibrium population, and reactivity of N-acylated intermediates.PostprintPeer reviewe

Interrogating Pd(II) anion metathesis using a bifunctional chemical probe : a transmetalation switch

Ligand metathesis of Pd(II) complexes is mechanistically essential for cross-coupling. We present a study of halide→OH anion metathesis of (Ar)Pd(II) complexes using vinylBPin as a bifunctional chemical probe with Pd(II)-dependent cross-coupling pathways. We identify the variables that profoundly impact this event and allow control to be leveraged. This then allows control of cross-coupling pathways via promotion or inhibition of organoboron transmetalation, leading to either Suzuki-Miyaura or Mizoroki-Heck products. We show how this transmetalation switch can be used to synthetic gain in a cascade cross-coupling/Diels-Alder reaction, delivering borylated or non-borylated carbocycles, including steroid-like scaffolds

The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine

Background: Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care. Methods/Design This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results. Discussion The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies. Trial registration ClinicalTrials.gov identifier NCT0173656

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Enantioselective isothiourea catalysis via C(1)-ammonium enolate intermediates : applications and mechanistic studies

The absolute stereochemistry of organic compounds can have a profound influence on the conformation, properties, and function of molecules. Therefore, sustainable synthetic methods that enable the catalytic, stereoselective preparation of enantioenriched compounds is a central research goal in chemistry. Catalytically generated C(1)-ammonium enolate intermediates, derived from chiral tertiary amine Lewis base catalysts such as isothioureas, have emerged as synthetically useful intermediates for the enantioselective synthesis of α-functionalised carbonyl compounds at the carboxylic acid oxidation level, motifs that are found in many biologically relevant molecules. Despite the widespread application of C(1)-ammonium enolates in the synthesis of chiral heterocycles, there is typically a requirement for relatively high catalyst loadings, stoichiometric additives and/or auxiliary base for effective reactivity in the formation of acyclic α-functionalised products. In addition, a fundamental mechanistic understanding of these processes, governed by intermolecular catalyst turnover via an aryloxide, remains elusive and compatible electrophiles are limited to alkene and carbonyl derivatives. The research goals of this thesis targeted the development of novel methodologies in isothiourea catalysis via C(1)-ammonium enolates using aryloxide catalyst turnover in reaction with alternative electrophiles, specifically looking to address the previous limitations of sustainability and mechanistic understanding (Scheme I). Herein, we report the base-free enantioselective α-functionalisation of esters via a Michael addition reaction of aryl esters to vinyl bis-sulfones enabled by a multifunctional aryloxide (Chapter 2). Using ¹⁹F{¹H} NMR reaction monitoring, a thorough mechanistic investigation was carried out to interrogate this methodology, enabling a large amount of mechanistic information to be collected, including elucidation of the turnover limiting step (Chapter 3). We also report the regio-, diastereo- and enantioselective dearomatisation of pyridinium salts using isothiourea catalysis via C(1)-ammonium enolate intermediates for the synthesis of 1,4-dihydropyridine heterocyclic motifs (Chapter 4). An enantioselective nucleophilic aromatic substitution protocol was also targeted, however, attempts to render both inter- and intramolecular variations of this transformation enantioselective proved challenging (Chapter 5)