Isothiourea-catalysed sequential kinetic resolution of acyclic (±)-1,2-diols

Authors thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1, R.M.N.) for funding. We thank the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC grant agreement no. 279850 (A.D.S.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.The isothiourea-catalysed acylative kinetic resolution of a range of acyclic (±)-1,2-diols using 1 mol% of catalyst under operationally simple conditions is reported. Significantly, the bifunctional nature of (±)-1,2-diols was exploited in a sequential double kinetic resolution, in which both kinetic resolutions operate synergistically to provide access to highly enantioenriched products. The principles that underpin this process are discussed, and selectivity factors for the individual kinetic resolution steps are reported in a model system.PostprintPeer reviewe

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

Authors acknowlege the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 279850 (A.T.D.). We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University.The N-heterocyclic carbene (NHC) catalyzed formal [2+2] cycloaddition between α-aroyloxyaldehydes and trifluoroacetophenones, followed by ring-opening with an amine or reducing agent is described. The resulting β-hydroxy-β-trifluoromethyl amide and alcohol products are produced with reasonable diastereocontrol (typically ~70:30 dr) and excellent enantioselectivity, and can be isolated in moderate to good yield as a single diastereoisomer.Publisher PDFPeer reviewe

Best practice considerations for using the selectivity factor, s, as a metric for the efficiency of kinetic resolutions

The research leading to these results has received funding from the ERC under the European Union’s Seventh Framework Programme (FP7/2007--2013)/E.R.C. grant agreement 279850. J.E.T. thanks The Leverhulme Trust [Early Career Fellowship ECF-2014-005] for financial support. A.D.S. thanks the Royal Society for a Wolfson Merit Award.The suitability of using the selectivity factor, s, as a reaction metric for kinetic resolution reactions and the errors associated with its measurement are considered. Investigation of the analytical error associated with HPLC analysis of a kinetic resolution reveals that one of the largest potential sources of variation arises from the ability of a practitioner to integrate the peaks from a single analysis. The consequences of this error on the reliability of reported s values are discussed, and some general rules for good practice regarding the use and reporting of s as a metric are suggested.PostprintPeer reviewe

TMEDA in Iron‐Catalyzed Hydromagnesiation: Formation of Iron(II)‐Alkyl Species for Controlled Reduction to Alkene‐Stabilized Iron(0)

N,N,N’,N’‐Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron‐catalysis, finding application in reactions as diverse as cross‐coupling, C‐H activation and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron‐catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular‐level insight into the role of TMEDA in achieving effective catalysis. Key is the initial formation of TMEDA‐iron(II) alkyl species which undergo a controlled reduction to selectively form catalytically active styrene‐stabilized iron(0)‐alkyl complexes. While TMEDA is not bound to the catalytically active species, these active iron(0) complexes cannot be accessed in the absence of TMEDA. This mode of action, allowing for controlled reduction and access to iron(0) species, represents a new paradigm for the role of this important reaction additive in iron catalysis

Enantioselective N-heterocyclic carbene catalyzed formal [3+2] cycloaddition using α-aroyloxyaldehydes and oxaziridines

We thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) (R.W.F.K.) for funding. The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC Grant Agreement No. 279850 is also acknowledged. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.An enantioselective N-heterocyclic carbene catalysed formal [3+2] cycloaddition has been developed for the synthesis of oxazolindin-4-one products. The reaction of oxaziridines and α-aroyloxyaldehydes under N-heterocyclic carbene catalysis provides the formal cycloaddition products with excellent control of the diastereo- and enantioselectivity (12 examples, up to >95:5 dr, >99:1 er). A matched-mismatched effect between the enantiomer of the catalyst and oxaziridine was identified, and preliminary mechanistic studies have allowed the proposal of a model to explain these observations.Publisher PDFPeer reviewe

Isothiourea-catalysed regioselective acylative kinetic resolution of axially chiral biaryl diols

The research leading to these results has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850. The Chinese Scholarship Scheme and University of St Andrews are thanked for a CSC Scholarship (S.Q.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.An operationally‐simple isothiourea‐catalyzed acylative kinetic resolution of unprotected 1,1′‐biaryl‐2,2′‐diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α‐disubstituted mixed anhydride (2,2‐diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3′‐positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3‐substituent. Based on the key observations identified, acylation transition state models have been proposed to explain the atropselectivity of this kinetic resolution.PostprintPeer reviewe

"I’ve got a sheep with three legs if anybody wants it?’" - re-visioning the rural economy

This paper reports on a study of 4CG, a cooperative enterprise located in rural Wales. 4CG operates for the good of the local economy and seeks to diversify its commercial portfolio through the creation of an online shop retailing goods and services from local suppliers. The paper compliments prior field studies focusing on rural enterprise and the challenges posed by this category of business for IT support. The current study is motivated by 4CG’s interest in setting up a local online shop and explicates the organisational issues that this venture turns upon and elaborates for broader sustainability agendas

Acylative kinetic resolution of alcohols using a recyclable polymer-supported isothiourea catalyst in batch and flow

The authors thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1, R.M.N.P.) for funding. Financial support from the EPSRC (EP/K000411/1) is gratefully acknowledged (R.C.). The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. C.R.-E. and M.A.P. acknowledge the financial support from CERCA Pro-gramme/Generalitat de Catalunya, MINECO (CTQ2015-69136-R, AEI/MINECO/FEDER, UE and Severo Ochoa Excellence Ac-creditation 2014–2018, SEV-2013-0319) and DEC Generalitat de Catalunya (Grant 2014SGR827).A polystyrene-supported isothiourea catalyst, based on the homogeneous catalyst HyperBTM, has been prepared and used for the acylative kinetic resolution of secondary alcohols. A wide range of alcohols, including benzylic, allylic and propargylic alcohols, cycloalkanol derivatives and a 1,2-diol, has been resolved using either propionic or isobutyric anhydride with good to excellent selectivity factors obtained (28 examples, s up to 622). The catalyst can be recovered and reused by a simple filtration and washing sequence, with no special precautions needed. The recyclability of the catalyst was demonstrated (15 cycles) with no significant loss in either activity or selectivity. The recyclable catalyst was also used for the sequential resolution of 10 different alcohols us-ing different anhydrides with no cross-contamination between cycles. Finally, successful application in a continuous flow process demonstrated the first example of an immobilized Lewis base catalyst used for the kinetic resolution of alcohols in flow.PostprintPeer reviewe