Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study

The research leading to these results (T. H. W., J. E. T., G. C. L.-J. and A.D.S) has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013) / E.R.C. grant agreements n° 279850 and n° 340163. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. P.H.-Y.C. is the Bert and Emelyn Christensen Professor and gratefully acknowledges financial support from the Stone Family of OSU. Financial support from the National Science Foundation (NSF) (CHE-1352663) is acknowledged. D.M.W. acknowledges the Bruce Graham and Johnson Fellowships of OSU. A.C.B. acknowledges the Johnson Fellowship of OSU. D.M.W., A.C.B., and R.C.J. and P.H.-Y.C. also acknowledge computing infrastructure in part provided by the NSF Phase2 CCI, Center for Sustainable Materials Chemistry (CHE1102637).A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically-relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle towards catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S•••O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-π interactions over C-H•••π is responsible for diastereoselectivity.Publisher PDFPeer reviewe

Catalytic stereoselective [2,3]-rearrangement reactions

The authors thank the Royal Society for a University Research Fellowship (A.D.S.), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-20013) ERC Grant Agreement No. 279850 (J.E.T., T.H.W., K.K.), and the European Union (Marie Curie ITN ‘SuBiCat’ PITN-GA-2013-607044) (S.S.M.S.) for financial support.[2,3]-Sigmatropic rearrangement processes of allylic ylides or their equivalents can be applied to a variety of different substrates and generate products of wide interest and applicability to organic synthesis. This review describes the development and applications of stereoselective [2,3]-rearrangement reactions in which a sub-stoichiometric amount of a catalyst is used in either the formation of the reactive intermediate or the [2,3]-rearrangement step itself.PostprintPeer reviewe

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

Preparation of Pyridinium and Diaminocarbonium Barbituric Acid Ylides

Through NMR experiments of the reaction of barbituric acid with carbodiimide, a general synthetic procedure for the preparation of 5-diaminomethylenebarbiturates (DABA) was developed. This procedure is very simple and applicable to the preparation of large quantities of DABA derivatives. Through the X-ray structural study of one of the DABA derivatives it was established that these compounds have a ylide-type structure with strong charge separation inside the molecule. 5-Ylide-pyridinium-methyl barbituric acid derivatives were investigated with the isolation of 4-dimethylamino-1-(2,4,6-trioxohexahydro- pyrimidin-5-ylide-methyl)-pyridinium as well as its corresponding 1,3- dimethylbarbituric acid derivative with quantitative yields. An alternative approach was attempted in order to prepare chiral 5-ylide-pyridinium-methyl-barbituric acid derivatives thus containing a chiral center between the charge separation. The extreme instability of the derivatives under investigation afforded the unique isolation of 4-dimethylamino-1- [(1,3-dimethyl-2,4,6-trioxo-hexahydro-pyrimidin-5-yl)-phenyl-methyl]-pyridinium in quantitative yield

Isothiourea-catalysed enantioselective [2,3]-sigmatropic rearrangements of allylic ammonium ylides : synthetic and mechanistic studies

The research in this thesis describes the development of an isothiourea-catalysed enantioselective [2,3]-rearrangement of allylic ammonium ylides, subsequent mechanistic and collaborative computational studies and the its application to the enantioselective synthesis of free α-amino esters. Chapter 1 aims to place this work in the context of the previous literature, highlighting a range of stereoselective [2,3]-rearrangements of allylic ammonium ylides. Examples of catalytic stereoselective [2,3]-rearrangement of allylic ammonium ylides as well as state-of-the-art examples of organocatalytic enantioselective variants of the related [2,3]-Wittig rearrangement are discussed. The aims of this research project are also set out. Chapter 2 describes the discovery and optimisation of the isothiourea-catalysed [2,3]-rearrangement of 4-nitrophenyl ester quaternary ammonium salts (either isolated or generated in situ) to give a range of syn-α-amino acid derivatives in excellent yields (33-89%) and stereocontrol (up to >95:5 dr and >99% ee). This represents the first catalytic enantioselective variant of a [2,3]-rearrangement of allylic ammonium ylides. Chapter 3 describes mechanistic studies. Reaction kinetic analysis by ¹⁹F NMR has allowed reaction profiles to be built up, orders of each component to be determined and catalyst resting state to be probed. A catalytic intermediate has been observed; its constitution was proved unambiguously by ¹³C and ¹⁵N isotopic labelling. Isotopic entrainment has proved the observed intermediate to be on-cycle and productive towards catalysis. Competition kinetic isotope effects have provided detailed insight into the [2,3]-rearrangement step of the process. The effect of HOBt upon stereocontrol and the resting state of the catalyst have been probed through in situ ¹⁹F NMR. Crossover experiments have given detailed insight into the reversibility of each of the proposed catalytic steps. Collaborative computational work has elucidated the origins of stereocontrol and has supported the experimentally proposed mechanism. Chapter 4 describes the application of this methodology to the enantioselective synthesis of free α-amino esters via [2,3]-rearrangement of N,N-diallyl allylic ammonium ylides. Enantio- and chemoselective [2,3]-rearrangement gave a range of N,N-diallyl α-amino esters, which could be readily selectively mono- or bis-N-allyl deprotected. Bis-N-allyl deprotection gave a range of enantioenriched free α-amino esters. Selective mono-N-allyl deprotection was employed in the synthesis of a functionalised piperidine motif. Chapter 5 summarises the work outlined in this thesis and draws conclusions, as well as giving insight into potential future projects within the area

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

The research leading to these results (T.H.W.) has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007–2013)/E.R.C. grant agreement n° 279850 and the European Union (Marie Curie ITN “SubiCat” PITN-GA-2013-607044) (S. S. M. S.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. The data underpinning this publication can be found at DOI: http://dx.doi.org/10.17630/f522b48d-ed02–42b3-a161-54687ea5af57The isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangement of N,N-diallyl allylic ammonium ylides is explored as a key part of a route to free functionalised α-amino esters and piperidines. The [2,3]-sigmatropic rearrangement proceeds with excellent diastereo- and enantiocontrol (>95:5 dr, up to 97% ee), with the resultant N,N-diallyl α-amino esters undergoing either mono- or bis-N-allyl deprotection. Bis-N-allyl deprotection leads to free α-amino esters, while the mono-deprotection strategy has been utilized in the synthesis of a target functionalised piperidine.PostprintPeer reviewe