A broad and fundamental interest in catalysis is at the heart of all our research. Specifically we are intrigued by the ability to develop unknown reactions mainly in the areas of organocatalysis and transition metal catalysis.
Reaction discovery can, and should, play a transformative role in complex target synthesis. Many of our studies in target synthesis draw upon our synthetic methods, or alternately targets continue to inform methodological studies.
Advances in chemical synthesis have the potential to inform many aspects of science. We collaborate broadly to realise this and, for example, have looked at questions in magnetism, polymer science, and medicinal chemistryChemMedChem, 2019, 14, 527; Chem. Sci. 2018, 9, 7370; Adv. Biosys. 2018, 2, 1700240
Remarkably, the RC-reaction of (bis)enoate molecules remains a challenge in enantioselective catalysis. This may, in part, be due to the lower reactivity of such species compared to the more common (bis)enone substrates. In this publication we exploit highly nucleophilic NHCs to achieve enantioselective catalysis with bis(enoates). A nice substrate design from Changhe, with early discovery work, characterisation by Rachel, but really this was a big study by Song, who managed to push this one over the line just as his PhD came to a close. Congratulations Song.
A study that unfolded over a few years focused on the possibility that conjugate acceptor umpolung could be achieved multiple times. This would potentially provide a new avenue to fully substitiuted olefins from simple conjugate acceptors. Discoveries from Xuan and Yuji, with a nice colloration with Martin Breugst, allowed us to develop a series of (5 + 1) annulations.
Catalytic imine umpolung has only emerged as a synthetic strategy in recent years, with the first NHC mediated version reported in 2016 by A. T. Biju. In this study we were able to achieve an intermolecular and enantioselective reaction design through careful reaction design, discovery, and optimization by Yuji and Jared.
Uttam and Sandeep, students cosupervised between the Maiti (IITB) and Lupton (Monash) labs of the Monash-IITB academy contributed to this study of Debs focused on directed para functionalisation using Rhodium catalysis.
Building on a strong methodological study (#62, Angew. Chem. Int. Ed., 2016, 55, 16374) led by Alison, Adam did some fantastic work to iron out a bunch of challenges. His work has resulted in a 10-step sequence that opens new opportunities for preparing unique THC analogs.
Exploiting cryoEM derived structural information it was possible to develop simple linozelid analogs in which subtle stereoelectronic effects allowed conformational changes to a side chain. Great early synthetic work from Samuel (exchange from University of Vienna), cleaned up by Alexander, stay tuned for a more comprehensive study.
Suprisingly simple to prepare substrates allowing access to highly enantioenriched cyclopentenes in as little as 5-steps. The second in our series of reactions involving conjugate acceptoir umpolung, discovered by Yuji and developed nicely by Lydia.
The first enantioselective reaction of the dienyl azolium. We first tried to access reactions of this type with Marcin in 2014 using a different reaction design (#48 Angew. Chem. Int. Ed., 2014, 53, 5314). Great perseverance from Rachel, supported by discovery work by Jared, allowed enantioselectivity to be achieved with this improved design. Some of my favourite examples allows tetracyclic products in less than 5-steps from commercial materials
A collaborative study with Joel Hooper focused on reimagining the RAFT end-group. In one step this undesirable functionality is replaced by an electron-rich arene, a nice route to functionalised polymers. Bodipy and biotin tagging was possible. Great work from Riley to make the original discovery as an undergraduate.
A new approach to enzyme immobilization developed by the Jackson lab. Support from Jacob, allowed this new approach to be developed into a continuous flow process. Incredible turnover numbers, great recyclability, and high enantioselectivity.
A Monash collaboration, with four groups contributing to this report led by Keith Murray. From our group Mousa played a key role in the ongoing delivery of novel persistent nitroxides.
Part of a larger collaboration with the Mayr labs (LMU) on the properties of catalysts and intermediates pivotal to NHC mediated reactions, in this report we clarify the impact of catalyst design on the electrophilcity of the unsaturated acyl azolium.
A big study by Changhe, taking the acyl fluoride chemistry to the limit, with a broad range of bifunctional materials prepared and subjected to NHC-catalysis. A powerful route to more than 40 enantioenriched indenes.
A comprehensive review on the chemistry of the unsaturated acyl azolium.
A useful and general transformylation reaction that was well suited to a variety of alcohols, including hindered tertiary examples.
Great study from Uttam, a student of the Monash IITB academy.
Some work from Kim's honours year. Highly hindered imidazolylidene NHCs allowed a variety of Mukaiyama aldo and Michael chemistry to be achieved.
The first enantioselective (4 + 2) annulation with a donor-acceptor cyclobutane. Alison covered a lot of ground in the early optimization before we really got a handle on the unique reactivity of these materials. Alison and Adam finished it up, paving the way for our later work on THC total synthesis.
The first example in our series of studies on conjugate acceptor umpolung. This proved to be a really tricky reaction to crack. Many false leads, and a lost 6 months with some catalyst issues. In the end Yuji managed to get some great conditions locked down.
A great effort from Alison who was able to calculate nucleophilcity parameters for 4 common N-substituents in NHC catalysis. A real pleasure for both of us to work in Munich with the Mayr group, and great support from Feng.
A personnal account of some of our studies on the use of Donor-Acceptor cyclopropanes in NHC organocatalysis. Hnbours to be invited by H.-U. Reissig and great to get to know D. B. Weix a few years later.
Not quite a first in class reaction but a pretty unusual transformation of an alkyne. Potentially applicable to the late stage introduction of nitrile functionality. One of the first papers from Deb and myself driven by the fantastic Uttam of the Monash-IITB academy.
Drawing upon the rich chemistry of sulfonyl fluorides originating in the Kodak labs in the 1970's, and a little ahead of the resurgence of interest in ESF, it was possible to develop a rare example of NHC organocatalysis that does not involve carbonyl compounds. One of Lisa's last studies, Andrei pushed it along, and Alison came in with some proof of principle enantioselectivity when we needed it most.
A follow up to one of our earlier diene regenerative (4 + 2) annulations, except with enantioselectivity and far simpler substrates. Alison and Changhe worked closely on this reaction allowing a nice route to enantioenriched cyclohexadienes.
A Monash collaboration in which Jacob provided some pretty simple imines and their isomerism was studies using Phil's 2D GC strategies.
A serendipitous discovey of a rare example of NHC redox isomerisation in which ester substrates give rise to aldehyde products. A lot of open questions in this reaction design which also allows a nice entry to axially chiral biaryls from point chiral b-lactones. Once more Lisa and Alison teamed up to drive this project forward.
One of Uttam's first papers communicates a useful approach to the halogenation of various heterocycles.
While we had developed other (4 + 2) annualtions this one involves a subtle olefin isomerisation that allowed us to unlock very high levels of enantioselectivity, while keeping the b-lactone functionality intact. A consistently high performing reaction, scoping studies for this reaction in all cases gave fantastic results. Also one of Alison and Lisa's first studies together, of which many more would follow
The first Polyzos/Lupton collaboration played to the chemical engineering strengths of Mousa and allowed an integrated approach to the Fukuyama reduction under flow. The process avoids some of the technical limitations with this type of chemistry.
Our first attempt at reaction discovery via a dienyl acyl azolium instead led to an unusual olefin isomerization Diels-Alder reaction. Patient work by Marcin got this study finalised, and a few years later underpinned our succussful use of the dienyl acyl azolium.
Another installment from one of our most long running Monash collaborations.
A further report by Keith Murray and Ian Gass, now with Mousa Asadi from our group making the nitroxides.
An interesting side reaction that came about in some of our work on Pd-catalysed decarboxylative allylation.
Yuji's undergraduate studies focused on the development of C-H oxidation approaches with hydrocarbazoles. Really nice work lead to a useful approach for the sp3 C-H oxidation directed by a dimethyl carbamoyl functionalised hydrocarbazole.
A review focused on highlighting the similarities and differences of Lewis base catalysis with some of the more common catalysts.
A reaction designed and discovered by Raphael at the CSIRO, supervised by Oliver. Marsewi did a great job taking this proof of principle and turning into a general story. The reaction itself provides a great way to oxygen containing tetracycles, from simple monocyclic vinylogous esters.
In this manuscript we introduce a number of new N-substiuents on the morpholinone scaffold, and examine their use in ester oxidation state NHC catalysis. A very thorough piece of work, and our first enantioselective reaction design. This was late in Lisa's PhD and allowed the group to address enantioselectivity in most of the reactions that followed.
Once more exploiting the Grob-Eschemoser fragmentation it was possible to assemble an array of dendrimers in a handful of steps. Judith also addressed some of the solubility issues with our earlier materials.
IPrMe proved essential to a number of our organocatalytic processes (most notably: J. Am. Chem. Soc. 2011 133, 4694). In this report we discuss its preparation and use in catalysis.
A full report on Chris' communication on this topic.
A research front highlighting chemistry from SynthCon2. This meeting was conceived by Richard Payne and myself during a trip to China. The focus then, and now, remains trying to create an open forum for Australian chemists to consider their science, and the unique challenges of working on this island continent.
Another collaborative study using our nitroxide ligands and lead by Keith Murray and Ian Gass.
Embedded in a range of alkaloids is a chiral carbazole ring system. In this study we exploit readily accessable carbazolone derivatises as substrates in a Trost-Stoltz enantioselective decarboxylative allyalation. This allowed a formal synthesis of (-)-kopsihainanine A and has gone to enable the synthesis of related alkaloids.
A review focused on reaction discovery with NHC organocatalysis in the absence of formation of the Breslow intermediate.
Our second study focused on considering the unsaturated acyl azolium as a system capable of reactions at the b-, a-, and acyl carbons. In this case a highly diastereoselective (3 + 2) annualtion was possible to give cyclopentyl b-lactones. Enantioselectivity was once more a challenge, but would soon be addressed.
Great mechanistic work, which I still use in undergraduate teaching, by Shveta in what proved to be a really challenging reaction design. While not the main focus of the study the first examples of reactions of the unsaturated acyl thiouronioum (adducts of isothiourea catalysts) are reported. This observation has been followed up by Andy Smith and Dan Romo with some really elegant reaction designs.
As part of a study focused on developing new approaches to ethyl acorate we developed a Beckwith-Dowd ring expansion segwayed into a series of 5-exo radical cyclizations. Great solo work from Judith building on her earlier work on Grob-Eschenmoser fragmentations.
Fantastic collaboration with Prof. Paddon-Row. The biggest outcome of this study was a far deeper appreciation of the decarboxylation chemistry. Exploiting this, a series of transformations with this key intermediate were possible.
Lisa's first reaction discovery. This is a really unusual transformation in which the NHC serves as both a Lewis and Bronsted base catalyst. Mechanistically we struggled with this for quite a while. A great conversation with SonBinh Nguyen (Northwestern), and some careful deuteration studies, were instrumental in allowing a viable mechanism to be devised.
Discvoered by Raphael under Oliver's supervision Marsewi was able to clean this study up and expand it. A really interesting reaction allowing various polycyclic oxygen containing heterocycles to be efficiently prepared.
In this second generation approach to the natural product many of the problems with our earlier synthesis are addressed allowing the target to be prepared in 10-steps.
An account regarding the discovery of the NHC catalysed (4 + 2) annualtion (J. Am. Chem. Soc., 2011, 133, 4694).
A lot of chemistry was developed to allow the related NHC catalysis (J. Am. Chem. Soc., 2011, 133, 4694) to be achieved. In this report we provide a thorough account of how the substrates, and other species, for this study can be prepared.
A collaborative study lead by Will from the Andrews/Junk group lead to some interesting coordination chemistry
In this study it was possible to exploit the unsaturated acyl azolium as a conjugate acceptor and latent enolate. As a consequence bond formation was possible at the b-, a-, and acyl carbons. Specifically this allow the preparation of cyclohexenyl b-lactones which underwent decarboxyaltion to give cyclohexadienes.
The first publication enabled by the oxazolidinone nitroxides prepared by Chris. Great to be able to support Ian and Keith by providing a simple ligand that gave them fascinating magnetism properties.
Building on our earlier dendrimer synthesis Judith was able to develop this fragementation chemistry into a general transformation. A very robust reaction as it turned out with more than 30 examples reported.
The chemistry of N-Cl compounds we first examined in the context of radical cyclisation chekmiostry. In this report we looked at their capacity to undergo halogen metal exchange and subseuqent b-hydride elimination. A really interesting report that unfortuantely became a neglected research area in the group.
As part of attempts to achieve TEMPO based oxidations in an enantioselective fashion we examined the use of oxazolidinone based nitroxides in oxidation chemnistry. Unfortuantetyl, oxoammonium chemistry could not be accessed, although the use of Cu-based oxidation conditions allowed some reactions to be developed. This study also lead to a host of collaborative studies wuth the Murray and Bond/Martin groups focused on the use of these nitroxides as spin active ligands in association with cobalt and other spin active metals.
At the start of Lisa's PhD she finished off her undergraduate research project and developed this total synthesis. While the carbene chemistry reported the previous year (JACS, 2009, 131 14176) could be used we needed to resort to far less hindered catalysts to allow the key rearrangement to be achieved. Specifically we used the IPrMe catalyst, also known as Optimus Prime, which we discussed in in eEros a few years later.
The last report from my PhD studies with our Pd-catalysed coupling chemistry now examined to make oxindoles.
Judith drove a very challenging project focused on the Grob-Eschenmoser fragmentation of simple b-keto esters. In this context it was possible to develop a new route to the preparation of dendrimers, including a G7 structures.
As a part of Marsewi's PhD we reviewed the chemistry of enantioselective reaction discovery with polyvalent iodine.
Work from Sarah and Lisa's honours year projects make up the bulk of this report. This is an early example of NHC catalysis with ester oxidation state substrates, and the first NHC catalysed reaction of the unsaturated acyl azolium that involved conjugate addition. A very robust reaction that was even possible with moderate levels of enantioselectivity.
In a study that came about while I wasnt paying attention Jeremy looked at an oxidation in the presence of HCl salts. From this observation it was possible to develop an unusual route for generating chloronium ions and exploit them in chemistry.
The groups first independent publication. As part of a broader idea in total synthesis we stumbled across, and somewhat reinvented, this interesting piece of olefination chemistry.
A relatively early example of the aza-Henry reaction. Using bimetallic catalysis it was possible to activate both coupling partners and deliver a highly enantioselective reaction.
An earlier strategy that I developed while Martin was an an AvH in Germany. In this work the great Athel Beckwith played a key advisory role, and in his humble way, made sure that the study had every chance to be succussfull.
Full paper follow up on our synthetic work.
The major component of my PhD studies. The synthesis was completed in the last months of my PhD and only with some great literature observations from my good friend Oliver Hutt, who I am lucky enough to continue to cllaborate with today.
Great to collaborative with Gregg Whited who did the heavy lifting on this paper.
The follow up to our indole synthesis this chemistry developed very quickly and introduced me to a wonderfully reliable haloformylation reaction that many of my students have subsequently revisited.
A reaction discovery focused around increasing the efficiency of an early step in a multistep sequence. Was great to do the early optimisation and scope work and then to work with more experienced researchers to finalise the study.
Thanks to Natalie and Tom for letting me make a minor contrinbution to this study. My first taste of enantioselecrtive catalysis.
Reporting my honours work this publication describes some mechanistic work that I remain proud of today. The execution could be improved, but the appraoches are solid.
BSc Honours 2019
PhD Scholar, 2019- [BSC Monash University, Lupton]
PhD Scholar, 2019- [BSC Monash University, Chan]
PhD Scholar, 2018- [MSC China Pharm. University, Du and Dong]
PhD Scholar (with J. Hooper), 2019- [BSC Monash University, Lupton]
PhD Scholar, 2017- [BSC Monash University, Lupton]
PhD Scholar, 2017- [MSC University of Madras]
PhD Scholar, 2017- [BSC Monash University, Lupton]
PhD Scholar, 2016- [BSC Auckland University, Brimble]
PhD Scholar, 2016- [BSC Auckland University, Sperry]
SUMMARY: David was born in South Australia, and recieved his undergraduate education at the Univeristy of Adelaide graduating with a BSc (Honours, 1st class) in 2001. In 2005 he completed his PhD studies at the Australian National University, supervised by Professor Martin G. Banwell. Between 2005 and 2007, Dr Lupton was a postdoctoral fellow with Professor Barry M. Trost (Stanford University) supported by the American Australian Association (Sir Keith Murdoch fellow). In 2007, he commenced an academic appointment at Monash University, receiving an Australian Research Council Future Fellowship in 2011 and promotion to Full Professor in 2018. His group is focused on the use of enantioselective catalysis to uncover novel reactivity and enable chemical synthesis.
MAJOR AWARDS: • Tarrant Lectureship, University of Florida 2018 • Alexander von Humboldt Ludwig-Leichardt Awardee (with Professor Herbert Mayr; LMU, Muenchen, Germany) 2015-2017 • Rennie Medal of the RACI 2013• Future Fellowship (FT110100319) 2011-2015 • Beckwith Lectureship of the RACI 2012• Thieme journal award of the Organic Editorial Board 2012• Monash Research Accelerator Program 2011-2012• Sir Keith Murdoch Postdoctoral Fellowship, American Australian Association 2005
EDUCATION: Postdoctoral Research Fellow, Department of Chemistry Stanford University, CA, USA. Supervisor: Professor Barry M. Trost Doctorate of Philosophy Research School of Chemistry, Australian National University, ACT, Australia. Supervisor: Professor Martin G. Banwell Bachelor of Science (Honours 1st) University of Adelaide, SA, Australia. Supervisor: Professor Dennis K. Taylor
CONTACT: david.lupton at monash.edu • twitter: @LuptonChemistryfull CV
PhDs in Australia normally take around 3.5 years. While theya re much shorter and those in the US there are fewer courses. So you spend most of your time working on a research project. For most students we aim to produce 3 or papers during their studies. Scholarships are paid at around 28K australian dollars tax free. In a city like Melbourne that is enough to live comfortably, although many students add to there salary through work as a teaching assistant.