ORCID Profile
0000-0002-7881-7761
Current Organisations
The University of Auckland
,
Cold Spring Harbor Laboratory
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Publisher: Wiley
Date: 07-12-2022
Abstract: SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S−O linkages upon exchange of S−F bonds with aryl silyl‐ether substrates, and while near‐perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2‐tert‐butyl‐1,1,3,3‐tetramethylguanidine BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S−O bond linkages in a single step often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click‐principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.
Publisher: American Chemical Society (ACS)
Date: 25-04-2022
DOI: 10.26434/CHEMRXIV-2022-4DC71
Abstract: Diversity Oriented Clicking (DOC) is a discovery method geared towards the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical ersification of core “SuFExable” hubs – exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) – enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented beta-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the biological function – another key objective of click chemistry – of this new scaffold as covalent inhibitors of human neutrophil elastase (hNE). The ease of ersification of SASFs through click pathways, enabling rapid access to biologically important molecules, further validates Diversity Oriented Clicking as an effective and robust method for lead discovery.
Publisher: American Chemical Society (ACS)
Date: 03-10-2022
DOI: 10.26434/CHEMRXIV-2022-NC91F
Abstract: We report catalytic Phosphorus Fluoride Exchange (PFEx) as the latest advance in connective click-reaction technology. Emulating Nature, PFEx reaches into the biological world and creates stable tetrahedral P(V)- connections through efficient phosphorus-fluoride exchange chemistry. We showcase PFEx through the coupling of P(V)-F hubs with aryl alcohols, alkyl alcohols, and amines, delivering stable, multidimensional P(V)-O and P(V)- N connected products. The reactivity profile of P-F hubs surpasses that of their P-Cl counterparts, both in reaction performance, rate, and outcome, qualifying PFEx as a true click reaction. The rate of PFEx transformations is significantly enhanced by Lewis amine base catalysis [e.g., 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)]. When using substrates comprising multiple P-F bonds, selective, serial exchange reactions are realized through judicious catalyst selection. Synthesis of the final products (in up to 4 steps) allows controlled projections to be deliberately installed along 3 of the 4 tetrahedral axes departing the P(V) central hub. The unique reactivity window of PFEx allows for selective, modular click-reactions to be performed in series (e.g., SuFEx-PFEx-CuAAC) to rapidly generate complex multidimensional molecules, rendering PFEX a perfect addition to the click chemistry toolbox.
Publisher: Wiley
Date: 07-12-2022
Abstract: SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S−O linkages upon exchange of S−F bonds with aryl silyl‐ether substrates, and while near‐perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2‐tert‐butyl‐1,1,3,3‐tetramethylguanidine BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S−O bond linkages in a single step often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click‐principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-04-2023
Abstract: The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d -Ala- d -Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3MD00049D
Abstract: We report an improved 4-step semisynthesis of (−)-jerantinine A and (−)-melodinine P from (−)-tabersonine, qualify their potency against TNBC cells and confirm they induce oxidative stress. JA also acts as a potent inhibitor of nucleotide metabolism.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2023
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Joshua Homer.