Transition Metal and Catalyst-Free Hydrogen Borrowing reactions

Lead Research Organisation: University of Oxford
Department Name: Synthesis for Biology & Medicine CDT

Abstract

This project falls within the EPSRC Synthetic Organic Chemistry research area
Synthesis of alicyclic compounds in a regio- and stereocontrolled manner is a highly desirable transformation for the development of new pharmaceuticals, agrochemicals and other bio-active molecules. Testament to this, Lawson and co-workers reported in 2014 that the cyclohexyl motif was the fifth most frequently used ring system in small molecule drugs. Given the significance of the cyclohexyl motif, there are surprisingly few general methods for accessing this structure, with the most common approaches depending on (4+2) or (6+0) disconnections via Diels-Alder reaction or arene hydrogenation. Recently, a practical method has been developed in the Donohoe group to access substituted cyclohexanes by a novel (5+1) disconnection, which utilises 1,5-diols, pentamethylacetophenone (Ph* ketone) and hydrogen borrowing catalysis. This transformation is mediated by an iridium catalyst, which oxidises a diol to generate the corresponding hydroxy-aldehyde in-situ and Ir-hydride. Following this, the hydroxyl-aldehyde undergoes a cross aldol reaction with Ph* ketone. This was enabled by the Ph* group, which prevented homo coupling of the ketone moiety by blocking 1,2-addition to the carbonyl. Following the aldol condensation, Ir-hydride reduces the enone using the 'borrowed' hydrogen to complete the catalytic cycle. Furthermore, by utilising the Ph* group, the products could be cleaved to a range of functional groups by a retro-Friedel-Crafts reaction.
We are interested in further investigating the application of transition metal-free hydrogen borrowing catalysis towards the synthesis of different alicyclic compounds. In particular, we have promising results to develop a complementary (5+1) approach towards the synthesis of substituted cyclohexenes using 1,5-diols with Ph* ketone. This would enable access to a range of medicinally relevant stereodefined cyclic enones, that would rival the Diels alder reaction. We also hope to explore the use of heteroatom-bearing 1,5-diols under analogous conditions, which would allow access to the corresponding saturated heterocycles. Similarly, we believe there is also potential to use chiral alcohols, which may yield enantioenriched products. We have recent success in discovering novel metal-free conditions for the hydrogen borrowing of 1,5 diols with Ph* ketone. This gives us the opportunity to make substituted cyclohexenes in a highly atom economical and environmentally friendly manner, with the only by-product being water, and without using a metal catalyst.
In addition to the academic interest in novel chemistry, we hope that the development of these methodologies will allow access to highly desirable structures, and enable advancements in the material science, pharmaceutical, and agrochemical industries.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512333/1 01/10/2017 30/09/2021
1947864 Studentship EP/R512333/1 01/10/2017 30/09/2021 Lewis Smith
 
Description An atom-economical methodology to access substituted acyl-cyclohexenes from pentamethylacetophenone and 1,5-diols is described. This process is catalyzed by an iridium(I) catalyst in conjunction with a bulky electron rich phosphine ligand (CataCXium A) which favors acceptorless dehydrogenation over conjugate reduction to the corresponding cyclohexane. The reaction produces water and hydrogen gas as the sole byproducts and a wide range of functionalized acyl-cyclohexene products can be synthesized using this method in very high yields. A series of control experiments were carried out, which revealed that the process is initiated by acceptorless dehydrogenation of the diol followed by a redox-neutral cascade process, which is independent of the iridium catalyst. Deuterium labeling studies established that the key step of this cascade involves a novel base-mediated [1,5]-hydride shift. The cyclohexenyl ketone products could readily be cleaved under mildly acidic conditions to access a range of valuable substituted cyclohexene derivatives.
Exploitation Route The findings of the research have presented a highly atom economical and practical methodology for accessing the cyclohexyl motif, which is ubiquitous in organic chemistry and industry. We might expect this reaction to be applied to the synthesis of important molecules. The research also provided significant insight into the mechanism of the discovered reaction, which has changed the understanding of the mechanism for related reactions of diols in hydrogen borrowing, making a correction to previously reported literature. This will open new avenues for redox-neutral C-C couplings via redistribution of hydrogen.
Sectors Chemicals

URL https://pubs.acs.org/doi/10.1021/jacs.9b12296
 
Description Department Tours for Prospective Organic Chemistry Undergraduate Students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Tours of the chemsitry research laboratory and Lincoln College were given to prospective undergraduate students from high school. Engaged in discussions about chemistry/university experience.
Year(s) Of Engagement Activity 2019
 
Description Tours to Prospective undergraduate Students (KS5) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Tours of CRL and discussions about chemistry/university to KS5 students
Year(s) Of Engagement Activity 2019