Research Guides

Department of Chemistry University of Oxford

Professor S.G. Davies

Research within the Davies group is concerned with investigations into a wide variety of topics including the development of new synthetic methodology, catalysis, mechanistic investigations, total synthesis and collaborative projects in medicinal chemistry. For example, this includes  new applications for the conjugate addition of enantiopure lithium amides, development of kinetic resolution processes for the preparation of functionalised molecular building blocks, new methods for nucleophilic fluorination, methodology for the chemoselective functionalisation of unsaturated amines at the olefin (rather than the nitrogen atom), and application of these methodologies to the total synthesis of natural products of biological significance (including pyrrolidines, piperidines, tropanes, pyrrolizidines, and imino- and aminosugars).
 


(i) Lithium Amide Conjugate Addition

Chiral lithium amides have been extensively used and studied within organic synthesis as effective reagents for a range of transformations including enantioselective reduction, alkylation, deprotonation, desymmetrisation and kinetic resolution. Lithium amides may also act as nucleophiles. Within this arena, we have shown that the conjugate addition of a range of secondary lithium amides, derived from enantiopure α-methylbenzylamine, to α,β-unsaturated esters represents an efficient method for the preparation of β-amino esters and their derivatives (including β-amino acids and various alkaloids). We have exploited this reaction in a range of synthetic applications, including the initiation of tandem processes, enantiorecognition phenomena, and total synthesis. More information is available here.

Lithium Amide Conjugate Addition Methodology

Key Publication:
The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part II: 2005–2011
Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2012, 23, 1111
[View Journal Page]

 
(ii) Ammonium Directed Oxidation of Allylic Amines

Treatment of allylic amines with acid followed by m-CPBA gives the corresponding amino diols as the major products, consistent with hydrogen-bond directed attack of the peracid to give the corresponding epoxide, followed by regioselective ring-opening. This metal free sequence of reactions leads to very highly diastereoselective transformations in both cyclic and acyclic systems. We have used this methodology as the key synthetic step to enable the asymmetric syntheses of iminosugars such as (+)-1-deoxynojirimycin and aminosugars such as L-acosamine. More information is available here.

Ammonium Directed Oxidation

Key Publication:
Concise and selective asymmetric synthesis of acosamine from sorbic acid
Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216 [View Journal Page]

 
(iii)  Ring-closing iodoamination

Treatment of a range of unsaturated amines with iodine promotes ring-closing iodoamination with concomitant N-debenzylation, providing an efficient and stereoselective route to azacycles such as pyrrolidines, pyrrolizidines and tropanes. This methodology has been used in a series of natural product syntheses including (‒)-7a-epi-hyacinthacine A1, (+)-pseudococaine and (‒)-codonopsinine. More information is available here.

Ring-closing Iodoamination Methodology

Key Publication:
Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation
Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594 [View Journal Page]
 

We have utilised the methodology developed in the group in total syntheses of a range of enantiopure compounds including natural products, their analogues and other potential therapeutic agents. Recently completed syntheses include (+)-pseudococaine, (−)-absouline, (−)-angustueine, (+)-pseudodistomin D, (+)-1-deoxynojirimycin, (−)-nakinadine D, (−)-codonopsinine and (−)-hopromalinol. More information, including more examples of recent target syntheses, is available here.

Total Synthesis of Natural Products

 

There is huge potential for chemistry to have an enormous impact on the biological and medicinal world. We have several highly successful multidisciplinary research collaborations including the development of small molecules to determine stem cell fate, novel protein tyrosine phosphatase inhibitors for treatment of cancer and transcriptional upregulation of utrophin in the treatment of Duchenne Muscular Dystrophy (DMD). More information is available here.

Medicinal Chemistry Programmes

 

Steve has published over 575 papers, and has an h-index (Web of Science) of 60. A full list of his publications is available here; the ten most recent papers are shown below.


(578).  (−)-Pseudodistomin E: first asymmetric synthesis and absolute configuration assignment
Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.; Zimmer, D. Org. Lett. 2017,
DOI: 10.1021/acs.orglett.7b00434 [View Journal Page]

(577).  Asymmetric syntheses of the 1-hydroxymethyl-2-hydroxy substituted pyrrolizidines
(–)-macronecine, (–)-petasinecine, (–)-1-epi-macronecine, (+)-1-epi-petasinecine and
(+)-2-epi-rosmarinecine
Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron201672, 7449 [View Journal Page]

(576).  Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.; Zimmer, D. Tetrahedron 201672, 7417 [View Journal Page]

(575).  Asymmetric syntheses of (–)-ADMJ and (+)-ADANJ: 2-deoxy-2-amino analogues of
(–)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin
Davies, S. G.; Figuccia A. L. A.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2016, 81, 6481 [View Journal Page]

(574).  Asymmetric syntheses of (–)-hastanecine, (–)-turneforcidine and (–)-platynecine
Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2016, 72, 4523 [View Journal Page]

(573).  Asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (–)-preussin B, and 3-deoxy-(+)-preussin B
Buchman, M.; Csatayová, K.; Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.; Roberts, P. M.; Rowe, S.; Thomson, J. E. J. Org. Chem. 2016, 81, 4907 [View Journal Page]

(572).  Strategies for the construction of morphinan alkaloid AB-rings: regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings
Davies, S. G.; Goddard, E, C.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Withey, J. M. Tetrahedron: Asymmetry 2016, 27, 274 [View Journal Page]

(571).  Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines from α-hydroxy-β-amino esters
Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Kennedy, M. S.; Roberts, P. M.; Thomson, J. E. Tetrahedron 201672, 2139 [View Journal Page]

(570).  Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C: structure and absolute configuration confirmation of 3-epi-xestoaminol C
Archer, S. G.; Csatayová, K.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron Lett. 2016, 57, 1270 [View Journal Page]

(569).  The asymmetric synthesis of enantiopure C(5)-substituted transpentacins via diastereoselective conjugate additions to a β'-amino-α,β-unsaturated ester
Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.; Zammit, C. M. Tetrahedron: Asymmetry 201627, 208 [View Journal Page]