Research Guides

Department of Chemistry University of Oxford

Dr Jim Thomson

Our research interests lie broadly in the areas of synthetic organic chemistry, the development of novel asymmetric transformations, and the total synthesis of natural products. Some selected examples of our chemistry are described below. For more information please visit the SGD Group web pages.
 

Aziridinium Rearrangements

A range of β-hydroxy-α-amino acids and β-fluoro-α-amino acids were prepared from the corresponding enantiopure α-hydroxy-β-amino esters via a rearrangement protocol which proceeds via the intermediacy of the corresponding aziridinium ions. Activation of the hydroxyl group within the α-hydroxy-β-amino esters via mesylation promoted aziridinium formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridiniums with H2O [which proceeds with inversion of configuration at C(3)] gave the corresponding β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the resultant anantiopure β-hydroxy-α-amino acids in good yield and high diastereoisomeric purity. By employing the alternative reagent system of XtalFluor-E® and Et3N·3HF, aziridinium formation and regioselective ring-opening with fluoride gives the corresponding β-fluoro-α-amino esters, which can be deprotected to give enantiopure β-fluoro-α-amino acids in good yield and high diastereoisomeric purity.

Asymmetric synthesis of beta-substituted-alpha-amino acids

Key Publications:
(1).  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]
(2).  Asymmetric synthesis of substituted anti-β-fluorophenylalanines
Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Org. Lett. 201517, 2254
[View Journal Page]
(3).  Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of
β-hydroxy-α-amino acids
Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Tetrahedron 201470, 5849
[View Journal Page]
 

Synthesis of Iminosugars

Our methodology concerning the ring-closing iodoamination of unsaturated amines has been combined with an aziridinium rearrangement procedure in the asymmetric synthesis of deoxyiminosugars such as (–)-1-deoxymannojirimycin. The ring-closing iodoamination of a bishomoallylic amine gave the corresponding 5-iodomethyl-pyrrolidine, and this was followed by in situ ring-expansion to give a diastereoisomerically pure (>99:1 dr) cyclic carbonate. The mechanism of this process involves aziridinium ion formation followed by ring-expansion via attack of the aziridinium ion by a tethered carbonic acid residue (which forms in situ by sequestering CO2 from the bicarbonate base used). Subsequent O-desilylation, methanolysis of the cyclic carbonate, and hydrogenolytic N- and O-deprotection gave the target iminosugar in good overall yield.

Asymmetric synthesis of (-)-deoxynojirimycin

Key Publications:
(1).  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. 201681, 6481 [View Journal Page]
(2).  Asymmetric syntheses of (–)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin via a
ring-expansion approach
Davies, S. G.; Figuccia, A. L. A.; Fletcher A. M.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2013, 15, 2042
[View Journal Page]
 

Ring-closing Iodoamination

We have shown that treatment of a range of unsaturated amines with iodine promotes ring-closing iodoamination with concomitant loss of the N-α-methyl-p-methoxybenzyl group, providing an efficient route to azacyclic derivatives such as pyrrolidines, pyrrolizidines and tropanes. This methodology has been used in the asymmetric syntheses of numerous natural products including, for example, (+)-pseudococaine as shown below.

Asymmetric synthesis of (+)-pseudococaine

Key Publications:
(1).  Asymmetric synthesis of the tropane alkaloid (+)-pseudococaine via ring-closing iodoamination
Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2012, 14, 4278
[View Journal Page]
(2).  Ring-closing iodoamination of homoallylic amines for the synthesis of polysubstituted pyrrolidines: application to the asymmetric synthesis of (–)-codonopsinine
Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron 201268, 4302
[View Journal Page]
 

(1).  Asymmetric synthesis of the tetraponerine alkaloids
Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 201782, 6689 [View Journal Page]

(2).  (−)-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. 201719, 1638
[View Journal Page]

(3).  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. 201681, 6481 [View Journal Page]

(4).  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. 201681, 4907 [View Journal Page]

(5).  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]

(6).  Asymmetric synthesis of substituted anti-β-fluorophenylalanines
Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Roberts, P. M.; Thomson, J. E. Org. Lett. 201517, 2254
[View Journal Page]

(7).  Asymmetric syntheses of polysubstituted homoprolines and homoprolinols
Csatayová, K.; Davies, S. G.; Figuccia, A. L. A.; Fletcher, A. M.; Ford, J. G.; Lee, J. A.; Roberts, P. M.; Saward, B. G.; Song, H.; Thomson, J. E. Tetrahedron 2015, 71, 9131 [View Journal Page]

(8).  Asymmetric syntheses of nakinadine D, nakinadine E and nakinadine F: confirmation of their relative (RS,SR)-configurations and proposal of their absolute (2S,3R)-configurations
Davies, S. G.; Fletcher, A. M.; Shah, R. S.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2015, 80, 4017 [View Journal Page]

(9).  Asymmetric syntheses of (–)-3-epi-fagomine, (2R,3S,4R)-dihydroxypipecolic acid and several polyhydroxylated homopipecolic acids
Csatayová, K.; Davies, S. G.; Fletcher, A. M.; Ford, J. G.; Klauber, D. J.; Roberts, P. M.; Thomson, J. E.
J. Org. Chem. 2014, 79, 10932 [View Journal Page]

(10).  Diastereoselective Ireland–Claisen rearrangements of substituted allyl β-amino esters: applications in the asymmetric synthesis of C(5)-substituted transpentacins
Davies, S. G; Fletcher, A. M.; Lee, J. A; Roberts, P. M.; Souleymanou, M. Y.; Thomson, J. E.; Zammit,
C. M. Org. Biomol. Chem. 2014, 12, 2702 [View Journal Page]