Research Guides

The Davies group is currently actively involved with investigations into a variety of topics including the development of novel asymmetric transformations and concepts, enantioselective recognition processes, the total synthesis of natural products of biological significance and medicinal chemistry.

 

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.Although many of these procedures rely upon lithium amides to act as chiral bases, 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 a-methylbenzylamine, to a,b-unsaturated esters represents an efficient method for the preparation of b-amino esters and their derivatives. We have exploited this reaction in a range of synthetic applications, including the initiation of tandem processes, enantiorecognition phenomena, and total synthesis.

Highly diastereoselective conjugate addition of lithium N-benzyl-N-(a-methylbenzyl)amide to a,b-unsaturated esters

Key Publications: (i) “The conjugate addition of enantiomerically pure lithium amides as homochiral ammonia equivalents: scope, limitations and synthetic applications”. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833. (ii) “Homochiral lithium amides for the asymmetric synthesis of b-amino acids”. Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793.

 

Tandem reactions that form relatively complex molecules with high levels of selectivity in a single step may be more efficacious than multi-step syntheses requiring several work-up and purification procedures. We have utilised the conjugate addition of lithium N-benzyl-N-(a-methylbenzyl)amide to di-tert-butyl nona-2,5-dienedioate and dimethyl 4,4′-(alkylazanediyl)dibut-2-enoates which promotes two highly diastereoselective, tandem conjugate addition reactions resulting in the production of polyfunctionalised aminocyclohexanes and 3-aminopiperidines.

X	R	dr	Yield % (dr)
CH2	tBu	>99:1	78 (>99:1)
NtBu	Me	95:5	77 (95:5)
N-(S)-a-methylbenzyl	Me	93:7	65 (93:7)
NBn	Me	89:11	76 (89:11)
NMe	Me	89:11	67 (89:11)

Synthesis of polyfunctionalised aminocyclohexanes and 3-aminopiperdines using tandem conjugate addition reactions

Key Publication: “Tandem asymmetric conjugate addition cyclisation reactions initiated by a homochiral lithium amide”. Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P. D.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 1284.

 

We recently reported a tandem conjugate addition/Mannich reaction for the preparation of polyfunctionalised 4-aminotetrahydroquinoline-3-carboxylic acid derivatives.

Synthesis of polyfunctionalised 4-aminotetrahydroquinoline-3-carboxylic acid derivatives
via sequential conjugate addition and intramolecular Mannich reaction

Key Publication: “A tandem conjugate addition/cyclisation protocol for the asymmetric synthesis of 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives”. Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009, 11, 1959.

Enantioselective molecular recognition phenomena are of extreme importance to the fields of both chemistry and biology. Synthetic chemists can contribute to the understanding of this arena through the development of novel kinetic, dynamic kinetic and parallel kinetic resolution protocols, or through the application of double asymmetric induction.

The efficient kinetic and parallel kinetic resolutions of a range of 3- and 5-substituted cyclopent-1-ene-carboxylates, utilising the conjugate addition of either homochiral or a pseudoenantiomeric mixture of homochiral lithium amides, respectively, has been developed by us as an expedient route to enantiopure 3- and 5-substituted analogues of the antifungal agents cispentacin and transpentacin, which are also useful b-amino acids for the construction of b-peptides.

Synthesis of 5-substituted cispentacin derivatives via a parallel kinetic resolution protocol

Key Publications: (i) “Parallel kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the asymmetric synthesis of 3-alkylcispentacin derivatives”. Davies, S. G; Garner, A. C.; Long, M. J. C.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355. (ii) “Kinetic resolution and parallel kinetic resolution of methyl (±)-5-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 5-alkyl-cispentacin derivatives”. Davies, S. G.; Garner, A. C.; Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005, 3, 2762. (iii) “Parallel kinetic resolution of tert-butyl (RS)-6-alkyl-cyclohex-1-ene-carboxylates for the asymmetric synthesis of 6-alkyl-substituted cishexacin and transhexacin derivatives”. Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870.

 

We have shown that enolates of (S)-N,N'-bis-(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione exhibit high levels of enantiodiscrimination in alkylations with (RS)-1-aryl-1-bromoethanes and (RS)-2-bromoesters, affording substituted diketopiperazines containing two new stereogenic centres in high diastereoisomeric purity (>99:1 dr). Deprotection and hydrolysis of the resultant substituted diketopiperazines provides a route to the asymmetric synthesis of enantiopure methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates (i.e., substituted a-amino acids).

Enantiodiscrimination of racemic electrophiles by enolates of (S)-N,N'-bis-(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione
for the synthesis of substituted a-amino acids

Key Publication: “Enantiodiscrimination of racemic electrophiles by diketopiperazine enolates: asymmetric synthesis of methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates”. Bull, S. D.; Davies, S. G.; Epstein, S. W.; Garner, A. C.; Mujtaba, N.; Roberts, P. M.; Savory, E. D.; Smith, A. D.; Tamayo, J. A.; Watkin, D. J. Tetrahedron 2006, 62, 7911.

Treatment of a range of unsaturated b-amino esters (containing a cis-dioxolane unit) with iodine promotes a novel ring-closing alkene iodoamination reaction which proceeds with concomitant N-debenzylation, providing a simple and stereoselective route to iodomethyl pyrrolidines. Functional group interconversion of the resulting iodomethyl pyrrolidines upon treatment with AgOAc proceeds via the corresponding aziridinium ion, with subsequent deprotection giving access to polyhydroxylated pyrrolidines.

Formation of polyhydroxylated pyrrolidines using a ring-closing iodoamination with concomitant N-debenzylation reaction

Key Publication: “Iodine-mediated ring closing iodoamination with concomitant N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines”. Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron: Asymmetry 2009, 20, 758.

 

There is sometimes a chemoselectivity issue associated with functionalisation of allylic amines as electrophiles often react preferentially with the (more nucleophilic) N-lone pair. We have demonstrated that treatment of allylic amines with trichloroacetic acid [Cl₃CCO₂H] followed by mCPBA gives the corresponding a-hydroxy trichloroacetate ester as the major product with no evidence of competing N-oxide formation. This outcome is consistent with initial protonation of the amine by the acid, which has the dual effect of rendering the nitrogen non-nucleophilic since it is protected as the ammonium ion, whilst simultaneously generating a species capable of acting as a hydrogen-bond donor. Attack of the peracid is then hydrogen-bond directed to give the corresponding epoxide. Ring-opening of the epoxide by the trichloroacetic acid gives the a-hydroxy trichloroacetate ester. This metal free sequence of reactions leads to very highly diastereoselective transformations in cyclic systems.

Ammonium-directed olefinic oxidation of 3-N,N-dibenzylaminocyclohex-1-ene

Key Publications: (i) “Ammonium directed dihydroxylation of 3-amino-cyclohex-1-enes: development of a metal-free dihydroxylation protocol”. Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008,6, 3751. (ii) “Ammonium directed dihydroxylation: metal-free synthesis of the diastereoisomers of 3-amino-cyclohexane-1,2-diol”. Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762. (iii) “Ammonium-directed oxidation of cyclic allylic and homoallylic amines”. Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735.

 

The propensity of allylic amines to undergo initial N-oxidation is not necessarily detritic. We have demonstrated that the oxidation of allylic N-oxides constitutes a useful process that is complementary to the ammonium-directed process. Oxidation of 3-N,N-dibenzylaminocyclohex-1-ene N-oxide in the presence of Cl₃CCO₂H proceeds with high levels of anti-diastereoselectivity (98:2 dr), with no competing side reactions.

Olefinic oxidation of 3-N,N-dibenzylaminocyclohex-1-ene N-oxide

Key Publication: “Highly diastereoselective anti-dihydroxylation of 3-N,N-dibenzylamino-cyclohex-1-ene N-oxide”. Aciro, C.; Davies, S. G.; Kurosawa, W.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Lett. 2009, 11, 1333.

 

We have also developed a chemo- and stereoselective cyclopropanation reaction of allylic amines, and a stereodivergent, diastereoselective cyclopropanation protocol of allylic carbamates using the Wittig-Furukawa reagent [Zn(CH₂I)₂] or Shi’s carbenoid [CF₃CO₂ZnCH₂I].

Stereodivergent cyclopropanation reactions of allylic carbamates

Key Publication: “Diastereoselective Simmons-Smith cyclopropanations of allylic amines and carbamates”. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Chem. Commun. 2007, 4029.

We have utilised some of the methods described above in the total synthesis of a range of natural products. Recently completed syntheses include jaspine B, deoxoprosophylline and sperabillin D. We are actively pursuing the synthesis of other natural products and their derivatives. Current targets include morphine, martinellic acid and pseudodistomin D.

Structures of jaspine B, deoxoprosophylline, sperabillin D, morphine, martinellic acid and pseudodistomin D

Key Publications: (i) “Asymmetric total synthesis of sperabillins B and D via lithium amide conjugate addition”. Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630. (ii) “Asymmetric synthesis of N,O,O,O-tetra-acetyl D-lyxo-phytosphingosine, jaspine B (pachastrissamine), C(2)-epi-jaspine B, and deoxoprosophylline via lithium amide conjugate addition”. Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665. “Jaspine B (pachastrissamine) and 2-epi-jaspine B: synthesis and structural assignment”. Abraham, E.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry 2008, 19, 1027.

(1) “An oxidation and ring-contraction approach to the synthesis of (±)-1-deoxynojirimycin and (±)-1-deoxyaltronojirimycin”. Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136.

 

(2) “On the origins of diastereoselectivity in the alkylation of enolates of N-acyl derivatives of N-1-(1¢-naphthyl)ethyl-O-tert-butylhydroxylamine: chiral Weinreb amide equivalents”. Davies, S. G.; Goodwin, C. J.; Hepworth, D.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75, 1214.

 

(3) “Asymmetric synthesis of piperidines and octahydroindolizidines”. Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567.

 

(4) “Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(a-methylbenzyl)amide: asymmetric synthesis of anti-b^2,3-disubstituted and b^2,2,3-trisubstituted amino acids”. Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron 2010, 66, 4604.

 

(5) “b-Fluoroamphetamines via the stereoselective synthesis of benzylic fluorides”. Cresswell, A. J.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Tyte, M. J. Org. Lett. 2010, 12, 2936.

 

(6) “Syntheses of trans-SCH-A and cis-SCH-A via a stereodivergent cyclopropanation protocol”. Csatayová, K.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Lett. 2010, 12, 3152.

 

(7) “The stereodivergent aziridination of allylic carbamates, amides and sulfonamides”. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Woods, P. A. Tetrahedron 2010, 66, 6806.

 

(8) “Chemo- and diastereoselective cyclopropanation of allylic amines and carbamates”. Csatayová, K.; Davies, S. G.; Lee, J. A.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron 2010, 66, 8420.

 

(9) “One-pot conversions of olefins to cyclic carbonates and secondary allylic and homoallylic amines to cyclic carbamates”. Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Poce, G.; Roberts, P. M.; Thomson, J. E.; Williamson, D. M. J. Org. Chem. 2010, 75, 7745.

 

(10) “Syntheses of the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin via chemo- and diastereoselective olefinic oxidation of unsaturated amines”. Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75, 8133.