Development Of Methodology Involving Chiral Lithium Amide Bases
Symmetrical cyclopentane oxides were some of the first substrates to be successfully transformed into chiral products using chiralbases, but there is still uncertainty as the role of the remote oxygen, which to date has always been required for a successful reaction. My group are evaluating the range of substrates A-H using a variety of bases, with and without chelating effects. In addition, novel 6,5-systems (G-H) are also being investigated and at the time of writing (February 2016) a paper summarizing these results has been subjected to Tetrahedron Asymmetry.
Symmetrical cyclopentane oxides were some of the first substrates to be successfully transformed into chiral products using chiralbases, but there is still uncertainty as the role of the remote oxygen, which to date has always been required for a successful reaction. My group are evaluating the range of substrates A-H using a variety of bases, with and without chelating effects. In addition, novel 6,5-systems (G-H) are also being investigated and at the time of writing (February 2016) a paper summarizing these results has been subjected to Tetrahedron Asymmetry.
Synthetic Strategies Towards The Development of CMP-KDO Synthetase Inhibitors
Synthetic strategies are under-way to synthesize potential antimicrobial agents relating to the key constituent of gram –ve bacterial cell walls, 2β-deoxy-KDO (1), which is a key component for the construction of bacterial cell walls that maintain their structural and chemical integrity to the microbial environment. Deficient cell wall formation might result in a bacterial cell more susceptible to their natural environment. Our synthetic strategies involve investigating the synthesis of a range of CMP-KDO synthetase inhibitors.1This enzyme is essential in all Gram-negative bacteria and loss of activity results in a loss in the integrity of the bacterial outer-membrane and cell death (α-KDO (1) is a key constituent in the outer membrane of Gram-negative bacteria). The proposal was built on earlier studies that demonstrated that the ammonium salt of 2β-deoxy KDO (2) was a very important inhibitor of this enzyme. Unfortunately 2 does not enter bacterial cells. To overcome this 2 was conjugated to oligo-peptides and uptake achieved using the active oligo-peptides uptake system. However this concept was undermined by the ready isolation of mutants with defects in their oligo-peptide system such that 2 was unable to enter the cell. Our new strategy used molecular modelling in order to design novel lipophilic derivates of 2 (such as 3 & 4) that will enter the cell by diffusion across the inner membrane thus avoiding the active uptake and resistance problems.
Synthetic strategies are under-way to synthesize potential antimicrobial agents relating to the key constituent of gram –ve bacterial cell walls, 2β-deoxy-KDO (1), which is a key component for the construction of bacterial cell walls that maintain their structural and chemical integrity to the microbial environment. Deficient cell wall formation might result in a bacterial cell more susceptible to their natural environment. Our synthetic strategies involve investigating the synthesis of a range of CMP-KDO synthetase inhibitors.1This enzyme is essential in all Gram-negative bacteria and loss of activity results in a loss in the integrity of the bacterial outer-membrane and cell death (α-KDO (1) is a key constituent in the outer membrane of Gram-negative bacteria). The proposal was built on earlier studies that demonstrated that the ammonium salt of 2β-deoxy KDO (2) was a very important inhibitor of this enzyme. Unfortunately 2 does not enter bacterial cells. To overcome this 2 was conjugated to oligo-peptides and uptake achieved using the active oligo-peptides uptake system. However this concept was undermined by the ready isolation of mutants with defects in their oligo-peptide system such that 2 was unable to enter the cell. Our new strategy used molecular modelling in order to design novel lipophilic derivates of 2 (such as 3 & 4) that will enter the cell by diffusion across the inner membrane thus avoiding the active uptake and resistance problems.
Preparation and Isolation of Isotoped Enriched Glycoaminoglycans
The major sulphated glycoaminoglycan (GAG) components of proteoglycans (PGs), namely heparin sulphate (HS)/heparin and chondroitin sulphate/dermatin sulphate (CS/DS) are complex linear polysaccharides. They are constructed initially of repeating disaccharide units of β-D-glucoronate linked to either α-D-N-acetylgalactosomine in CS/DS. These repeating units can then be subjected to considerable post-polymerisation modification, i.e. epimerisation and sulphation of a number of potential disaccharide units. Such qualitative and quantative variations give rise to complex GAGs that can differ in composition and sequence, in a regulated manner, between cell types, tissue and animal species.
The biological activities of complex GAGs are intimately related to their structural diversity and ability to interact with many cell surfaces and extracellular proteins, thereby modifying their behaviour. We have interesting results from 2011 onwards relating to the production of isotope enriched (15N, 34S) from crustacean sources which allows us to use ‘tagged’ GAGs in potential biological routes.
The major sulphated glycoaminoglycan (GAG) components of proteoglycans (PGs), namely heparin sulphate (HS)/heparin and chondroitin sulphate/dermatin sulphate (CS/DS) are complex linear polysaccharides. They are constructed initially of repeating disaccharide units of β-D-glucoronate linked to either α-D-N-acetylgalactosomine in CS/DS. These repeating units can then be subjected to considerable post-polymerisation modification, i.e. epimerisation and sulphation of a number of potential disaccharide units. Such qualitative and quantative variations give rise to complex GAGs that can differ in composition and sequence, in a regulated manner, between cell types, tissue and animal species.
The biological activities of complex GAGs are intimately related to their structural diversity and ability to interact with many cell surfaces and extracellular proteins, thereby modifying their behaviour. We have interesting results from 2011 onwards relating to the production of isotope enriched (15N, 34S) from crustacean sources which allows us to use ‘tagged’ GAGs in potential biological routes.
Enantioselective Deprotonation of Diarylmethane Systems
My doctoral work at the University of Salford under Dr James Wilkinson initially involved exploring the reaction of an achiral substrate which displayed readily available protons for deprotonation and investigating a range of chiral bases on these substrate, and examining if any subsequent reaction occurred in enantioselectivity. The nature of the substrate was varied from an original bicyclic epoxide substrate to a range of substituted 2-benzylphenol derivatives as outlined below.
These bicyclic epoxide systems (5) were investigated with respect to changing the nature of the R group. The systems were designed to investigate the effect of a change in substituent stereochemistry and the nature of the substituent itself on any enantioselective excess (ee) in the reaction. Various chiral bases and solvent systems were also investigated in terms of the yields and ee’s. We found that the ee of the reaction could vary significantly by the choice of solvent employed for the reaction, and that some bases gave substantially greater ee’s than others. Table 1 summarises some initial results from this area of work.
Table 1. Entry R1, R2 Solvent Base Yield (%) [α]D of 6 ee (%)
1 OCH2CH2O THF 7 39 +ve 64
2 OCH2CH2O THF 8 47 -ve 27
3 OCH2CH2O Benzene 9 81 +ve 42
4 OCH2CH2O Ether 10 26 -ve 37
My doctoral work at the University of Salford under Dr James Wilkinson initially involved exploring the reaction of an achiral substrate which displayed readily available protons for deprotonation and investigating a range of chiral bases on these substrate, and examining if any subsequent reaction occurred in enantioselectivity. The nature of the substrate was varied from an original bicyclic epoxide substrate to a range of substituted 2-benzylphenol derivatives as outlined below.
These bicyclic epoxide systems (5) were investigated with respect to changing the nature of the R group. The systems were designed to investigate the effect of a change in substituent stereochemistry and the nature of the substituent itself on any enantioselective excess (ee) in the reaction. Various chiral bases and solvent systems were also investigated in terms of the yields and ee’s. We found that the ee of the reaction could vary significantly by the choice of solvent employed for the reaction, and that some bases gave substantially greater ee’s than others. Table 1 summarises some initial results from this area of work.
Table 1. Entry R1, R2 Solvent Base Yield (%) [α]D of 6 ee (%)
1 OCH2CH2O THF 7 39 +ve 64
2 OCH2CH2O THF 8 47 -ve 27
3 OCH2CH2O Benzene 9 81 +ve 42
4 OCH2CH2O Ether 10 26 -ve 37
The work on the 2-benzylphenol derivatives (11) took the shape of investigating the nature of the substrate with respect to varying the R group for the substituted 2-benzylphenol systems through to investigating the reaction methodology itself (solvent system, temperature profile of reaction, nature of electrophile, etc.) using a sec-BuLi/chiral ligand base system. We found that some substrates needed differing conditions in order to form the chiral anion, and solvents systems such as THF and diethyl ether supported product formation and induced greater ee’s compared to solvents such as toluene and benzene. While the results were rather moderate when using methoxy or hydroxy stabilising groups (table 2, entries 1-3),2 the methoxyethoxy group provided excellent yields and ee’s.3 Additionally a pivaloylamido group has also been investigated in this role and produced respectable results.4 A further manuscript detailing the configurational stability of these systems indicated that system 11 (with R=OCH2CH2OMe) was the only configurationally stable species at -78oC in the presence of (-)-sparteine .5
Table 2. Entry R Electrophile ligand Yield (%) Config. ee (%)
1 OMe allylBr (-)-12 84 R 60
2 OMe allylBr (+)-13 98 S 56
3 OH allylBr (-)-12 74 S 46
4 OCH2CH2OMe allylOTs (-)-12 93 R 94
5 OCH2CH2OMe allylOTs (+)-13 90 S 92
6 NHPiv allylBr (-)-12 90 S 76
7 NHPiv allylBr (+)-13 89 R 80
We also looked to develop this methodology further by studying a number of other oxygen-based stabilising groups as well as groups based on a 1-carbon unit (14) as well as looking at the effect of the Y-group being electron withdrawing, such as 2-benzylpyridine substrates (15). Once methodology is developed with respect to 15, we envisage a short asymmetric synthesis towards the pheniramines, a class of pharmaceuticals which stop the uptake of neurotransmitters at receptors.
Additionally these diaryl systems led us to investigate the synthesis of a range of Fendiline derivatives (Fendiline is a classical anti-anginal drug which has been reviewed and has shown anti-cancer properties on prostrate cancer cell lines). The nature of the R groups is evaluated with respect to the newly created stereocentre on the bridging carbon of the molecule, and thus any new synthesised single diastereoisomer of a Fendiline derivative can be evaluated on human leukaemia cell lines (K562) against the racemically prepared Fendiline for the effect of both the R group and the inclusion of stereochemistry within the molecule:
Initial results suggested that certain diastereoisomers displayed greater activity on cancer cell lines when compared to racemic Fendiline. Additionally, in collaboration with The Department of Cardiology (School of Medicine, The University of Manchester) we have shown that certain novel diastereoisomers are (relatively) one-hundred times more active on Mesenteric Aortic tissue than the parental racemic Fendiline.6 To this cause methodology was developed which will allow the synthesis of the most active diasteroisomers in up to 95% de using the chiral ligands (-)-sparteine and O’Brien’s (+)-sparteine surrogate.
Expanding the Scope of the Babler-Dauber Reaction: The Oxidative Transposition of 2nd Allylic Alcohols to α,β-Unsaturated Carbonyls
Under Dr Killoran, from October 2015, we report the first chromium-mediated oxidation of secondary allylic alcohols to α,β-unsaturated aldehydes with exclusively E-stereoselectivity. This facile procedure employs catalytic amounts of PCC (5 mol%) and uses periodic acid (H5IO6) as a co-oxidant. This transformation requires R to be aromatic and it works well with both EWG/EWD substituents and a range of functional groups (Organic Letters, script in preparation).
Under Dr Killoran, from October 2015, we report the first chromium-mediated oxidation of secondary allylic alcohols to α,β-unsaturated aldehydes with exclusively E-stereoselectivity. This facile procedure employs catalytic amounts of PCC (5 mol%) and uses periodic acid (H5IO6) as a co-oxidant. This transformation requires R to be aromatic and it works well with both EWG/EWD substituents and a range of functional groups (Organic Letters, script in preparation).