Colin L. Gibson

A study of 4-substituted 5,5-diaryl oxazolidin-2-ones as efficacious chiral auxiliaries

Abstract A series of three 5,5-diaryl substituted oxazolidin-2-ones (diphenyl, dinaphthyl and ditolyl) have been prepared and shown to be particularly effective chiral auxiliaries to afford high yields and diastereoselectivities for alkylation and azidations of their N-acyl derivatives. The 5,5-ditolyl oxazolidin-2-one proved to be particularly efficacious in terms of diastereoselectivity, yield and solubility.

Diversity oriented syntheses of fused pyrimidines designed as potential antifolates

Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d]pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.

The synthesis of chiral annulet 1,4,7-triazacyclononanes

Novel and flexible routes for the synthesis of chiral ring annulet 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles are described. Efficient macrocyclisations were realised provided that chiral analogues of N,N-bis-[2-(toluene-sulfonylamino)ethyl]-toluene-4-sulfonamide were used as the nucleophilic components. Complexes prepared, in situ, from these 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles and manganese(II) catalysed the asymmetric epoxidation of styrene with hydrogen peroxide.

Synthesis of chiral β-amino sulfides and β-amino thiols from α-amino acids

Abstract Bifurcated routes to two series of chiral secondary s-amino sulfides 5a - c and 11a - c have been developed from L-proline and ( S )-phenylglycine, respectively. The developed methodology has also led to the synthesis of the tertiary s-amino thiol 7 and the primary s-amino sulfide 12 from L-proline and ( S )-phenylglycine, respectively.

Structure-based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases.

Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

Polystyrene and polymethacrylate resin-supported Jacobsen’s alkene epoxidation catalyst

Polystyrene and polymethacrylate-based resin supported Jacobsen’s chiral Mn salen complexes have been prepared. The resins are of defined molecular structure and morphology, and the complexes have been attached primarily in a pendant fashion. The loadings of Mn(III) are in the range ≈0.08–0.35 mmol g−1 to maximise the likelihood of site-isolation. The polymer-supported complexes have been used as enantioselective catalysts in the epoxidation of 1,2-dihydronaphthalene, indene, 1-phenylcyclohex-1-ene and 1-phenyl-3,4-dihydronaphthalene using m-chloroperbenzoic acid as the oxidant and 4-methylmorpholine N-oxide as the co-oxidant. Though the activities of the polymer catalysts are reduced relative to the soluble homogeneous analogue, the catalysts are sufficiently active to be useful. The corresponding reduction in enantioselectivity is more significant, and is both substrate and polymer resin dependent. However, in the case of 1-phenylcyclohex-1-ene and a macroporous polymethacrylate-based resin the enantioselectivity is equivalent to that of the soluble complex (91–92% ee). This is the first report of a polymer-supported analogue of Jacobsen’s catalyst being as selective as the homogeneous species. The catalysis data is discussed in detail in the context of the design of the polymer-supported system, and the existing data already available in the literature. Attempts have also been made to recycle the polymer catalysts with and without re-loading of Mn. In fact the level of leaching of Mn is very low, but the catalysts show a very rapid fall off in both activity and selectivity in the first and second cycles. Overall therefore it seems that the intrinsic stability of the chiral Mn(II) salen complex itself is too low to allow viable recycling, and the development of other more stable supported chiral metal salen complexes for use in other enantioselective reactions seems a better future option. p

Synthesis of a scalemic β-amino disulfide from (S)-phenylglycine and (R)-styrene oxide and use as a catalyst in enantioselective additions of diethylzinc to aldehydes

Two routes to the novel scalemic β-amino disulfide 7 have been developed from (S)-phenylglycine and (R)-styrene oxide. The β-amino disulfide 7 was used as a catalyst in the enantioselective addition of diethylzinc to aldehydes providing (R)-secondary alcohols in 39–80% ee.

The Synthesis of Fluorine-Containing Pterins

The introduction of fluorine into molecules has been well demonstrated to modify the biological properties significantly1. In heterocyclic compounds this effect is clearly demonstrated through the action of 5-fluorouracil and its nucleosides as inhibitors of thymidylate synthetase. In folic acid derivatives, fluorine has been introduced into the glutamate side chain2 and into the aminobenzoic acid ring to promote nmr observations of interactions with dihydrofolate reductase3. Some side-chain fluorinated pteridinones have been prepared previously4 but analogues of natural products appear to be novel. It would be of interest to investigate the properties of pterins with fluorine as a substituent of the pyrazine ring and also at C-9 of the methylene group. To approach this study we have examined the reactions of 2,4,5-triaminopteridin-6(lH)-one (1) with a number of readily available di-and trifluoromethyl carbonyl compounds. We have also examined the electrostatic potentials of the molecules associated with the introduction of fluorine into the pyrazine ring and its substituents.

A prototype solid phase synthesis of pteridines and related heterocyclic compounds

The development of a versatile solid phase synthesis of bicyclic polyaza heterocycles including pteridines, purines, and deazapurines is described. The strategy comprises the linking of a pre-formed pyrimidine through a thioether at the 2 or 4 position to a polystyrene resin, the cyclisation of the second ring, and the direct or oxidative cleavage of the product from the resin by nucleophilic substitution. This provides not only for substituent variation in the second ring, but also for variation at the site of cleavage. Limitations in the scope of the methodology are set by the intrinsic reactivity of pyrimidinyl 2- or 4-thioethers which, whilst undergoing ready nitration at C5, are surprisingly difficult to alkylate and acylate.

cis-Selective cyclopropanations using chiral 5,5-diaryl bis(oxazoline) catalysts

Abstract A series of 5,5-diaryl bis(oxazolines) have been prepared and used as ligands in the copper catalysed asymmetric cyclopropanation of styrene. Unusually, for bis(oxazolines), the diastereoselectivity of the process favoured the cis cyclopropanes with diastereomeric ratios of up to 65:35 being realised. The cis selectivity of the process was rationalised in terms of repulsion between the alkene substituent and the pro-R 5-aryl group of the bis(oxazoline).