Gregory Hughes

Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

Biocatalytic Boost Enzymes tend to direct reactions toward specific products much more selectively than synthetic catalysts. Unfortunately, this selectivity has evolved for cellular purposes and may not promote the sorts of reactions chemists are seeking to enhance (see the Perspective by Lutz). Siegel et al. (p. 309) now describe the design of enzymes that catalyze the bimolecular Diels-Alder reaction, a carbon-carbon bond formation reaction that is central to organic synthesis but unknown in natural metabolism. The enzymes display high stereoselectivity and substrate specificity, and an x-ray structure of the most active enzyme confirms that the structure matches the design. Savile et al. (p. 305, published online 17 June) applied a directed evolution approach to modify an existing transaminase enzyme so that it recognized a complex ketone in place of its smaller native substrate, and could tolerate the high temperature and organic cosolvent necessary to dissolve this ketone. This biocatalytic reaction improved the production efficiency of a drug that treats diabetes. An engineered enzyme offers substantial efficiency advantages in the production-scale synthesis of a drug. Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.

Electron-transporting materials for organic electroluminescent and electrophosphorescent devices

One of the requirements for efficient organic electroluminescent devices (OLEDs) is balanced charge injection from the two electrodes and efficient transport of both holes and electrons within the luminescent layer in the device structure. Many of the common luminescent conjugated polymers, e.g. derivatives of poly(phenylenevinylene) and poly(fluorene), are predominantly hole transporters (i.e. p-dopable). This article gives a brief overview of organic electroluminescence and electrophosphorescence and provides a more detailed consideration of ways in which electron transport in these systems has been enhanced by the incorporation of electron-deficient (i.e. n-dopable) small molecules and polymers into the devices, either as blends or by covalent attachment of sub-units to the luminophore or as an additional electron-transporting, hole-blocking (ETHB) layer adjacent to the cathode. The chemical structures of these systems are presented and their roles are assessed. Most of these ETHB molecules are electron-deficient aromatic nitrogen-containing heterocycles, e.g. derivatives of 1,3,4-oxadiazole, pyridine, pyrimidine, pyrazine, quinoline, etc. Non-aromatic thiophene-S,S-dioxide derivatives are also discussed. The article is written from an organic chemists perspective.

New 2,5-diaryl-1,3,4-oxadiazole–fluorene hybrids as electron transporting materials for blended-layer organic light emitting diodes

We describe the synthesis of 2,5-diaryl-1,3,4-oxadiazole–fluorene hybrid molecules, e.g. 2,7-bis[2-(4-tert-butylphenyl-1,3,4-oxadiazol-5-yl]-9,9-dihexylfluorene 6, 2,7-bis{4-[2-(4-tert-butylphenyl)-1,3,4-oxadiazol-5-yl]phenyl}-9,9-dihexylfluorene 10, 2,7-bis{4-[2-(4-dodecyloxyphenyl)-1,3,4-oxadiazol-5-yl]phenyl}-9,9-dihexylfluorene 11, 2,7-bis{4-[2-(4-dodecyloxyphenyl)-1,3,4-oxadiazol-5-yl]phenyl}-spirobifluorene 13 and analogue 16, comprising the 9,9-dihexylfluorene or spirobifluorene core units to which are attached aryl- or diaryl-oxadiazole units to provide linearly extended π-conjugated systems. The X-ray crystal structure is reported for compound 11. We have fabricated single-layer organic light-emitting diodes (OLEDs) using blends of poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) as the emissive material with the electron transport (ET) compounds 6, 10, 11, 13 and 16 added to enhance electron injection. For all the devices studied electroluminescence originates exclusively from the MEH-PPV material. The external quantum efficiencies of the devices increased with increasing concentration of the ET compound up to 95% by weight, and are greatly enhanced (>two orders of magnitude) compared to pure MEH-PPV reference devices. Further improvements have been achieved by adding a layer of PEDOT : PSS and efficiencies reach ca. 0.4% at 30 mA cm−2 for devices in the configuration ITO/PEDOT : PSS/MEH-PPV–13 (5 : 95% by weight)/Al.

New pyrimidine- and fluorene-containing oligo(arylene)s: synthesis, crystal structures, optoelectronic properties and a theoretical study

New pyrimidine containing oligo(arylene)s, notably the pyrimidine-fluorene hybrid systems 13-16, have been synthesised by Suzuki cross-coupling methodology. An efficient synthesis of the key reagent 9,9-dihexylfluorene-2,7-diboronic acid 10 from 2,7-dibromo-9,9-dihexylfluorene 9 is reported. Cross-coupling of 10 with two equivalents of 2-bromopyrimidine, 5-bromopyrimidine and 2,5-dibromopyrimidine gave 2,7-bis(2-pyrimidyl)-9,9-dihexylfluorene 13. 2,7-bis(5-pyrimidyl)-9,9-dihexylfluorene 14 and 2,7-bis(5-bromo-2-pyrimidyl)-9,9-dihexylfluorene 15 in 23-34% yields. A further two-fold Suzuki reaction of benzeneboronic acid with compound 15 gave 2,7-bis(5-phenyl-2-pyrimidyl)-9,9-dihexylfluorene 16 (35% yield). Ab initio calculations of the geometries and electronic structures at the Hartree Fock (HF) and density functional theory (DFT) levels of theory are reported for compounds 13, 14 and 16 (with ethyl substituents replacing hexyl) and for their dipyrazinyl and bistetraazenyl analogues, 17, 18, 20 and 21. The heterocyclic nitrogen atoms of 13 and 16 facilitate planarisation of the system, compared to 14, which is in agreement with X-ray structural data obtained for 5-bromo-2-phenylpyrimidine 6, 2,5-diphenylpyrimidine 7 and compound 15. Bistetrazenyl derivative 21 is calculated to be a fully planar system. The cyclic voltammogram (CV) of compound 16 in dichloromethane solution shows a quasi-reversible oxidation wave at E(1/2)0 = +1.36 V (vs. Ag/Ag+). Compound 13 is a poorer donor with an oxidation observed at Epa = +1.50 V which is in good agreement with the difference in the energies of their HOMO orbitals calculated at both HF and DFT levels of theory (0.11-0.12 eV). For compound 14 we were not able to measure an Eox potential which should lie at much more positive potentials. Compounds 15 and 16 are blue emitters in solution, with photoluminescence quantum yields (PLQY) of 25% and 85%, respectively. For thin films of 16 the PLQY is reduced to 21%. An OLED using compound 16 as the emissive layer has been fabricated in the configuration ITO/PEDOT/16/Ca/Al: blue-green light (lambda max 500 nm) most likely emanating primarily from excimer states is emitted at a high turn-on voltage.

A Practical Synthesis of 5-Lipoxygenase Inhibitor MK-0633

Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).

Phenylene–2,5-dimethylpyrazine co-oligomers: synthesis by Suzuki couplings, X-ray structures of neutral and diprotonated teraryl species and efficient blue emission

Phenylene–2,5-dimethylpyrazinyl co-oligomers and a dipyridylpyrazine derivative have been synthesised by Suzuki cross-coupling reactions starting from 2,5-dibromo-3,6-dimethylpyrazine. X-Ray crystal structures are reported for two teraryl derivatives, viz. 2,5-bis(2-methoxyphenyl)-3,6-dimethylpyrazine 2 and 2,5-bis(6-methoxypyridin-3-yl)-3,6-dimethylpyrazine 6, and a diprotonated pyrazinyl dication salt, viz. 2,5-bis(2-methoxyphenyl)-3,6-dimethylpyrazinium bis(tetrafluoroborate) salt 3. Compounds 2 and 6 and the dication in 3 have crystallographic Ci symmetry and adopt twisted conformations: dihedral angles between the aryl and pyrazine rings are 74.0° (2), 56.4° (3) and 44.6° (6). Violet-blue photoluminescence is seen for 2λmax 372 nm, 5λmax 418 nm and 6λmax 387 nm in ethanol solution. [Compound 5 is 1,4-dimethoxy-2,5-bis{2-(5-tert-butylphenyl-3,6-dimethylpyrazinyl)benzene}]. Blue electroluminescence, λmax 444 nm, is observed for the device structure ITO/PEDOT/5/Ca with no long-wavelength emission from π-aggregates or exciton states.

Ethynyl π-extended 2,5-diphenyl-1,3,4-oxadiazoles and 2-phenyl 5-(2-thienyl)-1,3,4-oxadiazoles: synthesis, X-ray crystal structures and optical properties

2-(4-tert-Butylphenyl)-5-(4-ethynylphenyl)-1,3,4-oxadiazole reacts with a series of heteroaryl iodides under standard Sonogashira cross-coupling conditions (Pd[PPh(3)](2)Cl(2), CuI, triethylamine, THF) to yield products 2a-g in 40-79% yields (heteroaryl = 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazyl, 5-bromo-2-pyrimidyl, 2-thienyl and 3-thienyl, respectively). Compound 2f was lithiated followed by electrophilic iodination (BuLi, perfluorohexyl iodide) to give 3, which by a two-step sequence gave the terminal ethynylthienyl derivative 5. Conversion of 5 into the terminal ethynylaldehyde derivative 7, via acetal derivative 6, proceeded in high yield. Starting from 2-iodo-5-methoxycarbonylthiophene, a five-step sequence afforded 2-(4-tert-butylphenyl)-5-(4-ethynylthienyl)-1,3,4-oxadiazole 13 (13% overall yield). Reactions of 13 gave terminal pyridyl, pyrazyl, pyrimidyl and thienyl derivatives, analogous to those obtained from 1. Two-fold reaction of 13 with 2,5-diiodothiophene gave the bis(ethynylthienyl)thiophene derivative 15 (30% yield). Solution UV-Vis absorption and photoluminescence spectra establish that replacement of the phenyl ring in the 2,5-diphenyl-1,3,4-oxadiazole series 2a-g by a thienyl ring [i.e. the 2-phenyl-5-(2-thienyl)-1,3,4-oxadiazole series 14a-g] leads to a red shift in the lowest energy band in both the absorption spectra and emission spectra. The X-ray crystal structures of compounds 2d, 2g, 5 and 14d.CHCl(3) reveal that the molecular structures are approximately planar although there are substantial differences in the conformations.

Remote Electronic Control in the Regioselective Reduction of Succinimides: A Practical, Scalable Synthesis of EP4 Antagonist MF-310

A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.