Philip J. Pye

[2.2]PHANEPHOS-Ruthenium(II) complexes: Highly active asymmetric catalysts for the hydrogenation of β-ketoesters

Abstract The application of the planar chiral [2.2]PHANEPHOS ligand in the Ru(II)-catalyzed asymmetric hydrogenation of β-ketoesters gave up to 96% ee involving a practical and reproducible procedure using the defined and readily prepared [2.2]PHANEPHOS-Ru(II)bis(trifluoroacetate) salt in the presence of a halide source.

AN EFFICIENT ASYMMETRIC HYDROGENATION APPROACH TO THE SYNTHESIS OF THE CRIXIVAN PIPERAZINE INTERMEDIATE

Abstract The Crixivan ® HIV protease inhibitor piperazine intermediate 2 was prepared by a four step sequence using a chiral hydrogenation of the tetrahydropyrazine 9 to establish the absolute stereochemistry.

Crystallization-induced diastereoselection: asymmetric synthesis of substance P inhibitors.

A novel three-component condensation followed by a crystallization-induced asymmetric transformation is used to build this key substance P inhibitor intermediate in a short synthetic sequence.

A Polar Radical Pair Pathway To Assemble the Pyrimidinone Core of the HIV Integrase Inhibitor Raltegravir Potassium

The UN and WHO currently estimate that 40 million people are living with HIV/AIDS worldwide. Combination therapies using reverse transcriptase and protease inhibitors have been highly successful, but the emergence of drug resistance prompts a search for alternative treatments. A rapidly expanding area of HIV/AIDS research targets a third enzyme, integrase, the catalyst responsible for the integration of proviral DNA into the host cell chromosome. Research at Merck has led to the identification of raltegravir potassium (1), a potent and well-tolerated HIV-1 integrase inhibitor that targets strand transfer, the second of two catalytic cycles mediated by the integrase enzyme. Raltegravir potassium (1) consists of a central hydroxypyrimidinone heterocyclic core that is rapidly assembled by a two-component coupling reaction between amidoxime 2 and dimethyl acetylenedicarboxylate (DMAD) to give 3Z/3E, followed by a thermal rearrangement to give product 4 (Scheme 1). Amidoxime–DMAD adduct isomers 3Z and 3E are converted to hydroxypyrimidinone 4 at significantly different rates: 3Z, the major isomer, reacts at a temperature of 125 8C within 2 h, while 3E only rearranges at an elevated temperature of 135 8C within 5 h. Plausible mechanisms for this reaction involving [1,3] and [3,3] shifts are shown in Scheme 2. N-enriched rearrangement precursors 3Z*/3E* (65:35) were synthesized. Thermolysis of 3Z*/3E* resulted in the formation of hydroxypyrimidinone 4’*, in which the N label was unexpectedly found to be exclusively at the position ortho to the ester substituent. Since this outcome is not consistent with a [3,3]-sigmatropic rearrangement mechanism (4’’*), a formal [1,3] rearrangement must have occurred. An in-depth experimental and computational study of the mechanism has now shown that the apparently attractive concerted [3,3]-pericyclic route is eschewed in favor of a direct N O cleavage to form a polar radical pair (PRP) with a substantial preference for recombination. Quantum mechanical calculations were used to determine how models 6Z and 6E, with CO2Me replacing CBz, undergo transformation to 5, a model for pyrimidinone 4. B3LYP density functional theory, as implemented in Gaussian03, was used to compute optimized geometries of intermediates and transition states. Energies were obtained from a calibration involving a smaller computational model where G3(MP2)B3, a high-accuracy method, and B3LYP energetics were compared (other functionals and methods involving CCSD(T) were also compared, see Supporting Information for details). As summarized in Scheme 3, the tautomerization of amidoxime adducts 6Z/E to 7Z/E is endothermic by 12 kcalmol . Acid-base catalysis is required to form 7, since concerted [1,3]-hydrogen shifts have prohibitively high barriers. Although the activation energies of the allowed [3,3] shifts of 7Z/E are 25 kcalmol 1 (cf. TS5), these rearScheme 1. Synthesis of raltegravir potassium. Cbz=benzyloxycarbonyl.

Serendipitous discovery of a pH-dependant atropisomer bond rotation: Toward a write-protectable chiral molecular switch?

Owing to slow rotation of a sterically constrained dimethylamide substituent, two slowly interconverting enantiomers of a preclinical candidate for pharmaceutical development, 1, (6-(3-Chloro-4-fluoro-benzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-[2,6]naphthyridine-1-carboxylic acid dimethylamide) are observed by chiral chromatography. Isolation of pure enantiomer by preparative chiral chromatography followed by enantiopurity analysis over time allowed for a study of the kinetics of enantiomer interconversion under a variety of conditions. Relatively slow racemization was observed in alcohol solvents, with a half life on the order of 5-10 h. A dramatic influence of aqueous buffer pH on racemization was noted, with higher pH leading to rapid racemization within a few minutes, and lower pH leading to essentially no racemization for periods up to a week. A hypothesis explaining this unusual effect of pH on carboxamide bond rotation is offered, and some suggestions for potential utility of such a system are considered.

Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

Abstract A highly convergent, asymmetric synthesis of L-768,673, an I ks Class III antiarrythmic drug candidate, is described. Synthesis of the recemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(±)-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolution-racemization of (±)-amine provided the desired (±)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)benzene with n-BuLi in the presence of a catalytic amount of 2,2′,6,6′-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.