Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305)

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.     

Facile and rapid DNA extraction and purification from food matrices using IFAST (immiscible filtration assisted by surface tension)

Extraction and purification of DNA is a prerequisite to detection and analytical techniques. While DNA sample preparation methods have improved over the last few decades, current methods are still time consuming and labor intensive. Here we demonstrate a technology termed IFAST (Immiscible Filtration Assisted by Surface Tension), that relies on immiscible phase filtration to reduce the time and effort required to purify DNA. IFAST replaces the multiple wash and centrifugation steps required by traditional DNA sample preparation methods with a single step. To operate, DNA from lysed cells is bound to paramagnetic particles (PMPs) and drawn through an immiscible fluid phase barrier (i.e. oil) by an external handheld magnet. Purified DNA is then eluted from the PMPs. Here, detection of Clostridium botulinum type A (BoNT/A) in food matrices (milk, orange juice), a bioterrorism concern, was used as a model system to establish IFAST's utility in detection assays. Data validated that the DNA purified by IFAST was functional as a qPCR template to amplify the bont/A gene. The sensitivity limit of IFAST was comparable to the commercially available Invitrogen ChargeSwitch? method. Notably, pathogen detection via IFAST required only 8.5 μL of sample and was accomplished in five-fold less time. The simplicity, rapidity and portability of IFAST offer significant advantages when compared to existing DNA sample preparation methods.     

Effect of a methoxy substituent on the vinylcyclobutane carbon migration

Over the temperature range 250-300 degrees C, 8-exo-methoxybicyclo[4.2.0]oct-2-ene (1a) undergoes a [1,3] sigmatropic rearrangement to 5-exo- and 5-endo-methoxybicyclo[2.2.2]oct-2-enes, 2a and 2b, respectively, with a clear preference for the si product: si/sr = 3.2. Both 1a and its 8-endo epimer 1b experience appreciable epimerization and fragmentation. A long-lived intermediate with weakly interacting diradical centers, one of which is stabilized by a methoxy substituent, can account for all such observations.     

A TEM and XRD study of the SbNbSe3 misfit layer structures

Two new misfit layer structures have been synthesized within the Sb-Nb-Se system. Powder X-ray diffraction and electron microscopy techniques (electron diffraction, HREM, XEDS) have been used to determine the nature of their structure. According to TEM and XEDS data (for more than 15 crystals studied) both phases are monolayer type, i.e. (SbSe)1+delta (NbSe2). Electron microscopy reveals a composite modulated structure that consists of the periodical intergrowth of a pseudotetragonal SbSe layer, denominated as Q, and a pseudohexagonal layer NbSe2, denominated as H. Both layers fit along b, stack along c and do not fit along a (misfit) giving rise to an incommensurate modulation along this direction. The two phases differ in the symmetry of the Q layers being in one case orthorhombic (for delta = 0.17) and monoclinic in the other (for delta = 0.19). After the characterization of the sample by electron microscopy the unit cells of the basic layers could be refined for both phases by powder X-ray diffraction: aQ = 5.824(2) A, bQ = 5.962(5) A, cQ = 23.927(6) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees and aH = 3.415(5) A, bH = 5.962(6) A,, cH = 11.962(1) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees for the orthorhombic phase; aQ = 5.844(2) A, bQ = 5.981(1) A, cQ = 23.919(5) A, alpha = 90 degrees, beta = 90 degrees and gamma = 96.00(3)degrees and aH = 3.439(1) A, bH = 5.994(2) A, cH = 11.956(3) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees for the monoclinic phase. The phase with the monoclinic Q-sublattice often appears as twinned crystals. The more abundant crystals are disordered intergrowths of both monolayer phases.     

Stereochemistry of cyclopropane formation involving group IV organometallic complexes

The reaction of (Z)-HDC=CHCH(OCH(3))C(6)H(5) (1) with Cp(2)Zr(D)Cl followed by BF(3).OEt(2) gave phenylcyclopropanes 3a and 3b, both having cis deuterium. This stereochemical outcome requires inversion of configuration at the carbon bound to zirconium and is consistent with a "W-shaped" transition state structure for cyclopropane formation. In a Kulinkovich hydroxycyclopropanation, trans-3-deutero-1-methyl-cis-2-phenyl-1-cyclopropanol (5) was formed stereospecifically from Ti(O-i-Pr)(4), ethyl acetate, EtMgBr, and trans-beta-deuterostyrene. This stereochemistry requires retention of configuration at the carbon bound to titanium and is consistent with frontside attack of the carbon-titanium bond on a carbonyl group coordinated to titanium. In a de Meijere cyclopropylamine synthesis, a 3:1 mixture of N,N-dimethyl-N-(trans-3-deutero-trans-2-phenylcyclopropyl)amine (6a) and N,N-dimethyl-N-(cis-3-deutero-cis-2-phenylcyclopropyl)amine (6b) was formed from Ti(O-i-Pr)(4), DMF, Grignard reagents, and trans-beta-deuterostyrene. This stereochemistry requires inversion of configuration at the carbon bound to titanium and is consistent with a W-shaped transition structure for ring closure.     

Furan forming reactions of cis-2-alken-4-yn-1-ones

[reactions: see text] The cis-2-alken-4-yn-1-one, 1-phenyl-cis-2-penten-4-yn-1-one (cis-1), readily dimerizes on treatment with weak acid to give the 1,2-difurylethylenes, trans- and cis-1,2 di(2-(5-phenylfuryl))ethene (trans-1 and cis-2), in 62% and 23% yields, respectively. Trimerization of cis-1 to trans,trans-1,2,3-tri(2-(5-phenylfuryl)cyclopropane (4) occurred as a byproduct of treatment with weak acid. These reactions demonstrate the 2-furylcarbenoid reactivity of cis-2-alken-4-yn-1-ones.     

Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C−H bond activation and exchange labeling with gaseous isotopes D₂ and T₂ are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe₃)₂ to be an efficient catalyst for selective HIE of benzylic C−H bonds with D₂ gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C−H bonds and D₂ gas. By virtue of multiple C−H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.     

Late-Stage 18O Labeling of Primary Sulfonamides via a Degradation–Reconstruction Pathway

A late-stage ¹⁸O labeling approach of sulfonamides that employs the corresponding unlabeled molecule as the starting material was developed. Upon deamination of the sulfonamide, a sulfinate intermediate was isotopically enriched using eco-friendly reagents H₂¹⁸O and ¹⁵NH₃(aq) to afford a M+5 isotopologue of the parent compound. This degradation–reconstruction approach afforded isolated yields of up to 96 % for the stable isotope labeled (SIL) sulfonamides, and was compatible with multiple marketed therapeutics, including celecoxib, on a gram scale. The SIL products also exhibited no ¹⁸O/¹⁶O back exchange under extreme conditions, further validating the utility of this green strategy for drug labeling for both in vitro and in vivo use. This procedure was also adapted to include pharmaceutically relevant methyl sulfones by using ¹³CH₃, affording M+5 isotopic enrichment, thereby illustrating the broad utility of this methodology.