Diastereoselective Reductive Etherification Via High-Throughput Experimentation: Access to Pharmaceutically Relevant Alkyl Ethers.

This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.

Preparation of 1-Hydroxy-2,5-hexanedione from HMF by the Combination of Commercial Pd/C and Acetic Acid.

The development of a simple and durable catalytic system for the production of chemicals from a high concentration of a substrate is important for biomass conversion. In this manuscript, 5-hydroxymethylfurfural (HMF) was converted to 1-hydroxy-2,5-hexanedione (HHD) using the combination of commercial Pd/C and acetic acid (AcOH) in water. The influence of temperature, H2 pressure, reaction time, catalyst amount and the concentration of AcOH and HMF on this transformation was investigated. A 68% yield of HHD was able to be obtained from HMF at a 13.6 wt% aqueous solution with a 98% conversion of HMF. The resinification of intermediates on the catalyst was characterized to be the main reason for the deactivation of Pd/C. The reusability of the used Pd/C was studied to find that most of the activity could be recovered by being washed in hot tetrahydrofuran.

Structure Guided Discovery of Novel Pan Metallo-ß-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.

Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives and the behavior of o- and p-(hydroxymethyl)benzoates under reductive alkylation conditions.

Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives, using lithium in ammonia-tetrahydrofuran in the presence of tert-butyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of o- and p-(hydroxymethyl)benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions.

Synthesis of alkaloid (-)-205B via stereoselective reductive cross-coupling and intramolecular [3+2] cycloaddition.

An asymmetric synthesis of alkaloid (-)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol-imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (E)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselective-features which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry.

Convergent and stereodivergent synthesis of complex 1-aza-7-oxabicyclo[2.2.1]heptanes.

A convergent and stereodivergent pathway to highly substituted 1-aza-7-oxabicyclo[2.2.1]heptanes is described. It begins with a coupling reaction involving allylic alcohol, aldehyde, and LiHMDS to produce stereodefined primary homoallylic amines. Subsequent N-oxidation and condensation with formaldehyde or glyoxylate defines a convenient entry to densely functionalized homoallylic nitrones whose intramolecular annulation can be controlled to deliver one of two distinct heterocyclic skeletons, each with ≥20:1 stereoselection. Control of the stereochemistry in these reactions results from both control of the nitrone geometry and selective partitioning of the reaction pathway between direct [3 + 2] cycloaddition and tandem [3,3] rearrangement/[3 + 2] cycloaddition.

Generation of quaternary centers by reductive cross-coupling: shifting of regioselectivity in a subset of allylic alcohol-based coupling reactions.

Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by formal metallo-[3,3]-rearrangement [thought to proceed by a sequence of: 1) directed carbometalation, and 2) syn-elimination]. While many examples have been described that support this reaction path, a collection of substrates have recently been identified that react by way of an alternative pathway, delivering a concise convergent route to coupled products bearing a quaternary center.

Preparation of stereodefined homoallylic amines from the reductive cross-coupling of allylic alcohols with imines.

Regio-, diastereo-, and enantioselective coupling reactions between imines and allylic alcohols have been developed. These coupling reactions deliver complex homoallylic amine products through a convergent C-C bond forming process that does not proceed through intermediate allylic organometallic reagents. In general, convergent coupling, by exposure of an allylic alkoxide to a preformed Ti-imine complex, occurs with allylic transposition in a predictable and stereocontrolled manner. While simple diastereoselection in these reactions is high, delivering anti-products with ≥20:1 selectivity, the organometallic transformation described is compatible with a diverse range of functionality and substrates (including aliphatic and aromatic imines, allylic silanes, trisubstituted alkenes, vinyl- and aryl halides, trifluoromethyl groups, thioethers, and aromatic heterocycles). Alkene geometry of the products is a complex function of the allylic alcohol structure and is consistent with a mechanistic proposal based on syn-carbometalation followed by syn-elimination by way of a boat-like transition state geometry. Single asymmetric coupling reactions provide a means to translate the stereochemical information of the allylic alcohol to the homoallylic amine or to control diastereoselection in the coupling reactions of achiral allylic alcohols with chiral imines. Double asymmetric coupling reactions are also described that afford a unique means to control stereoselection in these complex convergent coupling processes. Finally, empirical models are proposed that are consistent with the observed stereochemical course of these coupling reactions en route to chiral homoallylic amines possessing di- or trisubstituted alkenes and anti- or syn- relative stereochemistry at the allylic and homoallylic positions.

A convergent stereoselective synthesis of quinolizidines and indolizidines: chemoselective coupling of 2-hydroxymethyl-substituted allylic silanes with imines.

A convergent synthesis of stereodefined indolizidines and quinolizidines through chemoselective allyl transfer between 2-hydroxymethyl-substituted allylic silanes and imines is described. Overall, highly substituted heterocycles that contain three stereogenic centers and up to four fused rings can be accessed in two steps from relatively simple coupling partners.

Two approaches to diverting the course of a free-radical cyclization: application of cyclopropylcarbinyl radical fragmentations and allenes as radical acceptors.

Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along with considerable amounts of products derived from a cyclization-atom transfer-secondary cyclization process (6 and 9). Two approaches to avoiding these unexpected products were explored. Use of a cyclopropylcarbinyl fragmentation avoided the secondary cyclization reaction (25 or 43 --> 26 or 44), whereas use of an allene as a radical acceptor avoided the atom-transfer reaction altogether (49 --> 52).

Quassinoid support studies: fused carbocycle synthesis from benzoic acid derivatives via 5-hexynyl and 6-heptynyl radical cyclizations.

Eight bromoalkynes were prepared from substituted benzoic acids and treated with n-Bu3SnH to provide trans-fused perhydroindans or cis- and trans-fused perhydronaphthalenes. Atom-transfer reactions that accompany the free radical reactions resulted in several tandem radical cyclizations with formation of up to three carbon-carbon bonds in a single reaction. The relationship between these reactions and an approach to the quassinoid family of natural products is also described.

A novel imidazolate-bridged heterodinuclear Cu(II)Zn(II) complex derived from a unique macrocyclic ligand with two hydroxyethyl pendants.

[(CuimZnL-2H)(CuimZnL-H)](ClO4)3, the first imidazolate-bridged Cu(II)-Zn(II) complex of a unique single macrocyclic ligand with two flexible hydroxyethyl pendants, L (L = 3,6,9,16,19,22-hexaaza-6,19-bis(2-hydroxyethyl)tricyclo[22.2.2.2(11,14)]triaconta-1,11,13,24,27,29-hexaene) has been obtained, in which the macrocyclic ligand with two hydroxyethyl arms possesses a markedly different conformation compared to its dicopper analogue.

Kinetic analysis of carboxy ester hydrolysis by a dinuclear Zn(II) complex.

A dinuclear Zn(II) complex with hexaaza macrocyclic ligand bearing two 2-hydroxypropyl pendants, 3,6,9,16,19,22-hexaaza-6,19-bis(2-hydroxypropyl)-tricyclo [22,2,2,2(11,14)]triaconta-11,13,24,26,27,29-hexane (L) was synthesized and studied as a catalyst of the cleavage of 4-nitrophenyl acetate (NA). X-ray diffraction analysis of [Zn(2)LCl(2)]Cl(2)(.)6H(2)O revealed that Zn(II) adopts a trigonal-bipyramidal geometry. The complexation constants of L with Zn(II) have been determined at 298 K by means of potentiometric titration. [Zn(2)H(-2)L](2+) is the dominant species in aqueous solution around pH 8. The Zn(2)L-promoted hydrolysis of NA showed a second-order rate constant of 0.33 M(-1)s(-1) at pH 9.0, and the main promoter species are concluded to be the deprotonated species [Zn(2)H(-2)L](2+).

Stereochemical lability of azatitanacyclopropanes: dynamic kinetic resolution in reductive cross-coupling reactions with allylic alcohols.

Azatitanacyclopropanes (titanaziridines) are shown to be stereochemically labile under reaction conditions for reductive cross-coupling. This fundamental property has been employed to realize highly selective asymmetric coupling reactions with allylic alcohols that proceed by dynamic kinetic resolution.

Syntheses, structures, and properties of imidazolate-bridged Cu(II)-Cu(II) and Cu(II)-Zn(II) dinuclear complexes of a single macrocyclic ligand with two hydroxyethyl pendants.

The imidazolate-bridged homodinuclear Cu(II)-Cu(II) complex, [(CuimCu)L]ClO(4).0.5H(2)O (1), and heterodinuclear Cu(II)-Zn(II) complex, [(CuimZnL(-)(2H))(CuimZnL(-)(H))](ClO(4))(3) (2), of a single macrocyclic ligand with two hydroxyethyl pendants, L (L = 3,6,9,16,19,22-hexaaza-6,19-bis(2-hydroxyethyl)tricyclo[22,2,2,2(11,14)]triaconta-1,11,13,24,27,29-hexaene), have been synthesized as possible models for copper-zinc superoxide dismutase (Cu(2),Zn(2)-SOD). Their crystal structures analyzed by X-ray diffraction methods have shown that the structures of the two complexes are markedly different. Complex 1 crystallizes in the orthorhombic system, containing an imidazolate-bridged dicopper(II) [Cu-im-Cu](3+) core, in which the two copper(II) ions are pentacoordinated by virtue of an N4O environment with a Cu.Cu distance of 5.999(2) A, adopting the geometry of distorted trigonal bipyramid and tetragonal pyramid, respectively. Complex 2 crystallizes in the triclinic system, containing two similar Cu-im-Zn cores in the asymmetric unit, in which both the Cu(II) and Zn(II) ions are pentacoordinated in a distorted trigonal bipyramid geometry, with the Cu.Zn distance of 5.950(1)/5.939(1) A, respectively. Interestingly, the macrocyclic ligand with two arms possesses a chairlike (anti) conformation in complex 1, but a boatlike (syn) conformation in complex 2. Magnetic measurements and ESR spectroscopy of complex 1 have revealed the presence of an antiferromagnetic exchange interaction between the two Cu(II) ions. The ESR spectrum of the Cu(II)-Zn(II) heterodinuclear complex 2 displayed a typical signal for mononuclear trigonal bipyramidal Cu(II) complexes. From pH-dependent ESR and electronic spectroscopic studies, the imidazolate bridges in the two complexes have been found to be stable over broad pH ranges. The cyclic voltammograms of the two complexes have been investigated. Both of the two complexes can catalyze the dismutation of superoxide and show rather high activity.

A novel binucleating macrocyclic ligand with two alcohol pendants.

A novel binucleating 24-membered macrocyclic ligand, 6,20-bis(2-hydroxyethyl)-3,6,9,17,20,23-hexazatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene (L), was synthesized and crystallized as the tetrahydrobromide salt, i.e. 6,20-bis(2-hydroxyethyl)-6,20-diaza-3,9,17,23-hexaazoniatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene tetrabromide tetrahydrate, C28H50N6O2(4+)*4Br(-)*4H2O. A crystallographic inversion center is located in the macrocyclic cavity and the two hydroxyethyl pendants are on opposite sides of the macrocyclic plane. The benzene rings of the macrocycle are parallel to each other and a pi-pi-stacking interaction exists between the benzene rings of adjacent macrocycles, which are separated by 3.791 (9) A. An infinite intermolecular hydrogen-bond network stabilizes the crystal.

The interaction of glycine, aspartic acid, and lysine by the protonated macrocyclic ligand 6,19-bis(2-hydroxypropyl)-3,6,9,16,19,22-hexaaza-tricyclo-[22.2.2.2(11,14)]triaconta-11,13,24,26,27,29-hexaene.

A new hexaaza macrocyclic ligand (L) bearing two 2-hydroxypropyl pendants, 6,19-bis(2-hydroxypropyl)-3,6,9,16,19,22-hexaaza-tricyclo-[22.2.2.2(11,14)]triaconta-11,13,24,26,27,29-hexaene has been synthesized and characterized. The macrocyclic ligand was isolated as a colorless crystal, monoclinic, P2(1)/n, with a=10.757(2), b=14.214(3), c=13.746(3) A, beta=101.40(3) degrees, V=2060.3(7) A3, Z=2, R1=0.0695, and wR2=0.1538 [I>2sigma(I)]. Potentiometric studies of the macrocyclic ligand and three types of amino acids, glycine (equal numbers of carboxylate and amino groups), aspartic acid (more carboxylate groups than amino group), and lysine (more amino groups than carboxylate group) have been performed. The stability constants for the new macrocycle and binary complexes of the amino acid with the macrocyclic ligand are reported. Binary complexes are formed in aqueous solution as a result of hydrogen bonding interaction and electrostatic attraction between the host and the guest. The binding Schemes for the recognition of amino acids are suggested. From the results, it seems that this new macrocyclic ligand is able to bind three different amino acids with selectivity in aqueous solution, and the strength of binding is of the order lysine < glycine < aspartic acid.

Carboxyester hydrolysis catalyzed by a novel dicopper(II) complex with an alcohol-pendant macrocycle.

A novel hexaaza macrocycle bearing two hydroxyethyl pendants (L), 3,6,9,16,19,22-hexaaza-6,19-bis(2-hydroxyethyl)tricyclo[22,2,2,2(11,14)]triaconta-1,11,13,24,27,29-hexaene, was synthesized as a potential binucleating ligand. The corresponding Cu(II) complex [Cu(2)LCl(2)]Cl(2) small middle dot5.5H(2)O was isolated as a blue crystal, triclinic, space group P with a= 9.4920(19) A, b = 4.783(3) A, c = 16.553(3) A, alpha = 63.87(3) degrees, beta = 86.10(3) degrees, gamma = 83.8(3) degrees, V = 2072.8(7) A(-3), Z = 2, R1 = 0.0658, and wR2 = 0.1839. Both Cu ions adopt the geometry of a distorted trigonal bipyramid in a pentacoordinated environment. A complexation study on the novel title complex has revealed that the alcoholic OH groups of the complex Cu(2)L exhibit an obvious acidity with rather low pK(a) values at 25 degrees C. The Cu(II)-bound alkoxides, which act as reactive nucleophiles toward the hydrolysis of 4-nitrophenyl acetate in 10% (v/v) CH(3)CN at 25 degrees C, with I = 0.10 (NaNO(3)) and pH 9.3, have shown a second-order rate constant, 0.41 +/- 0.02 M(-1) s(-1), a value that is approximately 10 times greater than the corresponding value for the mononuclear Cu(II) complex formed by a relatively simple tripodal ligand (L1). The pH-rate profile gave a sigmoidal curve. The possible catalytic mechanism has been proposed, and the reason for the high catalytic activity of the title complex has been discussed.