trans-Diastereoselective Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Acetamido Benzocyclic Ketones via Dynamic Kinetic Resolution.

A highly efficient enantio- and diastereoselective catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution (DKR-ATH) of α,ß-dehydro-α-acetamido and α-acetamido benzocyclic ketones to ent- trans-ß-amido alcohols is disclosed employing a new ansa-Ru(II) complex of an enantiomerically pure syn- N, N-ligand, i.e. ent- syn-ULTAM-(CH2)3Ph. DFT calculations of the transition state structures revealed an atypical two-pronged substrate attractive stabilization engaging the commonly encountered CH/π electrostatic interaction and a new additional O═S═O···HNAc H-bond hence favoring the trans-configured products.

Stereoarrayed 2,3-Disubstituted 1-Indanols via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation.

Activated racemic 2,3-disubstituted 1-indanones 1 possessing two stereolabile centers were stereoselectively reduced to the corresponding chiral 2,3-disubstituted-1-indanols 2 by ruthenium(II)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation. In particular, this route offers a practical access to a new class of conformationally rigid enantiopure 1,4-diols 2k-m having four contiguous chiral centers. Transformation of ent-2k into a Pallidol analogue via a highly diastereo- and regioselective Friedel-Crafts benzylation of o-chloroanisole is presented.

Stereopure Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation.

A highly diastereo- and enantioselective Ru(II)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of α-(N-sulfonylimino) and α-(N-sulfonylamino) aryl ketones to 4-hydroxy-benzo-δ- and 3-(α-hydroxy-arylmethyl)-benzo-γ-sultams is presented. By employing enantiopure ansa-Ru[PipSO2DPEN(CH2)4Ph] cat. II with S/C = 10 000 in a HCO2H/Et3N binary mix, up to >99.9% ee and dr >99:1 are obtained with 100% conversion under mild conditions. Application to access the stereopure "structurally simplified TsDPEN" N,N-ligand syn-3-(α-aminobenzyl)-benzo-γ-sultam ("syn-ULTAM") and its structural isomer trans-4-amino-3-phenyl-benzo-δ-sultam (trans-4) is demonstrated.

Stereoarrayed CF3 -Substituted 1,3-Diols by Dynamic Kinetic Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation.

CF3 -substituted 1,3-diols were stereoselectively prepared in excellent enantiopurity and high yield from CF3 -substituted diketones by using an ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono-reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF3 C(O)-substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction.

γ-Sultam-cored N,N-ligands in the ruthenium(ii)-catalyzed asymmetric transfer hydrogenation of aryl ketones.

The synthesis of new enantiopure syn- and anti-3-(α-aminobenzyl)-benzo-γ-sultam ligands 6 and their application in the ruthenium(ii)-catalyzed asymmetric transfer hydrogenation (ATH) of ketones using formic acid/triethylamine is described. In particular, benzo-fused cyclic ketones afforded excellent enantioselectivities in reasonable time employing a low loading of the syn ligand-containing catalyst. A never-before-seen dynamic kinetic resolution (DKR) during reduction of a γ-keto carboxylic ester (S7) derivative of 1-indanone is realized leading as well to excellent induction.

Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.

Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.

Efficient asymmetric syntheses of 1-phenyl-phosphindane, derivatives, and 2- or 3-oxa analogues: mission accomplished.

A highly enantioselective synthesis of unsubstituted 1-phenyl-phosphindane and its P-borane and P-oxide derivatives was effectively established via a new fluoride-triggered desilylative carbocyclization strategy. Preparation of the "oxygen atom-doped" 1-phenyl-3-oxa-1-phosphindane-P-borane analogue was otherwise achieved via a tandem P-α-iodination-intra-O-alkylation.

P-stereogenic phospholanes or phosphorinanes from o-biarylylphosphines: two bridges not too far.

The discovery of a concise regiodivergent asymmetric route to nonclassical P-stereogenic 5- or 6-membered benzophosphacycles, under conditions-dependent radical (oxidative addition) versus anionic (S(N)Ar) benzannulation, is reported.

Asymmetric transfer hydrogenation of 1-naphthyl ketones by an ansa-Ru(II) complex of a DPEN-SO2N(Me)-(CH2)2(η(6)-p-Tol) combined ligand.

The first second-generation designer Ru(II) catalyst 1b featuring an enantiopure N,C-(N-ethylene-N-methyl-sulfamoyl)-tethered (DPEN-κ(2)N,N')/η(6)-toluene hybrid ligand is introduced. Using an S/C = 1000 in HCO2H-Et3N 5:2 transfer hydrogenation medium, secondary 1-naphthyl alcohols are obtained in up to >99.9% ee under mild conditions. Mechanistic factors are discussed.

Profiling the tuneable R-SMS-Phos structure in the rhodium(I)-catalyzed hydrogenation of olefins: the last stand?

A diversified family of enantiopure P-stereogenic "R-SMS-Phos" {R-SMS-Phos = 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(I)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified.

Impact on hydrogenation catalytic cycle of the R groups' cyclic feature in "R-SMS-Phos".

A series of R-SMS-Phos ligands was evaluated in the Rh(I)-catalyzed hydrogenation of a set of olefins showing a marked influence of the cyclic nature and structure of the R groups. Overall, cPen- and Cy-SMS-Phos performed efficiently, while Ph- and Bn-SMS-Phos exhibited slower kinetics and furnished lower ee's also compared with C(6)F(5)CH(2)-SMS-Phos. The Rh(I)-(Cy-SMS-Phos) catalyst was screened under mild conditions displaying excellent enantioselectivities and high TOFs. Cases of catalysis under catalyst or substrate control were identified.

Heavyweight "R-SMS-Phos" ligands in the olefins' hydrogenation arena.

A series of enantiopure P-stereogenic 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane (R-SMS-Phos) ligands wherein R = i-Pr, i-Bu, t-Bu, 3-Pen, and CH(2)TMS was assessed in the Rh(I)-catalyzed hydrogenation of an indicative set of olefins. The best performing t-Bu-SMS-Phos ligand was screened against a wide range of representative classes of standard and new olefinic substrates such as dehydroamido esters, dehydro-alpha-amido-phosphonates, enamides, itaconates, acrylates, enol acetates, alpha-phosphonovinyl benzoates, alpha-(2-pyridyl N-oxide)styrenes, and alpha-(1-hydroxyliminoethyl)styrenes. Excellent enantioselectivities and high TOFs were attained under mild conditions.

Study of the reaction of bulky aryllithium reagents with 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane derived from ephedrine.

The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with those obtained by others. In fact, several 2,6-disubstituted aryl groups were successfully appended to the phosphorus atom, furnishing the corresponding (N-ephedrino)phosphine boranes 2a-g with dr>99:1. However, when the attack on the phosphorus atom is hindered, deprotonation on the benzylic position occurs, leading to the formation of enantiomerically pure trans-(N-methylamino)(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3). While the attack of 2,2'-dilithio-1,1'-biarenes leads to the corresponding (P-phenyl)phosphole derivatives (4i,j) and to [bis(N-ephedrino)](phenyl)phosphine-P-borane (5), the attack of 1,1'-dilithiometallocenes (M=Fe, Ru) leads to a separable diastereomeric mixture of 1,1'-bis[(N-ephedrino)(phenyl)phosphino-P-borane]metallocenes (2k,l/2k',l') with dr approximately 80:20.

Highly enantioselective transfer hydrogenation of fluoroalkyl ketones.

[Structure: see text] The asymmetric transfer hydrogenation of fluoroalkyl ketones mediated by [Ru(eta6-arene)((S,S)-R2NSO2DPEN)] catalysts using HCO2H-Et3N afforded the corresponding alcohols with high ee's and in excellent yields.

Combination of antimicrobial and endotoxin-neutralizing activities of novel oleoylamines.

A combination of antimicrobial and endotoxin-neutralizing activities is desired in order to prevent progression from infection to sepsis due to the release of lipopolysaccharide from dying gram-negative bacteria. Lipopolyamines have emerged as a new type of endotoxin-neutralizing compound, but their antimicrobial activity has not been investigated. We synthesized a series of 10 oleoylamines differing in the polyamino head group, particularly in the number and separation between nitrogen atoms and the position of the oleoyl moiety. Compounds showed activity against both gram-negative and gram-positive bacteria in the micromolar range. Compounds were able to provide penetration of ethidium bromide into bacteria, indicating effects on the bacterial membrane. Oleoylamines neutralized endotoxin in Limulus amoebocyte lysate assays and by neutralization of tumor necrosis factor alpha release in human blood. Comparison of biological activities of compounds identified structural properties responsible for antimicrobial activity, and quantitative structure-property relationship analysis provided a quantitative model for prediction of activity of oleoylamines.

Electrophilic Fluorination Mediated by Cinchona Alkaloids: Highly Enantioselective Synthesis of α-Fluoro-α-phenylglycine Derivatives.

A decisive step forward: A one-step fluorination on modified cinchona alkaloids produced a new range of enantiopure fluorinating agents that display high enantioselectivities in electrophilic fluorination. The first enantioselective synthesis of N-protected α-fluorophenylglycine derivatives was achieved with an enantiomeric excess up to 94 % [Eq. (a); R=Et, CN; HMDS=hexamethyldisilazanide].