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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.

A highly efficient enantio- and diastereoselective catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution (DKR-ATH) of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones to ent- trans-β-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.

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.

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.

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.

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.

The preparation of a rigid C1-symmetric P-stereogenic diphosphine series possessing a P-o-diphenylphosphinophenyl moiety and its use in RhI-catalyzed hydrogenation of benchmark olefins, is presented. This simplified ligand design, wherein some specific features (backbone flexibility, identical nature of P,P′-substituents) of related C2-symmetric ethylene-bridged diphosphines were knocked out, is a useful study-tool with which to better understand the role of essential motifs that guide catalysis in the original model.

New 3rd generation designer ansa-ruthenium(II) complexes featuring N,C-alkylene-tethered N,N-dialkylsulfamoyl-DPEN/η6-arene ligands, exhibited good catalytic performance in the asymmetric transfer hydrogenation (ATH) of various classes of (het)aryl ketones in formic acid/triethylamine mixture. In particular, benzo-fused cyclic ketones furnished 98 to >99.9% ee using a low catalyst loading.

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.

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.

A series of sterically hindered o-(branched alkoxy)-tert-butoxybenzenes was efficiently prepared in good yields owing to a new practical and simple preparation of o-tert-butoxyphenol starting from catechol and isobutene. Use of DMF di-tert-butyl acetal reagent instead of isobutene/H2SO4 (cat.) for O-tert-butylation was very convenient in case of ortho bulky phenols affording the corresponding tert-butyl ethers in high yield and purity. This general route proved to be useful since no reliable access was available to o-di-t-BuO-substituted arenes. Application to the synthesis of congested phosphorus-based compounds is presented.

A large series of bulky 1,2-dialkoxy- and 1,2,3-trialkoxy-benzenes was efficiently prepared via Williamson etherification. Preparation of their contiguous bromine-containing derivatives was also achieved.

An efficient and high-yielding (up to 57% overall yield) asymmetric route to enantiopure P -stereogenic 1,2-bis[( o -hydroxyaryl)(phenyl)phosphino- P -borane]ethanes wherein aryl = phenyl and naphthyl, is presented. The occurring P -stereomutation is confirmed through X-ray crystal structure analysis of key intermediates.

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C6Me6)(S,S)–(CH2)5NSO2DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO2H–Et3N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.

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.

Switching Knowles DiPAMP's [DIPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]-ethane} MeO groups with i-PrO ones led to the i-Pr-SMS-Phos {i-Pr-SMS-Phos = 1,2-bis[(o-isopropoxyphenyl)(phenyl)phosphino]ethane} ligand which displayed a boosted catalyst activity coupled with an enhanced enantioselectivity in the rhodium(I)-catalyzed hydrogenation of a wide-range of representative olefinic substrates (dehydro-α-amido acids, itaconates, acrylates, enamides, enol acetates, α,α-diarylethylenes, etc). The rhodium(I)-(i-Pr-SMS-Phos) catalytic profile was investigated revealing its structural attributes and robustness, and in contrast to the usual trend, 31 P NMR analysis revealed that its methyl (Z)-α-acetamidocinnamate (MAC) adduct consisted of a reversed diastereomeric ratio of 1.4:1 in favour of the most reactive diastereomer.

The introduction of 1,2-bis[(o-anisyl)-(phenyl)phosphino]ethane (DiPAMP) as a P-stereo-genic ligand for rhodium(I)-catalyzed hydrogenation by Knowles et al. came after their evaluation of several diphosphines. However, no in-depth study was carried out on incorporating various substituents on its P-o-anisyl groups. In this work, we have prepared a large series of enantiopure and closely related DiPAMP analogues possessing various substituents (MeO, TMS, t-Bu, Ph, fused benzene ring) on the o-anisyl rings. The new ligands were evaluated in rhodium-catalyzed hydrogenation of several model substrates: methyl α-acetamidoacrylate, methyl (Z)-α-acetamidocinnamate, methyl (Z)-β-acetamidocrotonate, dimethyl itaconate, and atropic acid. They displayed enhanced activities and increased enantioselectivities, particularly the P-(2,3,4,5-tetra-MeO-C 6 H)-substituted ligand (4MeBigFUS). Interestingly enough, 88% ee was obtained in the hydrogenation of atropic acid using the Rh-(4MeBigFUS) catalyst under mild conditions (10 bar H 2 , room temperature) versus 7% ee using Rh-DiPAMP. Conversely, the ligand possessing P-(2,6-di-MeO-C 6 H 3 ) groups proved to slow down considerably the hydrogenation. X-Ray structures of their corresponding Rh complexes are presented and discussed.

New 3rd generation designer ansa-ruthenium(II) complexes, featuring N,C-alkylene-tethered N,N-dialkylsulfamoyl-DPEN/η6-arene ligands, exhibit good catalytic performance in the asymmetric transfer hydrogenation of various classes of (het)aryl ketones in a HCOOH/Et3N mixture.

[1217437-07-4] C34H40O2P2 (MW 542.63) InChI = 1S/C34H40O2P2/c1-33(2,3)35-29-21-13-15-23-31(29)37(27-17-9-7-10-18-27)25-26-38(28-19-11-8-12-20-28)32-24-16-14-22-30(32)36-34(4,5)6/h7-24H,25-26H2,1-6H3 InChIKey = UBYPIFSGFFMMDD-UHFFFAOYSA-N (P-chiral diphosphine ligand for asymmetric catalysis;1-4 rhodium complexes are efficient catalyst precursors for highly enantioselective hydrogenation of α-carboxy or α-aryl amidoethylenes, α-phosphono amidoethylenes, itaconates, enol acetates, α-carboxy or α-phosphono enol carboxylates) Alternate Name: (R,R)-ethylenebis[(2-tert-butoxyphenyl)phenylphosphine]. Physical Data: −99.4 (c = 1.0, CHCl3). Solubility: sol MeOH, EtOH, THF, EtOAc, CH2Cl2, toluene. Form Supplied in: glassy or white solid; commercially available (as well as the (S,S)-enantiomer). Analysis of Reagent Purity: optical rotation, 1H NMR, 31P NMR, 13C NMR. Preparative Method: the ligand is prepared via the Juge-Stephan route from (−)-oxazaPB derived from (1S,2R)-(+)-ephedrine (eq 1).2, 3 The (S,S)-enantiomer is accessible from (1R,2S)-(−)-ephedrine. (1) Handling, Storage, and Precautions: relatively air stable but should be kept under inert atmosphere in the cold for prolonged storage.

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.

Multi-step transformation of enantiomerically pure synthons, (1S,2S,3R,4R)-(4-hydroxymethyl-2,3-isopropylidenedioxy-l-cyclopentyl) methyl butyrate {(-)-5} and(1R,5R,6R,7S)-6,7-(isopropylidenedioxy)-3-oxabicyclo[3.2.1]octane-2-one {(+)-11} into carba-4-deoxypyrazofurin 1 and isomeric carba-4-deaza-oxoformycin 2 analogues is presented.

A variable temperature 600 MHz 1H NMR conformational analysis of 3JHH coupling constants in pyrazolo[4,3-c]pyridine carbaribo-C-nucleoside 1 in D2O has shown that the carbocyclic nucleoside analogu...

A series of optically enriched monofluorinated dipeptides incorporating an α-fluoro-α-amino acid were prepared by enantio- and diastereoselective electrophilic fluorination. This previously unsuccessful approach to fluorinated dipeptides can now be achieved with up to 73:27 enantiomeric ratio and high >98:2 diastereomeric ratio.

The catalyst is generated in situ from the corresponding shelf-stable chlorido Ru(II) dimer.

The title catalyst system displays high efficiency in the hydrogenation of α-amidostyrenes (I) and α-amidoacrylates (V).

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.

A series of α-keto esters and α,α,α-trifluoromethyl ketones were reduced in high yields and excellent enantioselectivities under Ru-catalysed transfer hydrogenation using novel chiral N-arenesulfonyl-1,2-diphenylethylenediamine ligands.

Enantiomerically pure chiral building blocks, lactone 1 in either enantiomeric form and cyclopentanecarbonitriles 10 and 15 , were prepared efficiently through lipase catalysed enantioselective hydrolysis of meso -diesters 5a-c or transesterification of their parent diol 2 with vinyl acetate in an organic solvent providing chiral monoesters 6a-c or ent - 6a of>99% ee in the crucial step. The combined HLADH catalysed and chemical oxidation of 2 resulted in (−)- 1 of 74% enantiomeric purity.

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.

Multi-step transformation of enantiomerically pure synthons, (1S,2S,3R,4R)-(4-hydroxymethyl-2,3-isopropylidenedioxy-l-cyclopentyl) methyl butyrate {(-)-5} and(1R,5R,6R,7S)-6,7-(isopropylidenedioxy)-3-oxabicyclo[3.2.1]octane-2-one {(+)-11} into carba-4-deoxypyrazofurin 1 and isomeric carba-4-deaza-oxoformycin 2 analogues is presented.

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.

β-(3,4-Dimethoxyphenyl)serine methyl ester was obtained in high diastereomeric and enantiomeric excesses under transfer hydrogenation using chiral Ru(η6-arene)-N-perfluorosulfonyl-1,2-diamine catalysts.

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].

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 dr99:1. 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.

[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.

The synthesis of (-)-3-[(1S,2S,3R,4R)-2,3-dihydroxy-4-(hydroxmethyl) cyclopentan-1-yl]-1H-pyrazolo[4,3-c]pyridme-4,6(5H,7H)-dione 3 was accomplished via enantiomerically pure carbocyclic 5-(β-D-ribofuranosyl)tetrazole 4.

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.

The rhodium(I)-{1,2-bis[(o-tert-butoxyphenyl)(phenyl)phosphino]ethane} [Rh(I)-(t-Bu-SMS-Phos)] catalyst system displayed prime efficiency in the hydrogenation of large series of α-amidostyrenes and α-amidoacrylates. Up to >99.9% enantiomeric excesses coupled with very high reaction rates were attained operating routinely under 1–10 bar of hydrogen at 22 °C in methanol. Examples include industrial substrates.

Chiral Ru(II) and Rh(III) complexes of N-(N,N-dialkylamino)sulfamoyl-1,2-diamine catalyze the transfer hydrogenation of various classes of aromatic ketones with high activity and excellent enantioselectivity.

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].

A stereoselective synthesis of (1′ S ,3 R ,4 R )-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate via asymmetric transfer hydrogenation catalyzed by [Ru(η 6 -arene)( S , S )-R 2 NSO 2 DPEN].

β-(3,4-Dimethoxyphenyl)serine methyl ester was obtained in high diastereomeric and enantiomeric excesses under transfer hydrogenation using chiral Ru(η6-arene)-N-perfluorosulfonyl-1,2-diamine catalysts.