Catalytic,asymmetric Mannich-type reactions of N-acylimino esters: reactivity,diastereo- and enantioselectivity,and application to synthesis of N-acylated amino acid derivatives

In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N-acylimino esters reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made. In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total yield was 82.9%.     

Bidentate carbenoid ester coordination in ruthenium(II) Schiff-base complexes leading to excellent levels of diastereo- and enantioselectivity in catalytic alkene cyclopropanation

Exceptionally high stereoselectivity (ee < or = 98%, dr < or = 99:1) in the cyclopropanation of alkenes with ethyl diazoacetate using a non-planar ruthenium(II) Schiff-base precatalyst is a result of eta 2C,O binding of the carbenoid ester intermediate, according to DFT calculations.     

Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.     

Bis(diphenylphosphino)acetonitrile: synthesis, ligand properties and application in catalytic carbon-carbon coupling

Treatment of acetonitrile (1 equiv.) with n-butyllithium (0.95 equiv.) followed by chlorodiphenylphosphine (0.95 equiv.) under optimised reaction conditions gave a ca. 60% yield of bis(diphenylphosphino)acetonitrile (dppmCN, 1). The bidentate ligand was employed in the synthesis of the four-membered chelate metal complexes (dppmCN)MCl(2) [M = Pd (6a), Pt (6b)] and (dppmCN)RuCp*(Cl) (7). A very active catalyst for bromobenzene/phenylboronic acid Suzuki-Miyaura coupling was in situ generated by treatment of Pd(OAc)(2) with bis(diphenylphosphino)acetonitrile [TOF (1 h) >600000].     

Development of a recyclable fluorous chiral phase-transfer catalyst: application to the catalytic asymmetric synthesis of alpha-amino acids

[structure: see text] A recyclable fluorous chiral phase-transfer catalyst was synthesized and successfully applied for the catalytic asymmetric synthesis of both natural and unnatural alpha-amino acids. The reaction involves alkylation of a glycine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent.     

A new polymer-supported reagent for the synthesis of beta-lactams in solution

A modified Mukaiyama reagent was prepared on a PS-DVB resin. This reagent was used for the preparation of beta-lactams, using the Staudinger reaction. The products were obtained by generating the ketene from a carboxylic acid under sonication with the resin followed by reaction with the imine. Excess of the imine was removed by reduction followed by acid scavenging.     

Practical application of new catalytic methods: a concise synthesis of a potent PDE IV inhibitor

An efficient synthesis of a potent PDE IV inhibitor 1 is described. The synthesis is highlighted by two practical and efficient catalytic reactions: a highly selective catalytic palladium mediated carbonylation of the pyridine side chain and an efficient palladium-catalyzed Suzuki-Miyaura coupling of a chloropyridine-N-oxide.     

Amphiphilic pyrimidinophane,a new dimeric surfactant: Synthesis,aggregation, and catalytic activity

Abstract Tensiometry, conductometry, dynamic light scattering, and potentiometry are used to study the aggregation of a new amphiphilic alkylated pyrimidinophane (APP) in aqueous solutions in the presence of polyethylen-imine. The new geminal surfactant is shown to possess high micellization ability (CMC = 0.00001 M) due to the presence of an additional alkyl radical in the pyrimidine fragment. APP aggregates are characterized by a low degree of counterion binding (lower than 50%). Spectrophotometry is employed to investigate the catalytic activities of individual surfactant solutions and solutions of APP—polyethylenimine binary mixtures with respect to the hydrolysis of phosphonic acid esters. The effect of APP on phosphonate hydrolysis is typical of cationic surfactants. The higher acceleration is observed for the hydrolysis of a more hydrophobic phophonate.     

The development of the first catalyzed reaction of ketenes and imines: catalytic,asymmetric synthesis of beta-lactams

We report practical methodology for the catalytic, asymmetric synthesis of beta-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the beta-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.     

SYNPHOS®, a new chiral diphosphine ligand: synthesis, molecular modeling and application in asymmetric hydrogenation

A new optically active diphosphine ligand, [(5,6),(5′,6′)-bis(ethylenedioxy)biphenyl-2,2′-diyl]bis(diphenylphosphine) (SYNPHOS®) has been synthesized and used in ruthenium-catalyzed asymmetric hydrogenation. This new ligand has been compared to other diphosphines (BINAP and MeO-BIPHEP), regarding their dihedral angles and the enantioselectivity in the ruthenium mediated hydrogenation reaction.     

Polystyrene-supported (R)-2-piperazino-1,1,2-triphenylethanol: a readily available supported ligand with unparalleled catalytic activity and enantioselectivity

A very active and highly enantioselective catalytic resin, designed for minimal perturbation of the catalytic center by the polymer matrix, has been assembled in two steps from (S)-triphenylethylene oxide, piperazine, and Merrifield resin and tested in the enantioselective ethylation of aldehydes. 1-Arylpropanols of 94-95% ee are obtained in high yield by the use of only 2 mol % of catalytic resin at 0 degrees C for 4 h.     

Diferric oxo-bridged complexes of a polydentate aminopyridyl ligand: synthesis,structure and catalytic reactivity

The catalytic reactivity of a group of diferric oxo-bridged complexes (1–3) of a tetradentate ligand (bpmen = N,N′-dimethyl-N,N′-bis(2-pyridylmethyl)-1,2-diaminoethane) toward alkane hydroxylation has been evaluated. Among the three complexes, the µ-oxo diiron(III) complex [Fe(bpmen)(µ-O)FeCl₃] (1) has been synthesized for the first time. The complex 1 has been characterized by spectroscopic analysis and X-ray crystallography. At room temperature, the µ-oxo diiron(III) complexes 1–3 have been found to be useful catalysts in hydroxylation of alkanes with m-chloroperbenzoic acid as oxidant. [Fe(bpmen)(µ-O)FeCl₃] (1) has been found to be the most active catalyst. Moreover, the catalytic ability of the complexes in the oxidation of alcohols to ketones with hydrogen peroxide at room temperature has also been investigated.     

A new catalytic route to synthesis of silylgermylethynes

Silylgermylethynes known to be potential organometallic reagents and precursors of optoelectronic materials can be efficiently synthesized via a recently reported catalytic method called silylative coupling of alkynes with vinylsilicon compounds. The reaction of triethylethynylgermane with vinyltrisubstituted silanes catalyzed by [RuHCl(CO)(PR₃)_n] (where R = ⁱPr, Cy, Ph; n = 2-3) under optimal conditions selectively yields respective silylgermylethynes. Silylation of ethynylgermane with divinylsilicon derivatives such as siloxanes, silazanes, bis(silyl)benzene and bis(silyl)ethane gives monoethynylgermyl substituted vinyldisilicon products with high yields and selectivity, however, accompanied by traces of dialkynylgermyl derivatives. All catalytic results as well as those of stoichiometric study on the insertion of ethynylgermane into Ru-Si bond have permitted proposing mechanistic schemes of the reaction examined.     

Selective synthesis of monomeric or dimeric titanatranes via fine tuning in triethanolateamine ligand

Monomeric titanatrane i-PrOTi(OCMe₂CH₂)₃N (1) and dimeric titanatranes [i-PrOTi(OCH₂CH₂)_nN(CH₂CMe₂O)_3−n]₂ (n = 1, 2; n = 2, 3) were synthesized by the reaction of Ti(O-i-Pr)₄ with a series of triethanolateamines such as (OCH₂CH₂)_nN(CH₂CMe₂O)_3−n³⁻ (n = 0, Lig¹; n = 1, Lig²; n = 2, Lig³), which vary by the number of CMe₂ groups adjacent to a OH functionality from 3 (Lig¹H₃) to 2 (Lig²H₃) to 1 (Lig³H₃). The resultant titanatranes 1–3 have been characterized by solution ¹H and ¹³C{¹H} NMR and their solid state structures have been determined by X-ray crystallography. Whereas compound 1 is monomeric in the solid state, compounds 2 and 3 are dimeric, due to the reduction of the steric congestion in the vicinity of the Ti.     

Asymmetric synthesis and antimicrobial activity of some new mono and bicyclic beta-lactams

Reaction of the amino acid D-phenylalanine ethyl ester (4) with cinnamaldehyde gave chiral Schiff base 5, which underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic beta-lactam 6 as a single stereoisomer. Ozonolysis of 6 followed by reduction with lithium aluminum tri(tert-butoxy) hydride afforded the hydroxymethyl beta-lactam 8. Treatment of 8 with methansulfonyl chloride gave the mesylated monocyclic beta-lactam 9, which was converted to the bicyclic beta-lactam 10 upon treatment with 1,8-diazabicyclo[5,4.0] undec-7-ene (DBU). Deprotection of the phthalimido group in beta-lactams 6 and 10 by methylhydrazine and subsequent acylation of the free amino beta-lactams with different acyl chlorides in the presence of pyridine afforded mono and bicyclic beta-lactams 14a-d and 15a-d respectively. The compounds prepared were tested against Escherichia coli, Staphilococcus citrus, Klebsiella pneumanie and Bacillus subtillis. Some of these compounds showed potential antimicrobial activities.     

Total synthesis of chloptosin: a dimeric cyclohexapeptide

Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme.     

A new chiral sulfonamide ligand based on tartaric acid: synthesis and application in the enantioselective addition of diethylzinc to aldehydes and ketones

A new sulfonamide ligand based on l-tartaric acid was synthesized and was employed as a chiral ligand in the enantioselective addition of diethylzinc to aldehydes, giving rise to the best enantiomeric excess up to 83% with 5 mol % of catalyst loading. Moreover, the addition of diethylzinc to ketones can also be achieved with good to excellent enantioselectivities by employing 7 mol % of the catalyst under mild conditions.