Search

The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.

A full account of catalytic direct asymmetric Mannich-type reactions is presented describing the scope of amino acid-catalyzed additions of unmodified ketones to a large variety of imines. These reactions are performed under very mild, operationally simple, and environmentally friendly and benign conditions employing a one-pot, three-component protocol as well as preformed imines. Typically, products were obtained with high regio- and diastereoselectivities and excellent enantioselectivities. The methodology developed was applied as a powerful approach toward the synthesis of enantiomerically pure functionalized α-amino acids, γ-lactones, oxime-functionalized amino acids as well as pharmacologically important targets such as (R)-cyclohexylglycine.

A long-standing problem in organic synthesis is the catalytic asymmetric addition of alkyl groups to ketones to establish chiral quaternary centers. Such compounds are valuable chiral building blocks that can be further elaborated. In this account, we describe the previously unreported story of the development of the first effective catalyst for the enantioselective addition of dialkyl- and diphenylzinc reagents to ketones. The scope of this reaction is outlined, including a tandem enantioselective addition to cyclic enones/diastereoselective epoxidation protocol that establishes three contiguous stereocenters in a one-pot procedure.

— Enantioselective direct Michael additions of ketones using ( S )-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst aredescribed. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivatedketones under mild reaction conditions. © 2001 Elsevier Science Ltd. All rights reserved. An increasing demand for optically active compoundshas stimulated the development of catalytic asymmetricbond-forming reactions. 1 Of the carbon carbon bondforming reactions, the enantioselective Michael reactionhas been one of the most studied in synthetic organicchemistry. 2 Typically, carbon nucleophiles that containan active methylene center such as malonic acid esters, -keto esters, nitroalkanes, etc. have been studied. 3 Ketones, however, while they are versatile carbonnucleophiles, have generally been used as donors onlyfollowing their pre-activation by conversion into highlyreactive enol or enamine equivalents. 4 In these cases,additional synthetic step(s), stoichiometric amounts ofbase, additional reagents (silylating agents to form theenol silyl ether or chiral amines to form the enaminederivative) or chiral ligands are required. A potentiallymore promising strategy would involve catalysis ofdirect additions of unmodified ketones to Michael-typeacceptors. The development of catalytic asymmetricvariants of this process would provide access to opti-cally enriched 1,5-dicarbonyl synthons.As part of our ongoing program directed towardsidentifying small organic molecules as catalysts ofasymmetric reactions, we explore here the direct addi-tion of ketones through an enamine-type mechanism toMichael-type acceptors. Chiral amines have been usedpreviously in catalytic asymmetric Michael additions

Reaction of the titanium tetraamide Ti(NMe2)4 with 2 equiv of racemic or resolved bis(sulfonamide) ligand resulted in the formation of the [bis(sulfonamido)]2Ti complexes (TiL2) and N,N-dimethylamine. We have characterized the resulting TiL2 complexes by X-ray crystallography and variable-temperature NMR spectrometry to explore differences in the bonding and geometry of the bis(sulfonamido) ligand in these complexes. When racemic ligand was used, the resulting TiL2 complexes consisted of the homochiral and heterochiral diastereomers. One of these heterochiral diastereomers was characterized by X-ray crystallography (7hetero). When resolved ligand was employed, it was found that the product composition was dependent on the size of the bis(sulfonamide) ligand employed in the synthesis. When the aryl group of the bis(sulfonamide) ligand was tolyl (1res), two diastereomeric compounds were observed that were in equilibrium. These complexes were the C2-6homo and Cs-6homo diastereomers. When the aryl group was 2,5-dimethylphenyl (Xyl) (3rac), the major product was determined to be the homochiral diastereomer, C2-8homo, by X-ray crystallography. The homochiral diastereomer generated from the bis(sulfonamide) ligand with the aryl group 5-chloro-2-methoxy phenyl (4res) also gave the homochiral diastereomer C2-9homo. By NMR spectrometry both C2-8homo and C2-9homo were found to be single diastereomers, and no signals that could be attributed to the Cssymmetric counterparts to Cs-6homo were observed. The structures of C2-6homo, 7hetero, C2-8homo, and C2-9homo were determined. Although the geometries between the homochiral and heterochiral diastereomers are very different, the metrical parameters are not. Each of the titanium centers in these structures is eight-coordinate. The ligand was found to bind through one of the sulfonyl oxygens of each sulfonyl group as well as the sulfonamido nitrogens. The Ti-N distances of the sulfonamido groups range from 2.070(3) to 2.095(3) A, while Ti-O sulfonyl distances range from 2.159(2) to 2.328(3) A. The bis(sulfonamide) ligands used in this work have also been used in the asymmetric addition of diethylzinc to aldehydes. This reaction is very efficient and gives excellent enantioselectivity with a wide variety of aldehydes. To determine if the TiL2 complexes were involved in the catalysis, an equilibrium mixture of the diastereomers C2-6homo/Cs-6homo was used in the asymmetric addition and compared with the catalyst generated under the reaction conditions from the ligand 1res. Although the mixture of C2-6homo/Cs-6homo gave high enantioselectivity, it exhibited different enantioselectivity and turnover frequency from the catalyst generated from 1res.

A two step procedure for the synthesis of chiral tetradentate sulfonamide ligands is reported. The ligands are easily prepared from the corresponding bissulfonamide complexes by directed metallation followed by quenching with either ketones or carbon dioxide in 47 to 82 % yield. Preliminary results indicate that these complexes are efficient catalysts in the asymmetric addition of alkyl groups to aldehydes.

A two step procedure for the synthesis of chiral tetradentate sulfonamide ligands is reported. The ligands are easily prepared from the corresponding bissulfonamide complexes by directed metallation followed by quenching with either ketones or carbon dioxide in 47 to 82 % yield. Preliminary results indicate that these complexes are efficient catalysts in the asymmetric addition of alkyl groups to aldehydes.

— Enantioselective direct Michael additions of ketones using ( S )-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst aredescribed. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivatedketones under mild reaction conditions. © 2001 Elsevier Science Ltd. All rights reserved. An increasing demand for optically active compoundshas stimulated the development of catalytic asymmetricbond-forming reactions. 1 Of the carbon carbon bondforming reactions, the enantioselective Michael reactionhas been one of the most studied in synthetic organicchemistry. 2 Typically, carbon nucleophiles that containan active methylene center such as malonic acid esters, -keto esters, nitroalkanes, etc. have been studied. 3 Ketones, however, while they are versatile carbonnucleophiles, have generally been used as donors onlyfollowing their pre-activation by conversion into highlyreactive enol or enamine equivalents. 4 In these cases,additional synthetic step(s), stoichiometric amounts ofbase, additional reagents (silylating agents to form theenol silyl ether or chiral amines to form the enaminederivative) or chiral ligands are required. A potentiallymore promising strategy would involve catalysis ofdirect additions of unmodified ketones to Michael-typeacceptors. The development of catalytic asymmetricvariants of this process would provide access to opti-cally enriched 1,5-dicarbonyl synthons.As part of our ongoing program directed towardsidentifying small organic molecules as catalysts ofasymmetric reactions, we explore here the direct addi-tion of ketones through an enamine-type mechanism toMichael-type acceptors. Chiral amines have been usedpreviously in catalytic asymmetric Michael additions

The development of syntheses providing enantiomerically pure α-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized α-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized α-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of ≥99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon−carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operation...

The synthesis and biochemical characterization of AX4697 , a fluorescent, bisindolylmaleimide-derived probe for PKCα and β, is described. AX4697 was able to quantify changes in PKC expression in drug-treated Jurkat cells and was shown to covalently label PKCα on C619, a residue that sits just outside the active site.

The Michael additions of a number of ketones and aldehydes to alkylidene malonates and nitro olefins were studied. The reactions employ small organic molecules as catalyst under mild reaction conditions and do not requirepreactivation of the carbonyl donors. These reactions afforded a variety of highly functionalized products in good yields with moderate to good enantioselectivity.

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values ofor = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.