Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

The reaction of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) with various nitrogen‐containing compounds, particularly tertiary amines (tert‐amines), has been studied for the preparation of 2‐(4,6‐dimethoxy‐1,3,5‐triazinyl)trialkylammonium salts [DMT‐Am(s)]. DMT‐Ams derived from aliphatic tert‐amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT‐Ams and tert‐amines by NMR and X‐ray diffraction methods, we concluded that a β‐alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert‐amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β‐alkyl groups in the stable conformations, does not react at all. The theory of “gauche β‐alkyl group effect” proposed here provides useful guidelines for the preparation of DMT‐Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert‐amines in a CDMT/tert‐amine system that involves in situ generation of DMT‐Am, showed that the gauche effect of the β‐alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert‐amines possessing an unavoidable gauche β‐alkyl group. Thus, the tert‐amine/CDMT systems are useful for judging whether tert‐amines can readily react with CDMT without isolation of DMT‐Ams.     

Tailoring D‐Amino Acid Oxidase from the Pig Kidney to R‐Stereoselective Amine Oxidase and its Use in the Deracemization of α‐Methylbenzylamine

The deracemization of racemic amines to yield enantioenriched amines using S‐stereoselective amine oxidases (AOx) has recently been attracting attention. However, R‐stereoselective AOx that are suitable for deracemization have not yet been identified. An R‐stereoselective AOx was now evolved from porcine kidney D ‐amino acid oxidase (pkDAO) and subsequently use for the deracemization of racemic amines. The engineered pkDAO, which was obtained by directed evolution, displayed a markedly changed substrate specificity towards R amines. The mutant enzyme exhibited a high preference towards the substrate α‐methylbenzylamine and was used to synthesize the S amine through deracemization. The findings of this study indicate that further investigations on the structure–activity relationship of AOx are warranted and also provide a new method for biotransformations in organic synthesis.     

Dimethylzinc‐Initiated Radical Coupling of β‐Bromostyrenes with Ethers and Amines

A new coupling reaction has been developed in which β‐bromostyrenes react with ethers and tertiary amines to introduce the styryl group in the α‐position. The transformation is mediated by Me₂Zn/O₂ with 10 % MnCl₂ and is believed to proceed by a radical addition–elimination mechanism. The ether and the amine are employed as solvent and the coupling takes place through the most stable α radical for unsymmetrical substrates. The products are obtained in moderate to good yields as the pure E isomers. The coupling can be achieved with a range of smaller cyclic and acyclic ethers/amines as well as various substituted β‐bromostyrenes.     

Dynamic Kinetic Asymmetric Transformations of β‐Stereogenic α‐Ketoesters by Direct Aldolization

Dynamic kinetic asymmetric transformations (DyKAT) of racemic β‐bromo‐α‐keto esters by direct aldolization of nitromethane and acetone provide access to fully substituted α‐glycolic acid derivatives bearing a β‐stereocenter. The aldol adducts are obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions. Mechanistic studies determined that the reactions proceed through a facile catalyst‐mediated racemization of the β‐bromo‐α‐keto esters under a DyKAT Type I manifold.     

Chemoselective Silylative Reduction of Conjugated Nitriles under Metal‐Free Catalytic Conditions: β‐Silyl Amines and Enamines

The B(C₆F₅)₃‐catalyzed silylative reduction of conjugated nitriles has been developed to afford synthetically valuable β‐silyl amines. The reaction is chemoselective and proceeds under mild conditions. Mechanistic elucidation indicates that it proceeds by rapid double hydrosilylation of the conjugated nitrile to an enamine intermediate which is subsequently reduced to the β‐silyl amine, thus forming a new C(sp³)? Si bond. Based on this mechanistic understanding, a preparative route to enamines was also established using bulky silanes.     

Acyclic Branched α‐Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β‐Tetrasubstituted β‐Fluoro Amines

The preparation of acyclic β‐fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol‐catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α‐fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo‐ (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert‐butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.     

Direct Zinc(II)‐Catalyzed Enantioconvergent Additions of Terminal Alkynes to α‐Keto Esters

The addition of terminal alkynes to racemic β‐stereogenic α‐keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by a non‐toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition.     

Redox‐Neutral α,β‐Difunctionalization of Cyclic Amines

In contrast to the continuously growing number of methods that allow for the efficient α‐functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β‐position. A general redox‐neutral strategy is outlined for amine β‐functionalization and α,β‐difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O‐acetals from simple 1‐(aminomethyl)‐β‐naphthols and 2‐(aminomethyl)‐phenols.     

Crystal Structure Investigations on Imines derived from 3‐Ferrocenyl‐prop‐2‐enal Crystallizing in Non‐centrosymmetric Space Groups

The condensation of 3‐ferrocenyl‐prop‐2‐enal with primary amines leads to the formation of the corresponding imines in good yields. The crystal structures of imines derived from p‐dimethylamino‐aniline and furfurylamine are determined by the ability of the functional groups to act as hydrogen bond donor or acceptor sites. Although N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine and furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are achiral molecules they crystallize in the non‐centrosymmetric space groups P2₁ and Pca2₁, respectively. The molecular architecture of N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine is realized by the incorporation of dichloromethane acting as hydrogen bond donor and acceptor with both hydrogen and both chlorine atoms. On the other hand, the molecules of furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are linked by hydrogen bonds towards the centroid of one of the cyclopentadienyl ligands and towards the oxygen atom of the furan ring to produce infinite chains.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Synthesis,Characterization, and Antimicrobial Activities of Novel N‐substituted β‐Hydroxy Amines and β‐Hydroxy Ethers that Contained 8‐Methoxy Fluoroquinolones

Synthesis of novel N‐substituted β‐hydroxy amines 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j and β‐hydroxy ethers 5a , 5b , 5c that contained 8‐methoxy fluoroquinolones has been described. 8‐Methoxy fluoroquinolone carboxylic acid 1 , reacted with piperizine in acetonitrile in the presence of triethyl amine under reflux, gave 7‐piperazine 8‐methoxyfluoroquinolone 2 . The latter is reacted with epichlorohydrine in the presence of NaOH in acetone to yield the N‐substituted epoxide 3 , which on treatment with aliphatic, aromatic, and cyclic amines gives β‐hydroxy amines 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j . On other hand, 3 on treatment with alcohols in the presence of NaOH afforded the corresponding β‐hydroxy ethers 5a , 5b , 5c . The structures of the synthesized compounds have been established on the basis of spectral and analytical data. Docking analysis was performed using Surflex‐Dock module in Sybyl X 1.0. The antimicrobial activities of newly synthesized compounds were evaluated against bacteria and fungi by using moxifloxacin as the reference. Many of the evaluated compounds exhibited remarkable activities.     

Kinetic Resolution of β‐Sulfonyl Ketones through Enantioselective β‐Elimination using a Cation‐Binding Polyether Catalyst

Reported herein is the first enantioselective β‐elimination reaction catalyzed by a chiral cation‐binding polyether. By using this catalytic protocol, a wide range of β‐sulfonyl ketones could be effectively resolved with high stereoselectivity (S up to >300). Key to the success of this process is the favorable secondary interactions of the catalyst with the Lewis basic groups on the sulfone substrate. The enone product of this process can be easily converted into the racemic starting material, and allows an effective recycling and overall synthesis of chiral β‐sulfonyl ketones in high yield and excellent enantioselectivity.     

Access to Versatile β‐Cyclodextrin Scaffolds through Guest‐Mediated Monoacylation

Herein, we report the selective mono‐derivatization of heptakis[6‐deoxy‐6‐(2‐aminoethylsulfanyl)]‐β‐CD ( 1 ) through a guest‐mediated covalent capture strategy. The use of guests functionalized with cleavable linkers enables the installation of an amine‐orthogonal thiol group on the primary rim of 1 as a handle for further transformations to the β‐CD scaffold. Applying this methodology, two novel monoderivatized β‐CDs were obtained in good yield and high purity. Both of these monoacylated CDs were amenable to facile linker cleavage and further modification at the resulting thiol group. This methodology can be applied towards the synthesis heterofunctionalized β‐CD constructs for analyte sensing, drug delivery, and other applications.     

N‐acyl and N‐alkoxycarbonyl derivatives of 1H‐1,2,3‐triazolo‐[4,5‐c]pyridine; Preparation and application

The N‐acylating and N‐alkoxycarbonylation ability of the N‐substituted 1,2,3‐triazolo[4,5‐c]pyridines 1a‐e have been investigated. The alkoxycarbonyl triazolopyridine derivatives ( 1c‐e ) were readily prepared in 81–96% yield (the corresponding tetrafluoroborate > 95%). Triazolo[4,5‐c]pyridine ( 1 ) has been shown to work as a good leaving group by the formation of amido‐ and carbamate protected derivatives of primary amines. The method was also successful for the N‐tert‐butoxycarbonyl (N‐BOC) protection of the amino acid, phenylalanine. The synthetic transformations are facilitated by the one‐pot preparation of 1a‐e followed by the direct reaction with the amines or amino acid. The present method thus offers an efficient and convenient protocol for the in situ preparation of triazolopyridine reagents to be used directly for the protection of amines and amino acids. N‐Acyl‐ and N‐alkoxycarbonyl triazolopyridines ( 1a‐e ) were readily prepared in 4 steps from 4‐aminopyridine ( 4 ) by amine protection, pyridine nitration, nitro reduction and diazotizations/cyclizations. All reactions offer the advantages of rapid conversions in high yields under very mild conditions.     

Theoretical study on mechanism of cinchona alkaloids catalyzed asymmetric conjugate addition of dimethyl malonate to β‐nitrostyrene

The mechanism and enantioselectivity of the asymmetric conjugate addition of dimethyl malonate to β‐nitrostyrene catalyzed by cinchona alkaloid QD‐4 as organic catalyst are investigated using density function theory and ab initio methods. Six different reaction pathways, corresponding to the different approach modes of β‐nitrostyrene to dimethyl malonate are considered. Calculations indicate that the reaction process through a dual‐activation mechanism, in which the tertiary amine of cinchona alkaloid QD‐4 first works as a Brønsted base to promote the activation of the dimethyl malonate by deprotonation, and then, the hydroxyl group of QD‐4 acts as Brønsted acid to activate the β‐nitrostyrene. The rate‐determining step is the proton transfer process from the tertiary amine of QD‐4 to α‐carbon of β‐nitrostyrene. The comparison of the mechanisms and energies of the six reaction channels enable us to learn the fact that QD‐4 has good catalytic activities for the system, and implies C9? OH in QD‐4 may not be involved in the activation. These calculation results account well for the observations in experiments. © 2014 Wiley Periodicals, Inc.     

Ir‐Catalyzed Asymmetric Hydrogenation of α‐Alkylidene β‐Lactams and Cyclobutanones

Chiral β‐lactams and cyclobutanones are present in numerous natural and pharmaceutical products. The stereoselective construction of chiral four‐membered cyclic compounds is an ongoing challenge for the chemical community. Herein, we report a highly stereocontrolled construction of four‐membered ring (mini‐sized) β‐lactams and cyclobutanones via an Ir/ In‐BiphPHOX ‐catalyzed asymmetric hydrogenation, providing the corresponding optically active four‐membered ring carbonyl products bearing an α‐chiral carbon center with excellent yields (up to 99%) and enantioselectivities (up to 98%) under mild reaction conditions (1.0—2.5 bar H₂ for 1.0—10 h). The reaction presents wide substrate scope. Diverse transformations of the catalyzed products were also conducted to show the potential utility of this protocol.     

Crystallization‐Induced Asymmetric Transformations. Enantiomerically pure (−)‐(R)‐ and (+)‐(S)‐2,3‐Dibromopropan‐1‐ol and Epibromohydrins. A Study of Dynamic Resolution via the Formation of Diastereoisomeric Esters

(S)‐2,3‐Dibromopropan‐1‐ol of high enantiomer excess was obtained by crystallization‐induced asymmetric transformations of racemic 2,3‐dibromopropan‐1‐ol esterified with N‐([1,1′‐biphenyl]‐4‐ylcarbonyl‐L ‐alanine; in particular, an asymmetric transformation of the first type (involving bromide exchange to equilibrate the diastereoisomeric esters) and an asymmetric transformation of the second type (involving a transesterification of diastereoisomeric esters with excess racemic alcohol) were devised.     

Structural Studies and Anticancer Activity of a Novel Class of β‐Peptides

Functionalized oligomeric organic compounds with well‐defined β‐proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β‐peptides was investigated by NMR spectroscopic and X‐ray methods determining the conformational shapes of the β‐proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β‐peptide bonds between 5‐arylpyrrolidine‐2‐carboxylic acid units existing in Z/E configurations. The whole library of short β‐peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone‐refractory prostate cancer cell line PC‐3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine‐substituted dimeric and trimeric acrylamides induced caspase‐dependent apoptosis of PC‐3 cells through cell‐cycle arrest and mitochondrial damage.     

A New 2H‐Azirin‐3‐amine as a Synthon for α‐Methyl Glutamate

The synthesis of a novel 2,2‐disubstituted 2H‐azirin‐3‐amine 10 as a building block for racemic Glu(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 10 with thiobenzoic S‐acid and the amino acid Z‐Val‐OH yielded the racemic monothiodiamide 17 and the dipeptide 18 as a mixture of diastereoisomers, respectively (Scheme 2). From 18 , each of the protecting groups was removed selectively (Scheme 3).     

Isomerization of Olefins Triggered by Rhodium‐Catalyzed CH Bond Activation: Control of Endocyclic β‐Hydrogen Elimination

Five‐membered metallacycles are typically reluctant to undergo endocyclic β‐hydrogen elimination. The rhodium‐catalyzed isomerization of 4‐pentenals into 3‐pentenals occurs through this elementary step and cleavage of two C? H bonds, as supported by deuterium‐labeling studies. The reaction proceeds without decarbonylation, leads to trans olefins exclusively, and tolerates other olefins normally prone to isomerization. Endocyclic β‐hydrogen elimination can also be controlled in an enantiodivergent reaction on a racemic mixture.