Chiral palladium complexes based on derivatives of benzylamine and 2α-hydroxypinan-3-one

Synthesized and characterized new chiral palladium complexes, some of which contain asymmetric donor nitrogen atom. Nitrogen-containing derivatives (+) - and (-)-2α-hydroxypinan-3-one- (1R,2R,5R)-3-(benzylimino)-2,6,6-trimethylbicy- clo[3.1.1]heptane-2-ol (HL1), (1S,2S,3S,5S)-3- (benzylamino)-2,6, 6-trimethylbicyclo[3.1.1]- heptane-2-ol (HL2), (1R,2R,5R)-3-((S)-α-methyl- benzylimino)-2,6,6-trimethylbicyclo[3.1.1]- heptane-2-ol (HL3), (1R,2R,3R,5R)-3-((S)-α-methyl- benzylamino)-2,6,6-trimethylbicyclo[3.1.1]- heptane-2-ol (HL4) -were studied as optically active ligands.

A Chiral Phosphorous Derivatizing Agent for the Determination of the Enantiomeric Excess of Chiral Alcohols, Amines by ^(31)P NMR

A chiral phosphorous derivatizing agent prepared from PCl3 and (S)-BINOL was described. It is used to determine the enantiomeric excess of chiral alcohols and amines by 31P NMR.

Reductive amination of ketones with ammonium catalyzed by a newly identified Brevibacterium epidermidis strain for the synthesis of(S)-chiral amines

The asymmetric reductive amination of achiral ketones with ammonia is a particularly attractive reaction for the synthesis of chiral amines.Although several engineered amine dehydrogenases have been developed by protein engineering for the asymmetric reductive amination of ketones,they all display(R)‐stereoselectivity.To date,there is no report of an(S)‐stereoselective biocatalyst for this reaction.Herein,a microorganism named Brevibacterium epidermidis ECU1015 that catalyzes the(S)‐selective reductive amination of ketones with ammonium has been successfully isolated from soil.Using B.epidermidis ECU1015 as the catalyst,the asymmetric reductive amination of a set of phenylacetone derivatives was successfully carried out,yielding the corresponding(S)‐chiral amines with moderate conversion and>99%enantiomeric excess.

4-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzo-furan-5-yl)-N-(pyridin-2-yl)thiazol-2-amine: Chiral Crystal from Achiral Molecule

The title compound 4-（7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl）-N- （pyridin-2-yl） thiazol-2-amine was synthesized by reacting 2-bromo-1-（7-methoxy-2,2-dime- thyl-2,3-dihydrobenzofuran-5-yl）ethanone with 1-（pyridine-2-yl）thiourea, and its crystal was determined by single-crystal X-ray diffraction. The crystal belongs to the monoclinic system, chiral space group C2 with a = 18.1328（14）, b = 5.5969（5）, c = 19.2195（15） A, β= 115.5420（10）°, V= 1759.9（2）A3, Z = 4, F（000） = 744, C19H19N3O2S, Mr= 353.43, Dc= 1.334 g/cm3, S = 1.15, μ = 0.201 mm-1, the final R = 0.035 and wR = 0.111 for 2307 observed reflections （I 〉 2σ（I））. The Flack parameter is -0.03（10）. The preliminary bioassay result indicated that the title compound exhibits strong insecticidal activity （93.75% mortality） against Mythimna separate at the concentration of 1.000 g/L.

Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Carboamination of Acrylamides with Arylamines: Access to Chiral α-Tertiary N-Arylamines

The asymmetric radical carboamination of 1,1-disubstituted alkenes from readily available alkyl halides and arylamines provides expedient access to valueadded chiralα-tertiary N-arylamines but has been less recognized.A challenge arises mainly from the difficult reaction initiation inherent in alkyl halides and the construction of fully substituted chiral C–N bonds from sterically congested tertiary alkyl radicals.Herein,we report a copper-catalyzed asymmetric three-component radical carboamination of acrylamides utilizing an anionic chiral N,N,N-ligand under mild conditions.This ligand was essential for the reaction initiation by enhancing the reducing capability of copper and enabling the enantiocontrol over tertiary alkyl radicals.The substrate scope was broad,covering an array of acrylamides,aryl-and heteroaryl-amines,as well as alkyl halides and sulfonyl chlorides,enabling good functional group tolerance.When combined with the follow-up transformation,this strategy provides a versatile platform for accessing structurally diverse chiralα-tertiary N-arylamine building blocks of interest in organic synthesis.

Screening primary racemic amines for enantioseparation by derivatized polysaccharide and cyclofructan columns

It is a challenge to separate the enantiomers of native chiral amines prone to deleterious silanol interactions. Aset of 39 underivatized chiral primary amines was screened for enantiomeric separation. Seven recentlyintroduced commercial chiral columns were tested. They included six polysaccharide based chiral stationaryphases (CSP) with bonded derivatives, ChiralPak? IA, IB, IC, ID, IE and IF columns and a cyclofructanderivatized CSP, Larihc? CF6-P column. Both the normal phase (NP) mode with heptane/alcohol mobile phasesand the polar organic (PO) mode with acetonitrile/alcohol were evaluated. It was found that the cyclofructanbased CSP demonstrated the highest success rate in separating primary amines in the PO mode with only onechiral amine not resolved. It is shown that, when screening the columns, there is no standard optimal condition;an excellent mobile phase composition for one column may be poorly suited to another one. Althoughbutylamine was a good mobile phase additive for the polysaccharide columns in both PO and NP modes, it wasdetrimental to the enantio-recognition capability of the cyclofructan column. Triethylamine was the appropriatesilanol screening agent for this latter column.

Asymmetric Reductive Amination of Carbonyl Compounds by Using<i>N,N,N</i>-Tributylpropanaminium Based Novel Chiral Ionic Liquid

Asymmetric reductive amination of carbonyl compounds was carried out using a novel class of aliphatic quarternary ammonium based chiral ionic liquid. S-(+)-2,3-dihydroxy-N,N,N-tributylpropanaminum bromide chiral ionic liquid has been synthesized, characterized and used for asymmetric reductive amination of carbonyl compounds in the presence of sodium borohydride. These preliminary results are encouraging and advocate dual role of novel ionic liquid as a medium and reducing agent for proficient conversion of ketones to amines, however, reductive amination reaction needs to be established for other substituents.

Atroposelective Synthesis of 2-Arylindoles via Chiral Phosphoric Acid-Catalyzed Direct Amination of Indoles

Indole-based atropisomers are a very important class of axially chiral compounds.However,the atroposelective synthesis of axially chiral 2-arylindole remains largely unexplored.In this study,we report the successful synthesis of atropisomeric 2-arylindoles using direct amination of indoles with p-quinonediimines in the presence of chiral phosphoric acid as a catalyst.Quinonediimine acts as an aminating reagent through formal polarity inversion of imine.The malonate group on the 2-aryl of 2-indoles was found to be essen-tial for high enantioselectivity of the products.This could be due to the additional interaction between the ester group and the cata-lyst,as well as the intramolecular hydrogen bonding.Our findings provide a new strategy for the asymmetric construction of 2-arylindole atropisomers.

手性菲咯啉叔胺衍生的N-氧化物的合成及其在吲哚的不对称烷基化反应中的应用

手性菲咯啉配体的多样性合成仍然是不对称催化领域重要的课题。本文以经济易得的各种取代的光学纯脯氨酰胺或羟脯氨酰胺(1)为起始原料,与菲咯啉-2-甲醛(2)发生缩合环化反应,合成了中间体3。中间体3继续在氧化剂间氯过氧苯甲酸(m-CPBA)的作用下发生叔胺氮原子上的氧化反应,合成了9个未见文献报道的手性菲咯啉叔胺衍生的N-氧化物4a~4i,总产率32%~35%,dr值为8/1~>20/1。化合物4结构经^(1)H NMR,^(13)C NMR和HR-MS(ESI-TOF)表征。此外,化合物4a~4i可用作配体参与金属催化吲哚(5)与β,γ-不饱和α-酮酯(6)的不对称Friedel-Crafts烷基化反应。其中,配体4i能够提供最好的手性环境,并得到最佳结果(81%的产率和39%的ee)。

新型手性联吡啶叔胺及其衍生的N-氧化物的合成

手性联吡啶配体和叔胺衍生的手性N-氧化物配体的合成是不对称催化领域研究的热点。本文以光学纯的各种取代脯氨酰胺(1)与联吡啶-6-甲醛(2)发生缩合环化反应,合成了8个未见文献报道的手性联吡啶叔胺3a~3h,收率75%~80%,dr>20∶1。化合物3在氧化剂m-CPBA(间氯过氧苯甲酸)的作用下发生氮原子上的氧化反应,合成了8个未见文献报道的手性联吡啶叔胺衍生的N-氧化物4a~4h,总产率45%~51%,dr>20∶1(4e为14/1)。化合物3和4结构经^(1)H NMR,^(13)C NMR和HR-MS(ESI-TOF)表征,化合物3h的绝对构型(3R,7aS)通过单晶X-射线衍射进一步进行了确定。手性联吡啶和手性N-氧化物作为优势配体,其骨架类化合物3和4的合成今后可以为不对称路易斯酸催化提供新配体筛选。

Divergent Protein Engineering of Transaminase for the Synthesis of Chiral Rivastigmine and Apremilast Precursors

Comprehensive Summary The implementation of divergent protein engineering on the natural transaminase Vf-ω-TA led to the development of two effective mutants(M2 and M8),enabling the enzymatic synthesis of chiral amine precursors of Rivastigmine and Apremilast,respectively.The evolution of the enzymes was guided by crystal structures and a focused mutagenesis strategy,allowing them to effectively address the challenging ketone substrates with significant steric hindrance.Under the optimized reaction parameters,transamination proceeded smoothly in good conversions and with perfect stereochemical control(>99%ee).These processes utilize inexpensiveα-methylbenzylamine as an amine donor and avoid the continuous acetone removal and costly LDH/GDH/NADH systems.

手性胺类医药中间体的绿色合成研究进展

医药生产中普遍存在高污染、高能耗、低效率等问题,急需开发经济、清洁、绿色、低碳的技术。对手性医药中间体进行分类并介绍了含手性胺结构的医药分子,综述了不对称还原胺化法、生物催化法等绿色合成方法应用于手性胺类医药中间体的研究进展,重点阐述了以铵盐、伯胺为氮源的不对称还原胺化法以及利用转氨酶、亚胺还原酶、胺脱氢酶、多酶级联和光-酶级联的生物催化法,并对手性胺类医药中间体领域所面临挑战及发展方向进行了展望。

生物酶在手性胺合成中的研究进展

手性胺类化合物是重要的医药中间体,是多种药物分子的重要结构单元,可通过生物催化的方式制备手性胺化合物。生物催化具有高效、绿色、可持续等优势,对于手性胺的合成以及在医药领域的应用具有重要的促进作用。本文概述了胺脱氢酶和亚胺还原酶在手性胺类化合物合成中的研究进展,着重介绍了天然酶的发现和酶的突变改造等相关研究。此外,还对酶法合成手性胺化合物所面临的挑战进行了总结,并对未来的研究方向进行展望。

Divergent synthesis of chiral amines via Ni-catalyzed chemo-and enantioselective hydrogenation of alkynone imines

Ligand-mediated nickel-catalyzed asymmetric hydrogenation of alkynone imines has been achieved. By using Ni(OAc)_2·4H_2O/(S,S)-Ph-BPE complex as a catalyst, the chemo-and enantioselective hydrogenation of alkynone imines occurred efficiently to afford chiral propargyl amines with high yields and excellent enantioselectivities(up to 99% yield, >99% ee), leaving the readily reducible alkynyl group intact. Both the C=N and C≡C bonds of alkynone imines were hydrogenated efficiently in the presence of Ni(OAc)_2·4H_2O and Josiphos SL-J011-1, furnishing unfunctionalized chiral imines efficiently(up to 99% yield, >99% ee).The(Z)-allylamines and(E)-allylamines were also efficiently prepared from alkynone imines by the combination of the different catalytic systems. The preliminary mechanism study revealed that the reduction of alkynone imines was a stepwise process and the C=N bonds were preferably hydrogenated in the complete reduction of alkynone imines. The synthetic utility of this method was demonstrated by its application in the late-stage modification of the antiviral drug Zidovudine and the concise synthesis of chiral dibenzoazepine.

Asymmetric α-Pentadienylation of β-Ketocarbonyls and Aldehydes by Synergistic Pd/Chiral Primary Amine Catalysis

Direct alkylation with skipped enynes or cyclopropropylacetylenes represents an ideal process for the installation of pentadienyl group in terms of atom- and step-economy.The development of catalytic asymmetric versions has been frequently pursued and most of the successes have been achieved with enolizable aldehydes.We herein describe a synergistic chiral primary amine/Pd catalysis for asymmetric α-pentadienylation of β-ketocarbonyls and aldehydes with skipped enynes or cyclopropropylacetylenes.The reaction features the construction of acyclic all-carbon quaternary centers with high enantioselectivity,and good functional group tolerance and scalability.

Access to N-a-quaternary chiral morpholines via Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy

Morpholines are widespread in many biologically and catalytically active agents,thus being an important aim of pharmaceutical and synthetic chemists.However,efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive.Herein,we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge.As a result,two kinds of structurally various chiral morpholines bearing rich functional groups and N-a-quaternary stereocenters were produced with high efficiency and selectivity(42 examples,up to91%yield,97:3 er and>19:1 dr).In addition,a series of transformations were performed to demonstrate the synthetic utility of this methodology.In particular,a hit compound for new antitumor drugs was identified through cellular evaluation.Furthermore,mechanistic investigations reveal that,hydrogen bonding in the key copper-allenylidene intermediate together withπ-πstacking aids remote enantioinduction.

Rhodium-Catalyzed Asymmetric Hydrogenation of Tetrasubstitutedα,β-Unsaturated Amides:Efficient Access to Chiralβ-Amino Amides

The first asymmetric hydrogenation of acyclic tetrasubstitutedα,β-unsaturated amides has been achieved by using Rh/DuanPhos complex as a catalyst,delivering chiralβ-amino amides with two contiguous chiral centers in excellent yields and high enantioselectivities(up to 99%yield,96%ee),which provides efficient and concise access to valuableβ-amino amide derivatives.The gram-scale reaction and efficient transformation ofβ-amino amide toβ-amino acid andβ-amino cyanide demonstrated the utility of this methodology.

Metal and organo-catalysed asymmetric hydroaminomethylation of styrenes

A new protocol that enables asymmetric hydroaminomethylation of styrenes to afford chiral amines has been developed. Catalysed by an Rh-phosphine species and a chiral phosphoric acid, styrenes are converted into β-chiral amines with good enantioselectivities under syngas in the presence of an amine and Hantzsch ester. The reaction involves two key steps, hydroformylation and reductive amination, with the former catalysed by the Rh species whilst the latter by the phosphoric acid.

亚胺还原酶的研究进展

含氮化合物广泛应用于医药、化工和材料等领域,因此含氮化合物的高效合成一直都是研究热点。亚胺还原酶是近年来发现的一类以NADPH作为辅因子的氧化还原酶,它能够催化环状亚胺的还原和酮的还原胺化合成各种含氮化合物。这类酶自2010年首次报道以来,已经取得了巨大的研究进展,引起了学术界和工业界的广泛关注。本文主要总结了近十多年来亚胺还原酶的研究进展,具体包括亚胺还原酶的发现、亚胺还原酶催化的亚胺还原和酮还原胺化、涉及亚胺还原酶催化的级联反应、亚胺还原酶的晶体结构与催化机制等内容,重点综述了亚胺还原酶的新功能和新应用。

Copper-Catalyzed Enantioconvergent Radical C(sp^(3))−N Cross- Coupling to Access Chiral α-Amino-β-lactams

A copper-catalyzed enantioconvergent radical C-(sp^(3))-N cross-coupling of racemic tertiaryα-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions.The use of a sterically demanded oxazoline-derived sulfonamide N,N,N-ligand is crucial for the reaction initiation and effective enantio-discrimination of the azetidinone-derived cyclic alkyl radicals.The strategy provides an attractive approach to access chiralα-amino-β-lactams,an important structural motif in many biologically active molecules.Preliminary mechanistic studies support the formation of azetidinone-derived alkyl radicals from the L*Cu(I)-amido complex andα-bromo-β-lactams.