Halbsandwich‐Komplexe von Ruthenium(II), Rhodium(III) und Iridium(III) mit Tripeptidestern aus α‐, β‐ und γ‐Aminosäuren als Liganden. — Peptidsynthese und Cyclisierung zu Cyclotripeptiden am Metallzentrum

Metal Complexes with Biological Important Ligands. CXLII. Half Sandwich Complexes of Ruthenium(II), Rhodium(III), and Iridium(III) with Tripeptide Esters from α‐, β‐, and γ‐Amino Acids as Ligands. — Peptide Synthesis and Cyclization to Cyclotripeptides at Metal Centers Halfsandwich complexes of ruthenium, rhodium and iridium with deprotonated N, N', N"‐tripeptide ester ligands were obtained from chloro bridged compounds and tripeptide methyl esters ( 1—6 ) or by peptide synthesis at a metal centre ( 9—15 ). For the peptide synthesis at the complex (C₆Me₆)Ru coordinated dipeptide methyl esters from glycine and β‐alanine or γ‐amino butyric acid were elongated by an a‐amino acid methylester. The tripeptide ester Ru(η⁶‐C₆Me₆) complexes with chiral amino acid components and an “asymmetric” metal atom are formed with high diastereoselectivity. The tripeptide esters Gly‐Gly‐β‐AlaOMe, Val‐Gly‐β‐AlaOMe and Phe‐Gly‐β‐AlaOMe can be condensated at the (C₆Me₆)Ru complex with sodium methanolate to give triple deprotonated cyclic tripeptides.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Organocatalytic Enantioselective Synthesis of Tetrasubstituted α‐Amino Allenoates by Dearomative γ‐Addition of 2,3‐Disubstituted Indoles to β,γ‐Alkynyl‐α‐imino Esters

The first asymmetric synthesis of tetrasubstituted α‐amino allenoates by a chiral phosphoric acid catalyzed dearomative γ‐addition reaction of 2,3‐disubstituted indoles to β,γ‐alkynyl‐α‐imino esters is reported. This method provides access to a series of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters in high yields, and with excellent regio‐, diastereo‐, and enantioselectivities under mild conditions without by‐product formation. Representative large‐scale reactions and diverse transformations of the products into various scaffolds with potential biological activities render are also disclosed. The mechanism of the reaction was elucidated by control reactions and DFT calculations.     

The Efficient Synthesis of the Optically Active β‐Hydroxyl‐γ‐Butyrolactone Derivatives

The optically active β‐hydroxyl‐γ‐butyrolactones were synthesized from nonchiral starting material by employing reductive cleavage reaction, sharpless asymmetric epoxidation and dihydroxylation, and Lewis acid‐catalysed cyclization as key steps. This strategy can be used to prepare many chiral β‐hydroxyl‐γ‐butyrolactone analogues.     

Preparation of “Si‐Centered” Chiral Silanes by Direct α‐Lithiation of Methylsilanes

The direct α‐lithiation of methyl‐substituted silanes as an efficient method for the preparation and elaboration of Si‐chiral compounds is reported. Deprotonation of chiral oligosilanes occurs selectively and with high yields at the methyl group of the stereogenic silicon center, even in the presence of multiple methylsilyl or methylgermyl substituents. Computational studies have confirmed this preference as a consequence of pre‐coordination of the lithiating agent by the amino side‐arm and repulsion effects in the corresponding transition state. This complexation is also obvious from X‐ray structure analyses of the α‐lithiated silanes, which exhibit intriguing structure formation patterns differing in the type of aggregation and the amount of alkyllithium used. An alternative route to Si‐chiral compounds is also presented, which involves desymmetrization of dimethylsilanes mediated by a chiral side‐arm. Structure analyses and computational studies have shown that the diastereoselectivity of this α‐lithiation is influenced by the selectivity of the formation of the stereogenic nitrogen upon complexation of the alkyllithium.     

Nickel/Photoredox‐Catalyzed Asymmetric Reductive Cross‐Coupling of Racemic α‐Chloro Esters with Aryl Iodides

A unique nickel/organic photoredox co‐catalyzed asymmetric reductive cross‐coupling between α‐chloro esters and aryl iodides is developed. This cross‐electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross‐coupling reactions use stoichiometric metals. A diverse array of valuable α‐aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α‐Aryl esters represent an important family of nonsteroidal anti‐inflammatory drugs. This novel synergistic strategy expands the scope of Ni‐catalyzed reductive asymmetric cross‐coupling reactions.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

Diastereocontrolled Monoprotodeboronation of β‐Sulfinimido gem‐Bis(boronates): A General and Stereoselective Route to α,β‐Disubstituted β‐Aminoalkylboronates

β‐Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β‐amino acids but few stereoselective methods exist for their preparation. The 1,2‐addition of lithiated 1,1‐diborylalkanes onto chiral N‐tert‐butanesulfinyl aldimines produces β‐sulfinimido gem‐bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents. Under these conditions, the geminal quaternary alkyl bis(pinacolatoboryl) intermediates undergo a highly diastereoselective monoprotodeboronation to afford a wide range of syn‐α,β‐disubstituted β‐aminoalkylboronates. This novel application of protodeboronation chemistry was shown to result from a kinetically controlled, diastereotopic‐group‐selective B?C bond protolysis dictated by the configuration of the adjacent stereogenic C?N center. Facile acidic cleavage of the sulfinimide auxiliary produces the free aminoboronates with high enantiomeric purity.     

Diastereoselective synthesis of substituted 2,3,4,5‐tetrahydro‐1H‐1‐benzazepine‐5‐carboxylic esters by a tandem reduction‐reductive animation reaction

An efficient, diastereoselective synthesis of substituted and unsubstituted 2,3,4,5‐tetrahydro‐1H‐1‐benzazepine‐5‐carboxylic esters has been developed based on the tandem reduction‐reductive amination reac tion. Catalytic hydrogenation of a series of 2‐(2‐nitrophenyl)‐5‐oxoalkanoic esters initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the N‐hydroxylamino (or amino) nitrogen with the side chain carbonyl, and (3) reduction of the seven‐membered cyclic imine. Cyclizations that produce 2‐alkyl‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepine‐5‐carboxylic esters are diastereose lective for the product having the C2 alkyl and the C5 ester groups cis. In these reactions, the transannular ester group exerts a strong stereodirecting effect on the reduction of the cyclic imine intermediate, though not as strong as that observed in previous closures of 2‐alkyl‐1,2,3,4‐tetrahydroquinoline‐4‐carboxylic esters. This decrease in diastereoselectivity is attributed to (1) the greater distance between the ester and the imine double bond and (2) the increased conformational mobility of the larger ring, both of which diminish the stereodirecting effect of the ester. Finally, formation of the seven‐membered ring is sufficiently slow that reaction with the side chain ester group competes with heterocycle formation in several of the reactions.     

Nickel‐Catalyzed Umpolung Arylation of Ambiphilic α‐Bromoalkyl Boronic Esters

A nickel‐catalyzed reductive arylation of ambiphilic α‐bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross‐coupling strategy that complements existing methods for the preparation of densely functionalized alkyl‐substituted organometallic reagents from simple and readily accessible precursors.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α‐methylbenzyl amine for cis‐aziridines from α‐diazo esters and for trans‐aziridines from α‐diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis‐aziridines involved the (R)‐amine with the (S)‐ligand, but curiously, for trans‐aziridines the matched case involved the (R)‐amine with the (R)‐ligand for imines derived from benzaldehyde and n‐butanal, and the (R)‐amine with the (S)‐ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.     

Construction of Chiral 2,3‐Allenols through a Copper(I)‐Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Chiral 2,3‐allenols were constructed through copper(I)‐catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)‐DTBM‐SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but‐2‐yn‐1‐ol as the substrates and (R,R)‐Ph‐BPE as the ligand were found to be crucial to get good to high regio‐ and diastereoselectivity. The produced chiral 2,3‐allenols are easily transformed into synthetically useful 2‐furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.     

Expanding the Scope of Enantioselective FerroPHANE‐Promoted [3+2] Annulations with α,β‐Unsaturated Ketones

The planar chiral 2‐phospha[3]ferrocenophane I has been shown to be the first efficient nucleophilic organocatalyst for the enantioselective synthesis of cyclopentenylphosphonates, through [3+2] cyclizations between diethyl allenylphosphonate and α,β‐unsaturated ketones. The same catalyst has also been applied to the highly enantioselective [3+2] cyclizations of allenic esters with dibenzylideneacetone and analogous bis‐enones, leading to functionalised cyclopentenes with either monocyclic or spirocyclic structures (ee 84–95 %). It has been shown that the residual enone functions in the resulting cyclopentenes can be involved in subsequent cyclization steps to afford unprecedented C₂‐symmetric bis‐cyclopentenylketones. In order to provide insight into the behaviour of FerroPHANE I as a chiral catalyst in [3+2] cyclisations, the energetically most favoured isomers of the key phosphine‐allene adduct have been calculated by DFT methods. Factors likely to control the chiral induction process are highlighted.     

Enantioseparation of Amino Acids on a Chiral Stationary Phase Derived from L‐α‐Norleucinyl‐ and Pyrrolidinyl‐disubstituted Cyanuric Chloride by High‐Performance Liquid Chromatography

A silica‐based chiral stationary phase (CSP) derived from L‐α‐norleucinyl‐ and pyrrolidinyl‐disubstituted cyanuric chloride was prepared for the enantioseparation of methyl esters of N‐(3,5‐dinitrobenzoyl) amino acids by high‐performance liquid chromatography. The chromatographic results show that effective enantioseparation of methyl esters of N‐(3,5‐dinitrobenzoyl)amino acids, except for proline, was achieved on this chiral stationary phase. The chromatographic resolution of racemic n‐propyl ester of N‐(3,5‐dinitrobenzoyl)valine on CSP‐B is better than that of racemic methyl ester of N‐(3,5‐dinitrobenzoyl)valine on CSP‐B or CSP‐A reported previously (J. Chromatogr. A, 676 (1994) 303). The comparison of the chromatographic results obtained in this study with those on CSP‐A reported previously reveals that steric effect, instead of hydrophobic interaction, between the n‐butyl group attached to the chiral center of the chiral selector and the alkyl group attached to the chiral center of the chiral selectand plays a significant role in chiral discrimination. The increase in the selectivity factor of methyl esters of N‐(3,5‐dinitrobenzoyl)amino acids with bulky alkyl groups was examined on CSP‐B.     

Synthesis of Diastereoenriched α‐Aminomethyl Enaminones via a Brønsted Acid‐Catalyzed Asymmetric aza‐Baylis‐Hillman Reaction of Chiral N‐Phosphonyl Imines

An effective chiral GAP methodology for preparing α‐aminomethyl enaminones through a (R)‐CSA‐catalyzed asymmetric aza‐Baylis‐Hillman reaction is reported. Excellent yields and high diastereoselectivity could be obtained under mild conditions and convenient GAP techniques. The confirmations of the absolute configuration of N‐phosphonyl imine and chiral enaminone by X‐ray diffraction provides an explicit explanation of the chirality mechanism for GAP chemistry.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Stereoselective Palladium‐Catalyzed Functionalization of Homoallylic Alcohols: A Convenient Synthesis of Di‐ and Trisubstituted Isoxazolidines and β‐Amino‐δ‐Hydroxy Esters

Enantiopure, Boc‐protected alkoxyamines 12 and 13 , derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd‐catalyzed ring‐closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N‐Boc‐protected esters of β‐amino‐δ‐hydroxy acids and their γ‐substituted homologues 37 . The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C?C bond ( 19 → 21 ), as revealed by the reaction of 15 , which afforded isoxazolidine 18 with high diastereoselectivity.     

Rhodium‐Catalyzed Asymmetric Arylation of β,γ‐Unsaturated α‐Ketoamides for the Construction of Nonracemic γ,γ‐Diarylcarbonyl Compounds

A highly regio‐ and enantioselective rhodium‐catalyzed 1,4‐addition of arylboronic acids to β,γ‐unsaturated α‐ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ‐diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline‐2‐carboxylamide.