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.     

Isosteviol‐amino Acid Conjugates as Highly Efficient Organocatalysts for the Asymmetric One‐pot Three‐component Mannich Reactions

Isosteviol‐amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric three‐component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent stereoselectivities (up to 97:3 dr and 99% ee) were achieved in a short reaction time. In addition, syn‐ or anti‐configurations of α‐hydroxy‐β‐amino carbonyl compounds were obtained as main products with different chiral catalysts.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

Copper‐Complex‐Catalyzed Asymmetric Aerobic Oxidative Cross‐Coupling of 2‐Naphthols: Enantioselective Synthesis of 3,3′‐Substituted C1‐Symmetric BINOLs

A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C₁‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C₁‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.     

Asymmetric Radical–Radical Cross‐Coupling through Visible‐Light‐Activated Iridium Catalysis

Combining single electron transfer between a donor substrate and a catalyst‐activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible‐light‐driven catalytic enantio‐ and diastereoselective synthesis of 1,2‐amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C? C bond formation mediated by single electron transfer.     

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni^II/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.     

Majority‐Rules‐Type Helical Poly(quinoxaline‐2,3‐diyl)s as Highly Efficient Chirality‐Amplification Systems for Asymmetric Catalysis

A highly efficient majority‐rules effect of poly(quinoxaline‐2,3‐diyl)s (PQXs) bearing 2‐butoxymethyl chiral side chains at the 6‐ and 7‐positions was established and attributed to large ΔG_h values (0.22–0.41 kJ mol^?1), which are defined as the energy difference between P‐ and M‐helical conformations per chiral unit. A PQX copolymer prepared from a monomer derived from (R)‐2‐octanol (23 % ee) and a monomer bearing a PPh₂ group adopted a single‐handed helical structure (>99 %) and could be used as a highly enantioselective chiral ligand in palladium‐catalyzed asymmetric reactions (products formed with up to 94 % ee), in which the enantioselectivity could be switched by solvent‐dependent inversion of the helical PQX backbone.     

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Chiral 2‐amino‐butanols ( 4 and 5 ) were obtained via the isolation of diastereomeric salt. Then, chiral compounds ( 6 – 9) were synthesized by a sequential procedure involving condensation of chiral 2‐amino‐butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, and element analysis. The absolute configurations of ( S )‐ 8 was determined by X‐ray crystallography.     

Diastereoselective addition of trimethylsilyl cyanide to chiral O‐, S‐ and N‐heterocyclic aldimines

Systematic investigation of asymmetric trimethylsilylcyanation of heterocyclic azomethines has been realized. The addition of trimethylsilyl cyanide to optically active furan, thiophene and pyridine aldimines, derived from (R)‐ and (S)‐1‐phenylethylamine, was studied in the presence of Lewis acids, and a series of the corresponding α‐amino nitriles was obtained in fair to good yields (up to 91%). Unsaturated nitriles were also formed from pyridine imines. The sense of asymmetric induction and the degree of diastereoselectivity in the synthesis of α‐amino nitriles were determined by means of ¹H NMR. The stereochemical outcome is a result of the same sense of asymmetric induction: Re face attack to the (S)‐imines and Si face addition to the (R)‐imines took place. The (R,R)‐ (up to 81%) or (S,S)‐ (up to 87%) α‐amino nitriles predominated in the products obtained from the all furan, thiophene and pyridine (R)‐ or (S)‐imines respectively. Copyright © 2002 John Wiley & Sons, Ltd.     

Practical Stereo‐ and Regioselective,Copper(I)‐Promoted Strecker Synthesis of Sugar‐Modified α,β‐Unsaturated Imines

The regio‐ and stereoselective, Lewis acid catalyzed Strecker reaction between Me₃SiCN and different aldimines incorporating a 2,3,4,6‐tetrakis‐O‐pivaloyl‐D ‐glucopyranosyl (Piv₄Glc) chiral auxiliary has been worked out. Depending on the conditions used, high yields (up to 95%) and good diastereoselectivities (de > 86%) were achieved under mild conditions (Table 1), especially with CuBr ? Me₂S as catalyst. Our protocol allows the ready preparation of asymmetric β,γ‐unsaturated α‐amino acids such as (R)‐2‐amino‐4‐phenylbut‐3‐enoic acid ( 13 ; Scheme 2) and congeners thereof.     

Intermolecular Asymmetric Carboesterification of Alkenes by Using Chiral Amine Auxiliaries under O2: Synthesis of Enantioenriched α‐Methylene‐γ‐Lactones through Chloropalladation of Alkynes

Herein, the first example of chloropalladation‐initiated asymmetric intermolecular carboesterification of alkenes with alkynes by using chiral amine auxiliaries is reported. The use of (1S,2S)‐N¹,N¹‐dimethylcyclohexane‐1,2‐diamine auxiliaries is essential for providing α‐methylene‐γ‐lactones products in moderate to high yields and excellent enantioselectivities at room temperature. Moreover, the chiral amine auxiliaries can be readily removed by hydrolysis during the reaction process to keep the absolute configuration. This oxygen‐ and water‐promoted asymmetric reaction opens a new window to study asymmetric processes in halopalladation reactions.     

Synthesis of Novel,Chiral Bicyclo[3.1.0]hex‐2‐ene Amino Acid Derivatives as Useful Synthons in Medicinal Chemistry

A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex‐2‐ene amino acid derivatives 13 and 14 has been developed. The key step is a stereo‐ and regioselective allylic amination of exo‐ and endo‐methyl bicyclo[3.1.0]hex‐2‐ene‐6‐carboxylates 8 and 9 , which were prepared from 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one ( 1 ). These amino acid derivatives are useful building blocks in medicinal chemistry and can be prepared as chiral compounds by using either (+)‐ 1 or (?)‐ 1 as starting material.     

Rhodium‐catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐amino Ketones

Rhodium/DuanPhos‐catalyzed asymmetric hydrogenation of aliphatic α‐dehydroamino ketones has been achieved and afforded chiral α‐amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β‐amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α‐amino ketones and chiral β‐amino alcohols.     

Two modes of asymmetric polymerization of phenylacetylenes having an L‐amino alcohol residue and two hydroxy groups

Four novel chiral phenylacetylenes having an L ‐amino alcohol residue and two hydroxymethyl groups were synthesized and polymerized by an achiral catalyst ((nbd)Rh⁺[η⁶‐(C₆H₅)B^?(C₆H₅)₃]) or a chiral catalytic system ([Rh(nbd)Cl]₂/(S)‐ or (R)‐phenylethylamine ((S)‐ or (R)‐PEA)). The two resulting polymers having an L ‐valinol or L ‐phenylalaninol residue showed Cotton effects at wavelengths around 430 nm. This observation indicated that they had an excess of one‐handed helical backbones. Positive and negative Cotton effects were observed only for the polymers having an L ‐valinol residue produced by using (R)‐ and (S)‐PEA as a cocatalyst, respectively, although the monomer had the same chirality. Even when the achiral catalyst was used, the two resulting polymers having an L ‐valinol or L ‐phenylalaninol residue showed Cotton effects despite the long distance between the chiral groups and the main chain. We have found the first example of a new type of chiral monomer, that is, a chiral phenylacetylene monomer having an L ‐amino alcohol residue and two hydroxy groups that was suitable for both modes of asymmetric polymerization, that is, the helix‐sense‐selective polymerization ( HSSP ) with the chiral catalytic system and the asymmetric‐induced polymerization ( AIP ) with the achiral catalyst. The other two monomers having L ‐alaninol and L ‐tyrosinol were found to be unsuitable to neither HSSP nor AIP because of their polymers' low solubility. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Efficient P‐Chiral Biaryl Bisphosphorus Ligands for Palladium‐Catalyzed Asymmetric Hydrogenation

A series of structurally novel P‐chiral biaryl bisphosphorus ligands L1‐L5 (BABIBOPs) are developed, providing high efficiency for the first time in palladium‐catalyzed asymmetric hydrogenation of β‐aryl and β‐alkyl substituted β‐keto esters. With the Pd‐ L3 (iPr‐BABIBOP) catalyst, a series of chiral β‐hydroxyl carboxylic esters are formed in excellent enantioselectivities (up to>99% ee) and yields at catalyst loading as low as 0.01 mol%.     

Helicity induction on a poly(phenylacetylene) derivative bearing aza‐18‐crown‐6 ether pendants in water

A stereoregular poly(phenylacetylene) bearing the bulky aza‐18‐crown‐6 ether as the pendant (poly‐ 1 ) formed a predominantly one‐handed helical conformation upon complexation with various chiral compounds, such as amino acids, peptides, aminosugars, amines, and amino alcohols in water. The complexes exhibited an induced circular dichroism (ICD) in the UV–visible region of the polymer main chain. Therefore, poly‐ 1 can be used as a novel probe for determining the chirality of chiral compounds in water. The assay of 19 common free L ‐amino acids gave the same ICD sign at 0 °C except for L ‐phenylalanine. The effects of pH, temperature, guest concentration, and organic solvent content on the ICD during the complexation of poly‐ 1 with chiral compounds were also investigated. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1004–1013, 2003     

Consecutive Intermolecular Reductive Amination/Asymmetric Hydrogenation: Facile Access to Sterically Tunable Chiral Vicinal Diamines and N‐Heterocyclic Carbenes

A highly enantioselective iridium‐ or ruthenium‐catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2‐quinoline aldehydes and aromatic amines has been developed. A broad range of sterically tunable chiral N,N′‐diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N‐heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition‐metal‐catalyzed asymmetric Suzuki–Miyaura cross‐coupling reaction and asymmetric ring‐opening cross‐metathesis, respectively.     

Asymmetric Michael Addition/Intramolecular Cyclization Catalyzed by Bifunctional Tertiary Amine–Squaramides: Construction of Chiral 2‐Amino‐4H‐chromene‐3‐Carbonitrile Derivatives

The efficient asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by a chiral bifunctional tertiary amine–squaramide catalyst for the synthesis of chiral 2‐amino‐4H‐chromene‐3‐carbonitrile derivatives was developed. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) for most of the bisarylidenecyclopentanones.     

Asymmetric Total Synthesis of (‐)‐Octahydro‐1H‐benzofuro[3,2‐e]isoquinoline,A Partial Structure of Morphine

Octahydro‐1 H‐benzofuro[3,2‐e]isoquinolines, which possess the ACNO partial structure of morphine, displayed potent oral analgesic and narcotic‐antagonism activity. However, due to inefficiency in their synthesis the ACNO derivatives have not been developed for clinical use. Here, we report in detail the first asymmetric total synthesis of (‐)‐octahydro‐1 H‐benzofuro[3,2‐e]isoquinoline as exemplified by the preparation of (‐)‐ 1 and (‐)‐ 2 . The key intermediate (+)‐5‐hydroxy‐3,4,5,6,7,8‐hexahydro‐1 H‐isoquinoline‐2‐carboxylic acid ethyl ester ((+)‐ 5 ) was prepared in 81% yield and with 100% ee by asymmetric reduction of 5‐oxo‐3,4,5,6,7,8‐hexahydro‐1 H‐isoquinoline‐2‐carboxylic acid ethyl ester ( 6 ) using RuCl[(R,R)‐Tsdpen](p‐cymene) as catalyst with a S/C of 200. The three chiral centers of ACNO skeleton were constructed via a reaction sequence of asymmetric transfer hydrogenation, Heck reaction, and catalytical hydrogenation, and all of these stereoselective reactions were metal‐catalyzed (i.e. Ru, Pd, and Pt, respectively).