Sense Of Asymmetric Induction Research Articles

Asymmetric Induction and Enantiodivergence in Catalytic Radical C–H Amination via Enantiodifferentiative H-Atom Abstraction and Stereoretentive Radical Substitution

Control of enantioselectivity remains a major challenge in radical chemistry. The emergence of metalloradical catalysis (MRC) offers a conceptually new strategy for addressing this and other outstanding issues. Through the employment of D2-symmetric chiral amidoporphyrins as the supporting ligands, Co(II)-based MRC has enabled the development of new catalytic systems for asymmetric radical transformations with a unique profile of reactivity and selectivity. With the support of new-generation HuPhyrin chiral ligands whose cavity environment can be fine-tuned, the Co-centered d-radicals enable to address challenging issues that require exquisite control of fundamental radical processes. As showcased with asymmetric 1,5-C-H amination of sulfamoyl azides, the enantiocontrol of which has proven difficult, the judicious use of HuPhyrin ligand by tuning the bridge length and other remote nonchiral elements allows for controlling both the degree and sense of asymmetric induction in a systematic manner. This effort leads to successful development of new Co(II)-based catalytic systems that are highly effective for enantiodivergent radical 1,5-C-H amination, producing both enantiomers of the strained five-membered cyclic sulfamides with excellent enantioselectivities. Detailed deuterium-labeling studies, together with DFT computation, have revealed an unprecedented mode of asymmetric induction that consists of enantiodifferentiative H-atom abstraction and stereoretentive radical substitution.

Enantioselective addition of diethylzinc to aldehydes catalyzed by 5-cis-substituted proline derivatives

5-Cis-substituted prolinols, prolinamines, and prolinamine sulfonamides proved to be efficient ligands for the enantioselective addition of diethylzinc to aldehydes, providing up to 99% ee. The sense of asymmetric induction can be controlled by the nature of the exocyclic functional group (CPh2OH vs. CH2NHR vs. CH2NHSO3R). The additional 5-cis substituent exerts a strong beneficial effect on the chirality transfer since it rigidifies the catalyst structure. The stereochemical outcome of the reactions is discussed in detail on the respective transition states.

Rhodium(I)‐Catalyzed Enantioselective Hydrogenation of Substituted Acrylic Acids with Sterically Similar β,β‐Diaryls

Distinct differentiation: β,β-Disubstituted acrylic acids with sterically similar geminal diaryl groups can be hydrogenated with excellent enantioselectivities in the presence of a RhI complex formed in situ with two-component ligands, a chiral secondary phosphine oxide (SPO) and an achiral phosphine (Ph3P). The sense of asymmetric induction was found to be controlled by the substrate configuration, thus allowing access to both enantiomers of the product with the same catalyst.

Asymmetric Diels–Alder and Ficini Reactions with Alkylidene β-Ketoesters Catalyzed by Chiral Ruthenium PNNP Complexes: Mechanistic Insight

Hydride abstraction from the β-position of the enolato ligand of the previously reported complex [Ru(3a-H)(PNNP)]PF(6) (5a; 3a-H is the enolate of 2-tert-butoxycarbonylcyclopentanone) with (Ph(3)C)PF(6) gives the dicationic complex [Ru(6a)(PNNP)](2+) (7a) as a single diastereoisomer, which contains the unsaturated β-ketoester 2-tert-butoxycarbonyl-2-cyclopenten-1-one (6a) as a chelating ligand. The methyl analogue 2-methoxycarbonylcyclopentanone (3b) gives [Ru(3b-H)(PNNP)]PF(6) as a mixture of noninterconverting diastereoisomers (ester group of 3b trans to P, 5b; or to N, 5c), which were separated by column chromatography. Hydride abstraction from 5b (or 5c) yields diastereomerically pure [Ru(6b)(PNNP)](2+) (7b or 7c). Complexes 7b and 7c do not interconvert at room temperature in CD(2)Cl(2) and form opposite enantiomers of the Diels-Alder adduct upon reaction with Dane's diene (1 equiv). X-ray studies of 7a, 5b, and 5c give insight into the origin of enantioselection and the sense of asymmetric induction in the previously reported asymmetric Diels-Alder and Ficini cycloaddition reactions with 2,3-disubstituted butadienes and ynamides, respectively. Stoichiometric reactions (substrate coordination, cycloaddition, and product displacement) between [Ru(OEt(2))(2)(PNNP)](2+) (2), 6b (or 6a), and Dane's diene (15, to give estrone derivatives) or N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (17, to give cyclobutenamides) suggest that product displacement from the catalyst is turnover limiting.

Straightforward synthesis of [(2 S,4 R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol and [(2 S,4 R)-1-cyclohexyl-4-methylpiperidin-2-yl](diphenyl)methanol: novel chiral ligands for the catalytic addition of diethylzinc to benzaldehyde to give rise to an extensive turn in the sense of asymmetric induction

Enantiopure [(2 S,4 R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol 5a and [(2 S,4 R)-1-cyclohexyl-4-methylpiperidin-2-yl]-(diphenyl)methanol 5b, new β-amino alcohols based on l-pipecolinic acid (homoproline), have been prepared straightforwardly from rac-alaninol and rac-2-amino-1,1-diphenylpropan-1-ol, respectively. The described route constitutes as a model procedure for the preparation of other related C(4) or/and C(3)-substituted 2-piperidinylmethanols. The new chiral ligands have shown a singular behaviour on the stereocontrol of the benchmark reaction of benzaldehyde and diethylzinc compared with other C(4)-unsubstituted analogues prepared by ourselves from l-pipecolinic acid (compounds 5c, 5d, 5e and 5f). The catalytic activity, the sense of asymmetric induction and the degree of the enantioselectivity depend on the appropriate combination of the substituents on the structural scaffold, but also on the metal-alkoxide involved in the catalysis (zinc or lithium alkoxides). The enantioselective addition of diethylzinc to benzaldehyde mediated by ligands 5a and 5c has been studied with DFT methods. The theoretical evaluation was performed in connection with a working hypothesis based on the different loadings of cis- and trans-catalysts in the reaction medium.

ChemInform Abstract: Carbohydrates as Chiral Templates: Diastereoselective Synthesis of N- Glycosyl-N-homoallylamines and β-Amino Acids from Imines.

Complexing properties and chirality of carbohydrates were utilized in diastereoselective reactions of 0-pivaloylated N-galactosylimines with allylsilanes and -stannaries. With dyltrimethylsilane in the presence of SnCl4, imines 2 of aromatic and heteroaromatic aldehydes were converted to homdylamines 3, giving ratios of diastereomers higher than 7:1. No addition products derived from α-anomeric aromatic imines were formed. Aliphatic homdylamines 3 were synthesized by using allyltributylstannane in the presence of SnCl4. Both α- and β-anomeric aliphatic imines reacted with the allylstannane. They gave the same ratio of diastereomers and showed the same sense of asymmetric induction.

ChemInform Abstract: General Asymmetric Synthesis of Isoquinoline Alkaloids. Enantioselective Hydrogenation of Enamides Catalyzed by BINAP- Ruthenium(II) Complexes.

In the presence of a small amount of RuX 2 [(R)- or (S)-BINAP] (X=anionic ligand) a wide range of (Z)-2-acyl-1-benzylidene-1,2,3,4-tetrahydro- isoquinolines are hydrogenated to give the saturated products in nearly quantitative yields and in high (up to 100%) optical yields. The enamide substrates are selectively prepared by N-acylation of the corresponding 1-benzylated 3,4-dihydroisoquinolines under suitable acylation condi- tions; some crystalline materials having low solubility are obtained by a second-order Z/E stereomutation technique utilizing the double-bond photolability and lattice energy effects. This asymmetric hydrogenation sets the key stereogenic center in predictable manner, either R or S flexibly, at the C(1) position of the benzylated tetrahydroisoquinoli- nes. The chiral products are converted by standard functional group modification to tetrahydropapaverine, laudanosine, etc. This enantio- selective hydrogenation is applied to the synthesis of morphine and its artificial analogues such as morphinans and benzomorphans of either chirality. A mnemonic device is presented for predicting the reactivity and enantiofacial selection of the BINAP-Ru catalyzed hydrogenation. Reaction with BINAP-Rh catalyst proceeds with a lower enantioselectivity and an opposite sense of asymmetric induction

ChemInform Abstract: Chiral Bis(oxazoline) Copper(II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions

A bis(oxazoline) (box) copper(II) complex and its hydrated counterpart (1 and 2) function as enantioselective Lewis acid catalysts for carbocyclic and hetero Diels−Alder, aldol, Michael, ene, and amination reactions with substrates capable of chelation through six- and five-membered rings. X-ray crystallography of the chiral complexes reveals a propensity for the formation of distorted square planar or square pyramidal geometries. The sense of asymmetric induction is identical for all the processes catalyzed by [Cu((S,S)-t-Bu-box)](X)2 complexes 1 and 2 (X = OTf and SbF) resulting from the intervention of a distorted square planar catalyst-substrate binary complex. These catalyzed processes exhibit excellent temperature−selectivity profiles. Reactions catalyzed by [Cu(S,S-Ph-pybox)](SbF6)2 and their derived chelation complexes are also discussed.

Enantioselective Trifunctional Organocatalysts for Rate‐ Enhanced Aza‐Morita–Baylis–Hillman Reactions at Room Temperature

Abstractmagnified imageA Brønsted acid‐activated trifunctional organocatalyst, based on the BINAP scaffold, was used for the first time to catalyze aza‐Morita‐Baylis–Hillman reactions between N‐tosylimines and methyl vinyl ketone with fast reaction rates and good enantioselectivity at room temperature. This trifunctional catalyst, containing a Lewis base, a Brønsted base, and a Brønsted acid, required acid activation to confer its enantioselectivity and rate improvement for both electron‐rich and electron‐deficient imine substrates. The role of the amino Lewis base of 1a was investigated and found to be the activity switch in response to an acid additive. The counterion of the acid additive was found to influence not only the excess ratio but also the sense of asymmetric induction.

Modular Chiral Bidentate Phosphonites: Design, Synthesis, and Application in Catalytic Asymmetric Hydroformylation Reactions

A new class of C2-symmetric chiral bidentate phosphonite ligands has been synthesized in moderate to good yields from readily available starting materials. Application of these air-stable chiral phosphonites in the Rh I-catalyzed asymmetric hydroformylation of styrene derivatives, vinyl acetate, and allyl cyanide afforded the corresponding chiral aldehydes with high regio- and enantioselectivities under mild reaction conditions. The modular nature of the ligands allows fine-tuning of the selectivities through judicious modifications of the substituents on the ligand backbone. X-ray structural analysis of the catalyst precursor suggested that the steric hindrance caused by the protruding remote substituents of the ligands into the vicinity of the metal center might be an important factor for the enantio-control of the reaction, whereas the sense of asymmetric induction can be rationalized on the basis of a trigonal-bipyramidal transition state diagram.

Titanium(IV)(salen) and Vanadium(V)(salen) Complexes Derived fromC2- andC1-Symmetric Diamines for Asymmetric Cyanohydrin Synthesis

Titanium and vanadium salen complexes have been prepared from C 2 - and Ci-symmetric acyclic diamines. All of the complexes catalysed the asymmetric addition of trimethylsilyl cyanide to benzaldehyde and the sense of asymmetric induction was determined by the nature of the substituents. The vanadium complex of a valine-derived diamine gave good results with a range of aromatic and aliphatic aldehydes.

Asymmetric Platinum Group Metal-Catalyzed Carbonyl-Ene Reactions: Carbon−Carbon Bond Formation versus Isomerization

A comparative study of the carbonyl-ene reaction between a range of 1,1'-disubstituted or trisubstituted alkenes and ethyl trifluoropyruvate catalyzed by Lewis acid-platinum group metal complexes of the type [M{(R)-BINAP}]2+ (M = Pt, Pd, Ni; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) revealed subtle but significant differences in their reactivity. For instance, the palladium-based Lewis acid [Pd{(R)-BINAP}]2+ catalyzes the ene reaction between methylene cycloalkane to afford the expected alpha-hydroxy ester in good yield and excellent diastereo- and enantioselectivity. In contrast, under the same conditions, the corresponding [M{(R)-BINAP}]2+ (M = Pt, Ni) catalyzes isomerization of methylene cycloalkane and the ene reaction of the resulting mixture of methylene cycloalkane and 1-methylcycloalkene at similar rates to afford a range of -hydroxy esters in high regioselectivity, good diastereoselectivity, and good to excellent enantioselectivity. In addition, [Pt{(R)-BINAP}]2+ also catalyzes postreaction isomerization of the ene product as well as consecutive ene reactions to afford a double carbonyl-ene product. The sense of asymmetric induction has been established by single-crystal X-ray crystallography, and a stereochemical model consistent with the formation of (S)-configured -hydroxy ester has been proposed; the same model also accounts for the observed exo-diastereoselectivity as well as the level of diastereoselectivity.

Organocatalytic Transfer Hydrogenation of Cyclic Enones

The first enantioselective organocatalytic transfer hydrogenation of cyclic enones has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated cycloalkenones, to generate beta-stereogenic cyclic ketones. The use of imidazolidinone 4 as the asymmetric catalyst has been found to mediate the hydrogenation of a large class of enone substrates with tert-butyl Hantzsch ester serving as an inexpensive source of hydrogen. The capacity of catalyst 4 to enable enantioselective transfer hydrogenation of cycloalkenones has been extended to five-, six-, and seven-membered ring systems. The sense of asymmetric induction is in complete accord with the stereochemical model first reported in conjunction with the use of catalyst 4 for enantioselective ketone Diels-Alder reactions.

Experimental and Theoretical Studies on the Hydrogen-Bond-Promoted Enantioselective Hetero-Diels−Alder Reaction of Danishefsky's Diene with Benzaldehyde

The enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky's diene with benzaldehyde has been achieved catalytically by a series of alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL) derivatives through hydrogen-bonding activation, affording 2-phenyl-2,3-dihydro-4H-pyran-4-one after trifluoroacetic acid workup in moderate yield and good enantioselectivity. The alpha,alpha'-aryl substituents in the TADDOL molecules are found to exert a significant impact on both the activity and the enantioselectivity of the catalysis. In combination with the experimental investigations, the mechanism of the present reaction has also been studied theoretically using the ONIOM (B3LYP/6-31G:PM3) method with trans-1,3-dimethoxy-1,3-butadiene as the model for Danishefsky's diene. In agreement with the experimental findings, the calculation results indicate that this TADDOL-catalyzed HDA reaction proceeds via a concerted mechanism through an asynchronous and zwitterionic transition structure (TS). The carbonyl group of benzaldehyde is activated by forming an intermolecular hydrogen bond with one of the hydroxy groups of TADDOL. Meanwhile, the intramolecular hydrogen bond between the two hydroxy groups in TADDOL is found to facilitate the intermolecular hydrogen bonding with benzaldehyde. The sense of asymmetric induction is well-rationalized by the analysis of the relative energies of TADDOL-complexed TSs, while the different stereocontrol capabilities exhibited by TADDOLs in the reaction can be qualitatively established on the basis of the structural features of their corresponding TSs.

A highly enantioselective, moderately anti-selective aldol reaction using a novel hydrazone moiety as stereo director

The use of novel hydrazones as stereo directors with a view to develop a highly enantioselective, anti-diastereoselective aldol addition procedure has been investigated. A number of proline-derived hydrazones were produced and their effectiveness in directing simple alkylation of aza-enolates investigated. The most promising of these hydrazones were then used in the aldol reaction. The substituent on the oxygen of the proline had a profound effect on both the magnitude and the sense of asymmetric induction. The optimum hydrazone for the formal aldol reaction between pentanone and propionaldehyde gave a diastereoselectivity of 37% in favour of the anti-isomer while both isomers had an ee of 83–84%.

Remote Asymmetric Induction in an Intramolecular Ionic Diels−Alder Reaction: Application to the Total Synthesis of (+)-Dihydrocompactin

The total synthesis of (+)-dihydrocompactin via an intramolecular ionic Diels-Alder reaction that proceeds with remote stereocontrol is described. This reaction proceeds by an intermediate vinyl-oxocarbenium ion (6), the conformational constraints of which lead to the observed asymmetric induction. The sense of asymmetric induction appears contrasteric and is explained by the proposed reactive conformation shown in Figure 1.

Asymmetric Alkylation of N-Pivaloyl-o-benzylaniline.

Abstract Alkylation of 2-methoxyethoxyphenyl phenylmethane using sec -BuLi and (−)-sparteine has been carried out in excellent yields and up to 76% ee. The use of O’Brien’s (+)-sparteine surrogate gave the opposite sense of asymmetric induction at 80% ee while the use of chiral lithium amide bases gave modest yields and ees.

Enantiocontrol in the [2,3]-Wittig rearrangement

The enantioselective [2,3]-Wittig rearrangement of benzyl prenyl ether has been studied. Treatment of this ether with butyl lithium bearing diamines or bis(oxazoline)s as external chiral ligands (ECL) gave the expected alcohol in up to 66% ee, the highest reported for this transformation. The optimum ECL is based on the bis(oxazoline) system and the C5 substituent on the bis(oxazoline) is crucial to determining both the degree and sense of asymmetric induction.

Stereoselective Alkylation of Chiral 2‐Imidoylphenols with Organolithium Reagents: Synthesis of Enantiopure 2‐Aminoalkylphenols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective alkylation of chiral 2-imidoylphenols with organolithium reagents: synthesis of enantiopure 2-aminoalkylphenols.

In this paper the addition of organolithium reagents to chiral imidoylphenols to prepare enantiopure phenolic Mannich-type bases is described. The experimental data show that this kind of imine is surprisingly reactive toward organolithium reagents, differently from classical imines, and does not need any Lewis acid or base activation. Moreover, interesting results have been obtained with aldimines but more unusually with ketimines. This reaction results in high yields and diastereoselectivities and allows the preparation of aminophenols quaternary at the C-1 carbon atom, which cannot be prepared with the methods available till now. The sense of asymmetric induction has been explained and confirmed in agreement with the results previously obtained by hydride reduction of the same substrates. In some cases this procedure is complementary to the reductive one, allowing the preparation of the diastereomers less abundant in the reduction. The reaction allows the synthesis of one or the other of the two diastereomers, choosing the opportune starting imidoylphenol and the organolithium reagent.