The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights

We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center. Lewis acids capable of adapting square planar geometries, such as Cu(OTf)2, Cu(ClO4)2, and Pd(ClO4)2, were found to be particularly effective at providing high selectivities. Additionally, substitution at the C-5 position of the pyrazolidinone templates has been shown to be critical for optimal selectivity. Reactions of the optimal pyrazolidinone appended with a number of common dienophiles and various dienes demonstrate the utility of this achiral template. Furthermore, catalytic loadings could be lowered to 2.5 mol % with essentially no loss in selectivity. Pi-Pi interactions were evaluated as a means to explain the unusually high selectivity observed at room temperature. Finally, non-C2-symmetric ligands were employed as a test to determine if chiral relay was operative.     

Investigation of Lewis acid-catalyzed asymmetric aza-Diels-Alder reactions of 2H-azirines

Asymmetric Diels-Alder reactions with 2H-azirines as dienophiles have been studied. Diastereoselective reactions with an enantiopure azirine 1b, bearing a chiral auxiliary, gave substituted bi- and tricyclic tetrahydropyridines in high yield and stereoselectivity, under the influence of a Lewis acid. The novel enantioselective [4+2] cycloaddition reaction of 3-benzyl-2H-azirine carboxylate with cyclopentadiene was investigated with various chiral Lewis acid complexes and provided the corresponding tetrahydropyridines in moderate to low yield and enantioselectivity.     

Mimicking enzymatic transaminations: attempts to understand and develop a catalytic asymmetric approach to chiral alpha-amino acids

Attempts are made to build a bridge between asymmetric catalysis and enzymatic reactions by mechanistic investigations and the development of a catalytic and enantioselective approach to amination of alpha-keto esters by primary amines catalyzed by chiral Lewis acids as a model for transamination enzymes. Different Lewis acids can catalyze the half-transamination of alpha-keto esters using primary amine nitrogen sources such as pyridoxamine and 4-picolylamine. The mechanistic studies of the Lewis-acid catalyzed half-transamination using deuterium-labelled compounds show the incorporation of deuterium atoms in several positions of the alpha-amino acid derivative, indicating that the enol of the alpha-keto ester plays an important role along the reaction path. The catalytic enantioselective reactions are dependent on the pKa-value of the solvent since enantioselectivities were only obtained in solvents with high pKa-values relative to methanol. However, stronger acidic conditions generally gave better yields, but poor enantioselectivities. A series of chiral Lewis acids were screened as catalysts for the enantioselective half-transamination reactions and moderate yields and enantioselectivities of up to 46% ee were obtained.     

Highly enantioselective Diels-Alder reactions of Danishefsky type dienes with electron-deficient alkenes catalyzed by Yb(III)-BINAMIDE complexes

1-Methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky's diene) is recognized as a synthetically useful diene due to its high reactivity in the Diels-Alder reaction with electron-deficient alkenes to give oxygen-functionalyzed cyclohexenes and substituted cyclohexenones, which are important building blocks for the total synthesis of natural products. However, the development of catalytic enantioselective versions of Diels-Alder reactions using Danishefsky type dienes with electron-deficient alkenes has been difficult because of the instability of the dienes under Lewis acidic conditions. Only highly reactive CO and CN double bonds are employed in a hetero-Diels-Alder reaction which proceeds under catalysis of chiral Lewis acids. We have developed a new chiral ligand, BINAMIDE, which is easily prepared from 1,1'-binaphtyl-2,2'-diamine by acylation. The highly diastereo- and enantioselective Diels-Alder reaction of Danishefsky type dienes with electron-deficient alkenes in the presence of an Yb(III)-BINAMIDE complex has been developed. The reaction proceeded in an exoselective mode and gave chiral highly functionalized cyclohexene derivatives in good yields.     

Recent Advances in Asymmetric Catalysis Using p-Block Elements

The development of new methods for enantioselective reactions that generate stereogenic centres within molecules are a cornerstone of organic synthesis. Typically, metal catalysts bearing chiral ligands as well as chiral organocatalysts have been employed for the enantioselective synthesis of organic compounds. In this review, we highlight the recent advances in main group catalysis for enantioselective reactions using the p-block elements (boron, aluminium, phosphorus, bismuth) as a complementary and sustainable approach to generate chiral molecules. Several of these catalysts benefit in terms of high abundance, low toxicity, high selectivity, and excellent reactivity. This minireview summarises the utilisation of chiral p-block element catalysts for asymmetric reactions to generate value-added compounds.     

Catalytic enantioselective addition of propionate units to imines: an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives

Optically active anti-alpha-methyl-beta-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C(2)F(5)BINOL). The reactions using geometrically isomeric ketene silyl acetals gave excellent anti-selectivity with high enantiomeric excess in both cases. Synthetic utility of this reaction has been demonstrated by the preparation of various anti-alpha-methyl-beta-amino acid and trans-3,4-disubstituted beta-lactam derivatives.     

Highly enantioselective 1,3-dipolar cycloaddition reactions of 2-benzopyrylium-4-olate catalyzed by chiral Lewis acids

We have found that significant levels of enantioselectivity are obtained in the 1,3-dipolar cycloadditions of 2-benzopyrylium-4-olate using chiral 2,6-bis(oxazolinyl)pyridine (Pybox)-rare earth metal triflate complexes as chiral Lewis acid catalysts. The reactions with benzyloxyacetaldehyde derivatives catalyzed by Sc(III)-Pybox-i-Pr (10 mol %) proceeded to give endo-adducts selectively with high enantioselectivity (up to 93% ee). The reaction with benzyl pyruvate under similar conditions gave an exo-adduct selectively with 87% ee. In the reaction with 3-acryloyl-2-oxazolidinone, Yb(III)-Pybox-Ph was found to be effective in providing an exo-adduct with extremely high enantioselectivity (98% ee).     

Water-tolerant enantioselective carbonyl-ene reactions with palladium(II) and platinum(II) Lewis acid catalysts bearing BINAP

Palladium(II) and platinum(II) Lewis acid catalysts bearing BINAP have been proved to be water-tolerant in enantioselective carbonyl-ene reactions, thus arylglyoxal monohydrate could be used directly as substrate achieving good to excellent enantioselectivities as high as 95.4% e.e.. The enantioselective carbonyl-ene reactions using phenylglyoxal monohydrate as substrate with four alkenes including methylenecyclohexane, 2,3-dimethyl-1-butene, 2,4,4-trimethyl-1-pentene and alpha-methylstyrene, were investigated demonstrating comparable or even higher yields and enantioselectivities in comparison with the corresponding carbonyl-ene reactions using dry phenylglyoxal as substrate for both palladium(II)-BINAP catalyst and platinum(II)-BINAP catalyst. The palladium(II) and platinum(II)-BINAP catalyzed enantioselective carbonyl-ene reactions between 4-methylphenylglyoxal monohydrate and the four alkenes were also investigated affording enantioselectivities between 76.2% and 91.8% e.e.. A mechanism involving the coordination of arylglyoxal and 2,2-dihydroxy-1-phenylethanone with chiral catalyst was proposed to interpret the enantioselective carbonyl-ene reactions using arylglyoxal monohydrate as substrate.     

Catalytic asymmetric allylation of aldehydes and related reactions with bis(((S)-binaphthoxy)(isopropoxy)titanium) oxide as a mu-oxo-type chiral Lewis acid

A new, chiral bis-Ti(IV) oxide of type 3 has been designed and can be utilized for strong activation of aldehyde carbonyls, thereby allowing a new catalytic enantioselective allylation of aldehydes with allyltributyltin. The chiral bis-Ti(IV) catalyst (S,S)-3 can be readily prepared either by treatment of bis(triisopropoxy)titanium oxide with (S)-BINOL or by treatment of ((S)-binaphthoxy)isopropoxytitanium chloride with silver(I) oxide. Treatment of hydrocinnamaldehyde with allyltributyltin under the influence of chiral bis-Ti(IV) oxide (S,S)-3 generated in situ (10 mol %) in CH(2)Cl(2) afforded an allylation product in 84 % yield and with 99 % ee. This asymmetric allylation with non-racemic bis-Ti(IV) oxide 3 and partially resolved (S)-BINOL shows a positive nonlinear effect in correlation of the enantiopurity of the allylation product with the ee of the (S)-BINOL. Chiral bis-Ti(IV) oxide (S,S)-3 can also be utilized for related reactions such as asymmetric methallylation and propargylation of aldehydes with high enantioselectivity. This asymmetric approach provides a very useful way of obtaining high reactivity and selectivity through the simple introduction of the M-O-M unit into the design of chiral Lewis acid catalysts.     

Synthesis and catalytic application of chiral 1,1'-Bi-2-naphthol- and biphenanthrol-based pincer complexes: selective allylation of sulfonimines with allyl stannane and allyl trifluoroborate

New easily accessible 1,1'-bi-2-naphthol- (BINOL-) and biphenanthrol-based chiral pincer complex catalysts were prepared for selective (up to 85% enantiomeric excess) allylation of sulfonimines. The chiral pincer complexes were prepared by a flexible modular approach allowing an efficient tuning of the selectivity of the catalysts. By employment of the different enantiomeric forms of the catalysts, both enantiomers of the homoallylic amines could be selectively obtained. Both allyl stannanes and allyl trifluoroborates can be employed as allyl sources in the reactions. The biphenanthrol-based complexes gave higher selectivity than the substituted BINOL-based analogues, probably because of the well-shaped chiral pocket generated by employment of the biphenanthrol complexes. The enantioselective allylation of sulfonimines presented in this study has important implications for the mechanism given for the pincer complex-catalyzed allylation reactions, confirming that this process takes place without involvement of palladium(0) species.     

Chiral Lewis base-assisted Brønsted acid (LBBA)-catalyzed enantioselective cyclization of 2-geranylphenols

Chiral Lewis base-assisted Br?nsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective cyclization. A salt of a chiral phosphonous acid diester with FSO(3)H catalyzes the enantioselective cyclization of 2-geranylphenols to give the desired trans-fused cyclized products with high diastereo- and enantioselectivities (up to 98:2 dr and 93% ee).     

Enantioselective Diels-Alder reactions with N-hydroxy-N-phenylacrylamide

[reaction: see text] The use of hydroxamic acids as templates for Lewis acid catalyzed enantioselective Diels-Alder reactions has been examined. A very simple chiral Lewis acid, prepared by mixing optically pure binaphthol with 3 equiv of trimethylaluminum, catalyzes the [4 + 2] cycloaddition of N-hydroxy-N-phenylacrylamide with cyclopentadiene at 0 degrees C in high yield (>96%) and with a fairly good level of enantioselectivity (91% ee). Facile conversion of the products to the corresponding alcohols or aldehydes makes the hydroxamic acid intermediates particularly useful.     

Asymmetric hetero-Diels-Alder reactions of N-sulfinyl dienophiles using chiral bis(oxazoline)-copper(II) and -zinc(II) triflates

Asymmetric hetero-Diels-Alder (HDA) reactions of N-sulfinyl dienophiles using bis(oxazoline)-copper(II) and -zinc(II) triflates are described. The cycloadditions with cyclic and acyclic 1,3-dienes have been studied. In most cases, good enantioselectivities (70-98% ee) and yields (60-85%) were obtained with stoichiometric amounts of the Lewis acids. Cyclic dienes gave the endo adducts as major products, while acyclic dienes provided cis adducts. The HDA adducts have been transformed into N-protected alpha-amino acid methyl esters, amino alcohols, and homoallylic amines. A stereochemical model, which accounts for the enantiofacial selectivity of the HDA reaction by a tetrahedral metal center, has been proposed. Mechanistic studies revealed positive nonlinear effects, assumed to arise from the formation of less-reactive heterochiral complexes. Investigation of the temperature dependence of the enantioselectivity indicated that at least two selective reaction steps exist in the zinc-catalyzed reaction. Reactions run with 10 mol % chiral Lewis acid gave poor yields and selectivities. However, in combination with TMSOTf (100 mol %), high yields (68-86%) and enantioselectivities (97-98% ee) were obtained.     

Asymmetric Diels-Alder reactions catalyzed by a triflic acid activated chiral oxazaborolidine

This paper reports a new method for the generation of chiral Lewis superacids by protonation of a non-Lewis acidic oxazaborolidine (1) with triflic acid. The resulting cationic species (3) are powerful and highly enantioselective catalysts for the Diels-Alder reaction of various 1,3-dienes with alpha,beta-enals. An optimization study (see Table 1) led to the selection of reaction conditions and catalysts (6A and 6B) which are very effective. The reactions are simple to conduct, reproducible, and economical, since only ca. 6 mol % of catalyst is required. In addition, the chiral catalyst precursor is readily recovered for reuse (>95% efficiency) and is commercially available. The broad scope of the process is documented by the 14 examples listed in Table 2. The absolute stereochemical course of the Diels-Alder reactions catalyzed by 6A and 6B was successfully predicted on the basis of the mechanistic principles which have recently been formulated for this type of catalytic enantioselective reaction involving re-face attack by the diene on complex 7. The mode of generation of Lewis superacids 6A and 6B allows an approximate comparison (or scale) connecting the catalytic power Lewis and protic acids.     

Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.     

Chiral Lewis acid-catalyzed enantioselective intramolecular carbonyl ene reactions of unsaturated alpha-keto esters

[reaction: see text] Chiral Lewis acid-promoted highly enantioselective intramolecular carbonyl ene reactions of unsaturated alpha-keto esters have been investigated. In the presence of chiral Lewis acids such as [Sc((R,R)-Ph-pybox)](OTf)(3) and [Cu((S,S)-Ph-box)](OTf)(2), several unsaturated alpha-keto esters underwent carbonyl ene reactions in CH(2)Cl(2) at room temperature to give monocyclic products in good yield and excellent enantioselectivity.     

Lipase-catalyzed kinetic resolution of β-borylated carboxylic esters

The kinetic resolution of chiral β-borylated carboxylic esters via lipase-catalyzed hydrolysis and transesterification reactions was studied. The enantioselective hydrolysis catalyzed by CAL-B furnished the β-borylated carboxylic acid with reasonable enantiomeric excess (62% ee), while both methyl and ethyl β-borylated carboxylic esters were recovered with excellent ee (>99%). Meanwhile, the transesterification reaction of β-borylated carboxylic esters and several alcohols, catalyzed by CAL-B, only indicated a high selectivity when ethanol and methyl-(β-pinacolylboronate)-butanoate were used as substrates, which gave ethyl-(β-pinacolylboronate)-butanoate with >99% ee.     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).     

铱(I)联萘胺Schiff碱(BPMBNDI)配合物催化苯乙酮的不对称氢转移反应

用旋光活性2, 2'-(1, 1'-联萘)二胺和2-吡啶基甲醛缩合得到的Schiff碱BPMBNDI[N, N'-二(2-吡啶基亚甲基)-(1, 1'-联萘)-2, 2'-二亚胺]为配体与[Ir(COD)Cl]2(COD=1, 5-环辛二烯)反应, 生成了10个光学活性铱配合物。研究它们在异丙醇对苯乙酮不对称氢转移反应中的光学诱导活性时, 发现10个催化剂均具有较高的立体选择性,其中[Ir(COD)(BPMBNDI)I]催化的光学产率高达84%。     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.