Synthesis of Dendritic Schiff Base Ligands for Titanium Catalyzed Enantioselective HDA Reaction of Danishelfsky‘ s Diene with Aldehydes

A new type of dendritic NOBIN derived Schiff base ligands has been synthesized and applied to titanium catalyzed hetero-Diels-Alder reaction of Danigheifsky‘ s diene and aldehydes, affording the corresponding 2-substituted 2,3-dihydro-4H-pyran-4-one in good yields and moderate enantioselectivities (up to 59.2% ee). It was found that the size of dendron attached to the tridentated ligands has slight impact on the enantioselectivtty of the reaction and the second generation of dendritic ligand exhibited the best enantioselectivity.     

The first example of a catalytic asymmetric aldol-Tishchenko reaction of aldehydes and aliphatic ketones

A number of combinations of Lewis acids and chiral ligands has been screened for the enantioselective direct tandem aldol condensation--Evans-Tishchenko reduction of aldehydes and ketones. Chiral ytterbium complexes were found to catalyze the condensation of aromatic aldehydes with 3-pentanone (and other ketones) giving rise to the anti-1,3-diol monoesters in good yield, and with high diastereocontrol and moderate levels of enantioselectivity. Three adjacent stereogenic centers are created in one reaction sequence in acyclic systems.     

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.     

Highly Efficient Enantioselective Synthesis of Optically Active Dihydropyrones by Chiral Titanium(IV) (5,5',6,6',7,7',8,8'-Octahydro-1,1'-Bi-2-Naphthol) Complexes

The formal hetero-Diels-Alder reaction between 1-methoxy-3-(trimethyl-silyl)oxy-1,3-butadiene and aldehydes provides useful access to dihydropyrones, a class of compounds with extensive utility in organic synthesis. Asymmetric catalysis of this reaction has been previously reported by a number of investigators. Herein we wish to describe that chiral 5,5',6,6',7,7',8,8'-octahydro-1, 1'-bi-2-naphthol (H₈-BINOL)/Ti(O-i-Pr)₄ complexes are more effective catalysts than BINOL/Ti(O-i-Pr)₄ and others for the asymmetric hetero-Diels-Alder reactions.     

Highly enantioselective synthesis of 2,6-disubstituted and 2,2,6-trisubstituted dihydropyrones: a one-step synthesis of (R)-(+)-hepialone and its analogues

An efficient enantioselective approach to chiral dihydropyrones has been developed by the hetero-Diels-Alder (HDA) reactions of (E)-4-methoxy-2-trimethylsiloxy-penta-1,3-diene (diene 1) with aldehydes and pyruvates. It has been found that the readily accessible (R)-BINOL-Ti(OiPr)(4) (1.1:1) complex was a very effective catalyst for this reaction. Aromatic, heteroaromatic, conjugated, and aliphatic aldehydes afforded the corresponding products in moderate to high isolated yields (up to 99%) with excellent enantioselectivities (up to 99% ee). The first example of highly enantioselective synthesis of 2,2,6-trisubstituted dihydropyrones by the catalytic reaction of diene 1 with pyruvates was reported. The isolated intermediates indicated that this asymmetric HDA reaction proceeded in a Mukaiyama aldol pathway. On the basis of the absolute configurations of the products, a possible mechanism was proposed. Moreover, the catalytic system could be used to synthesize a series of enantioenriched beta-hydroxyketones 4. Finally, this methodology was successfully applied for the one-step synthesis of the important natural product (R)-(+)-Hepialone with 88% isolated yield and 94% enantioselectivity.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of silyl ketene acetals to aldehydes

The concept of Lewis base activation of Lewis acids has been reduced to practice for catalysis of the aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl4), can be activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral Lewis acid. This species has proven to be a competent catalyst for the aldol addition of acetate-, propanoate-, and isobutyrate-derived silyl ketene acetals to conjugated and nonconjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo-, and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant.     

不对称双酸催化3,4-二氢-2H-吡喃的反电子Hetero-Diels-Alder反应

研究了双酸催化剂不对称催化烯醚和β,γ-不饱和α-酮酸酯的反电子Hetero-Diels-Alder (HDA)反应, 为手性合成3,4-二氢-2H-吡喃类化合物提供了一种新的催化合成方法. InBr₃与手性磷酸钙盐Ca(1c)₂组合的手性双路易斯酸催化体系能够有效催化3,4-二氢-2H-吡喃和β,γ-不饱和α-酮酸酯的反电子HDA反应, 反应给出优秀的产率(最高达98%), 中等到良好的非对映选择性(最高达89:11)和良好到优秀的对映选择性(最高可达94%). 并且该双酸催化体系也能成功实现其它烯醚(如: 2,3-二氢-2H-呋喃, 乙烯基乙醚)的HDA反应, 获得优秀的非对映选择性(>94:6)和良好的对映选择性.     

Ligand effects in aluminium-catalyzed asymmetric Baeyer-Villiger reactions

Asymmetric Baeyer-Villiger oxidations of racemic and prochiral cyclobutanones can be performed with chiral aluminium-based Lewis acids resulting in products with good enantioselectivities in high yields. By employing substituted BINOL derivatives as ligands, remarkable catalyst efficiencies have been achieved and γ-butyrolactones with up to 84% ee were obtained. The relation between the electronic properties of the ligand and the enantioselectivity of the reaction has been investigated, leading to a better understanding of the requirements for achieving a good enantioselectivity in this aluminium-catalyzed oxidative transformation.     

Assembled dendritic titanium catalysts for enantioselective hetero-Diels-Alder reaction of aldehydes with Danishefsky's diene

A new type of dendritic 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN)-derived Schiff-base ligands have been synthesized and applied to the titanium-catalyzed hetero-Diels-Alder reaction of Danishefsky's diene with aldehydes. These reactions afforded the corresponding 2-substituted 2,3-dihydro-4H-pyran-4-ones in quantitative yields and with excellent enantioselectivities (up to 97.2 % ee). The disposition of the dendritic wedges and the dendron size in the ligands were found to have significant impact on the enantioselectivity of the reaction. The recovered dendritic catalyst could be reused without further addition of the Ti source or a carboxylic acid additive for at least three cycles, retaining similar activity and enantioselectivity. The high stability of this type of assembled dendritic titanium catalyst may be attributed to the stabilization effect of large-sized dendron units in the catalyst molecule. The other important phenomenon observed with this catalyst system is that a higher degree of asymmetric amplification has been achieved by attachment of the dendron unit to the chiral ligand, which represents a new advantage of dendrimer catalysts for asymmetric reactions using chiral ligands of lower optical purity.     

Solvent enhancement of reaction selectivity: a unique property of cationic chiral dirhodium carboxamidates

1,3-Dipolar cycloaddition reactions of nitrones with α,β-unsaturated aldehydes catalyzed by a cationic chiral dirhodium(II,III) carboxamidate with (R)-menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands in toluene increase reaction rates, give optimum regioselectivities, and enhance stereoselectivities compared to the same reactions performed in traditionally used halocarbon solvents. Rate and enantioselectivity enhancements were also obtained in hetero-Diels-Alder and carbonyl-ene reactions performed in toluene over those obtained in dichloromethane using the diastereomeric chiral cationic dirhodium(II,III) carboxamidate with (S)-menthyl (S)-2-oxopyrrolidine-5-carboxylate ligands. These enhancements are attributed to diminished or absent association of toluene with the catalyst which lessens the relative importance of the uncatalyzed background reaction, and they may also be a consequence of different coordination angles for aldehyde association with rhodium in the different solvent environments. Overall, the enhancement of reaction rates and selectivities with cationic chiral dirhodium(II,III) carboxamidates in toluene suggests broad applications for them in Lewis acid catalyzed reactions.     

Chiral copper complexes of phosphino sulfenyl ferrocenes as efficient catalysts for enantioselective formal Aza Diels-Alder reactions of N-sulfonyl imines

In the presence of a catalytic amount of silver perchlorate, copper(I) bromide complexes of planar chiral 1-phosphino-2-sulfenylferrocenes behave as very efficient chiral Lewis acids catalysts in the formal Aza Diels-Alder reaction of N-arylsulfonyl aldimines with electron-rich dienes (Danishefsky's and related dienes). Mixing of equimolar amounts of the readily available enantiopure ferrocenyl P,S-bidentate ligand and CuBr quantitatively affords the precatalyst Cu complex as an air-stable solid. This catalytic asymmetric procedure has a broad structural scope: aldimines of aromatic, alpha,beta-unsaturated, and even enolizable aliphatic aldehydes have been successfully used. The corresponding 2,3-dihydro-4-pyridones were obtained in good yields (57-90%) and with homogeneously high enantioselectivity (82-97% ee).     

Enantioselective catalysis of the hetero-Diels-Alder reaction between Brassard's diene and aldehydes by hydrogen-bonding activation: a one-step synthesis of (S)-(+)-dihydrokawain

The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding delta-lactone derivatives in moderate-to-good yields and with high enantioselectivities (up to 91 % ee). The reactions can be carried out either under solvent-free conditions or in toluene. On the basis of the absolute configurations of the products and the hydrogen-bonding interaction pattern between TADDOL (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolan-4,5-dimethanol) and the carbonyl group disclosed by X-ray diffraction analysis, a possible mechanism for the catalytic reaction has been proposed. To demonstrate the usefulness of the methodology, a natural product, (S)-(+)-dihydrokawain, has also been prepared in 50 % isolated yield and with 69 % enantioselectivity in one step starting from 3-phenylpropionaldehyde by using this methodology. Therefore, this catalytic system is one of the most direct approaches to the construction of delta-lactone units, which will make the methodology very attractive for the synthesis of a variety of biologically important compounds and natural products.     

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.     

Catalytic asymmetric Henry reactions of silyl nitronates with aldehydes

A catalytic enantioselective Henry reaction of silyl nitronates with aldehydes has been developed. Different chiral Lewis acids have been tested for the reaction and it has been found that a variety of chiral copper-ligand complexes can catalyze the Henry reaction. The best yield, diastereo- and enantioselectivity of the nitroalcohols formed are obtained by the application of a copper(II)-diphenyl-bisoxazoline complex as the catalyst in the presence of tetrabutylammonium triphenylsilyldifluorosilicate (TBAT). In order to minimize the epimerization of the nitroaldol products they were converted into the corresponding Mosher esters. The reaction proceeds well for different aromatic aldehydes reacting with alkyl nitronates.     

New class of amino-phosphinite chiral catalysts for the highly enantioselective addition of arylzinc reagents to aldehydes

A new class of amino-phosphinite chiral ligands was prepared and applied in zinc-catalyzed addition of aryl boronic acids to aldehydes; the reaction furnished the diarylmethanols in excellent yields and with a high level of enantioselectivity (up to 93% ee).     

Asymmetric Henry reaction catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) complexes: metal-controlled reversal of enantioselectivity

[reaction: see text] C(2)-symmetric tridentate bis(oxazoline) and bis(thiazoline) ligands with a diphenylamine backbone have been investigated in the catalytic asymmetric Henry reaction of alpha-keto esters with different Lewis acids. Their Cu(OTf)(2) complexes furnished S enantiomers, while Et(2)Zn complexes afforded R enantiomers, both of them with higher enantioselectivities (up to 85% ee). Reversal of enantioselectivity in asymmetric Henry reactions was achieved with the same chiral ligand by changing the Lewis acid center from Cu(II) to Zn(II). The results show that the NH group in C(2)-symmetric tridentate chiral ligands plays a very important role in controlling both the yields and enantiofacial selectivity of the Henry products.     

Catalytic and enantioselective aza-ene and hetero-Diels-Alder reactions of alkenes and dienes with azodicarboxylates

Lewis acids such as Cu(OTf)(2), Zn(OTf)(2), Yb(OTf)(3) and Nd(OTf)(3) catalyze the aza-ene reaction of alkenes with azodicarboxylates, giving the allylic amination adducts. The use of bis(2,2,2-trichloroethyl)azodicarboxylate as the amination reagent and Cu(OTf)(2) and Yb(OTf)(3) as the catalysts gave the aza-ene reaction of different alkenes, leading to the corresponding allyl amines in high yields. Chiral copper complexes prepared from Cu(OTf)(2) and chiral bisoxazoline ligands were found to catalyze the enantioselective aza-ene reaction of azodicarboxylates with alkenes and the hetero-Diels-Alder reaction with cyclopentadiene, giving the corresponding aza-ene- and hetero-Diels-Alder adducts, respectively, in good yields and moderate enantioselectivities.     

Chiral Chromium Salen@rGO as Multipurpose and Recyclable Heterogeneous Catalyst

The first immobilization of a pyrene-tagged chromium salen complex through π-π noncovalent interactions on reduced graphene oxide (rGO) is described. A very robust supported catalytic system is obtained to promote asymmetric catalysis in repeated cycles, without loss of activity or enantioselectivity. This specific behavior was demonstrated in two different catalytic reactions (up to ten reuses) promoted by chromium salen complexes, the cyclohexene oxide ring-opening reaction and the hetero-Diels-Alder cycloaddition between various aldehydes and Danishefsky's diene. Furthermore, the chiral chromium salen@rGO has been found to be compatible with a multi-substrate type use, in which the structure of the substrate involved is modified each time the catalyst is reused.     

Development of an unusually highly enantioselective hetero-Diels-Alder reaction of benzaldehyde with activated dienes catalyzed by hypercoordinating chiral aluminum complexes

The effect of Lewis acid catalysis of the hetero-Diels-Alder reaction between benzaldehyde and activated dienes (e.g. the Danishefsky's diene) has been investigated. In the present work we decided to study a series of chiral aluminum complexes as potential catalysts for the hetero-Diels-Alder reaction in order to gain a better understanding of the effect on the chiral induction of varying the steric and electronic environment of the metal ion. The results of this study prompted us to conclude that steric effects in the ligand coordination sphere and hypercoordination are strongly contributing factors to the optical yield of the reaction. Optimization of the reaction culminated in the synthesis of the hetero-Diels-Alder product in 99.4% ee and 97% yield of the isolated product. Based on the experimental results the mechanism for the hetero-Diels-Alder reaction is discussed and it is postulated that hypercoordination to the chiral aluminum Lewis acid center is of importance for the reaction.     

The first series of chiral 2,2':6',2''-terpyridine tri-N-oxide ligands for Lewis base-catalyzed asymmetric allylation of aldehydes

The first series of chiral 2,2':6',2'-terpyridine tri-N-oxide ligands have been developed; They were showed to be active Lewis base-catalysts for asymmetric allylation of aldehydes using allyltrichlorosilane with optimal results at 0 degrees C for electron-deficient aromatic aldehydes (yields up to 97% and enantioselectivities up to 86% ee).