Diels chiral alcohol catalysts

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

Diels-Alder catalyst.2 The acrylates (4) of three chiral alcohols (1-3) have been found to undergo asymmetric Diels-Alder reactions with cyclopentadiene (equation I) in the presence of a Lewis acid catalyst. For this purpose, catalysts of the type TiCl2(X2) are superior to TiCl4 because they do not promote polymerization of the acrylate. The final products (6) all have the enrfo-orientation the configuration (R) or (S) depends upon the chiral alcohols. Those derived from 1 all have (S)-configuration ... 

An early example of chiral alcohol-based hydrogen bonding catalysts is the work by Braddock and coworkers in which they used paracydophanediols (PHANOLs) as dual H-bond donors [65, 66]. Significant rate enhancements were obtained in the Diels-Alder reactions of dienes with a,P-unsaturated aldehydes and ketones and in the epoxide-opening reactions with amines. However, little or no asymmetric induction was obtained when a chiral PHANOL catalyst was used. 

In 2010, Nakano, Takeshita, and coworkers reported an organocatalytic Diels-Alder reaction between 1,2-dihydropyridine 13 and acrolein 12 using a chiral oxazolidine catalyst 14 to produce the chiral isoquinucUdine 16 as an important synthetic intermediate of oseltanuvir (Tamiflu) in 90% yield with >99% ee (Scheme 38.5) [11a]. A simple chiral amino alcohol catalyst 15 containing a primary amine moiety was also developed by the same group for this transformation, giving excellent enantioselectivity (Scheme 38.5) [lib]. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Some chiral 1,3,2-dioxastannolanes were used as catalysts in asymmetric Diels-Alder reactions of cyclopentadiene with methyl acrylate <90JCR(S)278>. A-Alkenyl- and -cycloalkenyl 1,3,2-oxaza-stannolanes, generated in situ from chiral amino alcohols, gave optically active 2-substituted aldehydes and ketones in modest to high chemical and optical yields after alkylation with methyl acrylate or acrylonitrile (which is usual for enamines) and subsequent hydrolysis <85CC504,85JOC3863>. 

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone I. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Currently available chiral Diels-Alder catalysts have major limitations with regard to the range of dienes to which they can be applied successfully. Indeed, most of the reported catalytic enantioselective Diels-Alder reactions involve reactive dienes such as cyclopentadiene, but 1,3-butadiene and 1,3-cyclohexadiene have not been successfully utilized without reactive 2-bromoacrolein. To solve this problem, a new class of super-reactive chiral Lewis acid catalysts has been developed from chiral tertiary amino alcohols and BBr3 [24] (Eq. 8A.13). This type of chiral super Lewis acid works well for a,fj-acetylenic aldehydes [25],... 

Although several bifunctional chiral Lewis acids have been described in the literature and binding studies have been performed as outlined in Section 7.2, relatively little is known about their use as Lewis acid catalysts. Most notably, l,8-bis(dichloroboryl)naphthalene was treated with various chiral organic amines, alcohols, and acids. The resulting products were found to be efficient catalysts for asymmetric Diels-Alder reactions. The simultaneous coordination of the substrate by both Lewis acid centers is believed to play a significant role (see also Scheme 25). 

Catalytic Asymmetric Diels-Alder Reaction. Amino alcohol (1) combined with Boron Tribromide generates a chiral catalyst for the asymmetric Diels-Alder reaction (97% ee) of unsaturated aldehydes and dienes. ... 

Other Applications. Chiral oxazaborolidines derived from ephedrine have also been used in asymmetric hydroborations, and as reagents to determine the enantiomeric purity of secondary alcohols. Chiral l,3,2-oxazaborolidin-5-ones derived from amino acids have been used as asymmetric catalysts for the Diels-Alder reaction,and the aldol reaction. ... 

The earliest report of a reaction mediated by a chiral three coordinate aluminum species describes an asymmetric Meerwein-Poimdorf-Verley reduction of ketones with chiral aluminum alkoxides which resulted in low induction in the alcohol products [1]. Subsequent developments in the area were sparse until over a decade later when chiral aluminum Lewis acids began to be explored in polymerization reactions, with the first report describing the polymerization of benzofuran with catalysts prepared from and ethylaluminum dichloride and a variety of chiral compounds including /5-phenylalanine [2]. Curiously, these reports did not precipitate further studies at the time because the next development in the field did not occur until nearly two decades later when Hashimoto, Komeshima and Koga reported that a catalyst derived from ethylaluminum dichloride and menthol catalyzed the asymmetric Diels-Alder reaction shown in Sch. 1 [3,4]. This is especially curious because the discovery that a Diels-Alder reaction could be accelerated by aluminum chloride was known at the time the polymerization work appeared [5], Perhaps it was because of this long delay, that the report of this asymmetric catalytic Diels-Alder reaction was to become the inspiration for the dramatic increase in activity in this field that we have witnessed in the twenty years since its appearance. It is the intent of this review to present the development of the field of asymmetric catalytic synthesis with chiral aluminum Lewis acids that includes those reports that have appeared in the literature up to the end of 1998. This review will not cover polymerization reactions or supported reactions. The latter will appear in a separate chapter in this handbook. 

As shown above, asymmetric catalysis of Diels-Alder reactions has been achieved by use of chiral titanium complexes bearing chiral diol ligands. Yamamoto has reported a chiral helical titanium complex derived from Ti(OPr )4 and a BINOL-derived tetraol ligand (Sch. 54) [134], The Diels-Alder products are obtained with uniformly high enantioselectivity, irrespective of the substituent pattern of a,/3-unsaturated aldehydes. Corey has also reported a new type of chiral titanium complex derived from an amino alcohol ligand (Sch. 55) [135]. The chiral titanium complex serves as an efficient asymmetric catalyst for the reaction of 2-bromoacrolein the Diels-Alder product is obtained with high enantioselectivity. 

Kobayashi et al. developed chiral Lewis acids derived from A -benzyldiphenylproli-nol and boron tribromide and used these successfully as catalysts in enantioselective Diels-Alder reactions [89]. The corresponding polymeric catalyst 71 was prepared and used for the Diels-Alder reaction of cyclopentadiene with methacrolein [90]. Different polymeric catalysts 72, 73, 74 were prepared from supported chiral amino alcohols and diols fimctionalized with boron, aluminum and titanium [88,90]. In these polymers copolymerization of styrene with a chiral auxiliary containing two polymerizable groups is a new approach to the preparation of crosslinked chiral polymeric ligands. This chiral monomer unit acts as chiral ligand and as a crosslink. 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

During recent years, the homogeneous Lewis acid-catalyzed asymmetric Diels-Alder reactions and hetero-Diels-Alder (HDA) reactions have each undergone extensive study. Various chiral Lewis acids including aluminum, titanium or boron, and chiral ligands such as chiral amino alcohols, diols, salen, bisoxazoline or N-sulfonylamino acids have been used as the catalysts [84]. Much efforts have also been made in the investigation of heterogeneous diastereoselective Diels-Alder reactions. 

Other polymer-supported catalysts for the asymmetric Diels-Alder reaction include aluminum and titanium complexes of chiral amino alcohols [74],... 

The 3-amino alcohols 35a-g represent the latest variation on the theme of chiral promoters for the enantioselective addition of dialkylzinc reagents to im-ines (Scheme 17) [38]. Andersson and co-workers interest in the use of chiral, sterically constrained P-amino alcohols with the 2-azanorbornyl skeleton led them to consider such bicychc P-amino alcohols as chiral catalysts in the above-mentioned addition reaction. One important feature of these ligands is the fact that both enantiomers are equally available. The common precursor for all the ligands was 34 which could be constructed via an aza-Diels-Alder reaction. The synthesis of the bicychc amino alcohols 35a-g is depicted in Scheme 17. 

In 2002, Huang and Rawal found that the hetero Diels-Alder reaction of aminosiloxydienes with aldehydes was accelerated in alcoholic solvents [65], They subsequently elucidated that TADDOL (19) is an efficient chiral catalyst for the hetero-Diels-Alder reaction (Figure 10.17, Equation 10.33) [66]. The internal hydrogen bond in TADDOL observed in its crystal structure is expected to render the hydroxy proton more acidic, hence enabling it to participate better in intermolecular hydrogen bonding with the carbonyl group of the dienophile [67]. The Mukaiyama aldol reaction was also reported [68]. 

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