Alcohols, chiral Diels-Alder reaction

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. 

Chiral heterocyclic compounds containing vicinal oxygen and nitrogen atoms were achieved by an asymmetric Diels-Alder reaction [111] of chiral acylnitroso dienophiles 111. The latter were prepared in situ from alcohols 110, both antipodes of which are available from camphor, and trapped with dienes (Scheme 2.46). Both the yield (65-94 %i) and diastereoisomeric excess (91-96%) were high. 

Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of open-chain and cyclic dienes, rapidly undergo a Diels-Alder reaction [91]. Chiral a, -unsaturated ketones bearing a -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4, affording Diels-Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantios-electivity of the reaction is dependent on the size of the substituent R on the of-carbon high levels of asymmetric induction were observed with R = z-Pr (90 1) and R = t-Bu (150 1) and low levels with R = Me (2.7 1) and R = Ph (3.0 1). Scheme 4.24 shows the postulated reaction mechanism. 

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. 

In 2005, another class of chiral ligands, bis(thiazolines) derivatives, was prepared by Nishio et al. from chiral bis-(A-acylamino alcohols) by using Lawesson s reagent. These new compounds have proved to be useful chiral ligands for the Zn-catalysed Diels-Alder reaction of 3-acryloyloxazolidine-2-one with cyclopentadiene, giving the corresponding cycloadducts as a 94 6 diastereomeric mixture, where the major diastereomer was formed with 92% ee (Scheme 5.14). 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

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). ... 

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>. 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

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. 

Enantioselective Diels-Alder reaction,3 The reaction of the chiral acrylate ester 1 with butadiene catalyzed with this Lewis acid followed by hydride reduction gives the alcohol 2 in 70% chemical yield and 86-91% ee. A1C13 and SnCl4 are inferior in terms of either the chemical or optical yield. The product (2) was used for a chiral synthesis of (R)-(- )-sarkomycin (4). 

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],... 

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 ... 

The reagent has one handicap only (+)-pulegone is readily available. Consequently, Oppolzer and coworkers2 have examined a number of chiral alcohols, derived from various monoterpenes, in which the hydroxyl group is similarly shielded. The endo, e/.r-diphenylmethylisoboraeol (2), obtained from ( + )-camphor, and the enantiomer, obtained from ( —)-camphor, are almost as effective as 1 as chiral adjuncts in this Diels-Alder reaction. 

The hitherto discussed transformations clearly demonstrate the great value of using chiral dienophiles for hetero Diels-Alder reactions of nitroalkenes. Recent studies deal with the application of various chiral alcohols in order to get... 

Acryloyl and crotonoyl amides (9) derived from the sultam (8), available from ( + )-l, are somewhat more reactive dienophiles than the i orresponding esters (3) derived from 2. Diels-Alder reactions of 9 with cyclopentadiene catalyzed by TiCU or C2H,AIC1, proceed in high yield, with high endo selectivity ( 99%) ind diastereoselectivity of —95% de. The chiral auxiliary is removed by reduction witfi LiAIH4 to furnish 8 and the chiral alcohol in 89-95% yield.-... 

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. 

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