Diels-Alder reaction, Asymmetric

Figu re 7.9 Pt-complexes for asymmetric Diels-Alder reactions. 

Entry Solvent Catalyst (mol%) Run Conv. (%) (time) (h) % endo endo ee (%) 

The diastereoselectivity inherent to the Diels-Alder reaction can be seen in most of the examples in preceding reactions. The reaction is not, however, enantioselective since there is no facial control for intermolecular reactions (some facial control is available for intramolecular reactions). The ortho rule, the endo rule (secondary orbital interactions), and steric interactions provide some orientational control but facial control is also required for enantioselectivity. When ethyl acrylate reacts with 2-methyl-1,3-pentadiene, it can approach from the bottom as in 247A or from the top as in 247B. Clearly, the two products (248A and 248B) are mirror images and enantiomers. This lack of facial selectivity leads to racemic mixtures in all Diels-Alder cyclizations discussed to this point. 

As in Chapters(l-5, and 8-9, the key to enantioselectivity is providing both facial and orientational control in the transition state of the reaction. The orientational control (regioselection and endo selectivity) for the 

The focus of organocatalytic Bronsted bases will continue to evolve towards catalysts that can more efficiently activate reaction systems that may seem feasible in theory yet, in practice, encounter energy barriers that prevent the desired yields and selectivity. Our evolving knowledge of the asymmetric organocatalytic field, complemented by computational resources, can offer new avenues of exploration towards rational design of new scaffolds. 

(2009) Cinchona Alkaloids in Synthesis and Catalysis, Wiley-VCH Verlag GmbH Co. KGaA, Weinheim. 

4 Recent review papers on cinchona alkaloids (a) Chen, Y.C. (2008) Synlett, 1919-1930 (b) Marcelli, T. and Hiemstra, H. (2010) Synthesis, 1229-1279  

6 Morrison, J.D. and Mosher, H.S. (1971) Asymmetric Organic Reactions, Prentice-Hall, Englewood Cliffs. 

18 Recent review on enantioselective, organocatalytic Diels-Alder Merino, P., Marques-Lopez, E., Tejero, T., and Herrera, R.P. (2010) Synthesis, 

Two main approaches to the preparation of a single enantiomer of a Diels-Alder cycloadduct have been used in synthetic organic chemistry. A chiral auxiUary attached to the diene, or more commonly to the dienophile, is a popular method. Alternatively, the use of an external chiral catalyst can promote the preferential formation of one of the two enantiomeric cycloadducts. Many examples of highly selective Diels-Alder reactions have been documented.  

Most studies have centred on the use of optically active dienophUes, particularly with esters or amides of acrylic acid. Having performed their directing function, the optically active auxiliary group (alcohol or amine) is removed from the product and in some cases may be reused. Many optically active alcohols R OH, have been employed in this sequence. For example, good results with acryUc esters of the neopentyl alcohols 119 or its enantiomer 120, derived from or (5)-(—)- 

It is clear that a restricted orientation of the dienophile is crucial to the success of the asymmetric Diels-Alder reaction. A good method to lock the conformation is to use an auxiliary containing a carbonyl group, such that the two carbonyl groups of the dienophile can chelate to a Lewis acid. Thus, high levels of diastereofacial selectivity can be achieved in Diels-Alder reactions of the acrylates of ethyl lactate or of pantolactone, in the presence of the Lewis acid TICU (3.91). The adduct 124 is formed almost exclusively (93 7 ratio of diastereomers) using butadiene and the acrylate of (/f)-pantolactone and can be purified easily by crystallization. Simple hydrolysis gives enantiomerically pure carboxylic acid 125. In such chelated systems, the metal is co-ordinated anti to the alkene of the dienophile and the acrylate therefore adopts the s-cis conformation 126. 

Sobczak, H. Hartmann and G. Helmchen, Tetrahedron Lett, 26 (1985), 3095. 

Highly selective Diels-Alder reactions with other chiral auxiliaries attached to the dienophile have been documented. For example, chiral 2-oxazolidinones or the camphor sultam auxiliaries have proven particularly useful. Such cycloaddition reactions, catalysed by an alkylaluminium chloride, occur with a variety of dienes to give adducts in high yield and with very high diastereoselectivity. In many cases these adducts can be obtained diastereomerically pure by crystallization. The reactions are thought to occur by way of complexed ion pairs (e.g. 129), in which the substituent on the auxiliary shields one face of the dienophile from attack by the diene. For example, 2-methylbutadiene (isoprene) gave the adduct 127, which was converted into (i )-(+)-a-terpineol 128 (3.92).  

The highly ordered cyclic transition state of the Diels-Alder reaction permits design of reaction parameters which lead to a preference between the transition states leading to diastereomeric or enantiomeric adducts. (See Part A, Section 2.3, to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.The cycloaddition proceeds to give two diastereomeric products which can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best enantioselectivity is often observed in catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered upon hydrolysis of the adduct to give the enantiomerically pure carboxylic acid. 

Prediction and analysis of diastereoselectivity is based on steric, stereoelectronic, and complexing interactions in the transition state.  

The alkenyl oxonium ion dienophiles generated from dioxolanes have been made enantioselective by use of chiral diols. For example, dioxolanes derived from 5y -l,2-diphenylethane-l,2-diol react with dienes such as cyclopentadiene and isoprene, but the stereoselectivity is very modest in most cases. 

Acetals derived from a ft -pentane-2,4-diol react with dienes under the influence of TiCl4/Ti(/-OPr)4 to give adducts with stereoselectivity ranging from 3 1 to 15 1. 

Enantioselectivity can also be achieved with chiral catalysts. For example, additions of A/ -acryloyloxazolinones can be made enantioselective using Sc(03SCF3)3 in the presence of a BINOL ligand. Optimized conditions involved use of 5-20 mol % of the catalyst along with a hindered amine such as cw-l,2,6-trimethylpiperidine. A hexacoordinate transition state in which the amine is hydrogen-bonded to the BINOL has been proposed. 

Chiral dienophiles, prepared from an aldehyde and asparagine in water followed by reacting with acryloyl chloride, reacted with cyclopentadiene at room temperature in water or ethanol-water to provide cycloadducts diastereoselectively and chiral products upon separation and hydrolysis (47-64% ee for the endo isomers endo/exo 82 18) (Eq. 12.18).  

Recently, catalytic asymmetric Diels-Alder reactions have been investigated. Yamamoto reported a Brdnsted-acid-assisted chiral (BLA) Lewis acid, prepared from (R)-3-(2-hydroxy-3-phenylphenyl)-2,2 -dihydroxy-1,1 -binaphthyl and 3,5-Z7ri(trifluoromethyl)-benzeneboronic acid, that is effective in catalyzing the enantioselective Diels-Alder reaction between a,P-enals and various dienes. The interesting aspect is the role of water, THE, and MS 4A in the preparation of the catalyst (Eq. 12.19). To prevent the trimerization of the boronic acid during the preparation of the catalyst, the chiral triol and the boronic acid were mixed under aqueous conditions and then dried. Using the catalyst prepared in this manner, a 99% ee was obtained in the Diels-Alder reaction 

Kanemasa et al. reported that cationic aqua complexes prepared from the trani -chelating tridentate ligand (i ,i )-dibenzofuran-4,6-diyl-2,2 -fcA(4-phenyloxazoMne) (DBFOX/Ph) and various metal(II) perchlorates are effective catalysts that induce absolute chiral control in the Diels-Alder reactions of 3-alkenoyl-2-oxazoMdinone dienophiles (Eq. 12.20). The nickel(ll), cobalt(II), copper(II), and zinc(II) complexes are effective in the presence of six equivalents of water for cobalt and nickel and three equivalents of water for copper and zinc. 

Desimoni et al. have shown that the use of magnesium perchlorate or magnesium triflate, and three chiral Z w(oxazolines) and two equivalents of achiral auxiliary ligands such as water or tetramethylurea, induces a strong change of the enantiofacial selectivity with 94% ee in the 

Optically active Diels-Alder adducts were also prepared by using a one-pot preparative method and enantioselective formation of inclusion complex with optically active hosts in a water suspension medium. For example, A-ethylmaleimide reacts with 2-methyl-1,3-butadiene in water to give the racemic adduct 1. Racemic 1 and the optically active host 2 form enantioselectively a 1 1 inclusion complex of 2 with (-f)-l in a water suspension. The inclusion complex can be filtered and heated to release (-l-)-l with 94% ee (Eq. 12.23). 

8 Applications of Five-Membered Ring Products as Catalysts... 

Leug et al. [24,25] reported the effects of palladium or platinum metal templates of (l-(dimelhylamino)ethyl)naphthalene on asymmetric Diels-Alder reactions of 2-diphenylphospliinofuran with diphenylvinylphosphine and of l-phenyl-3,4-dimethlylphosphole with methyl cyanodithioformate. These are shown in Eqs. (8.6) and (8.7), respectively. 

A Diels-Alder reaction of 2-diphenylphosphinofuran with diphenylvinylphosphine in the presence of organoplatinum complex gives the chelating diphosphine exo-cycloadduct, 4(/ ), 5(if)-bis(diphenylphosphine)-7-oxabicyclo[2.2.1]hepta-2-ene 8.41 (M=Pt) in a 70 % isolated yield with many diastereoisomers, as shown in Eq. (8.6). The cycloaddition reaction proceeds at a significantly slower rate and exhibits a markedly lower stereoselectivity when the chiral platinum template is replaced with its organopalladium counterpart 8.41 (M=Pd) [24]. 

The reaction of ortto-palladated (l-(dimethylantino)ethyl)-naphthalene with a perchlorate complex proceeds by the exo-pathway and produces (+)-exo-syn-methylthio-substituted phosphanorbomene P-S bidentate chelate 8.42, as shown in Eq. (8.7). Generation of the chelating cycloadduct involved an intramolecular cycloaddition mechanism, in which both the cychc diene and the hetero dienophile were coordinated simultaneonsly to the chiral palladium template during the course of the cycloaddition reaction [25]. 

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Catalytic asymmetric Diels-Alder reactions are presented by Hayashi, who takes as the starting point the synthetically useful breakthrough in 1979 by Koga et al. The various chiral Lewis acids which can catalyze the reaction of different dieno-philes are presented. Closely related to the Diels-Alder reaction is the [3-1-2] carbo-cyclic cycloaddition of palladium trimethylenemethane with alkenes, discovered by Trost and Chan. In the second chapter Chan provides some brief background information about this class of cycloaddition reaction, but concentrates primarily on recent advances. The part of the book dealing with carbo-cycloaddition reactions is... 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

Table 1.1 Asymmetric Diels-Alder reactions of cyclopentadiene catalyzed by CAB catalyst 3 [5a,b ...

The polymer-supported chiral oxazaborolidinone catalyst 5 prepared from valine was found by Ituno and coworkers to be a practical catalyst of the asymmetric Diels-Alder reaction [7] (Scheme 1.12). Of the several cross-linked polymers with a... 

Table 1.3 Asymmetric Diels-Alder reactions of a-substituted aldehydes catalyzed by 7 [10a,d ...

Table 1.5 Asymmetric Diels-Alder reactions catalyzed by 8 [10d ...

Table 1.8 Asymmetric Diels-Alder reactions of alkynyl aldehydes catalyzed by 9 [12 ...

Kanemasa et al. discovered an asymmetric Diels-Alder reaction of acryloyl-oxazolidi-none and cyclopentadiene catalyzed by a chiral aqua complex of 4,6-dibenzofurani-dyl-2,2 -bis(4-phenyloxazoline) 16 (vide infra) [22]. Unlike the Diels-Alder reaction of acryloyloxazolidinone, for which NiBr2/AgC104 and Znl2/AgC104 are the most suitable sources of the central metal, the best for the Diels-Alder reaction of a-bromo-... 

The Asymmetric Diels-Alder Reaction of a,/ -Unsaturated Esters as Dienophiles... 

I 1 Catalytic Asymmetric Diels-Alder Reactions 1.2.3.1 Aluminum... 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

Table 1.17 Asymmetric Diels-Alder reactions of acryloyloxazolidinone catalyzed by 24b [23 ...

Since Evans s initial report, several chiral Lewis acids with copper as the central metal have been reported. Davies et al. and Ghosh et al. independently developed a bis(oxazoline) ligand prepared from aminoindanol, and applied the copper complex of this ligand to the asymmetric Diels-Alder reaction. Davies varied the link between the two oxazolines and found that cyclopropyl is the best connector (see catalyst 26), giving the cycloadduct of acryloyloxazolidinone and cyclopentadiene in high optical purity (98.4% ee) [35] (Scheme 1.45). Ghosh et al., on the other hand, obtained the same cycloadduct in 99% ee by the use of unsubstituted ligand (see catalyst 27) [36] (Scheme 1.46, Table 1.19). 

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