Enantioselective Hetero-Diels-Alder Reactions

Swindell CS, Tao M (1993) Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction - Enantioselective Synthesis of the Taxol A-Ring Side Chain. J Org Chem 58 5889... 

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

Jorgensen K. A. Development and application of catalytic highly enantioselective hetero-Diels-Alder reactions of aldehydes and ketones in Curr. Trends Org. Synth.,... 

Similar transformations have been performed with Danishefsky s diene and glyoxylate esters [85] catalyzed by bis (oxazoHne)-metal complexes to afford the hetero Diels-Alder product in 70% isolated yield and up to 72% ee. Jorgensen [86,87] reported a highly enantioselective, catalytic hetero Diels-Alder reaction of ketones and similar chiral copper(II) complexes leading to enantiomeric excesses up to 99% (Scheme 31, reaction 2). They also described [88] a highly diastereo- and enantioselective catalytic hetero Diels-Alder reaction of /I, y-imsaturated a-ketoesters with electron-rich alkenes... 

The enantioselectivity obtained in the hetero-Diels-Alder reaction (Scheme 12) was low (18% ee). This is, in part, due to the important temperature effect. For example, 50% ee was obtained in reactions carried out in homogeneous phase at - 60 °C and 95% ee in reactions at - 78 °C. However, at 0 °C the enantioselectivity dropped to 28% ee, a value closer to that obtained with the immobilized catalyst at the same temperature. Recycling was investigated and the solid was used four times with the same activity maintained. The 6b-Cu(OTf)2 catalyst proved to be less effective for this reaction and less stable in terms of recycling, a situation in agreement with the results obtained with exchanged catalysts [53]. 

The scope of this methodology was extended to the enantioselective hetero-Diels-Alder reaction between 1,3-cyclohexadiene and ethylglyoxylate,... 

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

Finally, the discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reactions was made possible by a combinatorial approach.121 The object was to find a chiral titanium catalyst for the reaction of aldehydes (51) with Danishefsky s diene (91), with formation of cycloadduct (92) in >99% enantipurity (Equation (11)). 

Stable aryl boronates derived from tartaric acid catalyze the reaction of cyclo-pentadiene with vinyl aldehyde with high selectivity. Chiral acyloxy borane (CAB), derived from tartaric acid, has proved to be a very powerful catalyst for the enantioselective Diels-Alder reaction and hetero Diels-Alder reaction. Scheme 5 23 presents an example of a CAB 73 (R = H) catalyzed Diels-Alder reaction of a-bromo-a,/i-cnal 74 with cyclopentadiene. The reaction product is another important intermediate for prostaglandin synthesis. In the presence of... 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

Jorgensen s group reported the aza Diels-Alder reactions in the presence of several chiral catalysts.52 They found that chiral bis(oxazoline) ligands 81, 83, 103, 104, and 105, which were effective in asymmetric oxo hetero Diels-Alder reactions, induced the aza Diels-Alder reaction of a-imino ester with Danishefsky s diene with only poor to moderate enantioselectivity. Selected results are listed in Scheme 5-40. 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

Asymmetric Diels-Alder reactions have also been achieved in the presence of poly(ethylene glycol)-supported chiral imidazohdin-4-one [113] and copper-loaded silica-grafted bis(oxazolines) [114]. Polymer-bound, camphor-based polysiloxane-fixed metal 1,3-diketonates (chirasil-metals) (37) have proven to catalyze the hetero Diels-Alder reaction of benzaldehyde and Danishefsky s diene. Best catalysts were obtained when oxovanadium(lV) and europium(III) where employed as coordinating metals. Despite excellent chemical yields the resulting pyran-4-ones were reported to be formed with only moderate stereoselectivity (Scheme 4.22). The polymeric catalysts are soluble in hexane and could be precipitated by addition of methanol. Interestingly, the polymeric oxovanadium(III)-catalysts invoke opposite enantioselectivities compared with their monomeric counterparts [115]. 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

The asymmetric hetero-Diels-Alder reaction of aldehydes with Danishefsky s diene catalyzed by Ti catalysts generated from a library of 13 chiral ligands or activators has also been reported (Scheme 8.18). The catalyst library contains 104 members. The Ti catalysts bearing L, L , L, and J are found to have a remarkable effect on both enantioselectivity (76.7-95.7% ee) and yield (63-100%). On the other hand, ligands bearing sterically demanding substituents at the 3,3 -positions are found to be detrimental to the reaction. The optimized catalysts, both L /Ti/L and L /Ti/L , are the most efficient for the reaction of a variety of aldehydes, including aromatic, olefinic, and aliphatic derivatives. 

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). ... 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

TADDOL-Promoted Enantioselective Hetero-Diels-Alder Reaction of Danishefsky s Diene 37... 

The enantioselechve hetero-Diels-Alder reaction of carbonyl compounds with 1,3-dienes represents an elegant access to optically active six-membered oxo-heterocy-cles. Since the pioneering work of Rawal et al. in 2003 [40], the enantioselective HDA reaction catalyzed by diols (such as TADDOLs) has become a flourishing field of research [41]. 

An enantioselective hetero-Diels-Alder reaction between activated enones and 1,3-dioxin was reported. The Evans catalyst (r-Bu-box, Cu(OTf)2) was applied to obtain the bicycles in 65-81% yield and 91-96% ee (Equation 38) <2000JOC4487>. 

The development and application of catalytic enantioselective 1,3-dipolar cycloadditions is a relatively new area. Compared to the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions (337,338), which has evolved since the mid-1980s, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloadditions remained almost unexplored until 1993 (5). In particular, the asymmetric metal-catalyzed reactions of nitrones with alkenes has received considerable attention during the past 5 years. 

TABLE 9.19. ENANTIOSELECTIVE HETERO-DIELS-ALDER REACTIONS USING DANISHEFSKY S DIENE ... 

---