Diels-Alder reactions of carbonyl compounds

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. 

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

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]. 

The advantagous use of Lewis acids in the hetero Diels-Alder reaction of carbonyl compounds has intensively been studied and employed by Danishefsky et al. [23,67-70], They also showed that rare earth cations are excellent and mild catalysts due to their high oxophilicity, even allowing the isolation of the highly sensitive primary cycloadducts. 

All investigations on the use of Lewis acids in the hetero Diels-Alder reaction of carbonyl compounds clearly show that a careful adjustment of the Lewis acidity for a given system is neccessary. Especially with trimethylsilyloxybuta-dienes a Mukayama type aldol reaction can easily take place instead of the desired hetero Diels-Alder reaction. 

For the diastereoselective hetero Diels-Alder reaction of carbonyl compounds using removable chiral auxiliaries, intensive studies of the uncatalyzed... 

In early work which have been summarized very recently [23], Danishefsky et al. have investigated hetero Diels-Alder reactions of carbonyl compounds in order to yield glycals. Numerous further contributions to the stereoselective synthesis of dihydropyran derivatives by high pressure or Lewis acid induced Diels-Alder reactions of carbonyl compounds have been made by Jurczak et al.,... 

Jorgensen, K. A. Catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines. Angew. Chem., Int. Ed. Engl. 2000,... 

Roberson, M., Jepsen, A. S., Jorgensen, K. A. On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes-a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedron 2001, 57, 907-913. Monnat, F., Vogel, P., Rayon, V. M., Sordo, J. A. Ab Initio and Experimental Studies on the Hetero-Diels-Alder and Cheletropic Additions of Sulfur Dioxide to (E)-I-Methoxybutadiene A Mechanism Involving Three Molecules of S02. J. Org. Chem. 2002, 67, 1882-1889. 

Catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds 00AG(E)3558. 

Among the Lewis acids studied in asymmetric hetero Diels-Alder reactions of carbonyl compounds rare earth cations proved to be mild and efficient catalysts. This is demonstrated by the results observed in reactions of camphor sultam (63) derivatives with achiral 1-methoxy-l,3-butadiene. 

H. Pelhssier, Asymmetric hetero-Diels—Alder reactions of carbonyl compounds. Tetrahedron 65 (2009) 2839-2877. 

R] For a review of catalytic enantioselective Diels-Alder reactions of carbonyl compounds, see Jorgensen, K. A. Cycloaddition Reactions in Organic Synthesis-, Kobayashi, S., Jorgensen, K. A., Eds. Wiley-VCH New York, 2002 pp 151-186. 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

Roberson M, Jepsen AS, J0rgensen KA (2001) On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes—a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedrrai 57 907—913... 

Several aluminum- and titanium-based compounds have been supported on silica and alumina [53]. Although silica and alumina themselves catalyze cycloaddition reactions, their catalytic activity is greatly increased when they complex a Lewis acid. Some of these catalysts are among the most active described to date for heterogeneous catalysis of the Diels-Alder reactions of carbonyl-containing dienophiles. The Si02-Et2AlCl catalyst is the most efficient and can be... 

Early applications of chiral Lewis acid catalyzed stereoselective Diels Alder reactions used either boron- or aluminum-derived systems in carbocyclic ring formation18 1Q, or studied the effect of chiral shift reagents, such as Eu(hfc)3, in hetero-Diels-Alder cycloadditions of carbonyl compounds to dienes20 23,77, 78. The latter type of transition metal catalyzed addition is classified as heterocarboration and is described in Section 1.5.8.4. 

The asymmetric hetero-Diels-Alder reaction involving carbonyl compounds as the heterodienophiles or heterodienes is among the most powerful methodologies for the construction of enantioenriched oxygen-containing heterocycles that have wide synthetic applications in biologically important natural or urmatural molecules. 

Some of the developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds have origin in Diels-Alder chemistry, where many of the catalysts have been applied. This is valid for catalysts which enable monodentate coordination of the carbonyl functionality, such as the chiral aluminum and boron complexes. New chiral catalysts for cycloaddition reactions of carbonyl compounds have, however, also been developed. 

Chiral boron(III) Lewis acid catalysts have also been used for enantioselective cycloaddition reactions of carbonyl compounds [17]. The chiral acyloxylborane catalysts 9a-9d, which are also efficient catalysts for asymmetric Diels-Alder reactions [17, 18], can also catalyze highly enantioselective cycloaddition reactions of aldehydes with activated dienes. The arylboron catalysts 9b-9c which are air- and moisture-stable have been shown by Yamamoto et al. to induce excellent chiral induction in the cycloaddition reaction between, e.g., benzaldehyde and Danishefsky s dienes such as 2b with up to 95% yield and 97% ee of the cycloaddition product CIS-3b (Scheme 4.9) [17]. 

Hetero-Diels-Alder reactions of ,/i-unsaturated carbonyl compounds 186 with ethoxyallene are promoted by acid-free silica gel to give the [4+2]-adducts along with a small amount of [2 + 2]-adducts [151]. 

Kelly and colleagues91 explored the use of bisphenylenediol 103 as a catalyst in Diels-Alder reactions of a,/i-unsaturated carbonyl compounds. Activation of the dieno-phile occurred through double hydrogen bonding of the two hydroxyl functions on 103 to the carbonyl group on the dienophile. The reaction of cyclopentadiene with methyl vinyl ketone (equation 31) at ambient temperature showed, after a reaction time of 10 minutes, 3% of product formation in the absence of 103 against 90% of product formation in the presence of 0.4 equivalents of 103. 

A further useful reaction sequence, reported by Aumann [219], is based on the Diels-Alder reaction of 2-pyranylidene complexes with enamines (Figure 2.36). Retro-Diels-AIder reaction of the initially formed 3-oxabicycIo[2.2.2]octan-2-ylidene complex leads to elimination of metal hexacarbonyl and formation of a substituted cyclohexadiene. Although this sequence can also be performed with the corresponding carbonyl compounds (2//-2-pyranones), these normally... 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

The inverse type hetero-Diels-Alder reaction of functionally substituted a, p-unsaturated carbonyl compounds was also possible with -alkyl substituted enol ethers (Scheme 9) (25). This was demonstrated in the synthesis... 

Because a comprehensive discussion of the transition state of hydrogen-bond catalysis will be presented by Berkessel in Chapter 3, the hydrogen bond catalyzed hetero Diels-Alder reaction of butadiene with carbonyl compounds will be discussed briefly here. Huang and Rawal reported that the hetero Diels-Alder reaction of aminodiene with aldehyde exhibited significant solvent effects (Scheme 2.7) [15]. The reaction in CHCfi was accelerated 30 times in comparison with that in THF, while that in i-PrOH was accelerated 630 times. They proposed that the Diels-Alder reaction was promoted by the hydrogen-bond activation of aldehyde. This finding resulted in the development of TADDOL catalyst [3]. 

M. Essers, C. Muck-Lichtenfeld, G. Flaufe, Diastereoselective diels-alder reactions of a-Fluorinated a, -unsaturated carbonyl compounds Chemical consequences of fluorine substitution, J. Crg. Chem. 67 (2002) 4715-4721. 

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

---