1,3-Cycloaddition enantioselective

We are now standing in the middle of the next step of the development of cycloaddition reactions - catalytic and catalytic enantioselective versions. The last two decades have been important in catalysis - how can we increase the reaction rate, and the chemo-, regio, diastereo-, and enantioselectivity of cycloaddition reactions. Metal catalysis can meet all these requirements ... 

One interesting phenomenon was the effect of the boron substituent on enantioselectivity. The stereochemistry of the reaction of a-substituted a,/ -unsatu-rated aldehydes was completely independent of the steric features of the boron substituents, probably because of a preference for the s-trans conformation in the transition state in all cases. On the other hand, the stereochemistry of the reaction of cyclopentadiene with a-unsubstituted a,/ -unsaturated aldehydes was dramatically reversed on altering the structure of the boron substituents, because the stable conformation changed from s-cis to s-trans, resulting in production of the opposite enantiomer. It should be noted that selective cycloadditions of a-unsubsti-tuted a,/ -unsaturated aldehydes are rarer than those of a-substituted a,/ -unsatu-... 

Enantioselective [2+1] Cycloaddition Cyclopropanation with Zinc Carbenoids... 

Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds... 

This chapter will focus on the development of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes (Scheme 4.1) [3]. 

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

To achieve catalytic enantioselective cycloaddition reactions of carbonyl compounds, coordination of a chiral Lewis acid to the carbonyl functionality is necessary. This coordination activates the substrate and provides the chiral environment that forces the approach of a diene to the substrate from the less sterically hindered face, introducing enantioselectivity into the reaction. 

The catalytic enantioselective cycloaddition reaction of carbonyl compounds with conjugated dienes has been in intensive development in recent years with the main focus on synthetic aspects the number of mechanistic studies has been limited. This chapter will focus on the development and understanding of cycloaddition reactions of carbonyl compounds with chiral Lewis acid catalysts for the preparation of optically active six-membered ring systems. 

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. 

Yamamoto et al. were probably the first to report that chiral aluminum(III) catalysts are effective in the cycloaddition reactions of aldehydes [11]. The use of chiral BINOL-AlMe complexes (R)-S was found to be highly effective in the cycloaddition reaction of a variety of aldehydes with activated Danishefsky-type dienes. The reaction of benzaldehyde la with Danishefsky s diene 2a and traws-l-methoxy-2-methyl-3-(trimethylsilyloxy)-l,3-pentadiene 2b affords cis dihydropyrones, cis-3, as the major product in high yield with up to 97% ee (Scheme 4.6). The choice of the bulky triarylsilyl moiety in catalyst (J )-8b is crucial for high yield and the en-antioselectivity of the reaction in contrast with this the catalysts derived from AlMe3 and (J )-3,3 -disubstituted binaphthol (substituent = H, Me, Ph) were effective in stoichiometric amounts only and were less satisfactory with regard to reactivity and enantioselectivity. 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

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]. 

Keck et al. reported that a catalyst generated from (S)- or (l )-BINOL 12 and Ti(0-i-Pr)4 in a 2 1 ratio is more selective than the catalyst formed from a 1 1 mixture [19fj. The former catalyst was shown to catalyze the cycloaddition reaction of aldehydes 1 with Danishefsky s diene 2a affording the dihydropyrones 3 with moderate to excellent enantioselectivity (Scheme 4.12). The reaction proceeds well for different aldehydes with up to 97% ee and good yield of the cycloaddition products. 

A chiral vanadium complex, bis(3-(heptafluorobutyryl)camphorato)oxovana-dium(IV), can catalyze the cycloaddition reaction of, mainly, benzaldehyde with dienes of the Danishefsky type with moderate to good enantioselectivity [21]. A thorough investigation was performed with benzaldehyde and different activated dienes, and reactions involving double stereo differentiation using a chiral aldehyde. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

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