Enantioselective Cycloaddition Reactions

The enantioselective cycloaddition reaction catalyzed by chiral BOX-copper(II) complexes has been used for conjugated cyclic dienes, e.g. 1,3-cyclohexadiene 5c, as shown in Scheme 4.21 [9, 32]. This cycloaddition reaction is dependent on sol- 

Enantioselective cycloaddition reactions of methyl 2-[(phenylsulfonyl)methyl]-2-propenylcar-bonate (13) with methyl acrylate and 3-buten-2-one in the presence of a chiral ferrocenylphos-phane-palladium catalyst gives optically active methylencyclopcntane derivatives 14 with up 

Enantioselective cycloaddition reactions of ketenes catalyzed by N-het-erocyclic carbenes 13SL1614. 

Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds 

I 4 Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds 4.3 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

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. 

Jprgensen, K. A. Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds. In Cycloaddition Reactions in Organic Synthesis-, Kobayashi, S., Jprgensen, K. A., Eds. Wiley-VCH Weinheim, 2001 pp 151-186. 

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. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II) 

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. 

S,3,)-(EBIH)Zr(=NAr)(THF)2 promotes highly enantioselective cycloaddition reactions with allenes and, in certain cases, this system allows conversion of an allene racemate into a mixture enriched in one enantiomer. Mechanistic studies about the enantioselective cycloaddition and stereoinversion of allenes mediated by imidozirconocenes have revealed that the initial [2 + 2]-cycloaddition to form the azazirconacyclobutane is stereospecific and is not involved in the racemization process.728 The reactive zirconocene imido precursor r -(EBIH)Zr(NHBut)(Me) 958 has been shown to activate a variety of hydrocarbons R-H with primary alkyl, alkenyl, and aryl G-H bonds to form the corresponding alkyl derivative r -(EBIH)Zr(NHBut)(R) 959 with concomitant elimination of methane729 (Scheme 240). Mechanistic experiments support the proposal of intramolecular elimination of methane followed by hydrocarbon G-H addition. 

Jacobsen et al. took an important step towards the development of a more general catalytic enantioselective cycloaddition reaction of carbonyl compounds by introducing chiral tridentate Schiff base chromium(III) complexes 15 (Scheme 4.15) 

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

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]. 

The chiral BOX-copper(II) complexes are effective catalysts for enantioselective cycloaddition reactions of a,/ -unsaturated acyl phosphonates [48] and a,/ -unsaturated keto esters [38b, 49]. 

Cationic BINAP-palladium and platinum complexes 30a,b can catalyze highly enantioselective cycloaddition reactions of arylglyoxals with acyclic and cyclic 

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. 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

Because ketones are generally less reactive than aldehydes, cycloaddition reaction of ketones should be expected to be more difficult to achieve. This is well reflected in the few reported catalytic enantioselective cycloaddition reactions of ketones compared with the many successful examples on the enantioselective reaction of aldehydes. Before our investigations of catalytic enantioselective cycloaddition reactions of activated ketones [43] there was probably only one example reported of such a reaction by Jankowski et al. using the menthoxyaluminum catalyst 34 and the chiral lanthanide catalyst 16, where the highest enantiomeric excess of the cycloaddition product 33 was 15% for the reaction of ketomalonate 32 with 1-methoxy-l,3-butadiene 5e catalyzed by 34, as outlined in Scheme 4.26 [16]. 

The interest in chiral titanium(IV) complexes as catalysts for reactions of carbonyl compounds has, e.g., been the application of BINOL-titanium(IV) complexes for ene reactions [8, 19]. In the field of catalytic enantioselective cycloaddition reactions, methyl glyoxylate 4b reacts with isoprene 5b catalyzed by BINOL-TiX2 20 to give the cycloaddition product 6c and the ene product 7b in 1 4 ratio enantio-selectivity is excellent - 97% ee for the cycloaddition product (Scheme 4.19) [28]. 

Chen et al. [51] recently developed a procedure to enhance the use of enantio-selective 1,3-dipolar cycloadditions ofazomethine ylides [52] with electron-deficient olefins. The reaction is of interest because its stereospecificity enables stereochemical diversification of up to four tetrahedral centers on a pyrrolidine ring skeleton. A commercial catalyst, (S)-QUINAP, in combination with Ag(l) acetate, was used to carry out the enantioselective cycloaddition reaction (Figure 15.19). Both enantiomers of the new catalyst system are easily prepared from commercially available reagents. 4-Hydroxybenzaldehyde was loaded onto 500-600-pm polystyrene alkylsilyl-derivatized macrobeads to result in 19.1, which was then subjected 

While copper and iron Lewis acids are the most prominent late transition metal Diels-Alder catalysts, there are reports on the use of other chiral complexes derived from ruthenium [97,98],rhodium [99],andzinc [100] in enantioselective cycloaddition reactions, with variable levels of success. As a comparison study, the reactions of a zinc(II)-bis(oxazoline) catalyst 41 and zinc(II)-pyridylbis(ox-azoline) catalyst 42 were evaluated side-by-side with their copper(II) counterparts (Scheme 34) [101]. The study concluded that zinc(II) Lewis acids catalyzed a few cycloadditions selectively, but, in contrast to the [Cu(f-Bubox)](SbFg)2 complex 31b (Sect. 3.2.1), enantioselectivity was not maintained over a range of temperatures or substitution patterns on the dienophile. An X-ray crystal structure of [Zn(Ph-box)] (01)2 revealed a tetrahedral metal center the absolute stereochemistry of the adduct was consistent with the reaction from that geometry and opposite that obtained with Cu(II) complex 31. 

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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