Enantioselectivity catalyzed reactions

The focus in this section is the electrophilic a-functionalization of 2,2-dimethyl-l,3-dioxan-5-one. Various reactions have been carried out, such as alkylations, aldol additions, Mannich reactions, and transition metal-catalyzed reactions. Conditions were described for diastereoselective transformations, or auxiliary controlled diastereoselective transformations, providing enantiomerically pure products, and enantioselectively catalyzed reactions using organo-catalysts. 

At present, the molecular recognition of CD and its derivatives has been successfully applied in antimer compounds, stereoselective separation in chromatography, modeling enzyme and enantioselective catalyzed reactions [46]. 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

Scheme 2.11. Enantioselective lyansfomiatlons Based on Enzyme-Catalyzed Reactions Which Differentiate Enantiotopic Substituents...

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]. 

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. 

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]. 

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-... 

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

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 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]. 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

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)... 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

In the nitrone cycloaddition reactions catalyzed by the l ,J -DBFOX/Ph transition metal complexes also, the diastereo- and enantioselectivities were found to depend upon the presence of MS 4 A [71]. Thus, both the selectivities were much lowered in the iron(II) or nickel(II) complex-catalyzed reactions without MS 4 A,... 

Ni(C104)2 6H2O showed a litde better enantioselectivity than the anhydrous complex. Although the uncatalyzed reaction was highly exo selective (cis/trans=i 97), the catalyzed reactions were very poor in diastereoselectivity, a mixture of endo and exo cycloadducts being formed. We expected that this poor diastereoselectivity would not be a serious problem since the same enantioface should be involved at the 2-position of the diastereomeric cycloadducts (Scheme 7.27). The best enantioselectivity (cis > 99% ee, trans 94% ee) was observed when the reaction was catalyzed by l ,J -DBFOX/Ph-Ni(SbF6)2 (50 mol%). With the decreased amount of catalyst (10 mol%) still a satisfactory level of enantioselectivity was observed for the cis cycloadduct (94% ee). 

Several approaches to enantioselective synthesis have been taken, but the most efficient are those that use chiral catalysts to temporarily hold a substrate molecule in an unsymmetrical environment—exactly the same strategy that nature uses when catalyzing reactions with chiral enzymes. While in that unsymmetrical environment, the substrate may be more open to reaction on one side than on another, leading to an excess of one enantiomeric product over another. As an analog)7, think about picking up a coffee mug in your... 

Good results were obtained with (R)-0-acryloylpantolactone (4) in which the dienophile was incorporated with a smaller chiral auxiliary. Some results are reported in Table 4.4, where the cycloadditions catalyzed by Zn(II)-, Fe(II)- and Ti(IV)-K-10 exchanged montmorillonite calcined at 120 °C and 550 °C are compared with those that were not catalyzed and with TiCU- and EtAlCh-catalyzed reactions. Among the metal-clays activated, the Ti(IV)-K-10 was the best catalyst with high conversion and acceptable enantioselectivity obtained after 2 h. 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

Metal-assisted enantioselective catalytic reactions are one of the most important areas in organic chemistry [1-3]. They require the appropriate design and the preparation of chiral transition metal complexes, a field also of major importance in modern synthetic chemistry. These complexes are selected on both their ability to catalyze a given reaction and their potential as asymmetric inducers. To fulfill the first function, it is absolutely required that the catalysts display accessible metal coordination sites where reactants can bind since activation would result from a direct interaction between the metal ion... 

However, the reactions were not enantioselective ones, though the most important aspect of the biocatalysis reaction should be in the enantioselective reaction. We and KragF independently reported the first enantioselective lipase-catalyzed reaction in February-March 2001. Since lipase was anchored by the IL solvent and remained in it after the extraction work-up of the product, we succeeded in demonstrating that recyclable use of the lipase in the [bmim][PFg] solvent system was possible (Fig. 2). ... 

Modified enantioselectivity was reported if the reaction was carried out in an IL solvent instead of traditional organic soivent. For instance, Kaziauskas and Kim independently reported that the regioselectivity of lipase-catalyzed reaction was enhanced if the reaction was carried out in an IL solvent system (Fig. 13). " " Recently Wu and co-workers reported another chip of iipase-catalyzed reaction a... 

An IL solvent system is applicable to not only lipase but also other enzymes, though examples are still limited for hpase-catalyzed reaction in a pure IL solvent. But several types of enzymatic reaction or microhe-mediated reaction have been reported in a mixed solvent of IL with water. Howarth reported Baker s yeast reduction of a ketone in a mixed solvent of [hmim] [PFg] with water (10 1) (Fig. 16). Enhanced enantioselectivity was obtained compared to the reaction in a buffer solution, while the chemical yield dropped. 

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