Enantioselectivity inversion

Our development of the catalytic enantioselective inverse electron-demand cycloaddition reaction [49], which was followed by related papers by Evans et al. [38, 48], focused in the initial phase on the reaction of mainly / , y-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a (Scheme 4.34). 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

Oxymercuration/demercuration provides a milder alternative for the conventional acid-catalyzed hydration of alkenes. The reaction also provides the Markovnikov regiochemistry for unsymmetrical alkenes.33 Interestingly, an enantioselective/inverse phase-transfer catalysis (IPTC) reaction for the Markovnikov hydration of double bonds by an oxymercuration-demercuration reaction with cyclodextrins as catalysts was recently reported.34 Relative to the more common phase-transfer... 

The enantioselective inverse electron-demand 1,3-dipolar cycloadditions of nitrones with alkenes described so far are catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminium complexes. However, the glyoxylate-derived nitrone 256 favors abidentate coordination to the catalyst, and this nitrone is an interesting substrate, since the products that are obtained from the reaction with alkenes are masked ot-amino acids (Scheme 12.81). 

Various allylic amines and protected allylic alcohols were tested using different cyclodextrins. Although only low to moderate enantioselectivity was obtained, the method demonstrated for the first time an enantioselective inverse phase-transfer catalysis hydration reaction via an oxymercuration-demercuration process. 

I. E. Marko, G. R. Evans, P. Seres, I. Chelle, Z. Janousek, Catalytic, Enantioselective, Inverse Eectron-Demand Diels-Alder Reactions of 2-Pyrone Derivatives, PureAppl. Chem. 1996, 68, 113. 

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

Scheme 3.26 Enantioselective inverse-electron-demand Hetero-Diels-Alder reaction of aldehyde and enone...

A highly enantioselective inverse-electron-demand aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes 88 and aldehydes 71 was reported by Chen and his co-workers. Scheme 3.31 [46]. Few chiral piperidine derivatives 89 were prepared via this methodology. The addition of water in the reaction media led to a dramatic acceleration of the reaction. Presumably, water is helpful for the hydrolysis of the catalyst-incorporated intermediate to release the catalyst and thus enable the catalytic turnover. Noteworthy, replacement of acetic acid to stronger acid, e.g. p-tolue-nesulfonic acid, resulted in no reaction. 

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

Marko and coworkers applied the similar chiral Yb/BINOL/amine catalyst to enantioselective inverse-electron demand Diels-Alder reactions as shown in Scheme 13.22 [55]. When the reaction of 3-carbomethoxy-2-pyrone with phenyl vinyl sulfide was carried out in the presence of THF additive (5-10 mol equiv to Yb), the bicyclic lactone was obtained in 92% yield and in more than 95% ee. The use of the THF additive was essential to achieve high enantioselectivity. In the absence of the THF additive, the enantioselectivity decreased significantly. Vinyl ethers were also applicable as a dienophile, giving products in excellent selectivities. 

The enantioselective inverse electron-demand HDA reaction promoted by titanium complexes was first reported by Wada using TADDOL as the chiral inducer [169], As shown in Scheme 14.73, the reaction of ( )-2-oxo-l-phenylsulfonyl-3-alkenes with a large excess of vinyl ethers in the presence of 10 mol% of TADDOL-TiBr2 at —78°C gave the adduct as a single cis isomer in 91% yield and 59% ee. The enantiomeric excesses of the adducts are highly dependent on the bulkiness of the alkoxy substituent R of the dienophiles. 

Nitrones activated by chiral 2,2 -dihydroxy-l,P-bisnaphthol (BINOL)-AlMe complexes undergo enantioselective inverse-electron-demand 1,3-dipolar cycloaddition reactions with electron-rich alkenes to produce exo-diastereoisomers of isoxazolidines. The diastereoselectivity of the 1,3-dipolar cycloaddition between diphenyl nitrone and 4-(5 )-benzyl-( )-but-2 -enoyl)-l,3-oxazolidin-2-one can be controlled by inorganic salts whose cations behave like Lewis acids.The Cu(OTf)2-bisoxazoline-catalysed asymmetric 1,3-dipolar cycloaddition of nitrones with electron-rich alkenes at room temperature gave isoxazolidines in good yields and diastereoselectivity and with high enantioselectivities of up to 94% ee. ° Kinetic studies have shown that the reaction rate of the 1,3-dipolar cycloaddition of C,tV-diphenyl nitrone with dibutyl fumarate increases dramatically in aqueous solutions... 

Employing a bifunctional enamine/metal Lewis acid catalyst enabled Wang and coworkers to perform a highly chemo-and enantioselective inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones with 8,y-unsaturated a-ketoesters (eq 12).21... 

Simonsen KB, Bayon P, Hazell RG, Gothelf KV, Jprgensen KA (1999) Catalytic enantioselective inverse-electron demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes. J Am Chem Soc 121 3845-3853... 

In 2009, Feng and coworkers developed new guanidine catalysts with an amino amide skeleton [139]. Among the various catalysts tested, guanidine 49 was found to be the most active for the enantioselective Michael reaction of a (i-ketoester with nitroolefins (Scheme 10.46). The conjugate addition products were obtained in high yields and excellent diastereo- and enantioselectivities. The same researchers used bis-guanidine catalysts for the enantioselective inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones (Scheme 10.47) [140] and enantioselective Mannich-type reaction of a-isothiocyanato imide and sulfonyl imines (Scheme 10.48) [141]. 

Scheme 10.47 Enantioselective inverse-electron-demand hetero-Diels-Alder reaction of azlactones.

In 2003, the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of p,Y-unsaturated-a-ketones 97 with aldehydes 98 promoted by a secondary amine catalyst (99) was accomplished by the j0rgensen group (41). After oxidation by pyridinium chlorochromate (PCC), various trans-lactones 100 were afforded with good yields and up to 94% ee (Scheme 38.27). The reaction is proposed to occur via an enamine intermediate generated from chiral secondary amine 99 and aldehydes 98 (transition state O). Notably, sUica gel is essential for regeneration of the chiral amine catalyst. 

An enantioselective inverse-electron-demand hetero-Diels-Alder reaction of o-quinones 104 and aldehydes 98 was disclosed by the Dixon group with the use of secondary amine catalyst 105 [44]. This reaction went smoothly through in situ generated enamines with o-quinone reagents to afford the corresponding products 106 (with up to 81% ee), which can be further converted into optically active 2,3-dihydro-benzo[l,4]dioxin compounds (Scheme 38.28). 

In 2006, Bode and coworkers reported the first enantioselective inverse-electron-demand hetero-Diels-Alder reaction of enals 130 with a,(i-unsaturated imines 131 under the catalysis of carbene precatalyst 123 in combination with Hiinig s base [59]. A broad range of substrates were well tolerated to afford synthetically important dihydropyridinone products 132 in good yields with remarkable enantioselec-tivities (Scheme 38.38). The need to introduce electron-withdrawing groups for enals only lies within the increased electrophilicity of these substrates, which enhances the rate of their reaction with the nucleophilic catalysts. The observed... 

Inverse-Electron-Demand [4+2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas group s ingenious design of Diels-Alder reactions using enamine-activated dienes, Jprgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse-electron-demand hetero-Diels-Alder reaction (Scheme 1.24) [26]. 

---