Imides a,P-unsaturated

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Diels-Alder Reactions. Chiral a,p-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eq 50 and 51). Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, p,3-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53). In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer. 

Organocuprates also undergo conjugate addition with chiral a,p-unsaturated imides. Treatment of the imides derived from... 

Dimethylaluminum chloride also catalyzes the ene reactions of chiral a,p-unsaturated imides with 1,1-disubstituted alkenes in moderate yields and selectivities. ... 

In 2005, Chen and coworkers found that the epi-cinchonidine/cinchonine-derived thiourea catalysts, 79a,b, can serve as highly active promoters of the Michael addition ofthiophenol to the a,P-unsaturated imide 80 however, the reaction proceeded with low enantioselectivity (up to 17% ee) (Scheme 9.28) [22]. 

Tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands synthesized from tartaric acid have been extensively employed by Narasaka as the chiral control element in selective Diels-Alder reactions. Initial experiments were conducted with simple dienes and a,P-unsaturated imides using complex 44 (Scheme 36) [104,105]. Several rather subtle features have contributed to the success of these endeavors 1) the use of the acetophenone-derived dioxolane rather than the ac-etonide resulted in an increase of 20% ee 2) the use of alkyl-substituted benzenes as solvent augmented enantioselectivities relative to more common organic solvents e.g., CH2CI2, THF) [106] 3) use of 4 A molecular sieves was typically required to achieve maximum enantioselectivity. 

Titanium alcoholates of diols 2.50 generated by exchange with (/-PrO TiC are also potent catalysts, and the most efficient catalyst is derived from 2.50 (R = Me, R = Ar=Ph). These catalysts promote the diastereo- and enantioselective cycloaddition of cyclopentadiene or acyclic dienes with some a,P-unsaturated imides 7.68 (R = H, Rg=Me, MeOOC) [45, 778] or of acyclic dienes with substituted benzoquinones at -78°C [1572, 1573] (Figure 9.20). Reactions occur at 0°C in the presence of molecular sieves, and only catalytic amounts of these alcoholates are used. Intramolecular cycloadditions also give useful sdectivities under these conditions [1574]. However, the process for preparation of the catalyst varies according to the reaction [778, 1573], and this is veiy important to the observation of high selectivities. 

Although the transformation is not an oxidation, Eric N. Jacobsen of Harvard University has developed (J. Am, Chem. Soc. 2004, J26, 14724) an elegant route to enantiomerically-pure alcohols, based on the conjugate addition of an oxime such as 13 to an a,P-unsaturated imide such as 14. 

Furthermore, this catalyst promotes asymmetric Mannich reactions [31] and Michael addition of active methylene compounds to a,p-unsaturated imides [32]. 

Inokuma, T, Hoashi, Y. and Takemoto, Y. (2006) Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to a,P-unsaturated imides Dual activation of imide by intra- and intermolecular hydrogen bonding. Journal of the American Chemical Society, 128, 9413-9419. 

Znl2 was applied successfiilly as Lewis-acid in order to increase the diastereoselectivity of the reaction of a cyclic nitrone with a,P-unsaturated imide derivatives. - It is noteworthy that chiral auxiliaries efficient in numerous other transformations, exhibit only low stereoselection in cycloadditions of nitrones. " ... 

Scheme 4.69 Enantioselective sulfa-Michael reaction of aryl and alkylthiols with a,P-unsaturated imides.

Scheme 3.13 1,3-Dipolar cycloaddition of nitrile oxides with a,p-unsaturated imides.

Scheme 2.96 Thiourea-catedyzed asymmetric Michael addition of activated methylenes to a,p-unsaturated imides...

Scheme 1.16 Michael additions of malononitrile to a,P-unsaturated imides catalysed by a tertiary amine thiourea.

In 2003, the Jacobsen group developed a novel enantioselective Michael addition of cyanide to a,p-unsaturated imides with (S,S)- salen)Al catalyst ent-3 as the catalyst (Scheme 19.18). It should be noted that the method used for generation of hydrogen cyanide proved particularly important no reaction was observed when hydrogen cyanide alone was used as a cyanide source, but good reactivity was obtained with hydrogen eyanide generated in situ from trimethylsilyl cyanide and an alcohol such as 2-propanol [vide infra). 

Scheme 19.18 As mimetric Michael additions of cyanide to a,p-unsaturated imides catalysed by an Al(salen) complex.

The covalently linked dinuclear (salen)Al complex 24 and the macrocyclic cyclooctene-supported salen-AlCl catalyst 25 were applied in the asymmetric Michael addition of cyanide to a,p-unsaturated imides (Scheme 19.20). The Jacobsen group found that the covalently linked catalyst 24 had several orders of magnitude greater reactivity than the mononuclear analogue [S,S)-Al(salen) ent-3, and the enantioselectivities were comparable.In the... 

The first catalytic asymmetric Michael addition of an mygen-centred addition of salicylaldoxime to a,p-unsaturated imides was achieved by the Jacobsen group in 2004 (Scheme 19.34). With p-oxo dimer catalyst [r,R)-[(salan)Al]20 5 as the catalyst, a series of a,p-unsaturated imides worked well. It should be noted that this method could tolerate ester, acetal, and silyl ether functionality, allowing its potential application as an acetate aldol alternative in polyketide natural product synthesis. When combined with efficient N-O bond hydrogenolysis, this (salen)aluminium-catalysed reaction enables the net enantioselective hydration of electron-deficient olefins with no need for purification of the intermediate oxime ethers. 

Scheme 19.34 Asymmetric Michael additions of oxime to a,p-unsaturated imides catalysed 1 [(salanjAlJjO.

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