Electron deficient asymmetric nucleophilic addition

Asymmetric Nucleophilic Addition to Electron Deficient Alkenes... 

A number of techniques are now available allowing the preparation of enantiomerically pure (or at least enriched) compounds via asymmetric nucleophilic addition to electron-deficient alkenes. Some of these transformations have already been successfully applied in total synthesis. In most cases, the methods are based on diastereoselective reactions, employing chirally modified substrates or nucleophiles. There are only very few useful enantioselective procedures accessible so far. The search for efficient en-antioselective methods, especially for those which are catalytic and do not require the use of stoichiometric amounts of chiral auxiliaries, remains a challenging task for the future. 

Schmalz, H.-G. Asymmetric Nucleophilic Addition to Electron Deficient Alkenes. in Comp. Org. Synth, (eds. Trost, B. M.,Eleming, I.), 4, 199-236 (Pergamon, Oxford, 1991). 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Although dimeric Sharpless ligands as catalysts showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 5.12) [70]. These compounds are bifunctional catalysts in the presence of acid additives one of the two amine function of the dimers forms a salt and serves as an effective Bronsted acid, while another tertiary amine of the catalyst acts as a nucleophile. Whereas salts derived from (DHQD)2PYR, or (DHQD)2PHAL afforded trace amounts of products in the addition of methyl acrylate 8a and electron-deficient aromatic aldehydes such as 27, (DHQD)2AQN, 56, mediated the same transformation in ee up to 77%, albeit in low yield. It should be noted that, without acid, the reaction afforded the opposite enantiomer in a slow conversion. 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

In connection with the total synthesis of grandisol, an asymmetric addition of ethylene on chiral heterocyclic aminals and ketals was examined (Scheme 23). The selectivity can be high, with a preferred approach of ethylene from the less hindered side, especially when chiral pyrrolidone 97 or furanones 100 were used in place of cyclic enones [70]. The diastereoisomeric excess of 101 or 102 remains modest with 5-menthyloxy furanone, even if the dark addition of nucleophiles or radicals on 100 occurs with a total facial selectivity. From a detailed analysis of the dependence of the product ratio with temperature and substituents, it was proposed that a pyramidalization of the 3-carbon in the relaxed -ir,- of the excited furanones and a homoanomeric effect were responsible for the observed selectivity [71]. Excited cyclopentenones also possess a biradical character in their relaxed state. However, no regio and no stereoselectivity could be detected when cyclopentenone was selectively excited in the presence of 5-men-thyloxyfuranone. An initial energy transfer, followed by a cycloaddition of the triplet excited furanone with cyclopentenone, explains these poor results. With more flexible or more electron deficient cyclenones the facial selectivity increases, but mixtures of regioisomers and syn/anti stereoisomers are obtained [72]. 

The double bonds of electron-deficient olefins (carbonyl compounds, nitriles, sulfones, sulfoxides, nitro derivatives, etc.) have a low-lying LUMO that can allow the attack of various nucleophiles. The nucleophiles can be neutral or negatively charged heteroatomic species, or they can be carbon species such as organometal-lic reagents or enolates. In the case of heteroatomic nucleophiles, asymmetric additions can be performed in the presence of chiral catalysts, with chiral reagents, or with substrates bearing chiral residues. 

Although simple isocyanates are not electrophilic enough to add to alkenes, electron-deficient isocyanates will add to alkenes. Chlorosulfonyl isocyanate is the most reactive and most commonly used isocyanate105-107. It undergoes stereospecific syn addition to alkenes. The carbonyl group adds to the most nucleophilic end of the double bond. The chlorosulfonyl group can be reductively hydrolyzed with sodium sulfite. Asymmetric induction will result from addition to... 

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