Asymmetric reactions heteroatomic nucleophiles

The first report of asymmetric heteroatom conjugate addition to a,P-unsaturated sulfoxides was made in 1971 [11,12], and has been followed by few studies in this area relative to the analogous asymmetric reactions with carbon nucleophiles. The addition of piperidine in methanol to (-)-(S)-cis-propenyl p-tolyl sulfoxide (133)... 

The organocatalytic asymmetric conjugate addition of heteroatom nucleophiles to different electrophilic olefins has become a very popular reaction during the last few years. Different nitrogen, oxygen, sulfur, and selenium nucleophilic species have been successfully used leading to enantiomerically emiched heterofunctionalized derivatives. 

Catalytic reactions of allylic electrophiles with carbon or heteroatom nucleophiles to form the products of formal S 2 or S 2 substitutions (Equation 20.1) are called "catalytic allylic substitution reactions." Tliese reactions have become classic processes catalyzed by transition metal complexes and are often conducted in an asymmetric fashion. The aUylic electrophile is typically an allylic chloride, acetate, carbonate, or other t)q e of ester derived from an allylic alcohol. The nucleophile is most commonly a so-called soft nucleophile, such as the anion of a p-dicarbonyl compound, or it is a heteroatom nucleophile, such as an amine or the anion of an imide. The reactions with carbon nucleophiles are often called allylic alkylations. 

Enantiosdective allyic substitution processes have been developed over the course of 30 years. Initial observations of the reactions of nucleophiles with paUadium-allyl complexes led to the observation of catalytic substitutions of aUylic ethers and esters, and then catalytic enantioselective aUylic substitutions. The use of catalysts based on ottier metals has led to reactions that occur with complementary regiochemistry. Moreover, flie scope of the reactions has expanded to include heteroatom and unstabilized carbon nucleophiles. Suitable electrophiles for these reactions indude allyhc esters of various types, allyhc ethers, aUylic alcohols, and aUylic halides. Enantioselective reactions can be conducted with monoesters or by selection for deavage of one of two equivalent esters. The mechanism of these reactions occurs by initial oxidative addition to form a metal-aUyl complex. The second step involves nudeophilic attadc on ttie aUyl ligand for reaction of "soft" nudeophiles or inner-sphere reductive eUmination for reactions of "hard" nudeophiles. The external nudeophilic attack typicaUy occurs by reaction of the nudeophile with a cationic aUyl complex at the face opposite to that to which Uie metal is bound. Exceptions indude reactions of certain molybdenum-aUyl complexes. Dissociation of product then regenerates the starting catalyst. Because of the diversity of the classes of these reactions, aUylic substitution—in particular asymmetric aUylic substitution—has been used to prepare a wide variety of natural products. 

Making acetals that contain A-atoms has been a fairly straightforward effort, following the advent of asymmetric phosphoric acid catalysis [9, 10]. Since the reports of Akiyama and Terada, asymmetric additions of nucleophiles to imines became a well-developed area of asymmetric Brpnsted acid catalysis [11, 12]. Consequently, heteroatom nucleophiles were shown to be viable nucleophiles and various N,N-, N,0-, and A,S -acetals could be prepared for the first time in a catalytic asymmetric fashion. These reactions are briefly summarized in the next section. 

Modifications to the standard Nicholas reaction generally fall into the following categories asymmetric reactions, use of heteroatom nucleophiles, use of metals other than cobalt, reactions of neutral electrophiles, reactions of carbocations not in the a-position, cycloadditions, and rearrangements. 

The propargylic cations [Co2(/i,i/2,Tj3-RC2CR2)(CO)6]+ react as electrophiles with a variety of heteroatom- and carbon-centered nucleophiles to provide, following demetalation, propargylated products with complete regioselectivity. Complexation of the triple bond circumvents isomerization to allenic products. Reaction with asymmetrical ketones results in attack by the cation exclusively (>95%) at the more substituted a-carbon.72,74 (See Scheme 11.)... 

The vast majority of work on asymmetric Diels-Alder reactions deals with additions of 1,3-dienes to a, -alkenic carbonyl derivatives XXI) where the chirophore R is attached to the carbonyl group eiAer directly or via a heteroatom X, permitting subsequent removal of the auxiliary (e.g. by attack of a nucleophile Nu Scheme 75). 

The Michael addition of nucleophiles on oc,P-unsaturated electron withdrawing groups, often carbonyl-containing functional groups, is a widely used reaction for the formation of C—C or C—heteroatom bonds. When the Michael acceptor bears a substituent on the a-position to the carbonyl, then an asymmetric carbon is created upon protonation of the transient enolate generated by the nucleophilic addition (Scheme 7.9). 

While no asymmetric induction was observed in the present instance, prior examples with more sterically biased imines had given high levels of induction. A solution to this problem for the monocyclic p-lactam case was provided by chiral carbene complex 125 [75]. A variety of other imine analogs with N-heteroatom bonds were examined in the reaction sequence without success, presumably due to insufficient nucleophilicity of the nitrogen atom for attack on the ketene complex or insufficient electrophilicity of the imine analog for the required ring closure. 

Heteroatom variation has been accomplished using NaSH as a nucleophile in the S,. reactions (Scheme 1.12). Treatment of 37 with an amine, followed by reaction with NaSH furnished asymmetric dinitroarene (46). Reduction and cyclization gave a hybrid structure (47) which was cleanly alkylated to give 48. Use of excess NaSH with 37 yielded 49 which was used en route to bis(thiazole) (50). Alkylation could be performed stepwise, as in the synthesis of 42, to ultimately yield asymmetric structures, such as 51, bearing two thiazolium moieties. 

Many transition metal complexes catalyse the reaction but palladium systems are the most widely used. Allylic substitution can be used to create C-C as well as C-X (X = heteroatom) bonds under very mild conditions, which are compatible with many functional groups. The allylic substitution reaction is unique in the sense that there are many mechanisms that can be responsible for asymmetric induction and because chiral elements can be placed at the nucleophile, the electrophile or both. 

Four reviews on allylic substitution reactions have been published. The first deals with the enantioselective allylic substitutions by carbon nucleophiles, in the presence of both palladium and non-palladium catalysts. The second reviews stere- 0 oselective allylic substitution reactions forming asymmetric C-C, C-N, and C-O bonds. The third review covers new developments in metal-catalysed asymmetric 0 allylic substitution reactions with heteroatom-centred nucleophiles. Several applications of this new methodology are included. Finally, the catalytic 5 2 and 5 2 reactions of allylic alcohols, most of which occur with a very high ee, have been reviewed. ... 

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