Enantioselective Alkylation Reactions

The easy preparation of the solid-supported substrate 72, the high enantioselectivity, and the very mild reaction conditions make this method very practical for the synthesis of the chiral non-natural R-amino acid library via combinatorial synthesis or parallel synthesis. 

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Interestingly, enantioselective alkylation reactions [64] were also developed using, for instance, Cu(OTf)2, [65], [Cu(SbF6)2, Zn(OTf)2] [66], Cu(C104)2-6H20 [67] or Sc (OTf)3 [68] in combination with diverse chiral ligands. Remarkably, organocatalytic alkylations of pyrroles, indoles and anilines by 3-phenylpropenal have been also developed [69]. 

The first example of the use of an alkaloid-based chiral phase-transfer catalyst as an efficient organocatalyst for enantioselective alkylation reactions was reported in 1984 [3, 4]. Researchers from Merck used a cinchoninium bromide, 8, as a catalyst... 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

The advantages of PTC reactions are moderate reaction conditions, practically no formation of by-products, a simple work-up procedure (the organic product is exclusively found in the organic phase), and the use of inexpensive solvents without a need for anhydrous reaction conditions. PTC reactions have been widely adopted, including in industrial processes, for substitution, displacement, condensation, oxidation and reduction, as well as polymerization reactions. The application of chiral ammonium salts such as A-(9-anthracenylmethyl)cinchonium and -cinchonidinium salts as PT catalysts even allows enantioselective alkylation reactions with ee values up to 80-90% see reference [883] for a review. Crown ethers, cryptands, and polyethylene glycol (PEG) dialkyl ethers have also been used as PT catalysts, particularly for solid-liquid PTC reactions cf. Eqs. (5-127) to (5-130) in Section 5.5.4. 

Scheme 4. Ru-catalyzed ring-closing methathesis processes, in conjunction with Zr-vatalyzed enantioselective alkylation reactions provide a convenient protocol for efficient synthesis of optically pure materials...

In the Zr-catalyzed enantioselective alkylation reactions discussed above, we discussed transformations that involve the addition of alkylmagnesium halides and alkylaluminum reagents to olefins. With the exception of studies carried out by Negishi and coworkers, all other processes involve the reaction of a C-C n system that is adjacent to a C-0 bond. Also with the exception of the Negishi study [Eqs. (6) and (7)], where direct olefin carbometallation occurs, all enantioselective alkylations involve the intermediacy of a metallacyclopentane (cf. Scheme 3). In this segment of our discussion, we will examine the Ni-catalyzed addition of hard nucleophiles (e.g., alkylmagnesium halides) to olefins that bear a neighboring C-0 unit. These reactions transpire by neither of the above two mechanistic manifolds (metallacyclopentane intermediacy or direct carbometallation). Rather, these processes take place via a Ni-Ti-allyl complex. 

In the Zr-calalyzed enantioselective alkylation reactions discussed above, we discussed transformations that involve the addition of alkylmag-nesium halides and alkylaluminum reagents to olefins. With the exception of studies carried out by Negishi and co-workers, all other processes... 

The most familiar of the sulfonic adds derived from camphor is 10-camphorsulfonic add (44, Reychler s acid45). Both enantiomers are commercially available and convenient procedures exist for their preparation by sulfonation of camphor (ref 46 exemplifies the racemate, but the procedure works equally well for optically active camphor). The free acid is often applied to the resolution of basic compounds such as amines. A detailed review on the use of derivatives of this acid as auxiliaries has been given3. Esters of this add are normally obtained by the reaction of the alcohols with the sulfonyl chloride which is also commerdally available (or readily obtained by the reaction of the free acid with phosphorus pentachloride or thionyl chloride46,48). Such esters with unsaturated alcohols have been used for diastereoselective [1,2] sigma tropic rearrangements (Section D.1.6.3.3.). Allyl esters have been used for enantioselective alkylation reactions, in which camphorsulfonic acid reacts as the chiral leaving group (Section D.1.1.2.2.). 

The presence of a strongly electron-attracting group, such as trifluoromethyl can both enhance the reactivity of the carbonyl group and stabilize the carbinol. As a result, such compounds have been the most successful in giving the carbinol product. One of the first successful enantioselective alkylation reactions was carried out using 3,3,3-trifluoropyruvate esters [122]. 

Gordillo R, Carter J, Houk KN (2004) Theoretical explorations of enantioselective alkylation reactions of pyrroles and indoles organoeatalyzed by chiral imidazolidinones. Adv Synth Catal 346 1175 1185. doi 10.1002/adsc.200404107... 

In the same year, Chi et al. developed an enantioselective oxidative coupling of tertiary amines with ahphatic aldehydes by combination of copper catalysis and aminocatalysis (Scheme 2.6) [31]. Both A -Aryl tetrohydroisoquinolines and simple A-Aryl tertiary amines can undergo this enantioselective alkylation reaction. Soon afterwards, organocatalytic enantioselective CDC reaction of ethers with aliphatic aldehydes [32] and Cu-catalyzed asymmetric CDC reaction of iV-carbamoyl tetrahydroisoquinohnes with terminal alkynes [33] were reported. 

Proline derivatives have also been used in enantioselective tandem Birch reduc-tion/alkylation sequence [33]. In 1984, Schultz reported the enantioselective alkylation reaction of an amide enolate derived in the course of a Birch reduction [34]. This reaction serves as a versatile tool for the enantioselective construction of highly substituted cyclohexanes bearing a chiral quaternary carbon center. A variety... 

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