Stereoselectivity Michael-aldol process

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

Scheme 2.94. Stereoselective domino Michael/aldol/lactonization process.

The intermediate enolate formed in a Michael reaction normally undergoes protonation to give the ketone product. However, in the presence of an aldehyde, a Michael/Aldol cascade can occur. Using the racemic Michael acceptor (11.41), Shibasaki has demonstrated an enantioselective and diastereoselective Michael/Aldol cascade involving the malonate nucleophile (11.42) and the aldehyde (11.43). The process also involves a kinetic resolution of the starting material. Not only is this a remarkable example of several aspects of stereoselectivity, the product (11.44) is a useful prostaglandin precursor. 

The first example of the application of pincer complex catalysts for selective synthesis involves aldol type of reactions involving imines and isocyanoacetates. In aldol [13-27] and Michael addition [13, 28-34] reactions, palladium pincer complexes have usually been employed as Lewis acid catalysts, for the first time by Richards and coworkers [13, 28]. This also means that the palladium(II) atom in these processes is not involved in redox reactions, and therefore reduction to palladium(O) does not happen. The aldol and the Michael reactions are useful C-C bond-forming reactions. In these processes, new stereocenters are generated, and therefore the processes can be used for stereoselective synthesis. A typical example is the reaction of suUbnimines (2) with isocyanoacetate (3) to form imidazohne (4) derivatives. The imidazolines can be easily hydrolyzed to diamino acid derivatives in a one-pot process (Figure 4.2) [24]. 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

Other Lewis acid mediated C-C bond forming reactions of silylated C-nucleophiles include the Mukaiyama aldol and Michael additions of enolsilanes ), the related reaction of allylsilanes described by Sakurai ) as well as similar reactions of Me3SiCN ). Other "inert C-nucleophiles such as dialkylzinc compounds also react with carbonyl compounds in the presence of Lewis acids ). We ourselves have utilized many of these processes in performing stereoselective reactions, particularly in achieving diastereofacial selectivity in the reactions... 

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