Hayashi methodology

The Hayashi methodology is particularly interesting as the original pre-catalyst Fe(acac)3 had already been reported as the best candidate for the coupling between aryl and vinyl halides in THF. This means that improved control over the selectivity of this cross-coupling is achieved just by changing the nature of the solvent. 

The power of their methodology was demonstrated by Hayashi and Ozawa in a remarkably short synthesis of 18, an antagonist of the plate-... 

Suzuki, H., Shirotori, T., and Hayashi, M. (2004). A liver micronucleus assay using young rats exposed to diethylnitrosamine Methodological establishment and evaluation. Cytogenet Genome Res 104, 299-303. 

In contrast to the plethora of methodologies showing stereoselective applications of the Jorgensen-Hayashi catalyst (Chapter 8), a few reports have addressed the catal3dic ability of prolinol carbon-ethers in asymmetric synthesis. These procedures focused on the employment of commercially available (5)- or (R)-2-metho3qmiethylpyrrolidine, a scaffold originally... 

Using a similar approach, but assisted by Jprgensen/Hayashi prolinol ether catalysts, Fustero et al. [103] and Carter and co-workers [104] have independently documented additional innovative applications of this intramolecular reaction providing a practical route to enantioenriched piperidines from the corresponding co-amino a,p-unsaturated aldehydes (Scheme 11.28). This methodology has been later expanded successfiiUy to the synthesis of quinoUzidine alkaloids such as... 

Ohnishi J, Mitsuhashi S, Hayashi M, Ando S, Yokoi H, Ochiai K, Ikeda M. (2002). A novel methodology employing Corynebacterium glutamicum genome information to generate a new L-lysine-producing mutant. Appl Microbiol Biotechnol, 58, 217-223. 

Higashihara T, Hayashi M, Hirao A. Synthesis of weU-deflned star branched polymers by stepwise iterative methodology using Uving anionic polymerization. Prog Polym Sci. 2011 36 323-75. 

Maltsev, O. V. A. O. Chizhov and S. G. Zlotin (2011). "chiral ionic liquid/esi-ms methodology as an efficient tool for the study of transformations of supported organocatalysts deactivation pathways of jorgensen-hayashi-type catalysts in asymmetric michael reactions." Chemistry, Vol.l7, No.22, (May 23, 2011), pp. 6109-6117, ISSN 1521-3765... 

Domino Sequences Involving Oxindoles as Pronucleophiles Another commonly used approach for the synthesis of spirooxindoles relies on the use of simple oxindoles as pronucleophiles with several Michael acceptors. For example, we developed a highly enantioselective methodology for the synthesis of spirooxindoles by a Michael-Michael-aldol cascade (Scheme 10.19) [30]. Simple 2-oxindole (58) undergoes two consecutive Michael reactions with enals 16 catalyzed by the Jprgensen-Hayashi catalyst I. Next, an intramolecular aldol reaction catalyzed by the same catalyst takes place to afford, after dehydration, the corresponding spirooxindoles 59. 

Hirao, A., Inoue, K., Higashihara, T., and Hayashi, M. (2008b) Successive synthesis of well-defined star-laanched polymers by iterative methodology based on living anionic polymerization. Polymer Journal, 40,923-941. 

To better evaluate both methods the results of the direct aldol reaction of acetone with selected aromatic aldehydes catalyzed by prohne are presented in Figure 21.2. Although in general the Kotsuki approach offers much better yields, in the Hayashi method higher enantioselectivities (temperature effect) can be obtained. This methodology was also tested in a solvent-free aldol reaction with cyclopentanone but no improvement was noticed [23]. 

Another key reaction for the addition of carbon nucleophiles to enals was reported by Wei Wang [34] and Hayashi in 2007 [35]. Hayashi developed the addition of nitromethane to enals catalyzed by 27. The reaction renders the final y-nitro-aldehydes in excellent yields and enantioselectivities with aromatic and aliphatic enals. At almost the same time Ye and coworkers reported the same reaction with slightly different reaction conditions (Scheme 33.11) [36]. The only limitation of the cited methodologies was the poor diastereoselectivities obtained when nitroalkanes other than nitromethane were reacted. Remarkably, these methodologies allow the synthesis of baclofen (a potent GABAP receptor agonist) or pregabalin in enantiopure form in a few chemical steps. 

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