MacMillan organocatalysis

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

Discussion Taddol-catalyzed DA reactions provide simple and direct routes to functionalized cyclohexenones in enantiomerically enriched form. As with the HDA reactions, the best results were obtained when pure diene and dienophile were used, and the reaction temperature was rigorously maintained. Traces of moisture or acid impact negatively upon diene stability and product enantio-purities. One important advantage of the method is the commercial availability of both taddol catalyst 119 and the diene. The best substrates for the taddol-catalyzed DA reactions were a-substituted acroleins. This reactivity profile is complementary to that found for the secondary amine-based organocatalysis developed by MacMillan and co-workers, in which -substituted acroleins provided the best results [116]. 

Nicewicz and MacMillan merged later photoredox catalysis and asymmetric organocatalysis to an efficient approach to the otherwise difficult asymmetric a-alkylation of aldehydes 118 by activated alkyl bromides 117 (Fig. 30) [183]. The concept of face differentiation at the a-position of aldehydes via chiral enamines 121 provides the basis for the method. This allows the formation of functionalized... 

Beeson TD, MacMillan DWC (2005) Enantioselective organocatalytic alpha-fluorination of aldehydes. J Am Chem Soc 127 8826-8828 Berkessel A, Groger H (2005) Asymmetric organocatalysis. Wiley-VCH, Weinheim... 

Iminium organocatalysis was key to the enantioselective total synthesis of (—)-flustramine B (157) from the marine bryozoan Flustra foliacea by MacMillan and co-workers (Scheme 31) [137], which is discussed here despite not incorporating the entire C5 unit in one step. On treatment of the Boc-protected... 

A decade has now passed since the studies of my laboratory and those of David MacMillan s refocused the considerable attention of the conununity on the profound potential of small organic molecules to catalyze asymmetric reactions. In this time, the scope of organocatalysis has enlarged considerably with respect both to the type of reactions catalyzed (aldol, cycloaddition, redox, asymmetric assembly and domino reactions, conjugate addition reactions, etc.) and the mechanisms used... 

However, all of these wonderfid contributions had a limited impact in the field of organic chemistry. The renaissance of organocatalysis came with the works of List, Barbas, and Lemer [27] in enamine chemistry and the works of D. W. C. MacMillan [28] in iminium chemistry in 2000. Since then, enormous efforts have been made by the chemical community toward the development of new catalysts and methodologies without the use of metals. 

The merging of photoredox catalysis with asymmetric organocatalysis was reported by MacMillan and Nicewicz in 2008 [104]. Initial studies in the MacMillan group were devoted to the imidazolidinone-catalyzed asymmetric a-functionaliza-tion of aldehydes with a-bromo ketones and esters [104a] and were subsequently expanded to enantioselective perfluoroalkylations [105] and benzylations [106]. The... 

In 2008, MacMillan and co-workers [13] reported the first total synthesis and structure revision of callipeltoside C (38), a cytotoxic marine macrolide, with amino acid proline as a suitable organocatalyst for the construction of three key intermediates. This elegant synthesis (18 steps, 12% overall yield) demonstrated the power of organocatalysis with unprecedented level of ease and efficiency, which involved a proline-catalyzed double diastereo-differentiating aldol reaction between propionaldehyde 18 and the Roche ester-derived aldehyde 28 to achieve 29 (12 1 dr, 99% ee), an organocatalytic a-oxyamination to afford 32 (99% ee), and proline-... 

In terms of modem organocatalysis, the publications of MacMillan et al. and List et al. in 2000 set the stage for two of the most important activation mechanisms employed in organocatalysis today iminium catalysis (27) and enamine catalysis (28). While MacMillan and co-workers used the chiral imidazolium salt 8 to... 

When summing up the recent achievements in iminium-activated natural product synthesis, the importance and versatility of this methodology cannot be overemphasized. Besides enamine catalysis, it is due particularly to the considerable achievements made in iminium catalysis that asymmetric organocatalysis has received so much attention over the last few years. As depicted in this chapter, the LUMO-lowering concept originally introduced by MacMillan has found widespread applications in natural product synthesis. In addition, it has been shown, that this activation mode works very well in cascade approaches. This methodology should become more widely utilized in the future (Table 2). 

Beeson TD, Mastracchio A, Hong JB, Ashton K, MacMillan DWC (2(X)7) Enantioselective Organocatalysis Using SOMO Activation. Science 316 582... 

Organocatalysis (See Chapter 2) MacMillan s group applied multiple asymmetric catalytic strategies to develop... 

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