Organocatalysts chiral

Finally, a highly efficient organocatalytic asymmetric approach was described by Gong et al. in 2006, using chiral phosphoric acids as catalysts. These results opened a window for the development of new optically active DHPMs synthesis (Scheme 19) [96, 97]. More recently, chiral organocatalysts such as Cinchona... 

An asymmetric Mannich reaction was recently successfully achieved by means of different types of catalyst, metal- and organocatalysts [20, 21]. With the latter the reaction can be performed asymmetrically by use of L-proline and related compounds as chiral organocatalyst [22-35]. A key advantage of the proline-catalyzed route is that unmodified ketones are used as donors, which is synthetically highly attractive. In contrast, many other asymmetric catalytic methods require preformed enolate equivalents as nucleophile. 

Trichlorosilylenolates of type 13 were used as nucleophiles. Such enolates are highly activated ketone derivatives and react spontaneously with several aldehydes at room temperature. At —78 °C, however, the uncatalyzed reaction can be suppressed almost completely (formation of the undesired racemic aldol adduct is only 4%). Thus, at —78 °C and in the presence of the chiral organocatalyst 14 the acetone-derived enolate and benzaldehyde gave the desired adduct in high yield... 

Scheme 2. Enantioselective variant of the Strecker reaction catalyzed by chiral organocatalysts [12d],...

Recently, a small library of novel axially chiral bis-arylthioureas 148-161 as chiral organocatalyst has been prepared and evaluated for the asymmetric addition of N-melhylindole to nitroolefins. Initial studies have shown that the relatively simple and readily prepared (S)-154 is the optimal structure (Scheme 40) [120]. 

The synthesis of the enantiomerically enriched (74% ee) tetrahydroin-dolizine 368 is the most crucial step for synthesis of (-)-rhazinal (369), (-)-rhazinilam (6), (-)-leucunolam (370) and (+)-epz-leucunolam (371) alkaloids [239]. The selective intramolecular conjugate additions of pyrrole to N-tethered Michael acceptors were achieved by using chiral organocatalyst 320c (Scheme 77). 

Even if chiral organocatalysts were used, the authors did not focus on the development of an asymmetric version of the reaction. 

All chiral organocatalysts developed to date that mediate Type I acyl transfer processes are believed to impart their acceleration and stereoinduction primarily via a nucleophilic catalytic cycle (Fig. 8.1) [35],... 

To date, there have been no examples of asymmetric reductions of ketones by Hantzsch esters and a chiral organocatalyst. 

Although the turnover frequency (TOF) and turnover number (TON) of the various above-described organocatalysts remain modest when compared to metal catalysis, the chiral organocatalysts are of relatively simple structure, and this permits easy tuning of the reaction. Clearly, one can predict many improvements in this area in the future, and undoubtedly new organocatalytic reactions relating to reduction will be introduced, using some of the basic processes described in Section 11.1. 

A selection of chiral organocatalysts is presented in this chapter. The compounds are classed according to the chiral inductor classes preset in their structure. Bold numbers below the molecules refer to the corresponding chapter where further information on typical reaction scope can be found. 

Breitenlechner, S., Selig, P., and Bach, T. (2007) Chiral organocatalysts for enantioselective photochemical reactions, in Ernst Sobering Foundation Symposium Proceedings, vol. 2 (eds. M.T. Reetz, B. List, S. Jaroch and H. Weinmann), Springer-Verlag, Berlin, pp. 255-279. 

Oxazinones of the general structure 7 are configurationally stable. Consequently, alcoholytic ring opening with a chiral organocatalyst was expected to afford kinetic resolution (KR), but no DKR (Scheme 6). In fact, a number of oxazinones could be resolved kinetically and with excellent selectivity (Scheme 7 Berkessel et al. 2005). Figure 6 shows a typical time course for the kinetic resolution of a P3-amino acid derived oxazinone. 

Figure 63 Some triazolium based chiral organocatalysts.

The enantioselective nucleophilic addition of prochiral C=0 and C=N moieties to the corresponding saturated chiral products is one of the most important stereoselective transformations on both the laboratory and the industrial scale. Although, over the past few decades, remarkable scientific achievements have been made in these research areas by using a variety of transitional metal-based catalysts, the sensitivity of the reaction to moisture and oxygen, as well as the toxic metal contamination of the product, usually restrict its practical application. Thus, currently, there is much interest in chiral organocatalysts, as they tend to be less toxic and more environmental friendly than traditional metal-based catalysts [1]. They are usually robust and thus tolerate moisture and oxygen, so that they usually do not demand any special reaction conditions. 

In the presence of the newly developed chiral organocatalyst le, the ring annu-lation reaction of acetylene dicarboxylates and 3-formylchromones successfully gave rise to tricyclic benzopyrones 7 in good yield (46-91%) and with enantioselectivity of 81-87% ee (Table 10.4) [14],... 

Chen et al. have further applied the TFA salt of 9-amino-9-deoxyepiquinine lo as chiral organocatalyst to the desymmetrization of prochiral a,a-dicyanoalkenes from 4-substituted cyclohexanones via domino Michael-Michael addition reactions with a, 3-unsaturated ketones. These reactions exhibited high synthetic efficacy and bicyclic products 16 with two new C—C bonds, and four stereogenic centers... 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

So far, cinchona chemistry has focused mainly on applications as chiral ligands and chiral organocatalysts. Chemical alterations in alkaloids have usually been a minor issue and also unfashionable in this context. In fact, the first 10 chapters of this handbook provide many impressive examples for these applications, but there is more to the chemistry of cinchona alkaloids than that. New reactions and new structures have come to light only recently in both fundamental and applied works. Landmark developments are... 

This multiauthor handbook will cover the whole spectrum of cinchona alkaloid chemistry ranging from the fundamentals to industrial applications. This book is organized in four units, namely, the use of cinchona alkaloids as chirality inducers in metal-promoted reactions (Chapters 2-4), the use of cinchona alkaloids as chiral organocatalysts (Chapters 5-11), the organic chemistry of cinchona alkaloids themselves (Chapter 12), and the use of cinchona alkaloids as chiral discriminating agents... 

Given these excellent results, it is surprising that this approach has not been used more extensively for chiral organic catalyst discovery. The success of this methodology is even more significant if it is considered that catalysts 6 are among the few chiral organocatalysts to be currently employed at the industrial level [12]. 

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