Intermediates organocatalytic

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The cyclopropane moiety is a fundamental class of functional group present in both natural products and numerous therapeutic agents. It has provided the impetus for significant breakthroughs in the use of metal carbenoids [151] and organocatalytic ylide intermediates [152, 153] such that rehable methods exist for most disconnective strategies on this ring system. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

A direct organocatalytic Michael reaction of ketones or aldehydes with /3-nitrostyrene has been reported in brine solution, using a bifunctional catalyst system proline-derived diamine (70) and TFA.203 In some cases the conversion, yield, de, and ee all exceeded 95%. Results in water were poor, mainly due to polymerization, which is catalysed by amines. It is proposed that sodium cations stabilize the anionic intermediate formed from (70) and /3-nitrostyrene, thus minimizing polymer formation. While organic co-solvent is not required, an organic-rich phase is proposed to concentrate the Michael reactants and catalysts, thus accelerating the reaction. 

Because of its efficiency and broad substrate tolerance with regard to the alkyl halide, organocatalytic asymmetric alkylation has been applied to the synthesis of several unusual amino acids. These non-natural amino acids are often key intermediates in the synthesis of biologically active peptides and other compounds of pharmaceutical importance. 

The organocatalytic asymmetric intramolecular aldol reaction has also been used in the synthesis of a gibbane framework [117]. The proline-catalyzed aldol cycliza-tion of the triketone 104 into the tricyclic system 106 proceeds via the unstable ketol 105 (Scheme 6.47). For this reaction, which occurred at room temperature, a catalytic amount (10 mol%) of L-proline was used. The enone 106 was furnished in 92% yield and a single recrystallization resulted in an enantiomerically pure sample of 106. This aldol product 106 served as a useful intermediate in the synthesis of the desired gibbane framework. 

The Danishefsky group reported the use of an organocatalytic intramolecular aldol reaction in the synthesis of a key intermediate, 108, for preparation of optically active estrone and commercially relevant 19-norsteroids [118, 119]. In the presence... 

In summary, several reports have shown that asymmetric modified aldol reactions using y-dienolates, nitroalkanes, or nitrones as donors can (in principal) be performed by use of organocatalysts. Often, however, enantioselectivity is moderate only, and must still be improved. Because these organocatalytic reactions give important intermediates, e.g. for synthesis of pharmaceuticals, it can be expected that this field of modified aldol reactions with organocatalysts will gain further synthetic importance in the future. 

Nucleophilic addition of sulfur ylides to C=0 double bonds is an important means of synthesis of epoxides [198], Because optically active epoxides are widely applied as versatile intermediates in the preparation of, e.g., pharmaceuticals, the asymmetric design of this sulfur ylide-based reaction has attracted much interest [199, 200, 212, 213], One aspect of this asymmetric organocatalytic process which has been realized by several groups is shown in Scheme 6.87A. In the first step a chiral sulfur ylide of type 204 is formed in a nucleophilic substitution reaction starting from a halogenated alkane, a base, and a chiral sulfide of type 203 as organocata-... 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

Peelen TJ, Chi Y, Gellman SH (2005) Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones cocatalyst effects and evidence for an enamine intermediate. J Am Chem Soc 127 11598— 11599... 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

All the examples reported so far for the enantioselective organocatalytic aminox-ylation (nucleophile attacks to the oxygen atom of the nitroso derivative) or hydro-xyamination (nucleophile attacks to the nitrogen atom of the nitroso derivative) have employed an enamine intermediate and nitrosobenzene, but O-selectivity is obtained in majority. In 2007, a selective a-hydroxyamination was disclosed with cinchona alkaloids by Jorgensen and coworkers (Scheme 6.43) [72]. They developed the organocatalytic asymmetric addition of a-aryl-a-cyanoacetates 133 to nitrosobenzene (144) catalyzed by (—(-quinine in high yields and moderate enantioselectivities up to 59% ee. 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

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