Organocatalytic asymmetric

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Abstract An overview of the area of organocatalytic asymmetric acyl transfer processes is presented inclnding O- andiV-acylation. The material has been ordered according to the structnral class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the varions reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates. 

Scheme 49 Organocatalytic asymmetric reductive Mannich reaction...

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... 

Martin NJA, Cheng X, List B (2008) Organocatalytic asymmetric transferhydrogenation of heta-nitroacrylates accessing beta(2)-amino acids. J Am Chem Soc 130 13862-13863... 

Jiang J, Yu J, Sun XX, Rao QQ, Gong LZ (2008) Organocatalytic asymmetric three-component cyclization of cinnamaldehydes and primary amines with 1,3-dicarbonyl compounds straightforward access to enantiomerically enriched dihydropyridines. Angew Chem Int Ed 47 2458-2462... 

An organocatalytic asymmetric hydroxylation was developed using spiro-Meldrum s acid derivatives, 20mol% proline, and nitrosobenzene. In fact, the heterocyclic moiety was necessary for a high-yielding asymmetric induction (Equation 67) <20050L1577, 2006OBC2685>. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

Chiral Quaternary Ammonium Fluorides Preparation and Application to Organocatalytic Asymmetric Reactions... 

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

Organocatalytic asymmetric alkylation methodology has also been efficiently applied in a practical multi-gram synthesis of pharmaceutically interesting, optically active (—)-physostigmine analogs [7]. In the presence of 15 mol% of the catalyst 13 alkylation of the oxindole substrate 12 with chloroacetonitrile furnished the desired product 14 in 83% yield and 73% ee (Scheme 3.3, Eq. 2). The counter-ion of the... 

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 Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

In the text below organocatalytic asymmetric aldol reactions are classified into indirect aldol reactions and direct aldol reactions . Indirect aldol reactions are syntheses which require a modified ketone as a starting material (Scheme 6.9, pathway 1). For example, enolates which are prepared in a previous step starting from the ketone are often used. Syntheses which allow the direct use of a ketone, in a non-activated form, as a nucleophile are defined as direct aldol reaction (Scheme 6.9, pathway 2). 

The intramolecular aldol reaction of triketones with asymmetric desymmetrization has been known for a long time. When Eder, Sauer, and Wiechert [97, 98], and in parallel Hajos and Parrish [99-101] reported this reaction in the early 1970s it was the first example of an asymmetric catalytic aldol reaction, and one of the first examples of an organocatalytic asymmetric synthesis [104]. 

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. 

Asymmetric addition of ketenes to aldehydes is a highly attractive synthetic access to yfi-lactones with perfect atom economy [134, 135]. This reaction can be catalyzed efficiently by using chiral amines as organocatalysts. As early as 1967 Borr-mann et al. described an organocatalytic asymmetric ketene addition to aldehydes [136] chiral tertiary amines, in particular (—)-N,N-dimethyl-a-phenylethylamine or (—)-brucine, were used as catalysts [136]. The resulting lactones were obtained with modest enantioselectivity of up to 44% ee. 

Wu in Comprehensive Asymmetric Catalysis I-III (Eds. Jacobsen, E. N. Pfaltz, A. Yamamoto H.), Springer, Berlin, 1999, p. 649f. (c) For organocatalytic asymmetric epoxidations, see chapter 10. 

In conclusion, the organocatalytic asymmetric a-amination of aldehydes and ketones using proline as catalyst is a new and attractive access to optically active N-protected a-amino aldehydes and ketones and related derivatives, e.g. a-amino acid esters. 

In summary, the organocatalytic asymmetric a-aminooxylation of aldehydes and ketones with proline as catalyst is a highly enantioselective means of preparation of a-hydroxy carbonyl compounds, and their derivatives. Because this field has been developed only recently, more examples and work on extension of organocatalyst screening and process development can be expected in the near future. 

Organocatalytic asymmetric carbonyl reductions have been achieved with boranes in the presence of oxazaborolidine and phosphorus-based catalysts (Section 11.1), with borohydride reagents in the presence of phase-transfer catalysts (Section 11.2), and with hydrosilanes in the presence of chiral nucleophilic activators (Section 11.3). 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

Scheme 14. Organocatalytic asymmetric reductive amination of ketones...

Scheme 20. Organocatalytic asymmetric transfer hydrogenation of different a, 3-unsaturated aldehydes...

Bertelsen S, Halland N, Bachmann S, Marigo M, Braunton A, Jprgensen KA (2005) Organocatalytic asymmetric alpha-bromination of aldehydes and ketones. Chem Commun (Camb) 14 4821 1823 Betancort JM, Barbas CF 3rd (2001) Catalytic direct asymmetric Michael reactions taming naked aldehyde donors. Qrg Lett 3 3737-3740... 

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