Brpnsted base chiral

Keywords Asymmetric organocatalysis Bifunctional catalyst Brpnsted base Chiral scaffold Cinchona akaloid Cyclohexane-diamine Guanidine... 

JMM, van HemertLJC, Quaedflieg PJLM, Rutjes FPJT Chem Soc Rev (2008) 37 29 (d) Gdmez Arrayas R, Carretero JC (2009) Chem Soc Rev 38 1940], The overview of the activities in this field is subdivided following the different types of catalysts that have been utilized. This includes catalysis by enanfine-fomfing chiral amines, chiral Brpnsted bases, chiral Brpnsted acids, and phase-transfer catalysts. 

Besides their use as Brpnsted bases, chiral tertiary amines have very successfully been used as asymmetric nucleophilic catalysts. Their catalytic potential has been known for decades, and systematic investigations have led to the development of a variety of powerful (a)chiral methodologies [88, 92]. Some of the most prominent applications involve the in situ generation of chiral ammonium enolates, which can then be employed for an impressively diverse variety of reactions as illustrated in Scheme 6.32 (for a detailed overview of this rather broad application field of chiral tertiary amines, please see more focused reviews and the literature cited therein [92]). Besides the good... 

Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brpnsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated a-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2-dihydrobenzo /j]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. 

The advent of chiral Brpnsted base catalysis began with the recognition that the Cinchona alkaloids serve as excellent catalysts [7-12] and privileged structures... 

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

Another type of Cinchona alkaloid catalyzed reactions that employs azodicarbo-xylates includes enantioselective allylic amination. Jprgensen [51-53] investigated the enantioselective electrophilic addition to aUyhc C-H bonds activated by a chiral Brpnsted base. Using Cinchona alkaloids, the first enantioselective, metal-free aUyhc amination was reported using alkylidene cyanoacetates with dialkyl azodi-carboxylates (Scheme 12). The product was further functionalized and used in subsequent tandem reactions to generate useful chiral building blocks (52, 53). Subsequent work was applied to other types of allylic nitriles in the addition to a,P-unsaturated aldehydes and P-substituted nitro-olefins (Scheme 13). 

Bifunctional catalysts have proven to be very powerful in asymmetric organic transformations [3], It is proposed that these chiral catalysts possess both Brpnsted base and acid character allowing for activation of both electrophile and nucleophile for enantioselective carbon-carbon bond formation [89], Pioneers Jacobsen, Takemoto, Johnston, Li, Wang and Tsogoeva have illustrated the synthetic utility of the bifunctional catalysts in various organic transformations with a class of cyclohexane-diamine derived catalysts (Fig. 6). In general, these catalysts contain a Brpnsted basic tertiary nitrogen, which activates the substrate for asymmetric catalysis, in conjunction with a Brpnsted acid moiety, such as urea or pyridinium proton. 

Michael-aldol for 2-mercaptobenzaldehydes and maleimides. Use of catalyst 166 provided a variety of fused heterocycles in high yield and high enantiomeric ratios (Scheme 44). The authors propose that the chiral catalyst simultaneously activates the thiol and the maleimide via Brpnsted base and acid interactions. It was proposed that the pre-transition state arrangement of the catalyst and substrates determines the stereochemical outcome. 

The authors proposed that the Brpnsted base interaction on the catalyst is imperative for reactivity. Catalysts lacking a basic amine moiety, specifically mono- and bis-ureas, did not promote the asymmetric catalytic addition well, if at all. In screening a variety of amine bases and bis-ureas, it became apparent that presence of a Brpnsted base was necessary for catalytic activity (Scheme 61) [113]. The reactivity was extremely low in absence of Brpnsted base (Table 2, entry 2), but slightly improved with presence of NEtj (Table 2, entry 1). Combined, a chiral Brpnsted acid and Brpnsted base increase conversion and showed some enantiose-lectivity (Fig. 8). 

While the significance of the bifunctional Brpnsted base catalysts has been illustrated in the previous sections, few examples rely solely on a Brpnsted base interaction for asymmetric catalysis. However, in the past few decades, a novel catalyst system has emerged as a powerful promoter of chiral transformations. The guanidines have gained the reputation as super bases in organic transformations. 

The authors reported the first chiral guanidine catalyzed addition of nitro-olefms to aldehydes (Scheme 62, Table 3). While reactivity and selectivity were not optimal, the discovery led to great developments in the field of asymmetric Brpnsted base catalysis. 

The chiral guanidine s role as a strong Brpnsted base for the reactions of protic substrates has been proposed. In 1999, Corey developed a C -symmetric chiral guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition of HCN to imines was promoted high yields and high enantioselectivities for both electron-withdrawing and electron-donating aromatic imines (Scheme 64). 

The authors also investigated the mode of activation of these BINOL-derived catalysts. They proposed an oligomeric structure, in which one Ln-BINOL moiety acts as a Brpnsted base, that deprotonates the hydroperoxide and the other moiety acts as Lewis acid, which activates the enone and controls its orientation towards the oxidant . This model explains the observed chiral amplification effect, that is the ee of the epoxide product exceeds the ee of the catalyst. The stereoselective synthesis of cw-epoxyketones from acyclic cw-enones is difficult due to the tendency of the cw-enones to isomerize to the more stable fraw5-derivatives during the oxidation. In 1998, Shibasaki and coworkers reported that the ytterbium-(f )-3-hydroxymethyl-BINOL system also showed catalytic activity for the oxidation of aliphatic (Z)-enones 129 to cw-epoxides 130 with good yields... 

In certain cases, seemingly simple enolates can have a chiral memory effect . For example, treatment of a-imino lactam (5)-88 with f-BuOK in CD3OD for 6-13 days at 25°C gave the corresponding enantiomerically deuteriated a-imino lactam l-d-(S)-89 in quantitative yield with 98% D incorporation and ee 97% (equation 15) , via a conformationally chiral enolate. This methodology has been extended towards enan-tioselective alkylation of enolates. Excellent levels of enantioselectivity (ee 88%) were achieved for a-imino lactam (S)-SS using KHMDS as Brpnsted base and benzyl iodide as the electrophile . Interestingly, to prevent unwanted racemization of the intermediate enolate, the reaction time for deprotonation was lowered to 10 seconds, and to ensure rapid alkylation, 20 equivalents of Bnl were used . 

With respect to the catalysts employed in conjugate additions, a big collection of efficient stable and environmentally friendly natural or newly designed chiral organocatalysts has already been developed. These catalysts are usually cheap to prepare and readily accessible in a range of quantities. They fall into four major classes Lewis bases, Lewis acids, Brpnsted bases, and Brpnsted acids [If]. The identification of the generic modes of activation of these catalysts has been crucial to the success of organocatalysis. 

Chiral ion pairs (B, Fig. 2.2) can be formed by deprotonation of the pronucleophile with a chiral Brpnsted base or employing an achiral base and a chiral phase-transfer catalyst. Chiral phase-transfer catalysis (PTC) [8] illustrates how ion pairing interactions can be used to carry out the enantioface discrimination in conjugate addition reactions. In both cases, the chiral cation is responsible for... 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

Schans and co-workers envisioned the apphcation of cinchona alkaloids 47a-d as chiral Brpnsted base catalysts in the asymmetric Mannich reaction of acetoacetates 45 with iV-acylimines 23a, 46a-c (Schane 5.25) [35]. Promising results were reported when the chiral base cinchonine (47a) was employed, while the cinchona alkaloid quinine (47b) gave considerably lower selectivities. Opposite selectivities were observed when the pseudo-ematiamers cinchoitidine (47c) and qniitidine (47d) were used. 

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

Instead of using Br0nsted bases, chiral Br0nsted acids can also be utilized to enanti-oselectively acquire Mannich products. The acidic catalyst assists in the Mannich reaction by protonating the imine, thereby forming an iminium ion to which the deprotonated Brpnsted acid catalyst coordinates. This chiral counterion directs the incoming nucleophile and leads to an optically active Mannich product. 

The new chiral ammonium betaine 112 was developed and utilized by Ooi et al. as a bifunctional organic base catalyst for Mannich-type reaction of a-nitrocarbox-ylates [63]. This quaternary ammonium compound is an internal salt, unlike the aforementioned intermolecular ion-pairing ammonium salts. Consequently, the anion could act as a Brpnsted base and deprotonate a pronucleophile. The resulting... 

Some bifunctional hydrogen-bond donor/Brpnsted base catalysts are shown in Figures 2.39 and 2.40. They comprise chiral amino alcohols and amino phenols, chiral amine-thiourea derivatives, and chiral guanidines, among others. In the absence of detailed experimental NMR or kinetic studies [179], most of our... 

Non-chiral imidazolium carbenes were also used as Brpnsted bases to directly generate the aldehyde enolates for an intramolecular Michael reaction of 0=CH(CH2)4CH=CXY (X = COPh, CO2R Y = H, CO2R) to produce 1,2-rran5-disubstituted cyclopentanes. ... 

Building upon these concepts, this chapter firstly gives an insight into the modes of action of a selection of non-covalent chiral organocatalysts, employing chiral Brpnsted acid catalysis, chiral Brpnsted base catalysis, and chiral phase-transfer catalysis (PTC). Further sections of this chapter describe two separate case studies that aim to compare and contrast selected covalent and non-covalent strategies for achieving two distinct processes, acyl transfer reactions and asymmetric pericyclic processes. 

Select applications of chiral Brpnsted acid, chiral Brpnsted base, and chiral PTC have been demonstrated in this chapter as representative examples of asymmetric non-covalent organocatalytic processes. To farther directly contrast covalent and non-covalent organocatalysis, two case studies that highlight select acyl transfer and pericyclic strategies follow. 

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