Phosphoric acids, chiral

Hiemstra et al. reported recently an asymmetric phosphoric acid-catalyzed Pictet-Spengler reaction of benzyltryptamines to gain access to chiral p-carbolines with good yields and selectivities 382). The versatility of this protocol was 

7 Chiral Br0nsted Acids and Hydiogtm Bonding Donors 

In 2(K)3, Rawal reported the use of TADDOLs (tetraaryl-1,3-dioxolan-4,5-dimethanol) as chiral H-bonding catalysts to facilitate highly enantioselective hetero-Diels-Alder reactions (393). Not surprisingly, this impressive protocol has soon found its way into the repertoire of organic chemists interested in natural product synthesis (394, 395). 

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At the same time, however, the iridium-catalyzed hydrogenation of 80 was reported using chiral phosphoric acid diester 17be based on BINOL [47a]. Full conversion and a maximum e.e. of 50% was observed, again in a slow reaction. Interestingly, a catalyst based on palladium and 17be afforded 39% e.e. and full conversion in the hydrogenation of aryl imine 87. 

The absolute configurations of the products have now been determined (23) and the reaction promises to be of considerable interest, since Jacques and his colleagues have shown that chiral phosphoric acids are useful resolving agents (86). 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

In this review, we present asymmetric reactions catalyzed by stronger Brpnsted acids. The scope and limitations of chiral phosphoric acids, iV-triflyl phosphoramides, and dicarboxylic acids are described considering articles published until the middle of 2008. Although the mechanisms of a few transformations have been investigated in some detail, they are not the focus of this review. 

Axially chiral phosphoric acid 3 was chosen as a potential catalyst due to its unique characteristics (Fig. 2). (1) The phosphorus atom and its optically active ligand form a seven-membered ring which prevents free rotation around the P-0 bond and therefore fixes the conformation of Brpnsted acid 3. This structural feature cannot be found in analogous carboxylic or sulfonic acids. (2) Phosphate 3 with the appropriate acid ity should activate potential substrates via protonation and hence increase their electrophilicity. Subsequent attack of a nucleophile and related processes could result in the formation of enantioenriched products via steren-chemical communication between the cationic protonated substrate and the chiral phosphate anion. (3) Since the phosphoryl oxygen atom of Brpnsted acid 3 provides an additional Lewis basic site, chiral BINOL phosphate 3 might act as bifunctional catalyst. 

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

In the presence of a primary amine (48) and chiral phosphoric acid R)-3o (5 mol%, R = a-branched aldehydes 50 undergo a quick racemiza-... 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

In 2008, the Rueping group reported the addition of nitroalkanes 78 to A-PMP-protected a-imino esters 79 in the presence of chiral phosphoric acid (R)-14r (10 mol%, R = SiPhj) (Scheme 29) [51]. This transformation provided P-nitro-a-amino esters 80 in good yields (57-93%), anrt-diastereoselectivities (2 1-13 1) and enan-tioselectivities (84-92% ee). 

In 2006, the Rueping group showed that chiral phosphoric acid (R)-31 (10 mol%, R = 9-phenanthryl) with 9-phenanthryl substituents promoted the addition of HCN to iV-benzylated aldimines 83 (Scheme 31) [53]. a-Amino nitriles 84 were obtained in good yields (53-97%) along with high enantioselectivities (85-99% ee) and could be transformed into the corresponding a-amino acids. 

Mechanistically the reaction is proposed to proceed via a nine-membered transition state with the chiral phosphoric acid simultaneously activating the imine by protonation and the phosphite by coordinating to the hydroxyl group (Fig. 9). 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

In 2007, Terada et al. extended their previously described chiral phosphoric acid-catalyzed aza-ene-type reaction of M-acyl aldimines with disubstituted enecarbamates (Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry to enantioenriched piperidines 121 (Scheme 48). The sequential process was rendered possible by using monosubstituted 122 instead of a disubstituted enecarbamate 76 to produce a reactive aldimine intermediate 123, which is prone to undergo a further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent intramolecular cychzation of intermediate 124 terminates the sequence. The optimal chiral BINOL phosphate (R)-3h (2-5 mol%, R = 4-Ph-C H ) provided the 2,4,6-sub-stituted M-Boc-protected piperidines 121 in good to exceUent yields (68 to > 99%) and accomplished the formation of three stereogenic centers with high diastereo- and exceUent enantiocontrol (7.3 1 to 19 1 transicis, 97 to > 99% ee(trans)) [72]. 

In 2007, AntiUa and coworkers described the Brpnsted add-catalyzed desymmetrization of me yo-aziridines giving vicinal diamines [75]. hi recent years, chiral phosphoric acids have been widely recognized as powerful catalysts for the activation of imines. However, prior to this work, electrophiles other than imines or related substrates like enecarbamates or enamides have been omitted. In the presence of VAPOL-derived phosphoric acid catalyst (5)-16 (10 mol%) and azidotrimethylsilane as the nucleophile, aziridines 129 were converted into the corresponding ring-opened prodncts 130 in good yields and enantioselectivities (49-97%, 70-95% ee) (Scheme 53). 

In the same year, chiral phosphoric acids were found to catalyze the enantioselective Baeyer-ViUiger (BY) oxidation of 3-substituted cyclobutanones 140 with aqueous... 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

Until 2006, a severe limitation in the field of chiral Brpnsted acid catalysis was the restriction to reactive substrates. The acidity of BINOL-derived chiral phosphoric acids is appropriate to activate various imine compounds through protonation and a broad range of efficient and highly enantioselective, phosphoric acid-catalyzed transformations involving imines have been developed. However, the activation of simple carbonyl compounds by means of Brpnsted acid catalysis proved to be rather challenging since the acid ity of the known BINOL-derived phosphoric acids is mostly insufficient. Carbonyl compounds and other less reactive substrates often require a stronger Brpnsted acid catalyst. 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

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... 

Scheme 19 Chiral phosphoric acid organocatalyzed Biginelli reaction...

Recently, an asymmetric version of this reaction has been reported by Gong and co-workers, allowing an efficient access to highly enantiomerically enriched 4-aryl-substituted 1,4-DHPs [152]. Thus, the use of chiral phosphoric acids as catalysts allowed the preparation of the desired products with enantiomeric excesses up to 97% (Scheme 53). To illustrate the importance of this asymmetric cyclization reaction, the authors developed the synthesis of some optically active heterocycles... 

Chiral phosphoric acids powerful organocatalysts for asymmetric addition reactions to imines (S. J. Connon, 2006) [5a]. 

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

Figure 5.2 Important structural and electronic properties of BINOL-derived chiral phosphoric acids.

In 2004, List reported that several ammonium salts including dibenzylammonium trifluoroacetate catalyzed the chemoselective 1,4 reduction of a, 5-unsaturated aldehydes with Hantszch esters as hydride sources [40]. It is assumed that substrate activation via iminium ion formation results in selective 1,4 addition of hydride. Subsequently, List [41] and MacMillan [42] reported asymmetric versions of this reaction promoted by chiral imidazoUdinone salts. In this context, several reports of this metal-free reductive process catalyzed by chiral phosphoric acids have appeared in the recent literature. 

While BINOL-derived chiral phosphoric acids have received great attention, a handful of reports implementing alternative chiral backbones have appeared [51]. 

Lastly, Antilla has disclosed a novel asymmetric desymmetrization of a wide range of aliphatic, aromatic, and heterocyclic meso-aziridines with TMS-N3 promoted by 11 and related 12 (Scheme 5.31) [56]. Uniquely, this is one of only several reports of electrophilic activation of nonimine substrates by a chiral phosphoric acid. Mechanistic studies suggest that silylation of 11 or 12 by displacement of azide generates the active catalytic species A. Consequently, the aziridine is activated through coordination of it carbonyl with chiral silane A to produce intermediate B. Nucleophilic ring opening by azide furnishes the desymmetrized product and regenerates 11 or 12. 

Prior to Yamamoto s entry into this field, the scope of chiral phosphoric acid catalysis was strictly limited to electrophiUc activation of imine substrates. By designing a catalyst with higher acidity it was suspected that activation of less Lewis basic substrates might be possible. To this end, Yamamoto reported incorporation of the strongly electron accepting N-triflyl group [57] into a phosphoric acid derivative to yield the highly acidic N-triflyl phosphoramide 13 (Scheme 5.32)... 

This novel Bronsted acid catalyzes the Diels-Alder reaction between ethyl vinyl ketone and various acycUc siloxy dienes to furnish adducts in uniformly high yields and ee s. Further, the corresponding chiral phosphoric acid was unable to catalyze this reaction. 

Mayer and used achiral amines and chiral phosphoric acids to form the... 

The last two catalytic systems available are intimately based on the stoichiometric ligands 22 and 23, derived from the dipeptide and the chiral phosphoric acid, respectively. The addition of basic additives to slow down or suppress the background reaction allowed the use of catalytic amounts of the ligand. In his initial report, Shi and coworkers have shown that adding 1 equivalent of ethyl methoxyacetate allowed the catalyst loading to be decreased to 0.25 equiv (equation 96) . Under these conditions, the enantioselectivities are similar to those reported in Figure 7. 

Another important means of mediation of metal-free catalytic enantioselective Mannich-type reactions is via electrophilic activation of the preformed imines by chiral Bronstedt acids [7, 8, 46], By using this strategy Terada and coworkers performed chiral phosphoric acid-catalyzed direct asymmetric Mannich-type reactions between Boc-protected imines and acetoacetone that furnished aryl /3-amino... 

Scheme 6. Chiral phosphoric acid-catalyzed direct asymmetric Mannich reactions.

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