Brpnsted acid catalyzed enantioselective

An intriguing feature is that the previously unknown bisindoles 154 display atropisomerism as a result of the rotation barrier about the bonds to the quaternary carbon center. With the use of A-triflyl phosphoramide (1 )-41 (5 mol%, R = 9-phenanthryl), bisindole 154a could be obtained in 62% ee. Based on their experimental results, the authors invoke a Brpnsted acid-catalyzed enantioselective, nucleophilic substitution following the 1,2-addition to rationalize the formation of the bisindoles 154 (Scheme 65). 

Akiyama T, Morita H, Itoh J, Fuchibe K (2005a) Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of alpha-amino phosphonates. Qrg Lett 7 2583-2585 Akiyama T, Saitoh Y, Morita H, Fuchibe K (2005b) Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid derived from TADDOL. Adv Synth Catal 347 1523-1526... 

The Brpnsted acid catalyzed enantioselective hydrogenation of the corresponding readily available 2-substituted quinolines (for an interesting approach to 2-alkyl tetrahydroquinolines by an aza-xylene Diels-Alder reaction, see Steinhagen and Corey 1999 Avemaria et al. 2003), which we prepared by simple alkylation of 2-methylquinoline, generated the tetrahydroquinoline derivatives in excellent enantioselectivities and subsequent A-methylation gave the desired natural products in good overall yields (Fig. 5). 

The development of this so far unprecedented, double Brpnsted acid catalyzed enantioselective synthesis of various aromatic and heteroaro-... 

The enantioselective Brpnsted acid catalyzed activation of a pure carbonyl compound using a chiral BINOL-phosphate had not previously been described. Hence, we decided to develop such a reaction, a so far unprecedented Brpnsted acid catalyzed enantioselective Nazarov cy-clization (Rueping et al. 2007c). 

Within the above context and building on our previous results (Rueping et al. 2005a,b, 2006a-e, 2007a Rueping and Azap 2006), we decided to examine a metal free, BINOL-phosphate catalyzed Nazarov reaction. This would not only be the first example of a Brpnsted acid catalyzed, enantioselective, electrocyclic reaction but would additionally provide a simple and direct route to optically pure cyclopentenones. 

G. Dagousset, F. Drouet, G. Masson, J. Zhu, Org. Lett. 2009, 11, 5546-5549. Chiral Brpnsted acid-catalyzed enantioselective multicomponent Mannich reaction synthesis of anti-1, 3-diamines using enecarbamates as nucleophiles. 

M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birkemeyer, C. Schneider, Chem.-Eur. J. 2010,16, 2806-2818. The Brpnsted acid catalyzed, enantioselective vinylogous Mannich reaction. 

Up to 2009, the development of an enantioselective version of these reactions remained a significant challenge. In that year, Wang and Zhu reported the first Brpnsted acid-catalyzed enantioselective Ugi-3CR [27], wherein a... 

T. Yue, M.-X. Wang, D.-X. Wang, G. Masson, J. Zhu, Angew. Chem. Int. Ed. 2009,48, 6717-6721. Brpnsted acid catalyzed enantioselective three-component reaction involving the a-addition of isocyanides to imines. 

Akiyama T, Morita H, Itoh J, Fuchibe K. Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of a-amino phosphonates. Org. Lett. 2005 7 2583-2585. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

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 2006, two groups independently developed an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder-type reaction of iV-aryl aldimines 86 with cyclohexenone 101 to provide isoquinuclidines 102 in good yields (51-84%), endo-diastereoselec-tivities (3 1-9 1), and enantioselectivities (76-88% ee) (Scheme 39). 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Specific Brpnsted acid catalysis is a popular field within the domain of asymmetric organocatalysis. Since the introduction of stronger chiral Brpnsted acids as powerful catalysts for enantioselective synthesis in 2004, numerous asymmetric Brpnsted acid-catalyzed transformations have been developed. 

The real promise of this catalytic reaction is the eventual development of an efficient enantioselective allylboration catalyzed by chiral Lewis acids. A stereoselective reaction using a substoichiometric amount of a chiral director has been reported, but only modest levels of stereo-induction were achieved with an aluminum-BINOL catalyst system (Eq. 19)P Recently, a chiral Brpnsted acid catalyzed system has been devised based on a diol-tin(IV) complex (Eq. 80). In this approach, aliphatic aldehydes provide enantioselectivities (up to 80% ee) higher than those of aromatic aldehydes when using the optimal complex 114. Although the levels of absolute stereoselectivity of this method remain too low for practical uses, promising applications are possible in double diastereoselection (see section on Double Diastereoselection ). 

The First Enantioselective Brpnsted Acid Catalyzed Transfer... 

Enantioselective Reduction of Benzoxazines, Benzthiazines, and Benzoxazinones Remarkably Low Catalyst Loading in the Asymmetric Brpnsted Acid Catalyzed... 

First Highly Enantioselective Brpnsted Acid Catalyzed Strecker Reaction Use of C-Nucleophiles... 

Table 2 Scope of the first enantioselective Brpnsted acid catalyzed transfer hydrogenation...

The first enantioselective Brpnsted acid catalyzed cascade reduction of pyridines provides the corresponding products in good yields and with excellent enantioselectivities (up to 92% ee). The hexahydroquino-linones and tetrahydropyridines isolated are not only known starting products for various natural products such as pumiliotoxin C but also for numerous interesting biologically active compounds. As previously only metal catalyzed hydrogenations of pyridines have been described, and these did not result in the valuable products described herein and gave lower enantioselectivities, our newly developed metal-free Brpn-sted acid catalyzed procedure represents an important contribution to the enantioselective reduction of pyridines. 

With the optimized conditions in hand we explored the scope of the Brpnsted acid catalyzed hydrocyanation of various imines (Table 8). In general, high enantioselectivities and good isolated yields of several aromatic and heteroaromatic, Af-benzyl- and /V-paramethoxy-benzyl protected amino nitriles, bearing either electron-withdrawing or electron-donating groups are obtained. These products are important precursors for the synthesis of amino acids and diamines. Hence, in order... 

The possibility of using C-nucleophiles in chiral ion pair catalysis encouraged us to investigate an enantioselective Brpnsted acid catalyzed imino ene reaction (Rueping et al. 2007a Scheme 5). The reaction consists of a new BINOL-phosphate catalyzed addition of methylene-hydrazines 22 to A-Boc-protected aldimines 23 to afford chiral amino-hydrazones 24. 

Development of the First Brpnsted Acid Assisted Enantioselective Brpnsted Acid Catalyzed Direct Mannich Reaction... 

At the outset of our experimental work we began by examining a suitable Brpnsted acid catalyst for the enantioselective electrocyclization of dienone 31. While the use of BINOL-phosphates resulted in the products 32 in good yields, better dia- and enantioselectivities were obtained with the corresponding iV-triflyl phosphoramides 33, which even at 0 °C gave complete conversion after 10 min. With the optimized conditions in hand, we applied various dienones to the Brpnsted acid catalyzed... 

We have developed the first enantioselective Brpnsted acid catalyzed Nazarov reaction. This efficient method is not only the first example of an organocatalytic electrocyclic reaction but it also provides the corre-... 

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