Brpnsted Acid Catalyzed Enantioselective Additions

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). 

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. 

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. 

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. 

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. 

Uraguchi D, Sorimachi K, Terada M (2004) Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. J Am Chem Soc 126 11804-11805 Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vachal P, Jacobsen EN (2000) Enantioselective catalytic addition of HCN to ketoimines. Catalytic synthesis of quaternary amino acids. Org Lett 2 867-870... 

In most Diels-Alder reactions, no catalyst is needed, but Lewis acids are effective catalysts in many cases, particularly those in which Z in the dienophile is a C=0 or C=N group. A Lewis acid catalyst usually increases both the regioselec-tivity of the reaction (in the sense given above) and the extent of endo addition, °° and, in the case of enantioselective reactions, the extent of enantioselectivity. It has been shown that InCla is an effective catalyst for aqueous Diels-Alder reactions,which is suitable for ionic Diels-Alder reactions, and there are other Lewis acid catalysts that are effective in water. °° Brpnsted acids have also been used to accelerate the rate of the Diels-Alder reaction.Lanthanum triflate [La(OTf)3] has been reported as a reusable catalyst ° ° and Me3SiNTf2 has been used as a green Lewis acid catalyst. ° Cationic Diels-Alder catalysts have been developed, particularly oxazaborolidine catalysts. ° Some Diels-Alder reactions can also be catalyzed by the addition of a stable cation radical, for... 

The vinylogous Mannich reaction of 2 silyloxy furans and imines may also be catalyzed through chiral Brpnsted acids, as shown by Akiyama et al. [10]. Previously, Akiyama [11] and Terada [12] had independently discovered that 3,3 substituted BINOL based phosphoric acids were excellent Bronsted acids for a broad range of mainly imine addition reactions via protonation of the imines and in situ formation of chiral iminium contact ion pairs. Using the slightly modified phosphoric acid 28 as catalyst carrying additional iodine substituents in the 6,6 positions, the y amino substituted butenolides 27 were obtained in excellent enantioselectivity and variable diastereoselectivity (Table 5.4). 

Miao, Chen, and coworkers have reported an efficient enantioselective Biginelli reaction catalyzed by a chiral bifunctional primary amine-thiourea derivative 43 with a carbohydrate in the catalyst skeleton and using an external Brpnsted acid in a cooperative way, with t-BuNH TFA as additive (Scheme 9.15) [54]. This protocol renders a wide range of optically active DHPMs 44 in high yields and with good to excellent enantioselectivities (up to 99% ee). 

Despite the massive advancements in asymmetric catalysis over the last several decades, the catalytic enantioselective generation of N,N-, N,0-, N.S-, and N,Se-acetals only recently became a possibility with the advent of asymmetric Brpnsted acid catalysis [16-22], Asymmetric syntheses of acyclic NJ -, N,0-, N,S-, and N, Se-acetals catalyzed by chiral phosphoric acids were developed in the Antilla group utilizing the addition of heteroatom nucleophiles to iV-protected imines (Scheme 4) [16-18, 22],... 

A similar reaction was reported by Bencivenni, Bartoli, and co-workers [21] about the nitrocyclopropanation of oxindoles. They reported the reaction between methyleneindoline and 1-bromonitromethane catalyzed by bifunctional Brpnsted base/Lewis acid catalyst VIII. The reaction requires one base equivalent for the final cyclization. Mechanistically, the nitromethane addition to methyleneindoline takes place first, and a subsequent intramolecular alkylation renders the final spirocyclic nitrocyclopropane with good yields and excellent diastereo- and enantioselectivities (Scheme 10.10). 

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