Cinchona catalysts hydrogen-bonding activation

A new cinchona alkaloid-derived catalyst has been developed for the enantioselective Strecker reaction of aryl aldimines via hydrogen-bonding activation. For reference, see Huang, J. Corey, E. J. Org. Lett. 2004, 6, 5027-5029. 

Chiral H-bond donors and acids have proven their potential many times over several decades. Some useful apphcations in natural product synthesis have been reported, using either hydrogen bonding activation as the sole catalytically active principle, or utilizing bifunctional catalysts. With respect to the catalytic moiety of choice, the considerable potential of thioureas can be emphasized, especially those based on Cinchona alkaloids (Table 6). 

The mechanism and stereochemistry of hydrophosphonylation of a-ketoesters by dimethylphosphonate [H-P(=0)(0Me)2l has been studied theoretically by the ONIOM method, for catalysis by cinchona-thioureas. Deprotonation of the phosphonate 0 is rate determining. It is followed by C-P bond formation (the stereo-controlhng step) via nucleophilic addition, and then reprotonation (regenerating the catalyst). Multiple hydrogen bonds activate the substrates, facilitate charge transfer and stabihze transition states. 

In the initial screening of various Cinchona alkaloids, the addition of diethyl phosphate 41 to IV-Boc imine 40 in toluene revealed the key role of the free hydroxyl group of the catalyst. Replacing the C(9)-OH group with esters or amides only results in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-hydroxyl group and quinuclidine base activation of the phosphonate into a nucleophilic phosphite species are key to the reactivity of this transformation (Scheme 9). 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Addition of the thiophenolate anion to the / -carbon atom of the enone is the chirality-determining step it is, at the same time, rate-determining. The transition state is a ternary complex comprising the catalytic base in the protonated form, the thiophenolate anion, and the enone. The last is activated to nucleophilic attack by hydrogen-bonding to the catalysts / -hydroxy group. The chiral cinchona bases thus act as bifunctional catalysts. 

In this chapter, we do not attempt to give a comprehensive overview of the field, but we would rather concentrate on results where both enantioselectivity and catalyst activity are relevant to preparative application. In the first section, results obtained with cinchona-mediated homogeneous systems for the reduction of ketones are briefly reviewed. Then, heterogeneous cinchona-modified Pt catalysts applied to the hydrogenation of a-functionalized ketones and cinchona-modified Pd catalysts for the hydrogenation of activated C=C bonds are discussed from a synthetic point... 

A few related recent examples are included in this section. Tautomerization of a H-phosphonate to the three-coordinate nucleophilic form (as in Fig. 1 and Schemes 5 and 29) is an important step in these reactions. Scheme 37 shows how a Ti catalyst was proposed to bind an aldehyde, while the P-OH nucleophile was simultaneously activated by hydrogen bonding to a pendant quinuclidine Lewis base, derived from a cinchona alkaloid [60]. The same two types of interactions were suggested in related Al-catalyzed reactions (Scheme 37) [61]. 

Corey et al investigated chiral Cinchona alkaloid-based ammonium salt (28) as a catalyst for the enantioselective Strecker reaction (Scheme 2.69) [131]. They proposed that the acid could be used to hold the aldehyde-derived part of an aldimine, which was activated by hydrogen bonding with the protonated quinuclidine moiety. 

---