Hydrogen-bonding activation cascades

Scheme 5 Unusual hydrogen migration/C—H bond activation cascade reactivity of orfho-metalated 2-phenylpyridine complexes of yttrium and lutetium.

The serine proteases are a dass of proteolytic enzyme (they catalyze the hydrolysis of either ester or peptide bonds in proteins) that require an active site residue for covalent catalysis. The active site residue, the catalytic Ser-195, is particularly activated by hydrogen-bonding interactions with His-57 and Asp-102. Crystal structures show that Ser-195, His-57, and Asp-102 are dose in space. Together these three residues, which are located in the substrate binding (SI) pocket, form the famed catalytic triad of the serine proteases. In humans and mammals serine proteases perform many important functions, especially the digestion of dietary protein, in the blood-dotting cascade, and in the complement system ... 

The proposed reaction mechanism is shown in Scheme 6.75. The nitroalkene moiety of bifunctional ortAo-alkyne-substituted nitrostyrenes 159 is activated through hydrogen bonding with catalyst 160 to incorporate the stereoehemieal information in the first AFC reaction. Then the alkyne is activated under gold catalysis to affect the seeond AFC/ring expansion cascade. 

The cyclization mechanism of type 11 terpene cyclases is exemplified by the reaction of the SHC (Scheme 87.19). Important insights into the reaction mechanisms have been obtained from structural data [199, 208]. One of the inner helices of the p-domain of SHC contains a conserved DxD(D,E) motif that is located in the central cavity at the interface between the p- and y-domains. Its central aspartate residue D376 is polarized via hydrogen bonding to an adjacent histidine residue and protonates the double bond of the squalene substrate to initiate the reaction cascade. Conserved aromatic residues stabilize the intermediate cations by cation-tt-interactions. A water molecule is a candidate to act as catalytic base, and this water may also account for the formation of the by-product hopanol. Another bridging water molecule connects D376 to a tyrosine residue and can restore the active site after catalysis by reprotonation of D376. 

Akiyama et al. disclosed a chiral phosphoric acid 13-catalyzed asymmetric cascade [l,5]-HT/cyclization of 11, which afforded tetrahydroquinolines 12 with good to excellent enantioselectivity (Scheme 6) [90]. The benzylidene malonate subunit forms hydrogen bonds with the proton of phosphoric acid 13, which not only increased the electrophilicity of hydride acceptor but also governed the asymmetric step. Presumably, the stereoselectivity is mostly controlled at the hydride shift step and the enantiotopic hydrogen is selectively activated by chiral phosphoric acid 13. 

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