Hydrogen-bonding activation cascade reactions

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. 

This Pd-catalyzed cascade bis-cyclization reaction can also be applied to trans linear substrates 40 and 41. It was possible to effect either 5-exo or 6-endo cyclizalion selectively by an appropriate choice of the electron-withdrawing substituents of the nucleophile, as illustrated in Scheme 20. Ero-cyclizations were observed when sterically encumbered nucleophiles were employed. Cyclopentanes were obtained as a result of steric interactions between the nucleophile and one of the allylic hydrogens of the linear substrate. Endo-cyclizations leading to trani-octahydrophenanthrene were the only reactions observed when less sterically demanding nucleophiles were employed. Notably, these cyclizations proceed in a completely stereoselective trans manner. Attack of the carbon nucleophile onto a double bond electrophilicaUy activated by the palladium species results in a trans configuration of the fused ring junction. This stereochemistry is defined by that of the double bond in the initial substrate the relative configuration of compound 42 or 43 is hereby controlled. 

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