Past exam of the chemistry B course of the University of Cambridge / 2021 / Paper 2 / B10

Treat the reacting carbon skeletons as an activated glycosyl donor and a 3-substituted indole. The new linkage is an anomeric-carbon–indole-C2 carbon–carbon bond, not a bond to indole nitrogen. A plausible purely chemical pathway is a dissociative electrophilic aromatic substitution:

The drawn donor and product have opposite anomeric faces: the anomeric leaving group is on the same face as the hydroxymethyl substituent, while the new carbon substituent is on the opposite face. Thus the target has net inversion at the anomeric carbon. A tight ion pair with the departing group shielding its original face can rationalize opposite-face capture in this proposed pathway. A freely solvated planar oxocarbenium ion would not by itself guarantee exclusive inversion; competing faces, hydrolysis and other products remain possible without an experimentally specified chemical promoter. This is a plausible non-enzymatic mechanism, not a claim that the uncatalysed reaction is rapid or clean in neutral water.

For the three elementary transformations just proposed, a qualitative free-energy profile has three transition states and two intermediates. The sugar substituents and indole C3 substituent stay unchanged, so the structural shorthand below suppresses them while retaining the reacting atoms.

The first transition state has a partially broken anomeric C1–O(leaving group) bond and developing oxocarbenium character, $[{\mathrm{O}}_{\mathrm{ring}}-{\mathrm{C}}_1^{\delta +}\cdots {\mathrm{O}}_{\mathrm{LG}}{]}^{‡}$. Its following minimum is the glycosyloxocarbenium ion plus counterion. The second transition state has a forming C1–C2 bond, $[{\mathrm{O}}_{\mathrm{ring}}-{\mathrm{C}}_1\cdots {\mathrm{C}}_2(\mathrm{H}{)}_{\mathrm{ind}}{]}^{‡}$, and developing positive charge in the indole. Its following minimum is the covalently joined arenium ion with an intact C2–H bond. The third transition state has simultaneous C2–H cleavage, B–H formation and restoration of the indole pi bond, $[\mathrm{B}\cdots \mathrm{H}\cdots {\mathrm{C}}_2-{\mathrm{C}}_3{]}^{‡}$. It leads to the aromatic C-linked product and protonated base.

The vertical separations are illustrative because no activation free energies or equilibrium constants are supplied. In particular, the highest barrier cannot be identified experimentally from this drawing alone. protonation of the leaving group is treated as an initial rapid equilibrium in the chosen mechanism; explicitly resolving it would add the corresponding proton-transfer state and intermediate.

TODO — user-deferred biology. The requested enzyme design, including all sites A–K, peptide recognition and residue-mediated catalysis at the specified pH, is deferred under the instruction to skip biological mechanism and design questions. No residue assignments are proposed.