Shuttle-deprotonation

Taggi, A.E., Hafez, A.M., Wack, H. et al. (2000) Catalytic, asymmetric synthesis of P-lactams. Journalof the American Chemical Society, 122,7831-7832 Taggi, A.E., Wack, H., Hafez, A.M. et al. (2002) Generation of ketenes from acid chlorides using NaH/crown ether shuttle-deprotonation for use in asymmetric catalysis. Organic Letters, 4,627-629 France, S.,... 

Carbon Acids. One of the more common uses of sodium hydride is the deprotonation of activated methylene compounds to generate highly reactive carbanions. A shuttle-deprotonation system has been described in which sodium hydride is the stoichiometric base and is used in conjunction with a crown ether cocatalyst to generate ketenes used in asymmetric catalysis. Enaminones can be converted to naphthyridinones using sodium hydride in THE (eq 47). ... 

Use of different bases allowed for in situ formation of the zwitterionic enolate species via a shuttle-deprotonation and circumvented the need for the ketene... 

In 2001, Lectka and co-workers [52] adapted their method for catalytic asymmetric a-halogenation of acid chlorides to include bromination reactions (Scheme 13.24). Through use of the same organocatalyst and shuttle-deprotonation strategy, and a polybromoquinone as the bromine source, the catalytic enantioselective... 

The wide reaction scope was facilitated by an extensive investigation into the in situ synthesis of monosubstituted ketenes. A shuttle deprotonation strategy was identified, by which a thermodynamically strong but kinetically slow base such as proton sponge is used as a proton sink, in combination with a substoichiometric kinetically fast tertiary amine (Figure 3.1). Under these conditions the zwitterionic ammonium enolate may be formed via two distinct pathways in... 

FIGURE 3.1 Lectka s shuttle deprotonation strategy in application to asymmetric p-lactam synthesis. 

Hafez AM, Taggi AE, Wack H, Esterbrook J, Lectka T. Reactive ketenes through a carbonate/amine shuttle deprotonation strategy catalytic, enantioselective a-bromination of acid chlorides. Org. Lett. 2001 3(13) 2049-2051. 

Taggi AE, Wack H, Hafez AM, France S, Lectka T. Generation of ketenes from acid chlorides using NaH/crown ether shuttle-deprotonation for use in asymmetric catalysis. Org. Lett. 2002 4(4) 627 29. 

These ideas have been illustrated in a recent study of the co-crystalline complex of 1-meCyt 5-FUra [19]. Using model calculations, it was shown how the hydrogen-bonding network of the crystal is able to sustain a proton shuttle which leads to the selective formation of certain radicals. Calculations predict that the site of reduction would be the cytosine base, yielding the N3 protonated cytosine anion, Cyt(N3-I-H), while the uracil base would be the site of oxidation, yielding the N1 deprotonated uracil cation, Ura(Nl—H) ... 

Roberts et al. (523) emphasized that the in-line mechanism almost requires that two different groups deprotonate the 2 0H and protonate 05 since they are on opposite sides of the basal plane. They are physically removed from each other with a negative P-0- between them to trap any shuttle. Since they observed 3 -CMP interactions with His 12 and 119 by NMR with the greater effect on His 119 and both histidines protonated and since the X-ray structure shows the phosphate between the two histidines, they believed that both histidines are directly involved. Furthermore, the interaction of His 119 is more sensitive to the specific... 

The mechanism can only be retained if a base very much better than water is present at the enzyme active site to deprotonate the Zn(OH2)2+ species. In fact, the structure determination reveals a histidine residue with its side chain positioned approximately halfway down the -15 A-deep cleft in the protein structure within which the Zn site is located. This arrangement could act as a proton shuttle between the Zn(OH2)2+ and external solvent water, possibly via another two water molecules also found within the cleft. As a consequence, the enhancement of ligand acidity by Zn11 is more important in the kinetic than the equilibrium sense (taken from http //www.chem.uwa.edu.aU/enrolled students/BIC sect4/sect4.2.htmll. 

A potential O-atom donor molecule, N2O, has been allowed to react with SiH+ to probe the formation of HSiO+, a higher energy isomer of SiOH+. The expectations were fulfilled (equation 13)43, as tested by reaction with a base capable of deprotonating HSiO+ but not SiOH+. The formal O-atom insertion product, SiOH+, was ascribed to a proton shuttle mechanism which is dominant when OX is SO2 and CO2 (equation 14). In fact, with these two neutrals the formation of HSiO+ and X as bare species is somewhat endothermic and the proton transfer process within the ion-neutral complex, driven by the stability of SiOH+, is allowed by the proton affinity (PA) of X which is intermediate between those of the Si and O sites of SiO. On the other hand, when O2 is used as the neutral reagent this pathway is not accessible and HSi02+ is the only observed product ion. 

Aminotransferases (transaminases) catalyze the reversible interconversions of pairs of a-amino and a-keto acids or of terminal primary amines and the corresponding aldehydes by a shuttle mechanism in which the enzyme alternates between its PLP form and the corresponding PMP form. In the first half-reaction the PLP form of the enzyme binds the amino acid (or amine) and forms the coenzyme-substrate Schiff s base. Cleavage of the C-a—H bond is then followed by protonation at C-4. Hydrolysis of the resulting ketimine then gives a keto acid (or aldehyde), leaving the enzyme in the PMP form. The latter is recycled to the PLP form by condensation with an a-keto acid, deprotonation at C-4, protonation at C-a and transaldimina-tion to release the a-amino acid formed. 

---