Tetrahedral diol intermediate

The reaction mechanism of proteases is to convert the carbonyl group of the target peptide bond into an enzyme-stabilized tetrahedral diol transition state intermediate. This intermediate further collapses to yield the two-peptide products. The enzyme binds the diol intermediate, the specificity being provided by specific contacts for the amino acids side chains PI, P2, P3, PI, P2, P3 (Fig. 1) and so on, with their respective binding sites on the protein (S1, S2, S3, S1, S2, S3 ). 

Fig. 33. The promoted-water tetrahedral intermediate (a) in the carboxypeptidase A mechanism is simulated by the binding of the ketomethylene substrate analog BBP (Fig. 32b) as the gm-diol(ate) (b). [Reprinted with permission from Christianson, D. W., Lipscomb, W. N. (1989) Acc. Chem. Res. 22,62-69. Copyright 1989 American Chemical Society.]...

Ozone oxidation of the trans-decal in di of benzylidene 133 has been carried out (71). Under kinetically controlled conditions, it produces the axial benzoate 134 in preference to the more stable equatorial benzoate 135. Similar results were obtained with an analogous case derived from cholestane-2e,3e-diol. These results are essentially identical to those obtained by King and Allbutt (60, 62) in their study on the hydrolysis of dioxolane orthoesters and dioxolenium salts (cf. p. 82), and can therefore be explained in the same manner. These results further confirm that the oxidation of acetals by ozone produces an intermediate which behaves like the hemiorthoester tetrahedral intermediate which is formed in the hydrolysis of orthoesters. 

We showed in Figs. 3-2 and 3-3 that the tetrahedral intermediate which is initially formed from the reaction of a nucleophile with a carbonyl compound may further react in a number of different ways. In this section, we will consider some reactions which proceed along the pathway indicated in Fig. 3-3. The hydration of ketones is a reaction analogous to the hydrolysis of an ester, with the first step of the reaction involving nucleophilic attack of water on the carbonyl group. The tetrahedral intermediate is trapped by reaction with a proton to yield the hydrated form of the ketone, the geminal diol (Fig. 3-15). Similar reactions occur with alcohols as nucleophiles to yield, initially, hemiacetals. 

Diisobutylaluminum hydride (DIBAL) is a reliable reagent for the reduction of lactone 29 to the corresponding lactol 67. This is due to the formation of stable tetrahedral intermediate 66, which prevents further reduction (via hydroxyaldehyde 68 to the diol) and decomposes during aqueous workup to provide the desired lactol 67. 

A stable structure that mimics this tetrahedral Intermediate would be a transition state analog inhibitor. A silicon diol structure, in which the C(OH)2NH group of the transition state is replaced by an Si(OH)2CH2 moiety, mimics that tetrahedral transition state, and it has recently been shown that incorporating silicon diol moieties into peptide mimetics results in potent and selective inhibitors for metallo and aspartyl proteases [1 - 3] (1 and 2, Fig. 2). 

Similarly, self-doped PABA can be prepared using excess of saccharide and one equivalent of fluoride to monomer. Complexation between saccharides and aromatic boronic acids is highly pH dependent, presumably due to the tetrahedral intermediate involved in complexation [25]. Because the pKa of 3-aminophenylboronic acid is 8.75, complexation requires pH values above 8.6. This pH range is not compatible with the electrochemical synthesis of polyaniline, which is typically carried out near a pH value of 0. However, Smith et al. have shown that the addition of fluoride can stabilize the complexation of molecules containing vicinal diols with aromatic boronic acids [23]. Based on this work, it was postulated that the electrochemical polymerization of a saccharide complex with 3-aminophenylboronic acid in the presence of one molar equivalent of fluoride at pH values lower than 8 is possible if a self-doped polymer is produced in the process. 

Synthesis of Derivatives of Thionocarboxylic Acids.—Thiono-esters are obtained by the reaction of dialkoxycarbonium ions with NajS or anhydrous NaHS in acetonitrile (Scheme 6). Cyclic carbonium salts from 1,2- or 1,3-diols give monothiono-esters of these diols. The tetrahedral intermediates in this process may be alkylated to give... 

---