Intermediates unmasking

Resonance Raman spectra have been recorded for transient phenoxyl radicals by pulse radiolysis. From the spectra recorded for various substituted and deuteriated radicals, it was possible to analyze the peaks in terms of the C—O and C—C stretching modes and C—C—C bending modes and to draw conclusions about the structures of the radicals. For example, the frequency assigned to the C—O bond in benzosemiquinone was found to be intermediate between those for the C=0 in benzoquinone and the C—O in hydroquinone, which led to the conclusion that the bond order in semiquinone is about 1.5. Raman spectroscopy also yielded information on the excited states of the radicals by examining which frequencies are resonance-enhanced ° ° . Furthermore, time-resolved experiments with Raman spectroscopy allowed kinetic measurements on a specific intermediate unmasked by changes in other species. ... 

Like Still s reagent, tributyl[(methoxymethoxy)methyl)etannane incorporates an alcohol protective group that can be conveniently unmasked under mild acidic conditions. However, an advantageous feature of this MOM ether derivative is that, in contrast to Still s reagent, it is achiral. In many applications the introduction of an additional chiral center into synthetic intermediates is undesirable because of the complications associated with the manipulation, analysis, and purification of diastereomeric mixtures. 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Mobashery and co-workers also reported the synthesis and inhibitory apph-cation of 2 -N02 derivatives of neamine and kanamycin (Scheme 4.28). Using the metal-chelating method, the 2 -NH2 was selectively unmasked and then oxidized into 2 -N02, which will increase the acidity of 2 -H. Upon phosphorylation at the 3 -0H, elimination of phosphate will lead to the formation of a nitroalkene intermediate, 198, that can function as a Michael acceptor and... 

The carbonyl group in 24 could be temporarily protected as the dioxolane,16 or somewhat more efficiently as the dimethyl acetal 25.17 Subsequent conventional hydroboration led stereoselectively to the P alcohol 26. Although our earliest considerations called for ultimate base-promoted elimination of the OR substituent in intermediates more advanced than 16, we later came to recognize that a methoxy derivative was not going to fulfill this role to our satisfaction. Alternatively, the tactic of forming the benzyl ether at this point ultimately proved well suited to the eventual return to an unmasked hydroxyl at this site.17,18... 

The synthesis of 3-benzylcyclobutanone (3) is an illustration of an overall intramolecular alkylation of an acyl anion equivalent (Section 5.9). The a,a>-dihalide is 2-benzyl-l,3-dibromopropane, and the acyl anion equivalent is methyl methylthiomethyl sulphoxide2 the product is 1-methylsulphinyl-l-methylthio-3-benzylcyclobutane which is obtained as a mixture of cis/trans isomers [(9) and (10)] (Expt 7.3). Aqueous acid hydrolysis in ethereal solution unmasks the carbonyl group. The possible mechanism of the reaction is via a Stevens-type rearrangement of the intermediate sulphur ylide, which may proceed in a pericylic, radical or ion pair fashion. 

A photoaffinity reagent (Fig. 1.1.) is a ligand that is chemically inert but conceals a highly reactive intermediate that is unmasked by irradiation with... 

With the exception of the diol 9, that was obtained from the corresponding aldehyde in up to 35% yield, most of the chiral diols mentioned above were isolated in yields of only 20-25%. The formation of the acyloin-type condensation products is in competition with the much more efficient reduction of the carbonyl carbon and saturation of the double bond of the unsaturated aldehydes that were used as substrates. We became interested in the mode of reduction of particular aldehydes such as 54-56 (Scheme 8) in a study of the total synthesis of natural a-tocopherol (vitamin E) (23). We expected to obtain chiral alcohols that would be useful for conversion into natural isoprenoids from the reduction of the a-double bond of the above aldehydes. Indeed, 54-56 afforded up to 75% yield of the saturated carbinols 57-59 by treatment with yeast. Whereas the ee of 57 and 58 was ca 85%-90%, that of 59 is 99%, as shown by NMR experiments on the (-)-MTPA derivative (24). The synthetic significance of carbinol 59 was based on the structural unit present in natural isoprenoids (see brackets in structural formulas). This protected synthon can be unmasked by ozonolysis, as indicated by the high yield conversion of 59 into (S)-(-) -3-methyl-y-butyrolactone 60 (Scheme 9). Product 59 is a bifunctional chiral intermediate which does not need protective manipulation in that... 

Octahydroacridine units must be oxidatively functionalized at carbon atoms 4 and 5 in order to build up the fused-ring backbone of torand 1. The key pyridine-forming reactions (steps 6 and 11 in Scheme 6.1) both involve the condensation of a ketone with an a,p-unsaturated ketone. Unsymmetrically functionalized octahydroacridine derivatives are required so that each unit can be fused to a new pyridine ring first at one end and then at the other. The benzylidene groups serve as latent carbonyl groups that can be unmasked by ozonolysis. Step 2 introduces both a C-O bond at C4 and a benzylidene group at C5 in a convenient, one-pot reaction sequence. Scheme 6.3 shows the intermediates involved in this sequence converting 6 to 7. 

A more narrowly defined group within this second set of compounds is the set of mechanism-activated inhibitors. These are compounds which do not have a second pre-existing reactive functionality. Rather, they use the normal catalytic machinery of the enzyme to generate, or unmask, a reactive species in the acyl-enzyme intermediate (E I). This new species then alkylates a second, suitably placed, active-site residue and permanently inactivates (binds to) the enzyme (even if deacylation of Ser-195 subsequently occurs). Efficient mechanism-activated inhibitors are those which have a high ratio of alkylation (Atj) to release k of the active enzyme. Because the second reactive functionality is only generated in the active site,... 

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