Amide, coupling hydrolysis

During our attempts to improve the overall convergency of the original route, we explored several options for installation of the side chain. For example, we attempted to isolate and utilize acyl chloride 109, which resulted from the prior coupling of the piperazine to oxalyl chloride (Scheme 25). This approach would have eliminated the need for the hydrolysis of 15 and amide coupling. While 109 was isolatable on lab scale, the preparation of this reagent was complicated by the formation of VUsmeier intermediate 110. Furthermore,... 

In the synthesis of GW-842166X (233), commercially available pyrimidine 268 reacted with 2,4-dichloroaniline to give ester 269, which was subjected to hydrolysis followed by amide coupling with 4-aminomethyltetrahydropyran (270) to afford 233 (Scheme 63) [236, 239, 240],... 

Enzymes are classified into six categories depending on the kind of reaction they catalyze, as shown in Table 26.2. Oxidoreductases catalyze oxidations and reductions hansferases catalyze the transfer of a group from one substrate to another hydrolases catalyze hydrolysis reactions of esters, amides, and related substrates lyases catalyze the elimination or addition of a small molecule such as H2O from or to a substrate isomerases catalyze isomerizalions and ligases catalyze the bonding together of two molecules, often coupled with the hydrolysis... 

Formation of glutamine is catalyzed by mitochondrial glutamine synthase (Figure 29-7). Since amide bond synthesis is coupled to the hydrolysis of ATP to ADP and P , the reaction strongly favors glutamine synthesis. One function of glutamine is to sequester ammonia in a nontoxic form. 

The purpose of the alkali is to convert the insoluble free naphthol into its colloidally soluble sodium salt. An excess of sodium hydroxide is generally needed but too much will tend to promote hydrolysis of the amide groups present in most azoic coupling components. The actual amount required varies with the naphthol and processing conditions the manufacturer s detailed literature must be consulted. 

Unfortunately, the size of the crystallographic problem presented by elastase coupled with the relatively short lifedme of the acyl-enzyme indicated that higher resolution X-ray data would be difficult to obtain without use of much lower temperatures or multidetector techniques to increase the rate of data acquisition. However, it was observed that the acyl-enzyme stability was a consequence of the known kinetic parameters for elastase action on ester substrates. Hydrolysis of esters by the enzyme involves both the formation and breakdown of the covalent intermediate, and even in alcohol-water mixtures at subzero temperatures the rate-limidng step is deacylation. It is this step which is most seriously affected by temperature, allowing the acyl-enzyme to accumulate relatively rapidly at — 55°C but to break down very slowly. Amide substrates display different kinetic behavior the slow step is acylation itself. It was predicted that use of a />-nitrophenyl amid substrate would give the structure of the pre-acyl-enzyme Michaelis complex or even the putadve tetrahedral intermediate (Alber et ai, 1976), but this experiment has not yet been carried out. Instead, over the following 7 years, attention shifted to the smaller enzyme bovine pancreatic ribonuclease A. 

Hydrolysis of the methyl ester and decarboxylation at C-18 occur only under forcing conditions. Alkaline hydrolysis of the C-18 ester of vinblastine requires refluxing m 5 N sodium hydroxide for several hours to give the diacid (18), and ammonialysis of this position in anhydrous methanol is accomplished in a sealed vessel at 100°C for 60 hr to yield the 18 -decarbomethoxy-4-deacetylvinblastine amide (19) (55). Bisindole derivatives lacking the C-22 carboxyl have also been prepared by coupling the vindoline portion with an appropriately chosen ibogane precursor (Section V,G) (54). 

Trichloromethyl keto derivatives 382 (Scheme 78, Section 5.1.1) undergo hydrolysis with sodium hydroxide in aqueous THF to produce acids in overall yields of 60-70%. Coupling of the acids with amines leads directly to amides 383 in 80-90% yield (2000BMCL783). 

---