Acyl-protected nucleophiles

Anomeric O-Alkylation of Acyl-Protected Nucleophiles with Primary Triflates... 

Conditions for the efficient use of Fmoc-protected amino acid chlorides in stepwise peptide synthesis have been delineated. The acid chlorides are reasonably stable solids that are readily aminolyzed if a base is added to neutralize the hydrogen chloride liberated in the reaction. They form the corresponding oxazol-5(4//)-ones and undergo stereomutation if left in the presence of tertiary amines, however, amide formation without stereomutation can be obtained under appropriate conditions. The acid chlorides are advantageously applied to acylate weak nucleophiles and sterically hindered amino components, but their application may be limited by the lack of stability of tert-butyl-type side-chain protecting groups toward conditions of acid chloride preparation. 

On the one hand, alternative basic deprotection cocktails were developed using various combinations of hydrazine, ethanolamine, and alcohol [146] or incorporating the use of more nucleophilic alkylamines [7,16]. The latter method favors 40% aqueous methylamine in place of or in addition to 30% ammonium hydroxide, which cleaves the acyl protecting groups present on the nucleobases in a few minutes at 65°C or in over 1 h at room temperature. 

Certain functionalised esters combine the virtues of acyl protection (ease of introduction, electronic deactivation, lability to base) with the ability to be deprotected under specialised conditions that leave other esters unaffected. Of these, the only example that has seen reasonably widespread application is the levulinate (Lev) derivative which, in chemistry that parallels the cleavage of ClAc derivatives with soft nucleophiles, are cleavable by conversion of the comparitively reactive ketone functionality into a nucleophilic entity that can cyclise onto the ester carbonyl releasing the protected hydroxyl. The example in Figure 2.45 shows that the acetates survive unscathed in Lev deprotection with hydrazine so that only the 2-OH is released [63]. 

Cyclic amide acetals have also been investigated by a Canadian group who found that acyclic amide acetals react smoothly with 1,2-diols giving 2-amino-1,3-dioxolans. These compounds are compatible with reaction conditions for acylation and nucleophilic displacement, so providing a useful protecting group. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Amino groups are often protected as their tert-butoxycarbonvl amide, or Boc, derivatives. The Boc protecting group is introduced by reaction of the amino acid with di-fert-butyl dicarbonate in a nucleophilic acyl substitution reaction and is removed by brief treatment with a strong organic acid such as trifluoro-acetic acid, CF3C02H. 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

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