FMoc chloride, reaction with amines

While there is evidence from IR investigations for the formation of traces of oxazol-5(4//)-one by treatment of Fmoc-protected amino acid fluorides, e.g. Fmoc-Val-F, with DIPEA, this reaction is not rapid enough to compete with the acylation process. In contrast to Fmoc amino acid chlorides, the related fluorides can be used in homogeneous systems with tertiary amines as efficient agents in peptide synthesis. 

Bisphosphonates were prepared and from naturally occurring 1-amino acids [141], In this case, initial protection of the amino acid-amine moiety was required. Insertion of a phosphorus atom was divided into two steps initial reaction with a suitable phosphorus reagent to produce the acylphosphonate, and a second phosphorus attack to form the bis-phosphonate. Since conversion to acid chloride served as the acid activation process, the amine-protecting group had to be either Fmoc or phtaUmide, both of which are stable in acidic conditions. Prolonged reaction times always resulted in partial rearrangement and formation of by-products. 

FIGURE 7.14 Activated esters for temporary protection and activation of Fmoc-amino acids for the synthesis of glycopeptides. (A) Reaction of a-D-glucopyranosyl bromide with esterified Fmoc-serine. (B) Reaction of 2-acetamido-2-deoxy-3,4,6-triacetyl- 3-D-glucopyranosyl amine with esterified Fmoc-aspartyl chloride.37-38 Pfp = pentafluorophenyl. 

FIGURE 7.18 Preparation of Fmoc-amino-acid chlorides by reaction (A) of thionyl chloride,47 phosgene from triphosgene,54 l-chloro-2,A7,A7-trimethyl-l-propene- 1-amine, [Schmidt et al., 1988] or oxalyl chloride, [Rodriguez, 1997] with the parent acid and (B) of hydrogen chloride with the mixed anhydride.51... 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

Based on a multi-component condensation approach related to the Doebner reaction,Gopalsamy et developed a solid-phase synthesis for this clinically useful pharmacophore. Thus, starting from Rink resin 65, acylation with the required N-Fmoc-amino acid 232 and deprotection with piperidine gave the polymer-supported amine 233 (90% yield) which was acylated with pyruvyl chloride (234). Immobilised pymvic amide 235 was refluxed with excess of preformed benzyUdene aniline 239 or alternatively condensed with an excess of an equimolecular mixture of aldehyde 236 and anilines 237. Cleavage of 238 with 45% TFA afforded compounds 240 in good yields and with high purities (>90%) (Scheme 4.3.5). 

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