Hexafluoroacetone as Protecting and Activating Reagent: Site-Selective Functionalization of α-Amino Alkanedioic Acids

Abstract

H e x a f l u o r o a c e t o n e a s P r o t e c t i n g a n d A c t i v a t i n g R e a g e n t Abstract: Methodology for the site-selective functionalization of a-amino alkanedioic acids (Asp, Glu and homologues) using hexafluoroacetone as protecting and activating reagent is described. Via new types of dielectrophiles, alternative approaches to multifunctional non-natural amino acids and some of their conjugates become readily available.Site-selective derivatizations of multifunctional compounds like w-carboxy-a-amino acids (Asp, Glu and homologues) require sophisticated protection/activation concepts. 1,2 Even relatively simple derivatives of aspartic acid like the sweetener aspartame 3 (a-functionalization) and isopeptides 4 (w-functionalization) demand laborious multi-step procedures. Therefore, the development of new methodology is a challenge, where activation of the a-carboxylic group and protection of the adjacent amino group as well as peptide bond formation and deprotection of the amino group are performed as tandem reactions. 5 This challenge can be met by using bidentate protective groups like phosgene, 6 and certain aldehydes and ketones. 7-9 However, on aminolysis of Leuchs anhydrides, formation of oligomers cannot be avoided. During aminolysis of the cyclic anhydride, the amino group of the newly formed dipeptide derivatives are so quickly deblocked, that they compete successfully with the amino acid ester as acyl acceptors. Furthermore, oxazolidinones derived from certain aldehydes like formaldehyde 10 require additional Nprotection and N-deprotection steps.Recently, hexafluoroacetone (HFA) has been successfully applied for simultaneous protection and activation of aamino-, 11 a-hydroxy-, 12 and a-mercapto acids 13 without the need of additional protection and deprotection steps. On reaction of aspartic, malic, and thiomalic acid with HFA the a-functionality and the adjacent carboxy group are simultaneously protected. Concomitantly, the a-carboxy group is activated, while the w-carboxy group remains unaffected and can be derivatized selectively after separate activation. Remarkably, orthogonal protection and w-activation can be achieved in only two steps.We now report on the application of HFA as protecting and activating reagent for w-derivatization of a-amino alkanedioic acids of different chain lengths (four to eight carbon atoms). HFA reacts with a-amino alkanedioic acids 1 in DMSO at room temperature to give 2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-ones (2) in 67-90% yield. A second equivalent of HFA is necessary to trap the water, which is eliminated during lactone formation. 1 H and 19 F NMR control of the progress of the reaction reveals that the five-membered lactone is formed exclusively, but there is some loss during work up, because of the water solubility of compounds 2. HFA hydrate is the only by-product formed. The extraction process with the biphase system CH 2 Cl 2 -H 2 O to remove the hydrate can be avoided when DMF is used as a solvent. For work-up, DMF is distilled off in v...

Hexafluoroacetone as Protecting and Activating Reagent: New Routes to Amino, Hydroxy, and Mercapto Acids and Their Application for Peptide and Glyco- and Depsipeptide Modification

“…For workup DMF can be distilled off under reduced pressure and the HFA hydrate is removed by lyophilization. However, this protocol can only be applied to high-boiling and nonvolatile compounds, but then nearly quantitative yields are obtained (Scheme , i) . A stepwise protection is described for an α-hydroxy acid methyl ester, where the hemiacetal is formed first and subsequent cyclization was achieved by adding K 2 CO 3 (Scheme , ii) …”

“…However, only certain HFA-protected α-amino acid chlorides are stabile compounds, like HFA[Asp(Cl)] and its higher homologues with chain length > 7, HFA(Glu), HFA(Aad), and HFA(Api) (chain length 5−7) on treatment with thionyl chloride cyclize spontaneously to give lactams ) .…”

“…Fluorides of N -protected α-amino acids have been applied in peptide chemistry as acylation agents . HFA[Xaa(F)] have been prepared from the corresponding acids by treatment with DAST and isolated as pure compounds by distillation in vacuo . Lactam formation was observed only in the case of HFA(Glu) {HFA[Glu(F)]:HFA(pGlu) 4:1} (Scheme ) …”