9‐Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents and Their Application in Peptide Synthesis

Abstract

Af undamentally simple,m ild, and practical procedure for peptide bond formation is reported that employs as toichiometric amount of easy-to-access 9-silafluorenyl dichlorides as the coupling agent. Without initial preactivation or elaboration of the carboxylic acid or amine termini of the amino acids,the developed reagent is proposed to act through an unprecedented chemical ligation mechanism, bringing the two coupling partners together before being subsequently eliminated. The desired amides or peptide bonds are thus furnished in good yields and with low to no epimerization.

Silyl Esters as Reactive Intermediates in Organic Synthesis

“…They noted that with this reagent the amino acids can be tethered together (Figure 10 ), which can rearrange upon heating to give the amide bond and a siloxane polymer. 60 They observed that a dipeptide with the bulkier α-side chain on the amino ester was obtained in higher yield than a dipeptide where the bulkier α-side chain is present on the free carboxylic acid amino acid residue. Their results suggested that the first addition to the silyl coupling reagent is that of the free amine residue, and the second, is that of the free carboxylic acid residue.…”

“…These results suggested that the 9-silafluorenyl dichloride mediated amide bond formation proceeds through the chemical ligation pathway. 60…”

“…Jiang, Bi and co-workers then considered the generation of the amide directly from a number of these potential intermediates. 79 The Charette group proposed that an anhydride was a potential intermediate, 60 and this pathway (Path A) was also studied (Scheme 38 ). The direct elimination possessed an inaccessibly high energy barrier; again, however, the unlikely ammonium salt assisted pathway is possible through TS-A1 .…”

“…In 2016, the Charette group synthesized and investigated novel 9-silafluorenyl dichlorides (Figure 3 ) as coupling reagents for peptide synthesis from unactivated amino esters and N -protected amino acids. 60 A simple amide coupling reaction of glycine methyl ester hydrochloride salt and phenylacetic acid with various commercially available chlorosilanes showed that this reaction can proceed in good yield using dichlorodiphenylsilane along with Et 3 N and DMAP. In reactions using more sterically hindered amino acid residues the yield significantly decreased.…”

Amine Activation: N‐Arylamino Acid Amide Synthesis from Isothioureas and Amino Acids

“…Sometimes, the activated carboxylic acids are generated in an extra step and activation requires unstable, expensive and waste‐intensive reagents. Recent advances in this field use acetylenes and a transition metal and ynamides to activate the carboxylic acid or Si ligation with 9‐silafluorenyl dichlorides –. Epimerization of sensitive α‐chiral acids through the formation of oxazolone intermediates is difficult to suppress with carboxylic acid activation.…”