Selective Access toE- andZ-ΔIle-Containing Peptides via a Stereospecific E2 Dehydration and an O → N Acyl Transfer

Abstract

A concise synthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues is reported. The key reaction is an unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction-O → N acyl transfer process forges an amide bond to the ΔIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process.

Bulky α,β-dehydroamino acids: their occurrence in nature, synthesis, and applications

“…In an effort to devise a route to DIle-containing peptides that does not require backbone amide protection, Castle and co-workers performed a one-pot Staudinger reductioneO/N acyl transfer reaction to convert azidoethyl esters 143 and 145 into the corresponding amides 144 and 146 (Scheme 26). 109 Both E-and Z-DIlecontaining peptides were accessed with minimal amounts of alkene isomerization (!10:1 dr), and the process could be conducted on branched azidoesters (i.e., a Val surrogate possessing an i-Pr group) with similar results. Oxidation of the primary alcohol groups of 144 and 146 yields acids that can participate in subsequent peptide couplings without isomerization of the alkene.…”

“…109 The stereospecificity of this process is noteworthy, as most dehydrations of tertiary alcohols by this reagent are believed to proceed via E1-like mechanisms. 110,111 Density functional calcuations performed by Ess and co-workers attribute the anti selectivity observed with 67 and 69 to a highly asynchronous E2 pathway.…”

“…110,111 Density functional calcuations performed by Ess and co-workers attribute the anti selectivity observed with 67 and 69 to a highly asynchronous E2 pathway. 109 Hiemstra and co-workers constructed trifluoroacetamideprotected bulky DAA derivatives via the sequence shown in Scheme 9. Treatment of amino acids 71 with TFAA furnished pseudoazlactones 72, which were transformed into bromides 73.…”

A general method for preparation of N‐Boc‐protected or N‐Fmoc‐protected α,β‐didehydropeptide building blocks and their use in the solid‐phase peptide synthesis

“…Despite the fact that N α -carbamate-protected α,β-didehydro-α-amino acids can be easily prepared from N α -carbamate β-hydroxy amino acids (eg, Thr, Ser, 3-phenylserine) through elimination reactions, [18][19][20][21][22][23][24][25][26][27] they are not fully useful in peptide synthesis. Enamine-imine tautomerism of free α,β-didehydro-α-amino acid moieties makes them susceptible to hydrolysis, so traces of water in commonly used laboratory solvents result in an increasing number of by-products containing α-oxomoieties as the N-terminal residue during synthesis of longer peptides.…”

“…A frequently used strategy in synthesis of dehydropeptides is elimination of water from threonine and serine which may be achieved by activation of the free hydroxyl group with various reagents. [18][19][20][21][22][23][24][25][26][27] Elimination of water may be also realised in the Z-stereoselective or E-stereoselective fashion.…”