Site‐Directed Asymmetric Quaternization of a Peptide Backbone at a C‐Terminal Azlactone

Abstract

Dual‐purpose activation: Peptide C‐terminal azlactones I undergo stereoselective alkylation with high efficiency by the use of a newly devised chiral tetraaminophosphonium salt as a phase‐transfer catalyst, and the alkylated azlactone products II can be employed directly for peptide ligation (see scheme, LG=leaving group). In this way, a wide range of chiral quaternary α‐amino acid residues can be incorporated at specific sites of a peptide strand.

Recent Advances in Asymmetric Catalytic Methods for the Formation of Acyclic α,α-Disubstituted α-Amino Acids

“…29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A recent method that allows site-specific incorporation of quaternary amino acids into peptide chains involves PTC alkylation of azlactones at the C-terminus of a peptide chain 25 (Scheme 6). 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Other Enolate Alkylations. There have also been advances in enolate alkylation of glycine and alanine Schiff base derivatives that do not involve PTC.…”

“…Ooi et al formed quaternary azlactones 27 derived from phenylalanine, tryptophan, and leucine (89-97% yield, 91:9-97:3) 32. This procedure was highlighted in the synthesis of a tetrapeptide containing two quaternary centers.…”

Phosphoric Acid Catalyzed Asymmetric [2+2] Cyclization/Penicillin–Penillonic Acid Rearrangement

“…[2] This reaction was first reported in 1964;h owever,t here are no variants of this reaction and ac atalytic asymmetric version still remains elusive to date.A fter carefully considering the reaction mechanism, [2c] we envisioned that the use of ac hiral acid might catalyze an asymmetric PPAr earrangement. [4] They can react with electrophiles at the C2 [5] or C4 site, [6] undergo [3+ +2] cycloaddition involving the C4 and C2 sites, [7] or undergo [2 + X] cyclization employing the C4 and C5 sites. [4] They can react with electrophiles at the C2 [5] or C4 site, [6] undergo [3+ +2] cycloaddition involving the C4 and C2 sites, [7] or undergo [2 + X] cyclization employing the C4 and C5 sites.…”

“…[3] Recently,azlactones have been shown to be synthetically robust and versatile building blocks that undergo various addition or cyclization reactions,s ince they possess three reactive sites at the C2, C4, and C5 atoms. [4] They can react with electrophiles at the C2 [5] or C4 site, [6] undergo [3+ +2] cycloaddition involving the C4 and C2 sites, [7] or undergo [2 + X] cyclization employing the C4 and C5 sites. [8] In the case of reaction with imines,e xcellent progress has been made with Mannich reactions (C4) [6n-r] or 1,3-dipolar cycloaddition (C4 and C2), [7c,h] but [2+ +2] cyclizations (C4 and C5) have been extremely limited.…”

Phosphonium salts and P-ylides

“…91 Under these conditions the reaction of 1,3-dimethylbarbituric or Meldrum's acid resulted in the 1,4-diionic products (55). Note that highly functionalized phosphorus ylides derived from the threecomponent reaction exist in solutions as a mixture of Z-and E-isomers of the corresponding zwitterionic species (56).The slow rotation about the partial double bond in (E)-3 and (Z)-3 geometrical isomers on the NMR timescale at room temperature allows an estimate of their mole ratio at equilibrium. For the zwitterionic salt of dimethyl 2(N-2-methylindole-1-yl)-3-(triphenylphosphoranylidene)butandioate (57) obtained via the above strategy from TPP, DAAD and 2-methylindole, a series of separate dynamic 1 H NMR effects at different temperatures were reported.…”