Synthesis of Cyclic Depsipeptides and Peptides via Direct Amide Cyclization

Abstract

The 2,2‐disubstituted 2H‐azirin‐3‐amines 7 (2,2‐disubstituted 3‐amino‐2H‐azirines) were used as amino‐acid synthons in the preparation of medium‐sized cyclic depsipeptides and peptides derived from salicylic acids 6 and anthranilic acid 19, respectively (Schemes 2‐‐4 and 5, resp.). The combination of the ‘azirine/oxazolone method’ for the synthesis of linear peptides containing α,α‐disubstituted α‐amino acids and the acid‐catalyzed amide cyclization in DMF at 60° proved to be an excellent preparative route to ten‐membered cyclic depsipeptides and peptides. In the case of the anthranilic‐acid derivative, a transannular ring‐closure reaction was observed (24 → 25). Larger rings proved to be extremely sensitive to hydrolysis.

Synthesis of a Regular 24-membered Cyclodepsipeptide by Direct Amide Cyclization

“…According to GP 12,18,3,9,9,15,15,21,7,13,10,16,5,8,11,14,17,20, Dry HCl gas was bubbled through a solution of 15 (300 mg, 0.31 mmol) in toluene (30 mL) at 100 • C for 4.5 min. The mixture was then heated under reflux for 20 min while a gentle stream of dry HCl gas was bubbled through the solution.…”

Synthesis of Enniatin‐like Cyclic Depsipeptides via ‘Direct Amide Cyclization’

“…According to GP 12,3,9,9,15,7,10,5,8,11,14, 6 ). All measurements were performed on a Nonius KappaCCD area-detector diffractometer [52] using graphite-monochromated MoK α radiation (λ 0.71073 Å) and an Oxford…”

“…Effective methods for the introduction of α,α-disubstituted α-amino acids and subsequent ring closure to give a cyclic depsipeptide are therefore of interest. A useful cyclization method for depsipeptides containing a C-terminal α,α-disubstituted α-amino acid, the so-called 'direct amide cyclization' method, has been developed in our laboratory [9][10][11][12][13][14][15][16][17][18][19][20]. The basic concept is shown in Scheme 1: if an amide of type 1 is treated with dry HCl-gas, the corresponding 1,3-oxazol-5(4H)-one derivative 2 is formed via ring closure and elimination of dimethylamine hydrochloride.…”

An Unexpected Formation of a 14‐Membered Cyclodepsipeptide

“…In the last few years, the number of reports on the use of macrolactonizations in the preparation of cyclodepsipeptides has increased remarkably [6][7][8][20] [21]. A useful method for the ring closure of depsipeptides which contain α,α−disubstituted α−amino acids is the so-called 'direct amide cyclization' method, developed in our laboratory [22][23][24][25][26][27][28]. The basic concept is that an amide of type 1 in a toluene solution or suspension is treated with dry HCl gas.…”