An Unexpected Formation of a 14‐Membered Cyclodepsipeptide

Abstract

The treatment of diluted solutions of the hydroxy diamides 6a and 6b in toluene with HCl gas at 100°gave the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3). The same product was formed from the linear dimer of 6b, the depsipeptide 11, under the same conditions (cf. Scheme 4). All attempts to prepare the cyclic seven-membered monomer 9, starting with different precursors and using different lactonization methods failed, and 10 was the only product which was isolated (cf. Scheme 6). For example, the reaction of the ester 20 with NaH in toluene at 80°led exclusively to the cyclodimer 10. On the other hand, the base-catalyzed cyclization of the hydroxy diester 22, which is the 'O-analogue' of 20, yielded neither the seven-membered dilactone, nor the 14-membered tetralactone, but only the known trimer 23 and tetramer 24 of 2,2-dimethylpropano-3-lactone (cf. Scheme 7). 2The treatment of diluted solutions of the hydroxydiamides 6a and 6b in toluene with HCl gas at 100 o gave the dimeric, 14-membered cyclodepsipeptide 10 in up to 72% yield (Scheme 3).The same product was formed from the linear dimer of 6b, the depsipeptide 11, under the same conditions (Scheme 4). All attempts to prepare the cyclic 7-membered monomer 9, starting with different precursors and using different lactonization methods failed, and 10 was the only product which was formed (Scheme 6). For example, the reaction of the ester 20 with NaH in toluene at 80 o led exclusively to the cyclodimer 10. On the other hand, the base catalyzed cyclization of the hydroxydiester 22, which is the 'O-analogue' of 20, yielded neither the 7-membered dilactone, nor the 14-membered tetralactone, but only the known trimer 23 and tetramer 24 of 2,2-dimethylpropiolactone (Scheme 7).3

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

“…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.…”

Transformation of 5‐Hydroxy‐ to (5‐Chloropentanoyl)amino Derivatives under ‘Direct Amide Cyclization’ Conditions

“…A correction for secondary extinction was applied. Refinement of the absolute structure parameter [19][20] yielded a value of 0.01 (6), which confirms that the refined model represents the true absolute structure. Neutral atom scattering factors for non-H atoms were taken form [21] and the scattering factors for H-atoms were taken from [22].…”

“…Recently, we have shown that diamides of type A, which contain β-hydroxy acids, i.e. 1 (n = 2), under these reaction conditions did not give the expected 7-membered cyclodepsipeptides, and only their dimers, the 14-membered rings 4 were isolated in good yields [6][7] (Scheme 2). Treatment of γ-hydroxy acid derivatives (1, n = 3) with HCl gas in toluene yielded no cyclodepsipeptides at all.…”

A New 2H‐Azirin‐3‐amine as a Synthon for α‐Methyl Glutamate.

“…A useful method for the introduction of such amino acids into peptides is the so-called 'azirine/oxazolone method' [1], which proved to be a convenient preparative access to such peptides. This strategy has been applied extensively in the synthesis of linear oligopeptides [2][3][4][5][6][7][8], endothiopeptides [9][10][11][12][13], conformationally restricted cyclic peptides [14][15][16][17], and cyclic depsipeptides [17][18][19][20][21][22][23][24][25][26] containing 2,2-disubstituted glycines.…”