Applications of Sugar Nitrones in Synthesis:  The Total Synthesis of (+)-Polyoxin J¹

Abstract

A convergent synthesis of the peptidyl nucleoside antibiotic (inhibitor of chitin biosynthesis) polyoxin J (2) by coupling of 5-O-carbamoyl polyoxamic acid (3) and thymine polyoxin C (4) is described. These compounds were prepared by chain elongation and amination of sugar-derived aldehydes employing their nitrones as iminium derivatives and the furan ring as a masked carboxyl. Thus, the stereoselective addition of 2-lithiofuran to the l-threose derived N-benzyl nitrone 5 followed by reduction of the resulting hydroxylamine to amine, carbamoylation of the free hydroxy group, and oxidative cleavage of the furan ring to the carboxylate group gave a protected derivative of 3 (30%). The same method was followed for the synthesis of the ribofuranosyl α-amino acid nucleoside 4 (12.6%) starting from the d-ribose derived nitrone 6. The final coupling was performed by the N-hydroxysuccinimide active ester method in DMSO with the Hünig base (i-Pr2EtNH) using a derivative of 3 and unprotected 4.

Synthesis of N-(Benzyloxyethyl)- and N-(Alkoxycarbonylmethyl)nitrones

“…1 2, 67.4, 72.3, 127.8, 127.9, 128.4 128.7 (2 C), 128.9, 133.3, 135.1, 146. Anal. Calcd for C 16 H 17 NO 2 : C,75.27;H,6.71;N,5.49. Found: C,75.03;H,6.83;N,5.50.…”

“…9, 68.1, 73.5, 123.7, 127.7, 127.9, 128.5, 128.9, 133.5, 135.9, 137.4, 147.3 ,5.37;N,9.33. Found: C,64.23;H,5.16;N,9.19.…”

Polyalkoxy Nitrones as Chiral Building Blocks in Asymmetric Synthesis

“…The total synthesis of Polyoxin J is outlined in Scheme 10. Application of our method to the Lthreose-derived aldehyde 39 afforded the protected polyoxamic acid 40 in a 25.8% overall yield from aldehyde 39 (7 steps) [26]. Several synthetic approaches to the thymine polyoxin C 36 were envisioned [27], the best of them being that illustrated in Scheme 10.…”

“…Glycosylation with 2,4-bis(trimethylsilyl)thymine of 42 gave the nucleoside amino acid 43. Complete deprotection of this derivative by reductive and hydrolytic methods furnished natural thymine polyoxin C 36 in a 9.6% overall yield from aldehyde 41 (10 steps) [26]. The final coupling between 36 and 40 was performed by the N,N-dicyclohexylcarbodiimide N-hydroxysuccinimide (DCC / HOSu) active ester method.…”

“…Thus protected polyoxamic acid 40 was converted into active ester 43 which was then treated with thymine polyoxin C 36 to afford the dipeptide 44. Finally, deprotection of 45 by treatment with aqueous trifluoroacetic acid gave, after purification by column chromatography, Polyoxin J in 46% yield [25,26]. 25,26 …”