An Efficient Synthesis of (-)-Deacetylanisomycin Starting from d-Tyrosine

Abstract

The antibiotic (-)-deacetylanisomycin was synthesized starting from D-tyrosine using Sharpless asymmetric dihydroxylation as a key reaction.Anisomycin (1) is an antibiotic that has been isolated from fermentation broth filtrates of various species of Streptomyces. 2 X-ray crystallographic analysis 3 and chemical studies 4 reveal the structure and relative stereochemistry of anisomycin to be that depicted in structure 1 (Figure 1). The absolute stereochemistry was established as 2R,3S,4S by chemical correlation studies. 5 Anisomycin possesses strong and selective activity against pathogenic protozoa and fungi and has been proved successful clinically in the treatment of amoebic dysentry and trichomonas vaginitis. 6 It has been shown to block ribosomal peptide synthesis. 6 Figure 1The structure of Anisomycin (1) Although a few total synthesis of (-)-anisomycin have been reported 7 previously, the molecule still continues to attract the attention of synthetic organic chemists owing to its high biological profile. Our continued interest in the development of new and efficient synthetic routes to clinically significant amino compounds prompted us to investigate the total synthesis of (-)-deacetylanisomycin (2). 8 We wish to report herein the synthesis of 2 from D-tyrosine, which also constitutes a formal total synthesis of 1. It appeared to us that an expedient approach to 2 from Dtyrosine would involve a reaction sequence outlined as below (Scheme 1).Compound 4 was obtained in 70% yield from D-tyrosine by protecting the amino functionality using di-tert-butyl dicarbonate, followed by methylation of the acid and phenolic hydroxyl group with MeI/K 2 CO 3 . Reduction of ester 4 with lithium borohydride 9 furnished the alcohol 5 (72%). A Swern oxidation 10 followed by Wittig reaction with (ethoxycarbonylmethylene)triphenylphosphorane in CH 2 Cl 2 yielded the trans a,b-unsaturated ester 6 (73%). In order to avoid or minimize any possible racemization at the chiral centre, the aldehyde was used immediately without purification.Our strategy required that the olefination product 6 contained the desired trans geometry at the double bond for the subsequent creation of chiral diol via Sharpless asymmetric dihydroxylation. Upon reacting the N-Boc-protected g-amino-a,b-unsaturated ester 6 with the modified Sharpless asymmetric dihydroxylation conditions using AD-mix-a, 11 the expected (2R,3S,4R) configured ester 7 (60%) was obtained with high stereoselectivity (Scheme 2). This result has precedence. 12,13 N H HO OR MeO 1 R = COCH 3 2 R = H Scheme 1 HO NH 2 COOH MeO NHBoc COOMe MeO NHBoc MeO NHBoc OEt O 1) NaOH/Dioxane/H 2 O Boc 2 O 2) MeI/Acetone K 2 CO 3 Et 2 O/MeOH reflux 1) (COCl) 2 , DMSO DCM, Et 3 N, -78 °C 2) Ph 3 P=CHCOOEt CH 2 Cl 2 , r.t. 4 (70%) 5 (72%) 6 (73%) D-tyrosine LiBH 4 OH Downloaded by: Queen's University. Copyrighted material.

Studies Towards the Synthesis of (+)- and (–)-Anisomycin and Their Analogues

“…37 Chandrasekhar and co-workers reported the synthesis of (-)-deacetylanisomycin [(-)-2] from D-tyrosine (D-3) involving Sharpless asymmetric dihydroxylation as a key reaction. 44 The free amine in D-tyrosine (D-3) was protected using Boc 2 O, followed by methylation of hydroxy and acid groups using MeI and K 2 CO 3 to give fully protected compound 189. The ester was reduced with LiBH 4 to produce alcohol 142, which was subjected to Swern oxidation followed by Wittig reaction with (ethoxycarbonylmethylene)triphenylphosphorane to produce α,β-unsaturated ester (E)-144 in 73% yield.…”

Effect of the 4′-substituted phenylalanine moiety of sansalvamide A peptide on antitumor activity

“…19 Methylation or allylation of the substituted phenylalanine was carried out according to that described in Scheme 1. 20,21 The synthesis of methyl L-2-amino-3-(4-methoxyphenyl)propanoate commenced from methylation of N-Boc tyrosine with iodomethane in acetone in the presence of K 2 CO 3 according to Reddy's method 22 to give the corresponding N-Boc-4-methoxylphenylalanine methyl ester in 96% yield. Subsequent treatment with TFA in DCM gave methyl 4-methoxylphenylalanine methyl ester in 93% yield.…”

Carbonylation of functionalized diamine diols to cyclic ureas: application to derivatives of DMP 450

“…The procedure was adapted from the literature. 57 To a suspension of diol 6a (1.14 g, 2.74 mmol) in 70 mL CH 2 Cl 2 was added 2,2-dimethoxypropane (1.99 g, 0.0192 mol) at 0 C. A catalytic amount of (AE)-camphor-10-sulfonic acid (50.0 mg) was added and the mixture was stirred overnight at room temperature under nitrogen. The reaction was then exposed to air and concentrated into a dark oil.…”