Tetramic acid antibiotics synthesis

It is somewhat surprising to find that there have been only three published reviews on tetramic acids. The first reports on the advances in tetramic acid chemistry up to 1993 [1], another describes the synthesis of tetramic acid antibiotics [3], and a third, dealing with the structure, isolation and synthesis of naturally occurring tetramic acids, was published in 1995 [4]. The present review is an attempt to cover the field of tetramic acid metabolites with particular emphasis on the structure, biosynthesis and biological activity of these compounds. 

Miscellaneous Reactions.- A full report has appeared of the use of /er/-butyl 4-diethylphosphono-3-oxobutanthioates (232) in olefination reactions for the preparation of homologated 3-oxobutanthioates and hence of tetramic acid derivatives. The reaction of the phosphonate dianion (234) with the aldehyde (233) is a key step in a total synthesis of the tetramic acid antibiotic ( .)-tirandamycin B (235). Olefinations involving both ylides and phosphonates have been used to construct the triene (236) en route to the spirotetronate subunit of the aglycone of the antitumour antibiotic... 

The Tetramic Acid Antibiotics a- and (5-Lipomycin Total Synthesis and Assignment of the Absolute Configuration of All Stereogenic Centers. Making Doubly Sure... 

Having thus established the main stereochemical features, the Claisen rearrangement of glycal esters could be further utilized to provide key intermediates for a number of natural product syntheses Carbohydrates served as starting materials in the total synthesis of the ionophore antibiotics lasalocid A 43 by Ireland et al. [15] and indanomycin 46 by Ley et al. [16] (Scheme 8), as well as the 3-acyl tetramic acid antibiotics tirandamycic acid 49 [17] and (+)-streptolic acid 52 [18] (Ireland et al.. Scheme 9). Several further examples have been reported in the literature [19-21]. 

The gross structural features, presence of a tetramic acid and E-decenoyl side chain, could be inferred from NMR studies. Methanolysis (HCl/MeOH) of 47 and pentane extraction of the quenched reaction mixture gave two compounds that were determined to be the methyl esters of decenoic acid and N-(2-decenoyl)leucine. The nature of the 3-acyl tetramic acid was deduced from the identification of 48 and 49 in the aqueous portion of the methanolysis reaction mixture following treatment with trifluoroacetic acid anhydride. The unusual C-C bond fragmentation under acidic conditions, and the structure of the antibiotic was confirmed by synthesis of racemic 47 [86]. The configuration at the lone chiral centre was established as R by chiral GC. The carbon NMR spectrum of 47 indicated an equilibrium between three tautomers in which the A2-pyrrolin-4-one form is preferred (60%) and the two internal tautomers (50, 51) make equal contributions (20% each). 

Magnesidin has been shown to be a 1 1 mixture of the salts (84 n = 4) and (84 n=6) by spectroscopic and chemical means and by its two-step synthesis (MgCl2, NaOH AczO, NaOAc)from the tetramic acids (85 = 4) and (85 n = 6)7 Magnesidin represents the first magnesium-containing antibiotic substance isolated from natural sources. 

A series of review articles on the synthesis of biofunctional molecules have appeared and several of these describe extensive use of phosphorus-based olefination reactions, for example, in the synthesis of vitamin D, tetramic acids, polyene macrolide antibiotics and bioactive marine macrolides. ... 

A Concise Approach to (-)-Tirandamycin A (2) and (+)-Tirandamycic Acid (3). Tirandamycin A (2) is a representative member of a novel class of naturally-occurring antibiotics that are characterized by the presence of an enolized 3-dienoyl tetramic acid moiety coupled with the unusual dioxabicyclo[3.3.1]nonane ring system. In addition to its antimicrobial activity, 2 inhibits bacterial DNA-directed RNA polymerase, and it interferes with oxidative phosphorylation. Early synthetic work in this area focused upon the preparation of (+)-tirandamycic acid (3), " which is a degradation product of tirandamycin A (2). The first major achievement in this area was Ireland s synthesis of 3 from D-glucose, but more recently 2 has also been prepared by total synthesisOur own investigations in this area culminated in a facile, asymmetric synthesis of 26, which played a pivotal role in Ireland s synthesis of 2 and Schlessinger s synthesis of 3. ... 

Tenuazonic acid (741), a phytotoxin produced by Alternaria spp., is structurally related to the tetramic acid family of compounds, and has been found to exhibit antibiotic activity (511). Since 1964, there have been several publications on the total synthesis of 741 (512-515), including the report by Poncet and his group in 1990 (516) (Scheme 11.10). A general method to synthesize the tetramic acids is an intramolecular Dieckmann cyclization of (V-acyl amino esters. Beginning with methyl L-isoleucinate 780, the A/-acyl compound 782 was obtained through a nucleophilic reaction (512), which then cyclized to tenuazonic acid 741 under basic conditions and neutralization by acidic work-up. The synthetic product showed a diastereomeric excess of 89%, with the major epimer presenting the same configuration as its precursor (517). 

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