Tetramic acid synthesis

Two alternative methods for the preparation of phosphorus-activated tetramic acid reagents have recently been described.These reagents have served to provide a workable solution to the problem of construction of the dienoyl tetramic acid unit required for the synthesis of tirandamycin-A, - " ... 

Thus, in the case of 3-unsubstituted tetramic acids (X), the synthesis would start from acetic acid and an a-amino carboxylic acid. (In practice the acid will be replaced by suitable carboxylic acid derivatives.) The problem in these syntheses is the low reactivity of the methyl group of acetic acid. 

Scheme 2. Strategy for the synthesis of tetramic acid derivatives (x-z).

Tetramic acid derivatives are valuable intermediates in the total synthesis of natural substances that is why a great number of experiments were carried out to find more convenient pathways to their preparation. In general, there are two different methods to reach this goal. 

Direct synthesis of tetramic acids (1/2) (see retrosynthesis X, Scheme 1) starting with an alkanoic acid and an amino acid have rarely been described. One example is a patent of the synthesis of 3,3-dipropyl-2,4-pyrrolidindione formed by bubbling HC1 gas through a mixture of valproic acid and glycine in methanol at 25°C (90JAP01/311061). 

A reaction by Clough et al. comes close to the direct synthesis shown in Scheme 1 (89TL7469). Here amides (62) react in a radical mechanism to 4-methylene compounds (63) that with 03/PPh3 are converted to tetramic acids (64). (See Fig. 29.) Several authors, however, prepared esters of 4-amino-3-oxo-butanoic acid, which served as precursors for intramolecular cyclization to tetramic acids (82JHC883). Koehler and Gerlach in an initial stage of a synthesis of dysidine, contained in marine sponge... 

As lactams of 4-amino-3-oxobutanoic acids, tetramic acids react with amines (87JPJ858) and with phenylhydrazine. The latter reaction is catalyzed with para-toluenesulfonic acid. Thus, for example, l/2b give phenyl-hydrazone 65 in 80% yield that, in turn, under the conditions of the Fischer indole synthesis, may give rise to pyrrolo[4,3-b]indolene 66 (90TH1). (See Fig. 31.)... 

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. 

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). 

Four mechanisms have been advanced for the prebiotic formation of amino acids. The first involves a cyanohydrin (reaction 2) and a related route (reaction 3) can be invoked to account for the presence of hydroxy acids. These particular reactions have been studied in considerable detail both kinetically and in terms of thermodynamic quantities.347 An alternative route (4) involves the hydrolysis of a-aminonitriles, which are themselves formed directly in anhydrous CH4/NH3 mixtures.344 Cyanoacetylene, formed in CH4/N2 irradiations,349 yields significant amounts of asparagine and aspartic acids (reaction 5). Finally, a number of workers336,350"354 have proposed that HCN oligomers, especially the trimer aminoacetonitrile and the tetramer diaminomaleonitrile, could have been important precursors for amino acid synthesis. Reaction mixtures involving such species have yielded up to 12 amino acids. Table 11 indicates the range of amino acids produced in these kinds of sparking syntheses. Of some interest is the fact that close parallels between these kinds of experiments and amino acid contents of carbonaceous chondrite meteorites exist.331,355,356... 

Solid-Phase Synthesis Terminated by Tetramic Acid Cyclative Cleavage (Scheme 2). The Fmoc-L-Val resin (loading 0.7 mmol/g) is first deprotected with 20% piperidine in DMF for 20 min, and the resin washed and dried. The resin ( 0.3 g, 0.67 mmol/g) is shaken with p-anisaldehyde (0.25 ml, 10 molar equiv.) and sodium triacetoxyborohydride (0.65 g, 15 molar equiv.) in 10 ml CH2C12 for 8 h, followed by washing and drying to give resin 4. 

However, it requires rather hindered /3-ketocstcrs to observe a significant drop in the yield of the arylation reaction with />-rn ethoxy phenyl lead triacetate 1 (Equation (3)).16 On the other hand, if the /3-dicarbonyl moiety is inserted into a cyclic structure, this difference disappears. For example, in the synthesis of functionalized tetramic acid derivatives, reaction of phenyllead triacetate 2 with the two five-membered cyclic pyrrolidinediones 3 and 4 afforded the diphenyl derivative 5 with a similar efficiency of the arylation step (Equations (4) and (5)).17... 

As an example of scaffold synthesis rather than decoration, we adapted the Lacey-Dieckmann synthesis of tetramic acids to a combinatorial strategy (Figure 6). The overall sequence is only three steps, and all the three reaction inputs involve readily available building blocks amino acids, aldehydes, and carboxylic acids. We published both solution- and solid-phase protocols, and this was followed soon thereafter by similar reports from industrial groups. Clearly, the ability to access this heterocycle with ample room for diversification was highly attractive, and each of us had independently developed this idea. 

A convergent route for the total synthesis of the cytotoxic tetramic acid cylindramide (1) with no linear sequence longer than 18 steps is described. 

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. 

In another approach, the two applications were combined and an ion-exchange resin was used both as a reagent and as the purification agent in a synthesis of tetramic acids [42] (Scheme 13). Starting from amino add esters 38, reductive amination and subsequent couphng with acids led, after extractive work-up, to... 

Boeckman. R.K.. and Thomas, A.J.. Methodology for the synthesis of phosphorus-activated tetramic acids. Applications to the synthesis of unsaturated 3-acyltetramic acids.Org. Chem.. 47, 2823. 1982. 

Schlessinger. R.H.. and Graves, D.D.. A synthesis of the tetramic acid subunit of sfreptolydigin. A reactivity definition of this subunit as an Emmons reagent. Tetrahedron Lett.. 28. 4385. 1987. 

The strongly acidic character of tetramic acids and their usual low solubility prompted us to delay the assembly of this heterocyclic unit until very late in the synthesis. Accordingly, the appropriate ornithine segment was constructed next (Scheme VII). The known amino acid 57 [26b] was transformed via the fully protected derivative 58 to 59 by chemoselective unmasking of the y-amino group with formic acid. The remaining two substituents on the a-amino group are to be removed at different times, with the allyl carbamate destined to precede the 2,4-dimethoxybenzyl functionality. 

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. ... 

Some phosphonates, e.g., (165), derived from tetramic acids have been prepared and shown to undergo normal olefination with ketones in work ultimately aimed at the synthesis of tetramic acid-containing natural products. A general method for the synthesis of 3-enoyl and 3-dienoyl tetramic acids, involving olefination with the phosphonate (166), has been reported. ... 

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... 

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