Azetidine carboxylic acid

Biosynthesis of Heterocycles From Isolation to Gene Cluster, First Edition. Patrizia Diana and Girolamo Cirrincione. 

FOUR-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

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The absolute configuration of naturally occurring 5(-)-azetidine-2-carboxylic acid has been established (73CL5), and the DL form has been resolved (69JHC993). ORD and CD curves have been determined for 2-methylazetidine and an octant rule has been proposed for the N-chloro- and N-cyano-2-methylazetidines (74T39). 

A number of 2-acylazetidines have been prepared by reaction of 1,3-dihaloacyl compounds with amino derivatives (Section 5.09.2.3.l(m)). This is illustrated for azetidine 2-carboxylic acid (56), the only known naturally occurring azetidine. Ring expansion of activated aziridines (43) and contraction of 4-oxazolines (55) has also found limited use (Section 5.09.2.3.2(f) and Hi)). 

Azetidine, 7V-bromo-, 7, 240 Azetidine, AT-r-butyl- N NMR, 7, 11 Azetidine, AT-t-butyl-3-chloro-transannular nucleophilic attack, 7, 25 Azetidine, 3-chloro-isomerization, 7, 42 Azetidine, AT-chloro-, 7, 240 dehydrohalogenation, 7, 275 Azetidine, 7V-chloro-2-methyl-inversion, 7, 7 Azetidine, 3-halo-synthesis, 7, 246 Azetidine, AT-halo-synthesis, 7, 246 Azetidine, AT-hydroxy-synthesis, 7, 271 Azetidine, 2-imino-stability, 7, 256 Azetidine, 2-methoxy-synthesis, 7, 246 Azetidine, 2-methyl-circular dichroism, 7, 239 optical rotatory dispersion, 7, 239 Azetidine, AT-nitroso-deoxygenation, 7, 241 oxidation, 7, 240 synthesis, 7, 246 Azetidine, thioacyl-ring expansion, 7, 241 Azetidine-4-carboxylic acid, 2-oxo-oxidative decarboxylation, 7, 251 Azetidine-2-carboxylic acids absolute configuration, 7, 239 azetidin-2-ones from, 7, 263 synthesis, 7, 246... 

Azetidine-2-carboxylic acid, the lower homolog of proline, has been isolated from Convallaria majalis (lily of the valley) 40,44), Polygonatum officinalis (Solomon s seal) 153), and Polygonatum multiflorum 45). Fowden and Steward 47) surveyed plants from 56 genera for nitrogenous compounds and found azetidine-2 -carboxylic acid to be restricted to members of the Liliaceae. In some species it was identified in leaf, stem, and root but was more commonly found in the seed. In Polygonatum, azetidine-2-carboxylic acid accounted for 75% or more of the total nonprotein nitrogen in the rhizome 45). There was no evidence that it occurred as a constituent of protein. 

Fowden and Richmond 46) found that azetidine-2-carboxylic acid was growth-inhibitory to Escherichia coli, but no inhibition was observed when both DL-proline and the homolog were present in the... 

Some members of the Liliaceae accumulate free azetidine-2-carboxylic acid in a much higher concentration than that found to be lethal to mung bean seedlings, but it is not incorporated into their proteins. Fowden (43) postulated that these plants either had a proline-incorporating system which was more specific than that found in other species, or some subcellular mechanism operated to prevent the homolog from reaching the sites involved in protein synthesis. Data which supported the first suggestion were subsequently obtained (116). 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

Scheme 6.18 Rh-catalysed cyclopropanation of styrene with sulfonamide ligands derived from aziridine- and azetidine-2-carboxylic acids.

Fig. 3. Lightmicroscope radioautographs ofintact tubes from pollen germinated 4 h in a medium containing [14C]-proline with or without the proline analogue, azetidine-2-carboxylic acid (AZC). A = 1.0 mM AZC, B = 0.1 mM AZC, C = 0.01 mM AZC, D = 0.001 mM AZC, E = Control. From Dashek and Mills (50), with permission. 

Krolak JM, Taylor N, Dashek WV, Mills R. Azetidine-2-carboxylic acid-induced suppression of 14C-proline incorporation into cytoplasmic macromolecules and cell wall of Lilium longiflorum pollen, in Advances in Plant Reproductive Physiology (Malik CP, ed.), Kalyani Publishers, New Delhi, India, 1978, pp. 62-71. 

Dashek WV, Mills RW. Azetidine-2-carboxylic acid and lily pollen tube elongation. Ann Bot 1980 45 1-12. 

Leete, E. Biosynthesis of azetidine-2 carboxylic acid from methionine in Nicotiana tahacum. Phytochemistry... 

A -(2-Aminobenzoyl)-peptides undergo acid-catalyzed cyclization to 1 -benzodiazepine, 5-diones. 187 Thus, Boc-Abz-Xaa-OH, where Xaa corresponds to various A-alkyl-amino acids such as Pro, Hyp, Thz, Pip, and azetidine-2-carboxylic acid and their methyl esters are readily converted into the corresponding l,4-benzodiazepine-2,5-diones in the acidolytic Boc-cleavage step by treatment with 95% aq TFA or 100% TFA (rt, 1 h). 

Efforts have been made to find stereoselective routes which provide disubstituted azetidines. Palladium catalysed cyclization of an enantiomer of allene-substituted amines and amino acids gives the azetidine ester 2 and a tetrahydropyridine in variable yield and ratio, depending on the substituents and conditions <990L717>. The (TRIS)- and (253I )-isomeis of the substituted azetidine-2-carboxylic acids 3 (R = COjH) are obtained in several steps from the corresponding 3 (R = CHjOSiMejBu ) which, in turn, is produced in high yield by photochemical intramolecular cyclization <98HCA1803>. 

In order to check the role of proline at the C-terminus, linear tripeptides with other imino acids at that position have been subjected to cyclization. Both (74) and (76), the former having L-azetidine-2-carboxylic acid, and the latter sarcosine, gave the respective cyclols (75) and (77). The difference is that (75) can be dissolved in alkali and regenerated by acidification, whereas (77) is isomerized to the N-acylpiperazinedione and hydrolyzed under these conditions (78TL1009). 

N-Acyl derivatives of azetidine have been studied (72CC788 720MRI45 78JCS(P2)1157) as derivatives of azetidine-2-carboxylic acid (87), since conformational properties of these compounds have been compared to those of N-acylprolines (90). 

In D O solution, the cyclic trimeric derivative of azetidine-2-carboxylic acid [cyclo(Aze)3] displayed (78MI2) more than one interconverting conformation, with peptide bonds slightly deviated from planarity. Circular di-chroism in methanol showed (78MI3) absorption very similar to that of... 

L-azetidine-2-carboxylic acid <3> (<3> 3mM, 50% inhibition [5]) [5] L-methionine-DL-sulphoximine <3> (<3> competitive with L-glutamate [5])... 

The four-membered azetidine ring remains unaffected by sodium in liquid ammonia, 94 methanolic ammonia, 95 5M barium hydroxide at 100 °C for 24 hours, 87 sodium hydroxide under ester saponification conditions, 87 HC1 at room temperature, 96,97 catalytic hydrogenation under normal conditions, 87,95 and ozonolysisJ87 Correspondingly, as observed for proline, the azetidine-2-carboxylic acid (2) raises no particular difficulties in the synthesis of related peptides. 

Azetidine-2-carboxylic acid (2) like proline gives an intense blue color with sodium nitroprusside in 10% acetaldehyde solution in the presence of sodium carbonate. 98,99 Upon usual acid hydrolysis (6M HC1, 110 °C, 24 h or more) as required for amino acid analysis, azetidine-2-carboxylic acid is completely decomposed, yielding mainly homoserine lactone, as well as other ninhydrin-positive compounds. 87,89,99 To enable an accurate quantification of this imino acid, azetidine-2-carboxylic acid peptides should be hydrolyzed by alkali (5M barium hydroxide, at 100 °C for 18 h 89 or 2 M sodium hydroxide at 110°C for 22h 100 ). There are extensive NMR spectroscopic data available 100-104 and the absolute configurations of A-acetyl-L-azetidine-2-carboxylic acid 105 and A-terf-butoxycarbonyl-L-azetidine-2-car-boxylic acid 106 have been determined by X-ray analysis. 

Azetidine-2-carboxylic acid (2) is commercially available. It is readily prepared as the racemate by refluxing 2,4-dibromobutyric acid ester with benzhydrylamine in acetonitrile. If benzyl 2,4-dibromobutyrate is treated with benzhydrylamine, the resulting benzyl TV-benz-hydryl-D,L-azetidine-2-carboxylate is hydrogenolytically processed to D,L-azetidine-2-car-boxylic acid in a one-step reaction. 101,107 Resolution of the racemate can be performed by the method of Vogler 108 via fractional crystallization of the Z-D,L-Aze-OH-H-Tyr-N2H3 salt thereby the salt of the D-imino acid precipitates first from methanol. 96 A stereoselective synthesis of A-tosyl-L-azetidine-2-carboxylic acid can be achieved by a two-step reaction from N-tosyl-L-homoserine lactone. 94 ... 

A-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid is obtained by reaction of azetidine-2-carboxylic acid with Boc-N3, m 112 Boc20, 113-"4 or 2-(fert-butoxycarbonyloxyimino)-2-phe-nylacetonitrile. 115 In a similar manner, the Fmoc derivative is prepared by the standard procedure using Fmoc-OSu as acylating agent.1"6 For derivatives of azetidine-2-carboxylic acid, see Table 4. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

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