Azetidine carboxylate

Use of an interesting enamine photooxidation reaction has teen made of in the synthesis of P-lactams from 2-azetidine carboxylic esters (6.19) 625>. 

Nicotianamine (= N-[N-(3-Amino-3-carboxypropyl)-3-amino-3-carboxypropyl]-azetidine-2-carboxylic acid) (azetidine carboxylic acid) Glycine max (soybean) (Fabaceae) (fermented soybean), Angelica keiskei (Apiaceae) ACE (0.3 pM) [71, 72]... 

In the course of studies on cyclopropanone—)5-lactam conversions, Wasserman and coworkers developed a route to the nocardicins by taking advantage of the reactivity of primary amines with cyclopropanone. The unusual susceptibility of the carbonyl group of cyclopropanone to attack by nucleophiles is well exemplified in this synthesis which involves the addition of the highly hindered malonate derivative (156) to generate the cyclopropanol adduct (157). The hindered amine (156) was previously found to be completely unreactive as a nucleophile in a displacement reaction with dibromoester (158) in an attempt to form the azetidine carboxylate (159). The further conversion of the amino malonate adduct (157) to the -lactam through a nitrenium ion rearrangement is illustrated in Scheme 59. 

Azetidine 2-carboxylic acid (39) is toxic both to plants and animals. When introduced into mung bean Phaseolus aureus), a plant tiiat does not normally have the compound, deleterious effects were noted. Azetidine 2-carboxylic acid is incorporated into protein instead of proline. Many of the Liliaceae have an altered prolyl tRNA synthetase that permits them to discriminate against 2-azetidine carboxylic acid (Rosenthal, 1991). 

Our interest in the polyoxin group of antibiotics [50] was focused on the nature of polyoximic acid [51], a deceptively simple azetidine carboxylic acid derivative which had eluded the efforts of synthetic chemists [52] since the original publication of the structure. Only recently was a synthesis reported for /rnatural product based on low field NMR stupes [51]. A total synthesis of this acid in our laboratory [54,55], and comparison of NMR spectra with a sample kindly provided by Professor Isono showed that they were different. The sample of the naturally-derived amino acid was suitable for X-ray analysis (even after 20 years of isolation and storage ), and it proved to be ci5-polyoximic acid [54]. A new synthesis of this isomer was undertaken and confirmed its structural as well as stereochemical identity (Scheme 9) [55]. TTie stereochemical revision of polyoximic acid could... 

Diaminobutyric acid can be converted via the aspartic acid semialdehyde into 2-azetidine carboxylic acid (XXI), which occurs, for example, in sugar beets (Table 17.5). 

Azetidines.—ay-Dibromoesters, which are prepared from y-lactones react with amines to give azetidine carboxylic esters. Oxygenation of the dianions produced from the latter then leads to 2-azetidinones (jS-lactams) by an oxidative decarboxylation described earlier by the same group of authors (Scheme 55). 

Wassermann has reported (19—21) the synthesis of ( )-3-ANA by way of the P-lactam (25). Various methods were used to prepare (25), such as cyclopropane ring expansion of (24), cyclisation of (26) or acylation of the azetidine carboxylate (27). In another approach (22) the a-methylene P-lactam (28) has also been elaborated to 3-ANA via the use of (29). 

Azetidine carboxylic add, which is especially rare, has been foimd in only a few terrestrial plants, particularly in the seed of Delonyx regia (flamboyant tree) in tropical regions. As for chondrine, which owes its name to the genus Chondria, it was identified later in the green and brown algae (Fattorusso and Piattelli, 1980). 

Serratia mane seem 3,4-dehydro-Pro prodegradation , thiazoline-4-carboxylate/ azetidine-2-carboxylate (transduction) 75 145... 

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)). 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

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. 

The use of HMDS (ca. 1.5 mmol) and saccharin (0.01 mmol) per mmol of substrate in refluxing dichloromethane or chloroform has been recommended (5) for easy silylation of carboxylic acids, including azetidin-2-one-4-carboxyIic acids. Clear solutions result, i.e., no ammonium salts are present at completion of the reaction, and consequently the silyl esters can be obtained by direct distillation, or merely by evaporation of solvent. 

Aminosilanes, 87-9 Artemisia ketone, 33 Aryl silyl ethers, 41 Arylsilanes, 39-43 Arylsulphonylhydrazones, 12 Aryltrimethylsilanes, 39, 42,43 Azetidin-2-ones, 70 Azetidin-2-one 4-carboxylic acids, 92... 

On the other hand, other chiral dirhodium(II) tetracarboxylate catalysts based on azetidine- and aziridine-2-carboxylic acids have been prepared by Zwanenburg et al. and submitted to the cyclopropanation of styrene with... 

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

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