Functionalized azetidines

A number of cycloadditions of imines or imino compounds with a variety of alkenes, including allenes (88HCA1025), vinyl ethers (88TL547), methyl acrylate (86ZOR636), ketene acetals (87JOC365) and electrophilic alkenes (85T1953), afford functionalized azetidines. 

Treatment of l,3-thiazolium-4-olates 526 with aliphatic aldehydes yielded a series of highly functionalized azetidin-2-ones 527 (Equation 216) <2003JOC6338>. The formation of this compound has been explained by ring fragmentation of an initial [3+2] cycloadduct. 

This has been nicely demonstrated and exploited by Woodward s syntheses of bicyclic systems of the penem type. They are typically formed in moderate to good yields upon refluxing the requisite substituted starting -lactams in toluene or xylene for extended periods. The key step is the introduction of the ylidic moiety into the 1-position of a 4-functionalized azetidin-2-one which itself can be obtained as a relay substance by degradation of natural penicillins or from easily available 4-acetoxyazetidin-2-one. The ester ylide function is built up by reaction first with alkyl hemiacetals of glyoxylates to give a hemiaminal and then successive replacement of the OH-group of the latter by Cl with thionyl chloride and finally of the chlorine atom by triphenylphosphane under basic conditions. 

Two roairangementa of i -functional azetidines under acid coji-ditions have been recorded. Tisler has observed that aryltliiouii o) (XXXlll of azetidine are convertad in nearly quantitative yield into... 

The Tadano group extended the use of the sugar-based chiral templates for the l 8-methyl carbapenem synthesis. As concerns the chemical synthesis of 1/3-methyl carbapenems such as 1 /S-methyl thienamycin, the most common approach is a late-stage ring closure for bicyclic skeleton construction using a C-4 functionalized azetidin-2-one, such as 113, namely (35, 45)-3-[(R)-l-(r-butyldimethylsilyloxy)ethyl]-4-[(R)-l-carboxyethyl]azetidin-2-one, which may be constructed via the Mannich-like reaction of commercial (3R,4R)-4-acetoxy-3-[(R)-l-(r-... 

Electrophiles, such as C—Hal functions, contained in side chains may be well positioned for interaction with ring heteroatoms. Thus, Af-t-butyl-2-tosyloxymethylaziridine in ethanol displaces tosylate ion from the side chain, and nucleophilic opening of the resulting azabicyclobutanonium ion by solvent gives 3-hydroxy- and 3-ethoxy-azetidine (Section 5.09.2.3.2). 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

The neutral azetidin-2-one 23 (Fig. 11.13), which has neither the latent leaving group northecarboxy substituent of the previous acidic azetidinone21, is a substrate of both HLE and PPE. Its functionalized analogue 24a inactivates these proteases by an... 

Vergely, I. Boggetto, N. Okochi, V. Golpayegani, S. Reboud-Ravaux, M. Kobaiter, R. Joyeau, R. Wakselman, M. Inhibition of human leucocyte elastase by functionalized V-aryl azetidin-2-ones substituent effects at C-3 and benzylic positions. Eur. J. Med. Chem. 1995, 30, 199-208. 

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments.208 Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the kcto-fi-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionalized hydroxy-ji-lactams (Eq. 8.82). 

Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-P-lactams . 

The only example known for the formation of azetidine 82 by direct intramolecular aza-Wittig reaction is the reaction of the /3-azidoketone 81 with triphenylphosphane (Scheme 41). Attempts to transfer this reaction to 83 and 84 were not successful (87NKK1250). This failure can be attributed to the formation of intermediates with highly energetic transition states, where the rate of intramolecular attack on the carbonyl function is so slow that oligo- and polymeric compounds are preferentially formed. 

About 300 different non-protein amino acids occur in plants. They may be incorporated into proteins in place of the correct amino acids. If they are incorporated into enzymes, they can prevent them from functioning. This often leads to death of the animal. For example, azetidine 2-carhoxylic acid in lily-of-the-valley, Comallaria majalis, and several legumes interferes with synthesis or utilization of structurally similar proline (Fig. 11.9). 

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

Treatment of Af-phenylazetidine 315 with lithium and a catalytic amount of DTBB (5%) in THF at — 15°C led to a solution of the corresponding y-functionalized organohthium intermediate 316, which by reaction with different electrophiles at temperatures ranging between —78 and 20 °C, and final hydrolysis, afforded the expected functionalized amines 317. The same reaction using azetidine 318 yielded products 320, functionalized at the benzylic position, intermediates 319 being involved in the process (Scheme 93) . ... 

Azetidines are often synthesized by reacting 1,3-dihalogenopropanes with an amine (ammonia gives poor yields), or from propane-1,3-diamines where one A-substituent can function as a leaving group. A reaction of the latter type is used to synthesize azetidine from A,A-bis(toluenesul-fonyl)-l,3-diaminopropane in two steps, the last being a reductive A-de-toluenesulfonation, caused by adding sodium to naphthalene in an inert solvent (Scheme 8.5). 

The main interest in azacyclobutanes is reserved for azetidin-2-ones ( 3-lactams), as this ring system is found in penicillin and cephalosporin antibiotics (Box 8.2). These compounds are effective because the (3-lactam ring is strained and readily reacts with the enzyme transpepidase, responsible for the development of the bacterial cell wall. The ring of the lactam is cleaved by this enzyme, which becomes 0-acylated in the process (Scheme 8.6). Once this occurs the enzyme s normal cross-linking function is lost and the cell wall is ruptured. 

Azetidine can be considered as a fairly typical cyclic amine. Strain in the four-membered ring is less than that in the three-membered aziridine system, and as a result azetidines show few, if any, of the exceptional properties associated with aziridines. Thus, ring cleavage reactions occur with greater ease than in larger ring cyclic amines, but much less readily than with aziridine for example, unlike aziridines, azetidines do not function as alkylating... 

---