Amino-2-azetidinones

CO)sCr=CHNBzli- (cf. 11, 400-401). This carbene, like typical Fischer carbenes, undergoes a photolytic addition to imines to give mixtures of cis- and trans-3-dibenzylamino-p-lactams in fair to good yield. The products are convertible into 3-amino-2-azetidinones.1 2 4 5... 

The ynamide-Kinugasa reaction has been used for the highly stereoselective synthesis of chiral cz-amino- (3-1 actams. The application of this reaction consists in the preparation of chiral a-amino-2-azetidinones starting from chiral ynamide (Scheme 64), [158]. 

Other compound classes in the synthesis of which chiral 3-carbon synthons were used include sphingosine chains (32), 3-amino-2-azetidinones (33), (3,y-unsaturated-a-amino acids 34), fluorinated macrocyclic bis(indolyl) maleimides35, fluorocyclopropyl alcohols (36), l-O-phosphocholine-2-O-acyl-octadecanes and l-Ophosphocholine-2-N-acyl-octadecane (37) diacyl glycerols 38-42) and analogs of fragments of leukotriene-B4 43). 

Acylation of a side chain of enaminones is essential for some heterocyclic synthesis although the enaminone moiety is not involved directly in the reaction. The enaminone moiety is used as protecting group in Dane s salt162,163, which is employed for synthesis of 3-amino-2-azetidinones according to a method by Bose and coworkers164 (equation 110). 

Chirality also has been introduced on the inline. After treatment with Na/NHg, 3-amino-2-azetidinones are obtained from reactions of (R)- or (5)-l-phe-nethylamine imines and zinc enolates of ethyl bis-silylaminoacetate 6.109 (R = Et) [131,1289]. In Et20, trans isomers are formed, while in THF-HMPA, cis isomers predominate. The facial selectivity depends upon the (R)- or ( configuration of the imine W-substituent (Figure 6.91). If the inline C-substituent R is h CsC, then the selectivity is lower. Cyclic transition-state models account for the observed selectivities. From the titanium enolate of 2-pyridylthioester Me2CHCOS-2-Py and benzaldehyde (S)-1 -phenethylimines 6.111, Cinquini, Cozzi and cowork-... 

In an application to asymmetric monobactam synthesis. Overman and Osawa observe a high level of 1,4-diastereofacial selectivity in the reaction of (5)-cyanoamine (235) with the enolate of STABASE-protected glycine ester (234), affording diastereomeric 3-amino-2-azetidinones (236) and (237) in a 10 1 ratio, respectively, and in 65% yield (Scheme 49). Based on the (E)-enolate geometry of glycine ester (234), determined in trapping experiments with TMSCl, the authors postulate a chelated, chair-like transition state (238) that is consistent with the observed stereoselectivity. 

Alkoxy-3-amino-2-azetidinone ring via quinone methidylimines... 

The stereoselective synthesis of vinyl ethers is accomplished by N -(arylidene (or alkylidene) amino) - 2-azetidinones reaction with ozone and NaBH treatment resulting in di- and trisubstituted olefins derivatives [78],... 

Formation of a 3-amino azetidinone and its N-Boc protected form from oxazolidinone precursors shows that various reactions can be performed with good yields (67-95%) without affecting the 7V-[bis(trimethylsilyl)methyl] group... 

It was thought that the Pen G amidase would exhibit only a limited substrate spectrum, since it does not hydrolyze the phenoxyacetyl side chain of penicillin V. Nevertheless, Eli Lilly shows that the Pen G amidase acylates the amino function of cis-3-amino-azetidinone with the methyl ester of phenoxyacetic acid (Fig. 19-33). The... 

Monocyclic azetidinones are useful building blocks in organic synthesis. Besides the wide use in the syntheses of monobactam antibiotics and nuclear analogues of natural bicyclic p-lactam antibiotics,1 2 3 new applications have appeared with the syntheses of unnatural a-amino acids, amino sugars4 and inhibitors of elastase.5 ... 

C. Hubschwerlen and J.-L. Specklin 14 (3S,4S)-3-AMINO-1 -(3,4-DIMETH-OXYBENZYL)-4-((R)-2,2-DIMETHYL-1,3-DIOXOLAN-4-YL]-2-AZETIDINONE... 

The diazo ketones that are synthesized as intermediates are not only useful for the preparation of p-amino acids but may serve as versatile starting materials in different reactions, e.g. preparation of 3-azetidinones or 2-aminocyclopentanones. ... 

Lactams substituted only in the 3 position cannot be prepared by the present procedure, since the lactam formed has the nitrogen of the chlorosulfonyl isocyanate attached to the more highly substituted carbon atom of the olefinic double bond in Markownikoff fashion. 2-Azetidinones substituted in the 3 position only have been prepared by Grignard reagent-catalyzed cyclizations of esters of appropriately substituted /3-amino acids.4,5... 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

The extension of the above radical intramolecular cyclization of /V-haloaryl-p-lactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a-c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104—108 gave the fused tricyclic (1-lactams llOa-c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

Scheme 46 Synthesis of 3-amino-4-alkyl-2-azetidinones by [2+2] cycloaddion of aliphatic hydra-zones to N-benzyl-A-(benzyloxycarbonyl)aminoketene...

By reacting the imine with the aminochromium(0)carbene complex, having the ferrocene group attached to the amino moiety, the corresponding 2-azetidinone was isolated as a cis-trans mixture (10 1), (Scheme 72). 

In 2001, 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones have been reported to be prepared by base-assisted intramolecular alkylation of /V-benzvI -/V-chloroacetyl amino acid derivatives [180]. /V-benzyl or /V--methoxvbenzvI) amino acid derivatives in THF, treated with propylene oxide and chloroacetyl chloride afforded the /V-chloroacetyl amino acid derivatives. The treatment of the latter in CH3CN with CS2CO3 (or NaH) produced the intramolecular cyclization of 4,4-disubstituted (3-lactams, (Scheme 81). 

A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

A further application of silylated amino acids is the formation of /3-lactams by treating N-TMS-0-amino acid-TMS-esters (497) with Grignard reagents under cycli-zation262 (Scheme 74). From N-TMS-a-phenyl-/ -alanin-TMS-ester (497) via the silylated product (498), 3-phenyl-2-azetidinone (499) can be obtained. 

A synthetic method of introducing a methoxy group into the alpha position of alpha-amino acid derivatives and a/p/ia-amino-fern-lactams has been exploited by employing an indirect electrooxidation process 23). For example, the electrolysis of the lactam 33a in a MeOH—NaCl—(Pt) system yields the methoxylated lactam 34a in 92% yield. The indirect methoxylation of fern-lactams proreeds successfully without cleavage of the azetidinone ring (Scheme 2-11). 

Amino-3-phenylazetidine is obtained in high yield in three steps from Al-benzhydryl-3-azetidinone by using dibenzylamine as an amine equivalent in a modified Strecker reaction (95SC803). 

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