Azetidinone 3-unsubstituted

The racemic form of the unsubstituted nucleus (1, X = CH2) was synthesized by several groups (32—34) prior to the disclosure of the natural material. One reaction path involved an azetidinone (21) where R = CH2OH or CH=CH2 converted to the corresponding phosphorane (22) where R = o-NO.-C,H, when R = CH.OH and R = COCH, when R=CH=CH.. 

Cyclization of (68) and depiotection tfien yield the monobactam nucleus (69) which may be coupled with various C-3 side chains (48). Direct alkylation of the JV-unsubstituted azetidinone (70) using fluorotetrazole [93607-94-4], CgH FN, also produced (69) after deprotection of (71) (49). 

JPR269>. 1,3,5-TriaIIyl-hexahydro-l,3,5-triazine has been used in the preparation of a C-4 unsubstituted azetidinone which is the starting material for the synthesis of penems and cephams <00S289>. A novel method for the preparation of AfW-disubstituted-Af"-nitroguanidines via 2-nitroimino-hexahydro-1,3,5-triazine derivatives has been studied <00TL7187>. 

Initial syntheses employed the sulfonation of an N-l unsubstituted azetidinone as the key step. The natural product SQ, 26,180 as well as other melhoxylated monohactams were synthesized, starting from either 7-aminocephalosporanic acid (7-ACA) or 6-aminopenicillanic acid (6-APA), via sulfonation of the N-l unsubstituled degradation products. Subsequently, many more C-3 side-chain analogues were prepared by this method. 

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). 

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]. 

The addition of CSI to cyclic alkenes has been used extensively to yield bicyclic azetidinones with an N-substitutent that is readily removed. The addition of the isocyanate to cyclopentene yielded 321 (R = SC>2C1), which yielded the unsubstituted compound 321 (R = H) on hydrolysis with aqueous sodium sulfite. Similarly, 322 and 323 were prepared among a range of other bicyclic azetidinones <2005BML1371>. 

Initial syntheses employed the sulfonarion of an N-l unsubstituted azetidinone as the key step. The natural product SQ 26,180 (3, R = OCH3) (8, R =... 

Many examples of the usual route to /S-lactams via imines and acid chlorides, ketens, or keten equivalents have appeared.These include syntheses of 3-[bis(alkylthio)methylenamino]-2-azetidinones, ° of spiro-azetidinones and bis-azetidinones, and the use of l-methyl-2-halogenopyridinium salts to activate carboxylic acids towards coupling with imines. A non-hazardous alternative route to 3-amido-2-azetidinones, avoiding the use of azidoacetyl chloride, involves the reaction of Schiff bases with salts of [(a-methyl-/3-methoxycar-bonyl)vinylamino]acetic acid, e.g. (20), in the presence of ethyl chloroformate, as shown in Scheme 5. Formaldimines can be generated from their trimers by treatment with Lewis acids immediately prior to reaction with acid chlorides, so allowing the formation of the nocardicin nucleus which is unsubstituted at C-4. ... 

Formation of the 3,4-bond of the lactam from threonine derivative 67 uses the acidity of the methine group <01TA89>. Similarly, 68 contains an activated methine carbon atom and cyclisation under basic conditions provides a simple route to 3-unsubstituted-4-alkyl-2-azetidinone 4-carboxylic acids 69 <01JOC3538>. 

In a series of papers [54-56], Palomo reported work leading to C-4-unsubstituted P-lactams including 3-aminonocardicinic acid. The cis. trans ratio of products of the ketene-imine cycloaddition was shown to be dependent on the bulk of the substituents in these groups. Thus while imine 78 gave an equimolar ratio of cis and trans azetidinones 79, use of the 2-methylcinnamaldehyde-derived imine 80 afforded only the c/5-compound 81. A useful method was... 

Racemic 4-acetoxy-3-unsubstituted azetidinone 10 and homochiral (3R,4R)-3-(IR)-hydroxyethyl derivative 11, commercially available intermediates industrially prepared by the so-called CSI route , testify to the importance of this ring formation strategy. By using vinyl acetate as the olefin partner in the chlorosulfonylisocyanate-alkene cycloaddition, in 1974, Clauss et al. [10] laid down the basis of this approach in the field of p-lactam antibiotics. The most recent efforts have been directed to the key intermediate 11 and its synthetic equivalents 12, 13. Starting from methyl 3R-hydroxybutyrate [11], three independent methodologies have been realized, the main difference being the type (ether, thioether, ester) of enolate used. 

This reaction usually works for nonenolizable imines (e.g., A -aryl aldimines) and has the features of readily accessible starting materials, and simple preparation of 3-substituted or unsubstituted 2-azetidinones (i.e., 3-lactams) with direct control of stereoselectivities. It has been reported that the yield of this reaction depends on the activation and the type of zinc. The stereochemistry of /3-lactams depends on the a-substituent of bromoacetates, the solvent, and the alkyl portion of the esters. For example, when the a-substituent is an alkyl group (e.g.. Me, Et, /-Pr, cyclohexyl, r-Bu), the major product has cis geometry, such a trend is especially prevailing for the reaction of acetate with a branched a-substituent (e.g., j-Pr, cyclohexyl, r-Bu) in THF. s For comparison, the reaction of isopropyl acetate in toluene tends to form jS-lactams of trans geometry. In addition, phenyl acetates favor the trans isomers regardless of the solvents. ... 

The Beecham group found that thiols add readily to the double bond of C(2)-unsubstituted 1-carbapenems, and this approach has been used to synthesise racemic PS-5 130). The A -silylated 4-allylazetidinone (157) was alkylated with ethyl iodide and the product (158) transformed to the phosphorane (159). Cyclisation to (1 ) was followed by reaction with acetamidoethane thiol to form three isomers of the addition product (161). These could be converted to the carbapenem (162) on reaction with iodobenzene dichloride in the presence of pyridine. Isomerization to (163) and deprotection afforded the racemic natural product. The ester (163) has also been prepared via the diazo-intermediate (164) derived from the 4-acetoxy azetidinone (165) 131). A total synthesis of chiral PS-5 has been achieved using the resolved acid (166) (132). This was converted to (164) and then to optically pure PS-5. It has also been possible to synthesise PS-5 and PS-7 from the olivanic acid derivatives MM 17880 and MM 13902 133). The benzyl ester of ( )-MM 22381 was obtained from the azabicyc-loheptane (167) derived from the addition of acetamidoethane thiol to the appropriate C(2)-unsubstituted nucleus 108). 

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