2- Azetidinones nucleophilic attack

Based on the early racemic synthesis of 4 (cis series), it had already been demonstrated that 2-azetidinone ring closure could be achieved via nucleophilic attack of a lithium amine anion on a (3-ester. Cyclization could be accomplished with other strong bases, but sodium bistrimethylsilylamide was found to effect efficient cyclization without significant racemization at C3. During the search for experimentally convenient bases, it was noted that Noyori (Nakamura et al., 1983) reported that tetrabutylammonium fluoride (TBAF) as well as LiF, KF, and CsF could serve as the base in Aldol reactions. Treatment of 17a or 17b with TBAF trihydrate in THF did not affect cyclization. After much experimentation it was found that addition of A,0-bistrimethylacetamide (BSA) to 19 followed by TBAF addition, effected 2-azetidinone ring closure. Further optimization found that use of catalytic TBAF (< 1%) in methylene chloride afforded near quantitative cyclization. 

Various nucleophilic attacks at C(3) and C(4) of -lactams have been employed to introduce desired functionalities. Nucleophilic displacement of a halogen at C(3) by nucleophiles, for example, potassium phthalimide, has been performed (93JCS(Pl)2357). The a-azidation of l-hydroxy-2-azetidi-nones, for example (37), with arenesulfonyl azides in the presence of triethylamine affords 3-azido-2-azetidinones (38) via Otosylation and SN2 -type of displacement of the tosyloxy group (92JA2741, 93JA548, 93BMC2429). 

Two mechanisms (i.e. direct hydrolysis and alternatively a path via an unstable acyl phosphate intermediate) are involved in the hydrolysis in phosphate buffer of N-arylsulfonyl / -lactams such as (130).107 The acyl phosphate intermediate can be trapped with hydrazine. The alkaline hydrolysis of some torsionally distorted lactams, i.e. the bridged benz[rfe]isoquinolin-l-ones (131), in 70% (v/v) DMSO-water has been compared under the same conditions with the hydrolysis of AvA-dimethyl-1 -naphthamide (132). The relative rates of reaction and activation parameters indicate the effect of torsional distortion.108 The reaction of the tricyclic azetidinones (133) with trifluoroacetic acid gives the bicyclic thioesters (135). The mechanism may involve acid-catalysed elimination of methanethiol to give an azetinone intermediate (134) which, after nucleophilic attack of the thiol, is converted into (135).109... 

Enamine 107 and monocyclic lactam 222 were formed by the cleavage of C(3)—C(4) and N(l)—C(4) bonds of hydroxy azetidinone derivative 652, respectively. An increase of solvent polarity alters the relative ratio of the C(3)—C(4) to N(l)—C(4) bond cleavage. Hydroxy azetidinone derivative 652 was formed from azetidinyl cation 647 by nucleophilic attack by water. 

The observed very high l,2-lk induction of the sto eocenter present in the side chain oi the imine upon the C4 stereocenter of the azetidinone may be rationalized via a Cram cyclic model by assuming coplanarity between oxygen and nitrogen atom of the imine due to chelation of lithium cation so that the nucleophile attacks from the less hindered diastereotopic face. 

That expulsion of the attacking amine nucleophile from [50] occurs more readily than fission of the P-lactam C—N bond is confirmed by the observation that 2-azetidinylideneammonium salts [53] react with hydroxide to give 2-azetidinones [54] presumably through the intermediate formation... 

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