Azetidinones formation

Ring contraction to cyclopropanes (413) with the formation of azo side-chains is observed in the photolysis of 5-phenylpyrazolines (71BSF1925) and to azetidinones (414) in the photolysis of 5-pyrazolidones (69JCS(C)2624, 83JCS(P2)llll). 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

In 1991, Ohfune and coworkers reported palladium(O)-catalyzed carbonylation of vinylaziridines 262 with carbon monoxide (1 atm.) in benzene (Scheme 2.65) [31]. Interestingly, 3,4-trans-azetidinone 264 was exclusively obtained from a dia-stereomeric mixture of trans- and cis-vinylaziridines 262 (3 1). Tanner and Somfai synthesized (+)-PS-5 (267) by use of palladium(O)-catalyzed trons-selective (3-lactam formation in the presence of Pd(dba)3 CHC13 (15mol%) and excess PPh3 in toluene. 

Organoiron complexes (7) are converted in high yield into ammonium salts (8) these in turn undergo oxidatively induced ligand transfer and cyclization to give azetidinones (9) in moderate yields (Scheme 9). Formation of the trans product (9b) indicates a stereochemical sequence of trans addition to the olefin complex followed by carboxamidation with retention of configuration at the C—Fe bond. 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

For the cis azetidinones 315, the first step is the formation of an amidine intermediate, followed by ring enlargement with transamidation [96-H(42)625]. The preceding amidine structure was revealed by TLC on silica gel when the formation of derivatives 316 was investigated (89MI1). 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

This reaction has since been used in a synthesis16 of (+)-thienamycin (4), a potent antibiotic from Streptomyces cattlaya. Thus cyclization of 1 with CHjMgBr resulted mainly in the desired frans-azetidinone 2. Cyclization with DCC favors formation of the undesired cfs-isomer (3). 

Inversion of secondary alcohols. Lattrell and Lohaus reported a few years ago that 3-sulfonyloxy-2-azetidinones react with various nucleophiles with inversion. Thus reaction of trans-i with KN02 in DMSO at 55° results in cis-2 in 77% yield. Presumably an intermediate nitrous ester undergoes hydrolysis under the reaction conditions. Use of potassium formate leads to the same result, hut requires higher temperatures. 

The formation of spirocyclic azetidinones 43 could be explained following a Pd (Il)-catalyzed mechanism. Initial Pd(II)-coordination gave an allenepalladium... 

Analogously, the thermal formation of fused strained tricycles 77 can be rationalized by a mechanism which includes an exocyclic diradical intermediate 80 through an initial carbon-carbon bond formation, involving the proximal allene carbon and the internal alkene carbon atom (path C, Scheme 28). The alternative pathway leading to tricyclic 2-azetidinones 77 is proposed in path D (Scheme 28). This proposal involves an endocyclic diradical intermediate 81 arising from the initial attack of the terminal olefinic carbon onto the central allene carbon. The final ring-closure step of the diradical intermediates account for the cyclobutane formation. 

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... 

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