Alkyne−Co₂(CO)₆ Complexes in the Synthesis of Fused Tricyclic β-Lactam and Azetidine Systems^,1

Abstract

A synthetic approach to racemic and enantiomerically pure, fused tricyclic 2-azetidinones and azetidines has been developed by using a Pauson-Khand (P-K) reaction on monocyclic enyne-beta-lactams as the key synthetic step. The access to cyclization precursors, monocyclic beta-lactams 1-7, was achieved by Staüdinger reaction of enyne imines 8 and 9 and D-glyceraldehyde imines 10 and (benzyloxy)- or phenoxyacetyl chlorides. Enyne imines 8 and 9 formed cis-2-azetidinones 1 and 2 having the required enyne moiety. cis-2-Azetidinones 11 were obtained as single diastereomers and transformed to enyne-2-azetidinones 3 and 5 by standard methodology. Alternatively, 4-formyl-2-azetidinones 14 were prepared by cyclization of p-anisyl glyoxal diimine and (benzyloxy)acetyl chloride and converted to racemic enyne-beta-lactams 4 and 6 by standard reactions. Enyne-2-azetidinones 1-7 were reacted with Co(2)(CO)(8) to quantitatively yield the corresponding alkyne-Co(2)(CO)(6) complexes. Reaction of such complexes with different promoters, especially heat and TMANO, formed tricyclic 2-azetidinones 15-19 with the ring system fused to the C3-C4 and C4-N1 lactam bonds. Yields were usually high, and the processes were highly diastereoselective. The exceptions were enyne-2-azetidinones 2 and 3a bearing N-propargyl moieties. These products decomposed to mixtures of unidentifiable products. Inhibition of the amide resonance was postulated as responsible for the failure of beta-lactams 2 and 3a to form tricyclic systems. In fact, the analogous enyne-azetidines 20a,b smoothly cyclized to form the corresponding tricyclic systems. This approach to tricyclic azetidines was extended to prepare different products. A new, unprecedented, N1-C2 bond breakage was also observed in the azetidine ring. The results described show that the P-K reaction is a suitable approach to tricyclic 2-azetidinones and azetidines. These are the first examples reported for a P-K reaction in with the enyne system is tethered to a strained heterocyclic four-membered ring.

A Straightforward Synthesis of Enantiopure Bicyclic Azetidines

“…Dichloromethane was distilled from calcium hydride. The mention of a "usual workup" means: (1) decantation of the organic layer, (2) extraction of the aqueous layer with ether, (3) drying the combined organic layers over MgSO 4 , and (4) solvent evaporation under reduced pressure. Stereoisomeric ratios were determined by NMR spectroscopic analysis of the crude reaction mixtures before purification.…”

“…The reaction was monitored by TLC and then quenched by the addition of an aqueous saturated solution of NH 4 Cl at 0°C. Extraction of the reaction mixture by using ether followed by the usual workup gave the crude residue of bicyclic azetidine.…”

“…Synthetic strategies towards this ring system include photoaddition of olefins to iminium ions, [1] intramolecular carbolithiation of phenylthioalkenes with α-amino organolithium species, [2] direct ring closure of a four-membered ring by N-alkylation, [3] PausonKhand reaction of suitably functionalized azetidines, [4] and reduction of the corresponding thiolactams. [5] However, all these approaches suffer from major drawbacks such as low yield or a lack of generality, and straightforward access to enantiomerically pure derivatives of this bicyclic nitrogen heterocycle still needs to be discovered.…”

Synthesis of 2‐Azetidinones Incorporating Carbenechromium(0) Moieties and Their Use in the Preparation of Penicillin‐ and Cephalosporin‐Containing Peptides

“…Structures in which a β-lactam nucleus is embedded in an organometallic complex are scarce, [15] and of those that exist, metallocene-derived 2-azetidinones are possibly the most abundant group.…”

Cascade Reactions Involving Pauson–Khand and Related Processes

“…The formation of 93 is believed to be a consequence of the ionization of the propargylic C -N bond at the cobaltacycle step. The crowded metallacycle formed after the insertion of the olefin (93), would prompt the cleavage of the C -N bond, forming an ionic species (94) that would trap a hydride, possibly from a cobalt hydride giving 95, which then would follow the usual pathway towards the cyclopentenone (Scheme 27) [124]. …”