Tricyclic p-lactams

Another study focused on aryl-substituted P-lactams, using the same set of teicoplanin-based CSPs and variable-temperature conditions [99]. Tricyclic P-lactams were investigated by the same group of authors, together with some bicyclic P-amino acids, on five different commercially available glycopeptides CSPs, namely ristocetin A, TE, TAG, vancomycin, and VAG, and on a new dimethylphenyl carbamate-derivatized 5-cyclodextrin-based CSP. The chromatographic results, achieved with different methods, were compared in systematic examinations [170]. 

Tricyclic P-lactams not having a bridgehead nitrogen atom have been obtained by intramolecular Friedel-Crafls reactions <99T5567> and from the intramolecular Diels-Alder reactions of 1,3-dienes generated from a mesylate 79 <99TL1015>. Other tricyclic P-lactams e.g., 80 have been obtained by intramolecular nitrone-alkene cycloaddition <99TL5391>. 

Keshava et al. (10) reported a facile synthesis of the fused tricyclic p-lactams 44 and 45 via an intramolecular 1,3-dipolar cycloaddition of an azide with an alkene (Scheme 9.10). 1,3-Dipolar cycloaddition of the azides 43 in benzene at reflux gave a mixture of cis and trans tricyclic p-lactams 44 and 45. As the ring size increased... 

Scheme 20 Preparation of tricyclic p-lactam 59 using Diels-Alder reaction...

Scheme 25 Preparation of tricyclic P-lactams 73 and 75 using [2+2] cycloaddition (i) Toluene, sealed tube, 220° C...

Scheme 32 Titanocene-promoted preparation of tricyclic P-lactam 98...

Scheme 40 Preparation of tricyclic p-lactams 116 and 119 using cascade radical cyclization...

Scheme 46 Preparation of tricyclic P-lactams 137 using radical cyclization (i) Ph3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux...

Scheme 60 Preparation of tricyclic P-lactams 173 using Pauson-Khand reaction (i) Co2(CO)8, Me3NO, CH2C12, RT...

Scheme 61 Preparation of tricyclic P-lactam 175 using amino-allene cyclization (i) TsNCO, THF, RT (ii) Pd (OAc)2 10 mol%, LiBr, Cu (OAc)2, k2co3, o2,...

Scheme 62 Mechanistic explanation for the formation of tricyclic P-lactam 175...

Scheme 69 Preparation of tricyclic P-lactams 193 using Kinugasa reaction...

Monocyclic, Bicyclic and Tricyclic P-Lactams An Overview 2.1 Monocyclic P-Lactams... 

Tricyclic-P-lactams Antibacterial and p-lactamase inhibitors Fig. 5 Biologically active tricyclic P-lactams... 

A similar approach was used by the Alcaide group [183] in the synthesis of tricyclic P-lactams 6/1-391 from 6/1-390 (Scheme 6/1.99). In this domino process the primarily obtained JT-allyl-Pd-complex reacts with the N-nudeophile of the urethane moiety to form a C-N-bond and a vinyl halide. The final step is then an intramolecular Heck-type reaction of the vinyl halide with the alkyne moiety and re-... 

Thermolysis of 3,4-cw ring-fused 5-spirocyclopropane isoxazolidines in the presence of a protic acid, yielded 3,4-cw ring-fused azetidin-2-ones 51 with concomitant extrusion of ethylene <03JOC3271>. Bicyclic isoxazolidines have been converted into the corresponding P-lactams by sequential N-O bond cleavage, oxidation and cyclization <03JOC1207>. Intramolecular aromatic nucleophilic substitution has been established as a route for tricyclic P-lactams 52 <03T5259>. 

Alcaide B, Almendros P, Alonso JM, Redondo MC (2003) Asymmetric synthesis of unusual fused tricyclic P-lactam structures via aza-cycloadditions/ring closing metathesis. J Org Chem 68 1426-1432, and references therein... 

A related approach was used for the synthesis of an interesting tricyclic p-lactam <05HCA1387>. However, only the allylic ether starting material, shown below, was able to undergo the subsequent ring-closing step. 

Intramolecular 1,3-DC of 2-azetidinone-tethered alkenyl nitrones afforded novel tricyclic P-lactams, such as 101 and 102, amenable for further elaboration <05EJ01680>. 

The different stereoselective routes explored toward the synthesis of the tricyclic p-lactam sanfetrinem cilexetil (GV 118819) [45] perfectly illustrate advantages and drawbacks of the approach to enantiomerically pure drugs based on the use of commercially available chiral non-racemic substrates. 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic p lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (—)-lasubine (I). Tin tetrachloride-mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be allylated with high diastereoselectivity to give optically active homoallylic amines (Scheme 87). 

Scheme 21 Preparation of tricyclic P lactam 61 using tandem elimination intramolecular Diels Alder (IMDA) reaction...

Scheme 29 Preparation of tricyclic p lactams 86 89 using nitrone alkene(alkyne) cycloadditions...

Scheme 30 Preparation of tricyclic P lactam 92 using azirine azomethine cycloaddition...

A mechanistic explanation for tricyclic p-lactams 104 and 106 is depicted in Scheme 35. The complete selectivity observed in the formation of benzocarbape-nems 104 and 106 and benzocarbacephems 105, 107, and 108 must be due to the preference of the radical intermediates for the conformation depicted in Scheme 36 for these cyclizations. 

The extension of the above radical intramolecular cychzation of A-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 p-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 synthesis of iV-fused tricyclic p-lactams involving a radical cascade sequence in enyne 2-azetidinones 114 and 115 bearing a methylenecyclopropane unit has been reported [82]. Slow addition of BusSnH/AIBN to a refluxing solution of 114 gave tricyclic vinylstannane 116 as a single stereoisomer in 42% yield, whereas cyclization of 115 under identical conditions gave fused heterocycles 117 and 118 in 73 and 11% yield, respectively, in all three cases via a 7-endo cyclization. Treatment of vinyl stannanes 117 and 118 with PPTS in dichloromethane yielded a common tricyclic product 119 (Scheme 40). 

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