Spirocyclic lactam

Schoemaker and Speckamp (8) have reported the quantitative conversion of hydroxy-lactam 26 (n=l) (HCOOH, 18 h, r.t.) into the spirocyclic lactam ester 27 (n=l). The other possible spiroisomer 28 (n=l) was not formed. 

Hydride abstraction from dienyl tricarbonyl iron complexes furnishes cationic dienyl tricarbonyl iron complexes. For example, reaction of the diene-iron tricarbonyl complex (115) with triphenyhnethyl hexafluorophosphate followed by trimethylsilyl cyanide furnished with excellent regio- and stereoselectivity a new diene iron tricarbonyl complex (116) (Scheme 170). Excellent regio- and stereoselectivity is seen upon reaction of the cationic complex (116) with trimethylsilyl cyanide (TMS-CN) (Scheme 170). Reduction of the nitrile affords a spirocyclic lactam complex. Intramolecular cyclization of in situ formed enols furnishes spirocyclic compounds again with excellent stereoconfrol (Scheme 171). An interesting example of hydride transfer from a cyclohexadiene ring to a pendant aldehyde followed by nucleophilic addition is seen in Scheme 172. 

Keto aldehyde 6 should be easily formed from lactam acetal ester 7, which should be readily available from isoxazolidine 8. The latter can be constructed by a convergent 1,3-dipolar cycloaddition of nitrone 9 with ethyl acrylate. This strategy to spirocyclic lactams is precedented with nitrones derived from A -benzylhydroxylamine [15]. 

Schoemaker and Speckamp (8) have reported the quantitative conversion of hydroxy-lactam (n=l) (HCOOH, 18 h, r.t.) into the spirocyclic lactam ester (n=l). The other possible spiroisomer (n=l) was not formed. Hydroxy-lactam 26 (n=2) gave spiroisomer (n=2), albeit in lower yield, under similar conditions. The same authors (9) have also reported the successful cyclization of hydroxy-lactam W into spirolactam Analogous results were obtained by Evans and Thomas (10) who found that the cycliza-tion of a 9 1 mixture of enamides and in anhydrous formic acid gave the spirocompound 30. This compound is a key intermediate in Kishi s total synthesis of perhydrohistrionicotoxin (11, 12). 

In another application of this chemistry, photolysis of the nitrite 26 was the key step in Corey s synthesis of perhydrohistrionicotoxin (4.26). The oxime 27 could be converted to the spirocyclic lactam 28 on Beckmann rearrangement. 

The spirocyclic- -lactam (1), which is readily prepared by the reaction of ketens with iminolactones, reacts readily with an alkoxide to provide esters (2) in good yield (Scheme 5). ... 

Notably, attempted intramolecular SnAr reactions of complex 44 under basic conditions to accomplish the formation of tetrahydroisoquinoline derivatives lead only to decomposition products. Nevertheless, when methyl tosylate is added to the reaction medium, the stable 7 -cyclohexadienyl spirocyclic lactam 45 can be isolated (Equation (3)). It results from the intramolecular attack of the m situ generated enolate at the /) i- -position of... 

In contrast, a Heck type of reaction will take place if a, P-unsaturated ester is used as the trapping reagent for vinylpalladium intermediates. For example, Alcaide et al. discovered a Pd-catalyzed cascade regioselective spirocyclization of a-allenols cross-coupling via oxopalladation and Heck reaction. Sonogashira and Suzuki reaction can also be incorporated in the sequence instead of the Heck reaction, affording the corresponding potentially bioactive spirocyclic lactam derivatives [117] (Scheme 6.90). 

SCHEME 6.90 Cascade reaction for the synthesis of spirocyclic lactams. 

Lin, X.C. and Weinreb, S.M. (2001) Model studies on total synthesis of the chartellines, spirocyclic -lactam alkaloids from a marine bryozoan. Tetrahedron Lett., 42,2631-2633. 

In a related reaction, treatment of spirocyclic oxaziridines with MnCl(TPP), where TPP = m o-tetraphenylporphyrinate (2 — ), or photolysis leads to a lactam. 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual p-Lactams... 

Keywords p-Lactams Cycloadditions Fused-rings Metals Spirocycles... 

Preparation of Spirocyclic-P-Lactams with Nonclassical Structure. 4... 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

Scheme 1 Preparation of spirocyclic P-lactams through Staudinger reaction...

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