4 Alkyliden /? lactams

The reaction can be done intramolecularly. N-Benzyl pent-4-ynamide reacted with tetrabutylammonium fluoride to an alkylidene lactam. Similar addition of a tosylamide-alkene, with a palladium catalyst, led to a vinyl Al-tosyl pyrrolidine. Similar cyclization reactions occur with tosylamide-alkynes. ... 

Insertion into Si-H bonds. a-Silyl esters are similarly obtained. From R2Si(Cl)H the products are readily converted into o-(alkoxysilyl)alkanoic esters. Heterocyclization. Formation of a-alkylidene lactams by carbonylation of alkynyl amines and cyclization of 2-allyloxybenzylamines with allylic rearrangement are reported. 

Epiderstatin (48), having a unique alkylidene lactam, was isolated as a potent inhibitor of the signal transduction induced by epidermal growth factor in quiescent Balb/MK cells [44-46]. However, the activity was later found to be due to contaminating 13-acetoxycycloheximide 21 [47]. The (3S, 5S)-absolute stereochemistry of 48 was established by X-ray analysis [48]. Dow s first synthesis also confirmed the relative stereochemistry [49] (Scheme 7). 

In addition to the intermolecular hydroamination reactions, a significant number of intramolecular versions have been developed. As an example, the palladium-catalyzed cyclization of aUcynylamides generated alkylidene lactams in moderate to good yield (Scheme 3.136) [146], The reactions were quite rapid and afforded formal Maikovnikov addition products. 

IR spectra of systems related to /3-lactams show the expected trends in the frequency of the carbonyl absorption, where present. For example, the presence of an exocyclic double bond at C-4 in an azetidin-2-one raises the value of vc=o considerably. Thus the 4-thioxoazetidin-2-one (62 Z=S) and the derived 4-alkylidene systems (62 Z = CR R ) exhibit /3-lactam carbonyl absorptions at 1835 and 1800-1810 cm respectively (80JOC1477, 80JOC1481), while the 4-iminoazetidin-2-ones (63) have vc=o at 1800-1825 cm (81CC41). Additional spectral data for these and similar systems may be found in the references in Table 5. 

Ungesattigte Lactame werden durch Diboran hydroboriert. In 2-Oxo-3-alkyliden-2,3-dihydro-indol-Derivaten ist die C=C-Doppelbindung stark elektrophil, so daB sie mit Natriumboranat selektiv gesattigt werden kann1 ... 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

Allenes react with isocyanates to give the a-alkylidene-/Mactams. The highly reactive chlorosulfonyl isocyanate (CSI) is often used. Initial nucleophilic attack of the central allenic carbon atom to the central isocyano carbon atom produces an allylic cation intermediate, which cyclizes to the /i-lactam. 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

Liebscher and Anklam [100] have introduced a facile access to novel optically active spiro-(5-lactams 112-113,115-116 through cycloaddition reaction of diazomethane to a-alkylidene-p-lactams (Scheme 29). Diazomethane gave a clean reaction to 7-methylene-(5-lactam 111 affording spiroazetidin-2-ones 112, 113 (d.r. 87 13, 93%) with preference of anti-addition with respect to the CH2OTBS substituent. The 7-ethylene-(5-lactam 114 reacted slowly with diazomethane and... 

Scheme 29 Synthesis of optically active spiro-P-lactams using a-alkylidene-P-lactams...

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