Y-lactam derivatives

Also, in this case, the RCM approach has been employed with success. Most of the examples present in the literature concerned the use of y-lactam derivatives (Scheme 32) <2002OL3497, 2000TA753, 2000SL319, 2004TL1559>. 

Sulfuryl chloride isocyanate with 1 gave the expected )5-lactam 177 only as a minor product, the principal product being the y-lactam derivative 178. It is reasonable to assume that the 1,4-zwitterionic intermediate 176 is responsible for the formation of 177 and 178 (Scheme 39) [104,130]. Sulfonation of 1 with SO3 also proceeds with ring opening of one of the cyclopropyl groups to give quantitatively the spirocyclopropane-y-sultone 179 (Scheme 39) [76,132]. 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

Similarly, both acyclic and cyclic allyl amine derivatives have been applied in 1,3-dipolar cycloadditions (134-138). Langlois et al. (139) used a,()-unsaturated-y-lactams derived from (5)-pyroglutaminol, such as 91 and 92, in the 1,3-dipolar cycloaddition with the A -benzylnitrone derived from formaldehyde (Scheme 12.30). For compound 91, one of the 1,3-dipolar cycloaddition product isomers obtained... 

Imhof et al. [47] reported that the reaction of a,/l-unsaturated imines with CO and alkenes in the presence of Ru3(CO)12 gives y-lactam derivatives (Eq. 30). It was proposed that an aldehyde 19 formed by the direct carbonylation at the C-H bond in the 3-position is the key intermediate. 

In recent years a wide variety of U-4CRs [103,104] educts of the carbonyl and carboxylic groups have been studied. Besides a few U-4CRs of a- and P-oxoacids [101b], many y-oxoacids were thus converted into their y-lactam derivatives, like 43 and 44 [102] (Scheme 4.23). 

Highly stereoselective preparation of either trans- or m-/J,y-dia1kyl-y-lactam derivatives is achieved by cyclization of l-methyl-2-propenyl trichloroacetamides. The choice of the nitrogen protecting group controls the steric outcome of the reaction. The mechanistic aspect that determines this stereoselectivity is unclear26. 

The 5-7V-tosylamino substituted a-diazo-P-keto carbonyl compounds 101 were obtained from the reaction between diazo ketone 100 and the tosylimine 99 in the presence of TiCU in dichloromethane. The diazo ketone 101 underwent Wolff rearrangement in benzene upon irradiation with a high-pressure Hg lamp to afford 102, which subsequently cyclized to give the expected y-lactam derivatives. ... 

A vinylcyclopropanedicarboxylate forms a zwitterionic 7r-allylpalladium intermediate, which undergoes attack by diethylamine to afford an allylic amine (Scheme Similarly, the reaction with phenyl isocyanate provides a y-lactam derivative... 

With a primary amino group, the reaction afforded y-lactam derivatives (Scheme 24), probably via Mechanism V, path j (Scheme 19)... 

Oxoepistephamiersine (14) was isolated from the roots of Stephania japonica as the seventh hasubanalactam congener (77). The UV spectrum of oxoepistephamiersine (14) showed an absorption maximum at 284 nm, and the IR spectrum exhibited bands of a six-membered ketone at 1745 cm-1 and y-lactam at 1690 cm-1. The mass spectrum (Table V) revealed the most abundant ion peak at m/z 257, indicating stephamiersine-type cleavage (13). Since oxoepistephamiersine was identical to the y-lactam (14) derived from permanganate oxidation of epistephamiersine (77), structure 14 was proposed for oxoepistephamiersine (77). 

In a related study Porter et al. showed that a-bromo-y lactams 185 containing a pyridyl moiety can react with allyltrimethylsilane enantiose-lectively in the presence of chiral Lewis acids derived from zinc and 189 (Scheme 49) [142], In contrast to the above study, the ligand of choice for substrates 185 was found to be the bisoxazoline ligand 189. Excellent ee s were obtained in the presence of two equivalents of the chiral Lewis acid. Under substoichiometric amounts of the catalyst, lower selectivities were obtained. Different substituents on the pyridyl moiety were also examined although no predictable trend was observed. A trans octahedral model simi-... 

Other potential elastase inhibitors based on the /3-lactam nucleus include cephem derivatives [64], penam derivatives [65], as well as novel bicyclic /3-lactams [66]. Monocyclic y-lactams (5.21) with appropriated substitution might also yield useful inhibitors [67]. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

In a similar manner, A-Cbz-a-Lys-OMe reacted with an electrophilic cyclopropane derivative, and a mixture of diastereomeric y-lactams was isolated. The reaction is postulated to proceed by an attack of the amino group on the methylene group with subsequent cyclization (Scheme 4) (85JOC3631). 

The synthesis of y-lactams has been achieved under similar reaction conditions (Table 18) [124]. Initially, Bode and co-workers screened a variety of acyl imines in order to find suitable electrophiles. Control experiments provided evidence for carbene addition to the acyl imine, yielding a stable complex with complete inhibition of the desired reactivity. Reversibility of this addition was key to the success of the reaction. A -4-Methoxybenzenesulfonyl imines 212 proved to be the most efficient partners for lactamization with cinnamaldehydes 228 to provide y-lactams 229 in moderate yields and good diastereoselectivities. Notably, no benzoin or S tetter products or their corresponding derivatives were observed during this reaction. 

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). 

Y. He, A. K. Bubb, K. A. Stubbs, T. M. Gloster, and G. J. Davies, Inhibition of a bacterial O-glcNAcase homologue by lactone and lactam derivatives Structural, kinetic and thermodynamic analyses, Amino Acids, 40 (2011) 829-839. 

Cui, C-B. et al., Davallioside A and B, novel flavan-3-ol derivatives with a y-lactam, from the rhizomes of Davallia mariesii Moore, Chem. Pharm. Bull, 38, 2620, 1990. 

Formation of the rigid, bicyclic lactams 58-60 facilitates the determination of the relative configurations at the C3 positions in the case of a-monosubstituted y-amino (1-hydroxy adds by H NMR spectroscopy116-62f<2l (Scheme 24). The cisltram stereochemistry of the lactam derived from the a,a-difluoride derivative cannot be assigned on the basis of the /4>5 coupling constant in this case, 13C NMR spectra1151 or NOE effects 78 are more informative. The signal from the C5 atom of the ds-isomer appears upfield relative to that of the /ram-isomer. 

Scheme 24 Bicyclic Lactams Derived from a-Substituted y-Amino-p-hydroxy Acids...

Titanium(IV) enolates derived from a-diazo-/i-keto esters or ketones (28) efficiently add to T1CI4-activated A-tosylimines to give the corresponding 5-A-tosylamino derivative.76 Subsequent diazo decomposition - catalysed by rhodium(II) or light - yields useful pyrroles or y -lactams, respectively. 

Cyclic amides are called lactams. A Creek letter is assigned to tire lactam to denote size, (i-lactams are 4-membered rings, y-lactams have 5 members, 5-lactams have 6 members, and so on. Although amides are the most stable of the carboxylic add derivatives, pdactams are highly reactive due to large ring strain. Nucleophiles easily react with (Mactams. p-lactams are found in several types of antibiotics. 

The synthesis of bicyclic y-lactam-piperazinone derivatives has been reported by Hulme et al. [8b] as an extension of the UDC strategy. Alternatively, the formation of y-lactams by reacting y-keto acids, amines, and isocyanides [89] has been ex-... 

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