Lactams esters

The use of (TMSlsSiH with acyl selenides can also yield new C-C bond formation, as shown with the a,/l-unsaturated lactam ester (Reaction 67). The resulting ketone can be envisaged as potentially useful for the synthesis of 2-acylindole alkaloids. Both the effects of H-donating ability and steric hindrance by the silicon hydride are evident. 

A convenient synthesis of ( )-l has been reported by Sakai et al. (105). The condensation of tryptamine with diethyl (2-formylethyl)malonate led to lactam ester 144. Deethoxycarbonylation of 144, followed by lithium aluminum hydride reduction, gave racemic octahydroindoloquinolizine (1). 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

F. P. Bonina, L. Montenegro, G. Trapani, M. Franco, G. Liso, In vitro Evaluation of N-Acyl Lactam Esters of Indomethacin as Dermal Prodrugs , Int. J. Pharm. 1995, 124, 45-51. 

The intramolecular Heck reaction of an iodobenzyl piperidone exo-trig cyclization) affords a mixture of regioisomers 89a and b, inseparable by flash chromatography (02S87). An analogous reaction gives lactam ester 89c (96H(42)155). 

The base-catalyzed [3+3] reaction of enamino ester with acrylic ester (103b) or more favorably acryloyl chloride (103a) by consecutive N-acylation and C-alkylation gives bicyclic lactam ester 104 (85S735). A... 

In addition to step and chain polymerizations, another mode of polymerization is of importance. This is the ring-opening polymerization (ROP) of cyclic monomers such as cyclic ethers, acetals, amides (lactams), esters (lactones), and siloxanes. Ring-opening polymerization is of commercial interest in a number of systems, including the polymerizations of ethylene oxide... 

Alkylation of the -lactam ester 8 displayed high yields and excellent diastereoselectivi-ties 132 133. In this case, an interesting temperature effect has been observed. When the enolate was generated at — 78 °C. the diastereoselectivity was low, however, when generated at 0°C, a diastereoselectivity of >95% was observed. The temperature at the addition of the electrophile is not crucial and can be — 78 °C or 0°C134. 

Besides the activation of the olefinic partner by a metal, the unfavorable thermodynamics associated with the addition of an enolate to a carbon—carbon multiple bond could be overwhelmed by using a strained alkene such as a cyclopropene derivative286. Indeed, Nakamura and workers demonstrated that the butylzinc enolate derived from A-methyl-5-valerolactam (447) smoothly reacted with the cyclopropenone ketal 78 and subsequent deuterolysis led to the -substituted cyclopropanone ketal 448, indicating that the carbometallation involved a syn addition process. Moreover, a high level of diastereoselectivity at the newly formed carbon—carbon bond was observed (de = 97%) (equation 191). The butylzinc enolates derived from other amides, lactams, esters and hydrazones also add successfully to the strained cyclopropenone ketal 78. Moreover, the cyclopropylzincs generated are stable and no rearrangements to the more stable zinc enolates occur after the addition. 

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. 

The FDA often considers such simple, uncomplicated amides, lactams, esters, and lactones as derivatives of the active drag substance in the same way as it treats salts (electrolytes) and ion-pair complexes (nonelectrolytes) of the same basic chemical structure. 

The unsaturated lactam ester 62 was also employed in a modified synthesis of ( )-lycorine (1) (109). In the event, O-ethylation of 62 with excess Meerwein reagent followed by reduction of the resulting imidate 77 with either sodium borohydride/stannic chloride dietherate (111) or sodium borohydride/stannous chloride gave an intermediate secondary amine, which cyclized on heating in methanol containing K2C03 to provide the lactam 78 (Scheme 5). When 78 was... 

The ( )-tricyclic lactam ester 39, yet another emetine precursor (34), was also prepared by Takano s group (32,33,35) from ( )-norcamphor (74). Baeyer-Villiger oxidation of ( )-74 and subsequent ethylation yielded the ( )-lactone 75, which was then condensed with 3,4-dimethoxyphenethyla-mine and oxidized. The resulting ( )-ketone 76 was cleaved through the ( )-thioketal 77 to afford the ( )-amido acid 78. Exposure of ( )-78 to Mel... 

A concise synthesis of highly substituted furans, pyrroles, butenolides, and 2-butene-4-lactam esters starts from alkynyl adducts of a Fischer carbene complex 21 (Scheme 27) < 1998JOC3164>. Incorporation of an aldehyde yields a reactive vinyl tungstencarbonyl complex 22 that can be oxidatively transformed to an ester group, furnishing the furan carboxylic ester 23. 

The nucleophiles include amides (and lactams), esters, aliphatic and... 

Aza-trieyclo 3.3.2.0J ]-deca-2,6,9-trien 9-Methoxy- E17b, 1219 (Lactam - Ester-imid) 3H-Azepin 2-Butyloxy- E9d, 158 (02N — Ar + RjP/R-OH) Azetidin l-Cyclohexyl-3-methylen-2-oxo- E16b, 136 (aus HO —A — CO-NHR)... 

Better inductions by a vicinal amino acid were observed by Ojima and coworkers in the benzylation of chiral /3-lactam ester enolates (255, equation 67) °. Interestingly, the enolate formation occurred at an uncommonly high temperature (0°C) to form the thermodynamic Li-chelated enolate 256, which allowed a stereoselective attack of the electrophile, while the diastereoselectivity with the nonchelated kinetic enolate 259 was significantly lower. Subsequent hydrogenolytic cleavage of lactam 257 delivered S)-a-methylphenylalanine derivative 258 in nearly quantitative yield and high diastereoselectivity. 

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

Protoemetinol [( )-34] was stereoselectively prepared by Hirai et al. from the ketoamide ( )-88 by intramolecular Michael reaction to give the tricycle ( )-89 and two-step reduction of ( )-89 through the lactam ester ( )-90 (74,75). 

The -lactam-ester (468), obtained by Beckmann rearrangement of the oxime (467), has been reduced and cyclised to give the /5-lactam (469). ... 

Danishefsky and co-workers have used activated cyclopropanes to promote intramolecular alkylation of an amino function, followed by lactam formation to provide a new entry to the pyrrolizidine ring system.20 This route is outlined in Scheme 1. Cyclopropanation of the phthalimido-olefin (19) was achieved with dimethyldiazomalonate in the presence of copper bronze. Treatment of the cyclopropane derivative (20) with hydrazine released the amine, which gave the lactam ester (21) in quantitative yield. This corresponds to intramolecular homoconjugate addition entirely in the spiro mode.21 It seems reasonable that the first step in this process is internal alkylation of the amine by the activated cyclopropane. The alternative... 

Occasionally transfer hydrogenolysis can cleave bonds resistant to classical methods. For example, the hydrogenolysis of the oxazoline moiety on Pd/C, Pd(OH)2/C, or Pd black in MeOH proved unsuccessful but transfer hydrogenolysis using Pd black and ammonium formate in AcOH afforded y-lactam ester [67]. 

Ziegler and co-workers (216, 217) have described a new approach to the quebrachamine skeleton involving internal cyclization of an acetic acid side chain to a 2-unsubstituted indole. The key intermediate is the disubstituted piperidine 466, which is treated with indolyl-3-acetyl chloride in aqueous sodium carbonate-methylene chloride to afford a lactam ester, 467. 

---