Lactams 9-membered

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

A few typical examples indicate the large variety of five-membered heterocycles, which can be synthesized efficiently by [2 + 3]-cycloadditions. [2 + 2]-Cycloadditions are useful in the synthesis of certain four-membered heterocycles (H. Ulrich, 1967), e.g. of 8-lactams (J.R. 

The "zip-reaction (U. Kramer, 1978, 1979) leads to giant macrocycles. Potassium 3- ami-nopropyl)amide = KAPA ( superbase ) in 1,3-diaminopropane is used to deprotonate amines. The amide anions are highly nucleophilic and may, for example, be used to transam-idate carboxylic amides. If N- 39-atnino-4,8,12,16,20,24,28,32,36-nonaazanonatriacontyl)do-decanolactam is treated with KAPA, the amino groups may be deprotonated and react with the macrocyclic lactam. The most probable reaction is the intramolecular formation of the six-membered ring intermediate indicated below. This intermediate opens spontaneously to produce the azalactam with seventeen atoms in the cycle. This reaction is repeated nine times in the presence of excess KAPA, and the 53-membered macrocycle is formed in reasonable yield. 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

Hydroxyoxaziridines like (117) undergo double ring cleavage to form, for example, a nine-membered keto lactam (81AG(E)670). 

This polymer may be prepared by stirring the molten w-aminoundecanoic acid at about 220°C. The reaction may be followed by measurements of the electrical conductivity of the melt and the intrinsic viscosity of solutions in w-cresol. During condensation 0.4-0.6% of a 12-membered ring lactam may be formed by intramolecular condensation but this is not normally removed since its presence has little effect on the properties of the polymer. 

This method of preparation has been developed primarily by Lukes (103,104). N-Methyl lactams (117) with five- and six-membered rings plus Grignard reagents yield the l-methyl-2-alkyl pyrroUnes (118, = 1) and l-methyl-2-alkylpiperideines(118, n = 2), respectively, plus 2,2-dialkylated bases (119) as by-products (103). For example, l,3-dimethyl-2-piperidone... 

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

Cyclic enamines with an isomeric position of the double bond have been obtained by the addition of Grignard reagents to five- (78-81), six- (82-86), seven- (87-90), and thirteen- (89-91) membered lactams, whereas other medium-sized (92,93) lactams furnished amino ketones. The reaction has been extended to substituted lactams (94-98), and iminoethers (99,100). 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

Electrophilic cyclizations of unsaturated amides to form 5- and 6-member lactams 98T13681. 

In conditions of base catalysis, the acetylenylpyrazolecarboxylic acid hydrazides, as opposed to benzene derivatives, are more difficult to cyclize compared with the benzoic acid derivatives and are isomerized only after heating in alcohol in the presence of KOH, forming not five- but six-membered lactams. The yields of pyri-dopyrazoles were 80-90% (Scheme 133 Table XXVIII) (85IZV1367 85MI2). 

An interesting method for preparing 2,6-dioxo-l,3-oxazine derivatives was described by Wasserman and Koch who stated that the five-membered ring of an a-keto-lactam could be transformed into the 1,3-oxazine (22) by ozone followed by reduction with zinc. 

Closely related to the penicillins are the cephalosporins, a group of /3-lactam antibiotics that contain an unsaturated six-membered, sulfur-containing ring. Cephalexin, marketed under the trade name Keflex, is an example. Cephalosporins generally have much greater antibacterial activity than penicillins, particularly against resistant strains of bacteria. 

Cyclization to the eight-membered lactams 8 is the key step in the synthesis of other 1,5-diazo-cine derivatives.1 In the first step methylation of amides 6 with diazomethane is nonselective, providing the 0-methylated derivatives 7, which are used for the cyclization, and also the (V-methylated derivatives, which are formed as byproducts. 

In 1997, Lindstrom and Somfai reported aza-[3,3]-Claisen enolate rearrangements of vinylaziridines (Scheme 2.45) [70]. Treatment of l-acyl-2-vinylaziridines 179 with LHMDS resulted in the stereoselective formation of seven-membered lactams 181, presumably through a boat-like transition state 180. 

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

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