Lactams carboxylic acids

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

In conclusion, then, the available evidence concerning the structure of dimeric units suggests that many H bonding compounds form cyclic dimers (carboxylic acids, lactams, alcohols, phenols, and some steri-cally hindered amides) but that some form open dimers (most amides). This conclusion is reassuring to the many quantitative studies which have been based upon the tacit assumption that the v, absorption of monomeric species is not coincident with terminal O—H absorption of polymers. 

F6n6ant (638) proposed that a mixture of cyclic and open dimers and higher polymers accounts for the breadth and diffuse character of v. Although there is no question that the band is caused by overlapping absorptions of a variety of species in some cases (e.g., in pure alcohol, phenol, amides), it is also clear that the breadth exists in many systems for which only a single H bonded species is important (e.g., in carboxylic acids, lactams see, for example, 979). Hence proposal (1)... 

Anolobine, aequaline, schefferine, anonaine, liriodenine, assimilobine, isoboldine, 10-amino-3,4-dimethoxyphenanthrene-l -carboxylic acid lactam... 

Amino-4-heptadecene-1,3-diol, A-20127 2-Amino-4-hexadecene-l, 3-diol, A-20128 2-Amino-5-hexynoic acid, A-20129 2-Amino-3-hydroxy-2-(hydroxymethyl) propanoic acid, A-10070 10-Amino-4-hydroxy-3-methoxyphenanthrene-1-carboxylic acid lactam, see P-10121... 

C9H12O8, D-Spiro[3.3]heptane-2,6-dicarboxylic acid, 38B, 203 C9H13CIO, 2-Chlorobicyclo[3.3.1]nonan-9-one, 32B, 144 C9H13NO2, 6-endo-Hydroxy-3-endo-aminomethylbicyclo[2.2.1]heptane-2-endo-carboxylic acid lactam, 43B, 232 C9H1n02, exo-7-Hydroxybicyclo[3.3.1]nonan-3-one, 45B, 172 C9H18O2S, 6-endo-(Methylthio)bicyclo[2.2.1]heptane-2-endo-carboxylic acid, 46B, 169... 

Cl1H17NO2 r 3-Amino-3-hydroxy-trans-bicyclo[4.4.0]decane-l-carboxylic acid lactam, 44B, 270... 

A soln. of cis-3-benzamidopyrrolid-2-one-4-carboxylic acid hydrazide in 3%-HCl cooled and treated with 10%-NaNO2-soln., the resulting azide (Y ca. 100%) treated with dioxane and heated 1 hr. on a water bath cis-l-benzoyl-4-amino-methylimidazolid-2-one-5-carboxylic acid lactam (Y 77.6%).—The trans-isomer undergoes normal Gurtius degradation. J. Sicher et al.. Coll. 24, 3719 (1959). 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Another method for deallylation of ally esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /f-lactam 664[419,420]. 

Silylation of alcohols, amines and carboxylic acids with hydrosilanes is catalyzed by Pd catalysts[l 19], Based on this reaction, silyl protection of alcohols, amines, and carboxylic acids can be carried out with /-butyldimethylsilane using Pd on carbon as a catalyst. This method is simpler and more convenient than the silylation with /-butyldimethylsilyl chloride, which is used commonly for the protection. Protection of P-hydroxymethyl-(3-lactam (125) is an example 120]. 

ANTTBIOTTCS - BETA-LACTAMS - PENICILLINS AND OTTiERS] (Vol 3) -pivaloyloxymethyl ester derivative [CARBOXYLIC ACIDS - TRIALKYLACETIC ACIDS] (Vol 5)... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

The reactivity of the methylene group adjacent to the lactam group affords the possibility of a Claisen condensation. Thus, treatment of 2-pyrrolidone or 2-piperidone with ethyl oxalate leads to the J -pyrroline-carboxylic (70) and, d -piperideine-2-carboxylic acids (71), respectively. N-methyl lactams furnish N-methyl derivatives (72,73) (Scheme 3). 

Closely related is the reaction of enamines with O-sulfonyl lactams (411-413), which has extended the versatility of Hiinig s carboxylic acid extension sequence to compounds with a terminal amine function. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

This lactamization process can be promoted by enzymes such as pancreatic porcine lipase. Reduction of co-azido carboxylic acids leads to macrocyclic lactams. Although treatment of carboxylic acids with amines does not directly give amides, the reaction can be made to proceed in good yield at room temperature or... 

Either or both of the R groups may be aryl. In general, dialkyl ketones and cyclic ketones react more rapidly than alkyl aryl ketones, and these more rapidly than diaryl ketones. The latter require sulfuric acid and do not react in concentrated HCl, which is strong enough for dialkyl ketones. Dialkyl and cyclic ketones react sufficiently faster than diaryl or aryl alkyl ketones or carboxylic acids or alcohols that these functions may be present in the same molecule without interference. Cyclic ketones give lactams. 

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