Lactams aldehydes

The total synthesis of ( )-geissoschizine (30) was reported by Yamada et al. (156) in 1974. The geometrically pure p-nitrophenyl ester 272 was condensed with tryptamine, and then the resulting amide 273 was transformed to lactam aldehyde 274 by hydroxylation with osmium tetroxide, metaperiodate oxidation, and Pictet-Spengler cyclization. 

In many of the syntheses, aza-/3-lactam aldehyde 151 has been used as a key synthon (Scheme 20). For example, aldehyde 151 gives epoxide 157 by treatment with NaH and Me3S+I in DMSO at low temperature. Similarly, alcohol 156 may be prepared from 151 by reduction with LiAlH4 in ether. When NaBH4 is used in methanol a cyclic product 159 was isolated along with alcohol 158 (Scheme 20) <1998J(P1)2597>. 

In the synthesis of (+)-dihydrocorynantheol (92) by Kametani et al.,56a the tetracyclic system (93) was constructed by Michael addition of an enamine, derived from the dihydro-/ -carboline (76), to dimethyl 3-methoxyallylidenemalonate, with closure of the lactam ring (Scheme 15). The product (93) was then converted (by unexceptional methods), via the lactam aldehyde (94), into ( )-dihydrocoryn-antheol, the normal stereochemistry in which follows from its mode of formation. 

Many of the known inhibitors of serine and cysteine proteases feature the same types of war-head (e.g. oc-ketoamide, 8-lactam, aldehyde) which are able to undergo a covalent interaction with the nucleophilic active site alcohol or thiol group [371-373]. Depending on the reactivity of the war-head this approach has led to irreversible inhibitors or reversible but tight-binding inhibitors. The problem with this approach is that it is difficult to achieve selectivity and so there is considerable interest in the discovery of inhibitors that bind in a non-covalent fashion to the active site. 

Cyclization and cycloadditi ketenes under photochemical co cyclization leads to aminonaphth with imines to form 3-lactams. aldehyde leads to 8-lactones. Th... 

Nonsensitized photochemical oxidation of dihydrodibenzo[a,5 ]quinolizinium compounds such as berberine (102) in the presence of nucleophilic reagents affords isoquinoline lactam aldehydes (103) (Scheme 13) <84H(22)10l>. A mechanistic proposal <81H(16)1735> involving the intermediacy of the dihydroberberine (104) was rejected on the basis of the results of direct irradiation of this compound. Participation of singlet oxygen was also excluded. 

A different approach to the synthesis of the protected hydroxy amino acid moiety was also described by Broady et al (ref.127) (see Scheme 7). Construction was from the IJ-lactam aldehyde (78) prepared from L-aspartic acid. Condensation of (78) with benzyl bis (2, 2,2-trifluoroethyl)phosphonoacetate (79) afforded the (Z)-ester (80) along with a small amount (11%) of (E)-isomer. The hydroxyl substituents were introduced by cis-hydroxylation using catalytic osmylation in the presence of NMO. This reaction was found to be moderately stereoselective and gave a mixture of diastereomers in the ratio ca. 80 20 with the major product being the correct diastereomer (81). The diol group was protected as the... 

NitroaUcenes derived from -lactam aldehydes may be converted into diverse bicyclic -lactams via intramolecular Michael addition and ozonolysis (eq 8). The method is appropriate for penam, carbapenam, carbacephem, and oxapenam arrays. In some cases, (benzyloxy)nitromethane is a superior reagent. This Michael addition-oxidation strategy is also useful for the... 

The reactions of HN3 with cyclic alcohols to yield mixtures of ketones, amines, and products with an enlarged ring are catalyzed by H2SO4 [1]. Tertiary alcohols are converted to azides in the presence of acid [12] or TiCU [13]. Aldehydes and ketones with HN3 undergo a Schmidt-type reaction by liberating N2 and inserting NH In the presence of H or Lewis acids [14]. Ketones yield secondary amides and, in the case of cyclic ketones, lactames. Aldehydes are converted to nitriles or N-formylamines. Tetrazole derivatives result with excess HN3 [1, 15]. However, a-azido ethers are obtained from aldehydes and HN3 in the presence of alcohols by catalysis of TiC [16]. Carboxylic acids and anhydrides form amines, N2, and CO2 in Schmidt reactions with HN3. Intermediates are carbamic acids which form by insertion of NH into the R-COOH bond [1, 14]. High yields result for acids of arenes [17]. 

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 some cases where there is a neighboring group participation effect, aldehydes are formed. The a-vinyl group in the / -lactam 29 is mainly oxidized to aldehyde 30[83],... 

PMVEMA, supphed as a white, fluffy powder, is soluble in ketones, esters, pyridine, lactams, and aldehydes, and insoluble in aUphatic, aromatic, or halogenated hydrocarbons, as well as in ethyl ether and nitroparaffins. When the copolymer dissolves in water or alcohols, the anhydride group is cleaved, forming the polymers in free acid form or the half-esters of the corresponding alcohol, respectively. Table 7 illustrates the commercially available alternating copolymers and derivatives. 

Ring expansions of suitable /3-lactams can also be achieved on treatment with base rearrangement of the Af-substituted azetidin-2-ones (133) occurs in the presence of LDA to give (134) (72JA9261). Aminolysis of the /3-lactam epoxide (135) and the aldehyde (137) affords (136) and (138) respectively (81JHC1239). 

Silylketenes in formation of (3-lactones and (3-lactams 98JCS(P1)2105. Syntheses of (3-lactams, (3-lactones, and 1,3- and 1,4-diazetidinediones by pho-tochemically induced cycloaddition reactions of chromium carbene complexes with imines, aldehydes, and azo compounds 97T4105. 

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

In addition to the Beckmann reaction, the Schmidt rearrangement is used to generate M-alkylated lactams, too. Alkyl azides 231 react with the cyclic ketones (and aldehydes) in the presence of proton or Lewis acids. On running the inter-molecular reactions, in most cases symmetric ketals 230 have been converted... 

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