Academic literature on the topic 'Δ-Lactams'

Spores are produced by many organisms as a survival mechanism activated in response to several environmental stresses. Bacterial spores are multilayered structures, one of which is a peptidoglycan layer called the cortex, containing muramic-δ-lactams that are synthesized by at least two bacterial enzymes, the muramoyl-l-alanine amidase CwlD and the N-deacetylase PdaA. This study focused on the spore cortex of Clostridium difficile, a Gram-positive, toxin-producing anaerobic bacterial pathogen that can colonize the human intestinal tract and is a leading cause of antibiotic-associated diarrhea. Using ultra-HPLC coupled with high-resolution MS, here we found that the spore cortex of the C. difficile 630Δerm strain differs from that of Bacillus subtilis. Among these differences, the muramic-δ-lactams represented only 24% in C. difficile, compared with 50% in B. subtilis. CD630_14300 and CD630_27190 were identified as genes encoding the C. difficile N-deacetylases PdaA1 and PdaA2, required for muramic-δ-lactam synthesis. In a pdaA1 mutant, only 0.4% of all muropeptides carried a muramic-δ-lactam modification, and muramic-δ-lactams were absent in the cortex of a pdaA1–pdaA2 double mutant. Of note, the pdaA1 mutant exhibited decreased sporulation, altered germination, decreased heat resistance, and delayed virulence in a hamster infection model. These results suggest a much greater role for muramic-δ-lactams in C. difficile than in other bacteria, including B. subtilis. In summary, the spore cortex of C. difficile contains lower levels of muramic-δ-lactams than that of B. subtilis, and PdaA1 is the major N-deacetylase for muramic-δ-lactam biosynthesis in C. difficile, contributing to sporulation, heat resistance, and virulence.

Cyclic N,N-dialkoxyamides have been made, for the first time, by hypervalent iodine oxidation of β- and γ-hydroxyhydroxamic esters 17, 19, and 21. The fused γ-lactam products, N-butoxy- and N-benzyloxybenzisoxazolones (22a and 22b), are stable while alicyclic γ-lactam and δ-lactam products, 24 and 25, although observable by NMR spectroscopy and ESI-MS are unstable at room temperature, undergoing HERON reactions. The γ-lactam 24 undergoes exclusive ring opening to give a butyl ester-functionalised alkoxynitrene 28. The δ-lactam 25, instead, undergoes a HERON ring contraction to give butyrolactone (27). The structures of model γ- and δ-lactams 6, 7, and 8 have been determined at the B3LYP/6-31G(d) level of theory and the γ-lactams are much more twisted than the acyclic N,N-dimethoxyacetamide (5) resulting in a computed amidicity for 6 of only 25 % that of N,N-dimethylacetamide (3). The HERON reactions of N,N-dimethoxyacetamide (5) and alicyclic models 6 and 8 have been modelled computationally. The facile ring opening of 6 (EA = 113 kJ mol–1) and ring contraction of 8 (EA = 145 kJ mol–1) are predicted well, when compared with the HERON rearrangement of 5 (EA = 178 kJ mol–1).

This review highlights recent progress in the construction of fluorinated lactams, including fluoro-β-lactams, fluoro-γ-lactams, and fluoro-δ-lactams, with an emphasis on the scopes, limitations and mechanisms of these different reactions.

An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100–250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).

β-Alkoxycarbonyl-γ-lactams and γ-alkoxycarbonyl-δ-lactams were synthesized via a conjugate alkylation/Mannich reaction/lactamization tandem reaction of unsaturated dicarboxylates with diethyl zinc and aldimines. The high yield, the ready availability of the reagents, and especially the high diastereoselectivity are promising characteristics of the approach that allows access to functionalized lactams.

The purpose of this investigation was to provide a systematic study of the cycloaddition pf (N-alkyl-N-phenylamino)- methoxy-and dichloroketenes to various imines and to investigate the stereochemistry of these cycloadditions.

Clostridium difficile est une bactérie anaérobie sporulante responsable de 15 à 25% des diarrhées post-antibiotiques. Les N-déacétylases sont largement distribuées parmi les bactéries à Gram positif et elles sont impliquées dans différentes fonctions de surface. L'analyse du génome de C. difficile montre que 13 gènes codent pour des N-déacétylases potentielles, et nous avons caractérisé l’ensemble de ces N-déacétylases.Le peptidoglycane de la cellule végétative de C. difficile est N-déacétylé sur 93% des glucosamines, et cette modification participe à la résistance de la bactérie au lysozyme, un composant majeur de l’immunité innée. Nous avons identifié les N-déacétylases PgdA, PgdB et PdaV responsables de cette N-déacétylation, et nous avons évalué leur impact au sein de la virulence de C. difficile. Nous avons également défini le rôle de deux N-déacétylases NagA dans le recyclage du peptidoglycane.Le peptidoglycane de la spore, ou cortex, a été analysé lors de ce travail et sa structure chez C. difficile est atypique par rapport au cortex décrit pour d’autres espèces bactériennes. Nous avons défini les N-déacétylases responsables de la N-déacétylation de la glucosamine du cortex. Nous avons également caractérisé les deux N-déacétylases PdaA1 et PdaA2 responsables de la synthèse des δ-lactames, une modification spécifique du cortex, ainsi que leur influence dans la virulence de C. difficile. Dans ce cadre, nous avons montré que les δ-lactames ont un rôle physiologique plus large pour C. difficile que chez Bacillus subtilis. De plus, nous avons identifié deux N-déacétylases potentiellement impliquées dans la synthèse de ce cortex.À travers ces résultats, ce travail apporte de nouvelles connaissances dans le rôle des N-déacétylases bactériennes
Clostridium difficile is an anaerobic and spore-forming bacteria responsible for 15 to 25% of post-antibiotic diarrhea. N-deacetylases are largely distributed among Gram positive bacteria and are involved in many surface processes. C. difficile genome analysis showed that 13 genes potentially encode N-deacetylases. In this work, we have characterized all of these enzymes.The vegetative cell peptidoglycan of C. difficile is deacetylated on 93% its glucosamine, and this modification is involved in the resistance of C. difficile against lysozyme, a major component of the innate immunity. We identified the N-deacetylases PgdA, PgdB and PdaV responsible for this N-deacetylation, and we assessed their impact on C. difficile virulence. The role of two N-deacetylases involved in peptidoglycan recycling has also been assessed.The spore peptidoglycan, known as the cortex, has also been characterized during this work, and its structure is atypical in C. difficile compared to other bacterial species. We showed that N-deacetylation of the glucosamine is present in the cortex peptidoglycan, and we identified the N-deacetylases responsible for this modification. Additionally, we characterized the N-deacetylases PdaA1 and PdaA2 responsible for the synthesis of muramic-δ-lactams, a cortex specific modification, as well as their impact on C. difficile virulence. In his context, we determined that muramic-δ-lactams have a broader role in C. difficile compared to their role in Bacillus subtilis. Moreover, two N-deacetylases involved in cortex synthesis have been identified.This work adds a contribution in the knowledge of the roles of bacterial N-deacetylases

Les hétérocycles azotés occupent une place importante en chimie organique et médicinale et, à ce titre, constituent des cibles de choix pour le développement de réactions toujours plus efficaces et faciles d’emploi. Les travaux antérieurs, réalisés au laboratoire URCOM sur l’accès aux γ-lactames, ont servi de base pour développer une méthodologie impliquant des conditions douces qui ont mis en évidence les propriétés spécifiques des N-alkoxy amides pour accéder aux γ- et δ-lactames hautement fonctionnalisés de manière hautement diastéréosélective selon un processus domino. Cette méthodologie a aussi pu être étendue aux hydantoïnes, 2-imino-thiazolidin-4-ones et thiazinan-4-ones qui constituent également des molécules étudiées en chimie médicinale. En parallèle, une comparaison de réactivité entre N-alkoxy amides et N-alkyl amides a montré la meilleure réactivité des composés N-alkoxylés pour l’obtention de ces différents hétérocycles azotés. Cette différence de réactivité a été attribuée à la possible chélation du contre anion alcalins des bases minérales utilisées dans notre approche par les N-alkoxy amides. Les conditions douces ont permis d’envisager des versions organocatalysées énantiosélectives ou multicomposantes des réactions précédentes conduisant à des résultats préliminaires intéressants
Nitrogen-containing heterocycles are key compounds in organic and medicinal chemistry and continue to attract synthetic effort for the development of more efficient and convenient reaction. Previous work carried out at the URCOM laboratory for the access to γ-lactams has provided the basis for developing a highly diastereoselective methodology under mild conditions that has demonstrated the specific properties of N-alkoxy amides, allowing the access to γ- and δ-lactams following a domino process. This methodology also allowed the access to hydantoïns, 2-imino thiazolidin-4-ones and thiazinan-4-ones which are compounds of importance in medicinal chemistry. In parallel, a comparison of reactivity between N-alkoxy and N-alkyl amides was carried out in order to demonstrate the better reactivity of the N-alkoxy amide compounds. This better reactivity was attributed to a possible chelation of the alkali metal counter anion of the mineral bases used in our conditions by the N-alkoxy amides. These mild conditions allowed organocatalyzed enantioselective or multicomponents approaches providing interesting preliminary results

La présence importante des hétérocycles azotés en chimie organique et médicinale explique le grand intérêt et les très nombreuses recherches dont ils font l’objet. Parmi tous ces motifs, les pyrrolidines ainsi que les γ- et δ-lactames bicycliques ont tout particulièrement focalisé notre attention. En se basant sur des résultats antérieurs obtenus au laboratoire nous avons mis au point deux nouvelles voies d’accès rapides et innovantes pour accéder diastéréosélectivement à ces motifs. D’une part une réaction tandem aza-MIRC (Michael Induced Ring Closure) a permis de former des pyrrolidines polysubstituées et d’autre part une séquence domino oxa-Michael/aza-MIRC a donné accès à de très nombreux γ- et δ-lactames bicycliques. Ces deux méthodes ont, en outre, été appliquées à la synthèse de composés d’intérêts connus pour leurs activités biologiques. La séquence aza-MIRC a été utilisée pour les synthèses totale et formelle respectivement des alcaloïdes Coerulescine et Martinelline, tandis que le processus oxa-Michael/aza-MIRC a été employé pour accéder de manière stéréosélective à des composés spirooxindoliques énantioenrichis. En parallèle du développement de ces deux méthodes, une étude mécanistique poussée de la séquence oxa-Michael/aza-MIRC a été réalisée au moyen de calculs théoriques. Cette étude a permis d’expliquer la majeure partie des résultats obtenus en fournissant un outil puissant capable d’anticiper, dans une certaine mesure, la réactivité de la séquence domino oxa-Michael/aza-MIRC
N-heterocycle scaffolds are found in many synthetic and medicinal chemical compounds explaining the high interest for developing efficient synthetic methodologies to reach such structures. In that field, our group has developed over the years innovative routes to y-lactams and bicyclic γ- and δ-lactams using tandem and domino reactions. Based on those previous works, we have developed two new methods to synthesize N-heterocycles. A tandem aza-MIRC (Michael Induced Ring Closure) sequence have been investigated to access pyrrolidines whereas the bicyclique scaffold of bislactames have been obtained using a domino oxa-Michael/aza-MIRC pathway. These two new methods have been then applied to the syntheses of more complexes and thus challenging backbones. The aza-MIRC tandem process have been used for the total and formal synthesis of alkaloids Coerulescine and Martinelline, respectively, whereas the domino oxa-Michael/aza-MIRC sequence has proved to be a powerful tool for stereoselective access to enantioenriched spirooxindolic compounds. DFT calculations studies have allowed elucidation of the diastereoselectivity and double chirality transfer of the domino reaction therefore could be used in the future to develop efficient total syntheses

Les hétérocycles azotés sont particulièrement présents en chimie médicinale et pharmaceutique. Les δ-lactames, en particulier, connaissent un essor croissant en raison de leur fort intérêt biologique et de leur utilisation en tant qu'intermédiaires réactionnels pour la synthèse de molécules d'intérêt. L’étude croissante de ces composés conduit à une recherche de nouvelles voies de synthèse pour accéder à ces motifs polyfonctionnalisés. Les réactions monotopes se distinguent comme une stratégie privilégiée, permettant, en une seule étape, la formation de multiples liaisons et centres stéréogènes au sein d'une même molécule, tout en évitant les purifications des intermédiaires réactionnels. Notre équipe s'est spécialisée dans ces approches monotopes pour la synthèse de γ- et δ-lactames. Dans ce manuscrit, nous avons souhaité exploiter la réactivité trivalente des N-alcoxyacrylamides pour développer une nouvelle voie réactionnelle. Ainsi, une réaction monotope séquencée d’aza-Michael/thia-Michael/aldolisation diastéréosélective a été réalisée à partir de l’optimisation préalable d’une réaction domino de thia-Michael/aldolisation. La gamme de nucléophiles capables d’effectuer cette séquence réactionnelle s’est révélée plus restreinte qu’attendue et seuls les dérivés de thiophénols se sont révélés particulièrement intéressants. C'est au cours de la modulation de ces composés que nous avons intégré une silylation in situ en amont de la séquence, permettant ainsi d'effectuer le processus monotope séquencé de silylation/thia-Michael/aldolisation diastéréosélectif. Puis, des applications pour accéder aux benzothiazépines, motifs ayant de nombreux intérêts biologiques, ont été entrepris. Par la suite, deux variantes organocatalytiques asymétriques de la cascade ont été envisagées afin d’accéder à des δ-lactames énantioenrichis. La première approche, concluante, utilise la séquence aza-Michael/thia-Michael/aldolisation avec l’application de la réaction d’aza-Michael énantiosélective développée auparavant au sein de notre laboratoire. La deuxième approche, reposant sur l’utilisation d’organocatalyseurs chiraux dans la séquence thia-Michael/aldolisation diastéréo- et énantiosélective, est toujours en cours de développement
Nitrogen-containing heterocycles are particularly prominent in medicinal and pharmaceutical chemistry. δ-Lactams, in particular, are experiencing increasing interest due to their significant biological relevance and their use as reactive intermediates for the synthesis of valuable molecules. The growing interest of these compounds drives the search for new synthetic routes to access these polyfunctional motifs. Monotope reactions stand out as a favored strategy, enabling the formation of multiple bonds and stereogenic centers within a molecule in a single one, while avoiding the purification of reaction intermediates. Our team has specialized in these monotope approaches for the synthesis of γ- and δ-lactams. In this manuscript, we aim to exploit the trivalent reactivity of N-alkoxyacrylamides to develop a new synthetic methodology. Thus, a sequenced monotope reaction of aza-Michael/thia-Michael/diastereoselective aldolization was performed based on the prior optimization of a domino thia-Michael/aldolization reaction. The range of nucleophiles capable of performing this reaction sequence proved to be more limited than expected, with only thiophenol derivatives showing particular promise. During the modulation of these compounds, we added an in situ silylation step prior to the sequence, allowing for a sequenced one-pot process of silylation/thia-Michael/diastereoselective aldolization. Subsequently, applications to access benzothiazepines, motifs with numerous biological interests, were undertaken. Furthermore, two asymmetric organocatalytic variants of the cascade were considered to access enantioenriched δ-lactams. The first approach involving the previously developed enantioselective aza-Michael reaction as a first stepproved succesful. The second approach, relying on the use of chiral organocatalysts in the diastereo- and enantioselective thia-Michael/aldolization sequence, is still under development

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CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Na Química Medicinal, dentre as várias técnicas de planejamento racional para a síntese de novas moléculas bioativas, a hibridação é umas das mais usadas. A união de dois ou mais compostos biologicamente ativos, no intuito de se criar um novo fármaco que conserve as propriedades biológicas das moléculas base e/ou crie uma nova atividade biológica para o composto híbrido, faz desta técnica um caminho rápido, eficaz e oportuno no descobrimento de novos candidatos a fármacos. Sinteticamente, dentre os vários métodos de junção de duas ou mais moléculas a Reação de Mannich está entre as metodologias aplicadas para isto. Este primeiro capítulo trata da síntese N-bases de Mannich derivadas da pirazinamida, que resultou na obtenção de dezenove compostos inéditos. Em um primeiro momento, foi realizada a tentativa de síntese de N-bases de Mannich derivadas da pirazinamida, utilizando três diferentes aminoálcoois Nalquilados. O desenvolvimento da metodologia mostrou que a reação era dependente do pH, tendo este que ser básico. No entanto, a baixa conversão da reação, juntamente com a difícil purificação do produto, uma vez que o mesmo apresentava o mesmo fator de retenção da pirazinamida e alta instabilidade impedindo qualquer funcionalização in situ inviabilizou qualquer possibilidade de continuação desta síntese. Desta forma, foi feita a substituição dos aminoálcoois N-aquilados por piperazinas N-substituídas, contendo cadeias lipofílicas, uma porção D-galactose, amidas lipofílicas, aminoalcoóis aromáticos e heteroaromáticos, sendo sintetizados 5 derivados inéditos da piperazina. A partir da reação de Mannich das piperazinas Nsubstituídas com a pirazinamida foram obtidas quatorze N-Bases de Mannich inéditas. Tanto as piperazinas N-substituídas como as N-bases de Mannich sintetizadas, foram submetidas à avaliação de suas atividades antibacterianas, antibiofilme e antituberculose, sendo que os resultados para atividade antibiofilme apresentaram bastante promissores. As lactamas são amidas cíclicas presentes em vários produtos naturais e em compostos sintéticos com atividade biológica. Devido a esta importância dentro da química medicinal, várias são as estratégias desenvolvidas para a síntese destes anéis heterocíclicos, com o objetivo de se conseguir uma síntese rápida, eficiente, estereoseletiva e utilizando a química verde para destes compostos. Dentre as várias metodologias sintéticas que permitem a obtenção estereoseletiva de Lactamas está à reação de Mannich-Acilação, inicialmente desenvolvida por Castagnoli em 1969 e aperfeiçoada recentemente pelo grupo de pesquisa do Professor Dr. Jared Shaw. Sendo assim, o segundo capítulo aborda desenvolvimento de uma metodologia a paritr da reação de Mannich-Acilação para a síntese de δ-lactamas como suporte para um estudo computacional sobre o mecanismo e estereoseletividade da reação. Para isso, a síntese do anidrido altamente reativo α-ciano glutárico, bem como, dos anidridos α- ciano glutárico substituídos com grupos metila ou fenila nas posições β ou γ foram realizadas. O escopo e as limitações da reação imina-anidrido com uma ampla variedade de iminas também foi investigada. As reações contendo aminas substituídas por grupos alquil volumosos e aromáticos foram mais diastereoseletivas. Já as reações envolvendo o uso dos anidridos α-ciano glutáricos não substituídos e contendo os grupos metila e fenila na posição β mostraram-se altamente diastereoseletivas, enquanto que para as reações envolvendo o anidrido α-ciano glutárico substituídos na posição γ houve uma perda da seletividade. Os estudos computacionais mostraram que a origem do estereocontrole da reação se dá na etapa de acilação, onde efeitos estéreos e trans anulares para o estado de transição na forma eclipsada justificam a formação do produto majoritário tendo uma relação syn entre os grupos carboxilato e fenil. Neste capítulo também foram exploradas algumas aplicações, no que diz respeito à utilização das δ-lactamas como possíveis inibidores da proteína FtsZ, em um estudo onde as δ-lactamas serviram como substratos na reação clássica de descarboxilação alilativa e na síntese dos produtos naturais Gelsidilam e Gelgamina B tendo a reação de Mannich-Acilação desenvolvida neste capítulo como uma das etapas chave.
In the Medicinal Chemistry, there are many techniques for development of new bioactive molecules. One way to do a rational planning of new drugs is using the molecular hybridization technique. In the molecular hybridization, the combination of two or more biologically active compounds in order to create a new pro-drug that preserves the biological properties or improve efficacy when compared to the parent drugs, makes this technique a quick way, effective and timely in the discovery of new drug candidates. Mannich reaction can be applicable to combine two or more fragments of drugs with biological activity. The first chapter will show the synthesis of new N-Mannich bases derived from pyrazinamide, which resulted in the synthesis of nineteen novel compounds. First of all, we tried to make the synthesis of new N-Mannich bases from of reaction between pyrazinamide, formaldehyde and N-alkylated amino alcohols. The development of this methodology showed that the reaction was pH dependent and it had to be basic. So we tried to control the pH of reaction using some bases, but the lower conversion of reaction together with the difficult purification of the product and the high instability led to an unsuccessful planning to get the products desired. Because of this, was made replacing of N-alkylated amino alcohols by N-substituted piperazines having lipophilic chain, D-galactose moiety, lipophilic amides, aromatic and heteroaromatic amino alcohols. With these new components we ran the Mannich reactions and was possible to synthesize fourteen novel N-Mannich bases. The N-substituted piperazines and N-Mannich bases synthesized were evaluated by antibacterial, antibiofilm and antituberculosis activities. The results of antibiofilm and antibacterial activity for some hybrids were very promising. In the second chapter, was developed a methodology to the synthesis of δ- lactams from cycloaddition between imines and cyano glutaric anhydrides like a support to mechanism and diastereoselectivity study of reaction. For this was made the synthesis of β, γ-substituted and unsubstituted cyano anhydrides. The scope of reaction was studied using differents amines and aldehydes. The reactions that were ran with bulky alkyl-substituted amines or aromatic amines were more selective than methylamine. The reactions involving the use of α-cyano-glutaric anhydrides unsubstituted or containing methyl groups and phenyl in the β position showed high diastereoselectivity. Reactions using the γ substituted anhydrides had a poor diastereoselectivity. Computational studies showed that acylation step is a determinant factor to diastereoselectivity, where the eclipsed transition state to anti product has steric and trans anular effects. Some applications of -lactams were made in other studies involving Tethering technique, decarboxylative allylation and total synthesis of Gelsedilam and Gelegamine B.

碩士
國立臺灣師範大學
化學系
105
The thesis contains two topics. The first part is the synthesis of bridged bicyclic δ-lactams via gold(I)-catalyzed intramolecular cycloisomerization/ox -idation of N-tosyl-4-ynamidomethylcyclohexenes. The second part is the synthesis of hexahydroisoquinolinone derivatives via BF3.OEt2-promoted intramolecular cyclization of alkyl- or aryl-substituted O-silyl-protected 2-((ethynylamino)methyl)cyclohex-2-enols. N-Tosyl-4-ynamidomethylcyclohexenes underwent cycloisomerization in the presence of a catalytic amount of a gold(I) complex delivering 4-azatricyclo[4.2.2.03,8]dec-2-ene derivatives as the major products under mild reaction conditions with high diastereoselectivities. Upon oxidation with osmium tetraoxide and N-methylmorpholine-N-oxide, alkyl- or aryl-substituted azatricycles led to bridged bicyclic δ-lactams. Under acidic conditions, the alkyl-substituted azatricycles were further transformed into 4-N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones derivatives. The BF3.OEt2-promoted intramolecular cyclization of alkyl- or aryl-substituted O-silyl-protected 2-((ethynylamino)methyl)cyclohex-2-enol enables a straightforward approach to hexahydroisoquinolinone derivatives. Upon epimerization with 1,8-diazabicyclo[5.4.0]undec-7-ene, the mixture of diastereomers afforded hexahydroquinolinone derivatives as a single isomer.

The inhibition effect of some lactams (Pyrrolidin‐2‐one, δ‐valerolactam, and ε‐caprolactam) on the corrosion behaviour of mild steel in 1M Hydrochloric acid solution was studied by weight loss and electrochemical techniques. The results demonstrated that both δ‐valerolactam, and ε‐caprolactam significantly inhibit corrosion. Specifically, δ‐valerolactam achieved an inhibition efficiency of 85.2%, while ε‐caprolactam exhibited a higher inhibition efficiency of 91.5%. The thermodynamic parameters governing the adsorption process such as adsorption heat, adsorption entropy, and adsorption free energy were determined and discussed. The adsorption of lactam compounds on the mild steel surface in 1M HCl follows the Langmuir adsorption isotherm model.

This chapter deals with the use of chiral auxiliaries for the asymmetric induction through a DKR process. In the last fifteen years, a wide number of various chiral auxiliaries have been employed in DKR processes occurring in different types of reactions, such as substitution reactions involving configurationally-labile alkyl halides or configurationally-labile anions, esterification and transesterification reactions, cyclocondensation reactions, reductions, cycloaddition reactions, and miscellaneous reactions. One of the most studied reactions has been the nucleophilic substitution on configurationally-labile alkyl halides, involving compounds with a bromo or iodo atom in the α-position with respect to a carboxylic acid derivative, in which the SN2 reaction is governed by a chiral auxiliary placed in the carboxylic moiety. Remarkable diastereoselectivities were particularly obtained by Caddick for nucleophilic substitution reactions of α-bromoacyl-imidazolidinones with nitrogen nucleophiles, together with those reported by Park for nucleophilic substitutions of α-bromo amides derived from chiral amino acids with nitrogen nucleophiles, allowing the synthesis of chiral di-, tri-, and tetrapeptides to be achieved. Several excellent results were also reported for esterification and transesterification reactions, such as the first example of DKR involving an intramolecular transesterification developed by Ishii, which provided a chiral 4-hydroxymethyl-2-oxazolidinone with an excellent diastereoselectivity starting from a serinol derivative. On the other hand, Bosch has developed highly diastereoselective DKR processes on the basis of cyclocondensation reactions of chiral aminoalcohols with δ-oxoacid derivatives, providing chiral bicyclic polysubstituted lactams. In addition, Ward has developed the synthesis of lairdinol A on the basis of a diastereoselective epoxidation of a (R)-carvone-derivative.

(-)-Nakadomarin A 4, isolated from the sponge Amphimedon sp. off the coast of Okinawa, shows interesting antifungal and antibacterial activity. The key step in the total synthesis of 4 reported (J. Am. Chem. Soc. 2009, 131, 16632) by Darren J. Dixon of the University of Oxford was the diastereoselective addition of the enantiomerically pure ester 1 to the prochiral nitroalkene 2. The assembly of 2 began with the linchpin ketophosphonate 5. Alkylation of the dianion of 5 with allyl bromide followed by direct condensation of the resulting monoanion with the diacetate 6 gave 7. On exposure to aqueous acid, 7 cyclized to the furan. Oxidation of the liberated primary alcohol followed by condensation with nitromethane then completed the preparation of 2. The starting material for the synthesis of 1 was the enantiomerically pure pyroglutamate derivative 8. Sulfide displacement followed by N-alkylation with the bromide 10 delivered 11 . Oxidation followed by deprotection then set the stage for the intramolecular Julia-Kocienski cyclization, which gave 12 with the expected (eight-membered ring) high geometric control. Addition of the ester 1 to Michael acceptors proceeded across the open face of the lactam, but it was still necessary to control the face of the nitro alkene 2 to which the lactam anion added. Catalysis of the addition with the urea 13 delivered 3 with 10:1 diasterocontrol. Mannich condensation of the nitroalkane 3 with formaldehyde and the amine 14 gave the bis-lactam 15, conveniently as a single diastereomer. After free radical removal of the nitro group, it was necessary to achieve selective reduction of the δ-lactam in the presence of the γ-lactam. Low-temperature LiAlH4 was found to be effective. Direct reduction of the resulting hemiaminal with formic acid led to the monolactam 16. The hemiaminal from monoreduction of 16 was found to be unstable and sensitive to overreduction. Nevertheless, exposure of 16 to Dibal at low temperature followed by acid-mediated cyclization delivered the diamine 17. Cyclization of the free base of 17 with the first generation Grubbs catalyst gave (-)-nakadomarin A 4 as the minor component of a 40:60 Z/E mixture. Carrying out the cyclization on the camphorsulfonate salt improved the ratio to 63:37 Z/E.

The pentacyclic alkaloid manzamine A 4, isolated from a sponge collected in the Okinawa Sea, displays a range of antibacterial, anticancer, and antimalarial activity. The preparation of 4 reported (J. Am. Chem. Soc. 2012, 134, 17482) by Darren J. Dixon of the University of Oxford showcases the versatility of the nitro group in organic synthesis. The nitro alkene 2 was prepared from the commercial bromide 5. Displacement with acetate followed by Swern oxidation led to the aldehyde 6, which was condensed with nitromethane to give 2. Lactam 1 was an intermediate in Professor Dixon’s synthesis (Org. Highlights May 3, 2010) of (–)-nakadomarin A. Lactam 1 was prepared from the tosylate 7, which was derived from pyroglutamic acid. The addition of 1 to the nitroalkene 2 delivered 3 as the dominant diastereomer of the four that were possible. Mannich condensation with formaldehyde and the amine 12 gave 13. The nitro group of 13 was removed by free radical reduction. Exposure of the reduced product to trimethylsilyl iodide gave, via ionization of the ketal, the primary iodide, which was carried onto the nitro compound 14. Dibal selectively reduced the δ-lactam. Partial reduction of the γ-lactam then gave an intermediate that engaged in Mannich condensation with the nitro-activated methylene to give 15. Although there are many protocols for the conversion of a nitro compound to a ketone, most of those were not compatible with the functional groups of 15. Fortunately, Ti(III) was effective. Ce-mediated addition of the Grignard reagent 16 to the ketone followed by deprotection and protection then delivered the silyl ether 17. Remarkably, the ketone 17 could be deprotonated and carried on to the enol triflate 18 without eliminating the TMSO group. Coupling with the stannane 19 then completed the synthesis of manzamine A 4. One-carbon homologation of 18 led to ircinol A, ircinal A, and methyl ircinate (not illustrated).