Many objective chemical tests have attempted to correlate with organoleptic evaluation of oxidative rancidity. Major chemical tests used to detect oxidative rancidity of lipids measure nonvolatile high molecular weight carbonylic substances which make no considerable contribution to rancid flavors. High molecular weight carbonyls are present at much greater concentrations than volatile low molecular weight carbonyls. Peroxides and other unknown substances also react in these chemical tests to give at best an empirical evaluation. A 3-methyl-2-benzothiazolinone hydrazone chemical test is proposed which corrected some deficiencies of earlier procedures, and was correlated with organoleptic evaluation of rancid turkey samples. The proposed test measures oxidative rancidity in terms of milligrams of acetaldehyde per kilogram of sample. A comparison of the 3-methyl-2-benzothiazolinone hydrazone method with a widely used chemical test was conducted. The thiobarbituric acid test was selected because it is used most often as an indicator of rancidity. The thiobarbituric acid test values increased followed by a definite leveling off as formation of malonaldehyde reached a maximum even though rancid flavor continued to increase. The 3-methyl-2-benzothiazolinone hydrazone test measured a continuing increase of volatile aliphatic aldehydes as rancid flavor increased .

The market of medicinal plants and herbs such as cilantro (Coriandrum sativum) and stevia (Stevia rebaudiana) has been growing due to the demand of the food, chemical and pharmaceutical industries. Leaves of C. sativum are used by many countries in the preparation of food and in folk medicine. The essential oil from the leaves has potential for use in the food industry as an antimicrobial agent and as a condiment to mask undesirable odors and flavors. Studies were conducted to evaluate the activity of the essential oil of cilantro against Leishmaniasis, and the results showed that the essential oil and its major compounds inhibited the growth of L. donovani in its different forms, indicating potential use of this plant for the production of new drugs against Leishmaniasis. From these results, another study was conducted to evaluate five materials of cilantro, a cultivar and four germplasm accessions from the North American Department of Agriculture regarding the quality of the raw material for the food and pharmaceutical industries. The materials with the highest potential to use were AMES 18596 and PI193770 for producing larger amount of dry biomass and the highest production of major compounds, which are desirable by industries. Stevia is a species with high potential to be consumed by diabetics and obese, it is a source of diterpene glycosides used as natural sweeteners. Sweeteners derived from stevia are ingredients in the production of foods, juices and soft drinks in Asia, Europe and in the Americas. The compounds responsible for the sweetness of stevia leaves are well characterized in the literature. However, good agronomic practices are still poorly studied. Some countries have worked on improving this culture and have achieved cultivars with higher yield. In the area of plant nutrition, calcium is one of the most important nutrients for the production of biomass and stevioside in stevia plants. Thus, a preliminary study was conducted to test the effect of calcium applied in nutrient solution in stevia yield, and stevioside and rebaudioside in hydroponic system. The leaf, stem and shoot biomass yield, by stevia plants were influenced by Ca rates in nutrient solutions and were maximal with 7.0, 5.7, 6.2 mmol L-1 of Ca, respectively. The production of stevioside and rebaudioside A was maximal with addition of 4.0 mmol of Ca L-1. / O mercado de plantas medicinais, condimentares e aromáticas tais como coentro (Coriandrum sativum) e estévia (Stevia rebaudiana) vêm crescendo devido à demanda das indústrias alimentícias, químicas e farmacêuticas. As folhas C. sativum são utilizadas por diversos países no preparo de alimentos e na medicina popular. O óleo essencial das folhas tem potencial para utilização na indústria de alimentos como agente antimicrobiano e como condimento para mascarar cheiros e sabores indesejáveis. Estudos foram realizados para avaliar a atividade do óleo essencial de coentro contra a leishmaniose, e os resultados revelaram que o óleo essencial e seus compostos majoritários inibiram o crescimento L. donovani em suas diferentes formas, indicando potencial de uso dessa planta para a produção de novos medicamentos contra Leishmaniose. A partir desses resultados, outro estudo foi realizado com o objetivo de avaliar cinco materiais de coentro, uma cultivar e quatro acessos do germoplasma do Departamento de Agricultura norte americano quanto à qualidade da matéria prima para as indústrias de alimentos e farmacêuticas. Os materiais variaram entre si quanto à produção de biomassa, acúmulo de nutrientes e produção de aldeídos alifáticos tais como (E)- 2-decenal, (E)- 2-dodecenal. Os materiais que apresentaram maior potencial de uso foram AMES 18596 e PI193770, pois, produziram maior quantidade de massa seca e produção de compostos majoritários, que são os desejáveis pelas indústrias. Quanto à estévia, essa espécie apresenta elevado potencial para ser usado por pessoas diabéticas e obesas, pois é fonte de diterpenos glicosídicos usados como adoçantes naturais. Os adoçantes derivados de estévia são usados na produção de alimentos, sucos e refrigerantes em diversos países asiáticos, europeus e no continente americano. Os compostos responsáveis pelo dulçor das folhas de estévia são bem caracterizados pela literatura, entretanto, as boas práticas agronômicas ainda são pouco estudadas. Alguns países trabalharam no melhoramento dessa cultura e conseguiram alcançar cultivares mais produtivas. Na área de nutrição, o cálcio está entre os nutrientes mais importantes para a produção de esteviosídeo e produção de biomassa de estévia. Assim, um estudo preliminar foi conduzido com o objetivo de estudar o efeito do cálcio aplicado em solução nutritiva na produção de estévia, e de esteviosídeos e rebaudiosídeos, em sistema hidropônico. A produção de folhas, caule e parte aérea por plantas de estévia foi influenciada por níveis de Ca na solução nutritiva e foram máximos com as doses de 7,0, 5,7, 6,2 mmol L-1 de Ca, respectivamente. A produção de esteviosídeo e rebaudiosídeo A foi máxima com a adição de 4,0 mmol L-1 de Ca.

The market of medicinal plants and herbs such as cilantro (Coriandrum sativum) and stevia (Stevia rebaudiana) has been growing due to the demand of the food, chemical and pharmaceutical industries. Leaves of C. sativum are used by many countries in the preparation of food and in folk medicine. The essential oil from the leaves has potential for use in the food industry as an antimicrobial agent and as a condiment to mask undesirable odors and flavors. Studies were conducted to evaluate the activity of the essential oil of cilantro against Leishmaniasis, and the results showed that the essential oil and its major compounds inhibited the growth of L. donovani in its different forms, indicating potential use of this plant for the production of new drugs against Leishmaniasis. From these results, another study was conducted to evaluate five materials of cilantro, a cultivar and four germplasm accessions from the North American Department of Agriculture regarding the quality of the raw material for the food and pharmaceutical industries. The materials with the highest potential to use were AMES 18596 and PI193770 for producing larger amount of dry biomass and the highest production of major compounds, which are desirable by industries. Stevia is a species with high potential to be consumed by diabetics and obese, it is a source of diterpene glycosides used as natural sweeteners. Sweeteners derived from stevia are ingredients in the production of foods, juices and soft drinks in Asia, Europe and in the Americas. The compounds responsible for the sweetness of stevia leaves are well characterized in the literature. However, good agronomic practices are still poorly studied. Some countries have worked on improving this culture and have achieved cultivars with higher yield. In the area of plant nutrition, calcium is one of the most important nutrients for the production of biomass and stevioside in stevia plants. Thus, a preliminary study was conducted to test the effect of calcium applied in nutrient solution in stevia yield, and stevioside and rebaudioside in hydroponic system. The leaf, stem and shoot biomass yield, by stevia plants were influenced by Ca rates in nutrient solutions and were maximal with 7.0, 5.7, 6.2 mmol L-1 of Ca, respectively. The production of stevioside and rebaudioside A was maximal with addition of 4.0 mmol of Ca L-1. / O mercado de plantas medicinais, condimentares e aromáticas tais como coentro (Coriandrum sativum) e estévia (Stevia rebaudiana) vêm crescendo devido à demanda das indústrias alimentícias, químicas e farmacêuticas. As folhas C. sativum são utilizadas por diversos países no preparo de alimentos e na medicina popular. O óleo essencial das folhas tem potencial para utilização na indústria de alimentos como agente antimicrobiano e como condimento para mascarar cheiros e sabores indesejáveis. Estudos foram realizados para avaliar a atividade do óleo essencial de coentro contra a leishmaniose, e os resultados revelaram que o óleo essencial e seus compostos majoritários inibiram o crescimento L. donovani em suas diferentes formas, indicando potencial de uso dessa planta para a produção de novos medicamentos contra Leishmaniose. A partir desses resultados, outro estudo foi realizado com o objetivo de avaliar cinco materiais de coentro, uma cultivar e quatro acessos do germoplasma do Departamento de Agricultura norte americano quanto à qualidade da matéria prima para as indústrias de alimentos e farmacêuticas. Os materiais variaram entre si quanto à produção de biomassa, acúmulo de nutrientes e produção de aldeídos alifáticos tais como (E)- 2-decenal, (E)- 2-dodecenal. Os materiais que apresentaram maior potencial de uso foram AMES 18596 e PI193770, pois, produziram maior quantidade de massa seca e produção de compostos majoritários, que são os desejáveis pelas indústrias. Quanto à estévia, essa espécie apresenta elevado potencial para ser usado por pessoas diabéticas e obesas, pois é fonte de diterpenos glicosídicos usados como adoçantes naturais. Os adoçantes derivados de estévia são usados na produção de alimentos, sucos e refrigerantes em diversos países asiáticos, europeus e no continente americano. Os compostos responsáveis pelo dulçor das folhas de estévia são bem caracterizados pela literatura, entretanto, as boas práticas agronômicas ainda são pouco estudadas. Alguns países trabalharam no melhoramento dessa cultura e conseguiram alcançar cultivares mais produtivas. Na área de nutrição, o cálcio está entre os nutrientes mais importantes para a produção de esteviosídeo e produção de biomassa de estévia. Assim, um estudo preliminar foi conduzido com o objetivo de estudar o efeito do cálcio aplicado em solução nutritiva na produção de estévia, e de esteviosídeos e rebaudiosídeos, em sistema hidropônico. A produção de folhas, caule e parte aérea por plantas de estévia foi influenciada por níveis de Ca na solução nutritiva e foram máximos com as doses de 7,0, 5,7, 6,2 mmol L-1 de Ca, respectivamente. A produção de esteviosídeo e rebaudiosídeo A foi máxima com a adição de 4,0 mmol L-1 de Ca.

No / Aliphatic aldehydes have a high affinity toward aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. In addition, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase, and xanthine oxidase activities in the oxidation of substituted benzaldehydes in separate preparations. The incubation of vanillin, isovanillin, and protocatechuic aldehyde with either guinea pig liver aldehyde oxidase, bovine milk xanthine oxidase, or guinea pig liver aldehyde dehydrogenase demonstrated that the three aldehyde oxidizing enzymes had a complementary substrate specificity. Incubations were also performed with specific inhibitors of each enzyme (isovanillin for aldehyde oxidase, allopurinol for xanthine oxidase, and disulfiram for aldehyde dehydrogenase) to determine the relative contribution of each enzyme in the oxidation of these aldehydes. Under these conditions, vanillin was rapidly oxidized by aldehyde oxidase, isovanillin was predominantly metabolized by aldehyde dehydrogenase activity, and protocatechuic aldehyde was slowly oxidized, possibly by all three enzymes. Thus, aldehyde oxidase activity may be a significant factor in the oxidation of aromatic aldehydes generated from amines and alkyl benzenes during drug metabolism. In addition, this enzyme may also have a role in the catabolism of biogenic amines such as dopamine and noradrenaline where 3-methoxyphenylacetic acids are major metabolites.

Chapter I deals with novel approaches for α-amino acids. This chapter has been divided into three sections. Section A describes the synthesis of α-amino acids via the Beckmann rearrangement of carboxyl-protected β-keto acid oximes. The synthesis of α-amino acids using the Beckmann rearrangement involves the preparation of the Z-oxime and efficient protection of the carboxyl group. Various 2-substituted benzoylacetic acids were synthesized, in which the carboxyl function was masked as a 2,4,10-trioxaadamantane unit (an orthoacetate), and were converted to their oximes (Scheme 1).1 The oximes were converted to the their mesylates, which underwent the Beckmann rearrangement with basic Al2O3 in refluxing CHCl3. The corresponding 2-substituted-N-benzoyl-α-amino orthoacetates were obtained in excellent overall yields. In Section B, the synthesis of α-amino acids via the Hofmann rearrangement of carboxyl-protected malonamic acids is described. The Hofmann rearrangement involves the migration of the alkyl moiety of the amide onto the N-centre. Various 2-substituted malonamic acids (malonic acid mono amides) were synthesized with the carboxyl group masked as a 2,4,10¬trioxaadamantane unit (an orthoacetate). These underwent the Hofmann rearrangement with phenyliodoso acetate and KOH/MeOH (Scheme 2). The resulting (N-methoxycarbonyl)¬trioxaadmantylmethylamines (carbamates) were formed in yields > 90%, and are α-amino acids with both carboxyl and amino protection.2 In Section C, an approach to chiral amino acids via the reductive amination of ketones, involving the hydride reduction of 1-(S)-phenethyl amine derived Schiff bases of C-protected α¬keto acids is described. An efficient synthesis of α-amino acids has thus been developed in high diastereoselectivity. Various 1-acyl-2,4,10-trioxaadamantanes were prepared from the corresponding 1-methoxycarbonyl derivatives, via conversion to the N-acylpiperidine derivative followed by reaction with a Grignard reagent in refluxing THF (Scheme 3). These α-keto orthoformates were converted to corresponding imines with 1-(S)-phenethyl amine (TiCl4/Et3N/toluene/reflux), the Schiff bases being reduced with NaBH4 (MeOH/0 °C) to the corresponding 1-(S)-phenethyl N-alkylamines (diastereomeric excess by NMR ~ 90:10).3 Hydrogenolysis of the phenethyl group (Pd-C/H2/MeOH) finally led to the (aminoalkyl)trioxaadamantanes, which are chiral C-protected α-amino acids, in excellent overall yields. Here a mild, inexpensive and efficient hydride reducing agent for the reductive amination of α-keto acids has been developed. Chapter II deals with the enantioselective synthesis of piperidines and its applications in the synthesis of piperidine alkaloids.4 This chapter has been divided into two sections. In Section A, the enantioselective synthesis of 2-substituted piperidines and its applications in the synthesis of (R)-(-)-coniine and (R)-(+)-anatabine are described. Various N-tert-butylsulfinyl imines were synthesized, which upon allyl Grignard addition followed by N-allylation gave the diallyl compound with good diastereoselectivity (Scheme 4). The diallyl compound underwent ring closing metathesis with Grubbs’ first generation catalyst and subsequent reduction of the double bond with H2-Pd/C, furnished N-sulfinyl-2-susbstituted piperidines. Using this methodology (R)¬(-)-coniine hydrochloride and (R)-(+)-anatabine were synthesized. In Section B, the enantioselective synthesis of (S)-tert-butyl 2-(2¬hydroxyethyl)piperidine-1-carboxylate and its elaboration to the synthesis of (S)-(+)-δ-coniceine and (S)-(+)-pelletierine are described. The (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate is a synthon used for the synthesis of various 2-substituted piperidine natural products. Using the above methodology (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate was synthesized starting from (S)-(+)-2-methyl-2-propanesulfinamide and 3¬(benzyloxy)propanal (Scheme 5). This alcohol was further elaborated to furnish two piperidine alkaloids (S)-(+)-pelletierine and (S)-(+)-δ-coniceine. Scheme 5. Enantioselective synthesis of (S)-tert-butyl 2-(2-hydroxyethyl)piperidine-1¬carboxylate, (S)-(+)-pelletierine and (S)-(+)-δ-coniceine. Chapter III deals with the formation of barbituric acid in an aprotic medium and related mechanistic studies. The generally accepted mechanism for the formation of barbituric acid involves the nucleophilic attack of urea anion on diethyl malonate.5 This is debatable for at least two reasons: (1) the normally employed base, sodium ethoxide, is too weak to deprotonate urea and (2) diethyl malonate is more acidic than urea, so the initial deprotonation by base has to be from diethyl malonate. When diethyl malonate (DEM) enolate was treated with urea in DMF, barbituric acid was formed in 61% yield. The reaction was also extended to several 2-substituted DEM derivatives, the corresponding substituted barbituric acids being formed in reasonable yields. The reaction between diethyl 2-(ethoxycarbonyl)malonate and urea, with potassium carbonate in refluxing ethanol, led to the formation of barbituric acid. This is apparently facilitated by hydrogen bonding involving the enolate oxygen atom, which renders one of the carbonyl groups relatively electrophilic (Scheme 6). Meldrum’s acid failed to react with urea, despite its greater acidity, indicating that the reaction requires the formation of the E from of the s-trans enolate ion, in which the hydrogen bonding interaction and nucleophilic attack can occur in concert. Scheme 6. Proposed transition state for formation of Barbituric acid. Chapter IV deals with an improved Erlenmeyer synthesis with 5-thiazolone and catalytic manganese (II) acetate for aliphatic and aromatic aldehydes. A serious limitation to the classical Erlenmeyer reaction is that it generally fails in the case of aliphatic aldehydes. This chapter describes a convenient approach to this problem that extends the scope of the Erlenmeyer synthesis. The present study was aimed at developing milder conditions for the synthesis of 4¬arylidene and alkylidenethioazlactones. Thus, N-(thiobenzoyl)glycine was treated with DCC in DCM at room temperature for 10 min., according to a reported procedure, to form the thioazlactone.6 The same reaction mixture was treated with catalytic Mn(II) acetate and an equivalent of an aromatic aldehyde, to furnish the corresponding 4-arylidenethioazlactones in good yields. The scope of the reaction was extended to alphatic aldehydes also under similar reaction conditions, to obtain the 4-alkylidene thioazlactones in good to moderate yields (Scheme 7). Scheme 7. The Erlenmeyer synthesis with 5-thiazolone and manganese acetate. (for figures & structural formula pl refer pdf file)

This thesis reports diverse synthetic and mechanistic studies in six chapters, as summarized below. Chapter 1. Revised mechanism and improved methodology for the perkin condensation.1 The generally accepted mechanism for the well-known Perkin condensation is unviable for at least two reasons: (1) the normally employed base, acetate ion, is too weak to deprotonate acetic anhydride (Ac2O, the substrate); and (2) even were Ac2O to be derprotonated , its anion would rapidly fragment to ketene and acetate ion at the high temperatures employed for the reaction. It has proved in this study that the Perkin condensation occurs most likely via the initial formation of a fem-diacetate (3, Scheme 1) from benzaldehyde (2) and acetic anhydride (1).1 The key nucleophile appears to be the enolate of 3 (and not of 1), which adds t the C=O group of the aldehyde 2 (present in equilibrium with 3). Thus cinnamic acid (4a) was formed in -75% yield with 3 as the substrate under the normal conditions of the Perkin reaction. The deprotonation of the diacetate appears to be electrophilically assisted by the neighbouring acetate group, the resulting enolate being also thermodynamically stabilized in form of an orthoester (I). The possibility that the diacetate 3 is the actual substrate in the Perkin reaction indicates that the reaction can be effected under far milder conditions, with a base much stronger than acetate ion. This was indeed realized with potassium t-butoxide in dioxane, which converted the gem-diacetates derived from a variety of aromatic aldehydes to the corresponding cinnamic acids (4), rapidly and in good yields at room temperature (Scheme 2). This represents a vast improvement in the synthetic protocol for the classical Perkin reaction, which remains an important carbon-carbon bond forming reaction to this day. Chapter 2. Aromaticity in azlactone anions and its sifnificance for the Erlenmeyer synthesis.2 The classical Erlenmeyer azlactone synthesis of amino acids occur via the formation of an intermediate azlactone, and its subsequent deprotonation by a relatively weak base(acetate ion),. The resulting azlactone anion (cf. II, Scheme 3) functions as a glycine enolate equilvalent, and is considered in situ with an aromatic aldehyde, subsequent dehydration leading to the 4-alkylidene oxazolone(analogously to the Perkin reaction). Interestingly, azlactone anions are possibly aromatic, as they possess 6π electrons in cyclic conjugation; this would explain their facile formation as also the overall success of the Erlenmeyer synthesis. The following studies evidence this possibility. The strategy involved studying the rates of base-catalyzed deprotonation in 2-phenyl-5(4H)-oxazolone (azlactone, 5) and its amide and ketone analogs, 3-methyl-2-phenyl-4(5H)-imidazolone (6), and 3,3-dimethyl-2-phenyl-493H)-pyrrolone (7) respectively.2 Two processes were studied, deuterium exchange and condensation with hexadeuteroacetone (Scheme3): both are presumably mediated by the anions II-IV, so their stabilities would govern the overall rates. These were followed by 1H NMR spectroscopy by monitoroing the disappearance of the resonance of the proton α to the carbonyl group. The order of deprotonation was found to be 6 > 5 > 7. However, the expected order based on pKa values would be ketone > ester > amide, i.e. 7 > 5 > 6. The inverted order observed strongly indicates the incursion of aromaticity, which would be enhanced by the electron-donor capabilities of the heteroatoms is 5 and 6. This is further substantiated by the greater reactivity in the case of the nitrogen analog 6 relative to the oxygen 5, which parallel the electronegativity order. (The aromaticity order would thus be: III > II > IV. The imidazole nucleus is indeed to be considerably more aromatic than the oxazole.) The synthesis of the analogs 6 and 7 was accomplished via an interesting intramolecular aza-Wittig reaction (Schemes 4 & 5) Chapter 3. Umpolung approach to the Erlenmeyer process in the synthesis of dehydro amino acids. These studies are based on the general observation that most of the strategies for the synthesis of α-amino acids introduce the side chain (or part was inverted in an umpolung sense. The key reaction studied was that of 2-phenyl-4-ethoxymethylne-5(4H)-oxazolone (11) with Grignard reagents: this resulted in the opening to yield a protected dehydro amino acid (12), in good to excellent yields (65-87%)(Scheme ^). As the azlactone reactant 11 is the ekectrophilic partner, this may be viewed as a partial umpolung version of the classical Erlenmeyer process. The readily available reactants, simple procedure and mild reaction conditions make this a very attractive method for the synthesis of a variety of α-dehydro amino acids. Chapter 4. The Erlenmeyer azlactone synthesis with aliphatic aldehydes under solvent-free microwave conditions. 3 A serious limitation to the classical Erlenmeyer reaction is that it generally fails in the case of aliphatic aldehydes. This chapter describes a convenient approach to this problem that extends the scope of the Erlenmeyer synthesis, via a novel microwave-induced, solvent-free process. This, it was observed that azlactones (5) react with aliphatic aldehydes (13) upon adsorption on neutral alumina and irradiation with microwaves (< 2 min), forming the corresponding Erlenmeyer products (14) in good yields (62-78%, Scheme 7). (The possible mechanistic basis of the procedure, which is presumably mediated by V , is discussed).3 Chapter 5. 2,4, 10-Trioxaadamantane as a carboxyl protecting group: application to the asymmetric synthesis of α-amino acids (umpolung approach).It is known that the 2,4,10-trioxaadamantane moiety is not only remarkably stable to nucleophilic attack, but can also be easily hydrolyzed to the corresponding carboxylic acid.4 It was of interest to apply this carboxyl protection strategy for designing a synthesis of α-amino acids, essentially by starting with a protected glyoxylic acid. The corresponding aldimine was expected to (nucleophilically) add organometallic reagents at the C=N moiety (cf. Shceme 8), the side chain of the amino acid being thus introduced in umpolung fashion. Also, a chiral aldimine would define an asymmetric synthesis of amino acids. Indeed, the chiral aldimine 17, derived from 2,4,10-troxaadamantane-3-carbaldehyde 15 and [(S)-(-)-1-phenylethylamine] 16, reacted with a variety of Grignard reagents to furnish the corresponding protected α-amino acids (18) in good yields, with moderate diastereometric excess (Scheme 8). Better yields and ‘de’ values were obtained with organolithium reagents. Chapter 6: possible one-pot oligopeptide synthesis with azlactones or amino acid N-carboxyanhydrides (NCAs). This chapter describes a novel approach to oligopeptide synthesis employing azlactones or NCA’s as amino acid equivalents which are simultaneously protected and activated (Scheme 9). Thus, the addition of the 4-substituted 2-benzyloxyazlactone (19) to an N-protected amino acid under basic conditions, was initially explored. The reaction was expected to yield a dipeptide (21) via the rearrangement of the mixed anhydride intermediate (VI) (Scheme 9). The subsequent addition of a different azlactone to the dipeptide (21) would analogously lead to the formation of a tripeptide (22). This may be performed repetitively to define a strategy for C-terminal extension of an oligopeptide chain, noting that no intervening deprotecting and activating steps are necessary. (In toto deprotection may be effected finally via the hydrogenolyis of the bvenzyloxy groups, to obtain 23.) A closely analogous strategy may also be envisaged by employing N.carboxyanhydrides (NCA’S, 24) instead of azlactones, as shown in Scheme 10 (forming dipeptide 26 and tripeptide 27). The main difference n this case is that the carbamic acid moiety of the intermediate mixed anhydride (VII) is expected to undergo decarboxylation to VIII (thus obviating the need for a deprotection step). However, this putative advantage is offset by the instability of NCA’s and their tendency toward polymerization. However, only partial success could be achieved in these attempts, although a variety of conditions were explored. The strategy and the experimental results have been analyzed in detail, as this interesting approach appears to be promising, and worth further study. (For structural formula pl refer the pdf file)