Proline Methyl Ester Research Articles

Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19.

Nirmatrelvir (Paxlovid) is an FDA approved drug that targets SARS-COV-2 3CLprotease. We report an optically active synthesis of nirmatrelvir that avoids a critical epimerization step. Our initial coupling of gem-dimethyl bicyclo[3.1.0]proline methyl ester with tert-leucine-trifluoroacetamide using standard coupling reagents, EDC and HOBt, provided the corresponding dipeptide derivative in excellent yield, however, a significant epimerization was observed at the tert-leucine bearing chiral center. To circumvent this epimerization problem, we developed a ZnCl2-mediated direct N-trifluroacetylation of Boc-derivatives for the synthesis of nirmatrelvir. This protocol has been utilized for N-acyl bond formation with other anhydrides without epimerization. The present synthetic route can be useful for the synthesis of structural variants of nirmatrelvir without significant epimerization.

N-Alkyl Carbamoylimidazoles as Isocyanate Equivalents: Exploration of the Reaction Scope for the Synthesis of Ureas, Hydantoins, Carbamates, Thiocarbamates, and Oxazolidinones.

The reaction of the HCl or trifluoroacetic acid salts of primary amines with carbonyldiimidazole (CDI) is shown to be a preparatively useful method for forming monosubstituted carbamoylimidazoles (28 examples) without the formation of symmetrical urea side products. The utility of these air- and water-stable crystalline carbamoylimidazole reagents was demonstrated by their reactions as blocked or masked isocyanate equivalents. Reaction with various classes of nucleophiles provides access to useful functional groups including ureas, carbamates, thiocarbamates, hydantoins, and oxazolidinones. A parallel synthesis library of 30 ureas was generated by the reaction of 6× carbamoylimidazole intermediates with 5× amines and triethylamine. The unsymmetrical urea-containing natural products macaurea A and pygmaniline A were also prepared in good yields (95% over four steps and 79% over three steps, respectively) using this approach. The reaction of carbamoylimidazoles with amino acid methyl esters followed by microwave irradiation in aqueous media gives hydantoins in high yields, further demonstrating the ability of carbamoylimidazoles as isocyanate surrogates. Three hydantoin-containing natural products including macahydantoin D and meyeniihydantoin A were prepared in nearly quantitative yields from proline methyl ester and carbamoylimidazoles. The reaction of carbamoylimidazoles with alcohols and thiols under basic conditions affords carbamates and thiocarbamates, respectively, in good yields. Lastly, a method for the preparation of chiral oxazolidinone heterocycles from chiral epoxy alcohols is demonstrated using a double displacement approach. The reactions occur with high regio- and stereoselectivity (dr ≥ 15:1 by 1H NMR) via a domino attack of the corresponding alkoxides with carbamoylimidazoles followed by an intramolecular attack of the in situ generated urea anion at the proximal position of the epoxide group.

Spick-and-span protocol for designing of silica-supported enantioselective organocatalyst for the asymmetric aldol reaction

In the present work, we report a ground-breaking strategy in the development of spick-and-span protocol for the synthesis of l-proline chiral scaffold tethered onto the silica matrix i.e., l-proline-(3°amine)-f-SiO2 via the reaction between l- proline methyl ester and N-methyl aminopropyl silica with absolutely no use of protecting/ deprotecting groups. The as-synthesized catalyst was well corroborated through various physicochemical techniques such as 13C CP MAS NMR, X-ray diffraction (XRD), HRTEM, N2 adsorption−desorption isotherms, elemental analysis and FT-IR spectral studies. Emphatically, l-proline-(3°amine)-f-SiO2 significantly promoted an asymmetric aldol reaction under ambient conditions with no use of redundant organic solvent, bestowing unprecedented activity with 100% conversion and (ee) > 99% enantioselectivity of S-isomer. Moreover, the as-synthesized catalyst was effortlessly recycled seven consecutive times with absolutely zero loss of activity as well.

Synthesis of Prolylproline

Prolylproline has been synthesized by both classical peptide synthesis method utilizing tert-butoxycarbonyl or trifluoroacetyl protection of the NH group and carbodiimide-promoted peptide bond formation and by opening of the dioxopiperazine ring in octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazine-5,10-dione obtained by thermolysis of proline methyl ester.

Intermolecular Diels-Alder Cycloaddition for the Construction of Bicyclo[2.2.2]diazaoctane Structures: Formal Synthesis of Brevianamide B and Premalbrancheamide.

A stereoselective intermolecular Diels-Alder cycloaddition of an intermediate pyrazinone with both achiral and chiral acrylate-derived dienophiles provides rapid access to the bicyclo[2.2.2]diazaoctane core shared among several prenylated indole alkaloids. The product derived from cycloaddition with 2-nitroacrylate required an additional five to six synthetic operations to intercept established precursors to premalbrancheamide and brevianamide B. The chemistry detailed in this manuscript constitutes a formal total synthesis (12 steps each) of these [2.2.2]diazabicyclic natural products from proline methyl ester.

Enantiodivergent asymmetric catalysis with the tropos BIPHEP ligand and a proline derivative as chiral selector.

A catalytic system based on the tropos ligand BIPHEP and (S)-proline methyl ester as chiral selector was studied for Rh-catalysed asymmetric catalysis. By careful control of the catalyst preformation conditions, the enantioselectivity could be completely reversed in asymmetric hydrogenation of prochiral olefins maintaining the same absolute level in favorable cases. The enantiodivergent asymmetric catalysis could be rationalised by the interplay of the dynamic chirality (tropos) of the phosphine ligand and the coordination of the proline selector. Treating a suitable Rh-BIPHEP precursor with the (Sc)-proline-based ionic liquid led to an equimolar mixture of (RaSc)- and (SaSc)-diastereomers that is kinetically stable at 0 °C. At higher temperature, an irreversible diastereomerisation process was observed resulting in the diastereomerically pure (RaSc)-complex [Rh{(Ra)-BIPHEP}{(Sc)-ProlOMe}]. Whereas the use of the pure (RaSc)-complex led to 51% ee (R) in the hydrogenation of methyl 2-acetamidoacrylate, the S-product was formed with almost identical enantioselectivity when the (RaSc)/(SaSc)-mixture was applied under identical conditions. This inversion was associated with the relative stability of the diastereomers in the equilibria forming the catalytically active substrate complex. The possibility to use this different reactivity to control the direction of enantioselectivity was demonstrated for the hydrogenation of different substrates whereby ee's of up to 80% could be achieved. Moreover, the (RaSc)-complex led to high enantioselectivities of up 86% ee in the asymmetric hydroboration of styrene, approaching the performance of the atropos BINAP ligand for this reaction.

Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions

AbstractThe organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo‐L and endo‐L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine‐based organocatalysts.

ChemInform Abstract: Asymmetric Modular Synthesis of a Semirigid Dipeptide Mimetic by Cascade Cycloaddition/Ring Rearrangement and Borohydride Reduction.

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments.

Preparation and enantioselectivity binding studies of a new chiral cobalt(II)porphyrin-Tröger's base conjugate.

A new bis[cobalt(II)porphyrin]-Tröger's base conjugate was studied as a potential receptor for methyl esters of several amino acids. The conjugate was prepared as racemate, and then resolved via preparative high-performance liquid chromatography (HPLC) on a chiral column. The high affinity to lysine, histidine, and proline methyl esters was found by complexation studies followed by UV-Vis spectroscopy. The studies of pure enantiomers, followed by UV-Vis and electronic circular dichroism spectroscopy, revealed the highest enantioselectivity for lysine methyl ester.

Asymmetric Modular Synthesis of a Semirigid Dipeptide Mimetic by Cascade Cycloaddition/Ring Rearrangement and Borohydride Reduction

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments.

Conformational Analysis and Intramolecular Interactions of l-Proline Methyl Ester and Its N-Acetylated Derivative through Spectroscopic and Theoretical Studies

This work reports a detailed study regarding the conformational preferences of L-proline methyl ester (ProOMe) and its N-acetylated derivative (AcProOMe) to elucidate the effects that rule their behaviors, through nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies combined with theoretical calculations. These compounds do not present a zwitterionic form in solution, simulating properly amino acid residues in biological media, in a way closer than amino acids in the gas phase. Experimental (3)JHH coupling constants and infrared data showed excellent agreement with theoretical calculations, indicating no variations in conformer populations on changing solvents. Natural bond orbital (NBO) results showed that hyperconjugative interactions are responsible for the higher stability of the most populated conformer of ProOMe, whereas for AcProOMe both hyperconjugative and steric effects rule its conformational equilibrium.

Synthesis of New Gold(I) Thiolates Containing Amino Acid Moieties with Potential Biological Interest

The reaction of the gold(I) complex [Au(SpyCOOH)(PPh3)], which contains nicotinic acid thiolate, with several amino acid esters such as glycine methyl ester or the enantiomerically pure L isomers of alanine methyl ester, phenylalanine methyl ester, valine methyl ester, methionine methyl ester, and proline methyl ester produces the gold(I) derivatives with the new thiolate containing amino acid ester ligands [Au{SpyCONHCH(R)COOMe}(PPh3)]. The reaction of these amino acid ester derivatives with LiOH in methanol and acidification with KHSO4 until pH 3-4 afford the corresponding acids, which are water-soluble species. These amino acid compounds can be further coupled with other amines, such as, for example, isopropylamine, to give the corresponding amide derivatives. The species with glycine methyl ester and valine methyl ester have been characterized by X-ray crystallography, showing, in the second case, only one of the enantiomers, which proves that retention of the configuration after reaction occurs.

A novel 2H-azirin-3-amine as a synthon for a sulfur-containing dipeptide segment

Starting with tetrahydro-2H-thiopyran-4-carboxylic acid and methyl prolinate, the novel 2H-azirin-3-amine [S]-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl ester was synthesized. In reactions with benzoic acid, thiobenzoic acid and Boc-valine, respectively, its usefulness as a synthon for the dipeptide [S]-N-[(4-aminotetrahydro-2H-thiopyran-4-yl)carbonyl]proline in peptide synthesis was demonstrated.

金龟甲对蓖麻叶挥发物的触角电位和行为反应

为了探明金龟甲偏爱选择有害非寄主植物蓖麻的原因，应用触角电位（EAG）仪和“Y”型嗅觉仪，分别测定了华北大黑鳃金龟、暗黑鳃金龟和铜绿丽金龟雌、雄虫对5种蓖麻叶挥发物的触角电位和选择行为反应。EAG测定结果表明，3种金龟甲雄虫对各处理挥发物的EAG反应值均比参照挥发物顺-3-己烯-醇强。华北大黑鳃金龟对邻苯二甲酸二丁酯和肉桂醛的EAG反应值相对较高，暗黑鳃金龟对苯甲醇的EAG反应值相对较高，铜绿丽金龟对邻苯二甲酸二丁酯和苯甲醇的EAG反应值相对较高。选择行为反应测定结果表明，当顺-3-己烯-醇与其他挥发物配对测试时，华北大黑鳃金龟对邻苯二甲酸二丁酯和肉桂醛2种蓖麻叶挥发物表现出明显的选择偏好，暗黑鳃金龟对蓖麻叶挥发物苯甲醇表现出明显的选择偏好，铜绿丽金龟则更偏好选择蓖麻的绿叶气味物质顺-3-己烯-醇。总之，蓖麻叶的挥发性物质与引诱金龟甲偏爱选择密切相关，且偏爱的挥发物因金龟甲的种类而异。;<em>Holotrichia oblita</em>, <em>H. parallela</em> and <em>Anomala corpulenta </em>are important pests in the dry land areas of North China, which feed roots or stems of plants in larvae stage and leaves of variety of plants in adult stage. Most interestingly, three species all prefer to feeding on leaves of <em>Ricinus communis</em>, a non-host plant, despite that the extract of <em>R. communis</em> leaf is toxic to their larvae and adults. In order to elucidate the mechanisms behind this phenomenon, in the present study, the electroantennographic and behavioural responses of the male and female adults of three scarab beetle species to five components of <em>R. communis</em> leaf volatiles were tested using the electroantennogram (EAG) and a Y-typed olfactometer, respectively. The EAG bioassay showed that the relative EAG values of three species male scarab beetles were higher to four components, i.e., dibutyl phthalate, cinnamaldehyde, 2-phenylethanol and benzyl alcohol, than that to control volatile (<em>Z</em>)-3-hexene-1-ol, especially the males of<em> H. oblita</em> exhibited strong responses to dibutyl phthalate and 2-phenylethanol, with 200.34% and 168.43% relative EAG values, respectively. Corresponding females of<em> H. oblita</em> responded strongly to cinnamaldehyde and dibutyl phthalate with the 146.01% and 135.12% relative EAG values, respectively. The relative EAG values of <em>H. parallela</em> to benzyl alcohol arrived 149.95%(male) and 167.86%(female). <em>A. corpulenta</em> exhibited responses to dibutyl phthalate with about 144% the relative EAG values. The response of <em>A. corpulenta</em> male to benzyl alcohol is strong with the 143.70% relative EAG values. The results of behavioural bioassay indicated the preference to volatiles derived from <em>R. communis</em>is is species-dependent, that is, <em>H. oblita</em> exhibited significant preferences to dibutyl phthalate and cinnamaldehyde, with the choice response percentages of 64% and 63% in females and 76% and 65% in males, significantly higher than that to (<em>Z</em>)-3-hexene-1-ol. Females and males of<em> H. parallela</em> showed significant preference to benzyl alcohol, with the 66% and 56% mean choice response percentages, respectively. <em>A. corpulenta</em> was most preferred to a green leaf volatile (<em>Z</em>)-3-hexene-1-ol, and the average choice response percentages of males and females to (<em>Z</em>)-3-hexene-1-ol were 88%, 87% and 89% in the controls of dibutyl phthalate, cinnamaldehyde and 2-phenylethanol, respectively. The results of comparison between <em>R. communis</em> volatiles and the female-produced sex pheromones of the tested scarab beetle species, found that <em>R. communis</em> leaves emitted abundant dibutyl phthalate, while the major components of <em>H. oblita</em> female-produced sex pheromone were glycine methyl ester and proline methyl ester, and the major component of <em>H. parallela</em> female-produced sex pheromone was methyl<em> L</em>-isoleucinate. Therefore, sex pheromone misleading may possibly answer for the preferences of two <em>Holotrichia</em> species to <em>R. communis</em>. The green leaf volatile (<em>Z</em>)-3-hexene-1-ol may possibly be the main attractant of <em>A. corpulenta</em> to <em>R. communis</em>.

The Mechanism of Betaine Accumulation by Mouse Oocytes.

Betaine (N,N,N-trimethylglycine) is transported into 1- and 2-cell embryos via SIT1, which mediates betaine transport that is dependent on Na+ and Cl-. SIT1 is activated at fertilization. In early embryos, betaine contributes to cell volume homeostasis, allowing normal development of preimplantation embryos cultured at approximately the osmolarity of the in vivo environment (~300 mOsM), and functions as a methyl donor at the blastocyst stage. We recently measured a high level of endogenous betaine in metaphase-II (MII) stage mouse eggs, before the SIT1 transporter has been activated. The mechanism by which oocytes accumulate betaine and its contribution to the betaine pool in preimplantation embryos are unknown. Since denuded oocytes from the germinal vesicle (GV) to MII stages cannot transport betaine, we hypothesise that cumulus cells of the cumulus-oocyte complex (COC) express a betaine transporter and that betaine transported through this putative transporter is transferred to the enclosed GV via gap junctions. Our data indicate that that there is indeed saturable betaine transport in COCs, since 5 mM unlabelled betaine significantly reduced the rate of transport of [3H]-betaine (1 μM). To determine the characteristics of the betaine transporter, we performed a competitive inhibition profile study. Proline is often transported by betaine transporters (e.g., SIT1). Proline (5 mM) significantly reduced the rate of [3H]-betaine transport by COCs, as did the proline derivative proline methyl ester. Alanine, methionine and methylaminoisobutyric acid all significantly reduced the rate of [3H]-betaine transport by COCs, while GABA (a substrate of the betaine/GABA transporter) and histidine did not significantly affect [3H]-betaine transport by COCs. The rate of [3H]-betaine transport by COCs was determined in the presence vs. absence of Na+ and Cl-, to determine whether co-transport of either is required. The rate of [3H]-betaine transport was significantly reduced in COCs in Na+-free media. However, omitting Cl- did not significantly affect betaine transport. These results indicate that likely candidates for the betaine transporter in COCs are either of the classical amino acid transport systems designated system A or ASC. Further inhibition profiling will determine which of these likely accounts for betaine transport in COCs. Funding: Canadian Institutes of Health Research.

Asymmetric Preparation of D-Phg-L-Pro Dipeptide-derived Chiral Ligands for Enantioselective Addition of Diethylzinc to Aldehydes

-Pro dipeptide analogues 2 and 3 as shown in Scheme1. The treatment of two diastereomeric mixture (1:1) of N-(α-bromo-α-phenylacetyl)-(L)-proline methyl ester 1 withan amine nucleophile (diphenylmethylamine or dibenzyl-amine) in the presence of tetrabutylammonium iodide (TBAI)and diisopropylethylamine (DIEA) in CH

Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans‐[18F]4‐fluoro‐l‐proline during the synthesis of cis‐[18F]4‐fluoro‐l‐proline

Fluorine‐18 labeled (2S,4S)‐4‐fluoro‐l‐proline (cis‐[18F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2S,4R)‐N‐tert‐butoxycarbonyl‐4‐(p‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis‐[18F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis‐[18F]4‐FPro or trans‐[18F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2S,4R) precursor produced a mixture of cis‐[18F]4‐FPro and trans‐[18F]4‐FPro diastereomers with cis‐[18F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C18 Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis‐[18F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis‐[18F]4‐FPro occurs during the two‐step hydrolysis (H+ followed by OH−) of the intermediate, resulting in 5 ± 3% trans‐[18F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis‐[18F]4‐FPro in the final product. Copyright © 2011 John Wiley &amp; Sons, Ltd.

Amino Acid-derived Protic Ionic Liquids: Physicochemical Properties and Behaviour as Amphiphile Self-assembly Media

The thermal phase transitions and physicochemical properties of a series of 21 amino acid-derived protic ionic liquids and four protic molten salts have been investigated. Structure–property comparisons for this series were investigated for alkyl- and cyclic amino acid cations, and ethoxy and methoxy groups on the cation, combined with nitrate or various carboxylate-containing anions. All the protic fused salts were found to be ‘fragile’. Most of the protic fused salts exhibited a glass transition, with the transition temperatures ranging from –90° to –42°C. Viscosities and conductivities ranged from 0.03 to 15.46 Pa s and 0.02 to 2.20 mS cm–1 at 25°C respectively. The protic ionic liquids alanine methyl ester glycolate, proline methyl ester nitrate, and proline methyl ester glycolate were found to be capable of supporting amphiphile self-assembly. Lamellar or hexagonal liquid crystalline phases were observed with the cationic surfactant hexadecyltrimethylammonium bromide and the non-ionic surfactant Myverol 18–99K.

A highly efficient flow reactor process for the synthesis of N-Boc-3,4-dehydro- l-proline methyl ester

The multi-step preparation of N-Boc-3,4-dehydro- l -proline methyl ester using a modular flow reactor is reported. The use of immobilised reagents and scavengers in pre-packed glass tubes allows us to obtain the pure product in 87% overall yield, 97% purity, and >98% enantiomeric excess without any additional purification step. Our flow-based protocol enables the rapid multi-gram synthesis (about 9 g/12 h) of the desired product.

The α-effect in cyclic secondary amines: new scaffolds for iminium ion accelerated transformations

Five-membered secondary amine heterocycles containing an α-heteroatom were prepared and shown to be ineffective as catalysts for the iminium ion catalysed Diels–Alder reaction between cinnamaldehyde and cyclopentadiene. Their six-membered counterparts proved to be highly active catalysts. In stark contrast, the catalytic activity observed when comparing the non α-heteroatom cyclic amines proline methyl ester and methyl pipecolinate showed the five-membered ring amine was significantly more active. Concurrent density functional theoretical calculations suggest a rationale for the observed trends in reactivity, highlighting that LUMO activation through an iminium ion intermediate plays a key role in catalytic activity.