Isocyanide‐Based Multicomponent Reaction: One‐Pot Synthesis of New Derivatives of Iminofuranone

The one‐pot multicomponent reaction of alkyl isocyanide, alkylidene‐substituted Meldrum's acid, and arylcarboxylic acids affords new derivatives of iminofuranone in fair yields. The structure of the products was deduced from their spectroscopic data. Two equivalents of the respective isocyanides participate in this reaction.     

Rapid Synthesis of Novel and Known Coumarin‐3‐carboxylic Acids Using Stannous Chloride Dihydrate under Solvent‐Free Conditions

Various coumarin‐3‐carboxylic acid (=2‐oxo‐2H‐1‐benzopyran‐3‐carboxylic acid; CcaH) derivatives have been synthesized in good yields using catalytic amounts of SnCl₂?2 H₂O under solvent‐free conditions. This inexpensive, nontoxic, and readily available catalytic system (10 mol‐%) efficiently catalyzes the Knoevenagel condensation and intramolecular cyclization of various 2‐hydroxybenzaldehydes or acetophenones with Meldrum's acid. High product yields, use of inexpensive and safe catalyst, and solvent‐free conditions display both economic and environmental advantages.     

Facile Knoevenagel and Domino Knoevenagel/Michael Reactions Using Gel‐Entrapped Base Catalysts

An efficient method for Knoevenagel condensation of arenecarbaldehydes with active methylene compounds such as barbituric acid and Meldrum's acid in the presence of gel‐entrapped base catalysts is reported. The method has been extended to the one‐pot synthesis of arylmethylene‐bis[3‐hydroxycyclohex‐2‐en‐1‐one] derivatives from dimedone (=5,5‐dimethylcyclohexane‐1,3‐dione) and arenecarbaldehydes by using domino Knoevenagel/Michael reaction sequence.     

Isocyanide‐Based Three‐Component Synthesis of Highly Substituted 1,6‐Dihydro‐6,6‐dimethylpyrazine‐2,3‐dicarbonitrile, 3,4‐Dihydrobenzo[g]quinoxalin‐2‐amine,and 3,4‐Dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine Derivatives

A novel and efficient isocyanide‐based multicomponent reaction between alkyl or aryl isocyanides 1 , 2,3‐diaminomaleonitrile ( 2 ), naphthalene‐2,3‐diamines ( 6 ) or benzene‐1,2‐diamine ( 9 ), and 3‐oxopentanedioic acid ( 3 ) or Meldrum's acid ( 4 ) or ketones 7 was developed for the ecologic synthesis, at room temperature under mild conditions, of 1,6‐dihydropyrazine‐2,3‐dicarbonitriles 5a – 5f in H₂O without using any catalyst, and of 3,4‐dihydrobenzo[g]quinoxalin‐2‐amine and 3,4‐dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine derivatives 8a – 8g and 10a – 10e , respectively, in the presence of a catalytic amount of p‐toluenesulfonic acid (TsOH) in EtOH, in good to excellent yields (Scheme 1).     

Mechanism of the Reaction of Amines with 5‐[(Aryl‐ or Alkylamino)hydroxymethylene]‐2,2‐dimethyl‐1,3‐dioxane‐4,6‐diones in the Presence of Chlorotrimethylsilane (Me3SiCl)

Addition of chlorotrimethylsilane (Me₃SiCl) to the mixture of a carbamoyl‐substituted Meldrum's acid, i.e., a 5‐[(arylamino)hydroxymethylene]‐2,2‐dimethyl‐1,3‐dioxane‐4,6‐dione of type 1 and a secondary amine as nucleophile strongly accelerated the rate of their reaction. The reason for this phenomenon observed, during our previous research, remained, however, unclear. To elucidate the mechanism of this reaction, we assumed and verified three possible pathways for the action of Me₃SiCl (cf. Scheme 2): The acceleration of the reaction is caused i) by formation of a O‐trimethylsilylated Meldrum's acid of type 2 , ii) by the silylated amine 3 , or iii) by the presence of HCl liberated from Me₃SiCl. The performed experiments revealed that the faster course of reaction is caused by the formation of N‐trimethylsilylated amines of type 3 .     

Synthesis of a New Library of Pyrano‐phenazine Derivatives via a Novel Three‐Component Protocol

The pyrano‐phenazine derivatives 6 were synthesized by an efficient procedure using the reaction between benzo[a]phenacin‐5‐ols with the condensation product of an aldehyde with Meldrum's acid in the presence of a catalytic amount of Et₃N at ambient temperature. The procedure is very simple, and products could be separated from the reaction media by simple filtration. High functional‐group tolerance both in the benzo[a]phenazin‐5‐ol and aldehyde moieties, facile reaction procedure, medium‐to‐high yields, and simple separation of the products from the reaction media are the advantages of this route.     

Thioalkylation of Meldrum's Acid: Protected alkylidene derivatives of isopropylidene malonate

Thioalkylated Meldrum's acid is easily by treatment of Meldrum's acid with an aldehyde and thiophenol in the presence of catalytical amounts of piperidinium acetate (→ 1–6 , Table 1). The adducts 1–6 are crystalline, stable compounds and they can be caused to react directly with nucleophiles and dienes (see 3→7–12 , Scheme 1). The regeneration of the parent olefin is effected thereby by simply dissolving the adduct under neutral or basic conditions. Extension of this method to thiocarboxylic acids allowed the preparation of the corresponding formaldehyde derivatives 13 and 15 (Table 3).     

Improved treatment of cyclic β‐amino acids and successful prediction of β‐peptide secondary structure using a modified force field: AMBER*C

We added parameters to the AMBER* force field to model cyclic β‐amino acid derivatives more accurately within the commonly used MacroModel program. In an effort to generate an improved treatment of cyclohexane and cyclopentane conformational preferences, carbon–carbon torsional parameters were modified and incorporated into a force field we call AMBER*C. Simulation of trans‐2‐aminocyclohexanecarboxylic acid (trans‐ACHC) and trans‐2‐aminocyclopentanecarboxylic acid (trans‐ACPC) derivatives using AMBER*C produces more realistic energy differences between (pseudo)diaxial and (pseudo)diequatorial conformations than does simulation using AMBER*. AMBER*C molecular dynamics simulations more accurately reproduce the experimental hydrogen‐bonding tendencies of simple diamide derivatives of trans‐ACHC and trans‐ACPC than do simulations using the AMBER* force field. More importantly, this modified force field allows accurate qualitative prediction of the helical secondary structures adopted by β‐amino acid homo‐oligomers. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 763–773, 2000     

Chromatographic Resolution of α‐Amino Acids by (R)‐(3,3'‐Halogen Substituted‐1,1'‐binaphthyl)‐20‐crown‐6 Stationary Phase in HPLC

Three new chiral stationary phases (CSPs ) for high‐performance liquid chromatography were prepared from R ‐(3,3'‐halogen substituted‐1,1'‐binaphthyl)‐20‐crown‐6 (halogen = Cl, Br and I). The experimental results showed that R ‐(3,3'‐dibromo‐1,1'‐binaphthyl)‐20‐crown‐6 ( CSP ‐1 ) possesses more prominent enantioselectivity than the two other halogen‐substituted crown ether derivatives. All twenty‐one α ‐amino acids have different degrees of separation on R ‐(3,3'‐dibromo‐1,1'‐binaphthyl)‐20‐crown‐6‐based CSP ‐1 at room temperature. The enantioselectivity of CSP ‐1 is also better than those of some commercial R ‐(1,1'‐binaphthyl)‐20‐crown‐6 derivatives. Both the separation factors (α ) and the resolution (R _s) are better than those of commercial crown ether‐based CSPs [CROWNPAK CR (+) from Daicel] under the same conditions for asparagine, threonine, proline, arginine, serine, histidine and valine, which cannot be separated by commercial CR (+). This study proves the commercial usefulness of the R ‐(3,3'‐dibromo‐1,1'‐binaphthyl)‐20‐crown‐6 chiral stationary phase.     

Lewis Acid‐Mediated Addition of Amino Acid‐Substituted α‐Allylsilanes to Aromatic Acetals

Unnatural amino acids extend the pharmacological formulator's toolkit. Strategies to prepare unnatural amino acid derivatives using Lewis acid‐activated allylsilane reactions are few. In this regard, we examined the utility of allylsilanes bearing an amino acid substituent in the reaction. Diastereoselective addition of methyl 2‐(N‐PG‐amino)‐3‐(trimethylsilyl)pent‐4‐enoate and methyl (E)‐2‐(N‐PG‐amino)‐3‐(trimethylsilyl)hex‐4‐enoate (PG=protecting group), 2 and 13 , respectively, to aromatic acetals in the presence of Lewis acids is described. Of those examined, TiCl₄ was found to be the most effective Lewis acid for promoting the addition. At least 1 equiv. of TiCl₄ was required to achieve high yields, whereas 2 equiv. of BF₃?OEt₂ were required for comparable outcomes. Excellent selectivity (>99% syn/anti) and high yield (up to 89%) were obtained with halo‐substituted aromatic acetals, while more electron‐rich electrophiles led to both lower yields and diastereoselectivities.     

Rhodium(II)‐Catalyzed Inter‐ and Intramolecular Cyclopropanations with Diazo Compounds and Phenyliodonium Ylides: Synthesis and Chiral Analysis

Different classes of cyclopropanes derived from Meldrum's acid (=2,2‐dimethyl‐1,3‐dioxane‐4,6‐dione; 4 ), dimethyl malonate ( 5 ), 2‐diazo‐3‐(silyloxy)but‐3‐enoate 16 , 2‐diazo‐3,3,3‐trifluoropropanoate 18 , diazo(triethylsilyl)acetate 24a , and diazo(dimethylphenylsilyl)acetate 24b were prepared via dirhodium(II)‐catalyzed intermolecular cyclopropanation of a set of olefins 3 (Schemes 1 and 4–6). The reactions proceeded with either diazo‐free phenyliodonium ylides or diazo compounds affording the desired cyclopropane derivatives in either racemic or enantiomer‐enriched forms. The intramolecular cyclopropanation of allyl diazo(triethylsilyl)acetates 28, 30 , and 33 were carried out in the presence of the chiral dirhodium(II) catalyst [Rh₂{(S)‐nttl)₄}] ( 9 ) in toluene to afford the corresponding cyclopropane derivatives 29, 31 and 34 with up to 37% ee (Scheme 7). An efficient enantioselective chiral separation method based on enantioselective GC and HPLC was developed. The method provides information about the chemical yields of the cyclopropane derivatives, enantioselectivity, substrate specifity, and catalytic activity of the chiral catalysts used in the inter‐ and intramolecular cyclopropanation reactions and avoids time‐consuming workup procedures.     

Synthesis of reactive three‐arm star‐shaped oligoimides with narrow molecular weight distribution

Series of star‐shaped three arms oligoimides (SOI) with terminal amino groups with narrow MWD ((M_w/M_n = 1.1–2) was synthesized by the one‐stage high‐temperature polycondensation in molten benzoic acid at 140 °C. The (B3+AB′) approach with the “slow addition of monomer” method was used for this synthesis, where B3 is 2,4,6‐tris(4‐aminophenoxy)toluene and AB′ is 3‐aminophenoxy phthalic acid. The SOI arm's length was controlled by the AB′/B3 mole ratio of 10:1, 20:1, 40:1, and 100:1. By the reaction of SOI's terminal amino groups with acetic anhydride, corresponding acetamide derivatives were obtained. SOI synthesized are soluble in selected organic solvents. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2004–2009     

5-Arylidene Derivatives of <Emphasis Type="Italic">Meldrum</Emphasis>’s Acid as Synthons in Pyrano[4,3-<Emphasis Type="Italic">b</Emphasis>]pyran Synthesis

Summary. The reactions of 5-arylidene derivatives of Meldrum’s acid with ethyl vinyl ether or N-vinyl-2-oxazolidinone yielded trans-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, cis-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, or diastereoisomeric mixtures of pyrano[4,3-b]pyrans and reactions with 3,4-dihydro-2H-pyran afforded Michael adducts. The reactions of 5-arylidene derivatives of Meldrum’s acid with cyanoacetic acid derivatives do not provide appropriate pyrans.     

Asymmetric and Geometry‐Selective α‐Alkenylation of α‐Amino Acids

Both E‐ and Z‐N′‐alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α‐amino acids. Generation of their enolate derivatives in the presence of K⁺ and [18]crown‐6 induces intramolecular migration of the alkenyl group from N′ to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α‐alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

Synthesis and Crystal Structure of Peptide‐2,2′‐Biphenyl Hybrids

1,1′‐Biphenyl derivatives with amino acid/peptide substitution at C(2) and C(2′) (‘peptide‐biphenyl hybrids', 6 – 8 ) have been prepared by direct N‐acylation of amino acid/peptide derivatives with 1,1′‐biphenyl‐2,2′‐dicarbonyl dichloride ( 5 ). Both conformers, which arise from the rotation around the aryl aryl bond, have been detected by ¹H‐NMR spectroscopy. Single atropisomers of each 6 ((R)‐configuration at the stereogenic axis) and 7 ((S)‐configuration at the stereogenic axis) have been obtained in quantitative yield by slow evaporation of methanolic solutions. The procedures are dynamic atropselective resolutions (asymmetric transformations of the second kind). The crystal structures of the peptide‐biphenyl hybrids 6 and 7 show highly ordered molecular and supramolecular structures with extensive intramolecular and intermolecular H‐bonding.     

Synthesis of N,N‐Dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides via the Reaction of (2‐Halophenyl)(2‐isothiocyanatophenyl)methanones with Secondary Amines,Followed by Cyclization with NaH

The first preparation of acridin‐9(10H)‐ones carrying a tertiary thiocarbamoyl group at C(10), i.e., N,N‐dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides 9 , is described. The method is based on the reaction of (2‐halophenyl)(2‐isothiocyanatophenyl)methanones 7 , prepared from (2‐aminophenyl)(2‐halophenyl)methanones 5 by a convenient three‐step sequence, with secondary amines in DMF at room temperature to generate the corresponding thiourea derivatives 8 in situ, which are treated with NaH at 100–120° to provide the desired products in one‐pot reactions in generally good yields.     

Nucleo‐β‐Amino Acids: Synthesis and Oligomerization to β‐Homoalanyl‐PNA

The synthesis of thyminyl‐, uracilyl‐, cytosinyl‐, and guaninyl‐β³‐amino acids and the oligomerization of the cytosinyl‐ and guaninyl‐β³‐amino acids to β‐homoalanyl‐PNA are presented. The pyrimidinyl nucleobases were connected to the γ‐position of β‐homoalanine by Mitsunobu reaction with a β‐homoserine derivative or by nucleophilic substitution of methanesulfonates. For the preparation of the guaninyl‐β³‐amino acid, a β‐lactam route was established that might be of interest also for the synthesis of other β³‐amino acid derivatives. The cytosinyl and guaninyl building blocks were oligomerized to hexamers. They form quite stable self‐pairing complexes in H₂O as indicated by temperature dependent UV and CD spectroscopy.     

Effective Methods for the Synthesis of N‐Methyl β‐Amino Acids from All Twenty Common α‐Amino Acids Using 1,3‐Oxazolidin‐5‐ones and 1,3‐Oxazinan‐6‐ones

N‐Methyl β‐amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3‐oxazolidin‐5‐ones to synthesise N‐methyl α‐amino acids. Starting from α‐amino acids, two approaches were used to prepare the corresponding N‐methyl β‐amino acids. First, α‐amino acids were converted to N‐methyl α‐amino acids by the so‐called ‘1,3‐oxazolidin‐5‐one strategy’, and these were then homologated by the Arndt–Eistert procedure to afford N‐protected N‐methyl β‐amino acids derived from the 20 common α‐amino acids. These compounds were prepared in yields of 23–57% (relative to N‐methyl α‐amino acid). In a second approach, twelve N‐protected α‐amino acids could be directly homologated by the Arndt–Eistert procedure, and the resulting β‐amino acids were converted to the 1,3‐oxazinan‐6‐ones in 30–45% yield. Finally, reductive cleavage afforded the desired N‐methyl β‐amino acids in 41–63% yield. One sterically congested β‐amino acid, 3‐methyl‐3‐aminobutanoic acid, did give a high yield (95%) of the 1,3‐oxazinan‐6‐one ( 65 ), and subsequent reductive cleavage gave the corresponding AIBN‐derived N‐methyl β‐amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N‐methyl β‐amino acids derived from the 20 proteinogenic α‐amino acids.