Anchoring of Fmoc-amino acids to hydroxymethyl resins

A method to anchor Fmoc-amino acids to p-alkoxybenzyl ester resins without using DMAP is described. Esterification takes place with 3–4 equiv. of Fmoc-amino acid plus DCC and a slightly lower excess of HOBt in good yields, without racemization or dipeptide formation. Addition of N-methylmorpholine to the reaction medium enhances the reaction yield but is accompanied by a small amount of racemization and dipeptide formation. Coupling via Fmoc-amino acid chlorides has also been evaluated.     

Untersuchungen an 1,3-Thiazinen, 26. Mitt. Neuartige N-Carbamoyl- und Thiocarbamoyl-2-thioxo-1,3-thiazinderivate

1,3-Thiazines, XXVI: Novel N-Carbamoyl- and Thiocarbamoyl-2-thioxo-1,3-thiazine Derivatives The N-unsubstituted 1,3-thiazine derivatives 1–3 were transformed into the N-carbamoyl- or N-thiocarbamoyl-1,3-thiazine derivatives 5–9 by carbamic acid chlorides or thiocarbamic acid chlorides in the presence of triethylamine or sodium hydride.     

1,5-Benzodiazepine, 1. Mitt.: Racemate und Enantiomere von 3,3-Dialkyl-1,5-benzodiazepin-2,4-dionen: Synthese,Konfiguration und enantiomere Reinheit

1,5-Benzodiazepines, I: Racemates und Enantiomers of 3,3-Dialkyl-1,5-benzodiazepine-2,4-diones: Synthesis, Configuration, and Enantiomeric Purity The syntheses of the rac. and the enantiomeric 3,3-dialkyl-1,5-benzodiazepine-2,4-diones 1 - 3 were performed as shown in Scheme 5, starting from 4- resp. 5-chloro-2-nitro-N-methylaniline ( 10/11 ) and the rac. or enantiomeric dialkylcyanoacetic acid chlorides 6a/6b . The enantiomers of ethylmethylcyanoacetic acid ( 5a ) are known. From butylmethylcyanoacetic acid ( 5b ) the (S)-(-)-enantiomer was obtained using codeine as resolving agent. By ring closure of 14/15 the benzodiazepines 16/17 were obtained, but the main products were the benzimidazoles 18/19 . The yield of 16/17 could be increased to 62–80 % when the conditions of the reaction were modified. The N-phenylation of 16/17 according to a modified Ullmann reaction gave the rac. and the enantiomeric 1,5-benzodiazepines 1 - 3 in high yields. - The absol. configurations of the new enantiomeric compounds are compiled in Tab. 1. The enantiomeric purities (e/e) of the 1,5-benzodiazepines 1 und 3 and of all intermediates are > 95 %. The enantiomeric purities of (R)-(-)-2 and the corresponding intermediates were not determined.     

Synthesis of some biologically active substituted thiazole and thiazoline-amino acid derivatives

Synthesis of a series of N-(2-acetylaminothiazole-5-sulphonyl) amino acids (II–VI) and some of their corresponding methyl esters (VII–XI) is described. Coupling of N-tosyl- or N-phthalylamino acid with 2-amino-2-thiazoline using the DCC method furnishes 2-(N-tosyl- or N-phthalylamino acyl)amino-2-thiazolines (XII–XXI). Hydrazinolysis of 2-(N-Pht-L-Phe or N-Pht-L-Ala)amino-2-thiazoline in ethanol afforded 2-(L-Phe or L-Ala) amino-2-thiazoline (XXII and XXIII) respectively. Synthesis of the dipeptide 2-(N-Tos-L-Val-L-Leu) amino-2-thiazoline (XXIV) has been achieved employing the azide method. Sixteen thiazole- and thiazoline-amino acid derivatives were found to be active against a number of microorganisms.     

Cer(IV)-Oxidationen von β-Aminoketonen. 3. Mitt.: Ein Syntheseweg zu 4-spirosubstituierten 1,2,3,4-Tetrahydroisochinolinen

Cerium(IV) Oxidations of β-Aminoketones. Part III: A Pathway to 4-Spiro-Substituted 1,2,3,4-Tetrahydroisoquinolines Substituted 2′-methyl-2′,3′-dihydro-1′H-spiro[cycloalkan-1,4′-isoquinolin]-2-ones and -[chroman-3,4′-isoquinolin]-4-ones are synthesized by cerium(IV) oxidation of (N-benzyl-N-methylamino)methylcycloalkan-1-ones or corresponding substituted chromanones.     

Use of Fmoc-N-(2-hydroxy-4-methoxybenzyl) amino acids in peptide synthesis

The use of N, O-bisFmoc-N-(2-hydroxy-4-methoxybenzyl) amino acid derivatives in the synthesis of peptides with difficult sequences has already been described. With these amino acid derivatives the reversible protecting group 2-hydroxy-4-methoxybenzyl (Hmb) for the backbone amide bonds of peptide chains is introduced, and thus the aggregation due to hydrogen-bond interchain association is inhibited. This paper describes the synthesis and use of Fmoc-N-(2-hydroxy-4-methoxybenzyl)amino acid derivatives as an alternative means of introducing Hmb backbone protection. These new monoFmoc derivatives were obtained in higher yield than the bisFmoc derivatives. Coupling yields to the amino peptide resin were the same as those obtained with bisFmoc derivatives, under the TBTU/HOBt/DIEA conditions. We also compared different syntheses of a difficult peptide with the Fmoc approach [triple coupling, capping, use of chaotropic agents, backbone protection using monoFmoc (Hmb)Ala] and with optimized Boc chemistry. Both the backbone protection and optimized Boc chemistry approaches gave the desired product in excellent yield and purity. © Munksgaard 1997.     

Synthesis of N-carboxyalkyl and N-aminoalkyl functionalized dipeptide building units for the assembly of backbone cyclic peptides

Abstract: To improve the assembly of backbone cyclic peptides, N-functionalized dipeptide building units were synthesized. The corresponding N-aminoalkyl or N-carboxyalkyl amino acids were formed by alkylation or reductive alkylation of amino acid benzyl or tert-butyl esters. In the case of N-aminoalkyl amino acid derivatives the aldehydes for reductive alkylation were obtained from N,O-dimethyl hydroxamates of N-protected amino acids by reduction with LiAlH₄. N-carboxymethyl amino acids were synthesized by alkylation using bromoacetic acid ester and the N-carboxyethyl amino acids via reductive alkylation using aldehydes derived from formyl Meldrums acid. Removal of the carboxy protecting group leads to free N-alkyl amino acids of very low solubility in organic solvents, allowing efficient purification by extraction of the crude product. These N-alkyl amino acids were converted to their tetramethylsilane-esters by silylation with N,O-bis-(trimethylsilyl)acetamide and could thus be used for the coupling with Fmoc-protected amino acid chlorides or fluorides. To avoid racemization the tert-butyl esters of N-alkyl amino acids were coupled with the Fmoc-amino acid halides in the presence of the weak base collidine. Both theN-aminoalkyl and N-carboxyalkyl functionalized dipeptide building units could be obtained in good yield and purity. For peptide assembly on the solid support, the allyl type protection of the branching moiety turned out to be most suitable. The Fmoc-protected N-functionalized dipeptide units can be used like any amino acid derivative under the standard conditions for Fmoc-solid phase synthesis.     

Antimykotische Wirkstoffe, 20. Mitt.: Bioisostere 6-Arylpyrimidin-Derivate

Antimycotic Agents, XX Bioisosteric 6-Arylpyrimidine Derivatives Condensation of N-(2-hydroxyethyl)-N-methylguanidine-sulfate ( 1 ) with the β-diketones 4a - e bearing 1-aryl substituents leads to the bioisosteric 2-[(2-hydroxyethyl)-methylamino]-6-arylpyrimidines 5a - e . Compounds 5a - c exhibit significant antimycotic in vivo and in vitro activities.     

Untersuchungen an 1,3-Thiazinen, 37. Mitt. Umsetzungen NH-acider Tetrahydro-1,3-thiazinderivate mit Sulfensäure- und Sulfonsäurechloriden

Investigations on 1.3-Thiazines, XXXVII; Reactions of NH-acidic Tetrahydro-1.3-thiazine Derivatives with Sulfenic and Sulfonic Acid Chlorides N-sulfenyl derivatives were obtained from 5,6-dihydro-2H-1,3-thiazine-2.4(3H)-diones 1 and sulfenic acid chlorides in the presence of triethylamine or from the sodium salts of 1, 3. 2-Thioxo-tetrahydro-4H-1,3-thiazine-4-ones 4 were on the other hand sulfenylated at sulfur to 5 which was easily cleaved hydrolytically to 1 . N-Sulfonylation was only achieved with methane sulfonyl chloride to yield 13.     

Über 3H-1,4-Benzodiazepine mit semicyclischer Hydroxyamidin-Struktur und deren oxidoreduktive 1,3-Umlagerung zu 2-Alkylamino-3-acyloxy-3H-1,4-benzodiazepinen

The Oxidoreductive 1,3-Rearrangement of 3H-1,4-Benzodiazepines with Semicyclic Hydroxyamidine Structure to 2-Alkylamino-3-acyloxy-3H-1,4-benzodiazepines On treatment of N-alkyl-N-(3H-1,4-benzodiazepin-2-yl)-hydroxylamines with carboxylic anhydrides or chlorides an oxidoreductive rearrangement is observed in the presence of protons that leads to 1,4-benzodiazepines bearing the acylated hydroxylaminic oxygen at position 3. When the acylation is carried out with derivatives of carbonic acid decarboxylation takes place in the course of the rearrangement in some cases.     

Über Umsetzungsprodukte von N-(Diphenylmethylen)aminomethanol

Reaction Products of N-(Diphenylmethylene)aminomethanol The lithium compound 4 of N-(diphenylmethylene)aminomethanol (2) has been converted with aliphatic acid chlorides, α-haloethers and chloro(trimethyl)silane into the substitution products 5, 10 and 11 . With nucleophiles such as sodium methanolate, 2-methyl-1,3-indanedione-sodium or sodium cyanide the acetoxy derivative 5a reacts presumably via a 1,1-diphenyl-2-azaallenium cation to yield 7 , 8 or 9 with newly formed N-O, C-C and N-C bonds.     

Untersuchungen an 1,3-Thiazinen, 42. Mitt.: Carbazoylierungen und Thiocarbazoylierungen von 2-Thioxo-tetrahydro-1,3-thiazin-Derivaten

Investigations on 1,3-Thlazines, XLII¹⁾: Carbazoylations and Thiocarbazoylations of 2-Thioxo-tetrahydro-1,3-thiazine Derivatives⁺⁾ Carbazic acid chlorides react with 2-thioxo-tetrahydro-1,3-thiazines 6 and 7 yielding N-Carbazoyl-thiazine derivatives 9 and 11 . Thiocarbazic acid chlorides attack under kinetic control at the 2-thioxo sulfur yielding S-substitution products 10 and 12 , which can thermally be rearranged intramolecularly to the more stable N-substituted products 9 and 11 .     

Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and tremor in mouse models of essential tremor

NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride], is a mibefradil derivative that retains potent in vitro T-type calcium channel antagonist efficacy. We compared the two compounds for behavioral toxicity, effects on cytochrome P450 activity, and efficacy against tremor in the γ-aminobutyric acid type A (GABA_A) receptor subunit α1-null mouse, and the harmaline tremor model of essential tremor in wild-type mice. NNC 55-0396 was better tolerated than mibefradil in the horizontal wire test of sedation/motor function, with 3/6 failing at 300 and 30 mg/kg respectively. To assess for a potential interaction with harmaline, mice were given the drugs, followed by harmaline or vehicle, and tested 30 min later in the inverted wire grid test. Mibefradil exacerbated, whereas NNC 55-0396 ameliorated harmaline-induced test deficits. In mouse liver microsomes, NNC 55-0396 was a less potent inhibitor of harmaline O-demethylation than mibefradil (K_i: 0.95 and 0.29 μM respectively), and also less potent at inhibiting testosterone 6-β-hydroxylation (K_i: 0.71 and 0.12 μM respectively). In the GABA_A α1-null model, NNC 55-0396 but not mibefradil, (each at 20 mg/kg), suppressed tremor while NNC 55-0396 at 12.5 mg/kg suppressed harmaline-induced tremor by half by 20–100 min, whereas mibefradil at the same dose did not significantly affect tremor. In contrast to mibefradil, NNC 55-0396 is well tolerated and suppresses tremor, and exerts less cytochrome P450 inhibition. These results suggest potential clinical utility for NNC 55-0396 or similar derivatives as a T-type calcium antagonist.     

Untersuchungen an 1,3-Thiazinen, 38. Mitt.: Iminiumkohlensäurederivat-Salze, 2. Mitt.: Synthese N-substituierter 2-Chlor-5,6-dihydro-4H-1,3-thiazinium-salze und deren Reaktionen mit primären Aminoverbindungen

Synthesis of N-Substituted 2-Chloro-5,6-dihydro-4H-1,3-thiazinium Salts and Their Reactions with Primary Amino Compounds After a short review of synthesis and reactions of halogeno(organothio)methaniminiumsalts, the reactions of tetrahydro-1,3-thiazine-2-thiones 9 with thionyl chloride or phosgene to yield 2-chloro-5,6-dihydro-4H-1,3-thiazinium chlorides 10 are described. Compounds 10 can be converted to the more stable tetrafluoroborates 13 and hexafluorophosphates 12 , which can be conveniently characterized. Chloroiminium chlorides 10 generated in situ, react with primary amino compounds such as aliphatic or aromatic amines, carboxamides, sulfonamides, diphenylphosphinamide, cyanamide or N-substituted ureas to yield the N,N′-disubstituted 2-iminotetrahydro-1,3-thiazines 17 – 24 .     

Contribution to the synthesis of aureobasidin A. Synthesis of cyclopeptolides containing the sequence leucyl-N-methyl-β-hydroxyvalyl- (2R)-oxy-(3R)-methyl-pentanoic acid *

The efficient antimycotic agent aureobasidin A, isolated from the culture broth of Aureobasidium pullulans R 106, and the [(R)-Pro⁹]-aureobasidin A were prepared starting from benzyl N-Boc-N-methyl-(S)-β-triethylsiloxyvalinate, the synthesis of which is described here. The easy accessibility of the tripeptolide benzyl Boc-leucyl-N-methyl-β-hydroxyvalyl-(2R)-oxy-(3R)-methylpentanoate [Boc-Leu-HOMeVal-(R)-HMP-OBn] facilitates the construction of the cyclopeptolides 28, 34, 45 and 47. The peptide bonds of the N-methylamino acids were formed with the help of O-(7-azabenzotria-zol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophophate. The rings of [(R)-Pro⁹]-aureobasidin A and of cyclopeptolides 28, 34, 45 and 47 were closed by way of pentafluorophenyl esters. The ring of aureobasidin A could only be formed with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate.     

Untersuchungen an 1,3-Thiazinen, 25. Mitt. Transacylierende N-Acyl-tetrahydro- und N-Acyl-dihydro-1,3-thiazin-derivate

1,3-Thiazines, XXV: Transacylating Derivatives of N-Acyltetrahydro- and N-Acyldihydro-1,3-thiazine Novel N-acyl-2-thioxo-3,4-dihydro-1,3-thiazine-4-ones 4 and N-acyl-tetrahydro-1,3-thiazine-2,4-diones 7 were preparee by acylation of the N-unsubstituted 1,3-thiazine derivatives 3 and 6 with acid chlorides. Their characteristics are compared with those of known N-acylthiazine derivatives.     

Carbazoylierungen und Thiocarbazoylierungen von 2-Thioxo-thiazolidinen

Carbazoylations and Thiocarbazoylations of 2-Thioxo-thiazolidines¹⁾ Reactions of thiazolidine-2-thione (1) with carbazic and thiocarbazic acid chlorides 5 lead to S-substitution products 6 which only in case of the carb-azoic derivatives can be thermally rearranged to N-carbazoyl derivatives 7. Not rearrangeable heteroaromatic thiazoles 9 are obtained from 5 and 5-methylen-thiazolidine-2-thione (8). Thiazolidine-2,4-dione (10) only yields N-substitution products 11.     

Absorption,Excretion and Metabolism of a New Dihydropyridine Diester Cerebral Vasodilator in Rats and Dogs

1. After oral administration of [¹⁴C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0·5 to 1?h and decreasing with a half life of about 3·5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration.

2. In both species, 66–72% of radioactivity was excreted in faeces and 23–29% in urine in 48?h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%.

3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.     

Regioselektive Kondensationen sowie N-Acylierungen an 3-Aminorhodaninen

Regioselective Condensations and N-Acylations of 3-Aminorhodanines 3-Aminorhodanines were condensed regioselectively with aldehydes at the 3-amino or 5-methylene group. The 3-amino function was acylated with acid chlorides or anhydrides.     

Preparation of [18F]‐N‐(2‐fluoro‐ethyl)‐N‐methylamine as a building block for PET radiopharmaceuticals

We have investigated the use of cyclic sulfamidates as precursors to yield secondary amines as building blocks for subsequent reaction with carboxylic acids and acyl chlorides. The preparation of the protonated form of [¹⁸F]‐N‐(2‐fluoro‐ethyl)‐N‐methylamine from the corresponding cyclic sulfamidate proceeded within a one pot two‐step procedure (81 ± 12%, n = 10). The secondary amine reacted readily with acyl chlorides and/or carboxylic acids giving amides with yields ranging from 4 to 17% at the end of synthesis (182 ± 12 min). The new methodology provides a practical approach for the labelling of molecules where intramolecular cyclisation of precursors is favoured under typical radiofluorination conditions.