Showing papers on "Piperidine published in 2009"

Solid-phase peptide synthesis using mild base cleavage of N alpha-fluorenylmethyloxycarbonylamino acids, exemplified by a synthesis of dihydrosomatostatin.

Abstract: N alpha-9-Fluorenylmethyloxycarbonyl (Fmoc) amino acids will be of advantage in solid phase peptide synthesis. The Fmoc-group is quantitatively cleaved by mild base (piperidine). This permits the use of tert-butyl-type side chain blocking and of peptide-to-resin linkage cleavable by mild acidolysis. Side reactions arising from repetitive acid deprotection and final HF cleavage in contemporary solid phase synthesis are avoided. Fully bioactive and homogeneous dihydrosomatostatin was obtained in 53% overall yield.

Solid phase synthesis without repetitive acidolysis. Preparation of leucyl-alanyl-glycyl-valine using 9-fluorenylmethyloxycarbonylamino acids.

Abstract: The utility of repetitive nonhydrolytic base cleavage of alpha-amino protective groups in solid phase peptide synthesis is shown by a preparation of the model tetrapeptide leucyl-alanyl-glycyl-valine on a p-benzyloxybenzyl ester polystyrene--1% divinylbenzene resin support. Nalpha-9-Fluorenylmethyloxycarbonyl (Fmoc: Carpino & Han, 1970, 1972) amino acids were coupled by the symmetrical anhydride procedure, followed by Fmoc group cleavage using 50% piperidine in methylene chloride. Quantitative removal of the Fmoc-tetrapeptide from the solid support was effected by treatment with 55% trifluoroacetic acid in methylene chloride. Homogeneous free tetrapeptide was obtained in 87% overall yield. The procedure is proposed to offer advantages over present solid phase methods which use acidolysis for repetitive alpha-amino group deblocking.

Direct Amide Synthesis from Alcohols and Amines by Phosphine‐Free Ruthenium Catalyst Systems

Abstract: Amides are synthesized directly from alcohols and amines in high yields using an in situ generated catalyst from easily available ruthenium complexes such as the (p-cymene)ruthenium dichloride dimer, [Ru(p-cymeme)Cl 2 ] 2 , or the (benzene)ruthenium dichloride dimer, [Ru(benzene)Cl 2 ] 2 , an N-heterocyclic carbene (NHC) ligand, and a nitrogen containing L-type ligand such as acetonitrile. The phosphine-free catalyst systems showed improved or comparable activity compared to previous phosphine-based catalytic systems. The in situ generated catalyst from [Ru(benzene)Cl 2 ] 2 , an NHC ligand, and acetonitrile showed excellent activity toward reactions with cyclic secondary amines such as piperidine and morpholine.

Selective Functionalization of sp3 C−H Bonds Adjacent to Nitrogen Using (Diacetoxyiodo)benzene (DIB)

Abstract: A PhI(OAc)(2) mediated selective functionalization of sp(3) C-H bonds adjacent to a nitrogen atom has been reported. When piperidine derivates were used, direct diacetoxylation of alpha and beta sp(3) C-H adjacent to a nitrogen atom were observed to afford various cis-2,3-diacetoxylated piperidines. On the other hand, tetrahydroisoquinoline derivatives gave various alpha-C-H functionalized products in the presence of PhI(OAc)(2). Nitroalkanes, dialkyl malonates, and beta-keto ester are active participants in this coupling reaction. Meanwhile, alpha-amino nitriles can also be obtained by oxidative coupling of amines with malononitrile.

Pd(0)/Cu(I)-mediated direct arylation of 2'-deoxyadenosines: mechanistic role of Cu(I) and reactivity comparisons with related purine nucleosides.

Abstract: Pd/Cu-mediated direct arylation of 2′-deoxyadenosine with various aryl iodides provides 8-arylated 2′-deoxyadenosine derivatives in good yields. Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)2[(CH2)5NH]2. Various copper(I) salts have been evaluated; only CuI provides good yields of the 8-arylated-2′-deoxyadenosines. Copper(I) appears to have a high binding affinity for 2′-deoxyadenosine, which explains the mandatory requirement for stoichiometric amounts of this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(I). In each case, no de...

Asymmetric Hydrogenation of Quinoxalines Catalyzed by Iridium/PipPhos

Abstract: A catalyst made in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl](2), and the monodentate phosphoramidite ligand (S)-PipPhos was used in the enantioselective hydrogenation of 2- and 2,6-substituted quinoxalines. In the presence of piperidine hydrochloride as additive full conversions and enantioselectivities of up to 96% are obtained.

Aminolysis of X-substituted phenyl diphenylphosphinates: effect of amine nature on reactivity and transition-state structure.

Abstract: A kinetic study is reported for aminolysis of X-substituted phenyl diphenylphosphinates (1a-i) in 80 mol % H(2)O/20 mol % dimethyl sulfoxide at 25.0 +/- 0.1 degrees C. The Bronsted-type plot for the reactions of 2,4-dinitrophenyl diphenylphosphinate (1a) with primary amines is linear with beta(nuc) = 0.53. The reactions of 1a-i with ethylamine also result in a linear Bronsted-type plot with beta(lg) = -0.81. These beta(nuc) and beta(lg) values are slightly larger than those reported previously for the reactions of 1a with secondary amines (beta(nuc) = 0.38) and for those of 1a-i with piperidine (beta(lg) = -0.66) but typical for reactions that proceed through a concerted mechanism. It has been concluded that aminolysis of 1a-i proceed through a concerted mechanism and the nature of amines does not affect the reaction mechanism. However, the reactions with primary amines have been suggested to proceed through a later transition state (i.e., more bond formation and bond rupture in the transition state) on the basis of the larger beta(nuc) and beta(lg) values. The concerted mechanism has been further supported from the fact that the Yukawa-Tsuno plot for the reactions of 1a-i with ethylamine exhibits an excellent linear correlation with rho = 2.24 and r = 0.22. Weakly basic primary amines are less reactive than secondary amines of similar basicity. However, strongly basic ethylamine is ca. 2-fold more reactive than piperidine toward 1a, although the former is 0.35 pK(a) units less basic than the latter.

SOLID‐PHASE PEPTIDE SYNTHESIS OF SOMATOSTATIN USING MILD BASE CLEAVAGE OF Nα‐9‐ FLUORENYLMETHYLOXYCARBONYLAMINO ACIDS

Abstract: Experimental details for the "Fmoc solid phase peptide synthesis" of somatostatin are described. The 9-fluorenylmethyloxycarbonyl group was rapidly and quantitatively cleaved by 55% piperidine in dimethylformamide and monitored (u.v.) manually. For a kinetic study, a centrifugal reactor with a photometric control system and reference cell was used at each stage. The symmetrical anhydride coupling reaction was rapid and either acetic anhydride or fluorescamine termination was incorporated to minimize formation of deletion peptides. Anchor-bond cleavage was effected with trifluoroacetic acid which simultaneously removed all the acid labile tert.-butyl side chain protecting groups. N alpha-9-fluorenylmethyloxycarbonyl peptides may be obtained by omitting the piperidine deprotection step after the last cycle of synthesis. From several syntheses, analytically pure di-S-protected somatostatin 14-peptide was obtained in 55-60% overall yield. The S-protecting groups were removed and the product was purified by gel filtration to give homogeneous dihydrosomatostatin (91%) yield. Oxidation of dihydrosomatostatin with potassium ferricyanide and purification by countercurrent distribution provided analytically pure homogeneous somatostatin.

Exploring catalyst and solvent effects in the multicomponent synthesis of pyridine-3,5-dicarbonitriles.

Abstract: The effects of an ionic base, tetrabutylammonium hydroxide (TBAH), and an amine base, piperidine, on the direct synthesis of pyridine-3,5-dicarbonitriles using a multicomponent reaction (MCR) from aldehydes, malononitrile, and thiols were systematically investigated. The amine base showed better results when the MCR was performed in ethanol, whereas employing the ionic base in acetonitrile resulted in similar yields but in a much shorter reaction time. A modified protocol to overcome the difficulty in the direct synthesis of pyridine-3,5-dicarbonitriles via the MCR from sterically hindered aldehydes using either base was realized by changing the reaction solvent from ethanol to acetonitrile. Mechanistically, the two catalysts were found to each promote different pathways in the final oxidation step of the penultimate product, 1,4-dihydropyridine 6. A reaction intermediate, Knoevenagel adduct 7, plays the major role in the amine base-catalyzed system, while in the presence of an ionic base, aerobic oxygen ...

An alternative CuCl–piperidine-catalyzed oxidative homocoupling of terminal alkynes affording 1,3-diynes in air

Abstract: CuCl with the use of a catalytic amount of piperidine as additive shows high catalytic activity for the oxidative homocoupling reactions of terminal alkynes in toluene at 60 °C in air to afford 1,3-diynes in high yields. Copyright © 2009 John Wiley & Sons, Ltd.

An efficient synthesis of 2- and 2,6-substituted piperidines using Pd(II)-catalyzed 1,3-chirality transfer reaction.

Abstract: An efficient and general method for 2- and 2,6-substituted piperidine syntheses using PdII-catalyzed 1,3-chirality transfer reaction has been developed. The various N-protected ζ-amino allylic alcohols cyclize in the presence of PdCl2(CH3CN)2 to give substituted piperidines with high stereoselectivities. The syntheses of (S)-(+)- and (R)-(−)-coniine were achieved in 3 steps from the optically pure allylic alcohols (S)-14c and (R)-14c, respectively. Although the rates of reactions were significantly accelerated in CH2Cl2, THF gave the highest stereoselectivity. PdCl2(CH3CN)2 was found to be the best catalyst for this transformation. A plausible reaction pathway involving the formation of the Pd π-complex directed by the chiral secondary allylic alcohol followed by syn-azapalladation, and subsequent syn-elimination of PdCl(OH) is proposed.

Stereoselective synthesis of 2,6-disubstituted piperidines using the iridium-catalyzed allylic cyclization as configurational switch: asymmetric total synthesis of (+)-241 d and related piperidine alkaloids

Abstract: Pressing the configurational switch: Use of enantiomeric Ir catalysts allows the vinylpiperidine building blocks 2 a and 2 b to be synthesized with high selectivity. Total syntheses of the dendrobate alkaloid (+)-241 D, its C6-epimer, and a spruce alkaloid are presented as applications.

A configurational switch based on iridium-catalyzed allylic cyclization: application in asymmetric total syntheses of prosopis, dendrobate, and spruce alkaloids.

Abstract: A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-vinylpiperidines with enantiomeric excesses (ee) of greater than 99%. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru-catalyzed cross-metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)-prosopinine, (+)-prosophylline, (+)-prosopine, and of the dendrobate alkaloid (+)-241D and its C6 epimer are described.

Total Synthesis of Alkaloid (±)-G. B. 13 Using a Rh(I)-Catalyzed Ketone Hydroarylation and Late-Stage Pyridine Reduction

Abstract: Total synthesis of the Galbulimima alkaloid G. B. 13 was achieved utilizing a functionalized pyridine moiety as a piperidine surrogate. Key to the success of the synthesis was the development of an unprecedented rhodium-catalyzed 1,2-addition of an arylboronic ester into an unactivated ketone.

Incomplete Fmoc deprotection in solid-phase synthesis of peptides.

Abstract: During solid-phase peptide synthesis of homo-oligopeptides containing leucine or alanine using the Fmoc strategy, we have observed ineffective N-alpha-deprotection with piperidine in a sequence-dependent manner. Incomplete deprotection was found to be associated with subsequent slow or incomplete amino acid coupling. Optimization of the deprotection step was carried out by varying the experimental conditions e.g. deprotection time, temperature, solvents and addition of chaotropes. Coupling and deprotection steps have been investigated using color monitoring, as well as FAB MS and HPLC for product analysis. The phenomena of difficult coupling and deprotection steps in the investigated systems have been demonstrated to have the same physical chemical origins, beta-sheet formation.

Asymmetric synthesis of (+)-castanospermine through enol ether metathesis–hydroboration/oxidation

Abstract: An asymmetric synthesis of (+)-castanospermine is presented in which enol ether metathesis–hydroboration/oxidation is used for stereoselective installation of the trans-transhydroxyl groups on the piperidine ring of the alkaloid.

Synthesis of Dihydrothiophenes or Spirocyclic Compounds by Domino Reactions of 1,3-Thiazolidinedione

Abstract: The domino reactions of 1,3-thiazolidinedione, malononitrile, and aromatic aldehydes in the presence of different organic amines were studied. Secondary amines such as pyrrolidine, piperidine, morpholine, and dimethylamine and primary amines such as benzylamine yield dihydrothiophene derivatives through a domino ring-opening/recyclization reaction of 1,3-thiazolidinedione. Bulky diethylamine, diisopropylamine, and 1,4-diazabicyclo[2.2.2]octane give spirocyclohexano-1,3-thiazole through a double Michael addition/spirocyclization reaction.

Mono- and dinuclear Zn(II) complexes of Schiff-base ligands: syntheses, characterization and studies of photoluminescence

Abstract: Six Schiff-bases HL1-HL4, L5 and L6 [HL1 = 2,6-bis[1-(2-aminoethyl)pyrolidine-iminomethyl]-4-methyl-phenol, HL2 = 2,6-bis[1-(2-aminoethyl)piperidine-iminomethyl]-4-methyl-phenol, HL3 = N-{1-(2-aminoethyl)pyrolidine}salicylideneimine, HL4 = N-{1-(2-aminoethyl)piperidine}salicylideneimine, L5 = 2-benzoyl pyridine-N-{1-(2-aminoethyl)pyrolidine}, L6 = 2-benzoylpyridine-N-{1-(2-aminoethyl)piperidine}] have been synthesized and characterized. Zn(II) complexes of those ligands have been prepared by conventional sequential route as well as by template synthesis. The same complexes are obtained from the two routes as evident from routine physicochemical characterizations. All the Schiff-bases exhibit photoluminescence originating from intraligand (π–π*) transitions. Metal mediated fluorescence enhancement is observed on complexation of HL1-HL4 with Zn(II), whereas metal mediated fluorescence quenching occurs in Zn(II) complexes of L5 and L6.

Stereocontrolled Synthesis of D- and L-β-Rhamnopyranosides with 4-O-6-S-α-Cyanobenzylidene-Protected 6-Thiorhamnopyranosyl Thioglycosides

Abstract: The synthesis of both enantiomers of a 4-O-6-S-α-cyanobenzylidene-protected 6-thiorhamnopyranosyl thioglycoside is described starting from d-mannnose and l-arabinose derivatives for the d- and l-series, respectively. This donor is effective in the preparation of the corresponding β-glycosides using the 1-benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride protocol. Following desulfurization and concomitant debenzylation with Raney nickel, the so-formed 6-thio-β-mannosides are converted in high yield to the β-rhamnopyranosides.

Derivatives of S-9-fluorenylmethyl-L-cysteine.

Abstract: The 9-fluorenylmethyl (Fm) group was examined with respect to its potential for blocking the sulfhydryl function. The S-Fm group is resistant to acids and to catalytic hydrogenation but is cleaved by ammonia in methanol or by organic bases, such as a 20% solution of piperidine in dimethylformamide. Synthesis of N-tert.-butyloxycarbonyl-S-9-fluorenylmethyl-L-cysteine p-nitrophenyl ester and of cysteinyl peptides protected with the S-Fm group are described.

Susceptibility of glycans to β-elimination in Fmoc-based O-glycopeptide synthesis

Abstract: In order to investigate the possible extent of beta-elimination occurring in Fmoc-based continuous-flow solid-phase glycopeptide synthesis, the influence of the pKb of the base used for N alpha-deprotection has been studied. A glycosylated pentapeptide was synthesized using 50% morpholine, 10% piperidine or 2% DBU, respectively, in DMF for deprotection. The dehydropentapeptide N alpha-Ac-Thr-Thr-delta Aba-Val-Thr-NH2, which would be formed in the case of beta-elimination, was prepared independently and used as a control in HPLC analysis; however, this product was not formed under any of the deprotection conditions applied. Furthermore, a 23 amino acid long glycopeptide from human intestinal mucin was prepared using 2% DBU as a base for Fmoc cleavage, and similarly no beta-elimination was observed. The glycopeptide products were subjected to a prolonged treatment with sodium hydroxide in methanol/water without significant formation of byproducts, and the pure glycopeptides were isolated and characterized by 1H-NMR spectroscopy.

A novel Fmoc-based anchorage for the synthesis of protected peptides on solid phase

Abstract: A novel bifunctional compound, 9-(hydroxymethyl)-2-fluoreneacetic acid, was synthesized, coupled to benzhydrylamine-resin, and evaluated for its application to the solid phase synthesis of protected peptide fragments. Anchor-bond cleavage was achieved with 15% piperidine/DMF. A protected heptapeptide, Boc-Val-Val-Ser(Bzl)-His(Tos)-Phe-Asn-Lys-(Z)-OH, corresponding to the sequence (1-7) of rat-transforming growth factor-alpha, was synthesized using this new support with an overall yield of 46%.

Multicomponent reactions for the synthesis of complex piperidine scaffolds.

Abstract: The structures of small natural molecules have been optimized by evolution and are therefore tailored to interact with natural macromolecules to induce a biological response. They represent an invaluable resource in the discovery process of new therapeutic agents. Since the natural product is usually not endowed with the biological properties desired for a chemotherapeutic agent, a series of skeletal and stereochemical analogues have to be generated by using synthesis. A promising strategy (diverted total synthesis, DTS) involves the production of a set of advanced intermediate scaffolds by using a multicomponent reaction (MCR) and subsequent transformations to additionally increase the molecular complexity and diversity. Polysubstituted piperidines are common subunits in natural alkaloids and many biologically relevant molecules, representing attractive scaffolds for the production of natural product analogues having interesting biological profiles. To the best of our knowledge there are only a few MCRs for the construction of structurally and stereochemically diverse polysubstituted piperidine derivatives. Some years ago we reported a new synthesis of polysubstituted piperidines by using the Diels–Alder reactions of 3-trialkylsilyloxy-2-azadienes with electron-poor olefins (Scheme 1). These dienes were prepared from the reaction of acid chlorides with Ntrialkylsilylimines derived from non-enolizable aldehydes. The drawback of the method resulted from the thermal instability of the azadienes, which are very reactive towards electrophilic reagents and either cyclize or decompose upon distillation. This instability resulted in severe limitations of the type of functional groups that could be introduced into the cycloadducts. We envisioned the synthesis of the diene and the cycloaddition reaction in a single operation. This four-component process involving the combination of readily available reactants (aldehyde, equivalent of ammonia, acyl chloride, and dienophile) should allow the incorporation of high levels of skeletal, functional, and stereochemical diversity in the piperidone products (Table 1). To establish the experimental conditions of this MCR we first prepared piperidone 1a (Table 1, entry 1), which we had previously synthesized by reacting the purified 2-azadiene with trans-methyl crotonate. The sequential addition of benzaldehyde, LiHMDS, and propionyl chloride in the presence of triethylamine in toluene generated the intermediate azadiene in situ. Then the cycloaddition, with moderately active dienophiles like trans-methyl crotonate, proceeded in refluxing toluene for a few hours, after which the triethylamine hydrochloride had to be filtered off to avoid competitive decomposition of the basic azadiene. Therefore, petroleum ether was first added to the precipitate triethylamine hydrochloride and then the filtrate was treated with trans-methyl crotonate and heated to reflux, and then the addition of methanol gave piperidone 1a. This simple procedure gave a much better yield (75%) than the earlier method using a purified azadiene (33% yield). When the MCR involved a more reactive dienophile (Table 1, entries 5 and 6), the reaction was conducted in one pot without the addition of petroleum ether and filtration of the triethylamine salt. There are interesting aspects to this one-pot four-component piperidone synthesis (Table 1). The scope of the method was considerably expanded by making possible the introduction of functional groups or substituents which would have prevented the isolation and purification of the corresponding 2-azadienes. A variety of functional groups were tolerated at C4 (Table 1, entries 4–6) and C5 (Table 1, entries 5 and 6). Scheme 1. Sequence of five reactions leading to piperidone scaffolds. TMS= trimethylsilyl, X = alkoxy, amide.