Regiospecific Suzuki coupling of 3,5-dichloroisothiazole-4-carbonitrile

3,5-Dichloroisothiazole-4-carbonitrile 1 react with aryl- and methylboronic acids to give in high yields the 3-chloro-5-(aryl and methyl)-isothiazole-4-carbonitrile 2 regiospecifically. The reaction was optimized with respect to base, phase transfer agent and palladium catalyst. Suzuki coupling at C-5 was also achieved in high yield using potassium phenyltrifluoroborate. The regiospecificity of either coupling method is maintained with 3,5-dibromoisothiazole-4-carbonitrile 4 to give exclusively 3-bromo-5-phenylisothiazole-4-carbonitrile 5. Suzuki cross-coupling conditions applied to 3-chloro-5-phenylisothiazole-4-carbonitrile 2a gave 3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, which was prepared independently, and not the 3-phenyl derivative. All isothiazole products were fully characterized.     

An exploration of Suzuki aryl cross coupling chemistry involving [2.2]paracyclophane derivatives

Suzuki aryl cross coupling reactions using derivatives of [2.2]paracyclophane were examined. A variety of aryl boronic acids and pinacolate esters were successfully cross coupled with 4-bromo[2.2]paracyclophane under standard Suzuki conditions. Whilst an excellent tolerance for electron donating and withdrawing groups was observed, cross coupling reactions with highly sterically demanding borates (e.g. mesityl) were unsuccessful. The preparation and stability of the previously unreported [2.2]paracyclophanyl-4-boronic acid, -pinacolate ester and -dimethyl ester are described, along with the utility of these systems in Suzuki aryl cross coupling reactions. Application of this methodology led to a dicyclophane containing two [2.2]paracyclophane units separated by a 4-4' connected biphenyl spacer group.     

Ethoxyethylidene protecting group prevents N-overacylation in aminooxy peptide synthesis

We report herein an improved synthetic route for the preparation of homogenous aminooxy peptides suitable for oxime ligation. Aminooxyacetic acid (Aoa) was protected with 1-ethoxyethylidene group (Eei) then incorporated either using PyBOP or as N-hydroxysuccinimidyl ester at N-terminal end or at a lysine side chain into model peptides in solution and on solid support. Due to the Eei protecting group, these new reagents prevent the N-overacylation side reaction in comparison with Boc-Aoa derivatives. Subsequent deprotection under mild acidic conditions gave the corresponding pure aminooxylated peptides.     

Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products

The details of the first syntheses of the unusual bis-oxazole natural products siphonazole and its O-methyl derivative are reported. The cinnamyl substituted oxazole was constructed using diazocarbonyl chemistry, whereby the cinnamamide was reacted with the rhodium carbene derived from methyl 2-diazo-3-oxobutanoate to give a beta-ketoamide that was cyclodehydrated to the corresponding oxazole-4-ester. Reduction to the corresponding aldehyde was followed by coupling with a zinc reagent derived from methyl 2-iodomethyl-5-methyloxazole-4-carboxylate, also prepared using rhodium carbene chemistry, to give, after oxidation of the resulting secondary alcohol, the desired bis-oxazole ketone. The syntheses were completed by hydrolysis of the ester and coupling of the 2,4-pentadienylamine side chain.     

Synthesis of dityrosine cross-linked peptide dimers using the Miyaura-Suzuki reaction

[reaction: see text] Since peroxidase-catalyzed dityrosine formation is inefficient for peptides, we have developed alternative conditions for intermolecular dityrosine formation using the Miyaura-Suzuki reaction. A one-pot reaction is effective for cross-linking short peptides, but longer peptides inhibit the Suzuki step, mandating a traditional two-step procedure using potassium acetate for the Miyaura reaction and potassium carbonate for the Suzuki coupling. These palladium-based methods are complementary to the well-established peroxidase-catalyzed oxidative phenolic coupling of full-length proteins.     

Silyl enol ethers as protective groups for alkyl 4-halo-3-oxobutanoates in the Arbuzov reaction with triethyl phosphite

Alkyl 4-bromo- and 4-chloro-3-oxobutanoates were protected as silyl enol ethers. The Arbuzov reaction of these new compounds with triethyl phosphite gave the corresponding silyl enol phosphonates in high yield. Facile deprotection of the silyl group with water gave alkyl 4-(diethoxyphosphinyl)-3-oxobutanoates in high yields. Protection of 1-methylethyl 4-bromo-3-oxobutanoate as the enol acetate followed by the subsequent reaction with triethyl phosphite gave the corresponding phosphonate in high yield. Deprotection with potassium 2-propoxide gave 1-methylethyl 4-(diethoxyphosphinyl)-3-oxobutanoate in good yield. © 1997 John Wiley & Sons, Inc.     

Efficient,Optimized Applications of p-Nitrophenyl Active Ester Temporarily Protecting Groups Together with Simultaneous Activation in Synthesis of Special Glu and Lys Peptides

Benzyloxycarbonyl-glutamylpeptide p-nitrophenylesters were prepared from protected amino acids, e.g.: p-nitrophenyl-glutamate as carboxyl component and aminoacid or peptide p-nitrophenylesters as amino components by different kinds of peptide coupling methods. Mixed carbonic anhydride and azide methods gave good results. The p-nitrophenylesters existed as temporary protecting groups, so the peptide couplings proceeded together with simultaneous activation. The conditions and applications of the procedure are discussed. The peptides having one or more active ester groups were used to form amides by their aminolysis with derivatives of ethylamine or were polycondensated (after deprotection) to obtain polypeptides.     

Regiospecific synthesis of 1,5-disubstituted-1H-pyrazoles containing differentiated 3,4-dicarboxylic acid esters via Suzuki coupling of the corresponding 5-trifluoromethane sulfonates

A general procedure is described for the regiospecific preparation of 1-substituted-5-hydroxy-1H-pyrazoles containing differentiated ester moieties at the 3- and 4-positions. This process involves the coupling of monosubstituted benzyl carbazates with various malonyl chlorides or acids, deprotection of the coupling products via catalytic hydrogenation, and subsequent derivatization of the resulting hydrazides with monoalkyl oxalyl chlorides. The 5-hydroxy-1H-pyrazoles are readily transformed to the corresponding trifluoromethane sulfonates, which undergo palladium-mediated Suzuki coupling with a variety of boronic acids (aryl, heteroaryl, and alkenyl) in moderate to excellent yields (24-92%). The ester groups present in one of the resulting 1,5-disubstituted-1H-pyrazoles are further modified by selective hydrolysis or conversion to the corresponding dicarboxylic acid derivative followed by selective mono-esterification.     

Transient silylation of the guanosine O6 and amino groups facilitates N-acylation

[reaction: see text] The formation of a guanosine derivative silylated at both the O6 and amino groups was identified by (15)N NMR. This intermediate allows facile reaction with acetyl chloride or phenoxyacetyl chloride to give in high yield the corresponding N-protected guanosine derivatives, suitable for use in RNA synthesis. The acetyl and phenoxyacetyl amino protecting groups are, respectively, 4 and 230 times more labile than the isobutyryl group to methylamine/ethanol deprotection.     

N(epsilon) functionalization of metal and organic protected L-histidine for a highly efficient,direct labeling of biomolecules with [Tc(OH2)3(CO)3]+

Two different pathways for the introduction of an acetyl group at N(epsilon ) in a N(alpha), N(delta), and -COO protected histidine to afford N(epsilon)-(CH(2)COOH)-histidine derivative 7 b are presented. The purpose of this study is the coupling of 7 b to amino groups in bioactive molecules such as peptides. After full deprotection of such a bioconjugate, histidine provides three coordination sites which efficiently coordinate to [(99m)Tc(OH(2))(3)(CO)(3)](+) or [Re(OH(2))(3)(CO)(3)](+) in a facial geometry. This allows the development of novel radiopharmaceuticals. Selective derivatization at the N(epsilon) position has conveniently been achieved by concomitant protection of N(alpha) and N(delta) with a carbonyl group forming a six-membered urea. Cyclic urea ring opening with Fm-OH, coupling of phenylalanine as a model to 7 b through its primary amine and removing of all protecting groups in one step gave a histidine derivative of phenylalanine which could be labeled at 10(-5) M with (99m)Tc in very high yield and even in about 50 % yield at 10(-6) M. The Xray structure of a complex with [Re(CO)(3)](+) in which anilin is coupled to 7 b confirms the facial arrangement of histidine. A second pathway applies directly the [Re(CO)(3)](+) moiety as a protecting group. This is one of the rare examples in which a metal fragment is used as a protecting group for organic functionalities. The coordination to histidine protects the N(alpha), N(delta) and COO group in one single step, subsequent alkylation with BrCH(2)COOH(R) at N(epsilon), coupling to phenylalanine and oxidative deprotection of [Re(CO)(3)](+) to [ReO(4)](-) gave the corresponding bioconjugate in which histidine is coupled to phenylalanine through an acetylamide at N(epsilon). Both methods offer convenient pathways to introduce histidine in a biomolecule under retention of its three coordination sites. The procedures are adaptable to any biomolecule with pendant amines and allow the development of novel radiopharmaceuticals or inversed peptides.     

Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation

[reaction: see text] An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO(t)Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.     

Design and Synthesis of Some New α‐Phenyl Cinnamoyl Derivatives for Selective Protection of Purine Nucleosides

Three new α‐phenylcinnamic acid derivatives [4‐methoxy‐α‐phenylcinnamic acid, α‐(4‐methoxyphenyl)‐cinnamic acid, and 4,4′‐bismethoxy‐α‐phenylcinnamic acid] were synthesized, characterized, and selectively used for protecting the exocyclic amino function of purine nucleosides (2′‐deoxyadenosine and 2′‐deoxyguanosine) via active ester generation. The acids were first activated using p‐nitrophenol, and these activated esters were used subsequently for the selective protection of amino groups. The N‐protected derivatives of 2′‐deoxyguanosine and 2′‐deoxyadenosine have been found to be sufficiently stable toward acids, thus minimizing depurination under oligodeoxyribonucleotide synthesis protocol. The ease of syntheses of N‐protected purine nucleosides, their stability under an acidic environment, and mild deprotection conditions are the key advantages of the new protecting groups.     

Efficient syntheses of 2-chloro-2'-deoxyadenosine (cladribine) from 2'-deoxyguanosine(1)

We report efficient syntheses of the clinical agent cladribine (2-chloro-2'-deoxyadenosine, CldAdo), which is the drug of choice against hairy-cell leukemia and other neoplasms, from 2'-deoxyguanosine. Treatment of 3',5'-di-O-acetyl- or benzoyl-2'-deoxyguanosine (1) with 2,4,6-triisopropyl- or 4-methylbenzenesulfonyl chloride gave high yields of the 6-O-arylsulfonyl derivatives 2 or 2'b. Deoxychlorination at C6 of 1 also proceeded to give the 2-amino-6-chloropurine derivative 5 in excellent yields. The nonaqueous diazotization/chloro dediazoniation (acetyl chloride/benzyltriethylammonium nitrite) of 2, 2'b, and 5 gave the 2-chloropurine derivatives 3, 3'b, and 6, respectively. The selective ammonolysis at C6 (arylsulfonate with 3 or chloride with 6) and accompanying deprotection of the sugar moiety gave CldAdo (64-75% overall yield from 1).     

Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot

The rapid and efficient synthesis of various 2,6-disubstituted-3-amino-imidazopyridines using a microwave-assisted one-pot cyclization/Suzuki coupling approach is described. The utility of a 2-aminopyridine-5-boronic acid pinacol ester as a robust and versatile building block for the synthesis of diverse compound libraries is emphasized. The boronate functional group is remarkably tolerant to the Lewis acid catalyzed cyclizations, and the subsequent Pd(0)-catalyzed Suzuki coupling reactions proceed cleanly in the presence of magnesium salts. This work highlights the vast potential of microwave-assisted, metal-catalyzed, multicomponent reactions.     

A generalised route for the synthesis of β-furyl-α,β-unsaturated aldehydes through Suzuki reactions

A general method for the synthesis of β-(2-furyl)-α,β-unsaturated aldehydes is described using the Suzuki coupling reaction of furan-2-boronic acids and β-bromo-α,β-unsaturated aldehyde derivatives.     

Synthesis of D- and L-myo-Inositol 1,4,6-Trisphosphate, Regioisomers of a Ubiquitous Second Messenger

A regioisomer of the second messenger D-myo-inositol 1,4,5-trisphosphate [D-Ins(1,4,5)P(3), 1], DL-myo-inositol 1,4,6-trisphosphate [DL-Ins(1,4,6)P(3), 4ab], together with the chiral antipodes D-Ins(1,4,6)P(3)(4a) and L-Ins(1,4,6)P(3)(4b), was synthesized from myo-inositol. The racemic diol 6, after removal of the trans-ketal of fully protected 5 was p-methoxybenzylated to give the 6-O-alkylated derivative 9, as the major product in 52% yield. Gentle acidic hydrolysis of 9, followed by benzylation of the resulting triol, gave the fully protected compound 11ab. Isomerization of the two allyl groups followed by acidic hydrolysis of the resulting cis-prop-1-enyl moieties and the p-methoxybenzyl group gave the triol 13ab. Phosphorylation of 13ab followed by deprotection of the resulting compound, 14ab, with sodium in liquid ammonia and purification by ion exchange chromatography provided 4ab in 60% yield. The intermediate 9 was converted into the cis-diol 16ab in two steps. Selective acylation at the equatorial hydroxyl group using (S)-(+)-O-acetylmandelic acid in the presence of DCC and DMAP provided two diastereoisomers, 18 and 19, which were separated by flash chromatography. Further transformations provided the corresponding D- and L-1,4,6 triols, 13a and 13b, respectively, and phosphorylation, followed by deprotection of the fully blocked products as for the racemic 4ab, gave 4a and 4b, respectively. The absolute configuration of fully protected 11a was determined by transformation to the known compound L-1,2,4,5-tetra-O-benzyl-myo-inositol (22). Compound 4a was a full agonist at the platelet Ins(1,4,5)P(3) receptor for Ca(2+) release, but 4b was devoid of activity.     

Studies on the generation of enolate anions from butane-2,3-diacetal protected glycolic acid derivatives and subsequent highly diastereoselective coupling reactions with aldehydes and acid chlorides

Highly diastereoselective coupling reactions of enolates derived from butane-2,3-diacetal protected glycolic acids 1 and 2 and their alkylated derivatives with aldehydes are reported together with their efficient acid-catalysed deprotection to yield enantiopure anti-2,3-dihydroxyesters. A procedure to provide the corresponding syn-2,3-dihydroxyesters is also described in two cases, proceeding via an acylation-reduction sequence. An usual double addition reaction of butane-2,3-diacetal protected glycolic acid to small aliphatic acid chlorides provides a synthetically useful, densely-functionalised lactone after acidic deprotection.     

ABSORPTION AND FLUORESCENCE STUDY OF TYROSINE-DERIVED CROSSLINKING AMINO ACIDS FROM COLLAGEN

Isotrityrosine, an isomer of trityrosine with an ether linkage, is a new crosslinking amino acid recently found in cuticle collagen of Ascaris lumbricoides . The absorption and fluorescence spectra of this new amino acid were examined and compared with other tyrosine-derived crosslinking amino acids. Isotrityrosine showed UV absorption maximum at 283 nm in acidic and neutral solutions and at 303 nm in strongly basic solution. The wavelengths are almost the same with those at dityrosine and trityrosine. The values of p K _a, for chromophore phenols are 7.5 and 11.0. This means that two proton dissociations occur progressively one by one. Boric acid did not have any influence on isotrityrosine, though the effect on dityrosine and trityrosine was substantial. These facts mentioned above may suggest structural inequality of two phenols in an ether-linked isomer. The wavelength of emission maximum was 450 nm, which was the longest wavelength among relative compounds examined. The fluorescence quantum yield was as small as 0.027, and the value was about one-tenth of those of dityrosine and trityrosine. Isotrityrosine was also found in cuticle collagen of other worms which belong to the phylum nematoda.     

Synthesis of Thiophene-fused Helicenes

The synthesis of three penta- and three hexahelicenes containing two terminal thiophene units is described. The syntheses of pentahelicenes consist of 1,4-bisalkynylation of a benzene precursor and double Suzuki coupling in 2,3-position to introduce thiophene units. The ortho,ortho’ fusion yielding the final products was achieved with Fürstner's protocol using platinum(II) chloride or JohnPhos-complexed gold(I) as catalysts. A similar approach to hexahelicenes started with a naphthalene derivative, where 2,7-bisalkynylation and subsequent double Suzuki coupling with thiophene-2-boronic acid at 1,8-position furnished precursors, in which ortho,ortho’ fusion to the respective hexahelicenes was achieved with platinum(II) chloride or, favourably, with indium(III) chloride. UV/Vis spectra and cyclic voltammograms were recorded for all helicenes and HOMO/LUMO gaps were calculated with DFT methods.     

A facile synthesis of 1,3,4-selenadiazolo[2,3-b]quinazoline derivatives via japp-klingemann reaction

Diazotized anthranilic acid and its methyl ester react with ethyl α-selenocyanatoacetate 3a and α-selenocyanatoacetoacetanilide 3b to give in both cases the corresponding 1,3,4-selenadiazolo[2,3-b]quinazoline derivatives 7a and 7b , respectively, in good yields (70-80%). A mechanism is proposed and it is substantiated by an alternate synthesis of 7a and 7b from the corresponding hydrazidoyl chlorides 9a and 9b with potassium selenocyanate, respectively. An evidence for the involvement of the 1,3,4-selenadiazoline derivative as an intermediate in these reactions is provided by the isolation of 11 from either coupling of 3b with diazotized ethyl p-aminobenzoate or the reaction of hydrazidoyl chloride 12 with potassium selenocyanate.