Palladium-catalyzed cross-coupling reactions of 2-indolyldimethylsilanols with substituted aryl halides

[reaction: see text] A mild and general cross-coupling reaction of 2-indolylsilanols has been developed. The experimental variables that lead to successful coupling are (1) the use of sodium tert-butoxide as the activator, (2) the use of copper(I) iodide in stoichiometric quantities, and (3) the use of Pd2(dba)3.CHCl3 as the catalyst. Under these conditions N-(Boc)-2-indolyldimethylsilanol reacts with a variety of aromatic iodides to afford the coupling products in good yield (70-84%).     

克唑替尼关键中间体(S)-1-(2,6-二氯-3-氟苯基)乙醇的不对称合成

(S)-1-(2,6-二氯-3-氟苯基)乙醇（2）是合成抗癌药物克唑替尼的关键手性前体。本文以1-(2,6-二氯-3-氟苯基)乙酮为起始原料,利用二异松莰基氯化硼［(-)-Ipc₂BCl］不对称还原制得光学纯的2;并将中间体2经Mitsunobu反应、还原、溴代、 Suzuki偶联及脱除Boc保护合成克唑替尼,其结构¹H NMR,¹³C NMR和HR-MS(ESI)确证。对关键中间体2的合成条件进行了优化,并其对反应机理进行了推测。     

Heck reaction of arenediazonium salts with N,N-diprotected allylamines. Synthesis of cinnamylamines and indoles

Novel palladium-catalyzed reactions of arenediazonium tetrafluoroborates with N,N-diprotected allylamines are presented. The reaction of arenediazonium tetrafluoroborates with N,N-(Boc)(2) allylamine allows for an easy approach to cinnamylamines whereas using 2-alkynyl-N-(allyl)trifluoroacetanilides and 2-iodo-N-(allyl)trifluoroacetanilide the reaction provides a useful tool for appending indole rings to aniline fragments.     

Efficient synthesis of enantiopure pyrrolizidinone amino acid

Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate beta-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-alpha,omega-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin-2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of (3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone dihedral angles (psi = -149 degrees, phi = -49 degrees ) were in good agreement with the ideal values for a type II' beta-turn. Proton NMR experiments on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23 demonstrated significantly different NH chemical displacements and temperature coefficients suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis should facilitate their application in the exploration of conformation-activity relationships of various biologically active peptides.     

Asymmetric lithiation-substitution sequences of substituted allylamines

[reaction: see text] (-)-Sparteine-mediated asymmetric lithiation-substitution sequences of 2- and 3-substituted N-(Boc)-N-(p-methoxyphenyl) allylic amines with electrophiles have been investigated. Asymmetric lithiation-substitutions of N-(Boc)-N-(p-methoxyphenyl) allylic amines 11, 12, 13, 14, and 15 provide highly enantioenriched enecarbamates in good yields. Further transformations to give aldehydes, acids, ketones, and a Diels-Alder adduct are reported. The 1,4-addition products from reactions of the lithiated allylic amines from 14 and 15 with conjugated activated alkenes gives enecarbamates with two and three stereogenic centers in good yields with high diastereomeric and enantiomeric ratios. Synthetic transformation of these products by acid hydrolysis and subsequent cyclization provide stereoselective access to bicyclic compounds containing four and five stereogenic centers with high diastereoselectivity and enantioselectivity. It is suggested that allyllithium complexes generated by asymmetric deprotonation react with most electrophiles with inversion of configuration.     

Synthesis and Gelation Capability of Fmoc and Boc Mono-substituted Cyclo(L-Lys-L-Lys)s

Fmoc or Boc mono-substituted cyclo(L-Lys-L-Lys)s were synthesized via the reaction of lysine cyclic dipeptide with Fmoc N-hydroxysuccinimide este(Fmoc-OSu) and di-tert-butyl dicarbonate[(Boc)₂O], respectively. The resulted mono-substituted cyclo(L-Lys-L-Lys)s(2-4) by means of test tube inversion method served as organogelators enabled to form stable thermo-reversible organogels in alcoholic, substituted benzene and chlorinated solvents, with the minimum gelation concentration(MGC) in a range of 1%-4%(mass fraction). The transmission electron microscopy(TEM) and scanning electron microscopy(SEM) observations reveal that these gelators self-assembled into 3D nanofiber, nanoribbon or nanotube network structures. The rheological measurement exhibited that the storage modulus of gels is higher than the loss one, and the complex viscosity is reduced linearly with the increasing of scanning frequency. The fluorescence spectrum of compound 2 in 1,2-dichloroethane and benzene demonstrates that the emission peak of Fmoc at 320 nm has red-shifted and the intensity decreases gradually, while the intensity of the emission peak at 460 nm substantially enhances as a function of concentration, indicating the existence of π-π sta- cking interactions and the formation of J-type aggregates. Meanwhile, compound 4 self-assembled into nanotubes via the stacking of multiple bilayer membranes. Fmoc and Boc disubstituted cyclo(L-Lys-L-Lys)(3) holds the relatively lower MGC values, showing the stronger gelation ability in most selected organic solvents due to the presence of both Fmoc and Boc groups.     

含可脱除侧基的功能化微凝胶及其在药物释放中的应用

环境敏感微凝胶由于其对外界刺激的快速响应能力在药物传输和释放领域得到广泛的关注.本文报道了一种侧链含可脱除基团的温敏微凝胶,并探讨了其在药物释放中的潜在应用.通过分子设计,合成出含侧链N-叔丁氧羰基(N-Boc)的疏水单体N-(N-叔丁氧羰基-乙二胺)甘氨酸二肽甲基丙烯酰胺(BEMAGG),然后将其与N-异丙基丙烯酰胺(NIPAAm)沉淀共聚合直接得到侧链含Boc基团的微凝胶MG-Boc.通过浊点法、粒径和Zeta电位测定研究了微凝胶中Boc基团在酸中的脱除过程及其对微凝胶性能的影响,研究表明Boc基团的脱除显著影响微凝胶的体积相转变温度、粒径和Zeta电位.对盐酸阿霉素药物的释放研究表明,释放明显依赖于释放介质的pH值.该响应性的微凝胶在药物控制释放领域具有潜在的应用前景.     

Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.     

Synthesis and Crystal Structure of a Mononuclear Zn(II) Complex with Tridentate Schiff Base,Zn(C_(12)H_(18)N_2O)(NCS)_2

1 INTRODUCTION In recent years there has been considerable and increasing interest in the synthesis of transition metal complexes with multidentate Schiff base ligands[1~4] because such ligands can accommodate one, two or more metal centers and may synthesize homo and/or heteronuclear metal complexes with interesting ste- reochemistry[5, 6]. In addition, these metal complexes can be used for biological modeling applications, catalysis, design of molecular ferromagnet and mate- rials chemis…     

Nickel(II) Complexes with Pentane-2,4-dione Bis(4-allylthiosemicarbazone)

Reaction of pentane-2,4-dione with N-(prop-2-en-1-yl)hydrazinecarbothioamide at a 1: 2 molar ratio in ethanol resulted in the formation of a pyrazole derivative. The latter reacted with nickel perchlorate at a 1: 1 molar ratio to form the nickel complex with pentane-2,4-dione bis(4-allylthiosemicarbazone). The same type of nickel complex was obtained as a result of N-(prop-2-en-1-yl)hydrazinecarbothioamide reaction with pentane-2,4-dione and nickel nitrate at a 2: 1: 1 molar ratio. Antimicrobial, antifungal, antioxidant, and anticancer activities of the obtained compounds were studied.     

Mild and facile procedure for clay-catalyzed acetonide protection and deprotection of N(Boc)-amino alcohols and protection of 1,2-diols

The application of clay as a catalyst for acetonide protection of N(Boc)-amino alcohols and 1,2-diols to obtain good to excellent yields of the acetonide derivatives is described. Acetonide deprotection to obtain the parent amino alcohol was carried out using a similar catalyst in the presence of methanol as solvent. The reaction takes place at room temperature within 2 h to give the parent amino alcohol in quantitative yield keeping the N(Boc) group intact.     

Solid-supported synthesis of cryptand-like macrobicyclic peptides

A straightforward method for the solid-supported synthesis of cryptand-like bicyclic peptides (1-5) on a backbone amide linker has been described. For the branching, two novel easily available building blocks, viz. N-(4-methoxytrityl)-N-(2-nitrobenzenesulfonyl)-protected N,N-bis(2-aminoethyl)-beta-alanine (6) and N-(9-fluorenylmethoxycarbonyl) protected iminodiacetic acid monoallyl ester (7), have been employed. The key steps of the synthesis are as follows: (i) stepwise coupling of one amino acid and 6 to the secondary amino group of the linker; (ii) removal of the 2-nitrobenzenesulfonyl group and SPPS by the Fmoc chemistry, using 7 as the penultimate and tert-butoxycarbonyl (Boc) protected glycine as the last amino acid; (iii) removal of the 4-methoxytrityl protection and subsequent SPPS by the Fmoc chemistry; (iv) removal of the allyl and Fmoc groups, followed by cyclization; and (v) removal of the Boc and tert-butyl groups, followed by cyclization. Final cleavage from the support and removal of benzyl-derived protecting groups gives the desired bicyclic products.     

Base-labile tert-butoxycarbonyl (Boc) group on phenols

Phenols are deprotected with weak bases from their tert-butoxycarbonyl (Boc) derivatives. Boc deprotection with bases can avoid side reactions during the deprotection with acids. We note the lability of the Boc to bases and are able to utilize it as a new cleavage condition for synthetic studies.     

Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones

This report presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole.     

N-5-(1H-1,2,4-三唑基）-N'-芳甲酰基脲的合成与生物活性

以5-氨基-1H-1，2，4-三唑-3-羧酸与酰基异氰酸酯反应，合成了15个新的N- 5-（1H-1，2，4-三唑基）-N'-芳甲酰基脲，用核磁共振氢谱、红外光谱和元素分 析确证了其结构，并进行了室内生物活性测试。生测试验证明部分酰基脲类化合物 具有良好的植物生长调节活性，其中N-5（3-羧基-1，2，4-三唑基）-N'-o-氯苯甲 酰基脲、N-5-（3-羧基-1，2，4-三唑基）-N'-o-溴苯甲酰基脲和N-5-(3-羧基-1， 2，4-三唑基）-N'-p(或m)-甲基苯甲酰基脲具有优良的生长素活性。     

N-(17-Phosphonooxylinolenoyl)glutamine and N-(17-phosphonooxylinoleoyl)glutamine from insect gut: the first backbone-phosphorylated fatty acid derivatives in nature

N-(17-Phosphonooxylinolenoyl)glutamine (1) and N-(17-phosphonooxylinoleoyl)glutamine (2) were isolated from the regurgitate of Spodoptora exigua and identified as the first natural alkyl chain-phosphorylated fatty acid derivatives. The compounds were characterized by HPLC-MS/MS and the assigned structures confirmed by synthesis via a dissymmetric bis-Wittig approach as the key reaction. Rearing of the larvae on a diet enriched with inorganic phosphate increased the amount of the phosphorylated N-acyl glutamines in the regurgitate.     

Chemical conjugation of linear and cyclic RGD moieties to a recombinant elastin-mimetic polypeptide--a versatile approach towards bioactive protein hydrogels

An elastin-mimetic polypeptide, (EMM)(7), with the amino-acid sequence GRDPSS [VPGVG VPGKG VPGVG VPGVG VPGEG VPGIG](7) was used for chemical conjugation of various integrin ligands (RGD peptides) to prepare bioactive hydrogels. The chemical approach involved (1) chemical protection of lysine residues with Fmoc or Boc groups, (2) chemical ligation of a protected linear or cyclic RGD ligand, with or without a hexanoic-acid spacer to the glutamic acid residue, (3) deprotection of the lysine functionalities and the RGD moieties and (4) cross-linking to form a bioactive hydrogel. (1)H NMR spectroscopy was used to quantify the multiple steps in the reaction. The chemical protection was found to be between 65 and 93% for Fmoc and Boc, respectively. The ligands studied included linear RGD cell-binding [H-FGRGDS-OH (1-l-RGD), H-Ahx--FGRGDS-OH (2-Ahx-FGRGDS) and a cyclic -H(2)N-(CH(2))(6)COHN-cyclo(-RGDfK-) (H-Ahx-c(-RGDfK-)) peptide also with a hexanoic-acid spacer. Cell adhesion with mouse osteoblast cells was dependent on the ligand type, ligand density and the use of a spacer.     

Phosphine-mediated dehalogenation reactions of trichloro(N-silyl)phosphoranimines

The reaction of N-(trimethylsilyl)phosphoranimine Cl3P=NSiMe3 (1) with nBu3P or Ph3P yields the N-(dichlorophosphino)phosphoranimines nBu3P=NPCl2 (4a) or Ph3P=NPCl2 (4b), respectively. Detailed studies of this reaction indicate a mechanism that involves the reductive dechlorination of 1 by the tertiary phosphine to yield nBu3PCl2 (5a) or Ph3PCl2 (5b) with the apparent formation of the transient chlorophosphinimine ClP=NSiMe3 (6), followed by condensation of 5a or 5b with 1 to form 4a or 4b and Me3SiCl. Convincing evidence for the proposed mechanism was revealed by studies of the analogous reaction between the N-(triphenylsilyl)phosphoranimine Cl3P=NSiPh3 (8) with nBu3P and Ph3P. These reactions quantitatively generated 5a and 5b and also allowed the correspondingly more stable chlorophosphinimine ClP=NSiPh3 (10) to be identified.     

Synthesis of new azo compounds based on N-(4-hydroxypheneyl)maleimide and N-(4-methylpheneyl)maleimide

Maleic anhydride was reacted with p-aminophenol and p-toluidine in the presence of di-phosphorus pentoxide (P?O?) as a catalyst to produce two compounds: N-(4-hydroxy-phenyl)maleimide (I) and N-(4-methylphenyl)maleimide (II). The new azo compounds I(a-c) and II(a-c) were prepared by the reaction of I and II with three different aromatic amines, namely aniline, p-aminophenol and p-toluidine. The structures of these compounds were confirmed by CHN, FT-IR, 1H-NMR, 13C-NMR, mass spectrum and UV/Vis spectroscopy.     

Allylic alcohol transposition by ortho ester-initiated carbonate extension. synthesis of the vasodilator 11(R),12(S),15(S)-trihydroxyeicosa- 5(Z),8(Z),13(E)-trienoic acid

[reaction: see text] The title compound 1 was obtained via methyl ester 2, which was synthesized in four steps from an isomeric 11,14,15-triol ester 5. In the key step, Boc orthoformate 9 was treated with TMS triflate to initiate intramolecular nucleophilic substitution with allylic transposition, forming cyclic carbonates 10 and 11.