Synthesis of a sialic acid alpha(2-3) galactose building block and its use in a linear synthesis of sialyl Lewis X

[reaction: see text] The ubiquity of the sialic acid alpha(2-3) galactose linkage in oligosaccharides of biological relevance necessitates a building block for the incorporation of this motif into oligosaccharides prepared by modular synthesis. The linear synthesis of the sialyl Lewis X tumor-associated antigen (1) has been accomplished in good yield using a sialic acid alpha(2-3) galactose disaccharide building block. The disaccharide building block was synthesized efficiently from readily available galactal by a high-yielding and selective sialylation reaction.     

Comprehensive Comparisons between 1-Phenyl-3-methyl-5-pyrazolones, 1-(4-Methoxyphenyl)-3-methyl-5-pyrazolones and 1-(2-Naphthyl)-3-methyl-5-pyrazolones as Labeling Reagents Used in LC-DAD-ESI-MS-MS Analysis of Neutral Aldoses and Uronic Acids

Comprehensive comparisons between three 1-aryl-3-methyl-5-pyrazolone (AMP) labeling reagents were carried out for the analysis of reductive monosaccharides using reversed phase high performance liquid chromatography diode array detection coupled to electrospray ionization mass spectrometry. AMP derivatives included 1-phenyl-3-methyl-5-pyrazolone (PMP), 1-(4-methoxyphenyl)-3-methyl-5-pyrazolone (PMPMP) and 1-(2-naphthyl)-3-methyl-5-pyrazolone (NMP). The separation of AMP-monosaccharides was found to be pH-dependent under reversed phase conditions and acceptable separations were obtained at pH < 4.5. The elution orders of AMP-aldoses were rationalized by geometric factors involved in the presence of hydroxyl groups at C2 and C3 positions of the saccharide moiety. When PMP or PMPMP were used as labeling agents Glucose and galactose were completely separated, while arabinose and xylose were observed to co-elute. The use of NMP revealed that arabinose and xylose could be separated while glucose and galactose were co-eluted. MS-MS data of AMP-monosaccharides gave characteristic fragment ions resulting from cleavage between the C2–C3 bond (m/z 373 for PMP derivatives, m/z 433 for PMPMP derivatives, and m/z 473 for NMP derivatives). Bond breakage between C1–C2 (m/z 359 for PMP derivatives, m/z 419 for PMPMP derivatives, and m/z 459 for NMP derivatives) of the saccharide moiety was also found to be characteristic for AMP-saccharides. Application to the analysis of hydrolyzed rape pollen polysaccharides revealed the presence of four unexpected monosaccharides, namely ribose, erythrose, threose and glyceraldehyde.     

Radical addition to oxime ethers for asymmetric synthesis of beta-amino acid derivatives

The diastereoselective alkyl radical addition to chiral oxime ethers was studied with a view to preparing enantiomerically pure alpha,beta-dialkyl-beta-amino acid derivatives. The phase transfer-catalyzed alkylation of Oppolzer's camphorsultam derivative of oxime ether proceeded smoothly to give the alkylated N-(beta-oximino)acyl derivatives. In the presence of BF3.OEt2, radical addition to the oxime ethers proceeded using triethylborane as the radical initiator to give alpha,beta-dialkyl-beta-amino acid derivatives with excellent diastereoselectivity.     

A novel redox reaction between 8-Aza-5,7-dimethyl-2-trifluoromethylchromone and alkyl mercaptoacetates. Facile synthesis of CF3-containing 2-pyridone derivatives

8-Aza-5,7-dimethyl-2-trifluoromethylchromone reacts with alkyl mercaptoacetates in the presence of triethylamine to give pyrido derivatives of 2-oxa-7-thiabicyclo[3.2.1]octane, which undergo the reductive ring opening to alkyl 2-[[3-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-oxo-1-(trifluoromethyl)propyl]sulfanyl]acetates.The latter can be also obtained directly from 8-aza-5,7-dimethyl-2-trifluoromethylchromone and behave as the masked alpha,beta-unsaturated ketone, 4,6-dimethyl-3-(4,4,4-trifluorobut-2-enoyl)pyridin-2(1H)-one. This compound was independently synthesized from 3-acetyl-4,6-dimethyl-2-pyridone, and its synthetic potential was studied. A wide variety of 2-pyridone derivatives containing the CF(3) group have been prepared in good to moderate yields.     

Lipase-catalyzed synthesis of novel galactosylated cholesterol

In an organic phase system,an enzymes lipase was used as a catalyst to synthesize galactosylated cholesterol,(5-cholesten-3b-yl)[(4-O-β-D-galactopyranosyl)D-glucitol-6]sebacate(CHS-SE-LA),which contains galactose residues.Its chemical structure was characterized by ESI-MS,and NMR.For HepG2 cells,the cellular fluorescence intensities of liposomes modified with CHS-SE-LA(GAL-FL) were as much as 2.6-fold(p 0.01) control liposomes(FL).Moreover,the presence of excess galactose significantly inhibited the uptake of GAL-FL suggesting ASGPR mediated uptake.In conclusion,the novel galactosylated ligand CHS-SE-LA was synthesized by lipase-catalyzation and revealed a great potential as drug carrier materials for hepatocyte-selective targeting.     

Stereoselective synthesis of 3-deoxy-piperidine iminosugars from l-lysine

A new method using electrochemical oxidation and/or OsO₄ oxidation has been used for the stereoselective synthesis of 2,3,6-trihydroxylated (5S)-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for the conversion of 2,3-didehydro-1-methoxypiperidine derivatives to 2,3-trans-1,2,3-triacetoxypiperidine derivatives. These triacetates were easily transformed into (2S,3S)-6-triacetoxy-(5S)-methylpiperidine and (2R,3R)-6-triacetoxy-(5S)-methylpiperidine. In addition, the 2,3-cis-dihydroxylation of 2,3-didehydro-1-methoxypiperidine derivatives with OsO₄ afforded (2R,3S)-6-triacetoxy-(5S)-methylpiperidine and (2S,3R)-6-triacetoxy-(5S)-methylpiperidine.     

Potential bile acid metabolites. 25. Synthesis and chemical properties of stereoisomeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids

Epimeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids and some related compounds were synthesized from chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. The key reaction involved one-step remote oxyfunctionalization of unactivated methine carbons at C-17 of CDCA and at C-14 of UDCA as their methyl ester-peracetate derivatives with dimethyldioxirane (DMDO). After dehydration of the resulting 17alpha- and 14alpha-hydroxy derivatives with POCl(3) or conc. H(2)SO(4), the respective Delta(16)- and Delta(14)-unsaturated products were subjected to hydration via hydroboration followed by oxidation to yield the 3,7,16- and 3,7,15-triketones, respectively. Stereoselective reduction of the respective triketones with tert-butylamine-borane complex afforded the epimeric 3alpha,7alpha,16- or 3alpha,7alpha,15-trihydroxy derivatives exclusively. A facile formation of the corresponding epsilon-lactones between the side chain carboxyl group at C-24 and the 16alpha- (or 16beta-) hydroxyl group in bile acids is also clarified.     

Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates

[reaction: see text] Glucal 3-carbamates 1 and 7 underwent oxidative cyclization with iodobenzene diacetate or iodosobenzene in the presence of Rh2(OAc)4, providing mannosamine 2-N,3-O-oxazolidinones. With iodosobenzene, incorporation of 4-penten-1-ol provided a readily separable anomeric mixture of n-pentenyl glycosides, with the anomers exhibiting pronounced differences in reactivity as glycosyl donors. N-acylation of the sugar oxazolidinones led to alpha-selective glycosyl donors for the elaboration of various 2-mannosamine frameworks. Alternatively, the anomeric n-pentenyl glycosides of N-Cbz 2-mannosamine oxazolidinones were converted separately to oxazolidinone-opened derivatives 28alpha and 28beta. These served as stereoconvergent glycosyl donors, and the alpha-linked products were readily advanced to a variety of N-acetylmannosamine (ManNAc) frameworks, using an intramolecular O-->N acetyl transfer as the final step.     

Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular N(alpha)-C(alpha)-cyclization strategy

A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of beta-lactams with quaternary centers at the C(4) position. Particularly noteworthy is that the intramolecular N(alpha)-C(alpha)-cyclization of Phe and Leu derivatives afforded the corresponding beta-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the alpha-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurs preferentially.     

Design and synthesis of new series of 3-cyanopyridine and pyrazolopyridine derivatives

Reaction of 3-cyano-4,6-dimethyl-2-pyridone with ethyl chloroacetate afforded ethyl 2-([3-cyano-4,6-dimethylpyridin-2-yl]oxy)acetate 2 and ethyl 2-(3-cyano-4,6-dimethyl-2-oxopyridin-1[2H]-yl)acetate 3 , the reaction product yield depend on the reaction condition (potassium carbonate concentration and reaction time). These compounds used as precursors to synthesize pyridine derivatives 4 , 6-10 , 15, 17-20 , furopyridines 5, 16 , pyrazolopyridine 12 , pyridopyrazolopyrimidines 14a,b . The structure of the newly synthesized compounds was confirmed by spectral data (IR, NMR, and mass spectra) and elemental analysis.     

硅胶键合N-丙基哌嗪n-丙酸钠作为可循环使用催化剂催化4H-吡喃衍生物合成(英文)

Silica‐bonded N‐propylpiperazine sodium n‐propionate(SBPPSP) was found to act as an efficient solid base for the preparation of a series of 4H‐benzo[b]pyran derivatives. SBPPSP was used as a recyclable heterogeneous solid base catalyst for the synthesis of 3,4‐dihydropyrano[c]chromenes, 2‐amino‐4H‐pyrans, 1,4‐dihydropyrano[2,3‐c]pyrazoles, and 2‐amino‐4H‐benzo[e]‐chromenes via the condensation reaction of dimedone, ethyl acetoacetate, 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐ one, and α‐naphthol, respectively, with aromatic aldehydes and malononitrile in refluxing aqueous ethanol. The heterogeneous solid base showed similar efficiency when reused in consecutive reactions.     

3, 4-二氢嘧啶-2-酮衍生物合成研究进展

综述了近十年来3,4-二氢嘧啶-2-酮衍生物合成的研究进展,包括催化合成、固相合成、微波促进合成及天然产物合成中的一些最新研究进展。     

Novel synthesis of the ortho ester derivative of 4,5-epoxymorphinan

[reaction: see text]. A method was found for the novel synthesis of ortho ester derivatives that are potentially useful as selective epsilon opioid receptor ligands. An unexpected 17-(cyclopropylmethyl)-4,5alpha-epoxy-6alpha-hydroxy-3,7,7-trimethoxy-8-oxa-6,14-endoethanomorphinan was produced when 17-(cyclopropylmethyl)-4,5alpha-epoxy-3-methoxy-6alpha,14-dihydroxy-6beta-(1,3-dithia-2-yl)-morphinan was treated in methanol with trimethyl orthoformate and CuO/CuCl2. This ortho ester derivative was then converted to an ester with acid. The structure of the ortho ester was determined by 2D NMR (HMBC) and mass spectra.     

Pd-catalyzed synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles

An efficient method for the stereoselective synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles via carbopalladation is described. In this approach, an Ugi-4-component reaction (4-CR) adduct was used as the starting material. A one-pot sequence involving intermolecular carbopalladation C-H activation/C-C bond formation efficiently afforded the oxindole derivatives.     

Mechanochemical synthesis and crystal structure of alpha'-AlD3 and alpha-AlD3

AlD3 AlD3 was synthesized by ball milling of 3LiAlD4 + AlCl3. Planetary ball milling at room temperature resulted in a mixture of AlD3 (alpha and alpha') and Al in addition to LiCl, whereas cryomilling at 77 K resulted in only AlD3 and LiCl. The AlD3 obtained was a mixture of about 2/3alpha and 1/3alpha'. Alpha' was determined by powder neutron diffraction to take the beta-AlF3 structure with space group Cmcm and a = 6.470(3), b = 11.117(5), and c = 6.562(2) A. It is built up of corner-sharing AlD6 octahedra in an open structure with hexagonal holes of radius 3.9 A. Alpha' slowly decomposes during storage at 40 degrees C. Alpha-AlD3 is also described by a corner-sharing AlD6 network but in a more dense ReO3-type arrangement. Both AlD3 modifications have slightly shorter Al-D distances compared to Na3AlD6, Na2LiAlD6, and K2NaAlH6.     

Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.     

Electron ionization mass spectral fragmentation of cholestane-3beta,4alpha,5alpha-triol and cholestane-3beta,5alpha,6alpha/beta-triol bis- and tris-trimethylsilyl derivatives

The electron ionization (EI) mass spectral fragmentation of the bis- and tris-trimethylsilyl derivatives of cholestane-3beta,4alpha,5alpha-triol, cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol was investigated. The EI mass spectrum of the 3beta,4alpha-bis-trimethylsilyl derivative of cholestane-3beta,4alpha,5alpha-triol exhibits interesting fragment ions at m/z 142 and 332 resulting from the initial loss of TMSOH between the carbons 2 and 3 and subsequent retro-Diels-Alder (RDA) cleavage of the ring A. Trimethylsilyl transfer between the 4alpha- and the 5alpha-hydroxy groups acts significantly before RDA cleavage affording an ion at m/z 404. Complete silylation of cholestane-3beta,4alpha,5alpha-triol strongly stabilizes the molecule, affording an abundant molecular ion at m/z 636 and decreasing the abundance of the RDA cleavage. Loss of water (from the non-silylated 5alpha-hydroxy group) plays a very important role during the decomposition of the molecular ion of 3beta,6alpha/beta-bis-trimethylsilyl derivatives of cholestane-3beta,5alpha,6alpha/beta-triols. These derivatives appear to be very useful in assigning the configuration of the carbon 6. This assignment is based on the abundance of the fragment ions at m/z 321, 367 and 403, which are more prominent in the EI mass spectrum of the beta-isomer. In contrast, EI mass spectra of the tris-trimethylsilyl derivatives of cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol differ only slightly and appear to be poorly informative.     

Chemoenzymatic synthesis of sialylated glycopeptides derived from mucins and T-cell stimulating peptides.

The Tn, T, sialyl-Tn, and 2,3-sialyl-T antigens are tumor-associated carbohydrate antigens expressed on mucins in epithelial cancers, such as those affecting the breast, ovary, stomach, and colon. Glycopeptides carrying these antigens are of interest for development of cancer vaccines and a short, chemoenzymatic strategy for their synthesis is reported. Building blocks corresponding to the Tn (GalNAc alpha-Ser/Thr) and T [Gal beta(1-->3)GalNAc alpha-Ser/Thr] antigens, which are relatively easy to obtain by chemical synthesis, were prepared and then used in the synthesis of glycopeptides on the solid phase. Introduction of sialic acid to give the sialyl-Tn [Neu5Ac alpha(2-->6)GalNAc alpha-Ser/Thr] and 2,3-sialyl-T [Neu5Ac alpha(2-->3)Gal beta(1-->3)GalNAc alpha-Ser/Thr] antigens is difficult when performed chemically at the building block level. Sialylation was therefore carried out with recombinant sialyltransferases in solution after cleavage of the Tn and T glycopeptides from the solid phase. In the same manner, the core 2 trisaccharide [Gal beta 1-->3(GlcNAc beta 1-->6)GalNAc] was incorporated in glycopeptides containing the T antigen by using a recombinant N-acetylglucosaminyltransferase. The outlined chemoenzymatic approach was applied to glycopeptides from the tandem repeat domain of the mucin MUC1, as well as to neoglycosylated derivatives of a T cell stimulating viral peptide.     

The synthesis of heteroaromatic nitro compounds from 3-nitrochromone

3-Nitrochromone ( 1 ) reacts with a series of nucleophiles by Michael addition followed by intramolecular condensation to yield pyrrolyl ( 2 ), phenyl ( 3 ), pyridyl ( 4 ), pyrido ( 5,6 ), pyrimidyl ( 7 ) and pyrazolyl ( 8 ) nitro derivatives. The reactions proceed under basic catalysis in 39–78% yields. Conversion of 4 to 3,4-dihydrobenzofuro[3,2-b]quinol-1-(2H)one ( 12 ) is also described. Carbon-13 data for 2, 5, 6 and 8 are discussed. The one bond C,H coupling constants in the nitropyridines are also reported and used as an analytical tool.     

Iodohydroxylation of alkylidenecyclopropanes. An efficient synthesis of iodocyclopropylmethanol and 3-iodobut-3-en-1-ol derivatives

A variety of iodocyclopropylmethanol and 3-iodobut-3-en-1-ol derivatives were readily prepared in good to excellent yields via the simple iodohydroxylation reaction of alkylidenecyclopropanes with I(2) and H(2)O. An unexpected rearrangement to give 4-hydroxy-1,2-diphenyl-butan-1-one derivatives was observed compared to the halohydroxylation products.