2,3-O-Methyl cellulose: studies on synthesis and structure characterization

The synthesis of methyl celluloses with a regioselective functionalization in position 2 and 3 starting from trityl cellulose is described. The effects of methylation conditions upon the degree of substitution (DS) and the distribution of the methyl moieties were investigated in detail. The synthesis was focused on products with a DS < 2. The methyl celluloses were characterized by one and two dimensional NMR spectroscopy in order to determine the substitution pattern and quantify the fractions of the different repeating units, i.e., 2,3-di-O-, 2-mono-O-, 3-mono-O-methyl units, and non-methylated anhydroglucose units.     

Polyglucane derivatives with regular substituent distribution

6-O-trialkylsilyl celluloses, 2,3-O-carboxymethylcelluloses, cellulose-3-O-sulfate, and carboxymethylcellulose block copolymers were synthesized by regioselective functionalization of cellulose and of soluble cellulose intermediates like silyl and methoxy-substituted trityl ethers as well as formates and trifluoroacetates. The preparation and structure characterization (NMR, FTIR, HPLC after chain degradation) of those polyglucane derivatives with regular substituent distribution is of importance to design self-assembly systems and supramolecular structures (liquid-crystalline media, ultrathin films, recognition and bioactive materials).     

Conformational study and electron density analysis of 9-[tetrahydropyran-3-yl]purine derivatives

A conformational analysis was carried out on cis-6-chloro-9-[2-(2-hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-yl]purine and several related model compounds at the HF/6-31++G(d,p) and B3LYP/6-311++G(2d,2p) levels, and also using the semiempirical methods AM1 and PM3. The result of this analysis shows that the molecule prefers an axial disposition of the purine ring, with an approximate cis orientation of C4-N9-C1′-H1′ dihedral angle. The stability of this conformation comes mainly from the formation of a C-H?O?H-O intramolecular three-center hydrogen bond. In this structure, the tetrahydropyran oxygen acts as an acceptor, while both H8 of the purine ring and the hydroxylic hydrogen of the hydroxyethyl group act as donors. Also, the equatorial disposition of the hydroxyethyl group in this conformer reduces its repulsions with the purine ring and the tetrahydropyran hydrogens. The quantum theory of atoms in molecules was applied to study the electronic effects produced by the conformational changes, bonding between tetrahydropyran and purine rings, chlorine substitution, and intramolecular hydrogen bonding.     

Synthesis of a tetrahydropyran NK1 receptor antagonist via asymmetric conjugate addition

Two asymmetric syntheses of the NK(1) receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpiperidine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereochemistry was established by asymmetric conjugate addition to an alpha,beta-unsaturated ester (6), using an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3) was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was appended to the Michael acceptor at the beginning.     

The development of an approach toward sterically-hindered chiral 2′-aryl-1,1′-binaphthalenes functionalized at position 2

Several approaches were examined for the preparation of 1,1′-binaphthalene derivatives bearing sterically demanding ortho-substituted aryl at position 2′ which are suitable for further functionalization at position 2. Steric hindrance of ortho-substituted aryl groups was critical for the approach through BINOL monotriflate. Among variations of cross-coupling reactions of 2,2′-dihalo-1,1′-binaphthalenes, Negishi arylation of an enantiopure 2,2′-dibromide was found to be the method of choice for regioselective and stereoconservative preparation of the target 2′-monoarylated precursor. Functionalization of the latter at position 2 was demonstrated by bromine substitution via lithiation followed by the reaction with several electrophiles.     

Stereoselective synthesis of both tetrahydropyran rings of the antitumor macrolide, (-)-lasonolide A

Stereoselective syntheses of both functionalized tetrahydropyran subunits of (-)-lasonolide A are described. These tetrahydropyran rings were constructed using catalytic asymmetric hetero Diels-Alder reactions as the key steps. The C22 quaternary stereocenter present in the upper tetrahydropyran ring was constructed by a stereoselective alkylation, and the C9 hydroxy stereochemistry of the bottom tetrahydropyran was constructed by a stereoselective epoxidation followed by a regioselective epoxide opening reaction.     

Studies on Non-natural Deoxyammonium Cellulose

Summary: Ammonium group containing cellulose derivatives are prepared from homogeneously synthesized cellulose p-toluenesulfonic acid esters (tosyl cellulose) by conversion with sodium azide and subsequent reduction of the azido moiety applying NaBH₄/CoBr₂/2,2′-bipyridine as reagent. Regarding the tosylation, cellulose samples of different degree of polymerization and hemicellulose content possess a different reactivity. The deoxyamino cellulose is water soluble in the protonated state. Elemental analysis, FTIR- and NMR spectroscopy were carried out to analyze the degree of substitution and functionalization pattern. It was also studied to synthesize deoxyazido celluloses without isolation of the tosyl cellulose. However, a predominant formation of deoxychloro moieties occurs.     

Hydrogen bonds in regioselectively substituted cellulose derivatives

Formation of hydrogen bonds in various cellulose derivatives, 2,3-di-O- and 6-O-substituted cellulose ethers, were characterized by FTIR and solid-state CP/MAS¹³C-NMR. The polymers were synthesized by regioselective substitution of hydroxyl groups and had a uniform structure. Since their three hydroxyl groups (OH) are selectively blocked, the cellulose derivatives appeared to form specific inter- and intramolecular hydrogen bonds. The characteristic OH stretching frequencies in IR spectra and the C-1 chemical shift in CP/MAS spectra of 6-O-substituted cellulose derivatives indicated existence of two equivalent intramolecular hydrogen bonds between ether oxygen and OH groups at 3-OH-O5′ and O6-HO-2′ [Figure 3(C)]. Influence of the substituents at the C-6 position on the formation was not significant except trityl group. Behavior of the hydrogen bonds in 6-O-tritylcellulose were also discussed. © 1994 John Wiley & Sons, Inc.     

A "click and activate" approach in one-pot synthesis of a triazolyl-pyridazinone library

A "click and activate" strategy was designed and executed in a four-component, stepwise condensation that led to a trisubstituted triazolyl-pyridazinone library. This one-pot process included regioselective azide substitution at 2-substituted-4,5-dichloropyridazinones, followed by a Cu(I) catalyzed triazole formation which triggered subsequent nucleophilic substitution at the neighboring position to achieve three points of diversity.     

Single and Consecutive Cyclization Reactions of Alkynyl Carbene Complexes and 8‐Azaheptafulvenes: Direct Access to Polycyclic Pyrrole and Indole Derivatives

The reactivity of alkynyl and enynyl Fischer carbene complexes towards 8‐azaheptafulvenes is examined. Alkynyl carbenes 1 a – f undergo regioselective [8+2] heterocyclization with 8‐aryl‐8‐azaheptafulvenes 2 a , b providing cycloheptapyrroles 3 and 4 with metal carbene or ester functionality at C3. Moreover, consecutive cyclization reactions are involved when enynyl carbenes are used. Thus, the cyclopenta[b]pyrrole framework 7 is formed by the consecutive [8+2] cyclization and cyclopentannulation reactions. The initially formed cyclopentannulation adduct can be intercepted through a Diels–Alder reaction with classic dienophiles to afford increasing structural complexity (compounds 8 and 9 ). More importantly, the construction of the indole skeleton is accomplished with a high degree of substitution and functionalization (compounds 11 – 15 ) by a one‐pot sequence that involves [8+2] cyclization, R? NC or CO insertion, and ring closure.     

Synthesis of angularly fused cyclopentanoids and analogous tricycles via photoinduced ketyl radical/radical anion fragmentation-cyclization reactions

Angular fused tricycles were synthesized through intramolecular tandem fragmentation-cyclization reactions by photochemically induced electron transfer (PET) of tricyclic α-cyclopropyl ketones with an unsaturated side chain at the position γ to the carbonyl group. The reactions resulted in regioselective cleavage of a β-cyclopropyl bond with formation of angular fused tricyclic ring systems via ketyl radical/radical anions as reactive intermediates. In general, triethylamine (TEA) was used as a strong reducing reagent in acetonitrile. The preferred regioselectivity of the cyclization step (exo vs endo) depending on the substitution pattern at the quaternary carbon center (Cβ′) of the tricyclic α-cyclopropyl ketones was investigated. In addition, we also checked a two-step pathway for the synthesis of angular dioxa-triquinanes including photolysis of an allyloxy-substituted cyclopenta[c]furanone derivative and subsequent β-cleavage of the resulted dioxa-[4.5.5.5]fenestrane under reductive PET conditions.     

Regioselection and orthogonality of the 1-phenyl-3-butenyl (PBU) protecting group in glucopyranosides

The 1-phenyl-3-butenyl (PBU) protecting group was alternatively introduced in position 4 or 6 by regioselective opening of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-alpha-D-glucopyranose with allyltrimethylsilane in the presence of the Lewis acid promoters TMSOTf or AlCl3. The PBU group was selectively removed, in presence of t-butyldimethylsilyl, trityl or acetyl protecting groups, with acids (TFA) or using Pd(CH3CN)2Cl2.     

Removal of acid-labile protecting groups on carbohydrates using water-tolerant and recoverable vanadyl triflate catalyst

Acetal, trityl, and TBDMS protecting groups on saccharides were subjected to alcoholysis using a catalytic amount of vanadyl triflate in an MeOH-CH2Cl2 solvent system. The configuration at the anomeric positions of saccharides was retained, and no glycosidic bond cleavage and oxidation of sulfides were observed. The presented method was easily implemented, compatible with diverse functional groups, and regioselective in some cases.     

Antimalarials: Synthesis of 4-aminoquinolines that circumvent drug resistance in malaria parasites

The strategies described here have permitted the synthesis of a series of 4-aminoquinoline antimalarials. Substantive improvements over previous syntheses include nucleophilic substitution with neat amine rather than in phenol, regioselective reductive alkylation to convert the terminal primary amine (12a–20a) on the diaminoalkane side chain to a diethylamino group, and purification by column chromatography with basic alumina. The ¹H nmr spectra obtained after regioselective reductive alkylation with sodium borodeuteride (in comparison with sodium borohydride) demonstrated that this reductive alkylation proceeds via formation and subsequent reduction of the corresponding diamides in situ.     

光引发剂多羟基胺连硫杂蒽酮的甲基取代效应

用¹³CNMR,UV-Vis及荧光光谱等研究甲基取代对2-[2-羟基-3-(双(2-羟乙基)氨基)]丙氧基硫杂蒽酮光引发剂分子构象及光化学性能的影响.发现当其1,3-位均有甲基取代时,2-位烷氧基受邻位两个甲基的空间排斥作用,导致其光谱性质和光化学性能异常.     

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho‐C?H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n‐hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2‐arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site‐selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron‐withdrawing substituents (e.g. chlorine and fluorine). By fine‐tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3‐trisubstitution, 1,2,3,4‐tetrasubstitution, and 1,2,3,4,5‐pentasubstitution, up to the exhaustive substitution of the aromatic ring.     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

Synthesis of polymers with hydroxyl end groups by atom transfer radical polymerization

Polymers prepared by atom transfer radical polymerization (ATRP) contain end groups defined by the initiator used. Alkyl halides, used as initiators, lead to polymers with an alkyl group at one end and a halide as the other chain end. Using functionalized initiators such as 2‐hydroxyethyl 2‐bromopropionate, hydroxyl groups can be directly incorporated at one polymer chain end while the other end functionality remains a halogen. The direct displacement of the halogen end groups with hydroxyl groups was unsuccessful due to side reactions such as elimination (for polystyrene) or hydrolysis of ester functions (for polyacrylate). Another approach to generate hydroxyl end groups was based on the substitution of the halogen end groups by ethanolamine. This was successful for polystyrene but additional substitution at the backbone esters was observed in polyacrylates. Multiple substitution reactions could be avoided by using 4‐aminobutanol instead of 2‐aminoethanol. Hydroxyl terminated polyacrylates were also obtained by extending the polyacrylate chain end with one allyl alcohol unit in a one‐pot process by adding an excess of allyl alcohol at the end of e polymerization of acrylate.     

Synthesis of C-19-functionalized 1alpha-hydroxyvitamin D(2) analogues via ring-closing metathesis

A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of 1alpha-hydroxy-5,6-trans-vitamin D(2) analogues. Applications of the reaction to form a range of analogues by manipulation of the tether using both organolithium reagents and Diels-Alder cycloadditions are described.