Benzyl N‐[(Benzyloxy)methyl]carbamate: An Improved Aminomethylation Electrophile for the Synthesis of (Benzyloxy)carbonyl (Cbz)‐Protected Chiral β2‐Amino Acids

α‐Aminomethylation of (R)‐DIOZ‐alkylated (DIOZ=4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐one) substrates is a key step in the asymmetric synthesis of β²‐amino acids, but it is unfortunately often accompanied by formation of transcarbamation by‐products. Aminomethylation was tested using a range of electrophiles, and the amount of by‐product formation was assessed in each case. Benzyl N‐[(benzyloxy)methyl]carbamate electrophile 3d is unable to form this by‐product due to its inherent benzyl substitution. Use of electrophile 3d showed an improved impurity profile in aminomethylation, thus leading to easier intermediate purification.     

Synthesis of Acyclic Nucleosides with N‐[(Benzyloxy)(aryl)methyl] Substituents as Potential HEPT,EBPU, and TNK‐651 Analogues

The syntheses of the novel acyclic nucleosides 5a – 5m , carrying different N‐[(benzyloxy)(aryl)methyl] substituents, are described (Scheme). These compounds could be prepared in medium‐to‐good yields by either direct or silyl‐assisted coupling of the electrophiles 6 with either purine or pyrimidine nucleobases, or with different imidazole derivatives. The reactivity of the positively charged electrophilic intermediates derived from 6 upon Cl^? abstraction was rationalized by ab initio HF/6‐311G quantum‐mechanic calculations. The positive charge was found to be dispersed differently, depending on the electronic properties of the aryl substituents.     

Synthesis of 5‐[(4‐phenylpiperazin‐1‐yl)methyl]pyrrolo‐[2,3‐d]pyrimidine derivatives as potential dopamine D4 receptor ligands

A series of pyrrolo[2,3‐d]pyrimidine Mannich bases of type 9, 12, 15 and 16 have been prepared as potential dopamine D4 receptor ligands. The syntheses start from 4‐aminopyrimidin‐6‐one 3 with pyrrole annulations and Mannich reactions with formaldehyde and phenylpiperazines 8 as new amine components.     

Synthesis of Selectively 15N‐Labeled 2′‐O‐{[(Triisopropylsilyl)oxy]methyl}(=tom)‐Protected Ribonucleoside Phosphoramidites and Their Incorporation into a Bistable 32Mer RNA Sequence

We present optimized reaction conditions for the conversion of 2′‐O‐{[(triisopropylsilyl)oxy]methyl}(=tom) protected uridine and adenosine nucleosides into the corresponding protected (3‐¹⁵N)‐labeled uridine and cytidine and (1‐¹⁵N)‐labeled adenosine and guanosine nucleosides 4, 6, 12 , and 18 , respectively (Schemes 1–4). On a DNA synthesizer, the resulting ¹⁵N‐labeled 2′‐O‐tom‐protected phosphoramidite building blocks 19 – 22 were efficiently incorporated into five selected positions of a bistable 32mer RNA sequence 23 (known to adopt two different structures) (Fig. 1). By 2D‐HSQC and HNN‐COSY experiments in H₂O/D₂O 9 : 1, the ¹⁵N‐signals of all base‐paired ¹⁵N‐labeled nucleotides could be identified and attributed to one of the two coexisting structures of 23 .     

5‐Aza‐7‐deazaguanine DNA: Recognition and Strand Orientation of Oligonucleotides Incorporating Anomeric Imidazo[1,2‐a]‐1,3,5‐triazine Nucleosides

The base‐pairing properties of oligonucleotides containing the anomeric 5‐aza‐7‐deazaguanine 2′‐deoxyribonucleosides 1 and 5 are described. The oligonucleotides were prepared by solid‐phase synthesis, employing phosphoramidite or phosphonate chemistry. Stable `purine'⋅purine duplexes with antiparallel (aps) chain orientation are formed, when the α‐D ‐anomer 5 alternates with the β‐D ‐anomeric 2′‐deoxyguanosine ( 2 ) within the same oligonucleotide chain. Parallel (ps) oligonucleotide duplexes are observed, when the β‐D anomer 1 alternates with 2 . A renewed reversal of the chain orientation (ps→aps) occurs when compound 1 pairs with 2′‐deoxyisoguanosine ( 6 ). In all cases, it is unnecessary to change the orientation within a single strand when α‐D units alternate with their β‐D counterparts. Heterochiral base pairs of 5 (α‐D ) with 2′‐deoxyisoguanosine (β‐D ) are well accommodated in duplexes with random base composition and parallel chain orientation. Base pairs of 5 (α‐D ) with 2′‐deoxyguanosine (β‐D ) destabilize duplexes with antiparallel chains.     

Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu Reaction: O2‐ vs. N1‐Alkylation

The Mitsunobu reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocyclic bases under mild conditions. Chemical evidences for an unusual competitive O²‐ vs. N¹‐alkylation of 3‐substituted pyrimidines is presented.     

Modeling the cyclopolymerization of diallyl ether and methyl α‐[(allyloxy)methyl]acrylate

The free‐radical cyclopolymerization of diallyl ether (1) and methyl α‐(allyloxymethyl)acrylate (2) has been modeled with the B3LYP/6‐31G* methodology, by making use of model compounds for the growing radicals. The cyclization of both monomers is exo, with activation barriers of 5.33 and 9.82 kcal/mol, respectively. To account for the polymerizabilities of these monomers, competing reactions have also been modeled. Although both monomers have a lower barrier for homopolymerization than for cyclization, cyclization dominates due to entropy. This explains the high cyclopolymerization vs. homopolymerization of monomer 2, although its monofunctional counterpart has been reported to homopolymerize well. It has also been shown that the degradative chain transfer by H‐abstraction from the allylic carbon is not effective with this monomer. Poor cyclopolymerization of the monomer 1 has been demonstrated by modeling the degradative chain transfer by H‐abstraction from the allylic carbon, which has been shown to compete very efficiently with polymerization reactions. Additionally, intermolecular propagation reaction has been shown to be facile due to cyclization, since the attacking monomer adopts a cyclic structure. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Incorporation of 5‐Hydroxyindazole into the Self‐Polymerization of Dopamine for Novel Polymer Synthesis

Investigation into the mussel‐inspired polymerization of dopamine has led to the realization that other compounds possessing potential quinone structures could undergo similar self‐polymerizations in mild buffered aqueous conditions. To this end, 5‐hydroxyindazole was added to a dopamine polymerization matrix in varying amounts, to study its incorporation into a polydopamine coating of silica particles. Solid‐state ¹³C NMR spectroscopy confirmed the presence of the indazole in the polymer shell when coated onto silica gel. SEM and DLS analysis also confirmed that the presence of the indazole in the reaction matrix yielded monodisperse polymer‐coated particles, which retained their polymer shell upon HF etching, except when high levels of the indazole were used. Characterization data and examination of incorporation mechanism suggests that the 5‐hydroxyindazole performs the function of a chain‐terminating agent. Cytotoxicity studies of the polymer particles containing 5‐hydroxyindazole showed dramatically lower toxicity levels compared to polydopamine alone.

     

Synthesis of (P)‐ and (M)‐6,7‐Bis[(diphenylphosphanyl)methyl]‐8,12‐diphenylbenzo[a]heptalenes – Potential Ligands for Homogeneous Asymmetric Catalysis

The title bis(phosphane) ligands have been prepared starting from optically pure diisopropyl (P)‐ and (M)‐8,12‐diphenylbenzo[a]heptalene‐6,7‐dicarboxylates ((P)‐ 1b and (M)‐ 1b ) that had been obtained by HPLC separation of rac‐ 1b on a semi‐preparative Chiralcel OD column. Reduction of (P)‐ 1b and (M)‐ 1b with diisobutylaluminum hydride (DIBAH) gave optically pure (P)‐ and (M)‐dimethanols 3 (Scheme 6 and Fig. 5). Unfortunately, the almost quantitative chlorination of rac‐ 3 with PCl₅ in CHCl₃ at −60° led with (M)‐ 3 to nearly complete loss of optical integrity. However, mesylate formation of (P)‐ 3 , followed by phosphanylation with LiP(BH₃)Ph₂ gave (P)‐ 6 with only a small loss of optical activity. Optically pure (P)‐ 6 was obtained by crystallization from Et₂O/hexane, which removed the nearly insoluble rac‐ 6 . The pure bis(phosphane) ligands (P)‐ 2 and (M)‐ 2 can be liberated quantitatively from 6 by warming 6 in toluene in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO). First Rh^I‐catalyzed asymmetric hydrogenation reactions of (Z)‐α‐(acetamido)cinnamic acid ((Z)‐ 14 ) in the presence of (P)‐ 2 led to (R)‐N‐acetylphenylalanin ((R)‐ 15 ) in optical purities up to 77% (see Table 1).     

Four related diethyl [(arylamino)(4‐ethynylphenyl)methyl]phosphonates

Crystal structures are reported for four related diethyl [(arylamino)(4‐ethynylphenyl)lmethyl]phosphonate derivatives, namely diethyl [(4‐bromoanilino)(4‐ethynylphenyl)methyl]phosphonate, C₁₉H₂₁BrNO₃P, (I), diethyl ((4‐chloro‐2‐methylanilino){4‐[2‐(trimethylsilyl)ethynyl]phenyl}methyl)phosphonate, C₂₃H₃₁ClNO₃PSi, (II), diethyl ((4‐fluoroanilino){4‐[2‐(trimethylsilyl)ethynyl]phenyl}methyl)phosphonate, C₂₂H₂₉FNO₃PSi, (III), and diethyl [(4‐ethynylphenyl)(naphthalen‐2‐ylamino)methyl]phosphonate, C₂₃H₂₄NO₃P, (IV). The conformation of the anilinobenzyl group is very similar in all four compounds. The P—C bond has an approximately staggered conformation, with the aniline and ethynylphenyl groups in gauche positions with respect to the P=O double bond. The two six‐membered rings are almost perpendicular. The sums of the valence angles about the N atoms vary from 344 (2) to 351 (2)°. In the crystal structures, molecules of (I), (III) and (IV) are arranged as centrosymmetric or pseudocentrosymmetric dimers connected by two N—H...O=P hydrogen bonds. The molecules of (II) are arranged as centrosymmetric dimers connected by C_methyl—H...O=P hydrogen bonds. The N—H bond of (II) is not involved in hydrogen bonding.     

Synthesis and Antimicrobial Evaluation of (1‐(2‐(Benzyloxy)‐2‐oxoethyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl Benzoate Analogues

A convenient one pot synthesis of 20 (1‐(2‐(benzyloxy)‐2‐oxoethyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl benzoate analogues ( 5a – 5t ) with ester functionality was carried out via Cu(I) catalyzed click reaction between prop‐2‐yn‐1‐yl benzoates and benzyl 2‐azidoacetates. The structure of synthesized triazoles were explicated by various spectral techniques like FT‐IR, ¹H NMR, ¹³C NMR, and high‐resolution mass spectrometry and evaluated for in vitro antimicrobial potential against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Candida albicans, and Aspergillus niger. Most of synthesized triazole derivatives exhibited average to excellent activity against tested microbial strains.     

Conformational isomers of the [(5‐methyl‐2‐pyridinio)aminomethylene]diphosphonate dianion and [(5‐methyl‐2‐pyridyl)aminomethylene]diphosphonate trianion in salts with 4‐aminopyridine and ammonia

The crystal structures of two salts, products of the reactions between [(5‐methyl‐2‐pyridyl)aminomethylene]bis(phosphonic acid) and 4‐aminopyridine or ammonia, namely bis(4‐aminopyridinium) hydrogen [(5‐methyl‐2‐pyridinio)aminomethylene]diphosphonate 2.4‐hydrate, 2C₅H₇N₂⁺·C₇H₁₀N₂O₆P₂²⁻·2.4H₂O, (I), and triammonium hydrogen [(5‐methyl‐2‐pyridyl)aminomethylene]diphosphonate monohydrate, 3NH₄⁺·C₇H₉N₂O₆P₂³⁻·H₂O, (II), have been determined. In (I), the Z configuration of the ring N—C and amino N—H bonds of the bisphosphonate dianion with respect to the C_ring—N_amino bond is consistent with that of the parent zwitterion. Removing the H atom from the pyridyl N atom results in the opposite E configuration of the bisphosphonate trianion in (II). Compound (I) exhibits a three‐dimensional hydrogen‐bonded network, in which 4‐aminopyridinium cations and water molecules are joined to ribbons composed of anionic dimers linked by O—H...O and N—H...O hydrogen bonds. The supramolecular motif resulting from a combination of these three interactions is a common phenomenon in crystals of all of the Z‐isomeric zwitterions of 4‐ and 5‐substituted (2‐pyridylaminomethylene)bis(phosphonic acid)s studied to date. In (II), ammonium cations and water molecules are linked to chains of trianions, resulting in the formation of double layers.     

[(4,4‐Dimethyl‐2‐oxo‐1,3‐oxazolidin‐3‐yl)methyl]phosphonic acid

The title compound, C₆H₁₂NO₅P, was synthesized as an inter­mediate phase in a search for new N‐(phosphono­methyl)glycine derivatives. The mol­ecules are held together by O—H⋯O hydrogen bonds, forming chains along the b axis in the crystal structure. The observed mol­ecular structure is compared with that calculated by the density functional theory method.     

Synthesis and Incorporation of C(5′)‐Ethynylated Uracil‐Derived Phosphoramidites into RNA

The D ‐allo‐ and L ‐talo‐hept‐6‐ynofuranosyluracil‐derived phosphoramidites 11A and 11T were prepared in 9–10% yield over eight steps from the previously described propargylic alcohols 1A and 1T , respectively. The corresponding nucleotides were incorporated into rU₁₄ by standard solid‐phase synthesis. While the duplex consisting of rU₁₄ with one L ‐talo‐hept‐6‐ynofuranosyluracil in the middle of the strand and rA₁₄ ( I ? V ) had the same melting point as the reference duplex rU₁₄?rA₁₄ ( I ? II ), the duplex with one D ‐allo‐hept‐6‐ynofuranosyluracil in the middle of rU₁₄ and rA₁₄ ( I ? III ) melted 1.5° lower than the reference duplex. The duplex I ? VI consisting of rU₁₄ with six L ‐talo‐hept‐6‐ynofuranosyluracils distributed over the entire strand and rA₁₄ showed a melting point that is 11° lower than the reference duplex. The corresponding duplex I ? IV of rU₁₄ possessing six D ‐allo‐hept‐6‐ynofuranosyluracils and rA₁₄ showed a melting point which is more than 20° below the one of the reference duplex. These results are in qualitative agreement with the predictions based on the conformational analysis of the nucleosides and the interference of the ethynyl moiety with the hydration of the oligonucleotides.     

Nucleosides XII.1 Synthesis of 5‐Modified Isoguanosines and Reinvestigation of 5′‐Deoxy‐N3,5′‐cycloisoguanosine

Isoguanosine ( 3 ) underwent a coupling reaction with diaryl disulfides in the presence of tri‐n‐butylphosphine when its 6‐amino group was protected by N,N‐dimethylaminomethylidene. The synthesis of 5′‐deoxy‐N³,5′‐cycloisoguanosine ( 6 ) and its 2′,3′‐O‐isopropylidene derivative ( 11 ) were accomplished in excellent yields from isoguanosines ( 3 & 10 ) in the presence of triphenylphospine and carbon tetrachloride in pyridine. Chlorination at the 5′‐position of isoguanosine ( 3 ) with thionyl chloride followed by the aqueous base‐promoted cyclization afforded the same product 6 . The structures were elucidated by spectroscopic analysis including IR, UV, 1‐D and 2‐D NMR.     

2‐Amino‐4‐chloro‐5‐formyl‐6‐[methyl(2‐methylphenyl)amino]pyrimidine and 2‐amino‐4‐chloro‐5‐formyl‐6‐[(2‐methoxyphenyl)methylamino]pyrimidine are isostructural and form hydrogen‐bonded sheets of R22(8) and R66(32) rings

2‐Amino‐4‐chloro‐5‐formyl‐6‐[methyl(2‐methylphenyl)amino]pyrimidine, C₁₃H₁₃ClN₄O, (I), and 2‐amino‐4‐chloro‐5‐formyl‐6‐[(2‐methoxyphenyl)methylamino]pyrimidine, C₁₃H₁₃ClN₄O₂, (II), are isostructural and essentially isomorphous. Although the pyrimidine rings in each compound are planar, the ring‐substituent atoms show significant displacements from this plane, and the bond distances provide evidence for polarization of the electronic structures. In each compound, a combination of N—H...N and N—H...O hydrogen bonds links the molecules into sheets built from centrosymmetric R₂²(8) and R₆⁶(32) rings. The significance of this study lies in its observation of the isostructural nature of (I) and (II), and in the comparison of their crystal and molecular structures with those of analogous compounds.     

Synthesis and Mesomorphic Properties of Poly(oxyethylene) with [(6‐Heptylsulfonyl)hexylthio]methyl Side Groups

[(6‐Heptylsulfonyl)hexylthio]methyl‐substituted poly(oxyethylene) bearing a very polar sulfone group in the middle of the alkyl side chain was successfully synthesized by the reaction of poly[oxy(chloromethyl)ethylene] and (6‐heptylsulfonyl)hexyl thioacetate with sodium ethoxide in N,N‐dimethylacetamide. The ordered phase of the polymer was studied using X‐ray diffraction, differential scanning calorimetry, and IR spectroscopy. The polymer was found to be liquid crystalline, although not having any conventional mesogenic group. It was suggested that the highly polar sulfone group in the side chain induces the self‐assembly of the liquid crystalline phase.     

Nucleosides CIII. Anhydropyrimidine-C-nueleosides. Synthesis of 4,2′-anhydro-5-(β-D-arabinofuranosyl)- and 5-(β-D-arabinofuranosyl)pyrimidine C-nucleosides

4,2′-Anhydro-5-(β-D -arabinofuranosyl)isocytosine and 4,2′-anhydro-5-(β-D -arabinofuranosyl)-uracil were synthesized. Treatment of Ψ-isocytidine with either α-acetoxyisobutyryl chloride or salicyloyl chloride in acetonitrile afforded the acylated anhydronucleoside. Deacylation of the product with methanol-hydrogen chloride afforded 4,2′-anhydro-5-(β-D -arabinofuranosyl)isocylosine hydrochloride in crystalline form. Analogous reaction of Ψ-uridine with the acyl chloride reagents, however, always gave a mixture of the acylated anhydronucleoside and 2′-chloro-2′-deoxy-Ψ-uridine. Treatment of these products either singly or as a mixture with sodium methoxide in methanol afforded 4,2′-anhydro-5-(β-D -arabinofuranosyl)uracil in crystalline form in good yield. 5-(β-D -Arabinofuranosyl)isocytosine was obtained upon treatment of the corresponding 4,2′-anhydronucleoside with 10% sodium hydroxide under reflux for 30 minutes. Treatment of the anhydro uracil nucleoside with a small amount of Dowex 50(H⁺) in water at 50° gave 5-(β-D -arabinofuranosyl)uracil.