Subsequent Condensations Research Articles

Proposal of 14- Step Total Synthesis Route of Dihydrolucilactaene, a Potent Antimalarial Compound

Malarial disease has been under heated discussion. The Osada group has extracted and purified pot antimalarial compounds, including dihydrolucilactaene and its derivatives. In this work, a 14-step total synthetic route of Dihydrolucilactaene, the compound with the highest pharmaceutical value among its derivatives, is designed and presented after considering and combining four partially feasible but hindered approaches. The complex molecule is first split into lactam-containing and long unsaturated fragments. The long unsaturated carbon chain can be effectively synthesized by two subsequent aldol condensations and the enabling Wittig reaction. Dicarbonyl synthesis and a basemediated intramolecular nucleophilic attack can synthesize the lactam fragment. The final connection between two fragments are conducted through an enolate attack of electrophilic nitrile followed by hydrolysis. Three protection groups, named trimethyl silyl, acetal, and N-Boc, facilitate the synthesis in the last step. This research successfully developed a 14-step efficient total synthetic route of dihydrolucilactaene with commercially available building blocks and catalysts. The proposed total synthesis route consists of developed and straightforward synthetic methodologies and therefore is expected to be efficient and have a high overall yield.

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides.

We describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long aliphatic chain and on the other side to a glutamic acid residue. The gelator bearing the free carboxylic groups showed a lower gelation capacity than its precursor diester derivative. Some selected gels were further studied by infrared spectroscopy, rheology and electron microscopy. Critical gelation concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition.

Synthesis and Self‐Assembly of NCN‐Pincer Pd‐Complex‐Bound Norvalines

The NCN-pincer Pd-complex-bound norvalines Boc-D/L-[PdCl(dpb)]Nva-OMe (1) were synthesized in multigram quantities. The molecular structure and absolute configuration of 1 were unequivocally determined by single-crystal X-ray structure analysis. The robustness of 1 under acidic/basic conditions provides a wide range of N-/C-terminus convertibility based on the related synthetic transformations. Installation of a variety of functional groups into the N-/C-terminus of 1 was readily carried out through N-Boc- or C-methyl ester deprotection and subsequent condensations with carboxylic acids, R(1)COOH, or amines, R(2)NH2 , to give the corresponding N-/C-functionalized norvalines R(1)-D/L-[PdCl(dpb)]Nva-R(2) 2-9. The dipeptide bearing two Pd units 10 was successfully synthesized through the condensation of C-free 1 with N-free 1. The robustness of these Pd-bound norvalines was adequately demonstrated by the preservation of the optical purity and Pd unit during the synthetic transformations. The lipophilic Pd-bound norvalines L-2, Boc-L-[PdCl(dpb)]Nva-NH-n-C11H23, and L-4, n-C4H9CO-L-[PdCl(dpb)]Nva-NH-n-C11H23, self-assembled in aromatic solvents to afford supramolecular gels. The assembled structures in a thermodynamically stable single crystal of L-2 and kinetically stable supramolecular aggregates of L-2 were precisely elucidated by cryo-TEM, WAX, SAXS, UV/Vis, IR analyses, and single-crystal X-ray crystallography. An antiparallel β-sheet-type aggregate consisting of an infinite one-dimensional hydrogen-bonding network of amide groups and π-stacking of PdCl(dpb) moieties was observed in the supramolecular gel fiber of L-2, even though discrete dimers are assembled through hydrogen bonding in the thermodynamically stable single crystal of L-2. The disparate DSC profiles of the single crystal and xerogel of L-2 indicate different thermodynamics of the molecular assembly process.

Intramolecular Cyclization Manifolds of 4-Alkylpyridines Bearing Ambiphilic Side Chains: Construction of Spirodihydropyridines or Benzylic Cyclization via Anhydrobase Intermediates

4-Alkylpyridines possessing nucleophilic β-dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(O(i)Pr)(4). Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.

Anti-oxidant and anti-bacterial activities of novel N′-arylmethylidene-2-(3, 4-dimethyl-5, 5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl) acetohydrazides

A series of potential anti-oxidant and anti-bacterial N′-arylmethylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetohydrazides was synthesized in a facile way starting from commercially available saccharine. 3,4-Dimethyl-2,4-dihydropyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide was obtained by ring expansion of 2-(2-oxopropyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide followed by N-methylation and cyclization with hydrazine using ultrasonic irradiation. N-alkylation of the cyclized product with methyl chloroacetate followed by its reaction with hydrazine and subsequent ultrasonic mediated condensations with aromatic aldehydes afforded the title compounds. All the synthesized compounds were subjected to the preliminary evaluation for their anti-oxidant and anti-bacterial activities.

Synthesis of 2-{2-hydroxy-3-[2-(vinyloxy)ethoxy]propoxy}-benzaldehyde and Schiff bases derived therefrom

Base-catalyzed reaction of 2-hydroxybenzaldehyde with 2-{[2-(vinyloxy)ethoxy]methyl}oxirane gave 2-{2-hydroxy-3-[2-(vinyloxy)ethoxy]propoxy}benzaldehyde in 42% yield, and subsequent condensations of the product with thiosemicarbazide and primary aliphatic amines afforded the corresponding thiosemicarbazone (yield 86%) and 1-{2-[(alkylimino)methyl]phenoxy}-3-[2-(vinyloxy)ethoxy]propan-2-ols (74–81%).

Enantioselective Synthesis of the Hydroazulene Core of 3α‐Hydroxy‐15‐rippertene

AbstractAs part of a project directed toward the total synthesis of the tetracyclic diterpene 3α‐hydroxy‐15‐rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved by starting from (–)‐isopulegol. A regio‐ and diastereoselective formal hydromethallylation and a regioselective ring expansion served as the key steps in the formation of the seven‐membered ring. Completion of the bicyclic title compounds was then achieved by cyclopentene annulation through diastereoselective conjugate addition of organocuprates and subsequent intramolecular aldol condensations.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Synthesis and characterization of acrylic rubber/silica hybrid composites prepared by sol‐gel technique

AbstractThe organic–inorganic hybrid composites comprising acrylic rubber and silica were synthesized through sol–gel technique at ambient temperature. The composites were generated through the acid‐catalyzed hydrolysis and subsequent condensations of inorganic tetraethoxysilane (TEOS) in the organic acrylic rubber (ACM), solvated in tetrahydrofuran. The morphology of the hybrid materials was investigated by using the transmission electron microscope (TEM) and scanning electron microscope (SEM). Transmission electron micrographs revealed that the silica particles, uniformly distributed over the rubber matrix, are of nanometer scale (20–90 nm). The scanning electron micrographs demonstrated the existence of silica frameworks dispersed in the rubber matrix of the hybrid composites. The X‐ray silicon mapping also supported that observation. There was no evidence of chemical interaction between the rubber phase and the dispersed inorganic phase, as confirmed from the infrared spectroscopic analysis and solubility measurements. Dynamic mechanical analysis indicated mechanical reinforcements within the hybrid composites. The composites containing in situ silica, formed by sol–gel technique, demonstrated superior tensile strengths and tensile modulus values at 300% elongations with increasing proportions of tetraethoxysilane. However, the improvements in physical properties with similar proportions of precipitated silica were not significant. Maximum tensile strength and tensile modulus were obtained when the rubber phase in the hybrid composites was cured with ammonium benzoate and hexamethylenediamine carbamate system, as compared with benzoyl peroxide cured system. Thermal stability of the hybrid composites was not improved appreciably with respect to the virgin rubber specimen. Residue analysis from thermogravimetric study together with infrared spectroscopic analysis indicated the presence of unhydrolyzed tetraethoxysilane in the hybrid composites. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 2579–2589, 2004

Rapid parallel synthesis of polymer-bound enones utilizing microwave-assisted solid-phase chemistry.

A microwave-assisted parallel solid-phase synthesis of a collection of 21 polymer-bound enones has been developed. The two-step protocol involves initial high-speed acetoacetylation of polystyrene Wang resin with a selection of seven common beta-ketoesters. When microwave flash heating at 170 degreesC was employed, complete conversions were achieved within 1-10 min, a significant improvement over the conventional thermal method, which takes several hours for completion. Significant rate enhancements were also observed for the subsequent microwave-heated Knoevenagel condensations with a second set of 13 different aldehydes. Reaction times were reduced to 30-60 min at 125 degreesC in the microwave protocol compared to 1-2 days using conventional thermal conditions. Kinetic comparison studies indicate that the observed rate enhancements can be attributed to the rapid direct heating of the solvent (1,2-dichlorobenzene) by microwaves rather than to any specific microwave effect. All reactions have been carried out in commercially available parallel reactors with on-line temperature measurement, designed specifically for use in multimode microwave cavities.

N-functionalized benzotriazole-1-carboximidoyl chlorides: synthetic equivalents for isocyanide dichlorides.

Readily prepared N-functionalized benzotriazole-1-carboximidoyl chlorides are proposed as stable and novel isocyanide dichloride synthetic equivalents. Subsequent condensations of these new intermediates afford polysubstituted guanidines, S-aryl isothioureas, and 2-aminoquinazolin-4-thiones.

The preparation of 1,5-dioxygenated-pent-2-ynes

1,5-Dioxygenated-pent-2-ynes were prepared via the reductive lithiations of 4-alkoxybut-2-ynylbenzotriazoles and subsequent condensations with ketones and aldehydes.

Free energies and equilibria of peptide bond hydrolysis and formation

For every n amino acids linked in a protein there are n − 1 peptide bonds. The free energy of peptide bond hydrolysis and formation in aqueous solution defines the equilibrium position between peptide and amino acid hydrolysis products. Yet few experimental values exist. With a minimum of assumptions, this paper deduces the free energies of hydrolysis of a variety of peptide bonds. Formation of a dipeptide from two amino acids is about eight times more difficult than subsequent condensations of an amino acid to a dipeptide or longer chain. Condensation of an amino acid to a peptide of any size is five times more difficult than joining two smaller peptides of at least dipeptide size. Thus in an abiogenesis scenario there is a kind of nucleation in peptide bond formation with the initial condensation of two amino acids to yield a dipeptide more difficult than subsequent condensations to a growing chain. © 1998 John Wiley & Sons, Inc. Biopoly 45: 351–353, 1998

Synthesis, properties, and identification of epimeric hepoxilins (−)-(10R)-B 3 and (+)-(10S)-B 3

To characterize the individual epimers of hepoxilin B 3, a new total synthesis procedure was developed consisting of subsequent condensations of enentiomerically pure (2R,3S)-epoxy-5-undecynal with LiCCCH 2Cl and HCC(CH 2) 3COOMe, followed by Lindlar hydrogenation, and finally epimer separation. Derivatives of hepoxilin syn -(10R,11R,12S)-B 3 (free acid, methyl ester and acetate of methyl ester) are more polar on silica gel, have negative optical rotations [α] 25 D −60.6°, −62.6°, −25.2°, respectively, and in 1H NMR spectra have the larger splitting of carbinolic H-10 signal (J 10,11 5.0–6.1 Hz). Corresponding values for less polar hepoxilin anti -(10S,11R,12S)-B 3 derivatives are: [α] 25 D +73.5°, +61.9°, and −2.0°; J 10–11 2.95–3.3 Hz. These data suggest that an epimer of hepoxilin B 3 recently isolated by W.H.Gerwick et al. from red algae is syn -(10R,11R,12S)-B 3.

Synthesis of protected peptide fragments and release from a solid support under neutral conditions

A linker has been developed for use in solid-phase peptide synthesis which allows a protected peptide to be cleaved from the resin under neutral conditions (nBu 3P, DMF, imidazole buffer pH 7) whilst retaining tBuO-, Boc- and Fmoc-protecting groups. The linker comprises a 2-azidomethyl-4-hydroxy-6,N-dimethylbenzamide moiety, which is coupled to polystyrene resin as a phenol ether and to the peptide via a N-hydroxymethyl group. The protected peptide fragments so produced may be useful, for example, in subsequent fragment condensations using the Fmoc-chemistry.

Bis(cyclopentadienyl)titanium(IV)zirconium(IV) derivatives with jäger-type ligands

Bis(cyclopentadienyl)titanium(IV)/zirconium(IV) complexes, [Cp 2M(J-R)] [where M = Ti or Zr and H 2J-R is a Jäger type ligand with bridging group R (ethylene, o-phenylene or 4-methyl- o-phenylene], have been synthesized. The subsequent condensations of the complexes (R = o-phenylene) with o-phenylenediamine have also been studied, which cause ring closure and the formation of cyclic complexes. All these derivatives were characterized by elemental analyses, electrical conductance, magnetic moment and spectral (electronic, IR, 1H NMR) data. 1H NMR spectra of these complexes indicate that there is rapid rotation of the cyclopentadienyl ring about the metal ring axis. The probable structures of the complexes are proposed.

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes : mechanistic and stereochemical details

A detailed investigation of the enolization of ketones with ethylenechloroboronate ( ECB ) in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The enolization with ECB- DPEA system was found to be regioselective except for the case of butanone. The stereochemistry of the enolates derived from ethyl ketones was defined as Z on the basis of 1H-NMR comparison to the Z enolates obtained by a stereodefined route. A mechanistic model for the enolization is proposed to explain the enolization selectivity. E enolates were found to be more reactive than the Z enolates. The product aldol stereochemistry ( syn ) was correlated to the enolate geometry via a chairlike transition state ( Z enolates ) or via a boatlike transition state ( E enolates ).

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes: synthetic applications using thioesters

A detailed Investigation of the enolization of phenyl thiopropionate with ethylenechloroboronate (ECB) and diisopropylethylamine (DPEA) and the subsequent aldol condensations of these enolates was conducted. Alkenyloxy dialkoxyboranes derived from thioesters were found to be stereoconvergent: both Z and E enolates give syn aldol condensation products. The thioester additions to chiral aldehydes were studied. Internal selectivity (syn) was usually very high, while the relative stereoselectivity ranged from poor to good, depending on the specific aldehyde used. The aldol products were transformed to known compounds for correlation.