Synthesis of chiral β-3-amino-2-hydroxyalkanoates and 3-alkyl-3-hydroxy-β-lactams by double asymmetric induction

Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (S_S)- and (S_R)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogonally protected 3-amino-2-hydroxyalkanoates in the form of N-sulfinyl protected 1′-aminodioxolan-4-ones. The product distribution showed that there is significant kinetic selectivity, due to the presence of ‘matched’ and ‘mismatched’ components, between the (S)- or (R)-tert-butylsulfinyl aldimines and the (2S)-enolates of the 1,3-dioxolan-4-ones. Selective methoxide-induced removal of the acetal group of the N-sulfinyl-1′-aminodioxolanones yielded the corresponding N-sulfinyl protected methyl alkanoates. In addition, the selective acid-induced removal of the sulfinyl group of the N-sulfinyl-1′-aminodioxolanones provided the corresponding N-unprotected 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding β-lactams.     

Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids

Enantiopure 1-acyl-3-hydroxyl-4-CF₂H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF₃-azetidin-2-ones serve as versatile intermediates for the syntheses of CF₂- and CF₃-containing α-hydroxy-β-amino acids, dipeptides, and taxoid anticancer agents. Both enantiomers of 3-hydroxy-4-CF₂H-β-lactams can be obtained in high yields through the diethylaminosulfur trifluoride (DAST) reaction of the corresponding enantiopure 4-formyl-β-lactam that is prepared through [2+2] cycloaddition of acetoxyketene to a 3-methyl-2-butenaldimine, followed by enzymatic optical resolution and ozonolysis. (+)-3-Hydroxy-4-CF₃-β-lactams and (−)-3-hydroxy-4-CF₃-β-lactams can also be readily obtained in enantiopure form through [2+2] cycloaddition of a CF₃-imine with a ketene, followed by enzymatic optical resolution. Practical processes for the preparations of these enantiopure 3-hydroxy-4-R_f-β-lactams as well as their synthetic applications are described.     

Influence of cyclodextrins on nitrosation of drugs

The World Health Organization issued a nitrosation procedure (NAP Test) which allows to carry out nitrosation under standard conditions. It has proved that the in vitro reaction rates of the fast nitrosatable drugs piperazine, cimetidine and ethambutol are not influenced by -, - and -cyclodextrin. On the contrary, -, -cyclodextrin and heptakis-2,6-di-O-methyl--cyclodextrin enhance the nitrosation of the slower nitrosatable 1-ephedrine and fencamfamine significantly. This possible reaction must be considered if nitrosatable drugs are formulated with cyclodextrins to be administered to human beings.     

Reaction of a 5α-bromo-6β,19-epoxysteroid with BF3·Et2O/Ac2O: An evidence of a cyclic bromonium cation

Treatment of 3β-acetoxy-5-bromo-6β,19-epoxy-5α-androstan-17-one with Ac₂O and BF₃·OEt₂, produced the cleavage of the epoxy moiety and migration of the bromine atom to afford 3β,19-diacetoxy-6α-bromo-5-hydroxy-5β-androst-17-one in high yield.     

Complexation of 6-Deoxy-6-(aminoethyl)amino-β-cyclodextrin with Sodium Cholate and Sodium Deoxycholate

In order to study its guest binding and the inclusion phenomena, 6-deoxy-6-(aminoethyl)amino--cyclodextrin (CDN) was synthesised and its binding properties examined. The complexation phenomena of sodium cholate (NaC) and sodium deoxycholate (NaDC) with CDN has been monitored by the NMR method using ¹³C chemical shift data. The method of continuous variation Job's method has been used to determine the stoichiometry of these supramolecular complexes. The Job's plot confirms the 1 : 1 supramolecular complex for NaC: CDN and the 1 : 2 supramolecular complex for NaDC: CDN. The interaction of NaC and NaDC with CDN has been obtained through two-dimensional Rotational Nuclear Overhauser Effect Spectroscopy (ROESY) NMR. Equilibrium constants were also obtained from ¹³C chemical shift data (C-1, C-3 & C-4) at different pH values (7, 9, & 11).     

Enhancement of Oral Bioavailability of Rofecoxib Using β-Cyclodextrin

The purpose of the present work was to investigate the effect ofcomplexation of rofecoxib with -cyclodextrin on its dissolutioncharacteristics and bioavailability. Inclusion complexes of rofecoxibwith -cyclodextrin were made by freeze-drying technique. Phasesolubility studies were conducted as suggested by Higuchi and Connors.The samples were characterized by performing dissolution studies, X-rayDiffraction studies and Differential Scanning Calorimetry. The complexeswere compressed into tablets and compared in-vitro with various marketedformulations. A single dose study on healthy human volunteers was performedin comparison with a marketed formulation of rofecoxib (without-cyclodextrin) to investigate the relative bioavailability.Phase solubility studies confirmed the formation of a 1 : 1complex in solution of rofecoxib with -cyclodextrin. Tablets ofsolid inclusion complexes of rofecoxib with -cyclodextrin preparedby freeze drying technique showed enhanced dissolution rate in distilledwater in comparison with all the marketed formulations analyzed. This isattributed to the increased solubility and wettability along with decreasedcrystallinity caused by complex formation, which is confirmed, by XRD and DSCstudies. The bioequivalence studies performed showed statistically significantenhancement in bioavailability as compared to the marketed formulation.Apparently, tablets containing complexes of rofecoxib with -cyclodextrinshows faster onset of action due to improved solubility, enhanced dissolutionand faster absorption of the molecule. The results of this investigation withrofecoxib in -cyclodextrin lend ample credence to its better oralbioavailability on complexation.     

Fabrication of MCM-41 mesoporous silica through the self-assembly supermolecule of β-CD and CTAB

Using the self-assembly β-cyclodextrin (β-CD) and cetyltrimethylammonium bromide (CTAB) as structure-directing agents, high-quality ordered MCM-41 silicas have been prepared. Small-angle X-ray diffraction (SXRD), N₂ adsorption-desorption and scanning electron microscope (SEM) techniques were used to characterize the calcined samples. Results showed that the pore structure of the resulting mesoporous silica belonged to the two-dimensional hexagonal structure (space group p6mm). The high-quality hexagonal structure was formed as n?1 (n denotes molar ratio of β-CD to CTAB). N₂ adsorption-desorption curves revealed type IV isotherms, H4 hysteresis loops, for all samples, and H1 hysteresis loops for samples at n=0, 0.1, 1 and 2, respectively. The pore size and the pore wall thickness of the samples increased with the increase in n values, respectively.     

Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes

Ternary complexes exploiting solubility synergism (SSn) between basic drugs and β-cyclodextrin (β-CD) in the presence of an organic hydoxy acid have been reported to provide the pharmaceutical technology with highly soluble ternary complexes, even with the least soluble β-CD. In this work, phase solubility techniques were used to study factors affecting SSn in aqueous solution, which may help in understanding the mechanism involved in ternary complex formation in solution, under equilibrium conditions. The equilibrium solubility of both β-CD and each of 8 structurally unrelated drugs were measured in tandem in the presence of different acid types at low and high pHs, and at different time intervals over a period of 1–40 days. The results indicate that SSn is evident regardless of acid type (organic and inorganic) at low pH, but the extent of SSn is acid type dependant and is limited by the drug salt solubility product constant (pK _sp). Among different drugs, no apparent trend exists between drug salt solubility and the extent of SSn, but lowering drug salt solubility by increasing pH depresses SSn. The results also reveal no apparent trend between the magnitude of the complex formation constant (K _ij) and SSn. For example, drugs of low K _ij values such as astemizole, cisapride and sildenafil do not show any SSn, yet ketotifen and pizotifen, which also have low K _ij values, exhibit substantial SSn. However, the solublizing power of β-CD represented by the slope of phase solubility diagram can be used as a marker for SSn (slopes exceeding 0.4 induce SSn).     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Synthesis of 2-(α-Hydroxyalkyl)-2-Oxazoline under Microwave Irradiation in Bluk

Four 2-(α-hydroxyalkyl)-2-oxazolines and a 2-(α-hydroxy-α,α-diphenyl)-2-benzooxazole were synthesized from β-amimoalcohols and α-hydroxy carboxylic acids under microwave irradiation in the absence of a solvent.