Ester 13a Research Articles

Regioselective synthesis and evaluation of novel sulfonamide 1,2,3-triazole derivatives as antitumor agents

A novel series of 1,2,3-triazole containing sulfonamide moiety was synthesized. Treatment of 4-acetyl 1,2,3-triazole 3 with different aldehydes gave α,β-unsaturated ketones 4a–c. Condensation of 3 with dimethylformamide dimethylacetal (DMF-DMA) gave formimidamide 5. Chalcone 7 was achieved via two ways from the reaction of 5 with benzaldehyde or from treatment of 4a with DMF-DMA. Reaction of 7 with hydrazine hydrate afforded pyrazoline 8. 5-Methyl pyrazole 12 was synthesized from Claisen condensation reaction of 3 or 5 with ethyl acetate to give 1,3-diketone adduct 9 or 10, respectively, followed by treatment with hydrazine hydrate. 5-Aminopyrazole 17 was synthesized from the reaction of ester 13 or formimidamide ester 13a with acetonitrile to afford cyanoacetyl derivatives 14 or 15, respectively, followed by treatment with hydrazine hydrate. The new compounds were screened for their in vitro antitumor activity. The results of this investigation revealed that compounds 12, 7, and 17 had a significant anticancer activity against MCF-7 cancer cell line with IC50 values 12.4, 19.8, and 23.4 µM, respectively, in relation to the standard drug, doxorubicin.

Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols.

The Ritter reaction of 1,2-diolmonoesters with nitriles to 1- vic-amido-2-esters proceeds through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction mechanism, novel forms of these cations were isolated, characterized, and studied by spectroscopic methods and single crystal X-ray analysis. Ground and transition state energies were determined both experimentally and theoretically. Taken together, these data suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed by rate determining yet reversible ring opening by acetonitrile to the corresponding nitrilium cation 10 (computed Δ G⧧ = 24.7 kcal at 50 °C). Rapid, irreversible hydration of the latter affords the corresponding vic-acetamido ester. Controlled addition of H2O to the dioxonium cation 9 in acetonitrile- d3 results in near-quantitative production of deuterated acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic, and the slow phase is ascribed to either direct cation 9 attack by acetamide to form cation 16 via O-alkylation or by reversible ether formation. Deuterium labeling studies suggest O-alkylated cation 16 does not directly isomerize to N-alkylated cation 18; instead, it reverts to vic-amidoester 13a via the nitrilium pathway. Preliminary results indicate high regioselectivity for primary amide formation in the diol-Ritter sequence.

Intermolecular Michael addition of substituted amines to a sugar-derived alpha,beta-unsaturated ester: synthesis of 1-deoxy-D-gluco- and -L-ido-homonojirimycin, 1-deoxy-castanospermine and 1-deoxy-8a-epi-castanospermine.

The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin 3a, 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and 1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular Michael addition of benzylamine to alpha,beta-unsaturated ester 1, derived from D-glucose, which afforded diastereomeric mixture of beta-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5, respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The beta-amino esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a and 6b, individually, gave beta-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation gave 3a and 3b, respectively. On the other hand, the beta-amino ester 6a was converted to gamma-amino ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate gave gamma-lactam 14a. The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good yield. The same sequence of reactions was applied to beta-amino ester 6b, which afforded 1-deoxy-8a-epi-castanospermine 5b.

Design of potential new HIV protease inhibitors: enantioconvergent synthesis of new pyrrolidin-3-ol, and pyrrolidin-3-one peptide conjugates

Novel potential HIV protease inhibitors are obtained by an enantioconvergent synthesis of mimicking Phe-Pro dipeptides, achieved through the coupling between Boc(L)Phe or Boc(L)Tyr and both enantiomers of syn-2-benzylpyrrolidin-3-ol and their corresponding pyrrolidin-3-one analogs. The stereochemistry and enantiopurity of intermediate 3-hydroxypyrrolidines 5a and 5b are determined through 1H NMR analysis, and through the synthesis and 19F NMR assignments of the corresponding Mosher’s esters 13a and 13b. The enantiopure compounds 5a and 5b are obtained with 100% diastereoselectivity using specific experimental reductive conditions upon Meldrum’s acid derivatives of activated aromatic amino acids.

Antitumor Agents. Part 184. Syntheses and antitubulin activity of compounds derived from reaction of thiocolchicone with amines: Lactams, alcohols, and ester analogs of allothiocolchicinoids

Abstract7‐O‐Substituted analogs of deaminodeoxycolchinol thiomethyl ether were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 9, a key compound in this study, was derived from thiocolchicone 6 by reaction with aniline. Reaction of compound 6 with MeNH2 or BuNH2 gave tetracyclic lactams 7 and 8, respectively. Optically active alcohols 11a and 11b were obtained from racemic 11 by chemical resolution including a separation of the comphanate diastereoisomers 12a and 12b, followed by basic hydrolysis. The (aR,7R)‐configuration of 12b was verified by X‐ray crystallographic analysis. Almost all racemic and optically active 7‐O‐acyl or 7‐O‐aroyl compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 5.1 μM. A few agents, such as the lactams 7 and 8, the camphanates 12a and 12b, the cyclohexanecarboxylates 19a and 19b, and, most notably, the (7S)‐benzoate 15a, had negligible effects on polymerization, yielding IC50 values greater than 40μM. Ketone 9 showed strong inhibition of tubulin polymerization comparable to that of thiocolchicone (6). Optically active alcohol 11a and acyl esters 13a and 14a with a (7S)‐configuration were more active than the (7R)‐esters 13b and 14b. However, the esters 15a–17a with a (7S)‐configuration were less active than the (7R)‐isomers 15b–17b, in which the (7R)‐benzoate 15b was at least 15‐fold more inhibitory than the (7S)‐isomer 15a. For the most part, the agents causing strongest inhibition of polymerization also caused the greatest inhibition of [3H]colchicine binding. NMR and optical rotatory data indicate that, in polar solvents, the equilibrium in esters with a 7‐O‐aroyl substituent, i.e., 15a,b, 16a,b, and 17a,b, is reversed from (aS) to (aR) or from (aR) to (aS), as compared to nonpolar solvents.

Total synthesis of Aklanonic Acid and Derivatives by Baker–Venkataraman Rearrangement

AbstractAklanonic acid (1) and the derivatives 2 and 15a–f were prepared by Baker‐Venkataraman rearrangement of the corresponding ortho‐acetyl anthraquinone esters 13a–e and 14 using lithium hydride in THF.

Synthesis and Reactions of 2(5)‐[Benzyl or Cyanomethyl]‐1,3,4‐oxadiazoles

AbstractA series of five membered heterocycles, namely 5‐(benzyl or cyanomethyl)‐3‐acetyl‐2,2‐disubstituted‐1,3,4‐oxadiazolines (3a‐e), 2,5‐disubstituted‐1,3,4‐oxadiazoles (4a, b), 2‐hydroxy‐5‐(benzyl or cyanomethyl)‐1,3,4‐oxadiazoles (5a, b), 1,2,5‐trisubstituted‐1,3,4‐triazoles (6a, b), and 2‐(benzyl or cyano‐methyl)‐1,3,4‐oxadiazole‐5‐thiols (10a, b), were synthesized. Also 5‐chloro‐2‐benzyl‐1,3,4‐oxadiazole 7 was prepared. Reaction of amines, hydrazines, and sodium azide with 7 gave the corresponding 2‐arylamino (8a, b), 5‐hydrazino or phenylhydrazino (8c, d) and 2‐azido derivatives 9, respectively. Mannich bases (11a, b) were prepared by the reaction of sec. amines with 9a. 5‐Carboxymethylthio‐1,3,4‐oxadiazoles (12a, b) and their ethyl esters (13a, b) were also prepared. The ester 13a reacted with amines and hydrazines to give the corresponding amides (14a‐d).

A chiral building block with bicyclo[2.2.2]octanone skeleton by the reduction with Baker's yeast.

Preparation of functionalized bicyclo[2.2.2]octan-2-one with high optical purity is described. Reduction of a bridged diketone 2 with baker's yeast gave an endo-hydroxyketone (+)-12 of 98.5≈99.5 %e.e. in 91 % yield. X-ray crystallography of its (S)-MTPA ester 13a determined the absolute configuration of (+)-12 as (1S,4S,6S).

Intramolecular Cyclizations of Allenic Acylureas and ‐Amides

AbstractAllenic acids are found to add to dicyclohexylcarbodiimide affording, in the presence of Et2NH, the 4H‐1,3‐oxazin‐4‐ones 5 via 4. Under neutral conditions, they add to diaryl‐ or pyridyl(cyclohexyl)carbodiimides and triphenylketene imine to give the corresponding tricyclo[5.2.2.01,5]undeca‐4,8,10‐trien‐3‐ones 7, 8, 9, and 12. The allenic phenyl ester 13a dimerises, on heating in a [2+2] head‐to‐head fashion, to 14 but fails to undergo intramolecular Diels‐Alder cyclization, to 15.

Reactions of β-keto esters with 2-cyano-1,2,5,6- tetrahydropyridines

Reaction of the sodium salts of β-keto esters 13a and 13b with the 2-cyano-tetrahydropyridines 11 and 12 afforded the 4-substituted piperidine derivatives 21– 23. The structures were assigned on the basis of their 1H- and 13C-NMR spectra and by comparison with the model compounds 24– 26. The stereochemistry and mechanism of the reactions are discussed.

Glykoside von Marsdenia erecta R. Br. 2. Mitteilung: Versuche zur Strukturbestimmung der Genine. Glykoside und Aglykone, 330. Mitteilung

AbstractStructures for the genins of the ester glycosides of Marsdenia erecta are suggested. They are based on the behaviour in alkaline hydrolysis of these ester glycosides, their NMR. and mass spectra and ORD. data. All genins are derived from three acyl‐free pregnane derivatives, i.e. drevogenin‐P (1), 17 β‐marsdenin (3) and marsectohexol (7). The structure of 1 is known, 3 and 7 are new compounds, i.e. 3 = 3β,8β,11α,12β,14β‐pentahydroxy‐Δ5‐pregnen‐20‐one and 7 = 3β,8β,11α,12β,14β,20ξ‐hexahydroxy‐Δ5‐pregnene.Formulae 13–17 were attributed to the acyl‐genins A‐1, A‐2, A‐3, A‐4 and A‐5, but only two of them were pure compounds, i.e. acyl‐genin A‐3 = 11,12‐di‐O‐tiglyl‐17β‐marsdenin (15) and acyl‐genin A‐5 = 11,12‐di‐O‐acetyl‐marsectohexoi (17). Acyl‐genin A‐1 is a mixture of the two esters 13a + 13b derived from drevogenin‐P, and similarly acyl‐genin A‐2 is a mixture of the esters 14a + 14b derived from 17β‐marsdenin. The poorly characterised acyl‐genin A‐4 is most probably a mixture of the esters 16a + 16b, also derived from 17β‐marsdenin.

Terpenoids—X: Chemical conversion of enmein into enantio-abietane and total synthesis of abientane

The acyloin condensation of the lactone ester 13a derived from enmein ( 1), a diterpenoid bitter principle from Isodon trichocarpus Kudo, was invesitgated. The acyloin products were converted into 33 through several steps of reactions, while abietic acid was transformed into 39. We propose the name “abietane” for the compound 39, hence “ enantio-abietane” for the compound 33. Since abietic acid has been synthesized, its conversion into abietane constitutes the total synthesis of the latter.