Design and synthesis of novel 1,2,3,4-tetrazines as new anti-leukemia cancer agents.

A series of novel 1,2,3,4-tetrazines were designed and synthesized. 1 H-NMR spectroscopy, 13 C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm-6, Reh, K562, and Molt-4) and one non-leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm-6, K562, Jurkat, and Molt-4 cell lines, IC50 values were found to be 15.98, 19.12, 23.15, and 25.80 µM, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4-tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents.

An Oxy-anion Accelerated [1,5]-o-Quinone Methide Shift During the Nucleophilic Epoxidation of Salicylfulvene.

A new facet of nucleophilic fulvene epoxidations has been uncovered. 6-Arylfulvenes containing an ortho or para hydroxyl group react with basic hydrogen peroxide in an unusual manner; the epoxidation of the fulvene exocyclic double bond is followed by a phenoxide ion initiated epoxide ring opening to form an o-quinone methide (o-QM) intermediate. The resulting cyclopentadienolate undergoes an unusual oxy-anion accelerated [1,5]-sigmatropic o-QM shift. Computational studies reveal that the activation energy for the [1,5]-QM-shift in the cyclopentadienolate intermediate is quite low, signifying the acceleration caused by the oxy-anion group. Placement of a second hydroxyl group in the 6-aryl ring at C5 epoxidation via electron donation to the o-QM carbon; instead, an intramolecular oxa-6-π-electrocyclization of the o-QM intermediate onto the cyclopentadiene is observed.

Singlet oxygenation of triquinacene, barrelene, and homobarrelene.

The singlet oxygenation of three polycyclic hydrocarbons, triquinacene, barrelene and homobarrelene was studied. Triquinacene reacted by way of a perepoxide intermediate, transferring an oxygen atom to another triquinacene molecule to give exclusively the mono epoxide. Barrelene, on the other hand, underwent a rare homo-Diels-Alder reaction with 1O2 to give the decomposition product from the initial tetracyclic 1,2-dioxolane leading to benzofuran. The latter reacted with 1O2 in a [2+2] cycloaddition to give an unstable 1,2-dioxetane which collapsed to 2-formylphenyl formate. The latter was independently synthesize via singlet oxygenation of authentic benzofuran. Homobarrelene reacted in a similar fashion to give a homoDiels product, decomposition of which led to a keto aldehyde which was characterized spectroscopically. Computational work confirms the barrelene and homobarrelene reactions with 1O2 as concerted [π2s+π2s+π2s] cycloadditions.

Imidazolidin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations onto (E)-Narylideneanilines.

In the course of our studies on the chemistry of oxyallyl species we uncovered a new (3+2) cycloaddition of aza-oxyallyl systems, generated in situ from N-benzyloxy-2-chloroamides in the presence of NEt3, onto N-arylimines yielding imidazolidin-4-ones in moderate to good yields. The cycloadditions are regioselective. Computational modelling using DFT at the M062×/6-311+G** level is in support the observed regioselectivities. Although the path to the trans imidazolin-4-one is favored, the cis product is preferred by almost 8 kcal/mol and could be formed by base-catalyzed epimerization. All products were isolated by chromatography and characterized by means of their FTIR, NMR and HRMS data.

C12H12 interconversions: two non-pyrolytic syntheses of tricyclo[5.3.2.04,8]dodeca-2,5,9,11-tetraene.

Herein, we describe two independent and non-pyrolytic syntheses of an important C12H12 hydrocarbon which had been prepared previously by gas phase thermolysis of compound 6. The first method is based on an unusual dipolar cycloaddition of dichloroketene onto bullvalene. After reductive dechlorination, a Shapiro-Heath reaction of the tosylhydrazone gave the title compound. Alternatively, compound 13 is also obtained from its isomer 6 by a Ag+ catalyzed reaction.

Diverse modes of reactivity of 6-(chloromethyl)-6-methylfulvene.

The title compound exhibits a number of reactivities toward nucleophiles/bases owing to the presence of several electrophilic and potentially nucleophilic sites in the molecule. We explored the reactions of 6-(chloromethyl)-6-methylfulvene with oxygen- and nitrogen nucleophiles and bases as well as a carbon-based nucleophile (an enamine) and realized all possible reactivity modes predicted on the basis of electrophilic and nucleophilic positions in this compound.

Cyclopentadienones via a tandem C-cyclopropylnitrone cyclization-cycloreversion sequence.

Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo a tandem uncatalyzed intramolecular cyclopropane-nitrone cyclization-5,6-dihydro-1,2-oxazine cycloreversion to give cyclopentadienones. Similarly, the NH-nitrone generated in situ from spiro[cyclopropane-1,1'-indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-inden-1-one) by the same mechanism. DFT calculations are in favor of a concerted yet highly asynchronous pathway for the cyclizations. Control experiments with the dihydro and tetrahydro derivatives show that the spirocyclopentadiene unit is essential for the success of the reaction, invoking spiroconjugative effects for increased cyclopropane reactivity.

Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine.

The interaction of various 1,2-dibromides with NEt3 under various conditions (THF and DMF, respectively) at different temperatures was investigated. Our results from these reactions show that substrate dependent dehydrobrominations compete with reductive debrominations. A comprehensive discussion of these competitive pathways is offered.

cis-ß-Bromostyrene derivatives from cinnamic acids via a tandem substitutive bromination-decarboxylation sequence.

cis-ß-Bromostyrene derivatives were synthesized stereospecifically from cinnamic acids through ß-lactone intermediates. The synthetic sequence did not require the purification of the ß-lactone intermediates although they were found to be stable and readily purified in most cases.

Unusual hydroxyl effect on fulvene endoperoxide decompositions.

The thermal decomposition of fulvene endoperoxides ordinarily proceeds via an allene oxide intermediate affording oxepin-2(3H)-one derivatives. We have now uncovered new, unusual pathways in these decompositions where the presence of a hydroxyl group on the alkyl or aryl attached to the fulvene exocyclic double bond has a profound effect on the fate of the reactive intermediates derived from the unstable endoperoxides. Computational work supports the proposed mechanistic pathways.

Reductive debromination of 1,2-dibromides with anisidines.

vic -Dibromides containing the α-bromocarbonyl or α-bromoaromatic moieties were reductively debrominated to furnish alkenes in high yield. o- and m-Anisidines but not p-anisidine were found to be effective debrominating agents. The reductive debrominations were found to be trans-stereospecific.

First ketene cycloaddition approach to (±)-junionone.

Junionone is the first monocyclic cyclobutane monoterpenoid isolated from a plant. Of the existing four syntheses of this compound, none employs a ketene cycloaddition to construct the four-membered ring. Herein, we report the first total synthesis of junionone that features a ketene cycloaddition for the synthesis of this compound, starting from the commercially available 1,5-hexadiene. 2009 Elsevier Ltd. All rights reserved.

Pyrrolidine catalyzed reactions of cyclopentadiene with α,ß-unsaturated carbonyl compounds: 1,2- versus 1,4-additions.

A systematic study of the reactions of cyclopentadiene with α,ß-unsaturated carbonyl compounds in the presence of catalytic pyrrolidine-H2O revealed that the reactions can either proceed with a Michael attack at the ß-carbon of enone, or 1,2-addition to the carbonyl, leadingeither to 4-cyclopentadienyl-2-butanones or 6-vinylfulvenes. The former can be isolated and/or converted to the corresponding 1,2-dihydropentalenes with base (or in one-pot at longer reaction times). Substitution pattern on the enones on the competing pathways have been studied and consistent mechanisms are proposed.

Effect of allylic groups on S(N)2 reactivity.

The activating effects of the benzyl and allyl groups on S(N)2 reactivity are well-known. 6-Chloromethyl-6-methylfulvene, also a primary, allylic halide, reacts 30 times faster with KI/acetone than does benzyl chloride at room temperature. The latter result, as well as new experimental observations, suggests that the fulvenyl group is a particularly activating allylic group in S(N)2 reactions. Computational work on identity S(N)2 reactions, e.g., chloride(-) displacing chloride(-) and ammonia displacing ammonia, shows that negatively charged S(N)2 transition states (tss) are activated by allylic groups according to the Galabov-Allen-Wu electrostatic model but with the fulvenyl group especially effective at helping to delocalize negative charge due to some cyclopentadienide character in the transition state (ts). In contrast, the triafulvenyl group is deactivating. However, the positively charged S(N)2 transition states of the ammonia reactions are dramatically stabilized by the triafulvenyl group, which directly conjugates with a reaction center having S(N)1 character in the ts. Experiments and calculations on the acidities of a variety of allylic alcohols and carboxylic acids support the special nature of the fulvenyl group in stabilizing nearby negative charge and highlight the ability of fulvene species to dramatically alter the energetics of processes even in the absence of direct conjugation.

Temperature-dependent, competitive 1,3-acyl shift versus decarbonylation of a cyclopropanone intermediate.

Photooxygenation of 1,1,3-trimethyl-1,2-dihydropentalene gives an unstable endoperoxide which upon decomposition delivers a bicyclic cyclopropanone intermediate; this species either extrudes CO to give a cycloheptadienone or undergoes a 1,3-acyl shift, both processes occurring most likely in a stepwise manner via diradical intermediates. Alternatively, C3a-C4 cleavage in the dioxygen diradical derived from the endoperoxide yields a 2-cyclopropyl substituted cyclopentadienone epoxide.

An expedient synthesis of 6-vinylfulvene.

6-Vinylfulvenes constitute a class of fulvenes that are difficult to access due to the lack of a general method for their synthesis. In particular, the unsubstituted parent system has been very difficult to obtain by existing methods. In this communication we describe a convenient 3-step protocol for the synthesis of the title compound by way of sulfide oxidation and subsequent sulfoxide elimination.

An efficient catalytic method for fulvene synthesis.

The effects of the nature and amount of base, substrate structure, amount of added water and solvent on the condensation of carbonyl compounds with cyclopentadiene in the presence of secondary amines were investigated. Based on these studies, a new efficient and green synthesis of fulvenes was developed.

1,2-Dihydropentalenes from fulvenes by [6 + 2] cycloadditions with 1-isopropenylpyrrolidine.

In situ generated acetone pyrrolidine enamine undergoes [6 + 2] cycloadditions with fulvenes to give 1,2-dihydropentalenes. This ring annulation method works particularly well with 6-monosubstituted fulvenes and is subject to steric hindrance at C-6 of the fulvene. On the basis of mechanistic studies, optimal conditions have been developed for a one-pot synthesis of 1,2-dihydropentalenes using catalytic amounts of pyrrolidine.

Triphenylphosphine reduction of saturated endoperoxides.

Triphenylphosphine reduction of saturated endoperoxides derived from 6,6-dimethylfulvene and spiro[2.4]hepta-4,6-diene in the presence of nucleophiles results in the formation of products that mainly stem from deoxygenation followed by carbocation formation. Nucleophilic attack by solvent proceeds by an S(N)1 like mechanism; allyl shifts and cyclopropylcarbinyl-cyclobutyl rearrangements also occur. With the systems lacking carbocation-stabilizing groups, the deoxygenation step is preceded by attack of H(2)O at the phosphorus.

Palladium Catalyzed Cyclopropanation of Unsaturated Endoperoxides. A New Peroxide Preserving Reaction.

Unsaturated bicyclic endoperoxides are efficiently cyclopropanated with excess diazomethane in the presence of catalytic Pd(OAc)2 in a stereoselective manner. This method represents a new peroxide preserving transformation. Whereas the unsaturated endoperoxides in the [2.2.1] series are attacked by the carbene from the exo face, the analogs with larger bridges are preferentially attacked from the face syn to the peroxo bridge. Only in the case of the benzannelated [2.2.2] system the attack occurs exclusively from the face proximal to the benzene ring. Certain strained cyclopropanated endoperoxides are reduced by diazomethane to give cis-diols. 1-Methylfuran endoperoxide gives rise to cis-1-formyl-2-acetylcyclopropane in excellent yield.