Synthesis of Highly Functionalised Furo[3,4-b]pyrans: Towards the Fungal Metabolite (−)-TAN-2483B

<p>Carbohydrate-derived cyclopropanes combine both the stereochemical wealth of carbohydrates and the reactivity of cyclopropanes. A diverse variety of reaction modes for these cyclopropyl carbohydrates can be harnessed for the synthesis of natural products and other targets. The natural products (−)-TAN-2483A and (−)-TAN-2483B are fungal secondary metabolites displaying a variety of bioactivities such as inhibition of c-src kinase action and parathyroid hormone-induced bone resorption. This thesis described several synthetic approaches to the natural product (−)-TAN-2483B and analogues of (−)-TAN-2483B employing cyclopropane ring expansion. The synthetic route to (−)-TAN-2483B began with the readily available substrate D-mannose. The pyran ring unsaturation of the natural product was established by a cyclopropanation-ring expansion sequence. A synthetic strategy via dichlorocyclopropane-based intermediates is described in chapter 2. This being unsuccessful, an alternative approach via 2-fomyl-glycal was developed in chapter 3. The chapter 2 and 3 provided a solid background for the achievement of the analogues synthesis illustrated in chapter 4 via dibromocyclopropane. Lewis acid-mediated alkynylation followed by Pdcatalysed carbonylative lactonisation was successfully utilised in the revelation of the furo[3,4-b]pyran ring skeleton. This route afforded analogues of TAN-2483B; the Z-and E-unsaturated ethyl esters 140 and 141 and hydroxy(−)-TAN-2483B 145. The total synthesis of (−)-TAN-2483B was not achieved due to unforeseen obstacles encountered in the deoxygenation of the side arm of 335 (Chapter 4) into the E-propenyl side arm of (−)-TAN-2483B.</p>

Synthesis of Highly Functionalised Furo[3,4-b]pyrans: Towards the Fungal Metabolite (−)-TAN-2483B

<p>Carbohydrate-derived cyclopropanes combine both the stereochemical wealth of carbohydrates and the reactivity of cyclopropanes. A diverse variety of reaction modes for these cyclopropyl carbohydrates can be harnessed for the synthesis of natural products and other targets. The natural products (−)-TAN-2483A and (−)-TAN-2483B are fungal secondary metabolites displaying a variety of bioactivities such as inhibition of c-src kinase action and parathyroid hormone-induced bone resorption. This thesis described several synthetic approaches to the natural product (−)-TAN-2483B and analogues of (−)-TAN-2483B employing cyclopropane ring expansion. The synthetic route to (−)-TAN-2483B began with the readily available substrate D-mannose. The pyran ring unsaturation of the natural product was established by a cyclopropanation-ring expansion sequence. A synthetic strategy via dichlorocyclopropane-based intermediates is described in chapter 2. This being unsuccessful, an alternative approach via 2-fomyl-glycal was developed in chapter 3. The chapter 2 and 3 provided a solid background for the achievement of the analogues synthesis illustrated in chapter 4 via dibromocyclopropane. Lewis acid-mediated alkynylation followed by Pdcatalysed carbonylative lactonisation was successfully utilised in the revelation of the furo[3,4-b]pyran ring skeleton. This route afforded analogues of TAN-2483B; the Z-and E-unsaturated ethyl esters 140 and 141 and hydroxy(−)-TAN-2483B 145. The total synthesis of (−)-TAN-2483B was not achieved due to unforeseen obstacles encountered in the deoxygenation of the side arm of 335 (Chapter 4) into the E-propenyl side arm of (−)-TAN-2483B.</p>

Crystal structure, Hirshfeld surface and frontier molecular orbital analysis of 9-(3-bromo-4-hydroxy-5-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione

In the fused ring system of the title compound, C24H27BrO5, the mean plane and maximum deviations of the central pyran ring are 0.0384 (2) and 0.0733 (2) Å, respectively. The cyclohexenone rings both adopt envelope conformations with the tetra-substituted C atoms as flap atoms, whereas the central pyran ring adopts a flattened boat conformation. The central pyran and phenyl substituent rings are almost perpendicular to each other, making a dihedral angle of 89.71 (2)°. In the crystal, pairs of molecules are linked via O—H...O hydrogen bonds, forming inversion dimers with an R 2 2(20) ring motif. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (50.6%), O...H/H...O (22.9%) and C...H/H...C (11.1%) contacts. Quantum chemical calculations for the frontier molecular orbitals were undertaken to determine the chemical reactivity of the title compound.

A Study of the Regiochemistry in the Synthesis of Pyrano[3,4-c]pyridines

Aims: Biological studies have shown that some condensed derivatives of pyrano[3,4-c]pyridines 6 exhibited pronounced biological activity. Considering these results, the principal aim of this work is to study the regiochemistry of the synthesis of pyrano[3,4-c]pyridines 6, optimize the reaction conditions, and increase the previously observed low yields of pyrano[3,4-c]pyridines. Background: Several years ago, a method for the preparation of 6-oxopyrano[3,4-c]pyridines 6 starting from 2,2-dimethyltetrahydro-4H-pyran-4-one 1 was developed. In this study, we have separated and identified only the most expected reaction products of 6-oxopyrano[3,4-c]pyridines 6. On the basis of this datum, we suggested that the enamines 2 and 3 reacting with acyl chlorides were not acylated at C-3 and that 5-acylpyran-4-ones 4 were the only products of the reaction. We have justified this result by considering the steric effects exerted by the two methyl groups present in the pyran ring. Moreover, we did not identify the products at the second reaction center: that is, the isomeric compounds 7. This result was justified considering the different reactivity of aliphatic and cyclic ketone groups. Objective: The main objectives of this work are as follows: a) implementation of the reaction of 2,2-dimethyltetrahydro-4H-pyran-4-one 1 with morpholine; b) acylation of the obtained enamines 2 and 3 with acyl chlorides under Stork conditions; c) synthesis of pyranopyridines 6–8 based on β-diketones: 3-acylpyran-4-ones 4 and 5-acylpyran-4-ones 5; d) confirmation of the structure of the obtained compounds. Method: For the synthesis of pyrano[3,4-c]pyridines, known methods were used. Thus, the reaction of starting 2,2-dimethyltetrahydro-4H-pyran-4-one 1 with morpholine in benzene led to the formation of isomeric enamines 2 and 3. Then, they were acylated with acyl chlorides under Stork conditions with the formation of two β-diketones: 3-acylpyran-4-ones 4 and 5-acylpyran-4-ones 5. Finally, in order to obtain the aimed pyrano[3,4-c]pyridines 6, the obtained β-dicarbonyl compounds 4 and 5 (as a mixture of isomers) were reacted with 2-cyanoacetamide in ethanol in the presence of diethylamine, according to the Knoevenagel condensation. The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physicochemical methods (NMR, IR, X-ray structural and elemental analysis) and, in the instance of compounds 7, also by an alternative synthesis. Results: Starting from the 2,2-dimethyltetrahydro-4H-pyran-4-one 1, a series of new and already known 6-oxopyrano[3,4-c]pyridines 6 were synthesized. As a result of the study of the regiochemistry in the synthesis of pyrano[3,4-c]pyridines, out of the four possible isomer pyranopyridines 6−9, we have succeeded to identify three of them (6−8). Thus, isomer pyranopyridines 7 and 8 were identified in the mixture with the main compounds 6. Moreover, isomeric pyrano[3,4-c]pyridines 8 were detected when alkyl groups are present in the starting compounds 4 and 5, while isomeric pyrano[4,3-b]pyridines 7 were detected in the case of the presence of aromatic groups. Unfortunately, we have not been able to isolate compounds 7 and 8 in the pure state from the reaction mixtures. Currently, we have not been able to detect and identify isomeric pyrano[4,3-b]pyridines 9. On the whole, we have been able to increase the effectiveness of the synthesis of pyrano[3,4-c]pyridines 6, increasing their yields by ≈ 5–15%. Conclusion: As a result of our investigation, we have found that the acylation reaction of enamines 2 and 3 and the cyclization reaction of β-diketones 4 and 5 are not regioselective. Therefore we can state that enamines 2 and 3 can be acylated at both C-3 and C-5 with the formation of a mixture of 3-acylpyran-4-ones 4 and 5-acylpyran-4-ones 5. Their condensation with 2-cyanoacetamide led to the formation of mixtures of regioisomeric pyranopyridines 6−8. In conclusion, as a result of our present research, we can say that we have been able to increase the effectiveness of the synthesis of pyranopyridines, largely improving our previous results։ Other: Currently, we are working to look for the fourth isomeric pyrano[4,3-b]pyridines 9 by using the most modern and fine methods. Moreover, we hope that we would be able to separate the mixtures of pyranopyridines 6–8 so that they can be used for further syntheses.

Periphery-Fused Chiral A2B-Type Subporphyrin

Despite significant interest, the chiroptical properties of subporphyrins have rarely been investigated because chiral subporphyrins are elusive. Here, inherently chiral subporphyrins are elaborated by forming a fused pyran ring at the periphery of an A2B-type meso-aryl-substituted subporphyrin. Their circular dichroism (CD) properties are largely affected by the peripheral substituents and the dihedral angles between the meso-aryl substituents and the subporphyrin core: the β-perbromo subporphyrin with an orthogonal arrangement of the meso-phenyl substituents to the subporphyrin core exhibits weak CD signals corresponding to the Q bands, whereas the unsubstituted species with smaller dihedral angles shows relatively intense CD signals. A detailed structure–property relationship of these chiral subporphyrins was elucidated by time-dependent (TD) DFT calculations. This study reveals that the CD properties of chiral subporphyrins can be controlled by peripheral substitution and meso-aryl substituents.

Molecular Diversity via Tetrasubstituted Alkenes Containing a Barbiturate Motif: Synthesis and Biological Activity

The synthesis of a molecularly diverse library of tetrasubstituted alkenes containing a barbiturate motif is described. Base-induced condensation of N1-substituted pyrimidine-2,4,6(1H,3H,5H)-triones with 5-(bis(methylthio)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione gave 3-substituted 5-(methylthio)-2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones (‘pyranopyrimidinones’), regioselectively. A sequence of reactions involving ring-opening of the pyran moiety, displacement of the methylthio group with an amine, re-formation of the pyran ring, and after its final cleavage with an amine, gave tetrasubstituted alkenes (3-amino-3-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)propanamides) with a diversity of substituents. Cleavage of the pyranopyrimidinones with an aniline was facilitated in 2,2,2-trifluoroethanol under microwave irradiation. Compounds were tested against Escherichia coli, Staphylococcus aureus, the yeast Schizosaccharomyces pombe, and the pathogenic fungus Candida albicans. No compounds exhibited activity against E. coli, whilst one compound was weakly active against S. aureus. Three compounds were strongly active against S. pombe, but none was active against C. albicans.

First Total Synthesis and Investigation of the X-ray Crystal Structure of the Pyrano[3,2-a]carbazole Alkaloid Clausenalansine A

We describe the first total synthesis of the recently discovered pyrano[3,2-a]carbazole alkaloid clausenalansine A. The synthetic strategy for the construction of this formylpyrano[3,2-a]carbazole is based on a sequence of Buchwald–Hartwig coupling, palladium(II)-catalyzed oxidative cyclization, Lewis acid promoted annulation of the pyran ring, and chemoselective oxidation of a methyl to a formyl group.

Inter- and Intramolecular [2+2+2] Cycloaddition of Alkyne Triple Bonds to the Carbonyl Function of Aldehydes and Ketones Enabled by η5-Cyclopentadienylcobalt(L)(L′)

Abstract1,7-Octadiyne underwent [2+2+2] cycloaddition to acetone in the presence of η5-cyclopentadienylcobalt(L)(L′) complexes to give (η5-cyclopentadienyl)[(1,4,4a,8a-η4)-5,6,7,8-tetrahydro-3,3-dimethyl-3H-2-benzopyran]cobalt, in which the two triple bonds and the carbonyl moiety have combined to engender a 2H-pyran ring complexed to CpCo. The scope of this reaction was explored, including cocyclizations of ynals and ynones with bis(trimethylsilyl)acetylene, as well as all-intramolecular reorganizations of α,ω-diynals and -diynones. Two major trajectories were observed in the case of aldehydes, the (often minor) [2+2+2] pathway and a competing trail featuring a formal 1,5-hydride shift that results in CpCo–dienones. The latter is obviated for ketone substrates. Preliminary chemistry of selected complexes uncovered unprecedented reactions, such as acid-catalyzed ring openings and additions of amines, the latter providing access to novel carbon frames.