Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones.

A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.

Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins.

Modular gram-scale syntheses of the trimethyl ethers of lamellarins G (6) and D (7) were achieved from readily accessible precursors in the highest overall yields reported to date (6, six steps, 82%; 7, seven steps, 86%). A novel demethylative lactonization between an aryl methyl ether and a neighboring carboxylic acid was developed for creating the chromenone unit of the targets to avoid the need for additional protection and deprotection steps. The central pyrrole core was constructed in a late-stage [4 + 1] condensation between ethyl bromoacetate and an enaminone possessing the remaining components of the lamellarin skeleton. Exhaustive demethylation of both permethyl ethers 6 and 7 gave the polyphenolic natural lamellarins A4 (3) and H (5), respectively.

A Xylochemically Inspired Synthesis of Lamellarin G Trimethyl Ether via an Enaminone Intermediate.

A concise high yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is avoided, and only a single aqueous workup is performed. The novelty of the synthesis lies in the intermediacy of an enaminone for the construction of the central pyrrole ring. The overall yield of the product is among the highest reported to date.

Binary polymorphic cocrystals: an update on the available literature in the Cambridge Structural Database, including a new polymorph of the pharmaceutical 1:1 cocrystal theophylline-3,4-dihydroxybenzoic acid.

An analysis and classification of the 2925 neutral binary organic cocrystals in the Cambridge Structural Database is reported, focusing specifically on those both showing polymorphism and containing an active pharmaceutical ingredient (API). The search was confined to molecules having only C, H, N, O, S and halogens atoms. It was found that 400 out of 2925 cocrystals can be classified as pharmaceutical cocrystals, containing at least one API, and that of those, 56 can be classified as being polymorphic cocrystals. In general, the total number of polymorphic cocrystal systems of any type stands at 125. In addition, a new polymorph of the pharmaceutical cocrystal theophylline-3,4-dihydroxybenzoic acid (1/1), C7H8N4O2·C7H6O4, is reported.

Acridone Alkaloids.

There have been substantial developments in the chemistry and biology of the acridone alkaloids in the 16years since the topic was last reviewed in this series of monographs (2000). The present survey covers the literature from mid-1999 to 2016. A brief overview of the biosynthesis of acridone alkaloids is followed by details of the occurrence and characterization of known alkaloids from new sources, and of novel alkaloids. The classes covered include simple acridone alkaloids, C-prenylacridones, furo[3,2-b]- and furo[2,3-c]acridones, pyrano[3,2-b]- and pyrano[2,3-c]acridones, and dimeric alkaloids containing acridone moieties. Syntheses of acridone alkaloids and certain analogs reported during the review period are comprehensively covered. The final section summarizes aspects of their bioactivity, including cytotoxicity and anticancer activity, antimicrobial and antiparasitic properties, and enzyme inhibition. The chapter concludes with a brief description of important bioactive synthetic analogs.

Simple Indolizidine and Quinolizidine Alkaloids.

This review of simple indolizidine and quinolizidine alkaloids (i.e., those in which the parent bicyclic systems are in general not embedded in polycyclic arrays) is an update of the previous coverage in Volume 55 of this series (2001). The present survey covers the literature from mid-1999 to the end of 2013; and in addition to aspects of the isolation, characterization, and biological activity of the alkaloids, much emphasis is placed on their total synthesis. A brief introduction to the topic is followed by an overview of relevant alkaloids from fungal and microbial sources, among them slaframine, cyclizidine, Steptomyces metabolites, and the pantocins. The important iminosugar alkaloids lentiginosine, steviamine, swainsonine, castanospermine, and related hydroxyindolizidines are dealt with in the subsequent section. The fourth and fifth sections cover metabolites from terrestrial plants. Pertinent plant alkaloids bearing alkyl, functionalized alkyl or alkenyl substituents include dendroprimine, anibamine, simple alkaloids belonging to the genera Prosopis, Elaeocarpus, Lycopodium, and Poranthera, and bicyclic alkaloids of the lupin family. Plant alkaloids bearing aryl or heteroaryl substituents include ipalbidine and analogs, secophenanthroindolizidine and secophenanthroquinolizidine alkaloids (among them septicine, julandine, and analogs), ficuseptine, lasubines, and other simple quinolizidines of the Lythraceae, the simple furyl-substituted Nuphar alkaloids, and a mixed quinolizidine-quinazoline alkaloid. The penultimate section of the review deals with the sizable group of simple indolizidine and quinolizidine alkaloids isolated from, or detected in, ants, mites, and terrestrial amphibians, and includes an overview of the "dietary hypothesis" for the origin of the amphibian metabolites. The final section surveys relevant alkaloids from marine sources, and includes clathryimines and analogs, stellettamides, the clavepictines and pictamine, and bis(quinolizidine) alkaloids.

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates.

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.

Double Sonogashira reactions on dihalogenated aminopyridines for the assembly of an array of 7-azaindoles bearing triazole and quinoxaline substituents at C-5: Inhibitory bioactivity against Giardia duodenalis trophozoites.

The synthesis of 2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7-azaindoles from 3,5-dihalogenated 2-aminopyridines is outlined. Using a double Sonogashira coupling reaction on 2-amino-3,5-diiodopyridine followed by the Cacchi reaction the synthesis of 2,3,5-trisubstituted 7-azaindoles was accomplished. In addition, using two sequential Sonogashira coupling reactions on 2-amino-5-bromo-3-iodopyridine and a potassium t-butoxide mediated ring closure reaction resulted in the assembly of 2,5-disubstituted 7-azaindoles. The 5-alkynyl substituent of the azaindole was easily converted into both quinoxaline and triazole substituents, the latter utilizing an alkyne-azide cycloaddition reaction. Some of these azaindole derivatives showed very promising biological activity against the gastrointestinal protozoal parasite Giardia duodenalis.

The synthesis of a corrole analogue of aquacobalamin (vitamin B12a) and its ligand substitution reactions.

The synthesis of a Co(III) corrole, [10-(2-[[4-(1H-imidazol-1-ylmethyl)benzoyl]amino]phenyl)-5,15-diphenylcorrolato]cobalt(III), DPTC-Co, bearing a tail motif terminating in an imidazole ligand that coordinates Co(III), is described. The corrole therefore places Co(III) in a similar environment to that in aquacobalamin (vitamin B12a, H2OCbl(+)) but with a different equatorial ligand. In coordinating solvents, DPTC-Co is a mixture of five- and six-coordinate species, with a solvent molecule occupying the axial coordination site trans to the proximal imidazole ligand. In an 80:20 MeOH/H2O solution, allowed to age for about 1 h, the predominant species is the six-coordinate aqua species [H2O-DPTC-Co]. It is monomeric at least up to concentrations of 60 µM. The coordinated H2O has a pKa = 9.76(6). Under the same conditions H2OCbl(+) has a pKa = 7.40(2). Equilibrium constants for the substitution of coordinated H2O by exogenous ligands are reported as log K values for neutral N-, P-, and S-donor ligands, and CN(-), NO2(-), N3(-), SCN(-), I(-), and Cys in 80:20 MeOH/H2O solution at low ionic strength. The log K values for [H2O-DPTC-Co] correlate reasonably well with those for H2OCbl(+); therefore, Co(III) displays a similar behavior toward these ligands irrespective of whether the equatorial ligand is a corrole or a corrin. Pyridine is an exception; it is poorly coordinated by H2OCbl(+) because of the sterically hindered coordination site of the corrin. With few exceptions, [H2O-DPTC-Co] has a higher affinity for neutral ligands than H2OCbl(+), but the converse is true for anionic ligands. Density functional theory (DFT) models (BP86/TZVP) show that the Co-ligand bonds tend to be longer in corrin than in corrole complexes, explaining the higher affinity of the latter for neutral ligands. It is argued that the residual charge at the metal center (+2 in corrin, 0 in corrole) increases the affinity of H2OCbl(+) for anionic ligands through an electrostatic attraction. The topological properties of the electron density in the DFT-modeled compounds are used to explore the nature of the bonding between the metal and the ligands.

The acid-catalysed synthesis of 7-azaindoles from 3-alkynyl-2-aminopyridines and their antimicrobial activity.

The synthesis of 7-azaindoles from 3-alkynyl-2-aminopyridines using acidic conditions, namely, a mixture of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA), is described. This methodology resulted in the synthesis of fifteen 7-azaindoles, with most containing substituents at the 2- and 5-positions. The majority of these were tested for antimicrobial activity against a range of bacteria and yeasts. The 7-azaindoles displayed the best activity against the yeasts, particularly against Cryptococcus neoformans, where activities as low as 3.9 µg ml(-1) were observed.

1-(2-Hy-droxy-4,5-dimeth-oxy-phen-yl)ethanone.

The mol-ecular structure of the title compound, C10H12O4, contains an intra-molecular hydrogen bond between the phenol and acetyl substituents. In the crystal, C-H⋯π inter-actions act between the mol-ecules in a cyclic manner to stabilize stacks of mol-ecules along the b axis. Several C-H⋯O inter-actions are present between the stacks.

(±)-3-Benz-yloxy-1-(4-meth-oxy-benz-yl)piperidine-2-thione.

The title mol-ecule, C20H23NO2S, adopts a twisted conformation in which the two aromatic rings connected to the central piperidine ring are orientated trans to each other. An intra-molecular C-H⋯S contact occurs. In the crystal, C-H⋯π and C-H⋯O inter-actions act to stabilize the structure in three dimensions.

3-Hy-droxy-1-(4-meth-oxy-benz-yl)piperidin-2-one.

The title compound, C13H17NO3, adopts a conformation in which the aromatic ring and the mean plane of the piperidine ring are almost perpendicular to each other [dihedral angle = 79.25 (6)°]. The presence of the carbonyl group alters the conformation of the piperidine ring from a chair to a twisted half-chair conformation. In the crystal, pairs of strong O-H⋯O hydrogen bonds link the mol-ecules into inversion dimers. Weak C-H⋯O inter-actions extend the hydrogen-bonding network into three dimensions.

2-[(2Z)-Azepan-2-yl-idene]-1-(4-nitro-phen-yl)ethanone.

The title compound, C(14)H(16)N(2)O(3), is an NH-vinyl-ogous amide (enaminone) produced by the reaction of 4-nitro-phenacyl bromide with azepane-2-thione. The conformation about the C=C bond [1.3927 (14) Å] is Z, which allows for the formation of an intra-molecular N-H⋯O hydrogen bond that leads to an S(6) loop. Inversion-related mol-ecules associate via N-H⋯O hydrogen bonds to form a 12-membered {⋯OC(3)NH}(2) synthon.

4-(Dimeth-oxy-meth-yl)phenyl 2,3,4,6-tetra-O-acetyl-ß-d-glucopyran-oside.

The enanti-omerically pure title compound, C(23)H(30)O(12), crystallizes in the chiral space group P2(1)2(1)2(1). The O-acetyl-ated-glucopyran-oside moiety adopts a chair conformation. Numerous C-H⋯O inter-actions as well as a C-H⋯π inter-action are present in the crystal structure.

(2-Amino-phen-yl)methanol.

The crystal strucure of the title compound, C(7)H(9)NO, displays N-H⋯O hydrogen bonds which link mol-ecules related by translation along the b axis, and O-H⋯N and further N-H⋯O hydrogen bonds which link mol-ecules related by the 2(1) screw axis along the c axis. The resulting combination is a hydrogen-bonded layer of mol-ecules parallel to (011).

(2E)-1-Phenyl-2-[1-(2-phenyl-prop-2-en-1-yl)pyrrolidin-2-yl-idene]ethanone.

The title compound, C21H21NO, is a vinyl-ogous amide (enaminone) produced by reaction of 1-(2-phenyl-prop-2-en-1-yl)pyrrolidine-2-thione with phenacyl bromide. In the mol-ecule, the phenyl rings are twisted from the mean plane of the pyrrolidine ring by 11.2 (1) and 67.3 (1)°. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules related by translation along the b axis into chains.

2,3-Dihydro-1H-pyrrolo-[1,2-a]indole-9-carbonitrile.

The asymmetric unit of the title compound, C12H10N2, which may serve as a model for mitosenes, contains two independent mol-ecules. The conformation of the five-membered rings in both molecules is envelope, with the central CH2-CH2-CH2 C atom at the flap in each case. In the crystal, they inter-act by a combination of weak C-H⋯N and π-π inter-actions [centroid-centroid distances = 3.616 (1) and 3.499 (1) Å] and C-H⋯π contacts.

(±)-(rel-3R,3'R)-1,1'-Dimethyl-3,3'-bipyrrolidine-2,2'-dithione.

The asymmetric unit of the racemic title compound, C(10)H(16)N(2)S(2), a C(2)-symmetric bis-(thiol-actam), contains one half-mol-ecule, the complete mol-ecule being generated by a twofold axis symmetry operation. The five-membered ring is nearly planar, with a maximum deviation of 0.025 (1) Å. In the crystal, the mol-ecules are linked via weak C-H⋯S inter-actions, forming infinite chains along the b-axis direction.