Review on asymmetric synthetic methodologies for chiral isoquinuclidines; 2008 to date

Isoquinuclidines constitute the central structural nucleus of numerous biologically active natural products, for example, iboga alkaloids such as ibogamine and catharanthine as well as non-indole-containing alkaloids such as the dioscorine and the cannivonines. Furthermore, in medicinal and pharmaceutical chemistry, the isoquinuclidine core is commonly employed as a rigid azabicyclic scaffold, thus providing significant precursors in the synthesis of numerous valuable alkaloids. Summarizing well-organized approaches to access the chiral isoquinuclidine structural centerpiece signifies a significant endeavor not only for developing biologically active natural products but also enhancing biological researches that can lead to possible drug discovery. Over time, the values and methodologies for the asymmetric synthesis of chiral isoquinuclidines are increasing; hence to advance asymmetric synthesis, this review combines and discusses the pros and cons of each synthesis techniques from 2008. This review should be helpful for promoting further developments of asymmetric synthetic methodologies and for medicinal chemistry.     

Resolution,absolute configuration and antifilarial activity of coumarinyl amino alcohols

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-l-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.     

Synthesis of p-coumaroylquinic acids and analysis of their interconversion

The synthesis of four isomers of p-coumaroylquinic acids was performed by esterification of p-acetylcoumaroylchloride with a suitably protected (?)-quinic acid. All isomers have been characterized by means of NMR spectroscopy and circular dichroism. Acyl migration was observed in the synthesis of 3-O-p-coumaroylquinic acid and 4-O-p-coumaroylquinic acid. Calculations on the most stable conformations of all isomers have also been performed to explain the acyl migration observed during the synthesis procedure.     

Withering timings affect the total free amino acids and mineral contents of tea leaves during black tea manufacturing

The aim of the present study was to investigate the effect of withering timings (i.e. 0, 21, 22, 23 and 24 h) on the moisture, total free amino acids, ash, essential and toxic mineral element contents of tea (Camellia sinensis L.) leaves during black tea manufacturing. Moisture, ash, Na, P, Mg, Cu, Zn, Mn, Al, Ni and Pb contents were significantly (P < 0.05) affected by withering, whereas non-significant (P > 0.05) results were noted for total free amino acids, K, Fe and Cd contents. The highest moisture content (76.4%) was examined in fresh leaves that progressively decreased to 63.8% in 24 h withering. Total free amino acid contents gradually increased up to 23 h and then decreased. Ash, P, Cu, Zn and Mn contents showed an increasing trend with withering time. Conversely, significantly lowered amounts of Na (162.5 mg/kg) and Mg (803 mg/kg) were recorded in tea leaves after 24 h withering. Among the toxic elements, Al, Ni and Pb contents were progressively increased over withering time. It was concluded that tea is a potential source of essential chemical constituents and during processing proper care should be taken to produce high quality black tea.     

Benzyl isobornyl amines: a simple and practical class of NMR discriminating agents for effective chiral recognition of acids

The design and synthesis of a few simple N-benzyl derivatives of isobornyl amine is presented. The derivatives have been assessed as chiral solvating agents for effective discrimination of the signals of some acids in NMR analysis. The single crystal X-ray analysis of the salts of (R)-mandelic acid with two of the title derivatives help to understand the supramolecular interactions and assign the induced chemical shifts in ¹H NMR analysis. The title derivative is found to be suitable for quantitative determination of the enantiomeric excess of unknown enantiomeric purity as well as being efficient in resolving racemic mandelic acid.     

Syntheses,characterization, in vitro antiglycation and DPPH radical scavenging activities of isatin salicylhydrazidehydrazone and its Mn (II), Co (II), Ni (II), Cu (II), and Zn (II) metal complexes

2-Hydroxy salicylhydrazide isatin hydrazone (L) and its Mn (II), Co (II), Ni (II), Cu (II), and Zn (II), metal complexes were synthesized. ¹H NMR, UV–Vis, IR spectroscopy and elemental (CHN/S) analysis techniques were applied for characterization. TG/DTA techniques revealed that all the synthetic compounds are thermally stable up to 300 °C. They were found non-electrolytes in nature. Furthermore, all these complexes were evaluated for antiglycation and DPPH radical scavenging activities. They showed varying degree of activity with IC₅₀ values between 168.23 and 269.0 μM in antiglycation and 29.63–57.71 μM in DPPH radical scavenging activity. Mn (II), Co (II), Ni (II), Cu (II), and Zn (II), metal complexes showed good antiglycation as well as DPPH radical scavenging activity. The IC₅₀ values for antiglycation activity are 168.23 ± 2.37, 234.27 ± 4.33, 257.1 ± 6.43, 267.7 ± 8.43, 269.0 ± 8.56 Ni for Co, Zn, Mn, Cu, and Ni complexes, respectively, while IC₅₀ value were found to be 29.63 ± 2.76, 31.13 ± 1.41, 35.16 ± 2.45, 43.53 ± 3.12, 57.71 ± 2.61 μM for Cu, Zn, Mn, Co and Ni complexes, respectively, for DPPH radical scavenging activity. These synthesized metal complexes were found to be better active than standards Rutin (IC₅₀ = 294.46 μM) for anti-glycation, and tert-butyl-4-hydroxyanisole (IC₅₀ = 44.7 μM) for DPPH radical scavenging activity.     

Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1S,2R)-tranylcypromine

Primary amidations of carboxylic acids 1 or 3 with NH₄Cl in the presence of ClCO₂Et and Et₃N were developed to afford the corresponding primary amides in 22% to quantitative yields. Additionally, we have applied the amidation to the preparation of various amides containing hydroxamic acids and achieved the synthesis of (1S,2R)-tranylcypromine as an antidepressant medicine via Lossen rearrangement.     

A versatile ternary ion pair complex of 2′-amino-1,1′-binaphthalen-2-ol for sensing enantiomers and assignment of absolute configuration

2′-Amino-1,1′-binaphthalen-2-ol (NOBIN) serves as a versatile chiral solvating agent (CSA) in the presence of trifluoromethanesulfonic acid (TFMS). The formation of a ternary complex has been established by NMR, UV–Vis, fluorescence and IR studies. The mechanism of interactions among the three components in the ternary complex has been proposed and the ternary complex structures of different diastereomers have been established by DFT based theoretical calculations. The present protocol has its ubiquity not only in the analysis of the enantiomeric composition of molecules possessing diverse functionalities, but also in determining the stereospecific assignment of hydroxy acids.     

Stereoselection in the Betti reaction of valine methyl esters

The multi-component Betti reaction of 2-naphthol, benzaldehyde and (S)-amines, that usually provides highly valuable aminobenzylnaphthol bearing two stereogenic centers, yielded a completely racemic product, when (S)-valine methyl ester was employed as the amine in the usual reaction protocol. The cause of this drawback, that appears to be overlooked in the literature, was investigated. As a result, new reaction conditions were set up, that were able to yield the expected useful product, having two fully resolved stereogenic centers. Furthermore, when the effect of substituents on the phenyl ring was preliminarily studied, we found that 4-fluoro- and 4-chlorobenzaldeyde gave stereoisomerically pure compounds also in the original reaction protocol.     

Chiral benzimidazoles and their applications in stereodiscrimination processes

Chiral aspects of benzimidazoles have been over-shadowed for a long time due to the large number of reports on benzimidazoles in the medical field in numerous categories of therapeutic agents. The vigorous research activity in chiral applications of benzimidazole derivatives started after bifunctional benzimidazoles made their appearance especially in the last 2–3 decades. Thus, chiral benzimidazoles form a comparatively young branch of chiral chemistry. The presence of pyridine and pyrrole type of nitrogens along with the fused benzene ring confer on this class of molecules, special properties including useful nucleophilicity, hydrogen bonding ability and a rigid backbone, all of which play decisive roles in proven chiral applications. The present review aims to cover the synthetic routes to access chiral benzimidazoles and their applications in a plethora of chiral fields including enantioselective organocatalysis, metal-based catalysis, asymmetric transformations involving benzimidazole-N-heterocyclic carbenes, kinetic resolution, benzimidazole-based macrocyclic hosts in chiral supramolecular chemistry and other miscellaneous chiral applications.     

Stereoselective synthesis and anticancer activity of broussonetine analogues

The stereoselective synthesis of two broussonetine analogues 14·HCl and ent-14·HCl with differing stereochemistry of the polyhydroxylated pyrrolidine core and a simple C₁₃ alkyl fragment has been achieved. For their construction, the known oxazolidinones 15 and 16 were chosen as appropriate advanced scaffolds. The common hydrophobic side chain was incorporated at an early stage of the synthesis through Grubbs’ cross metathesis chemistry. The required pyrrolidine skeleton was then formed by the cyclization of open chain intermediates 17 and 18. Four synthesized compounds were screened in vitro for antiproliferative/cytotoxic activity against six cancer cell lines by MTT assay. Compounds 14·HCl (HeLa and A-549) and ent-14·HCl (Caco-2 and Jurkat) showed comparable or higher potency than conventional anticancer agent cisplatin on at least two evaluated cancer cells, respectively.     

A diversity oriented synthesis of d-erythro-sphingosine and siblings

An efficient building block-based synthetic protocol has been developed for the synthesis of 3-ketosphingoids with various chain lengths using cross metathesis of a Garner’s aldehyde-derived α,β-unsaturated ketone as the key step. Stereoselective reduction of the biomimetic precursors thus obtained provided d-erythro-sphingosine and truncated anaogues in good overall yields.     

Synthesis and crystal structure of (S)-pindolol

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.     

Assessment of antioxidant activities of three wild medicinal plants from Bahrain

This study reports the antioxidant properties of three wild medicinal plants from Bahrain, namely Aizoon canariense L., Asphodelus tenuifolius Cav., and Emex spinosus (L.) Campdera. Antioxidant and antiradical activities of dried materials of these plants were investigated using FRAP, DPPH and ABTS assays. Total phenolics, free phenolics and total flavonoids were also determined. E. spinosus was ranked by the assays as the plant possessing the highest antioxidant and antiradical activities with an average FRAP value of 1.84 mmol/g and IC₅₀ of 10.7 and 7.75 mg/ml for DPPH and ABTS assays, respectively. A. tenuifolius ranked second with a mean FRAP value of 0.69, IC₅₀ DPPH of 1.72 and ABTS of 0.36. A. canariense possessed the lowest activities with a mean FRAP value of 0.6, and averaged IC₅₀ of 103.8 and ABTS of 14.6. E. spinosus possessed the highest content of free phenolics (mg/100 g) (64.64) followed by A. tenuifolius (45.21) and A. canariense (32.23). E. spinosus also exhibited the highest total flavonoids with an average 82.71 mg/100 g followed by A. canariense (55.92) and A. tenuifolius (49.10). The studied medicinal plants possess considerable antioxidant activities and may contribute to the well-being of individuals who consume them.     

Enantioselective total synthesis of a natural hydrocarbazolone alkaloid,identification of its stereochemistry,and revision of its spectroscopic data

The natural hydrocarbazolone alkaloid (1R,2R,3R)-3-hydroxy-1,2-dimethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one has been synthesized in a catalytic and enantioselective manner. A key hydrocarbazole derivative was constructed by the holmium-catalyzed Diels-Alder reaction of (silyloxyvinyl)indole as the diene. Total synthesis of the natural product clarified the ambiguity in the spectroscopic data reported for natural products.     

Asymmetric synthesis of tert-butyl ((1R,4aR,8R,8aR)-1-hydroxyoctahydro-1H-isochromen-8-yl)carbamate

The asymmetric synthesis of methyl (E)-4-((1R,2S,3R)-3-amino-2-((E)-2-methoxycarbonyl-eten-1-yl)cyclohexyl)but-2-enoate 14 has been achieved from dimethyl (2E,7E)-nona-2,7-dienedioate 2. A key step is the asymmetric synthesis of 1-hydroxyoctahydro-1H-isochromene derivative 5 whose X-ray analysis corroborated the stereochemistry of the new stereocenters. The asymmetric synthesis of the isochromenyl acetate derivative 11 shows the potential of this methodology for fused cyclohexanic system heterocyclic synthesis.     

Synthesis,crystal structure,and absolute configuration of the enantiomers of chiral drug xibenolol hydrochloride

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2, the synthetic precursor of the chiral drug xibenolol 1, was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes (S)- and (R)-3, and then into the xibenolol enantiomers. Single crystals of (+)- and (?)-1·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute (R)- and (S)-configurations were assigned to these compounds and to the other intermediate chiral substances.