Novel deoxy-selenylconduritols: chemoenzymatic synthesis and biological evaluation

The first synthesis of two selenyldeoxycyclitols (4-bromo-2-phenylselenyl conduritol F and 6-phenylselenylconduritol F) is reported via a chemoenzymatic enantioselective route. The key step of the synthesis is the selenolysis of a vinyl epoxide. The new compounds were evaluated for their capacity to inhibit the growth of different microorganisms using a modification of the agar diffusion technique with thin layer chromatography plates as support.     

Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.     

A chemoenzymatic synthesis of both enantiomers of a cis-lignan lactone

The stereoselective acetylation of meso-2,3-bis(3,4-dimethoxybenzyl)butanediol by vinyl acetate in the presence of Candida antarctica lipase in benzene gave the corresponding (+)-(2S,3R) monoester (ee ≥98%). Transesterification of meso-2,3-bis(3,4-dimethoxybenzyl)butyl diacetate, in the presence of the same enzyme, by ethanol in benzene/isopropyl ether gave the corresponding (−)-(2R,3S) monoester (ee ≥98%). Both enantiomers of the known cis-2,3-bis(3,4-dimethoxybenzyl)butyrolactone were synthesized from these monoesters.     

Stereoselective chemoenzymatic synthesis of both enantiomers of protected 4-amino-2-pentanone

An acetal protected 4-amino-2-pentanone was synthesised by two different routes in 10 and seven steps, respectively, the key step being a microbiological reduction. Both enantiomers of the amine were obtained enantiomerically pure.     

Asymmetric total synthesis of danicalipin A and evaluation of biological activity

Asymmetric total synthesis of danicalipin A was achieved. The synthesis was characterized by diastereoselective introduction of chlorine atoms. Biological activities with synthetic danicalipin A, its enantiomer, and racemate were also evaluated toward brine shrimp. Both enantiomers of danicalipin A showed almost the same activity.     

Improvement of the chemoenzymatic synthesis of both enantiomers of keto-protected 4-amino-2-pentanone

An improved enantioselective synthesis (five steps, 37–44% yield versus seven to 10 steps, 13.5 and 12% yield, respectively) of both enantiomers of keto-protected 4-amino-2-pentanone has been realized, the key step being the microbiological reduction of 2,4-pentanedione. This study shows that microbiological reductions of the mono acetal-protected 2,4-pentanedione afforded in most cases the corresponding ketol with moderate to excellent enantiomeric excesses, depending on the microorganism used.     

Practical synthesis of hydroxychromenes and evaluation of their biological activity

A simple and efficient seven steps synthesis of brodifacoum and difethialone from phenylacetyl chloride is described. The key synthetic strategies involve Friedel-Crafts acylation, intramolecular ring cyclization and condensation reaction in the presence of Br?nsted-Lowry acids. It was found that brodifacoum showed favorable inhibiting activities on LPS-stimulated nitrite production in BV-2 microglia cells. Brodifacoum exhibited superior anti-inflammatory effects than difethialone. We expect that an efficient linear synthesis of 4-hydroxycoumarin derivatives and key fragments that are useful agents for the modulation of inflammation as well as inhibition of coagulation will be of practical use.     

Solid-phase combinatorial synthesis of aeruginosin derivatives and their biological evaluation

A 24-member combinatorial library based on the structure of aeruginosin 298-A (1a) was synthesized utilizing solid-phase, and their inhibitory activity against trypsin was evaluated. Among the library, we found that D-Hpla-D-Leu-L-Choi-Agma (1h) is 300 times more potent than the parent natural product 1a.     

Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication,amplification of chirality and implication for the origin of biological enantioenriched chirality

We discovered asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product 5-pyrimidyl alkanol acts as a highly efficient asymmetric autocatalyst to afford more of itself (Soai reaction). Asymmetric autocatalysis proceeded quantitatively (>99% yield), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three rounds of consecutive asymmetric autocatalysis to >99.5% ee by asymmetric amplification. Circularly polarized light, and inorganic and organic crystals, act as the origin of chirality to trigger asymmetric autocatalysis. Asymmetric autocatalysis has enormous power to recognize and amplify the chirality of hydrogen, carbon, oxygen, and nitrogen isotopomers. Moreover, absolute asymmetric synthesis, i.e., the formation of enantioenriched compounds without the intervention of any chiral factor, is realized by asymmetric autocatalysis. By using designed molecules based on 5-pyrimidyl alkanol, the intramolecular asymmetric control, self-replication, and improvement of chiral multifunctionalized large molecules has been developed by applying asymmetric autocatalysis.     

Frontiers and opportunities in chemoenzymatic synthesis

Natural product biosynthetic pathways have evolved enzymes with myriad activities that represent an expansive array of chemical transformations for constructing secondary metabolites. Recently, harnessing the biosynthetic potential of these enzymes through chemoenzymatic synthesis has provided a powerful tool that often rivals the most sophisticated methodologies in modern synthetic chemistry and provides new opportunities for accessing chemical diversity. Herein, we describe our research efforts with enzymes from a broad collection of biosynthetic systems, highlighting recent progress in this exciting field.     

Stereoselective synthesis of trifluoro- and monofluoro-analogues of frontalin and evaluation of their biological activity.

The stereoselective synthesis of both enantiomers of trifluoro frontalin (-)-(1S,5R)- and (+)-(1R,5S)-8, as well as of diastereomeric monofluoro frontalines (-)-(1R,2R,5R)-18 and (-)-(1R,2S,5R)-20, analogues of the bioactive component of the aggregation pheromone of the Scolytidae insect family, has been accomplished starting from (-)-(1R)- and (+)-(1S)-menthyl (S)-toluene-4-sulfinate as a source of chirality and methyl trifluoroacetate or fluoroacetate, respectively, as sources of fluorine. The C-1 stereocenters were installed via stereoselective epoxidation of beta-sulfinyl ketones 2 and 13 with diazomethane. The bicyclic core was obtained by totally stereocontrolled and chemoselective tandem Wacker oxidation/intramolecular ketalization of the intermediate unsatured sulfinyl diols 5, 15, and 19. Axially fluorinated (-)-20 elicited a strong electroantennographic response in laboratory tests on females of Dendroctonus micans, whereas equatorially fluorinated (-)-18 and the trifluoroanalogue (-)-8 showed modest responses. Field trials using (-)-20 were not indicative owing to the locally scarce population of D. micans, but it showed some attractiveness for other Coleoptera families.     

Asymmetric synthesis of both the enantiomers of antidepressant venlafaxine and its analogues

Chemoenzymatic asymmetric synthesis of antidepressant agent venlafaxine and its analogue have been reported in this communication. The main highlight of the reported synthesis is the stereoselective synthesis of cyanohydrins by (S)-hydroxynitrile lyase (Hevea brasiliensis) followed by lipase catalyzed kinetic resolution.     

Asymmetric synthesis of both the enantiomers of trans-3-hydroxypipecolic acid

Both the enantiomers of trans-3-hydroxypipecolic acid have been synthesized employing the Sharpless asymmetric dihydroxylation and epoxidation as the key steps starting from a commercially available starting material 1,4-butanediol.     

Planar chiral indoles: synthesis and biological effects of the enantiomers

The paracyclophanyl triflates (R)-4 and (S)-4, which were obtained from racemic precursors through enzymatic-kinetic resolution, could be employed as key intermediates for the synthesis of planar chiral [2.2](4,7)indoloparacyclophanes. Subjecting the double-layered test compounds (R)-8 and (S)-8 to in vitro ligand-binding experiments displayed stereoselective receptor recognition.     

Total synthesis and biological evaluation of the nakijiquinones.

The Her-2/Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. The nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of the nakijiquinones may display inhibitory properties toward other receptor tyrosine kinases involved in cell signaling and proliferation. Here, we describe the first enantioselective synthesis of the nakijiquinones. Key elements of the synthesis are (i) the reductive alkylation of a Wieland-Miescher-type enone with a tetramethoxyaryl bromide, (ii) the oxidative conversion of the aryl ring into a p-quinoid system, (iii) the regioselective saponification of one of the two vinylogous esters incorporated therein, and (iv) the selective introduction of different amino acids via nucleophilic conversion of the remaining vinylogous ester into the corresponding vinylogous amide. The correct stereochemistry and substitution patterns are completed by conversion of two keto groups into a methyl group and an endocyclic olefin via olefination/reduction and olefination/isomerization sequences, respectively. This synthesis route also gave access to analogues of nakijiquinone C with inverted configuration at C-2 or with an exocyclic instead of an endocyclic double bond. Investigation of the kinase-inhibiting properties of the synthesized derivatives revealed that the C-2 epimer 30 of nakijiquinone C is a potent and selective inhibitor of the KDR receptor, a receptor tyrosine kinase involved in tumor angiogenesis. Molecular modeling studies based on the crystal structure of KDR and a model of the ATP binding site built from a crystal structure of FGF-R revealed an insight into the structural basis for the difference in activity between the natural product nakijiquinone C and the C-2 epimer 30.     

Asymmetric synthesis and biological evaluation of 3-nitro-2H-chromenes as potential antibacterial agents

A one-pot organocatalytic domino Henry/Michael/dehydration sequence of various salicylaldehyde derivatives with nitromethane as a dual-nucleophile is disclosed. This straightforward strategy assembles the optically active (R)-2-alkyl 3-nitro-2H-chromenes with good to excellent enantioselectivities (up to 93% ee) and a broad substrate scope. Preliminary in vitro antibacterial evaluation revealed most of the chiral 3-nitro-2H-chromene derivatives exhibit antibacterial activities against four Gram-positive bacteria. Compound 3p with two bromine substituents on the core scaffold was shown to be the best antibacterial agent in the series against S. aureus, B. subtilis and Bacillus cereus with minimal bactericidal concentration (MBC) values of 4?μg/mL, and against Staphylococcus epidermidis with a MBC value of 8?μg/mL.     

Short and efficient chemoenzymatic synthesis of goniothalamin

A high-yielding three-step synthesis of goniothalamin involving an enzymatic kinetic resolution in the presence of vinyl acrylate followed by ring-closing metathesis is discussed.     

Asymmetric alkyldifluoroboranes and their use in secondary amine synthesis

[reaction: see text] Asymmetric diol boronic esters with potassium bifluoride form the corresponding alkyltrifluoroborate and free diol under mild conditions. Defluoridation with tetrachlorosilane produces an alkyldifluoroborane intermediate. This conversion of relatively unreactive boronic esters to derivatives that are strong Lewis acids opens new synthetic opportunities, as illustrated by the preparation of (R)-2-phenylpyrrolidine in 98% ee from a pinanediol or 1,2-dicyclohexyl-1,2-ethanediol boronic ester via potassium (2-phenyl-4-azidobutyl)trifluoroborate.