Chemoenzymatic Synthesis of trans-β-Aryl-δ-hydroxy-γ-lactones and Enzymatic Kinetic Resolution of Their Racemic Mixtures (original) (raw)
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Scientific Reports
Lactone 2a of a bicyclo[4.3.0]nonane structure is a good starting material for synthesis of many attractive compounds. Enantiomerically enriched (−)-(3aR,7aS)-lactone 2a is produced by whole cells of bacteria. In order to examine the impact of the absolute configuration on biological activity we evaluated the process affording the opposite isomer. To this purpose Candida pelliculosa ZP22 characterized by high dehydrogenase activity was used. The goal of presented work was to perform bioreactor scale microbial one-pot oxidation of diol with selected yeast strain C. pelliculosa ZP22 to obtain chiral (+)-(3aS,7aR)-lactone 2a. The idea was to influence on alcohol dehydrogenase activity by increasing the activity of pro-(+)-ADH and simultanously diminishing the activity of pro-(−)-ADH. The optimization of biotransformation conditions involved the manipulation of the nutritional and physical parameters. Selection of the optimal medium in order to improve yield and process enantioselectivity was based on a two-level factorial design methodology. We have also studied the relationship between microbial growth and biosynthesis of lactone 2a. Preparative oxidation of diol 3a (400 mg/L, 2.9 mM) catalyzed by C. pelliculosa ZP22 in an optimized conditions afforded enantiomerically enriched (+)-(3aS,7aR)-isomer of lactone 2a with the isolated yield (30%). Asymmetric transformations catalyzed by whole cells of microorganisms or isolated enzymes have become an attractive alternative for traditional methods leading to optically pure compounds, which derive from either natural sources or by organic synthesis 1-4. It is particularly important in the synthesis of biologically active compounds in which biological activity usually depends on the absolute configuration in a molecule 5,6. Therefore, a growing need to find new biocatalysts for synthesis of optically pure molecules with various biological activities is of high importance in the current chemistry. To achieve this purpose in the field of the synthesis of lactones two biocatalytic strategies: kinetic resolutions 7-9 and stereoselective reactions 10-14 were applied so far. Previously Boratyński 12,14-16 presented a one-pot biotransformation of diols to chiral lactones. This method involves an asymmetric synthetic value leading to lactones that are well-known to be attractive chiral building blocks. Currently we are particularly interested in the development of a stereoselective biooxidation, which will be significant in the multi-step synthesis of optically active lactones of a bicyclo[4.3.0]nonane structure. Compounds of such structure represent a large group of natural phtalide derivatives 17. They have been isolated from plants of the Apiaceae family Lindl. (Ligusticum officinale (Loveroot, old English Lovage), L. chuanxiong, L. wallichii (Chinese Lovage), Angelica sinensis (Chinese Angelica), Apium graveolens (celeriac) and Petroselinum crispum (parsley)) used in herbal medicine, especially in Chinese folk medicine. More than 70 structures of these lactones were documented. The advantage of this group of compounds is a broad spectrum of biological activity, such as insecticidal 18,19 , fungicidal 18 , fragrance 20 , antioxidant 21 and anticoagulant 22 , anti-proliferative 23 , cytotoxic 24. However, obtaining these valuable natural compounds directly from a plant material is inefficient and thus uneconomic. Chemical synthesis, although efficient, does not recommend by the green chemistry. Alternative approach providing to the optically pure isomers is biocatalysis. It is worth mentioning that whole cells of yeast are well-known biocatalysts. They catalyze reduction reactions of a carbonyl group 25-28 and a carbon-carbon double bond 29,30 , hydrolase reaction 31 and formation of a carbon-carbon double bond 32,33. Additionally, reports published on oxidation reactions performed by yeast are
Biomolecules
Starting from 1-acetyl-1-cyclohexene, three enantiomeric pairs (ee ≥ 99%) of bicyclic δ-halo-γ-lactones with cyclohexane ring were obtained in five-step synthesis. The key stereochemical steps were lipase-catalyzed kinetic resolution of racemic 1-(cyclohex-1-en-1-yl) ethanol followed by transfer of chirality to ethyl 2-(2-ethylidenecyclohexyl) acetate in the Johnson–Claisen rearrangement. Synthesized halolactones exhibited antiproliferative activity towards canine B-cell leukemia cells (GL-1) and canine B-cell chronic leukemia cells (CLB70) and the most potent (IC50 18.43 ± 1.46 μg/mL against GL-1, IC50 11.40 ± 0.40 μg/mL against CLB70) comparable with the control etoposide, was (1R,6R,1′S)-1-(1′-chloroethyl)-9-oxabicyclo[4.3.0]nonan-8-one (8b). All halolactones did not have a toxic effect on erythrocytes and did not change the fluidity of membranes in the hydrophobic region of the lipid bilayer. Only weak changes in the hydrophilic area were observed, like the degree of lipid packi...
Journal of the Brazilian Chemical Society, 2021
This study describes the stereoselective synthesis of two new γ-lactones in 6 and 3 steps and 19 and 32% yield, respectively, directed toward the total synthesis of the natural product (−)-cleistenolide. The starting material was an enantiomerically pure diacetonide diol, derived from d-mannitol with the required stereocenters for (−)-cleistenolide synthesis. γ-Lactone syntheses were based on highly selective protection and deprotection of hydroxyls from d-mannitol. The formation of γ-lactone rings was the culmination of this approach, made possible by a Horner-Wadsworth-Emmons Z-olefination between diacetal aldehyde and ethyl 2-(bis(o-tolyloxy)phosphoryl)acetate to produce an unsaturated ester. The Z-isomer ester was highly favored in relation to the E-isomer (Z/E ratio of 94:6), allowing the formation of the γ-lactone ring under acid catalysis. This strategy precluded the use of chiral auxiliaries or catalysts for the control of stereocenters in the novel γ-lactones.
Expedient Approach to α,β-Unsaturated δ-Lactones through a Catalytic Asymmetric [2+2] Cycloaddition
European Journal of Organic Chemistry, 2017
The stereoselective synthesis of cis-γ,δ-disubstituted α,βunsaturated δ-lactone fragment of leustroducsins or phoslactomycins was accomplished according to an original strategy involving a catalytic asymmetric ketene-aldehyde [2+2] cycloaddition leading to the formation of a cis-disubstituted β-lactone. Ring extension by enolate condensation and subsequent recyclization gave the target δ-lactone in a straightforward fashion. Coupling studies with cyclohexanone are also reported. Supporting information for this article is given via a link at the end of the document: copies of NMR spectra and XRay data
Enantioselective hydrolysis of δ-acetoxy-γ-lactones
Tetrahedron: Asymmetry, 2004
Both enantiomers of 5-(1 0-acetoxy-3 0-methylbutyl)-4,4-dimethyl-tetrahydrofuran-2-one 1a have been prepared with high enantioselectivity by microbial resolution using cultures of Fusarium solani and F. tricinctum. Enantioselectivity of lipolitic activity of F. solani and F. tricinctum was tested on four homologues of d-acetoxy-c-lactones (±)-1b-e. Absolute configurations of the products were determined by spectroscopic methods (1 H NMR and CD) and an X-ray diffraction study.
Journal of Heterocyclic Chemistry, 2015
A new rapid synthesis of γ-lactones, cis fused with a cyclopentenic ring by thermal cyclization of 7-chloro-2-(methoxycarbonyl)-4-6-dimethylocta-7-phenyl (or methyl) (2E,4E,6E)-trienoic acids was reported. The key step implicates an intramolecular cyclization to a cyclopentenyl cation, according to an electrocyclic π 2s + π 2a conrotatory process, published in a recent paper (from the corresponding diacids). We have investigated the thermal behavior of the corresponding half-esters since; if the cyclization obeys to the proposed mechanism, the diacids, half-esters must also cyclize in a similar manner. Saponification of these led to γ-dilactones via intermediary cyclopropanes. Mechanistic pathways were investigated.