Regioselective Demethylation Research Articles

Chemo- and Regioselective Demethylation of 2-Bromo-α-resorcylic Acid Derivatives Using Alkylthiolate Salts

AbstractWe report here the chemo- and regioselective demethylation of 2-bromo-3,5-dimethoxy-α-resorcylic acid esters by a thiolate nucleophilic displacement reaction. Optimized conditions facilitate yields up to 93% for o-bromo-selective demethylation of diverse ester derivatives of dimethoxy 2-bromo-α-resorcylic acid. Our results highlight a new, efficient, and reliable demethylation reagent, as well as a useful steric bias directing strategy.

Total Synthesis of Carbazomycins E and F.

Total synthesis of carbazomycins E and F was achieved by double functionalization of an aryne intermediate generated from a 2-aminobiphenyl derivative. The tethered amino group underwent nucleophilic addition to the aryne intermediate to construct the carbazole skeleton. The resulting carbanion was formylated to give the multiply substituted carbazole. This formyl group caused several problems. For example, it was difficult to perform regioselective demethylation of the methoxy group proximal to the formyl group without protecting the carbazole nitrogen. In addition, the formyl group was unexpectedly reduced to give a methoxymethyl group under heating conditions with copper iodide and sodium methoxide. Oxidation of this compound in the presence of water was effective for obtaining the formylated carbazole, leading to the first total synthesis of carbazomycin F.

Total Synthesis and Antimalarial Activity of 2-(p-Hydroxybenzyl)-prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria.

Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(p-hydroxybenzyl)-prodigiosins (2-5), isoheptylprodigiosin (6), and geometric isomers of tambjamine MYP1 ((E/Z)-7) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines 24-27 in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel of Plasmodium falciparum parasites, with a great therapeutic index. Notably, prodiginines 6 and 24-27 provided curative in vivo efficacy against erythrocytic Plasmodium yoelii at 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.

Reactivity of Copper(I) Complexes Containing Ligands Derived from (1S,3R)‐Camphoric Acid with Dioxygen

AbstractAmine derivatives prepared from camphoric acid were used as ligands for the synthesis of corresponding copper(I) complexes. Their reactivity towards dioxygen was analyzed. The formation of a short‐lived bis(μ‐oxido)copper complex was spectroscopically observed during the reaction of the copper(I) complex with (1R, 3S)‐N1,N1,N3,N3‐Tetramethyl‐1,2,2‐trimethylcyclopentane‐1,3‐diamine as a ligand. Furthermore, a regioselective demethylation of the ligand system was detected. Deuteration of the methyl groups of the ligand allowed crystallization and characterization of the bis(μ‐oxido)copper complex. Derivatives of the ligand with pyridine residues caused suppression of the reactivity of the corresponding copper(I) complexes towards dioxygen. Additionally, the ligand system could be modified for intramolecular oxygenation reactions with benzaldehyde that led to the formation of salicylaldehyde, a selective hydroxylation in ortho position.

Oxygen-Free Regioselective Biocatalytic Demethylation of Methyl-phenyl Ethers via Methyltransfer Employing Veratrol-O-demethylase.

The cleavage of aryl methyl ethers is a common reaction in chemistry requiring rather harsh conditions; consequently, it is prone to undesired reactions and lacks regioselectivity. Nevertheless, O-demethylation of aryl methyl ethers is a tool to valorize natural and pharmaceutical compounds by deprotecting reactive hydroxyl moieties. Various oxidative enzymes are known to catalyze this reaction at the expense of molecular oxygen, which may lead in the case of phenols/catechols to undesired side reactions (e.g., oxidation, polymerization). Here an oxygen-independent demethylation via methyl transfer is presented employing a cobalamin-dependent veratrol-O-demethylase (vdmB). The biocatalytic demethylation transforms a variety of aryl methyl ethers with two functional methoxy moieties either in 1,2-position or in 1,3-position. Biocatalytic reactions enabled, for instance, the regioselective monodemethylation of substituted 3,4-dimethoxy phenol as well as the monodemethylation of 1,3,5-trimethoxybenzene. The methyltransferase vdmB was also successfully applied for the regioselective demethylation of natural compounds such as papaverine and rac-yatein. The approach presented here represents an alternative to chemical and enzymatic demethylation concepts and allows performing regioselective demethylation in the absence of oxygen under mild conditions, representing a valuable extension of the synthetic repertoire to modify pharmaceuticals and diversify natural products.

Synthesis and antiproliferative activities of polymethoxyflavones aminoalkyl and amino acid derivatives

Abstract Twelve novel aminoalkyl derivatives 3a-3f, 4a-4f and four novel amino acid derivatives 5a, 5b, 6a and 6b of polymethoxyflavones 1 and 2 were synthesized through regioselective demethylation, etherification, amination, EDCl-mediated amide condensation and alkaline hydrolysis, using tangeretin and nobiletin as starting materials. Their antiproliferative activities against four different human cancer cell lines (Aspc-1, SUN5, HepG-2 and HCT116) were evaluated by in vitro CCK-8 assay. The results show that the majority of the synthetic compounds exhibited moderate to good antiproliferative activity. In particular, the antiproliferative activity of compound 5b against HepG-2 cells (IC50 0.057 μM) was equal to the positive control drug Staurosporine (IC50 0.0575 μM).

Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine.

Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b–c and 4b–d) and 4 carbonates (2e–f and 4e–f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.

Enzyme-catalyzed regio-selective demethylation of papaverine by CYP105D1.

To investigate the regio-selective demethylation of papaverine by CYP105D1 and develop a whole-cell biocatalytic system for the preparative synthesis of 6-O-demethyl-papaverine. CYP105D1 from Streptomyces griseus ATCC 13273 was used for the regioselective demethylation of papaverine at C-6 using putidaredoxin reductase (PDR) and putidaredoxin (Pdx) as the electron transport system. The Km value of CYP105D1 towards papaverine was estimated to be 92.24μM. Furthermore, a CYP105D1-based whole-cell system was established in E. coli BL21(DE3). The whole cell biotransformation condition was optimized as 25°C, pH 7.5, 8g (cell dry weight) L-1 whole cell biomass and 3% (v/v) PEG-200 as cosolvent. Under the optimal condition, the conversion yield of papaverine reached to 61.15% within 24h. The selective demethylation of papaverine by CYP105D1 was accomplished. The CYP105D1-based whole-cell biocatalyst has a potential used for the efficient synthesis of 6-O-demethyl-papaverine.

Regio- and enantioselective O-demethylation of tetrahydroprotoberberines by cytochrome P450 enzyme system from Streptomyces griseus ATCC 13273.

Tetrahydroprotoberberines (THPBs), a class of naturally occurring isoquinoline alkaloids, contain substituent methoxyl or hydroxyl groups which play a significant role in the pharmacological properties of these molecules. In this study, we report a biocatalytic strategy for selective O-demethylation of THPBs. CYP105D1, a cytochrome P450 from Streptomyces griseus ATCC 13273, exhibited markedly regioselective demethylation of nonhydroxyl-THPBs and monohydroxyl-THPBs on the D-ring. A possible binding mode of THPBs with CYP105D1 was investigated by docking analysis, and the results revealed that the D-rings of THPBs were with the minimum distance to the heme iron. Tetrahydropalmatine was used as a model substrate and enantioselective demethylation was demonstrated. (S)-Tetrahydropalmatine was only demethylated at C-10, while (R)-tetrahydropalmatine was first demethylated at C-10 and then subsequently demethylated at C-9. The kcat/Km value for demethylation of (R)-tetrahydropalmatine by CYP105D1 was 3.7 times greater than that for demethylation of (S)-tetrahydropalmatine. Furthermore, selective demethylation of (S)-tetrahydropalmatine by the CYP105D1-based whole-cell system was demonstrated for the highly efficient production of (S)-corydalmine which has distinct pharmacological applications, such as providing relief from bone cancer pain and reducing morphine tolerance. Moreover, a homologous redox partner was identified to enhance the catalytic efficiency of the CYP105D1-based whole-cell system. This is the first enzymatic characterization of a cytochrome P450 that has regio- and enantioselective demethylation activity of THPBs for application purpose. The cytochrome P450 system could be a promising strategy for selective demethylation in the pharmaceutical industry.

Total Synthesis of the Natural Pyridocoumarins Goniothaline A and B

In this paper, we report the first total synthesis of goniothaline A and B, which are rare natural pyridocoumarins isolated from Goniothalamus australis. The key feature of the synthesis of goniothaline A is high-yielding silver-catalyzed cycloisomerization to afford the pyridine moiety. In addition, goniothaline B, a natural 8-hydroxyquinoline derivative, is readily synthesized by the regioselective demethylation of goniothaline A.

Synthesis of 9-Substituted Berberine Derivatives with Microwave Irradiation

Hyperglycemia is frequently accompanying with hyperlipidemia. To explore the potent drugs with dual-activity and dual-site effects that could reduce blood glucose and blood lipid at the same time, fibrate group with lipid-lowering effect on the 9th position of berberine(BBR) was introduced using the drug design combination principle and the multitarget collaborative treatment method. Moreover, the molecular structure of BBR was modified, and six 9-substituted derivatives of BBR were designed and synthesized, among which, five compounds have never been reported before. In addition, the molecular structures of these derivatives were identified using liquid chromatography-mass spectrometry(LC-MS), 1H nuclear magnetic resonance(1H NMR) and 13C NMR, respectively. Furthermore, the microwave irradiation experimental technique was applied in the synthesis reaction using the novel microwave synthesizer, which accelerated the reaction rate, enhanced the reaction yield, reduced the reaction by-products, and simplified the post-processing steps. In the meantime, the 9-position regioselective demethylation of BBR was explored through quantum chemical calculation during the synthesis of berberrubine. The computations were consistent with the experimental results, which contributed to deducing the mechanism of its selective methylation.

Formal total synthesis of stigmatellin A

An efficient and stereoselective approach for the formal total synthesis of Stigmatellin A has been described. The key steps involved in this synthesis are desymmetrization of the bicyclic olefin to introduce two methyl and two hydroxyl chiral centers, Friedel Crafts acylation, regioselective demethylation, Baker-Venkataraman rearrangement and Grubbs cross metathesis.

Microbial Catalyzed Regio-Selective Demethylation of Colchicine by Streptomyces griseus ATCC 13273.

Colchicinoids and their derivatives are of great importance in pharmaceutical applications, and colchicine is usually used as the first choice for the treatment of gout. To expand the structural diversities and clinical application of colchicinoids, many attempts have been established for the derivatives with better activity or less toxicity. Herein, in this paper, we report a direct microbial transformation of colchicine into 2-O-demethyl-colchicine (M1) and 3-O-demethl-colchicine (M2) by Streptomyces griseus ATCC 13273. It is noteworthy that when DMF was used as co-solvent, the yield of M1 and M2 could reach up to 51 and 31%, respectively. All the structures of the metabolites were elucidated unambiguously by ESI-MS, 1H-NMR, 13C-NMR, and 2D-NMR spectroscopy.

Synthesis of Citrus polymethoxyflavonoids and their antiproliferative activities on Hela cells

A series of polymethoxyflavonoids (3–16) were synthesized through dehydrogenation, O-methylation, glycoside hydrolysis, bromination, microwave-assisted aromatic nucleophilic substitution, dimethyldioxirane oxidation and regioselective demethylation, starting from abundant and inexpensive natural sources naringin and hesperidin. All the synthetic compounds were test for antiproliferative activities on human cervical carcinoma Hela cell line by the standard CCK-8 assay, the result showed that most of the target compounds exhibited moderate to potent antiproliferative activities on Hela cells comparable with the positive control cis-Platin. Among them, 5-hydroxypolymethoxy flavonoid 13 showed the strongest activity (IC50 0.791 μM).

Regioselective demethylation of quinoline derivatives. A DFT rationalization

Demethylation of compound 2,7-dimethoxyquinoline-3-carbaldehyde 1, is carried out using BBr3. However, all attempts led, either to the starting material or to the regioselective demethylation at position 2 affording the product 4a. The nature (donor or acceptor) and the position of the R (CHO or CN) group is likely to play a role in the preventing the demethylation at position 7. To address this phenomena, the demethylation of 2-chloro-7-methoxyquinoline-3-carbaldehyde 2 and 2,7-dimethoxyquinoline-3-carbaldehyde 3 has been carried out. To support the results obtained, theoretical computations at DFT level (vide infra) have been carried out upon compound 1. The exploration of how the gas-phase demethylation process on Quinoline can be affected at a position 7 center by stepwise substation effects using different electro-donor and attractor groups, show that demethylation process seems to be more favorable when substituent is an electro-donor. This is sustained by bond energy and thermodynamic analyses (vide infra).

Resonance driven regioselective demethylation of berberine. Microwave assisted synthesis of berberrubine and its assessment as fluorescent chemosensor for alkanes

Berberrubine has been synthesized by microwave assisted selective demethylation of berberine. The high selectivity observed in this reaction has been explained and justified by means of computational calculations using Density Functional Theory (DFT) and Natural Resonance Theory (NRT). The existence of two resonant structures of berberrubine is the driving force of regioselective demethylation. Berberrubine is a chemosensor of alkanes, and may have practical applications in petrochemical analysis as a ‘mass’ detector because fluorescent response of saturated hydrocarbons does not depend on hydrocarbon chain length. Berberrubine operates via dipole-induced dipole interactions. Likewise, it has two fluorescent forms in acidic and basic media, which correspond to a keto-enol tautomerism. The fluorescent signal for berberrubine and the amplification of berberrubine-alkane signals by heating can be rationalized from the predominance of enol form when berberrubine is adsorbed onto silica gel.

Semisynthesis of Polymethoxyflavonoids from Naringin and Hesperidin

Polymethoxyflavonoids (PMFs) possess important biological activities, notably as anticancer agents. Semisynthesis of a series of PMFs were performed by glycoside hydrolysis, dehydrogenation, bromination, aromatic nucleophilic substitution, O-methylation, dimethyldioxirane oxidation and regioselective demethylation, starting from abundant and inexpensive natural sources naringin and hesperidin. A new synthetic method for selective methylation using CuBr catalysed and microwave-assisted reaction was developed, and the dimethyl dioxirane oxidation of flavones to flavonols was much improved. The new semisynthetic route has the advantages of easy availability of starting materials, simple operation and good yields.

Biotransformation of Colchicinoids into Their Corresponding 3-O-Glucosyl Derivatives by Selected Strains of Bacillus megaterium

Natural colchicinoids and their semisynthetic derivatives are important active ingredients for pharmaceutical applications. Thiocolchicoside (3-demethoxy-3-glucosyloxythiocolchicine) is used in several countries as standard therapy for the treatment of diseases of the muscle-skeletal system, due to its potent antiinflammatory and myorelaxant properties. Manufacturing of thiocolchicoside requires a key step, the regioselective demethylation and glucosylation of chemically derivative thiocolchicine. High selectivity and efficiency of this transformation cannot be achieved in a satisfactory way with a chemical approach. In particular, the chemical demethylation, a part from requiring toxic and aggressive reagents, generates a complex mixture of products with no industrial usefulness. We report herein an efficient, direct and green biotransformation of thiocolchicine into thiocolchicoside, performed by a specific strain of Bacillus megaterium. The same process, with minor modifications, can be used to convert the by-product 3-O-demethyl-thiocolchicine into thiocolchicoside. In addition, we describe the B. megaterium strain selection process and the best conditions for this effective double biotransformation. The final product has a pharmaceutical quality, and the process has been industrialised.

Chemical and microbial semi-synthesis of tetrahydroprotoberberines as inhibitors on tissue factor procoagulant activity

To discover new inhibitors on tissue factor procoagulant activity, 21 tetrahydroprotoberberines were screened on the model of human THP-1 cells stimulated by lipopolysaccharide. Among these tetrahydroprotoberberines, several unique compounds were synthesized through microbial transformation: compound 6 (l-corydalmine) was obtained through regio-selective demethylation by Streptomyces griseus ATCC 13273, whereas compounds 4a, 4b, 5h, and 5i were microbial glycosylation products by Gliocladium deliquescens NRRL1086. The bioassay results showed that compounds 3 (tetrahydroberberine), 10 (tetrahydroberberrubine), and 5f (cinnamyl ester of 5) and 5i (glycosidic product of 5), exhibited the most potential effects, with IC50 values of 8.35, 6.75, 3.75, and 8.79nM, respectively. The preliminary structure and activity relationship analysis revealed that the 2,3-methylenedioxy group of the A ring was essential for the strong inhibitory effects, and the R configuration of the chiral center C-14 showed higher activity than S-form products. The formation of fatty acid or aromatic acid esters of compound 5, except the cinnamyl esters, would weaken its effects. It is also interesting to note that the glycosylation of tetrahydroprotoberberines will maintain and even enhance the inhibitory effects. Because of the importance of glycochemistry in new drug discovery and development, this deserves further exploration and may provide some guide on the semi-synthesis of tetrahydroprotoberberines as tissue factor pathway inhibitors. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.

ChemInform Abstract: Practical Demethylation of Podophyllotoxin and Efficient Preparation of 4‐Amino‐4‐deoxy‐4′‐demethylepipodophyllotoxin.

AbstractThe regioselective demethylation of podophyllotoxin (I) is smoothly achieved using methionine and methylsulfonic acid in TFA or in acetone/water.