Total synthesis of a dienynone from Echinacea pallida

The first total synthesis of (8Z,13Z)-pentadeca-8,13-dien-11-yn-2-one is described. This dienynone was recently isolated from the n-hexane extract of Echinacea pallida roots and displayed a selective cytotoxic activity toward cancer cells, thus featuring as a potential anticancer lead. The product was obtained in 11 steps in 25% overall yield.     

Studies towards diarylheptanoid synthesis. Part 1: Synthesis and ring cleavage reactions of hexahydro-2H,5H-pyrano[2,3-b]pyran-2-ones

Lewis acid promoted anomeric substitution reactions of a stereoselectively prepared hexahydro-2H,5H-pyrano[2,3-b]pyran-2-one derivative was studied as a model for diarylheptanoid synthesis. Aromatic nucleophiles consistently provided the expected thermodynamic C-aryl pyranoside product.     

One-pot multistep synthesis of 3,4-fused isoquinolin-1(2H)-one analogs

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as -OH, -SH, or -NHR (R = alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner.     

First stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one

A stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one is reported. The strategy utilizes an iterative Jacobsen hydrolytic kinetic resolution, ring opening with a chiral propargylic synthon and a preferential (Z)-Wittig olefination reaction and lactonization as the key steps.     

Synthesis of a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one derivative via a regioselective Meisenheimer N-oxide rearrangement

The synthetic strategy towards a 5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one is described utilizing a selective N-oxidation and subsequent regioselective Meisenheimer N-oxide rearrangement as key steps.     

The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.     

Efficient total syntheses of louisianins C and D

An efficient synthetic route for the preparation of louisianins C and D was developed starting with the commercially available 4-cyanopyridine. Louisianins C and D were synthesized in seven steps and with overall yields 22% and 20%, respectively, following a novel cyclization-decarboxylation sequence involving 4-bromo-6,7-dihydrocyclopenta[c]pyridin-5-one as the key intermediate.     

Synthesis of (3RS,3aSR,8aSR)-3-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one via the aza-Cope-Mannich rearrangement

A convenient and scalable method for the preparation of (3RS,3aSR,8aSR)-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one based on the aza-Cope-Mannich rearrangement is described. This approach allows us to synthesize the target compound in nine steps in a high overall yield (42%) with complete stereocontrol and up to 100 g scale.     

A concise synthesis of (−)-cytoxazone and (−)-4-epi-cytoxazone using chlorosulfonyl isocyanate

A concise synthesis of (−)-cytoxazone and its stereoisomer (−)-4-epi-cytoxazone, novel cytokine modulators, has been accomplished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include the regioselective and diastereoselective amination of anti- and syn-1,2-dimethyl ethers with chlorosulfonyl isocyanate and the subsequent regioselective cyclization of the diol to construct the oxazolidin-2-one core. The diastereoselectivity of amination reaction using CSI was explained by the Cieplak electronic model via S_N1 mechanism and neighboring group effect, leading to the retention of the configuration.     

Synthesis of enantiopure (S)-7-hydroxy-3-amino-3,4-dihydro-2H-1-benzopyran en route to (+)-scyphostatin

(S)-7-Hydroxy-3-amino-3,4-dihydro-2H-1-benzopyran, a key synthetic intermediate towards the total synthesis of (+)-scyphostatin, has been prepared in >98% ee. Key synthetic steps were (i) the oxidative dearomatization of an l-tyrosine derived phenol, (ii) the transformation of the resulting p-quinol acetate to the corresponding resorcinol upon exposure to Thiele reaction conditions and, (iii) the direct formation of the benzopyran ring upon treatment of an N-Boc protected 4-(2-acetoxybenzyl)oxazolidin-2-one with sodium methoxide.     

Synthesis of Δ-15-deoxy-PG-J1 methyl ester and epi-Δ-15-deoxy-PG-J1

The synthesis of racemic Δ^12,14-15-deoxy-PG-J₁ is readily achieved in six steps employing as the key transformation a one-pot conjugate addition-Peterson olefination sequence using exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinden-1-one. Additionally a Noyori-type three-component coupling approach is employed for the synthesis of enantioenriched epi-Δ¹²-15-deoxy-PG-J₁ from 4(S)-tert-butyldimethylsilyloxycyclopent-2-enone.     

One-pot three-component synthesis of functionalized spirolactones by means of reaction between aromatic ketones, dimethyl acetylenedicarboxylate, and N-heterocycles

A simple and convenient one-pot multi-component reaction has been described for the synthesis of functionalized spirolactones. This strategy demonstrated three-component reaction between aromatic ketones (11H-indeno[1,2-b]quinoxalin-11-one) and dimethyl acetylenedicarboxylate (DMAD) in the presence of N-heterocycles, such as pyridine, quinoline, and isoquinoline in CH₂Cl₂ at ambient temperature without use of any catalyst or activator.     

First straightforward synthesis of 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione and structure revision of a bioactive benz[g]isochromene-5,10-dione from Psychotria camponutans

For the first time, a synthesis of 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione (3), which is claimed to be a bioactive compound isolated from Psychotria camponutans, was achieved with a phthalide annulation reaction using 3-cyano-1(3H)-isobenzofuranone (5) and 5,6-dihydropyran-2-one (6) and subsequent reduction of the lactone moiety in the key steps. However, full spectral characterization of the synthesized target compound revealed that the isolated compound is not 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione (3). Structure revision shows the previously isolated compound to be the known psychorubrin (2).     

Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.     

Efficient production of raspberry ketone via ‘green’ biocatalytic oxidation

For the development of a ‘green’ oxidation method, the transformation of 4-(p-hydroxyphenyl)butan-2-ol (rhododendrol) into 4-(p-hydroxyphenyl)butan-2-one (raspberry ketone) was used as a model reaction. Different lyophilized cells of Rhodococcus spp. have been screened for their ability to perform the desired oxidation. Rhodococcus equi IFO 3730 and R. ruber DSM 44541 were able to use acetone as a hydrogen acceptor in a hydrogen transfer-like process. The oxidation can be performed at substrate concentrations up to 500 g/L.     

Limitations of the Wittig-Horner-type annulation of fluorobutenolide moiety to 3-hydroxyquinoline-2,4(2H,3H)-diones. Novel modifications of the Perkow reaction including fluorinated acyloxy leaving groups

3-(Fluoroacyloxy)quinoline-2,4(1H,3H)-diones react with triethyl phosphite to afford either the product of the Perkow reaction or the corresponding 4-ethoxyquinolin-2(1H)-one. In both reactions, the fluorocarboxylate anion acts as the leaving group. For the corresponding 3-(fluoroiodoacetoxy) derivative this observation precludes the application of the intramolecular Wittig-Horner synthesis to modify quinoline-2,4(1H,3H)-diones by the annulation of a fluorinated but-2-enolide moiety.     

Biotransformation of sinapic acid by the green algae Stichococcus bacillaris 155LTAP and Ankistrodesmus braunii C202.7a

Sinapic acid was bioconverted by the green alga Stichococcus bacillaris into 4-hydroxy-3,5-dimethoxybenzoic acid, 4-hydroxy-3,5-dimethoxybenzaldehyde and 4-hydroxy-3,5-dimethoxybenzylic alcohol. Incubation of sinapic acid in a culture of the alga Ankistrodesmus braunii gave 3,6-dihydroxy-2,4-dimethoxy-7H-benzocyclohepten-7-one, a new compound formed by bioconversion of thomasidioic acid, the primary oxidative product of sinapic acid.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.