Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was also possible for the O-isopropylidene-protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (±)-7a-epi-hyacinthacine A₁ (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and 14% overall yield. Enzymatic resolution of pyrrolidine (±)-36 provided a formal total synthesis to both enantiomers of 7.     

Oxidative synthesis of azacyclic derivatives through the nitrenium ion: application of a hypervalent iodine species electrochemically generated from iodobenzene

Oxidation of the methoxyamide derivatives 1, 4, and 7 has been examined to elaborate efficient synthetic methodology of the azacyclic derivatives 2, 3, 5, 6, and 8, which would be applicable as synthetic intermediates of complicated bioactive substances. In addition to direct anodic and PIFA [phenyliodine(III) bis(trifluoroacetate)] oxidations, an active species derived from iodobenzene generated under electrolytic conditions was examined as an oxidant, and its synthetic efficacy was demonstrated in comparison of the reaction outcomes with other oxidation methods. In the oxidation, the methoxy substitution of substrates modulated the cyclization mode to provide the azaspiro- (2, 8) or quinolinone-type (3, 5, 6) products.     

Manganese(III)-based oxidation of 1,2-disubstituted pyrazolidine-3,5-diones in the presence of alkenes

The manganese(III)-catalyzed aerobic oxidation of 1,2-disubstituted pyrazolidine-3,5-diones 1 in the presence of alkenes 2 gave the corresponding pyrazolidinediones 3 which were doubly hydroperoxyalkylated at the 4-position in high yields. On the other hand, pyrazolidinediones 1 were oxidized with manganese(III) acetate in the presence of alkenes 2 at elevated temperature to produce the 4,4-bis(alkenyl)pyrazolidinediones 4 in good yields instead of the pyrazolidine-fused dihydrofuran analogue IV. A similar cerium(IV)-mediated oxidation of pyrazolidinedione 1a with an alkene 2a afforded the doubly 4-methoxyethylated derivative 5. The stability of the free hydroperoxyl group and the reaction pathway for the aerobic and the metal-mediated oxidation reactions were also discussed.     

Amphiphilic perfluoroalkylated sulfones and sulfonate betaines

Two types of perfluoro alkyl-containing amphiphilic sulfones 7-9 and 13-15, respectively, and sulfonate betaines 23-32 were prepared using 2-[(perfluoroalkyl)methyl]oxiranes (1-3, R_F = C₄F₉, C₆F₁₃, C₈F₁₇) or 3-(perfluoroalkyl)propyl iodides (16 and 17, R_F = C₆F₁₃, C₈F₁₇) as the starting compounds. The overall yields of two-step syntheses were above 90%. The compounds 7-9 were prepared by the reaction of oxiranes 1-3 with 2-sulfanylethan-l-ol and subsequent oxidation of intermediate sulfides. Similarly, the amphiphiles 13-15 were obtained by analogous reaction of oxiranes 1-3 with thiomorpholine and subsequent oxidation of the sulfur atom in the morpholine ring. In the syntheses of betaines 23-32, the starting compounds 1-3 or 16 and 17 were first reacted with dimethylamine followed by the ring-opening reaction of the intermediate fluoroalkyl(dimethyl)amines with propane-1,3- or butane-1,4-sultones.     

A facile chemoenzymatic approach to natural cytotoxic ellipsoidone A and natural ellipsoidone B

Starting from citraconic anhydride (3) a facile four-step synthesis of deoxyellipsoidone 8 has been reported with 37% overall yield. An elegant six-step access to naturally occurring cytotoxic ellipsoidone A (1) and ellipsoidone B (2) has been reported with good overall yields, via the conversion of itaconic anhydride (9) to the acetoxymethylmaleic anhydride (11), regioselective sodium borohydride reduction of anhydride 11 to acetoxymethylbutyrolactone 12, Knoevenagel condensation of lactone 12 with 5-methylfurfural, selenium dioxide induced oxidation of the formed butenolide 13 and an Amano PS catalyzed deacylation of the formed diacetoxybutenolide 14 as a pathway.     

Chiral hypervalent iodine-catalyzed enantioselective oxidative Kita spirolactonization of 1-naphthol derivatives and one-pot diastereo-selective oxidation to epoxyspirolactones

We demonstrate here the rational design of a conformationally flexible C₂-symmetric iodosylarene 8g based on secondary n-σ^∗ or hydrogen-bonding interactions as a chiral catalyst for the enantioselective Kita oxidative spirolactonization of 1-naphthol derivatives 5. Iodosylarenes 8 were generated in situ from iodoarenes 7 and mCPBA as a co-oxidant. Furthermore, epoxyspirolactone 15 was obtained by the one-pot oxidation of 5 with mCBPA in the presence of 7g. Thus, the enantioselective oxidation of 5 to 6 and the successive enantio- and diastereo-selective oxidation of 5 to 15 proceeded in good yields when we controlled the amount of mCPBA.     

Fries rearrangement: scalable synthesis of key fluoro building blocks 3-fluoro-4-methoxybenzoyl chloride and 1,2-diethoxy-3-fluorobenzene

Lewis acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3) was performed on kg scale. The ortho5 and para4 isomers obtained were separated in an industrially feasible way. Compound 4 was then converted into fluorinated building block 3-fluoro-4-methoxybenzoyl chloride (1) while compound 5 was converted into 1,2-diethoxy-3-fluorobenzene (2) in high yields.     

Calix[4]quinones. Part 4: The ClO2 oxidation of calix[4]arene dialkyl ethers

Except for the special case of calix[4]arene diethyl ether 1, the chlorine dioxide oxidation of dialkyl ethers 2-5 yielded only the corresponding calix[4]diquinone dialkyl ethers 8-11. Chlorine dioxide oxidation of calix[4]arene diethyl ether 1 produced two isomeric products 6 and 7, which were stable enough to be isolated by column chromatography. However, a slow conformational interconversion between isomeric pair 6 and 7 was observed at room temperature, and the equilibrium was reached after 400 h at 18 °C with an amount of 5:3 in favor of syn-isomer.     

Synthesis and structural revision of annuionone A

Annuionones (1-5), allelopathic agents isolated from Helianthus annus (sunflower), were reported to be ionone-type bisnorsesquiterepenes. However, the proposed structures for annuionones A (1), B (2) and E (5) were thought to be incorrect. Thus, we have tentatively proposed a revised structure (6) for annuionone A based on careful re-analyses of the reported spectral data. The synthesis of (±)-6 was accomplished to prove the structure of natural annuionone A as 6.     

Synthesis of the first examples of p-bromodienone and transannular spirodienone calixarene derivatives

The first examples of p-bromodienone calixarene derivatives (6-7 and 9-10) have been obtained by treatment of 1,5-dihydroxy-hexaalkoxycalix[8]arenes 5 or tripropoxycalix[4]arene 8 with trimethylphenylammonium tribromide and a saturated solution of NaHCO₃. The first transannular spirodienone derivative 11 was only obtained in the presence of NaOH or using the KOH/I₂/PEG-200 oxidizing system.     

An efficient electrochemical method for a unique synthesis of new derivatives of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one

The electrochemical oxidation of catechols (1a-c) has been studied in the presence of 6-methyl-1,2,4-triazine-3-thion-5-one 3 in aqueous sodium acetate, using cyclic voltammetry and controlled-potential coulometry. A plausible mechanism for the oxidation of catechols and their reaction with 3 is presented. All the catechol derivatives (1a-c) were converted into 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives (6a-c) through a Michael-type addition reaction of 3 to anodically generated o-quinones. The electrochemical syntheses of 6a-c were successfully performed in one pot in an undivided cell using an environmentally friendly method with high atomic economy.     

Diester intrabridging of p-tert-butylcalix[8]arene and unexpected formation of the monospirodienone derivative

Reaction of p-tert-butylcalix[8]arene 1 with adipoyl chloride in the presence of NaH as the base yielded singly and doubly intrabridged esters 2-4 and 6. Surprisingly, calix[8]arene monospirodienone derivative 7 was also isolated, which was originated by O₂ oxidation. The conditions of this oxidation were optimized leading to a novel synthetic approach to calixarene monospirodienones based on the O₂/NaH/acyl-chloride oxidizing system. Xantheno calix[8]arenes 8-8a were obtained by rearrangement of 7.     

Synthesis of moenocinol and its analogs using BT-sulfone in Julia-Kocienski olefination

Moenocinol (C₂₅H₄₂O), the acyclic terpenoid unsaturated lipid part of moenomycin antibiotics, was prepared by an expedient method, which comprised organometallic reaction, Julia-Kocienski olefination, and enolate carbon bond formation as the key steps. The starting materials, nerol and 3-butyn-1-ol, were elaborated to the benzothiazole sulfone 2 and aldehyde 3, and the subsequent Julia-Kocienski olefination occurred in a stereospecific manner to give the desired 6E-configuration of moenocinol. Moenocinol (1) was thus synthesized by 10 linear steps in 12% overall yield, and its analogs 23, 24, and 28 with different chain lengths and unsaturation degrees were also realized by the similar reaction sequences.     

A mild and efficient CAN mediated oxidation of Morita-Baylis-Hillman adducts of 5-methyl-N-alkylisatin to 5-formyl-N-alkylisatin

A simple, mild and efficient CAN mediated oxidation of Morita-Baylis-Hillman adducts of 5-methyl-N-alkylisatins 1a-13a to 5-formyl-N-alkylisatins 1b-13b under ambient reaction conditions is reported. Simple and isomerized 5-methyl-N-alkylisatin derivatives 1-4 have also been tested and failed to provide the corresponding formylated products. A plausible reaction mechanism has been proposed.     

A unique peroxide formation based on the Mn(III)-catalyzed aerobic oxidation

The autoxidation of a mixture of 1,1-diarylsubstituted alkenes 4 and 4-hydroxy-1H-quinolin-2-ones 5 in the presence of a catalytic amount of manganese(III) acetate dihydrate in air gave 3,3-bis(2-hydroperoxyethyl)-1H-quinoline-2,4-diones 6 in 31-91% yields together with [4.4.3]propellane-type cyclic peroxides 7 (10-34%). A similar aerobic oxidation of 3-substituted quinolinones 8 yielded cyclic peroxide derivatives 9 and/or 3-hydroperoxyethylated quinolinediones 10 depending on the substituent. The structures of the bis(hydroperoxide) 6 (R¹=Me, Ar=4-ClC₆H₄) and the [4.4.3]propellane 7 (R¹=Me, Ar=Ph) have been corroborated by X-ray crystallography.     

Electrooxidation of activated α,ω-diols to cyclic tetramethylene acetals of the corresponding dials

Activated α,ω-diols such as ethylene glycol 1a, 1,3-propanediol 1b, but-2-ene-1,4-diol 1c and hexa-2,4-diyne-1,6-diol 1d can be converted into cyclic tetramethylene acetals of the corresponding α,ω-dials (2a-d) in 70% yield by a simple anodic oxidation in dry tetrahydrofuran on a glassy carbon anode. Glycerol 3 when subjected to similar anodic oxidation gave a structure 4 containing three seven-membered 1,3-dioxepane rings.     

Production mechanism of proepitheaflagallin, a precursor of benzotropolone-type black tea pigment, derived from epigallocatechin via a bicyclo[3.2.1]octane-type intermediate

An unstable intermediate proepitheaflagallin B (2), a precursor of proepitheaflagallin (3), was isolated as an enzymatic oxidation product of (−)-epigallocatechin (1), and the structure of 2 was determined based on spectroscopic data. The structure and its decomposition revealed that the detailed production mechanism of proepitheaflagallin (3) via a bicyclo[3.2.1]octane-type intermediate was related to that of major black tea pigments, theaflavins.     

Novel photo-induced oxidative cyclization of 1,3-dimethyl-5-(1-arylmethylidene)pyrimidine-2,4,6(1,3,5H)-triones: synthesis and properties of areno[5,6]pyrano[2,3-d]pyrimidine-2,4(1,3H)-dionylium ions and their photo-induced autorecycling oxidizing reaction toward some amines

Novel photo-induced oxidative cyclization was accomplished to synthesize areno[b]pyrimido[5,4-e]pyran-2,4(1,3H)-dionylium ions 13a-c⁺·ClO₄⁻. Furthermore, 13a-c⁺·BF₄⁻ and their phenyl-substituted derivatives 19a,b⁺·BF₄⁻ were alternatively synthesized by the reaction of salicylaldehyde and its naphthyl derivatives with barbituric acids and subsequent treatment with aq. HBF₄. Structural characteristics of 13a-c⁺ and 19a,b⁺ were clarified on inspection of the UV-vis and NMR spectral data as well as X-ray crystal analyses. The electrochemical properties were studied by the CV measurement. In a search for reactivity, reactions of 13a-c⁺·BF₄⁻ with some nucleophiles, hydride, benzylamine, and H₂O, were also carried out. The photo-induced autorecycling oxidation reactions of 13a-c⁺·BF₄⁻ toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) in 643-3600% yield (recycling number of 13a-c⁺·BF₄⁻: 6.4-36.0).     

Efficient, recoverable, copper-catalyzed aerobic oxidation of alcohols under FBS and thermomorphic mode

A series of fluorinated bipyridine derivatives, (4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy) {R_f = n-C₈F₁₇ (1a), n-C₉F₁₉ (1b), n-C₁₀F₂₁ (1c), n-C₁₁F₂₃ (1d)} have been successfully synthesized using 4,4′-bis(bromomethylene)-2,2′-bpy and fluorinated alkoxides. Bpy 1a-d have been characterized by multi-nuclei (¹H, ¹⁹F, and ¹³C) NMR, GC/MS and FTIR. The Cu complexes 2a-d could be generated in situ by stirring ligands 1a-d with CuBr·Me₂S at room temperature, respectively. The 3-component systems 3c-d, CuBr·Me₂S/Bpy (1c-d)/2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), were successfully used to the aerobic oxidation of alcohols under the fluorous biphasic system (FBS). The resulting products from FBS could be easily recovered by two phase separation with high yields up to 8 runs (>90%). In order to avoid using the expensive fluorous solvents, systems 3a-d, CuBr·Me₂S/Bpy (1a-d)/TEMPO, were also successfully shown to catalyze the aerobic alcohol oxidation under the thermomorphic condition (in C₆H₅Cl), and the yields of oxidation of 4-nitrobenzyl alcohol were close to 100% even after 8 runs. In particular, 3a was most effective under the thermomorphic mode in the chemoselectivity of aerobic oxidation of aliphatic primary alcohols to aldehydes without any overoxidized acids.     

Hypervalent iodine(III)/Et4NBr combination in water for green and racemization-free aqueous oxidation of alcohols

We have found that the use of the PhI(OAc)₂/Et₄N⁺Br⁻ combination in water can significantly enhance its oxidation ability and oxidize a wide range of alcohols 1 to carbonyl compounds 2 in good to excellent yields. This clean aqueous oxidation method shows no detectable racemization processes, and even an enolizable ketone 2m could be obtained in an optically pure form from the corresponding chiral alcohol 1m. Utilization of the recyclable reagent 3 as a more practical alternative to PhI(OAc)₂ is also successful in these reactions.