4-endo-Hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-one as a useful building block in the formal total syntheses of furofurandione natural products

4-endo-Hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-one (9) is a useful building block in the formal total syntheses of both Types A and B furofurandione natural products. The success of Pd-catalyzed epimerization of the γ-alkenyl substituent of the bislactones makes this methodology useful and versatile.     

8-Azabicyclo[3.2.1]oct-3-en-2-ones via asymmetric 1,3-dipolar cycloaddition of a homochiral 3-oxidopyridinium betaine

8-Azabicyclo[3.2.1]oct-3-en-2-ones were prepared by asymmetric 1,3-dipolar cycloadditions of homochiral pyridinium betaine 4. Excellent diastereofacial selectivity was achieved for the major 6-exo cycloadducts. The absolute stereochemistry of cycloadduct 7 was confirmed by a single-crystal X-ray diffraction study.     

The regioselectivity of the addition of benzeneselenyl chloride to 7-azanorborn-5-ene-2-yl derivatives is controlled by the 2-substituent: new entry into 3- and 4-hydroxy-5-substituted prolines

The electrophilic addition of benzeneselenyl chloride to the alkene moiety of 7-azabicyclo[2.2.1]hept-5-en-2-yl derivatives has been studied. With camphanates 8 and 9N-Boc-5-endo-chloro-6-exo-phenylseleno-7-azanorborn-2-yl camphanates 10 and 11 are obtained with high regioselectivity due to a steric control. With N-Boc-7-azanorbor-5-en-2-one (2) the corresponding 6-endo-chloro-5-exo-phenylseleno derivative 15 is obtained in high yield due to a kinetic control attributed to the electron-releasing ability of the homoconjugated carbonyl group. Bicyclic adducts 10 and 11 and 15 are readily converted into 4-hydroxy-(14) and 3-hydroxy-5-substituted proline derivatives 19, respectively.     

Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

Synthesis and chemistry of tricyclic cyclopropene-tricyclo[3.2.2.0]nona-2(4),6-diene

The 1,2-bridged tricyclic cyclopropene, tricyclo[3.2.2.0^2,4]nona-2(4),6-diene (1), has been synthesized by the elimination of 2-bromo-4-chlorotricyclo[3.2.2.0^2,4]-non-6-ene (5). Cyclopropene 1 will undergo different isomerizations in ether solution and in neat conditions. Compound 1 rearranged to an anti-Bredt compound 4 via diradical mechanism in ether and tricyclic compound 6 via vinyl carbene mechanism in neat conditions. Compound 1 can be trapped with DPIBF at different temperatures yielding different results: the exo-endo adduct 2 (exo-addition from the view of the cyclopropene and endo-addition from the view of bicyclo[2.2.2]octene) is a sole product at 0°C by slowly addition of methyllithium, and the exo-endo adduct 2, endo-endo adduct 9, anti-Bredt adduct 3, and styrene 8 are isolated at ether refluxing temperature. Styrene 8 is proposed to be formed from endo-endo adduct 9 by diradical mechanism. The chemistry of exo-endo adduct 2 and endo-endo adduct 9 is as well studied. The exo-endo adduct 2 undergoes hydration in trifluoroacetic acid to generate 1,3-cis-diol 11 followed by eliminations of water and formaldehyde to give naphthalene 12. The endo-endo adduct 9 reacts with water in tetrahydrofuran-containing silica gel to yield 1,4-cis-diol 10. Both 9 and 10 react with trifluoroacetic acid to form trans-3-hydroxy trifluoroacetate 13. Compound 13 will undergo hydrolysis and isomerization to generate 1,3-cis-diol 11 in trifluoroacetic acid.     

Heterotricyclodecane XXVII. Ein weiterer Zugang zu 2,6-Dioxatricyclo [3.3.2.03,7]decan

A Further Approach to 2,6-Dioxatricyclo[3.3.2.0^3,7]decane A further synthesis of 2,6-dioxatricyclo[3.3.2.0^3,7]decane ( 10 ) is described by bridging the 9-oxabicyclo[4.2.1]non-7-en-3endo-ol ( 9 ). The latter compound was prepared by ring expansion starting from the known 8-oxabicyclo[3.2.1]oct-6-en-3-on ( 1 ).     

Synthesis and ring opening reactions of 2-glyco-1,4-dimethyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes

The high-pressure asymmetric Diels-Alder reactions of d-galacto- (1a) and d-manno-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-nitrohept-1-enitol (1b) with 2,5-dimethylfuran (2) afforded mixtures of cycloadducts, from which the (2S,3R)-3-exo-nitro (3a and 3b), (2R,3S)-3-exo-nitro (4a and 4b), and (2R,3S)-1′,2′,3′,4′,5′-penta-O-acetyl-1′-C-(1,4-dimethyl-3-endo-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl)-d-galacto-pentitol (5b) were isolated pure. Deacetylation of these compounds led to new chiral mono-, bi-, and tricyclic ethers, being their asymmetric centers arising from the chiral inductor used in the cycloaddition reaction. A ring opening mechanism through a 1-nitro-1,3-cyclohexadiene intermediate has been proposed.     

Orbital control of stereochemistry in acid-catalysed addition reactions of endo -tricyclo[3.2.1.02,4]0ct-6-ene

The reaction of endo-tricyclo[3.2.1.0^2,4]oct-6-ene 1 with methanol in the presence of catalytic amounts of toluene-p-sulphonic acid has been shown to give 2-exo- and endo-methoxybicyclo[3.2.1]oct-3-ene (2c) and (2d) and 2-endo-methoxybicyclo[3.2.1]oct-6-ene (13). The formation of 2-exo- methoxybicyclo[3.2.1]oct-3-ene (2c), the major product of reaction, has been probed by deuterium labelling experiments and a series of 6-exo-7-exo- dideuterobicyclo[3.2.1]oct-3-enes synthesised for ²H, ¹H and ¹³C NMR spectral analysis in order unambiguously to determine the stereochemistry of proton attack on endo-tricyclo[3.2.1 0^2,4]oct-6-ene (1). The formation of 2-exo-methoxybicyclo[3.2.1]oct-3-ene (2c) has been determined to involve corner protonation of the cyclopropyl moiety and skeletal rearrangement to an allylic cation with a small but measurable memory effect     

Enantioselective Synthesis of Cyclopentyltetrahydrofuran (Cp-THF), an Important High-Affinity P2-Ligand for HIV-1 Protease Inhibitors

A convenient optically active synthesis of (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan, a high-affinity nonpeptidyl ligand for HIV-1 protease inhibitor 2, is described. The synthesis utilizes commercially available (1R,5S)-(+)-2-oxabicyclo[3.3.0]oct-6-en-3-one as the starting material and oxymercuration or bromohydrin reaction as the key step. Enantiopure ligand was converted to protease inhibitor 2.     

Selectfluor-promoted fluorination of piperidinyl olefins

A simple and straightforward synthesis of 1-substituted-4-aryl-5-fluoro-1,2,3,6-tetrahydropyridine (3) or 1-substituted 4-diarylmethanoyl-4-fluoropiperidine (6) by the treatment of piperidinyl exo- or endo-olefin with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate (Selectfluor) is reported. Two transformations from endo-olefin 1 to allylic fluoride 3 and from exo-olefin 2 to fluorohydrin 6 proceed via allylic fluorination and fluorohydroxylation in moderate yields. It presents two novel reactions promoted by Selectfluor and broadens the scope of application.     

Synthesis of 2,4-dimethyl-6-oxo-2,4-heptadienoic acid derivatives from 2,4,6-trimethylpyrylium salts

Reaction 2,4,6-trimethylpyrylium salts with sodium cyanide in boiling water yielded the bicyclic lactone 1,3,5-trimethyl-6,8-dioxabicyclo[3.2.1]oct-2-en-7-one (6) along with a series of stereoisomers of 2,4-dimethyl-6-oxo-2,4-heptadienonitrile (5), which were the sole products when the reaction was carried out at room temperature. Compound 6, along with 3,5-dimethylphenol (7), was also obtained by refluxing 5 briefly in aqueous sodium hydroxide. However, when 5 was refluxed for a prolonged period in aqueous sodium acetate, 3,5-dimethyl-5-(2-oxopropyl)-furan-2-one (8), along with some 7, was generated instead. Compound 8 could also be produced from 6 on prolonged refluxing with aqueous sodium acetate, indicating that 6 was the kinetically-controlled and 8 the thermodynamically-controlled product.     

Absolute configuration of gomadalactones A, B and C, the components of the contact sex pheromone of Anoplophora malasiaca

Absolute configuration of gomadalactones A (1), B (2) and C (3), the pheromone components of the white-spotted longicorn beetle (Anoplophora malasiaca) was assigned as (1S,4R,5S)-1, (1R,4R,5R)-2 and (1S,4R,5S,8S)-3 by comparing their published CD spectra with those of (1R,5R)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]oct-7-ene-2,6-dione (4) and (1S,5R,8S)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]octane-2,6-dione (5) prepared from (R)-(−)-carvone (6).     

Influence de la taille du cycle sur le mecanisme de l'acetolyse de p-bromobenzenesulfonates de cycloalkylmethyle et de cycloalkenylmethyle

Cycloheptylmethyl brosylate (1b) and cyclooctylmethyl brosylate (1c) undergo acetolysis at 80°, about four times faster than isobutyl brosylate; this acceleration appears to be due to β-hydrogen participation. 4-Cycloheptenylmethyl brosylate (2b) and 4-cyclooctenylmethyl brosylate (2c) undergo acetolysis at 80°, with double bond participation, 250 and 350 times faster than isobutyl brosylate, respectively, the major products being endo 2-bicyclo[3.2.1]octyl acetate 8a and endo 2-bicyclo[3.3.1]-nonyl acetate 11a. Acetolysis of 3-cyclohexenylmethyl brosylate (2a) leads (without participation) to 3-cyclohexenylmethyl acetate (7).     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Synthesis and phototransformations of novel styryl-substituted furo-benzobicyclo[3.2.1]octadiene derivatives

Novel cis- and trans-(o-H/Me/vinyl) substituted styryl furo-benzobicyclo[3.2.1]octadiene derivatives (7a,b, 8) were prepared and transformed to the novel naphthofuran derivatives of benzobicyclo[3.2.1]octadiene (6a,b) and novel phenanthrene-benzobicyclo[3.2.1]octadiene derivative (11) by photochemical electrocyclic ring closure in the presence of iodine and by intramolecular photoinduced [4+2] cycloaddition, respectively. These novel annelated bicyclo[3.2.1]octadiene derivatives (6a,b, 11) are especially interesting for their rigid methano-bridged junction of two aromatic units at defined geometrical arrangement and thereby as potentials for molecular clips.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Sodium dithionite initiated regio- and stereoselective radical addition of polyfluoroalkyl iodide with norbornene analogs

Sodium dithionite initiated free-radical addition of polyfluoroalkyl iodides (2m-2s) with norbornene 1a and its derivatives, such as norbornene-2-carboxylates 1b and 1c, and norbornene-2-carboxylic acids 1d and 1e was investigated. In all the cases, the addition of R_F group was stereoselectively delivered at exo-position and the predominant configuration of products was trans. Under the similar condition, norbornene-2-carboxylic ethyl ester 1b reacted with 2p to give 6-exo-R_F-5-endo-iodo adduct 3bp and 5-exo-R_F-6-endo-iodo adduct 5bp in the ratio of 4:1. While 1c, which has a heavy crowded group in the 2-endo-position, gave 6-exo-R_F-5-endo-iodo adduct 3cp and polyfluoroalkylated product 4cp retaining the trans-configuration and the exo-orientation of R_F group. The fluoroalkylation-lactonization reaction occurred in the reaction of norbornene-2-endo-carboxylic acids 1d and 1e with polyfluoroalkyl iodides to afford the corresponding fluoroalkylated γ-lactone products (7dp-7ds, and 7em-7er). The configuration of the products was further confirmed by 2D NMR and X-ray diffraction analyses for the first time.     

Catalytic enantioselective Diels-Alder reactions of furans and 1,1,1-trifluoroethyl acrylate

Catalytic enantioselective Diels-Alder reactions of furans and 1,1,1-trifluoroethyl acrylate in the presence of oxazaborolidium catalysts 2 or 3 provide 7-oxabicyclo[2.2.1]hept-5-enes with high endo-selectivity and excellent enantioselectivity.     

Manganese(III)-mediated facile synthesis of 3,4-dihydro-2(1H)-quinolinones: selectivity of the 6-endo and 5-exo cyclization

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1H)-quinolinones 2 were easily synthesized by the oxidative 6-endo-trig cyclization of 2-[2-(N-arylamino)-2-oxoethyl]malonates 1 with manganese(III) acetate in good to excellent yields. The same reaction of N-(2,4-dimethoxyphenyl)-substituted malonate 1t exclusively produced the 5-exo-cyclized 4,4-bis(ethoxycarbonyl)-1-azaspiro[4,5]deca-6,9-diene-2,8-dione 5t instead of the corresponding dihydroquinolinone. The regioselectivity during the cyclization could be explained by the difference in the activation energy of the transition state of the 6-endo/5-exo cyclization.     

Reversible pyranyl complex formation and the mechanism of rearrangement to (η-6-oxocycloheptadienyl)Mn(CO)3 complexes in the reaction of β-cyclomanganated 1,5-diarylpenta-1,4-dien-3-ones and alkynes; the crystal structure of [2,4-diphenyl-6-(2-phenylethenyl)pyranyl-η]tricarbonylmanganese

[1-Phenyl-2-[(E)-3-phenylprop-2-en-1-oyl-κO]ethenyl-κC¹]tetracarbonylmanganese (1a) reacts with PhCCH in CCl₄ at room temperature to form [2,4-diphenyl-6-(2-phenylethenyl)pyranyl-η⁵]tricarbonylmanganese (2a), whose X-ray crystal structure is reported to complement that of its isomer [6-oxo-2,4,7-triphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese (3a), previously obtained from the reaction under reflux; but for 1a and PhCCPh the pyranyl complex cannot be isolated before rearrangement to the 3a analogue occurs. More forcing reaction conditions for 1a with Me₃SiCCH and for [1-(2-trifluoromethylphenyl)-2-[(E)-3-(2-trifluoromethylphenyl)prop-2-en-1-oyl-κO]ethenyl-κC¹]tetracarbonylmanganese (1b) with Me₃SiCCH and PhCCH give new analogues of 3a where previously only 2a analogues had been isolated.The reaction in CCl₄ under reflux of PhCCH and the β-deuterio analogue of 1a, [1-phenyl-2-[(E)-3-phenylprop-2-en-1-oyl-3d-κO]ethenyl-κC¹]tetracarbonylmanganese, gave deuteriated 3a with exo-D at the α-carbon, C7. This is inconsistent with the Mn-mediated Ph migration mechanism originally proposed to accommodate the endo position of Ph in 3a, and instead it implicates a cyclopropyl carbonyl-addition intermediate or a cyclopropyl acyl-substitution transition state in the key rearrangement step for 2a → 3a.