Synthesis and some reductions of endo- and exo-3,6-epoxy-Δ4-tetrahydrophthalic anhydride

The synthesis of endo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride from the endo-adduct of furan and maleic acid is described. Reduction of endo- and exo-3,6-epoxy-Δ⁴-tetrahydrophthalic anhydride with sodium borohydride gave the corresponding lactones, while catalytic hydrogenation over 10% Pd/C gave anhydride and/or hemi-acylals, depending on the solvent.     

Vibrational circular dichroism DFT study on bicyclo[3.3.0]octane derivatives

The absolute configurations of four bicylco[3.3.0]octane derivatives: endo-bicyclo[3.3.0]octane-2,6-diol, endo-2,6-diacetoxybicyclo[3.3.0]octane, endo-bicyclo[3.3.0]octane-2,6-dione and bicyclo[3.3.0]octa-2,6-dien-2,6-bistriflate were studied by vibrational circular dichroism (VCD). These chiral derivates are of interest as intermediates in the asymmetric synthesis of enantiomerically pure natural products and chiral ligands for asymmetric catalysis. VCD has been used to determine the absolute configuration of each compound, proving the capability of VCD for molecules with several stereogenic centres. IR and VCD spectra have been simulated at the B3LYP/6-31G¹ level for all possible diastereomers. Based on the agreement between the experimental and the calculated spectrum, the stereochemistry of each compound could be assigned. The predicted absolute configurations are found to agree with literature data.     

Reactive species from aromatics and oxa-di-π-methane rearrangement: a stereoselective synthesis of (±)-hirsutene from salicyl alcohol

A total synthesis of hirsutene, a triquinane sesquiterpene, from salicyl alcohol is reported. Oxidation of salicyl alcohol in the presence of cyclopentadiene gave 9-spiroepoxy-endo-tricyclo[5.2.2.0^2,6]undeca-4,10-dien-8-one which was elaborated to the 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one containing major structural and functional features of hirsutene. Photochemical sigmatropic 1,2-acyl shift in 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one followed by radical induced cleavage of peripheral cyclopropane bond, olefination and Simmon-Smith reaction furnished 11-hydroxy-1-methyl-4-spirocyclopropanetricyclo[6.3.0.0^2,6]undecane that upon treatment with hydrogen on PtO₂ and PCC oxidation gave 1,4,4-trimethyltricyclo[6.3.0.0^2,6]undecan-11-one, a known precursor. Wittig methylenation on this precursor gave hirsutene.     

5-Nitroisocoumarins from tandem Castro-Stephens coupling—6-endo-dig cyclisation of 2-iodo-3-nitrobenzoic acid and arylethynes and ring-closure of methyl 2-alkynyl-3-nitrobenzoates with electrophiles

Reaction of 2-iodo-3-nitrobenzoic acid with arylalkynyl copper(I) reagent gave 3-aryl-5-nitroisocoumarins. Castro-Stephens coupling was followed by in situ Cu-catalysed ring-closure. ¹H NMR and X-ray crystallography showed the cyclisations to be 6-endo, contrasting with reports of 5-exo cyclisation of analogous 2-iodobenzoate esters with alkynes. Sonogashira couplings of methyl 2-iodo-3-nitrobenzoate with phenylacetylene and with trimethylsilylacetylene gave the corresponding 2-alkynyl-3-nitrobenzoate esters. With HgSO₄, the phenylalkyne underwent 6-endo cyclisation to give 5-nitro-3-phenylisocoumarin. The disubstituted alkyne esters gave 4-phenylselenylisocoumarins with PhSeCl. 5-Nitro-3-phenyl-4-phenylselenylisocoumarin shows significant sterically-driven distortion of the isocoumarin ring. Reaction of methyl 3-nitro-2-phenylethynylbenzoate with ICl gave the 4-iodoisocoumarin. Thus the nitro group tends to direct these electrophile-driven cyclisations towards the 6-endo mode.     

Dipolar cycloadditions of imidazoline 3-oxides with N-arylmaleimides. Synthesis and diethylamine induced ring-opening of exo and endo hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones

1,4-Diarylimidazoline 3-oxides react with N-arylmaleimides in benzene to give predominantly the corresponding endo adducts. Chiral imidazoline 3-oxides react diastereospecifically (cis configuration of the tetrahydroimidazo ring) and diastereoselectively to give cis-endo adducts. The effects of substituents on the aromatic ring of the maleimide was investigated. The presence of electron-withdrawing or releasing groups have minor effect on the total yields but more pronounced is the effect on the ratio of exo and endo diastereomers. The adducts undergo an interesting and unprecedented ring-opening in the presence of secondary amines to give deoxygenated 3-imidazoline 3-oxides instead of the expected double cis elimination products. Tertiary amines did not induce any reaction.     

XY-ZH compounds as potential 1,3-dipoles. Part 63: Silver catalysed azomethine ylide cycloaddition—the synthesis of spiro homoserine lactone analogues

A range of room temperature 1,3-dipolar cycloaddition reactions of imines of 2-amino-γ-lactone and thiolactone, catalysed by a combination of AgOAc or Ag₂O with NEt₃ or DBU, are described. The spiro lactones/thiolactones are formed regio- and stereoselectively as single cycloadducts in good yield via the syn dipoles and an endo-transition states.     

An experimental/theoretical approach to determine the optical purity and the absolute configuration of endo- and exo-norborn-5-en-2-ol using mandelate derivatives

The O-acetylmandelates and mandelates of endo- and exo-norborn-5-en-2-ol were prepared, both as a mixture and also as separate diastereomers. ¹H NMR spectroscopy of these derivatives was efficiently used to determine the enantiomeric ratios and to predict the absolute configuration of the alcohols. Theoretical calculations were performed to locate the predominant conformations of the mandelate derivatives and GIAO ¹H NMR Boltzmann-weighted average chemical shifts were computed, correctly reproducing the experimental δ and Δδ values.     

Reaction of <Emphasis Type="Italic">N</Emphasis>-(2,3-epoxypropyl)arenesulfonamides with (bicyclo[2.2.1]hept-5-en-<Emphasis Type="Italic">endo</Emphasis>-2-yl)methanamine

Reactions of bicyclo[2.2.1]hept-5-en-endo-2-ylmethanamine with N-(2,3-epoxypropyl)arenesulfonamides gave amino alcohols having a norbornene fragment and sulfonamide group. The major products were formed via opening of the oxirane ring according to the Krasuskii rule. The product structure was determined by ¹H and ¹³C NMR spectroscopy using DEPT and two-dimensional COSY, NOESY, HMQC, and HMBC techniques.     

Assignment of absolute configuration at phosphorus of P-chiral diastereomers of deoxyribonucleoside methanephosphonamidates by means of NMR spectroscopy

Recently, we have prepared a novel class of DNA analogues containing the [3′-NH-P(CH₃)(O)-O-5′] methanephosphonamidate linkage. Synthesis of such analogues requires preparation of the dinucleoside methanephosphonamidates N×N, where N is a 2′-deoxyribonucleoside moiety and × is the methanephosphonamidate linkage. Dimers T×T and C×T were obtained in a non-stereospecific manner giving rise to a pair of P-chiral diastereomers. Such diastereomers were effectively separated into fast and slow migrating ones by means of chromatographic methods (TLC). As described in our previous work (Nawrot et al. Nucleic Acids Res.1998, 26, 2650), the stereochemistry of the phosphorus chiral center of T×T fast migrating diastereomer is R_P and of T×T slow migrating diastereomer is S_P, as established by means of 2D ROESY experiments. Here we describe assignment of the absolute configuration at the phosphorus center of fast and slow migrating diastereomers of C×T dimer. The 2D ROESY sequence with phosphorus decoupling during acquisition used in these measurements allowed observation of the P-Me group as a singlet instead of a ¹H-³¹P-coupled doublet. The apparent advantage of this approach was a much better signal to noise ratio and improved resolution in the F1 dimension. For the fast migrating C×T diastereomer an R_P and for slow migrating C×T diastereomer an S_P configuration was assigned. Conformational analysis of both pairs of diastereomers T×T and C×T indicates significant differences in sugar ring puckering, which strongly depend on the nature of the nucleobase at the 5′-terminus of the dimer. The ribose rings of the 3′-amino-2′,3′-dideoxycytidine moiety of both diastereomers of C×T adopt predominantly a C3′-endo (North) conformation, while thymine-substituted ribofuranoses originating either from C×T or T×T dimers prefer a C2′-endo (South) conformation.     

Use of temporary tethers in the intramolecular [2+2] photocycloaddition reactions of tetrahydrophthalimide derivatives: a new approach to complex tricyclic lactones

The intramolecular [2+2] photocycloaddition reactions of a series of alkenols tethered to ethanolamine, l-(+)-valinol and R-(−)-2-phenylglycinol derived 3,4,5,6-tetrahydrophthalimides via a carbonate or silicon linkage have been examined. These [2+2] photocycloadditions gave the corresponding cyclobutanes in high yield with complete endo control in all cases and with diastereoselectivities as high as 8:1 with the chiral tethers. The cleavage of the temporary tethers by either desilylation or hydrolysis provided the endo diols. Cleavage of the ethanolamine linkage by reduction/hydrolysis precipitated an acid-catalysed fragmentation/ring expansion sequence to generate complex tricyclic lactones.     

Lactonization of epoxyendic anhydride in reactions with amines

Reactions of exo-5,6-epoxybicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboxylic anhydride (epoxyendic anhydride) with acyclic, aromatic, heteroaromatic, and nonaromatic heterocyclic amines afforded the corresponding heterocyclization products, substituted exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0^3,7]nonane-endo-9-carboxamides (oxabrendanes), whose structure was confirmed by the IR and ¹H and ¹³C NMR (including two-dimensional) spectra. Other approaches to the tricyclic compounds were also examined, in particular via reactions of organic peroxy acids with amido acids obtained by aminolysis of endic anhydride.     

Synthesis of 7-sulfonyl-substituted norpinan-6-ones and -thiones from 1-bromotricyclo[4.1.0.0<Superscript>2,7</Superscript>]heptane

1-Bromotricyclo[4.1.0.0^2,7]heptane reacted with benzene- and methanesulfonyl thiocyanates in benzene at 20°C via anti addition to the central C¹–C⁷ bicyclobutane bond with formation of 6-endo-bromo-6-exo-thiocyanato-7-syn-(R-sulfonyl)bicyclo[3.1.1]heptanes. Treatment of the benzenesulfonyl thiocyanate adduct with potassium tert-butoxide in THF at 20°C gave 7-endo-(benzenesulfonyl)norpinan-6-one, whereas the reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene in methylene chloride afforded 7-exo-(benzenesulfonyl)-norpinane-6-thione which was converted into 7-exo-(benzenesulfonyl)norpinan-6-one by alkaline hydrolysis.     

Diastereoselective approach to 11-aryl steroid skeletons through a cobalt(I)-mediated [2+2+2] cyclization of allenediynes

The cobalt(I)-mediated [2+2+2] cycloaddition reactions of allenediynes of yne-allene-yne type bearing an aryl group on the allene are described. The cyclizations are totally chemo- and regioselective and show low diastereoselectivities. η⁴-Complexed tricyclic (6,6,6) compounds were obtained in good yields as mixtures of endo/exo diastereomers. The cyclization is also compatible with an oxyfunctionality at C3. By designing an allenediyne having a preexisting D ring, we succeeded in building skeletons of 11-aryl steroids in one step and in a totally diastereoselective manner and with simultaneous introduction of an angular methyl group at C10 and an aryl substituent at C11.     

Bypassing the lack of reactivity of endo-substituted norbornenes with the catalytic rectification–insertion mechanism

The catalytic 1,2-insertion polymerization of polar norbornenes (NBEs) leads to the formation of functional rigid macromolecules with exceptional thermal, optical and mechanical properties. However, this remarkable reaction is plagued by the low reactivity of the polar monomers, and most notably of those bearing a functional group in endo position. We have examined the polymerization mechanism of NBEs bearing one or two CO₂Me groups either in exo or endo position catalyzed by the so-called naked allyl Pd⁺ SbF₆^– catalyst (1). Although endo dimethyl ester of 5-norbornene-2,3-dicarboxylic acid (NBE(CO₂Me)₂) is polymerized by 1, two endo units are never inserted consecutively along the polymer chain. Indeed, 1 is a tandem catalyst which not only catalyzes the insertion of the monomer but also the isomerization of endo and exo isomers. Thus, the polymerization of endo monomers proceeds via a novel mechanism, coined rectification–insertion mechanism, whereby half of the endo monomers are rectified into exo ones prior insertion, leading to the formation of an alternating endo–exo copolymer using an endo only feedstock. With this mechanism, the lack of reactivity of endo norbornenes is bypassed, and the polymerization of predominantly endo polar NBEs bearing a variety of functionalities such as esters, imides, acids, aldehydes, alcohols, anhydrides, or alkyl bromides proceeds with catalyst loadings as low as 0.002 mol%.     

Synthesis and Antimycotic Properties of Hydroxy Sulfides Derived from exo- and endo-4-phenyl-3,5,8-trioxabicyclo[5.1.0]octanes

Both exo- and endo-isomers of 4-phenyl-3,5,8-trioxabicyclo[5.1.0]octane were reacted with thiophenol to afford individual diastereomers of hydroxy sulfides which were further processed in search for new antimycotic substances.     

Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment

A synthesis of brasilibactin A, a cytotoxic siderophore from the actinomycete of Nocardia brasiliensis, and three unnatural diastereomers of the natural product is described. Four possible diastereomers of the β-hydroxy acid fragment were prepared via asymmetric aldol reactions and used to synthesize brasilibactin A and its diastereomers. Careful analysis of ¹H NMR data confirmed that brasilibactin A possesses the 17S,18R absolute stereochemistry.     

Diels-Alder reaction of optically active (E)-γ-keto-α,β-unsaturated p-tolylsulfoxides with cyclopentadiene

The Diels-Alder reaction of enantiomerically pure (E)-γ-keto-α,β-unsaturated p-tolylsulphoxides 3 with cyclopentadiene give four easily separable diastereomers. The effect of several Lewis acids on the reaction was studied, finding a high endo selectivity with respect to the carbonyl group and moderate π-diastereoselectivity using BF₃·Et₂O as catalyst. The reactivity of compounds 3 as well as their endo selectivity are both higher than those observed for the corresponding (E)-3-sulfinylacrylates.     

A chiral phosphazane reagent strategy for the determination of enantiomeric excess of amines

Methods for measuring enantiomeric excess (ee) of organic molecules by NMR spectroscopy provide rapid analysis using a standard technique that is readily available. Commonly this is accomplished by chiral derivatisation of the detector molecule (producing a chiral derivatisation agent, CDA), which is reacted with the mixture of enantiomers under investigation. However, these CDAs have almost exclusively been based on carbon frameworks, which are generally costly and/or difficult to prepare. In this work, a methodology based on the readily prepared inorganic cyclodiphosph(iii)azane CDA ClP(μ-N^tBu)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be highly effective in the measurement of ee’s of chiral amines, involving in situ reaction of the chiral amines (R*NH₂) with the P–Cl bond of the CDA followed by quaternization of the phosphorus framework with methyl iodide. This results in sharp ³¹P NMR signals with distinct chemical shift differences between the diastereomers that are formed, which can be used to obtain the ee directly by integration. Spectroscopic, X-ray structural and DFT studies suggest that the NMR chemical shift differences between diastereomers is steric in origin, with the sharpness of these signals resulting from conformational locking of the bornyl group relative to the P₂N₂ ring induced by the presence of the P(v)-bonded amino group (R*NH). This study showcases cheap inorganic phosphazane CDAs as simple alternatives to organic variants for the rapid determination of ee.

The simple inorganic cyclodiphosph(iii)azane chiral derivatisation agent ClP(μ-^tBuN)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be effective in the measurement of ee’s of chiral amines using ³¹P NMR spectroscopy.     

Stereoselective synthesis of chiral hydrocarbazoles via the catalytic Diels–Alder reaction of siloxyvinylindole and cyclic Z-olefin

The catalytic Diels–Alder reaction of siloxyvinylindole and cyclic Z-olefin derived from pyroglutamic acid gave optically active substituted hydrocarbazoles. The exo/endo selectivity of this reaction could be controlled by using an appropriate Lewis acid. Scandium triflate gave high exo-selectivity and copper triflate gave moderate endo-selectivity. Subsequent stereoselective alkylation of the cycloadduct led to the synthesis of highly substituted hydrocarbazoles with five continuous chiral centers including a quaternary carbon.     

Keto complexes from the oxidation of η6-xanthene or thioxanthene-η5-cyclopentadienyliron cation and some reactions of the fluorenone and xanthone complexes

Ligand exchange between xanthene and ferrocene gave the η⁶-xanthene-η⁵-cyclopentadienyliron cation which was oxidized in situ with KMnO₄ to give the η⁶-xanthone-η⁵-cyclopentadienyliron cation (III). Similar oxidation of the η⁶-thioxanthene-η⁶-cyclopentadienyliron cation gave a mixture of the thioxanthone complex IV and the corresponding complexed sulfone V. III and the η⁶-fluorenone-η⁵-cyclopentadienyliron cation (VI) were utilized as reactants in the synthesis of new complexes via reactions with a number of reagents. Stereospecific exo-addition to give complexed endo-alcohols were observed in the reaction of III with NaBH₄, NaBD₄ or CH₃Li, and in the reaction of VI with CH₃Li, the anion of acetonitrile, the anion of nitromethane or the phenylacetylide anion. Ring opening reactions to give complexed o,o′-disubstituted benzophenones were observed when III was treated with the anion of acetonitrile, the anion of nitromethane, methylamine, cyclohexylamine, benzylamine or pyrrolidine.