Synthesis of 1,3-cis-Fused Tricyclic System through Regio- and Stereoselective Epoxidation and Ring-Rearrangement Metathesis: Access To Basic Core of Presilphiperfolanols

Here, we report a new synthetic approach to a highly strained 1,3-fused cis-cis-cis-5/5/6 tricyclic system that appeared among the presilphiperfolanol analogues. The cis-fusion of six-membered ring to a diquinane moiety is accomplished by substrate-controlled regio- and stereoselective epoxidation, and ring-rearrangement metathesis (RRM) sequence. In this regard, both early-, and late-stage epoxidation and RRM reactions were studied. The target compound, cis-cis-cis-5/5/6 tricyclic ketone with an α,β-oxirane ring can serve as a key building block to produce various presilphiperfolanol analogues. The cis-cis-cis-5/5/6-tricyclic-α,β-epoxyketone can also act as masked enone and therefore useful for various chemical transformations in organic synthesis. The short synthetic sequence disclosed here may be useful to design various biologically important molecules. The newly reported molecules are well-characterized by NMR, HRMS, and IR spectral data.     

Synthetic Approaches to Taxodione. Synthesis of Methyl 12-Oxopodocarpa-5,9(11)-diene-8β-Carboxylate

In connection with studies leading to the total synthesis of taxodione¹ (1), we required the tricyclic enone 3. We have previously described² an AB→ABC approach to this intermediate which was flawed by a low yield in the penultimate closure of the C ring (2→3). We now wish to report an alternate synthesis of 3 which involves a BC→ABC approach for the construction of this tricyclic system.     

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

The first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S‐TBPTTL)₄, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐ 1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.     

An efficient construction of bridged chiral tetracyclic indolidines, a core structure of asperparaline, via stereocontrolled catalytic Pauson-Khand reaction

A reaction of chiral enyne 22 derived from l-proline with a catalytic amount of cobalt (0) octacarbonyl in the presence of N-methylmorphorine N-oxide gave tricyclic enone 24 in 54% yield (73% based on consumed starting material). Treatment of enone 11 with aqueous methylamine followed by silica gel afforded bridged tetracyclic indolidine 1, a common structural motif of natural metabolites, an asperparaline series of compounds and also a potential intermediate for the synthesis of a paralytic alkaloid, asperparaline C (4), in 70% yield.     

Diastereoselective π-facially controlled nucleophilic additions of chiral vinylorganometallics to chiral β,γ-unsaturated ketones. 2. A practical method for stereocontrolled elaboration of the decahydro-as-indacene subunit of ikarugamycin

7,7-Dimethoxy-5-norbornen-2-one has been converted in 7 steps to tricyclic enone 10, which comprises a principal subunit of the ikarugamycin structure.     

Photoannelation Reactions of 3‐(Alk‐1‐ynyl)cyclohept‐2‐en‐1‐ones

Irradiation (350 nm) of the newly synthesized 3‐(alk‐1‐ynyl)cyclohept‐2‐en‐1‐ones 1 and 2 leads to the selective formation of tricyclic head‐to‐head dimers. In the presence of 2,3‐dimethylbuta‐1,3‐diene, the (monocyclic) enone 1 affords trans‐fused 7‐alkynyl‐bicyclo[5.2.0]nonan‐2‐ones as major photoproducts, whereas photocycloaddition of benzocyclohept‐5‐en‐7‐one 2 to the same diene gives preferentially the eight‐membered cyclic allene 16 via ‘end‐to‐end’ cyclization of the intermediate allyl‐propargyl biradical 22 . On contact with acid, cycloocta‐1,2,5‐triene 16 isomerizes to cycloocta‐1,3,5‐triene 18 .     

Improved synthesis,X-ray structure,and antifungal activity of a sugar-psoralen conjugate: 4,4′-Dimethylxanthotoxol 2,3,4,6-tetra-O-Acetyl-β-D-glucoside

An improved synthesis for 4,4′-dimethylxanthotoxol 2,3,4,6-tetra-O-acetyl-β-D-glucoside (1) starting from resorcinol was developed. Crystallographic analysis of glucoside 1 indicated that the dihedral angles between the mean planes of the tricyclic ring system of adjacent molecules was 54.820(22)° probably due to the steric hindrance caused by the bulky O-glucoside moiety, which prevents the molecules from packing via π···π stacking between the tricyclic cores. The antifungal screening data revealed that glucoside 1 had higher inhibition than its parent compound 4,4′-dimethylxanthotoxol and azoxystrobin against Rhizoctonia solani, Pyricularia grisea, and Alternaria alternate Japanese pear pathotype, with the inhibitory rates of 75.4, 65.7 and 70.1%, respectively, at the 50?µg/mL concentration.     

Synthesis and Odor of Chiral Partial Structures of Khusimone. Part 2

Khusimone ( 1 ), one of the main odor-donating compounds of vetiver oil, is subject of the following study on structure/odor relationship. Ring opening of the carbonyl-functionalized bridge of the tricyclic khusimone leads to the bicyclic structures 2a / b . The enantioselective approach to these degraded structures is described, and the olfactory consequences are studied. Starting point of the synthesis is an enantiomerically pure enone ester which is easily obtainable from camphorsulfonic acid.     

Synthetic approaches to homochiral bicyclo[5.2.1]decanes based on d-camphor

The Reformatsky reaction of bornanic enone (10-nor-1-vinylcamphor) with ethyl iodoacetate followed by iodocyclization afforded tricyclic iodolactone. Fragmentation of the latter initiated by HgO—I₂ gave rise to bicyclic iodoxolactone. Attempts to perform cyclization of this iodoxolactone analogously to intramolecular alkylation of CH-acids with halogen-containing electrophiles failed.     

Thermal Reactions of Guaiazulene and Its 3-Methyl Derivative with Dimethyl Acetylenedicarboxylate

The thermal reaction of 7-isopropyl-1,3,4-trimethylazulene (3-methylguaiazulene; 2 ) with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° leads to the formation of the corresponding heptalene- ( 5a/5b and 6a/6b ; cf. Scheme 3) and azulene-1,2-dicarboxylates ( 7 and 8 , respectively). Together with small amounts of a corresponding tetracyclic compound (‘anti’- 13 ) these compounds are obtained via rearrangement (→ 5a/5b and 6a/6b ), retro-Diels-Alder reaction (→ 7 and 8 ), and Diels-Alder reaction with ADM (→ ‘anti’- 13 ) from the two primary tricyclic intermediates ( 14 and 15 ; cf. Scheme 5) which are formed by site-selective addition of ADM to the five-membered ring of 2 . In a competing Diels-Alder reaction, ADM is also added to the seven-membered ring of 2 , leading to the formation of the tricyclic compounds 9 and 10 and of the Diels-Alder adducts ‘anti’- 11 and ‘anti’- 12 , respectively of 9 and of a third tricyclic intermediate 16 which is at 200° in thermal equilibrium with 9 and 10 (cf. Scheme 6). The heptalenedicarboxylates 5a and 5b as well as 6a and 6b are interconverting slowly already at ambient temperature (Scheme 4). The thermal reaction of guaiazulene ( 1 ) with excess ADM in decalin at 190° leads alongside with the known heptalene- ( 3a ) and azulene-1,2-dicarboxylates ( 4 ; cf. Schemes 2 and 7) to the formation of six tetracyclic compounds ‘anti’- 17 to ‘anti’- 21 as well as ‘syn’- 19 and small amounts of a 4:1 mixture of the tricyclic tetracarboxylates 22 and 23 . The structure of the tetracyclic compounds can be traced back by a retro-Diels-Alder reaction to the corresponding structures of tricyclic compounds ( 24--29 ; cf. Scheme 8) which are thermally interconverting by [1,5]-C shifts at 190°. The tricyclic tetracarboxylates 22 and 23 , which are slowly equilibrating already at ambient temperature, are formed by thermal addition of ADM to the seven-membered ring of dimethyl 5-isopropyl-3,8-dimethylazulene-1,2-dicarboxylate ( 7 ; cf. Scheme 10). Azulene 7 which is electronically deactivated by the two MeOCO groups at C(1) and C(2) shows no more thermal reactivity in the presence of ADM at the five-membered ring (cf. Scheme 11). The tricyclic tetracarboxylates 22 and 23 react with excess ADM at 200° in a slow Diels-Alder reaction to form the tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 (cf. Schemes 10–12 as well as Scheme 13). A structural correlation of the tri- and tetracyclic compounds is only feasible if thermal equilibration via [1,5]-C shifts between all six possible tricyclic tetracarboxylates ( 22, 23 , and 35–38 ; cf. Scheme 13) is assumed. The tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 seem to arise from the most strained tricyclic intermediates ( 36–38 ) by the Diels-Alder reaction with ADM.     

Construction of tricyclic enone, a common precursor for aphidicolane and stemodane B/C/D-ring system

Synthesis of a tricyclic enone (B/C/D ring system), a common key precursor for the aphidicolane- and stemodane-type diterpene, is described. The key reaction for the construction of the quaternary carbon center is allylation of epoxide at the more substituted carbon with an organotitanium reagent. Asymmetric reduction with DIP-Cl followed by stereoselective cyclization of spirocyclic ketone and the functional group modification gave the desired tricyclic enone in good yield.     

A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones

The efficient construction of functionalized polycyclic structures is an important objective in organic synthesis. Herein, we disclose a three‐step “[2 + n]” annulation method for the transformation of cyclic ketones to fused enimines and enones. The method relies on the Suzuki coupling reaction and the amide reductive alkenylation reaction. A series of fused bicyclic (6/6, 6/7, 8/7) and tricyclic (6/6/6; 6/6/7, 6/5/7) ring systems bearing an α,β‐enimine or an α,β‐enone functionality have been synthetized in good overall yields.     

Enantioselective Synthesis of Functionalized Nitrocyclopropanes by Organocatalytic Conjugate Addition of Bromonitroalkanes to α,β‐Unsaturated Enones

A general enantioselective synthesis of functionalized nitrocyclopropanes by organocatalytic conjugate addition of a variety of bromonitroalkanes to α,β‐unsaturated enone systems is presented. The process, efficiently catalyzed by the salts of 9‐amino‐9‐deoxyepiquinine 1 d serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes with high levels of enantio‐ and diastereoselectivities. Since only 0.6 equivalents of bromonitromethane are used as a reagent, (S)‐ 2 e is obtained enantiomerically pure by employing chiral 1 d as a highly efficient catalyst for its kinetic resolution (97 % ee at 51 % conversion, selectivity s=120).     

An unexpected result in an intramolecular Ritter reaction induced by triflic anhydride

The treatment of the methyl 2-(cyanoethyl)-1-hydroxy-2-indane-carboxylate 1b in dichloromethane solution with triflic anhydride at 20°C afforded the tricyclic enone 3 in 65% yield, instead of the expected lactam 2b produced under the ‘classic’ conditions of the Ritter reaction.     

Light-Induced Cycloaddition of Furan and addition of methanol to a 4-thiacyclohex-2-enone ( = 2,3-dihydro-4H-thiin-4-one) and a 4-thiacyclopent-2-enone ( = thiophen-3(2H)-one)

Irradiation of newly synthesized 2,2-dimethyl-2,3-dihydro-4H-thiin-4-one ( 1 ) in furan affords the two [4 + 2] cycloadducts 3 and 4 and the [2 + 2] cycloadduct 5 in a 5:4:1 ratio (Scheme 1). Irradiation of 1 in MeOH gives a 3:2 mixture of 5- and 6-methoxy-2,2-dimethylthian-4-ones 6 and 7 . Irradiation in CD₃OD affords the same (deuterated) adducts with the CD₃O and D groups trans to each other, results compatible with cis-addition of MeOH to a trans -configurated ground-state enone. Irradiation of the same enone in furan/MeOH 1:1 gives only the furan cycloadducts 3–5 and no MeOH adducts, suggesting that furan interacts with the (excited) triplet enone before the deactivation of this species to a ground-state (E)-cyclohexenone, which then reacts with MeOH. On irradiation in furan, the corresponding five-membered thiaenone, 2,2-dimethylthiophen-3(2H)-one ( 2 ) affords only one, cis-fused, [4 + 2] cycloadduct with ‘exo’-configuration, i.e. 8 , and 2 does not undergo solvent addition but rather cyclodimerization (→ 9 ) on irradiation in MeOH (Scheme 1).     

Umcyclopropanisierung bei der Tetrabromierung eines tricyclischen Ketons zu 3exo, 4endo, 6exo-Tribrom-7-brommethyl-1,5-dimethyl-tricyclo[3.2.1.02,7]octan-8-on

Transcyclopropanation during the Tetrabromination of a Tricyclic Ketone to 3 exo, 4 endo, 6exo-Tribromo-7-bromomethyl-1,5-dimethyl-tricyclo[3.2.1.0^2,7]octan-8-one Bromination of the tricyclic ketone 1 with an excess of bromine at low temperature gives in approximately 30% yield the highly crystalline tricyclic tetrabromide 2 (Scheme 1). The structure of 2 was established by NMR.- and especially X-ray-analysis (Fig.1). Treatment of 1 with 1 mol-equ. of bromine gives an unstable dibromide, to which the structure 3 was assigned on the basis of its NMR.-spectrum and its further bromination to 2 (Scheme 1). In the course of the tetrabromination of 1 the original cyclopropane ring is opened in the first step ( 1 → 3 ) and another cyclopropane ring is formed in the second step ( 3 → 2 ) (cf. Scheme 3).     

Synthesis of 7-epineoptilocaulin, mirabilin B, and isoptilocaulin. A unified biosynthetic proposal for the ptilocaulin and batzelladine alkaloids. Synthesis and structure revision of netamines E and G

Addition of guanidine to a 6-methylhexahydroindenone in MeOH at 85 degrees C afforded 7-epineoptilocaulin. A similar reaction with a 6-propylhexahydroindenone afforded netamine E. MnO2 oxidation of 7-epineoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isoptilocaulin.     

Investigations of an annulation-fragmentation-spirocyclisation approach to fawcettimine-type Lycopodium alkaloids

This paper reports progress in the development of a furan oxidative N-spirocyclisation approach to the fawcettimine alkaloids huperzine Q and lycopladine D. A short synthesis is described of a key intermediate cyclopentaindolizidine that subsequently fragments by N-acylation and β-elimination. The stereochemistry of 1,4-addition of cyanide to the resulting enone is discussed with supporting molecular modelling calculations. N-Deprotection is shown to be accompanied by cyclisation onto the nitrile group, resulting in a tricyclic lactam with a twisted amide functionality. Elaboration of this lactam afforded four of the five rings present in lycopladine D with just the C(8) carbon lacking.     

Photochemische Reaktionen. 65.(vorläufige) Mitteilung. Spezifisch π → π*-induzierte Photoisomerisierungen von 10-Dimethoxymethyl-Δ1,9-octal-2-on. Ein photochemischer Zugang zu [4.4.3]-12-Oxapropellan-Derivaten

Selective n → π* excitation of the α,β-unsaturated enone 1 in hydrocarbon solvents resulted in a deconjugation reaction to 3 , reminiscent of results previously reported for similar systems [2], whereas the photoreactivity of 1 in alcohol solvents at wavelengths >3400 Å was so small that only product 4 has been identified as yet. Excitation of the π → π* transition of compound 1 at 2537 Å initiated additional phototransformations which could not be effected by irradiation in the first absorption band. The [4.4.3]-12-oxapropellane derivative 2 was identified as one of the two new major photo-isomers. A 6:8 mixture of products 2 and 3 , plus about 1 part of an isomer of still unknown structure (see however, the Addendum), were readily formed in hydrocarbon solvents, and a 1:10 ratio of 2 and the unknown product was obtained in methanol. Abstraction of a methoxyl hydrogen by the ketone oxygen is proposed to account for the primary photochemical step in the cyclization to 2 . A hydrogen-deuterium isotope effect of 2.7 was observed in a competitive experiment using 1 and 1-d _6. 34% of one deuterium atom were exchanged for hydrogen when 1-d ₆ was photolyzed to 2-d ₆ in t-butyl alcohol, which suggests an intermediate of type a in the pathway 1 → 2 possessing a readily exchangeable proton. Steric considerations would require a strongly distorted, non-planar excited-state geometry of the enone group of 1 for the oxygen to approach a methoxyl hydrogen. The transformation 1 → 2 represents a novel reaction type in photochemical processes of conjugated enones which are specifically induced by π → π* excitation only.     

Total Synthesis of Dimethyl Glolosiphone A via α-Carbonyl Radical Spiro-Cyclization

A general approach toward spiro[4.4]nonane structure based on the α-carbonyl radical cyclization has been developed. Efficient total synthesis of dimethyl gloiosiphone A ( 2 ) was achieved. Thus, alkylation of the anion of dimethylhydrazone of cyclopentanone with 5-iodopent-1-yne followed by hydrolysis gave ketone 4 . Iodination of 4 via its TMS-enol ether yielded iodo ketone 7 . Radical spiro-cyclization of 7 gave spiro ketone 10 . Iodination of 10 afford iodo spiro ketone 23 . Oxidation and iodination of 23 gave compound 24 . Methylation of 24 furnished methoxy iodo enone 25 . Substitution of iodide in 25 with methoxide produced dimethoxy enone 26 . Allylic oxidation of 26 gave diketone 27 . Treatment of 27 with OsO₄ and N-methylmorpholine N-oxide gave dihydroxy ketone 28 . Methylation of the primary alcohol group in 28 afforded dimethyl gloiosiphone A ( 2 ).