Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Alkoxide-Accelerated [1,3] Sigmatropic Shift of Bicyclo[3.2.1]oct-6-en-2-ols to 8-endo-Hydroxybicyclo[3.3.0]oct-2-en-4-ones

Bicyclo[3.2.1]oct-6-en-2-ols 6 are shown to undergo [1,3] sigmatropic shift to afford 8-endo-hydroxy-bicyclo[3.3.0]oct-2-en-4-ones 8 under the influence of potassium hydride.     

Enantioselective Synthesis of Bicyclo[3.2.1]octadienes via Palladium-Catalyzed Intramolecular Alkene-Alkyne Coupling Reaction

Bicyclo[3.2.1]octadiene compounds and derivatives exist in a number of natural products and bioactive compounds. Nevertheless, catalytic enantioselective protocols for the synthesis of these skeletons have not been disclosed. Herein we reported a palladium-catalyzed asymmetric intramolecular alkene-alkyne coupling of alkyne-tethered cyclopentenes, affording a library of enantionenriched bicyclo[3.2.1]octadienes in excellent yields and enantioselectivities (mostly >99 % ee). Moreover, the products could undergo an unusual iodination-induced 1,2-acyl migration, forming iodinated bicyclo[3.2.1]octadienes with three vicinal stereocenters. The enone and isolated olefin motifs embedded in the products provide useful handles for downstream elaboration.     

4-Aminobicyclo[2.2.2]octanone Derivatives with Antiprotozoal Activities

Summary.  4-Aminobicyclo[2.2.2]octanones which were prepared in one-pot-reactions from benzylidene acetone and dialkylammonium rhodanides were reduced stereoselectively to their corresponding alcohols. The activities of the bicyclic compounds against causative organisms of tropical deseases were examined. The 4-aminobicyclo[2.2.2]octan-2-ols were in general more active against Trypanosoma b. rhodesiense and Plasmodium falciparum than the corresponding keto compounds. Corresponding author. E-mail: robert.weis@uni-graz.at Received November 27, 2002; accepted December 2, 2002 Published online May 2, 2003     

4-Aminobicyclo[2.2.2]octanone Derivatives with Antiplasmodial and Antitrypanosomal Activities

Summary. 4-Aminobicyclo[2.2.2]octanones were converted to their N-oxides and to 4-aminobicyclo[2.2.2]octanes. Furthermore, the 6,7-bis-(4-methoxyphenyl) analogues were synthesized. All products were screened for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum. The pharmacological results were compared with those of formerly tested bicyclo[2.2.2]octanones and bicyclo[2.2.2]octanols. Structure-activity relationships are discussed.Received April 8, 2003; accepted April 14, 2003 Published online September 25, 2003     

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.     

Synthesis of 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids and anti-convulsant properties of the corresponding amides

Novel 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids have been made via [3+2]cycloaddition to alkyne 2. A number of the corresponding amides are anti-convulsant in mice.     

Allylsilane-interrupted homo-Nazarov cyclization and synthesis of bicyclo[3.2.1]octan-8-ones

The combination of homo-Nazarov cyclization of 2-(tert-butyldiphenylsilylmethyl)cyclopropyl vinyl ketone leading to oxyallyl cation and its subsequent [3+2] capture by allylsilane has been demonstrated as an useful strategy for the construction of functionalized bicyclo[3.2.1]octan-8-ones. The [3+2] capture proceeds exclusively in the exo mode to make the overall reaction diastereoselective. The less substituted end of the oxyallyl cation was found to react nearly two times faster than the more substituted end.     

2,6-二氧杂双环[3.2.1]辛烷类衍生物的串联合成

以2-甲基-4-戊烯-1,2-二醇和芳香醛为原料, 三氯化铟为催化剂, 得到了一系列1,3-二取代2,6-二氧杂双环[3.2.1]辛烷类衍生物. 整个反应采用一锅法, 反应条件简单且产率高. 所有的化合物均用¹H NMR, ¹³C NMR和质谱法进行了表征, 并用NOESY确立了分子的相对构型.     

Bicyclo[3.2.1]octenones as Building Blocks in Natural Product Synthesis (IV): Formal Synthesis of (±)-Hydroxyloganin Aglucone

A formal synthesis of (±)-hydroxyloganin aglucone from bicyclo[3.2.1]octenone 1 is described. Ring opening of syn-8-(methanesulfonyloxy)-1-phenylthiotricyclo[4.2.1.0^3,7]non-4-en-2-one 14 with potassium hydroxide is the key reaction.     

An improved and scalable process for 3,8-diazabicyclo[3.2.1]-octane analogues

An improved and scalable process for substituted 3,8-diazabicyclo[3.2.1]octane was developed.N-Benzyl-2,5-dicarbethoxy-pyrrolidine 2 was reduced to N-benzyl-2.5-dihydroxymethylpyrrolidine 9 and subsequently debenzylated to afford N-Boc-2,5- dihydroxymethylpyrrolidine 10.After mesylation of the diol 10 and cyclization with benzylamine,a diversity of scaffold,3,8- diazabicyclo[3.2.1]octane analogue 12 was obtained in a total yield of 42%in five steps.     

Enantioselective synthesis of bicylco[3.2.1]octan-8-ones using a tandem Michael-Henry reaction

Bicyclo[3.2.1]octan-8-ones have been prepared from a tandem Michael-Henry reaction between cyclohexane-1,2-diones and nitroalkenes using a quinine-derived thiourea as the catalyst. Although four stereogenic centers were created during the reaction, only two diastereomers were obtained in good diastereoselectivity and high enantioselectivity (92-99% ee). When 3-methylcyclohexane-1,2-dione (R¹=Me) was used as the substrate, only the regioisomeric product of the corresponding thermodynamic enolate was obtained.     

A simple and efficient synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and 3-substituted azatropanes therefrom using pyroglutamic acid

8-Methyl-3,8-diazabicyclo[3.2.1]octane (3-azatropane) is synthesized efficiently from pyroglutamic acid making use of amide activation. The key step of the synthesis involves reduction and cyclization of a nitroenamine intermediate. Several 3-substituted analogues of this azatropane were also synthesized via this methodology and evaluated for their affinity at D₂ and 5-HT_2A receptors.     

Synthesis of bicyclo[3.2.1]octanones via ketyl radical promoted rearrangements under reductive PET conditions

Photoinduced electron transfer (PET) reactions from triethylamine (TEA) to ketones have been utilized for a clean and efficient route to bicyclo[3.2.1]octanones. A one-pot conversion of bicyclo[2.2.2]octenones to such molecules has been described. MeOH as well as acetonitrile/LiClO₄ combinations have been found to be the most effective solvents for these reactions.     

Production and degradation mechanism of theacitrin C, a black tea pigment derived from epigallocatechin-3-O-gallate via a bicyclo[3.2.1]octane-type intermediate

Black tea is rich in polyphenols and has been shown to have various health benefits; however, its components have not yet been clarified in detail. Enzymatic oxidation of epigallocatechin-3-O-gallate, the most abundant polyphenol in tea, is thought to contribute significantly to the production of black tea polyphenols. We identified theacitrin C, an unstable black tea pigment, as an enzymatic oxidation product of epigallocatechin-3-O-gallate. Degradation of theacitrin C afforded theacitrinin A and 2,3,5,7-tetrahydroxychroman-3-O-gallate. Furthermore, theacitrinin B, which was isolated from black tea, is deduced to be a degradation product of theacitrin A, the desgalloyl analogue of theacitrin C. The structures of theacitrinins A and B were elucidated based on spectroscopic data. This is the first time that a degradation product of theacitrin has been isolated from black tea. We also examined the influence of esterification of the epigallocatechin C-3 hydroxyl group on the decomposition of bicyclo[3.2.1]octane-type intermediates.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

Novel design of 3,8-diazabicyclo[3.2.1]octane framework in oxidative sulfonamidation of 1,5-hexadiene

1,5-Hexadiene reacts with trifluoromethanesulfonamide in the oxidative system (t-BuOCl+NaI) to give trans-2,5-bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrrolidine 5 and 3,8-bis(trifluoromethylsulfonyl)-3,8-diazabicyclo[3.2.1]octane 6. With arenesulfonamides ArSO₂NH₂ (Ar=Ph, Tol), the reaction stops at the formation of the trans and cis isomers of 2,5-bis(iodomethyl)-1-(arenesulfonyl)pyrrolidine 7 and 8 (1:1). The cis isomers of 7 and 8 do not undergo cyclization to the corresponding 3,8-disubstituted 3,8-diazabicyclo[3.2.1]octanes. The reaction with triflamide represents the first example of one-pot two-step route to 3,8-diazabicyclo[3.2.1]octane system.     

Simple NMR method for assigning relative stereochemistry of bridged bicyclo[3.n.1]-2-enes and tricyclo[7.n.1.0]-2-enes

The stereochemistry of syn and anti-forms of bridged bicyclo[3.n.1]-2-ene, tricyclo[7.n.1.0]-2-ene (n=1-3) and bicyclo[4.3.1]dec-7-ene derivatives can be assigned from the ¹³C chemical shift difference of the double bond. Both syn-9-R-bicyclo[3.3.1]non-2-enes and syn-13-R-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes have a large shielding difference between sp² carbons, while the corresponding anti-forms have a smaller one. In contrast, 8-R-bicyclo[3.2.1]oct-2-enes and 12-R-tricyclo[7.2.1.0^2,7]dodec-2(7)-enes have an inverse correlation. The reason of this specificity is the influence of the γ-gauche effect on the chemical shift of C(2) atom. The GIAO theory has been applied to investigate the ¹³C chemical shifts. The conformational equilibrium in the formamide group of 13-formylamino-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes has been studied.     

Synthesis of orthogonally protected 3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid--a versatile building block for the synthesis of cocaine analogues

An eight-step synthesis of an orthogonally protected 3,8-diazabicyclo[3.2.1]octane from commercially available pyroglutamic acid was developed. The target compound can be used as a versatile building block for combinatorial synthesis of pharmacologically useful compounds and features a hidden α-, β-, δ- and ε-amino acid, which can also be seen as an example of a new class of cocaine analogues.     

A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones through [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with ring expansion

Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields. Heating of these enaminonitriles with H₃PO₄ in acetic acid gave 2-cyanobicyclo[3.3.0]oct-1-en-3-ones in good yield. On the other hand, treatment of the [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with cyanomethyllithium followed by lithium carbanion of the homologues of acetonitrile afforded enaminonitriles having a substituent at the 3-position. Heating of the enaminonitriles with H₃PO₄ in acetic acid gave 2-substituted bicyclo[3.3.0]oct-1-en-3-ones in good to high yields. This method offers a novel and versatile procedure for synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in good overall yields.