Diastereoselective Manipulations of Bicyclo[m.1.0]alkane Derivatives. 4. Reactions of Nucleophiles with Bicyclo[m.1.0]alk-3-en-2-ones

Enantiomerically enriched bicyclo[m.1.0]alk-3-en-2-ones possessing 8-, 12-, and 15-membered rings were prepared and subjected to additions of nucleophiles. 1,2-Additions of n-butyllithium were highly diastereoselective for all cyclopropyl enones examined. Reactions of (Z)-bicyclo[6.1.0]non-3-en-2-one and (E)-bicyclo[13.1.0]hexadec-3-en-2-one with dimethyloxosulfonium methylide were highly diastereoselective, while reaction of (E)-bicyclo[10.1.0]tridec-3-en-2-one with this reagent was not diastereoselective. In contrast, 1,4-additions of lithium diorganocuprates were highly diastereoselective for the 8- and 12-membered enones but were not diastereoselective for the 15-membered enone. All reactions were chemically efficient. The diastereoselectivities observed for 1,2-additions, which are thought to involve early transition states, can be rationalized by consideration of the low-energy conformations of each cyclopropyl enone. The diastereoselectivities observed for 1,4-additions, which may involve late transition states, do not correlate simply with the lowest energy conformations of these enones.     

Development of Molecular Mechanics Torsion Parameters for alpha,beta-Cyclopropyl Ketones and Conformational Analysis of Bicyclo[m.1.0]alkan-2-ones

Conformations of cyclopropyl methyl ketone have been studied using ab initio methods in an effort to quantify the effects of conjugative overlap between the cyclopropane ring and an adjacent ketone carbonyl. Results were comparable with previous experimental and theoretical studies. Cyclopropyl methyl ketone exhibits a global energy minimum in the s-cis conformer and a local energy minimum near the s-trans conformer. The potential energy curve obtained was used to derive torsion parameters which were employed in molecular mechanics studies of the conformations of the set of bicyclo[m.1.0]alkan-2-ones having larger ring sizes from five- to 16-membered. Similar conformations for the cyclopropyl ketone substructure are observed for all the medium and large ring systems examined. Possible synthetic ramifications of local conformational anchoring by this functional group array are discussed.     

Synergistic Catalysis: Metal/Proton‐Catalyzed Cyclization of Alkynones Toward Bicyclo[3.n.1]alkanones

A highly efficient and practical synergistically metal/proton‐catalyzed Conia–ene reaction for the synthesis of bicyclo[3.n.1]alkanones has been developed. This synergistic catalysis was successfully utilized in modifying natural compounds such as methyl dihydrojasmonate, α,β‐thujone, and 5α‐cholestan‐3‐one. Furthermore, the bridged carbonyl group of bicyclo[3.2.1]alkanones could be easily attacked by nucleophiles to give the ring‐opened cycloheptenone products or bicyclo[4.2.1]amide in excellent yields. These reactions provide rapid access to a diverse range of cyclic structures from simple starting materials or naturally occurring compounds.     

Bicyclo[3.2.1]octane synthons from cyclopropenes: functionalization of cycloadducts by nucleophilic additions

It has been known for several decades that a highly functionalized family of tetrahalobicyclo[3.2.1]octadienes are readily available through the cycloaddition of furan or cyclopentadiene with either tetrachloro- or tetrabromocyclopropene. However, the application of these highly functionalized building blocks in synthesis has remained relatively unexplored in relation to their better-known counterparts derived through oxyallyl cation additions. As a first step toward utilizing these highly versatile intermediates in synthesis, a study of the addition of various nucleophiles to the halogenated nucleus has been conducted. It has been found that these halogenated systems are amenable to a wide range of functionalizations in high yields and with good selectivities.     

13C-NMR-spektren von bicyclo[n.1.0]alkenen

The ¹³C-NMR spectra of some bicyclo[3.1.0]hex-3-en-2-ols and of some bicyclo[3.1.0]hex-3-en-2-ones are described. The bond parameters of bicyclo[3.1.0]hex-3-en-2-one are derived from a structure determination of endo-6-methoxy-1,3,6-triphenylbicyclo[3.1.0]hex-3-en-2-one. The electron density is calculated by the EHT method, and correlated with the ¹³C NMR shifts. For comparison the ¹³C NMR spectrum of a bicyclo[4.1.0]hepta-1,5-dione derivative is analysed. The influence of a cyclopropane system attached to a five-membered and to a six-membered ring is elucidated. Whereas the five-membered ring shows conjugation between the carbonyl group and the cyclopropane system, the same effect is not observed in the six-membered ring analogue. This is explained by the highly rigid structure of the five-membered ring.     

Synthesis of Bicyclo[n. 2. 0]alkanediols

Interest in the synthetic potential of rearrangement reactions of fused-ring cyclobutanediols^1,2 has led us to develop a general method for the synthesis of bicyclo[n.2.0] alkanediols in which the hydroxyl group are located on adjacent carbon atoms at the bridgehead and in the cyclobutane ring (e.g. 1). We report here the application of our new synthetic method to the synthesis of bicyclo [4.2.0] octane-1,8-diol (2) and bicyclo[3.2.0]-heptane-1,7-diol (3).     

Umwandlung von Bicyclo [3.2.0]hept-2-en-6-on in Cyclopentadienessigsäure-Derivate

Conversion of Bicyclo [3.2.0]hept-2-en-6-one into Cyclopentadienylacetic Acid Derivatives The reaction of a mixture of 4exo-bromobicyclo [3.2.0]hept-2-en-6-one ( 2 ) and -7-one ( 3 ) with O- or N-nucleophiles yielded cyclopentadien-5′-yl-acetates 4a–f or-acetamides 4g–h . Due to their rapid isomerization, the products 4 were not isolated, but some of them were demonstrated spectroscopically or captured in situ with maleimide as 10′-substituted norbornene derivatives 7 . The formation of 4 from 2/3 involves a fragmentation of the bond between the carbonyl and the bridge-head C-atom, induced by the attacking nucleophile and the leaving Br-ion and aided by the relief of the four-membered ring strain. Some of the isomerization products of 4 , i.e. the cyclopentadiene-1′-yl- and 2′-yl-acetyl derivatives were captured with maleimide as the 1′- and 8′-substituted norbornene-derivatives 8 and 9 . Two C-nucleophiles did not induce the fragmentation: sodium acetylacetonate substituted the Br-atom and sodium (diethoxyphosphoryl)ethoxycarbonylmethide condensed with the carbonyl group of 2/3 , yielding 11/12 and 13/14 , respectively.     

3 + 2] Cycloreversion of bicyclo[m.3.0]alkan-3-on-2-yl-1-oxonium ylides to alkenyloxyketenes. Stereospecific aspect

Rhodium(II)-catalyzed intramolecular reaction of diazoketones 1 bearing a cyclic ethereal moiety transiently formed bicyclo[m.3.0]octan-3-one-1-oxonium-2-ylides (2), which underwent sigmatropic and stereospecific [3 + 2] cycloreversion reaction to form alkenyloxyketenes 3. The ketenes were efficiently trapped by methanol to form the corresponding esters 4. Mechanistic studies revealed that the size of ethereal ring can be variable at least from THF to the THP, oxepane, and oxocane moiety, i.e., m = 3-6. On the other hand, the size of the ylide ring containing the carbonyl unit is limited to a five-membered ring. The cycloreversion was found to be stereospecific as was proven by the reactions of diastereoisomeric pairs bearing a methyl group at the bond-cleaving position. From threo isomers 7, (E)-alkenyloxyacetates 15 were exclusively formed (77-84%), whereas from erythro isomers 8, (Z)-isomers 16 were formed (80-88%). Mechanism of the cleavage from diazoacetonyl-substituted cyclic ethers to alkenyloxyketenes via bicyclic oxonium ylides was analyzed on the basis of calculations employing the hybrid density functional B3LYP and the highly correlated quadratic configuration interaction QCISD method to reveal that the concerted [3 + 2] cycloreversion is the key step of this reaction.     

Hydration and hemiacetal formation in oxo-[m . n]metacyclophanes

[m . 2]Metacyclophanes with an oxo-function in the C₂ bridge exhibit an enhanced carbonyl reactivity towards nucleophiles. The equilibrium constants for hydration and hemiacetal formation markedly decrease asm increases and qualitatively correlate with the ring strain present in the parent hydrocarbon. [m . n]Metacyclophanes withm,n 3 are almost free from intraanular steric strain. Accordingly, oxo-functions in the bridges do not exhibit an appreciable enhancement of reactivity.

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Hydrat- und Hemiacetalbildung bei Oxo-[m . n]metacyclophanen

Zusammenfassung [m . 2]Metacyclophane mit einer Oxo-Funktion in der C₂-Brücke zeigen eine erhöhte Carbonylreaktivität gegenüber Nucleophilen. Die Gleichgewichtskonstanten für die Hydratisierung und Hemiacetalbildung nehmen mit steigendemm ab und korrelieren qualitativ mit der Ringspannung des entsprechenden Kohlenwasserstoffs. Dagegen sind [m . n]Metacyclophane mitm,n 3 weitgehend frei von intraanularen sterischen Spannungen. Oxo-Funktionen in den Brücken besitzen deshalb keine nennenswert erhöhte Carbonylreaktivität.

     

7-substituted 2-azabicyclo[2.2.1]heptanes as key intermediates for the synthesis of novel epibatidine analogues; synthesis of syn-and anti-isoepiboxidine

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced epimerization alpha to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer and hence syn-isoepiboxidine.     

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted efficient and versatile aza-Michael addition

A convenient and versatile method was developed for aza-Michael addition using a substoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Various nitrogen nucleophiles were efficiently introduced to α,β-unsaturated carbonyl compounds employing 0.5 equiv of DBU. Furthermore, other heteroatomic nucleophiles could also be introduced successfully under the same reaction conditions.     

Reaction of pyrrolo[2,1-a]isoquinoline-2,3-diones with carbon-centered nucleophiles

Knoevenagel condensations of 5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-diones with malononitrile, ethyl cyanoacetate, indan-1,3-dione, and Drotaverine base involved the ketone carbonyl group in the former with formation of deeply colored dark blue substances. The lactam ring in the products can be opened by the action of nitrogen-centered nucleophiles, e.g., p-toluidine. The reaction of 5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione with methyl magnesium iodide gave 2-hydroxy-2,5,5-trimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-one.     

Regioselective Electrophilic Additions of Bicyclo[2.2.n]alk-2-enes Controlled by Remote Epoxide Functions

The electrophilic additions of 2-nitrobenzenesulfenyl chloride to (1RS,2SR,4RS)-spiro[bicyclo[2.2.1]hept-5-ene-2,2′-oxirane] ( 12 ) and (1RS,2SR,4RS)-spiro[bicyclo[2.2.2]oct-5-ene-2,2′-oxirane] ( 14 ) were not regioselective under condition of kinetic control. However, good regioselectivity was observed for the addition of 2-nitro-benzenesulfenyl chloride to (1RS,2RS,4RS)-spiro[bicyclo[2.2.1]hept-5-ene-2,2′-oxirane] ( 13 ), giving (1RS,2SR,4SR,5RS,6RS)-6-exo-(2-nitrophenylthio)spiro[bicyclo[2.2.1]heptane-2.2′-oxirane]-5-endo-yl chloride ( 24 ) and for the exo addition to (1RS,2RS.4RS)-spiro[bicyclo[2.2.2]oct05-ene-2,2′-oxirane] ( 15 ), giving preferntially (1RS,2SR,4SR,5RS,6 RS)-6-exo-(2-nitrophenylthio) spiro[bicyxlo[2.2.2]octane-2,2′-oxirane]-5-endo-yl chloride ( 30 ). The facial selectivity (electrophilic exo vs. endo attack on the bucyclic alkene) depended on the relative configuration of the spiroepoxide ring in the bicyclo[2.2.2]octenes 14 and 15 . The exo-epoxide 14 was attacked preferentially (6:1) on the endo face by sulfenyl whereas exo attack was preferred (7:2) in the case of the endo-epoxide 15 . No products resulting from transannular ring expansion of the spiro-epoxide moieties could be detected.     

Synthesis of anti-9-Bromo- and anti-9-Chlorobicyclo[4.2.1]nonatriene via Bicyclo[4.2.1]nonatriene→Bicyclo[4.2.1]nonatriene Rearrangement

The first syntheses of 9-bromo- and 9-chlorobicyclo[4.2.1]nona-2,4,6-trienes were each achieved in three stereoselective steps from the 9,9-bis(selenophenyl) derivative 9 in 79% overall yield for the bromide and 64% for the chloride. A deuterium-labeling experiment reveals the first rearrangement of a bicyclo[4.2.1]nonatriene which leaves the ring system intact.     

Functionalized Cycloheptanes from Bicyclo[4.2.1]nonanes

Several oxidative, reductive and C,C-cleavage reactions were performed starting from the three bicyclo[4.2.1]nona-3,7-diene-2-one derivatives 1, 5 and 18 . The oxidations were selective and led to the diols 2,8 and 9 , and the epoxides 6,9 , and 20 . The reductions were selective only in the case of 20 21 ; otherwise they led to mixtures of the alcohols 10 and 11 , and of the dienes 14 and 15 . The periodate ring cleavages afforded the functionalized cycloheptane derivatives 3, 12, 13 and 16 . Configurational assignments were made on the basis of detailed ¹H-NMR and X-ray analysis of 20 .     

Use of pi-allyltricarbonyliron lactone complexes in the synthesis of taurospongin A: a potent inhibitor of DNA polymerase beta and HIV revers transcriptase

The total synthesis of taurospongin A by two new approaches has been achieved where pi-allyltricarbonyliron lactone complexes have been used to control highly stereoselective additions of the nucleophiles to a carbonyl unit located in the side chain of these complexes.     

Synthesis and some transformations of benzo-substituted 2-bromomethyl-4-methyl-2-chloro-2,3-dihydrofuro[3.2-c]-quinolines

A convenient synthetic procedure for substituted 2-bromomethyl-4-methyl-2-chloro-2,3-dihydrofuro[3.2-c]quinolines hydrobromides was developed, synthons for preparation of new substituted furoquinolines. Reactions with various nucleophiles were performed, and 2-(R’-methyl)-4-methyl-furo[3.2-c]quinolines substituted in the benzene ring were obtained.     

α‐Selective Ring‐Opening Reactions of Bicyclo[1.1.0]butyl Boronic Ester with Nucleophiles

The reaction of bicyclo[1.1.0]butyl pinacol boronic ester (BCB‐Bpin) with nucleophiles has been studied. Unlike BCBs bearing electron‐withdrawing groups, which react with nucleophiles at the β‐position, BCB‐Bpin reacts with a diverse set of heteroatom (O, S, N)‐centred nucleophiles exclusively at the α‐position. Aliphatic alcohols, phenols, carboxylic acids, thiols and sulfonamides were found to be competent nucleophiles, providing ready access to α‐heteroatom‐substituted cyclobutyl boronic esters. In contrast, sterically hindered bis‐sulfonamides and related nucleophiles reacted with BCB‐Bpin at the β′‐position leading to cyclopropanes with high trans‐selectivity. The origin of selectivity is discussed.     

Synthesis of highly functionalized bicyclo[m.n.1]alkanones via a cationic reaction cascade

[reaction: see text] The acid-mediated Prins/pinacol and the triple domino reactions Diels-Alder/Prins/pinacol were used to construct highly functionalized bicyclo[m.n.1]alkanones 19-29 and 33a-c possessing various ring sizes from ketals 8-18 and 31a-c in 44-96% yields. This approach proves to be highly efficient and reliable to generate high molecular complexity in a single step.     

Conformation of bicyclo[n.1.0]-compounds: Part I. Bicyclo[5.1.0] octane and cycloheptene epoxide

MINDO/3 quantum-mechanical calculations indicate that the most stable conformations of cis-bicyclo[5.1.0]octane and cycloheptene epoxide are the chair—chair (CC) and boat—chair (BC) conformations, respectively. The possible pathways of interconversion have been studied and are discussed for each molecule. The geometry of trans-bicyclo[5.1.0]-octane has been calculated and a heat of isomerization of 3.8 kcal mol^?1 has been obtained. Theoretical results are compared with the experimental data available.