Fused bicyclic

Dihydroxyfurazan reacts with bis-electrophiles in the presence of a base and a phase transfer catalyst to form furazano fused bicyclic or polycyclic systems (Scheme 174) (92URP1715808, 92URP1715809, 92URP1752734, 97MI8). 

The relative stereochemistry of hyperaspine (1) was determined by 2D NMR and MS methods. It has a m-fused bicyclic conformation 82 (01TL4621). The tram-fused one is disfavored by an axial pentyl group at C(8) and by a destabilising dipole-dipole interaction between the N and O atoms, which does not exist in the alternative cis conformation. 

A single stereoisomer of 4-methyl-3-phenylperhydropyrido[2,l-c][l,4]oxa-zine 279, containing a phenyl)hydroxy-methyljpiperidine 280. 

Double Michael addiQoas of rutro compounds beanng tethered acidic carbons to 3-butyn-3-one under NaH catalysis give nitrocyclohexanes v/ith high stereoselectivity The products are transformed into rrruii -fused bicyclic compounds via the Dickmarm reaction on treatment with base fEq 4 139 ... 

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

A careful assessment of the constitution of compound 10 led to the development of a rather efficient strategy featuring the Diels-Alder reaction (see Scheme 3). Although the unassisted intermole-cular reaction between 3-hydroxy-2-pyrone (16)23 and a,/ -unsatu-rated ester 17 is unacceptable in terms of both regioselectivity and chemical yield, compounds 16 and 17 combine smoothly in refluxing benzene and in the presence of phenylboronic acid to give fused bicyclic lactone 12 (61% yield) after workup with 2,2-... 

Intramolecular allylzinc aldehyde additions lead, in one synthetic step, to bicyelic a-methylene-y-lactones41. Interestingly, the (Z)-isomer gave only the r/5-fused bicyclic products, which arises from a. vyw-selectivc addition, while the ( >isomeric bromide furnished a cisjtrans mixture (yield 56%, cisjtrans 72 28)41 indicating that the double-bond torsion and the intramolecular carbonyl addition have similar rates. A similar sequence was the key step in a confertin synthesis28. 

From ethyl 2-bromomethyl-8-oxo-2-octenoate, a d.v-fused bicyclic a-methylene-y-butyrolac-tone 7 is obtained in one synthetic step16. 

Analogous to the allylsilane cyclizations, alkynylsilanes can also be used to synthesize 1,2-fused bicyclic compounds. The intramolecular addition of 4-[5-(trimethylsilyl)-3-pentynyl]-2-cyclo-hexenone proceeded smoothly in the presence of various Lewis acids, yielding functionalized cw-fused octahydro-5/f-inden-5-ones containing the synthetically useful terminal allene unit45. 

Shao reported the microwave-assisted hetero-Diels-Alder cycloaddition reaction of a series of acetylenic pyrimidines to introduce a fused lactone/lactam ring, with no degradation of either reactants or products typical for the harsh thermal conditions (150-190°C, 15-144h) [131]. In contrast to the results reported when conventional heating was applied, the Diels-Alder cycloaddition under microwave irradiation gave a high yield of the desired fused lactones or lactams [132]. This reaction provided a practical and general method for the preparation of fused bicyclic pyridines 205 (Scheme 74). 

This suite of BVMOs is available via whole-cell expression systems and represents a complementary platform of biocatalysts for diverse applications in chiral synthesis. Representatives of this collection were utilized in the enantiodivergent synthesis of the indole alkaloids alloyohimbane and antirhine from a fused bicyclic precursor (Scheme 9.19) [151]. 

Fused bicyclic systems are those in which two rings share two and only two atoms. In such systems there is no new principle. The fusion may be cis or trans, as illustrated by cis- and /ran -decalin. However, when the rings are small enough, the trans configuration is impossible and the junction must be cis. The smallest trans junction that has been prepared when one ring is four-membered is a four-five... 

Simple Example Lewis acids, such as AlCl, catalyse the Diels-Alder reaction. Workers used a three-fold excess of butadiene to react with the AlCl complex of 5,6 and 7-membered cyclic enones, e.g, (5), giving excellent yields of eie fused bicyclic ketones (6), Me and H must be cis in (6) as they were aiv in (5). 

In addition, Pfizer has identified a number of related, fused bicyclic pyrazole analogues [286-292]. These compounds, of which structures (419 25) are specified examples, are claimed to be of use in the treatment of a number of diseases including alcoholism, psychosis, tobacco abuse, Parkinson s disease and obesity. 

Similarly, the cyclobutane-fused bicyclic peroxide 19 was prepared by diimide reduction of the corresponding bicyclic endoperoxide derived from 1,3,5-cyclooctatriene (Eq. 14)31a). 

The domino process can be catalyzed by a Cu-complex with (S.S)-tBu-bis(oxazo-line) to give 2-616 with excellent enantioselectivity (97-98% ee) [320b,c]. The use of 5 A molecular sieves turned out to be obligatory. Wada and coworkers also reported on a related transetherification/l,3-dipolar cycloaddition procedure to give access to trans-fused bicyclic y-lactones [321]. 

Grubbs and coworkers [238] used the ROM/RCM to prepare novel oxa- and aza-heterocyclic compounds, using their catalyst 6/3-15 (Scheme 6/3.9 see also Table 6/3.1). As an example, 6/3-35 gave 6/3-36, by which the more reactive terminal alkene moiety reacts first and the resulting alkylidene opens the five-membered ring. In a similar reaction, namely a domino enyne process, fused bicyclic ring systems were formed. In this case the catalyst also reacts preferentially with the terminal alkene moiety. 

A double RCM reaction of 367 permitted the efficient construction of the fused bicyclic quinolizidine skeleton 368 as the major product, together with a small amount of the other possible double-metathesis product 369 (Scheme 84) <20020L639, 2004CEJ3286>. Similarly, an RCEYM process from substrate 370, carried out in an atmosphere of ethylene, afforded the quinolizine derivative 371 <2004JOC6305>. 

The relative stereochemistry of hyperaspine 93 was determined by 2-D NMR spectroscopic and mass spectrometry (MS) methods. It has a m-fused bicyclic conformation 93a <2001TL4621>. The trans-fused one is disfavored by an axial pentyl group at C-8 and by a destabilizing dipole-dipole interaction between the N- and O-atoms, which does not exist in the alternative //.(-conformation. The geminal coupling constant of C( 1 )H2 in 93 (11.0 Hz), and that of its 6-hydroxy derivative (11.2 Hz), indicates that they exist preferentially in / //-conformations, whereas their 6-epimers adopt trans-conformations (9.3 and 8.4 Hz, respectively) <2005EJ01378>. Nuclear Overhauser enhancement spectroscopy (NOESY) studies also confirmed the stereochemistry of 93 by the marked nuclear Overhauser effect (NOE) correlation between H-3 and H-4a <20030L5063>. 

Thiopyrylium ions have been shown to behave as effective dienophiles. Shimizu and co-workers demonstrated that 2-benzothiopyrylium salts undergo [4+2+]-type cationic polar cycloadditions with various 1,3-dienes yield benzo-fused bicyclic sulfonium salts <1994J(P1)3129> (see Section 8.32.2.1.2 of CHEC-II(1996)). However, in this study the authors observed that cycloaddition of 2-benzothiopyrylium salt 40 with 2,3-dimethylbuta-l,3-diene 41a with prolonged reaction times caused a decrease in yield of the cycloadduct 22a (see entries 1 and 2 in Table 5 and Equation 10). In fact, stirring of the reaction mixture for 30 h did not afford the cycloadduct at all, see entry 3, but gave an undetermined complex mixture. 

Benzothiopyrylium salts have also been shown to undergo [4+2+]-polar cycloadditions with 1,3-dienes in dry 1,2-dichloroethane at room temperature <1996J(P1)2227>. Treatment of 43 with 2,3-dimethylbuta-l,3-diene 41a afforded benzo-fused bicyclic sulfonium salts 22, as shown in Equation (12) and Table 6. The 4-cyano-substituted benzothiopyrylium salt 43d proved to be the most reactive of these substrates (see entry 4). 

A well-known characteristic of medium-sized rings (8- to 11-membered) is their ability to undergo facile transannular reactions. Cere et al. found that acid-catalyzed transannular cyclizations of 8-10-membered 7,5-unsaturated cyclic sulfides yield fused bicyclic sulfonium salts independently of the geometry of the double bond <1998J(P2)977>. 

Fusion of a barbituric acid motif and a pyrone ring afforded compounds containing a novel pyranopyrimidine core (L) that were discovered as GPR109A agonists [92,93]. This core appears to be distinct from other fused bicyclic cores such as xanthine and anthranilide based on their poor overlap. Furthermore, several compounds, exemplified by 39 and 40, provided remarkable potency in the cAMP assay. The critical acidic functional group is present as the N-PI of barbituric acid motif which has a calculated pKa of 8 [82]. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

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