Fused Bicyclic Derivatives

Extension of the principle of axial-equatorial ring placement to fused bicyclic systems leads to two possible structural representations for a trigonal bipyramidal geometry, namely with either equatorial or axial annelation, which are capable of 

SsNOI NONONO U 0 d lOoiONvd(N JQSOP NONO vCN-hh5v s 0O00O0 

On the basis of the structural information for derivatives (I) — (VI) it is possible to recognise the following stereochemical trends in fused bicyclic derivatives  

The deviation from axial linearity increases on going from fused five/six- to five/five- to five/four-membered bicyclic systems, in accordance with increasing ring strain. The fused diazadiphosphetidines (5/4) (IV) and (V) assume an intermediate position between 5/5 and simple 5/4 bicyclic systems, which is to be expected on account of the lesser degree of strain in the centrosymmetric [PN]2 ring. 

The increase in the deviation on going from (II) to (I) is also predictable, because of the planar bicyclic system and shorter axial bond in the five-membered ring which lead to an increased ring strain in the latter derivative. 

---

The indirect cyclisation of bromoacetals via cobaloxime(I) complexes was first reported in 1985 [67], At that time the reactions were conducted in a divided cell in the presence of a base (40yo aqeous NaOH) and about 50% of chloropyridine cobaloximeflll) as catalyst precursor. It was recently found that the amount of catalyst can be reduced to 5% (turnover of ca. 50) and that the base is no longer necessary when the reactions are conducted in an undivided cell in the presence of a zinc anode [68, 69]. The method has now been applied with cobaloxime or Co[C2(DOXDOH)p ] to a variety of ethylenic and acetylenic compounds to prepare fused bicyclic derivatives (Table 7, entry 1). The cyclic product can be either saturated or unsaturated depending on the amount of catalyst used, the cathode potential, and the presence of a hydrogen donor, e.g., RSH (Table 7, entry 2). The electrochemical method was found with some model reactions to be more selective and more efficient than the chemical route using Zn as reductant [70]. 

Table 2.6.1. Bond lengths and angles in fused bicyclic derivatives of pentacoordinate phosphorus (Fig. 2.6.1.)... 

The trigonal bipyramid is the preferred configuration for acyclic, monocyclic and fused bicyclic derivatives. It has demonstrated itself as capable of very considerable distortion to allow for the accomodation of strained small ring systems. 

An extremely interesting example of electrocyclic thiophene formation is the intramolecular closure of a tropolone to form a thieno-fused bicyclic derivative this compound may be induced to undergo photochemical isomerization to produce a novel thienopyridine derivative (Scheme 6)... 

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). 

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>. 

The hydrolysis product 51 can alternatively be accessed directly from the reaction of the thiol derivative 48 with chloro acetamide. Other electrophiles for the reaction with the thiol derivative were also described which lead to functionalized tetrazole or 5-6 fused bicyclic ring systems. 

Tributyl tin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives led to highly functionalized cA-fused bicyclic ethers. The product could subsequently be transformed into optically active tricyclic nucleoside analogue or oxepine derivative (Fig. 51).67... 

The intermediate 452 resulting from the direct reaction of PPh3 with an allenyl ketone can also serve as an all-carbon 1,3-dipole to undergo [8 + 2]-annelation with tropone to yield fused bicyclic tetrahydrofuran derivatives 455 [203]. 

Upon oxidation, a cyclization reaction using a 4-methoxyphenyl ring-derived substrate did not form any of the fused bicyclic product. Instead, a spirocyclic product was formed in direct analogy to the chemistry of Yamamura and Swenton (Scheme 37). In general, cyclization reactions having... 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

The continuing interest in the chemistry of the 1,3-oxazines and the related thiazines and pyrimidines may arise in part from their versatile synthetic applicability and their pharmacological usefulness. Although six-membered saturated or partially saturated 1,3-heterocycles and their derivatives fused with a benzene ring have been thoroughly studied since the beginning of the twentieth century, much less attention has been paid to their saturated counterparts, the related cycloalkane-fused bicyclic 1,3-heterocycles. 

A base-promoted reaction between L-threitol and tetraethylene glycol di-tosylate afforded (165) the chiral bis(15-ctown-5) derivative l-146 as well as the trans-fused bicyclic system l-147 containing 15-crown-5 and 17-crown-5 rings. These constitutional isomers, which were separated chromatographically, were characterized by preparing l-147 unequivocally by a stepwise route from 2,3-O-isopropylidene-L-threitol. 

With respect to five-membered lactones fused to hexopyranose units, some approaches have been reported so far and the exploitation of their synthetic potential has led to the access of new carbohydrate derivatives. Bicyclic derivatives of this type are key intermediates in the synthesis of the epimer at C-3 of the sugar moiety contained in miharamycins [212, 213]. The latter are antibiotics known to inhibit strongly Pyricularia oryzae, which produces the rice blast disease. These compounds are also considered to be a potential bioterrorism agent (Scheme 42). Hence, the 3,3-spiroepoxide 176 was converted into the 3-C-cyanomethyl derivative 177, the hydrolysis of which led to spontaneous cyclization in the presence of... 

However, thermolysis of the same compound 31 at 60 °C under oxygen gave, in addition to the major products 34 (68%), a small amount (7%) of the fused bicyclic 8-membered endoperoxide 35, which derives from mesomeric diradical 36 . 

The palladium-phosphine-catalyzed cycloaddition reactions of vinyloxetanes 530 with aryl isocyanates or diaryl-carbodiimides led to 4-vinyl-l,3-oxazin-2-ones 531 or l,3-oxazin-2-imines 532, respectively (Scheme 101). In the absence of phosphine ligands (PPhs, bis(diphenylphosphino)ethane (DPPE), l,3-bis(diphenylphosphino)propane (dppp), no conversion of heterocumulenes was observed. Starting from fused-bicyclic vinyloxetanes, both types of cycloadditions proceeded in a highly stereoselective fashion, affording only the r-isomers of alicycle-condensed 1,3-oxazine derivatives <1999JOC4152>. 

---