Bicydes

The first mass spectrometric investigation of the thiazole ring was done by Clarke et al. (271). Shortly after, Cooks et al., in a study devoted to bicydic aromatic systems, demonstrated the influence of the benzo ring in benzothiazole (272). Since this time, many studies have been devoted to the influence of various types of substitution upon fragmentation schemes and rearrangements, in the case of alkylthiazoles by Buttery (273) arylthiazoles by Aune et al. (276), Rix et al. (277), Khnulnitskii et al. (278) functional derivatives by Salmona el al. (279) and Entenmann (280) and thiazoles isotopically labeled with deuterium and C by Bojesen et al. (113). More recently, Witzhum et al. have detected the presence of simple derivatives of thiazole in food aromas by mass spectrometry (281). 

It was found, during a study of synthetic routes leading to quinine analogues, that oxidation of a specific bicydic pyrazoline derivative with mercuric acetate gives an enamine-like pyrazole (87b). 

Syntlietic cliemists can now work witli tlitee-dlmensional pictures of tlie conjugate addition available on a website [80]. In tlie absence of steric hindrance i5-nietliylcydobexenone, for example), an "axial attack" tlitougb a balf-diait conformation is favored, while in tlie corLisone syntliesis an "equatorial attack" tliroLigli a half-boat conformation is favored because of tlie constraint imposed by tlie bicydic tings [83]. 

The most widely applicable method for the synthesis of 1-substituted J//-l,2-diazepines 8 is photoisomerization of pyridinium 1-imides 6. The reaction is presumed to proceed by way of the bicydic intermediates 7, which, however, have not been detected (see Houben-Weyl, Vol. 4/ 5a, p584ff) selected examples are given.75-77... 

The aza-[2,3]-Wittig rearrangement of a vinylaziridine-derived quaternary azir-idinium ylide (i.e., [2,3]-Stevens rearrangement) has recently been reported (Scheme 2.53) [86], The aziridinium ylide 219, generated by the intramolecular reaction of a copper carbenoid tethered to a vinylaziridine, underwent a [2,3]-Ste-vens rearrangement to furnish the bicydic amine 220 with the indolizidine skeleton. 

Hodgson et al. showed that a series of bis- and tris-homoallylic terminal epoxides underwent intramolecular cydopropanation to give a range of bicydic alcohols. A short asymmetric synthesis of sabina ketone based on this chemistry was demonstrated (Scheme 5.20). A practical advantage with this process is that the volatile epoxides can be replaced with readily available chlorohydrins, an extra... 

Although the enantioselective intermolecular addition of aliphatic alcohols to meso-epoxides with (salen)metal systems has not been reported, intramolecular asymmetric ring-opening of meso-epoxy alcohols has been demonstrated. By use of monomeric cobalt acetate catalyst 8, several complex cyclic and bicydic products can be accessed in highly enantioenriched form from the readily available meso-epoxy alcohols (Scheme 7.17) [32]. 

Scheme 8.5 Synthesis of the bicydic acetal core of zaragozic acid C.

Recently, 2,6-dioxabicyclo[2.2.1 Jheptane 33 and 2,7-dioxabicyclo[2.2.1 Jheptane 34 were synthesized, and their rates of acidic solvolysis were compared293. Table 1 summarizes the data, along with those for relevant bicydic acetals determined in a similar manner. Tremendous differences in reactivity among these compounds are noteworthy. The approximate relative reactivities under these conditions spun more than five powers of ten. These differences are attributable to ring strain and anomeric... 

Okada, Ma Ring-Opening Polymerization of Bicydic and Spiro Compounds. Reactivities and Polymerization Mechanisms. Vol. 102, pp. 1-46. 

An elimination/double Wagner-Meerwein rearrangement process has recently been developed by Langer and coworkers [39]. Treatment of compound 1-136, obtained by reaction of 1-134 and 1-135, with trifluoroacetic acid (TFA) led to the cationic species 1-137, which then underwent a twofold Wagner-Meerwein rearrangement to give the bicydic compound 1-139 via 1-138 (Scheme 1.34). 

Utilizing the same aryl fluoride linker on conventional MeOPEG polymer, these authors also presented a microwave-accelerated liquid-phase synthesis of benzimidazoles (Scheme 7.70) [79]. This bicydic pharmacophore is an important and valuable structural element in medicinal chemistry, showing a broad spectrum of pharmacological activities, such as antihistaminic, antiparasitic, and antiviral effects. 

Table 5. The B3LYP/6-31 G(d) Energies of Bicydic Compounds 3a and 3g-h, and of the Transition Structures for their Formation Relative to Carbenes 1 a and...

In contrast to the extensive studies on phosphine-phosphites, the corresponding phosphine-phosphinites are rarely exploited. Laschat introduced this design with a bicydic chiral skeleton derived from (lS)-(+)-camphorsulfonic acid [127]. The Rh-complex based on dimesitylphosphinite 154b was found to be the most reactive catalyst, and was used to produce methyl N-2-acetamidodnnamate, with 89% ee. 

Stoichiometric bicydization of enynes, diynes, and dienes by cyclic carbozirconation... 

Closely related to both allyl carbenoids and the allenyl carbenoids discussed above, propargyl carbenoids 101 are readily generated in situ and insert into zirconacycles to afford species 102 (Scheme 3.27), which are closely related to species 84 derived from allenyl carbenoids [65], Protonation affords a mixture of allene and alkyne products, but the Lewis acid assisted addition of aldehydes is regioselective and affords the homopropargylic alcohol products 103 in high yield. Bicydic zirconacyclopentenes react similarly, but there is little diastereocontrol from the ring junction to the newly formed stereocenters. The r 3-propargyl complexes derived from saturated zirconacycles are inert towards aldehyde addition. 

For application in organic synthesis, the regiochemistry of insertion of carbenoids into un-symmetrical zirconacydes needs to be predictable. In the case of insertion into mono- and bicydic zirconacydopentenes where there is an wide variety of metal carbenoids insert selectively into the zirconium—alkyl bond [48,59,86], For more complex systems, the regiocon-trol has only been studied for the insertion of lithium chloroallylides (as in Section 3.3.2) [60]. Representative examples of regiocontrol relating to the insertion of lithium chloroal-lylide are shown in Fig. 3.2. 

Treatment of a stannylenyne/enene compound with a low-valent zirconocene derivative results in a bicydization reaction leading to the 1,1-stanniozirconocene complex 99 (Scheme 7.29) in moderate yield [168], The product of carbonylation of 99 can be readily... 

Application of the above method to chiral 2-en-7-ynoates derived from optically active 8-phenylmenthol led to asymmetric ring-closure to give bicydic ketones bearing an angular substituent, with high ee values, as shown in Eq. 9.64, s.p. 349 [112]. 

This is the most convenient way to prepare quinuclidone hydrochloride. The second step illustrates the conversion of an N-alkyl-pyridinium salt to an N-alkylpiperidine. The third step illustrates the formation of a bicydic system by the Dieckmann condensation. 

Scheme 42 Enantioselective cyclization in tandem processes leading to bicydic systems...

Considerable attention has been devoted to the preparation and chemistry of a,/3-unsaturated carbonyl compounds, which are valuable intermediates in organic synthesis [125]. Acid-promoted hydrolysis of alkoxyallenes has therefore frequently been employed to prepare a variety of functionalized a,/8-unsaturated carbonyl compounds [12b, 41, 44, 60, 126]. A recent example is illustrated in Scheme 8.54with C-l-silylated alkoxyallene 218 as a convenient starting material for the synthesis of bicyclo[5.4.0]undec-4-en-2-one 221. Sequential deprotonation and silylation at the terminal C=C bond efficiently transformed 218 into a 1,3-disilylated allene which was converted into the acryloylsilane 219 under acidic conditions. A [3 + 4] annula-tion of intermediate 219 with lithium dienolate 220 furnished bicydic compound 221 in good yield [127]. 

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