Ring tetraenes

A cytotoxic compound, rhizopodin (Fig. 17, 92), is a 19-membered ring mac-rolide whose skeleton contains an oxazole [115]. It is produced by Myxococcus stipitatus. It caused formation of rhizopodia-like structures in animal cells and caused reorganization of the actin cytoskeleton [116]. Chivosazols (chivosazol A, 93) are oxazole-containing macrolides having 31-membered ring tetraene [117], They are produced by S. cellulosum. 

The interest in azacyclooctatetraenes is mainly due to their structural similarity to cycloocta-tetraene.1 3 Most synthetic efforts have concentrated on a comparison of the unusual chemical and physical properties of cyclooctatetraene with its aza analogs. Besides studies concerning the aromaticity, the primary focus of much work has concerned the stability of the eight-membered ring and its valence isomerization. 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

The tetraols were found to be highly sensitive toward acidic and basic conditions. Under Bronsted acidic conditions, the hemiaminals readily eliminated to generate a tetraene, while under basic conditions, the tetraol either decomposed or epimerized to generate a mixture of diastereomers. It is speculated that the base-mediated epimerization proceeds through ring-chain tautomerization involving a putative alpha-keto amide derivative. It is also of note that simple dissolution of tetraol (+)-95 in methanol also leads to its degradation to a complex mixture of products. 

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

The first electrocyclic ring closure involves eight electrons, so it is conrotatory under thermal conditions, and the two hydrogen atoms at the terminus of the tetraene, which are both in, become trans. The second electrocyclic ring closure involves six electrons, so it is disrotatory under thermal conditions, and the two hydrogen atoms at the terminus of the triene, which are both out, become cis. This is the arrangement observed in the natural product. 

Thus, the structure of viridenomycin was established except for the absolute configuration. This antibiotic is partially related to hitachimycin, which is a 19-membered lactam antibiotic possessing a phenyl group and a cyclopentene ring, but devoid of the tetraene systems and ester linkage. 

In connection with the behavior of the eight-membered ring system, it is interesting to mention that the uncatalyzed thermolysis of the open-chain tetraene ether 230 in toluene at 150 °C (11 h) gives rise to a mixture of four intramolecular Diels-Alder products 231-234 in 80% total yield (equation 74)88. The thermolysis of dimethyl homologue 235 (toluene, 150 °C, 11 h, 81%) affords the c/s-fused cyclohexene derivative 236 and... 

Scheme 6.27 considers other, formally confined, conformers of cycloocta-l,3,5,7-tetraene (COT) in complexes with metals. In the following text, M(l,5-COT) and M(l,3-COT) stand for the tube and chair structures, respectively. M(l,5-COT) is favored in neutral (18-electron) complexes with nickel, palladium, cobalt, or rhodium. One-electron reduction transforms these complexes into 19-electron forms, which we can identify as anion-radicals of metallocomplexes. Notably, the anion-radicals of the nickel and palladium complexes retain their M(l,5-COT) geometry in both the 18- and 19-electron forms. When the metal is cobalt or rhodium, transition in the 19-electron form causes quick conversion of M(l,5-COT) into M(l,3-COT) form (Shaw et al. 2004, reference therein). This difference should be connected with the manner of spin-charge distribution. The nickel and palladium complexes are essentially metal-based anion-radicals. In contrast, the SOMO is highly delocalized in the anion-radicals of cobalt and rhodium complexes, with at least half of the orbital residing in the COT ring. For this reason, cyclooctateraene flattens for a while and then acquires the conformation that is more favorable for the spatial structure of the whole complex, namely, M(l,3-COT) (see Schemes 6.1 and 6.27). 

The mechanism of the dehydrogenative transannular ring closure of cycloocta-tetraene in the presence of various inorganic reagents to provide complexes of pentalene has been the subject of debate... 

Photolysis (245 nm) of tetrazolo[l,5-/ ]pyridazine 21 in an argon matrix at 16 K leads to nitrogen extmsion and ring opening to form (2Z)-4-diazobut-2-enenitrile 22. Further photolysis produces predominantly cycloprop-2-ene-1-carbonitrile 23 and small amounts of l,3,7-triazacyclohepta-l,2,4,6-tetraene 24. No formation of triplet pyrid-azine-3-nitrene 25 is observed (Scheme 5) <2003PCP1051>. 

Cyclic ligands Square brackets designate that the ligand is cyclic and the number within the brackets is the number of atoms in the macrocyclic ring. Saturated macrocycles are designated by ane , while, for unsaturated ligands, ene is used preceded by a prefix to identify the number of double bonds (e.g. diene or tetraene). The donor atoms are then identified. Substituents attached to the macrocycle are indicated by either a prefix or suffix. 

The use of ring-closing metathesis for the preparation of unsaturated heterocyles is now established as a routine method for single cyclisation steps, and the method has been extended to the preparation of bicyclic systems in a single step One example is the cyclisation of the tetraene 43 leading to formation of tetrahydrooxepine 44 in 59% yield <99JOC3354>. The method is equally applicable to the formation of five- and six-membered systems. 

In a valence isomerization approach to the 5,6-dihydrodiazocine series, the all-cis-diazabicyclooctadiene (187) was isomerized at 120 °C to the thermodynamically more stable trans- diene (188) (69CB1928). As in the bicyclotriene-tetraene case, ring opening to the diazocine occurs, but is followed by ring flip and recyclization. The monocyclic valence isomer is not detected by NMR. 

Similarly, acetone sensitized irradiation of the epoxy tetraene 13 resulted in ring closure to the caged epoxide M.171... 

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