Cyclooctanes fused

Synthesis, Stereochemistry and Transformations of Cyclopentane-, Cyclohexane-, Cycloheptane-, and Cyclooctane-Fused 1,3-Oxazines, 1,3-Thiazines, and Pyrimidines... 

The final chapter in Volume 69 is concerned with the synthesis, stereochemistry, and transformation of cyclopentane-, cyclohexane-, cyclohep-tane-, and cyclooctane-fused 1,3-oxazines, 1,3-thiazines, and pyrimidines and is authored by Professors Ferenc Ftilop, Gabor Bernath, and Kalevi Pihlaja from the Universities of Szeged in Hungary and Turku in Finland. This is a field which has shown rapid development over the last dozen years because of the increased availability of spectroscopic and other analytical methods allowing definition of the precise steric chemistry of these compounds. 

The alicyclic analogs 4 with hydrogen bromide in diethyl ether at room temperature behave similarly to yield the 4,5-fused 7-bromo-3/7-azepin-2-amines 5 as their hydrobromide salts. Yields are high except for the cyclooctane derivative (n = 4). Once again, the free bases are liberated by treatment with sodium hydrogen carbonate. 

An illustrative example of the potency of the second-generation Ru catalyst C is found in Paquette s highly efficient total synthesis of the natural products teubrevin G (122) and teubrevin H (123), which feature a cyclooctane core fused and spiroannulated to smaller oxygen-containing rings [76]. In the retrosyn-thetic analysis, the viability of an RCM step for annulation of a cyclooctenone ring to the furan played a central role. 

Intramolecular cycloadditions of a,p-unsaturated lactones to alkenes have been used as key step in the synthesis of a precursor of the terpene reserpine 480) (4.68) and of fused cyclooctanes (4.69) 481 ... 

A seven-membered ring is formed in the cyclization of 195 (equation 95)105. The homologue 196 affords the fused cyclooctane 197, together with the cis- and trans-decalinones 198 (equation 96)106. Six-, seven- and eight-membered rings are produced in Lewis acid-catalysed reactions of various cyclohexenones with side-chains terminating in allylic trimethylsilyl groups (equations 97 - 99)107. 

In the ring closures of the 1,2-disubstituted 1,3-difunctional cyclohexane, cycloheptane, and cyclooctane derivatives discussed in Sections II,A,B, and C, no appreciable differences were found in the reactivities of the cis and trans isomers. In contrast, very significant differences were observed in the cyclization reactivities of the cis and trans 1,2-disubstituted 1,3-difunctional cyclopentane derivatives, such as 1,3-amino alcohols, 2-hydroxy-l-carboxamides or /S-amino acids. Whereas the cis isomers reacted readily, their trans counterparts did not undergo ring closure in most cases. This difference was manifested in the formation of both d - and e -fused derivatives. 

Side reactions that occur with intramolecular cycloaddition, such as linear oligomerization or dimerization of the nitrile oxide, are not very common when shorter chain lengths n < 1) are used due to the entropically favored intramolecular process. A rather unusual result in this regard involves the formation of a fused cyclooctane instead of the less-strained six-membered ring (also fused) in the cycloaddition of the nitrile oxide derived from p-naphthoquinone (Scheme 6.43). This result is consistent with the effect of electron-withdrawal in the enedione part, leading to increased reactivity (247), and also reflects the known sluggishness of cyclohexenes towards nitrile oxides (cf. Section 6.2.1.2). 

Intramolecular addition to conjugated dienones is particularly useful because it permits entry to fused cyclooctane or cyclohexane rings (Sakurai product).3 Example ... 

Photoinduced ring cleavage also occurs readily in heterocyclic systems containing both oxygen and nitrogen. A series of dihydro-oxadiazinones, for example, undergo decomposition, and the results obtained parallel those observed on thermal decomposition cis- and Jraras-stilbene are obtained from the diphenyl derivative (71), whereas cis-cyclooctene is the major product of photolysis of the fused cyclooctane (72).62... 

Fullerene, Cgo, undergoes photochemical 2 + 2-cycloaddition with /V,A-diethyl-4-methylpent-3-en-l-yn-l-amine to produce the stable Cgo-fused cyclobutenamine that is photo-oxidized to the dihydrofullerenone amide in high yield.15 The photochemical 2 + 2-cycloaddition of arylalkenes with Cgo has been shown to occur by a two-step mechanism involving the formation of a dipolar or diradical intermediate in the rate-determining step.16 The 2 + 2-photo-cycloaddition of cis- and irons-1 -(/j-methoxyphen-yl)-l-propene to C6o produces only trans-2 + 2-adduct. This is consistent with a two-step mechanism.17 The 2 + 2-photo-cycloaddition of cyclic 1,3-diones to Cgo results in the formation of two furanylfullerenes, one chiral and the other achiral. None of the expected De Mayo cyclooctane-1,3-dione addition products were formed.18... 

A crown-family conformation also cannot explain the nmr spectrum of the acetonide of five-membered ring fused to the cyclooctane ring. 46) A temperature-independent spectrum would be predicted, because a im s-fused five-membered ring can only be located at equatorial positions in crown-family conformations, and ring inversion is therefore prohibited. The nmr spectrum of this compound is actually strongly temperature-dependent at about — 70°C, thus excluding any conformation in the crown family, at least as the sole conformation. 

In the boat-chair, both set A and set B have positions where a trans-fused five-membered ring can be located, and thus ring inversion is possible, and a temperature-dependent spectrum is allowed, in agreement with experiment. The ring inversion barrier is somewhat higher than in cyclooctane, but this could be due to the restraint caused by the five-membered ring. An explanation based on a mixture of twist-chair-chair and boat-chcdr conformations is also possible, but appears less likely. 

Another common strategy for construction of fused cyclooctanones is to first build a fused cyclobutanone by [2 + 2] cycloaddition of a vinylketene to a cycloalkene. Equation (58) illustrates this approach with Paquette s synthesis of the tricyclic skeleton of the ophiobolins. Cyclobutanone (108) is assembled by addition of a vinylketene to cyclopentadiene. Cyclopentenyllithium then adds to the less-hindered face of (108), and the lithium alkoxide undergoes a spontaneous anionic oxy-Cope rearrangement to afford the central cyclooctane ring. 

Finally, a recent study by Majetich and Hull has demonstrated the feasibility of the carbanion-accel-erated divinylcyclobutane rearrangement. Whereas the thermal rearrangement of the divinylcyclobu-tane (273 Scheme 38) required extended heating at 180 C and proceeded in modest yield, the corresponding enolate was shown to rearrange smoothly at -35 C in 90% yield. As illustrated in Scheme 39, the enolate-accelerated DVCB rearrangement can be employed in tandem with the intramolecular fluoride-promoted Michael addition of allylsilanes to provide an attractive route to a variety of fused bi-cyclic cyclooctane derivatives. 

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