Cyclooctane derivatives

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. 

Fig. 32 Synthetic route from D-ribose towards cyclooctane derivative.

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. 

In a similar reaction, the reduction of 3,7-dimethyl-l,5-diazabicyclo[3.3.0]-octane-2,6-dione (VIII/127) to the cyclooctane derivative VIII/128 (Scheme VIII/23) was nearly quantitative. 

Because of the excellent performance of the new catalysts, many research groups use ringclosing metathesis as the key step in natural product synthesis [12]-[18]. Scheme 6 shows some examples. Via ring-closing metathesis of the olefin 37 to the hydroazulene 38, Blechert et al. [12] succeeded in synthesizing a cyclic system which is part of many sesquiterpenes. Cyclooctane derivatives, whose synthesis is the main problem in taxol synthesis, can be obtained in good yields (39 40), as demonstrated by Grubbs et al. [ 13]. 

Compound Structure Conformation and positions of substituents ) Dihedral angles Ref. for cyclooctane derivatives (in°)2)... 

In contrast to the parent compound, several cyclooctane derivatives and related compounds have had their structures determined by X-ray diffraction (Table 1). Most of these compounds have boat-chair conformations, but fra s-syM- m s-l,2,5,6-tetrabromocydooctane is a twist chair-chair, and crown conformations are found in octasulfur, the all-cfs tetramer of acetaldehyde, and related compounds. 

The internal angles in all the conformations given in Table 2 are considerably greater than the 111.5° found in cyclohexane. In the crown, chair-chair, twist-chair-chair, boat-chair, and twist-boat-chair, the angles are in the range of 115° to 117°. The experimentally determined internal and dihedral angles for several boat-chair cyclooctane derivatives (Table 1) are very similar to those calculated by Hendrickson and by Bixon and Lifson. 

The nmr spectra of various rather simple cyclooctane derivatives discussed below are only consistent with the boat-chair conformation. Furthermore the structures in the crystalline state are boat-chairs (Table 1), with one exception which can be rationaUzed (see below). The conclusion that cyclooctane exists in solution as the boat-chair therefore appears inescapable. 

Conformational energy barriers have been studied in various cyclooctane derivatives by mechanical relaxation methods. > b The frequency and temperature range of such measurements are very large, but the identities of the processes observed are not as clear as in nmr measurements. With poly(cyclooctyl methacrylate) a process with an activation energy of 10.6 kcal/mole is fovmd, and has been interpreted in terms of a boat-chair... 

In summary, the experimental nmr data presented in this Section stongly support the boat-chair as the lowest energy conformation for simple cyclooctane derivatives. The twist-chair-chair is of next lowest energy and the presence of certain substituents can make this conformation be the dominant one. Boat-boat family conformations are only (if ever) found in very special compounds. 

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. 

Conversion to a cyclooctane derivative. Under catalysis by bis-(triphenylphosphite) -nickel dicarbonyl, allene is converted into a tetramer shown to have the structure 1,3,5,7-tetramethylenecyclooctane. ... 

Annulated cyclooctane derivatives such as 13 have been prepared from Cope substrates of type 12 b38. Rearrangement of alcohol 14 has been used as the key step in the stereoselective synthesis of ( )-pleuromutilinl095. 

It is noteworthy that the ring closures of 1,2-disubstituted cyclohexane, cycloheptane and cyclooctane derivatives revealed no appreciable differences in the reactivities of the cis and trans isomers in the formation of six-membered 1,3-heterocycles [117]. In contrast, striking differences were observed in the cyclizations of the cis and trans cyclopentane derivatives. For instance, the above cyclizations to pyrimidinones, starting from the trans counterparts, were unsuccessful. The attempted ring closure from 104 did not result in the cyclized products, but gave hydrolysed derivatives 105 and 106 [111]. 

It has been reported that, while ring expansion by ionic fragmentation of a bicyclo[3.3.0]octanol could not be achieved, an alkoxyl radical generated from the octanol resulted in a selective P-cleavage of the fused bond to give a functionalized bridged cyclooctane derivative (Scheme 69). 

Saicic, R.N., Synthesis of bridged cyclooctane derivatives via alkoxy radical fragmentation. Tetrahedron Lett., 38, 295,1997. 

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