Cyclooctanone synthesis

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

Pyrroles 36 with n = 4, 8 have been isolated and characterized (Table XIX). These include4,5,6,7,8,9-hexahydro-l//-cycloocta >]pyrrole (yield 60%, optimal synthesis time about 3 hr), which shows a reduced stability as compared with other pyrroles of this series (n = 2,3,8). Nevertheless, the reason for the unsuccessful attempt to synthesize this compound from cyclooctanone oxime and acetylene [87JCS(P 1)2829] is not very clear. 

Indeed, cyclobutanones constitute challenging synthetic intermediates for a whole host of applications including cyclopentanone, cyclohexanone and cyclooctanone formation, olefin and diene synthesis, geminal alkylation, reductive acylation, among others,... (vide infra). 

The methyl ester of 3,7-dimethyl-8-hydroxyoctanoic acid have been prepared in good yields and with ee >98% by deprotonation of the starting trimethyl cyclooctanone 57, R = Me using (R,R) 3 and LiCl at — 78 °C (Scheme 37)77. This reaction is a key step in a versatile synthesis of optically active isoprenoid, which is present as a sub-unit in vitamins, plant metabolites, antibiotics and other naturally occurring compounds. 

A convenient regiospecific synthesis of a new conjugated tetrazole derivative 266 was reported via reaction of dienone 265 with the tetrachlorosilane and sodium azide (Equation 32) <2003M1241>. Similar transformation, started form cyclooctanone and A1C13, instead of tetrachlorosilane, afforded unsubstituted tetrazolo azonine in 75% yield <2005SC1115>. 

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. 

It is noteworthy that at the difference of what we met for arynic reactions, alcohols with a strained ring are isolated with cyclooctanone and with aliphatic ketones. Since the obtaining of these alcohols by us for the first time, a synthesis by photolysis of cyclenones has been published102. However, this last method seems, for the present time, much less general and above all much less stereoselective. 

The same year, Gerlach described a synthesis of optically active 1 from (/ )- ,3-butanediol (7) (Scheme 1.2). The diastereomeric esters produced from (-) camphorsulfonyl chloride and racemic 1,3-butanediol were fractionally recrystallized and then hydrolized to afford enantiomerically pure 7. Tosylation of the primary alcohol, displacement with sodium iodide, and conversion to the phosphonium salt 8 proceeded in 58% yield. Methyl-8-oxo-octanoate (10), the ozonolysis product of the enol ether of cyclooctanone (9), was subjected to Wittig condensation with the dilithio anion of 8 to give 11 as a mixture of olefin isomers in 32% yield. The ratio, initially 68 32 (E-.Z), was easily enriched further to 83 17 (E Z) by photolysis in the presence of diphenyl disulfide. The synthesis was then completed by hydrolysis of the ester to the seco acid, conversion to the 2-thiopyridyl ester, and silver-mediated ring closure to afford 1 (70%). Gerlach s synthesis, while producing the optically active natural product, still did not address the problem posed by the olefin geometry. 

The synthesis of lactames has interest for the production of chemicals and fine chemicals. In the case of more bulky lactames derived from cyclodedecanone-oxime and cyclooctanone-oxime, they are used for producing nylon-12 and for the preparation of the precursor of azacycloalkanediphosphonic derivates which have pharmaceutical interest for the treatment of Ca metabolism disorders, respectively. 

Synthesis of the lactames of cyclooctanone and cyclododecanone oxime at 430 C and 90 minutes reaction time on various catalyst with a Si/Al ratio of 50. 

Suggest a synthesis that converts (hydroxymethyl)cyclooctane to cyclooctanone. 

Scheme 19 Synthesis of cycloheptanones and cyclooctanones 63 via ring expansions...

---