(+)-Aromadendrene as chiral starting material for the synthesis of sesquiterpenes

One of the distillation tails of the oil of Eucalyptus globulus, which is commercially available, contains about 55-70% of (+)-aromadendrene ( 2 ), together with 10-15% of alloaromadendrene ( 3 ). In this thesis has been described how (+)-aromadendrene from Eucalyptus oil can be used as a chiral starting material for the synthesis of sesquiterpenes.

Two methods have been described to purify the crude distillation tail in order to obtain pure derivatives of 2 (and 3 ). In the first method, described in chapter 3, the crude distillation tail was ozonolyzed to give the crystallizable (+)-apoaromadendrone ( 222 ) (Scheme 9.1). In the second method, described in chapter 7, treatment of the crude distillation tail with potassium on aluminum oxide (K/Al ₂ O ₃ ) gave a quantitative conversion of 2 and 3 into isoledene ( 224 ). Oxidative cleavage of the central double bond in 224 produced bicyclogermacrane-1,8-dione ( 304 ).

Both derivatives 222 and 304 were used as starting materials for the synthesis of compounds with carbon skeletons from several classes of sesquiterpenes. Selective, acid-catalyzed cleavage of the C3-C4 bond of the cyclopropane ring in 222 (and 223 ) gave (-)-isoapoaromadendrone ( 253 ) in high yield (chapter 3, scheme 9.2). Ozonolysis of 253 afforded the keto alcohol 262 which is a suitable chiral intermediate for the syntheses of guaianes. This was demonstrated in the synthesis of (-)-kessane ( 264 ), which proceeded in a 9 steps reaction sequence in an overall yield of 43% from 262 (chapter 4).

The synthesis of the mono- and dihydroxy aromadendranes 4-7 , 31 , 40 , 41 , 227 , 276 , and 277 from 222 has been described in chapter 5. The cis -fused alloaromadendrone ( 223 ), the key intermediate for the synthesis of (-)-ledol ( 6 ) and (+)-viridiflorol ( 7 ), was obtained from the trans -fused apoaromadendrone ( 222 ) via a selective protonation of the thermodynamic enol trimethylsilylether 278 (Scheme 9.3). Hydroxylation of the tertiary C11 of 222 with RuO ₄ gave 226 , which could be transformed into (+)-spathulenol ( 31 ), (-)-allospathulenol ( 276 ), and the aromadendrane-diols 40 , 41 , 227 , and 277. Compounds 4-7 , 31 , 40 , 41 , 227 , 276 , and 277 were tested for antifungal properties, but their activity was only moderate.

A stereoselective epoxidation of the thermodynamic enol trimethylsilylether 278 gave the hydroazulene α-ketol 289 (chapter 6, scheme 9.4). Starting from this α-ketol, two different routes to hydronaphthalene compounds with a maaliane skeleton were developed, both in high overall yield. The first route via α-ketol 290 led to cis -fused maaliane ketone 293 ; the second one offered access to the trans -fused maaliane compound 299 . From 299 the naturally occurring (+)-maaliol ( 288 ) was synthesized.

Synthon 304 , obtained via the second purification method of the crude distillation tail (vide supra ), was used as starting material of compounds with a humulane or cadinane skeleton (chapter 7). The α-keto-cyclopropane compound 304 was found to be thermolabile. Thermal rearrangement of 304 gave via a homo [1,5] hydrogen shift at relatively low temperature (refluxing dioxane) the humulane compound 311 and at higher temperatures (Flash Vacuum Pyrolysis, 500°C and up) the products 313 and 314 , both with a cadinane skeleton (Scheme 9.5). Epimerization of 311 gave the naturally occurring humulenedione ( 306 ). Starting from 313 , the naturally occurring (-)-cubenol ( 310 ) was synthesized in a 4 steps reaction sequence.

The results described in this thesis are shortly summarized in scheme 9.6. With (+)-aromadendrene ( 2 ) from Eucalyptus oil as starting material, compounds have been synthesized with sesquiterpene skeletons belonging to the classes of the guaianes, the aromadendranes, the maalianes, the bicyclogermacranes, the humulanes, and the cadinanes. (-)-Kessane ( 264 ) (chapter 4), several mono- and dihydroxy aromadendranes (chapter 5 and 6), (+)-maaliol ( 288 ) (chapter 6), humulenedione ( 306 ) (chapter 7), and (-)-cubenol ( 310 ) (chapter 7) are naturally occurring sesquiterpenes which have been synthesized from 2 . On the basis of these results it can be concluded that (+)-aromadendrene from Eucalyptus oil is a versatile chiral starting material for the synthesis of sesquiterpenes.