S-(+)-Carvone as starting material in the enantioselective synthesis of natural products

In this thesis the applicability of S-(+)-carvone as chiral starting material in the synthesis of biologically active compounds is examined. S-(+)-carvone is the major compound of caraway essential oil. The essential oil content of caraway seed may vary from 2-7% and it contains about 50-60% of S-(+)-carvoneS-(+)-carvone exhibits a number of interesting biological activities, eg., antifungal, insecticidal and plant growth regulatory activities. Especially the inhibiting effect of S-(+)-carvone on the sprouting of potatoes attracted a lot of attention, and this was important for the start of a national caraway research program in the Netherlands. Within the framework of this "National Caraway Research Program" the potential of caraway for the production of non-food products was investigated. The outlines of this research are sketched in chapter 1. An overview of the application of S-(+)-carvone and R-(-)-carvone as chiral starting material in the synthesis of natural products is also given in chapter 1.The Lewis acid catalyzed Diels-Alder reaction of S-(+)-carvone with some silyloxy dienes is described in chapter 2. The anti -addition products 94 , with the angular methyl group and the isopropenyl group in a cis -position, are formed in high yields. The synthetic utility of these Diels-Alder adducts was demonstrated by the total synthesis of (+)-α-cyperone (95) from diketone 94b . (+)-α-Cyperone ( 95 ), that can be isolated from the tubers of Cuperus rotundus L., exhibits an interesting in vitro activity against Plasmodium flaciparum K1, a multidrug resistant malaria parasite (scheme 8.1). In chapter 3, the Robinson annulation products 33 and 96 were transformed into interesting chiral intermediates for organic synthesis and also into some biologically active compounds. The decalones 111 and 112 , were formed from 33 . Decalone 111 is a famous molecule in perfumery and 112 is an important intermediate in the synthesis of several drimanes and drimane-related natural products. Compound 33 was also converted into decalol 113 , a potent inhibitor of the cholesterol biosynthesis.(+)-Geosmin ( 97 ), an interesting olfactive compound was synthesized from decalone 96 (scheme 8.2).In chapter 4, the syntheses of the more functionalized decalones 98 , 99 , 131 and 132 from S-(+)-carvone via two different conjugate addition annulation methodologies are presented (scheme 8.3). The conjugate addition of potassium cyanide to S-(+)-carvone gave cyano ketone 135 in high yield. The base catalyzed Robinson annulation of 135 with methyl vinyl ketone followed by dehydration gave decalone 98 stereoselectively and also in high yield. The copper catalyzed conjugate addition of Grignard reagents gave alkyl substituted dihydrocarvones, which were annulated via their silyl enol ethers 127 . A Lewis acid catalyzed Michael addition of the silyl enol ether 129 to methyl vinyl ketone gave the intermediate diketones 130 in good yield. The diketones were cyclized to the substituted decalones 99 , 131 and 132 under basic conditions.Decalone 98 was used for a new chiral approach to 3-oxygenated drimanes as is described in chapter 5. Hydroxyketone 153 was formed via an ozonolysis/Criegee rearrangement procedure of the isopropenyl substituent (scheme 8.4). Hydroxyketone 153 was by total synthesis further transformed into (-)-3-β-acetoxydrimenin ( 100 ), that can be isolated from the leaves of Drimys winteri,. In chapter 6 the total synthesis of (-)-Ambrox ®( 101 ), a commercially interesting olfactive compound, from both the allyl substituted decalone 99 and the nitrile substituted decalone 98 is presented (scheme 8.5). In both synthetic sequences, alcohol 159 was formed as the key intermediate. (-)-Ambrox ®( 101 ), was synthesized by simple cyclization of alcohol 159 at room temperature under acidic conditions.