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 <strong>94</strong> , 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 <strong>94b</strong> . (+)-α-Cyperone ( <strong>95</strong> ), 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). <img src="/wda/abstracts/i1866_1.gif" height="191" width="600"/>In chapter 3, the Robinson annulation products <strong>33</strong> and <strong>96</strong> were transformed into interesting chiral intermediates for organic synthesis and also into some biologically active compounds. The decalones <strong>111</strong> and <strong>112</strong> , were formed from <strong>33</strong> . Decalone <strong>111</strong> is a famous molecule in perfumery and <strong>112</strong> is an important intermediate in the synthesis of several drimanes and drimane-related natural products. Compound <strong>33</strong> was also converted into decalol <strong>113</strong> , a potent inhibitor of the cholesterol biosynthesis.(+)-Geosmin ( <strong>97</strong> ), an interesting olfactive compound was synthesized from decalone <strong>96</strong> (scheme 8.2).<img src="/wda/abstracts/i1866_2.gif" height="263" width="600"/>In chapter 4, the syntheses of the more functionalized decalones <strong>98</strong> , <strong>99</strong> , <strong>131</strong> and <strong>132</strong> 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 <strong>135</strong> in high yield. The base catalyzed Robinson annulation of <strong>135</strong> with methyl vinyl ketone followed by dehydration gave decalone <strong>98</strong> stereoselectively and also in high yield. <img src="/wda/abstracts/i1866_3.gif" height="345" width="600"/>The copper catalyzed conjugate addition of Grignard reagents gave alkyl substituted dihydrocarvones, which were annulated via their silyl enol ethers <strong>127</strong> . A Lewis acid catalyzed Michael addition of the silyl enol ether <strong>129</strong> to methyl vinyl ketone gave the intermediate diketones <strong>130</strong> in good yield. The diketones were cyclized to the substituted decalones <strong>99</strong> , <strong>131</strong> and <strong>132</strong> under basic conditions.Decalone <strong>98</strong> was used for a new chiral approach to 3-oxygenated drimanes as is described in chapter 5. Hydroxyketone <strong>153</strong> was formed via an ozonolysis/Criegee rearrangement procedure of the isopropenyl substituent (scheme 8.4). Hydroxyketone <strong>153</strong> was by total synthesis further transformed into (-)-3-β-acetoxydrimenin ( <strong>100</strong> ), that can be isolated from the leaves of Drimys winteri,. <img src="/wda/abstracts/i1866_4.gif" height="158" width="600"/>In chapter 6 the total synthesis of (-)-Ambrox <sup>®</SUP>( <strong>101</strong> ), a commercially interesting olfactive compound, from both the allyl substituted decalone <strong>99</strong> and the nitrile substituted decalone <strong>98</strong> is presented (scheme 8.5). In both synthetic sequences, alcohol <strong>159</strong> was formed as the key intermediate. (-)-Ambrox <sup>®</SUP>( <strong>101</strong> ), was synthesized by simple cyclization of alcohol <strong>159</strong> at room temperature under acidic conditions.