Total synthesis of sesquiterpenes containing multiple quarternary carbons

Abstract

The synthesis of (±)-3a,4,4,7a-tetramethylhydrindan-2-one containing three contiguous quaternary carbons as present in thapsanes; first total synthesis of thapsanes 00 and 5, probable biogenetic precursors of thapsanes; and first total synthesis of a natural thapsane 27 are described.

Thus, orthoester Claisen rearrangement of cyclogeraniol (6), followed by hydrolysis of the resultant ester 65, furnished the eneacid 66. Anhydrous copper sulfate-catalyzed intramolecular cyclopropanation reaction of the diazo ketone 67, derived from the acid 66, generated the cyclopropyl ketone 61. Regiospecific reductive cleavage of cyclopropyl ketone 61 furnished the hydrindanone 56. Whereas the diazo ketone 75 furnished the hydrindanone 57 via cyclopropyl ketone 76. Wittig methylenation of the hydrindanone 57 furnished the thaps-7(15)-ene (80), which on isomerization gave the thaps-?-ene (81).

On the other hand, Claisen rearrangement of cyclogeraniol (67) with methoxypropene provided the enone 85. Rhodium acetate-catalyzed intramolecular cyclopropanation of the ?-diazo-6-keto ester 87, obtained from the enone 85 via the 6-keto ester 84, furnished the cyclopropyl ketone 83. Reductive cleavage of the cyclopropyl ketone 83 afforded a 1:1 mixture of hydrindanone 82 and ketol 88. Wittig olefination of the hydrindanone 82 furnished the eneester 107. Epoxidation of the eneester 107, followed by BF?·OEt?-catalyzed rearrangement of the epimeric epoxides 112, ionic hydrogenation of the hemiacetal afforded the hemiacetal, furnished the lactone 17, and finally DIBAL-H reduction of the lactone 17 furnished the natural hemiacetal, i.e., thapsane 27.

The first total synthesis of (±)-6-cuparenones (10) and epicyclolaurene (54), and new routes to (±)-6-cuparenone (9) are described in this chapter. The orthoester Claisen rearrangement of the cinnamyl alcohol 51, prepared in two steps from p-methylacetophenone (56), followed by hydrolysis of the resultant ester 60, furnished the olefinic acid 61. Anhydrous copper sulfate-catalyzed intramolecular cyclopropanation reaction of the diazo ketone 61, obtained from the acid 56, provided a diastereomeric mixture of cyclopropyl ketone 55. Huang–Minlon modified Wolff–Kishner reduction of the cyclopropyl ketones 55a and 55b resulted in the formation of (±)-cyclolaurene (1^) and (±)-spicyclolaurene (54).

Whereas regiospecific cyclopropane cleavage of the epimeric mixture of the ketone 55, using lithium–liquid ammonia reduction conditions, furnished the (±)-6-cuparenone (9). On the other hand, one-pot Claisen rearrangement of the cinnamyl alcohol 72, available in two steps from p-methylacetophenone (56), with methoxypropene provided the ?,?-unsaturated hexenone 73. Ozonolysis of the hexenone 73, followed by an intramolecular aldol condensation of the resultant ketoaldehyde with base, furnished the cyclopentenone, a known precursor to (±)-?-cuparenone (9).

Thermal rearrangement of ?,?-unsaturated ketones to iso-?,?-unsaturated ketones via an intramolecular ene reaction of the enol tautomer, followed by a retro-ene reaction (eno-ene rearrangement), is described in this chapter. Thermal activation of the enone 85, i.e., Claisen rearrangement product of the cinnamyl alcohol, in the presence of a catalytic amount of propionic acid furnished a 2:1 mixture of the rearranged and starting ?,?-enones. Similarly, thermolysis of the corresponding phenyl compound 25 generated the rearranged enone 26, which on ozonolysis furnished the known diketone 28, confirming the structure of the rearranged enones.

The formation of the enone 32, containing an extra methyl group on the styrene double bond, starting from cinnamyl alcohol 29, confirmed the proposed mechanism. Finally, the rearrangement has been extended to the enone 41 by its thermal conversion to the enone 41. Interestingly, microwave irradiation of the enone 41 on montmorillonite K-10 support, using a commercial microwave oven, furnished the naphthalene 20 via cyclization and aromatization of the rearranged enone.