Total Synthesis of (−)‐Rotundone and (−)‐epi‐Rotundone from Monoterpene Precursors

Abstract

The first total synthesis of (À)-rotundone has been accomplished from (+)-(R)-limonene and therefore for the first time from an unrelated monoterpene instead of modifying structurally closely related sesquiterpene precursors such as α-guaiene. Challenges such as intermediates with stereocenters prone to epimerization by enolization were overcome by designing a β-methyl-keto route starting from (+)-(R)-limonene which finally gave (À)-rotundone by Nazarov cyclization of a precursor 13a. Diastereomer (À)-epi-rotundone was separated from (À)-rotundone chromatographically. An alternative route from rac-citronellal provided a diastereomer mixture of racemic Nazarov precursor 13 through a TRIP-catalyzed intramolecular aldolization, thus indicating that the Nazarov cyclization precursor 13a is in principle accessible from (À)-(S)-citronellal. The 11-step synthesis from (+)-(R)-limonene with ca. 1 % overall yield confirmed the absolute configuration of (À)-rotundone and provided samples of good olfactory quality.

Novel Rearrangements of Guaiane Sesquiterpenes

“…A selection of the reported examples is shown in Figure 2. Singh et al reported the rearrangement of α-guaiene to 10-epi-zonarene (9) in concentrated sulfuric acid, [16] and the formation of corymbolone (10) was brought about by the oxidation of αguaiene. This transformation though was not a rearrangement in the classical sense but an oxidative cleavage of the endocyclic double bond followed by aldol reaction.…”

“…13 C-NMR (150 MHz, C 6 D 6 ): 74.1 (s), 57.2 (d), 45.7 (s), 38.0 (t), 37.8 (d), 37.4 (t), 35.2 (t), 33.9 (t), 32.2 (q), 30.7 (s), 29.9 (t), 29.0 (d), 26.6 (t), 19.9 (q), 14.3 (q) ppm. GC/MS (EI): m/z (%): 220 (7) [M + ], 205 (4), 163 (100), 154 (10), 121(39), 105 (9), 91 (10), 79 (10), 41 (13) (1R,3aS,4S,7S,9aS)-9a-Hydroxy-1,4,7-trimethyloctahydro-3a,7-methanocyclopenta [8]annulen-9(4H)-one (22) To a suspension of pyridinium chlorochromate (2.13 g, 9.89 mmol) and celite (2.13g) in CH 2 Cl 2 (38 mL), a solution of (1R,3aS,4S,7S)-1,4,7-trimethyldecahydro-3a,7-methanocyclopenta [8]annulen-9-ol (20, 2.00g, 8.99 mmol) in CH 2 Cl 2 (30 mL) was added over 30 min. The mixture was stirred at room temperature for 25h, filtered over a layer of celite and silica and washed with 50 mL CH 2 Cl 2 .…”

“…C-NMR (150 MHz, C 6 D 6 ): 211.6 (s), 68.5 (d), 50.8 (t), 50.2 (s), 39.4 (d), 37.9 (d), 37.1 (t), 36.8 (t), 35.4 (s), 33.6 (t), 31.6 (t), 31.3 (q), 28.2 (t), 20.2 (q), 15.1 (q) ppm. GC/ MS (EI): m/z (%): 220 (7) [M + ], 205 (4), 163 (100), 154 (10), 121(39), 105 (9), 91 (10), 79 (10), 41 (13) (3aS,4S,7S)-1,4,7-Trimethyl-2,3,5,6,7,8-hexahydro-3a,7-methanocyclopenta [8]annulen-9(4H)-one (24) and (1R,3aS,4S,7S)-1,4,7-trimethyl-2,3,4,5,6,7-hexahydro-3a,7-methanocyclopenta [8]annulen-8(1H)one (25) A solution of (1R,3aS,4S,7R)-1,4,7-trimethyl--1,2,3,4,5,6,7,8-octahydro-3a,7-methanocyclopenta [8]annulene (14, 3.0 g, 14.68 mmol) and N-Hydroxyphthalimide (NHPI, 0.239 g, 1.468 mmol) in MeCN (27 mL), cyclohexane (6 mL) and H 2 O (9 mL) was heated to 50 °C. Sodium chlorite (2.489 g, 22.02 mmol) was added in one portion.…”

“…13 13 C-NMR (150 MHz, C 6 D 6 ) : 72.9 (s), 66.1 (s), 45.8 (s), 39.9 (t), 36.5 (t), 35.0 (t), 32.5 (q), 32.4 (s), 31.4 (t), 30.7 (t), 30.2 (d), 29.9 (t), 26.4 (t), 18.4 (q), 15.4 (q) ppm. GC/MS (EI): m/z (%): 220 (28) [M + ], 205 (15), 191 (100), 177 (9), 163 (36), 147 (20), 133 (17), 121 (33), 105 (32), 91 (31), 79 (22), 55 (25) A solution of α-guaiene (13, 10.0 g, 48.9 mmol) in tetrahydrofuran (19 mL) was added dropwise to a solution of 9-BBN (127 mL, 63.6 mmol, 0.5 M in THF), cooled in an ice bath to 5 °C, over 45 min. The mixture was allowed to warm to room temperature and stirred for 2 h. H 2 O 2 (13.47 mL, 157 mmol) and NaOH (24.47 mL, 48.9 mmol) were dropwise added alternately to the ice cooled solution, keeping the temperature lower than < 10 °C.…”

“…Since then, rotundone was identified in a number of different species [5][6][7] and its economic value as woody, peppery odorant in perfumery has been recognized. [8] A total synthesis was recently reported, [9] and with the growing advance of synthetic biology, the engineering of sesquiterpene synthases becomes an attractive future perspective to access compounds such as rotundone in larger quantities. [10] Structure-odor-correlation studies of rotundone led to surprising findings.…”