Toward the Synthesis of Thapsigargin:  Enantioselective Synthesis of 7,11-Dihydroxyguaianolides

Abstract

[reaction: see text] The enantioselective synthesis of a 7,11-dihydroxyguaianolide bearing the stereochemistry present in thapsigargin, a potent and selective inhibitor of the Ca(2+) SERCA-ATPase pumps, is described. Starting from (+)-dihydrocarvone, the synthesis presents two key steps. The first one involves the photochemical rearrangement of a gamma,delta-unsaturated ketone eudesmane into the corresponding guaiane. The second step consists of the regioselective oxidation of an unprotected tetrahydroxylated ketone to provide a dihydroxylactone with the required stereochemistry.

Natural sesquiterpenoids

“…388 An enantioselective synthesis of a 7,11-dihydroxyguaianolide, possessing the stereochemistry of thapsigargin, has been described. 389 A study of a thapsigargin derivative has revealed the importance of the length and flexibility of the side chain attached to O-8 in the activity of this sesquiterpene lactone, and its analogues, towards prostate cancer cells. 390 Five novel pseudoguaianolides, dichrocepholides A-E 460-464, have been isolated from Dichrocephala integrifolia.…”

Acyloxylation of Cyclic Enones: Synthesis of Densely Oxygenated Guaianolides

“…12 On the other hand, guaiane 25 is an intermediate that can be prepared by following a methodology that we devised for the synthesis of analogues of thapsigargin. 13 To this end, compound 23 was subjected to photochemical rearrangement in AcOH, providing 24 in 72% yield. Subsequent protection of the primary hydroxyl group with TBDMSCl and imidazole afforded guaiane 25 in almost quantitative yield (Scheme 1b).…”

“…8,7.8,5.2,2.6 Hz,1H), 2.09 (dddd, J = 17. 1, 12.7, 12.7, 5.2 Hz, 1H), 1.97 (s, 3H), 1.70 (tq,J = 7.4,7.4 Hz,2H), 0.97 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz,CDCl 3 ) δ 193.7,173.0,162.3,125.6,72.9,36.2,30.6,28.4,24.3,18.6,13.7; IR (film) ν max 2966,2936,2876,1743,1689,1633,1381,1177,1104 7, 173.2, 162.3, 125.6, 72.9, 34.3, 31.4, 30.5, 28.4, 24.7, 24.2, 22.4, 14.0; IR (film) ν max 2956,2933,2872,1743,1690,1633,1380,1208,1167,1103 3-Methyl-6-octanoyloxycyclohex-2-enone (11). Yellow oil (47 mg, 74%); 1 H NMR (400 MHz, CDCl 3 ) δ 5.90 (br s, 1H), 5.31 (dd, J = 13.3, 5.4 Hz, 1H), 2.55 (m, 1H), 2.39 (m, 3H), 2.22 (dddd, J = 7.…”

“…9, 11.8, 11.8, 5.2 Hz, 1H), 1.97 (s, 3H), 1.67 (tt, J = 7.1, 7.1 Hz, 2H), 1.31 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 193. 7, 173.2, 162.3, 125.6, 72.9, 34.3, 31.8, 30.6, 29.2, 29.1, 28.4, 25.0, 24.3, 22.7, 14.2; IR (film) ν max 2930, 2856, 1743, 1691, 1633, 1380, 1162, 1105 cm 3, 170.8, 167.4, 139.6, 71.9, 38.9, 31.8, 28.0, 23.1, 22.6, 21.0, 17.3, 14.1;IR (film) ν max 2931IR (film) ν max , 2860IR (film) ν max , 1746IR (film) ν max , 1714IR (film) ν max , 1373IR (film) ν max , 1229IR (film) ν max , 1056 5-Butanoyloxy-3-methyl-2-pentylcyclopent-2-enone (13). Yellow oil (22 mg, 35%); 1 H NMR (500 MHz, CDCl 3 ) δ 5.12 (dd, J = 6.9, 3.0 Hz, 1H), 2.97 (dd, J = 18.0, 6.9 Hz, 1H), 2.36 (m, 3H), 2.18 (m, 2H), 2.05 (s, 3H), 1.67 (tq,J = 7.4,7.1 Hz,2H),1.39 (tt,J = 7.8,7.8 Hz,2H),1.27 (m,4H),0.96 (t,J = 7.4 Hz,3H), 0.86 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 203.3, 173.4, 167.2, 139.6, 71.8, 38.9, 36.0, 31.8, 28.0, 23.1, 22.6, 18.5, 17.3, 14.1, 13.7;IR (film) ν max 2959IR (film) ν max , 2932IR (film) ν max , 2874IR (film) ν max , 1743IR (film) ν max , 1714IR (film) ν max , 1643IR (film) ν max , 1388IR (film) ν max , 1174IR (film) ν max , 1055 5-Hexanoyloxy-3-methyl-2-pentylcyclopent-2-enone (14).…”

Synthesis of Biologically Active Guaianolides with a trans‐Annulated Lactone Moiety

“…[52] A high-yielding dehydration of 134 afforded the fully conjugated system 135, which underwent a remarkably chemoselective asymmetric dihydroxylation of the side chain to furnish diol 136. Upon irradiation in acetic acid, hydroazulene core 137 was formed.…”