Total Synthesis and Biological Evaluation of (−)-9-Deoxy-englerin A

Abstract

An effective total synthesis of (-)-9-deoxy-englerin (4), an analogue of the natural guaiane sesquiterpene englerin A (1), has been achieved. The synthesis features a transannular epoxide opening to construct the 5,7-fused ring system followed by transannular ether formation with mercury(II) trifluoroacetate.

Synthesis of Guaia-4(5)-en-11-ol, Guaia-5(6)-en-11-ol, Aciphyllene, 1-epi-Melicodenones C and E, and Other Guaiane-Type Sesquiterpenoids via the Diastereoselective Epoxidation of Guaiol

“…As highlighted in Table 1, α-epoxyguaiol (8b) may be prepared with a π facial selectivity of 95% α-orientation in 65% overall yield when using DMDO as oxidant. Ring-opening of 8b with AlH 3 in THF simply led to the formation of tricyclic guaioxide (19) via nucleophilic attack of the terminal hydroxy moiety on the bridged epoxy moiety without the formation of the expected diol (15b) (Scheme 3). Employing the α-epoxybenzyl ether (10b) under the same conditions (AlH 3 in THF) resulted in no reaction at RT, while employing elevated temperatures simply resulted in dehydration to regenerate the bridged olefin (1c).…”

“…Spectroscopic data were in agreement with those reported previously. 11 (1S,3aS,4S,7R,8aR)-1,4,9,9-Tetramethylhexahydro-1H-3a,7-(epoxymethano)azulen-8a(4H)-ol (19). This synthesis followed the same procedure as for diol 15a except that LiAlH 4 (41 mg, 1.1 mmol), anhydrous AlCl 3 ( 9, 85.9, 82.5, 44.3, 42.6, 37.9, 31.5, 31.18, 31.14, 29.48, 29.43, 28.8, 23.4, 18.3, 15. (53); other physical and spectroscopic data were in agreement with reported data.…”

“…13.5; EIMS m/z (rel intensity) 236(6), 207(19), 179(34), 163(44), 137(50), 107 (80), 81 (83), 67 (83), 55 (100). 14b (or 14a): 1 H NMR (CDCl 3 , 600 MHz) δ 2.55 (2H, s), 2.05−1.91 (3H, m), 1.64−1.54 (4H, m), 1.54−1.43 (3H, m), 1.36−1.24 (2H, m), 1.24 (3H, s), 1.03 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 0.94 (1H, m); 13 C NMR (CDCl 3 , 150 MHz) δ 73.1, 73.0, 59.8, 53.2, 41.6, 37.8, 34.0, 31.1, 28.4, 28.0, 27.9, 27.8, 18.0, 17.9(5), 13.5; EIMS m/z (rel intensity) 236 (15), 207 (35), 179 (37), 163 (71), 135 (49), 107 (89), 81 (86), 67 (78), 55 (100).…”

Englerins: A Comprehensive Review

“…26 Maier also confirmed the importance of the C-9 position with the synthesis of (−)-9-deoxyenglerin A ( 12 ) and reported it to be 1000-fold weaker than englerin A in A498 cells. 49 …”

Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

“…3 Several total synthesis of englerin A 4,5,6,7,8,9,10,11,12,13,14,15,16,17 and analogues 18,19,20,21,22,23,24,25 have been reported to date. Recently, two distinct mechanisms for englerin A’s anticancer activity have been proposed, agonism of PKCθ 26 and agonism of TRPC4/5.…”