Stereocontrolled Semisyntheses of Elliptone and 12aβ-Hydroxyelliptone

Abstract

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aβ-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aβ-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aβ-hydroxyelliptone is also described.

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“…47 Amorphigenol (6) was prepared from 1 as described previously. 48 Stereocontrolled reduction of the C-12-carbonyl group of 1 with NaBH 4 in MeOH afforded alcohol 10, 49 while E ́tard-like hydroxylation at C-12a of 1 using K 2 Cr 2 O 7 in aqueous AcOH provided rotenolone (7). 50 The diastereoselectivity of the last two reactions probably results from attack on the butterfly wing conformer of 1, 49,51 Reduction of keto-phenols 9 (Scheme 1) and 16 (Scheme 2) was not attempted, as this would have led to further rotenonic acid-like molecules, which would likely be inactive.…”

“…Anti-Markovnikov hydration, using an iridium-catalyzed hydroboration–oxidation sequence in which 1 was treated with pinacolborane in the presence of catalytic [Ir­(COD)­Cl] 2 and bis­(diphenylphosphino)­ethane followed by oxidation with H 2 O 2 under weakly basic conditions, provided dihydroamorphigenin ( 5 ) . Amorphigenol ( 6 ) was prepared from 1 as described previously . Stereocontrolled reduction of the C-12-carbonyl group of 1 with NaBH 4 in MeOH afforded alcohol 10 , while Étard-like hydroxylation at C-12a of 1 using K 2 Cr 2 O 7 in aqueous AcOH provided rotenolone ( 7 ) .…”

“…[Ir­(COD)­Cl] 2 , DPPE, HBPin, CH 2 Cl 2 , rt, 20 h; ii. H 2 O 2 , NaHCO 3 , THF, H 2 O, rt, 20 h, 14%; (e) OsO 4 , NMO, citric acid, acetone, H 2 O (see ref ); (f) SeO 2 , 4 Å MS, 1,4-dioxane, 80 °C, 3 h, 21%; (g) i. BH 3 ·SMe 2 , THF, 0 °C to rt, 1.5 h; ii. H 2 O 2 , NaOH, THF, H 2 O, 0 °C to rt, 18 h, 80%; (h) K 2 Cr 2 O 7 , AcOH, H 2 O, 60 °C, 0.5 h then rt, 18 h, 82%.…”

“…Rotenone ( 1 ) (Molekula Fine Chemicals, Darlington, UK, 90–95%) was crystallized from EtOH three times. Deguelin ( 2 ), amorphigenol ( 6 ), tephrosin ( 8 ), and rot-2′-enonic acid ( 25 ) were prepared from 1 as described previously. , N -(Phenylseleno)­phthalimide (Sigma-Aldrich, technical grade) was crystallized from dry CH 2 Cl 2 / n -hexane under N 2 . m- CPBA (Sigma-Aldrich, Gillingham, UK, <77%) was crystallized from CH 2 Cl 2 .…”