Direct Asymmetric Entry into the Cytotoxic 8,9-Secokaurene Diterpenoids. Total Synthesis of (−)-O-Methylshikoccin and (+)-O-(Methylepoxy)shikoccin

Natural Products with Anti‐Bredt and Bridgehead Double Bonds

“…Ergosterol (60), which was found to be produced by the fungi, [48,49] is the proposed biosynthetic precursor to these unusual steroids. The proposed mechanism relies on the enzymatic activation of the C19 position to generate an electrophilic center (61), which can react with the D 5,6 alkene with concomitant oxidation of the C6 carbon atom to produce cyclopropane intermediate 62.…”

“…Fujita and coworkers have also described the isolation and structure elucidation of O-methylshikoccin (77), which succumbed to total synthesis in 1996 by Paquette et al (Figure 15). [59,60] Paquette went on to write that "Although Bredts rule is not at all violated in 77 [presumably as S ! 9], sufficient ring strain evidently resides in its bridgehead double bond to endow this site with heightened reactivity."…”

“…9], sufficient ring strain evidently resides in its bridgehead double bond to endow this site with heightened reactivity." [60] Since the 1979 publication of Fujita et al, the structures of a variety of compounds related to shikoccin (76) have been determined. Although the isolation of shikodomedin (78) was described in 1979 ( Figure 16), [61] the structural determination of the major diterpenoid component of Rabdosia shikokiana (Makino) Hara var.…”

“…Additional cyclocitrinol family members isolated from Penicillium citrinum and P. janthinellum.Scheme 2. Top: The proposed biosynthetic pathway to the cyclocitrinols (63) starting from ergosterol(60). Bottom: Postulated oxidative transformation of the C17 side chain of the cyclocitrinols.…”

New avenues for the synthesis of ent-kaurene diterpenoids

“…Synthetic strategy towards the synthesis of (-)-O-methylshikoccin from the Wieland-Miesher ketone derivative 136.6.8 Synthesis of (-)-O-methylshikoccin (1997)O-methylshikoccin (54) is a well-known member of the 8,9-seco-ent-kaurene family that exhibits potent anti-tumor properties. Paquette became interested in developing a route for the synthesis of (-)-O-methylshikoccin (54) when he found that 135, which closely resembles the B/C ring system in (-)-Omethylshikoccin (57), could be readily accessed via an oxy-Cope rearrangement of the spirocyclopentenol 134 72. The synthesis began with the condensation of enantiopure Wieland-Miesher ketone derivative 136 with aldehyde 137.…”