Nature-inspired total synthesis of (-)-fusarisetin A

Abstract

A concise, protecting group-free total synthesis of (-)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(-)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.

Figure 1

Fusarisetin A (1) and its proposed biosynthesis from equisetin (2)

Scheme 1

Strategic bond disconnections of fusarisetin A

Scheme 2. Synthesis of decalin ester 5^a

^aReagents and conditions: (a) methacrolein (2.0 equiv), Grubbs^2nd gen. catalyst (5 mol%), CH₂Cl₂, 50 °C, 24 h, 75%, (90% brsm); (b) SeO₂ (3 mol%), ^tBuOOH (4.0 equiv), salicylic acid (0.1 equiv), CH₂Cl₂, 36 h, then IBX (1.4 equiv), DMSO, 1.5 h, 53%, (64% brsm); (c) 9 (1.0 equiv), n-BuLi (1.0 equiv), THF, −60 °C, 1 h, then −78 °C, 8, 1 min (see SI), 61% (d) I₂ (5 mol%), sunlamp (visible light), CH₂Cl₂, 5 min, then −78 °C, Et₂AlCl (1.0 equiv), 18 h, 82%; (e) activated zinc dust (3.0 equiv), ethyl bromoacetate (1.2 equiv), PhH, 45 min, 90 °C; (f) IBX (2.0 equiv), DMSO, 80 °C, 10 min, 91% for 2 steps.

Scheme 3. Completion of the synthesis^a

^aReagents and conditions: (a) LiHMDS (1.5 equiv), 1,2- dimethoxyethane, −78 °C, 30 min, then 0 °C, TEMPO (1.05 equiv), Cp₂FePF₆ (2.0 equiv), 5 min, 99%; (b) 14, 4-DMAP (2 equiv), PhMe, 4Å MS, 90 °C, 36 h, 70% (d.r. = ca. 1:1); (c) activated zinc dust (100 equiv), AcOH/THF/H₂O (3:1:1), 70 °C, 12 h; (d) NaOMe (5.0 equiv), MeOH, 10 min, 42% for 2 steps; (e) mCPBA (1.2 equiv), CH₂Cl₂, 0 °C, 15 min, 95%; (f) NaBH₄ (0.6 equiv), MeOH, −78 °C (d.r. = ca. 3:1); (g) NaOMe (5.0 equiv), MeOH, 10 min, 39% for 2 steps.