Asymmetric total synthesis of the epoxykinamycin FL-120 B'

Abstract

Turn up the heat: An asymmetric total synthesis of the epoxykinamycin FL-120B’ is reported. The synthesis establishes a route to epoxide-containing diazobenzofluorenes which could potentially serve as monomers to the dimeric lomaiviticins. Key steps include Sharpless asymmetric epoxidation, Stille coupling, and intramolecular Friedel-Crafts acylation of atropisomeric carboxylic acids at elevated temperatures to construct the FL-120B’ core structure.

Figure 1

Representative diazobenzofluorene natural products.

Figure 2

Biomimetic approaches to the lomaiviticins.

Figure 3

Retrosynthesis for FL-120B’ (4). P = protecting group, MOM = methoxymethyl. TBS = t-butyldimethylsilyl.

Figure 4

Variable temperature (VT) ¹H NMR (500 MHz, CD₃NO₂) stackplot of acid 20b.

Scheme 1

Enantioselective synthesis of epoxide 13. t-BuOOH (2.0 equiv), Ti(Oi-Pr)₄ (0.10 equiv), L-DIPT (0.13 equiv), 4Å MS, CH₂Cl₂, 0 °C, 60 h. DIPT = diisopropyl tartrate, MS = molecular sieves.

Scheme 2

Forward synthesis to carboxylic acids 20a–c. a) Na₂S₂O₄ (6.0 equiv), Et₂O, H₂O, rt, 10 min; b) MeI (6.0 equiv), K₂CO₃ (6.5 equiv), DMF, 0 °C→rt, 18 h, 66% yield (2 steps); c) (SnBu₃)₂ (1.3 equiv), Pd(PPh₃)₄ (0.1 equiv), toluene, 110 °C, 48 h, 74%; d) 11 (1.0 equiv), 10 (1.1 equiv), Pd₂(dba)₃·CHCl₃ (0.1 equiv), AsPh₃ (0.3 equiv), CuCl (0.6 equiv), i-Pr₂NEt (1.1 equiv), MeCN, 72 °C, 3 h, 90% yield; e) Ac₂O (30 equiv), pyr, rt, 6 h; f) Super-Hydride (LiHBEt₃) (2.1 equiv), THF; 74% (2 steps) g) 18a: Ac₂O (30 equiv), pyr, rt, 3 h, 96%; 18b: ClC(O)(CH₂)₃N₃ (1.1 equiv), CH₂Cl₂ / pyr, 0 °C, 1 h, 73%; 18c: Boc₂O (5.0 equiv), DMAP (5.5 equiv), CH₂Cl₂, rt, 4 h, 93%; h) HF·pyr (excess), THF / pyr, 0 °C; 15–20 h; i) DMP (2.0 equiv), pyr (2.1 equiv), CH₂Cl₂, rt, 3–5 h, 73–88% (2 steps); j) NaClO₂ (9 equiv), NaH₂PO₄ (8 equiv), 2-methyl-2-butene (excess), t-BuOH / H₂O, 0 °C→rt, 2–3 h, 78–90%. Dba = dibenzylideneacetone, DMF = N,N-dimethylformamide, pyr = pyridine, Boc = t-butoxycarbonyl, DMAP = N,N-dimethyl-4-aminopyridine, DMP = Dess-Martin periodinane.

Scheme 3

Proposed cyclization manifolds for intramolecular Friedel-Crafts acylation and lactone formation.

Scheme 4

Completion of FL-120B’ (4). a) TBDPSCl (15 equiv), imid (20 equiv), DMAP (0.5 equiv), CH₂Cl₂, rt, 20 h, 84%. b) MsNHNH₂ (25 equiv), TFA (8 equiv), i-PrOH / H₂O, 72 h; c) CAN (3 equiv), CH₃CN / pH 7 buffer, 0 °C, 1 h; d) NEt₃ (10 equiv), CH₂Cl₂, rt, 1 h, 16% (3 steps); e) HF·pyridine (excess), THF, 0 °C→rt, 3 h, 51%. TBDPS = t-butyldiphenylsilyl, imid = imidazole, Ms = methanesulfonyl, CAN = cerium (IV) ammonium nitrate.