First Total Synthesis of Dermocanarin 2

Abstract

The first total synthesis of dermocanarin 2 is described. The synthesis features the construction of the anthraquinone and naphthoquinone frameworks through annulation reactions onto an axially chiral biphenyl intermediate, obtained by an enzyme-catalyzed enantioselective desymmetrization of a σ-symmetric precursor, followed by a stereoselective aldol reaction to construct the stereogenic center in the side chain.

Key words

axial chirality - biphenyls - enzymes - desymmetrizations - annulations - total synthesis

• References and Notes

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• 30 Dermocanarin 2 (1); Experimental Procedure for the Final Synthetic Step NaH₂PO₄·2H₂O (32.7 mg, 210 μmol) and NaClO₂ (13.0 mg, 175 μmol) were added to a solution of aldehyde 30 (23.7 mg, 39.4 μmol) and 2-methylbut-2-ene (167 mg, 2.38 mmol) in t-BuOH (4.0 mL) and H₂O (1.0 mL) at r.t., and the mixture was stirred for 15 min. The mixture was then poured into brine at 0 °C, and the products were extracted with CH₂Cl₂. The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The crude product was dissolved in CH₂Cl₂ (6.0 mL) and added to a solution of 2-methyl-6-nitrobenzoic anhydride (33; 29.1 mg, 84.6 μmol) and DMAP (19.8 mg, 162 μmol) in CH₂Cl₂ (1.0 mL) at 0 °C. The mixture was then stirred for 15 min before the reaction was stopped by adding 0.1 M phosphate buffer (pH 7). The products were extracted with CH₂Cl₂, and the combined organic extracts were washed sequentially with 1 M aq HCl, brine, sat. aq NaHCO₃, and brine, then dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by preparative TLC [CHCl₃–MeOH (95:5)] to give dermocanarin 2 (1) as a yellow solid; yield: 16.6 mg (70%, 2 steps). Reprecipitation from hexane–CH₂Cl₂ followed by crystallization (EtOH, –20 °C) gave a yellow powder; mp 227–230 °C (dec.); R_f = 0.63 (CHCl₃–MeOH, 95:5); [α]_D ²² +2.1 × 10² (c 0.50, CHCl₃); IR (ATR): 3505, 1774, 1657, 1632, 1582 cm^–1; HRMS (ESI-TOF): m/z calcd [M + H]⁺ for C₃₃H₂₇O₁₁: 599.1553; found: 599.1563. The ¹H NMR (Table 3) and ¹³C NMR data (Table 4) for synthetic and natural dermocanarin 2 (1) are listed.