Study on Integrated Synthesis of Dimeric Pyranonaphthoquinones: Preparation of Versatile Synthetic Intermediate and Conversion into ent-Hemi-actinorhodin and ent-Hemi-γ-actinorhodin

In memory of Professor Yoshito Kishi

Abstract

For developing general synthetic access toward dimeric pyranonaphthoquinones including β-naphthocyclinone, actinorhodin, and γ-actinorhodin, we report stereodefined 6,9,10-trioxypyranonaphthalene as a versatile intermediate. Its robust preparation started from ethyl (S)-4-chloro-3-hydroxybutyrate. The pyranonaphthalene core was constructed by a Michael–Dieckmann sequence, and methylation using Me₃Al and BF₃·OEt₂ established the required trans structure in a scalable manner. Conversion of this intermediate into ent-hemi-actinorhodin and into ent-hemi-γ-actinorhodin are also reported, in which the conditions for the oxidative lactonization were optimized.

Key words

stereoselective synthesis - pyranonaphthoquinone - naphthazarin - natural product - oxidative lactonization

• References and Notes

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• 29 Experimental Procedures and Characterization Data of ent-Hemi-γ-acthinorhodin (12) To a solution of ent-hemi-actinorhodin (ent-8, 25.0 mg, 0.0785 mmol) in acetone (5.2 mL) and H₂O (0.5 mL) was added pyridine (320 μL, 3.96 mmol), and then a flask was thoroughly purged with O₂. After stirring for 24 h at room temperature, the reaction mixture was poured into mixed solvent of 1 M aqueous HCl and EtOAc, and the aqueous layer was removed. The combined organic extracts were washed with H₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography (oxalic acid coated silica gel, CH₂Cl₂/ EtOAc = 9/1) to afford ent-hemi-γ-actinorhodin (12, 18.7 mg, 75%) as a red solid. ent-Hemi-γ-actinorhodin (12) R_f = 0.86 (CHCl₃/MeOH = 9/1); mp 195 °C (decomp.). ¹H NMR (600 MHz, CDCl₃): δ = 1.57 (d, 3 H, J = 7.2 Hz), 2.71 (d, 1 H, J = 18.0 Hz), 2.98 (dd, 1 H, J = 18.0, 4.8 Hz), 4.72 (dd, 1 H, J = 4.8, 3.0 Hz), 5.16 (q, 1 H, J = 7.2 Hz), 5.30 (d, 1 H, J = 3.0 Hz), 7.23 (d, 1 H, J = 2.4 Hz), 7.25 (d, 1 H, J = 2.4 Hz), 12.49 (s, 1 H, OH), 12.53 (s, 1 H, OH). ¹³C NMR (150 MHz, CDCl₃): δ = 18.3, 36.9, 66.3, 66.6, 68.6, 111.0, 111.7, 132.5, 133.0 (2C), 148.7, 165.9, 166.3, 173.9, 176.7, 177.4. IR (neat): 2924, 2848, 1787, 1612, 1567, 1454, 1407, 1404, 1340, 1249, 1203, 1154, 1115, 1093, 1067, 1034, 800, 715, 707, 668 cm^–1. UV/Vis (MeCN): λ_max (ε) = 216 (41332), 277 (9025), 491 (6718), 518 (7270), 561 (4074) nm. HRMS (ESI-TOF): m/z calcd for C₁₆H₁₃O₇ [M + H]⁺: 317.0655; found: 317.0659.
• 30 This reaction starts from the enolization of ent-8, which was facilitated by pyridine as a base. For the proposed mechanism, see: Li T, Ellison RH. J. Am. Chem. Soc. 1978; 100: 6263 ; and ref 7a