Total Synthesis of 4α-Hydroxyallosecurinine and Securingine F, Securinega Alkaloids with a C4-Hydroxy Handle for Biofunctional Derivatizations

This work is dedicated to Professor Hee-Yoon Lee (1957–2023) in memory of his scientific contributions to the field of total synthesis.

Abstract

We describe the first total synthesis of the C4-hydroxylated securinega alkaloids 4α-hydroxyallosecurinine and securingine F. The synthetic route features an Ellman’s light-mediated hydrogen-atom-transfer-based epimerization reaction that effectively sets the desired configuration at the C2 position. Simultaneous skeletal rearrangement from neosecurinane to securinane frameworks and stereochemical reversal at the C4 site was achieved under Mitsunobu reaction conditions. The C4-hydroxy group is envisioned to serve as a handle for potential biofunctional derivatizations.

Key words

total synthesis - securinega alkaloids - biofunctional derivatizations - hydroxyallosecurinine - securingine F

Publication History

Received: 06 February 2023

Accepted after revision: 06 March 2023

Accepted Manuscript online:
06 March 2023

Article published online:
12 April 2023

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• 28 (–)-Securingine F (5) mCPBA (77%, 3.6 mg, 0.0160 mmol, 1.1 equiv) was added to a solution of 4α-hydroxyallosecurinine (4) (3.4 mg, 0.0146 mmol, 1.0 equiv) in CH₂Cl₂ (1 mL) at 0 °C. After 5 min, K₂CO₃ (6.0 mg, 0.0437 mmol, 3.0 equiv) was added, and the resulting mixture was slowly warmed to 23 °C. After 4 h, the reaction was quenched with brine (5 mL) and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography [silica gel, CH₂Cl₂–acetone (6:1)] to give a white amorphous solid; yield: 2.6 mg (72%); R_f = 0.44 (UV, KMnO₄); [α]_D ²⁵ –250.6 (c 0.1, MeOH) [Lit.⁴ −167.1 (c 0.1, MeOH)]. ¹H NMR (400 MHz, CDCl₃): δ = 6.86 (d, J = 9.4 Hz, 1 H), 6.29 (dd, J = 9.4, 5.8 Hz, 1 H), 5.83 (s, 1 H), 4.73 (dt, J = 5.8, 2.9 Hz, 1 H), 4.08–4.02 (m, 1 H), 3.30 (dd, J = 12.0, 2.6 Hz, 1 H), 3.07–2.95 (m, 2 H), 2.54 (dd, J = 11.5, 3.4 Hz, 1 H), 2.03 (dd, J = 11.4, 2.4 Hz, 1 H), 1.83 (dd, J = 13.7, 2.7 Hz, 1 H), 1.80–1.74 (m, 2 H), 1.18 (ddd, J = 14.0, 12.1, 2.7 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 172.1, 164.4, 134.6, 126.6, 113.6, 82.7, 71.2, 65.1, 63.6, 50.0, 40.8, 32.0, 31.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₅NNaO₄: 272.0893; found: 272.0894.