Divergent Two-Step Total Synthesis of Sclerotioloid A and B

Abstract

A two-step divergent total synthesis of the structurally unique N-propargylated alkaloids sclerotioloid A and B has been achieved. The synthesis relies on a robust aldol-propargylation domino reaction yielding the key divergent intermediate. Single-crystal X-ray structure studies of the natural product sclerotioloid A show that it exists as a helically chiral racemate in the solid state.

Key words

alkaloids - natural products - total synthesis - domino reaction

Publication History

Received: 15 July 2024

Accepted after revision: 27 January 2025

Accepted Manuscript online:
07 February 2025

Article published online:
12 May 2025

• References and Notes

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• 11 Sclerotioloid A (1): To a stirred suspension of 3 (20 mg, 1.0 equiv) in MeOH (1 mL), hydrazine hydrate (60 μL, 62 mmol, 80% v/v solution in water, 22 equiv) was added. The resulting suspension was stirred at room temperature for 5 min. TLC showed full conversion and all material had dissolved. The reaction mixture was concentrated in vacuo and purified using flash column chromatography (SiO₂, 75% EtOAc/Hexane) to yield sclerotioloid A (1) as a white solid (14.3 mg, 84%). Spectroscopic data matched those reported previously.² R_f 0.29 (25% EtOAc/Hex; UV, KMnO₄). ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (s, 1 H), 7.46–7.35 (m, 5 H), 4.56 (s, 2 H), 4.27 (d, J = 2.5 Hz, 2 H), 2.65 (s, 3 H), 2.14 (t, J = 2.5 Hz, 1 H). {¹H}¹³C NMR (101 MHz, CDCl₃): δ = 171.6, 164.7, 164.1, 132.5, 130.0, 129.6, 129.05, 128.95, 127.8, 77.0, 73.1, 45.3, 33.8, 26.8.
• 12 Sclerotioloid B (2): A solution of 3 (32 mg, 0.113 mmol, 1.00 equiv) in anhydrous MeOH (2 mL) was stirred at 50 °C for 2 days. The reaction mixture was concentrated in vacuo and purified using flash column chromatography (SiO₂, EtOAc) to yield sclerotioloid B (2) as a white crystalline solid (11.7 mg, 33%). Spectroscopic data matched those reported previously.² R_f 0.16 (75% EtOAc/Hex; UV, KMnO₄). ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.06 (t, J = 5.58 Hz, 1 H), 7.85 (s, 1 H), 7.75 (d, J = 1.2 Hz, 1 H), 7.73 (d, J = 1.8 Hz, 1 H), 7.45–7.50 (m, 3 H), 4.38 (dd, J = 17.6 Hz, 2.6 Hz, 1 H), 4.25 (dd, J = 17.6 Hz, 2.6 Hz, 1 H), 3.81 (s, 3 H), 3.67 (dd, J = 17.0 Hz, 5.7 Hz, 1 H), 3.56 (dd, J = 17.0 Hz, 5.6 Hz, 1 H), 3.14 (t, J = 2.6 Hz, 1 H), 1.77 (s, 3 H). {¹H}¹³C NMR (101 MHz, DMSO-d₆): δ = 169.3, 168.7, 164.7, 139.7, 131.8, 131.3, 130.5, 129.1, 126.9, 77.8, 76.1, 52.8, 40.7, 35.8, 22.2.
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• 14 CCDC 2338002 contains the supplementary crystallographic data for 1. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures