Efficient Total Synthesis of Khafrefungin: Convergent Approach Using Suzuki Coupling under Thallium-free Conditions Toward Multigram-scale Synthesis

Abstract

An efficient and practical synthetic route to khafrefungin, an antifungal agent, has been developed based on successive coupling of three components, 3, 4, and then 2. A key step of the synthesis is the Suzuki coupling of 2 and 10, in which the use of toxic thallium ethoxide has been avoided, and the coupling adduct (11) was obtained in multigram-scale quantities.

Key words

khafrefungin - total synthesis - antifungal agents - Suzuki coupling - multigram-scale synthesis

References

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5

Multigram-scale synthesis of alkyne 2, alkenyliodide 3, and alcohol 4: Alkyne 2 (5.2 g) was synthesized from methyl (R)-(-)-3-hydroxy-2-methylpropionate (10 mL) according to the literature (14 steps). [3b] In the present synthesis, chiral alcohol 9 was synthesized by the procedure shown in Scheme [2] . Alkenyliodide 3 (18.2 g) was prepared from diethyl methylmalonate (40 mL) according to the literature (9 steps). [3b] Alcohol 4 (5.5 g) was synthesized from d-arabinose (4.7 g) according to the literature (5 steps). [3a]

8

Suzuki coupling reaction of alkyne 2 with alkenyliodide 10: To a stirred solution of alkyne 2 (1.09 g, 2.82 mmol) in THF (18 mL) was added 9-BBN (6.00 mmol, 0.5 M solution in THF) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. Alkenyliodide 10 (2.76 g, 2.34 mmol) in THF (10 mL), H₂O (10 mL), K₃PO₄ (2.50 g, 11.8 mmol), and PdCl₂(dppf) (0.38 g, 0.47 mmol) were added subsequently, and the mixture was stirred for 30 min at 70 °C. After the mixture was cooled to room temperature, saturated aqueous NaHCO₃ was added and the organic layer was extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated. Purification by silica gel chromatography (EtOAc-hexane, 1:6) gave the coupled product 11 (2.93 g, 84%) as a colorless oil.