Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinazonazole (Jublia®)

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Supporting Information

An Enantioselective Synthesis of the Key Intermediate for Triazole

Antifungal Agents; Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

Keiji Tamura, Naoya Kumagai,* and Masakatsu Shibasaki*

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan

mshibasa@bikaken.or.jp, nkumagai@bikaken.or.jp

1. General S2 2. Materials S2 3. Attempts to Characterize Transient Compounds S2 4. HPLC Charts to Determine Enantiopurity S3 5. NMR Spectra S4–25

Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinazonazole (Jublia®)

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1. General The reaction vessels were fitted with a 3-way glass stopcock and reactions were run under Ar atmosphere unless otherwise noted. Air- and moisture-sensitive liquids were transferred via a gas-tight syringe and a stainless-steel needle. All work-up and purification procedures were carried out with reagent-grade solvents under ambient atmosphere. 2. Materials Unless otherwise noted, materials were purchased from commercial suppliers and were used without further purification. THF, MeCN, Toluene and CH2Cl2 were purified by passing through a solvent purification system (Glass Contour). EtCN was purchased from TCI and distilled before use. Gd(HMDS)3  was purchased from Sigma-Aldrich and used as received (opened and handled in a dry box). Ligand 4 was prepared by following the reported procedure.1

Column chromatography was performed with silica gel Merck 60 (230–400 mesh ASTM) or silica gel 60 N (spherical, neutral, 40–50 !m) from Kanto Chemical Co. Ltd. Preparative TLC plates (1.05744.0001, PLC Silica gel 60 F254) were purchased from Merck. 3. Attempts to Characterize Trasient Compounds Slight modification of the quenching conditions resulted in 2 diastereomers of 6 together with a trace amount of 2 diastereomers of 7. Irreversible TMS group migration from 6 to 7 was observed under basic conditions. Removal of TMS group on tertiary hydroxyl group of 6 with TBAF at 0 °C allowed for isolation of diol 8 without subsequent epoxide formation. Removal of TMS group and intramolecular cyclization of 6 was induced by the treatment with TBAF at room temperature to afford epoxide 9. Experimental procedures are provided in experimental section of the manuscript.

Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinazonazole (Jublia®)

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4. HPLC Charts to Determine Enantiopurity

Chart S1. HPLC trace for diol 10. HPLC conditions: DAICEL CHIRALPAK AD-H (φ 0.46 cm x 25 cm), n-hexane/EtOH = 85/15, flow rate 1.0 mL/min, detection at 254 nm, column temp. 23 °C, tR = 11.4 min (ent-10), 18.4 min (10).

Chart S1. HPLC trace for epoxide 1. HPLC conditions: DAICEL CHIRALCEL OD-H (φ 0.46 cm x 25 cm), n-hexane/EtOH = 85/15, flow rate 1.0 mL/min, detection at 254 nm, column temp. 23 °C, tR = 10.8 min (1), 12.6 min (ent-1).

Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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Supporting Information An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents;

Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia®)

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