Lithium‐Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3‐Sulfanyl‐Oxetanes as Bioisosteres

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  • Rosemary A. Croft
    Department of Chemistry Imperial College London South Kensington, London SW7 2AZ UK
  • James J. Mousseau
    Pfizer Medicine Design Eastern Point Road Groton CT 06340 USA
  • Chulho Choi
    Pfizer Medicine Design Eastern Point Road Groton CT 06340 USA
  • James A. Bull
    Department of Chemistry Imperial College London South Kensington, London SW7 2AZ UK

Abstract

<jats:title>Abstract</jats:title><jats:p>3‐Sulfanyl‐oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan‐3‐ols, a mild and inexpensive Li catalyst enables chemoselective C−OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various π‐activated secondary and tertiary alcohols are also successful. Derivatization of the oxetane sulfide linker provides further novel oxetane classes and building blocks. Comparisons of key physicochemical properties of the oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.</jats:p>

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