Application of Flow and Biocatalytic Transaminase Technology for the Synthesis of a 1-Oxa-8-azaspiro [4.5] decan-3-amine

• Jeffrey T. Kohrt^a
• Peter H. Dorff^a
• Michael Burns^b
• Chewah Lee^b
• Steven V. O’Neil^b
• Robert J. Maguire^b
• Rajesh Kumar^b
• Melissa Wagenaar^b
• Loren Price^a
• Manjinder S. Lall^a

• ^aMedicine Design, Pfizer Inc., 445 Eastern Point Road, Groton, Connecticut 06340, United States
• ^bChemical Research and Development, Pfizer Inc., 445 Eastern Point Road, Groton, Connecticut 06340, United States

Spirocyclic ring systems are useful intermediates in the design and synthesis of medicinally active agents and commonly found as cores in natural products. Recently, syntheses of a key intermediate Boc-protected-1-oxa-8-azaspiro[4.5]decan-3-amine 1 were examined. While multigram quantities of the racemic material could be made from the reduction of an energic azide intermediate, larger scale reactions and a chiral synthesis required further investigations. Herein, we describe the use of a continuous three-step flow process to scale the formation and reduction of an azide intermediate, and the use of a transaminase to prepare the desired enantiomer in high yield and enantiomeric excess.

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