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Synthesis 2005(19): 3245-3252  
DOI: 10.1055/s-2005-918454
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Straightforward and Efficiently Scaleable Synthesis of Novel Racemic 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives

Eva A. Krafft, Anke Kurt, Axel Maier, Andrew W. Thomas*, Daniel Zimmerli
F. Hoffmann-La Roche AG, Pharmaceuticals Division, Discovery Chemistry, 4070 Basel, Switzerland
Fax: +41(61)6888714; e-Mail: andrew.thomas@roche.com;
Further Information

Publication History

Received 31 August 2005
Publication Date:
28 October 2005 (online)

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Abstract

Novel and straightforward syntheses (3-5 steps, high yields) of racemic diazaspiropiperidine derivatives based on the Michael addition of pipecolate-derived enolates to a range of nitroalkenes have been developed. The reaction has been shown to have a general scope and can be conducted on a preparatively useful scale. Isolation and identification of diazaspiropiperidine enantiomers was efficiently achieved using normal phase chiral HPLC.

Key words

cyclizations - lactams - Michael additions - piperidines - spiro compounds

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9

Reduction using H2 (1 atm), Pd/C in EtOH, Fe/AcOH or SnCl2 in HCl-mediated reduction resulted in the formation of complex mixtures with the major component being the incompletely reduced hydroxylamine derivatives and their subsequent spiro-cyclized products.