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Synthesis of Four Novel Natural Product Inspired Scaffolds for Drug Discovery

Supporting Info

Ian D. Jenkins*^†, Fabienne Lacrampe^†, Justin Ripper^†, Lilian Alcaraz^‡, Phuc Van Le^†, George Nikolakopoulos^†, Priscila de Almeida Leone^†, Rodney H. White^† and Ronald J. Quinn^†

Eskitis Institute, Griffith University, Brisbane, QLD, 4111, Australia, and Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, LE11 5RH, U.K.

J. Org. Chem., 2009, 74 (3), pp 1304–1313

DOI: 10.1021/jo802456w

Publication Date (Web): December 23, 2008

* To whom correspondence should be addressed. Tel: + (07) 3735 6025. Fax: + (07) 3735 6001.

†

Griffith University.

‡

AstraZeneca R&D Charnwood.

Abstract

Inspired by the novel spiro structures of a number of bioactive natural products such as the histrionicotoxins, a series of novel spiro scaffolds have been designed and robust syntheses developed. The scaffolds are ready-to-use building blocks and can be easily prepared on a 5−20 g scale. They contain two amino groups (one Boc-protected) and have been designed for ease of conversion to a lead generation library, using either amide formation or reductive amination procedures. The synthesis of the 1,9-diazaspiro[5.5]undecane and 3,7-diazaspiro[5.6]dodecane ring systems was achieved using RCM as the key step. A simple workup procedure is reported for the removal of highly colored ruthenium residues. The synthesis of the 1,8-diazaspiro[4.5]decane scaffold has been achieved using a bromine-mediated 5-endo cyclization of the corresponding 4-aminobutene intermediate under acidic conditions. This is the first example of this type of cyclization to be reported. A novel mechanism involving a bromine transfer reaction from an initially formed bromonium ion to a neighboring nitrogen atom is suggested as the reason for the failure of this type of reaction under “normal” bromination conditions. An unusual rearrangement of a 1-acyl-1,9-diazaspiro[5.5]undecane to the corresponding 9-acyl-1,9-diazaspiro[5.5]undecane is reported.

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