Synthesis of cis,cis-6-aminospiro[4.4]nonan-1-ol and application of its derivatives as chiral ligands and auxiliaries

Abstract

A review showed that 1,3-amino-alcohols and their derivatives had proven useful as sources of chiral induction in organic synthesis and that there was much room for research in this area. Of particular interest was a cis,cis-spiro-1,3-amino-alcohol in which two spirocyclic pentacycles offered structural rigidity and the cis,cis geometry of the molecule held the amino and hydroxy moieties in close proximity. A synthesis of (1RS,5RS,6RS)-6-aminospiro[4.4 ]nonan-1-ol is reported in which only one diastereomer was produced in 22% yield over 6 steps. The structure of this amino-alcohol was confirmed by X-ray crystallography of the pivalamido-p­bromobenzoate derivative. Resolution of this amino-alcohol was achieved by co­crystallization with 0.5 equiv. mandelic acid in acetonitrile to give material that which appeared enantiopure by chiral GC. Conversion of (1R,5R,6R)-6-aminospiro[ 4.4]nonan-1-ol to (lR,5R,6R)-N-( 6-hydroxyspiro[ 4.4 ]non-1-yl)-2,2-dimethylpropionamide was accomplished in 1 step with 97% yield, and this amido-alcohol was used as a chiral auxiliary in BCh-catalyzed Diels­Alder reactions. Dienophiles were prepared in 1 step, in 74-77% yield, from (1R,5R,6R)­N-( 6-hydroxyspiro[ 4.4 ]non-l-yl)-2,2-dimethylpropionamide, and reaction of these dienophiles with a variety of dienes in the presence of 2 equiv. BCl₃ at -78°C gave Diels-Alder adducts with 77 to >98% de. The amido-alcohol auxiliary was readily cleaved from the Diels-Alder adducts by saponification and could be recovered in sufficient quantity and purity to warrant recycling. (1S,5S,6.5)-6-Aminospiro[4.4 ]nonan-1-ol was converted to phosphino-oxazine ligand (3aS,6aS,9aS)-5-(2-diphenylphosphanylphenyl)-1,2,3,3a,6a, 7,8,9-octahydro-4- oxa-6-azacyclopenta[ d]indene in 90% yield over 2 steps. Its structure was confirmed by X-ray crystallography of the ZnCh complex. The phosphino-oxazine was used as a ligand for asymmetric Pd-catalyzed alkylation of dimethyl malonate with 1,3-diphenyl acetate to give product with up to 91 % ee.