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

摘要

A review showed that 1,3-amino-alcohos 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-p-bromobenzoate derivative. Resolution of this amino-alcohol was achieved by co-crystallization 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 (1R,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 BCl3-catalyzed Diels Alder reactions. Dienophiles were prepared in 1 step, in 74--77% yield, from (1R,5R,6 R)-N-(6-hydroxyspiro[4.4]non-1-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,6S)-6-Aminospiro[4.4]nonan-1-ol was converted to phosphino-oxazine ligand (3aS,6a S,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 ZnCl2 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.