Divergent synthesis of chiral spiro (isoxazole–isoxazoline) hybrid ligands

An efficient synthetic method for chiral (isoxazole–isoxazoline) ligands based on a spiro[4.5]decane framework has been developed. A variety of enantiomerically pure ligands were readily prepared via the Suzuki–Miyaura coupling. The palladium complexes of these ligands have proven to be effective catalysts for the asymmetric Wacker-type cyclization of an alkenyl alcohol.

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(R,S)-3-Bromo-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C18H25BrN2O2Ee >99%[α]D19 = +177.3 (c 0.500, CHCl3)Source of chirality: resolution by HPLC (Chiralpak AD)Relative configuration: (R,S)

(S,R)-3-Phenyl-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C24H30N2O2Ee >99%[α]D22 = –185.5 (c 0.605, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(R,S)-3-(4-Methoxyphenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C25H32N2O3Ee >99%[α]D21 = +182.0 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (R,S)

(S,R)-3-(4-Methylthiophenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C25H32N2O2SEe >99%[α]D22 = –174.0 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(S,R)-3-(4-Dimethylaminophenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C26H35N3O2Ee >99%[α]D23 = –157.9 (c 0.615, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(S,R)-3-(4-Methoxylcarbonylphenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C26H32N2O4Ee >99%[α]D23 = –157.7 (c 0.615, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(S,R)-3-(4-Fluorophenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C24H29FN2O2Ee >99%[α]D23 = –153.9 (c 0.730, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(S,R)-3-(1-Naphthyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C28H32N2O2Ee >99%[α]D24 = –138.2 (c 0.455, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(S,R)-3-(2-Naphthyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C28H32N2O2Ee >99%[α]D23 = –87.1 (c 0.465, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(R,S)-3-(9-Anthryl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C32H34N2O2Ee >99%[α]D23 = +124.5 (c 0.805, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (R,S)

(S,R)-3-(2,6-Xylyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C26H34N2O2Ee >99%[α]D24 = –140.8 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)

(R,S)-3-(2-Biphenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C30H34N2O2Ee >99%[α]D24 = +158.1 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (R,S)

(R,S)-3-(2-Trifluoromethylphenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C25H29F3N2O2Ee >99%[α]D24 = +157.2 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (R,S)

(S,R)-3-(3,5-Bis(trifluoromethyl)phenyl)-3′,3′-diisopropyl-3′,3a′,4′,5,5′,6-hexahydro-4H-spiro[2,1-benzisoxazole-7,6′-cyclopenta[c]isoxazole]C26H28F6N2O2Ee >99%[α]D24 = –134.7 (c 0.500, CHCl3)Source of chirality: derivatized from the chiral precursorRelative configuration: (S,R)