A highly diastereoselective synthesis of isoindolinone-centered Meyers’ tetracyclic lactams. Application to the asymmetric synthesis of 3-alkylisoindolinones

A new methodology for the asymmetric synthesis of C-3 alkylated isoindolinones has been developed through a novel extension of Meyers’ lactamisation. The key polycyclic lactam precursor was prepared in high yield and high diastereoselectivity by a two step sequence involving phthalic anhydride and aminoprolinol. Metallation/alkylation followed by hydride reduction of the transient N-acylhydrazonium species and ultimate removal of the chiral auxiliary without a loss of stereochemical integrity completed the synthesis of the target compounds.

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2-[(S)-2-Hydroxymethylpyrrolidin-1-yl]-isoindole-1,3-dioneC13H14N2O3ee >95%[α]D25=-42.0 (c 0.50, CHCl3)Source of chirality: (S)-prolineAbsolute configuration: (2′S)

(3aS,5aR)-2,3,3a,4-Tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC13H14N2O2de >95%[α]D25=+81.6 (c 0.57, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aR)-5a-Methyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC14H16N2O2de >95%[α]D25=+10.5 (c 0.60, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aR)-5a-Propyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC16H20N2O2de >95%[α]D25=+19.7 (c 0.66, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aR)-5a-Isopropyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC16H20N2O2de >95%[α]D25=+9.0 (c 0.58, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aR)-5a-Allyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC16H18N2O2de >95%[α]D25=+12.2 (c 0.55, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aR)-5a-Benzyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC20H20N2O2de >95%[α]D25=+21.0 (c 0.67, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aR)

(3aS,5aS)-5a-[(S)-Hydroxy-(4-methoxyphenyl)methyl]-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-oneC21H22N2O4de >95%[α]D25=+58.3 (c 0.54, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3aS,5aS,1′S)

(R)-2-[(S)-2-Hydroxymethylpyrrolidin-1-yl]-3-propyl-2,3-dihydroisoindol-1-oneC16H22N2O2de >95%[α]D25=-3.3 (c 0.54, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (3R,2′S)