A concise and improved synthesis of (+)-eleutherin, (+)-allo-eleutherin and a formal synthesis of (+)-nocardione B

A concise and improved stereoselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and the formal synthesis of (+)-nocardione B is described. The synthesis is based on a Dötz benzannulation and an improved oxa-Pictet–Spengler cyclization as the key steps. The synthesis is achieved in six steps in overall yields of 18% for eleutherin and 20% for allo-eleutherin.

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(2S)-tert-Butyldimethyl(pent-4-yn-2-yloxy)silaneC11H22OSi[α]D25=+3.1 (c 1.0, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(2S)-2-(2-tert-Butyldimethylsilyloxy)propyl-4,5-dimethoxynaphthalen-1-olC21H32O4Si[α]D25=-45.9 (c 0.5, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(2S)-2-(2-Hydroxypropyl)-4,5-dimethoxynaphthalen-1-olC15H18O4[α]D25=-95 (c 0.4, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(4S)-7,8-Dimethoxy-2,4-dimethyl-4,5-dihydronaphtho[1,2-d][1,3]dioxepineC17H20O4[α]D25=-71.5 (c 0.34, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (4S)

(2S)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dioneC14H14O4[α]D25=+65 (c 0.48, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(2S)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-diolC14H16O4[α]D25=+16 (c 0.5, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(2S)-tert-Butyldimethyl-[1-(1,4,5-trimethoxynaphthalen-2-yl)propan-2-yloxy]silaneC22H34O4Si[α]D25=+16.4 (c 1.1, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(2S)-1-(1,4,5-Trimethoxynaphthalen-2-yl)propan-2-olC16H20O4[α]D25=+34.2 (c 0.38, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (2S)

(1R,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromeneC18H22O4[α]D25=+46.3 (c 0.8, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (1R,3S)

(1S,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromeneC18H22O4[α]D25=+37.5 (c 1.2, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (1S,3S)

(+)-EleutherinC16H16O4[α]D25=+338 (c 0.34, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (1R,3S)

(+)-Allo-eleutherinC16H16O4[α]D25=+65.6 (c 0.3, CHCl3)Initial source of chirality: (S)-ethyl 3-hydroxybutanoateAbsolute configuration: (1S,3S)