Asymmetric hydrogenation of trisubstituted N-acetyl enamides derived from 2-tetralones using ruthenium-SYNPHOS catalysts: a practical synthetic approach to the preparation of β3-adrenergic agonist SR58611A

The asymmetric hydrogenation of various trisubstituted enamides derived from 2-tetralones under mild reaction conditions using Ru-SYNPHOS catalysts is reported. This practical and clean method gives access to several chiral 2-aminotetralins derivatives in high isolated yields and enantiomeric excesses up to 95% depending on the substitution pattern of the aromatic ring and the nature of the amide moiety. In addition, the usefulness of the current method is demonstrated via a practical synthetic approach to the enantiomerically pure SR58611A compound, a potent and selective β3-adrenergic receptor agonist.

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(S)-N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamideC13H17NO2Ee = 95%[α]D25=-10.6 (c 1, CHCl3).Source of chirality : (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-acetamideC12H15NOEe = 95%[α]D25=-21.6 (c 1, CHCl3).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(7-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamideC13H15NO2Ee = 92%[α]D25=-31.6 (c 0.8, CHCl3).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(7-Carbethoxymethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamideC16H21NO4Ee = 95%[α]D25=-23.2 (c 1, CHCl3).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(7-Carbethoxymethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-trimethylacetamideC19H27NO4Ee = 78%[α]D25=-20.3 (c 1, CHCl3).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-formamideC12H15NO2Ee = 72%[α]D25=-36.6 (c 0.50, CHCl3).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(R)-N-(7-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-formamideC11H13NO2Ee = 75%[α]D25=+45.6 (c 0.40, CHCl3).Source of chirality: (R)-SYNPHOSAbsolute configuration: (R)

(S)-N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-amine, hydrochlorideC11H15NO·HClEe = 95%[α]D25=-66.1 (c 0.5, MeOH).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)

(S)-N-(7-Carbethoxyethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-amine, hydrochlorideC14H19NO3·HClEe = 95%[α]D25=-53.4 (c 1, MeOH).Source of chirality: (S)-SYNPHOSAbsolute configuration: (S)