Asymmetric Intramolecular Allylic Amination: Straightforward Approach to Chiral C1-Substituted Tetrahydroisoquinolines

Katsuji Ito; Suemi Akashi; Bunnai Saito; Tsutomu Katsuki

doi:10.1055/s-2003-41502

LETTER

Asymmetric Intramolecular Allylic Amination: Straightforward Approach to Chiral C1-Substituted Tetrahydroisoquinolines

Katsuji Ito*^a, Suemi Akashi^a, Bunnai Saito^b, Tsutomu Katsuki*^b
^a Department of Chemistry, Fukuoka University of Education, CREST,Japan Science and Technology (JST), Akama, Munakata, Fukuoka, 811-4192, Japan
Fax: +81(940)351711; e-Mail: itokat@fukuoka-edu.ac.jp;
^b Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, CREST, Japan Science and Technology (JST), Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

Abstract

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Abstract

Newly introduced Pd-catalyzed asymmetric intramolecular allylic amination provides an easy access to pharmaceutically important 1-substituted tetrahydroisoquinolines. With this amination as the key step, (R)-carnegine was synthesized in an enantioselective manner.

Key words

asymmetric allylic amination - tetrahydroisoquinoline - asymmetric catalysis - palladium - chiral P-N ligand

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Referenzen

References

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Example of intramolecular allylic amination:

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All the compounds in Scheme [2] gave satisfactory ¹H NMR (400 MHz) spectra. Compound 1a: δ = 6.73 (dt, J = 1.2 and 11.2 Hz, 1 H), 6.65 (s, 1 H), 6.64 (s, 1 H), 5.81 (dt, J = 6.8 and 11.2 Hz, 1 H), 4.71 (dd, J = 1.2 and 6.8 Hz, 2 H), 3.87 (s, 6 H), 3.52 (dt, J = 6.8 and 6.8 Hz, 2 H), 2.87 (t, J = 6.8 Hz, 2 H), 2.03 (s, 3 H). Compound 1b: δ = 6.95 (br s, 1 H), 6.74 (dt, J = 1.2 and 11.2 Hz, 1 H), 6.65 (s, 1 H), 6.62 (s, 1 H), 5.77 (dt, J = 6.8 and 11.2 Hz, 1 H), 4.73 (dd, J = 1.2 and 6.8 Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.53-3.43 (m, 2 H), 2.89 (t, J = 6.8 Hz, 2 H), 1.13 (s, 9 H).

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Typical Experimental Procedure for Allylic Amination: Tris(dibenzylideacetone)dipalladium(0) chloroform adduct (1.9 mg, 1.8 µmol) and ligand 2 (1.5 mg, 3.6 µmol) was placed in a flask under nitrogen and CH₂Cl₂ (0.36 mL) was added. After being stirred for 30 min at r.t., compound 1b (50 mg, 0.12 mmol) in CH₂Cl₂ (0.24 mL) and K₂CO₃ (49.8 mg, 0.36 mmol) was added successively and the mixture was stirred at the temperature for 12 d. The mixture was quenched with H₂O and extracted with CH₂Cl₂. The extract was dried over anhyd MgSO₄ and concentrated. Silica gel chromatography of the residue (hexane-EtOAc = 9:1) gave the desired product (33.7 mg, 89%) as an oil. [α]_D ²³ -157.7 (c 0.38, CHCl₃). ¹H NMR analysis of the product at 24 °C revealed that it existed as a 78:22 mixture of two rotamers based on the amide function. ¹H NMR (400 MHz): δ = 6.64 (s, 0.22 H), 6.61 (s, 0.78 H), 6.60 (s, 0.78 H), 6.56 (s, 0.22 H), 6.06-5.93 (m, 1.78 H), 5.48-5.45 (m, 0.22 H), 5.33-5.29 (m, 1 H), 5.17-5.11 (m, 0.78 H), 5.05 (d, J = 17.2 Hz, 0.22 H), 4.55-4.48 (m, 0.22 H), 4.09-3.98 (m, 0.78 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.56 (dt, J = 4.0 and 12.0 Hz, 0.78 H), 3.26 (dt, J = 4.8 and 12.4 Hz, 0.22 H), 3.02-2.92 (m, 1 H), 2.78-2.71 (m, 1 H). Anal. Calcd for C₁₅H₁₆F₃NO₃: C, 57.14; H, 5.12; N, 4.44. Found: C, 57.02; H, 5.16; N, 4.42. Enantiomeric excess of the product was determined to be 88% by HPLC using a chiral stationary phase column (Daicel Chiralcel OJ-H; hexane:i-PrOH= 9:1).

A larger scale cyclization of 1b (0.64 mmol scale) afforded 6 with slightly reduced enantioselectivity (85% ee). This compound 6 was used for the following reactions.

The specific rotation of 7a (98% ee) was [α]_D ²⁴ -91.0 (c 2.03, CHCl₃) {Lit. R-isomer [3d] [α]_D ²³ +88.8 (c 2.08, CHCl₃)}. Since the enantiomer of 7a has been converted into the enantiomers of (S)-calycotomine and (S)-N-methyl-calycotomine respectively, the synthesis of 7a means that formal total syntheses of those isoquinoline alkaloids have been achieved. [3d]