Download PDF
Synlett 2003(12): 1809-1812  
DOI: 10.1055/s-2003-41502
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Katsuji Ito*a, Suemi Akashia, Bunnai Saitob, 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
Further Information

Publication History

Received 6 June 2003
Publication Date:
19 September 2003 (online)

    Permissions and Reprints All articles of this category

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

13

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).

15

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).

16

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.

17

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]