Synlett 2011(5): 663-664  
DOI: 10.1055/s-0030-1259558
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of (±)-trans-Indolizidine-8-carboxylic Acid

Wen-Hua Chiou*, Yi-Huei Lin, Yu-Kai Gao
Department of Chemistry, National Chung Hsing University, Taichung, 402 Taiwan, R.O.C.
Fax: +886(4)22862547; e-Mail: wchiou@dragon.nchu.edu.tw;
Further Information

Publication History

Received 19 December 2010
Publication Date:
11 February 2011 (online)

Abstract

A facile synthesis of a novel amino acid, trans-indolizidine-8-carboxylic acid, is described.

    References and Notes

  • 1 Manahan-Vaughan D. Reiser M. Pin J.-P. Wilsch V. Bockaert J. Reymann KG. Riedel G. Neuroscience  1996,  72:  999 
  • 2 Ishida M. Saitoh T. Nakamura Y. Kataoka K. Shinozaki H. Neuropharmacology  1995,  34:  821 
  • 3 Chiou W.-H. Lin G.-H. Hsu C.-C. Chaterpaul SJ. Ojima I. Org. Lett.  2009,  11:  2659 
  • 4 Tellitu I. Serna S. Herrero MT. Moreno I. Domínguez E. SanMartin R. J. Org. Chem.  2007,  72:  1526 
  • 5 Billig E, Abatjoglou AG, and Bryant D. inventors; US  4769498.  1988; the complete chemical name of BIPHEPHOS is 6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diyl)bis(oxy)]bis(dibenzo[d,f][1,3,2]dioxaphosphepin).
  • 6 Cuny GD. Buchwald SL. J. Am. Chem. Soc.  1993,  115:  2066 
  • 9 ten Brink G.-J. Arends IWCE. Sheldon RA. Chem. Rev.  2004,  104:  4105 
  • 10 Kobayashi S. Tanaka H. Amii H. Uneyama K. Tetrahedron  2003,  59:  1547 
7

(E )-8-(α-acetyloxy-4′-methoxybenzylidenyl)-5-oxoindolizidine (2) Rh(acac)(CO)2 (3.9 mg, 15.0 µmol, 0.5 mol%) and BIPHEPHOS (23.4 mg, 30 µmol, 1.0 mol%) were dissolved in AcOH (1 mL) under nitrogen. The resulting catalyst solution was degassed by a freeze-thaw procedure at least three times. Amide 1 4 (730 mg, 3.0 mmol, 1.00 equiv) and PTSA (57 mg, 0.3 mmol, 10 mol%) were placed in a 100 mL flask. The catalyst solution was transferred to the reaction flask containing the substrate by a pipette, and the total volume was adjusted to 60 mL with AcOH. The reaction flask was placed in a 300 mL stainless steel autoclave and then was pressurized with CO (2 atm) followed by H2 (2 atm). The reaction mixture was stirred at 60 ˚C for 16-20 h. Upon completion of the reaction, the gas was carefully released in a good ventilated hood, and the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was partitioned with CH2Cl2 (20 mL) and aq NaHCO3 (10 mL). After separation of the organic layer, the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhyd Na2SO4, and then concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel using MeOH-CH2Cl2 as the eluant to give the product in 83% yield as a light yellow oil. R f = 0.45 (MeOH-CH2Cl2 = 1:9). ¹H NMR (600 MHz, 25 ˚C, CDCl3): δ = 1.35 (dq, J = 5.4, 10.8 Hz, 1 H, H-1), 1.57-1.63 (m, 1 H, H-2), 1.63-1.69 (m, 1 H, H-1), 1.76-1.84 (m, 1 H, H-2), 2.13 (s, 3 H, OCCH3), 2.24 (ddd, J = 3.6, 15.0, 15.0 Hz, 1 H, H-7), 2.36 (ddd, J = 4.2, 15.6, 15.6 Hz, 1 H, H-6), 2.52 (ddd, J = 3.6, 3.6, 15.6 Hz, 1 H, H-6), 2.65 (ddd, J = 3.0, 4.2, 14.4 Hz, 1 H, H-7), 3.30 (dd, J = 3.6, 11.4 Hz, 1 H, H-3), 3.64 (ddd, J = 8.4, 8.4, 12.0 Hz, 1 H, H-3), 3.82 (s, 3 H, OCH3), 4.18 (dd, J = 5.4, 10.8 Hz, 1 H, H-8a), 6.88 (d, J = 8.4 Hz, 2 H, H-3′), 7.28 (d, J = 8.4 Hz, 2 H, H-2′). ¹³C NMR (150 MHz, 25 ˚C, CDCl3): δ = 20.7 (q, CH3CO), 22.1 (t, C-2), 22.6 (t, C-7), 32.2 (t, C-6), 32.4 (t, C-1), 43.6 (t, C-3), 55.1 (q, CH3O), 58.0 (d, C-8a), 113.7 (d, C-3′), 124.8 (s, C-8), 127.3 (s, C-1′), 130.4 (d, C-2′), 142.2 (s, C-9), 159.8 (s, C-4′), 168.7 (s, CH3CO), 170.0 (s, C-5), HRMS-FAB: m/z
[M + H]+ calcd for C18H22NO4 +: 316.1549; found: 316.1541 (Δ = 2.5 ppm).

8

The results of DFT calculations for ketone trans-3 and cis-3 at the level of B3LYP/6-31G* showed trans-3 is more stable than cis-3 by 2.1 kcal/mol.