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

Abstract

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

Key words

amino acids - bicyclic compounds - heterocycles - ­hydroformylation - tandem reactions

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.  ; 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.