Synlett 2008(11): 1687-1689  
DOI: 10.1055/s-2008-1077793
LETTER
© Georg Thieme Verlag Stuttgart · New York

diexo-3-Aminonorbornane-2-carboxylic Acid as Highly Applicable Chiral Source for the Enantioselective Synthesis of Heterocycles

Ferenc Fülöp*a,b, Ferenc Miklósa, Enikő Forróa
a Institute of Pharmaceutical Chemistry, Hungarian Academy of Sciences, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary
Fax: +36(62)545705; e-Mail: fulop@pharm.u-szeged.hu;
b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary
Further Information

Publication History

Received 12 March 2008
Publication Date:
19 May 2008 (online)

Abstract

Diastereomers of tetracyclic pyrrolopyrimidine derivatives 2 and 3 were prepared in a three-step domino reaction from diexo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide with levulinic acid or p-toluoylpropionic acid. When subjected to a microwave-mediated retro-Diels-Alder reaction, these tetracycles furnished bicyclic pyrrolo[1,2-a]pyrimidines through the loss of cyclopentadiene. When enantiomeric diexo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide was used, the products were enantiomeric heterocycles with ee >99%, demonstrating that the title compound is an excellent chiral source.

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(1 S ,2 S ,3 R ,4 R)- 3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(-)-1] Ethyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate (2.5 g, 13.8 mmol) was left to stand at r.t. for 3 weeks in MeOH (50 mL) saturated with NH3. The solution was then evaporated and the solid residue was crystallized from MeOH-Et2O, which afforded (-)-1 (72%) as colorless needles, mp 131-133 °C; [α]D 25 -4.8 (c 0.51, MeOH).

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Synthesis of Pyrrolo[1,2- a ]quinazolines 2 and 3 diexo-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxamide

[(-)-1, (0.76 g, 5 mmol], levulinic acid or p-toluoylpropionic acid (5.2 mmol), and PTSA (0.05 g) in toluene (25 mL) was refluxed for 14 h. The solvent was then evaporated off, and the residue was dissolved in CHCl3 (10 mL) and the products were separated on a SiO2 column with a mixture of n-hexane-EtOAc-EtOH (5:4:1).
Compound (+)-2a: yield 86%, colorless crystals, mp 173-175 °C (EtOAc-i-Pr2O); [α]D 25 +49 (c 0.27, MeOH). IR (KBr): 3173, 1701, 1659, 707 cm-1. 1H NMR (400 MHz, DMSO): d = 8.69 (br s, NH), 6.29 (dd, J = 2.7, 5.5 Hz, H-7), 6.17 (dd, J = 2.7, 5.5 Hz, H-8), 4.05 (br s, H-9), 3.34 (d, J = 7.8 Hz, H-8a), 3.27 (br s, H-6), 2.39-2.32 (m, 2 H, H-2), 2.29 (d, J = 7.8 Hz, H-5a), 2.02 (m, H-3), 1.87 (m, H-3), 1.37 (s, 3 H, CH3-3a), 1.27 (d, J = 8.7 Hz, H-10), 1.20 (d, J = 8.7 Hz, H-10). 13C NMR (100 MHz, DMSO): d = 26.12, 29.49, 32.28, 41.69, 43.11, 43.38, 45.23, 52.32, 73.14, 135.70, 137.85, 169.96, 172.35. MS: m/z = 233 [M + H]+.
Compound (+)-2b: colorless crystals, mp 134-136 °C (Et2O-n-hexane); [a]D 25 +37 (c 0.25, MeOH). IR (KBr): 3178, 1705, 1661, 817 cm-1. 1H NMR (400 MHz, DMSO): d = 9.48 (br s, NH), 7.23-7.07 (m, 4 ArH), 6.15 (dd, J = 2.9, 5.8 Hz, H-7), 6.11 (dd, J = 3.0, 5.6 Hz, H-8), 4.21 (br s, H-9), 3.25 (br s, H-6), 3.13 (d, J = 7.9 Hz, H-9a), 2.54-2.35 (m, 2 H, H-2), 2.33-2.22 (m, H-3), 2.27 (s, 3 H, CH3-Ar), 2.04 (m, H-3), 1.62 (d, J = 7.7 Hz, H-5a), 1.33 (d, J = 8.8 Hz, H-10), 1.27 (d, J = 8.8 Hz, H-10). 13C NMR (100 MHz, DMSO): d = 20.43, 29.30, 34.67, 42.24, 42.63, 43.81, 44.86, 54,08, 77.14, 124.75 (2 × C), 129.56 (2 × C), 135.95, 137.23, 137.66, 140.45, 170.57, 173.36. MS: m/z = 309 [M + H]+.
Compound (+)-3b: colorless powder, mp 247-248 °C (EtOAc); [a]D 25 +40 (c 0.28, MeOH). IR (KBr): 3161, 1704, 1648, 815 cm-1. 1H NMR (400 MHz, DMSO): d = 9.58 (br s, NH), 7.28-7.17 (m, 4 ArH), 6.26 (dd, J = 3.2, 5.4 Hz, H-7), 6.20 (dd, J = 2.8, 5.6 Hz, H-8), 4.12 (d, J = 8.8 Hz, H-9a), 2.92 (br s, H-6), 2.62 (br s, H-9), 2.50-2.23 (m, 2 H, H-2), 2.30 (m, H-3a), 2.28 (s, 3 H, CH3-Ar), 2.20 (d, J = 8.8 Hz, H-3), 2.00 (m, H-3), 0.78 (d, J = 9.1 Hz, H-10), 0.60 (d, J = 9.1 Hz, H-10). 13C NMR (100 MHz, DMSO): d = 20.44, 28.05, 39.28, 39.70, 44.27, 46.45, 46.58, 50.95, 76.36, 123.76 (2 × C), 129.14 (2 × C), 136.73, 137.53, 137.79, 142.60, 168.98, 173.73. MS: m/z = 309 [M + H]+.

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Syntheses of Pyrrolo[1,2- a ]pyrimidines by Microwave-Induced Retro-Diels-Alder Reaction All microwave-induced reactions were performed in sealed reaction vials. Tetracycle 2a, 2b, or 3b (200 mg) was placed in a microwave test tube (10 mL) subsequently sealed with a Teflon cap, which contained a magnetic stirrer and o-DCB (2 mL). The test tube was placed in the microwave (CEM, Discover) cavity. The solutions were irradiated at 250 °C (power 250 W) for 10 min then cooled to r.t., CHCl3 (6 mL) was added, and the solution was transferred to a SiO2 column and eluted with EtOAc.
Compound (-)-4a: synthesized from (+)-2a, colorless crystals, mp 170-172 °C (i-Pr2O-EtOAc); [α]D 25 -445 (c 0.23, MeOH), ee >99%. IR (KBr): 3182, 1734, 1667, 826 cm-1. 1H NMR (400 MHz, DMSO): δ = 8.22 (br s, NH), 7.31 (d, J = 7.8 Hz, H-4), 5.25 (dd, J = 1.9, 7.8 Hz, H-3), 2.69-2.40 (m, 2 H, H-7), 2.20-2.02 (m, 2 H, H-8), 1.41 (s, 3 H, CH3). 13C NMR (100 MHz, DMSO): δ = 24.03, 29.00, 33.37, 73.08, 105.05, 130.65, 163.03, 170.28. MS: m/z = 167 [M + H]+.
Compound (-)-4b: synthesized from (+)-2b, colorless crystals, mp 198-200 °C (i-Pr2O-EtOAc); [α]D 25 -311 (c 0.14, MeOH), ee >99%. IR (KBr): 3184, 1728, 1667, 817 cm-1. 1H NMR (400 MHz, DMSO): δ = 9.17 (br s, NH), 7.49 (d, J = 7.7 Hz, H-4), 7.22-7.16 (m, 4 ArH), 5.21 (dd, J = 7.7, 1.9 Hz, H-3), 2.59-2.36 [m, 3 H, H-7 (2 H) and H-8 (1 H)], 2.28 (s, 3 H, CH3), 2.28-2.20 (m, 1 H, H-8). 13C NMR (100.62 MHz, DMSO): δ = 20.46, 28.54, 35.47, 76.14, 106.91, 124.33 (2×), 129.08 (2×), 131,62, 137.42, 139.98, 163.23, 171.26. MS: m/z = 243 [M + H]+.
Compound (+)-4b: synthesized from (+)-3b, colorless crystals, mp 197-199 °C (i-Pr2O×EtOAc); [α]D 25 +310 (c 0.11, MeOH), ee >99%. 1H NMR and 13C NMR data were identical to the compound (-)-4b.

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The ee value for pyrrolo[1,2-a]pyrimidine (-)-4a was determined by GC on a Chromopack Chiralsil-Dex CB column (25 m) [120 °C for 7 min → 190 °C (temperature rise 20 °C min-1; 100 kPa; (-)-4a: t R = 23.25 min (antipode: 24.70)]. The ee values for pyrrolo[1,2-a]pyrimidine (-)-4b and (+)-4b were determined by HPLC on a Chiralcel
OD-RH column (15 cm) [mobile phase, H2O-MeCN (75:25), 205 nm, 0.5 mL min-1, 25 °C; (-)-4b: t R = 13.29 min; (+)-4b: t R = 16.85 min].