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

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.

Key words

asymmetric synthesis - β-amino acids - retro reactions - ring closure - chiral source - chirality transfer - domino reactions

References and Notes

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20

(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).

21

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]⁺.

22

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.

23

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].