Highly Efficient Domino Reaction for the Synthesis of the Erythrina and B-Homoerythrina Alkaloid Skeleton

Abstract

A Lewis acid catalyzed domino-amidation-spirocyclization reaction is described which provides the spirocyclic core of the erythrina and B-homoerythrina alkaloids, forming three bonds in one process.

domino reactions - erythrina alkaloids - spiro compounds - Lewis acids - indolizidine - lactams

References and Notes

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6

General Procedure
To a stirred solution of amine 2 (1.00 equiv) in MeCN (0.5 mL/mmol) was added dropwise at 0 °C AlMe₃ (2.00 M in toluene, 2.00 equiv), then In(OTf)₃ (4-25 mol%) and the ester 3 (1.00 equiv), and stirring was continued for 3-17 h at r.t. or the mixture was heated to 100-180 °C under microwave irradiation. The reaction mixture was cooled to 0 °C, TfOH (3.5 equiv) was added dropwise and stirring was continued for 5 h at r.t. Subsequently, the mixture was quenched by addition of sat. aq NaHCO₃ at 0 °C with stirring for 20 min. The mixture was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The crude product was subjected to column chromatography to yield 38-99% of the spirocycle 4.
Compound 4a: ¹H NMR (300 MHz, DMSO): d = 1.35-1.60 (m, 5 H, 3-H₂, 2-H₂, 1-H_a), 1.75-1.82 (m, 2 H, 4-H₂), 1.95-1.99 (m, 1 H, 1-H_b), 2.12 (m_c, 2 H, 7-H₂), 2.54-2.60 (m, 1 H, 6-H), 2.63 (ddd, J = 3.0, 6.0, 16.5 Hz, 1 H, 11-H_a), 2.80 (ddd, J = 7.4, 10.0, 16.5 Hz, 1 H, 11-H_b), 3.15 (ddd, J = 6.0, 10.0, 13.2 Hz, 1 H, 10-H_a), 3.71 (s, 3 H, OCH₃), 3.76 (s, 3 H, OCH₃), 3.86 (ddd, J = 3.0, 7.4, 13.2 Hz, 1 H, 10-H_b), 6.67 (s, 1 H, 17-H), 6.91 (s, 1 H, 14-H). ¹³C NMR (300 MHz, DMSO): d = 20.06 (C-2), 20.57 (C-3), 26.14 (C-11), 27.17 (C-1), 34.26 (C-10), 35.01 (C-4), 36.29 (C-7), 36.67 (C-6), 55.42 (OCH₃), 55.74 (OCH₃), 61.75 (C-5), 108.7 (C-14), 112.5 (C-17), 125.5 (C-12), 134.7 (C-13), 147.0 (C-16), 147.5 (C-15), 173.6 (C-8).
Compound 4b: ¹H NMR (300 MHz, DMSO): d = 1.18-1.42 (m, 2 H, 11-H_a, 13*-H_a), 1.42-1.69 (m, 5 H, 2-H₂, 12*-H₂, 13*-H_b), 1.69-1.82 (m, 2 H, 1-H₂), 2.05 (dd, J = 18.5, 6.2 Hz, 1 H, 14-H_a), 2.18-2.26 (m, 1 H, 11-H_b), 2.33-2.47 (m, 1 H, 14-H_b), 2.52 (d, J = 5.9 Hz, 1 H, 6-H_a), 2.63 (m_c, 1 H, 14a-H), 2.84-2.99 (m, 1 H, 6-H_b), 3.19 (td, J = 12.3, 5.9 Hz, 1 H, 5-H_a), 3.70 (s, 3 H, OCH₃), 3.73 (s, 3 H, OCH₃), 4.53 (dd, J = 13.2, 7.5 Hz, 1 H, 5-H_b), 6.62 (s, 1 H, 7-H), 6.82 (s, 1 H, 10-H). ¹³C NMR (300 MHz, DMSO): d = 21.42 (C-13*), 22.15 (C-12*), 25.07 (C-1), 25.60 (C-2), 26.06 (C-6), 28.14 (C-14), 34.48 (C-5), 34.77 (C-14a), 39.58 (C-11), 55.32 (OCH₃), 55.89 (OCH₃), 60.99 (C-10b), 107.2 (C-10), 112.9 (C-7), 126.5 (C-6a), 135.8 (C-10a), 146.9 (C-9), 147.4 (C-8), 171.0 (C-3).
Compound 4c: ¹H NMR (300 MHz, DMSO): d = 1.28-1.48 (m, 3 H, 3-H₂, 1-H_a), 1.49-1.58 (m, 2 H, 2-H₂), 1.71-1.75 (m, 1 H, 4-H_a), 1.78-1.83 (m, 1 H, 4-H_b), 1.91-1.99, (m, 1 H, 1-H_b), 2.09-2.14 (m, 2 H, 7-H₂), 2.49-2.54 (m, 1 H, 6-H), 2.59-2.67 (m, 1 H, 11-H_a), 2.73-2.87 (m, 1 H, 11-H_b), 3.11-3.21 (m, 1 H, 10-H_a), 3.78-3.85 (m, 1 H, 10-H_b), 5.94 (s, 2 H, 18-H₂), 6.65 (s, 1 H, 17-H), 6.97 (s, 1 H, 14-H). ¹³C NMR (300 MHz, DMSO): d = 19.90 (C-2), 20.49 (C-3), 26.58 (C-11), 27.02 (C-1), 34.25 (C-10), 35.01 (C-4), 36.22 (C-7), 36.71 (C-6), 62.13 (C-5), 100.7 (C-18), 104.9 (C-14), 108.7 (C-17), 126.8 (C-12), 135.9 (C-13), 145.6 (C-16), 145.7 (C-15), 173.6 (C-8).
Compound 4d: ¹H NMR (300 MHz, DMSO): d = 1.20-1.35 (m, 2 H, 11-H_a, 13*-H_a), 1.35-1.52 (m, 2 H, 1-H₂), 1.50-1.80 (m, 5 H, 2-H₂, 12*-H₂, 13*-H_b), 2.04 (dd, J = 18.6, 6.6 Hz, 1 H, 14-H_a), 2.18-2.25 (m, 1 H, 11-H_b), 2.32-2.44 (m, 1 H, 14-H_b), 2.55-2.70 (m, 2 H, 6-H_a, 14a-H), 2.80-2.92 (m, 1 H, 6-H_b), 3.14 (td, J = 11.9, 5.8 Hz, 1 H, 5-H_a), 4.52 (dd, J = 13.7, 7.4 Hz, 1 H, 5-H_b), 5.96 (s, 2 H, OCH₂O), 6.61 (s, 1 H, 7-H), 6.92 (s, 1-H, 10-H).¹³C NMR (300 MHz, DMSO): d = 21.36 (C-13*), 22.07 (C-12*), 25.05 (C-1), 25.56 (C-2), 26.53 (C-6), 28.10 (C-14), 34.22 (C-5), 34.83 (C-14a), 39.62 (C-11), 61.12 (C-10b), 100.5 (OCH₂O), 103.3 (C-10), 109.1 (C-7), 127.6 (C-6a), 137.0 (C-10a), 145.4 (C-9), 145.5 (C-8), 170.8 (C-3).
Compound 4e: ¹H NMR (300 MHz, DMSO): d = 1.48-1.64 (m, 6 H, 11-H_a, 10-H₂, 9-H₂, 8-H_a), 1.82-1.87 (m, 1 H, 11-H_b), 1.94-1.99 (m, 1 H, 8-H_b), 2.10-2.19 (m, 2 H, 4-H_a, 8a-H), 2.39-2.48 (m, 1 H, 4-H_b), 2.48-2.74 (m, 2 H, 12-H₂), 2.96 (td, J = 12.3, 6.7 Hz, 1 H, 5-H_a), 4.00-4.11 (qd, 1 H, J = 6.5, 1.3 Hz, 5-H_b), 6.85 (d, J = 5.4 Hz, 1 H, 3-H), 7.35 (d, J = 5.4 Hz, 1 H, 2-H). ¹³C NMR (300 MHz, DMSO): d = 19.57 (C-10), 21.00 (C-9), 24.46 (C-11), 25.10 (C-12), 33.16 (C-5), 34.43 (C-8), 34.54 (C-4), 40.33 (C-8a), 61.03 (C-12a), 122.9 (C-2), 126.9 (C-3), 132.4 (C-12b), 139.2 (C-3a), 171.0 (C-7).
Compound 4f: ¹H NMR (300 MHz, DMSO-d ₆): d = 1.35-1.61 (m, 4 H, 12-H_a, 13-H₂, 12-H_b), 1.61-1.80 (m, 4 H, 10-H₂, 9-H_a, 11-H_a), 1.84-1.94 (m, 2 H, 11-H_b), 2.03-2.09 (m, 1 H, 9a-H), 2.11-2.25 (m, 2 H, 8-H_a, 9-H_b), 2.37-2.49 (m, 1 H, 8-H_b), 2.53 (ddd, J = 1.0, 5.3, 16.5 Hz, 1 H, 4-H_a), 2.70 (ddd, J = 6.8, 11.7, 16.5 Hz, 1 H, 4-H_b), 3.16 (ddd, J = 5.3, 11.7, 13.3 Hz, 1 H, 5-H_a), 4.58 (ddd, J = 1.0, 6.8, 13.3 Hz, 1 H, 5-H_b), 6.80 (d, J = 5.0 Hz, 1 H, 3-H), 7.34 (d, J = 5.0 Hz, 1 H, 2-H). ¹³C NMR (75 MHz, DMSO-d ₆): d = 21.69 (C-12), 22.77 (C-10), 23.10 (C-13), 24.30 (C-4), 26.82 (C-11), 29.68 (C-8), 34.88 (C-5), 38.20 (C-9), 39.34 (C-9a), 61.27 (C-13a), 122.8 (C-2), 127.3 (C-3), 134.3 (C-3a), 142.1 (C-13b), 170.2 (C-7).
Compound 4g: ¹H NMR (300 MHz, DMSO-d ₆): d = 1.46-1.68 (m, 6 H, 5-H₂, 6-H₂, 7-H_a, 4-H_a), 1.85-2.99 (m, 2 H, 7-H_b, 4-H_b), 2.14 (dd, J = 6.9, 14.0 Hz, 8-H_a), 2.21-2.29 (m, 1 H, 7a-H), 2.35 (ddd, J = 0.8, 8.9, 14.0 Hz, 1 H, 8-H_b), 2.70-2.86 (m, 2 H, 12-H₂), 3.01-3.11 (m, 1 H, 11-H_a), 4.09-4.16 (m, 1 H, 11-H_b), 7.18 (d, J = 5.3 Hz, 1 H, 3-H), 7.35 (d, J = 5.3 Hz, 1 H, 2-H). ¹³C NMR (75 MHz, DMSO-d ₆): d = 19.95 (C-5), 20.23 (C-6), 23.88 (C-12), 24.97 (C-7), 33.45 (C-11), 34.12 (C-4), 35.08 (C-8), 37.68 (C-7a), 61.10 (C-3b), 123.4 (C-2), 124.3 (C-3), 132.3 (C-12a), 140.8 (C-3a), 171.9 (C-9).
Compound 4h: ¹H NMR (300 MHz, DMSO-d ₆): d = 1.21-1.38 (m, 1 H, 4-H_a), 1.38-1.55 (m, 4 H, 4-H_b, 8-H₂, 6-H_a), 1.55-1.68 (m, 2 H, 5-H₂), 1.68-1.78 (m, 2 H, 7-H₂), 2.09 (m_c, 1 H, 9-H_a), 2.17-2.24 (m, 1 H, 6-H_b), 2.37-2.47 (m, 2 H, 7a-H, 9-H_b), 2.63 (dd, J = 5.3, 16.2 Hz, 1 H, 13-H_a), 2.90 (ddd, J = 6.9, 11.7, 16.2 Hz, 1 H, 13-H_b), 3.23 (ddd, J = 5.3, 11.7, 13.2 Hz, 1 H, 12-H_a), 4.58 (dd, J = 6.9, 13.2 Hz, 1 H, 12-H_b), 7.00 (d, J = 5.4 Hz, 1 H, 3-H), 7.27 (d, J = 5.4 Hz, 1 H, 2-H). ¹³C NMR (75 MHz, DMSO-d ₆): d = 21.35 (C-4), 22.78 (C-8), 23.06 (C-13), 24.69 (C-7), 25.76 (C-5), 28.67 (C-9), 35.06 (C-12), 36.46 (C-7a), 38.31 (C-6), 61.42 (C-3b), 122.7 (C-3), 123.2 (C-2), 134.1 (C-13a), 143.21 (C-3a), 171.3 (C-10).

7 El Bialy SAA. Braun H. Tietze LF. Angew. Chem. Int. Ed.  2004,  43:  5391