Asymmetric Construction of the Azaspiro[5.5]undec-8-ene System Towards Gymnodimine Synthesis

Abstract

In the course of the synthetic studies on gymnodimine, a potent shellfish toxin, the asymmetric construction of the azaspirocyclic part was achieved by the (-)-siam·Cu(SbF₆)₂ complex catalyzed intermolecular Diels-Alder reaction in high exo- and enantioselectivities.

asymmetric Diels-Alder reactions - gymnodimine - α-methylene lactam - azaspirocyclic system

References

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7

i) NaH, THF, CBZ-Cl, 25 °C, 5 h (89%); ii) TMSOTf,
i-Pr₂NEt, CH₂Cl₂, 25°C, 2 h; iii) Me₂N⁺=CH₂I^-, CH₂Cl₂,
25 °C, 12 h; iv) MeI, THF, 25 °C, 2 h (68% for 3 steps).

8

The stereochemistry for the regioisomer of 8 has not been fully assigned yet.

9

9 was prepared from l-glutamic acid in a 5-step process:
(i) NaNO₂, aq HCl, 25 °C, 20 h (77%); (ii) SOCl₂, 80 °C,
12 h (98%); (iii) (E)-1-t-Butyldimethylsilyloxy-3-tributyl-stannylbut-2-ene, Pd(PPh₃)₄, ClCH₂CH₂Cl, 65 °C, 20 h (82%); (iv) Ph₃P=CH₂, THF, -10 °C, 2 min (96%).

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18

21: A colorless oil; [α]_D ²⁴ -13.0 (c 0.24, CHCl₃); ¹H NMR (300 MHz, C₆D₆), δ 7.85-7.69 (m, 4 H), 7.52 (2 H, d, J = 7.3 Hz), 7.26-7.17 (8 H, m), 7.13 (1 H, t, J = 7.3 Hz), 5.78 (1 H, t, J = 5.5 Hz), 5.56 (1 H, d, J = 6.1 Hz), 5.28 (2 H, s), 4.84 (1 H, t, J = 6.6 Hz), 4.34 (2 H, d, J = 5.5 Hz), 3.79 (1 H, qui, J = 6.6 Hz), 3.65 (1 H, d, J = 8.0 Hz), 3.58-3.50 (1 H, m), 3.44-3.34 (1 H, m), 2.93 (1 H, brd, J = 17.1 Hz), 2.38 (1 H, brd, J = 17.1 Hz), 2.32 (1 H, dd, J = 11.5, 13.0 Hz), 2.18-2.05 (1 H, m), 1.86 (1 H, ddd, J = 2.7, 5.9, 13.2 Hz), 1.95-1.35 (12 H, m), 1.75, 1.74, 1.65, 1.60 (each 3 H, s), 1.11 (21 H, s), 1.08 (9 H, s), 0.80 (3 H, d, J = 6.6 Hz); IR(neat), 3071, 3048, 2951, 2930, 2891, 2863, 1782, 1771, 1714, 1612, 1471, 1461, 1428, 1389, 1297, 1252, 1180, 1111, 1060, 882, 837, 821, 777, 740, 701, 689, 658 cm^-1; FAB-HR-MS, calcd. for C₆₃H₈₉NO₈Si₂ (M⁺) 1043.6127, found 1043.6149.