Formal Synthesis of (+)-Anatoxin-a by Asymmetric [2+2] Cycloaddition

Abstract

A formal asymmetric synthesis of (+)-anatoxin-a, a neurotoxic alkaloid from Anabaena flos aquae, has been achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether.

N-acyliminium ion - asymmetric synthesis - cycloaddition - chiral enol ether - dichloroketene

References

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<A NAME="RG08205ST-14">14</A>

To a solution of 6 (600 mg, 1.10 mmol) in 18.0 mL of CH₂Cl₂ at 0 °C was added dropwise 3.2 mL of formic acid. The reaction mixture was stirred at 0 °C for 1.75 h and then quenched with a sat. solution of aq NaHCO₃ and extracted with CH₂Cl₂. The organic phase was washed successively with H₂O and brine and dried over anhyd Na₂SO₄. The crude product was purified by SiO₂ chromatography (10-20% diethyl ether in pentane) to afford 386 mg (77%) of 7, as a 2:1 mixture of isomers. Analytical data for the major isomer of 7a: colorless oil; [α]_D ²⁵ -84.3 (c 1.0, CHCl₃). IR: 3070, 1704, 1608, 1449, 1400, 1098, 1081 cm^-1. ¹H NMR (300 MHz, CDCl₃, two rotamers): δ = 1.17-1.29 (m, 18 H), 1.44-1.53 (m, 2 H), 1.52 (d, J = 6.8 Hz, 3 H), 1.68-1.81 (m, 4 H), 1.98-2.03 (m, 1 H), 2.32 (m, 1 H), 2.67-2.89 (m, 2 H), 3.12-3.17 (m, 1 H), 3.62 (s, 3 H), 3.86 (m, 2 H), 4.09-4.32 (m, 2 H), 4.86-5.09 (m, 3 H), 5.86-6.17 (m, 1 H), 6.93 (s, 1 H), 7.03 (s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃, two rotamers): δ = 23.2, 23.4, 24.0, 24.5, 24.9, 25.0, 25.3, 27.6, 28.2, 28.4, 29.2, 31.7, 32.0, 34.1, 40.0, 40.9, 52.1, 52.4, 52.7, 52.9, 58.3, 58.7, 58.8, 66.0, 71.5, 74.1, 74.8, 112.6, 112.7, 120.6, 123.4, 133,1, 143.8, 144.2, 145.8, 145.9, 147.5, 149.0, 155.3, 155.6. MS (CI): m/z (%) = 456 (100) [MH⁺]. Anal. Calcd for C₂₉H₄₅NO₃: C, 76.44; H, 9.95; N, 3.07. Found: C, 76.46; H, 10.11; N, 2.81.

<A NAME="RG08205ST-15">15</A>

Compound 7b (2:1 mixture of isomers): IR: 3432, 3073, 1683, 1463, 1403, 1347, 1122, 1087 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.40-2.00 (m, 7 H), 2.24-2.28 (m, 1 H), 2.47-2.78 (m, 2 H), 3.60-3.70 (4 s, 3 H), 4.00-4.50 (m, 3 H), 4.70-5.10 (m, 2 H), 5.60-6.15 (m, 1 H). MS (CI): m/z (%) = 226 (100) [MH⁺].

<A NAME="RG08205ST-16">16</A>

Compound 7c (2:1 mixture of isomers): IR: 3073, 1698, 1637, 1449, 1397, 1117 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.22-1.50 (m, 2 H), 1.60-1.80 (m, 4 H), 2.05-2.18 (m, 1 H), 2.38-2.53 (m, 1 H), 2.72-2.88 (m, 1 H), 3.73 (s, 3 H), 4.14-4.54 (m, 2 H), 4.60-4.78 (m, 1 H), 4.88-5.10 (m, 2 H), 5.54-6.13 (m, 1 H). HRMS (CI): m/z calcd for C₁₂H₁₉NO₂I [M + 1]: 336.0461; found: 336.0471.

<A NAME="RG08205ST-17">17</A>

Compound 7d (2:1 mixture of isomers): IR: 3074, 1699, 1638, 1450, 1397, 1340, 1113 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.24-1.86 (m, 8 H), 1.94-2.06 (m, 1 H), 2.14-2.27 (m, 2 H), 3.66 (br s, 3 H), 4.10-4.50 (m, 2 H), 4.85-5.10 (m, 2 H), 5.70-6.20 (m, 1 H).

<A NAME="RG08205ST-18">18</A> Tsuji J. Synthesis  1984,  369 

<A NAME="RG08205ST-19">19</A>

A single isomer was obtained. The ee of 8 was estimated to be 93% based on the rotation {[α]_D ²⁵ -13.7 (c 1.0, CH₃OH)] and ee (94%) of the comparison material. This purity is consistent with the observed diastereoselection (95:5) in the cycloaddition and a subsequent small enrichment.

<A NAME="RG08205ST-20">20</A> Skrinjar M. Nilsson C. Wistrand L.-G. Tetrahedron: Asymmetry  1992,  3:  1263