Total Synthesis of the Coccinellid Alkaloid (±)-Adalinine Utilizing a Nitrenium Ion Cyclization

Abstract

The total synthesis of (±)-adalinine, a piperidine alkaloid from the European two-spotted ladybird Adalia bipunctata, is reported. Central to this undertaking are (i) the use of an N-alkoxy-N-acylnitrenium ion-induced spirocyclization to rapidly access the 6,6′-disubstituted piperidinone ring of the natural product and (ii) exploitation of the cyclohexa-2,5-dienone system generated in this process as a latent 1,6-ketoaldehyde.

Key words

adalinine - piperidine alkaloid - nitrenium ions - dearomatization - polyvalent iodine

References

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12

Experimental Procedure for Preparation of Dienone 8: To a suspension of phenyliodine(III) bis(trifluoroacetate) (PIFA) (2.290 g, 5.16 mmol) in MeOH (10 mL), at -78 °C, was added a cold (-78 °C) solution of N-methoxyamide 9 (1.020 g, 4.30 mmol) in CH₂Cl₂ (10 mL) via cannula. The reaction mixture was then allowed to warm to 15 °C (internal temperature) over 1.5 h whereupon H₂O (10 mL) was added and the cooling bath removed. After stirring for 10 min, the organic and aqueous phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 ¥ 20 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure and the residue purified by flash chromatography over silica gel (EtOAc/hexanes, 1:1) to provide 8 (855 mg, 90%) as a colorless oil. Recrystallization from EtOAc/hexanes yielded 8 as white crystals: Mp 97-99 °C. R_f = 0.35 (EtOAc). FT-IR(film):
ν_max = 2933(br), 1674, 1642, 1445, 1376, 1071, 939,
823 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.89 (dd, J = 10.0, 3.2 Hz, 1 H) 6.70-6.68 (m, 1 H), 6.32 (d, J = 10.0 Hz, 1 H), 3.72 (s, 3 H), 2.59 (t, J = 2.6 Hz, 2 H), 2.07-1.99 (m, 2 H), 1.96-1.90 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 185.3, 168.4, 148.6, 143.9, 136.7, 129.9, 64.5, 64.0, 35.8, 33.3, 18.4, 15.9. HRMS-EI calcd for C₁₂H₁₅NO₃Na
[M + Na]⁺: 244.0950. Found: 244.0940. Anal. Calcd for C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.21; H, 6.84; N, 6.34.

17

Data for Synthetic (±)-Adalinine ( 5): Colorless oil; R_f = 0.23 (EtOAc); FT-IR(film): ν_max = 3380, 3206, 2930, 2862, 1712, 1657, 1458, 1402, 1363 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.62 (br s, 1 H), 2.70 (d, J = 17.8 Hz, 1 H), 2.64 (d, J = 17.8 Hz, 1 H), 2.33-2.27 (m, 2 H), 2.14 (s, 3 H), 1.83-1.54 (m, 6 H), 1.31-1.21 (m, 6 H), 0.88 (t, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 207.5, 171.7, 56.4, 51.5, 39.4, 32.1, 32.0, 31.6, 31.4, 24.1, 22.7, 17.4, 14.2. HRMS-EI calcd for C₁₃H₂₃NO₂Na [M + Na]⁺: 248.1610. Found: 248.1616.