Enantioselective Annulation Using Nazarov Reagent: Synthesis of (+)-Preoleanatetraene

Abstract

The enantioselective synthesis of preoleanatetraene (1) has been accomplished via a convergent approach of two C-15 synthons. The key step of this synthesis has been an interesting enantio­selective variant of the Robinson annulation using the Nazarov reagent and a chiral enamine to obtain the bicyclic moiety A. This asymmetric methodology opens the access to other irregular triterpene skeletons whose biogenetic implication should not be underestimated.

Key words

preoleanatetraene - annulation - asymmetric synthesis - terpenoids - natural products - total synthesis

References

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11

Procedure for the Enantioselective Variant of the Robinson Annulation Using the Nazarov Reagent and a Chiral Enamine: Synthesis of Bicyclic 12.
A stirred solution of enamine 9 (486 mg, 2 mmol) and Nazarov reagent 10 (256 mg, 2 mmol) in dry benzene (2 mL) was heated at 65-70 °C for 1 h. Then was added 0.5 mL of a solution of 125 g of NaOAc, 25 mL of H₂O and 25 mL of HOAc. The mixture was heated for 1 h, washed with H₂O, sat. aq NaHCO₃, and brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (hexane-t-BuOMe, 4:1) to afford 150 mg of 11 (20%) and 106 mg of 12 (21%). Keto ester 12 was isolated as colorless oil. [α]_D -49.7 (c 0.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 3.79 (s, 3 H), 2.52 (ddd, J = 5.4, 14.3, 17.0 Hz, 1 H), 2.40 (dt, J = 3.9, 17.0 Hz, 1 H), 2.15 (d, J = 14.6 Hz, 1 H), 1.98 (dd, J = 1.3, 14.6 Hz, 1 H), 1.86 (td, J = 4.6, 13.7 Hz, 1 H), 1.78 (dq, J = 3.2, 13.6 Hz, 1 H), 1.47-1.67 (m, 3 H), 1.28-1.37 (m, 1 H), 1.23 (s, 3 H), 1.00 (s, 3 H), 0.82 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.0, 167.7, 166.4, 132.3, 52.0, 43.0, 37.8, 37.1, 34.4, 34.0, 33.5, 32.4, 32.0, 24.6, 22.3. IR (film): 2945, 2866, 1735, 1671, 1617, 1465, 1353, 1227, 1131, 1008 cm^-1. HRMS-FAB: m/z calcd for C₁₅H₂₂O₃Na [M + Na]⁺: 273.1467; found: 273.1463.

12

The enantioselectivity of the annelation reaction could be measured after treating 15 with (S)-2-acetoxypropionyl chloride. The diastereomeric ratio of the corresponding lactates was determined by ¹H NMR (800 MHz) spectroscopy, by integrating the AB quartets of the major and minor components.

14

All new compounds gave satisfactory analytical and spectroscopic data.
Compound 14: colorless oil. [α]_D +30.8 (c 0.5, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 3.51 (s, 3 H), 2.68 (dd, J = 2.9, 12.4 Hz, 1 H), 2.03 (s, 3 H), 1.97-2.07 (m, 2 H), 1.84 (ddd, J = 6.8, 11.8, 24.5 Hz, 1 H), 1.57-1.65 (m, 2 H), 1.35 (dt, J = 3.9, 13.6 Hz, 1 H), 1.25 (td, J = 3.4, 13.6 Hz, 1 H), 1.15 (br d, J = 13.6 Hz, 1 H), 1.08 (t, J = 13.0 Hz, 1 H), 1.02 (s, 3 H), 0.93 (s, 3 H), 0.93 (s, 3 H), 0.73 (dd, J = 6.9, 14.7 Hz, 1 H). ¹³C NMR (100 MHz, C₆D₆): δ = 169.0, 142.8, 129.3, 50.7, 43.8, 40.0, 36.5, 34.8, 33.1, 31.4, 31.1, 31.0, 27.0, 26.3, 24.1, 21.9. IR (film): 2949, 2922, 2851, 1713, 1640, 1464, 1258, 1063, 804 cm^-1. HRMS-FAB: m/z calcd for C₁₆H₂₆O₂Na [M + Na]⁺: 273.1831; found: 273.1830.