Synlett 2005(5): 0789-0792  
DOI: 10.1055/s-2005-864798
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Alejandro F. Barrero*a, Simeón Arseniyadisb, José F. Quílez del Morala, M. Mar Herradora, Antonio Rosellóna
a Departament of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain
Fax: +34(95)8243318; e-Mail: afbarre@goliat.ugr.es;
b Institute de Chimie de Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Further Information

Publication History

Received 18 January 2005
Publication Date:
09 March 2005 (online)

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.

    References

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  • Although the biosynthesis of β-amyrin is known to proceed via 2,3-oxidosqualene, the fact that β-amyrin has been obtained after enzymatic cyclization of the 2,3-epoxide of racemic 1 should be also taken into account. Furthermore, oxidosqualene cyclase mutagenesis experiments, included those in which achilleol A and camelliol C are biosynthesized by mutant OSC, suggested that relatively few changes in the enzyme are needed to alter product specificity. These findings ultimately supported the existence of alternative pathways in the biosynthesis of terpenoids. For OCS mutagenesis experiments, see:
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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.