Formal Synthesis of (–)-Siccanin Using an Enantioselective Domino Wacker/Carbonylation/Methoxylation Reaction

Lutz F. Tietze; Stefan Jackenkroll; Dhandapani Ganapathy; Johannes R. Reiner

doi:10.1055/s-0035-1560752

Synlett, Table of Contents

Synlett 2016; 27(01): 96-100
DOI: 10.1055/s-0035-1560752

letter

Formal Synthesis of (–)-Siccanin Using an Enantioselective Domino Wacker/Carbonylation/Methoxylation Reaction

Authors

Lutz F. Tietze*

Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, 37077 Göttingen, Germany Email: ltietze@gwdg.de
Stefan Jackenkroll

Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, 37077 Göttingen, Germany Email: ltietze@gwdg.de
Dhandapani Ganapathy

Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, 37077 Göttingen, Germany Email: ltietze@gwdg.de
Johannes R. Reiner

Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, 37077 Göttingen, Germany Email: ltietze@gwdg.de

Abstract

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Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday

Abstract

A formal synthesis of (–)-siccanin was achieved through an enantioselective domino Wacker/carbonylation/methoxylation reaction as the key step to form the chroman ring with a quaternary stereogenic center with 95% ee. The pendant cyclohexyl moiety was introduced through a two-step aldol condensation.

Key words

natural products - domino reaction - aldol reaction - transition-metal catalysis - enantioselective reactions

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References

References and Notes

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11 Experimental Procedure for the Preparation of (R)-5: A solution of palladium(II) trifluoroacetate (48.2 mg, 145 μmol, 5 mol%) and the Bn-BOXAX ligand (R,R)-10 (332 mg, 580 μmol, 20 mol%) in MeOH (10 mL) was stirred at r.t. for 15 min. Alkenyl phenol 7 (598 mg, 2.90 mmol, 1.00 equiv) in MeOH (7 mL) and p-benzoquinone (1.25 g, 11.6 mmol, 4.00 equiv) were added at r.t. and CO gas (1 atm) was passed through the resulting reaction mixture for 5 min. After stirring at r.t. under a CO atmosphere (1 atm) for 19 h, the reaction was quenched at r.t. by addition of 1 M aq HCl (50 mL). The aqueous phase was extracted with MTBE (3 × 25 mL) and the combined organic phases were washed with 1 M aq NaOH (3 × 25 mL). The organic phase was dried over MgSO₄ and the solvent was removed in vacuo. Column chromatography on silica gel (n-hexane–Et₂O 10:1→8:2) gave ester (R)-5 (544 mg, 2.06 mmol, 71%, 95% ee) as a colorless oil; [α]_D = 8.2 (c = 0.50, CHCl₃, 24.0 °C). ¹H NMR (300 MHz, CDCl₃): δ = 1.42 (s, 3 H, 2'-CH₃), 1.85 (dt, J = 13.8, 6.8 Hz, 1 H, 3'-H_a), 1.99 (dt, J = 13.8, 6.8 Hz, 1 H, 3'-H_b), 2.26 (s, 3 H, 7'-CH₃), 2.55–2.66 (m, 4 H, 2-H₂, 4'-H₂), 3.68 (s, 3 H, 1-OCH₃), 3.79 (s, 3 H, 5'-OCH₃), 6.24, 6.29 (2 × s, 2 H, 6'-H, 8'-H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.4 (C-4'), 21.5 (7'-CH₃), 24.6 (2'-CH₃), 30.3 (C-3'), 43.5 (C-2), 51.5 (1-OCH₃), 55.3 (5'-OCH₃), 74.2 (C-2'), 102.9, 110.4 (C-6', C-8'), 106.8 (C-4a'), 137.1 (C-7'), 153.5 (C-5'), 157.5 (C-8a'), 170.9 (C-1). IR (ATR): 2936, 2856, 1734, 1619, 1584, 1352, 1224, 1103, 1020, 811 cm^–1. UV (MeCN): λ_max (lg ε) = 208.0 (4.678), 272.0 (3.087) nm. Analytical HPLC (Daicel Chiracel OD; 4.6 × 250 mm, 5 μm, n-hexane–i-PrOH 98:2; 0.8 mL/min; 234 nm): t_R = 18.2 [(–)-(S)-5, 2.3%], 26.6 [(+)-(R)-5, 97.7%] min; 95% ee. MS (ESI): m/z (%) = 551.3 (99) [2M + Na]⁺, 303.1 (11) [M + K]⁺, 287.1 (100) [M + Na]⁺, 265.2 (91) [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀O₄ (264.32): 265.1434; found: 265.1434; m/z [M + Na]⁺ calcd: 287.1251; found: 287.1254.

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