Enantioselective Synthesis of (+)-Ricciocarpin A Using an Auxiliary Hydroxyl Group and a Diastereofacial Selectivity Based Methodology

Elie Palombo; Gérard Audran; Honoré Monti

doi:10.1055/s-2005-871932

LETTER

Enantioselective Synthesis of (+)-Ricciocarpin A Using an Auxiliary Hydroxyl Group and a Diastereofacial Selectivity Based Methodology

Elie Palombo, Gérard Audran*, Honoré Monti
Laboratoire de Réactivité Organique Sélective, U.M.R. 6180 ‘Chirotechnologies : Catalyse et Biocatalyse’, Université Paul Cézanne, Aix-Marseille III, 13397 Marseille Cedex 20, France
Fax: +33(4)91288862; e-Mail: g.audran@univ.u-3mrs.fr;

Abstract

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Abstract

An enantioselective synthesis of (+)-ricciocarpin A is described starting from (+)-karahana lactone as an enantiopure building block. This synthesis involves a stereofacially directed diastereoselective hydroboration for the installation of the required stereogenic center, and the efficient conversion of an intermediate hydroxyaldehyde to the one-carbon homologated cyanide, using the mild formation of a cyanohydrin followed by an one-pot two-step Barton-McCombie double deoxygenation sequence of the hydroxyl moieties.

Key words

ricciocarpin A - total synthesis - natural products - cyanohydrin - one-carbon homologation

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References

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Preparation and Spectroscopic Data of (+)-7. To a stirred solution of cyanohydrin 6 (1.41 g, 4.30 mmol) in dry CH₂Cl₂ (40 mL) was added at 0 °C DMAP (4.20 g, 34 mmol) and phenyl chlorothionoformate (2.40 mL, 17.2 mmol) under an argon atmosphere. After 12 h at r.t., the reaction mixture was poured into H₂O and extracted with Et₂O. The combined organic extracts were washed with H₂O, dried, filtered and concentrated. To a stirred solution of the crude phenoxythiocarbonyl ester in toluene (30 mL) was added tri-n-butyltin hydride (4.56 mL, 17.2 mmol) and a catalytic amount of AIBN in toluene (20 mL) under an argon atmosphere. The reaction mixture was stirred under reflux for 1 h, cooled and concentrated. The resulting oily residue was purified by silica gel column chromatography to give 827 mg of pure (+)-7 (65% yield for the two steps); [α]_D ²⁵ +19.8 (c 1.0, CHCl₃). IR (neat): ν = 2958, 2243, 1168 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.67 and 3.56 (ABX, J = 10.4, 4.2, 3.0 Hz, 2 H), 2.47 and 2.40 (ABX, J = 17.5, 5.1, 3.9 Hz, 2 H), 1.73-1.60 (m, 2 H), 1.53-1.32 (m, 4 H), 1.25-1.10 (m, 2 H), 0.96 (s, 3 H), 0.94 (s, 3 H), 0.87 (s, 9 H), 0.03 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 120.1 (C), 65.6 (CH₂), 44.1 (CH), 41.9 (CH₂), 38.9 (CH), 34.1 (C), 30.8 (CH₃), 30.3 (CH₂), 25.8 (3 × CH₃), 21.4 (CH₂), 20.2 (CH₃), 18.2 (C), 15.3 (CH₂), -5.6 (2 × CH₃). Anal. Calcd for C₁₇H₃₃NOSi: C, 69.09; H, 11.25. Found: C, 68.92; H, 11.28.

Preparation and Spectroscopic Data of (-)-8. A suspension of nitrile (+)-7 (800 mg, 2.71 mmol) and para-toluenesulfonic acid monohydrate (1.13 g, 5.94 mmol) in toluene (20 mL) was placed in an oil bath at 120 °C. After 3.5 h, the solution was cooled to r.t. and filtered through a pad of Celite. The solvent was evaporated and a silica gel column chromatography gave 420 mg (85% yield) of (-)-8; [α]_D ²⁵ -33.9 (c 1.0, CHCl₃). IR (neat): ν = 2958, 1726, 1146 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.24 and 3.74 (ABX, J = 11.0, 11.0, 4.7 Hz, 2 H), 2.62 and 2.16 (ABX, J = 18.1, 12.4, 5.7 Hz, 2 H), 1.75-1.36 (m, 6 H), 1.32 (td, J = 11.5, 5.5 Hz, 1 H), 1.16 (td, J = 13.4, 4.3 Hz, 1 H), 0.84 (s, 3 H), 0.79 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.5 (C), 74.3 (CH₂), 44.6 (CH), 40.8 (CH₂), 32.7 (CH), 31.9 (C), 30.9 (CH₂), 29.1 (CH₃), 27.5 (CH₂), 20.4 (CH₂), 19.0 (CH₃). Anal. Calcd for C₁₁H₁₈O₂: C, 72.49; H, 9.95. Found: C, 72.76; H, 9.97.

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Preparation and Spectroscopic Data of (+)-11. To a stirred solution of (-)-10 (300 mg, 1.21 mmol) in a mixture of t-BuOH (20 mL) and 2-methyl-2-butene (2.5 mL), a solution of 80% NaClO₂ (683 mg, 6.04 mmol) and NaH₂PO₄ (1.16 g, 9.67 mmol) in H₂O (10 mL) was added at r.t. The resulting mixture was stirred for 15 min then diluted with brine. The aqueous phase was saturated with NaCl and extracted thoroughly three times with EtOAc. The combined organic phases were washed with brine, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 260 mg (81% yield) of pure acid (+)-11 as white crystals; mp 130 °C; [α]_D ²⁵ +7.9 (c 1.0, CHCl₃). IR (KBr): ν = 3426, 1702, 1668, 1162 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 9.58 (br s, 1 H), 8.02 (br s, 1 H), 7.39 (t, J = 1.8 Hz, 1 H), 6.73 (dd, J = 1.8, 0.6 Hz, 1 H), 2.78 and 2.64 (ABX, J = 17.0, 4.9, 4.4 Hz, 2 H), 2.32 (m, 2 H), 1.90 (m, 1 H), 1.65-1.25 (m, 5 H), 0.89 (s, 3 H), 0.85 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 194.3 (C), 181.6 (C), 146.9 (CH), 143.9 (CH), 127.6 (C), 108.7 (CH), 46.2 (CH), 42.5 (CH), 41.2 (CH₂), 40.9 (CH₂), 33.6 (C), 30.5 (CH₃), 30.1 (CH₂), 20.9 (CH₂), 20.0 (CH₃). Anal. Calcd for C₁₅H₂₀O₄: C, 68.16; H, 7.63. Found: C, 67.89; H, 7.67.

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Preparation and Spectroscopic Data of (+)-Ricciocarpin A (1). A solution of (+)-11 (160 mg, 0.60 mmol) and CeCl₃·7H₂O (450 mg, 1.21 mmol) in MeOH (20 mL) was stirred 12 h at r.t. The solution was cooled to -18 °C, NaBH₄ (204 mg, 5.40 mmol) was added in three portions (3 × 1 h) and the mixture was slowly allowed to rise to r.t. After 12 h, the reaction mixture was poured into ice-water, acidified (HCl 6 N, pH = 1) and stirred for 30 min at r.t. The solution was saturated with NaCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried and filtered. Concentration of the filtrate followed by silica gel column chromatography gave 127 mg (85% yield) of a 6:1 mixture of (+)-1 and the C-3 epimer. Two recrystallizations from MeOH afforded pure (+)-ricciocarpin A(1) as white needles; mp 109 °C [lit. [4] mp 110 °C]; [α]_D ²⁵ +17.5 (c 1.0, CH₂Cl₂). IR (KBr): ν = 2963, 1722, 1162, 1029 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.43 (br s, 1 H), 7.40 (m, 1 H), 6.39 (m, 1 H), 5.27 (dd, J = 9.5, 4.5 Hz, 1 H), 2.40 (td, J = 12.1, 3.5 Hz, 1 H), 2.24-2.14 (m, 1 H), 2.06 and 1.93 (ABMX, J _AB = 14.5 Hz, J _AX = J _AM = 9.5 Hz, J _BM = 7.0 Hz, J _BX = 4.5 Hz, 2 H), 1.68-1.23 (m, 5 H), 1.15 (td, J = 13.8, 4.3 Hz, 1 H), 0.91 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.1 (C), 143.6 (CH), 139.6 (CH), 124.8 (C), 108.5 (CH), 71.7 (CH), 42.3 (CH), 40.4 (CH₂), 38.9 (CH), 33.7 (C), 29.8 (CH₂), 29.7 (CH₃), 27.2 (CH₂), 21.0 (CH₂), 18.5 (CH₃). Anal. Calcd for C₁₅H₂₀O₃: C, 72.55; H, 8.12. Found: C, 72.31; H, 8.09.