Highly Improved Synthesis of (+)-Aureol via (-)-Neoavarone and (-)-Neo­avarol, by Employing Salcomine Oxidation and Acid-Induced Rearrangement/Cyclization Strategy

Abstract

A short and efficient synthesis of (+)-aureol (1), a structurally novel and biologically important marine natural product, was achieved starting with readily available (+)-Wieland-Miescher ketone analogue 7 via (-)-neoavarone (10) and (-)-neoavarol (11). The method features salcomine oxidation of the phenol derivative 9 to deliver 10 and BF₃·OEt₂-induced rearrangement/cyclization reaction of 11 to produce 1 as the crucial steps. The improved biomimetic synthesis required only 9 steps and proceeds in 31% overall yield.

aureol - neoavarone - neoavarol - marine natural product - rearrangement/cyclization reaction

References

For recent excellent reports on the clerodane diterpenoids and related compounds including marine natural products, see:

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The total synthesis of avarone (i)and avarol (ii, Figure 2), which correspond to the C4 endo-olefinic isomers of neoavarone(10) and neoavarol(11), respectively, have been previously achieved by several research groups, see:

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11 The starting material 8 was prepared from (+)-Wieland-Miescher ketone analogue 7 (>99% ee) according to the following Scheme 4. For further details, see: Nakatani M. Nakamura M. Suzuki A. Inoue M. Katoh T. Org. Lett.  2002,  4:  4483 

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13

Spectral Data for 9: ¹H NMR (500 MHz, CDCl₃): δ = 0.87 (s, 3 H), 0.98-1.03 (m, 1 H), 1.02 (d, J = 6.0 Hz, 3 H), 1.06 (s, 3 H), 1.19-1.44 (m, 5 H), 1.44-1.49 (m, 1 H), 1.51-1.62 (m, 1 H), 1.87-1.94 (m, 1 H), 2.02-2.12 (m, 2 H), 2.30-2.39 (m, 1 H), 2.56 (d, J = 14.4 Hz, 1 H), 2.68 (d, J = 14.4 Hz, 1 H), 4.35-4.39 (m, 1 H), 4.40-4.44 (m, 1 H), 4.61-4.65 (br s, 1 H), 6.68-6.73 (m, 1 H), 6.79-6.85 (m, 1 H), 7.00-7.09 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.6, 17.7, 20.6, 23.2, 27.8, 28.2, 33.0, 36.3, 36.5, 37.4, 40.2, 42.0, 48.1, 102.7, 115.5, 120.2, 125.1, 127.2, 132.9, 154.5, 160.1. IR (KBr): 3547, 3439, 2957, 2920, 2858, 1720, 1631, 1587, 1452, 1383, 1332, 1255, 1170, 1122, 1086, 1049, 1022, 991, 927, 891, 864, 754, 611, 530 cm^-1. MS (CI): m/z = 299 [(M + H)⁺]. Anal. Calcd for C₂₁H₃₀O: C, 84.51; H, 10.13. Found: C, 84.63; H, 10.33.

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15

Procedure for the Conversion of the Phenolic Compound 9 to (-)-Neoavarone 10. N,N-Bis(salicylidene)ethylenedi-iminocobalt(II) (55 mg, 0.17 mmol) was added to a stirred solution of 9 (101 mg, 0.34 mmol) in dry DMF (10 mL) at r.t. The suspension was stirred under an oxygen atmosphere (O₂ balloon) for 7 h at r.t. The mixture was concentrated in vacuo to afford a residue, which was purified by column chromatography (hexane-ethyl acetate, 20:1) to give 10 (96 mg, 91%) as a yellow solid. Recrystallization from diethyl ether-hexane afforded yellow prisms. ¹H NMR (500 MHz, CDCl₃): δ = 0.76 (dd, J = 12.1, 2.0 Hz, 1 H), 0.86 (s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 1.05 (s, 3 H), 1.10-1.21 (m, 2 H), 1.32-1.38 (m, 1 H), 1.42-1.46 (m, 2 H), 1.47-1.57 (m, 2 H), 1.85-1.91 (m, 2 H), 2.06-2.12 (m, 1 H), 2.27-2.35 (m, 1 H), 2.40 (dd, J = 13.5, 0.8 Hz, 1 H), 2.57 (d, J = 13.5 Hz, 1 H), 4.44 (t, J = 1.4, 1 H), 4.46 (t, J = 1.7 Hz, 1 H), 6.45-6.47 (m, 1 H), 6.70 (dd, J = 10.0, 2.4, 1 H), 6.74 (d, J = 10.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.8, 17.6, 20.6, 22.7, 27.4, 28.1, 32.8, 35.3, 36.7, 37.2, 40.3, 43.0, 49.3, 103.2, 135.9, 136.0, 137.1, 147.3, 159.6, 187.2, 187.4. IR (KBr): 3445, 2978, 2920, 2861, 1655, 1597, 1451, 1387, 1354, 1292, 1071, 897 cm^-1. HRMS (FAB): m/z calcd for C₂₁H₂₉O₂ [(M + H)⁺]: 313.2167. Found: 313.2195.

The reducing reagent Na₂S₂O₄ has been widely used for the conversion of sesquiterpenoidal quinones to the corresponding hydroquinones. For recent examples, see: ref.^10c,10d. For additional examples, see:

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17

Spectral Data for 11: ¹H NMR (500 MHz, CDCl₃): δ = 0.86 (s, 3 H), 1.01 (d, J = 6.0 Hz, 3 H), 0.98-1.02 (m, 1 H), 1.06 (s, 3 H), 1.24-1.36 (m, 2 H), 1.38-1.44 (m, 3 H), 1.46-1.51 (m, 1 H), 1.51-1.61 (m, 1 H), 1.87-1.92 (m, 1 H), 1.99-2.06 (m, 1 H), 2.07-2.12 (m, 1 H), 2.34 (tt, J = 8.3, 1.6 Hz, 1 H), 2.51 (d, J = 14.3 Hz, 1 H), 2.63 (d, J = 14.3, 1 H), 4.35 (s, 2 H), 4.40 (br s, 1 H), 4.43 (t, J = 1.8, 1 H), 6.52 (d, J = 2.8 Hz, 1 H), 6.55 (dd, J = 8.4, 2.9 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.6, 17.6, 20.6, 23.2, 27.7, 28.3, 33.0, 36.3, 36.5, 37.5, 40.3, 42.1, 48.2, 102.9, 113.9, 116.2, 119.4, 126.5, 148.6, 148.7, 160.0. IR (KBr): 3252, 2971, 2919, 2857, 1632, 1503, 1453, 1402, 1188, 1154, 891, 810, 752 cm^-1. HRMS (FAB): m/z calcd for C₂₁H₃₁O₂ [(M + H)⁺]: 315.2324. Found: 315.2344.

18

Procedure for the conversion of (-)-neoavarol (11) to(+)-aureol (1). BF₃ ·OEt₂ (148 µL, 1.1 mmol) was added to a stirred solution of 11 (35 mg, 0.1 mmol) in CH₂Cl₂ (20 mL) at -45 °C. The mixture was gradually warmed up to -5 °C over 4 h. The reaction was quenched with sat. aq NaHCO₃ (0.5 mL), and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined extracts were washed with brine, and then dried over Na₂SO₄. Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane-ethyl acetate, 10:1) to give 1 (33 mg, 93%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 0.78 (s, 3 H), 0.92 (s, 3 H), 1.06 (s, 3 H), 1.11 (d, J = 7.6 Hz, 3 H), 1.16-1.21 (m, 1 H), 1.32-1.38 (m, 1 H), 1.41-1.50 (m, 3 H), 1.52-1.61 (m, 1 H), 1.63-1.72 (m, 2 H), 1.74-1.87 (m, 2 H), 1.96 (d, J = 17.4 Hz, 1 H), 1.99-2.11 (m, 2 H), 3.37 (d, J = 17.4 Hz, 1 H), 4.29 (br s, 1 H), 6.49 (d, J = 2.7 Hz, 1 H), 6.54-6.63 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.3, 18.4, 20.2, 22.2, 27.9, 29.3, 29.8, 31.9, 33.8, 33.9, 37.4, 38.1, 39.3, 44.0, 82.4, 114.0, 115.1, 117.3, 122.2, 145.8, 148.3. IR (KBr): 17.3, 18.4, 20.2, 22.2, 27.9, 29.3, 29.8, 31.9, 33.8, 33.9, 37.4, 38.1, 39.3, 44.0, 82.4, 114.0, 115.1, 117.3, 122.2, 145.8, 148.3 cm^-1. HRMS (EI): m/z calcd for C₂₁H₃₀O₂ (M⁺): 314.2246. Found: 314.2241.

19

In our previous synthesis of (+)-aureol (1), [6] the cis-fused decalin system 6 [(+)-arenarol] was used as the substrate for the key acid-induced rearrangement/cyclization reaction, while in the present study the trans-fused decalin system 11 [(-)-neoavarol] is employed instead of 6. In these rearrangement/cyclization process, we believe that the same carbocation intermediate such as II would be generated in situ from 6 and 11, respectively, leading ultimately to the formation of (+)-aureol (1). And furthermore, we have already reported a similar carbocation-mediated domino process that is initiated by Lewis acid-induced epoxide-opening, followed by consecutive suprafacial methanide and hydride migrations. For further details, see the literature cited in ref. 11.