Gold-Catalyzed Double Intramolecular Alkyne Hydroalkoxylation: Synthesis of the Bisbenzannelated Spiroketal Core of Rubromycins

Abstract

The synthesis of the bisbenzannelated spiroketal core of natural bioactive rubromycins via a gold-catalyzed double intramolecular hydroalkoxylation was described. A comparative study on the formation of aliphatic and of aromatic spiroketals was also conducted.

Key words

alkyne hydroalkoxylation - spiroketal - rubromycin - gold catalysis - coupling

References and Notes

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16

On the basis of the protocol described by Uitimoto, [17] palladium reagents were tried initially but spiroketal 7a was isolated in very low yields. Treatment of 6a with 5 mol% of PdCl₂ in refluxing MeCN for 2 d afforded spiroketal 7a in only 5% yield. Even with 1.0 equiv of PdCl₂ or the reaction was performed in sealed tube at 120 °C, the yield of 7a was still as low as 20% and 10%, respectively. Only trace of 7a was isolated by using PdCl₂(PhCN)₂ and PdCl₂(MeCN)₂ in Et₂O at r.t.

18

We treated 6a with 10 mol% of Ph₃PAuCl/AgOTf and 20 mol% of PTSA in CH₂Cl₂ at r.t. for 2 d provided the aromatic spiroketal 7a in 61% yield.

19

General Procedure for Gold-Catalyzed Spiroketalization Under argon, PPh₃AuCl (9.5 mg, 0.02 mmol) and AgOTf (5.2 mg, 0.02 mmol) were added to a stirred solution of 6a (48.0 mg, 0.2 mmol) in CH₂Cl₂ (4 mL). After the reaction mixture had been stirred at r.t. for 2 d, the solvent was removed and the residue purified by flash chromatography on silica gel (hexane-EtOAc, 8:1 v/v) to give the bisspiroketal 7a (30.0 mg, 62%) as a white solid.

20

Spectral Data for Selected Compounds (Table 2) Compound 7b: white solid; mp 115-117 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.13-7.07 (m, 2 H), 7.04 (s, 1 H), 6.95-6.88 (m, 2 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.68 (d, J = 8.1 Hz, 1 H), 3.40 (d, J = 16.5 Hz, 1 H), 3.30-3.18 (m, 2 H), 2.81 (ddd, J = 16.5, 6.0, 2.4 Hz, 1 H), 2.35-2.29 (m, 4 H), 2.17 (td, J = 12.6, 6.3 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.8, 152.3, 130.4, 129.1, 128.4, 127.4, 125.4, 125.3, 121.4, 121.1, 117.1, 109.4, 109.0, 41.9, 30.4, 21.9, 20.8. IR: ν = 3020 (CH, arom.), 2925 (CH), 1584, 1489 (ArC=C), 1080, 1045 (CO) cm^-1. ESI-HRMS: m/z calcd for C₁₇H₁₆O₂Na [M + Na]⁺: 275.1043; found: 275.1046.
Compound 7c: pale yellow solid; mp 173-175 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.26 (s, 1 H), 7.19-7.08 (m, 3 H), 6.91 (td, J = 7.2, 1.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 3.44 (d, J = 16.2 Hz, 1 H), 3.31-3.19 (m, 2 H), 2.81 (ddd, J = 16.5, 6.0, 2.4 Hz, 1 H), 2.32 (ddd, J = 13.5, 6.0, 3.0 Hz, 1 H), 2.19 (td, J = 12.3, 6.3 Hz, 1 H), 1.31 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.7, 152.4, 144.1, 129.1, 127.4, 124.9, 124.8, 121.8, 121.4, 121.1, 117.1, 109.1, 109.0, 42.1, 34.3, 31.7, 30.5, 21.9. IR: ν = 3021 (CH, arom.), 2962 (CH), 1583, 1492 (ArC=C), 1076, 1046 (CO) cm^-1. ESI-HRMS: m/z calcd for C₂₀H₂₃O₂ [M + H]⁺: 295.1693; found: 295.1687.
Compound 7d: pale yellow solid; mp 154-155 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.54 (d, J = 8.2 Hz, 2 H), 7.47-7.37 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 8.1 Hz, 2 H), 6.94 (t, J = 7.5 Hz, 1 H), 6.88-6.81 (m, 2 H), 3.51 (d, J = 16.2 Hz, 1 H), 3.37-3.22 (m, 2 H), 2.84 (ddd, J = 16.5, 6.0, 2.7 Hz, 1 H), 2.36 (ddd, J = 13.5, 6.0, 2.7 Hz, 1 H), 2.22 (td, J = 12.9, 6.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 152.2, 141.3, 134.8, 129.1, 128.7, 127.5, 127.2, 126.9, 126.6, 126.0, 123.7, 121.4, 121.2, 117.1, 110.0, 109.4, 41.9, 30.4, 21.9. IR: ν = 3032 (CH, arom.), 2925 (CH), 1583, 1480 (ArC=C), 1082, 1046 (CO) cm^-1. ESI-HRMS: m/z calcd for C₂₂H₁₉O₂ [M + H]⁺: 315.1380; found: 315.1378.