Regioselectivity of Mercury-Promoted Oxacyclizations of Alkynyl Diols

Dedicated in celebration of the 80^th birthday of Professor Victor Snieckus

Abstract

Hg(OTf)₂-catalyzed cyclization of an alkynyl alcohol on a tetra­hydropyran template gives the bispyranyl ketone arising from dehydrative cyclization and alkyne hydration, rather than the targeted fused pyran-oxepane product. The combination of stoichiometric Hg(OTf)₂ and triethylsilane gives reductive cyclization, but affords the fused pyran-oxocane corresponding to an 8-endo-mode oxacyclization process.

Key words

alkynes - fused-ring systems - natural products - stereoselective synthesis - tandem reaction

• References and Notes

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Evaluation of gold catalysts (ref. 6a,b) gave elimination and benzyloxy migration, without evidence for oxacyclization:
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A silver catalyst gave only oxidation of both alcohols of alkynyl diol 4:
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• 13 Compound 13 shares many similar ¹H NMR resonances with a slightly different bispyranyl ketone reported from a gold-catalyzed dehydrative cyclization process: Ito H. Harada A. Ohmiya H. Sawamura M. Adv. Synth. Catal. 2013; 355: 647
• 14 Bispyranyl Ketone 13, from Diyne Triol Substrate 6 Hg(OTf)₂(11 mg, 0.023 mmol) was added to CH₂Cl₂(2.4 mL) and cooled to –20 °C. Diynyl triol (S,S)-6 (63 mg, 0.20 mmol) was dissolved in CH₂Cl₂ (3.0 mL) and added to the solution slowly and the reaction mixture turned bright yellow. After 15 min, the reaction was quenched with triethylsilane (195 μL, 1.20 mmol). After 15 h, the reaction was quenched with triethylamine and filtered through a plug of silica gel before being concentrated under reduced pressure. The crude oil was purified by flash column chromatography (10–30% EtOAc in hexanes) to afford bispyranyl ketone 13 as a clear yellow oil (14 mg, 0.044 mmol, 22% yield). HRMS (NSI): m/z calcd for C₁₉H₂₇O₄ [M + H⁺]: 319.19039; found: 319.18997. ¹H NMR (600 MHz, CDCl₃): δ = 7.36–7.25 (m, 5 H), 4.49 (s, 2 H), 3.92–3.80 (m, 2 H), 3.73 (m, 2 H), 3.37 (td, J = 11.7, 3.0 Hz, 1 H), 3.04 (ddd, J = 11.1, 8.8, 4.3 Hz, 1 H), 2.92 (ddd, J = 11.0, 8.8, 4.4 Hz, 1 H), 2.74 (t, J = 6.2 Hz, 2 H), 2.70 (dd, J = 15.9, 7.3 Hz, 1 H), 2.46 (dd, J = 16.0, 5.3 Hz, 1 H), 1.95 (m, 2 H), 1.84–1.75 (m, 1 H), 1.75–1.62 (m, 2 H), 1.50 (qd, J = 12.6, 12.2, 4.0 Hz, 1 H), 1.45–1.34 (m, 2 H). ¹H NMR (600 MHz, C₆D₆): δ = 7.40–7.18 (m, 3 H), 7.14–7.01 (m, 2 H), 4.28 (s, 2 H), 3.76 (dddd, J = 12.8, 7.3, 4.9, 2.2 Hz, 1 H), 3.68 (ddt, J = 11.3, 4.7, 1.6 Hz, 1 H), 3.61 (dt, J = 9.4, 6.3 Hz, 1 H), 3.56 (dt, J = 9.4, 6.2 Hz, 1 H), 3.07 (td, J = 12.4, 2.4 Hz, 1 H), 2.91 (ddd, J = 11.0, 8.7, 4.3 Hz, 1 H), 2.80 (ddd, J = 11.1, 8.8, 4.4 Hz, 1 H), 2.47 (dd, J = 15.8, 7.5 Hz, 1 H), 2.42 (td, J = 6.3, 1.8 Hz, 2 H), 2.07 (dd, J = 15.8, 4.9 Hz, 1 H), 1.91–1.86 (m, 1 H), 1.82 (m, 1 H), 1.51–1.24 (m, 3 H), 1.22–1.06 (m, 2 H), 1.06–0.84 (m, 1 H). ¹³C NMR (151 MHz, C₆D₆): δ = 205.6, 139.1, 128.6, 128.1, 128.0, 78.7, 78.5, 73.8, 73.3, 67.8, 65.6, 49.4, 43.9, 30.23, 30.17, 30.05, 26.1.
• 15 Hg(0) is presumably unreactive as a catalyst for the first three steps depicted in Scheme 5. We have not directly observed any of the hypothesized intermediates 14–17 in the reaction of diynyl triol 6.
• 16 The bispyranyl ketone 13 may also arise from an acid-catalyzed Meyer–Schuster rearrangement of the propargylic alcohol in 14 or 15 into an α,β-unsaturated enone, followed by intramolecular conjugate addition.
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Noyori hydrogenation gave 5.7:1 dr but did not go to full conversion, and catalyzed elimination of the alcohol with higher catalytic loadings. Oxazaborolidine-catalyzed reduction gave 1.5:1 dr; Alpine borane reductions gave 2:1 dr but did not proceed to full conversion even after 5 d with a neat reaction mixture. See:
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• 23 Bispyranyl Ketone ent-13, from Alkynyl Diol Substrate 25 Hg(OTf)₂ (9 mg, 0.017 mmol) was added to CH₂Cl₂ (2.4 mL) and cooled to –15 °C. Alkynyl diol 25 (36 mg, 0.13 mmol, 77:23 dr) was dissolved in CH₂Cl₂ (1.2 mL), and was slowly added to the Hg(OTf)₂ solution. After 20 min, triethyl­silane was added (75 μL, 0.45 mmol), and the mixture was stirred for 14 h at –15 °C. The reaction mixture was quenched with triethylamine, and filtered through a plug of silica gel before being concentrated under reduced pressure. The crude oil was purified by flash column chromatography (15–30% EtOAc in hexanes) to afford product ent- 13 as clear yellow oil (26 mg, 0.012 mmol, 72% yield); [α]_D ²⁵ –1.6 (c 1.12, CHCl₃). ¹H NMR and ¹³C NMR data were identical to that recorded for 13 (ref. 14).
• 24 In response to reviewer questions, we did not explore mercury-catalyzed cyclizations of 25 or 26 without subsequent addition of triethylsilane, as our objective was not the preparation of 13, but rather the synthesis of 5. The difference in isolated yields from 25 vs. the diastereomer 26 is probably not significant, as we were most interested in carefully purifying and characterizing the major product from these transformations, which was determined to be compound ent-13.
• 25 Bicyclic Product 28, from Cyclization of Alkynyl Diol Substrate 25 Hg(OTf)₂ (122 mg, 0.24 mmol) was added to CH₂Cl₂ (5 mL) and cooled to –15 °C. Alkynyl diol 25 (77 mg, 0.24 mmol, 73:27 R/S dr) was dissolved in CH₂Cl₂ (2.5 mL) and was slowly added to the Hg(OTf)₂ solution. Within 20 s of the last addition of alkynyl diol, triethylsilane (160 μL, 0.97 mmol) was added, and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with triethylamine, filtered through a plug of silica gel, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (25–50% EtOAc in hexanes) to afford the product 27 as a yellow oil (17 mg, 27% yield). ¹H NMR for compound 27 (600 MHz, CDCl₃): δ = 7.40–7.28 (m, 5 H), 4.52 (dd, J = 11.9, 11.6 Hz, 2 H), 4.06–3.99 (m, 1 H), 3.93–3.86 (m, 2 H), 3.70–3.58 (m, 3 H), 3.40 (td, J = 11.7, 3.0 Hz, 1 H), 3.10 (ddd, J = 11.2, 8.8, 4.3 Hz, 1 H), 2.97 (ddd, J = 10.4, 8.7, 4.4 Hz, 1 H), 1.99 (m, 2 H), 1.82–1.62 (m, 5 H), 1.62–1.55 (m, 1 H), 1.54–1.41 (m, 2 H). Compound 27 was dissolved in CH₂Cl₂ (1 mL), and Ac₂O (0.1 mL) and pyridine (0.1 mL) were added. The reaction mixture was stirred overnight. The crude product was concentrated under reduced pressure and purified by silica gel flash column chromatography to afford the acetate ester 28 as a yellow oil (16 mg, 0.46 mmol, 87% yield); [α]_D ²⁵ –5.2 (c 0.90, CHCl₃). IR (thin film): 2926, 2853, 1734, 1243, 1097, 734 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 7.39–7.27 (m, 5 H), 5.21 (dddd, J = 8.3, 6.9, 5.7, 4.4 Hz, 1 H), 4.55–4.40 (dd, J = 11.9, 3.2 Hz, 2 H), 3.89 (m, 1 H), 3.55–3.42 (m, 3 H), 3.38 (td, J = 11.6, 3.0 Hz, 1 H), 2.96 (m, 2 H), 2.18 (s, 3 H), 1.99–1.92 (m, 1 H), 1.93–1.81 (m, 4 H), 1.77 (m, 1 H), 1.75–1.65 (m, 2 H), 1.62 (m, 1 H), 1.51–1.34 (m, 3 H). ¹H NMR (600 MHz, C₆D₆): δ = 7.32–7.29 (m, 2 H), 7.20–7.17 (m, 2 H), 7.09 (ddt, J = 8.8, 6.9, 1.4 Hz, 1 H), 5.45 (tt, J = 7.4, 5.4 Hz, 1 H), 4.30 (m, 2 H), 3.70 (ddt, J = 11.3, 4.8, 1.6 Hz, 1 H), 3.39 (t, J = 6.3 Hz, 2 H), 3.37 (app dt, J = 7.3, 2.5, 1 H), 3.09 (ddd, J = 12.5, 11.3, 2.4 Hz, 1 H), 2.93 (ddd, J = 11.0, 10.8, 4.3, 1 H), 2.84 (ddd, J = 10.7, 8.7, 4.4 1 H), 1.92 (dddd, J = 10.7, 8.4, 3.8, 2.6 Hz, 1 H), 1.88 (m, 1 H), 1.87–1.82 (m, 2 H), 1.73 (s, 3 H), 1.52–1.42 (m, 4 H), 1.35–1.29 (m, 2 H), 1.23–1.17 (m, 2 H). ¹³C NMR (151 MHz, C₆D₆): δ = 170.1, 139.5, 128.9, 128.7, 128.0, 79.1, 78.8, 75.4, 73.5, 69.9, 68.1, 67.2, 41.3, 35.4, 32.2, 30.56, 30.51, 26.5, 21.3.
• 26 Stoltz KL. Alba A.-NR. McDonald FE. Wieliczko MB. Bacsa J. Heterocycles 2014; 88: 1519
• 27a A reviewer has asked why 8-endo-mode cyclization to form 27 is preferred over 7-exo-cyclization. We speculate that the propargylic alcohol may exert an electron-withdrawing effect that favors oxygen addition on the alkyne carbon distal to the hydroxyl substituent.
• 27b Pennell MN. Kyle MP. Gibson SM. Male L. Turner PG. Grainger RS. Sheppard TD. Adv. Synth. Catal. 2016; 358: 1519
• 27c Pennell MN. Unthank MG. Turner P. Sheppard TD. J. Org. Chem. 2011; 76: 1479
• 28 Hurtak, J. A.; McDonald, F. E. manuscript in preparation.