Stereoselective Total Synthesis of Rhoiptelol B via Prins Cyclization

Abstract

The stereoselective total synthesis of rhoiptelol B, a diaryl­heptanoid isolated from Rhoiptelea chiliantha is described. The tetrahydropyran ring was constructed by using Prins cyclization. The key steps involved in this synthesis are Prins cyclization, Mistunobu inversion, cross metathesis, Sharpless asymmetric dihydroxylation, and hydrogenolysis.

Key words

rhoiptelol B - natural products - diarylheptanoid - Prins cyclization - Mitsunobu inversion

• References and Notes

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Previous total synthesis of rhoiptelol B:
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• 15 Preparation of compound 4 from p-hydroxybenzaldehyde (Scheme 4).
• 16 (2R,4S,6R)-2-[2-(Benzyloxy)ethyl]-6-(4-hydroxy-3-methoxyphenyl)tetrahydro-2H-pyran-4-ol (7) [α]_D ²⁵ +38.3 (c 1.01, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.20–7.17 (m, 5 H), 6.83–6.78 (m, 2 H), 6.77–6.71 (m, 1 H), 5.45 (br s, OH, 1 H), 4.47 (s, 2 H), 4.23 (dd, J = 1.3, 11.3 Hz, 1 H), 3.86 (s, 3 H), 3.70–3.50 (m, 4 H), 2.18–2.08 (m, 1 H), 2.04–1.94 (m, 1 H), 1.93–1.74 (m, 2 H), 1.34–1.20 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.3, 144.9, 144.94, 138.4, 134.0, 128.3, 127.5, 127.5, 118.9, 114.0, 108.6, 77.1, 72.9, 68.4, 66.6, 55.8, 42.5, 40.9, 36.1. IR (neat): ν_max = 3385, 2921, 2853, 1517, 1273, 1074, 1033, 747 cm^–1. ESI-MS: m/z = 381 [M + Na]⁺. (2R,4R,6R)-2-[2-(Benzyloxy)ethyl]-6-(4-hydroxy-3-methoxyphenyl)tetrahydro-2H-pyran-4-ol (8) [α]_D ²⁵ +32.2 (c 0.83, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.34–7.29 (m, 5 H), 6.89–6.81 (m, 3 H), 4.77 (d, J = 10.6 Hz, 1 H), 4.51 (s, 2 H), 4.34–4.31 (m, 1 H), 4.17–4.09 (m, 1 H), 3.86 (s, 3 H), 3.69–3.59 (m, 2 H), 1.93–1.85 (m, 2 H), 1.84–1.76 (m, 1 H), 1.75–1.69 (m, 2 H), 1.64–1.57 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.3, 144.7, 138.5, 135.0, 128.2, 127.5, 127.4, 118.7, 114.0, 108.7, 73.2, 72.8, 69.2, 66.8, 64.9, 55.8, 40.1, 38.5, 36.2; IR (neat): ν_max = 3385, 2921, 2853, 1517, 1273, 1074, 1033, 747 cm^–1. ESI-MS: m/z = 381 [M + Na]⁺. (2R,4R,6R)-2-[2-(Benzyloxy)ethyl]-6-[3-methoxy-4-(methoxymethoxy)phenyl]-4-(methoxymethoxy)-tetrahydro-2H-pyran (9) [α]_D ²⁵ +34.2 (c 1.04, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.29–7.16 (m, 5 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.86–6.75 (m, 2 H), 5.13 (s, 2 H), 4.70–4.63 (m, 3 H), 4.43 (s, 2 H), 4.08–3.96 (m, 2 H), 3.78 (s, 2 H), 3.61–3.52 (m, 2 H), 3.43 (s, 3 H), 3.33 (s, 3 H), 1.99–1.88 (m, 1 H), 1.87–1.68 (m, 3 H), 1.67–1.57 (m, 1 H), 1.51–1.39 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.6, 145.5, 138.6, 137.5, 128.2, 127.4, 127.3, 118.1, 116.2, 109.7, 95.4, 95.0, 73.7, 72.9, 70.1, 69.9, 66.8, 56.0, 55.7, 55.3, 38.4, 36.4, 36.2. IR (neat): ν_max = 2927, 1513, 1267, 1153, 1037 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₅H₃₄O₇Na: 469.21792; found: 469.21967. 2-{(2R,4R,6R)-6-[3-Methoxy-4-(methoxymethoxy)-phenyl]-4-(methoxymethoxy)tetrahydro-2H-pyran-2-yl}ethanol (10) [α]_D ²⁵ +34.0 (c 0.65, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.03 (d, J = 8.3 Hz, 1 H), 6.84–6.74 (m, 2 H), 5.14 (s, 2 H), 4.72 (dd, J = 1.1, 11.3 Hz, 1 H), 4.67 (s, 2 H), 4.17–4.02 (m, 2 H), 3.81 (s, 3 H), 3.79–3.72 (m, 2 H), 3.44 (s, 3 H), 3.35 (s, 3 H), 2.03–1.94 (m, 1 H), 1.85–1.56 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.7, 145.7, 136.9, 118.0, 109.4, 95.4, 95.1, 74.2, 73.6, 69.9, 61.6, 56.0, 55.8, 55.4, 38.3, 37.8, 36.1. IR (neat): ν_max = 3417, 2924, 1516, 1036 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₈H₂₈O₇Na: 379.17191; found: 379.17272. (2S,4R,6R)-2-(2-Iodoethyl)-6-[3-methoxy-4-(methoxymethoxy)phenyl]-4-(methoxymethoxy)-tetrahydro-2H-pyran (11) [α]_D ²⁵ +28.4 (c 0.34, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.10 (d, J = 8.2 Hz, 1 H), 6.97 (d, J = 1.9 Hz, 1 H), 6.88 (dd, J = 1.6, 8.2 Hz, 1 H), 6.86–5.89 (m, 1 H), 5.31 (m, 1 H), 5.12 (m, 1 H), 5.20 (s, 2 H), 4.81 (dd, J = 1.8, 11.7 Hz, 1 H), 4.76 (d, J = 0.9 Hz, 2 H), 4.47–4.42 (m, 1 H), 4.16–4.13 (m, 2 H), 3.89 (s, 3 H), 3.50 (s, 3 H), 3.43 (s, 3 H), 2.04–1.98 (m, 1 H), 1.94–1.90 (m, 1 H), 1.75–1.69 (dtd, J = 2.7, 11.9, 14.3 Hz, 1 H), 1.64–1.58 (dtd, J = 2.7, 11.7, 14.3, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.6, 145.6, 139.0, 137.2, 118.2, 116.2, 4.8, 109.8, 95.5, 95.1, 73.9, 73.3, 70.0, 56.0, 55.8, 55.4, 38.2, 35.9. IR (neat): ν_max = 2923, 2851, 1513, 1266, 1153, 1075, 1037 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₈H₂₆O₆Na: 361.16163; found: 361.16216. (2R,4R,6S)-2-[3-Methoxy-4-(methoxymethoxy)phenyl]-4-(methoxymethoxy)-6-[(E)-4-(methoxymethoxy)styryl]-tetrahydro-2H-pyran (2) [α]_D ²⁵ +6.4 (c 0.74, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.34–7.28 (m, 2 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.01–6.89 (m, 4 H), 6.59 (d, J = 16.0 Hz, 1 H), 6.15 (d, J = 6.2, 16.0 Hz, 1 H), 5.21 (s, 2 H), 5.16 (s, 2 H), 4.89–4.82 (m, 1 H), 4.78 (s, 2 H), 4.65–4.55 (m, 1 H), 4.22–4.15 (m, 1 H), 3.90 (s, 3 H), 3.50 (s, 3 H), 3.47 (s, 3 H), 3.45 (s, 3 H), 2.06–1.94 (m, 2 H), 1.83–1.65 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.7, 149.6, 145.7, 137.1, 130.8, 129.6, 128.7, 127.5, 118.4, 116.3, 116.1, 109.9, 95.5, 95.1, 94.3, 74.1, 73.4, 70.1, 56.0, 55.9, 55.8, 55.4, 38.1, 36.3. IR (neat): ν_max = 2925, 2852, 1511, 1266, 1235, 1152, 1077, 1037, 999 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₆H₃₄O₈Na: 497.21229; found: 497.21459. (1S,2R)-1-{(2S,4S,6R)-6-[3-Methoxy-4-(methoxymethoxy)-phenyl]-4-(methoxymethoxy)tetrahydro-2H-pyran-2-yl}-2-[4-(methoxymethoxy)phenyl]ethane-1,2-diol (12) [α]_D ²⁵ +24.6 (c 0.44, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.32–7.28 (m, 2 H), 7.13 (d, J = 3.2 Hz, 1 H), 7.03–7.00 (m, 2 H), 6.91–6.86 (m, 2 H), 5.23 (s, 3 H), 5.16 (s, 3 H), 4.84 (d, J = 5.0 Hz, 1 H), 4.77 (dd, J = 1.6, 11.7 Hz, 1 H), 4.69 (s, 3 H), 4.17–3.69 (m, 1 H), 3.90 (s, 3 H), 3.52 (s, 3 H), 3.47 (s, 3 H), 3.32 (s, 3 H), 2.50–2.48 (m, 1 H), 2.02–1.94 (m, 1 H), 1.77–1.67 (m, 1 H), 1.63 (br s, OH, 1 H), 1.37–1.23 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.7, 149.7, 16.4, 134.2, 127.7, 118.2, 116.1, 109.7, 95.4, 95.1, 94.4, 74.7, 74.3, 73.6, 70.0, 56.1, 55.9, 55.4, 43.3, 37.9, 32.1, 29.6, 25.6. IR (neat): ν_max = 3449, 2925, 2852, 1512, 1266, 1153, 1076, 1036, 1000 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₆H₃₆O₁₀Na: 531.21809; found: 531.22007. (S)-1-{(2S,4S,6R)-6-[3-Methoxy-4-(methoxymethoxy)-phenyl]-4-(methoxymethoxy)tetrahydro-2H-pyran-2-yl}-2-[4-(methoxymethoxy)phenyl]ethanol (13) [α]_D ²⁵ +11.20 (c 0.87, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.19–7.09 (m, 3 H), 7.02–6.82 (m, 4 H), 5.23 (s, 2 H), 5.16 (s, 3 H), 4.81–4.64 (m, 3 H), 4.36–4.24 (m, 1 H), 4.25–4.19 (m, 1 H), 3.89 (s, 3 H), 3.78–3.60 (m, 1 H), 3.51 (s, 3 H), 3.46 (s, 3 H), 3.37 (s, 3 H), 2.90–2.70 (m, 2 H), 2.51 (br s, OH, 1 H), 2.08–1.87 (m, 2 H), 1.79–1.64 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.7, 149.6, 137.0, 131.8, 130.7, 130.3, 128.7, 118.2, 116.2, 114.1, 109.7, 95.5, 95.1, 94.5, 77.0, 74.4, 74.0, 70.1, 56.1, 55.8, 55.4, 38.6, 38.3, 31.9. IR (neat): ν_max = 3450, 2925, 2854, 1636 cm^–1. ESI-MS: m/z = 515 [M + Na]⁺. Rhoiptelol B (1): Mp 65–67 °C; [α]_D ²⁵ +87.4 (c 0.3, MeOH). ¹H NMR (300 MHz, CD₃OD): δ = 7.05 (br s, 1 H), 7.04 (d, J = 8.4 Hz, 2 H), 6.82 (dd, J = 8.4, 2.0 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 2 H), 4.67 (dd, J = 10.7, 3.2 Hz, 1 H), 4.26 (t, J = 3.2 Hz, 1 H), 3.85 (s, 3 H), 3.80 (dt, J = 12.7, 2.9 Hz, 1 H), 3.59 (dt, J = 7.4, 3.2 Hz, 1 H), 2.84 (dd, J = 13.0, 6.6 Hz, 1 H), 2.67 (dd, J = 13.0, 7.4 Hz, 1 H), 1.91 (dd, J = 13.3, 3.0 Hz, 1 H), 1.82 (dd, J = 14.3, 2.9 Hz, 1 H), 1.73 (ddd, J = 13.6, 10.9, 2.8 Hz, 1 H), 1.57 (dd, J = 13.6, 2.0 Hz, 1 H). ¹³C NMR (75 MHz, CD₃OD): δ = 156.7, 148.8, 146.8, 136.2, 131.4, 131.3, 131.1, 119.8, 116.0, 115.8, 115.7, 111.1, 76.4, 75.2, 74.3, 65.7, 56.4, 41.2, 39.7, 35.0; IR (neat): ν_max = 3392, 2953, 2928, 1595, 1502, 1365, 1174, 1083, 854, 716 cm^–1. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₄O₆Na: 383.1470; found: 383.1461.