Stereoselective Synthesis of Macrosphelide I

Abstract

An efficient total synthesis of macrosphelide I, has been achieved starting from commercially available chiral materials, ethyl (S)-lactate and methyl (R)-3-hydroxybutyrate. Titanium(IV) promoted the regioselective nucleophilic opening reaction of epoxy alcohol with benzoic acid, Sharpless epoxidation, ring-closing metathesis and Yamaguchi esterification as key steps for the construction of the 16-membered macrotriolide.

Key words

macrosphelide I - regioselective opening - Yamaguchi esterification - ring-closing metathesis

• References and Notes

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• 13 Spectroscopic Data for Selected Compounds: (2S,3R,E)-6-Ethoxy-2-(4-methoxybenzyloxy)-6-oxohex-4-en-3-ylbenzoate (5): yellow syrup; [α]_D ²⁵ +91.7 (c = 0.25, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 8.06 (d, J = 7.7 Hz, 2 H, ArH), 7.58 (t, J = 7.7 Hz, 1 H, ArH), 7.46 (t, J = 7.7 Hz, 2 H, ArH), 7.23–7.25 (m, 3 H, ArH), 7.04 (dd, J = 5.0, 15.5 Hz, 1 H, ArH), 6.82 (d, J = 8.6 Hz, 2 H, =CH), 6.04 (d, J = 16.0 Hz, 1 H, =CH), 5.77–5.78 (m, 1 H, OCHBz), 4.55 (dd, J = 11.4 Hz, 2 H, CH₂Ar), 4.19 (q, J = 6.8 Hz, 2 H, OCH), 3.76–3.84 (m, 4 H, OCH₂, OCH₂), 1.21–1.33 (m, 6 H, 2 × Me). ¹³C NMR (75 MHz, CDCl₃): δ = 165.7, 165.3, 159.2, 142.2, 133.2, 130.0, 129.7, 129.3, 128.4, 123.0, 113.7, 75.0, 74.6, 70.9, 60.5, 55.1, 15.9, 14.1. IR (neat): 3396, 3032, 2941, 1721, 1453, 1112 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₃H₂₆O₆Na: 421.1652; found: 421.4387. (3R,4S)-4-(4-Methoxybenzyloxy)pent-1-en-3-ylbenzoate (6): colorless syrup; [α]_D ²⁵ +43.7 (c = 1.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 8.06 (d, J = 6.9 Hz, 2 H, ArH), 7.57 (t, J = 7.1 Hz, 1 H, ArH), 7.42–7.47 (m, 2 H, ArH), 7.25–7.27 (m, 2 H, ArH), 6.81 (d, J = 8.4 Hz, 2 H, ArH), 5.93–6.05 (m, 1 H, =CH), 5.59–5.62 (m, 1 H, CHOBz), 5.29–5.41 (m, 2 H, =CH₂), 4.60 (dd, J = 11.3 Hz, 2 H, CH₂Ar), 3.74–3.85 (m, 4 H, OCH, OMe), 1.25 (d, J = 6.4 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 165.5, 159.1, 132.9, 130.4, 129.6, 129.2, 128.3, 118.3, 113.7, 76.5, 75.4, 70.8, 55.1, 15.8. IR (neat): 3396, 3067, 2967, 2969, 1721, 1597, 1453, 1279, 1113 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₂O₄Na: 349.1416; found: 349.3761. (4R,5S)-4-(tert-Butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)hexanoic Acid (15): colorless oil; [α]_D ²⁵ +44.6 (c = 1.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.25 (d, J = 7.9 Hz, 2 H, ArH), 6.85 (d, 2 H, J = 8.4 Hz, ArH), 4.48 (dd, J = 11.3 Hz, 2 H, CH₂Ar), 3.79 (s, 3 H, OMe), 3.67–3.71 (m, 1 H, OCH), 3.38–3.44 (m, 1 H, OCH), 2.36–2.44 (m, 2 H, CH₂CO), 1.88–1.96 (m, 1 H, CH), 1.75–1.82 (m, 1 H, CH), 1.16 (d, J = 6.4 Hz, 3 H, Me), 0.89 (br s, 9 H, 3 × Me), 0.05 (s, 6 H, 2 × Me). ¹³C NMR (75 MHz, CDCl₃): δ = 159.0, 130.7, 129.2, 113.7, 76.9, 74.1, 70.6, 60.2, 55.2, 29.4, 27.8, 25.9 (3 × C), 18.1, 15.6, –4.2, –4.6. IR (neat): 3031, 2930, 2857, 1710, 1097 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₃₄O₅NaSi: 405.2091; found: 405.2073. (4R,5S)-{(2S,3R)-3-[(2-Methoxyethoxy)methoxy]pent-4-en-2-yl}-4-(tert-butyldimethylsilyloxy)-5-hydroxy-hexanoate (3): colorless liquid; [α]_D ²⁵ –145.0 (c = 0.65, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 5.68–5.74 (m, 1 H, =CH=CH₂), 5.30 (d, J = 12.5 Hz, 2 H, =CH₂), 5.00–5.05 (m, 1 H, CHCO), 4.69–4.76 (m, 2 H, OCH₂), 4.07–4.11 (m, 1 H, OCH), 3.76–3.83 (m, 1 H, OCH), 3.71–3.72 (m, 1 H, OCH), 3.60–3.68 (m, 2 H, OCH₂), 3.54–3.56 (m, 2 H, OCH₂), 3.39 (s, 3 H, OMe), 2.42–2.50 (m, 1 H, CHC=O), 2.28–2.35 (m, 1 H, CHCO), 1.84–1.91 (m, 1 H, CH), 1.71–1.78 (m, 1 H, CH), 1.23 (d, J = 6.5 Hz, 3 H, Me), 1.13 (d, J = 6.5 Hz, 3 H, Me), 0.91 (s, 9 H, 3 × Me), 0.09 (s, 6 H, 2 × Me). ¹³C NMR (75 MHz, CDCl₃): δ = 173.3, 133.9, 119.7, 92.8, 78.7, 74.9, 71.6 (2 × C), 69.8, 66.9, 58.9, 29.8, 25.8 (3 × C), 25.6, 18.0, 17.7, 15.3, –4.5 (2 × C). IR (neat): 3430, 2957, 2930, 2856, 1719, 1654, 1465 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₁H₄₂O₇NaSi: 457.2592; found: 457.2590. (4R,5S)-{(2S,3R)-3-[(2-Methoxyethoxy)methoxy]pent-4-en-2-yl}-4-(tert-butyldimethylsilyloxy)-5-[(R)-3-hydroxybutanoyloxy]hexanoate (20): colorless liquid; [α]_D ²⁵ –127.8(c = 0.5, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 5.63–5.77 (m, 1 H, CH=CH₂), 5.25–5.33 (m, 2 H, =CH₂), 4.98–5.05 (m, 1 H, CHCO), 4.85–4.93 (m, 1 H, CHCO), 4.77 (d, J = 6.7 Hz, 1 H, OCH), 4.67 (d, J = 6.7 Hz, 2 H, OCH₂), 4.14–4.26 (m, 2 H, OCH₂), 4.04–4.15 (m, 2 H, OCH₂), 3.70–3.98 (m, 2 H, OCH₂), 3.58–3.67 (m, 1 H, OCH), 3.51–3.58 (m, 1 H, OCH), 3.39 (s, 3 H, OMe), 3.07–3.13 (m, 1 H, OCH), 2.29–2.48 (m, 4 H, CH₂CO, CH₂CO), 1.73–1.83 (m, 2 H, CH₂), 1.17–1.26 (m, 9 H, 3 × Me), 0.89 (s, 9 H, 3 × Me), 0.05 (s, 6 H, 2 × Me). ¹³C NMR (75 MHz, CDCl₃): δ = 172.7, 172.1, 133.9, 129.1, 119.8, 92.8, 78.7, 73.2, 72.9, 71.6 (2 × C), 66.9, 64.1, 59.0, 43.1, 30.1, 28.0, 25.8 (3 × C), 22.3, 18.1, 15.4, 14.6, –4.4, –4.6. IR (neat): 3352, 2983, 2842, 1719, 1654, 1553, 1402 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₅H₄₈O₉NaSi: 543.2959; found: 543.2963. (4R,9R,10S,15R,16S,E)-15-(tert-Butyldimethylsilyloxy)-9-[(2-methoxyethoxy)methoxy]-4,10,16-trimethyl-1,5,11-trioxacyclohexadec-7-ene-2,6,12-trione (21): yellow liquid; [α]_D ²⁵ –84.0(c = 0.45, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 6.77 (dd, J = 6.9, 15.4 Hz, 1 H, CH=CH), 6.02 (dd, J = 15.4 Hz, 1 H, CH=CH), 5.23–5.29 (m, 1 H, CHCO), 5.07–5.12 (m, 1 H, CHCO), 4.80–4.86 (m, 1 H, CHCO), 4.69 (dd, J = 16.9 Hz, 2 H, OCH₂), 4.19–4.21 (m, 1 H, OCH), 3.74–3.78 (m, 1 H, OCH), 3.61–3.67 (m, 2 H, OCH₂), 3.53–3.54 (m, 2 H, OCH₂), 3.38 (s, 3 H, OMe), 2.74 (dd, J = 3.9, 14.4 Hz, 1 H, =CHCH), 2.53 (dd, J = 6.4, 14.9 Hz, 1 H, =CHCH), 2.29–2.44 (m, 2 H, =CHCH₂), 1.55–1.79 (m, 2 H, CH₂), 1.43 (d, J = 6.4 Hz, 3 H, Me), 1.30 (d, J = 6.4 Hz, 3 H, Me), 1.17 (d, J = 6.4 Hz, 3 H, Me), 0.88 (s, 9 H, 3 × Me), 0.07 (d, J = 15.4 Hz, 6 H, 2 × Me). ¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 169.3, 164.6, 143.0, 125.0, 93.3, 77.5, 73.7, 73.1, 71.5, 71.1, 67.5, 67.2, 59.0, 40.5, 30.7, 29.6, 28.3, 25.7 (3 × C), 19.5, 17.3, 15.5, –4.4, –4.6. IR (neat): 2856, 1734, 1657, 1615, 1517, 1466, 1093 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₂₆H₄₆O₁₀NaSi: 569.2752; found: 569.2763. Macrosphelide I (1): colorless syrup; [α]_D ²⁵ +12.4 (c = 0.09, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.18 (d, J = 6.6 Hz, 3 H, Me), 1.32 (d, J = 6.6 Hz, 3 H, Me), 1.46–1.47 (m, 1 H, CH), 1.47 (d, J = 6.6 Hz, 3 H, Me), 1.68–1.74 (m, 1 H, CH), 2.36 (dt, J = 5.1, 14.7 Hz, 1 H, CH), 2.53 (br s, 1 H, OH), 2.62–2.68 (m, 2 H, CH₂), 2.70 (dd, J = 2.9, 16.1 Hz, 1 H, CH), 3.25 (d, J = 11.4 Hz, 1 H, CH), 3.83 (br s, 1 H, OH), 4.29 (br s, 1 H, CH), 4.83–4.87 (m, 2 H, 2 × CH), 5.65 (m, 1 H, CH), 6.24 (dd, J = 2.2, 15.4 Hz, 1 H, HC=CH), 7.21 (dd, J = 2.9, 15.4 Hz, 1 H, CH=CH). ¹³C NMR (150 MHz, CDCl₃): δ = 12.70, 18.60, 20.10, 27.50, 30.40, 41.80, 67.00, 71.10, 74.40, 74.80, 78.30, 121.90, 147.80, 166.90, 168.60, 175.30. IR (neat): 3447, 2925, 1628 cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₆H₂₄O₈Na: 367.1368; found: 367.1383.