A Highly Stereoselective Formal Synthesis of Hapalosin

Harish Kumar; A. Srinivas Reddy; J. S. Yadav; B. V. Subba Reddy

doi:10.1055/s-0033-1338952

Synlett, Table of Contents

Synlett 2013; 24(11): 1415-1419
DOI: 10.1055/s-0033-1338952

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A Highly Stereoselective Formal Synthesis of Hapalosin

Harish Kumar

Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 007, India Fax: +91(40)27160512 Email: basireddy@iict.res.in

,

A. Srinivas Reddy

Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 007, India Fax: +91(40)27160512 Email: basireddy@iict.res.in

,

J. S. Yadav

Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 007, India Fax: +91(40)27160512 Email: basireddy@iict.res.in

,

B. V. Subba Reddy*

Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 007, India Fax: +91(40)27160512 Email: basireddy@iict.res.in

› Author Affiliations

Abstract

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Abstract

A flexible and highly diastereoselective formal synthesis of hapalosin, a cyclodepsipeptide isolated from the blue green alga Hapalosiphon welwitschii and having multidrug-resistance-reversing activity is described. The synthetic route involves the addition of organometallic reagent to N-tert-butanesulfinylimine, Jung nonaldol aldol reaction, and Yamaguchi esterification as key steps.

Key words

Sharpless asymmetric epoxidation - Jung nonaldol aldol reaction - Yamaguchi esterification - hapalosin

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References

References and Notes

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10 [(2R,3R)-3-Heptyl-2-methyloxiran-2-yl]methanol (8) R_f = 0.50 (20% EtOAc–hexane); light yellow liquid; [α]_D ²⁵ +10.5 (c 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 3.73–3.52 (m, 2 H), 3.03 (t, J = 6.4 Hz, 1 H), 1.61–1.43 (m, 2 H), 1.40–1.23 (m, 13 H), 0.90–0.85 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 65.4, 63.8, 60.3, 31.7, 29.3, 29.1, 28.1, 26.4, 22.5, 14.0. IR (neat): ν_max = 3427, 2927, 2858, 1728, 1462, 1382, 1278, 1127, 1073, 1041, 872, 771, 744, 723, 704 cm^–1. ESI-HRMS: m/z calcd for C₁₁H₂₂O₂: 209.1517 [M + Na]⁺; found: 209.1524. (2S,3R)-[(S)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl]-3-(tert-butyldimethylsilyloxy)-2-methyldecanoate (9) R_f = 0.70 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ –18.0 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.37–7.30 (m, 5 H), 5.20–5.11 (dd, J = 12.8, 6.0 Hz, 2 H), 4.83 (d, J = 4.5 Hz, 1 H), 4.03–3.96 (dt, J = 6.0, 5.3 Hz, 1 H), 2.69–2.58 (dq, J = 6.8, 5.3 Hz, 1 H), 2.32–2.15 (d of sept, J = 6.8, 4.5 Hz, 1 H), 1.55–1.22 (m, 12 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 7.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.89 (t, J = 6.0 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.02 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.7, 169.5, 135.5, 128.5, 128.3, 128.1, 76.6, 73.0, 66.7, 44.6, 35.2, 31.8, 30.2, 29.7, 29.2, 25.8, 24.5, 22.6, 18.8, 18.1, 17.2, 14.1, 12.1, –4.6, –4.3. IR (neat): ν_max = 2959, 2929, 2861, 1730, 1600, 1581, 1463, 1381, 1277, 1072, 1040, 957, 772, 743 cm^–1. ESI-HRMS: m/z calcd for C₂₉H₅₀O₅Si: 529.3314 [M + Na]⁺; found: 529.3322. (2S,3R)-[(S)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl]-3-hydroxy-2-methyldecanoate (10) R_f = 0.40 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ –10.5 (c 1.0, CHCl₃). ¹H NMR (300 MHz, CDC0l₃): δ = 7.40–7.30 (m, 5 H), 5.25–5.13 (dd, J = 17.9, 12.1 Hz, 2 H), 4.99 (d, J = 3.8 Hz, 1 H), 4.12–4.03 (m, 1 H), 2.92–2.84 (br s, 1 H), 2.73–2.64 (dq, J = 6.9, 3.0 Hz, 1 H), 2.35–2.22 (d of sept, J = 6.9, 3.8 Hz, 1 H), 1.56–1.22 (m, 12 H), 1.17 (d, J = 6.9 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.88 (t, J = 6.7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.2, 170.3, 135.0, 128.6, 128.5, 128.4, 76.4, 71.9, 67.3, 44.4, 33.4, 31.8, 29.9, 29.5, 29.2, 26.2, 22.6, 18.8, 16.9, 14.1, 9.4. IR (neat): ν_max = 3064, 3017, 2921, 2853, 1609, 1577, 1525, 1456, 1346, 1305, 1142, 1071, 767, 741, 705, 567 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₃₆O₅: 415.2460 [M + Na]⁺; found: 415.2474. (E)-N-[(R)-2-(tert-Butyldimethylsilyloxy)pent-4-enylidene]-2-methylpropane-2-sulfinamide (12) R_f = 0.60 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ +159.0 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.95 (d, J = 4.5 Hz, 1 H), 5.90–5.75 (m, 1 H), 5.17–5.08 (m, 2 H), 4.53–4.46 (m, 1 H), 2.48–2.41 (m, 2 H), 1.20 (s, 9 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 133.1, 118.2, 74.0, 56.7, 40.2, 25.7, 22.4, 18.1, 4.9, 4.5. IR (neat): ν_max = 2959, 2930, 2861, 1729, 1600, 1580, 1462, 1381, 1274, 1122, 1072, 801, 772, 743 cm^–1. ESI-HRMS: m/z calcd for C₁₅H₃₁NO₂SSi: 318.1923; found: 318.193 [M + H]⁺ 7. N-[(2S,3R)-3-(tert-Butyldimethylsilyloxy)-1-phenylhex-5-en-2-yl]-2-methylpropane-2-sulfinamide (13) R_f = 0.60 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ +8.0 (c 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.28–7.23 (m, 2 H), 7.19–7.12 (m, 3 H), 5.87–5.77 (m, 1 H), 5.18–5.10 (m, 2 H), 3.63–3.59 (m, 1 H), 3.58–3.53 (m, 1 H), 2.90–2.84 (m, 1 H), 2.76–2.70 m, 1 H), 2.45–2.38 (m, 1 H), 2.36–2.28 (m, 1 H), 0.99 (s, 9 H), 0.93 (s, 9 H), 0.14 (s, 3 H), 0.08 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 139.0, 134.2, 129.3, 128.2, 126.0, 117.6, 74.5, 61.6, 55.7, 38.6, 34.9, 29.6, 25.9, 22.3, –4.4, –4.3. IR (neat): ν_max = 2958, 2929, 2860, 1729, 1600, 1580, 1462, 1381, 1276, 1123, 1072, 1040, 836, 774, 742 cm^–1. ESI-HRMS: m/z calcd for C₂₂H₃₉NO₂SSi: 410.2549; found: 410.2557 [M + H]⁺. Benzyl-(2S,3R)-3-(methoxymethoxy)-1-phenylhex-5-en-2-ylcarbamate (14) R_f = 0.60 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ –19.0 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.28–7.08 (m, 10 H), 5.87–5.68 (m, 1 H), 5.17–5.00 (m, 2 H), 4.90–4.86 (m, 2 H), 4.60 (s, 2 H), 4.00–3.90 (m, 1 H), 3.74–3.64 (m, 1 H), 3.33 (s, 3 H), 2.92 (dd, J = 4.5, 14.5 Hz, 1 H), 2.60–2.50 (m, 1 H), 2.40–2.30 (m, 1 H), 2.30–2.20 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.8, 138.2, 136.7, 134.1, 129.2, 128.4, 127.9, 127.8, 126.3, 117.8, 97.0, 80.8, 66.4, 55.9, 54.4, 36.7, 35.1. IR (neat): ν_max = 3376, 2960, 2930, 2864, 1729, 1600, 1581, 1461, 1381, 1278, 1124, 1072, 1040, 771, 743, 702 cm^–1. ESI-HRMS: m/z calcd for C₂₂H₂₇NO₄: 370.2018; found: 370.2020 [M + H]⁺. (3R,4R)-4-[(Benzyloxycarbonyl)(methyl) amino]-3-(methoxymethoxy)-5-phenylpentanoic Acid (3) R_f = 0.60 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ –31.4 (c 0.7, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ (both rotamers) = 7.43–7.03 (m, 10 H), 5.20–4.75 (m, 5 H), 4.20 (m, 1 H), 3.40 (major, s, 3 H), 3.38 (minor, s, 3 H), 3.27–3.17 (m, 1 H), 2.97–2.54 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.2 (175.7), 156.2 (156.4), 137.9 (138.0), 136.0 (136.5), 128.6, 128.2, 128.1, 127.8, 127.7, 127.6, 127.2, 126.1, 126.0, 96.8, 76.4 (76.5), 67.2, 66.7 (66.9), 55.8 (55.9), 36.9, 34.0 (34.2). IR (neat): ν_max = 3064, 3030, 2958, 2930, 2847, 1706, 1455, 1402, 1280, 1212, 1142, 1074, 1031, 919, 743, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₂H₂₇NO₆: 402.1916; found: 402.1925 [M + H]⁺. (2S,3R)-(R)-1-(Benzyloxy)-3-methyl-1-oxobutan-2-yl-3-{[(3R,4S)-4-{[(benzyloxy)carbonyl](methyl)amino}-3-(methoxymethoxy)-5-phenylpentanoyl]oxy}-2-methyldecanoate (2) R_f = 0.60 (10% EtOAc–hexane); yellow viscous liquid; [α]_D ²⁵ –22.5 (c 0.9, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ (both rotamers) = 7.38–7.04 (m, 15 H), 5.30–4.61 (m, 7 H), 4.35–4.25 (m, 1 H), 3.40 (major, s, 3 H), 3.39 (minor, s, 3 H), 3.27–3.16 (m, 1 H), 2.99–2.40 (m, 9 H), 2.30–2.20 (m, 1 H), 1.60–1.17 (m, 15 H), 0.95 (dd, J = 3.7, 6.8 Hz, 6 H), 0.90–0.84 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 177.5, 170.6, 166.5, 145.4, 138.5, 137.2, 128.8, 128.5, 128.4, 128.3, 127.9, 127.7, 127.4, 126.7, 126.3, 126.2, 122.4, 97.4, 97.2, 76.8, 76.6, 74.5, 74.4, 67.2, 66.8, 66.6, 60.6, 57.4, 56.2, 43.0, 42.8, 37.9, 37.7, 37.4, 34.3, 31.9, 31.7, 30.1, 29.7, 29.3, 29.1, 25.3, 22.6, 18.7, 17.1, 14.2, 14.0, 12.6, 12.3. IR (neat): ν_max = 2959, 2929, 2859, 1735, 1703, 1582, 1600, 1459, 1380, 1276, 1192, 1129, 1073, 1031, 963, 920, 743, 698 cm^–1. ESI-HRMS: m/z calcd for C₄₅H₆₁NO₁₀: 798.4193; found: 798.4200 [M]⁺.