Stereoselective Synthesis of (-)-Pironetin by an Iterative Prins Cyclisation and Reductive Cleavage Strategy

Abstract

A stereoselective synthesis of pironetin, a natural product which is highly immunosuppressive and shows remarkable plant growth regulatory and antitumoral activities, is described. The approach avails successfully the high stereoselection of Prins cyclisation. The route relies, in addition, on the reductive opening of cyclic ethers, olefin metathesis, and lithium acetylide displacement of tosylate.

natural products - Prins cyclisation - stereoselective synthesis - reductive cleavage - olefin metathesis

References and Notes

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As shown below, compound 10 was subjected to TBS ether cleavage and then transformed to the corresponding acetonide to confirm the anti relationship of hydroxyl groups by examination of the ^¹³C NMR spectrum. See:

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<A NAME="RD36609ST-11">11</A>

Spectroscopic and Physical Data of Selected Compounds(2 R ,3 S ,4 R ,6 R )-2-[( S )-1-(Benzyloxy)propan-2-yl]-tetra-hydro-6-hydroxymethyl)-3-methyl-2 H -pyran-4-ol (5)
[α]_D ^²5 +18.5 (c 1.0, CHCl₃); R _f  = 0.3 (SiO₂, 60% EtOAc in hexane). IR (neat): 3390, 2926, 2859, 1359, 1158, cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.23-7.30 (m, 5 H), 4.39-4.55 (m, 2 H), 3.21-3.56 (m, 7 H), 2.02-2.11 (m, 1 H), 1.77-1.86 (m, 1 H), 1.22-1.44 (m, 2 H), 0.96 (d, 3 H, J = 6.64 Hz), 0.85 (d, 3 H, J = 6.64 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 138.53, 128.30, 127.48, 79.47, 75.50, 73.33, 73.12, 72.97, 65.83, 40.40, 36.77, 34.10, 12.04, 9.54. ESI-HRMS: m/z
[M + Na]⁺ calcd for C₁₇H₂₆NaO₄: 317.1728; found: 317.1719.
(2 S ,3 R ,4 R ,5 R )-1-(Benzyloxy)-5-( tert -butyldimethyl-silyloxy)-2,4-dimethyloct-7-en-3-ol (10) [α]_D ^²5 +13.9 (c 0.65, CHCl₃); R _f  = 0.6 (SiO₂, 10% EtOAc in hexane). IR (neat): 3500, 2930, 2855, 1461, 1063, 911 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.27 (m, 5 H), 5.81-5.67 (m, 1 H), 5.08-4.49 (m, 2 H), 4.45-4.56 (m, 2 H), 3.97-3.92 (m, 1 H), 3.75 (d, 1 H, J = 9.82 Hz), 3.53-3.39 (m, 2 H), 2.37-2.20 (m, 2 H), 1.85-1.70 (m, 2 H), 1.46 (br, OH), 0.89-0.87 (m, 12 H), 0.75 (d, 3 H, J = 6.8 Hz), 0.06 (s, 3 H), 0.09 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 138.60, 135.13, 128.24, 127.47, 127.36, 116.90, 116.67, 81.09, 73.86, 72.82, 71.15, 60.70, 40.55, 39.38, 35.30, 26.02, 18.2, 9.7, 9.1,
-3.17, -4.37. ESI-HRMS: m/z [M + Na]⁺calcd for C₂₃H₄₀NaO₃Si: 415.2644; found: 415.4635.
(3 E ,6 R ,7 S ,8 R ,9 S ,11 E )-8-Methoxy-7,9-dimethyltridec-3,11-dien-6-ol (4)
[α]_D ^²5 +4.0 (c 1.3, CHCl₃); R _f  = 0.5 (SiO₂, 20% EtOAc in hexane); IR (neat): 3420, 2966, 2931, 1715, 1457, 1083, 971 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 5.62-5.29 (m, 4 H), 3.90-3.83 (m, 1 H), 3.48 (s, 3 H), 2.98 (m, 1 H), 2.57 (br, 1 H, OH), 2.27-1.75 (m, 8 H), 1.67 (d, 3 H, J = 6.40 Hz), 0.98 (t, 3 H, J = 7.34 Hz), 0.92 (d, 3 H, J = 7.9 Hz), 0.89 (d, 3 H, J = 7.8 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 134.69, 129.18, 126.58, 125.63, 89.80, 70.6, 61.63, 38.10, 37.8, 37.2, 36.05, 25.63, 17.93, 14.57, 13.8, 10.91. ESI-HRMS: m/z [M + Na]⁺calcd for C₁₆H₃₀NaO₂: 277.1987; found: 277.1977.
(2 R ,3 S ,4 R ,6 R )-3-Ethyl-tetrahydro-6-[( E ,2 S ,3 R ,4 S )-3-methoxy-4-methyloct-6-en-2-yl]-2-vinyl-2 H -pyran-4-ol (3a)
[α]_D ^²5 -27.6 (c 0.65, CHCl₃). IR (neat): 3427, 2967, 2929, 1718, 1457, 1089, 759 cm^-¹. ^¹H NMR (300 MHz, CDCl₃):
δ = 5.88-5.71 (m, 1 H), 5.49-5.36 (m, 2 H), 5.26-5.11 (m, 2 H), 3.69-3.45 (m, 3 H), 3.33 (s, 3 H), 3.05 (dd, 1 H, J = 9.55, 2.94 Hz), 2.32-2.27 (m, 1 H), 2.08-1.95 (m, 2 H), 1.76-1.41 (m, 7 H), 1.25-1.14 (m, 1 H), 1.02-0.75 (m, 11 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 130.65, 130.44, 128.71, 126.13, 84.8, 80.25, 74.34, 73.43, 70.67, 50.97, 49.21, 40.54, 38.99, 38.25, 35.49, 19.41, 17.96, 11.86, 10.18. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₉H₃₄NaO₃: 333.2405; found: 333.2409.
(4 R ,5 R ,7 R ,8 S ,9 R ,10 S ,12 E )-4-Ethyl-9-methoxy-5-(methoxymethoxy)-8,10-dimethyltetradeca-2,12-dien-7-yl acetate (17)
IR (neat): 2929, 2855, 1740, 1244, 1097, 966 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 5.51-5.03 (m, 5 H), 4.63-4.59 (m, 2 H), 3.56-3.41 (m, 1 H), 3.39 (s, 3 H), 3.37 (s, 3 H), 2.84-2.77 (m, 1 H), 2.03 (s, 3 H), 2.17-1.91 (m, 3 H), 1.66 (d, 6 H, J = 5.28 Hz), 1.75-1.50 (m, 4 H), 1.45-1.28 (m, 2 H), 0.92-0.79 (m, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 170.40, 134.51, 132.50, 125.50, 125.5, 96.30, 88.51, 66.99, 68.30, 58.0, 55.62, 49.06, 39.52, 36.42, 35.50, 33.75, 23.65, 21.20, 19.53, 19.35, 15.30, 12.42, 10.25. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₃H₂₄NaO₅: 421.2929; found: 421.2923.
(5 R ,6 R )-5-Ethyl-5,6-dihydro-6-[( E ,2 R ,3 S ,4 R ,5 S )-2-hydroxy-4-methoxy-3,5-dimethylnon-7-enyl]pyran-2-one (1)
[α]_D ^²5 -139.5 (c 0.35, CHCl₃); R _f  = 0.3 (SiO₂, 50% EtOAc in hexane); IR (neat): 3479, 2965, 2931, 1718, 1459, 1384, 1088 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.04 (dd, 1 H, J = 9.82, 6.04 Hz), 6.04 (d, 1 H, J = 9.82 Hz), 5.50-5.32 (m, 2 H), 4.76 (m, 1 H), 4.23 (br d, 1 H), 3.47 (s, 3 H), 3.39 (br, OH), 2.36-2.27 (m, 1 H), 3.00-2.97 (m, 1 H), 2.13-2.06 (m, 1 H), 1.97-1.63 (m, 6 H), 1.67 (d, 3 H, J = 5.27 Hz), 1.56-1.45 (m, 1 H), 1.01 (t, 3 H, J = 7.18 Hz), 0.97 (d, 3 H, J = 7.18 Hz), 0.95 (d, 3 H, J = 6.70 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 164.1, 144.8, 121.5, 96.1, 75.2, 69.7, 55.4, 41.8, 29.4, 20.1.164.75, 150.77, 130.08, 126.91, 120.72, 90.2, 77.73, 67.17, 61.55, 39.16, 39.05, 37.32, 36.73, 35.96, 20.76, 17.91, 15.1, 11.88, 10.96. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₉H₃₂NaO₄ 347.2198; found: 347.2205.