A relay ring-opening/double ring-closing metathesis strategy for the bicyclic macrolide-butenolide core structures

Abstract

A concise strategy has been developed for the synthesis of the bicyclic macrolide-butenolide core structures of various natural products with the macrolide ring size ranging from 12- to 16-membered. The bicyclic structure was easily assembled using the relay ring-opening/double ring-closing metathesis strategy. An efficient synthesis of (±)-desmethyl manshurolide has been achieved as an application of this strategy.

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Introduction

The bicyclic macrolide-butenolide core structure 1 is present in many natural products (Fig. 1). The macrolide size may vary and there could be the presence of one or more double bonds. Selected examples are shown in Fig. 1 with the macrolide size varying from 12- to 14-membered (2a–e) being the most common. Gersemolide 2a (12-membered macrolide) is a pseudopterane, isolated from the soft coral Gersemia rubiformis.¹ Manshurolide 2b, also a 12-membered macrolide is a sesquiterpene lactone isolated from the stems of Aristolochia manshuriensis.² It has three trans-double bonds in the macrolide ring (the butenolide double bond is apparently trans- in the macrolide ring but geometrically cis- in the butenonide).

Fig. 1 Bicyclic macrolide-butenolide natural products and related furano-structures.

Okilactomycins C 2c and D 2d have a 13-membered bicyclic macrolide-butenolide structure with an annulated cyclohexene and additional spiro functionality. These were isolated from Streptomyces scabrisporus.³ The cembranoid diterpenes, sarcophytonolides A-L were isolated from the soft coral of the genus Sarcophyton.⁴ These possess the 14-membered bicyclic macrolide-butenolide structure. The simpler member is sarcophytonolide L 2e. The bicyclic macrolide-butenolide structure is also present in many other natural products with various substituents and functionalities. Often there is the furan ring⁵ (or the oxidized diketo form) as another common feature in most of them (Fig. 1). These could be the furano-pseudopterane type 3a, furano-gersolene type 3b or the furano-cembrane type 3c (Fig. 1).⁵ The butenolide moiety gains it significance in medicinal chemistry as Michael acceptor to various biological nucleophiles.

With our continued interest in the synthesis of γ-lactones, butenolides and strained macrolides⁶ and considering the importance of these bicyclic structures we embarked on developing a strategy to rapidly construct both the rings (butenolide and macrolide) in an efficient manner based on a relay ring-opening/multiple ring-closing metathesis.⁷

Results and discussion

As shown in the retrosynthetic analysis (Scheme 1) the core structure 1 could be assembled through a double ring-closing metathesis of the tetraene 4. However this design would impose issues of regioselectivity in the ring-closure considering the competition of three available terminal mono-substituted double bonds. While the butenolide ring closure could occur with ease, the macrolide ring closure would be challenging. The latter would predominantly depend on ring size and would occur separately of the first ring-closure. We sought an alternative path to prevent competition by reducing the number of double bonds and hence the triene 5 seemed obvious choice. In this case during metathesis there would be carbene cascade which appeared promising for the challenging macrolide ring closure unlike the case of compound 4 where the two ring closures would occur separately. The substrate 5 can be considered as synthetic equivalent to compound 4. Compound 5 can easily be assembled through vinyl Grignard reaction on aldehyde 6 (of varying chain length) followed by esterification with cyclobutene carboxylic acid 7. An advantage of this strategy is the ready adaptability for chiral version where in the intermediate allyl alcohol 9 can be resolved through Sharpless kinetic resolution.⁸

Scheme 1 Retrosynthesis of bicyclic core structure 1.

The forward synthesis towards the bicyclic core structure 1 with macrolide ring size varying from 12- to 16-membered is shown in Scheme 2. The vinyl Grignard addition to various aldehydes from the alcohols 8a–e gave the corresponding allyl alcohols 9a–e in 84–89% yields. The esterification of 9a with the cyclobutene carboxylic acid 7 using DCC gave the corresponding ester 5a in 38% yield. The reaction using Yamaguchi conditions⁹ delivered 5a in 51% yield. This was further improved with the use of the anhydride of 7, i.e. 10, and LiHMDS that delivered the ester 5a in good 79% yield. Similarly, other esters 5b–e were prepared in 82–91% yields. The relay ring-opening/double ring-closing metathesis (RO/DRCM) reaction on 5a–e was carried out using Grubbs catalysts (G-I and G-II) and Grubbs-Hoveyda catalysts (GH-I and GH-II) in toluene, benzene and hexane solvent. The best results were obtained through a sequential addition of first G-I catalyst (10 mol%) followed by addition of G-II catalyst (5 mol%) in toluene solvent providing the macrolide-butenolide bicyclic compounds 1a–e in 42–48% yields with E-selectivity for the macrolide double bond.¹⁰ We believe, G-I catalyst is known for ring-opening metathesis of strained small rings (in this case the cyclobutene ring). Thus the above catalysts combination worked well in this case. However, we did not isolate any of the intermediate compounds in this relay metathesis reaction which may require quenching with ethylene.

Scheme 2 Synthesis of the macrolide-butenolides 1a–e using the relay RO/DRCM strategy.

The strategy was extended towards the protecting group free synthesis of (±)-desmethyl manshurolide 11 as shown in Scheme 3. Commercially available 5-hexene-1-ol 12 was oxidized to aldehyde and the subsequent modified de-carboxylative deconjugative Knoevenagel condensation¹¹ with half ester of malonic acid gave the ester 13 in 81% overall yield. DiBAL-H reduction of the ester group to aldehyde and subsequent vinyl Grignard reaction furnished the triene 9f (89% from 13). The esterification of 9f with the anhydride 10 using LiHMDS gave 5f in 78% yield. The subsequent relay RO/DRCM using G-I (10 mol%) and G-II (5 mol%) catalysts in toluene solvent delivered (±)-desmethyl manshurolide 11 in 44% yield.

Scheme 3 Synthesis of (±)-desmethyl manshurolide 11.

Conclusions

In conclusion an efficient strategy for bicyclic macrolide-butenolide core structures of various natural products has been developed. The macrolide rings ranging from 12- to 16-membered have been synthesized. The efficiency of the relay ring-opening/double ring-closing metathesis strategy was further demonstrated by the protecting group free synthesis of (±)-desmethyl manshurolide. The strategy has potential towards the synthesis of bicyclic macrolide-butenolide natural products.

Experimental section

General information

Flasks were oven- or flame-dried and cooled in a desiccator. Dry reactions were carried out under an atmosphere of Ar or N₂. Solvents and reagents were purified by standard methods. Thin-layer chromatography was performed on EM250 Kieselgel 60 F254 silica gel plates. The spots were visualized by staining with KMnO₄ or by UV lamp. ¹H NMR and ¹³C NMR were recorded with Bruker AVANCE III 400 or 500 and 100 or 125 MHz, respectively, and chemical shifts are based on TMS peak at δ = 0.00 pm for proton NMR and CDCl₃ peak at δ = 77.00 ppm (t) in carbon NMR. IR samples were prepared by evaporation from CHCl₃ on CsBr plates. High-resolution mass spectra were obtained using positive electrospray ionization by TOF method.

General procedure for synthesis of allyl alcohols 9a–e

To a solution of alcohol 8 (2.0 mmol) in CH₂Cl₂ (20 mL) was added Dess–Martin periodinate (DMP, 1.87 g, 4.40 mmol, 2.2 equiv.). The resulting mixture was stirred at room temperature for 2 h. It was then quenched with a solution of 10% aq. Na₂S₂O₃ and sat. aq. NaHCO₃ (1 : 1, 15 mL) and the solution extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was loaded on a short pad of silica gel and washed with petroleum ether/EtOAc (2 : 1) to give the aldehyde which was used directly for next step. Vinyl magnesium bromide (3.0 mL, 3.0 mmol, 1.5 equiv., 1 M solution in THF) was added to the aldehyde dissolved in THF (30 mL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C and warmed to room temperature. Saturated aq. NH₄Cl (15 mL) was added and the mixture extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the alcohols 9a–e in 84–89% yield.

Deca-1,9-dien-3-ol (9a). Isolated yield of 9a (0.268 g, 87%); colorless oil; IR (CHCl₃): ν_max 3417, 2925, 2851, 1637, 1459, 1371, 1305, 1245, 1023, 910, 666 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.91–5.75 (m, 2H), 5.27–5.10 (m, 2H), 5.04–4.90 (m, 2H), 4.11 (brq, J = 6.3 Hz, 1H), 3.30 (brs, 1H), 2.09–2.00 (m, 2H), 1.61–1.50 (m, 2H), 1.50–1.30 (m, 6H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 141.3, 139.0, 114.5, 114.2, 73.2, 37.0, 33.7, 29.0, 28.8, 25.1; HRMS m/z calcd for [C₁₀H₁₈ONa]⁺ 177.1250, found 177.1256.

Undeca-1,10-dien-3-ol (9b). Isolated yield of 9b (0.3 g, 89%); colorless oil; IR (CHCl₃): ν_max 3367, 3076, 2927, 2854, 1637, 1464, 1440, 991, 911, 663 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, ppm) δ 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H), 4.09 (brq, J = 6.2 Hz, 1H), 3.35 (brs, 1H), 2.09–2.01 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.25 (m, 8H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 141.3, 139.1, 114.6, 114.2, 73.3, 37.0, 33.7, 29.4, 29.0, 28.8, 25.3; HRMS m/z calcd for [C₁₁H₂₀ONa]⁺ 191.1395, found 191.1392.

Dodeca-1,11-dien-3-ol (9c). Isolated yield of 9c (0.313 g, 86%); colorless oil; IR (CHCl₃): ν_max 3369, 3071, 2926, 2854, 1640, 1464, 1437, 1259, 1166, 991, 911, 718 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H), 4.09 (brq, J = 6.2 Hz, 1H), 3.35 (brs, 1H), 2.09–2.01 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.25 (m, 10H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 141.3, 139.2, 114.5, 114.1, 73.3, 37.0, 33.8, 29.5, 29.4, 29.0, 28.9, 25.3; HRMS m/z calcd for [C₁₂H₂₂ONa]⁺ 205.1545, found 205.1539.

Trideca-1,12-dien-3-ol (9d). Isolated yield of 9d (0.334 g, 85%); colorless oil; IR (CHCl₃): ν_max 3364, 3071, 2927, 2855, 1640, 1462, 1434, 992, 911, 718 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H), 4.09 (brq, J = 6.2 Hz, 1H), 2.09–2.01 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.25 (m, 12H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 141.3, 139.2, 114.5, 114.1, 73.3, 37.0, 33.8, 29.5, 29.5, 29.4, 29.1, 28.9, 25.3; HRMS m/z calcd for [C₁₃H₂₄ONa]⁺ 219.1702, found 219.1697.

Tetradeca-1,13-dien-3-ol (9e). Isolated yield of 9e (0.353 g, 84%); colorless oil; IR (CHCl₃): ν_max 3351, 3076, 2926, 2851, 1637, 1459, 1314, 990, 910 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.90–5.75 (m, 2H), 5.25–5.18 (m, 2H), 5.04–4.91 (m, 2H), 4.09 (q, J = 6.2 Hz, 1H), 2.09–2.00 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.25 (m, 14H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 141.3, 139.2, 114.5, 114.1, 73.3, 37.0, 33.8, 29.53, 29.5, 29.5, 29.45, 29.1, 28.9, 25.3; HRMS m/z calcd for [C₁₄H₂₆OK]⁺ 249.1621, found 249.1619.

General procedure for synthesis of esters 5a–e

To a solution of allyl alcohol 9a–e (1.0 mmol) in dry THF (15 mL) at −78 °C was gradually added LiHMDS (0.75 mL, 1.5 mmol, 1.5 equiv., 2 M solution in THF) over a period of 5 min. After stirring for 15 min, a solution of anhydride 10 (0.267 g, 1.50 mmol, 1.5 equiv.) in dry THF (5 mL) was added and the reaction mixture stirred for 4 h at −78 °C. It was slowly warmed to room temperature and a solution of sat. aq. NH₄Cl (5 mL) was added. The mixture was extracted with EtOAc (3 × 50 mL) and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the esters 5a–e in 79–91% yield.

Deca-1,9-dien-3-yl cyclobut-1-enecarboxylate (5a). Isolated yield of 5a (0.185 g, 79%); colorless oil; IR (CHCl₃): ν_max 2927, 2854, 1730, 1646, 1462, 1367, 1250, 1173, 1114, 1050, 988, 966, 920, 695, 667 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 6.77 (s, 1H), 5.84–5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.00–4.91 (m, 2H), 2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.09–2.01 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.22 (m, 6H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.7, 146.4, 139.0, 138.9, 136.6, 116.5, 114.3, 74.4, 34.1, 33.6, 29.7, 29.1, 28.8, 27.0, 24.8; HRMS m/z calcd for [C₁₅H₂₂O₂Na]⁺ 257.1512, found 257.1518.

Undeca-1,10-dien-3-yl cyclobut-1-enecarboxylate (5b). Isolated yield of 5b (0.219 g, 88%); colorless oil; IR (CHCl₃): ν_max 2918, 2850, 1727, 1463, 1369, 1303, 1264, 1181, 1035, 984, 916, 666 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, ppm) δ 6.77 (s, 1H), 5.84–5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.00–4.91 (m, 2H), 2.73–2.72 (m, 2H), 2.48–2.46 (m, 2H), 2.09–2.00 (m, 2H), 1.68–1.50 (m, 2H), 1.45–1.22 (m, 8H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 161.6, 146.3, 139.1, 138.9, 136.6, 116.5, 114.2, 74.4, 34.1, 33.7, 29.2, 29.1, 28.9, 28.8, 27.0, 24.0; HRMS m/z calcd for [C₁₆H₂₄O₂Na]⁺ 271.1669, found 271.1673.

Dodeca-1,11-dien-3-yl cyclobut-1-enecarboxylate (5c). Isolated yield of 5c (0.231 g, 88%); colorless oil; IR (CHCl₃): ν_max 2929, 2857, 1732, 1641, 1465, 1414, 1371, 1253, 1175, 1090, 991, 918, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 6.77 (t, J = 1.2 Hz, 1H), 5.85–5.73 (m, 2H), 5.31–5.14 (m, 3H), 5.01–4.90 (m, 2H), 2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.08–2.00 (m, 2H), 1.61–1.48 (m, 2H), 1.46–1.22 (m, 10H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.7, 146.3, 139.2, 138.9, 136.6, 116.5, 114.1, 74.4, 34.1, 33.8, 29.7, 29.3, 29.1, 29.0, 28.9, 27.0, 25.0; HRMS m/z calcd for [C₁₇H₂₆O₂Na]⁺ 285.1825, found 285.1818.

Trideca-1,12-dien-3-ylcyclobut-1-enecarboxylate (5d). Isolated yield of 5d (0.215 g, 82%); colorless oil; IR (CHCl₃): ν_max 2928, 2851, 1731, 1644, 1459, 1374, 1308, 1251, 1171, 1127, 1045, 669, 631 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 6.77 (s, 1H), 5.84–5.74 (m, 2H), 5.30–5.14 (m, 3H), 5.02–4.91 (m, 2H), 2.73–2.72 (m, 2H), 2.47–2.45 (m, 2H), 2.09–2.00 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.22 (m, 12H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.7, 146.3, 139.2, 138.9, 136.6, 116.5, 114.1, 74.4, 34.2, 33.8, 29.4, 29.36, 29.3, 29.1, 29.07, 28.9, 27.0, 25.0; HRMS m/z calcd for [C₁₈H₂₈O₂Na]⁺ 299.1987, found 299.1979.

Tetradeca-1,13-dien-3-yl cyclobut-1-enecarboxylate (5e). Isolated yield of 5e (0.264 g, 91%); colorless oil; IR (CHCl₃): ν_max 2927, 2856, 1731, 1656, 1462, 1407, 1371, 1308, 1256, 1182, 1130, 1045, 968, 823 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 6.77 (t, J = 1.2 Hz, 1H), 5.85–5.75 (m, 2H), 5.30–5.15 (m, 3H), 5.01–4.91 (m, 2H), 2.73–2.71 (m, 2H), 2.47–2.45 (m, 2H), 2.09–2.00 (m, 2H), 1.61–1.48 (m, 2H), 1.45–1.22 (m, 14H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 161.7, 146.3, 139.2, 138.9, 136.6, 116.5, 114.1, 74.4, 34.2, 33.8, 29.4, 29.3, 29.1, 28.9, 27.0, 25.2, 25.18, 25.0; HRMS m/z calcd for [C₁₉H₃₀O₂Na]⁺ 313.2116, found 313.2121.

General procedure for synthesis of macrolide-butenolides 1a–e

To a solution of 5a–e (0.20 mmol) in dry and degassed toluene (150 mL) was added Grubbs-I catalyst (16.5 mg, 0.02 mmol, 10 mol%). The mixture was refluxed for 4 h under nitrogen atmosphere and then cooled and Grubbs-II catalyst (8.5 mg, 0.01 mmol, 5 mol%) was added. The mixture was further refluxed for 44 h under nitrogen atmosphere and then cooled and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the macrolide-butenolides1a–e.

(E)-12-Oxabicyclo[9.2.1]tetradeca-1(14),4-dien-13-one (1a). Isolated yield of 1a (17.3 mg, 42%); colorless oil; IR (CHCl₃): ν_max 3016, 2923, 2857, 1754, 1657, 1591, 1454, 1336, 1119, 971, 858, 669, 628 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, ppm) δ 6.90–6.87 (m, 1H), 5.26–5.13 (m, 2H), 5.12–5.08 (m, 1H), 2.67–2.56 (m, 1H), 2.48–2.38 (m, 1H), 2.36–2.29 (m, 2H), 2.20–2.11 (m, 2H), 1.70–1.50 (m, 2H), 1.40–1.20 (m, 6H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 173.8, 149.4, 133.9, 131.8, 130.0, 81.1, 31.6, 30.1, 29.9, 27.4, 25.7, 25.6, 21.7; HRMS m/z calcd for [C₁₃H₁₈O₂Na]⁺ 229.1199, found 229.1190.

(E)-13-Oxabicyclo[10.2.1]pentadeca-1(15),4-dien-14-one (1b). Isolated yield of 1b (19.8 mg, 45%); colorless oil; IR (CHCl₃): ν_max 2922, 2846, 1755, 1646, 1459, 1369, 1333, 1242, 1094, 1042, 965, 858, 694 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.00 (d, J = 1.3 Hz 1H), 5.43–5.33 (m, 1H), 5.30–5.22 (m, 1H), 5.06–5.01 (m, 1H), 2.58–2.45 (m, 2H), 2.36–2.25 (m, 2H), 2.10–2.0 (m, 2H), 1.82–1.71 (m, 2H), 1.45–1.10 (m, 8H); ¹³C NMR (125 MHz, CDCl₃; ppm) δ 174.3, 149.4, 133.9, 132.9, 128.8, 80.8, 33.2, 31.0, 29.6, 29.0, 28.7, 25.8, 24.5, 21.5; HRMS m/z calcd for [C₁₄H₂₀O₂Na]⁺ 243.1333, found 243.1327.

(E)-14-Oxabicyclo[11.2.1]hexadeca-1(16),4-dien-15-one (1c). Isolated yield of 1c (22.5 mg, 48%); colorless oil; IR (CHCl₃): ν_max 2923, 2851, 1755, 1646, 1456, 1437, 1369, 1242, 1094, 1042, 965, 691 cm⁻¹;¹H NMR (400 MHz, CDCl₃, ppm) δ 7.00 (d, J = 1.4 Hz, 1H), 5.43–5.28 (m, 1H), 5.28–5.22 (m, 1H), 5.04–4.99 (m, 1H), 2.58–2.45 (m, 1H), 2.36–2.25 (m, 3H), 2.10–1.98 (m, 2H), 1.83–1.71 (m, 2H), 1.45–1.10 (m, 10H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 174.2, 149.3, 133.4, 132.7, 129.5, 80.8, 31.7, 29.7, 29.65, 26.7, 25.0, 24.4, 23.9, 18.4; HRMS m/z calcd for [C₁₅H₂₂O₂Na]⁺ 257.1512, found 257.1518.

(E)-15-Oxabicyclo[12.2.1]heptadeca-1(17),4-dien-16-one (1d). Isolated yield of 1d (23.5 mg, 48%); colorless oil; IR (CHCl₃): ν_max 2929, 2857, 1748, 1621, 1459, 1108, 872, 666, 603 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.00 (d, J = 1.3 Hz, 1H), 5.45–5.36 (m, 1H), 5.35–5.25 (m, 1H), 5.02–4.95 (m, 1H), 2.53–2.45 (m, 2H), 2.42–2.30 (m, 2H), 2.10–2.00 (m, 2H), 1.89–1.79 (m, 2H), 1.45–1.25 (m, 12H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 174.2, 148.4, 133.5, 132.1, 129.2, 81.2, 31.7, 31.3, 29.0, 28.2, 27.9, 27.1, 27.0, 25.8, 24.3, 21.1; HRMS m/z calcd for [C₁₆H₂₄O₂Na]⁺ 271.1669, found 271.1662.

(E)-16-Oxabicyclo[13.2.1]octadeca-1(18),4-dien-17-one (1e). Isolated yield of 1e (23.6 mg, 45%); colorless oil; IR (CHCl₃): ν_max 2923, 2851, 1755, 1592, 1436, 1259, 1094, 1043, 960, 872, 771, 592 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 7.06 (d, J = 1.5 Hz, 1H), 5.48–5.41 (m, 1H), 5.32–5.25 (m, 1H), 4.92–4.85 (m, 1H), 2.52–2.41 (m, 2H), 2.40–2.25 (m, 2H), 2.06–1.95 (m, 2H), 1.88–1.78 (m, 2H), 1.48–1.15 (m, 14H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 173.9, 149.0, 133.4, 132.2, 128.4, 81.2, 32.3, 31.4, 29.4, 27.9, 26.9, 26.6, 26.3, 25.4, 25.38, 24.8, 21.8; HRMS m/z calcd for [C₁₇H₂₆O₂Na]⁺ 285.1802, found 285.1810.

(E)-Methyl octa-3,7-dienoate (13). To a solution of alcohol 12 (0.6 g, 6.0 mmol) in CH₂Cl₂ (30 mL) was added Dess–Martin periodinate (5.1 g, 12.0 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 2 h. It was then quenched with a solution of 10% aq. Na₂S₂O₃ and sat. aq. NaHCO₃ (1 : 1, 15 mL) and the solution extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was loaded on a short pad of silica gel and washed with petroleum ether/EtOAc (2 : 1) to give the aldehyde which was used for the next step. To the aldehyde (0.582 g) was added mono methylmalonate (1.06 g, 9.0 mmol, 1.5 equiv.) followed by Et₃N (1.2 mL, 12.0 mmol, 2.0 equiv.). The reaction mixture was refluxed for 12 h. It was then cooled and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (9 : 1) as eluent to give ester 13 (0.748 g, 81%) as colorless oil (analysis showed it to contain <9% α,β-unsaturated isomer. This was accounted for yield calculation). IR (CHCl₃): ν_max 3070, 2926, 2849, 1741, 1641, 1437, 1256, 1199, 1164, 996, 971, 914, 667 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.81–5.71 (m, 1H), 5.52–5.50 (m, 2H), 4.99–4.90 (m, 2H), 3.63 (s, 3H), 2.99 (d, J = 5.0 Hz, 2H), 2.10–2.02 (m, 4H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 172.4, 137.9, 133.8, 121.9, 114.6, 51.6, 37.7, 33.2, 31.7; HRMS m/z calcd for [C₉H₁₄O₂Na]⁺ 177.0863, found 177.0859.

(E)-Deca-1,5,9-trien-3-ol (9f). To a solution of the ester 13 (0.51 g, 3.3 mmol) in CH₂Cl₂ (20 mL) was added DIBAL-H (3.6 mL, 3.6 mmol, 1.1 equiv., 1 M solution in toluene) drop wise at −78 °C. The reaction mixture was stirred for 1 h. It was then quenched by adding a saturated aq. solution of potassium–sodium-tartrate (10 mL) and stirred for 2 h. It was then extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic extracts were washed with water, brine, dried (Na₂SO₄), and concentrated. The residue was used for next reaction without further purification.

To a solution of above aldehyde in THF (15 mL) was added vinyl magnesium bromide (5.0 mL, 5.0 mmol, 1.51 equiv., 1 M solution in THF) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C and then warmed to room temperature. Saturated aq. NH₄Cl (10 mL) was added and the mixture extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the allyl alcohol 9f (0.448 g, 89%) as colorless oil. IR (CHCl₃): ν_max 3444, 3077, 2926, 2855, 1641, 1618, 1577, 1481, 1467, 1378, 1252, 1176, 1127, 1070, 971, 914, 810, 694 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 5.90–5.83 (m, 1H), 5.82–5.75 (m, 1H), 5.57–5.53 (m, 1H), 5.44–5.37 (m, 1H), 5.24 (dt, J = 17.2, 1.5 Hz, 1H), 5.13 (dt, J = 10.5, 1.4 Hz, 1H), 5.03–4.94 (m, 2H), 4.1 (brd, J = 1.6 Hz, 1H), 2.31–2.19 (m, 1H), 2.18–2.16 (m, 1H), 2.14–2.12 (m, 4H), 1.7 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 140.4, 138.3, 134.1, 125.6, 114.8, 114.6, 71.8, 40.5, 33.6, 32.0; HRMS m/z calcd for [C₁₀H₁₆ONa]⁺ 175.1093, found 175.1085.

(E)-Deca-1,5,9-trien-3-yl cyclobut-1-enecarboxylate (5f). To a solution of allyl alcohol 9f (0.1 g, 0.657 mmol) in dry THF (10 mL) at −78 °C was gradually added LiHMDS (0.5 mL, 1.0 mmol, 1.52 equiv., 2 M soln. in THF) over a period of 5 min. After stirring for 15 min, a solution of anhydride 10 (0.176 g, 0.985 mmol, 1.5 equiv.) in dry THF (5 mL) was added and the reaction mixture stirred for 4 h at −78 °C. It was warmed to room temperature and a solution of saturated aq. NH₄Cl (5 mL) was added. The mixture was extracted with EtOAc (3 × 30 mL) and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the ester 5f (0.12 g, 78%) as colorless oil. IR (CHCl₃): ν_max 3075, 2929, 2857, 1731, 1641, 1464, 1252, 1180, 1046, 991, 917, 668 cm⁻¹;¹H NMR (500 MHz, CDCl₃, ppm) δ 6.8 (s, 1H), 5.86–5.76 (m, 2H), 5.55–5.45 (m, 1H), 5.41–5.33 (m, 1H), 5.32–5.22 (m, 2H), 5.21–5.16 (m, 1H), 5.08–4.82 (m, 2H), 2.78–2.70 (m, 2H), 2.49–2.44 (m, 2H), 2.40–2.30 (m, 2H), 2.12–2.00 (m, 4H); ¹³C NMR (125 MHz, CDCl₃, ppm) δ 161.5, 146.4, 138.9, 138.2, 136.1, 133.3, 124.8, 116.6, 114.6, 73.8, 37.6, 33.6, 32.0, 29.7, 27.0; HRMS m/z calcd for [C₁₅H₂₀O₂Na]⁺ 255.1356, found 255.1361.

(4E,8E)-12-Oxabicyclo[9.2.1]tetradeca-1(14),4,8-trien-13-one (11). To a solution of 5f (0.050 g, 0.213 mmol) in dry and degassed toluene (150 mL) was added Grubbs-I catalyst (17.5 mg, 0.0213 mmol, 10 mol%). The mixture was refluxed for 4 h under nitrogen atmosphere and then cooled and Grubbs-II catalyst (9.1 mg, 0.0107 mmol, 5 mol%) was added. The mixture was further refluxed for 44 h under nitrogen atmosphere and then cooled and concentrated. The residue was purified by silica gel flash column chromatography using petroleum ether/EtOAc (4 : 1) as eluent to give the desmethyl manshurolide 11 (19.1 mg, 44%) as colorless oil. IR (CHCl₃): ν_max 2923, 2851, 1753, 1651, 1593, 1434, 1360, 1259, 1122, 1091, 1039, 1017, 957, 932, 869, 666 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ppm) δ 6.75 (s, 1H), 5.18–5.11 (m, 1H), 5.06–5.02 (m, 2H), 5.00–4.98 (m, 2H), 2.80–2.75 (m, 1H), 2.56–2.52 (m, 1H), 2.36–2.18 (m, 6H), 1.88–1.79 (m, 2H); ¹³C NMR (100 MHz, CDCl₃, ppm) δ 173.8, 150.5, 135.3, 133.7, 132.9, 129.8, 123.3, 80.1, 34.1, 31.8, 31.5, 29.7, 25.5; HRMS m/z calcd for [C₁₃H₁₆O₂Na]⁺ 227.1043, found 227.1044.

Acknowledgements

We thank the Board of Research in Nuclear Sciences (BRNS), Government of India (Basic Sciences, Grant no. 2013/37C/59/BRNS/2443) for financial support. M.B.H. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for senior research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all the compounds. See DOI: 10.1039/c4ra10937f

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