Total synthesis of (+)-petromyroxol via tandem α-aminoxylation–allylation and asymmetric dihydroxylation–S_N2 cyclization approach

Abstract

The total synthesis of (+)-petromyroxol, a tetrahydrofuran (THF)-diol fatty acid, isolated from sea lamprey larvae (Petromyzon marinus) is reported. The present synthesis employs a tandem α-aminoxylationallylation, cross metathesis and tandem asymmetric dihydroxylation–S_N2 cyclization as key steps.

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Acetogenins, an important class of compounds containing tetrahydrofuran ring systems (Fig. 1), were isolated from Annonaceae plants. They are known to exhibit a wide range of biological activities such as antifeedant, antitumor, immunosuppressive and most significantly pesticidal and pheromonal activities.¹ This interesting biological profile along with varied structural features of the acetogenin family has aroused a lot of research interest in the synthesis of this class of compounds among organic chemists worldwide.² Isolation of one such mono acetogenin, petromyroxol containing a single THF ring has been reported recently by Li et al.³ Petromyroxol was known to have a possible biochemical role in the study of communication among sea lamprey, which are parasitic fish that have been known to cause damage to the fish population especially in the Great lakes area of North America. Significant efforts have been made to maintain the ecological balance and minimize the havoc caused by these invasive species.

Fig. 1 Some of the acetogenins based natural products.

Towards this end, many strategies have been employed to control the growth of sea lamprey and one such study was to understand the olfactory responses in these species. A non-racemic mixture of petromyroxol (2.9 mg) has been isolated from >100 000 L of water conditioned with the larvae of Petromyzon marinus. The (+)-enantiomer was found to be just 0.9 mg (∼36%) of the isolated mixture, nevertheless, was found to trigger a better olfactory response among the lamprey fish than it's (−)-antipode. The scarcity of the material has hampered further research in this area. The use of sex pheromones as a tool for biological control of pests has been under active consideration and along these lines petromyroxol is expected be a part of sex pheromones,³ of sea lamprey and could possibly help in development of eco-friendly pest controlling agents.

In recent years organocatalysis has emerged as a powerful tool box in the area of developing new methodologies and its application to the synthesis of biologically important natural products.⁴ It compliments both the metal catalysis and expensive protein catalysis.⁵ Proline is extensively used as organocatalyst since it is commercially available in both the enantiomeric forms.⁶ It has an advantage of operational simplicity, moisture tolerance and often products are obtained with high ee.

Petromyroxol is structurally interesting molecule with trisubstituted tetrahydrofurandiol. The construction of stereochemically defined THF ring has always been a major challenge which is evident from various literature reports.² The attractive structural features of petromyroxol along with biological importance and its low abundance drew our attention towards its synthesis. Accordingly we devised a simple and efficient route to (+)-petromyroxol via organocatalytic tandem process. While, the first synthesis of petromyroxol was reported by Boyer^7a using a protocol based on rhodium catalyzed denitrogenation and rearrangement of a 1-sulfonyl-1,2,3-triazole,^7b,c Ramana et al. described its synthesis from carbohydrate using a chiral pool approach.^7d Herein we report our successful endeavors towards the total synthesis of 1 employing proline catalyzed tandem α-aminoxylation–allylation, cross-metathesis and tandem asymmetric dihydroxylation–S_N2 cyclization as key steps.

Our synthetic strategy for the synthesis of 1 is outlined in Scheme 1. We envisioned that the target molecule could be achieved by hydrogenolysis of THF diol 20. The key tri-substituted THF moiety could be constructed diastereoselectively by using tandem asymmetric dihydroxylation–S_N2 cyclization of an olefin 19 which in turn could be derived from the cross metathesis of ester 18 and homoallylic alcohol 11. The homoallylic alcohol 11 could be synthesized from commercially available heptanal via organocatalytic tandem α-aminoxylation–allylation protocol⁸ developed by Zhong. The ester fragment 18 could be readily accessible from cyclohexanone.

Scheme 1 Retrosynthetic analysis of (+)-petromyroxol 1.

As illustrated in Scheme 2, synthesis of petromyroxol started from commercially available heptanal, which was subjected to α-aminoxylation using L-proline as a catalyst and nitrosobenzene as an oxygen source to provide chiral O-N-phenylaminoxyaldehyde. This intermediate was then subjected to in situ indium mediated allylation (In/allylbromide/NaI) to afford a mixture of O-amino-substituted allylic alcohols 6 & 7 respectively with a diastereomeric ratio of 3 : 2 (syn : anti) in 70% overall yield with excellent enantioselectivities.⁹ Both compounds 6 and 7 were cleanly separated by silica gel chromatography and fully characterized by spectroscopic means.

Scheme 2 Synthesis of alcohol fragment 11.

The anti compound 7 was then protected as its TBS ether using TBSOTf and NEt₃ to furnish the silyl ether 8. The crude compound 8 was subjected to N–O bond cleavage¹⁰ using copper(II) acetate in methanol to get compound 9 in 82% yield (2 steps). Further, the free alcohol was protected as its benzyl ether using NaHMDS and benzyl bromide at 0 °C to furnish the compound 10, which was then desilylated using TBAF in THF to obtain homoallylic alcohol 11.

Our next task was to convert the major syn compound 6 into the required homoallylic alcohol 11 (Scheme 3). Towards this end compound 15 was synthesized from 6 using a similar sequence of reactions as described in Scheme 2. Subsequently compound 15 was smoothly converted to the required fragment 11 via Mitsunobu inversion.

Scheme 3 Conversion of syn isomer 6 to desired anti alcohol fragment 11.

We then proceeded next to prepare the ester fragment, for that cyclohexanone was treated with 30% H₂O₂ to give hydroperoxide intermediate which was decomposed using ferrous sulfate–copper sulfate system to give the acid 17 in 62% yield¹¹ (Scheme 4). The olefinic acid 17 was subjected to esterification using K₂CO₃/BnBr to furnish the benzyl ester 18 in 95% yield.

Scheme 4 Synthesis of ester fragment 18.

After few optimizations with temperature and catalyst loading, the cross metathesis¹² reaction was performed between alcohol 11 (1 equiv.) and 18 (5 equiv.) in CH₂Cl₂ using 15 mol% Grubb's catalyst, resulting in the cross coupled 19 as major product in 70% yield (Scheme 5).

Scheme 5 Synthesis of (+)-petromyroxol 1.

After having substantial amounts of olefinic alcohol 19, the time was set for the construction of trans trisubstituted tetrahydrofuran ring 20 via intramolecular tandem Sharpless asymmetric dihydroxylation–S_N2 cyclization according to Marshall's protocol.¹³ Thus, the alcohol 19 was first converted into its mesylate and then subjected to Sharpless asymmetric dihydroxylation¹⁴ using commercially available AD-mix-α in t-BuOH–H₂O (1 : 1), however the reaction did not work. So we considered to optimizing the dihydroxylation reaction conditions with respect to ligand and OsO₄. Initially we carried out the reaction with standard conditions of Sharpless asymmetric dihydroxylation using 1 mol% ligand (DHQ)₂PHAL and 0.4 mol% OsO₄, but reaction did not work even after prolonged reaction time for a week at 0 °C. This prompted us to increase the amount of OsO₄ to 5 mol% in phased manner and to our delight starting material was completely consumed to give the crude diol. This crude product, without any extensive characterization, was immediately subjected to cyclization using pyridine as solvent. Though the reaction did not proceed at room temperature, refluxing the same in pyridine for 16 h furnished the desired cyclized compound 20 in 80% yield (3 steps) with excellent selectivity (single diastereomer, confirmed by ¹H and ¹³C NMR). Finally debenzylation of compound 20 using 10% w/w Pd/C under hydrogen balloon pressure gave the target molecule (+)-petromyroxol 1 in 95% yield.

Conclusions

In summary, we achieved the asymmetric synthesis of (+)-petromyroxol in 10 steps with an overall yield of 26.6% from easily accessible starting materials. Depending upon the catalyst (D/L-proline) used in the tandem aminoxylation–allylation step along with variation in chain length and the ligands (DHQ/DHQD) in the Sharpless asymmetric dihydroxylation step, one can have easy access to various stereoisomers of petromyroxol and its synthetic analogues.

Experimental section

(4R,5R)-5-((Phenylamino)oxy)hept-1-en-4-ol 6

To a stirred solution of heptanal (6.4 g, 56.0 mmol) and nitrosobenzene (5.0 g, 46.6 mmol) in DMSO (94 mL), L-proline (1.07 g, 9.3 mmol) was added. After being stirred for 20 min at rt (the endpoint of the reaction was monitored by its colour change from green to orange), allyl bromide (6.05 mL, 70.0 mmol), NaI (10.5 g, 70.0 mmol), and indium powder (8.03 g, 70.0 mmol) were added at rt. The stirring was kept at room temperature for 30 min. The reaction mixture was quenched with 0.5 M aq. HCl (50 mL) and the aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude was purified by flash column chromatography (EtOAc–petroleum ether, 3 : 97) to afford compound (4R,5R)-5-((phenylamino)oxy)hept-1-en-4-ol 6 (5.1 g, 42%) and the more quickly eluting (4S,5R)-isomer 7 (3.5 g, 28%). The diastereomeric ratios of the products were determined by weighing the separated isomers. The enantiomeric excess of the anti and the syn-diastereomer was measured by HPLC analysis after separation of the isomers using column chromatography.

syn-6. [α]^26.6_D: +28.7° (c 1.58, CHCl₃); IR (neat, cm⁻¹): ν_max 3394, 3275, 3074, 2929, 2863, 1640, 1600, 1484, 1459, 1375, 1320, 1041; ¹H NMR (500 MHz, CDCl₃) δ = 7.28 (s, 2H), 7.09 (s, 1H), 7.02–6.97 (m, 3H), 5.95–5.85 (m, 1H), 5.21–5.14 (m, 2H), 4.03 (t, J = 5.6 Hz, 1H), 3.89 (td, J = 2.9, 8.5 Hz, 1H), 2.57 (br s, 1H), 2.32 (t, J = 6.9 Hz, 2H), 1.76–1.66 (m, 2H), 1.65–1.56 (m, 2H), 1.55–1.36 (m, 4H), 0.93–0.90 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 148.3, 135.1, 129.0, 122.4, 117.7, 114.9, 85.8, 72.2, 36.9, 31.9, 28.2, 26.0, 22.5, 14.0; HRMS (ESI) for C₁₆H₂₅O₂ N (M + Na)⁺ found 286.1782, calcd 286.1778. The enantioselectivity of compound 6 was determined as 98% ee using chiral HPLC {Chiralcel OD-H (250 mm × 4.6 mm), iPrOH/hexane (10 : 90), flow rate 1 mL min⁻¹, λ = 230 nm, t_R = 5.40 (major), t_R = 6.31 (minor)}.

anti-7. [α]^26.6_D: +20.4° (c 1.43, CHCl₃); IR (neat, cm⁻¹): ν_max 3396, 3285, 3075, 2929, 2863, 1640, 1600, 1480, 1459, 1375, 1320, 1041; ¹H NMR (500 MHz, CDCl₃) δ = 7.31–7.27 (m, 2H), 7.04–6.98 (m, 3H), 5.98–5.82 (m, 1H), 5.21–5.12 (m, 2H), 3.87 (ddd, J = 4.1, 5.7, 8.2 Hz, 1H), 3.79 (q, J = 5.8 Hz, 1H), 2.51–2.38 (m, 1H), 2.33–2.25 (m, 1H), 1.75–1.61 (m, 2H), 1.53–1.42 (m, 2H), 1.38–1.30 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 148.0, 134.6, 129.0, 122.6, 117.9, 115.3, 85.4, 72.7, 38.2, 32.0, 29.4, 25.3, 22.5, 14.0; HRMS (ESI) for C₁₆H₂₅O₂ N (M + Na)⁺ found 286.1782, calcd 286.1778; the enantioselectivity of compound 7 was determined as 98% ee using chiral HPLC {Chiralcel OD-H (250 mm × 4.6 mm), ⁱPrOH/hexane (10 : 90), flow rate 1 mL min⁻¹, λ = 230 nm, t_R = 6.32 (major), t_R = 7.35 (minor)}.

(4S,5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-ol 9

To a stirred solution of compound 7 (3.0 g, 10.48 mmol) in CH₂Cl₂ (30.0 mL) at 0 °C was added Et₃N (3.5 mL, 25.09 mmol), followed by TBDMSOTf (3.2 mL, 13.6 mmol) and the mixture was stirred for 15 min. The reaction mixture was quenched with sat. NH₄Cl solution (20 mL) and the aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give the crude 8 as yellow oil.

To a stirred solution of the crude 8 in MeOH (50 mL) was added Cu(OAc)₂ (720 mg, 3.96 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with a cold sat. NH₄Cl solution and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc–pet ether, 2 : 98) to afford compound 9 as yellow colour oil (2.4 g, 2 steps 82%). [α]^27.7_D: +0.24° (c 1.74, CHCl₃); IR (neat, cm⁻¹): ν_max 3566, 3460, 3076, 2942, 2862, 1462, 1392, 1258, 1080; ¹H NMR (400 MHz, CDCl₃) δ = 5.90–5.77 (m, 1H), 5.12–5.01 (m, 2H), 3.70–3.64 (m, 1H), 3.61–3.56 (m, 1H), 2.35–2.26 (m, 1H), 2.25–2.17 (m, 1H), 1.92 (br s, 1H), 1.45–1.39 (m, 2H), 1.37–1.29 (m, 6H), 0.91 (s, 12H), 0.08 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ = 135.6, 116.8, 75.1, 74.6, 35.9, 31.9, 31.8, 25.8, 25.8, 22.6, 18.1, 14.0, −4.3, −4.6; HRMS (ESI) for C₁₆H₃₄O₂ Si (M + Na)⁺ found 309.2228, calcd 309.2220.

(((4S,5R)-5-(Benzyloxy)dec-1-en-4-yl)oxy)(tert-butyl)dimethylsilane 10

Sodium bis(trimethylsilyl)amide (1 M solution in THF, 10.48 mL, 10.48 mmol) was added to a stirred solution of 9 (2.0 g, 6.9 mmol), tetrabutylammonium iodide (258 mg, 0.69 mmol) and benzyl bromide (1.24 mL, 10.48 mmol) in THF (30 mL) at 0 °C. The mixture was stirred at ambient temperature for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (25 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc–pet ether, 1.5 : 98.5) to yield compound 10 as colourless oil (2.37 g, 92%). [α]^28.9_D: +15.67° (c 1.31, CHCl₃); IR (neat, cm⁻¹): ν_max 3075, 3029, 2940, 2861, 1462, 1370, 1317, 1252, 1208, 1095; ¹H NMR (400 MHz, CDCl₃) δ = 7.38–7.28 (m, 5H), 5.88 (tdd, J = 7.2, 10.1, 17.1 Hz, 1H), 5.11–5.02 (m, 2H), 4.71 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 3.79 (td, J = 4.3, 6.3 Hz, 1H), 3.38 (td, J = 3.6, 7.5 Hz, 1H), 2.45–2.36 (m, 1H), 2.32–2.24 (m, 1H), 1.54–1.48 (m, 2H), 1.36–1.24 (m, 6H), 0.92–0.87 (m, 12H), 0.07 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ = 139.1, 135.8, 128.2, 127.8, 127.4, 116.7, 82.3, 74.2, 72.5, 37.8, 32.0, 30.7, 25.9, 25.5, 22.6, 18.1, 14.1, −4.4, −4.4; HRMS (ESI) for C₂₃H₄₀O₂ Si (M + Na)⁺ found 399.2699, calcd 399.2690.

(4S,5R)-5-(Benzyloxy)dec-1-en-4-ol 11

To a stirred solution of 10 (2.0 g, 5.3 mmol) in THF (10 mL) was added 1.0 M TBAF in THF (10.6 mL, 10.6 mmol) at 0 °C. After being stirred for 12 h at rt, the reaction mixture was quenched with H₂O (10 mL) and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc–pet ether, 5 : 95) to afford compound 11 as colourless oil (1.3 g, 95%). [α]^28.9_D: −1.95° (c 0.6, CHCl₃); IR (neat, cm⁻¹): ν_max 3425, 3076, 3030, 2926, 2865, 1696, 1635, 1455, 1372, 1084, 1037; ¹H NMR (500 MHz, CDCl₃) δ = 7.36–7.28 (m, 5H), 5.95–5.79 (m, 1H), 5.19–5.11 (m, 2H), 4.64–4.56 (m, 2H), 3.87–3.81 (m, 1H), 3.44–3.38 (m, 1H), 2.35–2.25 (m, 2H), 1.93 (br s, 1H), 1.69–1.60 (m, 1H), 1.50 (d, J = 7.6 Hz, 2H), 1.38–1.25 (m, 5H), 0.92–0.87 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 138.5, 135.1, 128.4, 127.8, 127.7, 117.6, 81.7, 77.3, 76.7, 72.1, 71.4, 36.9, 32.0, 29.1, 25.2, 22.6, 14.0; HRMS (ESI) for C₁₇H₂₆O₂ (M + Na)⁺ found 285.1830, calcd 285.1825.

O-((4R,5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-yl)-N-phenylhydroxylamine 12

Procedure as described in the preparation of 9. Yellow colour liquid. Yield: 5.57 g, 97%. [α]^25.8_D: +22.7° (c 1.7, CHCl₃); IR (neat, cm⁻¹): ν_max 3296, 3074, 2942, 2861, 1641, 1601, 1463, 1421, 1372, 1252, 1081, 1010, 913, 835, 772, 728, 687; ¹H NMR (500 MHz, CDCl₃) δ = 7.32–7.26 (m, 3H), 7.02–6.94 (m, 3H), 5.90 (tdd, J = 7.2, 10.0, 17.1 Hz, 1H), 5.15–5.06 (m, 2H), 4.00 (ddd, J = 2.1, 5.0, 7.2 Hz, 1H), 3.87–3.82 (m, 1H), 2.41 (td, J = 7.1, 14.3 Hz, 1H), 2.34–2.27 (m, 1H), 1.73–1.62 (m, 2H), 1.56–1.44 (m, 2H), 1.42–1.34 (m, 4H), 0.98–0.93 (m, 12H), 0.13 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ = 148.8, 135.7, 128.8, 121.6, 116.9, 114.3, 86.6, 74.0, 37.6, 32.0, 29.4, 26.2, 25.9, 22.6, 18.2, 14.1, −4.3, −4.4; HRMS (ESI) for C₂₂H₃₉O₂ N Si (M + H)⁺ found 378.2830, calcd 378.2823.

(4R,5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-ol 13

Procedure as described in the preparation of 9. Yellow colour oil. Yield: 3.2 g, 85%. [α]^26.0_D: −7.8° (c 1.61, CHCl₃); IR (neat, cm⁻¹): ν_max 3568, 3460, 3076, 2942, 2862, 1463, 1392, 1255, 1079; ¹H NMR (500 MHz, CDCl₃) δ = 5.80 (tdd, J = 7.1, 10.1, 17.2 Hz, 1H), 5.12–5.05 (m, 2H), 3.56 (td, J = 4.3, 7.0 Hz, 1H), 3.47–3.43 (m, 1H), 2.43 (td, J = 7.1, 14.1 Hz, 1H), 2.25–2.18 (m, 1H), 1.91 (br s, 1H), 1.53–1.44 (m, 1H), 1.43–1.39 (m, 2H), 1.37–1.28 (m, 5H), 0.92–0.89 (m, 12H), 0.10 (d, J = 7.3 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ = 134.4, 117.4, 74.6, 72.4, 38.7, 33.9, 31.9, 25.9, 25.5, 22.6, 18.1, 14.1, −4.1, −4.7; HRMS (ESI) for C₁₆H₃₄O₂ Si (M + Na)⁺ found 309.2226, calcd 309.2220.

(((4R,5R)-5-(Benzyloxy)dec-1-en-4-yl)oxy)(tert-butyl)dimethylsilane 14

Procedure as described in the preparation of 10. Colourless oil. Yield: 3.4 g, 92%. [α]^27.6_D: +22.3° (c 2.8, CHCl₃); IR (neat, cm⁻¹): ν_max 3074, 3029, 2941, 2862, 1462, 1370, 1319, 1253, 1208, 1094; ¹H NMR (500 MHz, CDCl₃) δ = 7.37–7.28 (m, 5H), 5.84 (tdd, J = 7.2, 10.0, 17.2 Hz, 1H), 5.09–5.01 (m, 2H), 4.62 (d, J = 11.9 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H), 3.81 (td, J = 3.9, 8.3 Hz, 1H), 3.33 (ddd, J = 2.9, 4.4, 9.2 Hz, 1H), 2.41 (dddd, J = 1.8, 3.4, 5.1, 14.0 Hz, 1H), 2.17–2.10 (m, 1H), 1.67–1.61 (m, 1H), 1.55–1.48 (m, 1H), 1.42 (dtd, J = 4.6, 9.0, 13.5 Hz, 1H), 1.34–1.27 (m, 5H), 0.89 (s, 12H), 0.02 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ = 139.3, 136.7, 128.5, 128.1, 127.8, 116.7, 82.3, 77.3, 72.8, 72.6, 36.7, 32.2, 29.0, 26.3, 26.1, 22.9, 18.3, 14.3, −4.2, −4.2; HRMS (ESI) for C₂₃H₄₀O₂ Si (M + Na)⁺ found 399.2699, calcd 399.2690.

(4R,5R)-5-(Benzyloxy)dec-1-en-4-ol 15

Procedure as described in the preparation of 11. Colourless oil. Yield: 1.3 g, 95%. [α]^28.8_D: −18.6° (c 2.27, CHCl₃); IR (neat, cm⁻¹): ν_max 3421, 3073, 3030, 2927, 2862, 1638, 1695, 1457, 1373, 1080; ¹H NMR (400 MHz, CDCl₃) δ = 7.38–7.29 (m, 5H), 5.88 (tdd, J = 7.0, 10.3, 16.9 Hz, 1H), 5.16–5.07 (m, 2H), 4.67 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 11.2 Hz, 1H), 3.65 (td, J = 4.8, 7.8 Hz, 1H), 3.35 (q, J = 5.5 Hz, 1H), 2.40–2.31 (m, 1H), 2.30–2.21 (m, 1H), 2.16 (br s, 1H), 1.72–1.53 (m, 2H), 1.43–1.28 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 138.4, 135.0, 128.4, 127.8, 127.7, 117.3, 81.4, 72.3, 72.0, 38.1, 32.1, 30.1, 24.8, 22.6, 14.0; HRMS (ESI) for C₁₇H₂₆O₂ (M + Na)⁺ found 285.1831, calcd 285.1825.

(4S,5R)-5-(Benzyloxy)dec-1-en-4-yl-4-nitrobenzoate 16

To a stirred solution of alcohol 15 (1.0 g, 3.8 mmol) in dry toluene (15 mL) were added PPh₃ (0.393 g, 15.2 mmol), p-nitrobenzoic acid (PNBA) (0.143 g, 19.0 mmol) and diisopropylazodicarboxylate (DIAD) (0.29 mL, 15.2 mmol) at 0 °C and it was stirred for 2 h at rt. Toluene was concentrated and directly transferred into silica gel column and it was purified by silica gel column chromatography using (EtOAc–petroleum ether, 3 : 97) as eluent to furnish 16 as a yellow colour oil (1.5 g, 97%). [α]^28.9_D: +9.13° (c 1.18, CHCl₃); IR (neat, cm⁻¹): ν_max 3074, 3027, 2937, 2863, 1724, 1643, 1641, 1530, 1456, 1348, 1275; ¹H NMR (400 MHz, CDCl₃) δ = 8.32–8.26 (m, J = 8.8 Hz, 2H), 8.22–8.16 (m, J = 8.8 Hz, 2H), 7.38–7.27 (m, 5H), 5.82 (tdd, J = 7.0, 10.0, 17.1 Hz, 1H), 5.41 (td, J = 4.0, 8.4 Hz, 1H), 5.17–5.04 (m, 2H), 4.70 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 3.64 (td, J = 3.7, 7.8 Hz, 1H), 2.66–2.56 (m, 1H), 2.56–2.48 (m, 1H), 1.73–1.48 (m, 4H), 1.46–1.29 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 164.2, 150.5, 138.2, 135.8, 133.6, 130.7, 128.4, 127.9, 127.7, 123.5, 118.1, 79.6, 75.7, 72.4, 34.2, 31.8, 30.5, 25.3, 22.5, 14.0; HRMS (ESI) for C₂₄H₂₉O₅ N (M + Na)⁺ found 434.1949, calcd 434.1938.

Conversion of nitrobenzoate 16 to alcohol fragment 11

To a stirred solution of p-nitro benzoate ester 16 (1.1 g, 2.6 mmol) in THF : MeOH : H₂O (3 : 2 : 1, 12 mL) was added LiOH·H₂O (0.168 g, 4.0 mmol) and stirred at rt for 1 h. After completing the starting material (monitored by TLC), reaction was quenched with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuum. The crude was purified by column chromatography using an eluent (EtOAc–petroleum ether, 5 : 95) to give 11 as colourless oil (659 mg, 95%).

Hex-5-enoic acid 17

To a stirred solution of cyclohexanone (20.0 g, 203.7 mmol) in MeOH (20 mL), hydrogen peroxide (46 mL, 407.4 mmol) was added slowly at rt. The mixture was then added to a stirred solution of FeSO₄·7H₂O (56.7 g, 203.7 mmol) and CuSO₄·5H₂O (51 g, 203.7 mmol) in water (370 mL), maintaining the reaction temperature at 18–20 °C. The aqueous phase was separated and extracted with Et₂O (3 × 40 mL). The combined Et₂O extracts were washed with 20% NaOH (3 × 20 mL). The alkaline extract was acidified with 20% H₂SO₄ to pH 2 and extracted with Et₂O (3 × 40 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc–petroleum ether, 10 : 90) to afford compound 17 as colourless oil (14.4 g, 62%). IR (neat, cm⁻¹): ν_max 3077, 2933, 2670, 1711, 1420, 1251, 1110; ¹H NMR (200 MHz, CDCl₃) δ = 5.95–5.67 (m, 1H), 5.14–4.96 (m, 2H), 2.45–2.33 (m, 2H), 2.13 (q, J = 7.1 Hz, 2H), 1.75 (quin, J = 7.4 Hz, 2H).

Benzyl-hex-5-enoate 18

To a stirred solution of compound 17 (4.0 g, 35.04 mmol), in DMF (50 mL), K₂CO₃ (12.1 g, 87.6 mmol) was added under argon atmosphere at 0 °C. After 10 min stirring at 0 °C, BnBr (6.2 mL, 52.5 mmol) was added to the reaction mixture and stirred for 2 h at rt. After completion of reaction cold water was added into the reaction mixture and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc–petroleum ether, 5 : 95) to yield compound 18 as colourless oil (6.8 g, 95%). IR (neat, cm⁻¹): ν_max 3074, 2940, 1737, 1638, 1596, 1451, 1234, 1162, 1111; ¹H NMR (200 MHz, CDCl₃) δ = 7.47–7.32 (m, 5H), 5.91–5.65 (m, 1H), 5.13 (s, 2H), 5.09–4.94 (m, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.10 (q, J = 7.3 Hz, 2H), 1.88–1.65 (m, 2H); ¹³C NMR (50 MHz, CDCl₃) δ = 173.4, 137.6, 136.0, 128.5, 128.2, 115.4, 66.1, 33.5, 33.0, 24.0; HRMS (ESI) for C₁₃H₁₆O₂ (M + Na)⁺ found 227.1047, calcd 227.1043.

Benzyl-(8S,9R,E)-9-(benzyloxy)-8-hydroxytetradec-5-enoate 19

To a stirred solution of 11 (600 mg, 2.28 mmol) in CH₂Cl₂ (7.0 mL) was added compound 18 (2.3 g, 11.44 mmol) and degassed for 15 min. Then Grubb's II catalyst (290 mg, 15 mol%) was added to the reaction mixture and stirred for 16 h at rt. After completion of reaction solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (EtOAc–petroleum ether, 8 : 92) to afford compound 19 as yellow colour oil (700 mg, 70%). [α]^28.9_D: −1.11° (c 1.64, CHCl₃); IR (neat, cm⁻¹): ν_max 3456, 3030, 2930, 2861, 1734, 1598, 1454, 1378, 1219, 1155, 1083; ¹H NMR (400 MHz, CDCl₃) δ = 7.42–7.28 (m, 10H), 5.56–5.40 (m, 2H), 5.15–5.10 (m, 2H), 4.64–4.53 (m, 2H), 3.82–3.72 (m, 1H), 3.45–3.33 (m, 1H), 2.41–2.34 (m, 2H), 2.29–2.16 (m, 2H), 2.14–2.01 (m, 2H), 1.92–1.84 (m, 1H), 1.74 (quin, J = 7.5 Hz, 2H), 1.68–1.57 (m, 1H), 1.54–1.45 (m, 2H), 1.36–1.28 (m, 5H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 173.4, 138.5, 136.0, 132.5, 131.4, 128.5, 128.4, 128.2, 127.8, 127.6, 127.4, 126.7, 81.7, 72.1, 71.6, 66.1, 35.6, 33.6, 32.0, 31.9, 29.1, 25.2, 24.5, 22.6, 14.0; HRMS (ESI) for C₂₈H₃₈O₄ (M + Na)⁺ found 461.2672, calcd 461.2662.

Benzyl-4-((2S,3S,5R)-5-((R)-1-(benzyloxy)hexyl)-3-hydroxytetrahydrofuran-2-yl)butanoate 20

To a stirred solution of compound 19 (72 mg, 0.164 mmol) in dry CH₂Cl₂ was added triethylamine (0.057 mL, 0.41 mmol), followed by slow addition of mesyl chloride (0.018 mL, 0.246 mmol) at 0 °C, with further stirring for 15 min at the room temperature. The reaction mixture was quenched with addition of cold water at 0 °C. The two phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed with water (3 × 5 mL), brine, dried over Na₂SO₄ and concentrated to give crude mesylate.

To a mixture of K₃Fe(CN)₆ (0.192 g, 0.580 mmol), K₂CO₃ (0.081 g, 0.58 mmol) and (DHQ)₂PHAL (1.5 mg, 0.002 mmol, 1 mol%) in t-BuOH–H₂O (1 : 1, 10 mL) at 0 °C was added osmium tetroxide (95 μL, 0.1 M solution in toluene, 5 mol%), followed by methane sulfonamide (0.079 g, 0.83 mmol). After stirring for 5 min at 0 °C, the crude mesylate (0.100 g, 0.19 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 24 h and then quenched with solid sodium sulphite (286 mg, 1.48 mg mmol⁻¹). Stirring was continued for an additional 15 min and then the solution was extracted with EtOAc (3 × 10 mL). The combined extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to give the crude diol.

The crude diol was refluxed in pyridine at 150 °C for 16 h gave the cyclized compound. After completion of the reaction 10% CuSO₄·5H₂0 solution was added to the reaction mixture and extracted with EtOAc. The combined organic layers were washed with water (2 × 5 mL), brine, dried over Na₂SO₄ and concentrated to give crude cyclized compound. The crude material was purified by flash column chromatography (EtOAc–petroleum ether, 15 : 85) to give compound 20 as colourless oil (59 mg, 80%). [α]^24.8_D: +15.2° (c 1.49, CHCl₃); IR (neat, cm⁻¹): ν_max 3441, 2928, 2861, 1733, 1455, 1249, 1161, 1083; ¹H NMR (400 MHz, CDCl₃) δ = 7.38–7.28 (m, 10H), 5.13 (s, 2H), 4.70 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.7 Hz, 1H), 4.32 (td, J = 6.2, 9.1 Hz, 1H), 4.27 (t, J = 2.9 Hz, 1H), 3.81 (dt, J = 2.6, 6.5 Hz, 1H), 3.34–3.28 (m, 1H), 2.53–2.38 (m, 2H), 2.05–1.83 (m, 5H), 1.83–1.57 (m, 6H), 1.53–1.41 (m, 4H), 0.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 173.7, 139.0, 135.9, 128.5, 128.2, 127.9, 127.4, 82.1, 81.1, 79.3, 72.9, 72.7, 66.3, 37.5, 33.9, 32.0, 30.6, 28.4, 25.3, 22.6, 21.3, 14.0; HRMS (ESI) for C₂₈H₃₈O₅ (M + Na)⁺ found 477.2621, calcd 477.2611.

(+)-Petromyroxol 1

To a stirred solution of 20 (14 mg, 0.03 mmol) in EtOH (3 mL) was added 10% w/w Pd/C (2 mg, 0.1 w/w) and the mixture was stirred for 3 h under H₂ atmosphere. Then, the Pd/C was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (MeOH : CH₂Cl₂, 15 : 85) to afford compound 1 as a colourless liquid (8 mg, 95%). [α]^25.9_D: +8.5° (c 0.64, CHCl₃), {lit³. [α]²⁵_D = +17° (c 0.36, CHCl₃)}; IR (neat, cm⁻¹): ν_max 3400, 2935, 2861, 1710, 1408, 1248, 1072, 1065; ¹H NMR (500 MHz, CDCl₃) δ = 4.32–4.27 (dd, J = 3.5, 3.5, 1H), 4.10–4.04 (ddd, J = 6.4, 6.7, 8.9, 1H), 3.82–3.77 (ddd, J = 2.4, 6.5, 6.5, 1H), 3.43–3.37 (ddd, J = 4.0, 6.4, 7.3, 1H), 2.49–2.37 (m, 2H), 2.04 (dd, J = 6.6, 13.3 Hz, 1H), 1.89 (ddd, J = 4.6, 9.1, 13.5 Hz, 1H), 1.80–1.63 (m, 4H), 1.55–1.47 (m, 1H), 1.44–1.28 (m, 7H), 0.89 (t, J = 6.9 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ = 177.7, 82.4, 80.5, 74.1, 73.3, 37.6, 33.5, 33.1, 31.8, 28.2, 25.2, 22.6, 21.2, 14.0; HRMS (ESI) for C₁₄H₂₆O₅ (M + Na)⁺ found 297.1678, calcd 297.1672.

Acknowledgements

U.N.R thanks UGC, New Delhi for a senior research fellowship. The authors thank CSIR, New Delhi for financial support as part of XII Five Year Plan under the title ORIGIN (CSC0108).

Notes and references

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Footnotes

† Dedicated to Professor Richard R. Schmidt on the occasion of his 80^th birthday.

‡ Electronic supplementary information (ESI) available: Copies of NMR spectra (¹H & ¹³C) of all compounds. See DOI: 10.1039/c5ra10405j

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