Total Synthesis of (+)-Petromyroxol, (−)-iso-Petromyroxol, and Possible Diastereomers

Venkannababu Mullapudi; Iram Ahmad; Sibadatta Senapati; Chepuri V Ramana

doi:10.1021/acsomega.0c03674

. 2020 Sep 24;5(39):25334–25348. doi: 10.1021/acsomega.0c03674

Total Synthesis of (+)-Petromyroxol, (−)-iso-Petromyroxol, and Possible Diastereomers

Venkannababu Mullapudi ^†,^‡, Iram Ahmad ^†, Sibadatta Senapati ^†,^‡, Chepuri V Ramana ^†,^‡,^*

PMCID: PMC7542842 PMID: 33043213

Abstract

The total synthesis of (+)-petromyroxol (1) and its seven diastereomers including the (−)-iso-petromyroxol (2) is described. The employed strategy involves the use of easily available C5-epimeric epoxides 5 and 5′ and nonselective anomeric C1-allylation, proceeding with or without inversion at C2, thereby giving the possibility of synthesizing all possible diastereomers. Extensive two-dimensional (2D) NMR analyses of all eight diastereomers have been carried out to assign the chemical shifts of the central carbons and the corresponding attached hydrogens and to learn how the C/H-chemical shifts of the tetrahydrofuran ring were influenced by the adjacent centers.

Introduction

The Annonaceous acetogenins that are characterized by a long-chain fatty acid skeleton are a group of natural products belonging exclusively to the plant family Annonaceae, which are spread across tropical and subtropical regions.¹ Acetogenins are found to exhibit potent and diverse biological effects such as cytotoxic, pesticidal, antitumor, antimalarial, antihelminthic, insecticidal, and olfactory activities.^1,2 The acetogenins are composed of a common skeleton containing an unbranched long-chain fatty acid with an α,β-unsaturated γ-lactone. In addition, they contain mono- and bis-tetrahydrofuran, and tetrahydropyran units, along with functional groups such as hydroxyl, carbonyl, and epoxide with internal unsaturation.³ Acetogenins having multiple 2,5-disubstituted tetrahydrofuran rings, as well as a γ-lactone terminus, are classified as classical acetogenins. On the other hand, nonclassical acetogenins contain one unit of tetrahydrofuran (THF) or hydroxylated tetrahydrofuran or a 2,5-disubstituted tetrahydrofuran ring (Figure 1). The acetogenins with the hydroxylated 2,5-disubstituted tetrahydrofuran core occupy a special place in this family due to their promising broad-spectrum biological properties, which include antitumor, antimalarial, antimicrobial, immunosuppressant, antifeedant, and pesticidal activities.⁴⁻⁷

Structures of natural products containing 2,5-disubstituted-3-oxygenated tetrahydrofuran scaffolds.

Recently, a pair of two enantiomeric novel fatty acid enantiomers, named petromyroxol (1) and iso-petromyroxol (2) possessing cis- and trans-dihydroxytetrahydrofuran cores (Figure 1), was isolated from larval sea lamprey-conditioned water.^8,9 The sea lamprey are parasitic fish widely distributed along the shores of northern/western Atlantic and the western Mediterranean Sea. They are also found in the shores of the great lakes and are considered as pests and known to cut back the indigenous fish populations. Between the two enantiomers, (+)-petromyroxol (1) was found to have a good olfactory response (0.01–1 μM).^8a Petromyroxols represent the first members of the mono acetogenins family to be isolated from a vertebrate animal. Like the other family members, the structure of petromyroxols comprises a C₁₄ fatty acid with a central trans-dihydroxytetrahydrofuran core, which is flanked by a hydroxylated C₆ side chain and a butyrate group on the other side. The structural characterization of these enantiomers was carried out with NMR analysis and by comparing the NMR data with the known oxylipids-1/2.^4a,4b,7 The absolute configuration was established by employing the Mosher ester analysis. Interestingly, the absolute configuration of the active enantiomer (+)-petromyroxol (1) was found to be similar to that of oxylipid-1. In the case of iso-petromyroxols 2,⁹ the assignment of absolute configurations was hampered due to the scarcity of the natural product isolated from the larvae source. The relative configuration for one of the enantiomers of (−)-iso-petromyroxol has been specified arbitrarily based on the comparison of NMR data with known oxylipids having cis- and trans-2,5-disubstituted THF diol motifs.

The simple/unique structures of these compounds, as well as their promising olfactory activity against sea lamprey, have led to them attracting the attention of the synthetic community.¹⁰⁻¹⁴ The first total synthesis of (+)-petromyroxol (1) was executed single-handedly by Boyer.¹⁰ Subsequently, four more total syntheses of (+)-petromyroxol (1) have been documented.¹¹⁻¹⁴ Immediately after the report on the isolation of 1 and its enantiomer, we initiated its total synthesis. In general, considering the presence of four stereogenic centers present in petromyroxol 1, there exists the possibility of eight enantiomeric pairs. Keeping this in mind, and considering the ready availability of C5-epimeric epoxides 5 and 5′, we planned the synthesis of 1 along with all of the possible seven isomers (Figure 1). In parallel to the report of Boyer, we reported the synthesis of 1 along with three possible diastereomers.¹¹ Interestingly, one of the diastereomers was found to be (−)-iso-petromyroxol (2),⁹ the isolation of which appeared at the same time. In this manuscript, we document the complete details of the total synthesis of 1 and 2 along with the other six possible diastereomers and their NMR characterization details.

Results and Discussion

A simple retrosynthetic blueprint for the construction of the central carbon skeleton from key epoxide intermediates 5 and 5′ has been provided in Scheme 1. The opening of these epoxides with the cuprate derived from n-BuLi will install the left-hand C5-alkyl chain. On the other hand, the anomeric C-allylation followed by oxidative olefin cleavage and two-carbon Wittig homologation is planned for placing the butyrate side chain at the C5 position. From each epoxide, C-allylation is expected to provide a mixture of two anomers. From each anomer, there are two possibilities—proceeding with the existing stereochemistry of C2–OH or its inversion under Mitsunobu conditions.

Scheme 1 — Starting epoxides 5 and 5′ and the planning for the syntheses of eight possible diastereomers.

Having the detailed synthetic map for all of the possible isomers, we first focused on the synthesis of (+)-petromyroxol and the other three possible isomers from epoxide 5. As depicted in Scheme 2, the journey started with the synthesis of the key C-allyl glycosides 8 and 9. The known epoxide 5 was prepared from d-glucose in seven steps following the reported procedures.¹⁵ The selective opening of epoxide 5 with cuprate derived from n-BuLi at 40 °C followed by benzylation of C5–OH in the resulting compound 6 gave the benzyl ether 7.¹⁶ Next, compound 7 was subjected to C-allylation employing the standard conditions that involve the use of allylTMS (5 equiv) and BF₃·Et₂O (3 equiv) in dichloromethane at 0 °C to obtain α- and β-C-allyl glycosides 8 and 9, respectively, in 81% yield in a 2:7 ratio.¹⁷ The formation of β-C-allyl glycoside 9 as a major product is expected, and it is also the required diastereomer for the synthesis of the parent (+)-petromyroxol (1). However, as we planned to synthesize the other possible diastereomers by varying the stereochemistry of the anomeric carbon and the adjacent center, access to good quantities of the α-C-glycoside 8 is warranted. In this context, the C-allylation reaction was examined at low temperature. Interestingly, with the same composition, when the reaction was carried out at −40 °C, although the reaction was incomplete (45% conversion), the selectivity was switched to 1:1. To this end, carrying out the reaction in the presence of excess BF₃·Et₂O (5 equiv) and allylTMS (10 equiv), a complete conversion could be obtained and a ∼1:1 mixture of 8 and 9 was obtained in 72% isolated yield. For structural characterization, the corresponding acetates 8-Ac and 9-Ac were prepared. The ¹³C chemical shifts as well as the correlation spectroscopy (COSY) and NOE correlation spectroscopy (NOESY) analyses were instrumental in establishing the anomeric configuration of compounds 8-Ac and 9-Ac (Figure 2).

Characteristic ¹³C NMR chemical shifts^20c,21c and through space interactions that assisted to assign the anomeric configuration in compounds 8, 9, 8′, and 9′ and their acetates.

After having access to the two key allyl glycosides 8 and 9, our next concern was the total synthesis of (+)-petromyroxol (1). In this context, an inversion at the C2 center is warranted. For this purpose, allyl glycoside 9 was subjected to the Mitsunobu reaction employing diisopropylazodicarboxylate (DIAD) and triphenylphosphine (TPP) in dichloromethane and employing p-nitrobenzoic acid as the nucleophile.¹⁸ The resulting compound 10 has been advanced for oxidative olefin cleavage employing OsO₄/NaIO₄, followed by the two-carbon Wittig homologation to obtain the unsaturated ester 11 in 69% yield over two steps.¹⁹ The hydrogenation of 11 employing the Pearlman catalyst [20% Pd(OH)₂/C] resulted in the hydrogenolysis of benzyl ether and reduction of olefin and nitro groups to afford 4-aminobenzoate 12 in 89% yield. Finally, the saponification of both ester groups in compound 12 was carried out with methanolic KOH to obtain (+)-petromyroxol (1) in 77% yield. The spectral data of compound 1 was found to be comparable with the data reported by the isolation group.^8a In addition, the observed similar sign of specific rotation [α]_D²⁵ +7.9 (c = 0.8, CHCl₃) ^Lit[α]_D +17.0 (c = 0.36, CHCl₃)^8a revealed that the proposed absolute configuration (+)-petromyroxol (1) is correct.

Having synthesized the active sea lamprey pheromone (+)-petromyroxol (1), as intended, the synthesis of the other three possible diastereomers 2–4 was taken up. In this context, we first selected diastereomer 2 [which turned out to be the (-)-iso-petromyroxol] starting with the allyl glycoside 8-Ac. As shown in Scheme 3, compound 8-Ac was subjected to olefin dihydroxylation/cleavage followed by the two-carbon Wittig homologation to provide the unsaturated ester 13 in 69% yield over two steps. The hydrogenation of 13 employing 20% Pd(OH)₂/C in methanol resulted in debenzylation and olefin reduction giving compound 14, which upon hydrolysis of both of the esters employing KOH in methanol at rt afforded the natural product (−)-iso-petromyroxol (2) in 75% yield. Along with our publication, the isolation of both enantiomers of iso-petromyroxol has been documented by Li’s group.⁹ The spectral data of 2 was matched with the data reported for the natural products, the absolute configuration of which was tentatively proposed. The measured specific rotation [α]_D²⁵ −14.9 (c = 0.2, CHCl₃) of synthetic (−)-iso-petromyroxol (2) matched one of the natural products {^Lit[α]_D −12.0 (c = 0.2, CHCl₃)}, thus establishing its absolute configuration.⁹

After completing the synthesis of both natural products, we focused our attention on synthesizing the other two diastereomers 3 and 4, which are the C6-epimers of (+)-petromyroxol and (−)-iso-petromyroxol, respectively. The synthesis of diastereomer 3 started with the allyl glycoside 9-Ac, which was subjected to the established three-step protocol (Scheme 4) employed for (−)-iso-petromyroxol (2) to afford 6-epi-(+)-petromyroxol (3). Similarly, the synthesis of 4 started with the Mitsunobu inversion of the C2–OH of allyl glycoside 8 to obtain the benzoate 17 in 86% yield (Scheme 5). The one-pot olefin cleavage and Wittig homologation of compound 17 afforded the key intermediate 18 in 71% yield over two steps. Hydrogenation of compound 18 using the Pearlman catalyst in methanol followed by base-mediated ester hydrolysis of the resulting compound 19 afforded 6-epi-(−)-iso-petromyroxol (4).

As initially planned, after completing the synthesis of the natural products 1 and 2 and their 6-epimers 3 and 4, respectively, next we planned to synthesize the other four diastereomers 1′–4′ having the same relative configuration as the THF units in 1–4, respectively, but with a variation of stereochemistry at the C9 center. A comparison of the NMR spectra of each epimeric pair would reveal how the change in the stereochemistry influences the H- and C-chemical shifts of the pendant tetrahydrofuran ring. As shown in Scheme 6, the synthesis of compounds 1′–4′ started with the known epoxide 5′, and the same protocols that were used for the syntheses of 1–4 (Schemes 2–5) were adopted.²⁰

Scheme 6 — Reagents and Conditions: (a) n-BuLi, CuI, Et₂O, −40 → 0 °C, 2 h; (b) NaH, BnBr, THF, 0 °C → rt, 8 h; (c) AllylTMS, BF₃·Et₂O, CH₂Cl₂, 0 °C to rt, 3 h; (d) AllylTMS, BF_3.Et₂O, CH₂Cl₂, −40 °C, 3 h; (e) Ac₂O, Et₃N, CH₂Cl₂, rt, 2 h; (f) p-nitrobenzoic acid, DIAD, PPh₃, THF, 0 °C → rt, 6 h; (g) cat. OsO₄, NaIO₄, 2,6-lutidine, dioxane:H₂O (1:1), rt, 6 h; then, Ph₃P = CHCO₂Et, THF, 0 °C → rt, 10 h; (h) 20% Pd(OH)₂/C, H₂(1 atm), MeOH, rt, 3 h; (i) aq KOH, MeOH, rt, 10 h.

After having access to all eight isomers, we proceeded toward NMR analysis to understand how the H/C chemical shift of each center varied with respect to the stereochemistry of the adjacent centers.²¹ The two-dimensional (2D) NMR (COSY, heteronuclear single quantum coherence (HSQC), NOESY) spectra of these eight isomers were recorded and analyzed to assign/identify each H and C of the central THF core and the adjacent carbons (C4, and C9, C10). The characteristic H-/C-chemical shifts are provided in Table S1 (see the Supporting Information). For convenience of description, the terms 1,2-cis or 1,2-trans C-glycosides (borrowed from the carbohydrate terminology) have been used to represent the relative stereochemistry of C5/C6. Coming to the ¹H NMR chemical shifts, in general, there are no characteristic differences that are specific to the relative stereochemistry of the adjacent centers. In general, the net chemical shift of each ring proton seems to be influenced by the shielding/deshielding effects, due to its orientation with respect to the neighboring groups, and also by the configuration at the long-distance C9 center. This seems to be a reason for the absence of a particular trend in the chemical shifts of any of these ring protons. However, it has been noticed that the chemical shift of H5 was influenced mainly by its orientation with respect to C6–H, C8–H, and C9–H. The C5–H was shielded better in isomer 2 (3.67 ppm), where it is oriented cis to both C6–H and C8–H. When both C6–H and C8–H are oriented trans to C5–H, a deshielding effect was seen (in isomers 3 and 3′). In the case of C6–H, it was shielded better in isomer 3, where it was oriented trans to C5–H and cis to C8–H. In the cases of C7–H and C7–H′, a maximum difference between the chemical shifts of these two germinal-H was seen in isomers 2 and 3 (≥0.5 ppm) and a minimum difference was seen in isomer 4 (0.09 ppm). The main difference between 2/3 and 4 was the orientation of C6–OH, which is below the plane of the furanose ring in 4. Interestingly, in the case of the isomeric series 1′–4′, this difference between the chemical shifts of C7–H and C7–H′ was uniform (∼0.25 ppm) and they are also relatively shielded when compared to 1–4. Next, when it comes to C8–H, as such there was no systematic variation seen with respect to the change of the stereochemistry at C5 or C9. However, in the case of C9–H, it was more deshielded in the epimeric series (up to 0.44 ppm difference) when compared with the corresponding (9R) series.²² Here, it is worth mentioning that the change in the stereochemistry of the C9 center influenced the chemical shifts of C7–H/C7–H′ to a major extent, with indirect shielding or deshielding effects on C5–H/C6–H.

Coming to the ¹³C chemical shifts, the influence of adjacent centers over a particular carbon in this series is seen better in unprotected C-glycosides when compared with that of the protected C-allyl glycosides. For example, in the cases of the natural product/isomers 1–4/1′–4′, the main difference seen between 1 and 1′ is the stereochemistry of the pendant C9–OH that is altered. This change in stereochemistry has a strong influence on the chemical shifts of both C7 and C9, which are shielded by about ∼2 and ∼4 ppm, respectively, in 1′–4′ when compared with that in 1–4 (Figure 3). However, when one looks at the ¹³C chemical shifts of the corresponding protected allyl C-glycosides, such a trend is missing in the case of C9 (protected as benzyl ether). In general, the protection of −OH groups seem to have a deshielding effect on the corresponding carbons and they are also influenced by the nature of the adjacent carbons, which is nominal when the OH is protected. As can be noticed, the change in the stereochemistry of the C9 center influenced the chemical shifts of C7 and C10 to a major extent. Following are some of the important trends noticed in the ¹³C chemical shifts of eight isomeric compounds. In general, C4 was deshielded up to 3.1 ppm in 1,2-trans C-glycosides and C5 and C6 were shielded in 1,2-cis C-glycosides. Interestingly, the chemical shift of C7 is influenced more by the stereochemistry at the C9 center shielding up to 5.5 ppm seen in 1′–4′ when compared to that of 1–4. This might be due to the change in the conformation around the C8–C9 bond, which would result in hydrogen–hydrogen gauche interactions, leading to a shielding γ/δ-effect, which is evident from the shielding of C9 also in 1′–4′ when compared to that of 1–4.²³ However, the chemical shift of C8 did not vary to a large extent with respect to the stereochemistry at C9. Except in one case (isomer 3′), C10 appeared upfield in isomers 1′, 2′, and 4′ when compared to the corresponding 1, 2, and 4. Interestingly, among all eight isomers, in isomer 4′, C7, C9, and C10 carbons are shielded better and C5, C6, and C8 are more deshielded than in all other isomers.

Characteristic ¹³C chemical shifts that are more influenced by the change of stereochemistry of adjacent carbon center(s).

In conclusion, we have completed the total synthesis of (+)-petromyroxol (1) in parallel to the Boyer synthesis. Also, the total synthesis of (−)-iso-petromyroxol (2) was completed, and this established the absolute configuration that has been not determined previously. We employed a chiral pool approach in this study, starting with the commercially available glucose diacetonide. Our strategy is highly modular and practical, which is evident from the synthesis of all possible eight diastereomers having variation in the stereochemistry at C9, C5, and/or C6. The 2D NMR analysis of all of the eight isomers was carried out, and it was observed that inverting the stereochemistry at C9 has a greater effect on the chemical shifts of H7 and H9. The C5 is deshielded in 1,2-trans C-glycosides when compared to the 1,2-cis C-glycosides. Overall, the chemical shifts of both H and C are influenced with respect to the adjacent stereocenters. Currently, compilation of the spectral data reported for various 2,5-disubstituted-3,6-dihydroxy THF units in the literature and from our laboratory and developing a reliable NMR analysis method to determine the relative configuration of this core are under progress.

Experimental Section

General Information

Commercial reagents were used without purification. Air- and/or moisture-sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in oven-dried glassware. All anhydrous solvents were distilled prior to use: dichloromethane and dimethylformamide (DMF) from CaH₂; methanol from Mg cake; THF on Na/benzophenone; triethylamine over KOH; Ac₂O over NaOAc; and EtOAc over K₂CO₃. Column chromatography was carried out using spectrochem silica gel (60–120, 100–200, 230–400 mesh). Specific optical rotations [α]^D are given in 10^–1 × deg × cm² × g^–1. ¹H and ¹³C NMR spectroscopy measurements were carried out on 400 or 500 MHz spectrometers, and tetramethylsilane (TMS) was used as an internal standard. ¹H and ¹³C NMR chemical shifts are reported in ppm downfield from chloroform-d (δ = 7.27) or TMS, and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The multiplicity of ¹³C NMR signals was assigned with the help of DEPT spectra and the abbreviations used—s, singlet; d, doublet; t, triplet; and q, quartet—represent C (quaternary), CH, CH₂, and CH₃, respectively. High-resolution mass spectral analysis (HRMS) was performed on micromass ESI-TOF MS and Q Exactive Hybrid Quadrupole Orbitrap MS.

Opening of Epoxide 6

At −40 °C, a suspension of CuI (1.53 g, 8.06 mmol) in dry Et₂O (50 mL) was treated with n-BuLi (10.1 mL, 16.1 mmol) and the contents were stirred for 15 min. To this, a solution of epoxide 5 (1 g, 5.4 mmol) in Et₂O (5 mL) was introduced and the mixture was stirred for 3 h at 0 °C. After completion, the reaction mixture was quenched with saturated NH₄Cl (50 mL) and the layers were separated. The aqueous layer was extracted with Et₂O (2 × 30 mL), and the combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated. Purification of the residue was carried out by silica gel column chromatography (20 → 25% EtOAc in petroleum ether), which gave alcohol 6 (995 mg, 76%) as a colorless oil. R_f = 0.4 (30% EtOAc in petroleum ether); [α]_D²⁵: −1.4 (c = 2.2, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.89 (t, J = 6.4 Hz, 3H), 1.31 (s, 3H), 1.28–1.52 (m, 8H), 1.55 (s, 3H), 1.98 (ddd, J = 1.2, 3.2, 14.3 Hz, 1H), 2.11–2.26 (m,1H), 2.72 (d, J = 1.6 Hz, 1H), 3.76 (bt, J = 3.76 Hz, 1H), 3.95 (td, J = 3.2, 8.2 Hz, 1H), 4.76 (ddd, J = 1.1, 3.9, 7.3 Hz, 1H), 5.81 (d, J = 4.0 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 25.3 (t), 25.9 (q), 26.9 (q), 31.8 (t), 33.1 (t), 33.6 (t), 72.7 (d), 80.7 (d), 84.7 (d), 106.1 (d), 112.3 (s) ppm; HRMS (ESI⁺) calculated for C₁₃H₂₄O₄Na: 267.1572 [M + Na]⁺; found 267.1575.

Preparation of Benzyl Ether 7

To a cooled solution of the alcohol 6 (900 mg, 3.68 mmol) in anhydrous DMF (25 mL), NaH (60%, 221 mg, 5.53 mmol) was added slowly and stirred for 10 min. To this, benzyl bromide (0.57 mL, 4.8 mmol) was added dropwise and stirring was continued at rt for 6 h. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (8 → 10% EtOAc in petroleum ether) afforded 7 (1.06 g, 90%) as a colorless syrup. R_f = 0.6 (20% EtOAc in petroleum ether); [α]_D²⁵: −2.8 (c = 3.9, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (t, J = 6.9 Hz, 3H), 1.26–1.31 (m, 4H), 1.36 (s, 3H), 1.40–1.52 (m, 4H), 1.59 (s, 3H), 1.98 (ddd, J = 1.8, 5.0, 14.2 Hz, 1H), 2.18 (ddd, J = 6.4, 7.8, 14.2 Hz, 1H), 3.66 (td, J = 2.7, 8.2 Hz, 1H), 4.13 (td, J = 5.0, 8.2 Hz, 1H), 4.65 (d, J = 11.4 Hz, 1H), 4.76 (ddd, J = 1.8, 4.1, 6.4 Hz, 1H), 4.97 (d, J = 11.4 Hz, 1H), 5.81 (d, J = 4.1 Hz, 1H), 7.25–7.43 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 25.0 (t), 26.3 (q), 27.3 (q), 31.6 (t), 31.8 (t), 34.2 (t), 73.5 (t), 80.6 (d), 80.9 (d), 84.1 (d), 106.2 (d), 112.4 (s),127.3 (d), 128.0 (d, 2C), 128.1 (d, 2C), 139.2 (s) ppm; HRMS (ESI⁺) calculated for C₂₀H₃₀O₄Na: 357.204 [M + Na]⁺; found 357.2052.

C-Allylation of 7

To an ice-cold solution of 7 (1 g, 3.0 mmol) in dry CH₂Cl₂ (50 mL), allyl trimethylsilane (2.38 mL, 14.9 mmol) was added, and after 15 min of stirring, BF₃·Et₂O (1.1 mL, 8.97 mmol) was added slowly and the contents were stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO₃ (50 mL), and the organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic layer was washed with water (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The resulting crude was purified by silica gel chromatography (10 → 16% EtOAc in petroleum ether) to afford α-C-glycoside 8 (232 mg, 24%) and β-C-glycoside 9 (542 mg, 57%) as colorless gums.

Characterization Data of 8

R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵: −19.1 (c = 0.8, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.91 (t, J = 6.7 Hz, 3H), 1.30–1.49 (m, 6H), 1.74–1.78 (m, 3H), 2.27 (ddd, J = 5.9, 9.8, 14.9 Hz, 1H), 2.40–2.44 (m, 2H), 3.26 (ddd, J = 2.1, 5.8, 8.3 Hz, 1H), 3.59 (td, J = 2.4, 6.7 Hz, 1H), 3.75 (bs, 1H), 3.98 (ddd, J = 2.5, 5.2, 10.9 Hz, 1H), 4.14 (dt, J = 2.7, 10.1 Hz, 1H), 4.49 (d, J = 11.3 Hz, 1H), 4.72 (d, J = 11.3 Hz, 1H), 5.04 (dd, J = 2.0, 8.6 Hz,1H), 5.13 (dd, J = 1.8, 17.10 Hz, 1H), 5.86 (ddt, J = 7.1, 10.2, 14.1 Hz, 1H), 7.30–7.37 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 22.6 (t), 25.6 (t), 29.7 (t), 32.0 (t), 33.5 (t), 37.6 (t), 71.3 (d), 72.2 (t), 77.5 (d), 80.3 (d), 83.5 (d), 116.7 (t), 128.1 (d), 128.5 (d, 2C), 128.6 (d, 2C), 135.2 (d), 137.3 (s) ppm; HRMS (ESI⁺) calcd for C₂₀H₃₀O₃Na: 341.2092 [M + Na]⁺; found 341.2096.

Characterization Data of 9

R_f = 0.4 (20% EtOAc in petroleum ether); [α]_D²⁵ −24.3 (c = 1.7, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (t, J = 6.6 Hz, 3H), 1.27–1.45 (m, 6H), 1.72–1.76 (m, 3H), 2.07–2.25 (m, 2H), 2.32 (ddd, J = 6.1, 9.3, 15.4 Hz, 1H), 3.28 (td, J = 2.4, 6.6 Hz, 1H), 3.81 (d, J = 10.3 Hz, 1H), 3.97 (bt, J = 6.4 Hz, 2H), 4.21 (dt, J = 3.2, 9.3 Hz, 1H), 4.52 (d, J = 11.2 Hz, 1H), 4.72 (d, J = 11.5 Hz, 1H), 5.05 (dd, J = 1.8, 7.7 Hz, 1H), 5.09 (dd, J = 1.6, 14.0 Hz, 1H), 5.81 (ddt, J = 6.9, 10.2,13.9 Hz 1H), 7.30–7.37 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 22.6 (t), 25.5 (t), 29.7 (t), 32.0 (t), 36.3 (t), 37.8 (t), 72.1 (t), 74.6 (d), 78.1 (d), 80.8 (d), 86.6 (d), 117.1 (t), 128.1 (d), 128.5 (d, 4C), 134.4 (d), 137.4 (s) ppm; HRMS (ESI⁺) calculated for C₂₀H₃₀O₃Na: 341.2092 [M + Na]⁺; found 341.2097.

(2R,3R,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (8-Ac)

To a solution of alcohol 8 (500 mg, 1.57 mmol), Et₃N (0.65 mL, 4.7 mmol), and 4-dimethylaminopyridine (DMAP) (2 mg) in CH₂Cl₂ (20 mL) at 0 °C was added acetic anhydride (0.3 mL, 3.14 mmol) and stirred for 2 h. The reaction mixture was diluted with CH₂Cl₂ (20 mL), washed with brine (20 mL) dried (Na₂SO₄), and concentrated under reduced pressure. The purification of the residue by silica gel chromatography (8 → 12% EtOAc in petroleum ether) gave acetate 8-Ac (520 mg, 92%) as a colorless syrup. R_f = 0.7 (20% EtOAc in petroleum ether); [α]_D²⁵: −1.5 (c = 1.1, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.8 Hz, 3H), 1.27–1.49 (m, 8H), 1.71 (ddd, J = 2.7, 7.6, 14.2 Hz, 1H), 2.06 (s, 3H), 2.33–2.42 (m, 2H), 2.44–2.51 (m, 1H), 3.43–3.47 (m, 1H), 3.80 (ddd, J = 4.4, 6.4, 10.5 Hz, 1H), 3.96 (bq, J = 7.3 Hz,1H), 4.65 (d, J = 11.5 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H), 5.07 (dd, J = 1.7, 11.6 Hz, 1H), 5.12 (dd, J = 1.7, 17.1 Hz, 1H), 5.24 (ddd, J = 2.7, 4.2, 7.0 Hz, 1H), 5.86 (ddt, J = 7.0, 10.2, 14.0 Hz, 1H), 7.27–7.39 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.0 (q), 22.6 (t), 25.2 (t), 30.9 (t), 31.9 (t), 33.7 (t), 35.8 (t), 73.0 (t), 74.2 (d), 80.4 (d), 80.8 (d, 2C), 116.9 (t), 127.4 (d), 128.0 (d, 2C), 128.2 (d, 2C), 134.5 (d), 139.1 (s), 170.5 (s) ppm; HRMS (ESI⁺) calculated for C₂₂H₃₂O₄Na: 383.2198 [M + Na]⁺; found 383.2198.

(2S,3R,5R)-5-((R)-1-(Benzylxy)hexyl)tetrahydrofuran-3-yl-acetate (9-Ac)

At 0 °C, a solution of alcohol 9 (200 mg, 0.63 mmol), Et₃N (0.26 mL, 1.88 mmol), and DMAP (2 mg) in CH₂Cl₂ (15 mL) was treated with acetic anhydride (118 μL, 1.26 mmol) and stirred for 2 h. The reaction mixture was diluted with CH₂Cl₂ (10 mL), washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The resulting crude was purified by silica gel chromatography (6 → 8% EtOAc in petroleum ether) to give 9-Ac (214 mg, 95%) as a colorless syrup. R_f = 0.8 (20% EtOAc in petroleum ether); [α]_D²⁵: −9.5 (c = 1.9, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.26–1.50 (m, 8H), 1.81 (ddd, J = 5.1, 7.2, 13.5 Hz, 1H), 2.05 (s, 3H), 2.34 (br.t, J = 6.7 Hz, 2H), 2.43 (dt, J = 7.3, 13.0 Hz, 1H), 3.45 (dt, J = 4.9, 6.3 Hz, 1H), 4.08 (dt, J = 3.9, 6.4 Hz, 1H), 4.17 (bq, J = 7.1 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.76 (d, J = 11.5 Hz, 1H), 4.97 (dt, J = 4.5, 7.1 Hz, 1H), 5.09 (dd, J = 1.6, 10.8 Hz, 1H), 5.14 (dd, J = 1.7, 18.0 Hz, 1H), 5.86 (ddt, J = 7.0, 7.2, 14.0 Hz, 1H), 7.28–7.40 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.1 (q), 22.6 (t), 25.2 (t), 30.7 (t), 31.9 (t), 34.1 (t), 37.1 (t), 72.9 (t), 77.4 (d), 80.0 (d), 80.6 (d), 81.9 (d), 117.5 (t), 127.4 (d), 127.9 (d, 2C), 128.2 (d, 2c), 133.9 (d), 139 (s), 170.7 (s) ppm; HRMS (ESI⁺) calculated for C₂₂H₃₂O₄Na: 383.2198 [M + Na]⁺; found 383.2202.

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (10)

A solution of alcohol 9 (200 mg, 0.63 mmol), p-nitrobenzoic acid (315 mg,1.88 mmol), and TPP (330 mg, 1.26 mmol) in THF (15 mL) was cooled to 0 °C and treated with diisopropylazodicarboxylate (0.24 mL, 1.26 mmol), and stirring was continued at 0 °C for 1 h and then at rt for 5 h. After completion, the reaction mixture was concentrated and the resulting crude material was dissolved in EtOAc (60 mL), washed with aqueous NaHCO₃ (30 mL) and water (50 mL), dried (Na₂SO₄), and concentrated in vacuum. Purification of the resulting crude by silica gel column chromatography (10 → 12% EtOAc in petroleum ether) gave the ester 10 (238 mg, 81%) as a yellow oil. R_f = 0.6 (20% EtOAc in petroleum ether); [α]_D²⁵: +11.7 (c = 0.9, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.8 Hz, 3H), 1.28–1.56 (m, 8H), 2.12–2.24 (m, 2H), 2.39–2.57 (m, 2H), 3.36 (ddd, J = 5.4, 5.4,10.6 Hz, 1H), 4.19 (td, J = 3.2, 7.0 Hz, 1H), 4.38 (ddd, J = 5.1, 6.7, 12.2 Hz, 1H), 4.69 (d, J = 2.0 Hz, 2H), 5.05 (dd, J = 1.6, 9.6 Hz, 1H), 5.08 (dd, J = 1.6, 17.0 Hz, 1H), 5.59 (dd, J = 3.2, 3.2 Hz, 1H), 5.82 (ddt, J = 7.0, 10.2, 13.8 Hz, 1H), 7.28–7.38 (m, 5H), 8.24 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 22.6 (t), 25.3 (t), 30.6 (t), 32.0 (t), 34.1 (t), 35.5 (t), 72.9 (t), 76.8 (d), 79.8 (d), 80.7 (d), 80.9 (d), 117.3 (t), 123.6 (d, 2C), 127.6 (d,), 127.9 (d, 2C), 128.3 (d, 2C), 130.8 (d, 2C), 134.0 (d), 135.4 (s), 138.8 (s), 150.7 (s), 164.0 (s) ppm; HRMS (ESI⁺) calculated for C₂₇H₃₃NO₆Na: 490.2205 [M + Na]⁺; found 490. 2203.

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexy)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (11)

To a cooled solution of alkene 10 (200 mg, 0.43 mmol) in dioxane-water (3:1, 8 mL) were added 2,6-lutidine (0.1 mL, 0.86 mmol), OsO₄ (2.17 mg, 0.008 mmol), and NaIO₄ (366 mg, 1.71 mmol) and the contents were stirred at rt for 6 h. After the reaction was complete, water (20 mL) and CH₂Cl₂ (30 mL) were added. The organic layer was separated, the aqueous layer was extracted by CH₂Cl₂ (2 × 10 mL), and the combined organic layer was dried (Na₂SO₄) and concentrated under vacuum to get crude aldehyde.

The resulting crude aldehyde was dissolved in THF (15 mL), cooled to 0 °C, and treated with ethyl 2-(triphenyl-λ⁵-phosphanylidene) acetate (440 mg, 1.32 mmol), and the contents were stirred at rt for 10 h. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (2 × 30 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography (18 → 20% EtOAc in petroleum ether) to afford ester 11 (160 mg, 69% over two steps) as a white solid. R_f = 0.5 (30% EtOAc in petroleum ether); MP: 91–92 °C. [α]_D²⁵: +16.0 (c = 4.1, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.88 (t, J = 6.7 Hz, 3H), 1.23 (t, J = 7.3 Hz, 3H), 1.28–1.58 (m, 8H), 2.16 (dd, J = 6.7, 13.7 Hz, 1H), 2.22 (ddd, J = 5.2, 9.2, 14.0 Hz, 1H), 2.52–2.63 (m, 2H), 3.35 (ddd, J = 5.2, 6.7, 10.5 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 4.25 (ddd, J = 3.3, 5.8, 8.9 Hz, 1H), 4.38 (ddd, J = 5.0, 6.4, 11.8 Hz, 1H), 4.66 (s, 2H), 5.59 (dd, J = 3.4, 3.4 Hz, 1H), 5.86 (d, J = 15.9 Hz, 1H), 6.98 (dt, J = 7.0, 15.6 Hz, 1H), 7.26–7.36 (m, 5H), 8.20 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 14.1 (q), 22.5 (t), 25.2 (t), 30.6 (t), 31.9 (t), 32.5 (t), 35.4 (t), 60.2 (t), 72.8 (t), 76.9 (d), 79.4 (d), 79.8 (d), 80.8 (d), 123.4 (d), 123.6 (d, 2C), 127.5 (d), 127.9 (d, 2C), 128.3 (d, 2C),130.7 (d, 2C) 135.1 (s), 138.6 (s), 144.1 (d), 150.7 (s), 163.9 (s), 166.1 (s) ppm; HRMS (ESI⁺) calculated for C₃₀H₃₇NO₈Na: 562.2411 [M + Na]⁺; found 562.2405.

(2S,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((R)-1-hydrioxyhehyl)tetrahydrofuran-3-yl-4-aminobenzoate (12)

A suspension of ester 11 (150 mg, 0.27 mmol) and 20% Pd(OH)₂/C (13 mg) in MeOH (10 mL) was stirred at rt under a H₂ atmosphere (balloon) for 3 h. After completion, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed thoroughly with EtOAc. The combined filtrate was evaporated under vacuum. Purification of the resulting crude by silica gel column chromatography (25 → 30% EtOAc in petroleum ether) gave ester 12 (104 mg, 89%) as a colorless oil. R_f = 0.5 (40% EtOAc in petroleum ether); [α]_D²⁵: +12.2 (c = 1.5, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.4 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.28–1.53 (m, 8H), 1.64–1.82 (m, 4H), 2.03–2.10 (m, 2H), 2.15 (dd, J = 6.6, 13.9 Hz, 1H), 2.32 (t, J = 6.6 Hz, 2H), 3.43 (dt, J = 7.6, 10.8 Hz, 1H), 4.09 (q, J = 7.0, 14.2 Hz, 2H), 4.02–4.06 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 5.51 (dd, J = 3.5, 3.5 Hz, 1H), 6.65 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 14.2 (q), 21.8 (t), 22.6 (t), 25.2 (t), 28.9 (t), 31.8 (t), 33.3 (t), 34.2 (t), 35.7 (t), 60.3 (t), 74.0 (d), 75.4 (d), 80.8 (d), 81.2 (d), 113.8 (d, 2C), 119.3 (s), 131.7 (d, 2C), 151.1 (s), 165.8 (s), 173.4 (s) ppm; HRMS (ESI⁺) calculated for C₂₃H₃₅NO₆Na: 444.2361 [M + Na]⁺; found 444.2351.

(+)-Petromyroxol (1)

A solution of ester 12 (70 mg, 0.11 mmol) in MeOH (10 mL) was treated with KOH (13 mg, 0.25 mmol), and the contents were stirred for 10 h at rt. The reaction mixture was concentrated under vacuum, and the resulting crude material was partitioned between CH₂Cl₂ (20 mL) and water (10 mL) and acidified with dilute HCl. The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressured, and the crude was purified by silica gel column chromatography (100% EtOAc) to afford (+)-petromyroxol (1) (35 mg, 77%) as a colorless oil. R_f = 0.2 (100% EtOAc); [a]_D²⁵: +7.9 (c = 0.8, CHCl₃) ^Lit[α]_D: +17.0 (c = 0.36, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.89 (t, J = 7.0 Hz, 3H), 1.28–1.31 (m, 2H), 1.32–1.35 (m, 2H), 1.36–1.40 (m, 2H), 1.41–56 (m, 2H), 1.63–1.80 (m, 4H), 1.89 (ddd, J = 4.6, 9.2, 13.4 Hz, 1H), 2.03 (dd, J = 6.7, 13.4 Hz, 1H), 2.43 (m, 2H), 3.40 (ddd, J = 4.1, 6.3, 8.9 Hz, 1H), 3.80 (ddd, J = 2.9, 6.9, 8.9 Hz, 1H), 4.06 (ddd, J = 4.5, 6.4, 12.7 Hz, 1H), 4.30 (dd, J = 2.8, 5.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.2 (q), 21.4 (t), 22.7 (t), 25.4 (t), 28.3 (t), 32.0 (t), 33.2 (t), 33.8 (t), 37.7 (t), 73.4 (d), 74.3 (d), 80.7 (d), 82.5 (d), 178.0 (s) ppm; HRMS (ESI⁺) calculated for C₁₄H₂₆O₅Na: 297.1677 [M + Na]⁺; found 297.1678.

Ethyl (E)-4-((2R,3R,5R)-3-Acetoxy-5-((R)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (13)

Following the procedure used in the preparation of 11, the oxidative cleavage of 8-Ac (250 mg, 0.72 mmol) followed by two-carbon Wittig homologation gave the ester 13 (208 mg, 69% over two steps) as a colorless syrup. R_f = 0.5 (20% EtOAc in petroleum ether); [α]_D²⁵: +5.2 (c = 0.4, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.89 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.23–1.50 (m, 8H), 1.71 (ddd, J = 3.0, 7.9, 14.3 Hz, 1H), 2.06 (s, 3H), 2.40 (dt, J = 7.6, 14.6 Hz, 1H), 2.48–2.61 (m, 2H), 3.43 (dt, J = 3.9, 9.5 Hz, 1H), 3.87 (dt, J = 4.9, 9.5 Hz, 1H), 3.94 (q, J = 7.3 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 4.63 (d, J = 11.6 Hz,1H), 4.76 (d, J = 11.6 Hz, 1H), 5.24 (dt, J = 3.7, 7.3 Hz, 1H), 5.92 (d, J = 15.9 Hz, 1H), 6.99 (dt, J = 7.0, 14.9 Hz, 1H), 7.26–7.37 (m, 5H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 14.2 (q), 21.0 (q), 22.6 (t), 25.2 (t), 30.9 (t), 31.9 (t), 32.2 (t), 35.8 (t), 60.3 (t), 73.1 (t), 74.4 (d), 79.5 (d), 80.6 (d), 80.7 (d),123.3 (d), 127.5 (d,), 128.0 (d, 2C), 128.2 (d, 2C), 138.9 (s), 144.7 (d), 166.3 (s), 170.5 (s) ppm; HRMS (ESI⁺) calculated for C₂₅H₃₆O₆Na: 455.2404 [M + Na]⁺; found 455.2401.

Ethyl-4-((2R,3R,5R)-3-acetoxy-5-((R)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (14)

Following the procedure used in the preparation of 12, hydrogenation of unsaturated ester 13 (150 mg, 0.32 mmol) gave 14 (109 mg, 91%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵: −4.3 (c = 0.3, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (t, J = 6.8 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.28–1.56 (m, 8H), 1.61–1.1.72 (m, 3H), 1.73–1.84 (m, 2H), 2.07 (s, 3H), 2.36 (t, J = 7.3 Hz, 2H), 2.41 (dd, J = 6.6, 8.0 Hz, 1H), 3.47 (bs, 1H), 3.74–3.79 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 5.23 (ddd, J = 2.2, 3.9, 6.4 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 14.2 (q), 21.0 (q), 21.8 (t), 22.6 (t), 25.3 (t), 28.3 (t), 31.8 (t), 33.6 (t), 34.1 (t), 35.7 (t), 60.3 (t), 73.7 (d), 74.8 (d), 80.6 (d), 81.3 (d), 170.5 (s), 173.4 (s) ppm; HRMS (ESI⁺) calculated for C₁₈H₃₂O₆Na: 367.2091 [M + Na]⁺; found 367.2086.

(−)-Iso-Petromyroxol (2)

As described for the preparation of 1, saponification of ester 14 (80 mg, 0.23 mmol) gave (−)-iso-petromyroxol (2) (48 mg, 75%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵: −14.9 (c = 0.2, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.90 (t, J = 6.4 Hz, 3H), 1.28–1.30 (m, 2H), 1.31–1.33 (m, 2H), 1.34–1.38 (m, 2H), 1.51–164 (m, 2H), 1.66–1.80 (m, 4H), 1.89 (dd, J =3.3, 14.1 Hz, 1H), 2.39 (ddd, J = 4.9, 8.9, 14.0 Hz, 1H), 2.43 (t, J = 6.4 Hz, 2H), 3.50 (ddd, J = 2.2, 4.8, 7.2 Hz, 1H), 3.67 (ddd, J = 2.9, 6.1, 9.0 Hz, 1H), 4.0 (dt, J = 2.3, 9.7 Hz, 1H), 4.12 (dd, J = 2.9, 5.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 21.3 (t), 22.6 (t), 25.6 (t), 28.0 (t), 31.7 (t), 33.6 (t), 34.2 (t), 38.3 (t), 71.6 (d), 73.9 (d), 79.3 (d), 83.8 (d), 177.3 (s) ppm; HRMS (ESI⁺) calculated for C₁₄H₂₆O₅Na: 297.1672 [M + Na]⁺; found 297.1667.

Ethyl (E)-4-((2S,3R,5R)-3-Acetoxy-5-((R)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (15)

Following the procedure used in the preparation of 11, the oxidative cleavage of 9-Ac (150 mg, 0.4 mmol) followed by two-carbon Wittig homologation gave the ester 15 (125 mg, 69% over two steps) as a colorless oil. R_f = 0.5 (20% EtOAc in petroleum ether); [α]_D²⁵: −10.3 (c = 1.7, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.88 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.3 Hz, 3H), 1.23–1.49 (m, 8H), 1.81 (ddd, J = 5.5, 7.6, 13.1 Hz, 1H), 2.04 (s, 3H), 2.40 (dt, J = 7.3, 13.7 Hz, 1H), 2.44–2.53 (m, 2H), 3.42 (q, J = 5.8 Hz, 1H), 4.10 (dt, J = 5.2, 9.8 Hz, 1H), 4.15 (dd, J = 7.9, 14.3 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 4.63 (d, J = 11.6 Hz,1H), 4.72 (d, J = 11.6 Hz, 1H), 4.92 (ddd, J = 4.0, 5.2, 9.7 Hz, 1H), 5.93 (d, J = 15.6 Hz, 1H), 6.97 (dt, J = 7.0, 15.6 Hz, 1H), 7.26–7.38 (m, 5H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 14.2 (q), 21.0 (q), 22.6 (t), 25.2 (t), 30.7 (t), 31.9 (t), 34.0 (t), 35.4 (t), 60.2 (t), 72.9 (t), 77.4 (d), 80.1 (d), 80.5 (d), 80.9 (d), 123.8 (d), 127.5 (d), 127.9 (d, 2C), 128.2 (d, 2C), 138.8 (d), 144.0 (d), 166.2 (s), 170.7 (s) ppm; HRMS (ESI⁺) calculated for C₂₅H₃₆O₆Na: 455.2404 [M + Na]⁺; found 455.2398.

Ethyl-4-((2S,3R,5R)-3-acetoxy-5-((R)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (16)

Following the procedure used in the preparation of 12, hydrogenation of unsaturated ester 15 (100 mg, 0.23 mmol) gave 16 (73 mg, 92%) as a colorless oil. R_f = 0.6 (30% EtOAc in petroleum ether); [α]_D²⁵: −11.0 (c = 1.1, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.89 (t, J = 6.4 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H) 1.30–1.59 (m, 8H), 1.63–1.73 (m, 2H), 1.74–1.84 (m, 2H), 2.06 (s, 3H), 2.34 (t, J = 7.3 Hz, 2H), 2.43 (dd, J = 7.4, 14.6 Hz, 2H), 3.51 (dt, J = 5.7, 10.1 Hz, 1H), 3.87 (ddd, J = 6.5, 6.5, 12.8 Hz, 1H), 3.97 (ddd, J = 3.4, 5.6, 8.2 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 4.93 (ddd, J = 3.8, 3.8, 7.2 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.1 (q), 21.2 (t), 22.6 (t), 25.3 (t), 31.8 (t, 2C), 33.2 (t), 33.9 (t, 2C), 60.3 (t), 73.5 (d), 78.2 (d), 80.5 (d), 82.5 (d), 170.6 (s), 173.4 (s) ppm; HRMS (ESI⁺) calculated for C₁₈H₃₂O₆Na: 367.2091 [M + Na]⁺; found 367.2086.

6-Epi-(+)-Petromyroxol (3)

As described for the preparation of 1, saponification of ester 16 (60 mg, 0.17 mmol) afforded 6-epi-(+)-petromyroxol (3) (37 mg, 77%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵: −27.6 (c = 0.6, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.6 Hz, 3H), 1.27–1.32 (m, 3H), 1.33–1.39 (m, 2H), 1.41–1.47 (m, 2H), 1.48–1.52 (m, 2H), 1.53–1.74 (m, 2H), 1.75–1.82 (m, 2H), 2.35 (dd, J = 6.3, 8.9 Hz, 1H), 2.39 (t, J = 7.3 Hz, 2H), 3.51 (ddd, J = 3.2, 4.8, 8.8 Hz, 1H), 3.91 (ddd, J = 2.2, 5.2, 8.5 Hz, 1H), 4.0 (ddd, J = 2.9, 5.2, 9.3 Hz, 1H), 4.04 (ddd, J = 2.0, 3.2, 6.3 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.0 (t), 22.6 (t), 25.5 (t), 31.7 (t), 32.3 (t), 33.6 (t), 33.8 (t), 36.9 (t), 74.1 (d), 75.3 (d), 79.7 (d), 86.3 (d), 178.0 (s) ppm; HRMS (ESI⁺) calculated for C₁₄H₂₆O₅Na: 297.1672 [M + Na]⁺; found 297.1668.

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (17)

Following the procedure used in the preparation of 10, the Mitsunobu reaction of alcohol 8 (165 mg, 0.52 mmol) gave compound 17 (209 mg, 86%) as a yellow oil. R_f = 0.6 (20% EtOAc in petroleum ether); [α]_D²⁵: +19.8 (c = 2.3, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.9 Hz, 3H), 1.24–1.56 (m, 8H), 2.05 (q, J = 4.1 Hz, 2H), 2.45 (t, J = 6.4 Hz, 2H), 3.41 (ddd, J = 3.6, 4.1, 9.9 Hz, 1H), 4.18 (td, J = 2.3, 6.4 Hz, 1H), 4.26 (dt, J = 6.4, 14.1 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.78 (d, J = 11.4 Hz, 1H), 5.13 (dd, J = 1.7, 10.0 Hz, 1H), 5.18 (dd, J = 1.7, 17.0 Hz, 1H), 5.26 (ddd, J = 2.0, 2.7, 5.9 Hz, 1H), 5.89 (ddt, J = 6.9, 10.2, 14.0 Hz, 1H), 7.29–7.41 (m, 5H), 8.19–8.22 (m, 2H), 8.29–8.33 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 22.6 (t), 25.2 (t), 31.1 (t), 31.9 (t), 34.6 (t), 38.5 (t), 73.0 (t), 79.3 (d), 80.9 (d), 81.6 (d), 83.5 (d), 117.8 (t), 123.6 (d, 2C), 127.5 (d), 128.0 (d, 2C), 128.2 (d, 2C), 130.7 (d, 2C), 133.7 (d), 135.3 (s), 138.9 (s), 150.6 (s), 164.2 (s) ppm; HRMS (ESI⁺) calculated for C₂₇H₃₃NO₆Na: 490.2200 [M + Na]⁺; found 490.2193.

(2R,3S,5R)-5-((R)-1-(Benzyloxy)hexy)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (18)

Following the procedure used in the preparation of 11, the oxidative cleavage of 17 (200 mg, 0.43 mmol) followed by two-carbon Wittig homologation gave compound 18 (165 mg, 71% over two steps) as a white solid. R_f = 0.6 (30% EtOAc in petroleum ether); MP: 83–84 °C; [α]_D²⁵: +24.9 (c = 2.9, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.89 (t, J = 6.6 Hz, 3H), 1.27 (t, J = 7.2, Hz, 3H), 1.24–1.53 (m, 8H), 2.08 (dd, J = 4.0, 7.8 Hz, 2H), 2.48–2.72 (m, 2H), 3.39 (dt, J = 4.9, 10.9 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 4.26 (ddd, J = 5.9, 8.1, 14.5 Hz, 2H), 4.65 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 5.21 (ddd, J = 2.5, 4.2, 6.7 Hz, 1H), 5.97 (d, J = 15.7 Hz, 1H), 7.0 (dt, J = 7.2, 15.5 Hz, 1H), 7.31–7.40 (m, 5H), 8.21–8.33 (m, 4H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 22.6 (t), 25.1 (t), 31.1(t), 31.9 (t), 34.5 (t), 36.6 (t), 60.3 (t), 73.0 (t), 79.3 (d), 80.7 (d), 81.7 (d), 82.6 (d), 123.6 (d, 2C), 124.1 (d), 127.5 (d), 128.0 (d, 2C), 128.3 (d, 2C), 130.7 (d, 2C), 135.0 (s), 138.7 (s), 143.7 (d), 150.6 (s), 164.2 (s), 166.1 (s) ppm; HRMS (ESI⁺) calculated for C₃₀H₃₇NO₈Na: [M + Na]⁺ 562.2411; found 562.2405.

(2R,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((R)-1-hydrioxyhehyl)tetrahydrofuran-3-yl-4-aminobenzoate (19)

Following the procedure used in the preparation of 12, hydrogenation of the conjugated ester 18 (120 mg, 0.21 mmol) gave 19 (83 mg, 88%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵: +12.8 (c = 1.0, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.90 (t, J = 6.3 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 1.32–1.54 (m, 8H), 1.55–1.69 (m, 2H), 1.70–1.86 (m, 2H), 2.02–2.11 (m 2H), 2.37 (td, J = 2.9, 6.9 Hz, 2H), 3.46 (dt, J = 4.6, 9.5 Hz, 1H), 4.01–4.08 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 5.15 (dt, J = 2.1, 5.1 Hz, 1H), 6.61–6.68 (m, 2H), 7.81–7.88 (m, 2H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.3 (t), 22.6 (t), 25.4 (t), 31.8 (t), 33.5 (t), 33.9 (t), 34.0 (t), 34.2 (t), 60.4 (t), 73.6 (d), 78.8 (d), 81.9 (d), 84.0 (d), 113.7 (d, 2C), 119.3 (s), 131.7 (d, 2C), 151.0 (s), 166.1 (s), 173.5 (s) ppm; HRMS (ESI⁺) calculated for C₂₃H₃₅NO₆Na: 444.2357 [M + Na]⁺; found 444.2352.

5-Epi-(+)-Petromyroxol (4)

Following the procedure used in the preparation of 1, saponification of ester 19 (60 mg, 0.14 mmol) gave 5-epi-(+)-petromyroxol (4) (29 mg, 74%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵: +9.9 (c = 3.6, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (t, J = 6.8 Hz, 3H), 1.27–1.39 (m, 5H), 1.41–1.53 (m, 4H), 1.56–1.64 (m, 1H), 1.65–1.76 (m, 1H), 1.80–1.85 (m, 1H), 1.86 (ddd, J = 2.3, 6.1, 13.2 Hz, 1H), 1.95 (ddd, J = 6.0, 9.4, 15.4 Hz, 1H), 2.34–2.48 (m, 2H), 3.41 (ddd, J = 3.3, 5.0, 9.5 Hz, 1H), 3.80 (ddd, J = 2.4, 4.8, 7.8 Hz, 1H), 4.05 (ddd, J = 5.0, 6.7, 11.3 Hz, 1H), 4.10 (dt, J = 2.4, 5.4 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.1 (t), 22.6 (t), 25.3 (t), 31.8 (t), 33.3 (t), 33.5 (t), 33.7 (t), 36.7 (t), 74.0 (d), 76.2 (d), 81.3 (d), 86.1 (d), 177.7 (s) ppm; HRMS (ESI⁺) calculated for C₁₄H₂₆O₅Na: 297.1672 [M + Na]⁺; found 297.1688.

Opening of Epoxide 6′

As described in the preparation of 6, opening the epoxide 5′ (1.5 g, 8.06 mmol) with n-BuLi gave compound 6′ (1.70 g, 86%) as a colorless oil. R_f = 0.4 (30% EtOAc in petroleum ether); [α]_D²⁵: −2.1 (c 6.8, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.8 (t, J = 6.8 Hz, 3H), 1.30 (s, 3H), 1.31–1.52 (m, 8H), 1.52 (s, 3H), 2.06–2.12 (m, 1H), 2.20 (ddd, J = 2.3, 5.0, 14.1 Hz, 1H), 3.82–3.83 (m, 1H), 3.99 (dt, J = 5.2, 3.5 Hz, 1H), 4.72 (ddd, J = 2.1, 4.2, 6.6 Hz, 1H), 5.72 (d, J = 3.81 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 22.5 (t), 25.3 (t), 26.3 (q), 27.4 (q), 31.3 (t), 31.8 (t), 33.1 (t), 71.8 (d), 80.8 (d), 84.0 (d), 105.9 (d), 112.6 (s) ppm; HRMS (ESI⁺) calculated for C₁₃H₂₄O₄Na: 267.1567 [M + Na]⁺; found 267.1565.

Benzyl Ether 7′

Following the procedure used in the preparation of 7, benzylation 6′ (1.5 g, 6.14 mmol) afforded benzyl ether 7′ (1.91 g, 92%) as a colorless syrup. R_f = 0.6 (20% EtOAc in petroleum ether); [α]_D²⁵: +5.24 (c = 9.8, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.83 (t, J = 6.3 Hz, 3H), 1.23–1.41 (m, 6H), 1.25 (s, 3H), 1.45 (s, 3H), 1.52–1.71 (m, 2H), 2.05 (ddd, J = 6.3, 7.5, 14.0 Hz, 1H), 2.24 (ddd, J = 1.5, 3.7, 14.2 Hz, 1H), 3.67 (ddd, J = 4.2, 6.2, 10.1 Hz, 1H), 3.96 (td, J = 4.0, 8.2 16.1 Hz, 1H), 4.56 (s, 2H), 4.66 (ddd, J = 1.5, 4.1, 5.9 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 7.20–7.29 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 23.9 (t) 26.0 (q), 27.0 (q), 31.0 (t), 32.0 (t), 33.4 (t), 72.3 (t), 79.6 (d), 80.7 (d), 81.7 (d), 106.2 (d), 112.1 (s), 127.4 (d), 127.8 (d, 2C), 128.2 (d, 2C), 138.5 (s) ppm; HRMS (ESI⁺) calculated for C₂₀H₃₁O₄: 335.2217 [M + H]⁺; found 335.2214.

C-Allylation of 7′

Following the procedure used in the preparation of 8 and 9, C-allylation of compound 7′ (1.7 g, 5.08 mmol) afforded compounds 8′ (580 mg, 36%) and 9′ (580 mg, 36%) as colorless liquids.

Characterization of Compound 8′

R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵: −40.3 (c = 1.2, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (J = 6.8 Hz, 3H), 1.02 (d, J = 6.2 Hz, 1H), 1.15 (d, J = 6.2 Hz, 1H), 1.27–1.31 (m, 4H), 1.49–1.58 (m, 1H), 1.65 (bs, 1H), 1.98 (dd, J = 2.9, 14.1 Hz, 1H), 2.20 (ddd, J = 5.3, 10.3, 14.1 Hz, 1H), 2.42–2.47 (m, 2H), 3.63–3.69 (m, 2H), 3.77 (d, J = 11.1 Hz, 1H), 3.96 (ddd, J = 2.5, 5.1, 11.0 Hz, 1H), 4.13 (dt, J = 2.6, 10.3 Hz, 1H), 4.67 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.3 Hz, 1H), 5.08 (ddt, J = 1.0, 2.1, 10.3 Hz, 1H), 5.16 (ddt, J = 1.4, 2.1, 17.1 Hz, 1H), 5.90 (ddt, J = 7.1, 10.3, 17.1 Hz, 1H), 7.29–7.39 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 22.5 (t), 25.6 (t), 31.8 (t), 31.9 (t), 33.8 (t), 34.7 (t), 71.1 (d), 73.8 (t), 79.7 (d), 80.8 (d), 83.4 (d), 116.7 (t), 128.0 (d), 128.2 (d, 2C), 128.5 (d, 2C), 135.3 (d), 137.5 (s); HRMS (ESI⁺) calculated for C₂₀H₃₁O₃: 319.2268 [M + H]⁺; found 319.2263.

Characterization of Compound 9′

R_f = 0.4 (20% EtOAc in petroleum ether); [α]_D²⁵: −39.4 (c = 1.2, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.9 Hz, 3H), 1.27–1.40 (m, 7H), 1.49–1.58 (m, 1H), 1.71 (bs, 1H), 1.93 (dd, J = 2.6, 13.7 Hz, 1H), 2.12–2.17 (m, 2H), 2.23 (ddd, J = 6.1, 9.9, 13.7 Hz, 1H), 3.68 (td, J = 2.3, 6.0 Hz, 1H), 3.96 (dd, J = 6.1, 10.7 Hz, 1H), 4.08 (t, J = 6.9 Hz, 1H), 4.12 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 10.7 Hz, 1H), 4.70 (d, J = 10.7 Hz, 1H), 5.07–5.13 (m, 2H), 5.82 (ddt, J = 6.9, 10.7, 17.5 Hz, 1H), 7.28–7.38 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 25.6 (t), 31.8 (t), 31.9 (t), 33.3 (t), 38.2 (t), 73.9 (t), 74.4 (d), 80.4 (d), 81.4 (d), 87.0 (d), 117.2 (t), 128.0 (d), 128.2 (d, 2C), 128.5 (d, 2C), 134.4 (d), 137.5 (s). HRMS (ESI⁺) calculated for C₂₀H₃₁O₃: 319.2268 [M + H]⁺; found 319.2263.

(2R,3R,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (8′-Ac)

Following the procedure used in the preparation of 8-Ac, acetylation of allyl glycoside 8′ (500 mg, 1.57 mmol) afforded 8′-Ac (525 mg, 93%) as a colorless syrup. R_f = 0.8 (10% EtOAc in petroleum ether); [α]_D²⁵: −27.3 (c 1.34, CHCl3); ¹H NMR (CDCl₃, 400 MHz): δ 0.86 (t, J = 7.0 Hz, 3H), 1.24–1.32 (m, 5H), 1.41–1.48 (m, 3H), 1.93 (s, 3H), 2.02 (ddd, J = 2.1, 7.0, 14.4 Hz, 1H), 2.29–2.52 (m, 3H), 3.63 (dt, J = 3.9, 7.0 Hz, 1H), 3.74 (td, J = 3.8, 7.9 Hz, 1H), 3.89 (td, J = 3.8, 7.0 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H), 5.05 (d, J = 10.4 Hz, 1H), 5.10 (d, J = 17.1 Hz, 1H), 5.24 (ddd, J = 2.4, 4.3, 6.7 Hz, 1H), 5.81 (ddt, J = 7.3, 10.4, 17.1 Hz, 1H), 7.27–7.37 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 20.9 (q), 22.6 (t), 25.1 (t), 31.8 (t), 31.9 (t), 33.7 (t), 33.9 (t), 72.9 (t), 74.5 (d), 78.9 (d), 80.8 (d), 80.9 (d), 117.0 (t), 127.4 (d), 127.8 (d, 2C), 128.2 (d, 2C), 134.4 (d), 139.1 (s), 170.6 (s) ppm; HRMS (ESI⁺) calculated for C₂₂H₃₂O₄Na: 383.2193 [M + Na]⁺; found 383.2184.

(2S,3R,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (9′-Ac)

Following the procedure used in the preparation of 8-Ac, acetylation of allyl glycoside 9′ (300 mg, 0.94 mmol) gave 9′-Ac (305 mg, 90%) as a colorless syrup. R_f = 0.8 (20% EtOAc in petroleum ether); [α]_D²⁵: −25.3 (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.87 (t, J = 6.9 Hz, 3H), 1.28–1.49 (m, 8H), 1.96 (s, 3H), 2.06 (ddd, J = 4.5, 6.9, 13.5 Hz, 1H), 2.23–2.39 (m, 3H), 3.59 (dt, J = 4.2, 10.7 Hz, 1H), 4.08–4.13 (m, 2H), 4.60 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.97 (dt, J = 4.2, 7.7 Hz, 1H), 5.08 (J = 10.4 Hz, 1H), 5.12 (J = 17.1 Hz, 1H), 5.81 (ddt, J = 7.3, 10.4, 17.1 Hz, 1H), 7.26–7.36 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.0 (q), 22.6 (t), 25.0 (t), 31.5 (t), 31.9 (t), 32.4 (t), 37.1 (t), 72.9 (t), 77.5 (d), 79.9 (d), 80.3 (d), 82.0 (d), 117.5 (t), 127.4 (d), 127.7 (d, 2C), 128.3 (d, 2C), 133.9 (d), 139.0 (s), 170.8 (s) ppm; HRMS (ESI⁺) calculated for C₂₂H₃₂O₄: 383.2193 [M + Na]⁺; found 383.2186.

(2S,3S,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (10′)

The same procedure as in the preparation of 10 was used with 9′ (250 mg, 0.785 mmol), giving 4-nitrobenzoate ester 10′ (293 mg, 80%) as a colorless oil. R_f = 0.6 (20% EtOAc in petroleum ether). [α]_D²⁵ +9.21 (c = 4.36, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.80 (t, J = 6.4 Hz, 3H), 1.18–1.35 (m, 8H), 2.06 (dd, J = 6.8, 14.2 Hz, 1H), 2.33–2.45 (m, 3H), 3.60–3.66 (m, 1H), 4.10 (td, J = 3.0, 6.4 Hz, 1H), 4.27 (ddd, J = 3.4, 6.6, 10.0 Hz, 1H), 4.58 (d, J = 11.5 Hz, 1H), 4.65 (d, J = 11.5 Hz, 1H), 4.95–5.05 (m, 2H), 5.52 (t, J = 3.6 Hz, 1H), 5.64–5.84 (m, 1H), 7.19–7.29 (m, 5H), 8.15 (d, J = 9.0 Hz, 2H), 8.4 (d, J = 9.0 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 25.3 (t), 31.5 (t), 31.8 (t), 33.3 (t), 34.2 (t), 73.4 (d), 77.2 (d), 80.4 (d), 80.5 (d), 80.7 (d), 117.3 (t), 123.6 (d, 2C), 127.5 (d), 127.8 (d, 2C), 128.3 (d, 2C), 130.7 (d, 2C), 134.0 (d), 135.4 (s), 138.8 (s), 150.6 (s), 169.3 (s) ppm; HRMS (ESI) calculated for C₂₇H₃₄NO₆ [M + H]⁺ 468.2381; found 468.2384.

(2S,3S,5R)-5-((S)-1-(Benzyloxy)hexyl)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (11′)

The same procedure as in the preparation of 11 was used with 10′ (200 mg, 0.425 mmol), giving ester 11′ (162 mg, 70%) as a colorless oil. R_f = 0.6 (20% EtOAc in petroleum ether). [α]_D²⁵ +23.2 (c = 1.38, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.88 (t, J = 6.8 Hz, 3H), 1.26 (t, J = 7.3,Hz, 3H), 1.30–1.52 (m, 8H), 2.16 (dd, J = 6.6, 14.0 Hz, 1H), 2.48 (ddd J = 5.0, 9.3, 14.2 Hz, 2H), 2.53–2.59 (m, 2H), 3.69–3.72 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.22 (ddd, J = 3.1, 5.9, 9.2 Hz, 1H), 4.35 (ddd, J = 3.6, 6.6, 10.2 Hz,1H), 4.67 (s, 2H), 5.61 (t, J = 3.6 Hz, 1H), 5.86 (d, J = 16.0 Hz, 1H), 6.98 (dt, J = 7.0, 15.7 Hz, 1H), 7.28–-7.38 (m, 5H), 8.19–8.24 (m, 2H), 8.30–8.33 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 14.2 (q), 22.5 (t), 25.3 (t), 31.4(t), 31.9 (t), 32.6 (t), 33.2 (t), 60.3 (t), 73.4 (t), 77.4 (d), 79.6 (d), 80.3 (d), 80.6 (d), 123.5 (d), 123.6 (d, 2C), 127.6 (d), 127.7 (d, 2C), 128.3 (d, 2C), 130.8 (d, 2C), 135.2 (s), 138.8 (s), 144.2 (d), 150.7 (s), 163.9 (s), 166.1 (s) ppm; HRMS (ESI) calculated for C₃₀H₃₈NO₈ [M + H]⁺ 540.2592; found 540.2590.

(2S,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((S)-1-hydroxyhexyl)tetrahydrofuran-3-yl-4-aminobenzoate (12′)

The same procedure as in the preparation of 12 was used with ester 11′ (100 mg, 0.185 mmol), giving ester 12′ (70 mg, 89%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether). [α]_D²⁵ +12.4 (c = 2.2, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.87 (t, J = 6.4 Hz, 3H), 1.21 (t, J = 7.3 Hz, 3H), 1.25–1.36 (m, 8H), 1.62–1.75 (m, 2H), 2.01 (dd, J = 6.0, 13.8 Hz, 1H), 2.04 (s, 1H), 2.21–2.35 (m, 3H), 3.84–3.90 (m, 1H), 4.08 (q, J = 7.2 Hz, 3H), 4.19 (ddd, J = 3.3, 6.0, 10.1 Hz, 2H), 5.52 (t, J = 3.6 Hz, 1H), 6.63 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.1 (q), 21.8 (t), 22.5 (t), 25.5 (t), 29.1 (t), 31.7 (t), 32.2 (t), 34.2 (t, 2C), 60.2 (t), 71.8 (d), 75.3 (d), 80.6 (d), 81.9 (d), 113.7 (d, 2C), 119.3 (s), 131.6 (d, 2C), 151.1 (s), 165.8 (s), 173.5 (s) ppm; HRMS (ESI) calculated for C₂₃H₃₅NO₆ [M + Na]⁺ 444.2357; found 444.2349.

9-Epi-(+)-Petromyroxol (1′)

The same procedure as in the preparation of 1 was used with ester 12′ (20 mg, 0.047 mmol), affording 9-epi-(+)-petromyroxol 1′ (11 mg, 84%) as a colorless oil. R_f 0.2 (100% EtOAc). [α]_D²⁵ +12.1 (c = 0.6, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.87 (t, J = 6.5 Hz, 3H), 1.27–1.50 (m, 9H), 1.61–1.75 (m, 4H), 1.86 (dd, J = 6.0 Hz, 1H), 2.12 (ddd, J = 4.5, 10.3, 14.0 Hz, 1H), 2.36–2.46 (m, 2H), 3.84–3.86 (m, 2H), 4.18 (ddd, J = 3.1, 6.1, 9.9 Hz, 1H), 4.32 (bt, J = 4.0 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.1 (t), 22.5 (t), 25.6 (t), 28.4 (t), 31.8 (t), 32.1 (t), 33.5 (t), 33.8 (t), 72.1 (d), 73.0 (d), 80.4 (d), 83.2 (d), 177.8 (s) ppm; HRMS (ESI) calculated for C₁₄H₂₆O₅ [M + Na]⁺ 297.1672; found 297.1673.

Ethyl (E)-4-((2R,3R,5R)-3-Acetoxy-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (13′)

The same procedure as in the preparation of 11 was used with ester 8′-Ac (150 mg, 0.42 mmol), giving ester 13′ (125 mg, 69% over two steps) as a colorless syrup. R_f = 0.5 (20% EtOAc in petroleum ether). [α]_D²⁵ −7.02 (c = 0.59, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.88 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.26–1.47 (m, 8H), 1.96 (s, 3H), 2.03 (ddd, J = 2.4, 7.3, 14.2 Hz, 1H), 2.29–2.43 (m, 1H), 2.50–2.59 (m, 2H), 3.58–3.68 (m,1H), 3.78–3.96 (m, 2H), 4.19 (q, J = 4.2 Hz, 2H), 4.60 (d, J = 11.6 Hz, 1H), 4.77 (d, J = 11.6 Hz, 1H), 5.25 (ddd, J = 2.5, 4.0, 6.7 Hz, 1H), 5.94 (d, J = 15.7 Hz, 1H), 6.98 (dt, J = 7.1, 15.6 Hz, 1H), 7.30–7.37 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 20.9 (q), 22.56 (t), 25.1 (t), 31.8 (t, 2C), 32.2 (t), 33.8 (t), 60.3 (t), 72.9 (t), 74.7 (d), 78.9 (d), 79.5 (d), 80.9 (d), 123.3 (d), 127.4 (d,), 127.8 (d, 2C), 128.2 (d, 2C), 139.0 (s), 144.7 (d), 161.8 (s), 166.3 (s) ppm; HRMS (ESI) calculated for C₂₅H₃₇O₆ [M + H]⁺ 433.2585; found 433.2588.

Ethyl-4-((2R,3R,5R)-3-acetoxy-5-((S)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (14′)

The same procedure as in the preparation of 12 was used with ester 13′ (100 mg, 0.23 mmol), giving ester 14′ (71 mg, 89%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵ −11.8 (c = 1.08, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.89 (t, J = 6.4 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H) 1.26–1.32 (m, 8H), 1.64–1.81 (m, 3H), 1.96 (ddd, J = 2.0, 6.6, 14.1 Hz, 1H), 2.07 (s, 3H), 2.13–2.28 (m, 2H), 2.35 (t, J = 7.0 Hz, 2H), 3.66–3.78 (m, 1H), 3.80–3.90 (m, 2H), 4.15 (q, J = 7.2 Hz, 2H), 5.22 (ddd, J = 2.1, 3.8, 6.2 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.0 (q), 21.7 (t), 22.5 (t), 25.5 (t), 28.1 (t), 31.8 (t), 32.0 (t), 32.6 (t) 34.1 (t), 60.3 (t), 70.9 (d), 74.5 (d), 80.5 (d), 81.1 (d), 170.5 (s), 173.3 (s); HRMS (ESI) calculated for C₁₈H₃₃O₆ [M + H]⁺ 345.2272; found 345.2267.

5,6,9-Tris-epi-(+)-petromyroxol (2′)

The same procedure as in the preparation of 1 was used with ester 14′ (20 mg, 0.058 mmol), affording 5,6,9-tris-epi-(+)-petromyroxol 2′ (12 mg, 75%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵ −11.6 (c = 0.78, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.27–1.47 (m, 10H), 1.70–1.71 (m, 3H), 1.93 (dd, J = 3.1, 14.3 Hz, 1H), 2.18 (ddd, J = 5.4, 9.7, 15.3 Hz, 1H), 2.31–2.40 (m, 2H), 3.61 (m, 1H), 3.80 (bt, J = 6.1 Hz, 1H), 4.01 (dt, J = 2.5, 9.9 Hz, 1H), 4.07 (dd, J = 2.5, 5.3 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.4 (t), 22.5 (t), 25.6 (t), 28.0 (t), 31.7 (t), 31.9 (t), 33.3 (t), 34.0 (t), 71.1 (d), 71.9 (d), 80.3 (d), 83.5 (d), 177.6 (s) ppm; HRMS (ESI) calculated for C₁₄H₂₆O₅ [M + Na]⁺ 297.1672; found 297.1674.

Ethyl (E)-4-((2S,3R,5R)-3-Acetoxy-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (15′)

The same procedure as in the preparation of 11 was used with ester 9′-Ac (150 mg, 0.42 mmol), giving ester 15′ (130 mg, 72% over two steps) as a colorless syrup. R_f = 0.5 (20% EtOAc in petroleum ether); [α]_D²⁵ −21.0 (c = 0.77, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.88 (t, J = 6.5 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.26–1.47 (m, 8H), 1.99 (s, 3H), 2.09 (ddd, J = 5.4, 7.3, 13.0 Hz, 1H), 2.31–2.50 (m, 3H), 3.58–3.64 (m, 1H), 4.05–4.12 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.60 (d, J = 11.6 Hz, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.94 (ddd, J = 4.4, 5.7, 9.9 Hz, 1H), 5.94 (d, J = 15.7 Hz, 1H), 6.95 (dt, J = 7.1, 15.6 Hz, 1H), 7.30–7.37 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.0 (q), 22.5 (t), 25.0 (t), 31.5 (t), 31.9 (t), 32.2 (t), 35.4 (t), 60.3 (t), 72.9 (t), 77.5 (d), 79.9 (d), 80.3 (d), 81.0 (d),123.8 (d), 127.5 (d,), 127.7 (d, 2C), 128.3 (d, 2C), 138.9 (s), 144.0 (d), 166.2 (s), 170.7 (s) ppm; HRMS (ESI) calculated for C₂₅H₃₇O₆ [M + H]⁺ 433.2585; found 433.2587.

Ethyl-4-((2S,3R,5R)-3-acetoxy-5-((S)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (16′)

The same procedure as in the preparation of 12 was used with ester 15′ (100 mg, 0.23 mmol), giving ester 16′ (74 mg, 93%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵ −19.62 (c = 0.53, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.90 (t, J = 6.5 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.33–1.56 (m, 10H), 1.65–1.82 (m, 2H), 2.0 (ddd, J = 4.0, 7.4, 13.6 Hz, 1H), 2.06 (s, 3H), 2.07–2.08 (m, 1H), 2.26 (dd, J = 7.4, 14.5 Hz, 1H), 2.35 (t, J = 7.3 Hz, 1H), 3.82 (bm, 1H), 3.95 (dd, J = 3.2, 7.7 Hz, 1H), 4.01 (dd, J = 2.8, 6.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.96 (ddd, J = 3.0, 4.2, 7.1 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.1 (q), 21.2 (t), 22.5 (t), 25.5 (t), 30.6 (t), 31.4 (t), 31.8 (t), 32.7 (t), 33.9 (t), 60.3 (t), 71.5 (d), 78.1 (d), 80.0 (d), 82.9 (d), 173.3 (s), 179.2 (s) ppm; HRMS (ESI) calculated for C₁₈H₃₂O₆ [M + Na]⁺ 367.2091; found 367.2084.

6,9-Bis-epi-(+)-petromyroxol (3′)

The same procedure as in the preparation of 1 was used with ester 16′ (20 mg, 0.058 mmol), affording 6,9-bis-epi-(+)-petromyroxol 3′ (11 mg, 69%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵ −15.9 (c = 1.28, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (t, J = 6.3 Hz, 3H), 1.27–1.34 (m, 8H), 1.45–1.49 (m, 2H) 1.65–1.80 (m, 2H), 1.86–1.95 (bd, J = 13.7 Hz, 1H), 2.15–2.25 (m, 1H), 2.39 (t, J = 6.7 Hz, 2H), 3.83 (m, 1H), 3.98 (bs, 1H), 4.04 (bs, 1H), 4.08–4.12 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 14.0 (q), 21.1 (t), 22.5 (t), 25.6 (t), 29.3 (t), 31.7 (t), 32.2 (t), 32.7 (t), 33.2 (t), 72.3 (d), 74.9 (d), 80.4 (d), 83.5 (d), 177.9 (s) ppm; HRMS (ESI) calculated for C₁₄H₂₆O₅ [M + Na]⁺ 297.1672; found 297.1671.

(2R,3S,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (17′)

Following the procedure used in the preparation of 10, the Mitsunobu reaction of alcohol 8′ (220 mg, 0.69 mmol) gave 17′ (280 mg, 87%) as a yellow oil. R_f = 0.6 (20% EtOAc in petroleum ether); [α]_D²⁵: +19.4 (c = 2.12, CHCl₃); ¹H NMR (CDCl₃, 200 MHz): δ 0.89 (t, J = 6.6 Hz, 3H), 1.26–1.51 (m, 8H), 2.09 (ddd, J = 1.4, 5.6, 13.9 Hz, 1H), 2.34 (ddd, J = 6.2, 10.3, 16.5 Hz, 1H), 2.44 (t, J = 6.6 Hz, 1H), 3.68 (m, 1H), 4.14 (td, J = 2.5, 6.4, 13.3 Hz, 1H), 4.13 (td, J = 2.3, 6.3 Hz, 1H), 4.21 (td, J = 4.3, 5.2 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 5.03–5.19 (m, 2H), 5.29 (dt, J = 1.9, 6.3 Hz, 1H), 5.88 (ddt, J = 6.9, 13.8, 17.1 Hz, 1H), 7.27–7.38 (m, 5H), 8.20 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 22.5 (t), 25.2 (t), 31.8 (t), 32.0 (t), 32.8 (t), 38.5 (t), 73.4 (t), 79.3 (d), 79.7 (d), 81.7 (d), 83.5 (d), 117.8 (t), 123.5 (d, 2C), 127.5 (d,), 127.8 (d, 2C), 128.3 (d, 2C), 130.7 (d, 2C), 133.7 (d), 135.4 (s), 138.8 (s), 150.6 (s), 164.2 (s) ppm. HRMS (ESI⁺) calculated for C₂₇H₃₄NO₆: 468.2381 [M + H]⁺; found 468.2379.

(2R,3S,5R)-5-((S)-1-(Benzyloxy)hexyl)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (18′)

Following the procedure used in the preparation of 11, the oxidative cleavage of 17′ (200 mg, 0.43 mmol) followed by two-carbon Wittig homologation gave compound 18′ (167 mg, 71% over two steps) as a colorless liquid. R_f = 0.6 (30% EtOAc in petroleum ether); [α]_D²⁵: +18.4 (c = 1.1, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.87 (t, J = 6.9 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H), 1.28–1.58 (m, 6H), 1.43–1.53 (m, 2H), 2.10 (ddd, J = 1.3, 5.5, 13.8 Hz, 1H), 2.33 (ddd, J = 6.5, 10.2, 16.5 Hz, 1H), 2.46–2.53 (m, 1H), 2.55–2.60 (m, 1H), 3.63 (dt, J = 3.4, 7.2 Hz, 1H), 4.12–4.14 (m, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.20 (ddd, J = 3.8, 5.4, 10.0 Hz, 1H), 4.62 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 5.21 (dt, J = 2.1, 6.4 Hz, 1H), 6.0 (d, J = 15.6 Hz, 1H), 6.97 (dt, J = 7.2, 15.5 Hz, 1H), 7.27 (q, J = 4.2 Hz, 1H), 7.33 (d, J = 4.3 Hz, 4H), 8.18 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 14.2 (q), 22.5 (t), 25.2 (t), 31.8 (t), 31.9 (t), 32.7 (t), 36.7 (t), 60.3 (t), 73.3 (t), 79.3 (d), 79.7 (d), 8.8 (d), 82.6 (d), 123.6 (d, 2C), 124.0 (d), 127.5 (d), 127.9 (d, 2C), 128.3 (d, 2C),130.7 (d, 2C) 135.2 (s), 138.7 (s), 143.8 (d), 150.9 (s), 164.2 (s), 166.1 (s) ppm; HRMS (ESI⁺) calculated for C₃₀H₃₈NO₈: 540.2592 [M + H]⁺; found 540.2590.

(2R,3S)-2-(4-Ethoxy-4-oxobutyl)-5-((S)-1-hydroxyhexyl)tetrahydrofuran-3-yl-4-aminobenzoate (19′)

Following the procedure used in the preparation of 12, hydrogenation of the conjugated ester 18′ (100 mg, 0.185 mol) gave 19′ (72 mg, 92%) as a colorless oil. R_f = 0.5 (30% EtOAc in petroleum ether); [α]_D²⁵: +0.9 (c = 0.7, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (t, J = 6.7 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.29–1.39 (m, 6H), 1.49–1.59 (m,2H), 1.64–1.76 (m, 2H), 1.80–1.86 (m, 2H), 1.90 (dd, J = 5.2, 13.5 Hz, 1H), 2.22 (ddd, J = 6.1, 10.7, 16.8 Hz, 1H), 2.27–2.44 (m, 3H), 3.89 (td, J = 2.5, 6.7 Hz, 1H), 4.02 (ddd, J = 1.8, 4.6, 8.7 Hz, 1H), 4.10–4.18 (m, 4H), 5.13 (d, J = 5.9 Hz, 1H), 6.64 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz): δ 14.0 (q), 14.2 (q), 21.1 (t), 22.5 (t), 25.7 (t), 30.3 (t), 31.8 (t), 32.5 (t), 33.4 (t), 33.7 (t), 60.4 (t), 70.5 (d), 78.8 (d), 82.0 (d), 84.0 (d), 112.1 (d), 113.7 (d), 119.4 (s), 131.6 (d, 2C), 151.1 (s), 166.1 (s), 173.5 (s) ppm; HRMS (ESI⁺) calculated for C₂₃H₃₆NO₆: 422.2537 [M + H]⁺; found 422.2533.

5,9-Bis-epi-(+)-petromyroxol (4′)

Following the procedure used in the preparation of 1, saponification of ester 19′ (20 mg, 0.047 mmol) afforded 5,9-bis-epi-(+)-petromyroxol 4′ (10 mg, 77%) as a colorless oil. R_f = 0.2 (100% EtOAc); [α]_D²⁵: +20.5 (c = 1.32, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 0.87 (t, J = 6.8 Hz, 3H), 1.24–1.34 (m, 8H), 1.49–1.50 (m, 2H), 1.56 (ddd, J = 5.0, 10.6, 18.8 Hz, 1H), 1.62–1.66 (m, 1H), 1.70 (dd, J = 5.9, 12.7 Hz, 1H), 1.75–1.84 (m, 1H), 2.06 (ddd, J = 6.4, 9.8, 15.8 Hz, 1H), 2.32–2.44 (m, 2H), 3.77 (ddd, J = 2.6, 4.7, 7.8 Hz, 1H), 3.80–3.85 (m, 1H), 4.06–4.07 (m, 1H), 4.11 (ddd, J = 2.7, 5.9, 9.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.0 (q), 21.0 (t), 22.5 (t), 25.6 (t), 31.8 (t), 32.4 (t), 32.9 (t), 33.2 (t), 33.4 (t), 71.0 (d), 76.0 (d), 81.3 (d), 86.0 (d), 177.6 (s) ppm; HRMS (ESI⁺) calculated for C₁₄H₂₆O₅: 297.1672 [M + Na]⁺; found 297.1666.

Acknowledgments

We thank CSIR, New Delhi, for funding and for the award of a Research Fellowship to S.S. and UGC, New Delhi, for the award of a Research Fellowship to V.M.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c03674.

¹H and ¹³C NMR spectra of all new compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c03674_si_001.pdf^{(24.3MB, pdf)}

References

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Total Synthesis of (+)-Petromyroxol, (−)-iso-Petromyroxol, and Possible Diastereomers

Venkannababu Mullapudi

Iram Ahmad

Sibadatta Senapati

Chepuri V Ramana

Abstract

Introduction

Figure 1.

Results and Discussion

Scheme 1. Structures of (+)-Petromyroxol (1) and (−)-iso-Petromyroxol (2) and Other Possible Diastereomers.

Scheme 2. Total Synthesis of (+)-Petromyroxol (1).

Figure 2.

Scheme 3. Total Synthesis of (−)-iso-Petromyroxol (2).

Scheme 4. Synthesis of 6-epi-(+)-Petromyroxol (3).

Scheme 5. Synthesis of 6-epi-(−)-iso-Petromyroxol (4).

Scheme 6. Total Synthesis of Petromyroxol Diastereomers 1′–4′.

Figure 3.

Experimental Section

General Information

Opening of Epoxide 6

Preparation of Benzyl Ether 7

C-Allylation of 7

Characterization Data of 8

Characterization Data of 9

(2R,3R,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (8-Ac)

(2S,3R,5R)-5-((R)-1-(Benzylxy)hexyl)tetrahydrofuran-3-yl-acetate (9-Ac)

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (10)

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexy)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (11)

(2S,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((R)-1-hydrioxyhehyl)tetrahydrofuran-3-yl-4-aminobenzoate (12)

(+)-Petromyroxol (1)

Ethyl (E)-4-((2R,3R,5R)-3-Acetoxy-5-((R)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (13)

Ethyl-4-((2R,3R,5R)-3-acetoxy-5-((R)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (14)

(−)-Iso-Petromyroxol (2)

Ethyl (E)-4-((2S,3R,5R)-3-Acetoxy-5-((R)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (15)

Ethyl-4-((2S,3R,5R)-3-acetoxy-5-((R)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (16)

6-Epi-(+)-Petromyroxol (3)

(2S,3S,5R)-5-((R)-1-(Benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (17)

(2R,3S,5R)-5-((R)-1-(Benzyloxy)hexy)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (18)

(2R,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((R)-1-hydrioxyhehyl)tetrahydrofuran-3-yl-4-aminobenzoate (19)

5-Epi-(+)-Petromyroxol (4)

Opening of Epoxide 6′

Benzyl Ether 7′

C-Allylation of 7′

Characterization of Compound 8′

Characterization of Compound 9′

(2R,3R,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (8′-Ac)

(2S,3R,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-acetate (9′-Ac)

(2S,3S,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (10′)

(2S,3S,5R)-5-((S)-1-(Benzyloxy)hexyl)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (11′)

(2S,3S,5R)-2-(4-Ethoxy-4-oxobutyl)-5-((S)-1-hydroxyhexyl)tetrahydrofuran-3-yl-4-aminobenzoate (12′)

9-Epi-(+)-Petromyroxol (1′)

Ethyl (E)-4-((2R,3R,5R)-3-Acetoxy-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (13′)

Ethyl-4-((2R,3R,5R)-3-acetoxy-5-((S)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (14′)

5,6,9-Tris-epi-(+)-petromyroxol (2′)

Ethyl (E)-4-((2S,3R,5R)-3-Acetoxy-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-2-yl)but-2-enoate (15′)

Ethyl-4-((2S,3R,5R)-3-acetoxy-5-((S)-1-hydroxyhexyl)tetrahydrofuran-2-yl)butanoate (16′)

6,9-Bis-epi-(+)-petromyroxol (3′)

(2R,3S,5R)-2-Allyl-5-((S)-1-(benzyloxy)hexyl)tetrahydrofuran-3-yl-4-nitrobenzoate (17′)

(2R,3S,5R)-5-((S)-1-(Benzyloxy)hexyl)-2-((E)-4-ethoxy-4-oxobut-2-en-1-yl)tetrahydrofuran-3-yl-4-nitrobenzoate (18′)

(2R,3S)-2-(4-Ethoxy-4-oxobutyl)-5-((S)-1-hydroxyhexyl)tetrahydrofuran-3-yl-4-aminobenzoate (19′)

5,9-Bis-epi-(+)-petromyroxol (4′)

Acknowledgments

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