Stereoselective total synthesis of ent-hyptenolide

Abstract

A stereoselective total synthesis of ent-hyptenolide is reported involving asymmetric allylation, Horner–Wadsworth–Emmons olefination, stereoselective anti reduction and RCM as the key steps.

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Introduction

Hyptenolide (1, Fig. 1), a new α-pyrone was recently isolated from the aerial parts of Hyptis macrostachys Benth.¹ The structure of 1 was deciphered by extensive NMR techniques and CD spectral data. The intriguing structural features of 1 include a unique combination of a trans olefin (C3′/C4′) in conjugation with a cis olefin (C1′/C2′) and the diene connected to the α-pyranone motif at C6. The distal end of the diene fragment is endowed with an anti-diacetoxy propane moiety. Compound 1 showed a selective spasmolytic effect in guinea pig trachea and ileum.¹ In continuation of our interest in the synthesis of 5,6-dihydropyran-2-one² containing natural products, the hitherto unreported structural features of 1 coupled with its impressive bio-active profile encouraged us to undertake its total synthesis.

Fig. 1 Structure of hyptenolide and related pyranone polyaceates.

Results and discussion

The envisaged retrosynthetic analysis of compound 1 is depicted in Scheme 1. Accordingly, 1 could be obtained from diacetoxy acryloyl derivative 2 on RCM. Compound 2 in turn could be derived from enyne 3 upon few chemical transformations such as silyl deprotection, selective reduction, acetylation, MOM-deprotection followed by acryloylation. Further, compound 3 maybe assembled using the HWE-olefination reaction between chiral ynal 5 and chiral phosphonate 4. Ynal 5 is conveniently drawn from commercially available 1,4-butyne diol involving Keck allylation to garner the stereogenic carbon and other sequential transformations like deprotection–oxidation reaction set. While phosphonate 4 itself was prepared from ethyl L-lactate by a reported procedure.³

Scheme 1 Retrosynthetic analysis of hyptenolide 1.

Accordingly, the synthesis began from the commercially available 1,4-butyne diol 6 (Scheme 2). Diol 6 on selective protection as its monobenzoate⁴ under conventional reaction conditions followed by oxidation (IBX conditions) afforded the corresponding aldehyde which on Keck allylation⁵ (R-BINOL/Ti(OⁱPr₄)/TiCl₄/Ag₂O/allyltributyltin/CH₂Cl₂/−15 °C) provided the chiral propargylic alcohol 8 (75%). The absolute stereochemistry of the newly created stereogenic center was established using literature analogy and assigned as ‘R’.⁶ Next, protection of the secondary hydroxyl group as its MOM-ether (MOM-Cl/DIPEA/CH₂Cl₂/0 °C to rt) furnished compound 9 (88%). Subsequent hydrolysis (K₂CO₃/MeOH/0 °C–rt) of the benzoate 9 released the primary hydroxyl group to afford 10 (80%) in order to facilitate its oxidation (IBX/DMSO/CH₂Cl₂/0 °C to rt) and thus generate the crucial ynal fragment 5 (90%).

Scheme 2 Reagents and conditions: (a) ref. 4; (b) IBX, DMSO, CH₂Cl₂, 0 °C–rt, 90%, (ii) I, allyltributyltin (1.1 equiv.), CH₂Cl₂, −15 °C, 36 h (75%); (c) MOM-Cl, DIPEA, dry CH₂Cl₂, 0 °C–rt, 4 h, 88%; (d)K₂CO₃, CH₃OH, 0 °C–rt, 80%; (e) IBX, DMSO, CH₂Cl₂, 0 °C–rt, 90%.

Another synthon, chiral phosphonate 4 was accessed using a reported procedure.³ Having the phosphonate 4 in hand, Horner–Wadsworth–Emmons olefination reaction was performed between phosphonate 4 and ynal 5 (Scheme 3) to result in enyne 3 (60%) as the separable E-isomer (>85%) as the major isomer. The E-geometry was ascertained from the ¹H NMR spectrum wherein the newly formed olefinic protons resonated at δ 6.98 ppm as a doublet (J = 15.8 Hz, 1H) and another at δ 6.78 ppm as a dd (J = 1.8, 15.8 Hz, 1H). The other terminal olefinic protons appeared at their expected shifts. Next, we envisaged an anti-reduction of the accompanying keto group in enyne 3 would lead us to the total carbon framework with rightly positioned stereogenic centers. Firstly, desilylation of 3 (PPTS/MeOH/0 °C–rt) was effected to give the hydroxy ketone derivative 11 (78%). However, reduction⁷ (ZnBH₄/THF/0 °C) of 11 offered an chromatographically inseparable diastereomeric mixture 12 (89% combined yield) in favor of the anti-isomer (4 : 1, anti : syn) as the major compound. The diastereomeric ratio of 12 was determined from the ¹H NMR spectrum by measuring the integration of the separable protons. For instance, while the terminal methyl protons of the minor isomer resonated at δ 1.19 ppm as a doublet (J = 6.4 Hz, 0.75H), the same protons for the major isomer resonated at δ 1.14 ppm as doublet (J = 6.4 Hz, 3H). Also, one of the olefinic protons for the minor isomer resonated at δ 6.19 ppm as a dd (J = 6.13, 15.8 Hz, 0.25H) while the corresponding proton for the major isomer resonated at δ 6.11 ppm as a dd (J = 6.1, 15.8 Hz, 1H). The relative stereochemistry of the major isomer was initially assigned as anti based on literature precedence.^3,7 Thankfully, the diastereomeric mixture 12 could be chromatographically separated on its conversion to acetonide 13 (2,2 DMP/PPTS/CH₂Cl₂/0 °C to rt, 73%). As envisioned and to continue with the synthesis, optically pure anti-isomer (12a) was necessary. Hence, deprotection of the acetonide group was carried out under acidic conditions (60% aq. AcOH) to afford optically pure diol 12a (87%) that was diacetylated (Ac₂O/Et₃N/DMAP/CH₂Cl₂/0 °C to rt) to 14 (90%). In order to conclusively establish the anti-stereochemistry of the diol 12a, we conducted few more experiments. For example, keto compound 3 was subjected to Luche reduction⁸ followed by TBS-deprotection to afford syn-diol exclusively in 92% yield which was acetylated to afford 14a (90%) under conventional conditions. Likewise, the minor isomer obtained during the chromatographic separation of 13 was also converted into its diacetate after few transformations such as acetonide group deprotection followed by acetylation. Next, the comparative ¹H NMR study of the thus obtained diacetates was made which showed a complete match, thus unequivocally establishing their syn diol relationship. Having ascertained the relatively stereochemistry of minor isomer, a comparison of ¹H NMR data of 14 and 14a was also taken up (Fig. 2). Herein the two spectra displayed differences, notably the allylic proton H5′ in anti-isomer resonated downfield (δ 5.37 ppm) than its syn counter part (δ 5.33 ppm) in accordance with the literature report.⁹ Thus, the major compound 14 was conclusively proved as the anti-isomer drawing inference from all the above observations and its stereogenic carbon C5′ was assigned as ‘R’. Additionally, the absolute stereochemistry of the newly created stereogenic center was confirmed later through the synthesis.

Scheme 3 Reagents and conditions: (a) Cs₂CO₃, MeCN, −15 °C, 45 min, 60%; (b) PPTS, MeOH, 0 °C–rt, 12 h, 78%; (c)ZnBH₄, THF, 0 °C, 0.5 h, 89%; (d) 2,2 DMP, PPTS, CH₂Cl₂, 0 °C–rt, 73%; (e) 60% aq. AcOH, 6 h, rt, 87%; (f) Ac₂O, Et₃N, DMAP, CH₂Cl₂, 0 °C–rt, 90%; (g) TiCl₄, CH₂Cl₂, 0 °C, 1 h, 80%; (h) acryloyl chloride, Et₃N, DMAP, dry CH₂Cl₂, 0 °C, 1 h, 82%; (i) Grubbs-II, dry CH₂Cl₂, rt, 12 h, 65%; (j) H₂, Pd–CaCO₃ (Lindlar's catalyst), quinoline, EtOAc, 20 min, 90%.

Fig. 2 Comparative ¹H NMR data of anti- and syn-isomeric diacetates 14 and 14a.

Furthermore, diacetate 14 on deprotection of MOM group under Lewis acid conditions (TiCl₄/CH₂Cl₂/0 °C) provided the homoallyl alcohol derivative 15 (80%). Subsequent acryloylation of 15 (acryloyl chloride/Et₃N/DMAP/CH₂Cl₂/0 °C) afforded 2 (82%) which on Grubbs' catalyst¹⁰ assisted RCM (G-II/CH₂Cl₂/rt) resulted in the ring-closed product 16 (65%). Finally, partial hydrogenation of 16 under Lindlar's conditions gave the target compound 1 (90%).

All the spectral data of synthetic 1 matched^1,11 with the reported data excepting the specific rotation {synthetic 1: [α]²⁰_D = −45.8 (c 0.2, CHCl₃); natural 1 (ref. 1): [α]²⁰_D = +45.0 (c 0.001, CHCl₃)}, which showed an opposite sign of rotation implying the synthesis of an enantiomer.

Conclusion

In summary, we accomplished the total synthesis of ent-hyptenolide in an overall yield of 3.9% from 7 using asymmetric allylation, Horner–Wadsworth–Emmons olefination, stereoselective anti reduction and RCM as the key steps.

Experimental section

Reactions were carried out under N₂ in dry solvents. All reactions were monitored by tlc and silica-coated plates were visualized by exposure to ultraviolet light and/or α-naphthol charring. Organic solutions were dried (Na₂SO₄) and concentrated below 40 °C under reduced pressure in a Büchi rotary evaporator. All column chromatographic (CC) separations were performed using silica gel (SiO₂; 60–120 mesh) with EtOAc and hexane as eluents. Tlc was performed on Merck 60 F254 silica gel plates. Yields refer to chromatographically and spectroscopically (¹H and ¹³C-NMR) homogeneous material. Air-sensitive reagents were transferred by syringe and double-ended needle. Optical rotations were measured on Anton Paar mcp-200 polarimeter and ¹H NMR and ¹³C NMR spectra were recorded on Avance 300 or Avance 500 MHz nuclear magnetic resonance spectrometers. Chemical shifts were reported as (δ) in parts per million (ppm) with respect to internal TMS. Coupling constants J values are given in Hz. High-resolution mass spectra (HRMS) were obtained using either a TOF or a double focusing spectrometer.

(R)-4-Hydroxyhept-6-en-2-yn-1-yl benzoate (8)

To an ice-cooled solution of IBX (9.94 g, 35.52 mmol) in DMSO (8.39 mL, 107.56 mmol) and CH₂Cl₂ (45 mL), was added a solution of alcohol 7 (4.5 g, 23.68 mmol) in CH₂Cl₂ (10 mL). The mixture was stirred at room temperature for 2 h and then filtered through a Celite pad and washed with CH₂Cl₂ (3 × 30 mL). The organic filtrate was sequentially washed with H₂O, brine and later dried (Na₂SO₄) and concentrated in vacuo. The crude aldehyde (4.0 g, 90%, viscous liquid) was immediately subjected to the next reaction without further purification.

To a stirred solution of TiCl₄ (1 M solution in CH₂Cl₂, 2.1 mL, 2.1 mmol) in dry CH₂Cl₂ (40 mL) was added Ti(OⁱPr)₄ (1.82 mL, 6.40 mmol) at 0 °C under N₂. The solution was allowed to warm to room temperature. After 1 h, (R)-binaphthol (2.43 g, 8.49 mmol) was added at room temperature and the solution was stirred for 3 h. The mixture was cooled to 0 °C, and treated with silver(I) oxide (0.98 g, 4.25 mmol). The reaction mixture was allowed to warm to room temperature, and stirred there for 5 h under exclusion of direct light to furnish chiral bis Ti(IV) oxide (R,R)-I was treated with aldehyde (4.0 g, 21.27 mmol) and allyltributyltin (7.17 mL, 21.66 mmol) at −15 °C. The whole mixture was warmed to 0 °C and allowed to stir for 36 h. The reaction mixture was quenched with saturated NaHCO₃, and extracted with CH₂Cl₂ (3 × 50 mL). The organic extracts were washed with brine, dried (Na₂SO₄), concentrated, and the residue was purified by column chromatography (EtOAc : n-hexane, 3 : 7) to give the allylated product 8 (3.63 g, 75%) as yellow liquid.

[α]²⁰_D = −2.44 (c 1.4, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 8.07 (dd, J = 1.3, 8.3 Hz, 2H), 7.58 (m, 1H), 7.48–7.43 (m, 2H), 5.88 (m, 1H), 5.23–5.17 (m, 2H), 4.96 (d, J = 1.6 Hz, 2H), 4.49 (t, J = 6.1 Hz, 1H), 2.52–2.48 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 165.8, 133.2, 132.7, 129.7, 129.4, 128.3, 119.1, 87.1, 79.2, 61.5, 52.7, 41.8; HRMS: m/z calcd for C₁₄H₁₈O₃N [M + NH₄]⁺: 248.1281; found: 248.1273.

(R)-4-(Methoxymethoxy)hept-6-en-2-yn-1-yl benzoate (9)

To compound 8 (3.5 g, 15.21 mmol) in dry CH₂Cl₂ (25 mL) at 0 °C, were successively added DIPEA (7.8 mL, 60.46 mmol), catalytic DMAP and MOMCl (1.82 mL, 22.75 mmol). The mixture was stirred for 4 h at room temperature, then the reaction was quenched by adding water (20 mL) and the mixture was extracted with CH₂Cl₂ (3 × 30 mL). The organic extracts were washed with brine, dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The crude material was purified by column chromatography (EtOAc : n-hexane, 2 : 8) to afford product 9 (3.66 g, 88%) as an colorless liquid.

[α]²⁰_D = + 71.0 (c 1.2, CHCl₃);¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 5.89 (m, 1H), 5.23–5.08 (m, 2H), 5.0–4.90 (m, 3H), 4.61 (d, J = 6.7 Hz, 1H), 4.43 (t, J = 6.4 Hz, 1H), 3.38 (s, 3H), 2.52 (t, J = 6.6 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 165.7, 133.2, 133.2, 129.7, 129.5, 128.3, 118.0, 94.1 85.0, 79.9, 65.1, 55.6, 52.6, 39.8; HRMS: m/z calcd for C₁₆H₂₂O₄N [M + NH₄]⁺: 292.1543; found: 292.1535.

(R)-4-(Methoxymethoxy)hept-6-en-2-yn-1-ol (10)

To stirred solution of 9 (3.2 g, 11.11 mmol) in MeOH (35 mL) was added potassium carbonate solid (2.3 g, 16.66 mmol) at 0 °C and allowed it to stir at room temperature. After stirring for 3 h, solvent MeOH was removed under reduced pressure. The crude residue was washed with water (3 × 20 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried (Na₂SO₄), concentrated and purified by column chromatography (EtOAc : n-hexane, 3.5 : 6.5) to obtain alcohol 10 (1.56 g, 80%) as a colorless liquid.

[α]²⁰_D = +90.0 (c 4.45, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 5.88 (m, 1H), 5.23–5.09 (m, 2H), 4.94 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.42 (t, J = 6.4 Hz, 1H), 4.30 (d, J = 0.94 Hz, 2H), 3.38 (s, 3H), 2.50 (t, J = 6.6 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 133.2, 117.9, 93.9, 84.3, 83.5, 65.2, 55.6, 50.7, 39.9; m/z: C₉H₁₈O₃N (M + NH₄)⁺: 188.

(5R,11S,E)-5-Allyl-11,13,13,14,14-pentamethyl-2,4,12-trioxa-13-silapentadec-8-en-6-yn-10-one (3)

To an ice-cooled solution of IBX (3.45 g, 12.32 mmol) in DMSO (3.21 mL, 41.15 mmol) and CH₂Cl₂ (20 mL), was added a solution of alcohol 10 (1.40 g, 8.23 mmol) in CH₂Cl₂ (5 mL). The mixture was stirred at room temperature for 2 h and then filtered through a Celite pad and washed with CH₂Cl₂ (3 × 30 mL). The combined organic filtrates were washed with H₂O (2 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude aldehyde 5 (1.24 g, 90%) was immediately subjected to the next reaction without further purification.

Cs₂CO₃ (2.37 g, 7.29 mmol) was added to a solution of 4 (1.13 g, 3.64 mmol) in MeCN (10 mL), and was stirred for 45 min at room temperature. The reaction mixture was cooled to −15 °C and a solution of the aldehyde 5 (1.24 g, 7.29 mmol) in MeCN (10 mL) was added drop wise and stirred for 45 min at the same temperature. After completion of the reaction, it was cautiously quenched by addition of saturated citric acid (10 mL), poured into water (30 mL), and extracted with diethyl ether (3 × 50 mL). Combined organic layers were washed with brine (2 × 20 mL) and dried (Na₂SO₄). Evaporation of solvent gave the crude residue, which was purified by column chromatography using (EtOAc : n-hexane, 1 : 9) as eluent to furnish 3 (E-isomer, 1.54 g, 60%) as a light yellow oil.

[α]²⁰_D = +17.7 (c 1.1, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 6.98 (d, J = 15.8 Hz, 1H), 6.78 (dd, J = 1.6, 16.0 Hz, 1H), 5.88 (m, 1H), 5.22–5.13 (m, 2H), 4.91 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.55 (td, J = 1.6, 6.5 Hz, 1H), 4.26 (q, J = 6.8 Hz, 1H), 3.39 (s, 3H), 2.60–2.50 (m, 2H), 1.30 (d, J = 6.7 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 200.5, 132.9, 132.5, 123.5, 118.2, 97.1, 94.3, 83.9,74.2, 65.7, 55.7, 39.7, 25.7, 20.9, 18.1, −4.8, −5.0; HRMS: m/z calcd for C₁₉H₃₃O₄Si [M + H]⁺: 353.2142; found: 353.2181.

(2S,8R,E)-2-Hydroxy-8-(methoxymethoxy)undeca-4,10-dien-6-yn-3-one (11)

To a stirred solution of 3 (1.2 g, 3.40 mmol) in MeOH (20 mL) was added PPTS (1.71 g, 6.81 mmol) at room temperature and it was stirred for 12 h. After completion of the reaction (monitored by tlc), MeOH was evaporated under vacuum and the reaction mixture was diluted with CH₂Cl₂ (20 mL). Solid NaHCO₃ was added to the reaction mixture and was stirred for further 15 min. The reaction mixture was then filtered through a short pad of Celite and was washed with CH₂Cl₂ (3 × 20 mL) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc : n-hexane, 3 : 7) to obtain alcohol 11 (0.632 g, 78%) as a colorless oil.

[α]²⁰_D = +64.2 (c 0.3, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 6.86 (dd, J = 1.8, 15.8 Hz, 1H), 6.63 (d, J = 15.8 Hz, 1H), 5.87 (m, 1H), 5.22–5.14 (m, 2H), 4.91 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.56 (td, J = 1.6, 6.4 Hz, 1H), 4.42 (q, J = 7.0 Hz, 1H), 3.39 (s, 3H), 2.60–2.50 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 199.8, 132.8, 132.2, 124.7, 118.4, 98.8, 94.3, 83.1, 71.8, 65.6, 55.7, 39.6, 19.9; HRMS: m/z calcd for C₁₃H₁₈O₄Na [M + Na]⁺: 261.1097; found: 261.1106.

(4R,5S)-4-((R,E)-5-(Methoxymethoxy)octa-1,7-dien-3-yn-1-yl)-2,2,5-trimethyl-1,3 dioxolane (13)

To a solution of zinc borohydride (4.2 M solution in THF, 0.56 mL, 2.39 mmol) was added drop wise a solution of ketone 11 (0.570 g, 2.39 mmol) in dry THF (10 mL), at 0 °C and under N₂. It was stirred for 30 min. the mixture was quenched with sat. aq. NH₄Cl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc : n-hexane, 1 : 1) gave the 4 : 1 diastereomeric mixture of diol 12 (0.511 g, 89%) as colorless liquid.

To a solution of diol 12 (0.460 g, 1.91 mmol) in dry CH₂Cl₂ (5 mL), 2,2-dimethoxy propane (0.47 mL, 4.5 mmol) and PPTS (0.048 g, 0.19 mmol) were added at 0 °C. The mixture was stirred at room temperature for 3 h. Next, solid NaHCO₃ was added to the reaction mixture and was stirred for further 15 min and filtered. Removal of solvent and purification by column chromatography (EtOAc : n-hexane, 2 : 8) gave the required anti-isomer 13 (0.394 g, 73%) as a colorless liquid.

[α]²⁰_D = +55.2 (c 0.8, CHCl₃);¹H NMR (300 MHz, CDCl₃): δ 6.05 (dd, J = 7.1, 15.8 Hz, 1H), 5.90 (m, 1H), 5.79 (dt, J = 1.1, 15.8 Hz, 1H), 5.23–5.10 (m, 2H), 4.94 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.55–4.45 (m, 2H), 4.35 (quint, J = 6.4 Hz, 1H), 3.38 (s, 3H), 2.52 (t, J = 6.7 Hz, 2H), 1.49 (s, 3H), 1.36 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 139.5, 133.4, 117.8, 111.9, 108.3, 94.0, 88.3, 83.6, 78.8, 74.1, 65.6, 55.6, 40.0, 28.0, 25.4, 16.0; m/z: C₁₆H₂₄O₄Na[M + Na]⁺: 303.

(2S,3R,8R,E)-8-(Methoxymethoxy)undeca-4,10-dien-6-yne-2,3-diol (12a)

To a solution of 13 (0.3 g, 1.07 mmol) was added 3 mL of aqueous 60% acetic acid at room temperature and it was stirred for 6 h. After completion of the reaction, it was cautiously quenched by addition of solid NaHCO₃, filtered and washed with EtOAc (3 × 10 mL), dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc : n-hexane, 1 : 1) to obtain diol 12a (0.223 g, 87% yield) as a colorless liquid.

[α]²⁰_D = +88.9 (c 1.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 6.16 (dd, J = 6.2, 16.0 Hz, 1H), 5.96–5.76 (m, 2H), 5.22–5.10 (m, 2H), 4.94 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 4.49 (dt, J = 1.5, 6.4 Hz, 1H), 4.14 (m, 1H), 3.88 (m, 1H), 3.38 (s, 3H), 2.52 (t, J = 6.6 Hz, 2H), 1.14 (d, J = 6.42 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 141.1, 133.3, 117.9, 111.6, 94.0, 88.3, 83.6,75.4, 70.0, 65.6, 55.6, 40.0, 17.4; HRMS: m/z calcd for C₁₃H₂₀O₄Na [M + Na]⁺: 263.1253; found: 263.1262.

(2S,3R,8R,E)-8-(Methoxymethoxy)undeca-4,10-dien-6-yne-2,3-diyl diacetate (14)

To a solution of diol 12a (0.170 g, 0.708 mmol) in dry CH₂Cl₂ (6 mL), pyridine (0.17 mL, 2.15 mmol), Ac₂O (0.2 mL, 1.96 mmol) and DMAP (cat.) were added slowly. The mixture was then stirred for 2 h at room temperature. After completion of the reaction (tlc monitoring), the mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layer was washed with brine (5 mL), dried (Na₂SO₄), concentrated and purified by column chromatography (EtOAc : n-hexane, 2 : 8) to furnish 14 (0.206 g, 90%) as a viscous liquid.

[α]²⁰_D = +36.3 (c 1.9, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 6.05 (dd, J = 7.0, 16.0 Hz, 1H), 5.89 (m, 1H), 5.79 (d, J = 16.0 Hz, 1H), 5.37 (dd, J = 3.5, 7.0 Hz, 1H), 5.20–5.12 (m, 2H), 5.06 (dq, J = 3.6, 6.7, Hz, 1H), 4.92 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 6.86 Hz, 1H), 4.49 (t, J = 6.4 Hz, 1H), 3.38 (s, 3H), 2.55–2.48 (m, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.1, 169.6, 136.3, 133.2, 117.9, 113.9, 94.0, 89.3, 82.9, 74.4, 70.1, 65.4, 55.5, 39.9, 21.0, 20.8, 15.0; HRMS: m/z calcd for C₁₇H₂₄O₆Na [M + Na]⁺: 347.1465; found: 347.1475.

(2S,3R,8R,E)-8-Hydroxyundeca-4,10-dien-6-yne-2,3-diyl diacetate (15)

To a stirred solution of compound 14 (0.160 g, 0.493 mmol) in dry CH₂Cl₂ (20 mL) was added TiCl₄ (1 M solution in CH₂Cl₂, 0.396 mL, 0.396 mmol) at 0 °C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with solid NaHCO₃ (0.050 g) and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography (EtOAc : n-hexane, 4 : 6) to afford 15 (0.110 g, 80%) as a colorless liquid.

[α]²⁰_D = −5.8 (c 2.1, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 6.05 (dd, J = 7.0, 16.0 Hz, 1H), 5.88 (m, 1H), 5.79 (dt, J = 1.5, 16.0 Hz, 1H), 5.37 (ddd, J = 1.2, 3.6, 7.0 Hz, 1H), 5.22 (m, 1H), 5.19 (t, J = 1.0 Hz, 1H), 5.07 (dq, J = 3.5, 6.5 Hz, 1H), 4.54 (t, J = 5.4 Hz, 1H), 2.52–2.47 (m, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 1.20 (d, J = 6.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.2, 169.7, 136.4, 132.7, 119.1, 113.9, 91.4, 82.3, 74.5, 70.2, 61.8, 41.9, 21.0, 20.9, 15.1; HRMS: m/z calcd for C₁₅H₂₄O₅N [M + NH₄]⁺: 298.1649; found: 298.1658.

(2S,3R,8R,E)-8-(Acryloyloxy)undeca-4,10-dien-6-yne-2,3-diyl diacetate (2)

Acryloyl chloride (0.027 mL, 0.306 mmol) was added drop wise under N₂ to a stirred solution of 15 (0.080 g, 0.285 mmol), and Et₃N (0.047 mL, 0.46 mmol) in CH₂Cl₂ (5 mL). The mixture was stirred at 0 °C for 1 h. After completion, the mixture was poured into brine (5 mL), and extracted with CH₂Cl₂ (2 × 10 mL), dried (Na₂SO₄) and concentrated. The crude product was purified by column chromatography (EtOAc : n-hexane, 2 : 8) to afford the corresponding acrylic ester 2 (0.078 g, 82%) as a yellow color oil.

[α]²⁰_D = +0.17 (c 1.4, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 6.45 (d, J = 17.3 Hz, 1H), 6.18–6.04 (m, 2H), 5.90–5.75 (m, 3H), 5.59 (t, J = 6.4 Hz, 1H), 5.37 (dd, J = 3.5, 6.8 Hz, 1H), 5.22–5.13 (m, 2H), 5.06 (m, 1H), 2.59 (t, J = 6.5 Hz, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.2, 169.7, 164.9, 137.0, 131.9, 131.5, 127.9, 118.8, 113.5, 87.8, 82.9, 74.4, 70.1, 63.6, 39.0, 21.0, 20.8, 15.0; HRMS: m/z calcd for C₁₈H₂₂O₆Na [M + Na]⁺: 357.1308; found: 357.1320.

(2S,3R,E)-7-((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)hept-4-en-6-yne-2,3-diyl diacetate (16)

To a solution of compound 2 (0.040 g, 0.119 mmol) in CH₂Cl₂ (40 mL) was added Grubbs' second generation catalyst (0.01 g, 0.0117 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude product was purified by column chromatography (EtOAc : n-hexane, 4 : 6) to give lactone 16 (0.023 g, 65%) as a pale-yellow oil.

[α]²⁰_D = −0.36 (c 0.17, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 6.89 (m, 1H), 6.18–6.05 (m, 2H), 5.77 (d, J = 16.0 Hz, 1H), 5.40–5.28 (m, 2H), 5.07 (dq, J = 3.5, 6.4 Hz, 1H), 2.73–2.65 (m, 2H), 2.09 (s, 3H), 2.06 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.2, 169.7, 162.4, 143.8, 138.0, 121.5, 112.9, 86.3, 83.6, 74.3, 70.1, 67.3, 30.0, 21.0, 20.9, 15.1; HRMS: m/z calcd for C₁₆H₁₈O₆Na [M + Na]⁺: 329.0995; found: 329.1009.

(2S,3R,4E,6Z)-7-((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)hepta-4,6-diene-2,3-diyl diacetate {ent-hyptenolide 1}

To a solution of 16 (0.009 g, 0.0294 mmol) in EtOAc (2 mL), one drop of quinoline and Lindlar's catalyst (Pd/CaCO₃, catalytic amount) were added and the mixture was stirred at room temperature under H₂ for 20 min. After completion of the reaction, the mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAc : n-hexane, 1 : 1) to afford 1 (0.008 g, 90%) as an oil.

[α]²⁰_D = −45.8 (c 0.2, CHCl₃);¹H NMR (500 MHz, CDCl₃): δ 6.91 (ddd, J = 2.8, 5.4, 9.9 Hz, 1H), 6.51 (tdd, J = 1.0, 11.2, 15.1 Hz, 1H), 6.17 (br. t, J = 11.3 Hz, 1H), 6.08 (ddd, J = 1.2, 2.2, 9.7 Hz, 1H), 5.76 (dd, J = 7.1, 15.2 Hz, 1H), 5.64 (dd, J = 8.6, 10.8 Hz, 1H), 5.45 (ddd, J = 1.0, 3.3, 7.1 Hz, 1H), 5.35 (m, 1H), 5.07 (dq, J = 3.5, 6.5 Hz, 1H), 2.48–2.32 (m, 2H), 2.10 (s, 3H), 2.05 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.3, 169.9, 163.6, 144.5, 131.1, 130.3, 128.5, 128.1, 121.6, 74.5, 73.7, 70.4, 29.7, 21.1, 21.0, 14.9; HRMS: m/z calcd for C₁₆H₂₀O₆Na [M + Na]⁺: 331.1152; found: 331.1161.

Acknowledgements

Two of the authors (GM and GR) thank the UGC and CSIR, New Delhi respectively for financial support in the form of fellowships. Authors thank the CSIR, India for financial support as part of XII Five Year Plan program under title TREAT (BSC-0116).

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11. For all the spectral data please see the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13708f

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