Concise total synthesis of botryolide B

Abstract

An efficient total synthesis of botryolide B was achieved in 9 longest linear steps with 22% overall yield via esterification of a carboxylic acid with an alcohol fragment and a ring closing metathesis (RCM) reaction as pivotal steps to construct the macrolactone ring system. Our novel approach for the synthesis of the 2-alkene-1,5-diol fragment was achieved by a ring closing metathesis reaction followed by a reductive opening strategy, whereas the carboxylic acid fragment was accessed from commercially available (R)-(+)-α-hydroxy-γ-butyrolactone in three steps.

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Introduction

Many naturally occurring ten-membered lactones isolated from fungal metabolites, commonly known as decanolides, have attracted considerable attention from synthetic organic chemists as well as bioorganic chemists, because of their interesting structural features and various biological activities such as plant growth inhibition, antifeedant, antifungal, and antibacterial activities.¹ All decanolides shown in Fig. 1 posses some common interesting structural features; the olefinic moiety with well defined geometry as well as stereochemically pure hydroxyl appendages make them very challenging synthetic targets. In 2007, Gloer and co-workers isolated botryolide B from the cultures of a funiculus isolate of Botryotrichum sp. (NRRL 38180).² Very recently, Meshram and co-workers as well as Radha Krishna and co-workers reported the total synthesis of botryolide B employing a ring-closing metathesis (RCM) reaction to construct the macrolide with a cis double bond.³

Fig. 1 Structures of some epoxide containing decanolides.

As part of our ongoing research program exploring the ring closing metathesis⁴ reaction for macrolide synthesis, we investigated the scope of the RCM⁵ reaction for the most concise total synthesis of botryolide B.

According to our retrosynthetic analysis as shown in Scheme 1, we envisioned a convergent strategy for the target molecule 2 via the assembly of late stage intermediates 11 and 12, which could be realized by Yamaguchi esterification followed by a ring-closing metathesis (RCM) reaction. Intermediate 11 could be conveniently accessed from the inexpensive starting material propylene oxide while carboxylic acid fragment 12 could be prepared from commercially available (R)-(+)-α-hydroxy-γ-butyrolactone in three steps. Our idea for the generation of highly enantioenriched 2-alkene-1,5-diol was via a ring-closing metathesis reaction followed by reductive opening of an α,β-unsaturated δ-lactone moiety in a highly concise manner.

Scheme 1 Retrosynthetic analysis of botryolide B.

Results and discussion

The synthesis of fragment 11 began by the kinetic resolution of racemic propylene oxide under Jacobsen's reaction conditions, using the (R,R)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) catalyst to give the chiral epoxide 14 (98% ee).⁶ Treatment of epoxide 14 with vinylmagnesium bromide in the presence of CuI in diethyl ether at −78 °C to −40 °C for 6 h afforded homoallyl alcohol 17.⁷ As the product had a low boiling point, without silica gel column purification, the alcohol was acetylated with acryloyl chloride to furnish diene 18 in 78% yield over two steps (Scheme 2). Ring-closing metathesis of acryloyl ester 18 was achieved smoothly with 10 mol% of Grubbs 1^st generation catalyst under refluxing conditions in CH₂Cl₂ for 8 h to furnish 13 in 89% yield.⁸ 2-Alkene-1,5-diol 19 was prepared from α,β-unsaturated δ-lactone moiety 13 in 88% yield by a DIBAL-H reduction.⁹ Sharpless asymmetric epoxidation of 19 with (−)-DIPT, Ti(iPrO)₄ and TBHP in CH₂Cl₂ gave the epoxide 20 with the required stereoisomerism in 82% yield.¹⁰ Conversion of epoxy alcohol into 11 was accomplished in good yield by the oxidation of epoxy alcohol with BAIB/TEMPO in CH₂Cl₂ followed by one carbon homologation with PPh₃CH₃Br and NaHMDS in THF at −10 °C (75% over two steps).¹¹

Scheme 2 Reagents and conditions: (a) CH₂=CHMgBr, CuI, THF, −78 °C to −40 °C, 6 h; (b) acryloyl chloride, Et₃N, 0 °C, 6 h, 78% over two steps; (c) Grubbs' 1^st generation catalyst, CH₂Cl₂, reflux, 8 h, 89%; (d) DIBAL-H, 0 °C, 1 h, 88%; (e) (−)-DIPT, Ti(iPrO)₄, TBHP, CH₂Cl₂, −20 °C, 48 h, 82%; (f) (1) BAIB/TEMPO, CH₂Cl₂, 0 °C–rt, 1 h and (2) PPh₃CH₃Br, NaHMDS, THF, −10 °C, 2 h, 75% over two steps.

The synthesis of the carboxylic acid fragment started with commercially available (R)-(+)-α-hydroxy-γ-butyrolactone. Intermediate 15 was prepared from the known TBS-protected (R)-(+)-α-hydroxy-γ-butyrolactone 21 (ref. 12) in 80% yield by a convenient one-pot procedure, involving a DIBAL-H reduction followed by one carbon homologation (Scheme 3).^4e The primary alcohol 15 was converted to acid 12 (ref. 13) by BAIB/TEMPO in CH₃CN : H₂O (9 : 1) to afford acid 12 in 91% yield.¹⁴

Scheme 3 (a) TBSCl, imidazole, DMF, 0 °C, 3 h, 99%; (b) (i) DIBAL-H, −78 °C and (ii) PPh₃CH₃Br, n-BuLi, THF, −78 °C to −10 °C, 2 h, 80%; (c) BAIB/TEMPO, CH₃CN : H₂O (9 : 1), 91%, 3 h.

Having synthesized 11 and 12, we proceeded further with their coupling and the ring closing metathesis reaction. Coupling of the two fragments 11 and 12 was achieved under Yamaguchi conditions¹⁵ using 2,4,6-trichlorobenzoyl chloride to furnish diene ester 10 in 84% yield. This set the stage for the crucial ring closing metathesis (path A), which was successfully achieved with Grubbs' 2^nd generation catalyst (0.001 M dilution in degassed CH₂Cl₂ under reflux conditions afforded the lactone 26 with a Z-configured olefin as the exclusive product) (Scheme 4) (74% yield). Deprotection of TBS-ether with TBAF in CH₂Cl₂ led to the formation of the target botryolide B (2) in 92% yield. Similarly, through path B, initial deprotection of the silyl ether group using TBAF in THF followed by ring-closing metathesis under the same reaction conditions also afforded botryolide B in 78% yield (exclusively Z-isomer). The constitution and configuration of the assigned structure was unambiguous since the spectroscopic and analytical data were in excellent accord with the proposed structure and perfectly matched those reported in the literature.² In addition, density functional theory calculations have been done to compare the stability of the E- and Z-isomers of the botryolide B. The structures of the isomers were optimized without any constraints by employing the B3LYP/6-31G* basis set. They were characterised as minima on the potential energy surface by the frequency calculations. All the calculations were performed using the G09 programme package.¹⁶ The results indicate that the Z-isomer is more stable than the E-isomer as observed experimentally (Fig. 2).

Scheme 4 (a) 2,4,6-Trichlorobenzoyl chloride, Et₃N, DMAP, THF, toluene, 0 °C, 4 h, 84%; (b) Grubbs' 2^nd generation catalyst, CH₂Cl₂, reflux, 8 h, (path A = 74%, path B = 78%); (c) TBAF, THF, 0 °C–rt, 2 h, (path A = 92%, path B = 93%).

Fig. 2 Optimized geometries and relative energies (kcal mol⁻¹) of the E- and Z-isomers of the botryolide B at B3LYP/6-31G* level.

Conclusions

In summary, an efficient total synthesis of botryolide B was achieved in 9 longest linear steps with 22% overall yield following Yamaguchi esterification of carboxylic acid and alcohol fragments followed by a ring closing metathesis reaction as key steps to construct the ten-membered macrolactone. The 2-alkene-1,5-diol fragment was achieved by ring-closing metathesis followed by reductive opening strategy, whereas the carboxylic acid fragment was accessed from commercially available (R)-(+)-α-hydroxy-γ-butyrolactone in a concise manner.

Experimental section

General remarks

Air- and/or moisture-sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in oven- or flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene and diethyl ether from Na and benzophenone; CH₂Cl₂, quinoline and Et₃N from CaH₂; MeOH and EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out on silica gel (60–120 mesh). Infrared spectra were recorded in CHCl₃/neat (as mentioned) and are reported in wavenumbers (cm⁻¹). ¹H and ¹³C NMR chemical shifts are reported in ppm downfield from tetramethylsilane (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.

(R)-Pent-4-en-2-yl acrylate (18)

A round-bottomed flask was charged with copper(I) iodide (654 mg, 3.4 mmol) and anhydrous THF (20 mL) was added to it. The resulting suspension was cooled to −78 °C with vigorous stirring and then vinylmagnesium bromide (1 M in THF, 68.1 mL, 68.1 mmol) was injected into the mixture. A solution of propylene oxide 14 (2.0 g, 34.07 mmol) in THF (10 mL) was added slowly to the reaction and the mixture was stirred for 6 h at −40 °C. After completion of the reaction (monitored by TLC), it was quenched with saturated aqueous NH₄Cl solution (20 mL). The reaction mixture was diluted with ethyl acetate (40 mL) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (75 mL), dried (Na₂SO₄) and concentrated under reduced pressure to afford the crude homoallylic alcohol 17 (2.93 g) which was used for the next reaction without further purification.

To a stirred solution of the allylic alcohol 17 (2.93 g, 34.06 mmol) in CH₂Cl₂ (30 mL) at 0 °C, was added NEt₃ (14.7 mL, 102.1 mmol) followed by acryloyl chloride (5.5 mL, 8.13 mmol). The reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction (monitored by TLC), it was quenched with saturated aqueous NH₄Cl solution (30 mL). The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layer was washed with saturated aqueous brine (100 mL), dried (MgSO₄), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate : hexane = 1 : 4) to obtain diene 18 (3.72 g, 78%) as a colorless oil. [α]²⁵_D −189.3 (c 1.2, CHCl₃); IR (neat): 2978, 2929, 1725, 1695, 1390, 1252, 1109, 1055 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 6.38 (dd, J = 1.5, 17.3 Hz, 1H), 6.12 (dd, J = 10.3, 17.3 Hz, 1H), 5.84–5.7 (m, 2H), 5.12–5.01 (m, 3H), 2.42–2.3 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 165.4, 133.2, 130.2, 128.6, 117.5, 69.1, 39.8, 19.1; MS (ESI): m/z = 217 [M + H]⁺.

(R)-6-Methyl-5,6-dihydro-2H-pyran-2-one (13)

To a solution of diene 18 (1.5 g, 10.56 mmol) in degassed CH₂Cl₂ (1000 mL), was added Grubbs' first generation catalyst (863 mg, 1.05 mmol) at room temperature. The reaction mixture was stirred for 8 h at the same temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure. The resulting residue was then redissolved in a 10 : 1 hexane–ethyl acetate solvent mixture and filtered through a short pad of silica gel. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate : hexane = 2 : 3) to afford the lactone 13 (1.06 g, 89%) as a pale yellow liquid. [α]²⁵_D −196.2 (c 1.7, EtOH); IR (neat): 2924, 2854, 1725, 1456, 1271, 1195 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 6.91 (dt, J = 3.0, 9.8 Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 4.66 (m, 1H), 2.39–2.30 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 164.4, 145.1, 120.8, 74.2, 30.7, 20.4; HRMS (ESI) m/z calcd for C₆H₉O₂: [M + H]⁺ 113.0597, found 113.0599.

(R,Z)-Hex-2-ene-1,5-diol (19)

To a stirred solution of the lactone 13 (1.0 g, 8.92 mmol) in anhydrous CH₂Cl₂ (30 mL) at 0 °C under nitrogen, was added DIBAL-H (15.9 mL, 1.4 M in CH₂Cl₂, 22.3 mmol) and the mixture was stirred for 2 h. It was warmed to room temperature and stirred for an additional 30 min. The reaction was quenched with 2 N HCl (25 mL) at 0 °C and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layer was washed with water (60 mL), brine (60 mL), dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate : hexane = 3 : 2) to furnish 19 (0.9 g, 88%) as a colorless liquid. [α]²⁵_D −22.1 (c 2.3, CHCl₃); IR (KBr) ν_max: 3441, 2930, 2892, 2857, 1737, 1253, 1100, 1039 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.88 (dt, J = 7.3, 10.8 Hz, 1H), 5.69 (m, 1H), 4.21 (dd, J = 7.3, 19.3 Hz, 1H), 4.12 (dd, J = 6.8, 19.3 Hz, 1H), 3.87 (m, 1H), 2.21–2.39 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 131.4, 129.3, 66.8, 57.7, 31.9, 23.1; MS (ESI): m/z = 117 [M + H]⁺.

(R)-1-((2S,3R)-3-(Hydroxymethyl)oxiran-2-yl)propan-2-ol (20)

To a stirred solution of (−)-DIPT (0.32 mL, 1.55 mmol) in CH₂Cl₂ (40 mL) at −20 °C containing 4 Å molecular sieves (1.0 g), were added sequentially Ti(OiPr)₄ (0.61 mL, 2.06 mmol) and t-butyl hydroperoxide (5.16 mL, 33.6 mmol) and stirred for 20 min. A solution of 19 (600 mg, 5.17 mmol) in CH₂Cl₂ (10 mL) was added and stirred for 48 h at −20 °C. After completion of the reaction (monitored by TLC), it was quenched with 20% NaOH solution (25 mL). The reaction mixture was stirred for 3 h and the organic layer separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate : hexane = 3 : 2) to furnish 20 (559 mg, 82%) as a colorless liquid. [α]²⁵_D −32.2 (c 2.2, CHCl₃); IR (neat): 3423, 2923, 2858, 1611, 1513, 1363, 1247, 1032 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 4.18 (m, 1H), 3.86 (m, 1H), 3.52 (m, 1H), 2.38–2.13 (m, 2H), 1.42–1.52 (m, 2H), 1.23 (d, J = 5.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 68.0, 62.7, 57.7, 42.0, 38.8, 21.9; MS (ESI): m/z = 155.2 [M + Na]⁺.

(R)-1-((2S,3R)-3-Vinyloxiran-2-yl)propan-2-ol (11)

To a solution of 20 (400 mg, 3.03 mmol) in CH₂Cl₂ (20 mL) were added TEMPO (90 mg, 0.6 mmol) and BAIB (1.17 g, 3.6 mmol). After stirring at 0 °C for 2 h, the reaction mixture was diluted with CH₂Cl₂ (15 mL) and then washed with saturated aqueous Na₂S₂O₃ (2 × 20 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was passed through a small bed of silica gel (ethyl acetate : hexane = 1 : 4) to afford the epoxy aldehyde (400 mg) as a colorless liquid, which was used as such without further purification.

To a solution of (methylenetriphenyl)phosphonium bromide (6.59 g, 18.4 mmol) in anhydrous THF (70 mL), NaHMDS (15.3 mL, 1 M, 15.3 mmol) was added at −10 °C and the mixture was stirred for 1 h. Aldehyde (400 mg, 3.07 mmol) in anhydrous THF (4 mL) was added at −10 °C and the reaction mixture was stirred for an additional 2 h. After completion of the reaction (monitored by TLC), it was quenched with saturated NH₄Cl (30 mL) solution. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined extracts were washed with brine (70 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1 : 3) to afford 11 (290.9 g, 75%) as a colorless liquid. [α]²⁵_D −9.1 (c 1.0, CHCl₃); IR (neat): 2950, 2923, 1733, 1461, 1261, 1111, 772 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.72 (m, 1H), 5.47 (d, J = 17.5 Hz, 1H), 5.36 (d, J = 10.9 Hz, 1H), 4.07 (m, 1H), 3.46 (dd, J = 4.4, 10.9 Hz, 1H), 3.28 (dt, J = 4.4, 7.6 Hz, 1H), 1.76–1.61 (m, 2H), 1.27 (d, J = 6.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 132.3, 120.5, 65.9, 56.9, 55.9, 36.7, 23.7; HRMS (ESI) m/z calcd for C₇H₁₂O₂Na: [M + Na]⁺ 151.0729, found 151.0726.

(R)-3-(tert-Butyldimethylsilyloxy)dihydrofuran-2(3H)-one (21)

To a stirred solution of 16 (0.5 g, 4.9 mmol) in DMF (30 mL) was added imidazole (496 mg, 7.3 mmol) followed by TBSCl (1.1 g, 7.3 mmol) at 0 °C. The resulting mixture was then stirred for 3 h at room temperature. After completion of the reaction, the mixture was quenched by the addition of water (15 mL), diluted with Et₂O (3 × 20 mL), washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification of the crude compound by column chromatography afforded TBS ether 21 (1.04 g, 99%) as a colorless oil. [α]²⁵_D +35.4 (c 1.8, CHCl₃); IR (neat): 2954, 2932, 1721, 1656, 1612, 1513, 1465 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 4.45–4.35 (m, 2H), 4.21 (t, J = 9.0 Hz, 1H), 2.48 (m, 1H), 2.25 (m, 1H), 0.92 (s, 9H), 0.18 (s, 3H), 0.15 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): 175.9, 68.2, 64.7, 32.3, 25.6, 18.2, −4.7, −5.3; MS (ESI): m/z = 217.6 [M + H]⁺.

(R)-3-(tert-Butyldimethylsilyloxy)pent-4-en-1-ol (15)

To a solution of 21 (0.6 g, 2.77 mmol) in anhydrous CH₂Cl₂ (20 mL) was added a 1.4 M solution of DIBAL-H in toluene (1.97 mL, 2.7 mmol) at −78 °C and the mixture was stirred for 30 min at −78 °C. The reaction was quenched with methanol (1.0 mL) and saturated aqueous sodium potassium tartrate solution (10 mL). The mixture was stirred at room temperature for 2 h to obtain two clear layers. The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (2 × 25 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude lactol (0.6 g) which was used as such for the next reaction without further purification.

To a suspension of methyltriphenylphosphonium bromide (3.94 g, 11 mmol) in anhydrous THF (40 mL) maintained at 0 °C under an argon atmosphere was added a 1.6 M solution of n-BuLi in hexane (5.15 mL, 8.25 mmol), and the mixture was stirred for 30 min at 0 °C. The mixture was then cooled to −78 °C, and a solution of lactol (0.6 g, 2.75 mmol) in THF (6 mL) was added. The mixture was stirred for 2 h at room temperature, and the reaction was quenched with a saturated solution of NH₄Cl (25 mL). The mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were washed with saturated brine (75 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate : hexane = 1 : 4) to obtain 15 (480 mg, 80%) as a colorless liquid. [α]²⁵_D +4.2 (c 1.0, CHCl₃); IR (neat): 2954, 2857, 1613, 1513, 1249, 1091 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.77 (dt, J = 10.3, 17.3 Hz, 1H), 5.05 (d, J = 10.3 Hz, 2H), 3.9 (dt, J = 10.3, 6.4 Hz, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 1.82–1.75 (m, 2H), 0.92 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): 140.5, 114.3, 73.0, 59.9, 39.0, 25.7, 18.0, −4.4, −5.1; MS (ESI): m/z = 217.5 [M + H]⁺.

(R)-3-(tert-Butyldimethylsilyloxy)pent-4-enoic acid (12)

To a solution of alcohol 15 (400 mg, 1.85 mmol) in CH₃CN : H₂O (9 : 1, 4.0 mL) were added TEMPO (55 mg, 0.37 mmol) and BAIB (1.19 g, 3.7 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with CH₂Cl₂ (5 mL) and then washed with saturated aqueous Na₂S₂O₃ (10 mL). The organic layer was dried over Na₂SO₄ and filtered, and the filtrate was concentrated under reduced pressure to give the crude carboxylic acid, which was further purified by flash column chromatography (ethyl acetate : hexane = 1 : 4) to furnish acid 12 (387 mg, 91%) as a colorless oil. [α]²⁵_D −7.1 (c 1.8, CH₂Cl₂); IR (neat): 2956, 2858, 1785, 1714, 1219, 927, 835, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.85 (m, 1H), 5.26 (d, J = 16.9 Hz, 1H), 5.12 (d, J = 9.9 Hz, 1H), 4.58 (m, 1H), 2.55 (d, J = 9.9 Hz, 2H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 176.0, 139.5, 115.2, 77.4, 70.5, 4.1, 25.7, −4.4, −5.2; HRMS (ESI) m/z calcd for C₁₁H₂₂O₃NaSi: [M + Na]⁺ 253.1230, found 253.1227.

(R)-((R)-1-((2S,3R)-3-Vinyloxiran-2-yl)propan-2-yl)-3-(tert-butyldimethylsilyloxy)pent-4-enoate (10)

To a stirred solution of acid 12 (287 mg, 1.25 mmol) in anhydrous THF (20 mL) were added 2,4,6-trichlorobenzoyl chloride (0.25 mL, 1.56 mmol) and Et₃N (0.27 mL, 1.87 mmol) and the contents were stirred at 0 °C temperature. After 2 h, DMAP (153 mg, 1.25 mmol) and a solution of alcohol 11 (80 mg, 0.625 mmol) in THF (10 mL) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction was quenched with water (15 mL) and diluted with ethyl acetate (30 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated NaHCO₃ (50 mL) and brine (50 mL), dried over (Na₂SO₄) and evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 10 (179 mg, 84%) as a colorless liquid. [α]²⁵_D −12.5 (c 1.4, CHCl₃); IR (neat): 2928, 2856, 1737, 1219, 1082, 927, 772 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.90–5.63 (m, 2H), 5.51–5.33 (m, 2H), 5.22 (dt, J = 1.5, 17.3 Hz, 1H), 5.13–5.03 (m, 2H), 4.58 (m, 1H), 3.41 (dd, J = 4.5, 6.7 Hz, 1H), 3.15 (dt, J = 4.5, 10.5 Hz, 1H), 2.52 (dd, J = 7.6, 14.3 Hz, 1H), 2.39 (dd, J = 5.2, 14.3 Hz, 1H), 1.89–1.70 (m, 2H), 1.29 (d, J = 6.0 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 170.5, 140.2, 132.2, 120.7, 114.7, 70.8, 68.9, 56.8, 55.5, 43.7, 34.3, 29.7, 25.7, 20.3, −4.4, −5.1; HRMS (ESI) m/z calcd for C₁₈H₃₂O₄NaSi: [M + Na]⁺ 363.1962, found 363.1958.

(1S,3R,7R,10R,Z)-7-(tert-Butyldimethylsilyloxy)-3-methyl-4,11-dioxabicyclo[8.1.0]undec-8-en-5-one (26)

Grubbs’ second generation catalyst (12.4 mg, ca. 0.01 mmol) was dissolved in anhydrous, deoxygenated CH₂Cl₂ (50 mL) under an argon atmosphere. After the solution was heated at reflux, diene 10 (50 mg, 0.14 mmol) in dry, deoxygenated CH₂Cl₂ (50 mL) was added slowly (30 min) to the reaction mixture. The reaction mixture was then stirred at room temperature for an additional 4 h. After completion of the reaction, the solvent was evaporated under reduced pressure. Purification of the crude residue by silica gel column chromatography (ethyl acetate : hexane = 1 : 4) afforded 26 (33 mg, 74%) as a colorless viscous liquid. [α]²⁵_D −15.1 (c 1.0, CHCl₃); IR (neat): 2954, 2928, 2856, 1729, 1464, 1285, 1124, 1072 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.69 (ddd, J = 1.5, 7.5, 11.3 Hz, 1H), 5.37 (ddd, J = 1.5, 5.2, 11.3 Hz, 1H), 5.305 (m, 1H), 4.78 (m, 1H), 3.45 (m, 1H), 3.03 (dt, J = 3.7, 11.3 Hz, 1H), 2.56 (dd, J = 3.7, 10.5 Hz, 1H), 2.43 (t, J = 10.5 Hz, 1H), 2.19 (ddd, J = 1.5, 3.0, 11.3 Hz, 1H), 2.15 (m, 1H), 1.30 (d, J = 6.0 Hz, 3H), 1.26 (s, 1H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 170.3, 137.4, 126.2, 67.6, 68.4, 57.2, 53.5, 44.4, 38.1, 28.7, 20.5, −4.9, −4.7; HRMS (ESI) m/z calcd for C₁₆H₂₉O₄Si: [M + H]⁺ 313.1829, found 313.1827.

(R)-((R)-1-((2S,3R)-3-Vinyloxiran-2-yl)propan-2-yl)-3-hydroxypent-4-enoate (27)

Same procedure followed as mentioned for the synthesis of compound 2 given below. [α]²⁵_D −9.9 (c 1.5, CHCl₃); IR (neat): 3389, 2956, 2926, 2854, 1714, 1633, 1378, 1276, 1045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.89 (m, 1H), 5.71 (ddd, J = 3.9, 5.9, 16.9 Hz, 1H), 5.47 (d, J = 16.9 Hz, 1H), 5.42–5.29 (m, 2H), 5.17 (m, 1H), 4.55 (m, 1H), 4.22 (m, 1H), 3.43 (dd, J = 3.4, 5.9 Hz, 1H), 3.18 (dt, J = 5.9, 10.9 Hz, 1H), 2.60–2.47 (m, 2H), 1.88–1.76 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): 171.6, 138.1, 132.10, 120.8, 115.4, 69.3, 68.9, 56.8, 55.2, 41.4, 34.0, 20.1; HRMS (ESI) m/z calcd for C₁₂H₁₈O₄Na: [M + Na]⁺ 249.1097, found 249.1094.

(1S,3R,7R,10R,Z)-7-Hydroxy-3-methyl-4,11-dioxabicyclo-[8.1.0]undec-8-en-5-one (2)

To a solution of 26 (20 mg, 0.06 mmol) in THF (5 mL) at 0 °C, TBAF (0.12 mL, 0.12 mmol, 1 M in THF) was added and the reaction mixture was stirred for 30 min at room temperature. After completion of the reaction (monitored by TLC), it was quenched with a saturated solution of NH₄Cl (5 mL) and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate : hexane = 2 : 3) to afford 2 (12 mg, 92%) as a colorless liquid. [α]²⁵_D −139 (c 1.2, CHCl₃); IR (neat): 3458, 2950, 2924, 2854, 1729, 1219 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 5.72 (ddd, J = 2.0, 7.9, 11.9 Hz, 1H), 5.47 (ddd, J = 1.0, 5.9, 10.9 Hz, 1H), 5.31 (ddq, J = 1.0, 5.9, 11.9 Hz, 1H), 4.88 (m, 1H), 3.48 (m, 1H), 3.03 (dt, J = 3.9, 10.9 Hz, 1H), 2.68 (dd, J = 3.9, 10.9 Hz, 1H), 2.45 (t, J = 10.9 Hz, 1H), 2.21 (dd, J = 2.0, 13.9 Hz, 1H), 1.32 (d, J = 6.0 Hz, 3H), 1.26 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): 170.0, 135.7, 127.9, 67.8, 67.7, 57.1, 53.4, 43.5, 38.0, 20.4; HRMS (ESI) m/z calcd for C₁₀H₁₅O₄: [M + H]⁺ 199.0964, found 199.0965.

Acknowledgements

D.K.M. thanks CSIR, New Delhi, for financial support as part of XII Five Year Plan Programme under title ORIGIN (CSC-0108). The authors thank Dr G. N. Sastry for helpful discussions on DFT studies. G.U. thanks the University Grants Commission (UGC), New Delhi, India, and M.M.R. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for financial assistance in the form of a research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Scanned copies of ¹H and ¹³C NMR data. See DOI: 10.1039/c3ra44478c

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