Asymmetric Total Synthesis of Lobophopyranone A and B

Dedicated to Prof. H. Ila on her 80^th Birthday celebrations, JNCASR, Bangalore, India

Abstract

The first asymmetric total synthesis and structural confirmation of lobophopyranone A and B have been accomplished from commercially available starting materials. Reagent-controlled Keck–Maruoka allylation, Grignard reaction, chelation-controlled Sakurai allylation, and acid-mediated one-step TBS ether deprotection followed by cyclization are the crucial stages in this synthesis that create the 2,6-disubstituted dihydropyranone component.

Six-membered oxygen heterocyclic natural products with intricate and interesting structures that have beneficial biological effects are abundant in nature.[1] Among them, the pyranone ring system is a crucial structural motif in organic synthesis since it serves as a key link in the production of complex natural compounds with intriguing biological properties and therapeutic value.[2] These natural products were isolated from various microorganisms and plants species, and their phytochemical studies led to the isolation of bioactive secondary metabolites such as prenylated chromans, lignans, amides, flavonoids, phenolic derivatives,[3`] [d] [e] including the cell cycle-arresting pyridone alkaloids,[3a] polyketide tenuipyrone,[3b] and powerful immunosuppressant myriocin. Most of these substances[3f] exhibit a variety of biological activities, including antibacterial,[4a] [k] anti-inflammatory,[4b] antioxidant, antiparasitic, anti-protozoal,[4c] anti-leishmanial,[4h] anticoagulant properties,[4e] HIV reverse transcriptase inhibition,[4f] sub-micromolar antifungal activity, actin filament aggregation, and cytotoxic disruption[4d] to many cancer cell lines.[4g] [i] [j] In terms of structure, it has been discovered that the pyranone moiety in natural products can undergo a number of substitutions at the C-2, C-3, C-5, and C-6 positions of the ring, including polyacetoxy, polyhydroxy, a combination of the two, or even a simple alkane attached to an aromatic or heterocyclic moiety.

From specimens of algae (Lobophora variegata) procured from the Canary Islands, Souto et al. in 2015 identified nonadecaketides, lobophopyranones A (1), and B (2) (Figure [1]).[4a] Staphylococcus aureus was the target of their antibacterial action (MIC₉₀ = –8.5 ± 2 at 0.5 μg/mL).[4a] Both lobophopyranones A and B are composed structurally of 2,3-dihydropyranone, which has been substituted twice by a vinylic methyl group, a lengthy aliphatic chain, and an extra hydroxy group in lobophopyranone B. Interesting biological activity of these types of molecules in combination with research interest on the synthesis of pyran and pyranone ring containing complex molecules[5] in optically pure form, attracted our attention towards their total syntheses.

According to the retrosynthesis analysis (Scheme [1]), we hypothesized that the lobophopyranones A (1) and B (2) might be produced from the diketones 9 and 12, respectively, using a one-pot silyl deprotection method mediated by trifluoroacetic acid and a cyclization strategy. Through the Grignard process and Keck–Maruoka allylation reaction sequences, the diketone compound 9 could be obtained from 1-tetradecanol (11, myristyl alcohol). Similar to how the precursor 12 was created from 1-dodecanol (14, lauryl alcohol), the key steps in this process are the Grignard reaction, Sakurai allylation, and Keck–Maruoka allylation.

The commercially available 1-tetradecanol (11) was used as the first step in the stepwise production of the lobophopyranone A (1), as described in Scheme [2]. The IBX[6] oxidation of alcohol 11 to aldehyde was followed by the Keck–Maruoka allylation[7`] [b] [c] [d] [e] with allyltributyltin in the presence of Ti( ⁱ PrO)₄, (R)-BINOL and Ag₂O in CH₂Cl₂ at –20 °C, which furnished the homoallyl alcohol 15 [7f] in 77% yield over two steps (er = 93:7 as per the NMR data of its Mosher’s ester derivatives). The newly generated hydroxyl group in 15 was protected as its silyl ether with TBSCl[8] in the presence of imidazole in CH₂Cl₂ to obtain compound 16 in 92% yield.

Using Jin’s one-step dihydroxylation-oxidation protocol,[9] the terminal olefin in 16 was oxidatively cleaved, producing the intermediate aldehyde in 83% yield. The resulting aldehyde was immediately treated with 2-methylallyl Grignard (generated in situ by treatment of 3-bromo-2-methylpropene with magnesium) at –40 °C to afford the alcohol 10 as a diastereomeric mixture (7:3 ratio by ¹H NMR data) in 78% yield. Using Dess–Martin periodinane[10] in CH₂Cl_2­, the secondary hydroxyl group in 10 was then oxidized to the corresponding ketone to produce 17 in 92% yield. Compound 17 was then treated with catalytic OsO₄ in the presence of NMO as co-oxidant (Upjohn dihydroxylation[11]) to furnish a diastereomeric mixture of the intermediate 1,2-diol. The oxidative cleavage of the resulting 1,2-diol was carried out by silica gel-supported sodium metaperiodate[12] to furnish diketone compound 9 (the ratio of keto/enol forms is 93:7 by ¹H NMR analysis) in 72% yield over two steps.

With the crucial diketone 9 in hand, our focus shifted to the demonstration of one-pot silyl ether deprotection followed by cyclization method[13] with trifluoroacetic acid in CH₂Cl₂ at 0 °C, which led to the formation of the target lobophopyranone A (1) in 92% yield. Analysis of ¹H and ¹³C NMR spectra revealed that the chemical shift and coupling constants of the compound 1 completely match those reported for natural sample[4a] (Table [1]). It was also discovered that the optical rotation of the synthetic compound was [α]_D ²⁵ –110.0 (c 0.8, CHCl₃), which is in good agreement with the previously reported value of [α]_D ²⁵ –116.0 (c 1.14, CHCl₃) for the natural compound.[4a]

After successful achievement of the total synthesis of lobophopyranone A, our next focus was to further assess the synthetic efficacy of this specific strategy towards the total synthesis of lobophopyranone B (2) by using the identical reaction sequences as shown in Scheme [2].

Our initial goal, in accordance with the retrosynthesis plan outlined above, was to get alcohol 13 from the readily accessible lauryl alcohol (14), as indicated in Scheme [3]. The oxidation[6] of alcohol 14 and Keck–Maruoka allylation[7`] [b] [c] [d] [e] of the corresponding aldehyde afforded homoallylic alcohol 18 [7f] in 79% yield for the two steps (er = 95:5 as per the ¹H NMR data of its Mosher’s ester derivatives). Protection of the hydroxy group present in 18 as its benzyl ether under basic conditions (BnBr, NaH and cat. TBAI) in THF afforded compound 19 [14] in 88% yield. The terminal olefin in compound 19 was oxidatively cleaved to aldehyde under Jin’s protocol[9] followed by Keck allylation conditions[15] using MgBr₂­·OEt₂ and allyltributyltin at –5 °C to provide homoallylic alcohol 20 in 70% yield (two steps) as a single diastereomer (judged by NMR analysis).

Then, using the Mitsunobu protocol,[16] the configuration of the hydroxyl group in 20 was inverted by using 4-nitrobenzoic acid, diisopropyl azodicarboxylate (DIAD), and triphenylphosphine to produce benzoate ester, which, when hydrolyzed with K₂CO₃ in MeOH, produced the homoallylic alcohol 21 in two steps in a 66% yield along with the desired configuration. Then, using TBSCl[8] and imidazole in CH₂Cl₂, alcohol 21 was quantitatively transformed into its equivalent silyl ether 22 in 94% yield. Next, Jin’s one-step dihydroxylation–oxidation[9] of 22 and subsequent addition of the 2-methylallyl Grignard reagent (generated in situ by treatment of 3-bromo-2-methylpropene with magnesium) to the aldehyde at –40 °C afforded the secondary alcohol 13 as a diastereomeric mixture (3:2 ratio by ¹H NMR data) in 67% yield over two steps (Scheme [3]).

After obtaining sufficient amounts of alcohol 13, we focused on oxidizing the newly created secondary hydroxyl group with DMP[10] in CH₂Cl₂ to get the keto compound 23 in 88% yield (Scheme [4]). Then, using a two-step reaction sequence, diketone 12 (the ratio of keto/enol forms is 9:1 by ¹H NMR analysis) was obtained in 80% yield over two steps; dihydroxylation[11] of the olefin in 23 with OsO₄ and NMO, followed by oxidative cleavage of the resultant diol with silica gel supported NaIO₄.[12] Having the key intermediate 12 in hand, our next concern was the construction of γ-pyranone using trifluoroacetic acid mediated one-pot sillyl ether deprotection followed by cyclization protocol,[13] which produced compound 24 in 89% yield. Finally, benzyl ether was unmasked using Li/naphthalene[17] in THF at –20 °C, producing lobophopyranone B (2)[4a] in 77% yield, completing the overall synthesis of the target compound.

Comparison of the spectral data (¹H NMR and ¹³C NMR) of the synthetic material 2 with the natural product revealed that they are identical to each other (Table [2]). Optical rotation value {[α]_D ²⁵ +35.3 (c 0.50, CHCl₃)} of the synthetic compound was good agreement with the reported value {([α]_D ²⁵ +33.0 (c 0.20, CHCl₃)}.[4a]

In summary, using the longest linear sequence of nine steps for lobophopyranone A and fifteen steps for B, respectively, starting from commercially available inexpensive starting materials, we were able to complete the first total synthesis of these compounds. The key reactions include 2,6-disubstituted dihydropyranone subunit construction through acid-mediated one-step deprotection of the TBS ether followed by cyclization, chelation-controlled Sakurai allylation, Grignard reaction, and reagent-controlled Keck–Maruoka allylation.

All experiments were carried out in flame-dried glassware with anhydrous solvents under an inert atmosphere. Anhydrous solvents were freshly distilled prior to use: THF from Na and benzophenone, CH₂Cl₂, CH₃CN, 1,4-dioxane from CaH₂, and MeOH from Mg cake under an argon atmosphere. Commercial grade reagents were used as received without further purification. Column chromatography separations were performed on a silica gel (60–120 mesh) to furnish the corresponding products. TLC was run on plates (0.25 mm) with precoated silica gel GF_254, for monitoring the reactions. The TLC plates were visualized with UV light and p-anisaldehyde stain. HPLC was carried out by Shimadzu HPLC systems consisting of the following mobile phase, CH₃CN, H₂O, i-PrOH, and hexane; flow rate, 1 mL/min. Melting points were measured using Stuart SMP3 apparatus. Specific rotations [α]_D were recorded with Anton Paar MCP 200 digital polarimeter at 20 °C and reported in 10^–1 degcm²g^–1. IR spectra were recorded in CHCl₃ with Bruker Alpha spectrophotometer and reported in wave number (cm^–1). HRMS spectra were recorded on Waters Q-TOF mass spectrometer. ¹H NMR spectral data were acquired on 300, 400, 500 MHz spectrometers and ¹³C NMR data were acquired on spectrometers operating at 75, 100, 125 MHz with CDCl₃ as internal reference. Chemical shifts were reported in parts per million downfield from TMS (δ) as the internal standard relative to the CDCl₃, 7.26 ppm for ¹H NMR and 77.00 ppm for ¹³C NMR, respectively and coupling constants (J) were reported in hertz (Hz). The following abbreviations are used to designate signal multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.

(S)-Heptadec-1-en-4-ol (15)

To a stirred solution of alcohol 11 (1.0 g, 4.67 mmol, 1.0 equiv.) in EtOAc, was added IBX (1.96 g, 7.0 mmol, 1.5 equiv.) at rt. The resulting mixture was refluxed for 12 h. After completion of the reaction (monitored by TLC), it was cooled to rt and filtered through a bed of Celite and washed with EtOAc. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (R_f = 0.60; EtOAc/hexane 1:19) to obtain tetradecanal as a white solid (893 mg, 90%), which was used immediately without further characterization.

To a stirred solution of TiCl₄ (43 μL, 0.40 mmol, 10 mol%) in CH₂Cl₂ (5 mL) was added Ti( ⁱ PrO)₄ (0.36 mL, 1.20 mmol, 30 mol%) at 0 °C under argon. The reaction mixture was brought to rt. After 3 h, Ag₂O (185 mg, 0.80 mmol, 20 mol%) was added and the mixture was stirred in the dark for 6 h. The mixture was diluted with CH₂Cl₂ (5 mL) and (R)-binaphthol (230 mg, 0.80 mmol, 20 mol%) was added at rt to furnish chiral bis(R)-Ti^IV oxide. The in situ generated bis(R)-Ti^IV oxide in CH₂Cl_2­ was cooled to –15 °C and treated sequentially with tetradecanal (850 mg, 4.0 mmol, 1.0 equiv.) dissolved in CH₂Cl₂ (10 mL) and allyltributyltin (1.85 mL, 6.0 mmol, 1.5 equiv.). The reaction mixture was warmed to 0 °C and stirred for 24 h. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NaHCO₃ (20 mL) and extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were dried (anhyd Na₂SO₄), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 1:9) to afford homoallylic alcohol 15 as a pale yellow liquid; yield: 865 mg (85%); [α]_D ²⁰ –5.0 (c 1.06, CHCl₃).

IR (CHCl₃): 3371, 2923, 2855, 1641, 1460, 1215, 916, 752 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 5.88–5.79 (m, 1 H), 5.16–5.13 (m, 1 H), 5.12–5.10 (m, 1 H), 3.67–3.61 (m, 1 H), 2.34–2.27 (m, 1 H), 2.17–2.11 (m, 1 H), 1.75–1.64 (br s, 1 H), 1.47–1.43 (m, 2 H), 1.34–1.23 (m, 22 H), 0.88 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.0, 117.8, 70.7, 41.9, 36.8, 31.9, 29.7, 29.6, 29.4, 25.7, 22.7, 14.1.

ESI-MS: m/z for C₁₇H₃₆O₂ [M + H₂O]⁺: 272.

(S)-Heptadec-1-en-4-yl (R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (15a)

To a stirred solution of (R)-(–)-(α)-methoxy-α-(trifluoromethyl)phenylacetic acid (R-MTPA; 94 mg, 0.4 mmol, 2.0 equiv.) in anhyd toluene (2 mL) were added Et₃N (55 μL, 0.4 mmol, 2.0 equiv.) and 2,4,6-trichlorobenzoyl chloride (65 μL, 0.4 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was allowed to stir at rt for 45 min. Then a solution of alcohol 15 (50 mg, 0.2 mmol, 1.0 equiv.) and DMAP (49 mg, 0.4 mmol, 2.0 equiv.) in anhyd toluene (1 mL) was added to the reaction mixture at 0 °C. The mixture was brought to rt and allowed to stir for 8 h. After completion of the reaction (monitored by TLC), it was quenched with H₂O (2 mL) and extracted with EtOAc (3 × 4 mL). The combined organic layers were dried (anhyd Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 5:95) to afford (R)-MTPA ester 15a as a colorless liquid; yield: 75 mg (82%).

¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.52 (m, 2 H), 7.39 (dd, J = 5.0, 2.0 Hz, 3 H), 5.70–5.58 (m, 1 H), 5.14 (dt, J = 12.6, 5.9 Hz, 1 H), 5.05–5.01 (m, 1 H), 4.99 (d, J = 1.3 Hz, 1 H), 3.54 (d, J = 4.0 Hz, 3 H), 2.37–2.32 (m, 2 H), 1.68–1.58 (m, 2 H), 1.27–1.22 (m, 22 H), 0.88 (t, J = 8.0 Hz, 3 H).

(S)-Heptadec-1-en-4-yl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (15b)

Compound 15b was synthesized from compound 15 (50 mg, 0.2 mmol, 1.0 equiv.) with (S)-(+)-(α)-methoxy-α-(trifluoromethyl)phenylacetic acid (S-MTPA; 94 mg, 0.4 mmol, 2.0 equiv.) by following the procedure for the synthesis of compound 15a; yield: 78 mg (84%); R_f = 0.40 (EtOAc/hexane 5:95).

¹H NMR (400 MHz, CDCl₃): δ = 7.57–7.53 (m, 2 H), 7.38 (dd, J = 5.3, 1.9 Hz, 3 H), 5.81–5.70 (m, 1 H), 5.19–5.14 (m, 1 H), 5.12 (d, J = 6.9 Hz, 1 H), 5.09–5.07 (m, 1 H), 3.56 (d, J = 1.2 Hz, 3 H), 2.44–2.39 (m, 2 H), 1.56–1.53 (s, 2 H), 1.29–1.22 (s, 22 H), 0.87 (t, J = 8.0 Hz, 3 H).

(S)-tert-Butyl(heptadec-1-en-4-yloxy)dimethylsilane (16)

To a stirred solution of 15 (700 mg, 2.75 mmol, 1.0 equiv.) in anhyd CH₂Cl₂ (20 mL) were added imidazole (280 mg, 4.12 mmol, 1.5 equiv.) and TBSCl (620 mg, 4.12 mmol, 1.5 equiv.) followed by DMAP (34 mg, 0.27 mmol, 10 mol%) at 0 °C. After stirring for 6 h at rt, the reaction was quenched with sat. aq NaHCO₃ (20 mL). The layers were then separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (R_f = 0.70; EtOAc/hexane 1:49) to obtain compound 16 as a colorless liquid; yield: 934 mg (92%); [α]_D ²⁰ –10.13 (c 1.5, CHCl₃).

IR (CHCl₃): 2927, 2856, 1640, 1464, 1215, 1057, 1003, 915, 750 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 5.81–5.73 (m, 1 H), 5.01–4.97 (m, 1 H), 4.96–4.95 (m, 1 H), 3.68–3.60 (m, 1 H), 2.22–2.11 (m, 2 H), 1.42–1.30 (m, 2 H), 1.28–1.17 (m, 22 H), 0.86–0.81 (m, 12 H), 0.00 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 116.5, 72.1, 42.0, 36.9, 32.0, 29.8, 29.7, 29.4, 25.9, 25.4, 22.7, 18.2, 14.1, –4.4, –4.5.

ESI-MS: m/z for C₂₃H₄₉OSi [M + H]⁺: 369.

(6S)-6-((tert-Butyldimethylsilyl)oxy)-2-methylnonadec-1-en-4-ol (10)

To a stirred solution of 16 (600 mg, 1.63 mmol, 1.0 equiv.) in 1,4-dioxane and H₂O (3:1, 20 mL) were sequentially added 2,6-lutidine (0.76 mL, 6.52 mmol, 4.0 equiv.), OsO₄ (7.5 mL, 0.03 mmol, 0.004 M solution in toluene, 2 mol%) followed by NaIO₄ (1.39 g, 6.52 mmol, 4.0 equiv.) at rt and allowed to stir for 2 h. After completion of the reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure and the residual aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The CH₂Cl₂ layer was quickly washed with aq 1 N HCl (2 × 10 mL) to remove excess 2,6-lutidine followed by brine (2 × 10 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure to get the crude aldehyde (500 mg, 83%), which was used immediately without further characterization.

To the above aldehyde (500 mg, 1.35 mmol, 1.0 equiv.) in anhyd THF (10 mL) was slowly added 2-methylallyl Grignard [freshly prepared from 3-cholro-2-methylpropene (0.66 mL, 6.75 mmol, 5.0 equiv.), Mg (32 mg, 13.5 mmol, 10.0 equiv.) in anhyd THF (10 mL)] at –40 °C. The reaction mixture was allowed to stir for another 2 h at the same temperature. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NH₄Cl (20 mL) and diluted with EtOAc (20 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (anhyd Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 1:9) to obtain compound 10 (7:3 diastereomeric ratio by ¹H NMR data) as a light yellow liquid; yield: 423 mg (78%); [α]_D ²⁰ +11.40 (c 1.5, CHCl₃).

IR (CHCl₃): 3459, 2927, 2856, 1731, 1646, 1462, 1373, 1216, 1076, 751 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.76–4.73 (m, 1 H), 4.68–4.66 (m, 1 H), 4.03–3.86 (m, 1 H), 3.85–3.78 (m, 1 H), 2.24–2.06 (m, 1 H), 2.15–2.08 (m, 1 H), 2.06–1.97 (m, 1 H), 1.66 (d, J = 3.5 Hz, 3 H), 1.57–1.43 (m, 3 H), 1.41–1.38 (m, 1 H), 1.22–1.15 (m, 22 H), 0.81–0.77 (m, 12 H), 0.08–0.02 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.7, 142.6, 113.0, 112.9, 72.7, 71.1, 68.2, 65.7, 46.6, 46.3, 42.9, 41.7, 37.9, 36.7, 31.9, 29.8, 29.7, 29.7, 29.63, 29.60, 29.4, 25.9, 25.5, 24.7, 22.7, 22.6, 22.5, 17.9, 14.1, –4.1, –4.5, –4.6, –4.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₅₅O₂Si: 427.3971; found: 427.3966.

(S)-6-((tert-Butyldimethylsilyl)oxy)-2-methylnonadec-1-en-4-one (17)

Dess–Martin periodinane (522 mg, 1.23 mmol, 1.5 equiv.) was added to a stirred solution of secondary alcohol 10 (350 mg, 0.82 mmol, 1.0 equiv.) in CH₂Cl₂ (20 mL) at 0 °C and allowed to stir for 1 h at the same temperature. After completion of reaction (monitored by TLC), the mixture was diluted with Et₂O and the precipitate was filtered off on a small pad Celite using Et₂O as a solvent. The filtrate was washed with sat. aq NaHCO₃ (10 mL), H₂O and brine (10 mL) and dried (anhyd Na₂SO₄). Evaporation of the solvent and purification by silica gel column chromatography (R_f = 0.70; EtOAc/hexane 1:19) afforded the ketone 17 as a colorless liquid; yield: 321 mg (92%); [α]_D ²⁰ +22.63 (c 1.7, CHCl₃).

IR (CHCl₃): 2927, 2856, 1712, 1462, 1372, 1216, 1075, 897, 748 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.93–4.91 (m, 1 H), 4.79–4.78 (m, 1 H), 4.13 (ddd, J = 5.7, 6.8, 12.7 Hz, 1 H), 3.10 (dq, J = 0.85, 15.1 Hz, 2 H), 2.62 (dd, J = 6.9, 15.5 Hz, 1 H), 2.45 (dd, J = 5.1, 15.5 Hz, 1 H), 1.72 (m, 3 H), 1.44–1.39 (m, 2 H), 1.28–1.23 (m, 22 H), 0.87 (t, J = 6.6 Hz, 3 H), 0.84 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 207.5, 139.0, 115.0, 68.9, 53.6, 49.2, 37.7, 31.9, 29.7, 29.6, 29.4, 25.7, 25.0, 22.7, 22.7, 18.0, 14.1, –4.6, –4.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₅₃O₂Si: 425.3815; found: 425.3811.

(S)-6-((tert-Butyldimethylsilyl)oxy)nonadecane-2,4-dione (9)

To a stirred solution of 17 (250 mg, 0.59 mmol, 1.0 equiv.) in acetone (10 mL) was added OsO₄ (5.0 mL, 0.02 mmol, 0.004 M solution in toluene, 3 mol%) and NMO (50 wt% in H₂O, 0.49 mL, 2.36 mmol, 4.0 equiv.) at 25 °C, and allowed to stir for 48 h at the same temperature. After completion of the reaction, solid Na₂SO₃ was added and stirred for another 30 min. Acetone was removed in vacuum and the residue was diluted with EtOAc (20 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure. Purification by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 3:7) afforded the intermediate diol compound (243 mg, 90%) as a viscous oil.

To the solution of above diol compound (200 mg, 0.44 mmol, 1.0 equiv.) in CH₂Cl₂ (10 mL) was added silica gel-supported NaIO₄ (873 mg, 2.0 equiv.) at rt. After completion of the reaction (monitored by TLC), the reaction mixture was filtered over Celite and the solvent was removed under reduced pressure to obtain the crude product, which on purification by silica gel column chromatography (R_f = 0.60; EtOAc/hexane 1:9) furnished the corresponding diketone 9 as a yellow liquid; yield: 151 mg (80%); [α]_D ²⁰ +32.9 (c 1.1, CHCl₃).

The compound 9 is partially enolized in solution. The ratio of the keto/enol form is 93:7 by ¹H NMR analysis.

IR (CHCl₃): 2972, 2856, 1716, 1610, 1462, 1364, 1216, 1086, 932, 748 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 5.48 (s, 1 H), 4.07–4.01 (m, 1 H), 2.32–2.30 (m, 2 H), 2.01 (s, 3 H), 1.46–1.39 (m, 2 H), 1.28–1.22 (m, 23 H), 0.84 (t, J = 5.7 Hz, 3 H), 0.82 (s, 9 H), 0.00 (s, 3 H), –0.05 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 192.0, 190.9, 101.6, 69.8, 46.1, 37.8 31.9, 29.7, 29.6, 29.4, 25.7, 25.0, 24.9, 22.7, 18.0, 14.1, –4.6, –5.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₅H₅₁O₃Si: 427.3607; found: 427.3602.

(S)-6-Methyl-2-tridecyl-2H-pyran-4(3H)-one (1)

To a stirred solution of 9 (50 mg, 0.12 mmol, 1.0 equiv.) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid (13 μL, 0.18 mmol, 1.5 equiv.) at 0 °C, and allowed to stirred for 10 h at rt. After completion of the reaction (monitored by TLC), the mixture was diluted with CH₂Cl₂ (10 mL) and quenched with sat. aq NaHCO₃ (5 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 1:4) to furnish the desired lobophopyranone A (1) as a yellow oil; yield: 32 mg (92%); {[α]_D ²⁵ –110 (c 0.8, CHCl₃), Lit.[4a] [α]_D ²⁵ –116 (c 1.14, CHCl₃)}.

IR (CHCl₃): 2932, 2845, 1698, 1614, 1452, 1360, 1225, 1049, 743 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 5.30 (s, 1 H), 4.35 (dddd, J = 4.7, 5.1, 7.4, 12.5 Hz, 1 H), 2.40 (dd, J = 12.8, 16.6 Hz, 1 H), 2.35 (dd, J = 0.8, 4.7, 16.6 Hz, 1 H), 1.99 (s, 3 H), 1.79 (m, 1 H), 1.64 (m, 1 H), 1.45 (m, 1 H), 1.38 (m, 1 H), 1.34–1.29 (m, 6 H), 1.27–1.25 (m, 14 H), 0.87 (t, J = 7.1 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 193.2, 174.5, 104.7, 79.3, 40.7, 34.4, 31.9, 29.64, 29.62, 29.5, 29.4, 29.3, 24.8, 22.7, 21.1, 14.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₃₅O₂: 295.2637; found: 295.2634.

(S)-Pentadec-1-en-4-ol (18)

To a stirred solution of alcohol 14 (1.5 g, 8.06 mmol, 1.0 equiv.) in EtOAc was added IBX (3.4 g, 12.09 mmol, 1.5 equiv.) at rt, and the resulting mixture was refluxed for 12 h. After completion of the reaction (monitored by TLC), the mixture was cooled to rt and filtered through a Celite bed and washed with EtOAc. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (R_f = 0.55; EtOAc/hexane 1:19) to obtain dodecanal as a white solid (1.35 g, 91%); which was used immediately without further characterization.

To a stirred solution of TiCl₄ (0.77 mL, 0.71 mmol, 10 mol%) in CH₂Cl₂ (15 mL) was added Ti( ⁱ PrO)₄ (0.64 mL, 2.12 mmol, 30 mol%) at 0 °C under argon atmosphere. The reaction mixture was brought to rt and allowed to stir for 3 h at the same temperature. To this was added Ag₂O (0.33 g, 1.41 mmol, 20 mol%) and stirred in the dark for 6 h. The reaction mixture was diluted with CH₂Cl₂ (15 mL) and treated with (R)-binaphthol (0.40 g, 7.06 mmol, 10 mol%) at rt for 3 h to furnish chiral bis(R)-Ti^IV oxide. The in situ generated bis(R)-Ti^IV oxide in CH₂Cl₂ was cooled to –15 °C and treated sequentially with dodecanal (1.3 g, 7.06 mmol, 1.0 equiv.) dissolved in CH₂Cl₂ (10 mL) and allyltributyltin (3.28 mL, 10.59 mmol). The reaction mixture was warmed to 0 °C and stirred for 24 h. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NaHCO₃ (20 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 1:19) to afford homoallylic alcohol 18 as a white solid; yield: 1.39 g (87%); mp 55–57 °C; [α]_D ²⁰ –4.6 (c 1.0, CHCl₃).

IR (CHCl₃): 3385, 3074, 2923, 2855, 1640, 1459, 1216, 1076, 915, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 5.88–5.78 (m, 1 H), 5.15 (br d, J = 3.4 Hz, 1 H), 5.11 (s, 1 H), 3.67–3.61 (m, 1 H), 2.33–2.27 (m, 1 H), 2.17–2.10 (m, 1 H), 1.63 (s, 1 H), 1.49–1.42 (m, 3 H), 1.34–1.26 (m, 17 H), 0.88 (t, J = 6.7 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 135.0, 117.9, 70.7, 42.0, 36.8, 31.9, 29.7, 29.6, 29.4, 25.7, 22.7, 14.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₃₁O: 227.0260; found: 227.0268.

(S)-Pentadec-1-en-4-yl (R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (18a)

To a stirred solution of (R)-(–)-(α)-methoxy-α-(trifluoromethyl)phenylacetic acid (R-MTPA) (94 mg, 0.4 mmol, 2.0 equiv.) in anhyd toluene (2 mL) were added Et₃N (55 μL, 0.4 mmol, 2.0 equiv.) and 2,4,6-trichlorobenzoyl chloride (65 μL, 0.4 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was allowed to stir at rt for 45 min. Then a solution of alcohol 18 (50 mg, 0.2 mmol, 1.0 equiv.) and DMAP (49 mg, 0.4 mmol, 2.0 equiv.) in anhyd toluene (1 mL) was added to the mixture at 0 °C. The mixture was brought to rt and allowed to stir for 8 h. After completion of the reaction (monitored by TLC), it was quenched with H₂O (2 mL) and the mixture was extracted with EtOAc (3 × 4 mL). The combined organic layers were dried (anhyd Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 5:95) to furnish (R)-MTPA ester 18a as a colorless liquid; yield: 83 mg (85%).

¹H NMR (400 MHz, CDCl₃): δ = 7.55–7.52 (m, 2 H), 7.39 (dd, J = 5.1, 2.1 Hz, 3 H), 5.70–5.58 (m, 1 H), 5.16–5.10 (m, 1 H), 5.05–5.01 (m, 1 H), 4.99 (t, J = 1.3 Hz, 1 H), 3.54 (d, J = 1.2 Hz, 3 H), 2.38–2.32 (m, 2 H), 1.68–1.59 (m, 2 H), 1.28–1.25 (m, 18 H), 0.89 (t, J = 6.4 Hz, 3 H).

(S)-Pentadec-1-en-4-yl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (18b)

Compound 18b was synthesized from compound 18 (50 mg, 0.2 mmol, 1.0 equiv.) with (S)-(+)-(α)-methoxy-α-(trifluoromethyl)phenylacetic acid (S-MTPA; 94 mg, 0.4 mmol, 2.0 equiv.) by following the procedure for the synthesis of compound 18a; yield: 85 mg (87%); R_f = 0.40 (EtOAc/hexane 5:95).

¹H NMR (400 MHz, CDCl₃): δ = 7.57–7.53 (m, 2 H), 7.41–7.36 (m, 3 H), 5.76 (ddt, J = 16.2, 10.5, 7.0 Hz, 1 H), 5.19–5.10 (m, 2 H), 5.10–5.06 (m, 1 H), 3.58–3.52 (m, 3 H), 2.41 (ddt, J = 7.3, 6.1, 1.4 Hz, 2 H), 1.61–1.56 (m, 2 H), 1.30–1.24 (m, 18 H), 0.88 (t, J = 6.5 Hz, 3 H).

(S)-((Pentadec-1-en-4-yloxy)methyl)benzene (19)

To a stirred solution of alcohol 18 (1.2 g, 5.31 mmol, 1.0 equiv.) in anhyd THF (20 mL) was added 60% NaH (0.317 g, 7.96 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was brought to rt and allowed to stir for 1 h. To this was added benzyl bromide (0.76 mL, 6.37 mmol, 1.2 equiv.) followed by Bu₄NI (0.140 g, 0.531 mmol, 10 mol%) at 0 °C and allowed stir at rt for 12 h. After completion of the reaction (monitored by TLC), it was quenched with aq NH₄Cl (20 mL) solution at 0 °C. The mixture was diluted with EtOAc (20 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure. Purification of the crude residue by silica gel column chromatography (R_f = 0.60; EtOAc/hexane 1:20) to furnish the compound 19 as a colorless liquid; yield: 1.48 g (88%); [α]_D ²⁰ –10.60 (c 1.0, CHCl₃).

IR (CHCl₃): 3018, 2926, 2856, 1638, 1457, 1350, 1215, 1064, 916, 746 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.24 (m, 5 H), 5.91–5.80 (m, 1 H), 5.11–5.04 (m, 2 H), 4.52 (ABq, J = 30.2, 11.6 Hz, 2 H), 3.46–3.40 (m, 1 H), 2.34–2.30 (m, 2 H), 1.55–1.47 (m, 2 H), 1.30–1.26 (m, 18 H), 0.88 (t, J = 6.9 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.0, 135.2, 128.3, 127.8, 127.5, 116.8, 78.6, 70.9, 38.4, 33.9, 32.0, 29.8, 29.7, 29.5, 25.4, 22.8, 14.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₃₇O: 317.2844; found: 317.2832.

(4S,6S)-6-(Benzyloxy)heptadec-1-en-4-ol (20)

To a solution of 19 (800 mg, 2.50 mmol, 1.0 equiv.) in 1,4-dioxane and H₂O (3:1, 20 mL) were sequentially added 2,6-lutidine (1.16 mL, 10.0 mmol, 4.0 equiv.) and OsO₄ (12.5 mL, 0.05 mmol, 0.004 M solution in toluene, 2 mol%) followed by NaIO₄ (2.14 g, 10.0 mmol, 4.0 equiv.) at rt and stirred for 3 h. After completion of the reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure and the residual aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The CH₂Cl₂ layer was quickly washed with aq 1 N HCl (2 × 10 mL) to remove excess 2,6-lutidine followed by brine (2 × 10 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure to get the crude aldehyde (653 mg, 82%), which was used immediately without further characterization.

To a solution of the above aldehyde (640 mg, 2.01 mmol, 1.0 equiv.) in CH₂Cl₂ (15 mL) were added MgBr₂·OEt₂ (1.30 g, 5.03 mmol, 2.5 equiv.) followed by allyltrimethylsilane (3.73 mL, 12.06 mmol, 6.0 equiv.) at 0 °C, and allowed to stir for overnight at the same temperature. After completion of the reaction (monitored by TLC), it was quenched with aq 1 M HCl (10 mL) at 0 °C. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were washed with sat. aq NaHCO₃ (10 mL) and dried (anhyd Na₂SO₄). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 1:9) to afford compound 20 as a colorless liquid with good diastereoselectivity (dr 99:1); yield: 615 mg (85%); [α]_D ²⁰ +17.88 (c 0.8, CHCl₃).

IR (CHCl₃): 3455, 3071, 2923, 2855, 1640, 1457, 1354, 1066, 913, 736 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.26 (m, 5 H), 5.87–5.77 (m, 1 H), 5.13–5.06 (m, 2 H), 4.54 (ABq, J = 11.4, 23.1 Hz, 2 H), 3.99–3.93 (m, 1 H), 3.73–3.69 (m, 1 H), 2.79 (br s, 1 H), 2.24–2.20 (m, 2 H), 1.73–1.63 (m, 3 H), 1.55–1.48 (m, 1 H), 1.30–1.24 (m, 18 H), 0.88 (t, J = 6.9 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 138.5, 135.0, 128.4, 127.9, 127.7, 117.5, 77.1, 71.3, 67.8, 42.3, 39.5, 32.0, 29.8, 29.71, 29.70, 29.4, 25.5, 22.7, 14.2.

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₄₀O₂Na: 383.2926; found: 383.2906.

(4R,6S)-6-(Benzyloxy)heptadec-1-en-4-ol (21)

To a stirred solution of alcohol 20 (600 mg, 1.66 mmol, 1.0 equiv.) in THF (15 mL) were added Ph₃P (2.18 g, 8.3 mmol, 5.0 equiv.), p-nitrobenzoic acid (1.39 g, 8.3 mmol, 5.0 equiv.), and DIAD (1.6 mL, 8.3 mmol, 5.0 equiv.) at 0 °C, and allowed to stirred at rt for 2 h. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NaHCO₃ (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with H₂O (10 mL) and brine (10 mL), dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography over silica gel (R_f = 0.70; EtOAc/hexane 1:19) gave the intermediate p-nitrobenzoate (690 mg, 82%) as a pale yellow oil.

To a stirred solution of the above p-nitrobenzoate (670 mg, 1.32 mmol, 1.0 equiv.) in MeOH (20 mL) was added K₂CO₃ (265 mg, 1.92 mmol, 1.5 equiv.) at 0 °C and allowed to stir at rt for 1 h. After completion of the reaction (monitored by TLC), excess MeOH was evaporated under reduced pressure and diluted with EtOAc (20 mL), and H₂O (20 mL) was added. Two layers were separated, and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (15 mL), dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel (R_f = 0.40; EtOAc/hexane 1:9) to afford alcohol 21 as a colorless oil; yield: 380 mg (80%); [α]_D ²⁰ +26.51 (c 0.6, CHCl₃).

IR (CHCl₃): 3439, 3012, 2926, 2857, 1637, 1457, 1361, 1063, 918, 747 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.35–7.28 (m, 5 H), 5.87–5.79 (m, 1 H), 5.11–5.07 (m, 2 H), 4.50 (AB q, J = 11.4, 23.1 Hz, 2 H), 3.86–3.81 (m, 1 H), 3.69–3.65 (m, 1 H), 3.57 (br s, 1 H), 2.26–2.16 (m, 2 H), 1.69–1.61 (m, 3 H), 1.61–1.55 (m, 1 H), 1.33–1.27 (m, 18 H), 0.88 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 138.1, 135.0, 128.5, 127.9, 127.8, 117.5, 117.3, 79.9, 71.0, 70.6, 42.2, 40.3, 32.0, 29.9, 29.7, 29.6, 29.4, 24.6, 22.7, 14.2.

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₄₀O₂Na: 383.2926; found: 383.2907.

(((4R,6S)-6-(Benzyloxy)heptadec-1-en-4-yl)oxy)(tert-butyl)dimethylsilane (22)

To a stirred solution of 21 (370 mg, 1.03 mmol, 1.0 equiv.) in anhyd CH₂Cl₂ (10 mL) were sequentially added imidazole (105 mg, 1.55 mmol, 1.5 equiv.) and TBSCl (233 mg, 1.55 mmol, 1.5 equiv.) followed by DMAP (12 mg, 0.10 mmol, 10 mol%) at 0 °C, and allowed to sitr for 6 h at rt. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NaHCO₃ (10 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were dried (anhyd Na₂SO₄) and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 1:19) afforded the compound 22 as a colorless liquid; yield: 460 mg (94%); [α]_D ²⁰ +3.70 (c 1.0, CHCl₃).

IR (CHCl₃): 3020, 2929, 2858, 1635, 1461, 1215, 1064, 919, 743 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.39–7.30 (m, 5 H), 5.92–5.78 (m, 1 H), 5.09–5.03 (m, 2 H), 4.53 (s, 2 H), 3.92–3.84 (m, 1 H), 3.57–3.49 (m, 1 H), 2.34–2.18 (m, 2 H), 1.89–1.80 (m, 1 H), 1.68–1.63 (m, 1 H), 1.58–1.54 (m, 2 H), 1.43–1.32 (m, 18 H), 0.94–0.92 (m, 12 H), 0.11 (s, 3 H), 0.09 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.1, 135.1, 128.3, 127.8, 127.4, 117.0, 76.1, 70.5, 69.3, 42.0, 41.5, 34.1, 32.0, 29.9, 29.7, 29.4, 26.0, 25.3, 22.8, 18.1, 14.2, –4.2, –4.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₀H₅₅O₂Si: 475.3971; found: 475.3965.

(6R,8S)-8-(Benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-2-methylnonadec-1-en-4-ol (13)

To a stirred solution of 22 (450 mg, 0.95 mmol, 1.0 equiv.) in 1,4-dioxane and H₂O (3:1, 15 mL) were sequentially added 2,6-lutidine (0.44 mL, 3.80 mmol, 4.0 equiv.) and OsO₄ (5.0 mL, 0.02 mmol, 0.004 M solution in toluene, 2 mol%) followed by NaIO₄ (812 mg, 3.80 mmol, 4.0 equiv.) at rt and stirred for 2 h. After completion of the reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure and the residual aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The CH₂Cl₂ layer was quickly washed with aq 1 N HCl (2 × 10 mL) to remove excess 2,6-lutidine followed by brine (2 × 10 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure to afford the intermediate crude aldehyde (380 mg, 84%), which was used immediately without further characterization.

To the solution of the above aldehyde (360 mg, 0.76 mmol, 1.0 equiv.) in anhyd THF (10 mL) was slowly added 2-methylallyl Grignard [freshly prepared from 3-cholro-2-methylpropene (0.15 mL, 1.52 mmol, 2.0 equiv.), Mg (54 mg, 2.28 mmol, 3.0 equiv.) in 10 mL of anhyd THF] at −40 °C. The reaction mixture was allowed to stir for another 2 h at the same temperature. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NH₄Cl (10 mL). The mixture was diluted with tert-butyl methyl ether (10 mL), the two layers were separated, and the aqueous layer was extracted with tert-butyl methyl ether (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried (anhyd Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.30; EtOAc/hexane 1:9) to obtain compound 13 (3:2 diastereomeric ratio by ¹H NMR data) as a yellow liquid; yield: 325 mg (80%); [α]_D ²⁰ –16.39 (c 0.8, CHCl₃).

IR (CHCl₃): 3490, 3017, 2928, 2858, 1728, 1642, 1459, 1215, 1062, 899, 745 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.25–7.22 (m, 4 H), 7.19–7.15 (m, 1 H), 4.72–4.71 (m, 1 H), 4.65–4.63 (m, 1 H), 4.44 (dd, J = 4.6, 11.6 Hz, 1 H), 4.29 (dd, J = 10.1, 11.6 Hz, 1 H), 4.12–4.04 (m, 0.5 H), 4.01–3.88 (m, 1 H), 3.78–3.71 (m, 0.5 H), 3.41–3.24 (m, 1 H), 2.15–2.04 (m, 1 H), 2.02–1.94 (m, 1 H), 1.77–1.73 (m, 1 H), 1.63 (s, 3 H), 1.54–1.46 (m, 2 H), 1.45–1.37 (m, 2 H), 1.27–1.14 (m, 20 H), 0.83–0.76 (m, 12 H), 0.02–0.03 (m, 6 H).

¹³C NMR (125 MHz, CDCl₃): δ = 142.8, 142.7, 138.9, 138.8, 128.3, 127.8, 127.5, 113.0, 112.9, 76.0, 75.8, 70.6, 70.0, 68.7, 67.9, 66.0, 46.5, 46.2, 43.1, 42.8, 41.4, 41.2, 34.1, 34.0, 31.9, 29.9, 29.7, 29.4, 25.9, 25.1, 22.7, 22.6, 22.6, 14.2, –4.0, –4.5, –4.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₃H₆₁O₃Si: 533.4390; found: 533.4365.

(6S,8S)-8-(Benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-2-methylnonadec-1-en-4-one (23)

To a stirred solution of secondary alcohol 13 (300 mg, 0.56 mmol, 1.0 equiv.) in CH₂Cl₂ (10 mL) was added Dess–Martin periodinane (356 mg, 0.84 mmol, 1.5 equiv.) at 0 °C, and allowed to stir for 1 h. After completion of reaction (monitored by TLC), it was diluted with Et₂O and the precipitate was filtered off on a small pad Celite using Et₂O as the solvent. The filtrate was washed with sat. aq NaHCO₃ (10 mL), H₂O, brine (10 mL) and dried (Na₂SO₄). Evaporation of the solvent and purification by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 1:19) afforded the ketone 23 as a colorless liquid; yield: 261 mg (88%); [α]_D ²⁰ –8.49 (c 0.5, CHCl₃).

IR (CHCl₃): 3019, 2928, 2857, 1715, 1615, 1458, 1374, 1215, 1072, 897, 746 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.28–7.25 (m, 5 H), 4.91–4.90 (m, 1 H), 4.75–4.74 (m, 1 H), 4.42 (ABq, J = 11.6, 36.6 Hz, 2 H), 4.30–4.25 (m, 1 H), 3.46–3.42 (m, 1 H), 2.99 (br d, J = 4.4 Hz, 2 H), 2.56 (dd, J = 6.9, 15.9 Hz, 1 H), 2.49 (dd, J = 5.0, 15.9 Hz, 1 H), 1.72 (ddd, J = 5.1, 7.4, 14.0 Hz, 1 H), 1.65 (s, 3 H), 1.55 (ddd, J = 4.7, 6.8, 14.0 Hz, 1 H), 1.51–1.46 (m, 2 H), 1.26–1.21 (m, 18 H), 0.84–0.80 (m, 12 H), 0.00 (s, 3 H), –0.03 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 207.4, 139.1, 138.9, 128.3, 127.8, 127.5, 115.0, 75.7, 70.5, 66.4, 53.5, 49.1, 41.9, 33.9, 32.0, 29.9, 29.7, 29.4, 25.9, 25.2, 22.7, 22.7, 18.0, 14.2, –4.5, –4.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₃H₅₉O₃Si: 531.4233; found: 531.4229.

(6S,8S)-8-(Benzyloxy)-6-((tert-butyldimethylsilyl)oxy)nonadecane-2,4-dione (12)

To a stirred solution of 23 (200 mg, 0.38 mmol, 1.0 equiv.) in acetone (10 mL) was added OsO₄ (2.5 mL, 0.01 mmol, 0.004 M solution in toluene, 3 mol%) and NMO (50 wt% in H₂O, 0.32 mL, 1.52 mmol, 4.0 equiv.) at 25 °C. The resulting solution was stirred for 48 h at the same temperature. After completion of the reaction (monitored by TLC), solid Na₂SO₃ was added and stirred for another 30 min. Acetone was removed under reduced pressure, and the residue was diluted with EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (4 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (anhyd Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (R_f = 0.30; EtOAc/hexane 2:3) to furnish the intermediate diol compound (190 mg, 89%) as a viscous oil, which was used without further characterization.

To a vigorously stirred solution of the above diol compound (170 mg, 0.30 mmol, 1.0 equiv.) in CH₂Cl₂ (10 mL) was added silica gel-supported NaIO₄ (602 mg, 2.0 equiv.) at rt. After 10 min, the mixture was filtered over Celite and concentrated. The residue was purified by silica gel column chromatography (R_f = 0.40; EtOAc/hexane 1:9) to afford diketone 12 as a yellow oil; yield: 143 mg (90%); [α]_D ²⁰ –7.83 (c 0.6, CHCl₃).

The compound 12 is partially enolized in solution. The ratio of the keto/enol form is 9:1 by ¹H NMR analysis.

IR (CHCl₃): 3020, 2927, 2857, 1715, 1612, 1459, 1215, 1077, 930, 747 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.28 (m, 5 H), 5.42 (s, 1 H), 4.50 (ABq, J = 11.5, 34.3 Hz, 2 H), 4.25–4.20 (m, 1 H), 3.50–3.45 (m, 1 H), 2.40 (dd, J = 5.0, 13.7 Hz, 1 H), 2.31 (dd, J = 7.5, 13.7 Hz, 1 H), 1.99 (s, 3 H), 1.78 (ddd, J = 5.1, 7.4, 14.0 Hz, 1 H), 1.60 (ddd, J = 4.8, 6.7, 14.0 Hz, 1 H), 1.53–1.48 (m, 2 H), 1.28–1.23 (m, 18 H), 0.85 (t, J = 6.7 Hz, 3 H), 0.83–0.82 (m, 10 H), 0.00 (s, 3 H), –0.04 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 192.2, 190.7, 138.9, 128.3, 127.8, 127.5, 101.8, 75.8, 70.6, 67.4, 46.1, 42.3, 34.0, 32.0, 29.9, 29.7, 29.4, 25.8, 25.2, 22.7, 18.0, 14.2, –4.5, –4.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₂H₅₇O₄Si: 533.4026; found: 533.4023.

(S)-2-((S)-2-(Benzyloxy)tridecyl)-6-methyl-2H-pyran-4(3H)-one (24)

To a stirred solution of 12 (100 mg, 0.19 mmol, 1.0 equiv.) in CH₂Cl₂ (8 mL) was added TFA (21 μL, 0.28 mmol, 1.5 equiv.) at 0 °C, and allowed to stir for overnight at rt. After completion of the reaction (monitored by TLC), it was diluted with CH₂Cl₂ (10 mL), and quenched with sat. aq NaHCO₃ (5 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (anhyd Na₂SO₄), filtered, and concentrated. Purification of the crude residue by silica gel column chromatography (R_f = 0.40; EtOAc/ hexane 1:4) to furnish the cyclized compound 24 as a colorless liquid; yield: 69 mg (89%); [α]_D ²⁰ +15.66 (c 0.5, CHCl₃).

IR (CHCl₃): 3017, 2927, 2858, 1715, 1659, 1401, 1343, 1215, 1063, 742 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.28 (m, 5 H), 5.31 (s, 1 H), 4.55 (dddd, J = 5.0, 6.4, 7.2, 11.1 Hz, 2 H), 4.43 (br d, J = 11.1 Hz, 1 H), 3.58–3.52 (m, 1 H), 2.38 (dd, J = 11.1, 16.9 Hz, 1 H), 2.30 (br dd, J = 5.0, 16.9 Hz, 1 H), 2.15 (ddd, J = 7.2, 8.4, 14.3 Hz, 1 H), 1.97 (s, 3 H), 1.81 (ddd, J = 4.8, 6.4, 14.3 Hz, 1 H), 1.64–1.56 (m, 2 H), 1.39–1.34 (m, 2 H), 1.30–1.26 (m, 16 H), 0.88 (t, J = 6.9 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 192.7, 174.3, 138.4, 128.5, 127.8, 127.7, 104.9, 75.1, 70.8, 40.8, 38.7, 31.9, 29.7, 29.7, 29.6, 29.4, 22.7, 14.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₄₁O₃: 401.3056; found: 401.3057.

(S)-2-((S)-2-Hydroxytridecyl)-6-methyl-2H-pyran-4(3H)-one (2)

To a stirred solution of naphthalene (133 mg, 1.04 mmol, 8.0 equiv.) in anhyd THF (10 mL) was added Li metal (7.2 mg, 1.04 mmol, 8.0 equiv.) at rt. After 30 min, a dark-green color developed, which turned dark-blue after 1 h. To the reaction mixture, compound 24 (50 mg, 0.13 mmol, 1.0 equiv.) in anhyd THF (5 mL) was added slowly at –20 °C. The resulting mixture was stirred for 1 h at the same temperature. After completion of the reaction (monitored by TLC), it was quenched with sat. aq NH₄Cl (5 mL) and diluted with EtOAc (5 mL). The resulting mixture was stirred for 1 h at rt. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried (anhyd Na₂SO₄) and concentrated under reduced pressure to obtain a crude mass, which on purification by silica gel column chromatography (R_f = 0.50; EtOAc/hexane 3:7) furnished the desired lobophopyranone B as a white amorphous solid; yield: 30 mg (77%); mp 60–62 °C; {[α]_D ²⁵ +35.3 (c 0.5, CHCl₃); Lit.[4a] [α]_D ²⁵ +33 (c 0.20, CHCl₃)}.

IR (CHCl₃): 3442, 2930, 2851, 1690, 1620, 1423, 1337, 1145, 1035, 746 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 5.34 (s, 1 H), 4.63 (dddd, J = 5.2, 5.4, 7.3, 12.1 Hz, 1 H), 3.86–3.82 (m, 1 H), 2.46 (dd, J = 12.1, 16.7 Hz, 1 H), 2.44 (br dd, J = 5.4, 16.7 Hz, 1 H), 2.0 (s, 3 H), 1.99 (ddd, J = 7.3, 8.1, 14.6 Hz, 1 H), 1.80 (ddd, J = 3.3, 5.2, 14.6 Hz, 1 H), 1.53–1.49 (m, 2 H), 1.46–1.41 (m, 1 H), 1.33–1.36 (m, 17 H), 0.87 (t, J = 7.0 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 192.5, 173.8, 105.2, 78.5, 69.4, 41.6, 40.9, 37.7, 31.9, 29.64, 29.61, 29.60, 29.6, 29.3, 25.4, 22.7, 21.1, 14.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₃₄O₃: 311.2586; found: 311.2580.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank the Director, CSIR-IICT for his constant support and for providing excellent research facilities (Manuscript communication number IICT/Pubs/2024/199). G.S.R. and U.M.C. thank UGC, New Delhi, India, for financial assistance in the form of fellowships.

• References

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Corresponding Author

Publication History

Received: 06 May 2024

Accepted after revision: 04 June 2024

Accepted Manuscript online:
04 June 2024

Article published online:
08 July 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Gradillas A, Castells JP. Angew. Chem. Int. Ed. 2006; 45: 6086
  CrossrefPubMedSearch in Google Scholar
• 2a Faul MM, Huff BE. Chem. Rev. 2000; 100: 2407
  CrossrefPubMedSearch in Google Scholar
• 2b Fleming I, Barbero A, Walter D. Chem. Rev. 1997; 97: 2063
  CrossrefPubMedSearch in Google Scholar
• 2c Danishefsky SJ, Biolodeau MT. Angew. Chem., Int. Ed. Engl. 1996; 35: 1380
  CrossrefSearch in Google Scholar
• 3a Hosoya T, Takagi M, Shinya K. J. Antibiot. 2013; 66: 235
  CrossrefPubMedSearch in Google Scholar
• 3b Asai T, Chung YM, Sakurai H, Ozeki T, Chang FR, Yamashita K, Oshima Y. Org. Lett. 2012; 14: 513
  CrossrefPubMedSearch in Google Scholar
• 3c Batista JM. Jr, Batista AN. L, Mota JS, Cass QB, Kato MJ, Bolzani VS, Freedman TB, López SN, Furlan M, Nafie LA. J. Org. Chem. 2011; 76: 2603
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• 3e Tanaka T, Asai F, Iinuma M. Phytochemistry 1998; 49: 229
  CrossrefSearch in Google Scholar
• 3f Fujita T, Inoue K, Yamamoto S, Ikumoto T, Sasaki S, Toyama R, Chiba K, Hoshino Y, Okumoto T. J. Antibiot. 1994; 47: 208
  CrossrefPubMedSearch in Google Scholar
• 4a Gutiérrez-Cepeda A, Fernández JJ, Norte M, Montalvao S, Tammela P, Souto ML. J. Nat. Prod. 2015; 78: 1716
  CrossrefPubMedSearch in Google Scholar
• 4b Morais-Urano RP, Chagas AC. S, Berlinck RG. S. Exp. Parasitol. 2012; 132: 362
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• 4c Cantillo-Ciau Z, Moo-Puc R, Quijano L, Freile-Pelegrin Y. Mar. Drugs 2010; 8: 1292
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• 4d Blain JC, Mok Y.-F, Kubanek J, Allingham JS. Chem. Biol. 2010; 17: 802
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• 4e Medeiros VP, Queiroz KS. C, Cardoso ML, Monteiro GR. G, Oliveira FW, Chavante SF, Guimaraes LA, Rocha HA. O, Leite EL. Biochemistry 2008; 73: 1018
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• 4f Queiroz KS. C, Medeiros VP, Queiroz LS, Abreu LR. D, Rocha HA. O, Ferreira CV, Jucá MB, Aoyama H, Leite EL. Biomed. Pharmacother. 2008; 62: 303
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• 4g Kubanek J, Jensen PR, Keifer PA, Sullards MC, Collins DO, Fenical W. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 6916
  CrossrefPubMedSearch in Google Scholar
• 4h Compagnone RC, Pina IC, Rangel HR, Dagger F, Suárez AI, Reddy MV. R, Faulkner DJ. Tetrahedron 1998; 54: 3057
  CrossrefSearch in Google Scholar
• 4i Fontana A, Ishibashi M, Kobayashi J. Tetrahedron 1998; 54: 2041
  CrossrefSearch in Google Scholar
• 4j Rudi A, Kashman Y. J. Nat. Prod. 1993; 56: 1827
  CrossrefPubMedSearch in Google Scholar
• 4k Gunasekera SP, Gunasekera M, Gunawardana G, McCarthy P, Burres N. J. Nat. Prod. 1990; 53: 669
  CrossrefSearch in Google Scholar
• 5a Padhi B, Reddy GS, Mallampudi NA, Choudhury UM, Mohapatra DK. Org. Biomol. Chem. 2020; 18: 2685
  CrossrefPubMedSearch in Google Scholar
• 5b Srinivas B, Reddy DS, Mallampudi NA, Mohapatra DK. Org. Lett. 2018; 20: 6910
  CrossrefPubMedSearch in Google Scholar
• 5c Reddy GS, Padhi B, Bharath Y, Mohapatra DK. Org. Lett. 2017; 19: 6506
  CrossrefPubMedSearch in Google Scholar
• 5d Reddy DS, Mohapatra DK. Eur. J. Org. Chem. 2013; 1051
  Crossref
• 5e Mohapatra DK, Bhimireddy E, Krishnarao PS, Das PP, Yadav JS. Org. Lett. 2011; 13: 744
  CrossrefPubMedSearch in Google Scholar
• 5f Yadav JS, Pattanayak MR, Das PP, Mohapatra DK. Org. Lett. 2011; 13: 1710
  CrossrefPubMedSearch in Google Scholar
• 5g Mohapatra DK, Das PP, Sai Reddy D, Yadav JS. Tetrahedron Lett. 2009; 50: 5941
  CrossrefSearch in Google Scholar
• 6a Frigerio M, Santagostino M, Sputore S, Palmisano G. J. Org. Chem. 1995; 60: 7272
  CrossrefSearch in Google Scholar
• 6b Frigerio M, Santagostino M. Tetrahedron Lett. 1994; 35: 8019
  CrossrefSearch in Google Scholar
• 7a Hanawa H, Hashimoto T, Maruoka K. J. Am. Chem. Soc. 2003; 125: 1708
  CrossrefPubMedSearch in Google Scholar
• 7b Hanawa H, Uraguchi D, Konishi S, Hashimoto T, Maruoka K. Chem. Eur. J. 2003; 9: 4405
  CrossrefPubMedSearch in Google Scholar
• 7c Keck GE, Tarbet KH, Geraci LS. J. Am. Chem. Soc. 1993; 115: 8467
  CrossrefSearch in Google Scholar
• 7d Keck GE, Geraci LS. Tetrahedron Lett. 1993; 34: 7827
  CrossrefSearch in Google Scholar
• 7e Wang Y, O’Doherty GA. J. Org. Chem. 2022; 87: 6006
  CrossrefPubMedSearch in Google Scholar
• 7f Yang P.-Y, Liu K, Ngai MH, Lear MJ, Wenk MR, Yao SQ. J. Am. Chem. Soc. 2010; 132: 656
  CrossrefPubMedSearch in Google Scholar
• 8 Corey EJ, Venkateswarlu A. J. Am. Chem. Soc. 1972; 94: 6190
  CrossrefPubMedSearch in Google Scholar
• 9 Yu W, Mei Y, Hua Z, Jin Z.. Org. Lett. 2004; 6: 3217
  CrossrefPubMedSearch in Google Scholar
• 10a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
  CrossrefPubMedSearch in Google Scholar
• 10b Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
  CrossrefPubMedSearch in Google Scholar
• 11 VanRheenen V, Kelly RC, Cha DY. Tetrahedron Lett. 1976; 1973
  Crossref
• 12 Zhong Y.-L, Shing TK. M. J. Org. Chem. 1997; 62: 2622
  CrossrefPubMedSearch in Google Scholar
• 13 Wang H, Shuhler BJ, Xian M. J. Org. Chem. 2007; 72: 4280
  CrossrefPubMedSearch in Google Scholar
• 14 Dirat O, Kouklovsky C, Langlois Y. Org. Lett. 1999; 1: 753
  CrossrefPubMedSearch in Google Scholar
• 15 Keck GE, Boden EP. Tetrahedron Lett. 1984; 25: 265
  CrossrefSearch in Google Scholar
• 16 Mitsunobu O, Yamada M. Bull. Chem. Soc. Jpn. 1967; 40: 2380
  CrossrefSearch in Google Scholar
• 17 Liu H.-J, Yip J, Shia K.-S. Tetrahedron Lett. 1997; 38: 2253
  CrossrefSearch in Google Scholar

• Supplementary Material