A Concise Asymmetric Total Synthesis of (+)-8-Epigrosheimin via Catalyst-Free Tandem Allylboration–Lactonization

Dedicated to Professor B. C. Ranu on the occasion of his 75^th birthday

Abstract

A concise and scalable asymmetric synthesis of (+)-8-epigrosheimin is reported in nine steps using only three column chromatographic purifications with an overall yield 47.0% from (R)-(–)-carvone. Two synthetic routes are evaluated by catalyst-free tandem allylboration–lactonization of two carvone-derived aldehydes and subsequent ene cyclization, where strategy via Lee–Lay aldehyde is found to be more effective for 8-epigrosheimin.

Guaianolide (GNL) is a large subclass of naturally occurring sesquiterpene lactone. Many have a broad spectrum of biological activities such as anti-inflammatory, anthelmintic, antitumor, plant growth, and many more.[1] Some of the sesquiterpene lactones are into human clinical trials.[2] There are several classes of guaianolides, the most common are 6,12- and 8,12-guaianolides (Figure [1]). These are polyoxygenated 5-7-5 tricyclic ring systems containing a cis-fused hydroazulene core and a trans-annulated γ-butyrolactone moiety with multiple stereocenters. There are several thousands of natural products found in the last few decades having γ-butyrolactone, which plays a key role in the biological activities of these natural products.[3] Important biological activities along with their unique structural features are very fascinating to organic chemists for their synthesis. Several synthetic strategies are, therefore, developed and most of them are commenced with carvone as a chiral synthon. However, still, there are some challenges to their efficient synthesis.[4] [5] One of the hurdles is the efficient construction of trans-fused-γ-butyrolactone with α-methyl or methylene unit in the early stage.

(+)-8-Epigrosheimin, a 6,12-guaianolide, was isolated from Crepis virens in 1979 as an amoebicidal and antibiotic agent.[6] [7] Interestingly, its unnatural (–)-isomer is known to show promising anticancer activities.[8] It has six stereogenic centers where five are contiguous. The stereoselective construction of a 5-7-5 tricyclic guaianolides core with trans-fused α-methylene-γ-butyrolactone along with the desired stereochemistry of the C8-hydroxyl group is a very challenging task. Important biological activities and complex molecular framework of 8-epigrosheimin make it an attractive target compound in medicinal and synthetic chemistry. There are only three reports for both the natural and unnatural isomers.[8] [9] [10] In 2009, the Xu group reported the first total synthesis of (–)-8-epigrosheimin from (S)-carvone in 15 steps, where the 5-7-5-tricyclic core was built up in 7 steps via Mukaiyama aldol reaction of silyl enol ether of butyrolactone and O-MOM Lee–Ley aldehyde[11] derived from (S)-carvone with moderate diastereoselectivity (dr 76:24) and the α-methylene unit of the tricyclic butyrolactone core was introduced at a late stage.[8] Later, the same group developed a nice strategy with a prior construction of α-methylene-γ-butyrolactone via Reformatsky-type reaction of (S)-carvone-derived ketoaldehyde and accomplished the synthesis of (–)-epigrosheimin in 11–14 steps, which needs additional steps for trans-lactonization and protection–deprotection of the α-methylene unit of the butyrolactone unit for successful ene cyclization.[9] In 2017, our group reported[10] the first unified strategy for asymmetric total synthesis of naturally occurring (+)-chinensiolide B and (+)-8-epigrosheimin from (R)-(–)-carvone where the 5-7-5-tricyclic butyrolactone core was constructed in 4 steps via Evans syn-aldol reaction of the O-TBS Lee–Lay aldehyde[11] and succinyl acid derivative and chemoselective reductive lactonization reaction with excellent diastereoselectivity (dr >99:1) followed by oxidation and ene cyclization with the desired stereochemistry (dr: >99:1). The α-methylene unit of butyrolactone moiety was also fixed at the late stage using Eschenmoser’s salt.

Recently, we have designed and developed an efficient catalyst-free tandem allylboration–lactonization reaction for single-step trans-fused α-methylene-γ-butyrolactone motif in the early stage and accomplished a concise and scalable synthesis of eupalinilide E, a promoter of human hematopoietic stem and progenitor cells (HSPCs), from (R)-(–)- carvone in 12 steps with high overall yield.[12] Our interest in the asymmetric synthesis of butyrolactone natural products[10] ^, [12] [13] [14] encouraged us to explore our recently developed tandem allylboration–lactonization strategy in the synthesis of biologically important 8-epigrosheimin. Herein, we unveil an efficient and scalable asymmetric total synthesis of (+)-8-epigrosheimin from commercially available (R)-(–)-carvone with high overall yield using minimum column chromatography.

Based on our earlier work,[10] [12] we envisioned that (+)-8-epigrosheimin (1) can be obtained via tandem allylboration–lactonization of aldehyde 2 or 3 with (Z)-allylboronate 4 and subsequent ene cyclization (Scheme [1]). Z-Stereochemistry of 4 is mandatory for the desired trans-lactone. Both the aldehydes can be synthesized from (R)-(–)- carvone (5) and allylboronate 4 from O-TBS propargyl alcohol 6.

Total synthesis of (+)-8-epigrosheimin commenced with the preparation of both the aldehydes 2/3 and allylboronate 4. The O-TBS-protected Lee–Lay aldehyde 2 was synthesized in six steps from (R)-(–)-carvone with a high overall yield (86%) using the literature procedure with few modifications,[11] where multigram scale sequential reactions were developed without any column chromatographic purification of the intermediate compounds 7–9 (Scheme [2]). This afforded a higher overall yield than the reported one. We have recently developed an efficient tandem Favorskii rearrangement and elimination reaction for the chromatographic-free multigram scale synthesis of aldehyde 3 in six steps from (R)-(–)-carvone with 66% of overall yield (Scheme [2]).[12] It is worth noting here that the Siegel group earlier reported the synthesis of aldehyde 3 in eight steps from (R)-(–)-carvone with an overall yield of 22%, where an intermediate compound produced a mixture of regioisomers.[15] This β,γ-unsaturated aldehyde, namely Seigel–Hajra aldehyde 3, is found to be very prone to isomerization even under mild acidic or basic conditions. So, base-free Dess–Martin periodinane (DMP) oxidation of the intermediate alcohol was developed in the presence of a trace amount of water (5 equiv.), and silica gel column chromatographic purification was avoided in the final step. The periodinane impurities were removed by precipitation from hexane at –78 °C.

Allylboronate 4 was prepared from O-TBS propargyl alcohol 6 in two steps following the method developed in our lab.[12] Reaction of O-TBS-propargyl alcohol with n-BuLi and methyl chloroformate at –78 °C gave methyl 4-[(tert-butyldimethylsilyl)oxy]but-2-ynoate (12). Reductive alkylation of 12 was carried out by treatment with DIBAL-H and BpinCH₂I at 0 °C in the presence of HMPA and gave allylboronate 4 with 2.1:1 Z-selectivity, and it showed excellent Z-selectivity of 4 (>25:1) at –55 °C, but with lower yield (40%).

With a sufficient quantity of aldehydes 2/3 and allylboronate 4 in hand, we made our effort for their tandem allylboration–lactonization reaction (Scheme [3]). Usually, allylboration is known to undergo in the presence of Lewis/Brønsted acid catalyst.[16] Since aldehyde 3 was found to be sensitive to acid, we recently developed catalyst-free tandem allylboration–lactonization at 65 °C under sealed tube conditions for the total synthesis of eupalinilide E, where trifluoroethanol (TFE) was found to be an efficient promoter and solvent. We further observed that only a Z-isomer of 4 undergoes selective allylboration–lactonization under the optimized conditions. Since high Z-selectivity of allylboronate compromises with its yield and required cryogenic conditions, here we intended to explore the tandem allylboration–lactonization with 4 of moderate Z-selectivity (Z/E 2.1:1).

We initially followed the same reaction conditions as earlier optimized for the aldehyde 3. But heating the solution of 2 and 4 (Z/E = 2.1:1) in TFE at 65 °C showed incomplete conversion even after 5 days. Pleasingly, increasing the temperature to 90 °C, the reaction was completed within 3 days and afforded the α-methylene-γ-butyrolactone derivative 13 with excellent diastereoselectivity (dr >99:1) in 70% yield after acidic workup of the reaction mixture, where both primary and secondary O-TBS groups were deprotected.[17] When we used 4 with Z/E >25:1, it gave 13 with 74% yield. This observation indicates that the Z/E ratio of 4 has minimal effect on the allylboration–lactonization reaction step. It is to be noted that in both cases, a Z-isomer of 4 was used as a limiting substrate, which was calculated based on their Z/E ratio in the mixture. Further, >90% of TFE was recovered by distillation before the acidification for bulk-scale reaction. Furthermore, the high desired stereoselectivity of 13 might be owing to a hybrid chairlike transition structure model A, where a combined effect of multiple H-bonding of TFE, particularly with alkoxy groups of boronate, boosts up the reactivity and selectivity.[12] [16b] Its stereochemistry was reconfirmed later with the total synthesis of the target compound. The next crucial step was the oxidation of both hydroxyl groups and subsequent selective ene cyclization between the aldehyde and isopropylene units of 14 over ketocarbonyl. Here also, the aldehyde is prone to isomerization, which was also reported by the Xu group, where they used pyridine as a solvent that might be the cause of isomerization.[9] We have overcome earlier the hitches by using base-free DMP oxidation followed by ene cyclization of the crude aldehyde.[12] We followed a similar protocol here. DMP-mediated dual oxidation of 13 gave the ketoaldehyde 14, where ketoaldehyde formation was monitored by MS analysis. The crude compound 14 was treated with diethyl aluminum chloride at –78 °C in CH₂Cl₂. It underwent smoothly the desired aldehyde–ene cyclization affording directly (+)-8-epigrosheimin (1) with 13:1 diastereoselectivity. Colum chromatographic purification gave pure 1 (dr >99:1) in 78% yield over two steps.[18] So, we accomplished the total synthesis of (+)-8-epigrosheimin (1) in three steps from Lee–Lay aldehyde with an overall yield of 54.6% and a total of nine steps from (R)-carvone with an overall yield of 47.0% involving only three column chromatographic purifications.

Alternatively, we also executed the synthesis of (+)-8-epigrosheimin from tricyclic butyrolactone 16, which was previously synthesized in 75% yield by allylboration–lactonization of 3 and 4 (Z/E >25:1).[12] Interestingly, when the allylboration–lactonization of 3 and 4 (Z/E = 2.1:1) was carried out under earlier optimized conditions at 65 °C, it gave a similar yield of 15 (70%). Regioselective epoxidation of the more substituted alkene unit of the cyclopentyl ring followed by BF₃·Et₂O-mediated epoxide rearrangement reaction[19] gave crude 1 with 5:1 diastereoselectivity at the C4-methyl center and column chromatographic purification afforded (+)-8-epigrosheimin (1) with >99:1 diastereoselectivity in 70% yield. So, the total synthesis of (+)-8-epigrosheimin (1) from 3 is completed in five steps with an overall yield of 36.8% and a total of eleven steps from (R)-carvone with an overall yield of 24.3%.[20]

In conclusion, we accomplished the synthesis of natural isomer (+)-8-epigrosheimin from (R)-(–)- carvone via tandem allylboration–lactonization with high overall yield. The total synthesis via Lee–Lay aldehyde is more efficient and concise affording 47.0% overall yield from (R)-carvone in a total of nine steps that require only three column chromatographic purifications. On the other hand, synthesis through Seigel–Hajra aldehyde requires eleven steps and provides 24.3% overall yield. Other key features of our synthesis are (i) pot economy, (ii) minimum column chromatography, (iii) installation of an α-methylene-γ-butyrolactone motif in a single step and early stage, (iv) catalyst-free tandem allylboration–lactonization, (v) scalability, and (vi) recovery and reusability of TFE. Furthermore, the developed tandem allylboration–lactonization followed by ene cyclization could be a versatile strategy for the synthesis of both enantiomers of the tricyclic framework of many guaianolides and their total synthesis.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 17 Synthesis of Compound 13 Trifluoroethanol (15 mL) was stirred with a mixture of solid anhydrous NaHCO₃ and a pinch of solid anhydrous MgSO₄ and filtered through a sintered glass funnel. A solution of (R)-carvone-derived aldehyde 2 (1.7 g, 5.95 mmol, 1.3 equiv.) and O-TBS allylboronate 4 (1.7 g, 4.75 mmol, 1.0 equiv.) in pretreated trifluoroethanol (10 mL) were charged in a sealed tube and it was heated to 90 °C in a pre-heated oil bath. After 3.0 days, the reaction mixture was cooled to room temperature. Trifluoroethanol was removed in vacuo and recovered for reuse in the next batch. The crude materials were dissolved in a 1:1 mixture of THF (20 mL) and MeOH (20 mL). 1(N) HCl (10 mL) was then added and stirred at rt for 3 h. The reaction mixture was diluted with a saturated aqueous KH₂PO₄ solution and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo affords crude oil. The purification of crude product using flash chromatography (silica gel, EtOAc/PE = 3:2) yielded lactone alcohol 13 (0.88 g, 3.2 mmol, 70%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.29 (d, J = 2.7 Hz, 1 H), 5.69 (d, J = 2.4 Hz, 1 H), 4.93 (s, 1 H), 4.86 (s, 1 H), 4.38 (dd, J = 5.2, 2.6 Hz, 1 H), 4.22 (m, 1 H), 3.72 (dd, J = 6.3, 10.7 Hz, 2 H), 3.11–3.01 (m, 1 H), 2.95 (m, 1 H), 2.14–1.89 (m, 4 H), 1.78 (s, 3 H), 1.71 (dd, J = 13.1, 6.2 Hz, 2 H), 1.12 (d, J = 6.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 144.0, 136.3, 123.2, 112.9, 81.0, 74.4, 64.0, 50.7, 46.2, 45.5, 39.2, 38.3, 23.4, 16.2. [α]_D ²⁵ 46.25 (c 0.16, CHCl₃). HRMS (ESI): m/z calcd for C₁₅H₂₃O₄ [M + H]⁺: 267.1591; found: 267.1585; C₁₅H₂₂NaO₄ [M + Na]⁺: 289.1410; found: 289.1403.
• 18 Synthesis of (+)-8-Epigrosheimin 1 from Compound 13 To a stirred solution of lactone alcohol 13 (0.12 g, 0.45 mmol, 1.0 equiv.) in CH₂Cl₂ (4.5 mL) at 0 °C Dess–Martin periodinane (0.76 g, 1.8 mmol, 4.0 equiv.) and H₂O (0.032 mL, 1.8 mmol, 4.0 equiv.) were added successively. The mixture was stirred at rt for 6 h. After the total consumption of lactone alcohol 13, saturated aqueous NaHCO₃ was added dropwise, followed by a saturated aqueous Na₂S₂O₃ solution. Two layers were separated after standing. The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). First, the combined organic layers were washed with NaHCO₃, then brine, dried over anhydrous MgSO₄, and filtered. The CH₂Cl₂ solution (ca. 20 mL) was charged in a flame-dried two-neck round-bottomed flask and flashed with Ar. The reaction mixture was stirred for ca. 0.5 h at –78 °C. Et₂AlCl (0.5 mL, 0.45 mmol, 1.0 equiv., 0.9 M in toluene) was added dropwise. After 0.5 h, a saturated aqueous KH₂PO₄ solution was added and stirred at rt for 2 h. Finally, the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo afforded crude product. The purification of the crude mixture using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (80 mg, 0.31 mmol, 78%; dr >99:1) as a white solid; mp 132–135 °C, lit.⁸ 137–138 °C (diethyl ether/petroleum ether); [[α]_D ²⁵ 30.5 (c 0.24, CHCl₃), lit.⁸ [α]_D ²⁵ 31.5 ± 1 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.45 (d, J = 3.5 Hz, 1 H), 5.68 (d, J = 3.0 Hz, 1 H), 5.09 (s, 1 H), 4.84 (s, 1 H), 4.55 (t, J = 9.2 Hz, 1 H), 4.46 (s, 1 H), 3.17–3.12 (m, 1 H), 3.06 (td, J = 8.1, 3.3 Hz, 1 H), 2.69 (dd, J = 13.9, 3.0 Hz, 1 H), 2.60–2.54 (m, 2 H), 2.50 (dd, J =13.7, 4.1 Hz, 1 H) 2.39–2.24 (m, 2 H), 1.28 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 219.2, 169.5, 143.8, 136.2, 122.2, 116.2, 81.2, 66.2, 50.5, 48.7, 47.3, 46.8, 44.0, 40.1, 14.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085.
• 19 Fernandes RA, Ramakrishna GV. J. Org. Chem. 2024; 89: 815
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• 20 Synthesis of (+)-8-Epigrosheimin 1 from Compound 16 To a stirred solution of 16 (0.03 g, 0.12 mmol, 1.0 equiv.) in CH₂Cl₂ (3 mL) at 0 °C, m-CPBA (65 wt%, 0.03 g, 0.12 mmol, 1.0 equiv.) was added to it at the same temperature. The resulting suspension was stirred for 1 h at the same temperature. After complete consumption 16, the reaction was quenched with saturated Na₂SO₃ solution (30 mL). The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude epoxide product 17. The crude product 17 was used directly in the next step. ¹H NMR (400 MHz, CDCl₃): δ = 6.41 (d, J = 3.6 Hz, 1 H), 5.57 (d, J = 3.2 Hz, 1 H), 5.00 (d, J = 1.8 Hz, 1 H), 4.84 (d, J = 1.8 Hz, 1 H), 4.40 (dd, J = 11.2, 8.3 Hz, 1 H), 4.29 (td, J = 8.0, 3.4 Hz, 1 H), 3.37 (s, 1 H), 3.04–2.92 (m, 2 H), 2.74 (dd, J = 13.6, 8.0 Hz, 1 H), 2.28 (dd, J = 11.3, 8.4 Hz, 1 H), 2.10–2.00 (m, 2 H), 1.83 (dd, J = 14.3, 11.0, 1 H), 1.59 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.6, 142.22, 135.5, 122.0, 117.6, 75.7, 66.5, 66.0, 63.3, 51.3, 49.4, 45.1, 37.2, 33.1, 18.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085. The crude product 17 was used directly in the next step. To a stirred solution of epoxide (0.12 mmol) in dry CH₂Cl₂ (5 mL) at 0 °C, BF₃·OEt₂ (35 mg, 0.14 mmol, 2.0 equiv.) was added under nitrogen at the same temperature and stirred for 1 h. After complete consumption of 17 monitored by TLC, a saturated NaHCO₃ solution was added to it to quench the reaction. The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude product 1 (dr: 5:1). The purification of the crude product using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (22 mg, 0.084 mmol, 70%; dr >99:1) as a white solid.

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Eingereicht: 09. August 2024

Angenommen nach Revision: 10. September 2024

Accepted Manuscript online:
10. September 2024

Artikel online veröffentlicht:
09. Oktober 2024

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• References and Notes

• 1 Ando M, Ibayashi K, Minami N, Nalmjra T, Isogal K, Yoshimlir H. J. Nat. Prod. 1994; 57: 433
  CrossrefSuche in Google Scholar
• 2a Hu X, Musacchio AJ, Shen X, Tao Y, Maimone TJ. J. Am. Chem. Soc. 2019; 141: 14904
  CrossrefPubMedSuche in Google Scholar
• 2b Andersen TB, López CQ, Manczak T, Martinez K, Simonsen HT. Molecules 2015; 20: 6113
  CrossrefPubMedSuche in Google Scholar
• 2c Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N. Drug Discovery Today 2010; 15: 668
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• 2d Li J, Li S, Guo J, Li Q, Long J, Ma C, Ding Y, Yan C, Li L, Wu Z, Zhu H, Li KK, Wen L, Zhang Q, Xue Q, Zhao C, Liu N, Ivanov I, Luo M, Xi R, Long H, Wang PG, Chen Y. J. Med. Chem. 2018; 61: 4155
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• 4 Brill ZG, Condakes ML, Ting CP, Maimone TJ. Chem. Rev. 2017; 117: 11753
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• 7 Barbetti P, Casinovi CG, Santurbano B, Longo R. Collect. Czech. Chem. Commun. 1979; 44: 3123
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• 8 Yang H, Qiao X, Li F, Ma H, Xie L, Xu X. Tetrahedron Lett. 2009; 50: 1110
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• 9 Yang H, Gao Y, Qiao X, Xie L, Xu X. Org. Lett. 2011; 13: 3670
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  Thieme Connect

For selected examples, see:
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• 17 Synthesis of Compound 13 Trifluoroethanol (15 mL) was stirred with a mixture of solid anhydrous NaHCO₃ and a pinch of solid anhydrous MgSO₄ and filtered through a sintered glass funnel. A solution of (R)-carvone-derived aldehyde 2 (1.7 g, 5.95 mmol, 1.3 equiv.) and O-TBS allylboronate 4 (1.7 g, 4.75 mmol, 1.0 equiv.) in pretreated trifluoroethanol (10 mL) were charged in a sealed tube and it was heated to 90 °C in a pre-heated oil bath. After 3.0 days, the reaction mixture was cooled to room temperature. Trifluoroethanol was removed in vacuo and recovered for reuse in the next batch. The crude materials were dissolved in a 1:1 mixture of THF (20 mL) and MeOH (20 mL). 1(N) HCl (10 mL) was then added and stirred at rt for 3 h. The reaction mixture was diluted with a saturated aqueous KH₂PO₄ solution and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo affords crude oil. The purification of crude product using flash chromatography (silica gel, EtOAc/PE = 3:2) yielded lactone alcohol 13 (0.88 g, 3.2 mmol, 70%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.29 (d, J = 2.7 Hz, 1 H), 5.69 (d, J = 2.4 Hz, 1 H), 4.93 (s, 1 H), 4.86 (s, 1 H), 4.38 (dd, J = 5.2, 2.6 Hz, 1 H), 4.22 (m, 1 H), 3.72 (dd, J = 6.3, 10.7 Hz, 2 H), 3.11–3.01 (m, 1 H), 2.95 (m, 1 H), 2.14–1.89 (m, 4 H), 1.78 (s, 3 H), 1.71 (dd, J = 13.1, 6.2 Hz, 2 H), 1.12 (d, J = 6.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 144.0, 136.3, 123.2, 112.9, 81.0, 74.4, 64.0, 50.7, 46.2, 45.5, 39.2, 38.3, 23.4, 16.2. [α]_D ²⁵ 46.25 (c 0.16, CHCl₃). HRMS (ESI): m/z calcd for C₁₅H₂₃O₄ [M + H]⁺: 267.1591; found: 267.1585; C₁₅H₂₂NaO₄ [M + Na]⁺: 289.1410; found: 289.1403.
• 18 Synthesis of (+)-8-Epigrosheimin 1 from Compound 13 To a stirred solution of lactone alcohol 13 (0.12 g, 0.45 mmol, 1.0 equiv.) in CH₂Cl₂ (4.5 mL) at 0 °C Dess–Martin periodinane (0.76 g, 1.8 mmol, 4.0 equiv.) and H₂O (0.032 mL, 1.8 mmol, 4.0 equiv.) were added successively. The mixture was stirred at rt for 6 h. After the total consumption of lactone alcohol 13, saturated aqueous NaHCO₃ was added dropwise, followed by a saturated aqueous Na₂S₂O₃ solution. Two layers were separated after standing. The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). First, the combined organic layers were washed with NaHCO₃, then brine, dried over anhydrous MgSO₄, and filtered. The CH₂Cl₂ solution (ca. 20 mL) was charged in a flame-dried two-neck round-bottomed flask and flashed with Ar. The reaction mixture was stirred for ca. 0.5 h at –78 °C. Et₂AlCl (0.5 mL, 0.45 mmol, 1.0 equiv., 0.9 M in toluene) was added dropwise. After 0.5 h, a saturated aqueous KH₂PO₄ solution was added and stirred at rt for 2 h. Finally, the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo afforded crude product. The purification of the crude mixture using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (80 mg, 0.31 mmol, 78%; dr >99:1) as a white solid; mp 132–135 °C, lit.⁸ 137–138 °C (diethyl ether/petroleum ether); [[α]_D ²⁵ 30.5 (c 0.24, CHCl₃), lit.⁸ [α]_D ²⁵ 31.5 ± 1 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.45 (d, J = 3.5 Hz, 1 H), 5.68 (d, J = 3.0 Hz, 1 H), 5.09 (s, 1 H), 4.84 (s, 1 H), 4.55 (t, J = 9.2 Hz, 1 H), 4.46 (s, 1 H), 3.17–3.12 (m, 1 H), 3.06 (td, J = 8.1, 3.3 Hz, 1 H), 2.69 (dd, J = 13.9, 3.0 Hz, 1 H), 2.60–2.54 (m, 2 H), 2.50 (dd, J =13.7, 4.1 Hz, 1 H) 2.39–2.24 (m, 2 H), 1.28 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 219.2, 169.5, 143.8, 136.2, 122.2, 116.2, 81.2, 66.2, 50.5, 48.7, 47.3, 46.8, 44.0, 40.1, 14.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085.
• 19 Fernandes RA, Ramakrishna GV. J. Org. Chem. 2024; 89: 815
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• 20 Synthesis of (+)-8-Epigrosheimin 1 from Compound 16 To a stirred solution of 16 (0.03 g, 0.12 mmol, 1.0 equiv.) in CH₂Cl₂ (3 mL) at 0 °C, m-CPBA (65 wt%, 0.03 g, 0.12 mmol, 1.0 equiv.) was added to it at the same temperature. The resulting suspension was stirred for 1 h at the same temperature. After complete consumption 16, the reaction was quenched with saturated Na₂SO₃ solution (30 mL). The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude epoxide product 17. The crude product 17 was used directly in the next step. ¹H NMR (400 MHz, CDCl₃): δ = 6.41 (d, J = 3.6 Hz, 1 H), 5.57 (d, J = 3.2 Hz, 1 H), 5.00 (d, J = 1.8 Hz, 1 H), 4.84 (d, J = 1.8 Hz, 1 H), 4.40 (dd, J = 11.2, 8.3 Hz, 1 H), 4.29 (td, J = 8.0, 3.4 Hz, 1 H), 3.37 (s, 1 H), 3.04–2.92 (m, 2 H), 2.74 (dd, J = 13.6, 8.0 Hz, 1 H), 2.28 (dd, J = 11.3, 8.4 Hz, 1 H), 2.10–2.00 (m, 2 H), 1.83 (dd, J = 14.3, 11.0, 1 H), 1.59 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.6, 142.22, 135.5, 122.0, 117.6, 75.7, 66.5, 66.0, 63.3, 51.3, 49.4, 45.1, 37.2, 33.1, 18.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085. The crude product 17 was used directly in the next step. To a stirred solution of epoxide (0.12 mmol) in dry CH₂Cl₂ (5 mL) at 0 °C, BF₃·OEt₂ (35 mg, 0.14 mmol, 2.0 equiv.) was added under nitrogen at the same temperature and stirred for 1 h. After complete consumption of 17 monitored by TLC, a saturated NaHCO₃ solution was added to it to quench the reaction. The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude product 1 (dr: 5:1). The purification of the crude product using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (22 mg, 0.084 mmol, 70%; dr >99:1) as a white solid.

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