2024 Volume 72 Issue 6 Pages 547-558
Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson–Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3–C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.
Iridoids are a group of monoterpenoids that are isolated from various plant species.1–5) Natural iridoids are used in traditional medicine in order to prevent and treat inflammation, cancer, neurological disorders and aging.6) Due to such variety in biological activities, iridoids have attracted research attention in the field of drug discovery. Iridoids mostly possess a cis-fused cyclopenta[c]pyran ring as a basic skeleton. Representative chemical structures of iridoids are shown in Fig. 1 to overview the categories of this class of natural products. Compounds modified by glycosylation, such as aucubin (1)7) and secologanin (2),8) are categorized into iridoid glycosides. Iridoid glycoside 2 along with oleonin (3)9) are subdivided into secoiridoid that are characterized by a cleavage between C7 and C8 bond in the cyclopentane ring. The iridoids that contain a lactone moiety at the 6-membered ring constitute a series of iridoid lactones including nepetalactone (4),10) teucriumlactone (5),11) umbellatolide B (6)12) and viteoid II (7).13,14) Compounds that lack C11 part are categorized as 11-noriridoids. In addition to 1, aucubigenin (8), 10-O-benzoylglobularigenin (9),15) and iridoid lactones 6 and 7 belong to this class of compounds. The compounds presented in Fig. 1 demonstrate the diversity of chemical structures of natural iridoids. Subtle structural differences in the basic skeletons contribute to a wide range of biological activities. These properties increase the utility of iridoids in drug development.
Aucubin (1) and secologanin (2) are depicted as the representative compounds of iridoid glycosides in the red square. Compound 2 and oleonin (3) are depicted as the representative compounds of secoiridoids in the green square. Nepetalactone (4), teucriumlactone (5), umbellatolide B (6) and viteoid II (7) are depicted as the representative compounds of iridoid lactones in the gray square. Compounds 1, 6, 7, aucubigenin (8) and 10-O-benzoylglobularigenin (9) that are drawn in blue are depicted as the representative compounds of 11-noriridoids. Glc: glucose.
The characteristic skeleton of iridoids has long been an intriguing target in total synthesis. Several groups have reported synthetic studies of iridoids focusing on the construction of the cyclopenta[c]pyran skeleton.16) In the last two decades, to the best of our knowledge, total syntheses of semperoside A,17) brasoside and littoralisone,18) geniposide,19) 7-deoxyloganin,20) 2 and related indole alkaloid glycosides21–23) have been achieved. In addition, some iridoid lactones, such as jatamanins, gastrolactone, 424) and 5,25,26) have been synthesized in a comprehensive fashion via the transformation of the bicyclic lactones. The synthetic routes developed in these studies are ingenious, and versatile iridoids were furnished. On the other hand, the diverse chemical structures of iridoids motivate further efforts to synthesize different types of iridoid natural products. In particular, highly functionalized iridoids that have multiple hydroxy groups on the cyclopentane ring still need to be investigated in order to establish a new concise synthetic route, because the reported synthetic routes for natural iridoids are mostly designed for obtaining compounds that contain a monohydroxy cyclopentane ring.
Among polyfunctionalized iridoids, aucubin (1) was isolated from several plants, including Aucuba japonica, Eucommia ulmoides and Plantago asiatica.7) Because compound 1 has a wide range of biological activities; anti-aging, anti-inflammatory, anti-microbial, anti-virous and neuroprotective effects, the development of a synthetic route for aglycon part 8 is advantageous for building a library of iridoid-related compounds. Meanwhile, only a few amount of 11-noriridoids, including 6 and 9, have been isolated from natural sources12,15) and the biological activities of these rare iridoids remain unexplored. To date, it was reported that 7 exhibits inhibitory activity against paclitaxel-induced mechanical allodynia.14) This example suggests that 11-noriridoids have a potential for the discovery of new interesting biological activities.
In this paper, our efforts for the synthesis of 11-noriridoids, including 6, 9, and 1-O-protected aucubigenin, are described.
To synthesize 11-noriridoids, the examination of a common synthetic strategy was thought to be effective for the construction of the cyclopenta[c]pyran core skeleton that have two hydroxy groups. As shown in Chart 1a, Marco-Contelles and Ruiz reported the synthesis of tricyclic enone 11 via the Pauson–Khand reaction.27) While various conditions are examined, the tricyclic enone 11 is obtained in a moderate yield due to the decomposition of the substrate 10 under the Pauson–Khand reaction conditions. Similar types of Pauson-Khand reaction using carbohydrate derivatives, which contain a slightly different substituents or an opposite stereochemistry on a dihydropyran ring, were reported.28–31) These substrates are tolerated with this strategy to provide moderate to good yields of the cyclic products. Therefore, optimization of substrates for this reaction by replacing the substituent or investigation of the stereochemistry at C3 of 10 might be effective for this process. Although it was suggested that 11 can be a synthetic intermediate for the iridoid synthesis, no effective synthetic pathway using 11 has been developed. Hence, we decided to incorporate this efficient synthetic strategy with the Pauson–Khand reaction into our synthesis.
(a) Reported synthetic strategy for tricyclic enone 11. (b) Retrosynthetic analysis of 6, 8 and 9.
The retrosynthetic analysis of 11-noriridoids 6, 8, and 9 is shown in Chart 1b. The transformation into the alcohol at C6 of 6, 8, and 9 was planned via 1,2-reduction of enone 12. Cis-fused cyclopenta[c]pyran 12 would be synthesized by cleavage of the acetal bond of tricyclic enone 13. Tricyclic skeleton 13 can be obtained by the Pauson–Khand reaction of 14.
For the synthesis of 6 and 9, dihydropyran 15 was converted to (±)-enyne 16 in two steps via bromoetherification and dehydrobromination32) (Chart 2). The Pauson–Khand reaction using Co2(CO)8 and N-methylmorpholine N-oxide (NMO) with 16 smoothly proceeded to provide tricyclic enone 17 in a yield of 79%.27,32) Then, ring opening of the tetrahydrofurane moiety upon the acetal cleavage of 17 in the presence of Sm(OTf)333) was examined to furnish enone 18 (Table 1).
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Methanol was first tested to cleave the acetal bond of 17, and 18a was selectively obtained in 40% yield (entry 1). The tetrahydrofuran ring of 17 was selectively opened, and the desired cis-fused cyclopenta[c]pyran skeleton was generated under these conditions. This selectivity of the acetal cleavage could be due to the thermodynamic stability of the 5,6-fused ring skeleton 18 compared to that of the other 5,5-fused ring skeleton. Then, the alcohols used for the acetal-bond cleavage of 17 were examined. In the case of 2-methylpropan-2-ol or benzyl alcohol, 18b and 18c were afforded in moderate yields (entries 2 and 3). Subsequently, the use of allyl alcohol and 4-pentene-1-ol with the reaction time of 3–5 h improved the chemical yields of the products, and 18d and 18e were obtained in yields of 79% (entry 4) and 67% (entry 5), respectively.
The relative configuration at C1 of 18e was determined by nuclear Overhauser effect (NOE) experiments (Fig. 2). The positions of H9 and H5 showed a high correlation, while H9 and H1 showed a low correlation. Moreover, a correlation between H1 and H3 was observed with 5.3%. These results suggested that the alcohol was integrated from the convex surface of 17 in this acetal-bond cleavage.
In the initial attempt toward the synthesis of natural products, 18d was used for a further transformation; however, the allylic moiety of 18d could not be removed (PdCl2 then NIS, potassium tert-butoxide (tert-BuOK) and 18-crown-6 for isomerization of the allylic moiety to a vinyl ether). Therefore, 18e was selected as the substrate for the next examination.
The enone 18e was converted to a diol via 1,2-reduction (Chart 3). The mixture of diastereomers at C6 was not separated by silica gel column chromatography. Therefore, the alcohol moieties of the mixture were protected by picolinoyl groups,34) and then the diastereomers were separated to give the picolinate ester 19. The 1,2-reduction of 18e progressed preferentially from the convex surface, hence the minor diastereomer 19 was used for the next step. The pentenyl group of 19 was removed by using iodonium di-sym-collidine trifluoromethanesulfonate (IDCT),35,36) and the resulting lactol was oxidized to lactone 20. The picolinoyl groups of 20 were successfully removed by using Cu(OAc)2 in MeOH34) in a yield of 63% over three steps from 19. All the spectral data of the obtained compound were in good agreement with those previously reported for 6.12)
Further synthetic application using 18e was demonstrated with the synthesis of (±)-9. As shown in Chart 4, a benzoyl moiety was incorporated into the primary alcohol of 18e, and the enone moiety of 21 was reduced to the secondary alcohols 22 and 23 as a mixture of diastereomers at C6. After the separation of the minor diastereomer 23 by silica gel column chromatography, the removal of the pentenyl group with IDCT was examined. This deprotection successfully proceeded, and the spectroscopic data of the obtained compound showed good agreement with those of the isolated 9.15)
Subsequently, the synthesis of 8 that is an aglycon part of aucubin (1) was examined. As shown in Chart 5, the Pauson–Khand reaction was investigated for the synthesis of a tricyclic enone. According to the report by Marco-Contelles27) (Chart 1a), commercially available 3,4-di-O-acetyl-L-arabinal (24) was transformed into trans-dihydropyran 10 via Ferrier rearrangement. The β anomer of 10 was used as the substrate for the Pauson-Khand reaction to synthesize 11.27) Although generation of a cobalt-complex was observed, the desired compound 11 was not obtained due to substrate decomposition and product instability, regardless of the addition of a large amount of NMO or heating. Because modifications at the C3 position of 10 affect the reaction progress,27–31) the stereochemistry of the C3 substituent would also contribute this cycloaddition via the formation of the cobalt-complex. Therefore, trans-dihydropyran 10 was converted to cis-dihydropyran 25 in three steps in excellent yield. The Pauson-Khand reaction using 25 proceeded smoothly, and tricyclic enone 26 was obtained in a yield of 78%. The stereochemistry at C3 of 25 had an effect on the formation of the cobalt-complex and the progression of the cycloaddition while suppressing side reactions.
The acetal moiety of 26 was cleaved by using 4-penten-1-ol in the presence of a catalytic amount of Sm(OTf)3 to afford 27 (Chart 6). To construct the secondary alcohol at C6 in a stereoselective manner, transformation of the acetoxy group at C4 of 27 to a hydroxy group was thought to be effective in utilization as a directing group. At an initial examination, the removal of the acetyl group was attempted, however, this investigation induced the formation of undesired products [NaOMe in MeOH, Ba(OH)2 in MeOH] or decomposition of substrates (Et3N in MeOH/H2O, Me3SnNMe2 in toluene). Hence, the carbonyl group of 27 was selectively reduced using NaBH4 from the convex face, and the acetyl group at C4 was removed under basic conditions. The primary alcohol of triol 28 was protected with the Ac group for 29, and the allyl alcohol was selectively oxidized by using PDC in the presence of AcOH and MS4Å to provide 30. Then, the carbonyl group was reduced using NaBH(OAc)3 with the C4 alcohol as a directing group. This reduction proceeded effectively and the desired diol 31 was furnished as a single diastereomer in a yield of 90%.
The NOE correlation was compared for diols 29 and 31 to determine the absolute configuration of C6 (Fig. 3). For 29, the NOE correlations between H5 and H4 and between H5 and H6 were similar values. The NOE correlation between H5 and H4 of 31 was similar to that of 29, whereas the correlation between H5 and H6 of 31 was weaker compared to that of 29. These results suggested that the alcohol at C6 of 31 was inverted to the R configuration as the natural product.
The allyl alcohol of 31 was selectively protected by a benzoyl group to afford 32 (Chart 6). Then, the olefination of the tetrahydropyran ring was examined. In the initial investigation, the secondary alcohol at C4 was tried to convert to enol triflate. However, both the oxidation of the C4 alcohol to a corresponding ketone and its transformation into the enol triflate were unsuccessful due to the instability of the ketone. Hence, an elimination reaction was examined. Syn-elimination was expected to provide the desired olefin between C3 and C4. The secondary alcohol at C4 of 32 was converted to thiocarbamate 33 using 1,1-thiocarbonyldiimidazole in an excellent yield. Compound 33 was heated at 150 °C under microwave irradiation conditions in N,N-dimethylformamide (DMF) to furnish the syn-eliminated product. Then, the removal of the benzoyl and acetyl groups under basic conditions provided optically active 1-O-pentenylaucubigenin (34) in a yield of 88% over two steps. Although the removal of the pentenyl group of 34 was tried, examined conditions provided a complex mixture, most likely due to the instability of the lactol moiety.
In conclusion, our synthetic efforts toward the concise synthesis of 11-noriridoids, including (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34), were described. The common synthetic intermediates, tricyclic enones 17 and 26, were synthesized via the Pauson–Khand reaction in high yields. In particular, the use of cis-dihydropyran 25 to improve the yields of the Pauson–Khand reaction and the cleavage of the acetal bond contributed to the synthesis of the iridoid skeleton in a practical approach. Moreover, syn-elimination of the thiocarbamate of 33 successfully provided the C3–C4 olefin moiety of the cis-fused cyclopenta[c]pyran ring system for the synthesis of 34. Although the selection of the protecting groups was difficult, the removal of the pentenyl group was demonstrated for the syntheses of 6 and 9, and the picolinoyl group was removed in a final stage for 6. The developed synthetic route for 6, 9, and 34, as well as the synthetic intermediates can be utilized for the synthesis of iridoid derivatives in order to develop a library of iridoid-related compounds.
All reactions except those carried out in aqueous phase were performed under argon atmosphere, unless otherwise noted. Materials were purchased from commercial suppliers and used without further purification, unless otherwise noted. Solvents (CH2Cl2, MeOH, MeCN, EtOAc, pyridine, toluene and DMF) were distilled according to the standard protocol. Water was purified through Millipore Millia-Q Advantage A10. All reactions requiring heating were heated by using SynFlex. Microwave irradiation was performed by using Biotage Initiator 2.5. The weight of the starting materials and the products were not calibrated. Isolated yields were calculated by weighing products. Analytical TLC was performed on Merck silica gel 60 F254 plates. Normal-phase column chromatography was performed on Merck silica gel 60 (63–200 µm). Flash column chromatography was performed on Kanto Chemical Silica Gel 60N (spherical, neutral, 40–50 µm). High flash column chromatography was performed on YAMAZEN Hi-FlashTM column silica gel (40 µm) or Fuji Silysia Chromatorex MB/PSQ (50–200 µm). 1H-NMR were measured in CDCl3 or CD3OD solution, and reported in parts per million (ppm) relative to tetramethylsilane (0.00 ppm) as internal standard using JEOL JNM-ECA-500, JMM-ECS-400, JNM-ECX-400P and JNM-ECZ-400, unless otherwise noted. 13C-NMR were measured in CDCl3 or CD3OD solution, and referenced to residual solvent peaks of CDCl3 (77.16 ppm) or CD3OD (49.00 ppm) using JEOL JNM-ECA-500, JMM-ECS-400, JNM-ECX-400P and JNM-ECZ-400. Coupling constant (J) was reported in hertz (Hz). Abbreviations of multiplicity were as follows; s: singlet, d: doublet, t: triplet, q: quartet, quin: quintet, sext: sextet, m: multiplet, br: broad. Data were presented as follows; chemical shift (multiplicity, integration, coupling constant). Assignment was based on 1H–1H correlation spectroscopy (COSY) NMR spectra. Mass spectra were obtained on Advion expression CMS-L01 or Waters Xevo G2 QTof. Optical rotation was measured on a Rudolph Research Analytical Autopol IV automatic polarimeter.
Synthesis of Compounds(±)-6-(Prop-2-yn-1-yloxy)-3,6-dihydro-2H-pyran (16)To a solution of 3,4-dihydro-2H-pyran (15, 5.00 mL, 55.2 mmol) and propargyl alcohol (9.64 mL, 166 mmol) in CH2Cl2 (74 mL) was added N-bromosuccinimide (NBS) (10.8 g, 60.7 mmol, 1.1 equivalent (equiv.)) in small portions over 30 min at −30 °C. The mixture was warmed to room temperature and stirred for 1.5 h. The reaction was quenched with sat. aq. Na2S2O3/sat. aq. NaHCO3 (v/v 1/1) and the resulting mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ4.0 × 22 cm, 10% EtOAc/hexane) to afford an inseparable mixture containing bromotetrahydropyran (11.3 g). A solution of the mixture (11.3 g) in 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (38.7 mL, 259 mmol) was heated at 110 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with Et2O. The mixture was filtered through a plug of Celite and the residue was washed with Et2O. The filtrate was concentrated in vacuo at 0 °C. The residue was purified by flash silica gel column chromatography (Φ8.0 × 10 cm, 15% Et2O/pentane) to afford (±)-16 (1.43 g, 0.861 mmol, 79% over 2 steps) as a brown oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.12–6.04 (m, 1H, H-6), 5.73 (dddd, 1H, H-5, J5,6 = 10.2, J5,4 = J5,4 = 2.9, J5,1 = 1.4 Hz), 5.10 (s, 1H, H-1), 4.28 (m, 2H, H-8), 3.89 (ddd, 1H, H-3, Jgem = 11.5, J3,4 = J3,4 = 3.5 Hz), 3.72 (dddd, 1H, H-3, Jgem = 11.5, J3,4 = 5.8, J3,4 = J3,5 = 1.1 Hz), 2.42 (dd, 1H, H-10, J10,8 = J10,8 = 2.5 Hz), 2.37–2.26 (m, 1H, H-4), 1.93-1.86 (m, 1H, H-4). This is a known compound.32)
(±)-2a1,5,6,7a-Tetrahydro-2H-1,7-dioxacyclopenta[cd]inden-4(4aH)-one (17)A solution of (±)-16 (1.50 g, 10.9 mmol) in CH2Cl2 (435 mL) was treated with Co2(CO)8 (1.34 g, 11.4 mmol, 1.05 equiv.) at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and NMO (11.5 g, 98.1 mmol, 9.0 equiv.) was added to the mixture at once. After stirring for 3 h, the mixture was concentrated in vacuo. The residue was roughly purified by silica gel column chromatography (Φ6.0 × 12 cm, EtOAc) to afford crude products. The crude products were further purified by hi-flash silica gel column chromatography (Φ3.0 × 60 cm, 80→90% EtOAc/hexane) to afford (±)-17 (1.43 g, 0.861 mmol, 79%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.12 (dd, 1H, H-7, J7,10 = 1.5, J7,10 = 1.4 Hz), 5.40 (d, 1H, H-1, J1,9 = 5.0 Hz), 4.82 (ddd, 1H, H-10, Jgem = 15.7, J10,9 = 1.6, J10,7 = 1.4 Hz), 4.74 (ddd, 1H, H-10, Jgem = 15.7, J10,9 = 1.9, J10,7 = 1.5 Hz), 3.70 (ddd, 1H, H-3, Jgem = 12.4, J3,4 = 5.5, J3,4 = 4.1 Hz), 3.46 (ddd, 1H, H-3, Jgem = 12.4, J3,4 = 9.6, J3,4 = 3.2 Hz), 3.26–3.21 (m, 1H, H-9), 3.00 (ddd, 1H, H-5, J5,4 = 9.1, J5,9 = J5,4 = 6.4 Hz), 2.01–1.93 (m, 1H, H-4), 1.59–1.51 (m, 1H, H-4). This is a known compound.32)
(±)-7-(Hydroxymethyl)-1-methoxy-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-5(1H)-one (18a)A solution of (±)-17 (5.0 mg, 30.1 µmol) in MeOH (112 µL) was treated with Sm(OTf)3 (1.4 mg, 2.41 µmol, 0.08 equiv.) at room temperature for 2 h. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (80% EtOAc/hexane) to afford (±)-18a (2.40 mg, 12.1 µmol, 40%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.24 (s, 1H, H-7), 4.62 (d, 1H, H-10, Jgem = 17.6 Hz), 4.50 (d, 1H, H-10, Jgem = 17.6 Hz), 4.10 (d, 1H, H-1, J1,9 = 6.4 Hz), 3.92 (ddd, 1H, H-3, Jgem = 11.7, J3,4 = 5.9, J3,4 = 2.4 Hz), 3.48 (s, 3H, Me), 3.33 (ddd, 1H, H-3, J3,4 = 11.9, Jgem = 11.7, J3,4 = 3.2 Hz), 3.04 (dd, 1H, H-9, J9,5 = 6.7, J9,1 = 6.4 Hz), 2.73 (dd, 1H, H-5, J5,4 = 6.9, J5,9 = 6.7 Hz), 2.59 (br s, 1H), 2.12 (dddd, 1H, H-4, Jgem = 14.2, J4,3 = 3.2, J4,5 = 2.7, J4,3 = 2.4 Hz), 2.05–1.95 (m, 1H, H-4); 13C-NMR (CDCl3, 100 MHz) δ: 207.9, 178.6, 128.1, 104.8, 62.6, 62.3, 56.3, 46.2, 45.0, 22.3; electrospray ionization (ESI)MS-high resolution (HR) (ESI) m/z: [M + H]+ Calcd for C10H15O4 199.0970. Found 199.0971.
(±)-1-(tert-Butoxy)-7-(hydroxymethyl)-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-5(1H)-one (18b)A solution of (±)-17 (5.0 mg, 30.1 µmol) in tert-BuOH (112 µL) was treated with Sm(OTf)3 (1.44 mg, 2.41 µmol, 0.08 equiv.) at room temperature for 2 h. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc, and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (60% EtOAc/hexane) to afford (±)-18b (3.20 mg, 13.3 µmol, 44%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.16 (s, 1H, H-7), 4.66 (d, 1H, H-10, Jgem = 18.0 Hz), 4.52 (ddd, 1H, H-10, Jgem = 18.0, J10,7 = J10,9 = 0.9 Hz) 4.22 (d, 1H, H-1, J1,9 = 7.0 Hz), 3.91 (dddd, 1H, H-3, Jgem = 11.9, J3,4 = 6.3, J3,4 = 1.8, J3,5 = 0.9 Hz), 3.26 (ddd, 1H, H-3, J3,4 = 12.0, Jgem = 11.9, J3,4 = 3.6 Hz), 3.12 (dd, 1H, H-9, J9,1 = 7.0, J9,5 = 6.6 Hz), 2.75 (br s, 1H, OH-10), 2.73 (dd, 1H, H-5, J5,9 = 6.6, J5,4 = 6.3 Hz), 2.13 (dddd, 1H, H-4, Jgem = 14.5, J4,3 = 3.6, J4,3 = J4,5 = 1.8 Hz), 1.98–1.88 (m, 1H, H-4), 1.28 (s, 9H, tert-Bu); 13C-NMR (CDCl3, 100 MHz) δ: 207.6, 178.9, 127.5, 107.3, 100.9, 63.0, 62.8, 62.1, 47.0, 46.1, 29.0, 22.0; ESIMS-HR (ESI) m/z: [M + H]+ Calcd for C13H21O4 241.1440. Found 241.1445.
(±)-1-(Benzyloxy)-7-(hydroxymethyl)-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-5(1H)-one (18c)A solution of (±)-17 (5.0 mg, 30.1 µmol) in BnOH (112 µL) was treated with Sm(OTf)3 (1.44 mg, 2.41 µmol, 0.08 equiv.) at room temperature for 1 h. The reaction was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.0 × 6.0 cm, 60% EtOAc/hexane) to afford (±)-18c (3.40 mg, 12.4 µmol, 41%).
1H-NMR (CDCl3, 400 MHz) δ: 7.43–7.30 (m, 5H, Ph), 6.19 (s, 1H, H-7), 4.88 (d, 1H, H-12, Jgem = 11.3 Hz), 4.55 (d, 1H, H-10, Jgem = 17.3 Hz), 4.53 (d, 1H, H-12, Jgem = 11.3 Hz), 4.41 (d, 1H, H-10, Jgem = 17.3 Hz), 4.27 (d, 1H, H-1, J1,9 = 6.5 Hz), 3.98–3.93 (m, 1H, H-3), 3.35 (dd, 1H, H-3, Jgem = J3,4 = 11.6, J3,4 = 4.1 Hz), 3.12 (dd, 1H, H-9, J9,5 = 6.8, J9,1 = 6.5 Hz), 2.74 (ddd, 1H, H-5, J5,4 = 7.0, J5,9 = 6.8, J5,4 = 2.7 Hz), 2.37 (br s, 1H, OH-10), 2.16–1.99 (m, 2H, H-4); 13C-NMR (CDCl3, 100 MHz) δ: 207.8, 178.4, 136.8, 128.8, 128.5, 128.4, 128.2, 102.7, 70.6, 62.8, 62.2, 46.1, 45.0, 22.3; ESIMS-LR (ESI) m/z 297.2 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H18O4Na 297.1103. Found 297.1103.
(±)-1-(Allyloxy)-7-(hydroxymethyl)-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-5(1H)-one (18d)A solution of (±)-17 (493 mg, 2.97 mmol) in allyl alcohol (14.9 mL) was treated with Sm(OTf)3 (142 mg, 0.238 mmol, 0.08 equiv.) at room temperature for 5 h. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 40% EtOAc/hexane) to afford (±)-18d (527 mg, 2.35 mmol, 79%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.23 (s, 1H, H-7), 5.92 (dddd, 1H, H-13, J13,14 = 17.4, J13,14 = 10.3, J13,12 = 6.7, J13,12 = 5.6 Hz), 5.30 (dddd, 1H, H-14, J14,13 = 17.4, Jgem = J14,12 = J14,12 = 1.5 Hz), 5.23 (dd, 1H, H-14, J14,13 = 10.3, Jgem = 1.5 Hz), 4.64 (d, 1H, H-10, Jgem = 17.8 Hz), 4.50 (ddd, 1H, H-10, Jgem = 17.8, J10,7 = J10,9 = 0.9 Hz), 4.35 (dddd, 1H, H-12, Jgem = 12.5, J12,13 = 5.6, J12,14 = 1.5, J12,14 = 1.4 Hz), 4.21 (d, 1H, H-1, J1,9 = 6.5 Hz), 4.03 (dddd, 1H, H-12, Jgem = 12.5, J12,13 = 6.7, J12,14 = 1.5, J12,14 = 1.4 Hz), 3.91 (ddd, 1H, H-3, Jgem = 11.2, J3,4 = 5.5, J3,4 = 1.8 Hz), 3.32 (ddd, 1H, H-3, J3,4 = 11.4, Jgem = 11.2, J3,4 = 3.7 Hz), 3.09 (dd, 1H, H-9, J9,5 = 6.9, J9,1 = 6.5 Hz), 2.74 (ddd, 1H, H-5, J5,4 = 7.1, J5,9 = 6.9, J5,4 = 2.6 Hz), 2.34 (br s, 1H, OH-10), 2.15–2.09 (m, 1H, H-4), 2.06–1.96 (m, 1H, H-4); 13C-NMR (CDCl3, 100 MHz) δ: 208.3, 179.3, 133.5, 128.0, 118.2, 102.2, 69.3, 62.3, 62.1, 46.1, 44.7, 22.2; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C12H16O4Na 247.0946. Found 247.0950.
(±)-7-(Hydroxymethyl)-1-(pent-4-en-1-yloxy)-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-5(1H)-one (18e)A solution of (±)-17 (500 mg, 3.01 mmol) in 4-pentene-1-ol (5.0 mL) was treated with Sm(OTf)3 (35.9 mg, 0.150 mmol, 0.02 equiv.) at room temperature for 3 h. The reaction was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ3.0 × 10 cm, 50% EtOAc/hexane) to afford (±)-18e (610 mg, 2.42 mmol, 80%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.22 (s, 1H, H-7), 5.81 (dddd, 1H, H-15, J15,16 = 17.1, J15,16 = 10.3, J15,14 = J15,14 = 6.7 Hz), 5.04 (dddd, 1H, H-16, J16,15 = 17.1, Jgem = J16,14 = J16,14 = 1.6 Hz), 4.99 (dddd, 1H, H-16, J16,15 = 10.3, Jgem = 1.6, J16,14 = J16,14 = 1.5 Hz), 4.64 (dd, 1H, H-10, Jgem = 18.5, J10,OH-10 = 8.1 Hz), 4.51 (dd, 1H, H-10, Jgem = 18.5, J10,OH-10 = 4.0 Hz), 4.11 (d, 1H, H-1, J1,9 = 6.7 Hz), 3.94–3.85 (m, 2H, H-3, H-12), 3.44 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.7 Hz), 3.30 (ddd, 1H, H-3, Jgem = 11.9, J3,4 = J3,4 = 3.9 Hz), 3.06 (dd, 1H, H-9, J9,5 = 7.0, J9,1 = 6.7 Hz), 2.74 (ddd, 1H, H-5, J5,9 = J5,4 = 7.0, J5,4 = 2.2 Hz), 2.43 (dd, 1H, OH-10, JOH-10,10 = 7.1, JOH-10,10 = 5.1 Hz), 2.16–2.09 (m, 3H, H-4, H-14, H-14), 2.04–1.94 (m, 1H, H-4), 1.76–1.69 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 208.1, 179.1, 137.8, 128.0, 115.2, 103.7, 68.4, 62.6, 62.2, 46.2, 45.0, 30.3, 28.9, 22.2; ESIMS-LR (ESI) m/z 275.1 [M + Na]+; ESIMS-HR (ESI) m/z: [M + H]+ Calcd for C14H21O4 253.1440. Found 253.1446.
(±)-1-(Pent-4-en-1-yloxy)-5-(picolinoyloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Picolinate (19)A solution of (±)-18e (200 mg, 0.793 mmol) and CeCl3·7H2O (443 mg, 1.19 mmol, 1.5 equiv.) in MeOH (3.96 mL) was treated with NaBH4 (45.0 mg, 1.19 mmol, 1.5 equiv.) at 0 °C for 30 min. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ3.0 × 15 cm, 20% acetone/CHCl3) to afford an inseparable mixture of diastereomers (48.1 mg) as a colorless oil. A solution of the mixture (48.1 mg), Et3N (591 µL, 4.22 mmol) and DMAP (7.67 mg, 0.106 mmol) in CH2Cl2 (53.7 mL) was treated with picolinoyl chloride (PicCl, 598 mg, 4.22 mmol) at 0 °C for 12 h. The reaction mixture was diluted with CH2Cl2. The resulting mixture was partitioned between CH2Cl2 and H2O. The organic phase was washed with 1 M aq. HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (Φ1.8 × 10 cm, 80→90% EtOAc/hexane) to afford (±)-19 (56.4 mg, 0.121 mmol, 15% over 2 steps) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 8.77–8.75 (m, 2H, Pic), 8.15–8.08 (m, 2H, Pic), 7.87–7.80 (m, 2H, Pic), 7.50–7.44 (m, 2H, Pic), 6.03 (s, 1H, H-7), 5.88 (ddd, 1H, H-6, J6,5 = 3.7, J6,10 = J6,10 = 1.8 Hz), 5.80 (dddd, 1H, H-15, J15,16 = 17.2, J15,16 = 10.3, J15,14 = J15,14 = 6.7 Hz), 5.13–5.03 (m, 2H, H-10), 5.02 (dddd, 1H, H-16, J16,15 = 17.2, Jgem = J16,14 = J16,14 = 1.7 Hz), 4.95 (dddd, 1H, H-16, J16,15 = 10.3, Jgem = J16,14 = J16,14 = 1.8 Hz), 4.42 (d, 1H, H-1, J1,9 = 5.4 Hz), 3.96 (ddd, 1H, H-3, Jgem = 11.6, J3,4 = 5.1, J3,4 = 4.8 Hz), 3.84 (ddd, 1H, H-12, Jgem = 9.7, J12,13 = J12,13 = 6.7 Hz), 3.61 (ddd, 1H, H-3, Jgem = 11.6, J3,4 = 9.9, J3,4 = 3.6 Hz), 3.45 (ddd, 1H, H-12, Jgem = 9.7, J12,13 = J12,13 = 6.7 Hz), 2.93–2.86 (m, 2H, H-5, H-9), 2.15–2.10 (m, 2H, H-14), 1.90 (dddd, 1H, H-4, Jgem = 10.3, J4,3 = 9.9, J4,5 = 5.4, J4,3 = 5.1 Hz), 1.78–1.59 (m, 3H, H-4, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 165.4, 164.6, 150.1, 148.0, 147.8, 145.7, 138.2, 137.1, 137.1, 127.1, 127.0, 126.4, 125.4, 125.3, 115.0, 102.5, 82.3, 68.2, 63.4, 60.9, 48.0, 42.3, 30.4, 29.0, 24.3; ESIMS-LR (ESI) m/z 487.4 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C9H12O4Na 487.1845. Found 487.1841.
(±)-Umbellatolide B (6)A solution of (±)-19 (24.8 mg, 53.4 µmol) in MeCN (2.48 mL) was treated with iodonium di-sym-collidine trifluoromethanesulfonate (IDCT, 74.7 mg, 0.144 mmol) at room temperature for 30 min. The reaction was quenched with sat. aq. Na2S2O3/sat. aq. NaHCO3 (v/v 1/1), and the resulting mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.8 × 10 cm, 20→25% acetone/CHCl3) to afford inseparable diastereomers of a lactol. A solution of the mixture of the lactol in CH2Cl2 was treated with Dess-Martin periodinane (DMP, 34.0 mg, 81.0 µmol) at 0 °C. The mixture was warmed to room temperature and stirred for 18 h. The reaction was quenched with sat. aq. Na2S2O3/sat. aq. NaHCO3 (v/v 1/1), and the resulting mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a crude product containing 20. A solution of the crude product in MeOH (1.68 mL) was treated with Cu(OAc)2·H2O (10.7 mg, 53.4 µmol) at room temperature for 30 min. The mixture was filtered off through a short pad of silica gel, and washed with MeOH. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.2 × 10 cm, 10% MeOH/CHCl3) to afford (±)-umbellatolide B (6, 6.20 mg, 33.6 µmol, 63% over 3 steps) as a brown solid.
1H-NMR (CD3OD, 400 MHz) δ: 5.87 (br t, 1H, H-7, J7,10 = 1.6 Hz), 4.54 (br t, 1H, H-6, J = 1.8 Hz), 4.35–4.27 (m, 2H, H-3), 4.23 (d, 1H, H-10, Jgem = 15.3 Hz), 3.83 (d, 1H, H-9, J9,5 = 9.0 Hz), 2.66 (dddd, 1H, H-5, J5,9 = 9.0, J5,4 = 7.3, J5,4 = 7.1, J5,6 = 4.1 Hz), 2.23 (dddd, 1H, H-4, Jgem = 14.4, J4,5 = J4,3 = 7.3, J4,3 = 4.1 Hz), 1.78 (dddd, 1H, H-4, Jgem = 14.4, J4,5 = 7.1, J4,3 = 6.9, J4,3 = 3.2 Hz); 13C-NMR (CDCl3, 100 MHz) δ: 173.9, 145.3, 131.6, 83.0, 68.6, 61.1, 49.9, 46.3, 28.5; ESIMS-LR (ESI) m/z 239.1 [M + MeOH + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C9H12O4Na 207.0639. Found 207.0639.
(±)-5-Oxo-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Benzoate (21)A solution of (±)-18e (50.0 mg, 0.198 mmol), Et3N (83.5 µL, 0.570 mmol, 2.9 equiv.) and DMAP (7.25 mg, 57.0 µmol, 0.29 equiv.) in MeCN (1.98 mL) was treated with Bz2O (135 mg, 0.570 mmol, 2.9 equiv.) at room temperature for 1 h. The reaction mixture was diluted with EtOAc. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was washed with 1 M aq. HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 17% EtOAc/hexane) to afford (±)-21 (64.0 mg, 0.180 mmol, 91%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 8.10–8.07 (m, 2H, H-2′, H-6′), 7.61 (tt, 1H, H-4′, J4′,3′ = J4′,5′ = 7.6, J4′,2′ = J4′,6′ = 1.4 Hz), 7.50–7.46 (m, 2H, H-3′, H-5′), 6.27 (s, 1H, H-7), 5.82 (dddd, 1H, H-15, J15,16 = 17.2, J15,16 = 10.1, J15,14 = J15,14 = 6.7 Hz), 5.31 (dd, 1H, H-10, Jgem = 17.5, J10,7 = 1.8 Hz), 5.15 (ddd, 1H, H-10, Jgem = 17.5, J10,7 = J10,9 = 0.9 Hz), 5.04 (dddd, 1H, H-16, J16,15 = 17.2, Jgem = J16,14 = J16,14 = 1.7 Hz), 4.97 (dddd, 1H, H-16, J16,15 = 10.1, Jgem = J16,14 = J16,14 = 1.8 Hz), 4.24 (d, 1H, H-1, J1,9 = 6.3 Hz), 3.93–3.85 (m, 2H, H-3, H-12), 3.49 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.7 Hz), 3.33 (ddd, 1H, H-3, Jgem = J3,4 = 11.8, J3,4 = 4.3 Hz), 3.07 (dd, 1H, H-9, J9,5 = 6.8, J9,1 = 6.3 Hz), 2.77 (ddd, 1H, H-5, J5,4 = 7.2, J5,9 = 6.8, J5,4 = 2.7 Hz), 2.18–1.98 (m, 4H, H-4, H-14), 1.78–1.71 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 207.3, 173.1, 165.8, 138.0, 133.6, 129.8, 129.4, 128.9, 128.7, 128.5, 115.1, 103.5, 68.5, 63.3, 62.4, 46.6, 45.0, 30.4, 29.0, 22.2; ESIMS-LR (ESI) m/z 411.4 [M + MeOH + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C21H24O5Na 379.1521. Found 379.1514.
(±)-5-Hydroxy-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Benzoates (22 and 23)A solution of (±)-21 (64.0 mg, 0.180 mmol) and CeCl3·7H2O (101 mg, 0.270 mmol, 1.5 equiv.) in MeOH (1.8 mL) was treated with NaBH4 (10.2 mg, 0.270 mmol, 1.5 equiv.) at 0 °C for 20 min. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.2 × 10 cm, 20% EtOAc/hexane) to afford major diastereomer 22 (39.4 mg, 0.127 mmol, 71%) as a colorless oil, and minor diastereomer 23 (18.4 mg, 51.3 µmol, 29%) as a colorless oil.
Data for 22
1H-NMR (CDCl3, 400 MHz) δ: 8.09–8.06 (m, 2H, H-2′, H-6′), 7.58 (tt, 1H, H-4′, J4′,3′ = J4′,5′ = 7.4, J4′,2′ = J4′,6′ = 1.6 Hz), 7.47–7.43 (m, 2H, H-3′, H-5′), 5.96 (dd, 1H, H-7, J7,10 = J7,10 = 1.8 Hz), 5.81 (dddd, 1H, H-15, J15,16 = 16.6, J15,16 = 10.3, J15,14 = J15,14 = 6.7 Hz), 5.07–4.93 (m, 4H, H-10, H-16), 4.70 (d, 1H, H-6, J6,5 = 5.8 Hz), 4.50 (d, 1H, H-1, J = 6.2 Hz), 3.91 (ddd, 1H, H-3, Jgem = 11.2, J3,4 = J3,4 = 4.3 Hz), 3.84 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.7 Hz), 3.64 (ddd, 1H, H-3, Jgem = 11.2, J3,4 = 9.0, J3,4 = 4.5 Hz), 3.45 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.7 Hz), 2.62 (dd, 1H, H-9, J9,5 = 6.5, J9,1 = 6.2 Hz), 2.57–2.50 (m, 1H, H-5), 2.16–2.10 (m, 2H, H-14), 1.88–1.67 (m, 4H, H-4, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 166.2, 144.7, 138.2, 133.2, 130.4, 130.0, 129.7, 128.5, 114.9, 102.7, 77.3, 67.9, 62.9, 62.5, 48.0, 39.5, 30.4, 29.0, 22.4; ESIMS-LR (ESI) m/z 381.5 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C21H26O5Na 381.1678. Found 381.1661.
Data for 23
1H-NMR (CDCl3, 400 MHz) δ: 8.09–8.07 (m, 2H, H-2′, H-6′), 7.58 (tt, 1H, H-4′, J4′,3′ = J4′,5′ = 7.5, J4′,2′ = J4′,6′ = 1.5 Hz), 7.47–7.44 (m, 2H), 5.89 (s, 1H, H-7), 5.80 (dddd, 1H, H-15, J15,16 = 16.9, J15,16 = 10.1, J15,14 = J15,14 = 6.9 Hz), 5.03–4.98 (m, 2H, H-10, H-16), 4.94 (dddd, 1H, H-16, J16,15 = 10.1, Jgem = J16,14 = J16,14 = 1.6 Hz), 4.89 (d, 1H, H-10, Jgem = 15.1 Hz), 4.66 (br d, 1H, H-6, J6,5 = 6.3 Hz), 4.26 (d, 1H, H-1, J1,9 = 7.0 Hz), 3.96 (ddd, 1H, H-3, Jgem = 11.4, J3,4 = 5.0, J3,4 = 4.5 Hz), 3.83 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.9 Hz), 3.53 (ddd, 1H, H-3, Jgem = 11.4, J3,4 = 11.2, J3,4 = 3.4 Hz), 3.43 (ddd, 1H, H-12, Jgem = 9.4, J12,13 = J12,13 = 6.9 Hz), 2.74 (dd, 1H, H-9, J9,1 = 7.0, J9,5 = 6.9 Hz), 2.40 (dddd, 1H, H-5, J5,9 = 6.9, J5,6 = 6.3, J5,4 = 6.1, J5,4 = 4.0 Hz), 2.14–2.08 (m, 2H, H-14), 1.86 (dddd, 1H, H-4, J4,3 = 11.2, Jgem = 11.0, J4,5 = 6.1, J4,3 = 5.0 Hz), 1.75–1.66 (m, 3H, H-4, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 166.2, 143.3, 138.2, 133.2, 130.7, 130.0, 129.7, 128.5, 114.9, 103.5, 78.5, 68.2, 62.9, 61.3, 48.0, 46.6, 30.4, 29.0, 24.1; ESIMS-LR (ESI) m/z 381.1 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C21H26O5Na 381.1678. Found 381.1661.
(±)-10-O-Benzoylglobularigenin (9)A solution of 23 (5.75 mg, 16.1 µmol) in MeCN (3.2 mL) was treated with iodonium di-sym-collidine trifluoromethanesulfonate (IDCT) (45.8 mg, 88.0 µmol) at room temperature for 30 min. The reaction was quenched with sat. aq. Na2S2O3/sat. aq. NaHCO3 (v/v 1/1), and the resulting mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.2 × 10 cm, 20% EtOAc/hexane) to afford an inseparable mixture of (±)-10-O-benzoylglobularigenin (9) and 2,4,6-collidine. A solution of the mixture in MeOH (3.2 mL) was treated with Cu(OAc)2·H2O (9.60 mg, 48.2 µmol) at room temperature for 30 min. The mixture was directly filtered through a short pad of silica gel and washed with MeOH. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH/CHCl3) to afford (±)-10-O-benzoylglobularigenin (9, 3.30 mg, 11.4 µmol, 71%) as a colorless oil.
1H-NMR (CD3OD, 400 MHz) δ: 8.06 (dd, 2H, H-2′, H-6′, J2′,3′ = J6′,5′ = 7.4, J2′,4′ = J6′,4′ = 1.4 Hz), 7.64–7.60 (m, 1H, H-4′), 7.50 (dd, 2H, H-3′, H-5′, J3′,4′ = J5′,4′ = 7.6, J3′,2′ = J5′,6′ = 7.4 Hz), 5.86 (br s, 1H, H-7), 5.01 (d, 1H, H-10, Jgem = 15.0 Hz), 4.91 (d, 1H, H-10, Jgem = 15.0 Hz), 4.69 (br d, 1H, H-6, J6,5 = 8.2 Hz), 4.43 (d, 1H, H-7, J1,9 = 7.6 Hz), 3.94 (ddd, 1H, H-3, Jgem = 12.0, J3,4 = 4.5, J3,4 = 2.7 Hz), 3.63 (ddd, 1H, H-3, Jgem = 12.0, J3,4 = 11.8, J3,4 = 3.2 Hz), 2.59 (dd, 1H, H-9, J9,1 = J9,5 = 7.6 Hz), 2.40–2.35 (m, 1H, H-5), 1.88–1.73 (m, 2H, H-3); 13C-NMR (CD3OD, 100 MHz) δ: 167.6, 144.0, 134.4, 132.6, 131.4, 130.6, 129.6, 100.0, 78.2, 64.2, 63.0, 50.9, 48.4, 25.1; ESIMS-LR (ESI) m/z 313.1 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H18O5Na 313.1052. Found 313.1051.
(3R,6S)-6-(Prop-2-yn-1-yloxy)-3,6-dihydro-2H-pyran-3-yl Acetate (10)To a solution of 3,4-di-O-acetyl-L-alabinal (24, 50.0 mg, 0.250 mmol) and propargyl alcohol (15.6 µL, 0.270 mmol, 1.08 equiv.) in THF (1.0 mL) was added iodine (6.35 mg, 25.0 µmol, 0.1 equiv.) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with sat. aq. Na2S2O3/sat. aq. NaHCO3 (v/v 1/1), and the resulting mixture was extracted with Et2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.8 × 10 cm, 10% EtOAc/hexane) to afford 10 (30.8 mg, 0.157 mmol, 63%) as a brown oil.
1H-NMR (CD3OD, 400 MHz) δ: 6.11 (dd, 1H, H-5, J5,6 = 10.4, J5,4 = 5.5 Hz), 6.04 (dd, 1H, H-6, J6,5 = 10.4, J6,1 = 3.0 Hz), 5.22 (d, 1H, H-1, J1,6 = 3.0 Hz), 4.95 (dd, 1H, H-4, J4,5 = 5.5, J4,3 = 2.4 Hz), 4.30 (s, 2H, H-8), 4.13 (dd, 1H, H-3, Jgem = 13.1, J3,4 = 2.4 Hz), 3.85 (d, 1H, H-3, Jgem = 13.1 Hz), 2.45 (t, 1H, H-10, J10,8 = 2.3 Hz), 2.09 (s, 3H, Ac). This is a known compound.27)
(3S,6S)-6-(Prop-2-yn-1-yloxy)-3,6-dihydro-2H-pyran-3-yl Acetate (25)A solution of 10 (905 mg, 4.62 mmol) in MeOH (46.2 mL) was treated with K2CO3 (958 mg, 6.93 mmol, 1.5 equiv.) at 0 °C for 20 min. The reaction mixture was diluted with EtOAc. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. A solution of the residue and Et3N (1.84 mL, 13.3 mmol) in CH2Cl2 (68 mL) was treated with MsCl (1.03 mL, 13.3 mmol) at 0 °C for 30 min. The reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. A solution of the residue and 18-crown-6 (687 mg, 2.60 mmol) in benzene (96.0 mL) was treated with CsOAc (2.57 g, 13.3 mmol) at room temperature. The reaction mixture was stirred at refluxed temperature for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 19→40% EtOAc/hexane) to afford 25 (824 mg, 4.20 mmol, 91% over 3 steps) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 5.98 (dddd, 1H, H-5, J5,6 = 10.2, J5,4 = 2.1, J5,3 = J5,3 = 0.9 Hz), 5.87 (ddd, 1H, H-6, J6,5 = 10.2, J6,1 = 2.2, J6,4 = 2.0 Hz), 5.32 (dddd, 1H, H-4, J4,3 = 8.9, J4,3 = 5.5, J4,5 = 2.1, J6,4 = 2.0 Hz), 5.16 (br s, 1H, H-1), 4.32–4.31 (m, 2H, H-8), 3.87 (ddd, 1H, H-3, Jgem = 11.0, J3,4 = 5.5, J3,5 = 0.9 Hz), 3.77 (dd, 1H, H-3, Jgem = 11.0, J3,4 = 8.9 Hz), 2.45 (t, 1H, H-10, J10,8 = 2.5 Hz), 2.07 (s, 3H, Ac); 13C-NMR (CDCl3, 100 MHz) δ: 170.5, 129.6, 128.5, 92.3, 79.2, 74.8, 65.0, 60.0, 55.0, 21.0; ESIMS-LR (ESI) m/z 219.3 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C10H12O4Na 219.0633. Found 219.0620; [α]21D +181.8 (c 0.50, CHCl3).
(2a1S,4aS,5S,7aS)-4-Oxo-2a1,4,4a,5,6,7a-hexahydro-2H-1,7-dioxacyclopenta[cd]inden-5-yl Acetate (26)A solution of 25 (700 mg, 3.57 mmol) in CH2Cl2 (142 mL) was treated with Co2(CO)8 (1.34 g, 3.93 mmol, 1.1 equiv.) at room temperature for 1 h. The mixture was cooled to 0 °C and NMO (2.63 g, 22.5 mmol, 6.3 equiv.) was added to the mixture at once. The mixture was stirred for 5 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ3.0 × 14 cm, 50% EtOAc/hexane) to afford 26 (623 mg, 2.78 mmol, 79%) as a brown solid.
1H-NMR (CDCl3, 400 MHz) δ: 6.20 (s, 1H, H-7), 5.43 (d, 1H, H-1, J1,9 = 5.5 Hz), 5.18 (ddd, 1H, H-4, J4,5 = 8.6, J4,3 = 6.0, J4,3 = 3.0 Hz), 4.89 (ddd, 1H, H-10, Jgem = 15.6, J10,7 = J10,9 = 1.4 Hz), 4.74 (ddd, 1H, H-10, Jgem = 15.6, J10,7 = J10,9 = 2.1 Hz), 3.76 (dd, 1H, H-3, Jgem = 12.8, J3,4 = 6.0 Hz), 3.57 (dd, 1H, H-3, Jgem = 12.8, J3,4 = 3.0 Hz), 3.41 (dd, 1H, H-5, J5,4 = 8.6, J5,9 = 6.9 Hz), 3.32–3.25 (m, 1H, H-9), 2.03 (s, 3H, Ac); 13C-NMR (CDCl3, 100 MHz) δ: 206.4, 179.7, 170.2, 126.1, 97.6, 66.5, 64.6, 63.1, 47.4, 47.2, 21.0; ESIMS-LR (ESI) m/z 279.2 [M + MeOH + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C11H12O5Na 247.0582. Found 247.0589; [α]21D −265.8 (c 0.50, CHCl3).
(1R,4S,4aS,7aS)-7-(Hydroxymethyl)-5-oxo-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-4-yl Acetate (27)A solution of 26 (200 mg, 0.892 mmol) in 4-pentene-1-ol (4.5 mL) was treated with Sm(OTf)3 (53.3 mg, 89.2 µmol, 0.1 equiv.) at room temperature for 5 h. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ3.0 × 10 cm, 65% EtOAc/hexane) to afford 27 (223 mg, 0.719 mmol, 81%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 6.23 (dddd, 1H, H-7, J7,5 = J7,9 = J7,10 = J7,10 = 1.5 Hz), 5.82 (dddd, 1H, H-15, J15,16 = 17.0, J15,16 = 10.4, J15,14 = J15,14 = 6.8 Hz), 5.53–5.50 (m, 1H, H-4), 5.05 (dddd, 1H, H-16, J16,15 = 17.0, Jgem = J16,14 = J16,14 = 1.7 Hz), 5.01 (d, 1H, H-16, J16,15 = 10.2 Hz), 4.72 (d,1H, H-1, J1,9 = 6.9 Hz), 4.61 (dd, 1H, H-10, Jgem = 17.6, J10,OH = 7.0 Hz), 4.51 (dd, 1H, H-10, Jgem = 17.6, J10,OH = 4.1 Hz), 4.06 (dd, 1H, H-3, Jgem = 12.2, J3,4 = 4.1 Hz), 3.93–3.83 (m, 2H, H-3, H-12), 3.49 (ddd, 1H, H-12, Jgem = 9.5, J12,13 = J12,13 = 6.3 Hz), 3.21 (dd, 1H, H-9, J9,1 = 6.9, J9,5 = 7.3 Hz), 3.00 (dd, 1H, H-5 J5,9 = 7.3, J5,4 = 5.7 Hz), 2.49 (br s, 1H, OH), 2.18 (d, 1H, H-14, Jgem = 7.4 Hz), 2.14 (d, 1H, H-14, Jgem = 7.4 Hz), 2.01 (s, 3H, Ac), 1.79–1.72 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 204.9, 178.7, 169.9, 137.8, 130.1, 115.4, 98.7, 68.7, 67.5, 66.0, 62.0, 46.3, 45.5, 30.3, 28.9, 21.1; ESIMS-low resolution (LR) (ESI) m/z 333.2 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H22O6Na 333.1314. Found 333.1322; [α]24D −168.2 (c 0.50, CHCl3).
(1R,4S,4aR,5S,7aS)-7-(Hydroxymethyl)-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-4,5-diol (28)A solution of 27 (175 mg, 0.564 mmol) and CeCl3·7H2O (315 mg, 0.846 mmol, 1.5 equiv.) in MeOH (5.6 mL) was treated with NaBH4 (32.0 mg, 0.846 mmol, 1.5 equiv.) at 0 °C for 30 min. The mixture was diluted with EtOAc, and the reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. A solution of the residue in MeOH (5.64 mL) was treated with K2CO3 (39.0 mg, 0.282 mmol) at 0 °C for 5 h. The mixture was concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 5% MeOH/CHCl3) to afford 28 (141 mg, 0.522 mmol, 92% over 2 steps) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 5.88 (br s, 1H, H-7), 5.81 (dddd, 1H, H-15, J15,16 = 17.2, J15,16 = 10.6, J15,14 = J15,14 = 6.9 Hz), 5.03 (dddd, 1H, H-16, J16,15 = 17.2, Jgem = J16,14 = J16,14 = 1.6 Hz), 4.99–4.90 (m, 2H, H-16, H-6), 4.69 (d, 1H, H-1 J1,9 = 5.4 Hz), 4.30 (d, 1H, H-10, Jgem = 15.3 Hz), 4.25 (d, 1H, H-10, Jgem = 15.3 Hz), 4.14 (br s, 1H, H-4), 3.97 (dd, 1H, H-3 Jgem = 11.4, J3,4 = 4.7 Hz) 3.83 (ddd, 1H, H-12, Jgem = 9.8, J12,13 = J12,13 = 7.2 Hz), 3.59 (dd, 1H, H-3, Jgem = 11.4, J3,4 = 7.4 Hz), 3.46 (ddd, 1H, H-12, Jgem = 9.8, J12,13 = J12,13 = 6.8 Hz), 2.77–2.68 (m, 4H, H-5, H-9, OH-4, OH-6), 2.40 (br s, 1H, OH-10), 2.15 (d, 1H, H-14, J14,15 = 6.9 Hz), 2.11 (d, 1H, H-14, J14,15 = 6.9 Hz), 1.75–1.67 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 148.2, 138.0, 130.0, 115.1, 101.7, 76.8, 68.1, 66.2, 65.9, 60.8, 48.0, 43.7, 30.3, 28.9; ESIMS-LR (ESI) m/z 293.0 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C14H22O5Na 293.1365. Found 293.1363; [α]25D −51.8 (c 0.50, CHCl3).
((1R,4S,4aR,5S,7aS)-4,5-Dihydroxy-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Acetate (29)A solution of 28 (157 mg, 0.582 mmol) and 2,6-lutidine (228 µL, 1.74 mmol, 3.0 equiv.) in CH2Cl2 (5.8 mL) was treated with AcCl (123 µL, 1.74 mmol, 3.0 equiv.) at −78 °C for 20 min. The reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with 1 M aq. HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 60→80% EtOAc/hexane) to afford 29 (159 mg, 0.509 mmol, 87%) as a white solid.
1H-NMR (CDCl3, 400 MHz) δ: 5.92 (dd, 1H, H-7, J7,10 = J7,10 = 1.8 Hz), 5.82 (dddd, 1H, H-15, J15,16 = 17.1, J15,16 = 10.1, J15,14 = J15,14 = 6.4 Hz), 5.03 (dddd, 1H, H-16, J16,15 = 17.1, Jgem = J16,14 = J16,14 = 1.8 Hz), 4.98 (dd, 1H, H-16, J16,15 = 10.1, Jgem = 1.8 Hz), 4.92 (dd, 1H, H-6, J6,OH = 8.1, J6,5 = 6.7 Hz), 4.78–4.67 (m, 3H, H-1, H-10), 4.10–4.04 (m, 1H, H-4), 3.95 (dd, 1H, H-3, Jgem = 11.4, J3,4 = 4.1 Hz), 3.77 (ddd, 1H, H-12, Jgem = 9.6, J12,13 = J12,13 = 6.9 Hz), 3.56 (dd, 1H, H-3, Jgem = 11.4, J3,4 = 6.4 Hz), 3.43 (ddd, 1H, H-12, Jgem = 9.6, J12,13 = J12,13 = 6.9 Hz), 2.92 (d, 1H, OH-6, JOH-6,6 = 8.1 Hz), 2.77 (ddd, 1H, H-5, J5,6 = 6.7, J5,9 = J5,4 = 6.6 Hz), 2.65 (br s, 1H, H-9), 2.55 (d, 1H, OH-4, JOH-4,4 = 9.6 Hz), 2.16–2.06 (m, 5H, H-14, Ac), 1.73–1.66 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 171.0, 142.2, 138.2, 133.3, 115.1, 100.1, 67.9, 65.9, 65.1, 62.0, 47.4, 43.6, 30.5, 28.9, 21.0; ESIMS-LR (ESI) m/z 335.3 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H24O6Na 335.1471. Found 335.1466; [α]22D −73.0 (c 0.50, CHCl3).
((1R,4S,4aS,7aS)-4-Hydroxy-5-oxo-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Acetate (30)A suspension of 29 (139 mg, 0.446 mmol), MS4Å (4.46 g) and AcOH (255 µL, 4.46 mmol, 10 equiv.) in EtOAc (44.6 mL) was treated with pyridinium dichromate (PDC) (83.8 mg, 0.223 mmol, 0.5 equiv.) at room temperature for 1 h. Insoluble materials were filtered off through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 40→60% EtOAc/hexane) to afford 30 (109 mg, 0.351 mmol, 79%) as a white solid.
1H-NMR (CDCl3, 400 MHz) δ: 6.19 (s, 1H, H-7), 5.81 (dddd, 1H, H-15, J15,16 = 16.9, J15,16 = 10.1, J15,14 = J15,14 = 6.4 Hz), 5.06–4.97 (m, 3H, H-10, H-16), 4.90 (d, 1H, H-10, Jgem = 17.8 Hz), 4.53 (d, 1H, H-1, J1,9 = 5.2 Hz), 4.48–4.40 (m, 1H, H-4), 4.08 (d, 1H, OH-4, JOH-4,4 = 8.7 Hz), 3.98 (dd, 1H, H-3, Jgem = J3,4 = 5.5 Hz), 3.81 (ddd, 1H, H-12, Jgem = 9.6, J12,13 = J12,13 = 6.8 Hz), 3.50–3.41 (m, 2H, H-3, H-12), 3.14 (dd, 1H, H-9, J9,1 = 5.2, J9,5 = 6.2 Hz), 2.95 (dd, 1H, H-5, J5,4 = 6.6, J5,9 = 6.2 Hz), 2.22–2.11 (m, 5H, H-14, Ac), 1.75–1.68 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 209.8, 174.6, 170.2, 137.9, 130.2, 115.2, 99.9, 68.5, 67.3, 65.8, 62.5, 48.0, 47.1, 30.3, 28.9, 20.7; ESIMS-LR (ESI) m/z 333.3 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H22O6Na 333.1314. Found 333.1323; [α]24D −96.4 (c 0.50, CHCl3).
((1R,4S,4aR,5R,7aS)-4,5-Dihydroxy-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-7-yl)methyl Acetate (31)A solution of 30 (109 mg, 0.351 mmol) in MeCN (7.2 mL) was treated with NaBH(OAc)3 (297 mg, 1.40 mmol, 4.0 equiv.) at room temperature for 24 h. The reaction was quenched with H2O. The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by hi-flash silica gel column chromatography (Φ3.0 × 10 cm, 80→90% EtOAc/hexane) to afford 31 (98.6 mg, 0.316 mmol, 90%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 5.84–5.74 (m, 2H, H-7, H-15), 5.09 (d, 1H, H-6, J6,5 = 7.3 Hz), 5.01 (dd, 1H, H-16, J16,15 = 17.2, Jgem = 1.4 Hz), 4.96 (dd, 1H, H-16, J16,15 = 10.3, Jgem = 1.4 Hz), 4.69 (d, 1H, H-10, Jgem = 14.6 Hz), 4.63 (d, 1H, H-10, Jgem = 14.6 Hz), 4.24–4.20 (m, 1H, H-4), 4.10 (d, 1H, H-1, J1,9 = 7.4 Hz), 3.96 (dd, 1H, H-3, Jgem = 11.2, J3,4 = 5.6 Hz), 3.81 (ddd, 1H, H-12, Jgem = 8.8, J12,13 = J12,13 = 7.2 Hz), 3.43–3.33 (m, 2H, H-3, H-12), 2.73 (dd, 1H, H-9, J9,1 = J9,5 = 7.4 Hz), 2.59 (ddd, 1H, H-5, J5,4 = J5,6 = 7.3, J5,9 = 7.4 Hz), 2.34–2.25 (m, 2H, OH-4, OH-6), 2.12–2.07 (m, 5H, H-14, Ac), 1.71–1.60 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 170.8, 141.8, 138.0, 130.9, 115.0, 104.5, 75.0, 68.8, 65.6, 65.4, 62.2, 52.2, 49.1, 30.3, 28.9, 20.9; ESIMS-LR (ESI) m/z 335.4 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C16H24O6Na 335.1471. Found 335.1466; [α]22D −119.6 (c 0.50, CHCl3).
(1R,4S,4aS,5R,7aS)-7-(Acetoxymethyl)-4-hydroxy-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-5-yl Benzoate (32)A solution of 31 (5.0 mg, 16.0 µmol) in pyridine (0.50 mL) was treated with BzCl (11.1 µL, 96.0 µmol, 6.0 equiv.) at 0 °C for 30 min. The reaction was quenched with MeOH. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was washed with 1 M aq. HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.0 × 10 cm, 40% EtOAc/hexane) to afford 32 (4.10 mg, 9.84 µmol, 62%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 8.05–8.01 (m, 2H, H-2′, H-6′), 7.59–7.55 (m, 1H, H-4′), 7.46–7.42 (m, 2H, H-3′, H-5′), 6.12 (ddd, 1H, H-6, J6,5 = 5.4, J6,10 = J6,10 = 1.8 Hz), 5.94 (dd, 1H, H-7, J7,10 = J7,10 = 1.6 Hz), 5.82 (dddd, 1H, H-15, J15,16 = 16.8, J15,16 = 10.0, J15,14 = J15,14 = 6.3 Hz), 5.03 (dddd, 1H, H-16, J16,15 = 17.2, Jgem = 1.8, J16,14 = J16,14 = 1.7 Hz), 4.98 (dddd, 1H, H-16, J16,15 = 10.0, Jgem = J16,14 = J16,14 = 1.8 Hz), 4.78–4.68 (m, 2H, H-10), 4.46 (d, 1H, H-1, J1,9 = 5.0 Hz), 4.25 (br s, 1H, H-4), 3.97 (dd, 1H, H-3, Jgem = 11.2, J3,4 = 4.1 Hz), 3.80 (ddd, 1H, H-12, Jgem = 9.5, J12,13 = J12,13 = 6.8 Hz), 3.52 (dd, 1H, H-3, Jgem = 11.2, J3,4 = 8.4 Hz), 3.44 (ddd, 1H, H-12, Jgem = 9.5, J12,13 = J12,13 = 6.3 Hz), 3.01–2.98 (m, 1H, H-9), 2.94–2.89 (m, 1H, H-5), 2.59 (d, 1H, OH-4, JOH-4, 4 = 7.2 Hz), 2.18–2.10 (m, 5H, H-14, Ac), 1.74–1.67 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 170.6, 167.4, 144.8, 138.1, 133.5, 130.0, 129.9, 128.6, 127.9, 115.1, 101.2, 78.8, 68.4, 65.2, 64.7, 61.9, 49.3, 48.4, 30.4, 29.0, 21.0; ESIMS-LR (ESI) m/z 439.1 [M + Na]+; ESIMS-HR (ESI) m/z: [M + Na]+ Calcd for C23H28O7Na 439.1733. Found 439.1731; [α]22D −0.8 (c 0.41, CHCl3).
(1R,4S,4aR,5R,7aS)-4-((1H-Imidazole-1-carbonothioyl)oxy)-7-(acetoxymethyl)-1-(pent-4-en-1-yloxy)-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran-5-yl Benzoate (33)A mixture of 32 (4.1 mg, 9.84 µmol), 1,1′-thiocarbonyldiimidazole (26.3 mg, 0.148 mmol, 15.0 equiv.) and DMAP (1.20 mg, 9.84 µmol, 1.0 equiv.) in toluene (984 µL) was refluxed for 1 h. The mixture was directly purified by flash silica gel column chromatography (Φ1.2 × 8.0 cm, 60% EtOAc/hexane) to afford 33 (5.00 mg, 9.49 mmol, 96%) as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ: 8.05 (s, 1H, H-1”), 7.83–7.80 (m, 2H, H-2′, H-6′), 7.51–7.45 (m, 1H, H-4′), 7.35–7.28 (m, 3H, H-3′, H-5′, H-3”), 6.67 (s, 1H, H-1”), 6.17 (dt, 1H, H-6, J6,5 = 6.9, J6,10 = 1.7 Hz), 6.00 (ddd, 1H, H-4, J4,3 = 9.1, J4,5 = 5.9, J4,3 = 5.8 Hz), 5.94 (s, 1H, H-7), 5.82 (dddd, 1H, H-15, J15,16 = 17.0, J15,16 = 10.0, J15,14 = J15,14 = 6.3 Hz), 5.05 (dddd, 1H, H-16, J16,15 = 17.0, Jgem = J16,14 = J16,14 = 1.7 Hz), 4.99 (dddd, 1H, H-16, J16,15 = 10.0, Jgem = 1.7, J16,14 = J16,14 = 1.6 Hz), 4.79–4.64 (m, 2H, H-10), 4.41 (d, 1H, H-1, J1,9 = 6.7 Hz), 4.20 (dd, 1H, H-3, Jgem = 11.8, J3,4 = 5.8 Hz), 3.88–3.80 (m, 2H, H-3, H-12), 3.52–3.46 (m, 2H, H-5, H-12), 3.05 (dd, 1H, H-9, J9,5 = 7.0, J9,1 = 6.7 Hz), 2.18–2.11 (m, 5H, H-14, Ac), 1.77–1.69 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 183.0, 170.5, 166.3, 144.4, 138.0, 133.5, 130.9, 129.4, 129.1, 128.4, 127.7, 117.3, 115.3, 103.0, 78.1, 75.3, 68.9, 61.9, 61.7, 48.9, 43.7, 30.4, 28.9, 20.9; ESIMS-LR (ESI) m/z 549.4 [M + Na]+; ESIMS-HR (ESI) m/z: [M + H]+ Calcd for C27H31N2O7S 527.1854. Found 527.1874; [α]23D −161.4 (c 0.50, CHCl3).
1-O-Pentenylaucubigenin (34)A solution of 33 (5.0 mg, 9.49 µmol) in DMF (949 µL) was irradiated by a microwave reactor at 150 °C for 1 h. The reaction mixture was diluted with EtOAc/hexane (v/v 1/1). The resulting mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.2 × 8.0 cm, 20% EtOAc/hexane) to afford an inseparable mixture containing 33. A solution of the mixture in MeOH (949 µL) was treated with K2CO3 (6.56 mg, 47.5 µmol) for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (Φ1.2 × 8.0 cm, 5% MeOH/CHCl3) to afford 34 (2.10 mg, 8.32 µmol, 88% over 2 steps) as a white solid.
1H-NMR (CDCl3, 400 MHz) δ: 6.36 (dd, 1H, H-3, J3,4 = 6.2, J3,5 = 2.1 Hz), 5.86–5.75 (m, 2H, H-7, H-15), 5.14 (dd, 1H, H-4, J4,3 = 6.2, J4,5 = 4.1 Hz), 5.03 (dddd, 1H, H-16, J16,15 = 16.9, Jgem = J16,14 = J16,14 = 1.6 Hz), 4.98 (dddd, 1H, H-16, J16,15 = 10.1, Jgem = J16,14 = J16,14 = 1.6 Hz), 4.54 (br d, 1H, H-6, J6,5 = 6.3 Hz), 4.36 (d, 1H, H-1, J1,9 = 7.8 Hz), 4.35–4.25 (m, 2H, H-10), 3.94 (ddd, 1H, H-12, Jgem = 9.6, J12,13 = J12,13 = 6.9 Hz), 3.53 (ddd, 1H, H-12, Jgem = 9.6, J12,13 = J12,13 = 6.9 Hz), 2.86 (dd, 1H, H-9, J9.5 = 8.0, J9.1 = 7.8 Hz), 2.66 (dddd, 1H, H-5, J5.9 = 8.0, J5,6 = 6.3, J5,4 = 4.1, J5,3 = 2.1 Hz), 2.16–2.10 (m, 2H, H-14), 1.76–1.68 (m, 2H, H-13); 13C-NMR (CDCl3, 100 MHz) δ: 146.8, 141.3, 137.9, 130.5, 115.3, 104.1, 101.4, 82.8, 69.0, 61.5, 47.9, 46.8, 30.3, 28.9; ESIMS-HR (ESI) m/z: [M + H2O + H]+ Calcd for C14H23O5 271.1545. Found 271.1543; [α]22D −38.8 (c 0.21, CHCl3).
This research was financially supported in part by Grants-in-Aid for Regional R&D Proposal-Based Program from Northern Advancement Center for Science & Technology of Hokkaido Japan, the Japan Agency for Medical Research and Development (AMED) under Grant number for 18ae0101047h0001 and 19ae0101047h0002, Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System,” and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from AMED.
The authors declare no conflict of interest.
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