Neotripterifordin from Stevioside - ACS Publications - American

Nov 16, 2017 - ABSTRACT: We report short syntheses of (−)-tripterifordin and (−)-neotripterifordin, potent inhibitors of HIV replication, from ste...
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Note Cite This: J. Org. Chem. 2018, 83, 1606−1613

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Syntheses of (−)-Tripterifordin and (−)-Neotripterifordin from Stevioside Shoji Kobayashi,* Keisuke Shibukawa, Yoshiki Hamada, Takuma Kuruma, Asako Kawabata, and Araki Masuyama Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan S Supporting Information *

ABSTRACT: We report short syntheses of (−)-tripterifordin and (−)-neotripterifordin, potent inhibitors of HIV replication, from stevioside, a natural sweetener used worldwide. The key transformations are reduction at C13 through the formation of a tertiary chloride and subsequent three-step lactonization including a selective iodination at C20 by the photoreaction of the C19alcohol. The title compounds were reliably obtained from stevioside in 9 and 11 steps (with 5−7 isolation steps), respectively. Additionally, the related lactone-containing ent-kaurenes, doianoterpenes A and B, and two more natural products were synthesized.

P

Scheme 1. An Overview of the Preceding Results and This Study

lants produce a wide variety of structurally complex secondary metabolites of biological interest. Tripterifordin (1) and neotripterifordin (2), isolated from the roots of Tripterygium wilfordii, are members of the ent-kaurene diterpenoids, which have been shown to possess significant anti-HIV replication activities in H9 lymphocyte cells with EC50 values of 3100 and 25 nM, respectively (Figure 1).1,2 Although

Figure 1. Structures of (−)-tripterifordin (1) and (−)-neotripterifordin (2).

the threat of HIV infection has gradually decreased with the development of innovative medicines and therapeutic methods,3 continued research is still demanded to overcome drug resistance and to improve patient quality of life. In this regard, naturally occurring diterpenoids such as 1 and 2 are attractive candidates with unique HIV inhibitory mechanisms.4 In addition to their significant biological activities, the highly complex structures, which include a condensed five ring system and seven chiral centers, represent a great synthetic challenge. To date, only a racemic total synthesis of (±)-tripterifordin (1) and an asymmetric total synthesis of (−)-neotripterifordin (2) have been reported by the Mori and the Corey groups, respectively (Scheme 1a,b).5,6 Although their landmark achievements paved the way for synthetic routes of highly complex plant-derived diterpenoids,7 the relatively lengthy © 2018 American Chemical Society

number of steps (more than 25 steps from the commercial reagents) limits the supply of the target molecules for further research. Therefore, more accessible routes to such complex molecules from abundant natural products have been investigated extensively in recent years.8 Herein, we report short, reliable synthetic routes of both (−)-1 and (−)-2, Received: November 16, 2017 Published: January 12, 2018 1606

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

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The Journal of Organic Chemistry

submitted to similar lactonization conditions15 (Scheme 2c). The 1H NMR of some isolated products indicated that the labile allylic alcohol (or the allylic silyl ether) moiety has reacted in part under these conditions, as the exo-olefin resonances were missing. On the basis of these unpromising experimental results coupled with Baran’s previous work, we decided to explore alternative practical routes for approaching the lactone ring. Before addressing the modified synthetic route, we initially directed our attention to the sustainable preparation of steviol (4) from stevioside (3). The major issues reported were the undesired Wagner−Meerwein rearrangement leading to isosteviol,16 and hydration and isomerization of the labile C16− C17 double bond.17 To prevent such side reactions, a variety of chemical and enzymatic methods have been investigated.9b Among them, we chose a two-step, chemical-based method consisting of periodate oxidation and alkaline hydrolysis,18 due to the ease of implementation in common synthetic laboratories. According to the literature,18 commercial grade 3 (>80% purity by HPLC) was treated with NaIO4 and subsequently hydrolyzed with aqueous KOH (Scheme 3). As a minor modification, the alkaline solution was carefully neutralized to ca. pH 6 by sequential addition of AcOH and saturated aqueous NH4Cl, which prevented the undesired acidcatalyzed side reactions. Extraction of the crude steviol (4), followed by methylation,11 afforded steviol methyl ester 11 reproducibly in 40−43% overall yield from 3.19 These reactions were easily carried out by several undergraduates on a gram scale. The next step, deoxygenation at C13, was more difficult than expected.20 The corresponding xanthate, a precursor for the Barton−McCombie radical deoxygenation,21 could not be prepared even though excess NaH, CS2, and MeI were used with heating. A variety of solvents such as toluene, n-hexane, THF, Et2O, CPME, DMF, and CH2Cl2 were applied, but the reaction did not occur. When 1 equiv of imidazole was added,22 a small amount of xanthate was formed, which was converted into alcohol 13 by sequential reductions with n-Bu3SnH/Et3B (in toluene) and DIBAL-H (in Et2O) in 36% overall yield from 11. However, the formation of xanthate was variable and the procedure was not reproducible. Therefore, we searched for more reliable conditions that could preserve the labile allylic alcohol. After extensive trials, we found that halogenation and reduction proved to be practical. Thus, the tertiary alcohol of 11 was first chlorinated with SOCl2 and pyridine, and the resulting chloride 12 was reduced with LiAlH4 at reflux. In addition to reduction of the methyl ester, the tertiary chloride was also reduced in part, providing alcohol 13 in 47% yield. Not surprisingly, reduction of the tertiary chloride was slow and harsher conditions using excess LiAlH4 with prolonged heating resulted in a decrease of the yield. Fortunately, this issue could be resolved by resorting to a two-step method utilizing LiAlH4 for ester reduction and Li/t-BuOH for halide reduction.23 In this way, the desired alcohol 13 was reproducibly obtained in 92−94% yield. After achieving the reduction at C13, we set out to perform the photoreaction of 13 under Suárez conditions24 with the expectation that the C20 position would be selectively iodinated through radical [1,6]-H-abstraction, although the corresponding photoreaction with a C19-free alcohol has not been reported.11 In practice, a solution of 13 in cyclohexane was irradiated with a fluorescent lamp (27 W) in the presence of PhI(OAc)2 (1.5 equiv) and I2 (1 equiv). Within 1 h at 40 °C,

starting from commercially available stevioside (3), a natural sweetener used worldwide (Scheme 1c). Stevioside (3) and its aglycone, steviol (4), have long been used as starting materials in pharmaceutical development due to their ready availabilities in spite of their remarkable structural complexities.9 A large number of derivatives have been synthesized to modify their biological properties and to develop structurally novel drug lead compounds.10 However, most precedents using 4 as the starting material focused mainly on modifications of the D- and C-rings due to the existence of the reactive C16−C17 double bond and C13-alcohol.9,10a−h With the exception of conventional esterification, amide formation, and reduction, modifications around the AB ring starting from derivatization of the C19-carboxylic acid have not been extensively studied9,10i until the breakthrough publication by the Baran group, where the atisine and hetidine skeletons were constructed by utilizing photoreactions of C19-phosphoramidates.11 Importantly, they showed that, under the Suárez photoreaction conditions, activation of the inert C20−H bond (not the C2−H or C6−H bond) occurred through a [1,6]hydrogen transfer from the nitrogen radicals generated in the axially disposed phosphoramidate directing group, whereby the iodo group was selectively introduced at C20 (Scheme 2a). Of Scheme 2. Related Studies and Attempted Lactonization from Amide Precursors

special note is that other amide directing groups failed to activate the C20−H bond. At that point, their research focused on the construction of the piperidine ring rather than the lactone ring.11 In early studies, the C19−C20 bridged lactones of the entkaurane diterpenoids had been constructed by employing photoreactions of the corresponding C19-amides.5b,12,13 For instance, en route to (±)-1, the bridged lactone was constructed by photolysis of amide 7, followed by alkaline/ acid treatment (Scheme 2b).5b It is likely that the reaction involved C20−H activation by amidyl radicals (RCONH·) derived from the N-iodoamide intermediate (RCONHI) that was transiently generated by photoirradiation of 7 with Pb(OAc)4 and I2.12,14 However, the reported yields of the lactones were generally low5b,12,13 and the method appeared impractical. In fact, many unidentifiable products were formed when amides 9a and 9b derived from steviol (4) were 1607

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

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The Journal of Organic Chemistry Scheme 3. Synthesis of (−)-Tripterifordin and (−)-Neotripterifordin

followed by elimination of HI after the formation of the hypoiodite species (iii → iv → 14) (Scheme 4).24b,30 Without photoirradiation, the reaction became sluggish with recovery of the starting material. The commercially available, standard fluorescent lamp (27 W) was found to be better than blacklight (27 W, λmax = 368 nm). More detailed investigation indicated that the concentration was important; if the photoreaction was carried out at concentrations above 0.02 M, unidentifiable byproducts increased with the decrease of 14. With the requisite lactone 16 in hand, we undertook the synthesis of the target molecules. The final step for the synthesis of tripterifordin (1) was Markovnikov-type hydration of the C16−C17 double bond, which was already established by Mori et al.5c With a slight modification of the reported conditions, lactone 16 was exposed to 3 M aqueous HCl using THF as a cosolvent (Scheme 3). After column chromatography, (−)-tripterifordin (1) was isolated as a colorless solid in 76% yield. The spectral data of synthetic (−)-1 were identical to those of the natural product.1 On the other hand, neotripterifordin (2) was synthesized via a reduction−oxidation sequence from the common intermediate 16.31 Thus, reduction of 16 with LiAlH4 at reflux afforded diol 17 in 76% yield. Various oxidation conditions32 were examined to selectively obtain the C20-carbonylated lactone 18 (Table 1). 33 Ultimately, oxidation with the Dess−Martin reagent (DMP)34 in the presence of NaHCO3 resulted in the formation of 18 in 44% yield along with 35% of the isomer 16 (entry 7). At this point, we cannot rationally explain the selectivity. However, it is likely that the selectivity is somewhat dependent on the reaction time. In short, the sterically less hindered C19-alcohol tends to undergo oxidation faster than the C20-alcohol, but they compete as the reaction becomes sluggish. It should be noted that lactone 18 is also the natural product isolated from the branches of Tripterygium doianum (Celastraceae), doianoterpene B.35 Finally, lactone 18 was subjected to hydration in the same manner as above to provide (−)-neotripterifordin (2) in 73% yield. All spectral data of synthetic (−)-2 were in accordance with those of the natural product.2

alcohol 13 disappeared on TLC and a less polar product, which later turned out to be iodoaldehyde 14 by 1H NMR analysis, appeared on TLC as a major spot. Isolation of 14 by Florisil chromatography was possible, but the product degraded immediately in the absence of solvent. Therefore, iodoaldehyde 14 was submitted, after careful concentration, to Lindgren− Kraus oxidation25 and the crude carboxylic acid 15 was treated with n-Bu4NF to provoke lactonization. After extraction and purification by silica gel chromatography, lactone 16 was isolated in 43−46% overall yield for three steps.26−28 It is noteworthy that iodoalcohol (iii) shown in Scheme 4 was not Scheme 4. A Possible Reaction Mechanism Leading to Iodoaldehyde 14

detected at all and the other products obtained were less polar hydrocarbons whose structures could not be determined as they were inseparable by chromatography. The optimal solvent for the photoreaction was cyclohexane, and the use of benzene, CH2Cl2, ClCH2CH2Cl, or CH3CN resulted in lower yields of 14. When PhI(OAc)2 was replaced by Pb(OAc)4,29 the photoreaction turned sluggish and 14 was obtained in less than 15% yield after 6 h. Although the mechanism to produce 14 remains elusive, we speculate that the reaction involves [1,6]-hydrogen transfer (HT) (i → ii), trapping the carbon radicals by iodine (ii → iii), 1608

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

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The Journal of Organic Chemistry Table 1. Oxidation of Diol 17

yield (%)a

a

entry

conditions

16

18

1 2 3 4 5 6 7

(COCl)2, DMSO, Et3N, CH2Cl2, −78 to 0 °C AZADOL (cat), PhI(OAc)2, CH2Cl2, rt Ag2CO3 on Celite, toluene, 120 °C IBX, DMSO, rt DMP, CH2Cl2, rt DMP, pyridine, CH2Cl2, rt DMP, NaHCO3, CH2Cl2, rt

57 71 81 33 47 35

12

Isolated yield.

100

■

Additionally, we studied isomerization of the C16−C17 double bond to obtain insights into the biogenesis of ent-kaur15-en-19,20-olide (20)28 and doianoterpene A (21)35 as they were simultaneously isolated with their isomers (16 and 18, respectively) (Scheme 5). Although relatively weaker protic

19

22 14 44

4 6 4

EXPERIMENTAL SECTION

General Techniques. All reactions utilizing air- or moisturesensitive reagents were performed under an atmosphere of argon. Commercially available dry solvents were used for THF, CH2Cl2, CHCl3, CH3CN, DMF, and DMSO. Triethylamine, pyridine, and 1,2dichloroethane were distilled from CaH2. Cyclohexane, toluene, CPME, and benzene were dried over molecular sieves prior to use. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60-F254) that were analyzed by fluorescence upon 254 nm irradiation or by staining with panisaldeyde/AcOH/H 2 SO 4 /EtOH, 12MoO 3 ·H 3 PO 4 /EtOH, or (NH4)6Mo7O24·4H2O/H2SO4. The products were purified by either open chromatography on silica gel (spherical, neutral, 70−230 μm) or flash chromatography on silica gel (spherical, neutral, 40−50 μm) and, if necessary, HPLC equipped with a prepacked column with an eluent of n-hexane/EtOAc. NMR spectra were recorded with a 300 MHz (1H: 300 MHz, 13C: 75 MHz) or a 400 MHz (1H: 400 MHz, 13C: 100 MHz) spectrometer and referenced to the solvent peak at 7.26 ppm (1H) and 77.16 ppm (13C) for CDCl3. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, multiplet. Infrared spectra were recorded with an FT/IR spectrometer and reported as wavenumber (cm−1). High-resolution ESI mass spectra were recorded with an Orbitrap analyzer in positive or negative ion mode. The carbon numbering of all synthetic compounds corresponds to that of natural products. TMS Ether (9b). Pyridine (1 mL) and TMSCl (88 μL, 0.70 mmol) were added to a mixture of amide 9a11 (101 mg, 0.317 mmol) and DMAP (4.6 mg, 0.038 mmol). After 2.2 h at room temperature, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with n-hexane (2 × 10 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 30 v/v → EtOAc only) to give TMS ether 9b (92.9 mg, 0.257 mmol) as a colorless solid. Mp 63−64 1 °C; [α]28 D −51.4° (c 0.49, CHCl3); H NMR (300 MHz, CDCl3) δ 5.64 (1H, br s), 5.39 (1H, br s), 4.96 (1H, br s), 4.78 (1H, br s), 2.19− 1.99 (4H, m), 1.93−1.67 (6H, m), 1.62−1.35 (5H, m), 1.30−1.23 (1H, m), 1.21 (3H, s), 1.17−1.06 (2H, m), 0.99 (3H, s), 0.94 (1H, d, J = 7.6 Hz), 0.84 (1H, td, J = 13.6, 5.6 Hz), 0.11 (9H, s); 13C NMR (100 MHz, CDCl3) δ 155.8, 103.5, 82.3, 57.3, 53.9, 47.2, 46.5, 43.9, 42.2, 41.8, 41.3, 41.1, 39.6, 38.6, 30.2, 22.5, 20.7, 19.4, 16.5, 15.8, 2.63; FT-IR (film on ZnSe) 3343, 3192, 3075, 2949, 1667, 1599, 1250, 1136, 1115 cm−1; HRMS (ESI-neg) m/z: [M + Cl]− Calcd for C23H39O2NClSi 424.2444; Found 424.2458. Methyl Ester (11).11 The commercially available stevioside (3) (5.02 g, purity > 80%, >4.99 mmol) and NaIO4 (6.45 g, 30.2 mmol) were completely dissolved in distilled water (375 mL), and the mixture was stirred at room temperature for 18 h. As the reaction progressed, the solution turned into a suspension, at which point KOH (44.1 g, 668 mmol) was added. The resulting mixture was refluxed for 2 h and

Scheme 5. Isomerization of the C16−C17 Double Bond

acids such as pyridinium p-toluenesulfonate and trifluoroacetic acid were inert, addition of 10-(±)-camphorsulfonic acid (CSA) facilitated isomerization at 50 °C to give isomers 20 and 21 in 44% and 79% yields, respectively.36 These isomers (20 and 21) were separated from the starting exo-olefins (16 and 18, respectively) by normal phase HPLC, and their spectral data were in accordance with those of the natural products.28,35,37 In conclusion, (−)-tripterifordin (1) and (−)-neotripterifordin (2), potent inhibitors of HIV replication, were synthesized from commercially available stevioside (3) in 9 and 11 steps (5−7 isolation steps) with overall yields of 12% and 3.8%, respectively.19 In addition, four related lactonecontaining natural products, (−)-20-hydroxykaur-16-en-19-oic acid lactone (16), ent-kaur-15-en-19,20-olide (20), and doianoterpenes A (21) and B (18), were synthesized. The key transformations were reduction at the C13 position via the formation of a tertiary chloride and a subsequent three-step lactonization including a photoreaction of the C19-alcohol. It is noteworthy that the present method does not require an additional directing group at C19 to install the iodo functional group at C20. We believe that the present method would be valuable not only for synthesizing the lactone-containing entkaurene natural products but also in the development of structurally complex novel drug lead compounds of biological interest. 1609

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

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The Journal of Organic Chemistry

1 colorless solid. Mp 132−133 °C; [α]28 D −69.9° (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 4.79 (1H, br s), 4.73 (1H, br s), 3.75 (1H, d, J = 10.8 Hz), 3.44 (1H, dd, J = 11.2, 0.8 Hz), 2.63 (1H, br s), 2.06− 2.03 (2H, m), 1.96−1.93 (1H, m), 1.86−1.75 (2H, m), 1.67−1.28 (11H, m), 1.11−1.07 (2H, m), 1.00 (3H, s), 0.96 (3H, s), 0.97−0.89 (2H, m), 0.78 (1H, td, J = 12.8, 3.6 Hz); 13C NMR (100 MHz, CDCl3) δ 156.1, 103.1, 65.7, 56.9, 56.3, 49.2, 44.3, 44.1, 41.7, 40.6, 39.8, 39.3, 38.8, 35.7, 33.3, 27.2, 20.6, 18.4, 18.34, 18.25; FT-IR (film on ZnSe) 3358, 3065, 2924, 2857, 1655, 1476, 1458, 1439, 1385, 1366, 1022 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H33O 289.2526; Found 289.2521. (−)-20-Hydroxykaur-16-en-19-oic Acid Lactone (16).5c PhI(OAc)2 (2.71 g, 8.40 mmol) and I2 (1.46 g, 5.74 mmol) were added to a solution of alcohol 13 (1.61 g, 5.58 mmol) in cyclohexane (372 mL). The mixture was warmed to 40 °C and irradiated with a fluorescent lamp (27 W, FPL27EX-N) for 1 h. After cooled at room temperature, the reaction mixture was quenched by the addition of saturated aqueous Na2S2O3 (30 mL) and extracted with n-hexane (2 × 30 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and carefully concentrated to ca. 0.5 mL volume with turning off the water bath. (Caution! Iodoaldehyde 14 must be kept in solution; otherwise, it readily decomposes.) The following spectral data were collected after purification by Florisil chromatography (n-hexane/EtOAc = hexane only → 200 v/v). Data for 14: 1H NMR (400 MHz, CDCl3) δ 9.74 (1H, d, J = 1.2 Hz), 4.83 (1H, br s), 4.75 (1H, br s), 3.83 (1H, dd, J = 11.2, 1.6 Hz), 3.02 (1H, dd, J = 11.2, 1.6 Hz), 2.71 (1H, m), 2.33 (1H, br d, J = 13.6 Hz), 2.25 (1H, br d, J = 13.2 Hz), 2.11−2.02 (1H, m), 1.95−1.86 (4H, m), 1.72−1.35 (10H, m), 1.05 (3H, s), 1.11−1.01 (2H, m) 0.97−0.89 (1H, m); 13C NMR (100 MHz, CDCl3) δ 205.1, 155.0, 103.6, 57.5, 54.3, 49.7, 48.9, 44.2, 43.5, 42.2, 41.8, 41.2, 39.4, 34.5, 33.7, 24.8, 20.7, 18.8, 17.0, 11.9. THF (16 mL) and t-BuOH (32 mL) were added to a solution of crude iodoaldehyde 14. 2-Methyl-2-butene (4.43 mL, 41.9 mmol) and a solution of NaH2PO4 (3.02 g, 25.2 mmol) and NaClO2 (2.84 g, 25.1 mmol) in water (8 mL) were successively added at 0 °C. After 1 h at 0 °C, the mixture was extracted with Et2O (2 × 15 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The resulting carboxylic acid 15 was dissolved in THF (56 mL), which was followed by the addition of nBu4NF (1.0 M in THF, 11.2 mL, 11.2 mmol) at 0 °C. After 1 h at room temperature, the reaction mixture was quenched by the addition of water and extracted with n-hexane/EtOAc (5:1 v/v) (15 mL + 2 × 10 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 30 → 15 v/v) to give lactone 16 (767 mg, 2.55 mmol, 46% for three steps) as a 1 colorless solid. Mp 161−164 °C; [α]28 D −102° (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 5.17 (1H, dd, J = 12.0, 2.4 Hz), 4.83 (1H, br s), 4.79 (1H, br s), 4.14 (1H, d, J = 12.0 Hz), 2.70 (1H, br s, H13), 2.21 (1H, br d, J = 12.8 Hz), 2.09 (2H, m), 1.98 (1H, d, J = 12.0 Hz), 1.88−1.46 (10H, m), 1.36−1.19 (5H, m), 1.20 (3H, s), 1.12−0.98 (1H, m); 13C NMR (100 MHz, CDCl3) δ 176.8, 154.4, 104.3, 74.4, 51.3, 49.8, 49.4, 43.8, 43.2, 43.0, 40.7, 40.5, 40.2, 39.0, 38.8, 32.1, 23.2, 22.3, 21.1, 17.9; FT-IR (film on ZnSe) 3067, 2968, 2930, 2853, 1719, 1653, 1165, 1138 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H29O2 301.2162; Found 301.2155; Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.71; H, 9.55. Tripterifordin (1).1 A solution of lactone 16 (15.7 mg, 0.0523 mmol) in THF (1.7 mL) and 3 M aqueous HCl (7 mL) was stirred at 40 °C for 7.5 h. The reaction mixture was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 3 → 1 v/v) to give tripterifordin (1) (12.7 mg, 0.0399 mmol, 76%) as a colorless solid. Mp 245−248 °C; [α]26 D −70.3° (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.20 (1H, dd, J = 12.0, 2.4 Hz), 4.13 (1H, d, J = 12.0 Hz), 2.16 (1H, br d, J = 12.8 Hz), 1.92−1.43 (15H, m), 1.39 (3H, s), 1.31−1.17 (4H, m), 1.19 (3H, s), 1.04 (1H, m); 13C NMR (100 MHz, CDCl3) δ 176.7, 79.2, 74.1, 57.9, 51.3, 50.3, 48.3, 44.9, 43.1, 40.74, 40.70, 39.8, 38.8, 38.1, 26.1,

left at room temperature for 1 h. The solution was carefully neutralized to ca. pH 7 by the addition of acetic acid (35 mL, 611 mmol) and to ca. pH 6 by the addition of saturated aqueous NH4Cl (30 mL). The resulting mixture was extracted with ether (3 × 30 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude steviol (4) (735 mg) thus obtained was dissolved in THF (23 mL), which was followed by the addition of n-Bu4NF (1.0 M in THF, 4.61 mL, 4.61 mmol) and MeI (287 μL, 4.61 mmol). After 20 min at room temperature, the solution was concentrated, followed by the addition of water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 1 v/v) to give methyl ester 11 (706 mg, 2.12 mmol, 43% for two steps based on the assumption that the purity of stevioside was 80%) as a colorless 1 solid. Mp 107−108 °C; [α]28 D −76.4° (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 4.97 (1H, br s), 4.81 (1H, br s), 3.64 (3H, s), 2.22− 2.14 (2H, m), 2.12−2.04 (2H, m), 1.88−1.72 (6H, m), 1.65−1.49 (4H, m), 1.47−1.38 (2H, m), 1.28−1.25 (1H, m), 1.17 (3H, s), 1.05 (1H, d, J = 12.4, 3.8 Hz), 1.01 (1H, d, J = 13.6, 4.8 Hz), 0.95 (1H, d, J = 8.0 Hz), 0.82 (3H, s), 0.86−0.77 (1H, m); 13C NMR (100 MHz, CDCl3) δ 178.1, 156.3, 103.1, 80.4, 57.0, 53.9, 51.3, 47.5, 47.1, 43.9, 41.8, 41.4, 40.8, 39.36, 39.35, 38.2, 28.8, 22.0, 20.6, 19.2, 15.4; FT-IR (film on ZnSe) 3401, 3071, 2986, 2947, 2851, 1728, 1662, 1447, 1335, 1238, 1207, 1190, 1169, 1150 cm−1. Chloride (12). Pyridine (4.74 mL, 58.9 mmol) and SOCl2 (1.71 mL, 23.5 mmol) were added to a solution of alcohol 9 (3.91 g, 11.8 mmol) in ClCH2CH2Cl (118 mL). The reaction mixture was stirred at 65 °C for 20 h and quenched by the addition of water (70 mL) after cooling at room temperature. The resulting mixture was extracted with EtOAc (50 mL + 4 × 20 mL), and the combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (nhexane/EtOAc = 100 v/v) to give chloride 12 (3.42 g, 9.76 mmol, 83%) as a colorless solid. Mp 126−127 °C; [α]25 D −41.8° (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.20 (1H, t, J = 2.6 Hz), 4.97 (1H, br s,), 3.64 (3H, s), 2.40 (1H, dd, J = 11.6, 2.6 Hz), 2.24 (1H, dt, J = 17.2, 2.6 Hz), 2.21−2.10 (2H, m), 2.03 (1H, ddd, J = 13.2, 12.4, 6.0 Hz), 1.89−1.54 (9H, m), 1.48−1.40 (2H, m), 1.17 (3H, s,), 1.06− 0.95 (3H, m) 0.83 (3H, s), 0.84−0.77 (1H, m); 13C NMR (75 MHz, CDCl3) δ 178.0, 152.9, 106.7, 74.1, 56.9, 53.3, 51.3, 49.3, 47.6, 43.9, 43.2, 43.1, 41.1, 40.8, 39.4, 38.2, 28.8, 21.9, 21.4, 19.2, 15.5; FT-IR (film on ZnSe) 3082, 2992, 2951, 2924, 2872, 1722, 1661, 1472, 1447, 1333, 1238, 1207, 1188, 1170, 1148 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C21H32O2Cl 351.2085; Found 351.2085. Alcohol (13). LiAlH4 (631 mg, 16.6 mmol) was added to a solution of chloride 12 (3.42 g, 9.76 mmol) in THF (98 mL) at 0 °C. The mixture was warmed and refluxed for 1 h. After cooling at 0 °C, the reaction mixture was quenched by the addition of saturated aqueous Rochelle salt (20 mL). The resulting mixture was extracted with nhexane (2 × 30 mL), and the combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give the corresponding chloroalcohol (3.13 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.20 (1H, t, J = 2.4 Hz), 4.96 (1H, br s), 3.74 (1H, d, J = 11.2 Hz), 3.44 (1H, dd, J = 11.2, 1.2 Hz), 2.39 (1H, dd, J = 11.2, 2.4 Hz), 2.24 (1H, dt, J = 16.8, 2.8 Hz), 2.16−2.05 (2H, m), 1.89−1.28 (13H, m), 1.01 (3H, s), 1.03−0.89 (3H, m) 0.96 (3H, s), 0.79 (1H, td, J = 12.8, 3.6 Hz); 13C NMR (100 MHz, CDCl3) δ 152.9, 106.7, 74.2, 65.5, 56.7, 54.3, 49.3, 47.7, 43.2, 43.0, 41.4, 40.4, 39.1, 38.8, 35.6, 27.2, 21.2, 20.4, 18.3, 18.1. Without purification, the crude chloroalcohol (3.13 g) was dissolved in THF (97 mL), which was followed by the addition of t-BuOH (30.3 mL, 320 mmol) and lithium granular (1.46 g, 210 mmol). The reaction mixture was stirred at reflux for 80 min, and the precipitate was filtered through a pad of Celite. Water (20 mL) was added to the filtrate, which was extracted with ether (2 × 30 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 10 v/v) to give alcohol 13 (2.64 g, 9.16 mmol, 94% for two steps) as a 1610

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

Note

The Journal of Organic Chemistry 24.6, 23.2, 22.5, 21.0, 17.6; FT-IR (film on ZnSe) 3294, 2980, 2922, 2855, 1728, 1464, 1443, 1134, 1036 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H31O3 319.2268; Found 319.2262; Anal. Calcd for C20H30O3: C, 75.43; H, 9.50. Found: C, 75.35; H, 9.24. Diol (17). LiAlH4 (484 mg, 12.8 mmol) was added to a solution of lactone 16 (767 mg, 2.55 mmol) in THF (26 mL) at 0 °C. After 18 h at reflux, the reaction mixture was diluted with Et2O (15 mL) and quenched by the addition of saturated aqueous Rochelle salt (15 mL) at 0 °C. The resulting mixture was vigorously stirred until two layers clearly separated. The resulting mixture was extracted with n-hexane/ EtOAc (3:1 v/v) (2 × 20 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (nhexane/EtOAc = 10 → 3 v/v) to give diol 17 (593 mg, 1.94 mmol, 76%) as a colorless solid. Mp 131−134 °C; [α]24 D −70.9° (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.80 (1H, m), 4.74 (1H, br s), 4.06 (1H, d, J = 12.4 Hz), 3.94 (1H, d, J = 11.6 Hz), 3.90 (1H, d, J = 12.4 Hz), 3.48 (1H, d, J = 11.2 Hz), 2.65 (1H, br t, J = 4.2 Hz), 2.49 (1H, d, J = 11.6 Hz), 2.08−2.07 (2H, m), 1.95−1.79 (3H, m), 1.70− 1.39 (10H, m), 1.30−1.07 (3H, m), 1.02 (3H, s), 0.77 (1H, td, J = 13.2, 4.8 Hz); 13C NMR (75 MHz, CDCl3) δ 156.5, 102.9, 69.5, 65.0, 57.2, 56.1, 49.4, 44.2, 44.1, 42.5, 42.4, 39.3, 38.6, 38.0, 37.6, 33.4, 28.6, 22.4, 19.2, 18.7; FT-IR (film on ZnSe) 3251, 3067, 2924, 2859, 1657, 1487, 1454, 1265, 1047 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H33O2 305.2475; Found 305.2471. Doianoterpene B (18).35 NaHCO3 (85.7 mg, 1.02 mmol) and Dess−Martin periodinane (178 mg, 0.408 mmol) were added to a solution of diol 17 (62.0 mg, 0.204 mmol) in CH2Cl2 (20 mL) at 0 °C. After 3 h at room temperature, the reaction mixture was sequentially quenched by the addition of saturated aqueous NaHCO3 (5 mL) and saturated aqueous Na2S2O3 (5 mL). The resulting mixture was extracted with n-hexane (2 × 15 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (nhexane/EtOAc = 20 v/v) to give a 10:1 mixture of doianoterpene B (18) and dialdehyde 19 (29.7 mg) as a colorless solid, and 16 (21.7 mg, 0.0723 mmol, 35%) as a colorless solid. The calculated yields of 18 and 19 were 44% (27.0 mg, 0.0899 mmol) and 4% (2.7 mg, 0.0090 mmol), respectively. A small amount of 19 was removed by treating the mixture with NaBH4 in MeOH for 0.5 h at 0 °C. The lactone 18 remained intact under these conditions and was isolated in pure form by flash chromatography (n-hexane/EtOAc = 20 v/v). Data for 18: 1 Mp 112−115 °C; [α]26 D −90.1° (c 0.95, CHCl3); H NMR (400 MHz, CDCl3) δ 4.81 (1H, br s), 4.70 (1H, br s), 4.24 (1H, dd, J = 11.6, 2.4 Hz), 4.04 (1H, dd, J = 11.6, 1.4 Hz), 2.66 (1H, m), 2.44 (1H, tdd, J = 12.4, 6.0, 2.8 Hz), 2.35 (1H, m), 2.18 (1H, m), 2.11 (1H, br dd, J = 14.8, 6.0 Hz), 2.08 (1H, dt, J = 16.8, 2.6 Hz), 1.81 (1H, m), 1.76−1.02 (14H, m), 0.91 (3H, s); 13C NMR (100 MHz, CDCl3) δ 174.9, 156.4, 102.6, 76.9, 53.2, 50.2, 48.4, 48.2, 44.9, 44.1, 40.9, 39.44, 39.42, 37.5, 33.3, 31.1, 23.9, 22.7, 20.9, 19.3; FT-IR (film on ZnSe) 3065, 2943, 2913, 2864, 1719, 1653, 1458, 1136 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H29O2 301.2168; Found 301.2160; Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.94; H, 9.18. Data for 19: 1 H NMR (400 MHz, CDCl3) δ 9.72 (1H, d, J = 1.6 Hz), 9.67 (1H, d, J = 1.2 Hz), 4.80 (1H, br s), 4.75 (1H, br s), 2.65 (1H, m), 2.47 (1H, m), 2.17 (1H, m), 2.13−2.02 (2H, m), 1.98−1.91 (2H, m), 1.80 (1H, m), 1.64−1.48 (7H, m), 1.36 (1H, tdd, J = 13.6, 5.6, 2.4 Hz), 1.27− 1.11 (3H, m), 1.05 (3H, s), 1.03−0.90 (2H, m); 13C NMR (100 MHz, CDCl3) δ 206.8, 202.1, 154.9, 104.0, 55.1, 54.5, 53.2, 47.9, 47.8, 44.5, 43.8, 40.9, 39.3, 34.2, 33.8, 33.2, 25.0, 19.9, 19.8, 18.2; FT-IR (film on ZnSe) 3071, 2928, 2853, 1713, 1659, 1462, 1445, 1402, 1206, 1007 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H29O2 301.2162; Found 301.2155. Neotripterifordin (2).2 A solution of doianoterpene B (18) (15.7 mg, 0.0523 mmol) in THF (1.7 mL) and 3 M aqueous HCl (7 mL) was stirred at 40 °C for 2 h. The reaction mixture was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 3 → 1 v/v) to give neo-

tripterifordin (2) (12.1 mg, 0.0379 mmol, 73%) as a colorless solid. 1 Mp 190−191 °C; [α]28 D −38.6° (c 0.71, CHCl3); H NMR (400 MHz, CDCl3) δ 4.24 (1H, dd, J = 11.6, 2.4 Hz), 4.03 (1H, d, J = 11.6, 1.2 Hz), 2.34−2.24 (2H, m), 2.15 (1H, dd, J = 15.0, 7.0 Hz), 1.84 (1H, m), 1.79 (1H, dddd, J = 13.0, 3.2, 3.0, 2.8 Hz), 1.70−1.36 (12H, m), 1.36 (3H, s), 1.31−1.21 (2H, m), 1.17−1.08 (2H, m), 0.90 (3H, s); 13 C NMR (100 MHz, CDCl3) δ 175.1, 79.8, 76.8, 56.8, 53.5, 50.0, 49.7, 48.0, 45.0, 40.9, 40.0, 39.5, 35.6, 33.2, 24.7, 24.2, 23.9, 22.8, 20.9, 19.1; FT-IR (film on ZnSe) 3337, 2959, 2932, 2870, 1734, 1126 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H31O3 319.2268; Found 319.2265. ent-Kaur-15-en-19,20-olide (20).28 10-(±)-Camphorsulfonic acid (34.6 mg, 0.149 mmol) was added to a solution of lactone (16) (29.8 mg, 0.0992 mmol) in CHCl3 (3 mL). After 3.5 h at 50 °C, the reaction mixture was directly subjected to flash chromatography (n-hexane/EtOAc = 15 v/v) to give a 1.5:1 mixture of lactones 20 and 16 (22.0 mg, 0.0732 mmol, 74%). The calculated yields of 20 and 16 were 44% (13.2 mg, 0.0439 mmol) and 30% (8.8 mg, 0.0293 mmol), respectively. These isomers were separated by normal-phase HPLC equipped with a prepacked column [Mightysil, Si 60 250−20 (5 μm)] using 20% EtOAc in n-hexane as an eluent. Data for 20: Colorless 1 solid. Mp 180−181 °C; [α]26 D −23.2° (c 0.56, CHCl3); H NMR (400 MHz, CDCl3) δ 5.17 (1H, dd, J = 12.0, 2.4 Hz), 5.10 (1H, m), 4.18 (1H, br d, J = 12.0 Hz), 2.36 (1H, m), 2.15 (1H, m), 1.99 (1H, br d, J = 10.8 Hz), 1.85 (1H, m), 1.78 (1H, m), 1.73−1.42 (9H, m), 1.71 (3H, d, J = 1.6 Hz), 1.30−1.13 (4H, m), 1.19 (3H, s), 1.04 (1H, m); 13 C NMR (100 MHz, CDCl3) δ 176.9, 143.5, 134.7, 74.2, 51.2, 48.8, 44.4, 44.2, 43.2, 42.5, 40.82, 40.77, 38.7, 37.4, 24.4, 23.3, 21.21, 21.19, 18.2, 15.6; FT-IR (film on ZnSe) 3036, 3013, 2974, 2928, 2851, 1726, 1441, 1404, 1385, 1348, 1161, 1140 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H29O2 301.2162; Found 301.2156. Doianoterpene A (21).35 10-(±)-Camphorsulfonic acid (35.3 mg, 0.152 mmol) was added to a solution of doianoterpene B (18) (30.6 mg, 0.102 mmol) in CHCl3 (3 mL). After 3 h at 50 °C, the reaction mixture was directly subjected to flash chromatography (n-hexane/ EtOAc = 15 v/v) to give a 5.7:1 mixture of doianoterpene A (21) and doianoterpene B (18) (28.6 mg, 0.0952 mmol, 93%). The calculated yields of 21 and 18 were 79% (24.3 mg, 0.0809 mmol) and 14% (4.3 mg, 0.0143 mmol), respectively. These isomers were separated by normal-phase HPLC equipped with a prepacked column [Mightysil, Si 60 250−20 (5 μm)] using 14% EtOAc in n-hexane as an eluent. Data for 21: Colorless solid. Mp 104−106 °C; [α]26 D −35.1° (c 1.34, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.01 (1H, br s), 4.23 (1H, dd, J = 11.6, 2.4 Hz), 4.03 (1H, dd, J = 11.6, 1.2 Hz), 2.37−2.31 (2H, m), 2.20−2.08 (2H, m), 1.83 (1H, br d, J = 10 Hz), 1.78 (1H, m), 1.71 (3H, d, J = 1.6 Hz), 1.72−1.54 (6H, m), 1.46−1.08 (7H, m), 0.90 (3H, s); 13C NMR (100 MHz, CDCl3) δ 175.4, 144.3, 132.7, 76.9, 50.1, 49.1, 48.4, 45.8, 45.5, 41.6, 41.1, 39.6, 37.4, 33.3, 24.0, 22.6, 21.6, 20.9, 19.9, 15.4; FT-IR (film on ZnSe) 3021, 2922, 2859, 1732, 1445, 1406, 1379, 1348, 1231, 1136 cm−1; HRMS (ESI-pos) m/z: [M + H]+ Calcd for C20H29O2 301.2162; Found 301.2155; Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.97; H 8.96.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02916. Comparisons of 13C NMR data of natural and synthetic compounds (Tables S1 and S2), and 1H and 13C NMR spectra of all synthetic compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +81-6-6954-4081. Fax: +81-6-6954-4081. E-mail: shoji. [email protected]. ORCID

Shoji Kobayashi: 0000-0002-8496-3685 1611

DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613

Note

The Journal of Organic Chemistry Notes

(15) Since our laboratory does not possess a mercury lamp, we used a standard fluorescent lamp for irradiation. We followed the conditions reported by Poulsen et al., who succeeded in lactonization by use of a 6 W UV lamp or sunlamp in the course of the total synthesis of strongylophorines: Yu, W.; Hjerrild, P.; Overgaard, J.; Poulsen, T. B. Angew. Chem., Int. Ed. 2016, 55, 8294. (16) (a) Bridel, M.; Lavielle, R. Bull. Soc. Chim. Biol. 1931, 13, 781. (b) Mosettig, E.; Beglinger, U.; Dolder, F.; Lichti, H.; Quitt, P.; Waters, J. A. J. Am. Chem. Soc. 1963, 85, 2305. (c) Moons, N.; De Borggraeve, W.; Dehaen, W. Curr. Org. Chem. 2011, 15, 2731. (d) Khaibullin, R. N.; Strobykina, I. Y.; Kataev, V. E.; Lodochnikova, O. A.; Gubaidullin, A. T.; Balandina, A. A.; Latypov, S. K. Russ. J. Org. Chem. 2010, 46, 1006. (17) Avent, A. G.; Hanson, J. R.; De Oliveira, B. H. Phytochemistry 1990, 29, 2712. (18) Ogawa, T.; Nozaki, M.; Matsui, M. Tetrahedron 1980, 36, 2641. (19) The yield was calculated on the assumption that the purity of stevioside was 80%. (20) For successful examples of the reduction of tertiary alcohols in condensed systems, see: (a) Dolan, S. C.; MacMillan, J. J. Chem. Soc., Perkin Trans. 1 1985, 2741. (b) Chu, A.; Mander, L. N. Tetrahedron Lett. 1988, 29, 2727. (c) Fowles, A. M.; Beale, M. H.; Jones, D. N. M.; MacMillan, J.; Willis, C. L. J. Chem. Soc., Perkin Trans. 1 1988, 1983. (d) Phuoc, L. T.; Mander, L. N.; Koshioka, M.; Oyama-Okubo, N.; Nakayama, M.; Ito, A. Tetrahedron 2008, 64, 4835−4851. (21) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. (b) Barton, D. H. R.; Dorchak, J.; Jaszberenyi, J. C. Tetrahedron 1992, 48, 7435−7446. (22) (a) Sun, W.; Hu, J.; Shi, Y. Synlett 1997, 1997, 1279. (b) Lee, K.; Boger, D. L. J. Am. Chem. Soc. 2014, 136, 3312. (23) Fessner, W. D.; Sedelmeier, G.; Spurr, P. R.; Rihs, G.; Prinzbach, H. J. Am. Chem. Soc. 1987, 109, 4626. (24) (a) Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. Tetrahedron Lett. 1984, 25, 1953. (b) de Armas, P.; Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. J. Chem. Soc., Perkin Trans. 1 1989, 405. (25) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175. (c) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (d) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. (26) The lactone 16 has been reported as the “odolide” isolated from the roots of Gynocardia odorata.27 However, the NMR data of synthetic 16 did not match those of the original paper. The authors also reported isolation of tripterifordin (named “16-hydroxyl odolide”), but their spectral data were different from those of Lee’s report.1 It is therefore conceivable that the structures suggested by Pradhan include misassignments, although the correct structures are unknown at this point. The synthesis of 16 is independently reported by Mori and Maki,5b and our NMR data matched theirs (Table S2). Isolation of 16 from the stems of Celastrus orbiculatus Thunb. (Celastraceae) was later reported by Wang et al.28 (27) Pradhan, B. P.; Chakraborty, S.; Ghosh, R. K.; Roy, A. Phytochemistry 1995, 39, 1399. (28) Li, J. J.; Yang, J.; Wu, F. H.; Wang, S.-S.; Wang, Q. Chem. Nat. Compd. 2014, 49, 1032. (29) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Mylari, B. L.; Wenkert, E. J. Org. Chem. 1986, 51, 1505. (30) For mechanistic discussions on intramolecular free-radical reactions including hypoiodite reactions, see: Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. Engl. 1964, 3, 525. (31) We initially attempted installation of the oxygen functionality at C20 by Kornblum oxidation (NaHCO3/DMSO or Me3NO/DMSO) with the corresponding C20-iodides. However, the reaction generated complex mixtures and the desired aldehyde could not be obtained at all. Similar observations were reported by previous authors.11 (32) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (c) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412. (d) Fetizon, M.; Golfier, M. C. R. C. R. Seances

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number JP17K07779. We are grateful to Dr. Tadamasa Terai, a Professor Emeritus of Osaka Institute of Technology, for the initial supply of steviol and to Mr. Yasunori Hashimoto for preparation of intermediates and checking the reproducibility. We also thank Ms. Sayaka Kado and Ms. Makiko Fujinami, Center for Analytical Instrumentation, Chiba University, and Ms. Ayako Sato, A Rabbit Science Japan Co., Ltd., for measurement of mass spectra and elemental analysis, respectively. Finally, we thank Prof. Naonobu Tanaka, Tokushima University, for providing us NMR spectra of the natural product.

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DOI: 10.1021/acs.joc.7b02916 J. Org. Chem. 2018, 83, 1606−1613