Abstract
Herein, the total syntheses of (+)-aquatolide, a humulane-derived sesquiterpenoid lactone, and five other related humulanolides are described. The key reactions in these syntheses are a cascade metathesis reaction of cyclobutenecarboxylate to construct a γ-butenolide with an unsaturated aldehyde side chain, an intramolecular Nozaki–Hiyama–Takai–Kishi reaction to form an all-trans-humulene lactone skeleton, and a biosynthesis-inspired [2 + 2] photocycloaddition to provide a bridged 5/5/4/8-ring system. A cycloaddition giving a 5/4/4/7-ring system was also found. In addition, biological studies were conducted using the synthesized samples.
You have full access to this open access chapter, Download chapter PDF
Keywords
13.1 Introduction
In 2012, the structure of (+)-aquatolide, a humulane-derived sesquiterpenoid lactone, was revised from 1a to 1b (Fig. 13.1) by Shaw et al. [1]. This terpenoid was originally isolated by San Feliciano et al. from Asteriscus aquaticus [2]. Previously, structurally related sesquiterpenoids asteriscunolides A–D (2–5), called humulanolides, were isolated from the same source [3,4,5]. The proposed structure of aquatolide 1a consisted of a tetracyclic 5/4/4/7-ring system with a characteristic bicyclo[2.2.0]hexane motif. However, the Shaw and Tantillo group found that the calculated NMR data for structure 1a were inconsistent with those reported by San Feliciano et al. Revised structure 1b was assigned by computational chemistry and confirmed by X-ray crystallography. We were interested in structure 1b, which has an unusual, intricate bridged 5/5/4/8-ring system.
The biosynthesis of aquatolide has been proposed to involve a transannular [2 + 2] cycloaddition of (–)-asteriscunolide C (4) (Fig. 13.2). Parallel addition forms the C2–C10 and C3–C9 bonds in proposed structure 1a, whereas crossed addition forms the alternate bonds (C2–C9 and C3–C10) to afford real structure 1b. Although the racemic synthesis of 1b has been completed by two groups [6, 7], the total synthesis via a biomimetic [2 + 2] cycloaddition has not been reported. We decided to attempt the biomimetic approach, and then complete the total synthesis of the natural enantiomer (+)-aquatolide (1b). After much effort, we have achieved the total synthesis of 1b [8]. In this chapter, we described our endeavors toward the synthesis of 1b, including some unsuccessful approaches.
13.2 Unsuccessful Route: ROM/RCM/RCM Approach
Our retrosynthetic analysis of (+)-aquatolide (1b) is shown in Scheme 13.1. The advanced intermediate was a putative biosynthetic precursor of 1b, (–)-asteriscunolide C (4), which has a disubstituted γ-butenolide skeleton. For concise access to γ-butenolides, we have reported the ring-opening/ring-closing metathesis (ROM/RCM) reaction of cyclobutenecarboxylates in the total synthesis of (+)-clavilactone A (9) [9,10,11]. In the present work, we expected to construct the asteriscunolide skeleton through a combination of the ROM/RCM approach and a ring-closing metathesis (RCM) reaction. Namely, compound 4 could be obtained by RCM expelling ethylene from γ-butenolide 6, which would be derived from cyclobutenecarboxylate 7 by the ROM/RCM reaction. Sequential metathesis reactions can be performed as one-pot reactions. Substrate 7 would be synthesized by our acylation method from alcohol 8.
Preliminary experiments were performed as racemates (Scheme 13.2). Known racemic secondary alcohol 10 [12] was treated with DDQ under anhydrous conditions to provide acetal 11, which was reduced with DIBAL-H to primary alcohol 12. Parikh–Doering oxidation of 12 afforded aldehyde 13. The lithium enolate generated from ketone 14 reacted with aldehyde 13 to give aldol adduct 15 as a diastereomeric mixture (d.r. = 2:1). β-Elimination of 15, followed by removal of the MPM group in resultant dienone 16, provided alcohol rac-8. According to our previous procedure [9,10,11], the acylation of rac-8 was achieved by using acid anhydride 17. Cyclobutenecarboxylate rac-7 was obtained, and a substrate for the planned sequential metathesis was synthesized.
With substrate rac-7 in hand, we attempted the ROM/RCM/RCM reaction (Scheme 13.3). Cyclobutenecarboxylate rac-7 was treated with the Grubbs catalyst in hot toluene. Unfortunately, desired (±)-asteriscunolide C (rac-4) was not obtained, and only dimerized product 18 was obtained in approximately 30% yield. The ROM/RCM reaction proceeded to form a γ-butenolide skeleton-like compound 6 (Scheme 13.1), but the final RCM reaction failed. In anticipation of different reactivity, several additional substrates (19–21) were synthesized. However, the asteriscunolide skeleton could not be constructed by any of the metathesis reactions.
The conformational inflexibility of the substrates was thought to be responsible for the failure of the RCM. It was presumed that the E-olefin in rac-7 and 19 or the oxygen substituents in 20 and 21 could have an adverse effect, preventing the alkene partners from getting close enough for metathesis. Therefore, we next turned our attention to preparing more flexible substrates for the sequential metathesis reaction (Scheme 13.4). Chemoselective addition of a vinyl group to known cyanoaldehyde 22 [13] afforded alcohol 23. After silylation of 23, resulting nitrile 24 was reduced to aldehyde 25 by DIBAL-H reduction followed by hydrolytic work-up. The isopropenyl Grignard reagent reacted with aldehyde 25 to provide adduct 26 as a mixture of diastereomers (d.r. = 1:1). Via a simple sequence of reactions, TBS ether 26 was converted to MPM ether 27, which was acylated by the same method as in the synthesis of rac-7 to give cyclobutenecarboxylate 28. As further substrates for metathesis, alcohol 29 and ketone 30 were synthesized from 28 by removal of the MPM group and Dess–Martin oxidation.
Using new substrates 28–30, the ROM/RCM/RCM reaction was attempted again (Scheme 13.5). When the second-generation Hoveyda–Grubbs catalyst was applied to substrates 28 and 29, the reaction proceeded and moderate yields of the 11-membered products were obtained (15% and 27%, respectively). However, NOE experiments on the products showed that the geometry of the ring-closing site olefin was the undesired E-configuration, and compounds 32 and 34 were produced by the RCM. Furthermore, no cyclized product was obtained from the reaction of ketone 30. At this stage, we decided to abandon this approach because the metathesis yields were lower than expected and we believed that the Z-configuration was required for preparing the precursor of (+)-aquatolide (1b). Later, we realized that the E-configuration would work. This allowed us to develop a concise, high-yielding synthetic route for 1b. Independently, Li et al. have reported the total synthesis of (–)-asteriscunolide D (5) by the ROM/RCM/RCM approach [14, 15].
13.3 Successful Synthetic Strategy Toward (+)-Aquatolide
Next, we combined cross-metathesis (CM) with the ROM/RCM approach instead of RCM. This approach required a reaction to construct the 11-membered ring. We planned to rely on an intramolecular Nozaki–Hiyama–Takai–Kishi (NHTK) reaction [16,17,18,19,20], which we have used extensively [21,22,23,24]. A second-generation retrosynthetic analysis of (+)-aquatolide (1b) was conducted (Scheme 13.6). In this analysis, all-trans-humulene lactone 36 was set as a key intermediate. By tuning the structure of 36, we expected to find asteriscunolide-type compound 35 that could undergo the transannular [2 + 2] cycloaddition. Key intermediate 36 could be cleaved to iodoalkene–aldehyde 37 by the intramolecular NHTK reaction, and then 37 would be synthesized by the ROM/RCM/CM reaction of cyclobutenecarboxylate 38 with methacrolein (39).
13.4 Construction of the Asteriscunolide Skeleton
The second-generation synthesis was performed asymmetrically. Readily available D-(–)-pantolactone (40) was chosen as the starting material (Scheme 13.7). After protection of 40, DIBAL-H reduction of MPM ether 41 followed by Wittig reaction of resulting lactol 42 provided known alcohol S-12 [25] in 98% ee, confirmed by chiral HPLC analysis. Dess–Martin oxidation of S-12 afforded aldehyde S-13, and a large-scale Takai–Utimoto olefination [26] was investigated, for which economic conditions were found. Chromium(II) chloride (CrCl2) reduced from less expensive CrCl3 with LiAlH4 [27] was also effective in this reaction, yielding E-iodoalkene 43. Cyclobutenecarboxylate 38 was obtained by deprotection of 43 and acylation of alcohol 44 with acid anhydride 17, and the stage was set to develop the ROM/RCM/CM reaction.
First, we examined the ROM/RCM and CM reactions in a stepwise manner (Scheme 13.8). In our previous work [9,10,11], we used the first-generation Grubbs catalyst for the ROM/RCM, but the same conditions were not suitable for the reaction of 38. Fortunately, the second-generation Grubbs catalyst showed good activity and corresponding γ-butenolide 45 and its dimerized product were obtained. Both products were reacted with methacrolein (39) in the presence of the second-generation Grubbs catalyst to afford α,β-unsaturated aldehyde 37 as a single E-isomer in 30% overall yield. Next, a cascade method was examined. A mixture of 38, the catalyst, and methacrolein (39) in toluene was heated, and desired product 37 was produced directly in an improved yield (60%). As expected, the iodoalkene moiety was not involved in the metathesis. The cascade ROM/RCM/CM reaction was established and became a central part of this work.
The next task was forming the 11-membered ring (Scheme 13.9). The intramolecular NHTK reaction of 37 formed the asteriscunolide skeleton to provide 36 in a remarkable yield (96%). Once again, the NHTK reaction exhibited tremendous power. Cyclized product 36 was obtained as a single diastereomer with a pseudoequatorial hydroxy group. This is a common trend in NHTK reactions [20,21,22,23,24]. Alcohol 36 was oxidized to (–)-asteriscunolide D (5). Thus, the total synthesis of 5 was achieved in 10 steps from 40 with an overall yield of 32%, which was approximately four or seven times higher than the yields of previously reported syntheses [14, 15, 28].
13.5 Synthesis of the Proposed Structure of Aquatolide (1a)
Because asteriscunolide and asteriscunolide-type compounds were obtained, the [2 + 2] cycloaddition was investigated (Scheme 13.10). First, we irradiated (–)-asteriscunolide D (5) with a high-pressure Hg lamp (100 W). However, only olefin isomerization was observed and (–)-asteriscunolide A (2) was obtained as the major product. Although a small amount of (–)-asteriscunolide C (4) was produced, [2 + 2] cycloadducts were not detected. The Li group reported that irradiation of 5 with a UV lamp (10 W, 254 nm) gave similar results [14, 15]. We concluded that compound 5 was an unsuitable substrate for the direct synthesis of (+)-aquatolide (1b) via a photochemical reaction.
Next, we irradiated dienol 36 instead of dienone 5 (Scheme 13.11). In this reaction, chemoselective isomerization of the trisubstituted olefin gave compound 46, but the desired [2 + 2] cycloaddition did not occur. We thought that the more reactive trisubstituted olefin needed to be masked. Therefore, 46 was epoxidized with m-CPBA. The reagent approached from the outside of the 11-membered ring, yielding only isomer 47. As expected, the photoreaction of epoxide 47 gave a [2 + 2] cycloadduct. In fact, the cycloaddition proceeded in parallel mode and ladder-like adduct 48 was formed, although at this stage, we did not notice the undesired result. Oxidation of 48 afforded keto-epoxide 49, which was reduced to the final compound. Unfortunately, the compound was not (+)-aquatolide (1b). The 1H and 13C NMR data for the synthetic sample did not match those for 1b, but were consistent with those calculated by Shaw and Tantillo’s group for the proposed structure of aquatolide (1a) [1]. Consequently, we realized that it was non-natural product 1a.
13.6 Completion of the Total Synthesis of (+)-Aquatolide (1b)
We used an oxy-Michael reaction as an alternative way to mask the olefin and expected the corresponding adduct to give different results from epoxide 47. Therefore, we investigated the conditions for regioselective 1,4-addition of methanol to (–)-asteriscunolide D (5) (Scheme 13.12). Under basic conditions (NaOMe/MeOH), low regioselectivity was observed, giving a complex mixture of 1,4-adducts to di- and/or tri-substituted olefins. Fortunately, the reaction with acids such as BF3·OEt2 in methanol provided 1,4-adduct 50 with high regio and stereoselectivity. The crossed [2 + 2] cycloaddition of 50 proceeded to provide desired product 51 with the bicyclo[2.1.1]hexane core. Thus, we achieved the first biomimetic transannular [2 + 2] cycloaddition for the synthesis of aquatolide. Treatment of 51 with BF3·OEt2 afforded the eliminated product and completed the total synthesis of (+)-aquatolide (1b). Compared with previous racemic syntheses [6, 7], our route was shorter (13 steps from 40) and resulted in a high yield (5.7% overall yield).
Although the transannular [2 + 2] photocycloaddition of compound 47 provided parallel product 48 (Scheme 13.11), the reaction of compound 50 gave crossed adduct 51 (Scheme 13.12). We analyzed the extremely high regioselectivity in these reactions by conformational searches of the substrates (Fig. 13.3). H-2 and H-10 were cis to each other in the most stable conformer of epoxide 47. In contrast, these hydrogens were trans in 50. Therefore, the parallel cycloaddition of 50 would not proceed because a trans-fused 4/4-ring system is impossible. These results suggested that the parallel or crossed modes of cycloaddition are controlled by the conformation of the substrates.
13.7 Total Syntheses of Related Humulanolides
In addition, we investigated the syntheses of other related humulanolides (Scheme 13.13). In the photoreaction of (–)-asteriscunolide D (5), the total synthesis of (–)-asteriscunolide A (2) was achieved (11 steps from 40 with an overall yield of 14%) (Scheme 13.10), but pure (–)-asteriscunolide C (4) was not isolated. In contrast, the oxidation of alcohol 46 (Scheme 13.11) afforded pure 4 (11 steps from 40 with an overall yield of 13%). Chemo and stereoselective epoxidation of alcohol 36 with m-CPBA achieved the first total synthesis of (–)-asteriscunolide I (52) [29], a recently isolated humulanolide (10 steps from 40 with an overall yield of 26%). Our next goal was to construct the asteriscanolide skeleton, a tricyclic 5/5/8-ring system. A clue to its construction was found by chance in a study of the 1,4-addition of methanol to 5 (Scheme 13.12). When 5 was treated with n-Bu3P in methanol, an intramolecular Rauhut–Currier (vinylogous Morita–Baylis–Hillman) reaction [30, 31] occurred to afford (+)-tetradehydroasteriscanolide (53) [32]. After optimization, the yield was improved and the efficient total synthesis of 53 was also completed (11 steps from 40 with an overall yield of 32%).
13.8 Biological Activity of Natural Humulanolides and Analogs
Although several humulanolides show anti-tumor activity [33, 34], their target molecule has not been identified. We conducted a structure–activity relationship study using synthetic samples of natural humulanolides and their analogs, expecting to elucidate the mode of action. First, two additional compounds, 54 and 55, were prepared by oxidation of the corresponding alcohols (Scheme 13.14) [35].
Twelve compounds were selected, and anti-proliferative activity was examined against eight human cancer cell lines. Whereas most compounds, including aquatolide, were inactive (1a, 1b, 36, 47, 49, 52, 53, and 55), asteriscunolide A (2), asteriscunolide C (4), and asteriscunolide D (5) showed some activity. 54 was the most potent compound, exhibiting anti-proliferative activity against all tested cell lines (e.g., the IC50 values against human gingival carcinoma cell line Ca9-22: 9.9 μM for 2, 7.5 μM for 4, 4.8 μM for 5, and 2.9 μM for 54). The results suggested that the unsaturated carbonyl moiety on the 11-membered ring is essential for the anti-cancer activity and that the stereochemistry around the epoxide moiety is also important.
A further biological study was conducted using 54. 54 caused morphological changes in cells similar to those observed during geldanamycin treatment. Thus, heat-shock protein 90 (HSP90), which is a chaperone that helps proper protein folding, was probably the target protein. Actually, we confirmed that 54 increased the expression of HSP70 and decreased that of HSP90 client proteins, such as AKT and CDK4.
13.9 Conclusion
We were inspired by the biosynthesis of (+)-aquatolide (1b) to achieve the efficient total synthesis of 1b. In the early stage of the synthesis, the cascade ROM/RCM/CM reaction of cyclobutenecarboxylate was developed to construct the γ-butenolide with an unsaturated aldehyde side chain. The intramolecular NHTK reaction efficiently formed an all-trans-humulene lactone skeleton. Finally, the transannular [2 + 2] photocycloaddition of an asteriscunolide-like compound was realized in a crossed mode. In addition, the [2 + 2] cycloaddition proceeding in a parallel mode was also found. Thus, we established a concise, high-yielding synthetic route to 1b. Related humulanolides (2, 4, 5, 52, and 53) were also synthesized with our strategy and a structure–activity relationship study was performed using the synthesized samples. We hope that our findings will contribute to the development of natural product synthesis.
References
Lodewyk MW, Soldi C, Jones PB, Olmstead MM, Rita J, Shaw JT, Tantillo DJ (2012) The correct structure of aquatolide–experimental validation of a theoretically-predicted structural revision. J Am Chem Soc 134: 18550–18553. https://doi.org/10.1021/ja3089394
San Feliciano A, Medarde M, Miguel del Corral JM, Aramburu A, Gordaliza M, Barrero AF (1989) Aquatolide. A new type of humulane-related sesquiterpene lactone. Tetrahedron Lett 30: 2851–2854. https://doi.org/10.1016/S0040-4039(00)99142-1
San Feliciano A, Barrero AF, Medarde M, Miguel del Corral JM, Ledesma E, Sánchez-Ferrando F (1982) Asteriscunolide A: humulanolide from Asteriscus aquaticus. Tetrahedron Lett 23: 3097–3100. https://doi.org/10.1016/S0040-4039(00)87542-5
San Feliciano A, Barrero AF, Medarde M, Miguel del Corral JM, Aramburu Aizpiri A, Sánchez-Ferrando F (1984) Asteriscunolides A, B, C and D, the first humulanolides; two pairs of conformationally stable stereoisomers. Tetrahedron 40: 873–878. https://doi.org/10.1016/S0040-4020(01)91476-0
San Feliciano A, Barrero AF, Medarde M, Miguel del Corral JM, Aramburu A, Perales A, Fayos J, Sánchez-Ferrando F (1985) The stereochemistry of asteriscunolides: an X-ray based correction. Tetrahedron 41: 5711–5717. https://doi.org/10.1016/S0040-4020(01)91377-8
Saya JM, Vos K, Kleinnijenhuis RA, van Maarseveen JH, Ingemann S, Hiemstra H (2015) Total synthesis of aquatolide. Org Lett 17: 3892–3894. https://doi.org/10.1021/acs.orglett.5b01888
Wang B, Xie Y, Yang Q, Zhang G, Gu Z (2016) Total synthesis of aquatolide: Wolff ring contraction and late-stage Nozaki–Hiyama–Kishi medium-ring formation. Org Lett 18: 5388–5391. https://doi.org/10.1021/acs.orglett.6b02767
Takao K, Kai H, Yamada A, Fukushima Y, Komatsu D, Ogura A, Yoshida K (2019) Total syntheses of (+)-aquatolide and related humulanolides. Angew Chem Int Ed 58: 9851–9855. https://doi.org/10.1002/anie.201904404
Takao K, Nanamiya R, Fukushima Y, Namba A, Yoshida K, Tadano K (2013) Total synthesis of (+)-clavilactone A and (–)-clavilactone B by ring-opening/ring-closing metathesis. Org Lett 15: 5582–5585. https://doi.org/10.1021/ol4027842
Takao K, Nemoto R, Mori K, Namba A, Yoshida K, Ogura A (2017) Total synthesis and structural revision of clavilactone D. Chem Eur J 23: 3828–3831. https://doi.org/10.1002/chem.201700483
Takao K, Mori K, Kasuga K, Nanamiya R, Namba A, Fukushima Y, Nemoto R, Mogi T, Yasui H, Ogura A, Yoshida K, Tadano K (2018) Total synthesis of clavilactones. J Org Chem 83: 7060–7075. https://doi.org/10.1021/acs.joc.7b03268
Fuwa H, Noto K, Sasaki M (2010) Stereoselective synthesis of substituted tetrahydropyrans via domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization. Org Lett 12: 1636–1639. https://doi.org/10.1021/ol100431m
Bret G, Harling SJ, Herbal K, Langlade N, Loft M, Negus A, Sanganee M, Shanahan S, Strachan JB, Turner PG, Whiting MP (2011) Development of the route of manufacture of an oral H1–H3 antagonist. Org Process Res Dev 15: 112–122. https://doi.org/10.1021/op1002598
Han JC, Li F, Li CC (2014) Collective synthesis of humulanolides using a metathesis cascade reaction. J Am Chem Soc 136: 13610–13613. https://doi.org/10.1021/ja5084927
Han JC, Li CC (2015) Collective synthesis of natural products by using metathesis cascade reactions. Synlett 26: 1289–1304. https://doi.org/10.1055/s-0034-1380180
Okude Y, Hirano S, Hiyama T, Nozaki H (1977) Grignard-type carbonyl addition of allyl halides by means of chromous salt. A chemospecific synthesis of homoallyl alcohols. J Am Chem Soc 99: 3179–3181. https://doi.org/10.1021/ja00451a061
Takai K, Kimura K, Kuroda T, Hiyama T, Nozaki H (1983) Selective Grignard-type carbonyl addition of alkenyl halides mediated by chromium(II) chloride. Tetrahedron Lett 24: 5281–5284. https://doi.org/10.1016/S0040-4039(00)88417-8
Jin H, Uenishi J, Christ WJ, Kishi Y (1986) Catalytic effect of nickel(II) chloride and palladium(II) acetate on chromium(II)-mediated coupling reaction of iodo olefins with aldehydes. J Am Chem Soc 108: 5644–5646. https://doi.org/10.1021/ja00278a057
Takai K, Tagashira M, Kuroda T, Oshima K, Utimoto K, Nozaki H (1986) Reactions of alkenylchromium reagents prepared from alkenyl trifluoromethanesulfonates (triflates) with chromium(II) chloride under nickel catalysis. J Am Chem Soc 108: 6048–6050. https://doi.org/10.1021/ja00279a068
For a review on the NHTK reaction in natural products synthesis, see: Gil A, Albericio F, Álvarez M (2017) Role of the Nozaki–Hiyama–Takai–Kishi reaction in the synthesis of natural products. Chem Rev 117: 8420–8446. https://doi.org/10.1021/acs.chemrev.7b00144
Takao K, Hayakawa N, Yamada R, Yamaguchi T, Morita U, Kawasaki S, Tadano K (2008) Total synthesis of (–)-pestalotiopsin A. Angew Chem Int Ed 47: 3426–3429. https://doi.org/10.1002/anie.200800253
Takao K, Hayakawa N, Yamada R, Yamaguchi T, Saegusa H, Uchida M, Samejima S, Tadano K (2009) Total syntheses of (+)- and (–)-pestalotiopsin A. J Org Chem 74: 6452–6461. https://doi.org/10.1021/jo9012546
Takao K, Tsunoda K, Kurisu T, Sakama A, Nishimura Y, Yoshida K, Tadano K (2015) Total synthesis of (+)-vibsanin A. Org Lett 17: 756–759. https://doi.org/10.1021/acs.orglett.5b00086
Takao K, Ogura A, Yoshida K, Simizu S (2020) Total synthesis of natural products using intramolecular Nozaki–Hiyama–Takai–Kishi reactions. Synlett 31: 421–433. https://doi.org/10.1055/s-0039-1691580
Gregson T, Thomas EJ (2017) Synthesis of vinylic iodides for incorporation into the C17–C27 fragment of bryostatins. Tetrahedron 73: 3316–3328. https://doi.org/10.1016/j.tet.2017.04.048
Takai K, Nitta K, Utimoto K (1986) Simple and selective method for aldehydes (RCHO) .fwdarw. (E)-haloalkenes (RCH:CHX) conversion by means of a haloform-chromous chloride system. J Am Chem Soc 108: 7408–7410. https://doi.org/10.1021/ja00283a046
Hiyama T, Kimura K, Nozaki H (1981) Chromium(II) mediated threo selective synthesis of homoallyl alcohols. Tetrahedron Lett 22: 1037–1040. https://doi.org/10.1016/S0040-4039(01)82859-8
Trost BM, Burns AC, Bartlett MJ, Tautz T, Weiss AH (2012) Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D. J Am Chem Soc 134: 1474–1477. https://doi.org/10.1021/ja210986f
Hammoud L, León F, Brouard I, Gonzalez-Platas J, Benayache S, Mosset P, Benayache F (2018) Humulene derivatives from Saharian Asteriscus graveolens. Tetrahedron Lett 59: 2668–2670. https://doi.org/10.1016/j.tetlet.2018.05.079
Wang LC, Luis AL, Agapiou K, Jang HY, Krische MJ (2002) Organocatalytic Michael cycloisomerization of bis(enones): the intramolecular Rauhut–Currier reaction. J Am Chem Soc 124: 2402–2403. https://doi.org/10.1021/ja0121686
Frank SA, Mergott DJ, Roush WR (2002) The vinylogous intramolecular Morita–Baylis–Hillman reaction: synthesis of functionalized cyclopentenes and cyclohexenes with trialkylphosphines as nucleophilic catalysts. J Am Chem Soc 124: 2404–2405. https://doi.org/10.1021/ja017123j
El Dahmy S, Jakupovic J, Bohlmann F, Sarg TM (1985) New humulene derivatives from Asteriscus graveolens. Tetrahedron 41: 309–316. https://doi.org/10.1016/S0040-4020(01)96422-1
Negrín G, Eiroa JL, Morales M, Triana J, Quintana J, Estévez F (2010) Naturally occurring asteriscunolide A induces apoptosis and activation of mitogen-activated protein kinase pathway in human tumor cell lines. Mol Carcinog 49: 488–499. https://doi.org/10.1002/mc.20629
Rauter AP, Branco I, Bermejo J, González AG, García-Grávalos MD, San Feliciano A (2001) Bioactive humulene derivatives from Asteriscus vogelii. Phytochemistry 56: 167–171. https://doi.org/10.1016/S0031-9422(00)00304-6
Saegusa J, Osada Y, Miura K, Sasazawa Y, Ogura A, Takao K, Simizu S (2022) Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor. Bioorg Med Chem Lett 60: 128589. https://doi.org/10.1016/j.bmcl.2022.128589
Acknowledgements
We are grateful to our co-workers whose names appear in the references. This research was supported by JSPS KAKENHI Grant Number 15K05504 and the Naito Foundation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Copyright information
© 2024 The Author(s)
About this chapter
Cite this chapter
Ogura, A., Takao, Ki. (2024). Total Syntheses of (+)-Aquatolide and Related Humulanolides. In: Nakada, M., Tanino, K., Nagasawa, K., Yokoshima, S. (eds) Modern Natural Product Synthesis. Springer, Singapore. https://doi.org/10.1007/978-981-97-1619-7_13
Download citation
DOI: https://doi.org/10.1007/978-981-97-1619-7_13
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-97-1618-0
Online ISBN: 978-981-97-1619-7
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)