JP6984819B2

JP6984819B2 - Zernbon-inducing compounds and cancer cell growth inhibitors and methods for producing them

Info

Publication number: JP6984819B2
Application number: JP2017168861A
Authority: JP
Inventors: 隆北山; 芳美宇高; 幸子田島; 智広伊藤
Original assignee: Mie University NUC; Kinki University
Current assignee: Mie University NUC; Kinki University
Priority date: 2017-09-01
Filing date: 2017-09-01
Publication date: 2021-12-22
Anticipated expiration: 2037-09-01
Also published as: JP2019043894A

Description

本発明はゼルンボンから誘導される新規物質（ゼルンボン誘導化合物）と、それを用いた癌細胞増殖抑制剤およびそれらの製造方法に関するものである。 The present invention relates to a novel substance derived from Zernbon (Zernbon-inducing compound), a cancer cell growth inhibitor using the same, and a method for producing the same.

新規医薬開発のために様々な手法が開発されているが、低分子医薬は現在でも最も重要な役割を担っている。その中でも天然物医薬は新規かつ複雑な構造体によって選択的な薬理効果をもたらしている。しかし、複雑な構造体をリード化合物としてさらに開発を進めるには、技術的限界があるのも現実である。 Although various methods have been developed for the development of new drugs, small molecule drugs still play the most important role. Among them, natural product drugs bring about selective pharmacological effects due to their novel and complicated structures. However, the reality is that there are technical limitations in further development of complex structures as lead compounds.

またこれまで、優れた薬理活性を有し、かつ分子量の小さいリード化合物を選択して誘導化する医薬開発も行われているが(例えばコンビナトリアルケミストリーなど)、母骨格に変化をもたらすことが困難であるため、薬理活性を制御する活性部位（受容体やタンパク質）への結合活性に劇的な効果を示すことができないことも、現在の医薬開発に大きな問題点を投げかけている。 In addition, although drug development has been carried out to select and induce lead compounds having excellent pharmacological activity and small molecular weight (for example, combinatorial chemistry), it is difficult to bring about changes in the mother skeleton. Therefore, the inability to show a dramatic effect on the binding activity to active sites (receptors and proteins) that control pharmacological activity also poses a major problem in the current drug development.

これらの問題点の大きなポイントは、新たな母骨格を得ることが困難である点に尽きる。すなわち、本研究では比較的分子量が小さく、非常に多岐に富んだ薬理活性を有しながら、かつ多様な反応性を有する天然物が求められていた。ハナショウガの主成分であるゼルンボンはこれまでに抗癌効果や、抗ＨＩＶ、抗炎症作用など、多岐に亘る生理活性が発見されている。ゼルンボンは１１員環のフムレン骨格を基本とするセスキテルペンで、炭化水素骨格に酸素が一つ結合している比較的単純な元素のみで構成されている。しかし、酸素の結合によって、二重共役系をもつことが最大の特徴であり、この構造こそが新規骨格でもある。 The major point of these problems is that it is difficult to obtain a new mother skeleton. That is, in this study, a natural product having a relatively small molecular weight, having a very wide variety of pharmacological activities, and having various reactivity was required. Zelumbon, which is the main component of Hanashoga, has been discovered to have a wide range of physiological activities such as anti-cancer effect, anti-HIV, and anti-inflammatory effect. Zernbon is a sesquiterpene based on the 11-membered ring humulene skeleton, and is composed of only relatively simple elements in which one oxygen is bonded to the hydrocarbon skeleton. However, the biggest feature is that it has a double conjugated system due to the binding of oxygen, and this structure is also a new skeleton.

発明者は、この二重共役系の存在が反応多様性を生み出すことをこれまでに示している。そして、この部位の反応性を抑制し、ゼルンボンの特徴的構造を崩さない新規反応を見いだすことにも成功している（特許文献１、非特許文献１）。この発明こそが新薬開発の鍵となると考えている。 The inventor has previously shown that the existence of this double conjugated system creates reaction diversity. We have also succeeded in finding a novel reaction that suppresses the reactivity of this site and does not destroy the characteristic structure of Zernbon (Patent Document 1, Non-Patent Document 1). We believe that this invention is the key to new drug development.

特開２００６−２４１０５６号公報（特許第４４１８８７８号）Japanese Unexamined Patent Publication No. 2006-241056 (Patent No. 4418878)

Ｔｅｔｒａｈｅｄｒｏｎ，６９，１０１５２−１０１６０（２０１３）Tetrahedron, 69, 10152-10160 (2013)

本発明は、リード化合物としてのゼルンボンの有用性を、新規物質を得ることで具体的に示し、さらに得られた新規物質は薬剤としての効果を有することを実際に示すことにある。 The present invention specifically demonstrates the usefulness of zerumbon as a lead compound by obtaining a novel substance, and further demonstrates that the obtained new substance has an effect as a drug.

より具体的に本発明に係る化合物は、ゼルンボンから誘導される７−ブロモゼルンボンに脂肪酸を組み込んだ新規物質を提供する。求核剤として用いられた塩は、サリチル酸ナトリウム、テレフタル酸、テレフタル酸モノメチルカリウム、テレフタル酸モノ−ｔｅｒｔ−ブチルナトリウム、ｏ−メトキシ安息香酸ナトリウム、ｐ−メトキシ安息香酸ナトリウム、ｏ−ニトロ安息香酸ナトリウム、ｐ−ニトロ安息香酸ナトリウムであった。 More specifically, the compound according to the present invention provides a novel substance in which a fatty acid is incorporated into 7-bromozerumbone derived from zerumbone. The salts used as nucleating agents were sodium salicylate , terephthalic acid, monomethylpotassium terephthalate, mono-tert-butyl sodium terephthalate, sodium o-methoxybenzoate, sodium p-methoxybenzoate, sodium o-nitrobenzoate. , P-nitrosodium benzoate.

本発明に係る化合物では、非常に多くの生理活性が知られる、脂肪酸の一つであるサリチル酸を用い、ゼルンボンとのカップリングに初めて成功した。そして予想通りサリチル酸等のベンゼン構造を有する物質等とゼルンボンとのカップリング体の多くがヒト白血病細胞増殖抑制効果を有することを見いだした。 In the compound according to the present invention, salicylic acid, which is one of the fatty acids known to have a large number of physiological activities, was used and successfully coupled with zerumbon for the first time. Then, as expected, it was found that most of the couplings of substances having a benzene structure such as salicylic acid and zerumbon have an effect of suppressing human leukemia cell proliferation.

以下に本発明に係る新規物質（ゼルンボン誘導化合物）について実施例を示し説明を行う。なお、以下の説明は、本発明の一実施形態および一実施例を例示するものであり、本発明が以下の説明に限定されるものではない。以下の説明は本発明の趣旨を逸脱しない範囲で改変することができる。 Examples of the novel substance (Zelumbon-derived compound) according to the present invention will be described below. The following description exemplifies one embodiment and one embodiment of the present invention, and the present invention is not limited to the following description. The following description can be modified without departing from the spirit of the present invention.

また以下の説明において、合成した化合物については、以下の機器を用いて各種測定を行い反応および生成物を確認した。 Further, in the following description, for the synthesized compound, various measurements were carried out using the following instruments to confirm the reaction and the product.

ＮＭＲ（ＮｕｃｌｅａｒＭａｇｎｅｔｉｃＲｅｓｏｎａｎｃｅ：核磁気共鳴）装置は、日本電子製ＦＴ−ＮＭＲＪＮＭ−２７０ＥＸ，ＢｒｕｋｅｒＡＶＡＮＣＥＩＩＩＮａｎｏｂａｙ４００を用いた。 As an NMR (Nuclear Magnetic Resonance) apparatus, FT-NMR JNM-270EX and Bruker AVANCE III Nanobay 400 manufactured by JEOL Ltd. were used.

ＧＣ（ＧａｓＣｈｒｏｍａｔｏｇｒａｐｈｙ）装置は、島津製作所ＧＣ−２０１０を用いた。カラムは、ＩｎｅａｒｔＣａｐ５（ＧＬＳｃｉｅｎｃｅ）を用いた。 As the GC (Gas Chromatography) apparatus, Shimadzu GC-2010 was used. As the column, Ineart Cap5 (GL Science) was used.

ＧＣＭＳ（ＧａｓＣｈｒｏｍａｔｏｇｒａｐｈｙＭａｓｓＳｐｅｃｔｒｏｍｅｔｒｙ：クロマトグラフ質量分析）装置は、６８９０Ｎ（ＡｇｉｌｅｎｔＪ＆ＷＴｅｃｈｎｏｌｏｇｉｅｓ）を用いた。カラムは、ＨＰ−５（ＡｇｉｌｅｎｔＪ＆Ｗｔｅｃｈｎｏｌｏｇｉｅｓ）を用いた。 As a GCMS (Gas Chromatography Mass Spectrometry) apparatus, 6890N (Agilent J & W Technologies) was used. As the column, HP-5 (Agilent J & W technologies) was used.

減圧機器は、真空機工株式会社ＧＬＤ−０５０を用いた。ロータリーバキュームエバポレーターは、東京理化機械株式会社Ｎ−１０００を用いた。ＵＶランプは、井内盛栄堂ＳＥ−１４０を用いた。融点測定器は、ヤナコグループＭＰ−Ｊ３を用いた。 As the decompression device, GLD-050 of Vacuum Kiko Co., Ltd. was used. As the rotary vacuum evaporator, Tokyo Rika Kikai Co., Ltd. N-1000 was used. As the UV lamp, Inuchi Seieidou SE-140 was used. As the melting point measuring instrument, Yanaco Group MP-J3 was used.

本発明に係る化合物を得るための基本的な反応を説明する。ゼルンボン（化合物１）から誘導された７−ブロモ−２，９，９−トリメチル−６−メチレンシクロウンデカ−２，１０−ジエノン（エキソオレフィン型臭素化ゼルンボン、以下「７−ブロモゼルンボン」と呼ぶ：化合物２）をリード化合物とし、（１）式で表す反応でゼルンボン誘導化合物を得た。なお、以下の構造式の下の数字は化合物番号を示す（以下同じ）。 The basic reaction for obtaining the compound according to the present invention will be described. 7-bromo-2,9,9-trimethyl-6-methylenecycloundeca-2,10-dienone (exoolefin-type brominated zelumbon, hereinafter referred to as "7-bromozelumbon") derived from zelumbon (Compound 1): Using compound 2) as a lead compound, a zelumbon-derived compound was obtained by the reaction represented by the formula (1). The numbers below the structural formula below indicate the compound numbers (the same applies hereinafter).

（１）式で示されるように７−ブロモゼルンボンにＤＭＦ（Ｎ，Ｎ−ジメチルホルムアミド）と求核剤となる塩を加え、室温で反応させることで、ゼルンボンに求核物質を導入した新規化合物を得る。 As shown in the formula (1), DMF (N, N-dimethylformamide) and a salt as a nucleophile are added to 7-bromozelumbon and reacted at room temperature to obtain a novel compound in which the nucleophile is introduced into zelumbon. obtain.

まず、ゼルンボンから７−ブロモゼルンボンを得る方法について説明する。
＜エキソオレフィン型臭素化ゼルンボンの合成＞
２０ｍＬスクリュー管にゼルンボン（化合物１）を２００ｍｇ（０．９２ｍｍｏｌ）入れ、ＣＨ_３ＣＮ／Ｈ_２Ｏ（１／１）３ｍＬを加えて溶解し、ＮＢＳ（Ｎ−ブロモスクシンイミド）１．１ｅｑ（１８０．１ｍｇ，１．０１ｍｍｏｌ）を加えて室温で１分間激しく攪拌した。その後Ｈ_２Ｏを適量加え、反応溶液を吸引ろ過し、水でよく洗浄した。得られた白色固体を乾燥し、化合物２（７−ブロモゼルンボン）を収率８５．５％で２３３．９ｍｇ得た。なお、「ｅｑ」は「モル当量」を表す（以下同じ）。 First, a method for obtaining 7-bromozerumbone from zerumbon will be described.
<Synthesis of exoolefin-type brominated zelumbon>
200 mg (0.92 mmol) of zerumbon (Compound 1) was placed in a 20 mL screw tube, and _{3 mL of CH 3} CN / H ₂ O (1/1) was added to dissolve the mixture, and NBS (N-bromosuccinimide) 1.1 eq (180. 1 mg (1.01 mmol) was added, and the mixture was vigorously stirred at room temperature for 1 minute. Thereafter was added an appropriate amount of H _{2 O,} the reaction solution was filtered off with suction and washed well with water. The obtained white solid was dried to obtain 233.9 mg of compound 2 (7-bromozelumbon) in a yield of 85.5%. In addition, "eq" represents "molar equivalent" (the same applies hereinafter).

（２Ｅ，１０Ｅ）−７−ブロモ−２，９，９−トリメチル−６−メチレンシクロウンデカ−２，１０−ジエン−１−オン：（（２Ｅ，１０Ｅ）−７−Ｂｒｏｍｏ−２，９，９−ｔｒｉｍｅｔｈｙｌ−６−ｍｅｔｈｙｌｅｎｅｃｙｃｌｏｕｎｄｅｃａ−２，１０−ｄｉｅｎ−１−ｏｎｅ）：化合物２，
融点：８３．０−８４．０℃，
ＩＲ（ＫＢｒ）：１６５５ｃｍ^−１，
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１０（ｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．１９（ｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７４（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），２．２１（ｄｄ，１Ｈ，Ｊ＝２．１ａｎｄ１４．７Ｈｚ，ＣＨａｔＣ３），２．３７−２．５９（ｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７５（ｄ，１Ｈ，Ｊ＝１４．７Ｈｚ，ＣＨａｔＣ２），５．１０（ｓ，１Ｈ，ＣＨ_２ａｔＣ１），５．４５（ｓ，１Ｈ，ＣＨ_２ａｔＣ１），５．８６（ｔ，１Ｈ，Ｊ＝６．３Ｈｚ，ＣＨａｔＣ９），５．９７（ｄ，１Ｈ，Ｊ＝１６．２Ｈｚ，ＣＨａｔＣ５），６．５６（ｄ，１Ｈ，Ｊ＝１６．２Ｈｚ，ＣＨａｔＣ６）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．４（ＣＨ_３ａｔＣ８），２４．０（ＣＨ_３ａｔＣ４），２７．２（ＣＨ_３ａｔＣ４），２８．０（Ｃ２），３１．８（Ｃ１１），３８．９（Ｃ４），５０．３（Ｃ１０），５５．３（Ｃ２），１１４．７（Ｃ１），１２７．７（Ｃ１１），１３８．９（Ｃ８），１４８．０（Ｃ９），１５０．１（Ｃ１），１６０．３（Ｃ６），２０３．１（Ｃ７）；
ＨＲＭＳ：ｍ／ｚ計算値（Ｃ_１５Ｈ_２１ＢｒＯ）：２９６．０７７６，実測値：２９６．０７８６． (2E, 10E) -7-bromo-2,9,9-trimethyl-6-methylenecycloundeca-2,10-diene-1-on: ((2E, 10E) -7-Bromo-2, 9, 9-trimethyl-6-methylnecyclundecca-2, 10-dien-1-one): Compound 2,
Melting point: 83.0-84.0 ° C,
IR (KBr): 1655cm ^-1 ,
^{1 1} H NMR (CDCl ₃ ): δ1.10 (s, 3H, CH ₃ at C4), 1.19 (s, 3H, CH ₃ at C4), 1.74 (s, 3H, CH ₃ at C8), 2.21 (dd, 1H, J = 2.1 and 14.7Hz, CH at C3), 2.37-2.59 (m, 6H, CH ₂ at C3, C10, and C11), 4.75 ( d, 1H, J = 14.7Hz, CH at C2), 5.10 (s, 1H, CH ₂ at C1), 5.45 (s, 1H, CH ₂ at C1), 5.86 (t, 1H) , J = 6.3Hz, CH at C9), 5.97 (d, 1H, J = 16.2Hz, CH at C5), 6.56 (d, 1H, J = 16.2Hz, CH at C6);
¹³ C NMR (CDCl ₃ ): δ12.4 (CH ₃ at C8), 24.0 (CH ₃ at C4), 27.2 (CH ₃ at C4), 28.0 (C2), 31.8 (C11) ), 38.9 (C4), 50.3 (C10), 55.3 (C2), 114.7 (C1), 127.7 (C11), 138.9 (C8), 148.0 (C9) , 150.1 (C1), 160.3 (C6), 203.1 (C7);
HRMS: m / z calculated value (C ₁₅ H ₂₁ BrO): 296.0776, measured value: 296.0786.

以下、７−ブロモゼルンボンに求核剤を用いて作成した新規な化合物を示す。
＜求核剤にサリチル酸を用いた反応＞
遮光ビンに化合物２を２００ｍｇ（０．６７ｍｍｏｌ）入れ、ＤＭＦ１０ｍＬを加えて攪拌し、サリチル酸ナトリウム１．５ｅｑ（１６２ｍｇ，１．０１ｍｍｏｌ）を加え、室温で５時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝５／１）で反応終了を確認し、反応を止めた。なお、「ＴＬＣ」は「Ｔｈｉｎ−Ｌａｙｅｒ−Ｃｈｒｏｍａｔｏｇｒａｐｈｙ」であり、「Ｈｅｘａｎｅ」はヘキサン、「ＡｃＯＥｔ」はエチルアセテートである。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。 Hereinafter, a novel compound prepared by using a nucleophile on 7-bromozelumbon is shown.
<Reaction using salicylic acid as a nucleophile>
200 mg (0.67 mmol) of compound 2 was placed in a light-shielding bottle, 10 mL of DMF was added and stirred, 1.5 eq (162 mg, 1.01 mmol) of sodium salicylate was added, and the mixture was stirred at room temperature for 5 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 5/1), and the reaction was stopped. In addition, "TLC" is "Thin-Layer-Chromatography", "Hexane" is hexane, and "AcOEt" is ethyl acetate. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried.

得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１０／１→８／１→６／１→２／１）で分離精製し、化合物３（Ｒｆ＝０．３５）を収率１９．５％で４６．６ｍｇ，化合物４（Ｒｆ＝０．０７５）を収率１１．６％で２２．４ｍｇ，化合物３ａ（Ｒｆ＝０．４２５）を６６．５ｍｇ，化合物３ｂ（Ｒｆ＝０．２７５）を１０．５ｍｇ，化合物３ｃ（Ｒｆ＝０．５５）を２．６ｍｇ得た。化合物３ａ、化合物３ｂ、化合物３ｃの構造については未決定である。 The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 10/1 → 8/1 → 6/1 → 2/1), and the yield of compound 3 (Rf = 0.35) was 19. 46.6 mg at 5%, 22.4 mg at 11.6% yield of compound 4 (Rf = 0.075), 66.5 mg at compound 3a (Rf = 0.425), compound 3b (Rf = 0.275). ) Was obtained in an amount of 10.5 mg, and compound 3c (Rf = 0.55) was obtained in an amount of 2.6 mg. The structures of compound 3a, compound 3b, and compound 3c have not been determined.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリメチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル２−ヒドロキシベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ２−ｈｙｄｒｏｘｙｂｅｎｚｏａｔｅ）：化合物３，
Ｙｉｅｌｄ（１９．４％：ｗｈｉｔｅｓｏｌｉｄ），
融点：１３０．０−１３１．５℃，
ＩＲ（ＫＢｒ）：３４１３，２９５９，１６７４，１６４０，ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１３（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２６（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７３（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９５−２．８４（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９７（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５４（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．８７（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＣＨａｔＣ５），６．０２（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＣＨａｔＣ６），６．０６（ｂｒｍ，１Ｈ，ＣＨａｔＣ９），６．８８（ｄｄｄ，１Ｈ，Ｊ＝１．０，７．０，ａｎｄ８．１Ｈｚ，ＣＨａｔＣ５ｏｆＰｈ），７．００（ｄｄ，１Ｈ，Ｊ＝１．０ａｎｄ８．４Ｈｚ，ＣＨａｔＣ３ｏｆＰｈ），７．４７（ｄｄｄ，１Ｈ，Ｊ＝１．７，７．０，ａｎｄ８．４Ｈｚ，ＣＨａｔＣ４ｏｆＰｈ），７．８１（ｄｄ，１Ｈ，Ｊ＝１．７ａｎｄ８．１Ｈｚ，ＣＨａｔＣ６ｏｆＰｈ），１０．７０（ｓ，１Ｈ，ＯＨａｔＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ７），２４．１（ＣＨ_３ａｔＣ８），２４．８（Ｃ１０），２９．４（ＣＨ_３ａｔＣ４），３５．５（Ｃ１１），３７．５（Ｃ４），４２．４（Ｃ３），６１．７（ＣＨ_２ＯＣＯ），１１２．２（Ｃ２ｏｆＰｈ），１１７．８（Ｃ３ｏｆＰｈ），１１９．３（Ｃ５ｏｆＰｈ），１２７．４（Ｃ６），１２９．７（Ｃ６ｏｆＰｈ），１３２．０（Ｃ２），１３４．０（Ｃ１），１３６．０（Ｃ４ｏｆＰｈ），１３８．６（Ｃ８），１４９．０（Ｃ９），１５９．６（Ｃ５），１６１．８（Ｃ１ｏｆＰｈ），１７０．０（ＣＯＯａｔＰｈ），２０３．６（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２２Ｈ_２６ＮａＯ_４）：３７７．１７２９，実測値：３７７．１７４２． ((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl2-hydroxybenzoate (((1Z, 5E, 8E)) -4,4,8-Trimethyl-7-oxocyclondeca-1,5,8-trien-1-yl) methyl 2-hydroxybenzoate): Compound 3,
Yield (19.4%: white solid),
Melting point: 130.0-131.5 ° C,
IR (KBr): 3413, 2959, 1674, 1640, cm ^-1 ,
The assignment number was based on zerumbone.
¹ H NMR (CDCl ₃ ): δ1.13 (brs, 3H, CH ₃ at C4), 1.26 (brs, 3H, CH ₃ at C4), 1.73 (s, 3H, CH ₃ at C8), 1.95-2.84 (brm, 6H, CH ₂ at C3, C10, and C11), 4.71 (brd, 1H, CH at CH ₂ OCO), 4.97 (brd, 1H, CH at CH ₂₎ OCO), 5.54 (t, 1H, J = 8.3Hz, CH at C2), 5.87 (d, 1H, J = 16.5Hz, CH at C5), 6.02 (d, 1H, J) = 16.5Hz, CH at C6), 6.06 (brm, 1H, CH at C9), 6.88 (ddd, 1H, J = 1.0, 7.0, and 8.1Hz, CH at C5 of Ph), 7.00 (dd, 1H, J = 1.0 and 8.4Hz, CH at C3 of Ph), 7.47 (ddd, 1H, J = 1.7, 7.0, and 8.4Hz) , CH at C4 of Ph), 7.81 (dd, 1H, J = 1.7 and 8.1 Hz, CH at C6 of Ph), 10.70 (s, 1H, OH at Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C7), 24.1 (CH ₃ at C8), 24.8 (C10), 29.4 (CH ₃ at C4), 35.5 (C11) ), 37.5 (C4), 42.4 (C3), 61.7 (CH ₂ OCO), 112.2 (C2 of Ph), 117.8 (C3 of Ph), 119.3 (C5 of Ph). ), 127.4 (C6), 129.7 (C6 of Ph), 132.0 (C2), 134.0 (C1), 136.0 (C4 of Ph), 138.6 (C8), 149. 0 (C9), 159.6 (C5), 161.8 (C1 of Ph), 170.0 (COO at Ph), 203.6 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₂ H ₂₆ _{NaO 4} ): 377.1729, measured value: 377.1742.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル２−（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メトキシ）ベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ２−（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｏｘｙ）ｂｅｎｚｏａｔｅ）：化合物４，
Ｙｉｅｌｄ（１１．６％：ｗｈｉｔｅｏｉｌ），
ＩＲ（ＫＢｒ）：２９６１，１７３２，１６５５，ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４’），１．２５（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２５（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４’），１．６９ａｎｄ１．７８（ｓ，３Ｈ，ＣＨ_３ａｔＣ８，Ｃ８’），１．９４−３．０２（ｂｒｍ，１２Ｈ，ＣＨ_２ａｔＣ３，Ｃ３’，Ｃ１０，Ｃ１０’，Ｃ１１，ａｎｄＣ１１’），４．２７（ｂｒ，１Ｈ，ＣＨａｔＣＨ_２Ｏ），４．７０（ｂｒ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．７５−５．００（ｂｒ，２Ｈ，ＣＨａｔＣＨ_２ＯＣＯａｎｄＣＨ_２Ｏ），５．５０（ｔ，１Ｈ，ＣＨａｔＣ２），５．５１（ｔ，１Ｈ，ＣＨａｔＣ２’），５．７９ａｎｄ５．８７（ｄ，１Ｈ，Ｊ＝１６．５ａｎｄ１６．４Ｈｚ，ＣＨａｔＣ５ａｎｄＣ５’），６．０１ａｎｄ６．０３（ｄ，１Ｈ，Ｊ＝１６．４ａｎｄ１６．５Ｈｚ，ＣＨａｔＣ６ａｎｄＣ６’），６．０６（ｍ，２Ｈ，ＣＨａｔＣ９ａｎｄＣ９’），６．９４−７．０５（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ），７．４７（ｄｄｄ，１Ｈ，Ｊ＝１．８，６．７，ａｎｄ８．４Ｈｚ，ＣＨａｔＣ４ｏｆＰｈ），７．７８（ｄｄ，１Ｈ，Ｊ＝１．８ａｎｄ７．７Ｈｚ，ＣＨａｔＣ６ｏｆＰｈ），
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１１．９（ＣＨ_３ａｔＣ８），１１．９（ＣＨ_３ａｔＣ８’），２４．１（ＣＨ_３ａｔＣ４），２４．１（ＣＨ_３ａｔＣ４’），２４．６ａｎｄ２４．８（Ｃ１０，Ｃ１０’），２９．４（ＣＨ_３ａｔＣ４），２９．４（ＣＨ_３ａｔＣ４’），３４．９ａｎｄ３５．６（Ｃ１１，Ｃ１１’），３７．４ａｎｄ３７．６（Ｃ４，Ｃ４’），４２．４（Ｃ３），４２．４（Ｃ３’），６１．３（［Ｃ］Ｈ_２ＯＣＯ），６５．３（ＣＨ_２Ｏ），１１３．５（Ｃ３ｏｆＰｈ），１２０．６（Ｃ２ｏｆＰｈ），１２０．７（Ｃ５ｏｆＰｈ），１２７．３ａｎｄ１２７．５（Ｃ６，Ｃ６’），１２９．５（Ｃ２），１３１．２（Ｃ２’），１３１．７（Ｃ６ｏｆＰｈ），１３３．６（Ｃ４ｏｆＰｈ），１３４．７ａｎｄ１３５．９（Ｃ１，Ｃ１’），１３８．５ａｎｄ１３８．６（Ｃ８，Ｃ８’），１４９．１ａｎｄ１４９．６（Ｃ９，Ｃ９’），１５８．２（Ｃ１ｏｆＰｈ），１５９．３ａｎｄ１５９．８（Ｃ８，Ｃ８’），１６５．９（ＣＯＯａｔＰｈ），２０３．７ａｎｄ２０３．８（Ｃ７，Ｃ７’）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_３７Ｈ_４６ＮａＯ_５）：５９３．３２４３，実測値：５９３．３２２４． ((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl 2-(((1Z, 5E, 8E) -4) , 4,8-Triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) methoxy) benzoate (((1Z, 5E, 8E) -4,4,8-Trimethyl-7-oxoxyclondeca) -1,5,8-trien-1-yl) methoxy2-(((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxyclondeca-1, 5,8-trien-1-yl) ethoxyxy ) Benzoate): Compound 4,
Yield (11.6%: white oil),
IR (KBr): 2961, 1732, 1655, cm ^-1 ,
The assignment number was based on zerumbone.
¹ H NMR (CDCl ₃ ): δ1.12 (brs, 3H, CH ₃ at C4), 1.12 (brs, 3H, CH ₃ at C4'), 1.25 (brs, 3H, CH ₃ at C4) , 1.25 (brs, 3H, CH ₃ at C4'), 1.69 and 1.78 (s, 3H, CH ₃ at C8, C8'), 1.94-3.02 (brm, 12H, CH) ₂ at C3, C3', C10, C10', C11, and C11'), 4.27 (br, 1H, CH at CH ₂ O), 4.70 (br, 1H, CH at CH ₂ OCO), 4 .75-5.00 (br, 2H, CH at CH ₂ OCO and CH ₂ O), 5.50 (t, 1H, CH at C2), 5.51 (t, 1H, CH at C2'), 5 .79 and 5.87 (d, 1H, J = 16.5 and 16.4Hz, CH at C5 and C5'), 6.01 and 6.03 (d, 1H, J = 16.4 and 16.5Hz) , CH at C6 and C6'), 6.06 (m, 2H, CH at C9 and C9'), 6.94-7.05 (m, 2H, CH at C3 and C5 of Ph), 7.47 ( ddd, 1H, J = 1.8, 6.7, and 8.4Hz, CH at C4 of Ph), 7.78 (dd, 1H, J = 1.8 and 7.7Hz, CH at C6 of Ph) ，
¹³ C NMR (CDCl ₃ ): δ11.9 (CH ₃ at C8), 11.9 (CH ₃ at C8'), 24.1 (CH ₃ at C4), 24.1 (CH ₃ at C4'), 24.6 and 24.8 (C10, C10'), 29.4 (CH ₃ at C4), 29.4 (CH ₃ at C4'), 34.9 and 35.6 (C11, C11'), 37 .4 and 37.6 (C4, C4'), 42.4 (C3), 42.4 (C3'), 61.3 ([C] H ₂ OCO), 65.3 (CH ₂ O), 113 .5 (C3 of Ph), 120.6 (C2 of Ph), 120.7 (C5 of Ph), 127.3 and 127.5 (C6, C6'), 129.5 (C2), 131.2. (C2'), 131.7 (C6 of Ph), 133.6 (C4 of Ph), 134.7 and 135.9 (C1, C1'), 138.5 and 138.6 (C8, C8') , 149.1 and 149.6 (C9, C9'), 158.2 (C1 of Ph), 159.3 and 159.8 (C8, C8'), 165.9 (COO at Ph), 203.7 and 203.8 (C7, C7');
HRMS (M + Na ⁺ ): m / z calculated value (C ₃₇ H ₄₆ _{NaO 5} ): 593.3243, measured value: 593.3224.

なお、^１３Ｃ帰属データ中に記載した鍵括弧（［］）は、帰属箇所を特定・明示するために付記したもので、通常はアンダーラインが付記される（以下、同様）。また、「’」はダッシュの意味である。 The ^{key brackets ([]) described in the 13C} attribution data are added to specify and clearly indicate the attribution location, and are usually underlined (hereinafter, the same applies). Also, "'" means a dash.

＜求核剤に安息香酸を用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ６ｍＬを加えて攪拌し、安息香酸ナトリウム１．５ｅｑ（７２．６ｍｇ，０．５０ｍｍｏｌ）を加え、室温で５時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄し、無水硫酸ナトリウムで乾燥させ、減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝８／１）で分離精製し、透明固体（化合物）５を収率７９．９％で９０．９ｍｇ得た。 <Reaction using benzoic acid as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 6 mL of DMF was added and stirred, 1.5 eq (72.6 mg, 0.50 mmol) of sodium benzoate was added, and the mixture was stirred at room temperature for 5 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 4/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 8/1) to obtain 90.9 mg of a transparent solid (compound) 5 in a yield of 79.9%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリメチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチルベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌｂｅｎｚｏａｔｅ）：化合物５，
Ｙｉｅｌｄ（７９．９％：ｃｏｌｏｒｌｅｓｓｓｏｌｉｄ），
融点：７７．８−８０．３℃，
ＩＲ（ＫＢｒ）：２９５６，１７１３，１６４１ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２６（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７１（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），２．０１−２．８２（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７０（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９５（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５２（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．９１（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＣＨａｔＣ５），６．０２（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＣＨａｔＣ６），６．０７（ｍ，１Ｈ，ＣＨａｔＣ９），７．４９−７．４２（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ），７．５８（ｔｔ，１Ｈ，Ｊ＝１．３ａｎｄ７．４Ｈｚ，ＣＨａｔＣ４ｏｆＰｈ），８．０１−８．０６（ｍ，２Ｈ，ＣＨａｔＣ２ａｎｄＣ６ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ５），２４．８（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．６（Ｃ１１），３７．４（Ｃ４），４２．４（Ｃ３），６１．５（［Ｃ］Ｈ_２ＯＣＯ），１２７．３（Ｃ６），１２８．５（Ｃ２ａｎｄＣ７ｏｆＰｈ），１２９．６（Ｃ３ａｎｄＣ５ｏｆＰｈ），１３０．０（Ｃ１ｏｆＰｈ），１３１．４（Ｃ２），１３３．２（Ｃ４ｏｆＰｈ），１３４．６（Ｃ１），１３８．５（Ｃ８），１４９．２（Ｃ９），１５９．８（Ｃ５），１６６．５（ＣＯＯａｔＰｈ），２０３．７（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２２Ｈ_２６ＮａＯ_３）：３６１．１７８０，実測値：３６１．１７８７． ((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methylbenzoate (((1Z, 5E, 8E) -4, 4,8-Trimethyl-7-oxosyclundeca-1, 5,8-trien-1-yl) methyl benzoate): Compound 5,
Yield (79.9%: colorless solid),
Melting point: 77.8-80.3 ° C,
IR (KBr): 2956, ^{1713, 1641 cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.12 (brs, 3H, CH ₃ at C4), 1.26 (brs, 3H, CH ₃ at C4), 1.71 (s, 3H, CH ₃ at C8), 2.01-2.82 (brm, 6H, CH ₂ at C3, C10, and C11), 4.70 (brd, 1H, CH at CH ₂ OCO), 4.95 (brd, 1H, CH at CH ₂₎ OCO), 5.52 (t, 1H, J = 8.3Hz, CH at C2), 5.91 (d, 1H, J = 16.5Hz, CH at C5), 6.02 (d, 1H, J) = 16.5Hz, CH at C6), 6.07 (m, 1H, CH at C9), 7.49-7.42 (m, 2H, CH at C3 and C5 of Ph), 7.58 (tt, 1H, J = 1.3 and 7.4Hz, CH at C4 of Ph), 8.01-8.06 (m, 2H, CH at C2 and C6 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C5), 24.8 (C10), 29.3 (CH ₃ at C4), 35.6 (C11) ), 37.4 (C4), 42.4 (C3), 61.5 ([C] H ₂ OCO), 127.3 (C6), 128.5 (C2 and C7 of Ph), 129.6 ( C3 and C5 of Ph), 130.0 (C1 of Ph), 131.4 (C2), 133.2 (C4 of Ph), 134.6 (C1), 138.5 (C8), 149.2 ( C9), 159.8 (C5), 166.5 (COO at Ph), 203.7 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₂ H ₂₆ _{NaO 3} ): 361.1780, measured value: 361.1787.

＜求核剤にフェノールを用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ６ｍｌを加えて攪拌し、ナトリウムフェノキシド３．０ｅｑ（１１７ｍｇ，１．００ｍｍｏｌ）を加え、室温で７時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝８／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１８／１）で分離精製し、化合物６（Ｒｆ＝０．３５）を収率１１．６％で１２．１ｍｇ、化合物６ａ（Ｒｆ＝０．４５）を２６．６ｍｇ、化合物６ｂを２３．１ｍｇ得た。化合物６ａ−ｂの構造については、まだ明らかになっていない。 <Reaction using phenol as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 6 ml of DMF was added and stirred, sodium phenoxide 3.0 eq (117 mg, 1.00 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 8/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 18/1) to obtain 12.1 mg of compound 6 (Rf = 0.35) in a yield of 11.6% and compound 6a (Rf = 1). 0.45) was obtained at 26.6 mg and compound 6b was obtained at 23.1 mg. The structure of compound 6ab has not yet been clarified.

（２Ｅ，６Ｚ，１０Ｅ）−２，９，９−トリエチル−６−（フェノキシメチル）シクロウンデカ−２，６，１０−トリエン−１−オン（（２Ｅ，６Ｚ，１０Ｅ）−２，９，９−Ｔｒｉｍｅｔｈｙｌ−６−（ｐｈｅｎｏｘｙｍｅｔｈｙｌ）ｃｙｃｌｏｕｎｄｅｃａ−２，６，１０−ｔｒｉｅｎ−１−ｏｎｅ）：化合物６，
Ｙｉｅｌｄ（１１．６％：ｗｈｉｔｅｓｏｌｉｄ），
融点：８９．０−９２．９℃，
ＩＲ（ＫＢｒ）：２９６２，１６４１，１２３６ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１５（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ９），１．２３（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ９），１．９３（ｓ，３Ｈ，ＣＨ_３ａｔＣ２），１．９６−２．５６（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ４，Ｃ５，ａｎｄＣ８），４．３６（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２Ｏ），４．６５（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２Ｏ），５．４０（ｔ，１Ｈ，Ｊ＝８．４Ｈｚ，ＣＨａｔＣ７），５．５７（ｍ，１Ｈ，ＣＨａｔＣ３），５．９２（ｄ，１Ｈ，Ｊ＝１６．２Ｈｚ，ＣＨａｔＣ１１），６．３８（ｄ，１Ｈ，Ｊ＝１６．２Ｈｚ，ＣＨａｔＣ１０），６．９１−６．９５（ｍ，２Ｈ，ＣＨａｔＣ２ａｎｄＣ６ｏｆＰｈ），６．９７（ｔｔ，１Ｈ，Ｊ＝１．０ａｎｄ７．４Ｈｚ，ＣＨａｔＣ４ｏｆＰｈ），７．２８−７．３４（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ２１．２（ＣＨ_３ａｔＣ２），２４．０（ＣＨ_３ａｔＣ９），２９．３（ＣＨ_３ａｔＣ９），３２．０（Ｃ４），３３．６（Ｃ５），３６．９（Ｃ９），３９．７（Ｃ８），６７．５（ＣＨ_２Ｏ），１１４．７（Ｃ２ａｎｄＣ６ｏｆＰｈ），１２０．９（Ｃ４ｏｆＰｈ），１２７．３（Ｃ１１），１２９．５（Ｃ７），１２９．５（Ｃ３ａｎｄＣ５ｏｆＰｈ），１３１．５（Ｃ３），１３６．６（Ｃ６），１３７．７（Ｃ２），１５８．８（Ｃ１ｏｆＰｈ），１６０．５（Ｃ１０），２０２．９（Ｃ１）；
ＨＲＭＳ：ｍ／ｚ計算値（Ｃ_２２Ｈ_２６ＮａＯ_２）：３３３．１８３０，実測値：３３３．１８３１． (2E, 6Z, 10E) -2,9,9-triethyl-6- (phenoxymethyl) cycloundeca-2,6,10-triene-1-one ((2E, 6Z, 10E) -2,9,9- Trimethyl-6- (phenoxymethyl) cyclondecca-2, 6,10-trien-1-one): Compound 6,
Yield (11.6%: white solid),
Melting point: 89.0-92.9 ° C,
IR (KBr): 2962,1641,1236cm ^-1 ,
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.15 (brs, 3H, CH ₃ at C9), 1.23 (brs, 3H, CH ₃ at C9), 1.93 (s, 3H, CH ₃ at C2), 1.96-2.56 (brm, 6H, CH ₂ at C4, C5, and C8), 4.36 (brd, 1H, CH at CH ₂ O), 4.65 (brd, 1H, CH at CH ₂₎ O), 5.40 (t, 1H, J = 8.4Hz, CH at C7), 5.57 (m, 1H, CH at C3), 5.92 (d, 1H, J = 16.2Hz, CH at C11), 6.38 (d, 1H, J = 16.2Hz, CH at C10), 6.91-6.95 (m, 2H, CH at C2 and C6 of Ph), 6.97 (tt, 1H, J = 1.0 and 7.4Hz, CH at C4 of Ph), 7.28-7.34 (m, 2H, CH at C3 and C5 of Ph);
¹³ C NMR (CDCl ₃ ): δ21.2 (CH ₃ at C2), 24.0 (CH ₃ at C9), 29.3 (CH ₃ at C9), 32.0 (C4), 33.6 (C5) ), 36.9 (C9), 39.7 (C8), 67.5 (CH ₂ O), 114.7 (C2 and C6 of Ph), 120.9 (C4 of Ph), 127.3 (C11) ), 129.5 (C7), 129.5 (C3 and C5 of Ph), 131.5 (C3), 136.6 (C6), 137.7 (C2), 158.8 (C1 of Ph), 160.5 (C10), 202.9 (C1);
HRMS: calculated value of m / z (C ₂₂ H ₂₆ _{NaO 2} ): 333.1830, measured value: 333.1831.

＜求核剤にテレフタル酸を用いた反応＞
［化合物７の合成］
ナスフラスコにテレフタル酸１５．０ｅｑ（１．００ｇ，６．０２ｍｍｏｌ）を入れＤＭＦ２０ｍｌを加えて攪拌し、０．５Ｍの水酸化ナトリウム水溶液１．５ｅｑ（１．２０ｍｌ，０．６０２ｍｍｏｌ）を滴下して加えた。さらに、反応液に４ｍｌのＤＭＦで溶解した化合物２を１１９ｍｇ（０．４０ｍｍｏｌ）滴下して加え、４８時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で反応終了を確認し、水を加え反応を止めた。吸引ろ過で未反応のテレフタル酸を除去し、反応液を酢酸エチルで３回抽出した。飽和食塩水で３回洗浄し、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１→１／５）で分離精製し、化合物７を収率２５．２％で８．７ｍｇ得た。 <Reaction using terephthalic acid as a nucleophile>
[Synthesis of compound 7]
Put 15.0 eq (1.00 g, 6.02 mmol) of terephthalic acid in an eggplant flask, add 20 ml of DMF, stir, and add 1.5 eq (1.20 ml, 0.602 mmol) of 0.5 M sodium hydroxide aqueous solution. added. Further, 119 mg (0.40 mmol) of Compound 2 dissolved in 4 ml of DMF was added dropwise to the reaction solution, and the mixture was stirred for 48 hours. The completion of the reaction was confirmed by TLC (Hexane / AcOEt = 4/1), and water was added to stop the reaction. Unreacted terephthalic acid was removed by suction filtration, and the reaction solution was extracted 3 times with ethyl acetate. The cells were washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure using a rotary evaporator, and dried under vacuum. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 4/1 → 1/5) to obtain 8.7 mg of compound 7 in a yield of 25.2%.

４−（（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メトキシ）カルボニル）ベンゾニックエイシド（４−（（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｏｘｙ）ｃａｒｂｏｎｙｌ）ｂｅｎｚｏｉｃａｃｉｄ）：化合物７，
Ｙｉｅｌｄ（２５．２％：ｗｈｉｔｅｓｏｌｉｄ），
融点：１６２．８−１６５．０℃，
ＩＲ（ＫＢｒ）：３５１４，２９２８，１７１７，１６４７ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１３（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２７（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７３（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９５−２．８６（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．００（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５５（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．８８（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０３（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０９（ｍ，１Ｈ，ＣＨａｔＣ９），８．１１−８．１６（ｍ，２Ｈ，ＣＨａｔＣ２ａｎｄＣ６ｏｆＰｈ），８．１７−８．２１（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．８（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．４（Ｃ１１），３７．５（Ｃ４），４２．４（Ｃ３），６１．９（［Ｃ］Ｈ_２ＯＣＯ），１２７．３（Ｃ６），１２９．７（Ｃ２ａｎｄＣ６ｏｆＰｈ），１３０．３（Ｃ３ａｎｄＣ５ｏｆＰｈ），１３１．８（Ｃ２），１３３．２（Ｃ１ｏｆＰｈ），１３４．２（Ｃ４ｏｆＰｈ），１３４．５（Ｃ１），１３８．６（Ｃ８），１４９．２（Ｃ９），１５９．８（Ｃ５），１６５．６（ＣＯＯＨｏｆＰｈ），１６９．６（ＣＯＯｏｆＰｈ），２０３．７（Ｃ２）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２２Ｈ_２５ＮＮａＯ_５）：４０６．１６３０，実測値：４０６．１６４２． 4-((((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) methoxy) carbonyl) benzonic acid (4) -((((1Z, 5E, 8E) -4,4,8-Trimethyl-7-oxocyclondeca-1, 5,8-trien-1-yl) methoxy) carbonyl) bentoic acid): Compound 7,
Yield (25.2%: white solid),
Melting point: 162.8-165.0 ° C,
IR (KBr): 3514, ^{2928, 1717, 1647 cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.13 (brs, 3H, CH ₃ at C4), 1.27 (brs, 3H, CH ₃ at C4), 1.73 (s, 3H, CH ₃ at C8), 1.95-2.86 (brm, 6H, CH ₂ at C3, C10, and C11), 4.71 (brd, 1H, CH at CH ₂ OCO), 5.00 (brd, 1H, CH at CH ₂₎ OCO), 5.55 (t, 1H, J = 8.3Hz, CH at C2), 5.88 (d, 1H, J = 16.4Hz, CH at C5), 6.03 (d, 1H, J) = 16.4Hz, CH at C6), 6.09 (m, 1H, CH at C9), 8.11-8.16 (m, 2H, CH at C2 and C6 of Ph), 8.17-8. 21 (m, 2H, CH at C3 and C5 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.8 (C10), 29.3 (CH ₃ at C4), 35.4 (C11) ), 37.5 (C4), 42.4 (C3), 61.9 ([C] H ₂ OCO), 127.3 (C6), 129.7 (C2 and C6 of Ph), 130.3 ( C3 and C5 of Ph), 131.8 (C2), 133.2 (C1 of Ph), 134.2 (C4 of Ph), 134.5 (C1), 138.6 (C8), 149.2 ( C9), 159.8 (C5), 165.6 (COOH of Ph), 169.6 (COO of Ph), 203.7 (C2);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₂ H ₂₅ NNaO ₅ ): 406.1630, measured value: 406.1642.

［化合物８の合成］
遮光ビンに化合物２を３００ｍｇ（１．００ｍｍｏｌ）入れ、ＤＭＦ２０ｍｌを加えて攪拌し、テレフタル酸ニナトリウム１．０ｅｑ（２１２ｍｇ，１．０１ｍｍｏｌ）を加え、室温で４日間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物を中圧カラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１２／１）で分離精製し、白色固体（化合物８）を収率１６．５％で４９．７ｍｇ得た。 [Synthesis of Compound 8]
300 mg (1.00 mmol) of compound 2 was placed in a light-shielding bottle, 20 ml of DMF was added and stirred, 1.0 eq (212 mg, 1.01 mmol) of disodium terephthalate was added, and the mixture was stirred at room temperature for 4 days. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 4/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by medium pressure column chromatography (Hexane / AcOEt = 12/1) to obtain 49.7 mg of a white solid (Compound 8) in a yield of 16.5%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル２−（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メトキシ）ベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ２−（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｏｘｙ）ｂｅｎｚｏａｔｅ）：化合物８，
Ｙｉｅｌｄ（１６．５％：ｗｈｉｔｅｓｏｌｉｄ），
融点：２１０．０−２１１．０℃，
ＩＲ（ＫＢｒ）；２９５９，１７１７，１６４３ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，６Ｈ，ＣＨ_３ａｔＣ４ａｎｄＣ４’），１．２６（ｂｒｓ，６Ｈ，ＣＨ_３ａｔＣ４ａｎｄＣ４’），１．７１（ｓ，６Ｈ，ＣＨ_３ａｔＣ８ａｎｄＣ８’），１．９４−２．８７（ｂｒｍ，１２Ｈ，ＣＨ_２ａｔＣ３，Ｃ３’，Ｃ１０，Ｃ１０’，Ｃ１１，ａｎｄＣ１１’），４．７１（ｂｒｄ，２Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９８（ｂｒｄ，２Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５５（ｔ，２Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２ａｎｄＣ２’），５．８８（ｄ，２Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５ａｎｄＣ５’），６．０２（ｄ，２Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６ａｎｄＣ６’），６．０６（ｍ，２Ｈ，ＣＨａｔＣ９），８．１０（ｓ，４Ｈ，ＣＨａｔＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８，Ｃ８’），２４．１（ＣＨ_３ａｔＣ４，Ｃ４’），２４．７（Ｃ１０，Ｃ１０’），２９．３（ＣＨ_３ａｔＣ４，Ｃ４’），３５．５（Ｃ１１，Ｃ１１’），３７．４（Ｃ４，Ｃ４’），４２．４（Ｃ３，Ｃ３’），６１．９（ＣＨ_２ＯＣＯ），１２７．３（Ｃ６），１２９．７（Ｃ２），１３１．９（ＣＨｏｆＰｈ），１３４．０（ＣｏｆＰｈ），１３４．２（Ｃ１），１３８．５（Ｃ８，Ｃ８’），１４９．２（Ｃ９，Ｃ９’），１５９．７（Ｃ５），１６５．６（ＣＯＯｏｆＰｈ），２０３．７（Ｃ７，Ｃ７’）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_３８Ｈ_４６ＮａＯ_６）：６２１．３１９２，実測値：６２１．３１７４． ((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl 2-(((1Z, 5E, 8E) -4) , 4,8-Triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) methoxy) benzoate (((1Z, 5E, 8E) -4,4,8-Trimethyl-7-oxyclondeca) -1,5,8-trien-1-yl) ethoxy2-yl (((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxyclondeca-1, 5,8-trien-1-yl)) Methyl) benzoate): Compound 8,
Yield (16.5%: white solid),
Melting point: 210.0-211.0 ° C,
IR (KBr); 2959, ^{1717, 1643 cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.12 (brs, 6H, CH ₃ at C4 and C4'), 1.26 (brs, 6H, CH ₃ at C4 and C4'), 1.71 (s, 6H, CH ₃ at C8 and C8'), 1.94-2.87 (brm, 12H, CH ₂ at C3, C3', C10, C10', C11, and C11'), 4.71 (brd, 2H, CH) at CH ₂ OCO), 4.98 (brd, 2H, CH at CH ₂ OCO), 5.55 (t, 2H, J = 8.3Hz, CH at C2 and C2'), 5.88 (d, 2H) , J = 16.4Hz, CH at C5 and C5'), 6.02 (d, 2H, J = 16.4Hz, CH at C6 and C6'), 6.06 (m, 2H, CH at C9), 8.10 (s, 4H, CH at Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8, C8'), 24.1 (CH ₃ at C4, C4'), 24.7 (C10, C10'), 29.3 (CH ₃₎ at C4, C4'), 35.5 (C11, C11'), 37.4 (C4, C4'), 42.4 (C3, C3'), 61.9 (CH ₂ OCO), 127.3 ( C6), 129.7 (C2), 131.9 (CH of Ph), 134.0 (Cof Ph), 134.2 (C1), 138.5 (C8, C8'), 149.2 (C9) , C9'), 159.7 (C5), 165.6 (COO of Ph), 203.7 (C7, C7');
HRMS (M + Na ⁺ ): m / z calculated value (C ₃₈ H ₄₆ _{NaO 6} ): 621.31922, actually measured value: 621.3174.

＜求核剤にテレフタル酸モノメチルを用いた反応＞
遮光ビンに化合物２を５４．１ｍｇ（０．１８ｍｍｏｌ）入れ、ＤＭＦ５．４ｍｌを加えて攪拌し、テレフタル酸モノメチルカリウム１．５ｅｑ（５９．６ｍｇ，０．２７ｍｍｏｌ）を加え、室温で７時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で分離精製し、白色固体（化合物９）を収率８５．９％で６２．０ｍｇで得た。 <Reaction using monomethyl terephthalate as a nucleophile>
54.1 mg (0.18 mmol) of compound 2 was placed in a light-shielding bottle, 5.4 ml of DMF was added and stirred, 1.5 eq (59.6 mg, 0.27 mmol) of monomethylpotassium terephthalate was added, and the mixture was stirred at room temperature for 7 hours. .. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 4/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 4/1) to obtain a white solid (Compound 9) in a yield of 85.9% in 62.0 mg.

メチル（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリメチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル）テレフタレート（Ｍｅｔｈｙｌ（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ）ｔｅｒｅｐｈｔｈａｌａｔｅ）：化合物９，
Ｙｉｅｌｄ（８５．９％：ｗｈｉｔｅｓｏｌｉｄ），
融点：７６．０−７８．０℃，
ＩＲ（ＫＢｒ）：２９５５，１７２１，１６５５，１２７７ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２６（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７１（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），２．００−２．８３（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０ａｎｄＣ１１），３．９６（ｓ，３Ｈ，ＣＨ_３ａｔＣＨ_３ＯＣＯ），４．７１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９７（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５４（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．８９（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０２（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０７（ｍ，１Ｈ，ＣＨａｔＣ９），８．０６−８．１５（ｍ，４Ｈ，ＣＨａｔＣ２，Ｃ３，Ｃ５，ａｎｄＣ６ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．８（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．５（Ｃ１１），３７．４（Ｃ４），４２．４（Ｃ３），５２．５（［Ｃ］Ｈ_３ＯＣＯ），６１．８（［Ｃ］Ｈ_２ＯＣＯ），１２７．３（Ｃ６），１２９．６（Ｃ２ａｎｄＣ６ｏｆＰｈ），１２９．７（Ｃ３ａｎｄＣ５ｏｆＰｈ），１３３．７（Ｃ２），１３４．１８（Ｃ１），１３４．２３（Ｃ１ａｎｄＣ４ｏｆＰｈ），１３８．５（Ｃ８），１４９．１（Ｃ９），１５９．７（Ｃ５），１６５．７（ＣＯＯｏｆＰｈ），１６６．２（［Ｃ］ＯＯＣＨ_３ｏｆＰｈ），２０３．７（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２４Ｈ_２８ＮａＯ_５）：４１９．１８３４，実測値：４１９．１８４０． Methyl (((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxocycloundeca-1,5,8-trien-1-yl) methyl) terephthalate (Methyl (((1Z, 5E,) 8E) -4,4,8-Trimethyl-7-oxyclondeca-1,5,8-trien-1-yl) methyl) terephthalate): Compound 9,
Yield (85.9%: white solid),
Melting point: 76.0-78.0 ° C,
IR (KBr): 2955,1721,1655,1277cm ^-1 ,
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.12 (brs, 3H, CH ₃ at C4), 1.26 (brs, 3H, CH ₃ at C4), 1.71 (s, 3H, CH ₃ at C8), 2.00-2.83 (brm, 6H, CH ₂ at C3, C10 and C11), 3.96 (s, 3H, CH ₃ at CH ₃ OCO), 4.71 (brd, 1H, CH at CH ₂₎ OCO), 4.97 (brd, 1H, CH at CH ₂ OCO), 5.54 (t, 1H, J = 8.3Hz, CH at C2), 5.89 (d, 1H, J = 16.4Hz) , CH at C5), 6.02 (d, 1H, J = 16.4Hz, CH at C6), 6.07 (m, 1H, CH at C9), 8.06-8.15 (m, 4H, CH at C2, C3, C5, and C6 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.8 (C10), 29.3 (CH ₃ at C4), 35.5 (C11) ), 37.4 (C4), 42.4 (C3), 52.5 ([C] H ₃ OCO), 61.8 ([C] H ₂ OCO), 127.3 (C6), 129.6 (C2 and C6 of Ph), 129.7 (C3 and C5 of Ph), 133.7 (C2), 134.18 (C1), 134.23 (C1 and C4 of Ph), 138.5 (C8) , 149.1 (C9), 159.7 (C5), 165.7 (COO of Ph), 166.2 ([C] _{OOCH 3} of Ph), 203.7 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₄ H ₂₈ _{NaO 5} ): 419.1834, measured value: 419.1840.

＜求核剤にテレフタル酸モノ−ｔｅｒｔ−ブチルを用いた反応＞
遮光ビンに化合物２を５６．８ｍｇ（０．１９ｍｍｏｌ）入れ、ＤＭＦ５．７ｍｌを加えて攪拌し、テレフタル酸モノ−ｔｅｒｔ−ブチルナトリウム１．５ｅｑ（７０．１ｍｇ，０．２９ｍｍｏｌ）を加え、室温で５時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝８／１）で分離精製し、白色固体（化合物１０）を収率９８．４％で８２．５ｍｇで得た。 <Reaction using mono-tert-butyl terephthalate as a nucleophile>
Put 56.8 mg (0.19 mmol) of compound 2 in a light-shielding bottle, add 5.7 ml of DMF, stir, add 1.5 eq (70.1 mg, 0.29 mmol) of mono-tert-butyl sodium terephthalate, and at room temperature. The mixture was stirred for 5 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 4/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 8/1) to obtain a white solid (Compound 10) in a yield of 98.4% at 82.5 mg.

ターシャリーブチル（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチレン−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル）テレフタレート（ｔｅｒｔ−Ｂｕｔｙｌ（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ）ｔｅｒｅｐｈｔｈａｌａｔｅ）：化合物１０，
Ｙｉｅｌｄ（９８．４％：ｗｈｉｔｅｓｏｌｉｄ），
融点：１４３．０−１４５．０℃，
ＩＲ（ＫＢｒ）：２９７０，１７１３，１６５９，１３００，１２６１ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２６（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．６１（ｓ，３Ｈ，ＣＨ_３ａｔＣ７），１．７１（ｓ，９Ｈ，ＣＨ_３ａｔ（ＣＨ_３）_３ＣＯ），２．００−２．８４（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７０（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９７（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５４（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．８９（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０２（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０６（ｍ，１Ｈ，ＣＨａｔＣ９），８．０２−８．０９（ｍ，４Ｈ，ＣＨａｔＣ２，Ｃ３，Ｃ５，ａｎｄＣ６ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．７（Ｃ１０），２８．１（（［Ｃ］Ｈ_３）_３ＣＯ），２９．３（ＣＨ_３ａｔＣ４），３５．５（Ｃ１１），３７．４（Ｃ４），４２．４（Ｃ３），６１．８（［Ｃ］Ｈ_２ＯＣＯ），８２．８（（ＣＨ_３）_３［Ｃ］）Ｏ），１２７．３（Ｃ６），１２９．４（Ｃ３ａｎｄＣ５ｏｆＰｈ），１２９．５（Ｃ２ａｎｄＣ６ｏｆＰｈ），１３１．７（Ｃ２），１３３．２（Ｃ４ｏｆＰｈ），１３４．３（Ｃ１），１３６．１（Ｃ１ｏｆＰｈ），１３８．５（Ｃ８），１４９．２（Ｃ９），１５９．８（Ｃ５），１６４．８（（ＣＨ_３）_３ＣＯ［Ｃ］ＯｏｆＰｈ），１６５．８（ＣＯＯｏｆＰｈ），２０３．７（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２７Ｈ_３４ＮａＯ_５）：４６１．２３０４，実測値：４６１．２３０７． Tersial butyl (((1Z, 5E, 8E) -4,4,8-triethylene-7-oxocycloundeca-1,5,8-triene-1-yl) methyl) terephthalate (tert-Butyl (((1Z, 5E, 8E)) (1Z, 5E, 8E) -4,4,8-trimethyl-7-oxyclondeca-1,5,8-thylene-1-yl) methyl) terephthalate): Compound 10,
Yield (98.4%: white solid),
Melting point: 143.0-145.0 ° C,
IR (KBr): 2970, ^{1713, 1659, 1300, 1261 cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.12 (brs, 3H, CH ₃ at C4), 1.26 (brs, 3H, CH ₃ at C4), 1.61 (s, 3H, CH ₃ at C7), 1.71 (s, 9H, CH ₃ at (CH ₃ ) ₃ CO), 2.00-2.84 (brm, 6H, CH ₂ at C3, C10, and C11), 4.70 (brd, 1H, CH at CH ₂ OCO), 4.97 (brd, 1H, CH at CH ₂ OCO), 5.54 (t, 1H, J = 8.3Hz, CH at C2), 5.89 (d, 1H, J) = 16.4Hz, CH at C5), 6.02 (d, 1H, J = 16.4Hz, CH at C6), 6.06 (m, 1H, CH at C9), 8.02-8.09 ( m, 4H, CH at C2, C3, C5, and C6 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.7 (C10), 28.1 (([C] H ₃ ) ₃ CO), 29.3 (CH ₃ at C4), 35.5 (C11), 37.4 (C4), 42.4 (C3), 61.8 ([C] H ₂ OCO), 82.8 ((CH ₃₎ ₃ [C]) O), 127.3 (C6), 129.4 (C3 and C5 of Ph), 129.5 (C2 and C6 of Ph), 131.7 (C2), 133.2 (C4) of Ph), 134.3 (C1), 136.1 (C1 of Ph), 138.5 (C8), 149.2 (C9), 159.8 (C5), 164.8 ((CH ₃ ) ₃₎ CO [C] Of Ph), 165.8 (COO of Ph), 203.7 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₇ H ₃₄ _{NaO 5} ): 461.2304, measured value: 461.2307.

＜求核剤にｏ−メトキシ安息香酸を用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ１０ｍｌを加えて攪拌し、ｏ−メトキシ安息香酸ナトリウム２．０ｅｑ（１１７ｍｇ，０．６７ｍｍｏｌ）を加え、室温で４時間半攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝５／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝５／１）で分離精製し、無色オイル（化合物１１）を収率８１．０％で１００ｍｇ得た。 <Reaction using o-methoxybenzoic acid as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 10 ml of DMF was added and stirred, 2.0 eq (117 mg, 0.67 mmol) of sodium o-methoxybenzoate was added, and the mixture was stirred at room temperature for 4 and a half hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 5/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 5/1) to obtain 100 mg of a colorless oil (Compound 11) in a yield of 81.0%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル２−メトキシベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ２−ｍｅｔｈｏｘｙｂｅｎｚｏａｔｅ）：化合物１１，
Ｙｉｅｌｄ（８１．０％：ｃｏｌｏｒｌｅｓｓｏｉｌ），
ＩＲ（ＫＢｒ）：２９６１，１７２６，１６５２ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１１（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２５（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．６６（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９７−２．８８（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），３．８９（ｓ，３Ｈ，ＯＣＨ_３ａｔＰｈ），４．６７（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５０（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．９１（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０１（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０６（ｍ，１Ｈ，ＣＨａｔＣ９），６．９５−７．０１（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ），７．４８（ｄｄｄ，１Ｈ，Ｊ＝１．８，７．４ａｎｄ８．２Ｈｚ，ＣＨａｔＣ４ｏｆＰｈ），７．７６（ｄｄ，１Ｈ，Ｊ＝１．８ａｎｄ７．８Ｈｚ，ＣＨａｔＣ６ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１１．８（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．８（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．７（Ｃ１１），３７．４（Ｃ４），４２．４（Ｃ３），５５．９（Ｏ［Ｃ］Ｈ_３ａｔＰｈ），６１．５（［Ｃ］Ｈ_２ＯＣＯ），１１２．０（Ｃ５ｏｆＰｈ），１２０（Ｃ１ｏｆＰｈ），１２０．２（Ｃ３ｏｆＰｈ），１２７．２（Ｃ６），１３１．３（Ｃ２），１３１．５（Ｃ６ｏｆＰｈ），１３３．７（Ｃ４ｏｆＰｈ），１３４．７（Ｃ１），１３８．５（Ｃ８），１４９．４（Ｃ９），１５９．１（Ｃ４ｏｆＰｈ），１５９．９（Ｃ５），１６６．３（［Ｃ］ＯＯａｔＰｈ），２０３．９（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２３Ｈ_２８ＮａＯ_４）：３９１．１８８５，実測値：３９１．１８７０． ((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl2-methoxybenzoate (((1Z, 5E, 8E)) -4,4,8-Trimethyl-7-oxyclondeca-1,5,8-trien-1-yl) methyl 2-methoxybendoate): Compound 11,
Yield (81.0%: colorless oil),
IR (KBr): 2961, ^{1726, 1652cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.11 (brs, 3H, CH ₃ at C4), 1.25 (brs, 3H, CH ₃ at C4), 1.66 (s, 3H, CH ₃ at C8), 1.97-2.88 (brm, 6H, CH ₂ at C3, C10, and C11), 3.89 (s, 3H, OCH ₃ at Ph), 4.67 (brd, 1H, CH at CH ₂ OCO) ), 4.91 (brd, 1H, CH at CH ₂ OCO), 5.50 (t, 1H, J = 8.3Hz, CH at C2), 5.91 (d, 1H, J = 16.4Hz, CH at C5), 6.01 (d, 1H, J = 16.4Hz, CH at C6), 6.06 (m, 1H, CH at C9), 6.95-7.01 (m, 2H, CH) at C3 and C5 of Ph), 7.48 (ddd, 1H, J = 1.8, 7.4 and 8.2Hz, CH at C4 of Ph), 7.76 (dd, 1H, J = 1.8) and 7.8Hz, CH at C6 of Ph);
¹³ C NMR (CDCl ₃ ): δ11.8 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.8 (C10), 29.3 (CH ₃ at C4), 35.7 (C11) ), 37.4 (C4), 42.4 (C3), 55.9 (O [C] H ₃ at Ph), 61.5 ([C] H ₂ OCO), 112.0 (C5 of Ph) , 120 (C1 of Ph), 120.2 (C3 of Ph), 127.2 (C6), 131.3 (C2), 131.5 (C6 of Ph), 133.7 (C4 of Ph), 134 .7 (C1), 138.5 (C8), 149.4 (C9), 159.1 (C4 of Ph), 159.9 (C5), 166.3 ([C] OO at Ph), 203. 9 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₃ H ₂₈ _{NaO 4} ): 391.1885, actually measured value: 391.1870.

＜求核剤にｐ−メトキシ安息香酸を用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ１０ｍｌを加えて攪拌し、ｐ−メトキシ安息香酸ナトリウム２．０ｅｑ（１１７ｍｇ，０．６７ｍｍｏｌ）を加え、室温で４時間攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で分離精製し、白色固体（化合物１２）を収率７６．２％で９３．８ｍｇ得た。 <Reaction using p-methoxybenzoic acid as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 10 ml of DMF was added and stirred, 2.0 eq (117 mg, 0.67 mmol) of sodium p-methoxybenzoate was added, and the mixture was stirred at room temperature for 4 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 3/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 3/1) to obtain 93.8 mg of a white solid (Compound 12) in a yield of 76.2%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル４−メトキシベンゾエートｅ（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ４−ｍｅｔｈｏｘｙｂｅｎｚｏａｔｅ）：化合物１２，
Ｙｉｅｌｄ（７６．２％：ｗｈｉｔｅｓｏｌｉｄ），
融点：６６．２−６８．０℃，
ＩＲ（ＫＢｒ）：２９６３，１７１１，１６３９，１６０３，１２５６ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１１（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２５（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７１（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９７−２．８２（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），３．８７（ｓ，３Ｈ，ＯＣＨ_３ａｔＰｈ），４．６７（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５１（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．９２（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０１（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０７（ｍ，１Ｈ，ＣＨａｔＣ９），６．９０−６．９５（ｍ，２Ｈ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ），７．９６−８．０１（ｍ，２Ｈ，ＣＨａｔＣ２ａｎｄＣ６ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．８（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．６（Ｃ１１），３７．４（Ｃ４），４２．４（Ｃ３），５５．５（Ｏ［Ｃ］Ｈ_３ｏｆＰｈ），６１．３（［Ｃ］Ｈ_２ＯＣＯ），１１３．７（Ｃ３ａｎｄＣ５ｏｆＰｈ），１２２．４（Ｃ１ｏｆＰｈ），１２７．２（Ｃ６），１３１．３（Ｃ２），１３１．７（Ｃ２ａｎｄＣ６ｏｆＰｈ），１３４．８（Ｃ１），１３８．５（Ｃ８），１４９．３（Ｃ９），１６０．０（Ｃ５），１６３．６（Ｃ４ｏｆＰｈ），１６６．２（［Ｃ］ＯＯａｔＰｈ），２０３．９（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２３Ｈ_２８ＮａＯ_４）：３９１．１８８５，実測値：３９１．１８９９． ((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl 4-methoxybenzoate e (((1Z, 5E, 8E)) ) -4,4,8-Trimethyl-7-oxyclondeca-1,5,8-trien-1-yl) methyl 4-methoxybenzoate): Compound 12,
Yield (76.2%: white solid),
Melting point: 66.2-68.0 ° C,
IR (KBr): 2963, ^{1711, 1639, 1603, 1256cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.11 (brs, 3H, CH ₃ at C4), 1.25 (brs, 3H, CH ₃ at C4), 1.71 (s, 3H, CH ₃ at C8), 1.97-2.82 (brm, 6H, CH ₂ at C3, C10, and C11), 3.87 (s, 3H, OCH ₃ at Ph), 4.67 (brd, 1H, CH at CH ₂ OCO) ), 4.91 (brd, 1H, CH at CH ₂ OCO), 5.51 (t, 1H, J = 8.3Hz, CH at C2), 5.92 (d, 1H, J = 16.4Hz, CH at C5), 6.01 (d, 1H, J = 16.4Hz, CH at C6), 6.07 (m, 1H, CH at C9), 6.90-6.95 (m, 2H, CH) at C3 and C5 of Ph), 7.96-8.01 (m, 2H, CH at C2 and C6 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.8 (C10), 29.3 (CH ₃ at C4), 35.6 (C11) ), 37.4 (C4), 42.4 (C3), 55.5 (O [C] H ₃ of Ph), 61.3 ([C] H ₂ OCO), 113.7 (C3 and C5 of) Ph), 122.4 (C1 of Ph), 127.2 (C6), 131.3 (C2), 131.7 (C2 and C6 of Ph), 134.8 (C1), 138.5 (C8) , 149.3 (C9), 160.0 (C5), 163.6 (C4 of Ph), 166.2 ([C] OO at Ph), 203.9 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₃ H ₂₈ _{NaO 4} ): 391.1885, actually measured value: 391.899.

＜求核剤にｏ−ニトロ安息香酸を用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ５ｍｌを加えて攪拌し、ｏ−ニトロ安息香酸ナトリウム２．０ｅｑ（１２６ｍｇ，０．６７ｍｍｏｌ）を加え、室温で３時間半攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で分離精製し、白色固体（化合物１３）を収率８１．０％で１０４ｍｇ得た。 <Reaction using o-nitrobenzoic acid as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 5 ml of DMF was added, and the mixture was stirred. Sodium o-nitrobenzoate 2.0 eq (126 mg, 0.67 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 3/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 3/1) to obtain 104 mg of a white solid (Compound 13) in a yield of 81.0%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリエチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル２−ニトロベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ２−ｎｉｔｒｏｂｅｎｚｏａｔｅ）：化合物１３，
Ｙｉｅｌｄ（８１．０％：ｗｈｉｔｅｓｏｌｉｄ），
融点：１１９．８−１２３．０℃，
ＩＲ（ＫＢｒ）：２９３０，２８６０，１７３６，１６４７，１５３０ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１２（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２４（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．６２（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９５−２．９２（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．６９（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．９１（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５３（ｔ，１Ｈ，Ｊ＝８．３Ｈｚ，ＣＨａｔＣ２），５．７９（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），５．９８（ｍ，１Ｈ，ＣＨａｔＣ９），６．００（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），７．６２−７．７４（ｍ，３Ｈ，ＣＨａｔＣ４，Ｃ５，ａｎｄＣ６ｏｆＰｈ），７．９７（ｂｒｄｔ，１Ｈ，Ｊ＝０．８ａｎｄ８．２Ｈｚ，ＣＨａｔＣ３ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１１．８（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．７（Ｃ１０），２９．３（ＣＨ_３ａｔＣ４），３５．７（Ｃ１１），３７．４（［Ｃ］Ｈ_２ＯＣＯ），１２４．１（Ｃ３ｏｆＰｈ），１２７．４（Ｃ６），１２７．９（Ｃ２ｏｆＰｈ），１２９．６（Ｃ６ｏｆＰｈ），１３１．８（Ｃ４ｏｆＰｈ），１３２．５（Ｃ２），１３３．２（Ｃ５ｏｆＰｈ），１３３．６（Ｃ１），１３８．５（Ｃ８），１４７．９（Ｃ１ｏｆＰｈ），１４９．１（Ｃ９），１５９．７（Ｃ５），１６５．７（［Ｃ］ＯＯａｔＰｈ），２０３．７（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２２Ｈ_２５ＮＮａＯ_５）：４０６．１６３０，実測値：４０６．１６４６． ((1Z, 5E, 8E) -4,4,8-triethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl 2-nitrobenzoate (((1Z, 5E, 8E)) -4,4,8-Trimethyl-7-oxocyclondeca-1, 5,8-trien-1-yl) methyl 2-nitrobenzoate): Compound 13,
Yield (81.0%: white solid),
Melting point: 119.8-123.0 ° C,
IR (KBr): 2930, ^{2860, 1736, 1647, 1530 cm -1,}
The assignment number was based on zerumbone.
¹ H NMR (CDCl ₃ ): δ1.12 (brs, 3H, CH ₃ at C4), 1.24 (brs, 3H, CH ₃ at C4), 1.62 (s, 3H, CH ₃ at C8), 1.95-2.92 (brm, 6H, CH ₂ at C3, C10, and C11), 4.69 (brd, 1H, CH at CH ₂ OCO), 4.91 (brd, 1H, CH at CH ₂₎ OCO), 5.53 (t, 1H, J = 8.3Hz, CH at C2), 5.79 (d, 1H, J = 16.4Hz, CH at C5), 5.98 (m, 1H, CH) at C9), 6.00 (d, 1H, J = 16.4Hz, CH at C6), 7.62-7.74 (m, 3H, CH at C4, C5, and C6 of Ph), 7.97 (Brdt, 1H, J = 0.8 and 8.2Hz, CH at C3 of Ph);
¹³ C NMR (CDCl ₃ ): δ11.8 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.7 (C10), 29.3 (CH ₃ at C4), 35.7 (C11) ), 37.4 ([C] H ₂ OCO), 124.1 (C3 of Ph), 127.4 (C6), 127.9 (C2 of Ph), 129.6 (C6 of Ph), 131. 8 (C4 of Ph), 132.5 (C2), 133.2 (C5 of Ph), 133.6 (C1), 138.5 (C8), 147.9 (C1 of Ph), 149.1 ( C9), 159.7 (C5), 165.7 ([C] OO at Ph), 203.7 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₂ H ₂₅ NNaO ₅ ): 406.1630, measured value: 406.1646.

＜求核剤にｐ−ニトロ安息香酸を用いた反応＞
遮光ビンに化合物２を１００ｍｇ（０．３４ｍｍｏｌ）入れ、ＤＭＦ５ｍｌを加えて攪拌し、ｐ−ニトロ安息香酸ナトリウム１．５ｅｑ（９５．３ｍｇ，０．５０ｍｍｏｌ）を加え、室温で２時間半攪拌した。ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝５／１）で反応終了を確認し、反応を止めた。反応液を酢酸エチルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物を中圧カラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１２／１）で分離精製し、黄色固体（化合物１４）を収率６８．１％で８７．８ｍｇ得た。 <Reaction using p-nitrobenzoic acid as a nucleophile>
100 mg (0.34 mmol) of compound 2 was placed in a light-shielding bottle, 5 ml of DMF was added and stirred, 1.5 eq (95.3 mg, 0.50 mmol) of sodium p-nitrobenzoate was added, and the mixture was stirred at room temperature for 2 and a half hours. The end of the reaction was confirmed by TLC (Hexane / AcOEt = 5/1), and the reaction was stopped. The reaction mixture was extracted 3 times with ethyl acetate and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by medium pressure column chromatography (Hexane / AcOEt = 12/1) to obtain 87.8 mg of a yellow solid (Compound 14) in a yield of 68.1%.

（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−トリメチル−７−オキソシクロウンデカ−１，５，８−トリエン−１−イル）メチル４−ニトロベンゾエート（（（１Ｚ，５Ｅ，８Ｅ）−４，４，８−Ｔｒｉｍｅｔｈｙｌ−７−ｏｘｏｃｙｃｌｏｕｎｄｅｃａ−１，５，８−ｔｒｉｅｎ−１−ｙｌ）ｍｅｔｈｙｌ４−ｎｉｔｒｏｂｅｎｚｏａｔｅ）：化合物１４，
Ｙｉｅｌｄ（６８．１％：ｙｅｌｌｏｗｓｏｌｉｄ），
融点：１０３．０−１０７．０℃，
ＩＲ（ＫＢｒ）：２９５５，１７２４，１６５５，１５２８，１２６７ｃｍ^−１，
Ｔｈｅａｓｓｉｇｎｍｅｎｔｎｕｍｂｅｒｗａｓｂａｓｅｄｏｎｚｅｒｕｍｂｏｎｅ．
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１３（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．２６（ｂｒｓ，３Ｈ，ＣＨ_３ａｔＣ４），１．７４（ｓ，３Ｈ，ＣＨ_３ａｔＣ８），１．９７−２．８４（ｂｒｍ，６Ｈ，ＣＨ_２ａｔＣ３，Ｃ１０，ａｎｄＣ１１），４．７０（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．０２（ｂｒｄ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．５６（ｔ，１Ｈ，Ｊ＝８．４Ｈｚ，ＣＨａｔＣ２），５．８３（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ５），６．０３（ｄ，１Ｈ，Ｊ＝１６．４Ｈｚ，ＣＨａｔＣ６），６．０６（ｍ，１Ｈ，ＣＨａｔＣ９），８．２１（ｄｔ，２Ｈ，Ｊ＝２．１ａｎｄ９．０Ｈｚ，ＣＨａｔＣ２ａｎｄＣ６ｏｆＰｈ），８．３１（ｄｔ，２Ｈ，Ｊ＝２．１ａｎｄ９．０Ｈｚ，ＣＨａｔＣ３ａｎｄＣ５ｏｆＰｈ）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ８），２４．１（ＣＨ_３ａｔＣ４），２４．７（Ｃ１０），２９．４（ＣＨ_３ａｔＣ４），３５．３（Ｃ１１），３７．５（Ｃ４），４２．４（Ｃ３），６２．２（［Ｃ］Ｈ_２ＯＣＯ），１２３．７（Ｃ３ａｎｄＣ５ｏｆＰｈ），１２７．４（Ｃ６），１３０．８（Ｃ２ａｎｄＣ６ｏｆＰｈ），１３２．１（Ｃ２），１３３．９（Ｃ１），１３５．３（Ｃ４ｏｆＰｈ），１３８．６（Ｃ８），１４９．０（Ｃ９），１５０．７（Ｃ１ｏｆＰｈ），１５９．５（Ｃ５），１６４．４（［Ｃ］ＯＯａｔＰｈ），２０３．５（Ｃ７）；
ＨＲＭＳ（Ｍ＋Ｎａ^＋）：ｍ／ｚ計算値（Ｃ_２２Ｈ_２５ＮＮａＯ_５）：４０６．１６３０，実測値：４０６．１６４２． ((1Z, 5E, 8E) -4,4,8-trimethyl-7-oxocycloundeca-1,5,8-triene-1-yl) Methyl 4-nitrobenzoate (((1Z, 5E, 8E)) -4,4,8-Trimethyl-7-oxocyclondeca-1, 5,8-trien-1-yl) methyl 4-nitrobenzoate): Compound 14,
Yield (68.1%: hello solid),
Melting point: 103.0-17.0 ° C,
IR (KBr): 2955, ^{1724, 1655, 1528, 1267 cm -1,}
The assignment number was based on zerumbone.
^{1 1} H NMR (CDCl ₃ ): δ1.13 (brs, 3H, CH ₃ at C4), 1.26 (brs, 3H, CH ₃ at C4), 1.74 (s, 3H, CH ₃ at C8), 1.97-2.84 (brm, 6H, CH ₂ at C3, C10, and C11), 4.70 (brd, 1H, CH at CH ₂ OCO), 5.02 (brd, 1H, CH at CH ₂₎ OCO), 5.56 (t, 1H, J = 8.4Hz, CH at C2), 5.83 (d, 1H, J = 16.4Hz, CH at C5), 6.03 (d, 1H, J) = 16.4Hz, CH at C6), 6.06 (m, 1H, CH at C9), 8.21 (dt, 2H, J = 2.1 and 9.0Hz, CH at C2 and C6 of Ph), 8.31 (dt, 2H, J = 2.1 and 9.0 Hz, CH at C3 and C5 of Ph);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C8), 24.1 (CH ₃ at C4), 24.7 (C10), 29.4 (CH ₃ at C4), 35.3 (C11) ), 37.5 (C4), 42.4 (C3), 62.2 ([C] H ₂ OCO), 123.7 (C3 and C5 of Ph), 127.4 (C6), 130.8 ( C2 and C6 of Ph), 132.1 (C2), 133.9 (C1), 135.3 (C4 of Ph), 138.6 (C8), 149.0 (C9), 150.7 (C1 of) Ph), 159.5 (C5), 164.4 ([C] OO at Ph), 203.5 (C7);
HRMS (M + Na ⁺ ): m / z calculated value (C ₂₂ H ₂₅ NNaO ₅ ): 406.1630, measured value: 406.1642.

＜求核剤に酢酸ナトリウムを用いた反応＞
遮光ビンに化合物２を２００ｍｇ（０．６７ｍｍｏｌ）入れ、ＤＭＦ２０ｍＬを加えて攪拌し、酢酸ナトリウム２．０ｅｑ（８２．８ｍｇ，１．０ｍｍｏｌ）を加え、室温で１６時間攪拌しＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／２）で反応終了を確認し、反応を止めた。反応液をジクロロメタンで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝２／１）で分離精製し、透明オイル（化合物１５）を収率９１％で８４７ｍｇ得た。 <Reaction using sodium acetate as a nucleophile>
Put 200 mg (0.67 mmol) of compound 2 in a light-shielding bottle, add 20 mL of DMF and stir, add 2.0 eq (82.8 mg, 1.0 mmol) of sodium acetate, stir at room temperature for 16 hours, and stir TLC (Hexane / AcOEt =). The end of the reaction was confirmed in 3/2), and the reaction was stopped. The reaction was extracted 3 times with dichloromethane and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 2/1) to obtain 847 mg of a transparent oil (Compound 15) in a yield of 91%.

６−アセトキシメチル−２，９，９−トリメチルシクロウンデカ−２，６，１０−トリエンオン（６−Ａｃｅｔｏｘｙｍｅｔｈｙｌ−２，９，９−ｔｒｉｍｅｔｈｙｌｃｙｃｌｏｕｎｄｅｃａ−２，６，１０−ｔｒｉｅｎｏｎｅ）：化合物１５，
Ｙｉｅｌｄ（９１％：ａｃｏｌｏｒｌｅｓｓｏｉｌ），
ＩＲ（ＮａＣｌｆｉｌｍ）：１７３６，１６５５ｃｍ^−１，
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．１０（ｓ，３Ｈ，ＣＨ_３ａｔＣ９），１．２４（ｓ，３Ｈ，ＣＨ_３ａｔＣ９），１．７９（ｓ，３Ｈ，ＣＨ_３ａｔＣ２），２．０８（ｓ，３Ｈ，ＣＨ_３ａｔＣＨ_３ＣＯ），２．１４−２．６０（ｍ，６Ｈ，ＣＨ_２ａｔＣ４，Ｃ５，ａｎｄＣ８），４．４５（ｂｒｍ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．６５（ｂｒｍ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．４５（ｂｒｍ，１Ｈ，ＣＨａｔＣ７），５．８４（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１０），６．０１（ｍ，１Ｈ，ＣＨａｔＣ３），６．０２（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１１）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１２．０（ＣＨ_３ａｔＣ２），２０．９（ＣＨ_３ＣＯ），２３．９（ＣＨ_３ａｔＣ９），２４．７（Ｃ４），２９．２（ＣＨ_３ａｔＣ９），３５．５（Ｃ５），３７．２（Ｃ９），４２．２（Ｃ８），６１．０（ＣＨ_２ＯＣＯ），１２７．２（Ｃ１１），１３１．３（Ｃ７），１３４．２（Ｃ２），１３８．３（Ｃ６），１４９．０（Ｃ３），１５９．８（Ｃ１０），１７０．８（ＯＣＯ），２０３．７（Ｃ１）；
ＨＭＲＳ：ｍ／ｚ計算値（Ｃ_１７Ｈ_２４Ｏ_３）：２７６．１７２５，実測値：２７６．１７２３．
帰属データについては、ＫｉｔａｙａｍａＴ．ｅｔａｌ．，Ｔｅｔｒａｈｅｄｒｏｎ，６９，１０１５２−１０１６０（２０１３）を元に記載した。 6-Acetoxymethyl-2,9,9-trimethylcycloundeca-2,6,10-trienone (6-acetoxymethyl-2,9,9-trimethylcyclondeca-2, 6,10-trienone): Compound 15,
Yield (91%: a colorless oil),
IR (NaCl film): 1736, ^{1655cm -1,}
^{1 1} H NMR (CDCl ₃ ): δ1.10 (s, 3H, CH ₃ at C9), 1.24 (s, 3H, CH ₃ at C9), 1.79 (s, 3H, CH ₃ at C2), 2.08 (s, 3H, CH ₃ at CH ₃ CO), 2.14-2.60 (m, 6H, CH ₂ at C4, C5, and C8), 4.45 (brm, 1H, CH at CH) ₂ OCO), 4.65 (brm, 1H, CH at CH ₂ OCO), 5.45 (brm, 1H, CH at C7), 5.84 (d, 1H, J = 16.5 Hz, Hat C10) , 6.01 (m, 1H, CH at C3), 6.02 (d, 1H, J = 16.5Hz, Hat C11);
¹³ C NMR (CDCl ₃ ): δ12.0 (CH ₃ at C2), 20.9 (CH ₃ CO), 23.9 (CH ₃ at C9), 24.7 (C4), 29.2 (CH ₃₎ at C9), 35.5 (C5), 37.2 (C9), 42.2 (C8), 61.0 (CH ₂ OCO), 127.2 (C11), 131.3 (C7), 134. 2 (C2), 138.3 (C6), 149.0 (C3), 159.8 (C10), 170.8 (OCO), 203.7 (C1);
HMRS: m / z calculated value (C ₁₇ H ₂₄ O ₃ ): 276.1725, measured value: 276.1723.
For the attribution data, see Kitayama T. et al. et al. , Tetrahedron, 69, 10152-10160 (2013).

＜ヒドロキシゼルンボンの合成＞
遮光ビンに化合物２を１０００ｍｇ（３．６ｍｍｏｌ）入れ、水酸化ナトリウム水溶液を６０ｍＬ（１．５ｅｑ）加えて攪拌し、室温で１時間攪拌しＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝２／１）で反応終了を確認し、反応を止めた。反応液をエーテルで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝４／１）で分離精製し、透明固体（化合物１６）を収率８４％で７０７ｍｇ得た。 <Synthesis of hydroxyzerumbon>
Put 1000 mg (3.6 mmol) of compound 2 in a light-shielding bottle, add 60 mL (1.5 eq) of aqueous sodium hydroxide solution, stir, stir at room temperature for 1 hour, and complete the reaction with TLC (Hexane / AcOEt = 2/1). Confirmed and stopped the reaction. The reaction mixture was extracted 3 times with ether and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 4/1) to obtain 707 mg of a transparent solid (Compound 16) in a yield of 84%.

６−ヒドロキシメチル−２，９，９−トリメチルシクロウンデカ−２，６，１０−トリエンオン（６−Ｈｙｄｒｏｘｙｍｅｔｈｙｌ−２，９，９−ｔｒｉｍｅｔｈｙｌｃｙｃｌｏｕｎｄｅｃａ−２，６，１０−ｔｒｉｅｎｏｎｅ）：化合物１６，
Ｙｉｅｌｄ（８４％：ａｃｏｌｏｒｌｅｓｓｓｏｌｉｄ），
融点：７８．５−７９．０℃，
ＩＲ（ＫＢｒ）：３２８８，１６５５ｃｍ^−１，
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．０８（ｓ，３Ｈ，ＣＨ_３ａｔＣ９），１．２２（ｓ，３ＨＣＨ_３ａｔＣ９），１．７８（ｓ，３Ｈ，ＣＨ_３ａｔＣ２），２．２２−２．４５（ｍ，６Ｈ，ＣＨ_２ａｔＣ４，Ｃ５，ａｎｄＣ８），２．７９（ｓ，１Ｈ，ＯＨａｔＣＨ_２ＯＣＯ），３．８７（ｂｒｍ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），４．３３（ｂｒｍ，１Ｈ，ＣＨａｔＣＨ_２ＯＣＯ），５．３３−５．３９（ｂｒｍ，１Ｈ，ＣＨａｔＣ７），５．８２（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１０），５．９８（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１１），６．０５（ｍ，１Ｈ，ＣＨａｔＣ３）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ１１．８（ＣＨ_３ａｔＣ２），２３．９（ＣＨ_３ａｔＣ９），２４．６（Ｃ４），２９．２（ＣＨ_３ａｔＣ９），３４．９（Ｃ５），３７．２（Ｃ９），４１．９（Ｃ８），５８．８（ＣＨ_２Ｏ），１２７．０（Ｃ１１），１２７．９（Ｃ７），１３８．０（Ｃ２），１３９．２（Ｃ６），１４９．８（Ｃ３），１６０．４（Ｃ１０），２０４．３（Ｃ１）；
ＨＭＲＳ：ｍ／ｚ計算値（Ｃ_１５Ｈ_２２Ｏ_２）：２３４．１６２０，実測値：２３４．１６１９．
帰属データについては、ＫｉｔａｙａｍａＴ．ｅｔａｌ．，Ｔｅｔｒａｈｅｄｒｏｎ，６９，１０１５２−１０１６０（２０１３）を元に記載した。 6-Hydroxymethyl-2,9,9-trimethylcycloundeca-2,6,10-trienone (6-Hydroxymethyl-2,9,9-trimethylcyclondeca-2, 6,10-trienone): Compound 16,
Yield (84%: a colorless solid),
Melting point: 78.5-79.0 ° C,
IR (KBr): 3288, ^{1655cm -1,}
^{1 1} H NMR (CDCl ₃ ): δ1.08 (s, 3H, CH ₃ at C9), 1.22 (s, 3H CH ₃ at C9), 1.78 (s, 3H, CH ₃ at C2), 2 .22-2.45 (m, 6H, CH ₂ at C4, C5, and C8), 2.79 (s, 1H, OH at CH ₂ OCO), 3.87 (brm, 1H, CH at CH ₂ OCO) ), 4.33 (brm, 1H, CH at CH ₂ OCO), 5.33-5.39 (brm, 1H, CH at C7), 5.82 (d, 1H, J = 16.5Hz, Hat C10), 5.98 (d, 1H, J = 16.5Hz, Hat C11), 6.05 (m, 1H, CH at C3);
¹³ C NMR (CDCl ₃ ): δ11.8 (CH ₃ at C2), 23.9 (CH ₃ at C9), 24.6 (C4), 29.2 (CH ₃ at C9), 34.9 (C5) ), 37.2 (C9), 41.9 (C8), 58.8 (CH ₂ O), 127.0 (C11), 127.9 (C7), 138.0 (C2), 139.2 ( C6), 149.8 (C3), 160.4 (C10), 204.3 (C1);
HMRS: Calculated m / z value (C ₁₅ H ₂₂ O ₂ ): 234.1620, Measured value: 234.1619.
For the attribution data, see Kitayama T. et al. et al. , Tetrahedron, 69, 10152-10160 (2013).

＜求核剤にメチルアミンを用いた反応＞
遮光ビンに化合物２を１０００ｍｇ（３．４ｍｍｏｌ）入れ、ＤＭＦ１０ｍＬを加えて攪拌し、メチルアミン２．０ｅｑ（３８０μｌ，４．４ｍｍｏｌ）を加え、室温で８９時間攪拌しＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で反応終了を確認し、反応を止めた。反応液をジクロロメタンで３回抽出し、飽和食塩水で３回洗浄した。その後、無水硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで減圧濃縮し、真空乾燥した。得られた生成物をオープンカラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３／１）で分離精製し、褐色固体（化合物１７）を収率４１％で６４１ｍｇ得た。 <Reaction using methylamine as a nucleophile>
Put 1000 mg (3.4 mmol) of compound 2 in a light-shielding bottle, add 10 mL of DMF and stir, add 2.0 eq (380 μl, 4.4 mmol) of methylamine, stir at room temperature for 89 hours, and stir TLC (Hexane / AcOEt = 3 /). The end of the reaction was confirmed in 1), and the reaction was stopped. The reaction was extracted 3 times with dichloromethane and washed 3 times with saturated brine. Then, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure with a rotary evaporator, and vacuum dried. The obtained product was separated and purified by open column chromatography (Hexane / AcOEt = 3/1) to obtain 641 mg of a brown solid (Compound 17) in a yield of 41%.

Ｎ，Ｎ−ビス［６−（１−オクソ−２，９，９−トリメチルシクロウンデカ−２，６，１０−トリエニル）メチル］メチルアミン（Ｎ，Ｎ−Ｂｉｓ［６−（１−ｏｘｏ−２，９，９−ｔｒｉｍｅｔｈｙｌｃｙｃｌｏｕｎｄｅｃａ−２，６，１０−ｔｒｉｅｎｙｌ）ｍｅｔｈｙｌ］ｍｅｔｈｙｌａｍｉｎｅ）：化合物１７，
Ｙｉｅｌｄ（４１％：ａｌｉｇｈｔｂｒｏｗｎｓｏｌｉｄ），
ＩＲ（ＫＢｒ）：１６５１ｃｍ^−１，
^１ＨＮＭＲ（ＣＤＣｌ_３）：δ１．０８（ｓ，６Ｈ，ＣＨ_３ａｔＣ９），１．２２（ｓ，６Ｈ，ＣＨ_３ａｔＣ９），１．７７（ｓ，６Ｈ，ＣＨ_３ａｔＣ２），１．８８−３．００（ｍ，１９Ｈ，ＣＨ_２ａｔＣ４，Ｃ５，Ｃ８，ａｎｄＣＨ_２ＮａｎｄＮ−ＣＨ_３），５．４６（ｔ，１Ｈ，Ｊ＝８．０Ｈｚ，ＨａｔＣ７），５．７３（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１０），５．９９（ｄ，１Ｈ，Ｊ＝１６．５Ｈｚ，ＨａｔＣ１１），６．０２（ｍ，１Ｈ，ＣＨａｔＣ３）；
^１３ＣＮＭＲ（ＣＤＣｌ_３）：δ９．５（ＣＨ_３ａｔＣ２），２１．９（ＣＨ_３ａｔＣ９），２２．３（Ｃ４），２７．１（ＣＨ_３ａｔＣ９），３３．３（Ｃ５），３５．４（Ｃ９），３９．４（Ｃ８），５１．６（ＣＨ_２Ｎ），１２４．９（Ｃ１１），１２６．３（Ｃ７），１３５．７（Ｃ２），１３６．２（Ｃ６），１４７．５（Ｃ３），１５７．８（Ｃ１０），２０１．７（Ｃ１）；
ＨＲＭＳ：ｍ／ｚ計算値（Ｃ_３１Ｈ_４５ＮＯ_２）：４６３．３４５０，実測値：４６３．３４１８．
帰属データについては、ＫｉｔａｙａｍａＴ．ｅｔａｌ．，Ｔｅｔｒａｈｅｄｒｏｎ，６９，１０１５２−１０１６０（２０１３）を元に記載した。 N, N-bis [6- (1-oxo-2,9,9-trimethylcycloundeca-2,6,10-trienyl) methyl] methylamine (N, N-Bis [6- (1-oxo-) 2,9,9-trimethylcyclondeca-2,6,10-trienyl) methyl] methylamine): Compound 17,
Yield (41%: a bright brown solid),
IR (KBr): 1651cm ^-1 ,
^{1 1} H NMR (CDCl ₃ ): δ1.08 (s, 6H, CH ₃ at C9), 1.22 (s, 6H, CH ₃ at C9), 1.77 (s, 6H, CH ₃ at C2), 1.88-3.00 (m, 19H, CH ₂ at C4, C5, C8, and CH ₂ N and N-CH ₃ ), 5.46 (t, 1H, J = 8.0Hz, Hat C7) , 5.73 (d, 1H, J = 16.5Hz, Hat C10), 5.99 (d, 1H, J = 16.5Hz, Hat C11), 6.02 (m, 1H, CH at C3) );
¹³ C NMR (CDCl ₃ ): δ9.5 (CH ₃ at C2), 21.9 (CH ₃ at C9), 22.3 (C4), 27.1 (CH ₃ at C9), 33.3 (C5) _{), 35.4 (C9), 39.4} (C8), 51.6 (CH 2 N), 124.9 (C11), 126.3 (C7), 135.7 (C2), 136.2 ( C6), 147.5 (C3), 157.8 (C10), 201.7 (C1);
HRMS: m / z calculated value (C ₃₁ H ₄₅ NO ₂ ): 463.3450, measured value: 463.3418.
For the attribution data, see Kitayama T. et al. et al. , Tetrahedron, 69, 10152-10160 (2013).

＜細胞培養＞
次に上記の化合物による癌細胞増殖抑制効果について調べた。ヒト白血病Ｔ細胞株Ｊｕｒｋａｔ細胞は、独立行政法人理化学研究所バイオリソースセンター（つくば市、茨城県）より入手した。１０％牛胎児血清（ＴｈｅｒｍｏＦｉｓｈｅｒＳｃｉｅｎｔｉｆｉｃｓ、Ｋ．Ｋ．、ＭＡ、ＵＳＡ）、１００Ｕ／ｍＬペニシリンおよび１００μｇ／ｍＬスプレトマイシン（共にＬｉｆｅＴｅｃｈｎｏｌｏｇｉｅｓ、Ｃａｒｌｓｂａｄ、ＣＡ、ＵＳＡ）を含んだＲＰＭＩ１６４０培地（和光純薬工業株式会社、大阪市、大阪府）により３７℃、９５％空気−５％ＣＯ_２環境下で培養した。 <Cell culture>
Next, the cancer cell growth inhibitory effect of the above compounds was investigated. Human leukemia T cell line Jurkat cells were obtained from RIKEN BioResource Center (Tsukuba City, Ibaraki Prefecture). RPMI1640 medium containing 10% bovine fetal serum (Thermo Fisher Scientifics, KK, MA, USA), 100 U / mL penicillin and 100 μg / mL spretomycin (both Life Technologies, Carlsbad, CA, USA). It was cultured by Yakuhin Kogyo Co., Ltd. (Osaka City, Osaka Prefecture) at 37 ° C. in a 95% air-5% CO _{2 environment.}

＜癌細胞増殖抑制効果＞
Ｊｕｒｋａｔ細胞を１×１０^５ｃｅｌｌｓ／ｍＬに調整し、２４ウェルマルチプレート（ＴｈｅｒｍｏＦｉｓｈｅｒＳｃｉｅｎｔｉｆｉｃｓＫ．Ｋ．）に５００μＬ／ｗｅｌｌずつ播種した。播種後、上記の化合物３乃至１７で処理し、培養した。サンプル処理２４、４８、７２時間後に細胞をトライパンブルー（ＬｉｆｅＴｅｃｈｎｏｌｏｇｉｅｓ）で染色し、血球計算盤を用いて生細胞を計数した。 <Cancer cell growth inhibitory effect>
Jurkat cells were adjusted to 1 × 10 ⁵ cells / mL and seeded at 500 μL / well on a 24-well multiplate (Thermo Fisher Scientifics KK). After sowing, it was treated with the above compounds 3 to 17 and cultured. After 24, 48, and 72 hours of sample treatment, cells were stained with Life Technologies and live cells were counted using a hemocytometer.

表１に各化合物に対するＩＣ_５０、１／ＩＣ_５０および求核剤を共に示した。また、化合物１のゼルンボンは求核剤の欄に括弧付でゼルンボン自体を示した。 Table 1 shows the IC ₅₀ , 1 / IC ₅₀ and nucleophile for each compound. In addition, the nucleophile of compound 1 is shown in parentheses in the column of nucleophile.

表１を参照して、化合物３、４、５、７、９、１０、１１、１２、１３、１４、１５、１７は、ゼルンボン自体のＩＣ_５０より癌細胞増殖の抑制効果が高かった。癌細胞増殖の抑制効果が非常に高いと言われるパクリタキセルのＩＣ_５０が、数十ｎＭ〜数百ｎＭとされている。したがって、これらの化合物は、パクリタキセルに近い程度の癌細胞増殖抑制効果を有すると言える。 Referring to Table 1, compound 3,4,5,7,9,10,11,12,13,14,15,17 was higher effect of suppressing the cancer cell growth than _{IC 50} of zerumbone itself. IC ₅₀ of paclitaxel effect of suppressing the cancer cell growth is said to be very high, there is a few tens nM~ several hundred nM. Therefore, it can be said that these compounds have a cancer cell growth inhibitory effect close to that of paclitaxel.

また、求核剤として用いた化合物のＪｕｒｋａｔ細胞に対するＩＣ_５０を表２に示す。表２を参照して、求核剤として用いた化合物のＩＣ_５０は何れもゼルンボンとの化合物よりも大きかった。これより、上記の化合物１乃至１７のいずれについても癌細胞増殖抑制効果を有しているといえる。また、少なくとも、ＩＣ_５０が１０以下の物質は癌細胞増殖抑制効果があるといえる。 Also shows the _{IC 50} for Jurkat cells of the compounds used as a nucleophile in Table 2. Referring to Table 2, IC ₅₀ of the compounds used as a nucleophile are both larger than the compounds of the zerumbone. From this, it can be said that any of the above compounds 1 to 17 has a cancer cell growth inhibitory effect. Further, at least, _{it can be said that a substance having an IC 50} of 10 or less has a cancer cell growth inhibitory effect.

本発明に係る化合物は、リード化合物として好適に利用できるほか、抗癌剤としても好適に利用することができる。 The compound according to the present invention can be suitably used as a lead compound and also as an anticancer agent.

Claims

One of Compound 3 , Compound 7, Compound 9 and Compound 14.

Compound 3, Compound 5, Compound 7, cancer cell proliferation inhibitor having a higher cancer cell proliferation inhibitory effect zerumbone containing a compound of any one of the compounds 9 to Compound 1 4.

The process of reacting Zernbon with N-bromosuccinimide to obtain 7-bromoZernbon, and
The step of adding N, N-dimethylformamide to the 7-bromozelumbon and stirring, and
A step of adding a nucleophile to the stirred product of 7-bromozelumbon and N, N-dimethylformamide and continuing stirring for a predetermined time is included.
The nucleating agent is sodium salicylate , terephthalic acid, monomethylpotassium terephthalate, mono-tert-butyl sodium terephthalate, sodium o-methoxybenzoate, sodium p-methoxybenzoate, sodium o-nitrobenzoate, p-nitro. A method for producing a zerumbone-inducing compound, which is one of sodium benzoate.

The process of reacting Zernbon with N-bromosuccinimide to obtain 7-bromoZernbon, and
The step of adding N, N-dimethylformamide to the 7-bromozelumbon and stirring, and
A step of adding a nucleophile to the stirred product of 7-bromozelumbon and N, N-dimethylformamide and continuing stirring for a predetermined time is included.
The nucleating agent is sodium salicylate, sodium benzoate , terephthalic acid, monomethylpotassium terephthalate, mono-tert-butyl sodium terephthalate, sodium o-methoxybenzoate, sodium p-methoxybenzoate, sodium o-nitrobenzoate. the method of cancer cell proliferation inhibitor having high cancer cell proliferation inhibitory effect than is one wherein zerumbone of p- nitrobenzoic acid sodium.