JP2711762B2 - Bicyclo [8.3.0] trideca-9,13-diene-2,7-diyne derivative - Google Patents

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【産業上の利用分野】本発明は抗腫瘍剤として有用なビ
シクロ［８．３．０］トリデカ−９，１３−ジエン−
２，７−ジイン誘導体に関する。The present invention relates to bicyclo [8.3.0] trideca-9,13-diene which is useful as an antitumor agent.
It relates to a 2,7-diyne derivative.

【０００２】[0002]

【従来の技術及び発明が解決しようとする課題】抗腫瘍
抗生物質ネオカルチノスタチンはすでに胃癌、スイ臓
癌、急性白血病等の治療剤として臨床において広く使用
されている。このネオカルチノスタチンは分子量11000
のタンパク部分と分子量６５９のＮＣＳ−Ｃから構成さ
れている。そしてその抗腫瘍活性はＮＣＳ−Ｃが担って
おり、これは次のような構造を有している〔テトラヘド
ロン レターズ，２６巻，３３１ページ，１９８５〕。
しかし、このＮＣＳ−Ｃは熱、光に対して極めて不安定
であることが知られている〔特公昭60-30679号公報〕。2. Description of the Related Art Neocarzinostatin, an antitumor antibiotic, has already been widely used in the clinic as a therapeutic agent for gastric cancer, watermelon cancer, acute leukemia and the like. This neocarzinostatin has a molecular weight of 11000
And NCS-C having a molecular weight of 659. Its antitumor activity is borne by NCS-C, which has the following structure [Tetrahedron Letters, 26, 331, 1985].
However, it is known that this NCS-C is extremely unstable to heat and light (Japanese Patent Publication No. 60-30679).

【化２】 Embedded image

【０００３】[0003]

【課題を解決するための手段】斯かる実情において、本
発明者は、熱、光に対して安定なＮＣＳ−Ｃの類似体、
誘導体を化学合成的に製造すべく鋭意検討した結果、Ｎ
ＣＳ−Ｃの活性発現に必須のビシクロ［７．３．０］ド
デカ−８，１２−ジエン−２，６−ジイン環と類似する
ビシクロ［８．３．０］トリデカ−９，１３−ジエン−
２，７−ジイン環の合成に成功し、更に、得られたアル
カノイルチオエチル基を有するビシクロ［８．３．０］
トリデカ−９，１３−ジエン−２，７−ジイン誘導体
は、ＮＣＳ−Ｃの製造中間体として有用でかつＮＣＳ−
Ｃと類似の抗腫瘍活性を有することを見出し、本発明を
完成した。In such circumstances, the present inventors have developed an analog of NCS-C that is heat and light stable,
As a result of intensive studies to produce derivatives synthetically, N
Bicyclo [8.3.0] tridec-9,13-diene- which is similar to bicyclo [7.3.0] dodeca-8,12-diene-2,6-diyne ring essential for CS-C activity expression.
The 2,7-diyne ring was successfully synthesized, and the obtained bicyclo [8.3.0] having an alkanoylthioethyl group was obtained.
Trideca-9,13-diene-2,7-diyne derivatives are useful as intermediates for the production of NCS-C and
The present inventors have found that they have an antitumor activity similar to that of C, and completed the present invention.

【０００４】すなわち、本発明の次の一般式（１）That is, the following general formula (1) of the present invention:

【化３】 〔式中、Ｒ¹ は低級アルカノイル基を示し、Ｒ² 及びＲ
³ は同一か又は異なって水素原子又は低級アルキル基を
示す〕で表わされるビシクロ［８．３．０］トリデカ−
９，１３−ジエン−２，７−ジイン誘導体を提供するも
のである。Embedded image Wherein R ¹ represents a lower alkanoyl group, R ² and R
³ are the same or different and each represent a hydrogen atom or a lower alkyl group].
It is intended to provide a 9,13-diene-2,7-diyne derivative.

【０００５】上記一般式（１）中、Ｒ¹ で示される低級
アルカノイル基としては、炭素数１〜６の直鎖又は分岐
鎖のアルカノイル基、例えばホルミル基、アセチル基、
プロピオニル基、ブチリル基、ペンタノイル基、ヘキサ
ノイル基等が挙げられる。また、Ｒ² 及びＲ³ で示され
る低級アルキル基としては、炭素数１〜６の直鎖又は分
岐鎖のアルキル基、例えばメチル基、エチル基、イソプ
ロピル基、ｎ−ブチル基、 sec−ブチル基、アミル基、
ヘキシル基等が挙げられる。In the above general formula (1), the lower alkanoyl group represented by R ¹ is a linear or branched alkanoyl group having 1 to 6 carbon atoms, for example, formyl group, acetyl group,
Examples include a propionyl group, a butyryl group, a pentanoyl group, and a hexanoyl group. Examples of the lower alkyl group represented by R ² and R ³ include a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, an n-butyl group, and a sec-butyl group. , Amyl group,
Hexyl group and the like.

【０００６】本発明のビシクロ［８．３．０］トリデカ
−９，１３−ジエン−２，７−ジイン誘導体は文献未記
載の新規化合物であり、例えば以下に述べる（１）〜
（７）の方法に従って製造することができる。The bicyclo [8.3.0] trideca-9,13-diene-2,7-diyne derivative of the present invention is a novel compound which has not been described in the literature.
It can be manufactured according to the method (7).

【０００７】（１）次式に従って、シクロペンタジエン
から、ビシクロ［２．２．１］ヘプト−５−エン−２−
オン（Ａ）を製造する。(1) According to the following formula, bicyclo [2.2.1] hept-5-ene-2-
On (A) is manufactured.

【化４】 すなわち、シクロペンタジエンに２−クロロアクリロニ
トリルを反応させて２−クロロ−２−シアノビシクロ
［２．２．１］ヘプト−５−エンを得〔Synthesis pp87
6(1974)〕、次いでこれを水酸化カリウムで処理するこ
とにより、ビシクロ［２．２．１］ヘプト−５−エン−
２−オン（Ａ）が得られる。Embedded image That is, 2-chloroacrylonitrile is reacted with cyclopentadiene to obtain 2-chloro-2-cyanobicyclo [2.2.1] hept-5-ene [Synthesis pp87.
6 (1974)], and then treated with potassium hydroxide to give bicyclo [2.2.1] hept-5-ene-
2-one (A) is obtained.

【０００８】（２）次式に従って、ビシクロ［２．２．
１］ヘプト−５−エン−２−オン（Ａ）から sec−ブチ
ル（３−ブロモ−４−オキソ−２−シクロペンテニル）
アセテート（Ｂ）を製造する。(2) Bicyclo [2.2.
1] From hept-5-en-2-one (A) to sec-butyl (3-bromo-4-oxo-2-cyclopentenyl)
Acetate (B) is produced.

【化５】 すなわち、ビシクロ［２．２．１］ヘプト−５−エン−
２−オン（Ａ）に過酸化水素を反応させ、次いで sec−
ブチルアイオダイドを反応させて sec−ブチル（４−ヒ
ドロキシ−２−シクロペンテニル）アセテートを得〔Te
t. Letter，27,1255(1986)〕、これにオキザリルクロリ
ド、ジメチルスルホキシド(DMSO)及びアミンを反応さ
せ、次いで臭素化することにより、 sec−ブチル（３−
ブロモ−４−オキソ−２−シクロペンテニル）アセテー
ト（Ｂ）が得られる。Embedded image That is, bicyclo [2.2.1] hept-5-ene-
The 2-one (A) is reacted with hydrogen peroxide and then sec-
Reaction of butyl iodide gives sec-butyl (4-hydroxy-2-cyclopentenyl) acetate [Te
t. Letter, 27 , 1255 (1986)], which is reacted with oxalyl chloride, dimethyl sulfoxide (DMSO) and an amine, and then brominated to obtain sec-butyl (3-
Bromo-4-oxo-2-cyclopentenyl) acetate (B) is obtained.

【０００９】（３）次式に従って sec−ブチル（３−ブ
ロモ−４−オキソ−２−シクロペンテニル）アセテート
（Ｂ）から２−ブロモ−４−（２−トリエチルシリルオ
キシエチル）−１−（２−プロピニル）−２−シクロペ
ンテン−１−オール（Ｃ）を製造する。(3) From sec-butyl (3-bromo-4-oxo-2-cyclopentenyl) acetate (B) according to the following formula, 2-bromo-4- (2-triethylsilyloxyethyl) -1- (2 -Propinyl) -2-cyclopenten-1-ol (C) is prepared.

【化６】 すなわち、 sec−ブチル（３−ブロモ−４−オキソ−２
−シクロペンテニル）アセテート（Ｂ）にグリニャール
試薬を反応させてプロパルギル化し、次いで水素化ジイ
ソブチルリチウムを用いて還元して２−ブロモ−４−
（２−ヒドロキシエチル）−１−（２−プロピニル）−
２−シクロペンテン−１−オールとなし、これにトリエ
チルシリルクロリドを反応させることにより、２−ブロ
モ−４−（２−トリエチルシリルオキシエチル）−１−
（２−プロピニル）−２−シクロペンテン−１−オール
（Ｃ）が得られる。Embedded image That is, sec-butyl (3-bromo-4-oxo-2
-Cyclopentenyl) acetate (B) was reacted with a Grignard reagent to propargylate and then reduced with diisobutyllithium hydride to give 2-bromo-4-
(2-hydroxyethyl) -1- (2-propynyl)-
By reacting with 2-cyclopenten-1-ol and reacting with triethylsilyl chloride, 2-bromo-4- (2-triethylsilyloxyethyl) -1- was obtained.
(2-propynyl) -2-cyclopenten-1-ol (C) is obtained.

【００１０】（４）次式に従って、２−ブロモ−４−
（２−トリエチルシリルオキシエチル）−１−（２−プ
ロピニル）−２−シクロペンテン−１−オール（Ｃ）か
ら２−ブロモ−１−（４−トリエチルシリルオキシ−８
−トリノルマルブチルスタニル−２，７−オクタジイニ
ル）−４−（２−トリエチルシリルオキシ）−２−シク
ロペンテン−１−オール化合物（Ｄ）を製造する。(4) According to the following formula, 2-bromo-4-
(2-triethylsilyloxyethyl) -1- (2-propynyl) -2-cyclopenten-1-ol (C) to 2-bromo-1- (4-triethylsilyloxy-8)
-Trinormalbutylstannyl-2,7-octadiynyl) -4- (2-triethylsilyloxy) -2-cyclopenten-1-ol compound (D) is produced.

【化７】 すなわち、２−ブロモ−４−（２−トリエチルシリルオ
キシエチル）−１−（２−プロピニル）−２−シクロペ
ンテン−１−オール（Ｃ）にグリニャール試薬を反応さ
せ、続いてアルデヒド化合物を反応させて１−［１−ヒ
ドロキシ−２−ブロモ−４−（２−トリエチルシリルオ
キシエチル）−２−シクロペンテニル］−２，７−ジイ
ニル−４−オクタノール化合物を得、これをトリエチル
シリル化後、塩化トリブチルスズと反応させて２−ブロ
モ−１−（４−トリエチルシリルオキシ−８−トリノル
マルブチルスタニル−２，７−オクタジイニル）−４−
（２−トリエチルシリルオキシ）−２−シクロペンテン
−１−オール化合物（Ｄ）を得る。Embedded image That is, a Grignard reagent is reacted with 2-bromo-4- (2-triethylsilyloxyethyl) -1- (2-propynyl) -2-cyclopenten-1-ol (C), followed by a reaction with an aldehyde compound. A 1- [1-hydroxy-2-bromo-4- (2-triethylsilyloxyethyl) -2-cyclopentenyl] -2,7-diynyl-4-octanol compound was obtained, which was triethylsilylated and then tributyltin chloride. To give 2-bromo-1- (4-triethylsilyloxy-8-trinormalbutylstannyl-2,7-octadiynyl) -4-
(2-triethylsilyloxy) -2-cyclopenten-1-ol compound (D) is obtained.

【００１１】（５）次式に従って、２−ブロモ−１−
（４−トリエチルシリルオキシ−８−トリノルマルブチ
ルスタニル−２，７−オクタジイニル）−４−（２−ト
リエチルシリルオキシ）−２−シクロペンテン−１−オ
ール化合物（Ｃ）にテトラキストリフェニルホスフィン
パラジウムを反応させて１−ヒドロキシ−５−トリエチ
ルシリルオキシ−１２−（２−トリエチルシリルオキシ
エチル）−ビシクロ［８．３．０］トリデカ−１０−エ
ン−３，８−ジイン化合物（Ｅ）を製造する。(5) According to the following formula, 2-bromo-1-
(4-triethylsilyloxy-8-trinormalbutylstannyl-2,7-octadynyl) -4- (2-triethylsilyloxy) -2-cyclopenten-1-ol Compound (C) is treated with tetrakistriphenylphosphine palladium. The reaction is carried out to produce 1-hydroxy-5-triethylsilyloxy-12- (2-triethylsilyloxyethyl) -bicyclo [8.3.0] trideca-10-ene-3,8-diyne compound (E). .

【化８】 Embedded image

【００１２】（６）次式に従って、１−ヒドロキシ−５
−トリエチルシリルオキシ−１２−（２−トリエチルシ
リルオキシエチル）−ビシクロ［８．３．０］トリデカ
−１０−エン−３，８−ジイン化合物（Ｅ）から１，５
−ジヒドロキシ−１２−（２−アルカノイルチオエチ
ル）ビシクロ［８．３．０］トリデカ−１０−エン−
３，８−ジイン化合物（Ｆ）を製造する。(6) According to the following formula, 1-hydroxy-5
-Triethylsilyloxy-12- (2-triethylsilyloxyethyl) -bicyclo [8.3.0] tridec-10-ene-3,8-diyne From compound (E), 1,5
-Dihydroxy-12- (2-alkanoylthioethyl) bicyclo [8.3.0] tridec-10-ene-
A 3,8-diyne compound (F) is produced.

【化９】 すなわち、１−ヒドロキシ−５−トリエチルシリルオキ
シ−１２−（２−トリエチルシリルオキシエチル）−ビ
シクロ［８．３．０］トリデカ−１０−エン−３，８−
ジイン化合物（Ｅ）を加水分解し、次いでこれにパラト
ルエンスルホニルクロリドを反応させ、更にチオアルカ
ン酸又はその反応性誘導体を反応させることにより、
１，５−ジヒドロキシ−１２−（２−アルカノイルチオ
エチル）ビシクロ［８．３．０］トリデカ−１０−エン
−３，８−ジイン化合物（Ｆ）が得られる。Embedded image That is, 1-hydroxy-5-triethylsilyloxy-12- (2-triethylsilyloxyethyl) -bicyclo [8.3.0] trideca-10-ene-3,8-
By hydrolyzing the diyne compound (E), then reacting it with paratoluenesulfonyl chloride, and further reacting with thioalkanoic acid or a reactive derivative thereof,
1,5-Dihydroxy-12- (2-alkanoylthioethyl) bicyclo [8.3.0] tridec-10-ene-3,8-diyne compound (F) is obtained.

【００１３】（７）次式に従って、１，５−ジヒドロキ
シ−１２−（２−アルカノイルチオエチル）ビシクロ
［８．３．０］トリデカ−１０−エン−３，８−ジイン
化合物（Ｆ）にオキザリルクロリド、ＤＭＳＯ及びアミ
ンを反応させ、本発明化合物である１２−（２−アルカ
ノイルチオエチル）−５−オキシビシクロ［８．３．
０］トリデカ−１，１０−ジエン−３，８−ジイン化合
物（１）を製造する。(7) According to the following formula, 1,5-dihydroxy-12- (2-alkanoylthioethyl) bicyclo [8.3.0] tridec-10-ene-3,8-diyne compound (F) is oxidized. The compound of the present invention, 12- (2-alkanoylthioethyl) -5-oxybicyclo [8.3.
0] Trideca-1,10-diene-3,8-diyne compound (1) is produced.

【化１０】 Embedded image

【００１４】実施例 以下に実施例を挙げて本発明を更に説明する。The present invention will be further described below with reference to examples.

【００１５】実施例１ ２−クロロ−２−シアノビシク
ロ［２．２．１］ヘプタ−５−エンの製造： ジシクロペンタジエンを蒸留により熱分解して得たシク
ロペンタジエン2.21g(0.025mol)を４mlトルエン中７０
℃に加熱し、これに２−クロロアクリロニトリル2.1ml
(0.025mol) を１０分間で滴下した。滴下終了後４５℃
で一晩攪拌し、溶媒を蒸留により除いた。残渣をシリカ
ゲル５０ｇ、ヘキサン：酢酸エチル＝１０：１のカラム
クロマトグラフィーにより精製して目的物を得た。 形状：半透明白色固体 3.43g(0.022mol, 収率８９％) 融点：４６℃ その他： 3.6:１のジアステレオマー混合物¹ H-NMR(400MHz,CDCl₃ ):δ 1.711(m,0.78H), 1.75-1.85(m,1.78H),1.950(m,0.22H),
2.228(bdd,0.22H,J=13.5,3.0Hz),2.366(ddd,0.22H,J=1
3.5,3.5,0.5Hz),2.719(dd,0.78H,J=13.3,3.8Hz), 3.094
(m,1H),3.355(m,0.22H),3.508(m,0.78H),6.120(ddd,0.7
8H,J=5.8,3.1,0.5Hz),6.223(ddd,0.22H,J=5.8,3.1,0.5H
z),6.424(dd,0.78H,J=5.8,3.1Hz), 6.466(dd,0.22H,J=
5.8,3.0Hz) IR(film)：ν4400, 4282, 4020, 3930,3444, 2998, 291
6, 2334, 2238,2106, 1995, 1661, 1437, 1408, 1336,
1313,1056, 955,932, 897, 872, 806, 772,729, 698, 6
69, 505cm^-1 Example 1 Preparation of 2-chloro-2-cyanobicyclo [2.2.1] hept-5-ene: 2.21 g (0.025 mol) of cyclopentadiene obtained by pyrolyzing dicyclopentadiene by distillation was obtained. 70 in 4 ml toluene
To 2-chloroacrylonitrile 2.1 ml
(0.025 mol) was added dropwise over 10 minutes. 45 ° C after dropping
And the solvent was removed by distillation. The residue was purified by column chromatography using 50 g of silica gel and hexane: ethyl acetate = 10: 1 to obtain the desired product. Form: translucent white solid 3.43 g (0.022 mol, 89% yield) Melting point: 46 ° C. Other: 3.6: 1 diastereomer mixture ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.711 (m, 0.78H) , 1.75-1.85 (m, 1.78H), 1.950 (m, 0.22H),
2.228 (bdd, 0.22H, J = 13.5,3.0Hz), 2.366 (ddd, 0.22H, J = 1
3.5,3.5,0.5Hz), 2.719 (dd, 0.78H, J = 13.3,3.8Hz), 3.094
(m, 1H), 3.355 (m, 0.22H), 3.508 (m, 0.78H), 6.120 (ddd, 0.7
8H, J = 5.8,3.1,0.5Hz), 6.223 (ddd, 0.22H, J = 5.8,3.1,0.5H
z), 6.424 (dd, 0.78H, J = 5.8,3.1Hz), 6.466 (dd, 0.22H, J =
5.8,3.0Hz) IR (film): ν4400, 4282, 4020, 3930,3444, 2998, 291
6, 2334, 2238,2106, 1995, 1661, 1437, 1408, 1336,
1313,1056, 955,932, 897, 872, 806, 772,729, 698, 6
69, 505cm ^-1

【００１６】実施例２ ビシクロ［２．２．１］ヘプタ
−５−エン−２−オンの製造： ８５％KOH 50.7g(0.769mol) を水１５mlに加熱溶解し
て、これに３０mlのＤＭＳＯに溶かした実施例１で得ら
れた２−クロロ−２−シアノ−ビシクロ［２．２．１］
ヘプタ−５−エンを37.7g(0.245mol) を加え、４０時間
室温で激しく攪拌した。攪拌後、水２３０mlを加え、２
００mlのエーテルで３回抽出し、水２００mlで２回及び
飽和食塩水２００mlで１回有機層を洗浄し、硫酸マグネ
シウムで乾燥した。濾過・除媒後アスピレーター減圧下
（〜２０mmHg）蒸留精製して、目的物を得た。 形状：無色油状物 21.9g(0.203mol, 収率８３％) 沸点：５９〜６０℃／２０mmHg¹ H-NMR(400MHz,CDCl₃ ):δ 1.854(dd,1H,J=16.5,4.3Hz), 1.961(ddd,1H,J=16.5,3.
3,0.3Hz),1.987(m,1H), 2.201(m,1H), 3.011(m,1H), 3.
192(m,1H),6.111(m,1H), 6.569(dd,1H,J=5.5,2.8Hz) IR(film)：ν4392, 4228, 3900, 3854,3782, 3630, 347
4, 3136, 3070,2978, 2940, 2884, 2866, 2818, 2356,
2196,2052, 2018,1889, 1850, 1744, 1642,1570, 1535,
1458, 1419, 1325,1284, 1263, 1226, 1195, 1162, 11
41, 1125,1083, 988,936, 913, 895, 855, 822,768, 73
7, 708, 613, 584, 499,435, 424cm^-1 MS(m/e) ：108(M⁺,49), 66(100)Example 2 Preparation of bicyclo [2.2.1] hepta-5-en-2-one: 50.7 g (0.769 mol) of 85% KOH was dissolved in 15 ml of water while heating, and the solution was dissolved in 30 ml of DMSO. 2-chloro-2-cyano-bicyclo [2.2.1] obtained in Example 1 dissolved
37.7 g (0.245 mol) of hepta-5-ene was added, followed by vigorous stirring at room temperature for 40 hours. After stirring, add 230 ml of water and add
The mixture was extracted three times with 00 ml of ether, and the organic layer was washed twice with 200 ml of water and once with 200 ml of saturated saline, and dried over magnesium sulfate. After filtration and removal of the solvent, purification was carried out by distillation under reduced pressure of an aspirator (up to 20 mmHg) to obtain the desired product. Shape: colorless oil 21.9 g (0.203 mol, yield 83%) Boiling point: 59-60 ° C./20 mmHg ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.854 (dd, 1H, J = 16.5, 4.3 Hz), 1.961 (ddd, 1H, J = 16.5,3.
3,0.3Hz), 1.987 (m, 1H), 2.201 (m, 1H), 3.011 (m, 1H), 3.
192 (m, 1H), 6.111 (m, 1H), 6.569 (dd, 1H, J = 5.5,2.8Hz) IR (film): ν4392,4228,3900,3854,3782,3630,347
4, 3136, 3070,2978, 2940, 2884, 2866, 2818, 2356,
2196,2052, 2018,1889, 1850, 1744, 1642,1570, 1535,
1458, 1419, 1325,1284, 1263, 1226, 1195, 1162, 11
41, 1125,1083, 988,936, 913, 895, 855, 822,768, 73
7, 708, 613, 584, 499, 435, 424 cm ^-1 MS (m / e): 108 (M ⁺ , 49), 66 (100)

【００１７】実施例３ イソブチル（４−ヒドロキシ−
２−シクロペンテニル）アセテートの製造： 実施例２で得られたビシクロ［２．２．１］ヘプタ−５
−エン−２−オン21.6g(0.200mol) を８０mlのエーテル
に溶かし、攪拌しながら９３％NaOH水溶液を13.1g(0.30
4mol) を加えた。アルゴン気流下この二層系の反応液を
１０℃に冷やし、３０％H₂O₂ 24ml(0.235mol)を９５分
間で滴下した。更に室温で１５分間攪拌し、ヨウ化カリ
−澱粉紙で過剰の過酸化水素水の存在しないことを確認
した後に二層を分離し、水層を８０mlのエーテルで２回
洗浄後、濃縮した。残渣を６００mlのヘキサメチルリン
酸トリアミド（ＨＭＰＡ）に溶かし、これにsecBuI ９
２ml(0.799mol)を加え、室温で８８時間攪拌した。これ
を飽和炭酸水素ナトリウム溶液で中和し、酢酸エチル１
ｌ、水1.2lを加えて二層を分離した。５００mlの酢酸エ
チルで５回抽出し、５００mlの水で１回、飽和食塩水で
１回有機層を洗浄し、硫酸マグネシウムで乾燥、濾過及
び除媒して、シリカゲル２２kg及びヘキサン：酢酸エチ
ル＝2.28：１のカラムクロマトグラフィーで精製して目
的のイソブチル（４−ヒドロキシ−２−シクロペンテニ
ル）アセテート及び２−オキサビシクロ［３．３．０］
オクタ−７−エン−３−オンの混合物を26.0g 得た。こ
の混合物同士を分離するのは不可能であり、この混合物
はそのまま次の合成工程に使用した。尚、計算上、イソ
ブチル（４−ヒドロキシ−２−シクロペンテニル）アセ
テートの収率は５９％、２−オキサビシクロ［３．３．
０］オクタ−７−エン−３−オンの収率は１１％である
ことがわかった。 イソブチル（４−ヒドロキシ−２−シクロペンテニル）
アセテート：¹ H-NMR(90MHz,CDCl₃ ) δ： 0.89(t,3H,J=7.4Hz), 1.20(d,3H,J=6.4Hz), 1.25-1.78
(m,2H),2.04(bs,1H), 2.30-2.75(m,3H), 2.98(m,1H),
4.83(m,1H),4.85(m,1H), 5.86(s,2H) 混合物IR(film)：ν3856*, 3488, 3060*, 2974, 2938*,
2882, 2334,1775*, 1727*, 1618*, 1450*, 1419*, 136
3*, 1340*,1311*, 1270*, 1172*, 1127, 1114*, 1096,
1069,1023*, 1009*, 957*, 917*, 861*, 791*, 764, 73
7,712*, 545, 511*, 453*cm^-1 ２−オキサビシクロ［３．３．０］オクタ−７−エン−
３−オン：IR(film)：ν上記の＊に加えて、3510, 286
0, 2078, 1717, 1290cm^-1 EXAMPLE 3 Isobutyl (4-hydroxy-
Preparation of 2-cyclopentenyl) acetate: Bicyclo [2.2.1] hepta-5 obtained in Example 2.
Dissolve 21.6 g (0.200 mol) of -en-2-one in 80 ml of ether, and add 13.1 g (0.30
4 mol) was added. This two-layer reaction solution was cooled to 10 ° C. in an argon stream, and 24 ml (0.235 mol) of 30% H ₂ O _{2 was} added dropwise over 95 minutes. The mixture was further stirred at room temperature for 15 minutes, and after confirming that no excess hydrogen peroxide solution was present with potassium iodide-starch paper, the two layers were separated, and the aqueous layer was washed twice with 80 ml of ether and concentrated. The residue was dissolved in 600 ml of hexamethylphosphoric triamide (HMPA).
2 ml (0.799 mol) was added, and the mixture was stirred at room temperature for 88 hours. This was neutralized with a saturated sodium hydrogen carbonate solution, and ethyl acetate 1 was added.
and 1.2 liters of water were added to separate two layers. Extract 5 times with 500 ml of ethyl acetate, wash the organic layer once with 500 ml of water and once with saturated saline, dry over magnesium sulfate, filter and remove the solvent. 22 kg of silica gel and hexane: ethyl acetate = 2.28 : Purified by column chromatography, and isobutyl (4-hydroxy-2-cyclopentenyl) acetate and 2-oxabicyclo [3.3.0] were obtained.
26.0 g of a mixture of oct-7-en-3-one was obtained. It was not possible to separate the mixtures, and this mixture was used as such in the next synthesis step. From a calculation, the yield of isobutyl (4-hydroxy-2-cyclopentenyl) acetate was 59%, and 2-oxabicyclo [3.3.
[0] Oct-7-en-3-one yield was found to be 11%. Isobutyl (4-hydroxy-2-cyclopentenyl)
Acetate: ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 0.89 (t, 3H, J = 7.4 Hz), 1.20 (d, 3H, J = 6.4 Hz), 1.25-1.78
(m, 2H), 2.04 (bs, 1H), 2.30-2.75 (m, 3H), 2.98 (m, 1H),
4.83 (m, 1H), 4.85 (m, 1H), 5.86 (s, 2H) Mixture IR (film): ν3856 *, 3488, 3060 *, 2974, 2938 *,
2882, 2334,1775 *, 1727 *, 1618 *, 1450 *, 1419 *, 136
3 *, 1340 *, 1311 *, 1270 *, 1172 *, 1127, 1114 *, 1096,
1069,1023 *, 1009 *, 957 *, 917 *, 861 *, 791 *, 764, 73
7,712 *, 545, 511 *, 453 * cm ^-1 2-oxabicyclo [3.3.0] oct-7-ene-
3-one: IR (film): ν In addition to the above *, 3510, 286
0, 2078, 1717, 1290cm ^-1

【００１８】実施例４ イソブチル（４−オキソ−２−
シクロペンテニル）アセテートの製造： アルゴン雰囲気下でオキザリルクロリド23.0ml(0.264mo
l)を無水の塩化メチレン６３０mlに溶かし、−７８℃に
冷却した。これに無水の塩化メチレン２００mlに溶解し
た実施例２で得られた混合物26.0g を１８分間かけて滴
下後、５０分間攪拌した。攪拌後、トリエチルアミン１
２８ml(0.918mol)を２５分間かけて滴下した。滴下後２
７分間攪拌した後に水５００mlを加えた。水添後、室温
に戻し、水層と有機層の二層に分離し、水層を２００ml
の塩化メチレンで３回抽出し、有機層と合わせて２００
mlの飽和食塩水で洗って硫酸マグネシウムで乾燥、濾過
及び除媒後、シリカゲル１kg及びヘキサン：酢酸エチル
＝3.47：１のカラムクロマトグラフィーで精製して、黄
色油状のイソブチル（４−オキソ−２−シクロペンテニ
ル）アセテートを20.9g(0.107mol) と２−オキサビシク
ロ［３．３．０］オクタ−７−エン−３−オン2.78g(0.
0223mol)が得られた。計算上イソブチル（４−オキソ−
２−シクロペンテニル）アセテートの収率は９１％であ
った。¹ H-NMR(200MHz,CDCl₃ ):δ 0.900(t,3H,J=7.5Hz), 1.217(d,3H,J=6.3Hz), 1.580(m,
2H),2.085(dd,1H,J=19,2.5Hz), 2.454(dd,1H,J=16,8.0H
z),2.540(dd,1H,J=16,7.0Hz), 2.651(dd,1H,J=19,6.8H
z),3.380(dddddd,1H,J=8.0,7.0,6.8,2.5,2.3,2.0Hz),4.
888(h,1H,J=6.3Hz), 6.208(dd,1H,J=5.5,2.0Hz),7.663
(dd,1H,J=5.5,2.3Hz) IR(film)：ν4348, 3526, 3060, 2976,2940, 2884, 236
2, 1717, 1591,1458, 1410, 1379, 1350, 1317, 1272,
1232,1185, 1152,1127, 1114, 1096, 1069,1044, 1029,
996, 969, 946, 884,861, 835, 787, 638, 574, 478,
420cm^-1 Example 4 Isobutyl (4-oxo-2-
Preparation of cyclopentenyl) acetate: 23.0 ml of oxalyl chloride (0.264 mol
l) was dissolved in 630 ml of anhydrous methylene chloride and cooled to -78 ° C. 26.0 g of the mixture obtained in Example 2 dissolved in 200 ml of anhydrous methylene chloride was added dropwise thereto over 18 minutes, followed by stirring for 50 minutes. After stirring, triethylamine 1
28 ml (0.918 mol) were added dropwise over 25 minutes. After dripping 2
After stirring for 7 minutes, 500 ml of water was added. After hydrogenation, the temperature was returned to room temperature, and the aqueous layer and the organic layer were separated into two layers.
Extracted with methylene chloride three times, and combined with the organic layer for 200 times.
After washing with saturated sodium chloride solution, drying over magnesium sulfate, filtering and removing the solvent, the residue was purified by column chromatography with 1 kg of silica gel and hexane: ethyl acetate = 3.47: 1 to obtain isobutyl (4-oxo-2-yl) as a yellow oil. 20.9 g (0.107 mol) of cyclopentenyl) acetate and 2.78 g (0.2%) of 2-oxabicyclo [3.3.0] oct-7-en-3-one.
0223 mol) was obtained. Calculated as isobutyl (4-oxo-
The yield of 2-cyclopentenyl) acetate was 91%. ¹ H-NMR (200 MHz, CDCl ₃ ): δ 0.900 (t, 3H, J = 7.5 Hz), 1.217 (d, 3H, J = 6.3 Hz), 1.580 (m,
2H), 2.085 (dd, 1H, J = 19,2.5Hz), 2.454 (dd, 1H, J = 16,8.0H
z), 2.540 (dd, 1H, J = 16,7.0Hz), 2.651 (dd, 1H, J = 19,6.8H
z), 3.380 (dddddd, 1H, J = 8.0,7.0,6.8,2.5,2.3,2.0Hz), 4.
888 (h, 1H, J = 6.3Hz), 6.208 (dd, 1H, J = 5.5,2.0Hz), 7.663
(dd, 1H, J = 5.5,2.3Hz) IR (film): ν4348, 3526, 3060, 2976,2940, 2884, 236
2, 1717, 1591,1458, 1410, 1379, 1350, 1317, 1272,
1232,1185, 1152,1127, 1114, 1096, 1069,1044, 1029,
996, 969, 946, 884,861, 835, 787, 638, 574, 478,
420cm ^-1

【００１９】実施例５ イソブチル（３−ブロモ−４−
オキソ−２−シクロペンテニル）アセテートの製造： アルゴン気流下、実施例４で得られたイソブチル（４−
オキソ−２−シクロペンテニル）アセテートを6.85g(0.
0349mol)を１４０mlの無水の塩化メチレンに溶かし、−
１０℃に冷却した。冷却後、無水の塩化メチレン１４０
mlに溶解した臭素1.8ml(0.0354mol)を９０分間かけて滴
下し、１０分間攪拌した。更にトリエチルアミン9.8ml
(0.0703mol)を７０mlの無水の塩化メチレンに溶かした
溶液を３５分間かけて滴下し、１０分間攪拌した後に１
Ｎ塩酸７０mlを加えた。水層と有機層を分離して、有機
層を１Ｎ塩酸７０mlで１回、水７０mlで２回、更に飽和
食塩水７０mlで１回洗浄した。最後に硫酸マグネシウム
で乾燥、濾過及び除媒して、シリカゲル４００ｇ，ヘキ
サン：酢酸エチル＝４：１のカラムクロマトグラフィー
で精製して結果物を得た。 形状：赤褐色油状物 8.50g(0.0309mol, 収率８９％) その他： １：１ジアステレオマー混合物¹ H-NMR(400MHz,CDCl₃ ):δ0.900(t,1.5H,J=7.5Hz), 0.9
05(t,1.5H,J=7.5Hz),1.219(d,1.5H,J=6.3Hz), 1.221(d,
1.5H,J=6.3Hz),1.578(m,2H), 2.250(dd,1H,J=19,2.0H
z),2.515(dd,1H,J=16,8.0Hz), 2.569(dd,1H,J=16,7.0H
z),2.811(dd,0.5,J=19,6.5Hz), 2.814(dd,0.5H,J=19,6.
5Hz),3.358(ddddd,1H,J=8.0,7.0,6.5,2.7,2.0Hz),4.883
(h,1H,J=6.3Hz), 7.760(d,1H,J=2.7Hz), IR(film)：ν3436, 3068, 2976, 2940,2882, 1725, 159
3, 1458, 1408,1379, 1321, 1270, 1187, 1127, 1114,
1096,1029, 990,969, 926, 878, 833, 725,656, 588, 5
28, 418cm^-1 Example 5 Isobutyl (3-bromo-4-
Preparation of oxo-2-cyclopentenyl) acetate: The isobutyl (4-
6.85 g of oxo-2-cyclopentenyl) acetate (0.
0349 mol) in 140 ml of anhydrous methylene chloride,
Cooled to 10 ° C. After cooling, anhydrous methylene chloride 140
1.8 ml (0.0354 mol) of bromine dissolved in ml was dropped over 90 minutes and stirred for 10 minutes. 9.8 ml of triethylamine
(0.0703 mol) in 70 ml of anhydrous methylene chloride was added dropwise over 35 minutes.
70 ml of N hydrochloric acid were added. The aqueous layer and the organic layer were separated, and the organic layer was washed once with 70 ml of 1N hydrochloric acid, twice with 70 ml of water, and once with 70 ml of saturated saline. Finally, it was dried over magnesium sulfate, filtered, and solvent-removed, and purified by column chromatography using 400 g of silica gel and hexane: ethyl acetate = 4: 1 to obtain a result. Shape: reddish-brown oil 8.50 g (0.0309 mol, yield 89%) Other: 1: 1 diastereomeric mixture ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.900 (t, 1.5 H, J = 7.5 Hz) , 0.9
05 (t, 1.5H, J = 7.5Hz), 1.219 (d, 1.5H, J = 6.3Hz), 1.221 (d,
1.5H, J = 6.3Hz), 1.578 (m, 2H), 2.250 (dd, 1H, J = 19,2.0H
z), 2.515 (dd, 1H, J = 16,8.0Hz), 2.569 (dd, 1H, J = 16,7.0H)
z), 2.811 (dd, 0.5, J = 19,6.5Hz), 2.814 (dd, 0.5H, J = 19,6.
5Hz), 3.358 (ddddd, 1H, J = 8.0,7.0,6.5,2.7,2.0Hz), 4.883
(h, 1H, J = 6.3Hz), 7.760 (d, 1H, J = 2.7Hz), IR (film): ν3436, 3068, 2976, 2940,2882, 1725, 159
3, 1458, 1408,1379, 1321, 1270, 1187, 1127, 1114,
1096,1029, 990,969, 926, 878, 833, 725,656, 588, 5
28, 418cm ^-1

【００２０】実施例６ イソブチル（３−ブロモ−４−
ヒドロキシ−４−（２−プロピニル）−２−シクロペン
テニル）アセテートの製造： アルゴン気流下３口フラスコにすりつぶしたマグネシウ
ム1.79g(0.0737mol)と塩化第二水銀0.0641g(0.236mmol)
を入れ、湿気を完全に除いた。これに無水のエーテル３
２０mlを加えてプロパルギルブロミド5.00ml(0.0645mo
l) を１分間で滴下した。そして反応を促進するためド
ライアーで数分間加熱し、その後白濁発熱が終わるまで
４０分間攪拌してプロパルギルグリニャール試薬を調製
した。別のフラスコにアルゴン気流下、実施例５で得た
イソブチル（３−ブロモ−４−オキソ−２−シクロペン
テニル）アセテートを11.9g(0.0433mol)を無水のエーテ
ル４３０mlに溶解したものを、−８０℃に冷却した。か
かる溶液に先に調製したプロパルギルグリニャール試薬
を激しく攪拌しながら、７０分間かけて滴下した。更に
２分間攪拌後、水を３００ml、続いて飽和塩化アンモニ
ウム水３００mlを加えて室温に戻した。水層を１５０ml
のエーテルで３回抽出して有機層と合わせて飽和食塩水
２００mlで洗浄した。そして硫酸マグネシウムで乾燥し
て、濾過及び除媒後、未精製の赤褐色油状物を得た。か
かる赤褐色油状物は、¹H-NMR 分析によると、大部分
が、イソブチル（３−ブロモ−４−ヒドロキシ−４−
（２−プロピニル）−２−シクロペンテニル）アセテー
トであるが、若干未反応物であるイソブチル（３−ブロ
モ−４−オキソ−２−シクロペンテニル）アセテートが
混在していることが判明した。かかるイソブチル（３−
ブロモ−４−オキソ−２−シクロペンテニル）アセテー
トを除くためにこれを還元反応に付した。すなわち、得
られた赤褐色油状物をメタノール４０mlに溶解し、０℃
で攪拌下水素化ホウ素ナトリウム1.68g(0.0444mol)を少
しずつ加えた。発泡終了後、飽和塩化アンモウニム水８
０mlを加え、続いて水４０mlを加えた。水層を４０mlの
エーテルで３回抽出し、有機層と合わせて３０mlの飽和
食塩水で洗浄し、硫酸マグネシウムで乾燥後、濾過及び
除媒して残渣を、シリカゲル２００ｇ，ヘキサン：酢酸
エチル＝3.2 ：１のカラムクロマトグラフィーで精製
し、イソブチル（３−ブロモ−４−ヒドロキシ−４−
（２−プロピニル）−２−シクロペンテニル）アセテー
ト及びイソブチル（３−ブロモ−４−オキソ−２−シク
ロペンテニル）アセテートの還元物を14.8g 得た。これ
を更に分取用の液体クロマトグラフィーにより精製して
目的物を得た。なおかかるグリニャール反応によって生
じた化合物の３級アルコール部分についての立体化学は
¹H-NMR より１種類であることが判明した。 形状：淡黄色油状物 8.39g(0.0266mol,収率６２％)¹ H-NMR(400MHz,CDCl₃ ):δ 0.898(t,3H,J=7.5Hz), 1.208(d,1.5H,J=6.3Hz),1.209
(d,1.5H,J=6.3Hz), 1.566(m,2H), 1.828(dd,1H,J=14,5.
0Hz),2.011(t,1H,J=2.6Hz), 2.467(d,2H,J=6.5Hz),2.52
6(dd,1H,J=16.5,2.8Hz), 2.628(dd,1H,J=16.5,2.8Hz),
2.750(dd,0.5H,J=14,8.5Hz), 2.751(dd,0.5H,J=14,8.5H
z),2.858(s,0.5H), 2.865(s,0.5H), 3.016(m,1H),4.860
(h,1H,J=6.3Hz), 6.021(d,1H,J=2.5Hz), IR(film)：ν3922, 3454, 3300, 2976,2940, 2882, 212
4, 1725, 1624,1458, 1419, 1379, 1274, 1176, 1129,
1114,1094, 1029,994, 969, 955, 920, 866, 706, 640,
503, 408cm^-1 Example 6 Isobutyl (3-bromo-4-
Preparation of hydroxy-4- (2-propynyl) -2-cyclopentenyl) acetate: 1.79 g (0.0737 mol) of magnesium and 0.0641 g (0.236 mmol) of mercuric chloride ground in a three-neck flask under a stream of argon.
To remove all moisture. Add anhydrous ether 3
After adding 20 ml, propargyl bromide 5.00 ml (0.0645mo
l) was added dropwise over 1 minute. Then, the mixture was heated with a dryer for several minutes in order to promote the reaction, and then stirred for 40 minutes until the generation of cloudiness was completed, thereby preparing a propargyl Grignard reagent. In a separate flask under an argon stream, 11.9 g (0.0433 mol) of isobutyl (3-bromo-4-oxo-2-cyclopentenyl) acetate obtained in Example 5 was dissolved in 430 ml of anhydrous ether. Cooled to ° C. The propargyl Grignard reagent prepared above was added dropwise to the solution over 70 minutes with vigorous stirring. After stirring for another 2 minutes, 300 ml of water and subsequently 300 ml of saturated aqueous ammonium chloride were added, and the mixture was returned to room temperature. 150ml water layer
This was extracted three times with ether and combined with the organic layer and washed with 200 ml of saturated saline. After drying over magnesium sulfate, filtration and removal of the solvent gave an unpurified red-brown oil. According to ¹ H-NMR analysis, such reddish brown oils are mostly isobutyl (3-bromo-4-hydroxy-4-).
It was found that (2-propynyl) -2-cyclopentenyl) acetate was mixed with isobutyl (3-bromo-4-oxo-2-cyclopentenyl) acetate which was a little unreacted. Such isobutyl (3-
This was subjected to a reduction reaction in order to remove bromo-4-oxo-2-cyclopentenyl) acetate. That is, the obtained reddish brown oil was dissolved in 40 ml of methanol,
Under stirring, 1.68 g (0.0444 mol) of sodium borohydride was added little by little. After foaming, saturated ammonium chloride water 8
0 ml was added, followed by 40 ml of water. The aqueous layer was extracted three times with 40 ml of ether, combined with the organic layer, washed with 30 ml of saturated saline, dried over magnesium sulfate, filtered and the solvent was removed, and the residue was treated with silica gel (200 g, hexane: ethyl acetate = 3.2). : 1 column chromatography, isobutyl (3-bromo-4-hydroxy-4-
14.8 g of a reduced product of (2-propynyl) -2-cyclopentenyl) acetate and isobutyl (3-bromo-4-oxo-2-cyclopentenyl) acetate were obtained. This was further purified by preparative liquid chromatography to obtain the desired product. The stereochemistry of the tertiary alcohol moiety of the compound produced by the Grignard reaction is
¹ H-NMR revealed that it was of one type. Form: pale yellow oil 8.39 g (0.0266 mol, yield 62%) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.898 (t, 3 H, J = 7.5 Hz), 1.208 (d, 1.5 H, J = 6.3Hz), 1.209
(d, 1.5H, J = 6.3Hz), 1.566 (m, 2H), 1.828 (dd, 1H, J = 14,5.
0Hz), 2.011 (t, 1H, J = 2.6Hz), 2.467 (d, 2H, J = 6.5Hz), 2.52
6 (dd, 1H, J = 16.5,2.8Hz), 2.628 (dd, 1H, J = 16.5,2.8Hz),
2.750 (dd, 0.5H, J = 14,8.5Hz), 2.751 (dd, 0.5H, J = 14,8.5H
z), 2.858 (s, 0.5H), 2.865 (s, 0.5H), 3.016 (m, 1H), 4.860
(h, 1H, J = 6.3Hz), 6.021 (d, 1H, J = 2.5Hz), IR (film): ν3922, 3454, 3300, 2976,2940, 2882, 212
4, 1725, 1624,1458, 1419, 1379, 1274, 1176, 1129,
1114,1094, 1029,994, 969, 955, 920, 866, 706, 640,
503, 408cm ^-1

【００２１】実施例７ ２−ブロモ−４−（２−ヒドロ
キシエチル）−１−（２−プロピニル）−２−シクロペ
ンテン−１−オールの製造： アルゴン雰囲気下実施例６で得たイソブチル（３−ブロ
モ−４−ヒドロキシ−４−（２−プロピニル）−２−シ
クロペンテニル）アセテート11.9g(0.0377mol)を水素化
カルシウムで乾燥したジクロロメタン１５０mlに溶か
し、−７８℃に冷却した。これに水素化ジイソブチルア
ルミニウムの0.94Ｍヘキサン溶液１００ml(0.094mol)を
３５分間で滴下し、滴下終了後冷浴中で自然昇温させ
た。19.5時間後イソブチル（３−ブロモ−４−ヒドロキ
シ−４−（２−プロピニル）−２−シクロペンテニルア
セテートがＴＬＣで少量確認できたので再び−７８℃に
冷却し、水素化ジイソブチルアルミニウムの0.94Ｍヘキ
サン溶液を１０ml(9.4mmol) ５分間で滴下した。自然昇
温後（滴下終了後７時間経過）、飽和塩化アンモニウム
水５０mlを加え、更に２Ｎ塩酸を加えて生じる沈殿を溶
かした。水層を５０mlのジクロロメタンで８回抽出し、
硫酸マグネシウムで乾燥後、濾過及び除媒し、再結晶さ
せることにより目的物を得た。 形状：無色針状晶 4.72g(0.0193mol,収率５１％) 融点：１１１〜１１２℃¹ H-NMR(400MHz,CDCl₃ ):δ 1.673(dddd,1H,J=14,7.0,6.0,5.5Hz), 1.684(bs,1H),1.
801(dddd,1H,J=14,7.8,6.0,5.8Hz), 1.828(dd,1H,J=13.
5,5.0Hz),2.017(t,1H,J=2.7Hz), 2.494(dd,1H,J=16.5,
2.7Hz),2.638(dd,1H,J=16.5,2.7Hz), 2.683(dd,1H,J=1
3.5,8.2Hz),2.815(ddddd,1H,J=8.2,7.0,5.8,5.0,2.5H
z), 2.908(bs,1H),3.738(ddd,1H,J=11,7.8,5.5Hz), 3.7
49(dt,1H,J=11,6.0Hz),6.053(d,1H,J=2.5Hz) IR(film)：ν3920, 3270, 2964, 2934,2864, 2120, 171
9, 1618, 1441,1342, 1309, 1265, 1228, 1183, 1137,
1120,1098, 1060,1042, 1017, 990, 961, 924, 903, 87
6, 851, 714, 646, 516,505, 464, 408cm^-1 Example 7 Preparation of 2-bromo-4- (2-hydroxyethyl) -1- (2-propynyl) -2-cyclopenten-1-ol The isobutyl (3- 11.9 g (0.0377 mol) of bromo-4-hydroxy-4- (2-propynyl) -2-cyclopentenyl) acetate were dissolved in 150 ml of dichloromethane dried over calcium hydride and cooled to -78 ° C. 100 ml (0.094 mol) of a 0.94 M solution of diisobutylaluminum hydride in hexane was added dropwise thereto over 35 minutes, and after the completion of the addition, the temperature was raised naturally in a cooling bath. After 19.5 hours, a small amount of isobutyl (3-bromo-4-hydroxy-4- (2-propynyl) -2-cyclopentenyl acetate was confirmed by TLC. The mixture was cooled again to -78 ° C, and diisobutylaluminum hydride in 0.94M hexane was used. The solution was added dropwise over 10 ml (9.4 mmol) over 5 minutes, and after natural temperature rise (7 hours after completion of the dropwise addition), 50 ml of saturated aqueous ammonium chloride solution was added, and 2N hydrochloric acid was further added to dissolve the resulting precipitate. 8 times with dichloromethane
After drying over magnesium sulfate, filtration, removal of the solvent, and recrystallization gave the desired product. Shape: colorless needles 4.72 g (0.0193 mol, yield 51%) Melting point: 111-112 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.673 (dddd, 1H, J = 14, 7.0, 6.0, 5.5) Hz), 1.684 (bs, 1H), 1.
801 (dddd, 1H, J = 14,7.8,6.0,5.8Hz), 1.828 (dd, 1H, J = 13.
5,5.0Hz), 2.017 (t, 1H, J = 2.7Hz), 2.494 (dd, 1H, J = 16.5,
2.7Hz), 2.638 (dd, 1H, J = 16.5,2.7Hz), 2.683 (dd, 1H, J = 1
3.5,8.2Hz), 2.815 (ddddd, 1H, J = 8.2,7.0,5.8,5.0,2.5H
z), 2.908 (bs, 1H), 3.738 (ddd, 1H, J = 11,7.8,5.5Hz), 3.7
49 (dt, 1H, J = 11,6.0Hz), 6.053 (d, 1H, J = 2.5Hz) IR (film): ν3920,3270,2964,2934,2864,2120,171
9, 1618, 1441,1342, 1309, 1265, 1228, 1183, 1137,
1120,1098, 1060,1042, 1017, 990, 961, 924, 903, 87
6, 851, 714, 646, 516,505, 464, 408cm ^-1

【００２２】実施例８ ２−ブロモ−４−（２−トリエ
チルシリルオキシエチル）−１−（２−プロピニル）−
２−シクロペンテン−１−オールの製造： アルゴン気流下実施例７で得た２−ブロモ−４−（２−
ヒドロキシエチル）−１−（２−プロピニル）−２−シ
クロペンテン−１−オール4.72g(0.0193mol)を２０mlの
ピリジンに溶かし、０℃に冷却した。これにクロロトリ
エチルシラン3.55ml(0.0212mol) をゆっくり加えた。２
５分間攪拌後、室温に昇温し、更に４０分間攪拌した。
２−ブロモ−４−（２−ヒドロキシエチル）−１−（２
−プロピニル）−２−シクロペンテン−１−オールが少
しＴＬＣ上確認できたので０℃に再び冷やしクロロトリ
エチルシランを0.32ml(1.91mmol)加え、１０分間攪拌後
室温に昇温した。１５分間攪拌を続けた後に飽和炭酸水
素ナトリウム水を１２０ml加え、反応液をジクロロメタ
ン４０mlで３回抽出した。１００mlの飽和食塩水で洗浄
後、硫酸マグネシウムで乾燥、濾過、除媒して、更にベ
ンゼン共沸によってピリジンを除いた。残渣をカラムク
ロマトグラフィーにより（シリカゲル２５０ｇ，ヘキサ
ン：酢酸エチル＝７：１）目的物を得た。 形状：淡黄色油状物 7.08g(0.0197mol)¹ H-NMR(90MHz,CDCl₃ ): δ 0.64(m,6H), 0.96(m,9H), 1.4-1.9(m,4H), 2.00(t,1H,J
=2.7Hz),2.58(m,2H),2.76(m,2H), 3.69(t,2H,J=9.3Hz),
6.03(d,1H,J=2.3Hz) IR(film)：ν3416, 3314, 2958, 2914,2878, 2124, 162
2, 1460, 1417,1388, 1241, 1096, 1011, 961, 905, 86
2, 745, 638cm^-1 Example 8 2-Bromo-4- (2-triethylsilyloxyethyl) -1- (2-propynyl)-
Production of 2-cyclopenten-1-ol: 2-bromo-4- (2-
4.72 g (0.0193 mol) of (hydroxyethyl) -1- (2-propynyl) -2-cyclopenten-1-ol was dissolved in 20 ml of pyridine and cooled to 0 ° C. To this, 3.55 ml (0.0212 mol) of chlorotriethylsilane was slowly added. 2
After stirring for 5 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 40 minutes.
2-bromo-4- (2-hydroxyethyl) -1- (2
-Propinyl) -2-cyclopenten-1-ol was slightly confirmed by TLC. The mixture was cooled again to 0 ° C, 0.32 ml (1.91 mmol) of chlorotriethylsilane was added, and the mixture was stirred for 10 minutes and then heated to room temperature. After stirring was continued for 15 minutes, 120 ml of saturated aqueous sodium hydrogen carbonate was added, and the reaction solution was extracted three times with 40 ml of dichloromethane. After washing with 100 ml of a saturated saline solution, drying with magnesium sulfate, filtration, and solvent removal, pyridine was removed by azeotropic distillation with benzene. The residue was subjected to column chromatography (250 g of silica gel, hexane: ethyl acetate = 7: 1) to obtain the desired product. Form: pale yellow oil 7.08 g (0.0197 mol) ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.64 (m, 6H), 0.96 (m, 9H), 1.4-1.9 (m, 4H), 2.00 (t , 1H, J
= 2.7Hz), 2.58 (m, 2H), 2.76 (m, 2H), 3.69 (t, 2H, J = 9.3Hz),
6.03 (d, 1H, J = 2.3Hz) IR (film): ν3416, 3314, 2958, 2914,2878, 2124, 162
2, 1460, 1417,1388, 1241, 1096, 1011, 961, 905, 86
2, 745, 638cm ^-1

【００２３】実施例９ １−（１−ヒドロキシ−２−ブ
ロモ−４−（２−トリエチルシリルオキシエチル）−２
−シクロペンテニル）−６，６−ジメチル−２，７−ジ
イニル−４−オクタノールの製造： マグネシウムを細くすりつぶしたもの1.47g(0.0603mol)
を３口のフラスコに入れ、完全に湿気を除いた。アルゴ
ン雰囲気下のこのものに無水のＴＨＦ４０mlを加え、室
温で臭化エチル4.5ml(0.0603mol)を１０分間で滴下し
た。１５分間攪拌した後実施例８で得られた２−ブロモ
−４−（２−トリエチルシリルオキシエチル）−１−
（２−プロピニル）−２−シクロペンテン−１−オール
7.08g(0.0197mol)を４０mlの無水ＴＨＦに溶かしたもの
を４５分間で滴下した。反応液を５０℃に加熱し、７０
分間攪拌し、室温に戻してから３，３−ジメチル−４−
ペンチナール4.38g(0.0398mol)を２０mlの無水のＴＨＦ
に溶かしたものを２０分間で滴下した。３５分間攪拌し
た後、水５０mlを加え、エーテルで抽出、飽和食塩水で
洗浄、硫酸マグネシウムで乾燥、濾過、除媒後カラムク
ロマトグラフィー（シリカゲル４５０ｇ，ヘキサン：酢
酸エチル＝５：１）で精製し目的物を得た。 形状：淡黄色油状物 5.06g(0.0108mol,収率５５％) その他： 1:1 のジアステレオマー混合物 1.54g(4.29mmol) の原料を回収¹ H-NMR(400MHz,CDCl₃ ):δ0.607(q,6H,J=8.0Hz), 0.960
(t,9H,J=8.0Hz),1.289(s,3H),1.305(s,3H), 1.609(ddt,
1H,J=14,7.0,5.5Hz),1.738(ddt,1H,J=14,6.0,6.5Hz),
1.769(dd,1H,J=13.5,5.0Hz),1.798(dd,0.5H,J=14,4.5H
z), 1.802(dd,0.5H,J=14,4.5Hz),1.911(dd,0.5H,J=14,
8.0Hz), 1.913(dd,0.5H,J=14,8.0Hz),2.210(s,0.5H),
2.211(s,0.5H), 2.492(dd,1H,J=16.5,2.0Hz),2.492(bs,
1H), 2.623(dd,1H,J=13.5,8.0Hz),2.643(dd,1H,J=16.5,
2.0Hz),2.764(ddddd,1H,J=8.0,7.0,6.0,5.0,2.3Hz),2.9
13(bs,1H),3.689(m,2H), 4.692(bm,1H), 6.011(d,0.5H,
J=2.3Hz),6.013(d,0.5H,J=2.3Hz) IR(film)：ν3310, 2960, 2880, 1620,1458, 1419, 138
6, 1241, 1207,1062,1006, 924, 841, 741, 636cm^-1 Example 9 1- (1-hydroxy-2-bromo-4- (2-triethylsilyloxyethyl) -2
Preparation of -cyclopentenyl) -6,6-dimethyl-2,7-diynyl-4-octanol: Magnesium 1.47 g (0.0603 mol)
Was placed in a three-necked flask to completely remove moisture. Under an argon atmosphere, anhydrous THF (40 ml) was added thereto, and ethyl bromide (4.5 ml, 0.0603 mol) was added dropwise at room temperature over 10 minutes. After stirring for 15 minutes, the 2-bromo-4- (2-triethylsilyloxyethyl) -1- obtained in Example 8 was obtained.
(2-propynyl) -2-cyclopenten-1-ol
A solution of 7.08 g (0.0197 mol) in 40 ml of anhydrous THF was added dropwise over 45 minutes. Heat the reaction to 50 ° C.
After stirring for 3 minutes and returning to room temperature, 3,3-dimethyl-4-
4.38 g (0.0398 mol) of pentinal are added to 20 ml of anhydrous THF.
Was dissolved and dropped in 20 minutes. After stirring for 35 minutes, add 50 ml of water, extract with ether, wash with saturated saline, dry over magnesium sulfate, filter, remove the solvent, and purify by column chromatography (450 g of silica gel, hexane: ethyl acetate = 5: 1). The desired product was obtained. Form: pale yellow oil 5.06 g (0.0108 mol, yield 55%) Others: 1.54 g (4.29 mmol) of a 1: 1 diastereomer mixture was recovered. ¹ H-NMR (400 MHz, CDCl ₃ ): δ0. 607 (q, 6H, J = 8.0Hz), 0.960
(t, 9H, J = 8.0Hz), 1.289 (s, 3H), 1.305 (s, 3H), 1.609 (ddt,
1H, J = 14,7.0,5.5Hz), 1.738 (ddt, 1H, J = 14,6.0,6.5Hz),
1.769 (dd, 1H, J = 13.5,5.0Hz), 1.798 (dd, 0.5H, J = 14,4.5H
z), 1.802 (dd, 0.5H, J = 14,4.5Hz), 1.911 (dd, 0.5H, J = 14,
8.0Hz), 1.913 (dd, 0.5H, J = 14,8.0Hz), 2.210 (s, 0.5H),
2.211 (s, 0.5H), 2.492 (dd, 1H, J = 16.5,2.0Hz), 2.492 (bs,
1H), 2.623 (dd, 1H, J = 13.5,8.0Hz), 2.643 (dd, 1H, J = 16.5,
2.0Hz), 2.764 (ddddd, 1H, J = 8.0,7.0,6.0,5.0,2.3Hz), 2.9
13 (bs, 1H), 3.689 (m, 2H), 4.692 (bm, 1H), 6.011 (d, 0.5H,
J = 2.3Hz), 6.013 (d, 0.5H, J = 2.3Hz) IR (film): ν3310,2960,2880,1620,1458,1419,138
6, 1241, 1207,1062,1006, 924, 841, 741, 636cm ^-1

【００２４】実施例１０ ２−ブロモ−１−（６，６−
ジメチル−４−トリエチルシリルオキシ−２，７−ジイ
ニル）−４−（２−トリエチルシリルオキシエチル）−
２−シクロペンテン−１−オールの製造： アルゴン雰囲気下実施例９で得られた１−（２−ヒドロ
キシ−２−ブロモ−４−（２−トリエチルシリルオキシ
エチル）−２−シクロペンテニル）−６，６−ジメチル
−２，７−ジイニル−４−オクタノール5.06g(0.0108mo
l)を１１mlのピリジンに溶かし、０℃に冷却した。この
溶液にクロロトリエチルシラン2.15ml(0.0128mol) を３
分間で滴下した。２７分間攪拌後、飽和炭酸水素ナトリ
ウム水６０mlを加え、２５mlのジクロロメタンで３回抽
出、３０mlの飽和食塩水で洗浄後、硫酸マグネシウムで
乾燥後、濾過、除媒し、更にベンゼンを加えて共沸によ
りピリジンを除いた。シリカゲル２００ｇ，ヘキサン：
酢酸エチル＝８：１のカラムクロマトグラフィーで精製
して目的物を得た。 形状：黄色油状物 5.97g(0.0102mol,収率９５％)¹ H-NMR(90MHz,CDCl₃ ): δ 0.66(m,12H), 0.97(m,18H), 1.27(s,6H), 1.4-1.98(m,6
H),2.13(s,1H), 2.57(m,2H), 2.72(m,2H), 3.68(t,2H,J
=6.1Hz),4.68(bt,1H), 6.00(d,1H,J=2.0Hz) IR(film)：ν3312, 2960, 2916, 2880,1620, 1460, 141
7, 1386, 1348,1241, 1160, 1096, 1009, 961, 893, 83
2, 745, 632, 418cm^-1 Example 10 2-bromo-1- (6,6-
Dimethyl-4-triethylsilyloxy-2,7-diynyl) -4- (2-triethylsilyloxyethyl)-
Production of 2-cyclopenten-1-ol: 1- (2-hydroxy-2-bromo-4- (2-triethylsilyloxyethyl) -2-cyclopentenyl) -6 obtained in Example 9 under an argon atmosphere. 5.06 g of 6-dimethyl-2,7-diynyl-4-octanol (0.0108mo
l) was dissolved in 11 ml of pyridine and cooled to 0 ° C. To this solution was added 2.15 ml (0.0128 mol) of chlorotriethylsilane.
In minutes. After stirring for 27 minutes, 60 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with 25 ml of dichloromethane, washed with 30 ml of a saturated saline solution, dried over magnesium sulfate, filtered, the solvent was removed, benzene was added, and azeotrope was added To remove pyridine. Silica gel 200 g, hexane:
Purification by column chromatography with ethyl acetate = 8: 1 gave the desired product. Form: yellow oil 5.97 g (0.0102 mol, yield 95%) ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.66 (m, 12 H), 0.97 (m, 18 H), 1.27 (s, 6 H), 1.4 -1.98 (m, 6
H), 2.13 (s, 1H), 2.57 (m, 2H), 2.72 (m, 2H), 3.68 (t, 2H, J
= 6.1Hz), 4.68 (bt, 1H), 6.00 (d, 1H, J = 2.0Hz) IR (film): ν3312,2960,2916,2880,1620,1460,141
7, 1386, 1348,1241, 1160, 1096, 1009, 961, 893, 83
2, 745, 632, 418cm ^-1

【００２５】実施例１１ ２−ブロモ−１−（６，６−
ジメチル−４−トリエチルシリルオキシ−８−トリノル
マルブチルスタニル−２，７−オクタジイニル）−４−
（２−トリエチルシリルオキシ）−２−シクロペンテン
−１−オールの製造： アルゴン気流下実施例１０で得られた２−ブロモ−１−
（６，６−ジメチル−４−トリエチルシリルオキシ−
２，７−ジイニル）−４−（２−トリエチルシリルオキ
シエチル）−２−シクロペンテン−１−オール5.01g(8.
58mmol) を無水ＴＨＦ８６mlに溶かし、−７８℃まで冷
却した。これにノルマルブチルリチウムの1.6 Ｍヘキサ
ン溶液を12.5ml(20.0mmol)７分間で滴下し、２２分間攪
拌した。ここに塩化ノルマルトリブチルスズ3.00ml(11.
1mmol)の１１ml無水ＴＨＦ溶液を２１分間で滴下した。
滴下後冷浴中で自然昇温させ、攪拌を続け、２−ブロモ
−１−（６，６−ジメチル−４−トリエチルシリルオキ
シ−２，７−ジイニル）−４−（２−トリエチルシリル
オキシエチル）−２−シクロペンテン−１−オールのス
ポットがＴＬＣ上確認できなくなってから（６０分後）
飽和炭酸水素ナトリウム水５０mlを加えた。水層を７０
mlのエーテルで３回抽出し、有機層と合わせて３０mlの
飽和食塩水で１回洗い、更にこの洗液をエーテルで再抽
出した有機層と合わせて硫酸マグネシウムで乾燥後、濾
過、除媒し、カラムクロマトグラフィー（シリカゲル４
００ｇ，ヘキサン：酢酸エチル＝１０：１）で精製して
目的物を得た。 形状：無色油状物 7.02g(8.045mmol,収率９４％)¹ H-NMR(90MHz,CDCl₃ ): δ 0.4-1.1(m,57H), 1.24(s,6H), 1.25-1.85(m,6H), 2.57
(m,2H),2.73(m,2H), 3.68(t,2H,J=6.2Hz), 4.75(m,1H),
6.00(d,1H,J=1.3Hz)Example 11 2-bromo-1- (6,6-
Dimethyl-4-triethylsilyloxy-8-trinormalbutylstannyl-2,7-octadiynyl) -4-
Production of (2-triethylsilyloxy) -2-cyclopenten-1-ol: 2-bromo-1- obtained in Example 10 under a stream of argon.
(6,6-dimethyl-4-triethylsilyloxy-
5.01 g of 2,7-diynyl) -4- (2-triethylsilyloxyethyl) -2-cyclopenten-1-ol (8.
(58 mmol) was dissolved in 86 ml of anhydrous THF and cooled to -78 ° C. 12.5 ml (20.0 mmol) of a 1.6 M hexane solution of normal butyllithium was added dropwise thereto over 7 minutes, followed by stirring for 22 minutes. Here 3.00 ml of normal tributyltin chloride (11.
(1 mmol) in 11 ml of anhydrous THF was added dropwise over 21 minutes.
After the dropwise addition, the temperature was raised naturally in a cooling bath, stirring was continued, and 2-bromo-1- (6,6-dimethyl-4-triethylsilyloxy-2,7-diynyl) -4- (2-triethylsilyloxyethyl ) After the spot of 2-cyclopenten-1-ol could not be confirmed on TLC (after 60 minutes)
50 ml of saturated aqueous sodium bicarbonate were added. 70 water layers
The mixture was extracted three times with ether (3 times), combined with the organic layer, washed once with 30 ml of saturated saline, and the washed solution was combined with the organic layer re-extracted with ether, dried over magnesium sulfate, filtered, and solvent-removed. , Column chromatography (silica gel 4)
00g, hexane: ethyl acetate = 10: 1) to obtain the desired product. Form: colorless oil 7.02 g (8.045 mmol, yield 94%) ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.4-1.1 (m, 57H), 1.24 (s, 6H), 1.25-1.85 (m, 6H), 2.57
(m, 2H), 2.73 (m, 2H), 3.68 (t, 2H, J = 6.2Hz), 4.75 (m, 1H),
6.00 (d, 1H, J = 1.3Hz)

【００２６】実施例１２ ７，７−ジメチル−１−ヒド
ロキシ−５−トリエチルシリルオキシ−１２−（２−ト
リエチルシリルオキシエチル）−ビシクロ［８．３．
０］トリデカ−１０−エン−３，８−ジインの製造： アルゴン雰囲気下実施例１１で得られた２−ブロモ−１
−（６，６−ジメチル−４−トリエチルシリルオキシ−
８−トリノルマルブチルスタニル−２，７−オクタジイ
ニル）−４−（２−トリエチルシリルオキシエチル）−
２−シクロペンテン−１−オール4.00g(4.58mmol) を２
００mlの無水のＴＨＦに溶かした。これにテトラキスト
リフェニルホスフィンパラジウム0.274g(0.235mmol) を
無水のＴＨＦ５mlに溶かして加え、５０℃に加熱して９
１時間攪拌した。テトラキストリフェニルホスフィンパ
ラジウム0.306g(0.265mmol) を無水のＴＨＦ６mlに溶か
して再び加え、２２時間攪拌した。反応溶液にヘキサン
１００mlを加え、１０％アンモニア水５０mlで３回洗浄
した。２−ブロモ−１−（６，６−ジメチル−４−トリ
エチルシリルオキシ−８−トリノルマルブチルスタニル
−２，７−オクタジイニル）−４−（２−トリエチルシ
リルオキシエチル）−２−シクロペンテン−１−オール
2.15g(2.46mmol) 、テトラキス−トリフェニルホスフィ
ンパラジウム0.154g(0.132mmol) 及び0.158g(0.136mmo
l) を用いて同時に同様の操作で得た有機層と合わせて
飽和食塩水５０mlで１回洗浄し、この洗液を５０mlのヘ
キサンで再抽出して有機層と合わせ、硫酸マグネシウム
で乾燥、濾過、除媒してカラムクロマトグラフィー（シ
リカゲル１６０ｇ，ヘキサン：酢酸エチル＝７：１）で
精製、更にシリカゲル１００ｇ，ヘキサン：酢酸エチル
＝１０：１のカラムクロマトグラフィーで精製し、環化
した目的物を得た。 形状：黄色油状物 1.01g(2.00mmol, 収率２８％)¹ H-NMR(90MHz,CDCl₃ ): δ 0.65(m,12H), 0.96(m,18H), 1.25(s,3H), 1.28(s,3H),
1.4-2.2(m,6H), 2.58(m,2H), 2.76(m,1H), 2.98(m,0.5
H),3.20(m,0.5H), 3.64(t,2H,J=6.4Hz), 4.50(m,1H),
5.83(m,1H)Example 12 7,7-Dimethyl-1-hydroxy-5-triethylsilyloxy-12- (2-triethylsilyloxyethyl) -bicyclo [8.3.
0] Production of Trideca-10-ene-3,8-diyne: 2-bromo-1 obtained in Example 11 under an argon atmosphere.
-(6,6-dimethyl-4-triethylsilyloxy-
8-trinormalbutylstannyl-2,7-octadiynyl) -4- (2-triethylsilyloxyethyl)-
4.00 g (4.58 mmol) of 2-cyclopenten-1-ol was added to 2
Dissolved in 00 ml of anhydrous THF. To this was added 0.274 g (0.235 mmol) of tetrakistriphenylphosphine palladium dissolved in 5 ml of anhydrous THF, and the mixture was heated to 50 ° C.
Stir for 1 hour. 0.306 g (0.265 mmol) of tetrakistriphenylphosphine palladium was dissolved in 6 ml of anhydrous THF, added again, and stirred for 22 hours. 100 ml of hexane was added to the reaction solution, and the mixture was washed three times with 50 ml of 10% aqueous ammonia. 2-bromo-1- (6,6-dimethyl-4-triethylsilyloxy-8-trinormalbutylstannyl-2,7-octadynyl) -4- (2-triethylsilyloxyethyl) -2-cyclopentene-1 -All
2.15 g (2.46 mmol), tetrakis-triphenylphosphine palladium 0.154 g (0.132 mmol) and 0.158 g (0.136 mmol)
Using l) together with the organic layer obtained by the same operation at the same time, washing once with 50 ml of a saturated saline solution, re-extracting this washing solution with 50 ml of hexane, combining with the organic layer, drying over magnesium sulfate, and filtering. The solvent was removed and the residue was purified by column chromatography (silica gel 160 g, hexane: ethyl acetate = 7: 1), and further purified by column chromatography of 100 g silica gel, hexane: ethyl acetate = 10: 1 to give the cyclized target product. Obtained. Form: yellow oil 1.01 g (2.00 mmol, yield 28%) ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.65 (m, 12 H), 0.96 (m, 18 H), 1.25 (s, 3 H), 1.28 (s, 3H),
1.4-2.2 (m, 6H), 2.58 (m, 2H), 2.76 (m, 1H), 2.98 (m, 0.5
H), 3.20 (m, 0.5H), 3.64 (t, 2H, J = 6.4Hz), 4.50 (m, 1H),
5.83 (m, 1H)

【００２７】実施例１３ ７，７−ジメチル−１−ヒド
ロキシ−５−ヒドロキシ−１２−（２−ヒドロキシエチ
ル）−ビシクロ［８．３．０］トリデカ−１０−エン−
３，８−ジインの製造： アルゴン気流下実施例１２により得られた７，７−ジメ
チル−１−ヒドロキシ−５−トリエチルシリルオキシ−
１２−（２−トリエチルシリルオキシエチル）−ビシク
ロ［８．３．０］トリデカ−１０−エン−３，８−ジイ
ン1.01g(2.00mmol) をＴＨＦ２mlに溶かし、これに水２
ml、酢酸２mlを加え、室温で９時間攪拌した。飽和炭酸
水素ナトリウム水１６mlを加え、２５mlの酢酸エチルで
３回抽出し、有機層を１０mlの飽和食塩水で１回洗浄し
た。硫酸マグネシウムで乾燥後、濾過、除媒し、シリカ
ゲル５０ｇ、酢酸エチルで精製して目的物を得た。 形状：黄白色アモファルス 0.473g(1.72mmol,収率８６
％)¹ H-NMR(400MHz,CDCl₃ ):δ 1.261(s,3H), 1.295(s,3H), 1.625(ddt,1H,J=14,7.5,5.
5Hz),1.775(ddt,1H,J=13,6.0,6.5Hz), 1.186(dd,1H,J=1
3.5,6.0Hz),1.840(m,1H), 1.916(dd,1H,J=13.5,11Hz),
2.048(s,0.5H), 2.088(s,0.5H), 2.083(dd,0.5H,J=14,
8.0Hz),2.100(dd,0.5H,J=14,9.0Hz), 2.579(dd,0.5H,J=
16.5,3.0Hz),2.590(dd,0.5H,J=17,3.0Hz), 2.659(dd,0.
5H,J=16.5,2.0Hz),2.646(dd,0.5H,J=17,1.0Hz), 2.814
(m,1H), 3.698(m,2H),4.525(m,1H), 5.848(d,0.5H,J=2.
5Hz), 5.874(d,0.5H,J=2.5Hz) IR(film)：ν3346, 2970, 2930, 2218,1655, 1444, 136
5, 1166, 1042,1019,986, 913, 861, 731, 646cm^-1 Example 13 7,7-Dimethyl-1-hydroxy-5-hydroxy-12- (2-hydroxyethyl) -bicyclo [8.3.0] trideca-10-ene-
Production of 3,8-diyne: 7,7-dimethyl-1-hydroxy-5-triethylsilyloxy- obtained in Example 12 under a stream of argon.
1.01 g (2.00 mmol) of 12- (2-triethylsilyloxyethyl) -bicyclo [8.3.0] trideca-10-ene-3,8-diyne was dissolved in 2 ml of THF, and water was added thereto.
and 2 ml of acetic acid, and the mixture was stirred at room temperature for 9 hours. 16 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with 25 ml of ethyl acetate, and the organic layer was washed once with 10 ml of saturated saline. After drying over magnesium sulfate, filtration and removal of the solvent were carried out, followed by purification with 50 g of silica gel and ethyl acetate to obtain the desired product. Shape: yellow-white amofarth 0.473 g (1.72 mmol, yield 86)
%) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.261 (s, 3H), 1.295 (s, 3H), 1.625 (ddt, 1H, J = 14, 7.5, 5.
5Hz), 1.775 (ddt, 1H, J = 13,6.0,6.5Hz), 1.186 (dd, 1H, J = 1
3.5,6.0Hz), 1.840 (m, 1H), 1.916 (dd, 1H, J = 13.5,11Hz),
2.048 (s, 0.5H), 2.088 (s, 0.5H), 2.083 (dd, 0.5H, J = 14,
8.0Hz), 2.100 (dd, 0.5H, J = 14,9.0Hz), 2.579 (dd, 0.5H, J =
16.5,3.0Hz), 2.590 (dd, 0.5H, J = 17,3.0Hz), 2.659 (dd, 0.
5H, J = 16.5,2.0Hz), 2.646 (dd, 0.5H, J = 17,1.0Hz), 2.814
(m, 1H), 3.698 (m, 2H), 4.525 (m, 1H), 5.848 (d, 0.5H, J = 2.
5Hz), 5.874 (d, 0.5H, J = 2.5Hz) IR (film): ν3346, 2970, 2930, 2218,1655, 1444, 136
5, 1166, 1042,1019,986, 913, 861, 731, 646cm ^-1

【００２８】実施例１４ ７，７−ジメチル−１，５−
ジヒドロキシ−１２−（２−パラトルエンスルホニルオ
キシエチル）−ビシクロ［８．３．０］トリデカ−１０
−エン−３，８−ジインの製造： アルゴン雰囲気下実施例１３で得られた７，７−ジメチ
ル−１−ヒドロキシ−５−ヒドロキシ−１２−（２−ヒ
ドロキシエチル）−ビシクロ［８．３．０］トリデカ−
１０−エン−３，８−ジイン0.329g(1.20mmol)を無水の
ジクロロメタン１０mlに溶かし、０℃に冷却した。ピリ
ジン0.20ml(2.47mmol)を加え、更に無水のジクロロメタ
ン２mlに溶かしたパラトルエンスルホン酸塩化物0.458g
(2.40mmol)を加えた。室温まで昇温し、９３時間攪拌し
た。飽和炭酸水素ナトリウム水１５mlを加え、３０mlの
酢酸エチルで３回抽出し、１５mlの飽和食塩水で洗浄
後、硫酸マグネシウムで乾燥後、濾過、除媒した。シリ
カゲル２５ｇ、ヘキサン：酢酸エチル＝1.57：１のカラ
ムで精製して目的物を得た。 形状：乳白色結晶 0.267g(0.622mmol, 収率５２％)¹ H-NMR(90MHz,CDCl₃ ): δ 1.26(s,3H), 1.27(s,3H), 1.4-2.12(m,7H), 2.57(m,2
H),2.46(s,3H), 2.70(m,1H), 4.05(t,2H,J=6.3Hz), 4.5
1(m,1H),5.71(t,1H,J=2.3Hz), 7.34(d,2H,J=8.4Hz), 7.
79(d,2H,J=8.4Hz)Example 14 7,7-Dimethyl-1,5-
Dihydroxy-12- (2-paratoluenesulfonyloxyethyl) -bicyclo [8.3.0] trideca-10
Production of -ene-3,8-diyne: 7,7-dimethyl-1-hydroxy-5-hydroxy-12- (2-hydroxyethyl) -bicyclo [8.3. 0] Trideka
0.329 g (1.20 mmol) of 10-ene-3,8-diyne was dissolved in 10 ml of anhydrous dichloromethane and cooled to 0 ° C. 0.20 ml (2.47 mmol) of pyridine was added, and 0.458 g of paratoluenesulfonic acid chloride dissolved in 2 ml of anhydrous dichloromethane was further added.
(2.40 mmol) was added. The mixture was heated to room temperature and stirred for 93 hours. 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with 30 ml of ethyl acetate, washed with 15 ml of a saturated saline solution, dried over magnesium sulfate, filtered, and removed. Purification was performed using 25 g of silica gel and a column of hexane: ethyl acetate = 1.57: 1 to obtain the desired product. Form: Milky white crystals 0.267 g (0.622 mmol, yield 52%) ¹ H-NMR (90 MHz, CDCl ₃ ): δ 1.26 (s, 3H), 1.27 (s, 3H), 1.4-2.12 (m, 7H), 2.57 (m, 2
H), 2.46 (s, 3H), 2.70 (m, 1H), 4.05 (t, 2H, J = 6.3Hz), 4.5
1 (m, 1H), 5.71 (t, 1H, J = 2.3Hz), 7.34 (d, 2H, J = 8.4Hz), 7.
79 (d, 2H, J = 8.4Hz)

【００２９】実施例１５ ７，７−ジメチル−１，５−
ジヒドロキシ−１２−（２−アセチルチオエチル）−ビ
シクロ［８．３．０］トリデカ−１０−エン−３，８−
ジインの製造： アルゴン雰囲気下無水のＴＨＦに実施例１４で得られた
７，７−ジメチル−１，５−ジヒドロキシ−１２−（２
−パラトルエンスルホニルオキシエチル）−ビシクロ
［８．３．０］トリデカ−１０−エン−３，８−ジイン
0.267g(0.622mmol) を溶かし、 0.1Ｍ溶液とした。これ
にチオ酢酸２６７μl(3.74mmol) 、トリエチルアミン８
７０μl(6.24mmol) を加え、５０℃に加熱した。３時間
攪拌後、飽和塩化アンモニウム水１０mlを加え、１０ml
の酢酸エチルで４回抽出し、１０mlの飽和食塩水で有機
層を洗った。硫酸マグネシウムで乾燥後、濾過、除媒
し、カラムクロマトグラフィー（シリカゲル１２ｇ，ヘ
キサン：酢酸エチル＝１：１）で精製して目的物を得
た。 形状：淡橙色結晶 0.171g(0.515mmol, 収率８３％)¹ H-NMR(400MHz,CDCl₃ ):δ 1.259(s,1.5H), 1.275(s,1.5H), 1.291(s,1.5H), 1.294
(s,1.5H),1.546(m,1H), 1.70-1.78(m,2H), 1.794(dd,0.
5H,J=13,4.0Hz),1.826(dd,0.5H,J=13,4.0Hz), 1.834(d
d,0.5H,J=13,10.5Hz),1.909(dd,0.5H,J=12,10.5Hz), 2.
081(dd,0.5H,J=14,8.0Hz),2.100(dd,0.5H,J=14,7.5Hz),
2.324(s,3H),2.565(dd,0.5H,J=16.5,3.0Hz), 2.577(d
d,0.5H,J=17,3.0Hz),2.629(dd,0.5H,J=17,1.0Hz), 2.64
6(dd,0.5H,J=16.5,2.0Hz),2.692(m,1H), 2.876(bt,2H),
2.924(bs,0.5H), 3.084(bs,0.5H),4.524(m,1H), 5.821
(d,0.5H,J=2.5Hz), 5.845(d,0.5H,J=2.5Hz) IR(film)：ν3314, 2968, 2934, 1688,1419, 1352, 113
3, 1042, 1019,982, 911, 870, 733, 625cm^-1 HRMS：calcd for C₁₉H₂₄O₃S:332.1446 found 332.1449
(M⁺ )Example 15 7,7-Dimethyl-1,5-
Dihydroxy-12- (2-acetylthioethyl) -bicyclo [8.3.0] trideca-10-ene-3,8-
Production of diyne: The 7,7-dimethyl-1,5-dihydroxy-12- (2) obtained in Example 14 was added to anhydrous THF under an argon atmosphere.
-Paratoluenesulfonyloxyethyl) -bicyclo [8.3.0] trideca-10-ene-3,8-diyne
0.267 g (0.622 mmol) was dissolved to prepare a 0.1 M solution. To this, 267 μl (3.74 mmol) of thioacetic acid, triethylamine 8
70 μl (6.24 mmol) was added and heated to 50 ° C. After stirring for 3 hours, 10 ml of a saturated aqueous ammonium chloride solution was added, and 10 ml
The mixture was extracted four times with ethyl acetate, and the organic layer was washed with 10 ml of saturated saline. After drying over magnesium sulfate, filtration, removal of the solvent and purification by column chromatography (silica gel 12 g, hexane: ethyl acetate = 1: 1) gave the desired product. Shape: pale orange crystal 0.171 g (0.515 mmol, yield 83%) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.259 (s, 1.5 H), 1.275 (s, 1.5 H), 1.291 (s, 1.5 H ), 1.294
(s, 1.5H), 1.546 (m, 1H), 1.70-1.78 (m, 2H), 1.794 (dd, 0.
5H, J = 13,4.0Hz), 1.826 (dd, 0.5H, J = 13,4.0Hz), 1.834 (d
d, 0.5H, J = 13,10.5Hz), 1.909 (dd, 0.5H, J = 12,10.5Hz), 2.
081 (dd, 0.5H, J = 14,8.0Hz), 2.100 (dd, 0.5H, J = 14,7.5Hz),
2.324 (s, 3H), 2.565 (dd, 0.5H, J = 16.5,3.0Hz), 2.577 (d
d, 0.5H, J = 17,3.0Hz), 2.629 (dd, 0.5H, J = 17,1.0Hz), 2.64
6 (dd, 0.5H, J = 16.5,2.0Hz), 2.692 (m, 1H), 2.876 (bt, 2H),
2.924 (bs, 0.5H), 3.084 (bs, 0.5H), 4.524 (m, 1H), 5.821
(d, 0.5H, J = 2.5Hz), 5.845 (d, 0.5H, J = 2.5Hz) IR (film): ν3314, 2968, 2934, 1688,1419, 1352, 113
3, 1042, 1019,982, 911, 870, 733, 625cm ^-1 HRMS: calcd for C ₁₉ H ₂₄ O ₃ S: 332.1446 found 332.1449
(M ⁺ )

【００３０】実施例１６ １２−（２−アセチルチオエ
チル）−７，７−ジメチル−５−オキソビシクロ［８．
３．０］トリデカ−１，１０−ジエン−３，８−ジイン
（本発明化合物１）の製造： アルゴン気流下無水のジクロロメタンにオキザリルクロ
リド６５μl(0.745mmol)を溶かし、−７８℃に冷却し
た。無水のジクロロメタン１mlに溶かしたＤＭＳＯ １
００μl( 1.41 mmol) を６分間で滴下し、１２分間攪拌
した。白濁した反応液に実施例１５で得た７，７−ジメ
チル−１，５−ジヒドロキシ−１２−（２−アセチルチ
オエチル）ビシクロ［８．３．０］トリデカ−１０−エ
ン−３，８−ジイン0.0492g(0.148mmol)を無水のジクロ
ロメタン1.5 mlに溶かしたものを１５分間で滴下した。
このとき７，７−ジメチル−１，５−ジヒドロキシ−１
２−（２−アセチルチオエチル）−ビシクロ［８．３．
０］トリデカ−１０−エン−３，８−ジインのジクロロ
メタン溶液を入れていた容器を0.5ml の無水のジクロロ
メタンで洗ったものも加えた。−７５℃で６０分間攪拌
を続け、ここにトリエチルアミン３１０μl(2.22mmol)
を１分間で滴下した。−６０℃に昇温して１８分間、０
℃にして１分間攪拌した後、水を加えて反応を止める。
ジクロロメタン１０mlで３回抽出し、有機層を飽和食塩
水８mlで洗浄、硫酸マグネシウムで乾燥後、濾過、除媒
した。除媒は室温で速やかに行い、またこの際若干の溶
媒が残る程度にしておいた。この残渣をすぐにシリカゲ
ル４ｇ，ヘキサン：酢酸エチル＝4.4 ：１のカラムクロ
マトグラフィーにより精製し、除媒は室温以下で速やか
に行って、目的物を得た。 形状：黄色油状物 0.0366mg(0.117mmol, 収率７９％) その他：易分解性¹ H-NMR(400MHz,CDCl₃ ):δ 1.291(s,3H), 1.294(s,3H), 1.627(m,1H), 1.733(m,1
H),2.340(s,3H), 2.418(ddd,1H,J=16,2.0,0.5Hz), 2.61
9(s,2H),2.81-2.90(m,4H), 5.521(ddt,1H,J=1.5,1.0,2.
0Hz),6.499(ddd,1H,J=2.5,1.5,0.5Hz) IR(film)：ν2930, 2168, 1690, 1657,1589, 1423, 125
5, 1135, 953,625cm^-1 Example 16 12- (2-acetylthioethyl) -7,7-dimethyl-5-oxobicyclo [8.
3.0] Production of trideca-1,10-diene-3,8-diyne (Compound 1 of the present invention): 65 μl (0.745 mmol) of oxalyl chloride was dissolved in anhydrous dichloromethane under a stream of argon and cooled to −78 ° C. . DMSO 1 dissolved in 1 ml of anhydrous dichloromethane
00 μl (1.41 mmol) was added dropwise over 6 minutes and stirred for 12 minutes. The 7,7-dimethyl-1,5-dihydroxy-12- (2-acetylthioethyl) bicyclo [8.3.0] tridec-10-ene-3,8- obtained in Example 15 was added to the cloudy reaction solution. A solution of 0.0492 g (0.148 mmol) of diyne in 1.5 ml of anhydrous dichloromethane was added dropwise over 15 minutes.
At this time, 7,7-dimethyl-1,5-dihydroxy-1
2- (2-acetylthioethyl) -bicyclo [8.3.
0] A container containing a dichloromethane solution of tridec-10-ene-3,8-diyne was washed with 0.5 ml of anhydrous dichloromethane. Stirring was continued at −75 ° C. for 60 minutes, whereupon 310 μl (2.22 mmol) of triethylamine was added.
Was added dropwise over 1 minute. Heat to -60 ° C for 18 minutes, 0
After stirring at 1 ° C. for 1 minute, the reaction was stopped by adding water.
The mixture was extracted three times with 10 ml of dichloromethane, and the organic layer was washed with 8 ml of saturated saline, dried over magnesium sulfate, filtered and the solvent was removed. The removal of the solvent was carried out promptly at room temperature, and at this time, the solvent was kept small enough. The residue was immediately purified by column chromatography using 4 g of silica gel and hexane: ethyl acetate = 4.4: 1, and the solvent was quickly removed at room temperature or lower to obtain the desired product. Shape: yellow oil 0.0366 mg (0.117 mmol, yield 79%) Others: easily decomposable ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.291 (s, 3H), 1.294 (s, 3H), 1.627 (m , 1H), 1.733 (m, 1
H), 2.340 (s, 3H), 2.418 (ddd, 1H, J = 16,2.0,0.5Hz), 2.61
9 (s, 2H), 2.81-2.90 (m, 4H), 5.521 (ddt, 1H, J = 1.5,1.0,2.
0Hz), 6.499 (ddd, 1H, J = 2.5,1.5,0.5Hz) IR (film): ν2930,2168,1690,1657,1589,1423,125
5, 1135, 953,625cm ^-1

【００３１】実施例１７ 抗腫瘍活性の測定： 本発明化合物の抗腫瘍活性をBioassay法(Jap. J. ofAnt
ibiotics 23(5,6):471-478, 1970 「Neocarzinostatin
の体内分布と不活性化」) に従い、Micrococcus luteus
ATCC9341 に対する抗菌活性を指標にして測定した。M.
luteus を常法に従い、STA 培地（日本水産（株）製）
で3.4 ×１０⁵ ／ml培地となるまで増殖させ、これを２
号角シャーレ（１４×１０cm）に２０ml分注し３mmの厚
さに固化させたものを検定板として使用した。直径８mm
のパルプディスク（株式会社東洋製作所社製）に、実施
例１６で得られた本発明化合物（２mg／ml）３０μl を
添加し、しみ込ませ、上記検定板に貼り付けた。４℃で
３時間サンプルを検定板に拡散させた後、これを２５℃
で一晩培養した。結果は阻止円の直径（mm）を測定して
示した（dia-m(mm))。Example 17 Measurement of Antitumor Activity: The antitumor activity of the compound of the present invention was determined by the Bioassay method (Jap. J. of Ant).
ibiotics 23 (5,6): 471-478, 1970 `` Neocarzinostatin
Micrococcus luteus
It was measured using the antibacterial activity against ATCC9341 as an index. M.
luteus and STA medium (Nippon Suisan KK)
And grow to 3.4 × 10 ⁵ / ml medium.
A test plate was prepared by dispensing 20 ml into a No. 10-cm petri dish (14 × 10 cm) and solidifying it to a thickness of 3 mm. 8mm diameter
Of the compound of the present invention (2 mg / ml) obtained in Example 16 was added to a pulp disk (manufactured by Toyo Seisakusho Co., Ltd.), soaked and attached to the above-mentioned test plate. After spreading the sample on the assay plate at 4 ° C for 3 hours,
Overnight. The results were shown by measuring the diameter (mm) of the inhibition circle (dia-m (mm)).

【表１】 この結果、本発明化合物は強い抗腫瘍活性を有すること
が明らかとなった。[Table 1] As a result, it was revealed that the compound of the present invention has strong antitumor activity.

【００３２】[0032]

【発明の効果】本発明ビシクロ［８．３．０］トリデカ
−９，１３−ジエン−２，７−ジイン誘導体（１）は、
ＮＣＳ−Ｃ製造中間体として有用であり、かつ抗腫瘍剤
としても有用である。The bicyclo [8.3.0] trideca-9,13-diene-2,7-diyne derivative (1) of the present invention is
It is useful as an NCS-C production intermediate and also useful as an antitumor agent.

Claims (1)

(57)【特許請求の範囲】(57) [Claims] 【請求項１】 次の一般式（１） 【化１】 〔式中、Ｒ¹ は低級アルカノイル基を示し、Ｒ² 及びＲ
³ は同一か又は異なって水素原子又は低級アルキル基を
示す〕で表わされるビシクロ［８．３．０］トリデカ−
９，１３−ジエン−２，７−ジイン誘導体。1. The following general formula (1): Wherein R ¹ represents a lower alkanoyl group, R ² and R
³ are the same or different and each represent a hydrogen atom or a lower alkyl group].
9,13-diene-2,7-diyne derivatives.