JP4180033B2

JP4180033B2 - Method for synthesizing polycyclic ether compound and gymnosin-A

Info

Publication number: JP4180033B2
Application number: JP2004271783A
Authority: JP
Inventors: 誠佐々木; 千尋塚野
Original assignee: Japan Science and Technology Agency; National Institute of Japan Science and Technology Agency
Current assignee: Japan Science and Technology Agency; National Institute of Japan Science and Technology Agency
Priority date: 2003-09-22
Filing date: 2004-09-17
Publication date: 2008-11-12
Anticipated expiration: 2024-09-17
Also published as: JP2005120077A

Description

この出願の発明は、ポリ環状エーテル化合物と細胞毒性を有するギムノシン−Ａの合成
方法に関するものである。 The invention of this application relates to a method of synthesizing a polycyclic ether compound and cytotoxic gymnosin-A.

次式で表わされるギムノシン−Ａは赤潮原因渦鞭毛藻Karenia mikimotiから単離、構造
決定された１４環性ポリ環状エーテル化合物であり、マウスリンパ腫細胞Ｐ３８８に対し
て細胞毒性（ＥＣ₅₀＝１．３μｇ／ｍＬ）を示す（非特許文献１）。しかし、その作用機
構はまったく不明であり、活性発現機構解明のためには化学合成による試料供給と構造類
縁体の構成が望まれている。 Gymnosine-A represented by the following formula is a 14-ring polycyclic ether compound isolated from the red tide-causing dinoflagellate Karenia mikimoti and whose structure has been determined, and is cytotoxic (EC ₅₀ = 1.3 μg) against mouse lymphoma cell P388. / ML) (Non-Patent Document 1). However, its mechanism of action is completely unknown, and in order to elucidate the mechanism of expression of activity, sample supply by chemical synthesis and construction of structural analogs are desired.

このような巨大分子を効率的に合成することは有機合成化学上の挑戦的なテーマの一つ
であるが、これまでのところ、ギムノシン−Ａの全合成は成功していないのが実情である
。

Efficient synthesis of such macromolecules is one of the most challenging themes in organic synthetic chemistry, but so far the total synthesis of gymnosin-A has not been successful. .

一方、この出願の発明者らは、天然物合成を目的として、巨大分子、特にポリ環状エー
テルの合成について検討を進め、Ｂ−アルキル鈴木−宮浦カップリング反応を基盤とする
新しいポリ環状エーテル合成法を開発してきた（非特許文献２）。そして、ギムノシン−
Ａの全合成に向けて、すでに以下のとおりの合成法を確立してきている。
（１）ＦＧＨＩＪＫＬＭＮ環部エノールトリフラートの合成
次の反応式に従って、ＧＨＩ環部エキソエノールエーテルをヒドロホウ素化して得られ
るアルキルボランと、ＫＬＭＮ環部エノールホスフェートをＤＭＦ中Ｃｓ₂ＣＯ₃水溶液と
触媒量のＰｄＣｌ₂（ｄｐｐｆ）の存在下、５０℃でカップリング反応させてエンドエノ
ールエーテルを合成し、このものを立体選択的ヒドロホウ素化、ＲｕＣｌ₂（ＰＰｈ）₃に
よるジオールのラクトンへの酸化を含む８工程でＦＧＨＩＪＫＬＭＮ環部ラクトンの合成を行った（非特許文献３）。 On the other hand, the inventors of this application have studied the synthesis of macromolecules, particularly polycyclic ethers, for the purpose of natural product synthesis, and a new polycyclic ether synthesis method based on the B-alkyl Suzuki-Miyaura coupling reaction. Has been developed (Non-Patent Document 2). And Gymnosin-
For the total synthesis of A, the following synthesis methods have already been established.
(1) Synthesis of FGHIJKLMN ring part enol triflate According to the following reaction formula, alkylborane obtained by hydroborating GHI ring part exoenol ether, KLMN ring part enol phosphate with Cs ₂ CO ₃ aqueous solution in DMF and catalytic amount An endoenol ether was synthesized by coupling reaction at 50 ° C. in the presence of PdCl ₂ (dppf), including stereoselective hydroboration, oxidation of diol to lactone with RuCl ₂ (PPh) ₃ In the process, FGHIJKLMN ring lactone was synthesized (Non-patent Document 3).

（２）ＡＢＣＤ’環部エキソオレフィンの合成
一方、次の反応式に示したように、エキソエノールエーテルとエノールホスフェートを
上記と同様に鈴木−宮浦カップリング反応により連結し、エノールエーテルとし、このエ
ノールエーテルよりＣ環を閉環後、Ｂ環上１０位水酸基を導入してヒドロキシケトンとし
、さらに、ラジカル環化反応を含む数工程でＡＢＣＤ’環部エキソエノールエーテルを合
成することに成功した（非特許文献４）。

(2) Synthesis of ABCD 'ring part exoolefin On the other hand, as shown in the following reaction formula, exoenol ether and enol phosphate are coupled by the Suzuki-Miyaura coupling reaction in the same manner as above to obtain enol ether. After C ring was closed from ether, 10-position hydroxyl group on B ring was introduced to make hydroxyketone, and ABCD 'ring part exoenol ether was successfully synthesized in several steps including radical cyclization reaction (non-patent) Reference 4).

Satake, M .; Shoji, M .; Oshima, Y .; Naoki, H .; Fujita, T .; Yasumoto, T. Tetrahedron Lett. 2002, 43, 5829. (a) Sasaki, M .; Fuwa, H .; Inoue, M .; Tachibana, K. Tetrahedron Lett. 1998, 39, 9027. (b) Sasaki, M .; Fuwa, H .; Ishikawa, M .; Tachibana , K. Org. Lett. 1999, 1, 1075. (c) Sasaki, M .; Ishikawa, M .; Fuwa, F ,; Tachibana, K. Tetrahedron. 2002, 58, 1889. Sasaki, M .; Tsukano, C ,; Tachibana, K. Org. Lett. 2002, 4, 1747. Sasaki, M .; Tsukano, C .; Tachibana, K. Tetrahedron Lett. 2003, 44, 4351.

この出願の発明は、上記のとおりの背景を踏まえてなされたものであって、天然からの
試料調達が困難であって、詳細な生物活性の発現機能の究明が求められているギムノシン
−Ａの化学合成による供給を実現し、そのための、ギムノシン−Ａをはじめとするポリ環
状エーテルの合成のための新しい方法を提供することを課題としている。 The invention of this application has been made in light of the background as described above, and it is difficult to procure samples from nature, and it is necessary to investigate the expression function of detailed biological activity. It is an object of the present invention to provide a new method for the synthesis of polycyclic ethers including gymnosine-A for realizing the supply by chemical synthesis.

この出願は、上記の課題を解決するものとして、次式

（式中のBnはベンジル基を示し、TBSはtert-ブチルジメチルシリル基を示し、PMBはp-メトキシベンジル基を示す。）で表わされるエキソエノールエーテル化合物もしくはそのアルキルボラン化合物を、次式

（式中のTBSはtert-ブチルジメチルシリル基を示し、Tfはトリフラート基を示す。）で表わされるエノールフルオロアルキルスルホン酸エステル化合物とカップリング反応させて、次式

（式中のBnはベンジル基を示し、TBSはtert-ブチルジメチルシリル基を示し、PMBはp-メトキシベンジル基を示す。）で表わされる化合物を得ることを特徴とするポリ環状エーテル化合物の合成方法を提供する。 This application, as to solve the above problem, the following equation

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and PMB represents a p-methoxybenzyl group.) An exoenol ether compound or an alkylborane compound thereof is represented by the following formula:

(Wherein TBS represents a tert-butyldimethylsilyl group and Tf represents a triflate group). A coupling reaction with an enolfluoroalkylsulfonic acid ester compound represented by

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and PMB represents a p-methoxybenzyl group.) Provide a method.

そしてまた、この出願の発明は、上記の方法により得られたポリ環状エーテル化合物をヒドロホウ素化および酸化し、得られたアルコールを2,6-ルチジンおよびTESOTfで処理してトリエチルシリル（TES）エーテル体とした後、2,3-ジクロロ-5,6-ジシアノベンゾキノン（DDQ）で酸化して、次式

（式中のBnはベンジル基を示し、TBSはtert-ブチルジメチルシリル基を示し、TESはトリエチルシリル基を示す。）で表されるアルコールとし、このアルコールをテトラ-n-プロピルアンモニウムペルルテナート（TPAP）およびN-メチルモルホリン-N-オキシド（NMO）で処理してケトンとし、このケトンをシリルエノールエーテルに変換した後、このシリルエノールエーテルを酸化してα-ヒドロキシケトンとし、このα-ヒドロキシケトンの水酸基をTIPS（トリイソプロピルシリル）基により保護して次式

（式中のBnはベンジル基を示し、TBSはtert-ブチルジメチルシリル基を示し、TESはトリエチルシリル基を示し、TIPSはトリイソプロピルシリル基を示す。）で表されるα-シロキシケトンとし、このα-シロキシケトンをEtSHおよびZn(OTf) ₂ で処理して次式

（式中のBnはベンジル基を示し、TBSはtert-ブチルジメチルシリル基を示し、TIPSはトリイソプロピルシリル基を示す。）で表されるチオケタールを得た後、このチオケタールをPh ₃ SnHおよびアゾビスイソブチロニトリルで処理して次式

で表されるポリ環状エーテル化合物を得ることを特徴とするポリ環状エーテル化合物の合成方法を提供する。 The invention of this application is also directed to hydroboration and oxidation of the polycyclic ether compound obtained by the above method, and treating the resulting alcohol with 2,6-lutidine and TESOTf to obtain triethylsilyl (TES) ether. And then oxidized with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)

(Wherein Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and TES represents a triethylsilyl group), and the alcohol is tetra-n-propylammonium perruthenate. (TPAP) and N-methylmorpholine-N-oxide (NMO) to give a ketone, which is converted to a silyl enol ether, then the silyl enol ether is oxidized to an α-hydroxy ketone, Protect the hydroxyl group of hydroxyketone with TIPS (triisopropylsilyl) group

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, TES represents a triethylsilyl group, and TIPS represents a triisopropylsilyl group.) This α-siloxy ketone is treated with EtSH and Zn (OTf) ₂ to give

(Bn in the formula represents a benzyl group, TBS represents a tert- butyldimethylsilyl group, TIPS is. Showing a triisopropylsilyl group) after obtaining the thioketal represented by, the thioketal Ph ₃ SnH and azo Treatment with bisisobutyronitrile gives the following formula

A method for synthesizing a polycyclic ether compound is provided.

さらにこの出願の発明は、上記の方法により得られたポリ環状エーテル化合物をフッ化テトラブチルアンモニウムで処理してトリオール体を得た後、このトリオール体を2,6-ルチジンおよびTESOTfで処理してTESエーテル体とし、このTESエーテル体をLiDBB溶液で処理して次式Furthermore, the invention of this application is to treat the polycyclic ether compound obtained by the above method with tetrabutylammonium fluoride to obtain a triol body, and then treat this triol body with 2,6-lutidine and TESOTf. Treat the TES ether with a LiDBB solution to form the following formula:

Is obtained, and the alcohol is treated with tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) to form an aldehyde. _3Three P = C (Me) COOMe is reacted to form an ester, which is treated with diisobutylaluminum hydride

This allyl alcohol is treated with tris (dimethylamino) sulfonium difluorotrimethylsilicate to form a tetraol, and this tetraol is converted to MnO. ₂₂ Processed by the following formula

A method for synthesizing a polycyclic ether compound, characterized in that it is a gymnosin-A represented by the formula:

さらにこの出願の発明は、次式Furthermore, the invention of this application has the following formula:

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, TES represents a triethylsilyl group, and TIPS represents a triisopropylsilyl group.) Α-siloxy ketone represented by EtSH And Zn (OTf) ₂₂ Processed by the following formula

(Wherein Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, TIPS represents a triisopropylsilyl group, and R represents a hydrogen atom or a tert-butyldimethylsilyl group). After obtaining a mixed thioketal, R of the mixed thioketal is treated with 2,6-lutidine and TESOTf to form a thioketal having a triethylsilyl group. _3Three Treatment with SnH and azobisisobutyronitrile gives the following formula

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and TIPS represents a triisopropylsilyl group.) Methods for synthesizing compounds are provided.

上記のとおりのこの出願の発明によって、天然からの試料調達が困難であって、詳細な
生物活性の発現機能の究明が求めえられているギムノシン−Ａの化学合成による供給を実
現し、そのための、ギムノシン−Ａをはじめとするポリ環状エーテルの合成のための新し
い方法が提供される。 According to the invention of this application as described above, it is difficult to procure samples from nature, and it is possible to provide a supply of gymnosin-A by chemical synthesis, for which detailed investigation of the expression function of biological activity is required. A new method is provided for the synthesis of polycyclic ethers, including gymnosin-A.

この出願の発明は上記のとおりの特徴をもつものであるが、以下にその実施のための最
良の形態について説明する。 The invention of this application has the features as described above, and the best mode for its implementation will be described below.

この出願の発明については、より具体的には、ギムノシン−Ａの全合成が可能とされた
ことが強調される。すなわち、発明者らのこれまでの検討を踏まえて、さらに、たとえば
次の反応式に示したように、 With regard to the invention of this application, more specifically, it is emphasized that total synthesis of gymnosin-A has been made possible. That is, based on the inventors' previous studies, for example, as shown in the following reaction formula,

このギムノシン−Ａの全合成のための方法は、ポリ環状エーテル化合物一般の合成方法として有用である。そして、たとえば、上記の反応式において示されている保護基についても、同様の保護機能と良好な反応操作性をもつものならば任意のものであってよいことが理解される。 This method for total synthesis of gymnosin-A is useful as a general synthesis method for polycyclic ether compounds. For example, it is understood that the protecting group shown in the above reaction formula may be any as long as it has a similar protective function and good reaction operability .

そして、以下の実施例に示した反応条件や反応用試薬等が従来公知の知識や経験から適
宜に変更されてよいことも容易に理解される。以下の実施例は、ギムノシン−Ａの合成に
ついて例示したものである。 And it is also easily understood that the reaction conditions, reaction reagents and the like shown in the following examples may be appropriately changed from conventionally known knowledge and experience. The following examples illustrate the synthesis of gymnosin-A.

以下の全ての反応は、特に断りのない限り不活性ガス（窒素またはアルゴン）雰囲気下
、乾燥溶媒中で行い、実験器具は乾燥したものを用いた。アセトニトリル、THF, CH₂Cl₂
は市販の脱水溶媒（関東化学またはアルドリッチ）を、TMSClはCaH₂から蒸留したものを
、HMPAはCaH₂から減圧蒸留したものを、2-[N,N-bis- (trifluoromethylsulfonyl) amino]
-5- chloropyridineはKugelrhorを用いて減圧蒸留したものを、上記以外の液体または固
体試薬は市販のものをそのまま用いた。シリカゲルカラムクロマトグラフィーには、富士
シリシアのシリカゲル(BW-300)を用いた。 All the following reactions were carried out in a dry solvent under an inert gas (nitrogen or argon) atmosphere unless otherwise specified, and the laboratory equipment used was dried. Acetonitrile, THF, CH ₂ Cl ₂
Is a commercially available dehydrated solvent (Kanto Chemical or Aldrich), TMSCl is distilled from CaH ₂ , HMPA is distilled from CaH _{2 under} reduced pressure, 2- [N, N-bis- (trifluoromethylsulfonyl) amino]
-5-chloropyridine was distilled under reduced pressure using Kugelrhor, and a commercially available liquid or solid reagent other than the above was used as it was. For silica gel column chromatography, silica gel of Fuji Silysia (BW-300) was used.

旋光度([α]_D)は日本分光社のデジタル旋光度計DIP-370を用いて測定した。NMRはバリ
アン社のINOVA 600とINOVA 500を用いて測定した。化学シフト値は、重溶媒中の溶媒を内
部標準 [¹H NMR: 7.24 (CHCl₃/CDCl₃); 7.15 (C₆H₆/C₆D₆); 8.71 (C₅H₅N/C₅HD₄N); 77.0
(CDCl₃); 128.0 (C₆D₆); 149.9 (C₅D₅N)]としてδ値として表示し、シグナルの多重度は
、s: singlet, d : doublet, t: triplet, q: quartet, m: multiplet, br: broadの略号
を用いて示した。スピン結合定数は、J 値(Hz)で表示した。高分解能質量分析スペクトル
(HRMS)には日本電子社のJMS-700を用い、マトリックスとしてm-ニトロベンジルアルコー
ル(NBA)またはグリセロールを用いてFABモードで測定した。
＜Ａ＞カップリング反応と閉環
次の反応式に従って、順次に反応を行った。 The optical rotation ([α] _D ) was measured using a digital spectrorotometer DIP-370 manufactured by JASCO. NMR was measured with INOVA 600 and INOVA 500 from Varian. Chemical shift values were determined using the internal standard [ ¹ H NMR: 7.24 (CHCl ₃ / CDCl ₃ ); 7.15 (C ₆ H ₆ / C ₆ D ₆ ); 8.71 (C ₅ H ₅ N / C ₅ HD ₄ N); 77.0
(CDCl ₃ ); 128.0 (C ₆ D ₆ ); 149.9 (C ₅ D ₅ N)], expressed as a δ value, and the signal multiplicity is s: singlet, d: doublet, t: triplet, q: quartet , m: multiplet, br: broad. The spin coupling constant is expressed in J value (Hz). High resolution mass spectrometry spectrum
For (HRMS), JEOL's JMS-700 was used, and measurement was performed in FAB mode using m-nitrobenzyl alcohol (NBA) or glycerol as a matrix.
<A> Coupling reaction and ring closure Reactions were sequentially performed according to the following reaction formula.

上記の粗シリルエノールエーテルをTHF/H₂O (3:1, v/v, 6.5 mL)に溶解させ、室温でNM
O (50 w% 水溶液, 0.50 mL) と OsO₄ (100 mL中1 gのt-BuOH溶液, 0.50mL, 0.0020 mmol)
を加え、室温で16時間攪拌した。反応溶液を酢酸エチルで希釈し、飽和食塩水で洗浄し、
有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲル
カラムクロマトグラフィー (0-50% 酢酸エチル/ヘキサン)により精製し、α-ヒドロキシ
ケトン (20.0 mg, quant.)を無色油状物として得た。
上記のα-ヒドロキシケトン (20.0 mg, 0.0138 mmol)をCH₂Cl₂ (2.0 mL)に溶解し、2,6
-ルチジン (0.0125 mL, 0.107 mmol)、TIPSOTf (0.20 mL, 0.744 mmol)を加え、室温で5
時間攪拌した。反応溶液を酢酸エチルで希釈し、飽和食塩水で洗浄後、無水硫酸ナトリウ
ムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー
(0-50% 酢酸エチル/ヘキサン)により精製し、α-シロキシケトン6 (18.7 mg, 3工程85%)
を無色油状物として得た：[α]_D ²⁴ +39.1 (c 0.94, benzene); ¹H NMR (500 MHz, C₆D₆)
δ 7.26-7.24 (m, 2H), 7.17-7.15 (m, 2H), 7.08 (m, 1H), 5.19 (dd, J = 11.9, 2.6 H
z, 1H), 4.52 (dd, J = 7.6, 6.6 Hz, 1H), 4.42 (ddd, J = 8.1, 7.7, 7.7 Hz, 1H), 4.
28 (d, J = 12.7 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.17 (m, 1H), 4.03 (br d, J
= 6.1, <1 Hz, 1H), 3.96 (ddd, J = 11.9, 9.2, 5.1 Hz, 1H), 3.72 (ddd, J = 11.4, 8
.9, 5.1 Hz, 1H), 3.59 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 3.50-3.35 (m, 5H), 3.31-3
.17 (m, 6H), 3.14 (m, 1H), 3.10-3.04 (m, 2H), 3.02-2.88 (m, 8H), 2.57-2.52 (m, 2
H), 2.52-2.46 (m, 2H), 2.43-2.34 (m, 5H), 2.29-2.21 (m, 2H), 2.20-1.98 (m, 5H),
1.91-1.59 (m, 18H), 1.33 (d, J = 5.1 Hz, 3H), 1.18-1.14 (m, 21H),1.11 (s, 3H), 1
.11 (s, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.93 (s, 9H), 0.92 (s, 9H), 0.57 (q, J =
8.0 Hz, 6H), 0.00 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H), -0.01 (s, 3H); ¹³C NMR (
125 MHz, C₆D₆) δ 211.3, 139.3, 128.5 (x2), 127.6 (x2), 127.5, 84.3, 83.8, 83.3,
82.9, 82.4, 80.5, 80.1, 80.0, 79.5, 79.4, 78.7, 78.0, 77.9, 77.61, 77.56, 77.3,
77.2, 76.6, 76.5, 76.2, 76.0, 75.7, 75.0, 73.0, 72.8, 72.3, 71.8, 71.0, 70.8, 7
0.7, 70.6, 67.4, 49.8, 45.4, 41.2, 40.0, 38.5, 38.3, 38.22, 38.18, 37.2, 37.0, 3
6.3, 36.0, 35.9, 29.8, 29.7, 26.0 (x3), 25.9 (x3), 25.6, 25.5, 18.6, 18.31 (x3),
18.27 (x3), 18.0 (x2), 16.7, 16.5, 12.7 (x3), 7.1 (x3), 5.5 (x3), -4.1, -4.2, -
4.7, -5.0; HRMS (FAB) calcd for C₈₆H₁₄₆O₁₉Si₄Na [(M+Na)⁺] 1617.9433, found 1617.
9441.
混合チオケタール7および8の合成
α-シロキシケトン6 (13.5 mg, 0.00846 mmol)のMeNO₂/EtSH (4:1, v/v, 2.5 mL)溶液を0℃に冷却し、Zn(OTf)₂(3.9 mg, 0.0107 mmol)を加えて0℃で45分間攪拌した。Et₃N
を加えて反応を停止し、溶媒を減圧留去した後、得られた残渣をシリカゲルカラムクロマ
トグラフィー (20-40% 酢酸エチル/ヘキサン)により精製し、混合チオケタール7 (4.8 mg
, 40%)および8 (4.9 mg, 38%)を得た。7 : [α]_D ²⁵ +52.2 (c 0.34, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ 7.27-7.25 (m, 2H), 7.17-7.15 (m, 2H), 7.08 (m, 1H), 4.56-4.48 (m, 2H), 4.29 (d, J = 12.7 Hz, 1H), 4.27 (d, J = 12.7 Hz, 1H), 4.15 (m, 1H), 4.09 (br d, J = 4.9, <1 Hz, 1H), 4.02-3.90 (m, 3H), 3.81 (ddd, J = 10.8, 10.8, 4.9 Hz, 1H), 3.58 (ddd, J = 8.3, 8.3, 8.3 Hz, 1H), 3.51-3.39 (m, 4H), 3.25-3.13 (m, 5H), 3.09-2.81 (m, 11H), 2.79 (br d, J = 8.8, <1 Hz, 1H), 2.61(m, 1H), 2.53-2.42 (m, 3H), 2.40-2.32 (m, 5H), 2.28-2.20 (m, 3H), 2.09-1.97 (m,5H), 1.90-1.57 (m, 19H), 1.37 (ddd, J = 11.2 Hz, 1H), 1.25 (d, J = 5.9 Hz, 3H),1.18-1.15 (m, 21H),1.14 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 1.11 (s, 3H), 1.02 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H); ¹³C NMR (125 MHz, pyr-d₅) δ 139.5, 128.7 (x2), 127.9 (x2), 127.8, 94.9, 83.9, 83.0, 82.7, 82.5, 80.1, 79.9, 79.5, 79.3, 78.5, 77.9, 77.4 (x2), 77.3, 77.1, 77.0, 76.9, 76.58, 76.57, 76.45, 76.38, 76.2, 75.0, 74.7, 73.0 (x2), 72.1, 71.3, 70.9, 70.6, 70.5, 69.7, 67.6, 45.4, 44.6, 40.8, 39.9, 39.0, 38.5, 38.2, 37.2, 37.0, 35.91, 35.85, 33.9, 30.0, 29.9, 29.8, 26.2 (x3), 25.6, 20.5, 20.1, 18.69 (x3), 18.66 (x3), 18.6, 18.3, 16.8, 16.7, 15.3, 13.0 (x3), -3.9, -4.9; HRMS (FAB) calcd for C₇₆H₁₂₂O₁₈Si₂SNa [(M+Na)⁺] 1433.7788, found 1433.7794.; 8:[α]_D ²⁴ +48.5 (c 0.57, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ 7.27-7.25 (m, 2H), 7.18-7.15 (m, 2H), 7.08 (m, 1H), 4.56-4.48 (m, 2H), 4.29 (d, J = 12.7 Hz, 1H), 4.27 (d, J = 12.7 Hz, 1H), 4.15 (m, 1H), 4.09 (br d, J = 5.0, <1 Hz, 1H), 4.02-3.90 (m, 3H), 3.81 (ddd, J = 10.3, 10.3, 5.3 Hz, 1H), 3.58 (ddd, J = 8.5, 8.5, 8.5 Hz, 1H), 3.51-3.40 (m, 4H), 3.31-3.29 (m, 2H), 3.25-3.13 (m, 5H), 3.08-2.84 (m, 9H), 2.79 (br d, J = 8.5, <1 Hz, 1H), 2.61 (m, 1H), 2.51-2.43 (m, 2H), 2.40-2.32 (m, 7H), 2.28-2.22 (m, 2H), 2.13-1.97 (m, 5H), 1.90-1.58 (m, 19H), 1.33 (d, J = 5.3 Hz, 3H), 1.18-1.16 (m, 21H),1.14 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 1.12 (s, 3H), 1.02 (s, 9H), 0.92 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H), 0.00 (s, 3H), 0.00 (s, 3H); ¹³C NMR (125 MHz, pyr-d₅) δ 139.5, 128.7 (x2), 127.9 (x2), 127.8, 94.9, 83.9, 83.8, 82.7, 82.5, 80.1, 79.9, 79.5, 78.6, 78.5, 77.9, 77.4 (x2), 77.3, 77.1, 77.0, 76.9, 76.5, 76.45, 76.38, 76.2, 76.0, 75.0, 74.7, 73.0 (x2), 72.6, 72.1, 70.8, 70.6, 70.5, 69.7, 67.6, 45.3, 44.6, 40.8, 39.9, 39.0, 38.44, 38.37, 38.2, 37.2, 37.0, 35.9, 35.8, 33.9, 30.0 29.84, 29.76, 26.2 (x3), 25.9 (x3), 25.6, 20.1, 18.69 (x3), 18.67 (x3), 18.6, 18.3, 18.1, 16.8, 16.7, 15.3, 13.0 (x3), -3.9, -4.1, -4.7, -4.9; HRMS (FAB) calcd for C₈₂H₁₃₆O₁₈Si₃SNa [(M+Na)⁺] 1547.8653, found 1547.8654.
混合チオケタール8の合成
混合チオケタール7 (4.7 mg, 0.0033 mmol)のCH₂Cl₂ (1.0 mL)に溶液に2,6-ルチジン (
0.025 mL, 0.215 mmol)、TESOTf (0.030 mL, 0.134 mmol)を加え、室温で40分間攪拌した
。反応溶液を酢酸エチルで希釈し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した
。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (10-30% 酢
酸エチル/ヘキサン)により精製し、混合チオケタール8 (3.6 mg, 71%)を得た。
＜Ｂ＞ギムノシン−Ａ
次の反応式に従って、最終目的生成物としてギムノシン−Ａを合成した。 Dissolve the above crude silyl enol ether in THF / H ₂ O (3: 1, v / v, 6.5 mL) and add NM at room temperature.
O (50 w% aqueous solution, 0.50 mL) and OsO ₄ (1 g t-BuOH solution in 100 mL, 0.50 mL, 0.0020 mmol)
And stirred at room temperature for 16 hours. The reaction solution is diluted with ethyl acetate, washed with saturated brine,
The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to obtain α-hydroxyketone (20.0 mg, quant.) As a colorless oil.
The above α-hydroxyketone (20.0 mg, 0.0138 mmol) was dissolved in CH ₂ Cl ₂ (2.0 mL) and 2,6
-Lutidine (0.0125 mL, 0.107 mmol) and TIPSOTf (0.20 mL, 0.744 mmol) were added, and 5 at room temperature was added.
Stir for hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
(0-50% ethyl acetate / hexane) and purified by α-siloxy ketone 6 (18.7 mg, 85% over 3 steps)
Was obtained as a colorless oil: [α] _D ²⁴ +39.1 (c 0.94, benzene); ¹ H NMR (500 MHz, C ₆ D ₆ )
δ 7.26-7.24 (m, 2H), 7.17-7.15 (m, 2H), 7.08 (m, 1H), 5.19 (dd, J = 11.9, 2.6 H
z, 1H), 4.52 (dd, J = 7.6, 6.6 Hz, 1H), 4.42 (ddd, J = 8.1, 7.7, 7.7 Hz, 1H), 4.
28 (d, J = 12.7 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.17 (m, 1H), 4.03 (br d, J
= 6.1, <1 Hz, 1H), 3.96 (ddd, J = 11.9, 9.2, 5.1 Hz, 1H), 3.72 (ddd, J = 11.4, 8
.9, 5.1 Hz, 1H), 3.59 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 3.50-3.35 (m, 5H), 3.31-3
.17 (m, 6H), 3.14 (m, 1H), 3.10-3.04 (m, 2H), 3.02-2.88 (m, 8H), 2.57-2.52 (m, 2
H), 2.52-2.46 (m, 2H), 2.43-2.34 (m, 5H), 2.29-2.21 (m, 2H), 2.20-1.98 (m, 5H),
1.91-1.59 (m, 18H), 1.33 (d, J = 5.1 Hz, 3H), 1.18-1.14 (m, 21H), 1.11 (s, 3H), 1
.11 (s, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.93 (s, 9H), 0.92 (s, 9H), 0.57 (q, J =
8.0 Hz, 6H), 0.00 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H), -0.01 (s, 3H); ¹³ C NMR (
125 MHz, C ₆ D ₆ ) δ 211.3, 139.3, 128.5 (x2), 127.6 (x2), 127.5, 84.3, 83.8, 83.3,
82.9, 82.4, 80.5, 80.1, 80.0, 79.5, 79.4, 78.7, 78.0, 77.9, 77.61, 77.56, 77.3,
77.2, 76.6, 76.5, 76.2, 76.0, 75.7, 75.0, 73.0, 72.8, 72.3, 71.8, 71.0, 70.8, 7
0.7, 70.6, 67.4, 49.8, 45.4, 41.2, 40.0, 38.5, 38.3, 38.22, 38.18, 37.2, 37.0, 3
6.3, 36.0, 35.9, 29.8, 29.7, 26.0 (x3), 25.9 (x3), 25.6, 25.5, 18.6, 18.31 (x3),
18.27 (x3), 18.0 (x2), 16.7, 16.5, 12.7 (x3), 7.1 (x3), 5.5 (x3), -4.1, -4.2,-
4.7, -5.0; HRMS (FAB) calcd for C ₈₆ H ₁₄₆ O ₁₉ Si ₄ Na [(M + Na) ⁺ ] 1617.9433, found 1617.
9441.
Synthesis of mixed thioketals 7 and 8 A solution of α-siloxyketone 6 (13.5 mg, 0.00846 mmol) in MeNO ₂ / EtSH (4: 1, v / v, 2.5 mL) was cooled to 0 ° C. and Zn (OTf) ₂ ( 3.9 mg, 0.0107 mmol) was added, and the mixture was stirred at 0 ° C. for 45 minutes. Et ₃ N
The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (20-40% ethyl acetate / hexane) to give mixed thioketal 7 (4.8 mg
, 40%) and 8 (4.9 mg, 38%). 7: [α] _D ²⁵ +52.2 (c 0.34, CHCl ₃ ); ¹ H NMR (500 MHz, C ₆ D ₆ ) δ 7.27-7.25 (m, 2H), 7.17-7.15 (m, 2H), 7.08 ( m, 1H), 4.56-4.48 (m, 2H), 4.29 (d, J = 12.7 Hz, 1H), 4.27 (d, J = 12.7 Hz, 1H), 4.15 (m, 1H), 4.09 (br d, J = 4.9, <1 Hz, 1H), 4.02-3.90 (m, 3H), 3.81 (ddd, J = 10.8, 10.8, 4.9 Hz, 1H), 3.58 (ddd, J = 8.3, 8.3, 8.3 Hz, 1H ), 3.51-3.39 (m, 4H), 3.25-3.13 (m, 5H), 3.09-2.81 (m, 11H), 2.79 (br d, J = 8.8, <1 Hz, 1H), 2.61 (m, 1H ), 2.53-2.42 (m, 3H), 2.40-2.32 (m, 5H), 2.28-2.20 (m, 3H), 2.09-1.97 (m, 5H), 1.90-1.57 (m, 19H), 1.37 (ddd , J = 11.2 Hz, 1H), 1.25 (d, J = 5.9 Hz, 3H), 1.18-1.15 (m, 21H), 1.14 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 1.11 (s, 3H), 1.02 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H); ¹³ C NMR (125 MHz, pyr-d ₅ ) δ 139.5, 128.7 (x2), 127.9 (x2 ), 127.8, 94.9, 83.9, 83.0, 82.7, 82.5, 80.1, 79.9, 79.5, 79.3, 78.5, 77.9, 77.4 (x2), 77.3, 77.1, 77.0, 76.9, 76.58, 76.57, 76.45, 76.38, 76.2, 75.0 , 74.7, 73.0 (x2), 72.1, 71.3, 70.9, 70.6, 70.5, 69.7, 67.6, 45.4, 44.6, 40.8, 39.9, 39.0, 38.5, 38.2, 37.2, 37.0, 35.91, 35.85, 33.9, 30.0, 29.9, 29.8, 26.2 (x3), 25.6, 20.5, 20.1, 18.69 (x3), 18.66 (x3), 18.6, 18.3, 16.8, 16.7 , 15.3, 13.0 (x3), -3.9, -4.9; HRMS (FAB) calcd for C ₇₆ H ₁₂₂ O ₁₈ Si ₂ SNa [(M + Na) ⁺ ] 1433.7788, found 1433.7794 .; 8: [α] _D ²⁴ +48.5 (c 0.57, CHCl ₃ ); ¹ H NMR (500 MHz, C ₆ D ₆ ) δ 7.27-7.25 (m, 2H), 7.18-7.15 (m, 2H), 7.08 (m, 1H), 4.56- 4.48 (m, 2H), 4.29 (d, J = 12.7 Hz, 1H), 4.27 (d, J = 12.7 Hz, 1H), 4.15 (m, 1H), 4.09 (br d, J = 5.0, <1 Hz , 1H), 4.02-3.90 (m, 3H), 3.81 (ddd, J = 10.3, 10.3, 5.3 Hz, 1H), 3.58 (ddd, J = 8.5, 8.5, 8.5 Hz, 1H), 3.51-3.40 (m , 4H), 3.31-3.29 (m, 2H), 3.25-3.13 (m, 5H), 3.08-2.84 (m, 9H), 2.79 (br d, J = 8.5, <1 Hz, 1H), 2.61 (m , 1H), 2.51-2.43 (m, 2H), 2.40-2.32 (m, 7H), 2.28-2.22 (m, 2H), 2.13-1.97 (m, 5H), 1.90-1.58 (m, 19H), 1.33 (d, J = 5.3 Hz, 3H), 1.18-1.16 (m, 21H), 1.14 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 1.12 (s, 3H), 1.02 (s, 9H), 0.92 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H), 0.00 (s, 3H), 0.00 (s, 3H); ¹³ C NMR (125 MHz, pyr-d ₅ ) δ 139.5, 128.7 (x2), 127.9 (x2), 127.8, 94.9, 83.9, 83.8, 82.7, 82.5, 80.1, 79.9, 79.5, 78.6, 78.5, 77.9, 77.4 (x2), 77.3, 77.1, 77.0, 76.9, 76.5, 76.45, 76.38, 76.2, 76.0, 75.0, 74.7, 73.0 (x2), 72.6, 72.1, 70.8, 70.6, 70.5, 69.7, 67.6, 45.3, 44.6, 40.8 , 39.9, 39.0, 38.44, 38.37, 38.2, 37.2, 37.0, 35.9, 35.8, 33.9, 30.0 29.84, 29.76, 26.2 (x3), 25.9 (x3), 25.6, 20.1, 18.69 (x3), 18.67 (x3), 18.6, 18.3, 18.1, 16.8, 16.7, 15.3, 13.0 (x3), -3.9, -4.1, -4.7, -4.9; HRMS (FAB) calcd for C ₈₂ H ₁₃₆ O ₁₈ Si ₃ SNa [(M + Na) ⁺ ] 1547.8653, found 1547.8654.
Synthesis of mixed thioketal 8 mixed thioketal 7 (4.7 mg, 0.0033 mmol) in CH ₂ Cl ₂ (1.0 mL) in solution with 2,6-lutidine (
0.025 mL, 0.215 mmol) and TESOTf (0.030 mL, 0.134 mmol) were added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (10-30% ethyl acetate / hexane) to obtain mixed thioketal 8 (3.6 mg, 71%).
<B> Gymnosine-A
According to the following reaction formula, gymnosin-A was synthesized as the final target product.

上記の粗トリオール体 (3.0 mg)をCH₂Cl₂ (2.0 mL)に溶解し、0℃に冷却した後、2,6-
ルチジン (0.020 mL, 0.171 mmol)、TESOTf (0.030 mL, 0.134 mmol)を加え、0℃で50分
間攪拌した。反応溶液を酢酸エチルで希釈し、飽和食塩水で洗浄し、無水硫酸ナトリウム
で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (
20-50% 酢酸エチル/ヘキサン)により精製し、粗TESエーテル体 (3.0 mg)を白色固体とし
て得た。 The above crude triol compound (3.0 mg) was dissolved in CH ₂ Cl ₂ (2.0 mL), cooled to 0 ° C., then 2,6-
Lutidine (0.020 mL, 0.171 mmol) and TESOTf (0.030 mL, 0.134 mmol) were added, and the mixture was stirred at 0 ° C. for 50 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (
20-50% ethyl acetate / hexane) to obtain a crude TES ether (3.0 mg) as a white solid.

4,4'-ジ-t-ブチルビフェニル (542.7 mg, 2.04 mmol)のTHF (2.0 mL)にリチウムワイヤ
ー（ca. 40 mg, 5.8 mmol)を加え、アルゴン雰囲気下、超音波照射を行いLiDBB溶液を調
整した。 Lithium wire (ca. 40 mg, 5.8 mmol) was added to THF (2.0 mL) of 4,4'-di-t-butylbiphenyl (542.7 mg, 2.04 mmol), and ultrasonic irradiation was performed in an argon atmosphere to produce a LiDBB solution. Adjusted.

上記の粗TESエーテル体 (3.0 mg)のTHF (3.0 mL)溶液を-78℃に冷却した後、反応溶液
が濃青色となるまで上記のLiDBB溶液を加え、さらに30分間攪拌した。メタノールを加え
て反応を停止し、固体の飽和塩化アンモニウムを加えた。不溶物を濾過し、溶媒を減圧留
去した後、残渣をシリカゲルカラムクロマトグラフィー (20-70% 酢酸エチル/ヘキサン)
により精製し、アルコール 10 (2.6 mg, 3工程73%)を白色固体として得た：[α]_D ²⁶ +37.
3 (c 0.31, CHCl₃); ¹H NMR (500 MHz, C₆D₆) δ 4.53 (ddd, J = 7.7, 7.7, 7.7 Hz, 1H
), 4.20 (br d, J = 5.1, <1 Hz, 1H), 4.09 (m, 1H), 4.07-3.95 (m, 4H), 3.62-3.53 (
m, 3H), 3.50-3.42 (m, 2H), 3.38-3.32 (m, 2H), 3.27-3.17 (m, 5H), 3.09-2.91 (m, 1
0H), 2.85 (br d, J = 9.3, <1 Hz, 1H), 2.83 (br d, J = 8.3, <1 Hz, 1H), 2.66 (m,
1H), 2.54 (m, 1H), 2.50-2.47 (m, 2H), 2.42-2.36 (m, 3H), 2.26-2.15 (m, 4H), 2.12
-2.01 (m, 2H), 1.94-1.60 (m, 21H), 1.53 (m, 1H), 1.36 (d, J = 5.5 Hz, 3H), 1.14
(s, 3H), 1.12 (s, 3H), 1.08 (t, J = 7.7 Hz, 9H), 1.07 (t, J = 8.0 Hz, 9H), 0.95
(t, J = 8.0 Hz, 9H), 0.71 (q, J = 7.7 Hz, 6H), 0.70 (q, J = 8.0 Hz, 6H), 0.54 (q
, J = 8.0 Hz, 6H); ¹³C NMR (125 MHz, pyr-d₅) δ 84.1, 83.8, 83.6, 83.1, 82.6, 80
.1, 80.0, 79.9, 78.7 (x2), 77.9, 77.5, 77.43, 77.40, 77.1, 77.0, 76.5, 76.4, 76.
3, 76.21, 76.16, 76.0, 75.3, 75.1, 72.5, 72.1, 72.04, 71.98, 70.8, 70.7, 70.5, 5
9.1, 45.32, 45.29, 40.4, 40.0, 39.4, 38.9, 38.7, 38.4, 38.2, 37.3, 37.2, 35.92,
35.85, 30.0, 29.84, 29.77, 25.6, 18.5, 16.80, 16.79, 7.4 (x3), 7.3 (x3), 7.1 (x3
), 5.30 (x3), 5.28 (x3), 5.26 (x3); HRMS (FAB) calcd for C₇₀H₁₂₀O₁₈Si₃Na [(M+Na)
⁺] 1355.7680, found 1355.7686.
アリルアルコール11の合成
アルコール10 (3.7 mg, 0.00277 mmol)のCH₂Cl₂ (1.0 mL)溶液を0 ℃に冷却した後、MS
4Å (10.9 mg)、NMO (3.7 mg, 0.0316 mmol)、TPAP (0.9 mg, 0.00252 mmol)を加え、室
温で25分間攪拌した。反応溶液をシリカゲルカラムクロマトグラフィー(60% 酢酸エチル/
ヘキサン)により精製し、粗精製アルデヒドを白色固体として得た。 A solution of the above crude TES ether form (3.0 mg) in THF (3.0 mL) was cooled to −78 ° C., and then the above LiDBB solution was added until the reaction solution became dark blue, followed by further stirring for 30 minutes. The reaction was stopped by adding methanol, and solid saturated ammonium chloride was added. Insoluble material was filtered off and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (20-70% ethyl acetate / hexane).
To give alcohol 10 (2.6 mg, 73% over 3 steps) as a white solid: [α] _D ²⁶ +37.
3 (c 0.31, CHCl ₃ ); ¹ H NMR (500 MHz, C ₆ D ₆ ) δ 4.53 (ddd, J = 7.7, 7.7, 7.7 Hz, 1H
), 4.20 (br d, J = 5.1, <1 Hz, 1H), 4.09 (m, 1H), 4.07-3.95 (m, 4H), 3.62-3.53 (
m, 3H), 3.50-3.42 (m, 2H), 3.38-3.32 (m, 2H), 3.27-3.17 (m, 5H), 3.09-2.91 (m, 1
0H), 2.85 (br d, J = 9.3, <1 Hz, 1H), 2.83 (br d, J = 8.3, <1 Hz, 1H), 2.66 (m,
1H), 2.54 (m, 1H), 2.50-2.47 (m, 2H), 2.42-2.36 (m, 3H), 2.26-2.15 (m, 4H), 2.12
-2.01 (m, 2H), 1.94-1.60 (m, 21H), 1.53 (m, 1H), 1.36 (d, J = 5.5 Hz, 3H), 1.14
(s, 3H), 1.12 (s, 3H), 1.08 (t, J = 7.7 Hz, 9H), 1.07 (t, J = 8.0 Hz, 9H), 0.95
(t, J = 8.0 Hz, 9H), 0.71 (q, J = 7.7 Hz, 6H), 0.70 (q, J = 8.0 Hz, 6H), 0.54 (q
, J = 8.0 Hz, 6H); ¹³ C NMR (125 MHz, pyr-d ₅ ) δ 84.1, 83.8, 83.6, 83.1, 82.6, 80
.1, 80.0, 79.9, 78.7 (x2), 77.9, 77.5, 77.43, 77.40, 77.1, 77.0, 76.5, 76.4, 76.
3, 76.21, 76.16, 76.0, 75.3, 75.1, 72.5, 72.1, 72.04, 71.98, 70.8, 70.7, 70.5, 5
9.1, 45.32, 45.29, 40.4, 40.0, 39.4, 38.9, 38.7, 38.4, 38.2, 37.3, 37.2, 35.92,
35.85, 30.0, 29.84, 29.77, 25.6, 18.5, 16.80, 16.79, 7.4 (x3), 7.3 (x3), 7.1 (x3
), 5.30 (x3), 5.28 (x3), 5.26 (x3); HRMS (FAB) calcd for C ₇₀ H ₁₂₀ O ₁₈ Si ₃ Na [(M + Na)
⁺ ] 1355.7680, found 1355.7686.
A solution of allyl alcohol 11 in synthetic alcohol 10 (3.7 mg, 0.00277 mmol) in CH ₂ Cl ₂ (1.0 mL) was cooled to 0 ° C., then MS
4Å (10.9 mg), NMO (3.7 mg, 0.0316 mmol), TPAP (0.9 mg, 0.00252 mmol) were added, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was subjected to silica gel column chromatography (60% ethyl acetate /
The crude aldehyde was obtained as a white solid.

上記アルデヒドをCH₂Cl₂ (1.0 mL)に溶解させ、methyl 2-(triphenyl-phosphoranylide
ne)propionate (3.5 mg, 0.010 mmol)を加えて、室温で17.5時間攪拌した。反応溶液をシ
リカゲルカラムクロマトグラフィー(40% 酢酸エチル/ヘキサン)により精製し、粗精製エ
ステルを白色固体として得た。 The above aldehyde is dissolved in CH ₂ Cl ₂ (1.0 mL) and methyl 2- (triphenyl-phosphoranylide
ne) propionate (3.5 mg, 0.010 mmol) was added, and the mixture was stirred at room temperature for 17.5 hours. The reaction solution was purified by silica gel column chromatography (40% ethyl acetate / hexane) to obtain a crude purified ester as a white solid.

上記の粗精製エステルをCH₂Cl₂ (1.0 mL)に溶解させ、-78℃に冷却後、DIBAL (0.95 M
ヘキサン溶液, 0.050 mL, 0.0475 mmol)加えて-78 ℃で30分間攪拌した。酢酸エチルを加
えて反応を停止し、飽和酒石酸ナトリウムカリウム水溶液を加えた後、酢酸エチルで希釈
して2時間攪拌した。有機層と水層を分けた後、水層を酢酸エチル(5 mL x 5)で抽出し、
無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムク
ロマトグラフィー (30-80% 酢酸エチル/ヘキサン)により精製し、アリルアルコール11 (2
.5 mg, 3工程66%)を無色油状物として得た：[α]_D ²⁵ +28.8 (c 0.21, CHCl₃); ¹H NMR (6
00 MHz, pyr-d₅) δ 5.78 (dd, J = 5.8, 5.8 Hz, 1H), 4.59 (ddd, J= 7.9, 7.9, 7.9 H
z, 1H), 4.27 (s, 2H), 4.25 (m, 1H), 4.19 (m, 1H), 4.09 (m, 1H), 4.08-4.02 (m, 3H
), 3.77-3.70 (m, 3H), 3.45-3.06 (m, 19H), 2.64 (m, 1H), 2.56-2.50 (m, 5H), 2.46-
2.41 (m, 4H), 2.32-2.21 (m, 4H), 2.17 (m, 1H), 2.01-1.61 (m, 20H), 1.75 (s, 3H),
1.37 (s, 3H), 1.34 (s, 3H), 1.31 (d, J = 5.8 Hz, 3H), 1.06 (t, J = 8.1 Hz, 9H),
1.05 (t, J = 8.1 Hz, 9H), 0.94 (t, J = 7.9 Hz, 9H), 0.71 (q, J = 8.1 Hz, 6H), 0
.70 (q, J = 8.1 Hz, 6H), 0.58 (q, J = 7.9 Hz, 6H); ¹³C NMR (150 MHz, pyr-d₅) d 1
38.5, 120.0, 84.1, 83.8, 83.6, 83.1, 82.6, 81.1, 80.0, 79.9, 78.7, 78.6, 77.9, 7
7.5, 77.43 (x2), 77.40, 77.1, 77.0, 76.5, 76.4, 76.3, 76.22, 76.17, 76.0, 75.1,
72.5, 72.09, 72.05, 72.0, 70.8, 70.7, 70.5, 67.9, 45.33, 45.29, 40.0, 39.5, 38.9
, 38.4, 38.2, 38.0, 37.4, 37.2, 35.9 (x2), 34.9, 29.84, 29.77, 25.57, 25.55, 18.
5, 16.81, 16.79, 14.1, 7.41 (x3), 7.35 (x3), 7.1 (x3), 5.30 (x3), 5.29 (x3), 5.2
6 (x3); HRMS (FAB) calcd for C₇₃H₁₂₄O₁₈Si₃Na [(M+Na)⁺] 1395.7993, found 1395.799
6.
ギムノシン-A 12の合成
アリルアルコール11(19.2 mg, 0.0339 mmol)のTHF/DMF (4:1, v/v, 1.25 mL)溶液を0
°Cに冷却し、TASF (10.0 mg, 0.0363 mmol)加え、0℃で2.5時間攪拌した。反応溶液を室
温に昇温し、さらに6時間攪拌した後、水を加えて反応を停止した。反応溶液をクロロホ
ルム (5 mL x5)で抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥
した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(40%アセ
トン/ベンゼン、10%メタノール/クロロホルム)により精製し、粗テトラオール体を白色固
体として得た。 The above crude ester was dissolved in CH ₂ Cl ₂ (1.0 mL), cooled to −78 ° C., and then DIBAL (0.95 M
(Hexane solution, 0.050 mL, 0.0475 mmol) was added, and the mixture was stirred at -78 ° C for 30 minutes. Ethyl acetate was added to stop the reaction, a saturated aqueous sodium potassium tartrate solution was added, and the mixture was diluted with ethyl acetate and stirred for 2 hours. After separating the organic and aqueous layers, the aqueous layer was extracted with ethyl acetate (5 mL x 5)
Dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (30-80% ethyl acetate / hexane) to give allyl alcohol 11 (2
.5 mg, 66% over 3 steps) was obtained as a colorless oil: [α] _D ²⁵ +28.8 (c 0.21, CHCl ₃ ); ¹ H NMR (6
00 MHz, pyr-d ₅ ) δ 5.78 (dd, J = 5.8, 5.8 Hz, 1H), 4.59 (ddd, J = 7.9, 7.9, 7.9 H
z, 1H), 4.27 (s, 2H), 4.25 (m, 1H), 4.19 (m, 1H), 4.09 (m, 1H), 4.08-4.02 (m, 3H
), 3.77-3.70 (m, 3H), 3.45-3.06 (m, 19H), 2.64 (m, 1H), 2.56-2.50 (m, 5H), 2.46-
2.41 (m, 4H), 2.32-2.21 (m, 4H), 2.17 (m, 1H), 2.01-1.61 (m, 20H), 1.75 (s, 3H),
1.37 (s, 3H), 1.34 (s, 3H), 1.31 (d, J = 5.8 Hz, 3H), 1.06 (t, J = 8.1 Hz, 9H),
1.05 (t, J = 8.1 Hz, 9H), 0.94 (t, J = 7.9 Hz, 9H), 0.71 (q, J = 8.1 Hz, 6H), 0
.70 (q, J = 8.1 Hz, 6H), 0.58 (q, J = 7.9 Hz, 6H); ¹³ C NMR (150 MHz, pyr-d ₅ ) d 1
38.5, 120.0, 84.1, 83.8, 83.6, 83.1, 82.6, 81.1, 80.0, 79.9, 78.7, 78.6, 77.9, 7
7.5, 77.43 (x2), 77.40, 77.1, 77.0, 76.5, 76.4, 76.3, 76.22, 76.17, 76.0, 75.1,
72.5, 72.09, 72.05, 72.0, 70.8, 70.7, 70.5, 67.9, 45.33, 45.29, 40.0, 39.5, 38.9
, 38.4, 38.2, 38.0, 37.4, 37.2, 35.9 (x2), 34.9, 29.84, 29.77, 25.57, 25.55, 18.
5, 16.81, 16.79, 14.1, 7.41 (x3), 7.35 (x3), 7.1 (x3), 5.30 (x3), 5.29 (x3), 5.2
6 (x3); HRMS (FAB) calcd for C ₇₃ H ₁₂₄ O ₁₈ Si ₃ Na [(M + Na) ⁺ ] 1395.7993, found 1395.799
6.
Synthesis of Gymnosin-A 12 A solution of allyl alcohol 11 (19.2 mg, 0.0339 mmol) in THF / DMF (4: 1, v / v, 1.25 mL) was added to 0.
The mixture was cooled to ° C, TASF (10.0 mg, 0.0363 mmol) was added, and the mixture was stirred at 0 ° C for 2.5 hours. The reaction solution was warmed to room temperature and further stirred for 6 hours, and then water was added to stop the reaction. The reaction solution was extracted with chloroform (5 mL × 5), and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (40% acetone / benzene, 10% methanol / chloroform) to obtain a crude tetraol form as a white solid.

上記の粗テトラオール体のクロロホルム (1.0 mL)溶液に、MnO₂ (8.2 mg, 0.094 mmol)
を加え、室温で3時間攪拌した。反応溶液をシリカゲルカラムクロマトグラフィー (10%
クロロホルム/メタノール)により精製し、ギムノシン-A 12 (1.7 mg, 2工程91%) を得た
：[α]_D ²⁶ +27.3 (c 0.055, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 9.37 (s, 1H), 6.47
(dd, J = 6.6, 6.6 Hz, 1H), 4.18 (br d, J = 7.8, <1 Hz, 1H), 4.15-4.11 (m, 2H), 4
.01 (ddd, J= 8.2, 8.2, 8.2 Hz, 1H), 3.78 (ddd, J= 9.6, 9.6, 4.8 Hz, 1H), 3.65 (d
dd, J= 9.6, 9.6, 4.8 Hz, 1H), 3.60 (m, 2H), 3.54-3.46 (m, 3H), 3.29-3.23 (m, 2H)
, 3.19-3.10 (m, 5H), 3.06-2.88 (m, 12H), 2.52-2.49 (m, 2H), 2.45 (m, 1H), 2.34-2
.23 (m, 6H), 2.18-2.12 (m, 3H), 2.08-2.04 (m, 2H), 2.02-1.91 (m, 5H), 1.83-1.78
(m, 3H), 1.74-1.62 (m, 5H), 1.70 (s, 3H), 1.50-1.32 (m, 9H), 1.23 (d, J = 5.8 Hz
, 3H), 1.20 (s, 3H), 1.19 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 195.2, 149.5, 141
,0, 84.0, 83.61, 83.56, 82.7, 81.9, 80.1, 79.8, 79.6, 78.9, 78.1, 77.4, 77.2, 77
.1, 77.0, 76.7 (x2), 76.5, 76.1, 76.0 (x2), 75.75, 75.71, 75.69, 75.65, 73.6, 71
.50, 70.49, 70.3, 70.2, 70.1, 69.9, 44.6, 44.5, 38.5, 38.3, 37.7, 37.5, 37.4, 36
.5, 36.0, 35.5, 35.2 (x2), 34.5, 29.40, 29.37, 25.1(x2), 17.8, 16.6 (x2), 9.5; H
RMS (FAB) calcd for C₅₅H₈₀O₁₈Na [(M+Na)⁺] 1051.5242, found 1051.5251. To a solution of the above crude tetraol form in chloroform (1.0 mL), MnO ₂ (8.2 mg, 0.094 mmol)
And stirred at room temperature for 3 hours. The reaction solution was subjected to silica gel column chromatography (10%
Purification by chloroform / methanol) gave gymnosine-A 12 (1.7 mg, 2 steps 91%): [α] _D ²⁶ +27.3 (c 0.055, CHCl ₃ ); ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.37 (s, 1H), 6.47
(dd, J = 6.6, 6.6 Hz, 1H), 4.18 (br d, J = 7.8, <1 Hz, 1H), 4.15-4.11 (m, 2H), 4
.01 (ddd, J = 8.2, 8.2, 8.2 Hz, 1H), 3.78 (ddd, J = 9.6, 9.6, 4.8 Hz, 1H), 3.65 (d
dd, J = 9.6, 9.6, 4.8 Hz, 1H), 3.60 (m, 2H), 3.54-3.46 (m, 3H), 3.29-3.23 (m, 2H)
, 3.19-3.10 (m, 5H), 3.06-2.88 (m, 12H), 2.52-2.49 (m, 2H), 2.45 (m, 1H), 2.34-2
.23 (m, 6H), 2.18-2.12 (m, 3H), 2.08-2.04 (m, 2H), 2.02-1.91 (m, 5H), 1.83-1.78
(m, 3H), 1.74-1.62 (m, 5H), 1.70 (s, 3H), 1.50-1.32 (m, 9H), 1.23 (d, J = 5.8 Hz
, 3H), 1.20 (s, 3H), 1.19 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 195.2, 149.5, 141
, 0, 84.0, 83.61, 83.56, 82.7, 81.9, 80.1, 79.8, 79.6, 78.9, 78.1, 77.4, 77.2, 77
.1, 77.0, 76.7 (x2), 76.5, 76.1, 76.0 (x2), 75.75, 75.71, 75.69, 75.65, 73.6, 71
.50, 70.49, 70.3, 70.2, 70.1, 69.9, 44.6, 44.5, 38.5, 38.3, 37.7, 37.5, 37.4, 36
.5, 36.0, 35.5, 35.2 (x2), 34.5, 29.40, 29.37, 25.1 (x2), 17.8, 16.6 (x2), 9.5; H
RMS (FAB) calcd for C ₅₅ H ₈₀ O ₁₈ Na [(M + Na) ⁺ ] 1051.5242, found 1051.5251.

この出願の発明によれば、天然物質の試料供給が困難であり、これまで構造決定された
ポリ環状エーテルの中では、連続して縮環したエーテル環の数が最大（１４個）のギムノ
シン−Ａが、化学合成により製造されて量的供給が実現されるとともに、ポリ環状エーテ
ル分子の一般的合成への適用が可能になる。 According to the invention of this application, it is difficult to supply a sample of a natural substance. Among the polycyclic ethers whose structures have been determined so far, the number of consecutively condensed ether rings (14) A is produced by chemical synthesis to realize a quantitative supply and can be applied to general synthesis of polycyclic ether molecules.

Claims

Next formula

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and PMB represents a p-methoxybenzyl group.) Method.

The polycyclic ether compound obtained by the method according to claim 1 is hydroborated and oxidized, and the obtained alcohol is treated with 2,6-lutidine and TESOTf to obtain a triethylsilyl (TES) ether form. Oxidized with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, TES represents a triethylsilyl group, and TIPS represents a triisopropylsilyl group.) This α-siloxy ketone is converted into EtSH and Zn (OTf) ₂₂ Processed by the following formula

(In the formula, Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and TIPS represents a triisopropylsilyl group.) After obtaining the thioketal represented by _3Three Treatment with SnH and azobisisobutyronitrile gives the following formula

A method for synthesizing a polycyclic ether compound, comprising obtaining a polycyclic ether compound represented by the formula:

The polycyclic ether compound obtained by the method according to claim 2 is treated with tetrabutylammonium fluoride to obtain a triol body, and then this triol body is treated with 2,6-lutidine and TESOTf to obtain a TES ether body. And treating the TES ether with LiDBB solution

Next formula

3. A polycyclic ether compound represented by the formula: (wherein Bn represents a benzyl group, TBS represents a tert-butyldimethylsilyl group, and TIPS represents a triisopropylsilyl group). Or a method for synthesizing the polycyclic ether compound according to 3.