JP2000247976A - Construction of indolocarbazole skeleton - Google Patents
Construction of indolocarbazole skeletonInfo
- Publication number
- JP2000247976A JP2000247976A JP11052498A JP5249899A JP2000247976A JP 2000247976 A JP2000247976 A JP 2000247976A JP 11052498 A JP11052498 A JP 11052498A JP 5249899 A JP5249899 A JP 5249899A JP 2000247976 A JP2000247976 A JP 2000247976A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】この出願の発明は、インドロ
カルバゾール骨格の構築方法に関するものである。さら
に詳しくは、この出願の発明は、生理活性を有するアル
カロイドの合成法として有用な、温和な条件で再現性良
く、効率的にインドロカルバゾール骨格を構築すること
のできる新しい方法に関するものである。TECHNICAL FIELD The invention of this application relates to a method for constructing an indolocarbazole skeleton. More specifically, the invention of this application relates to a novel method that is useful as a method for synthesizing an alkaloid having a physiological activity and that can efficiently and efficiently construct an indolocarbazole skeleton under mild conditions.
【０００２】[0002]
【従来の技術とその課題課題】次式（１）2. Description of the Related Art The following equation (1)
【０００３】[0003]
【化１１】 Embedded image
【０００４】で表わされる化合物Ｋ２５２ａはインドロ
カルバゾール骨格を有するアルカロイドとして、次式
（２）Compound K252a represented by the following formula (2) is an alkaloid having an indolocarbazole skeleton.
【０００５】[0005]
【化１２】 Embedded image
【０００６】で表わされるstaurosporine とともに強力
なプロテインキナーゼＣ阻害活性を有することが知られ
ている。たとえばこれら物質にみられるように、アルカ
ロイド等としてインドロカルバゾール骨格を有する化合
物がその生理活性の点からも注目されているが、その合
成は必ずしも容易でないのが実情である。It is known that staurosporine represented by the formula (1) has potent protein kinase C inhibitory activity. For example, as seen in these substances, compounds having an indolocarbazole skeleton as alkaloids and the like have attracted attention from the viewpoint of their physiological activities, but the fact is that their synthesis is not always easy.
【０００７】たとえば前記のＫ２５２ａ（１）は、アグ
リコン部の２つのインドール窒素原子が糖部分と環状の
グリコシドを形成していることから、それらのグリコシ
ル結合の生成における、アグリコン部のラクタムと糖部
分の位置異性の制御が合成上の最大の問題となってい
る。実際、Woodらや、Ｄanishefskyらによりそれぞれ
（１）、（２）の全合成が達成されたが、いずれもこの
問題の克服には至っていない。For example, K252a (1) is characterized in that the two indole nitrogen atoms of the aglycone moiety form a cyclic glycoside with the sugar moiety, and thus the lactam and sugar moiety of the aglycone moiety in their glycosyl bond formation. Is the biggest problem in the synthesis. In fact, Wood, et al., And Danishefsky, et al. Achieved total synthesis of (1) and (2), respectively, but none of them has overcome this problem.
【０００８】位置異性体の副生を伴うことなくＫ２５２
ａを合成するには、２つのグリコシル結合を段階的かつ
位置選択的に形成させる必要がある。そこで問題となる
のが、このような位置選択性を実現するために、いかに
してインドロカルバゾール骨格を構築するのかの点であ
る。この出願の発明者によっても様々なアプローチとし
て検討されてきたが、より温和な条件でしかも高い合成
選択性として効率的にインドロカルバゾール骨格を構築
することには成功していなかった。そして、このインド
ロカルバゾール骨格の構築法の検討においては、前記Ｋ
２５２ａ（１）に限られることなしに、より広範な化合
物の合成に適用可能とされる一般法を確立することが大
きな命題であった。K252 without regioisomer by-product
To synthesize a, it is necessary to form two glycosyl bonds stepwise and regioselectively. The problem is how to construct an indolocarbazole skeleton in order to achieve such regioselectivity. Although various approaches have been studied by the inventor of this application, it has not been successful to construct an indolocarbazole skeleton efficiently under milder conditions and with higher synthetic selectivity. In the study of the method for constructing the indolocarbazole skeleton,
It was a great proposition to establish a general method that could be applied to the synthesis of a wider range of compounds without being limited to 252a (1).
【０００９】この出願の発明は、以上のとおりの背景を
踏まえてなされたものであり、アルカロイド等のインド
ロカルバゾール骨格を有する化合物のできるだけ簡便
で、かつ効率のよい合成方法として、インドロカルバゾ
ール骨格の新しい構築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 view of the above background, and has been proposed as a method for synthesizing a compound having an indolocarbazole skeleton such as an alkaloid as simple and efficient as possible. It is an object to provide a new construction method.
【００１０】[0010]
【課題を解決するための手段】この出願の発明は、上記
の課題を解決するものとして、第１には、次式（Ａ）Means for Solving the Problems The invention of the present application solves the above-mentioned problems.
【００１１】[0011]
【化１３】 Embedded image
【００１２】（式中のＲ1 、Ｒ2 およびＲ3 は、各々、
水素原子、保護基もしくは置換基を示す。）で表わされ
るインドロカルバゾール骨格の構築方法であって、次式
（Ｂ）(Wherein R 1 , R 2 and R 3 are each
Represents a hydrogen atom, a protecting group or a substituent. A method for constructing an indolocarbazole skeleton represented by the following formula (B):
【００１３】[0013]
【化１４】 Embedded image
【００１４】（Ｒ4 は置換基もしくは水素原子を示
す。）で表わされる２−ブロモインドール酢酸化合物を
トリプタミンと縮合反応させて次式（Ｃ）[0014] (R 4 is. Indicating a substituent or a hydrogen atom) with 2-bromoindole acid compound represented by was tryptamine and condensation reaction following formula (C)
【００１５】[0015]
【化１５】 Embedded image
【００１６】で表わされるアミド化合物を生成させ、酸
化反応とこれに続く窒素原子のアセチル化によって次式
（Ｄ）The amide compound represented by the formula (D) is produced by an oxidation reaction and subsequent acetylation of a nitrogen atom.
【００１７】[0017]
【化１６】 Embedded image
【００１８】で表わされるアシル化合物に導いた後に閉
環脱水反応させて次式（Ｅ）The acyl compound represented by the formula (E) is subjected to a ring-closing dehydration reaction to give the following formula (E)
【００１９】[0019]
【化１７】 Embedded image
【００２０】で表わされる化合物を生成させ、次いで光
照射と脱ＨＢｒ反応とを経由させて次式（Ｆ）A compound represented by the following formula (F) is produced through light irradiation and HBr removal reaction.
【００２１】[0021]
【化１８】 Embedded image
【００２２】で表わされる化合物を導くか、さらに所望
により脱アシル化反応させるかもしくは保護基または置
換基を導入することを特徴とするインドロカルバゾール
骨格の構築方法を提供する。また、この出願の発明は、
第２には、Ｒ2 が糖基である前記第１の発明のインドロ
カルバゾール骨格の構築方法を提供する。The present invention provides a method for constructing an indolocarbazole skeleton, which comprises deriving a compound represented by the formula, further performing a deacylation reaction as required, or introducing a protecting group or a substituent. Also, the invention of this application
Secondly, the present invention provides the method for constructing an indolocarbazole skeleton according to the first invention, wherein R 2 is a sugar group.
【００２３】そして、この出願の発明は、第３には、次
式（Ｇ）Third, the invention of this application is based on the following formula (G):
【００２４】[0024]
【化１９】 Embedded image
【００２５】で表わされる化合物から、次式（Ｈ）From the compound represented by the following formula (H)
【００２６】[0026]
【化２０】 Embedded image
【００２７】で表わされる化合物を製造するインドロカ
ルバゾール骨格の構築方法を、第４には、請求項３の方
法により導かれた式（Ｈ）の化合物から、次式（Ｉ）Fourth, a method for constructing the indolocarbazole skeleton for producing the compound represented by the formula (I) is to convert the compound of the formula (H) derived by the method of claim 3 into the following formula (I)
【００２８】[0028]
【化２１】 Embedded image
【００２９】で表わされる糖ケトン化合物を製造し、次
いで次式（Ｊ）A sugar ketone compound represented by the following formula (J) is prepared.
【００３０】[0030]
【化２２】 Embedded image
【００３１】で表わされるインドロカルバゾール（＋）
−Ｋ２５２ａを製造することを特徴とするインドロカル
バゾール骨格の構築方法を提供する。Indolocarbazole (+) represented by
A method for constructing an indolocarbazole skeleton characterized by producing -K252a.
【００３２】[0032]
【発明の実施の形態】この出願の発明は、以上のとおり
の特徴を有するものであるが以下にその実施の形態を合
成例に沿って説明する。なお、前記の符号Ｒ1 、Ｒ2 、
Ｒ3 、そしてＲ4 は許容される各種の保護基や置換基で
あってよく、目的に応じて選択されてよいことは言うま
でもない。BEST MODE FOR CARRYING OUT THE INVENTION The invention of this application has the features as described above, and the embodiments thereof will be described below along with synthesis examples. Note that the above symbols R 1 , R 2 ,
R 3 and R 4 may be various acceptable protecting groups and substituents, and may be selected according to the purpose.
【００３３】また、前記式（Ａ）〜（Ｊ）の化合物が、
カルバゾール環にさらに適宜な置換基を有してもよいこ
とも当然のことである。この発明はインドロカルバゾー
ル骨格の構築法であってみれば、原料、中間体そして目
的物に様々な態様が許容されることも言うまでもない。 （合成例１）次の反応式に従って、インドロカルバゾー
ル（１９）化合物を合成した。Further, the compounds of the formulas (A) to (J)
It is a matter of course that the carbazole ring may further have an appropriate substituent. If the present invention is concerned with a method for constructing an indolocarbazole skeleton, it goes without saying that various embodiments are permissible for the raw materials, intermediates and target products. (Synthesis Example 1) According to the following reaction formula, an indolocarbazole (19) compound was synthesized.
【００３４】[0034]
【化２３】 Embedded image
【００３５】すなわち、インドール酢酸から容易に誘導
可能な２−ブロモインドール（１５）とトリプタミンと
の縮合によりアミド（１６）を得た。このアミド（１
６）のＤＤＱによるアルキルインドールからアシルイン
ドールへの酸化（J.Org.Chem1977．42,1213）は位置選
択的に進行し、続いてインドールとアミドの窒素原子の
アセチル化により活性化された中間体（１７）を得た。
モレキュラーシーブスと触媒量のＤＢＵで閉環脱水反応
が容易に進行しビスインドール（１８）を得た。閉環反
応は可視光（自然太陽光またはハロゲンランプ）による
光反応とそれに続く脱ＨＢｒ反応でほぼ定量的に進行し
インドロカルバソール（１９）を得た。これは光反応に
より同旋的に閉環し、水素原子と臭素原子がantiperipl
anarの位置関係になるために臭化水素の脱離による芳香
環化反応が容易に進行するためである。こうして、３−
インドール酢酸を原料として８段階でインドロカルバゾ
ール（１９）が合成でき、穏やかな条件で効率的なイン
ドロカルバゾール骨格の構築法を開発することができ
た。 （合成例２）合成例１の方法を利用して、Ｋ２５２ａを
次の反応式に従って合成した。That is, condensation of 2-bromoindole (15), which can be easily derived from indoleacetic acid, with tryptamine yielded amide (16). This amide (1
6) Oxidation of alkyl indole to acyl indole by DDQ (J. Org. Chem 1977.42, 1213) proceeds regioselectively, followed by an intermediate activated by acetylation of the nitrogen atom of indole and amide (17) was obtained.
The ring-closing dehydration reaction easily proceeded with molecular sieves and a catalytic amount of DBU to obtain bisindole (18). The ring closure reaction proceeded almost quantitatively by a photoreaction with visible light (natural sunlight or a halogen lamp) followed by a de-HBr reaction to obtain indolocarbazole (19). It is closed in a helical manner by a photoreaction, and hydrogen and bromine atoms become antiperipl
This is because the aromatic cyclization reaction due to elimination of hydrogen bromide easily proceeds due to the positional relationship of anar. Thus, 3-
Indoleacetic acid was used as a raw material to synthesize indolocarbazole (19) in eight steps, and a method for constructing an efficient indolocarbazole skeleton under mild conditions could be developed. (Synthesis Example 2) Using the method of Synthesis Example 1, K252a was synthesized according to the following reaction formula.
【００３６】[0036]
【化２４】 Embedded image
【００３７】２−ブロモインドール酢酸アリルエステル
とリボシルクロリド（１１）とのグリコシル化反応は立
体選択的に進行（収率９７％）し化合物（２０）が得ら
れた。この化合物（２０）から合成例１のインドロカル
バゾール骨格構築法で７段階、収率４６％で、位置異性
をコントロールした合成のための重要鍵中間体であるイ
ンドロカルバゾール（２１）がアノマー位の異性化を伴
うことなく得られた。これを一級アルコールの選択的ヨ
ウ素化を経て、フェニルセレニドへと変換した後、ＭＣ
ＰＢＡによる酸化後のセレノキシド脱離によりエノール
エーテル（２２）とした。第二の鍵反応である環状グリ
コシル化反応について種々検討したこところ、ヨウ化カ
リウム−ヨウ素を用いる方法が最も良い収率で化合物
（２３）を与えた。続いて脱ヨウ素化を行い、脱アセチ
ル化および酸化によりケトン（２４）を得た。The glycosylation reaction between 2-bromoindole acetic acid allyl ester and ribosilyl chloride (11) proceeded stereoselectively (yield 97%) to give compound (20). From this compound (20), indolocarbazole (21), which is an important key intermediate for the synthesis in which regioisomerism is controlled, is obtained in seven steps in a yield of 46% in the indolocarbazole skeleton construction method of Synthesis Example 1 in the anomeric position. Without isomerization. This is converted to phenyl selenide through selective iodination of primary alcohol, and then MC
Enol ether (22) was obtained by elimination of selenoxide after oxidation with PBA. After various studies on the cyclic glycosylation reaction, which is the second key reaction, the method using potassium iodide-iodine gave compound (23) in the best yield. Subsequently, deiodination was performed, and ketone (24) was obtained by deacetylation and oxidation.
【００３８】最後に、糖部分のケトンに対して立体選択
的に一炭素ユニットを導入した。ケトン体（２４）の青
酸−ピリジンによるシアノヒドリン形成は完全に立体選
択的に起こり、化合物（２５）を得た。塩酸−ギ酸によ
りニトリルをアミドとしたのちアルカリ加水分解、カル
ボン酸をジアゾメタンでメチルエステルとして（＋）−
Ｋ２５２ａを得た。このものは、天然の（＋）−Ｋ２５
２ａと各種スペクトルデータが完全に一致した。こうし
て、インドロカルバゾール骨格を介しての環状グリコシ
ド構造の立体化学と上部ラクタムとの位置異性を完全に
制御した（＋）−Ｋ２５２ａの全合成を完了した。Finally, one carbon unit was introduced stereoselectively with respect to the ketone of the sugar moiety. Cyanohydrin formation of the ketone body (24) by hydrocyanic acid-pyridine occurred completely stereoselectively, and a compound (25) was obtained. The nitrile is converted to an amide with hydrochloric acid-formic acid, and then subjected to alkali hydrolysis.
K252a was obtained. This is natural (+)-K25
2a and various spectrum data completely matched. Thus, the complete synthesis of (+)-K252a in which the stereochemistry of the cyclic glycoside structure via the indolocarbazole skeleton and the positional isomerism of the upper lactam were completely controlled was completed.
【００３９】[0039]
【発明の効果】以上詳しく説明したように、この出願の
発明によって、温和な条件で、再現性良く、効率的にイ
ンドロカルバゾール骨格の構築が可視とされる。この発
明の方法は、一般的方法として広く応用可能とされるも
のである。As described in detail above, according to the invention of this application, the construction of an indolocarbazole skeleton can be made visible under mild conditions with good reproducibility and efficiency. The method of the present invention is widely applicable as a general method.
Claims (4)
護基もしくは置換基を示す。で表わされるインドロカル
バゾール骨格の構築方法であって、次式（Ｂ） 【化２】 （Ｒ4 は置換基もしくは水素原子を示す。）で表わされ
る２−ブロモインドール酢酸化合物をトリプタミンと縮
合反応させて次式（Ｃ） 【化３】 で表わされるアミド化合物を生成させ、酸化反応とこれ
に続く窒素原子のアセチル化によって次式（Ｄ） 【化４】 で表わされるアシル化合物に導いた後に閉環脱水反応さ
せて次式（Ｅ） 【化５】 で表わされる化合物を生成させ、次いで光照射と脱ＨＢ
ｒ反応とを経由させて次式（Ｆ） 【化６】 で表わされる化合物を導くか、さらに所望により脱アシ
ル化反応させるかもしくは保護基または置換基を導入す
ることを特徴とするインドロカルバゾール骨格の構築方
法。(1) The following formula (A): (Wherein R 1 , R 2 and R 3 each represent a hydrogen atom, a protecting group or a substituent. A method for constructing an indolocarbazole skeleton represented by the following formula (B): (R 4 represents a substituent or a hydrogen atom.) A 2-bromoindoleacetic acid compound represented by the following formula (C) is subjected to a condensation reaction with tryptamine. An amide compound represented by the following formula is generated, and the amide compound is subjected to an oxidation reaction and subsequent acetylation of a nitrogen atom to obtain the following formula (D). And then subjected to a ring-closing dehydration reaction to obtain an acyl compound represented by the following formula (E): To produce a compound represented by the formula
The following formula (F) via the r reaction A method for constructing an indolocarbazole skeleton, which comprises deriving a compound represented by the formula (I), further subjecting the compound to a deacylation reaction as required, or introducing a protecting group or a substituent.
バゾール骨格の構築方法。2. The method for constructing an indolocarbazole skeleton according to claim 1, wherein R 2 is a sugar group.
ドロカルバゾール骨格の構築方法。3. The following formula (G): From the compound represented by the following formula (H): 3. The method for constructing an indolocarbazole skeleton according to claim 1 or 2, wherein the compound represented by the formula is produced.
化合物から、次式（Ｉ） 【化９】 で表わされる糖ケトン化合物を製造し、次いで次式
（Ｊ） 【化１０】 で表わされるインドロカルバゾール（＋）−Ｋ２５２ａ
を製造することを特徴とするインドロカルバゾール骨格
の構築方法。4. A compound of the formula (H) derived by the method of claim 3, A sugar ketone compound represented by the following formula is produced, and then the following formula (J) is prepared. Indolocarbazole (+)-K252a represented by
And a method for constructing an indolocarbazole skeleton.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05249899A JP3916791B2 (en) | 1999-03-01 | 1999-03-01 | Method for producing indolocarbazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05249899A JP3916791B2 (en) | 1999-03-01 | 1999-03-01 | Method for producing indolocarbazole |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006275816A Division JP4558697B2 (en) | 2006-10-06 | 2006-10-06 | Method for producing indolocarbazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000247976A true JP2000247976A (en) | 2000-09-12 |
| JP3916791B2 JP3916791B2 (en) | 2007-05-23 |
Family
ID=12916396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP05249899A Expired - Fee Related JP3916791B2 (en) | 1999-03-01 | 1999-03-01 | Method for producing indolocarbazole |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3916791B2 (en) |
-
1999
- 1999-03-01 JP JP05249899A patent/JP3916791B2/en not_active Expired - Fee Related
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|---|---|
| JP3916791B2 (en) | 2007-05-23 |
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