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JP4825947B2 - Process for producing unsaturated aminodiols - Google Patents

Process for producing unsaturated aminodiols Download PDF

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JP4825947B2
JP4825947B2 JP2005024062A JP2005024062A JP4825947B2 JP 4825947 B2 JP4825947 B2 JP 4825947B2 JP 2005024062 A JP2005024062 A JP 2005024062A JP 2005024062 A JP2005024062 A JP 2005024062A JP 4825947 B2 JP4825947 B2 JP 4825947B2
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成雄 勝村
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Kwansei Gakuin Educational Foundation
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2278—Complexes comprising two carbene ligands differing from each other, e.g. Grubbs second generation catalysts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2269—Heterocyclic carbenes
    • B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07F7/02—Silicon compounds
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    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
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Description

本発明はメタセシス反応を利用した不飽和アミノジオール類の製造方法に関するものである。   The present invention relates to a method for producing unsaturated aminodiols utilizing a metathesis reaction.

不飽和アミノジオール類はスフィンゴシン誘導体であり、ドラッグデリバリーシステム等に有効なスフィンゴミエリンなどの合成原料として有用な物質である。   Unsaturated aminodiols are sphingosine derivatives and are useful as synthetic raw materials for sphingomyelin and the like effective for drug delivery systems and the like.

従来、不飽和アミノジオール類の製造方法に関しては、糖を原料とした合成方法、Sharpless不斉エポキシ化を用いた方法、Garnerアルデヒドを用いた方法、不斉アルドール反応を用いた方法などが報告されている（たとえば、非特許文献１）が、いずれも工程が煩雑であったり、立体選択性が悪いといった問題を抱えている。   Conventionally, methods for producing unsaturated aminodiols have been reported, such as synthesis methods using sugar as a raw material, methods using Sharpless asymmetric epoxidation, methods using Garner aldehyde, methods using asymmetric aldol reactions, etc. (For example, Non-Patent Document 1) all have problems such as complicated processes and poor stereoselectivity.

最近になって、(S)−3−ベンジル−4−((R)−1−ヒドロキシアリル)オキサゾリジン−2−オン（(S)-3-Benzyl-4-((R)-1-hydroxyallyl)oxazolidin-2-one）のような環状保護基を有する化合物のメタセシスを利用したスフィンゴシン誘導体の合成方法が報告されている（非特許文献２）が、このオキサゾリジノン（oxazolidinone）骨格を有するものではホモメタセシス生成物が主生成物であったり、Ｅ／Ｚ選択性が悪かったり、反応性に劣っていたり、さらに収率が悪いといった問題がある。
勝村成雄、箱木敏和，「蛋白質核酸酵素」, Vol47, No4, 526-536 (2002) S. Torssell and P. Somfai, "Org. Biomol. Chem"., 2, 1643-1646 (2004) Recently, (S) -3-Benzyl-4-((R) -1-hydroxyallyl) (S) -3-Benzyl-4-((R) -1-hydroxyallyl) Although a method for synthesizing sphingosine derivatives utilizing metathesis of a compound having a cyclic protecting group such as oxazolidin-2-one) has been reported (Non-patent Document 2), homometathesis in the case of having an oxazolidinone skeleton is reported. There are problems that the product is a main product, E / Z selectivity is poor, reactivity is poor, and yield is poor.
Natsuo Katsumura, Toshikazu Hakogi, "Protein Nucleic Acid Enzyme", Vol47, No4, 526-536 (2002) S. Torssell and P. Somfai, "Org. Biomol. Chem"., 2, 1643-1646 (2004)

本発明はメタセシス反応を利用して、簡便かつ安価に不飽和アミノジオール類を製造する方法を提供することを目的とするものである。   An object of this invention is to provide the method of manufacturing unsaturated aminodiols simply and cheaply using a metathesis reaction.

本発明者らは、かかる問題を解決すべく鋭意研究を行った結果、メタセシス触媒の存在下、非環状保護基を有する不飽和アミノジオール類とオレフィンを反応させることにより、スフィンゴミエリン等の合成中間体として有用な不飽和アミノジオール類を簡便かつ安価に製造できることを見出し、本発明を完成するに至った。   As a result of intensive studies to solve such a problem, the present inventors have made synthesis intermediates such as sphingomyelin by reacting an unsaturated aminodiol having an acyclic protecting group with an olefin in the presence of a metathesis catalyst. The present inventors have found that unsaturated aminodiols useful as a body can be easily and inexpensively produced and have completed the present invention.

すなわち、本発明の不飽和アミノジオール類の製造方法は下記一般式（Ｉ）

Figure 0004825947
That is, the method for producing the unsaturated aminodiols of the present invention comprises the following general formula (I):
Figure 0004825947

（式中、Ｒ１およびＲ４は水素原子または水酸基の保護基であり、Ｒ２およびＲ３は水素原子またはアミノ基の保護基であり、Ｒ５は水素原子または低級アルキル基である。）で表される不飽和アミノジオール類と、下記一般式（II）

Figure 0004825947
(Wherein R 1 and R 4 are a hydrogen atom or a hydroxyl protecting group, R 2 and R 3 are a hydrogen atom or an amino group protecting group, and R 5 is a hydrogen atom or a lower alkyl group.) An unsaturated aminodiol represented by the following general formula (II)
Figure 0004825947

（式中、Ｒ６は炭素数1〜２０のアルキル基である）で表されるオレフィン類をメタセシス触媒存在下で反応させ下記一般式（III）

Figure 0004825947
(Wherein R 6 is an alkyl group having 1 to 20 carbon atoms) is reacted in the presence of a metathesis catalyst, and the following general formula (III)
Figure 0004825947

（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ６は上記と同じである。）で表される不飽和アミノジオール類を製造することを特徴とするものである。 (Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as described above).

前記メタセシス触媒はルテニウムカルベン錯体であることが好ましく、ルテニウムカルベン錯体としては、下記一般式（IＶ）

Figure 0004825947
The metathesis catalyst is preferably a ruthenium carbene complex, and the ruthenium carbene complex is represented by the following general formula (IV)
Figure 0004825947

（式中、Ｒ７およびＲ８はアルキル基またはアリール基であり、Ｒ９はホスフィン配位子であり、Ｘはハロゲン原子である。）で表される錯体であることが好ましい。 (Wherein R 7 and R 8 are an alkyl group or an aryl group, R 9 is a phosphine ligand, and X is a halogen atom).

本発明の不飽和アミノジオール類の製造方法は、不飽和アミノジオール類とオレフィン類をメタセシス触媒存在下で反応させるため、従来の反応工程に比べて簡便で汎用性及び反応性が高く、立体選択性（Ｅ／Ｚ選択性）がよいため高い収率で目的化合物である不飽和アミノジオール類を製造することが可能である。   Since the method for producing unsaturated aminodiols of the present invention reacts unsaturated aminodiols and olefins in the presence of a metathesis catalyst, it is simpler, versatile and reactive than conventional reaction steps, and is stereoselective. Since the property (E / Z selectivity) is good, it is possible to produce unsaturated aminodiols that are target compounds in a high yield.

加えて、本発明の不飽和アミノジオール類の製造方法に使用する不飽和アミノジオール類、オレフィン類およびメタセシス触媒は比較的安価であるため、不飽和アミノジオール類を安価に製造することが可能であり、ドラッグデリバリーシステム等に有効なスフィンゴミエリンなどの合成原料を経済的に提供することが可能である。   In addition, since unsaturated aminodiols, olefins and metathesis catalysts used in the method for producing unsaturated aminodiols of the present invention are relatively inexpensive, it is possible to produce unsaturated aminodiols at low cost. In addition, it is possible to economically provide synthetic raw materials such as sphingomyelin that are effective for drug delivery systems and the like.

本発明の不飽和アミノジオール類の製造方法は下記一般式（Ｉ）

Figure 0004825947
The process for producing the unsaturated aminodiols of the present invention comprises the following general formula (I)
Figure 0004825947

（式中、Ｒ１およびＲ４は水素原子または水酸基の保護基であり、Ｒ２およびＲ３は水素原子またはアミノ基の保護基であり、Ｒ５は水素原子または低級アルキル基である。）で表される不飽和アミノジオール類と、下記一般式（II）

Figure 0004825947
(Wherein R 1 and R 4 are a hydrogen atom or a hydroxyl protecting group, R 2 and R 3 are a hydrogen atom or an amino group protecting group, and R 5 is a hydrogen atom or a lower alkyl group.) An unsaturated aminodiol represented by the following general formula (II)
Figure 0004825947

（式中、Ｒ６は炭素数1〜２０のアルキル基である）で表されるオレフィン類をメタセシス触媒存在下で反応させ下記一般式（III）

Figure 0004825947
(Wherein R 6 is an alkyl group having 1 to 20 carbon atoms) is reacted in the presence of a metathesis catalyst, and the following general formula (III)
Figure 0004825947

（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ６は上記と同じである。）で表される不飽和アミノジオール類を製造することを特徴とする。 (Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as described above).

上記低級アルキル基としては、枝分かれを有していてもよい炭素数１から５のアルキル基であり、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ−ブチル基、ｔ−ブチル基、ペンチル基等を例示することができる。   The lower alkyl group is an alkyl group having 1 to 5 carbon atoms which may be branched, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, and a t-butyl group. And a pentyl group.

炭素数１〜２０のアルキル基とは、反応に関与しない置換基を有していてもよい炭素数１から２０のアルキル基である。   A C1-C20 alkyl group is a C1-C20 alkyl group which may have a substituent which does not participate in reaction.

水酸基の保護基としては、トリメチルシリル、トリエチルシリル、ｔ−ブチルジメチルシリル、トリイソプロピルシリル等のシリル系保護基、メトキシメチル、テトラヒドロピラニル、エトキシエチル等のエーテル系保護基、アセチル、ベンゾイル等のエステル系保護基等をあげることができる。   Examples of hydroxyl protecting groups include silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl, ether protecting groups such as methoxymethyl, tetrahydropyranyl and ethoxyethyl, and esters such as acetyl and benzoyl. Examples thereof include a system protecting group.

アミノ基の保護基としては、トリメチルシリル、トリエチルシリル、ｔ−ブチルジメチルシリル、トリイソプロピルシリル等のシリル系保護基、ｔ−ブトキシカルボニル、ベンジルカルボニル等のカルバメート系保護基、アセチル、ベンゾイル等のエステル系保護基等をあげることができる。   Examples of amino protecting groups include silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl, carbamate protecting groups such as t-butoxycarbonyl and benzylcarbonyl, and ester groups such as acetyl and benzoyl. Protecting groups and the like can be mentioned.

本発明の製造方法はメタセシス触媒存在下に反応行うものであり、メタセシス触媒としては、既存の各種メタセシス触媒が好適に用いられるが、中でもルテニウムカルベン錯体が反応効率の点で好ましい。   The production method of the present invention is carried out in the presence of a metathesis catalyst. As the metathesis catalyst, various existing metathesis catalysts are suitably used, and among them, a ruthenium carbene complex is preferable in terms of reaction efficiency.

ルテニウムカルベン錯体としては、既存のルテニウムカルベン錯体が好適に用いられるが、下記一般式（IＶ）

Figure 0004825947
As the ruthenium carbene complex, an existing ruthenium carbene complex is preferably used, but the following general formula (IV)
Figure 0004825947

（式中、Ｒ７およびＲ８はアルキル基またはアリール基であり、Ｒ９はホスフィン配位子であり、Ｘはハロゲン原子である。）で表される錯体が反応効率、収率、入手の容易さ等の点で好ましい。 (Wherein R 7 and R 8 are an alkyl group or an aryl group, R 9 is a phosphine ligand, and X is a halogen atom). It is preferable in terms of ease.

ここで、上記アルキル基は反応に関与しない置換基を有していてもよい炭素数１から２０のアルキル基であり、アリール基とは、反応に関与しない置換基を有していてもよいフェニル基、ナフチル基、フラン基、ピロール基、チオフェン基等を例示することができる。上記ホスフィン配位子とは、上記アルキル基またはアリール基が置換したホスフィン配位子である。ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。   Here, the alkyl group is an alkyl group having 1 to 20 carbon atoms which may have a substituent which does not participate in the reaction, and the aryl group is a phenyl which may have a substituent which does not participate in the reaction. Examples thereof include a group, a naphthyl group, a furan group, a pyrrole group, and a thiophene group. The phosphine ligand is a phosphine ligand substituted with the alkyl group or aryl group. A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

本発明の実施にあたっては、反応に関与しない溶媒中で行うことが好ましく、ベンゼン、トルエン、キシレン、ヘキサン、シクロヘキサン等の炭化水素系溶媒、テトラヒドロフラン、ジメトキシエタン、ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化溶媒等を例示することができる。   The present invention is preferably carried out in a solvent not involved in the reaction, hydrocarbon solvents such as benzene, toluene, xylene, hexane and cyclohexane, ether solvents such as tetrahydrofuran, dimethoxyethane and dioxane, dichloromethane and chloroform. And halogenated solvents such as dichloroethane.

反応温度は、0℃ないし150℃の温度範囲から適宜選択することができるが、反応速度ならびに経済的観点から室温ないし８０℃の範囲が好ましい。
以下、本発明を実施例および参考例によりさらに詳しく説明する。 The reaction temperature can be appropriately selected from a temperature range of 0 ° C. to 150 ° C., but a range of room temperature to 80 ° C. is preferred from the viewpoint of reaction rate and economics.
Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.

（参考例１）

Figure 0004825947
(Reference Example 1)
Figure 0004825947

テトラヒドロピラニルプロパギルエーテル（Tetrahydropyranyl propargyl ether：0.656 g, 4.68 mmol )のTHF( 29.8 ml ) 溶液に-78 ℃で n−ブチルリチウム の1.6 Nヘキサン溶液( 2.80 ml, 4.47 mmol )を滴下し、そのままの温度で15分攪拌した。この溶液を-100℃以下に冷却した。(4S)−3−ベンジル−2−オキソ−オキサゾリジン−４−カルボン酸メチルエステル（上記１)(（4S)-3-Benzyl-2-oxo-oxazolidine-4-carboxylic acid methyl ester：1.00 g, 4.25 mmol )のTHF溶液に滴下した後、10分攪拌した。反応混合物に1N−HCl 及びジエチルエーテルを滴下し、ジエチルエーテルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー(ヘキサンに25％〜50％の酢酸エチルを溶かしたもの )により精製し、(4S)−3−ベンジル−4−[4'−(テトラヒドロピラン−2'−イルオキシ)−ブタ−2'−イノイル]−オキサゾリジン−2−オン（上記２)（(4S)-3-Benzyl-4-[4'-(tetrahydro-pyran-2'-yloxy)-but-2'-ynoyl]-oxazolidin-2-one：1.12g, 76.4% )を得た。   Tetrahydropyranyl propargyl ether (0.656 g, 4.68 mmol) in THF (29.8 ml) was added dropwise with 1.6 N hexane solution (2.80 ml, 4.47 mmol) in n-butyllithium at -78 ° C. The mixture was stirred at the temperature of 15 minutes. The solution was cooled to -100 ° C or lower. (4S) -3-Benzyl-2-oxo-oxazolidine-4-carboxylic acid methyl ester (above 1) ((4S) -3-Benzyl-2-oxo-oxazolidine-4-carboxylic acid methyl ester: 1.00 g, 4.25 mmol) in THF and stirred for 10 minutes. 1N-HCl and diethyl ether were added dropwise to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25% -50% ethyl acetate in hexane) and (4S) -3-benzyl-4- [4 '-(tetrahydropyran-2'-yloxy) -buta -2'-inoyl] -oxazolidine-2-one (above 2) ((4S) -3-Benzyl-4- [4 '-(tetrahydro-pyran-2'-yloxy) -but-2'-ynoyl]- oxazolidin-2-one: 1.12 g, 76.4%).

（参考例２）

Figure 0004825947
(Reference Example 2)
Figure 0004825947

(4S)−3−ベンジル−4−[4'−(テトラヒドロピラン−2'−イルオキシ)−ブタ−2'−イノイル]−オキサゾリジン−2−オン（上記２)のトルエン( 13.64 ml )溶液に、0℃でジイソプロピルアルミニウム 2, 6−ジ−t−ブチル−4−メチルフェノキシドの0.5 M トルエン溶液 ( 13.6 ml, 6.00 mmol ) を滴下した。15分攪拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー ( ヘキサンに20％〜50％の酢酸エチルを溶かしたもの)により精製し、(4S)−3−ベンジル−4−[4'−(テトラヒドロピラン−2'−イル−1’−ヒドロキシ)−ブタ−2'−イニル]−オキサゾリジン−2−オン（上記３)((4S)-3-Benzyl-4-[4'-(tetrahydro-pyran-2'-yl-1’-hydroxy)-but-2'-ynyl]-oxazolidin-2-one： 0.680g, 72% )を得た。   To a toluene (13.64 ml) solution of (4S) -3-benzyl-4- [4 '-(tetrahydropyran-2'-yloxy) -buta-2'-inoyl] -oxazolidine-2-one (above 2), A 0.5 M toluene solution (13.6 ml, 6.00 mmol) of diisopropylaluminum 2,6-di-t-butyl-4-methylphenoxide was added dropwise at 0 ° C. After stirring for 15 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% -50% ethyl acetate in hexane) and (4S) -3-benzyl-4- [4 '-(tetrahydropyran-2'-yl-1' -Hydroxy) -buta-2'-ynyl] -oxazolidine-2-one (above 3) ((4S) -3-Benzyl-4- [4 '-(tetrahydro-pyran-2'-yl-1'-hydroxy ) -but-2′-ynyl] -oxazolidin-2-one: 0.680 g, 72%).

（参考例３）

Figure 0004825947
(Reference Example 3)
Figure 0004825947

液体アンモニア( 142 ml )に−78℃で(4S)−3−ベンジル−4−[4'−(テトラヒドロピラン−2'−イル−1’−ヒドロキシ)−ブタ−2'−イニル]−オキサゾリジン−2−オン（上記３)(3.27 g, 9.47 mmol )のTHF( 47.4 ml )溶液を加えた後、リチウム( 0.789 g, 100 mmol ) を加えた。アイスバスを除去し3時間還流させた後、−78℃で固体の塩化アンモニウムを加え、アンモニアを留去した。セライト濾過、続いて減圧濃縮を行い、(4S,1'R,2'E)−(4−(1'−ヒドロキシ−ブタ−2'−エニル)−オキサゾリジン−2−オン（上記４)（(4S,1'R,2'E)-(4-(1'-Hydroxy-but-2'-enyl)-oxazolidin-2-one ）を得た。   (4S) -3-Benzyl-4- [4 '-(tetrahydropyran-2'-yl-1'-hydroxy) -but-2'-ynyl] -oxazolidine- in liquid ammonia (142 ml) at -78 ° C A solution of 2-one (above 3) (3.27 g, 9.47 mmol) in THF (47.4 ml) was added followed by lithium (0.789 g, 100 mmol). After removing the ice bath and refluxing for 3 hours, solid ammonium chloride was added at −78 ° C., and ammonia was distilled off. Celite filtration followed by vacuum concentration gave (4S, 1'R, 2'E)-(4- (1'-hydroxy-but-2'-enyl) -oxazolidine-2-one (above 4) (( 4S, 1′R, 2′E)-(4- (1′-Hydroxy-but-2′-enyl) -oxazolidin-2-one) was obtained.

（参考例４）

Figure 0004825947
(Reference Example 4)
Figure 0004825947

参考例３で得た(4S,1'R,2'E)−(4−(1'−ヒドロキシ−ブタ−2'−エニル)−オキサゾリジン−2−オン（上記４)のDMF( 108 ml )溶液に室温でイミダゾール ( 0.967 g, 14.2 mmol ), ｔ−ブチルジメチルシリルクロリド ( 2.14 g, 14.2 mmol ) を順に加えた。同温にて3時間攪拌し、反応混合物に氷を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー (ヘキサンに20％〜50％の酢酸エチルを溶かしたもの)により精製し、(4S,1'R,2'E)−4−[1'−(ｔ−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−オキサゾリジン−2−オン（上記５)（(4S,1'R,2'E)-4-[1'-(tert-Butyl-dimethyl-silyloxy)-but-2'-enyl]-oxazolidin-2-one ：1.81 g, 参考例３，４の２段階で収率70％ )を得た。(4S,1'R,2'E)−4−[1'−(ｔ−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−オキサゾリジン−2−オン（上記５)のIR、1H NMR、13C NMRデータを以下に示す。 DMF (108 ml) of (4S, 1′R, 2′E)-(4- (1′-hydroxy-but-2′-enyl) -oxazolidin-2-one (above 4) obtained in Reference Example 3 To the solution were added imidazole (0.967 g, 14.2 mmol) and t-butyldimethylsilyl chloride (2.14 g, 14.2 mmol) in this order at room temperature, followed by stirring at the same temperature for 3 hours, adding ice to the reaction mixture, and adding ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (20% -50% ethyl acetate dissolved in hexane). , (4S, 1′R, 2′E) -4- [1 ′-(t-butyldimethylsilyloxy) -buta-2′-enyl] -oxazolidine-2-one (above 5) ((4S, 1 'R, 2'E) -4- [1'-(tert-Butyl-dimethyl-silyloxy) -but-2'-enyl] -oxazolidin-2-one: 1.81 g, Reference Example 3 and 4 in two steps (4S, 1'R, 2'E) -4- [1 '-(t- IR, 1 H NMR, and 13 C NMR data of butyldimethylsilyloxy) -buta-2′-enyl] -oxazolidine-2-one (above 5) are shown below.

IR( KBr disk ) = 3399, 2932, 1713, 1418, 1038, 856 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.74 ( dqd, J= 15.4, 6.6, 0.5 Hz, 1H ), 5.36 ( brm, 1H ), 5.33 ( ddq, J= 15.4, 7.6, 1.7 Hz, 1H ), 4.38 ( dd, J= 8.8, 8.8 Hz, 1H ), 4.27 ( dd, J= 9.0, 4.9 Hz, 1H ), 3.97( dd, J= 6.6, 6.6 Hz, 1H ), 3.71 ( ddd, J= 8.5, 5.6, 5.6 Hz), 1.72 ( dd, J= 6.6, 1.5 Hz, 3H ), 0.87 ( s, 9H ), 0.06 ( s, 3H ), 0.02 ( s, 3H )
13C NMR (CDCl3, 100MHz) δ: 159.8, 130.1, 129.5, 75.1, 66.7, 56.8, 25.7, 17.9, 17.7, -4.1, -5.0 IR (KBr disk) = 3399, 2932, 1713, 1418, 1038, 856 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.74 (dqd, J = 15.4, 6.6, 0.5 Hz, 1H), 5.36 (brm, 1H), 5.33 (ddq, J = 15.4, 7.6, 1.7 Hz, 1H), 4.38 (dd, J = 8.8, 8.8 Hz, 1H), 4.27 (dd, J = 9.0, 4.9 Hz, 1H), 3.97 (dd, J = 6.6, 6.6 Hz, 1H), 3.71 (ddd, J = 8.5, 5.6, 5.6 Hz), 1.72 (dd, J = 6.6, 1.5 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 159.8, 130.1, 129.5, 75.1, 66.7, 56.8, 25.7, 17.9, 17.7, -4.1, -5.0

（参考例５）

Figure 0004825947
(Reference Example 5)
Figure 0004825947

(4S,1'R,2'E)−4−[1'−(ｔ−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−オキサゾリジン−2−オン（上記５)（ 0.969 g, 3.57mnmol ) のDMF (17.9ml) 溶液に0℃でジメチルアミノピリジン (0.217 g, 1.78 mmol )、 トリエチルアミン (0.75 ml, 5.36 mmol ) 、炭酸ジ−ｔ−ブチル(1.17 g, 5.36 mmol )を順次加えた。同温にて10分間攪拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー ( ヘキサンに９％〜20％の酢酸エチルを溶かしたもの) により精製し、(4S,1'R,2'E)−4−[1'−(t−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−2−オキソ−オキサゾリジン−3−カルボン酸t−ブチルエステル（上記６)（(4S,1'R,2'E)-4-[1'-(tert-Butyl-dimethyl-silyloxy)-but-2'-enyl]-2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester：1.11g, 84%)を得た。(4S,1'R,2'E)−4−[1'−(t−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−2−オキソ−オキサゾリジン−3−カルボン酸t−ブチルエステル（上記６)のIR、1H NMR、13C NMRデータを以下に示す。 (4S, 1'R, 2'E) -4- [1 '-(t-Butyldimethylsilyloxy) -buta-2'-enyl] -oxazolidine-2-one (5 above) (0.969 g, 3.57 mnmol ) In a DMF (17.9 ml) solution at 0 ° C. were successively added dimethylaminopyridine (0.217 g, 1.78 mmol), triethylamine (0.75 ml, 5.36 mmol) and di-t-butyl carbonate (1.17 g, 5.36 mmol). After stirring at the same temperature for 10 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (9% -20% ethyl acetate in hexane) and (4S, 1'R, 2'E) -4- [1 '-(t-butyldimethylsilyloxy) ) -Buta-2'-enyl] -2-oxo-oxazolidine-3-carboxylic acid t-butyl ester (above 6) ((4S, 1'R, 2'E) -4- [1 '-(tert- Butyl-dimethyl-silyloxy) -but-2'-enyl] -2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester: 1.11 g, 84%). (4S, 1′R, 2′E) -4- [1 ′-(t-Butyldimethylsilyloxy) -buta-2′-enyl] -2-oxo-oxazolidine-3-carboxylic acid t-butyl ester ( IR, 1 H NMR and 13 C NMR data of the above 6) are shown below.

IR( KBr disk ) = 2934, 1804, 1719, 1372, 1069, 837 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.80 ( dqd, J= 15.4, 6.6, 1.5 Hz, 1H ), 5.34 ( ddq, J= 15.4, 5.4, 1.7Hz, 1H ), 4.65 ( m, 1H ), 4.38 ( dd, J= 7.1, 2.0 Hz, 1H ), 4.15 ( m, 2H ), 1.73 ( ddd, J= 6.6, 1.5, 1.5 Hz, 3H ), 1.57 ( s, 9H ), 0.90 ( s, 9H ), 0.04 ( s, 3H ), 0.02 ( s, 3H )
13C NMR (CDCl3, 100MHz) δ: 152.2, 149.7, 128.9, 128.7, 83.6, 70.7, 61.4, 58.9, 28.0, 25.6, 17.8, 17.7, -4.6, -5.2 IR (KBr disk) = 2934, 1804, 1719, 1372, 1069, 837 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.80 (dqd, J = 15.4, 6.6, 1.5 Hz, 1H), 5.34 (ddq, J = 15.4, 5.4, 1.7 Hz, 1H), 4.65 (m, 1H), 4.38 (dd, J = 7.1, 2.0 Hz, 1H), 4.15 (m, 2H), 1.73 (ddd, J = 6.6, 1.5, 1.5 Hz, 3H), 1.57 (s, 9H), 0.90 (s, 9H) , 0.04 (s, 3H), 0.02 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 152.2, 149.7, 128.9, 128.7, 83.6, 70.7, 61.4, 58.9, 28.0, 25.6, 17.8, 17.7, -4.6, -5.2

（参考例６）

Figure 0004825947
(Reference Example 6)
Figure 0004825947

(4S,1'R,2'E)−4−[1'−(t−ブチルジメチルシリルオキシ)−ブタ−2'−エニル]−2−オキソ−オキサゾリジン−3−カルボン酸t−ブチルエステル（上記６)（0.468 g, 1.31 mmol ) のメタノール ( 6.54 ml ) 溶液に室温で炭酸セシウム ( 0.508 g, 1.31 mmol )を加え、同温で3時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー（ヘキサンに９％〜17％の酢酸エチルを溶かしたもの) により精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−ヘキセン−1−オール（上記８）（(2S,3R,4E)-2-tert-Butyloxycarbonylamino-3-(tert-butyl-dimethyl-silyloxy)-4-hexene-1-ol ：0.351 g, 78% )を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−ヘキセン−1−オール（上記８）のIR、1H NMR、13C NMRデータを以下に示す。 (4S, 1′R, 2′E) -4- [1 ′-(t-Butyldimethylsilyloxy) -buta-2′-enyl] -2-oxo-oxazolidine-3-carboxylic acid t-butyl ester ( Cesium carbonate (0.508 g, 1.31 mmol) was added to a methanol (6.54 ml) solution of the above 6) (0.468 g, 1.31 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (9 to 17% ethyl acetate in hexane) and (2S, 3R, 4E) -2-t-butyloxycarbonylamino-3- (t-butyldimethylsilyl). Oxy) -4-hexen-1-ol (above 8) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-3- (tert-butyl-dimethyl-silyloxy) -4-hexene-1-ol: 0.351 g, 78%). IR, 1 H NMR, 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-3- (t-butyldimethylsilyloxy) -4-hexen-1-ol (above 8) Is shown below.

IR( NaCl, Neat ) = 3449, 2959, 1699, 1503, 1254, 966 cm-1
1H NMR (CDCl3, 400MHz) δ:5.72( m, 1H ), 5.48( ddq, J= 15.4, 6.3, 1.7 Hz, 1H ) , 5.32(brd, J= 7.1 Hz, 1H ), 4.45( m, 1H ), 4.01( m, 1H ), 3.58( m, 1H ), 3.46( m, 1H ), 3.03-2.96( brm, 1H ), 1.71( m, 3H ), 1.45( s, 9H ), 0.90( s, 9H ), 0.07( s, 3H ), 0.03( s, 3H )
13C NMR (CDCl3, 100MHz) δ: 155.7, 130.6, 127.7, 79.3, 76.1, 62.2, 55.2, 28.4, 25.8, 18.0, 17.6, -4.6, -5.2. IR (NaCl, Neat) = 3449, 2959, 1699, 1503, 1254, 966 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.72 (m, 1H), 5.48 (ddq, J = 15.4, 6.3, 1.7 Hz, 1H), 5.32 (brd, J = 7.1 Hz, 1H), 4.45 (m, 1H), 4.01 (m, 1H), 3.58 (m, 1H), 3.46 (m, 1H), 3.03-2.96 (brm, 1H), 1.71 (m, 3H), 1.45 (s, 9H), 0.90 (s , 9H), 0.07 (s, 3H), 0.03 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.7, 130.6, 127.7, 79.3, 76.1, 62.2, 55.2, 28.4, 25.8, 18.0, 17.6, -4.6, -5.2.

（参考例７）

Figure 0004825947
(Reference Example 7)
Figure 0004825947

(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−ヘキセン−1−オール （上記８）（150 mg, 0.434 mmol ) の DMF ( 2.17 ml ) 溶液に室温でイミダゾール ( 44 mg, 0.651 mmol ), ｔ−ブチルジメチルシリルクロリド ( 98 mg, 0.651 mmol ) を順次に加えた。同温にて3時間攪拌し、反応混合物に氷を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー (ヘキサンに１％〜２％の酢酸エチルを溶かしたもの) により精製し、(2S,3R,4E)−1,3−ジ(t−ブチルジメチルシリルオキシ)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン（上記９）（(2S,3R,4E)-1,3-di(tert-Butyl-dimethyl-silyloxy)-2-tert-butyloxycarbonylamino-4-hexene：199 mg, quant)を得た。(2S,3R,4E)−1,3−ジ(t−ブチルジメチルシリルオキシ)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン（上記９）のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-3- (t-butyldimethylsilyloxy) -4-hexen-1-ol (above 8) (150 mg, 0.434 mmol) DMF (2.17 ml) Imidazole (44 mg, 0.651 mmol) and t-butyldimethylsilyl chloride (98 mg, 0.651 mmol) were sequentially added to the solution at room temperature. The mixture was stirred at the same temperature for 3 hours, ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1% -2% ethyl acetate in hexane) and (2S, 3R, 4E) -1,3-di (t-butyldimethylsilyloxy) -2-t -Butyloxycarbonylamino-4-hexene (above 9) ((2S, 3R, 4E) -1,3-di (tert-Butyl-dimethyl-silyloxy) -2-tert-butyloxycarbonylamino-4-hexene: 199 mg, quant). IR, 1 H NMR and 13 C NMR data of (2S, 3R, 4E) -1,3-di (t-butyldimethylsilyloxy) -2-t-butyloxycarbonylamino-4-hexene (above 9) It is shown below.

IR( KBr disk ) = 3459, 2957, 1723, 1501, 1256, 966 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.61 ( dqd, J= 15.4, 6.3, 0.7 Hz, 1H ), 5.45 ( m, 1H ), 4.73 ( m, 1H ), 4.18 ( m, 1H ), 3.79 ( dd, J= 10.0, 4.2 Hz, 1H ), 3.58 ( m, 2H ), 1.68 ( dd, J= 6.3, 1.0 Hz), 0.90 ( s, 9H ), 0.87 ( s, 9H ), 0.05 ( s, 6H ), 0.03 ( s, 3H ), 0.01 ( s, 3H )
13C NMR (CDCl3, 100MHz) δ: 155.6, 131.5, 127.5, 78.8, 73.0, 61.4, 56.5, 28.4. 25.89, 25.85, 18.2, 18.1, 17.7, -4.1, -4.9, -5.3, -5.5 IR (KBr disk) = 3459, 2957, 1723, 1501, 1256, 966 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.61 (dqd, J = 15.4, 6.3, 0.7 Hz, 1H), 5.45 (m, 1H), 4.73 (m, 1H), 4.18 (m, 1H), 3.79 ( dd, J = 10.0, 4.2 Hz, 1H), 3.58 (m, 2H), 1.68 (dd, J = 6.3, 1.0 Hz), 0.90 (s, 9H), 0.87 (s, 9H), 0.05 (s, 6H ), 0.03 (s, 3H), 0.01 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.6, 131.5, 127.5, 78.8, 73.0, 61.4, 56.5, 28.4. 25.89, 25.85, 18.2, 18.1, 17.7, -4.1, -4.9, -5.3, -5.5

（参考例８）

Figure 0004825947
(Reference Example 8)
Figure 0004825947

(2S,3R,4E)−1,3−ジ(t−ブチルジメチルシリルオキシ)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン（上記９）（0.398 g, 1.15 mmol ) のTHF ( 2.88 ml ) 溶液に0℃でテトラブチルアンモニウムフロリド ( 0.452 g, 1.73 mmol ) のTHF ( 1.73 ml ) 溶液を加え、同温にて30分攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー(ヘキサンに33％〜67％の酢酸エチルを溶かしたもの) により精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン−1,3−ジオール（上記10）（ (2S,3R,4E)-2-tert-Butyloxycarbonylamino-4-hexene-1,3-diol：0.251g, 94%)を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン−1,3−ジオール（上記10）のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -1,3-di (t-butyldimethylsilyloxy) -2-t-butyloxycarbonylamino-4-hexene (above 9) (0.398 g, 1.15 mmol) in THF (2.88 ml ) A solution of tetrabutylammonium fluoride (0.452 g, 1.73 mmol) in THF (1.73 ml) was added to the solution at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (33% to 67% ethyl acetate in hexane) and (2S, 3R, 4E) -2-t-butyloxycarbonylamino-4-hexene-1,3- Diol (10 above) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-4-hexene-1,3-diol: 0.251 g, 94%) was obtained. IR, 1 H NMR and 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-4-hexene-1,3-diol (above 10) are shown below.

IR( KBr disk ) = 3354, 1666, 1541, 1170, 1059 cm-1
1H NMR (CDCl3, 400MHz) δ:5.79 (dqd, J= 15.3, 6.6, 1.2 Hz, 1H ), 5.56 ( ddq J= 15.4, 6.6, 1.5 Hz, 1H ), 5.30 (brm, 1H), 4.29 (m, 1H), 3.93 (m, 1H), 3.71 (m, 1H), 3.60 (m, 1H), 2.90-2.60 (brm, 2H ), 1.73 ( ddd, J= 6.6, 1.7, 1.0 Hz, 3H ), 1.45 (s, 9H )
13C NMR (CDCl3, 100MHz) δ: 156.3, 130.3, 128.7, 79.8, 74.6, 62.6, 55.4, 28.3, 17.8. IR (KBr disk) = 3354, 1666, 1541, 1170, 1059 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.79 (dqd, J = 15.3, 6.6, 1.2 Hz, 1H), 5.56 (ddq J = 15.4, 6.6, 1.5 Hz, 1H), 5.30 (brm, 1H), 4.29 (m, 1H), 3.93 (m, 1H), 3.71 (m, 1H), 3.60 (m, 1H), 2.90-2.60 (brm, 2H), 1.73 (ddd, J = 6.6, 1.7, 1.0 Hz, 3H ), 1.45 (s, 9H)
13 C NMR (CDCl 3 , 100 MHz) δ: 156.3, 130.3, 128.7, 79.8, 74.6, 62.6, 55.4, 28.3, 17.8.

（参考例９）

Figure 0004825947
(Reference Example 9)
Figure 0004825947

(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン−1,3−ジオール（上記10）（200mg, 0.864mmol ) の DMF ( 4.32ml ) 溶液に室温でイミダゾール ( 88 mg, 1.29 mmol ), ｔ−ブチルジメチルシリルクロリド (169 mg, 1.12 mmol ) を順次加えた。同温にて5分間攪拌し、反応混合物に氷を加え、酢酸エチルで抽出した。有機層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー (ヘキサンに12％〜33％の酢酸エチルを溶かしたもの)により精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ)−4−ヘキセン−3−オール(上記11)((2S,3R,4E)-2-tert-Butyloxycarbonylamino-1-tert-butyl-dimethyl-silyloxy)-4-hexene-3-ol：72 mg, 24% )を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ)−4−ヘキセン−3−オール(上記11)のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-4-hexene-1,3-diol (above 10) (200mg, 0.864mmol) in DMF (4.32ml) solution at room temperature with imidazole (88mg , 1.29 mmol), t-butyldimethylsilyl chloride (169 mg, 1.12 mmol) were sequentially added. The mixture was stirred at the same temperature for 5 minutes, ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12% to 33% ethyl acetate in hexane) and (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy ) -4-hexen-3-ol (above 11) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-1-tert-butyl-dimethyl-silyloxy) -4-hexene-3-ol: 72 mg, 24%). IR, 1 H NMR, 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy) -4-hexen-3-ol (11 above) It is shown below.

IR( NaCl, Neat ) = 3453, 2932, 1701, 1503, 1175, 837 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.75 ( dqd, J= 15.4, 6.6, 1.2 Hz, 1H ), 5.52 ( ddq, J= 15.4, 6.1, 1.5Hz, 1H ), 5.20 ( brd, J= 7.3 Hz, 1H ), 4.16 ( m, 1H ), 3.92 ( dd, J= 10.3, 3.1 Hz, 1H ), 3.73 ( dd, J= 10.3, 2.7 Hz, 1H ), 3.56 ( m, 1H ), 3.30 ( brm, 1H ), 1.72 ( ddd, J= 6.6, 1.5 Hz, 3H ), 1.43 ( s, 9H ), 0.88 ( s, 9H ), 0.06 ( s, 6H )
13C NMR (CDCl3, 100MHz) δ: 155.7, 130.8, 127.6, 79.3, 74.4, 63.3, 54.5, 28.3, 25.7, 18.1, 17.7, -5.68, -5.71 IR (NaCl, Neat) = 3453, 2932, 1701, 1503, 1175, 837 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.75 (dqd, J = 15.4, 6.6, 1.2 Hz, 1H), 5.52 (ddq, J = 15.4, 6.1, 1.5 Hz, 1H), 5.20 (brd, J = 7.3 Hz, 1H), 4.16 (m, 1H), 3.92 (dd, J = 10.3, 3.1 Hz, 1H), 3.73 (dd, J = 10.3, 2.7 Hz, 1H), 3.56 (m, 1H), 3.30 (brm , 1H), 1.72 (ddd, J = 6.6, 1.5 Hz, 3H), 1.43 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H)
13 C NMR (CDCl 3 , 100MHz) δ: 155.7, 130.8, 127.6, 79.3, 74.4, 63.3, 54.5, 28.3, 25.7, 18.1, 17.7, -5.68, -5.71

（実施例１）

Figure 0004825947
Example 1
Figure 0004825947

(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−ヘキセン−1−オール （上記８）(46mg, 0.133mmol )のベンゼン( 1.33 ml )溶液に室温で１−ペンタデセン( 280 mg, 1.33 mmol )を加え、55 ℃まで昇温し、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（IV）ジクロリド( 6 mg, 0.00666 mmol )を一時間毎に6回加えた。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに９％〜25％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−オクタデセン−1−オール（上記12）（(2S,3R,4E)-2-tert-Butyloxycarbonylamino-3-(tert-butyl-dimethyl-silyloxy)-4-octadecene-1-ol：12mg, 18%，Ｅ体のみ)を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−(t−ブチルジメチルシリルオキシ)−4−オクタデセン−1−オール（上記12）のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-3- (t-butyldimethylsilyloxy) -4-hexen-1-ol (above 8) (46 mg, 0.133 mmol) of benzene (1.33 ml ) 1-pentadecene (280 mg, 1.33 mmol) was added to the solution at room temperature, the temperature was raised to 55 ° C., and then tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5 -Dihydroimidazol-2-ylidene] (benzylidene) ruthenium (IV) dichloride (6 mg, 0.00666 mmol) was added 6 times every hour. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9 to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 3- (t-butyldimethylsilyloxy) -4-octadecen-1-ol (above 12) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-3- (tert-butyl-dimethyl-silyloxy) -4 -octadecene-1-ol: 12 mg, 18%, E form only). IR, 1 H NMR, 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-3- (t-butyldimethylsilyloxy) -4-octadecen-1-ol (12 above) Is shown below.

IR( NaCl, Neat ) = 3451, 2928, 1701, 1366, 1173, 1055 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.71 ( m, 1H ), 5.45 ( ddt, J= 15.4, 6.1, 1.2 Hz, 1H ), 5.34 ( brd, J= 7.6 Hz, 1H ), 4.48 ( m, 1H ), 4.04 ( m, 1H ), 3.57 ( m, 1H ), 3.46 ( m, 1H ), 3.05-2.94 ( brm, 1H ), 1.62 ( m, 2H ), 1.45 ( s, 9H ), 1.26 ( s, 22H ), 0.90 ( m, 12H ), 0.08 ( s, 3H ), 0.04 (s, 3H ), 0.09 ( s, 9H )
13C NMR (CDCl3, 100MHz) δ: 155.7, 134.3, 133.3, 79.4, 76.3, 62.3, 55.2, 32.2, 31.9, 29.7, 29.6, 29.50, 29.46, 29.3, 29.1, 28.4, 25.8, 22.7, 18.0, 14.1, -4.5, -5.1 IR (NaCl, Neat) = 3451, 2928, 1701, 1366, 1173, 1055 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.71 (m, 1H), 5.45 (ddt, J = 15.4, 6.1, 1.2 Hz, 1H), 5.34 (brd, J = 7.6 Hz, 1H), 4.48 (m, 1H), 4.04 (m, 1H), 3.57 (m, 1H), 3.46 (m, 1H), 3.05-2.94 (brm, 1H), 1.62 (m, 2H), 1.45 (s, 9H), 1.26 (s , 22H), 0.90 (m, 12H), 0.08 (s, 3H), 0.04 (s, 3H), 0.09 (s, 9H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.7, 134.3, 133.3, 79.4, 76.3, 62.3, 55.2, 32.2, 31.9, 29.7, 29.6, 29.50, 29.46, 29.3, 29.1, 28.4, 25.8, 22.7, 18.0, 14.1 , -4.5, -5.1

（実施例２）

Figure 0004825947
(Example 2)
Figure 0004825947

(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−ヘキセン−1,3−ジオール（上記10）（65 mg, 0.281 mmol）のベンゼン( 2.16 ml )溶液に室温で、１−ペンタデセン（590 mg, 2.81 mmol）を加え、55 ℃まで昇温し、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（IV）ジクロリド（12 mg, 0.0140 mmol）を加え１時間攪拌した。更にトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（IV）ジクロリド（6 mg, 0.007 mmol）を加え30分攪拌した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに33％〜67％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−オクタデセン−1,3−ジオール(上記13)（(2S,3R,4E)-2-tert-Butyloxycarbonylamino-4-octadecene-1,3-diol：69mg, 62%，Ｅ体のみ)を得た。(2S,3R,4E)−2−tert−ブチルオキシカルボニルアミノ−4−オクタデセン−1,3−ジオール(上記13)のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-4-hexene-1,3-diol (above 10) (65 mg, 0.281 mmol) in benzene (2.16 ml) at room temperature Pentadecene (590 mg, 2.81 mmol) was added and the temperature was raised to 55 ° C., followed by tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2- Iridene] (benzylidene) ruthenium (IV) dichloride (12 mg, 0.0140 mmol) was added and stirred for 1 hour. Further, add tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] (benzylidene) ruthenium (IV) dichloride (6 mg, 0.007 mmol) Stir for 30 minutes. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (33% to 67% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 4-octadecene-1,3-diol (13 above) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-4-octadecene-1,3-diol: 69 mg, 62%, E form only) was obtained. . IR, 1 H NMR and 13 C NMR data of (2S, 3R, 4E) -2-tert-butyloxycarbonylamino-4-octadecene-1,3-diol (13 above) are shown below.

IR (KBr disk): 3335, 2909, 1692, 1528, 1177, 1057, 664 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.77 (td, J= 6.8, 15.4 Hz, 1H), 5.52 (dd, J= 6.3, 15.4, 1H), 5.33 (d,J= 7.1Hz, 1H), 4.29 (brm, 1H), 3.92 (ddd, 3.7, 3.7, 11.5 Hz, 1H), 3.70 (ddd, J= 3.7, 6.8, 11.2 Hz, 1H), 3.59 (brm, 1H), 2.99 (brm, 1H), 2.91 (brm, 1H), 2.05 (dt, J= 7.1, 7.1 Hz), 1.45 (s, 9H), 1.39-1.26 (m, 22H), 0.88 (t, J= 7.1 Hz, 3H)
13C NMR (CDCl3, 100MHz) δ: 156.2, 134.1, 128.9, 79.8, 74.6, 62.6, 55.4, 32.3, 31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 28.3, 22.7, 14.1. IR (KBr disk): 3335, 2909, 1692, 1528, 1177, 1057, 664 cm -1
1 H NMR (CDCl 3 , 400MHz) δ: 5.77 (td, J = 6.8, 15.4 Hz, 1H), 5.52 (dd, J = 6.3, 15.4, 1H), 5.33 (d, J = 7.1Hz, 1H), 4.29 (brm, 1H), 3.92 (ddd, 3.7, 3.7, 11.5 Hz, 1H), 3.70 (ddd, J = 3.7, 6.8, 11.2 Hz, 1H), 3.59 (brm, 1H), 2.99 (brm, 1H) , 2.91 (brm, 1H), 2.05 (dt, J = 7.1, 7.1 Hz), 1.45 (s, 9H), 1.39-1.26 (m, 22H), 0.88 (t, J = 7.1 Hz, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 156.2, 134.1, 128.9, 79.8, 74.6, 62.6, 55.4, 32.3, 31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 28.3, 22.7, 14.1.

（実施例３）

Figure 0004825947
(Example 3)
Figure 0004825947

(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ)−4−ヘキセン−3−オール(上記11)（68mg, 0.197mmol )のベンゼン( 2.00 ml )溶液に室温で１−ペンタデセン( 414 mg, 1.97 mmol )を加え、55 ℃まで昇温し、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（IV）ジクロリド( 8 mg, 0.00984 mmol )を一時間毎に6回加えた。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに９％〜25％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ)−4−オクタデセン−3−オール(上記14)（(2S,3R,4E)-2-tert-Butyloxycarbonylamino-1-tert-butyl-dimethyl-silyloxy)-4-octadecene-3-ol：58mg, 57%，Ｅ体のみ)を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ)−4−オクタデセン−3−オール(上記14)のIR、1H NMR、13C NMRデータを以下に示す。 (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-1-t-butyldimethylsilyloxy) -4-hexen-3-ol (above 11) (68 mg, 0.197 mmol) in benzene (2.00 ml) 1-Pentadecene (414 mg, 1.97 mmol) was added to the solution at room temperature, the temperature was raised to 55 ° C., and then tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5- Dihydroimidazol-2-ylidene] (benzylidene) ruthenium (IV) dichloride (8 mg, 0.00984 mmol) was added 6 times every hour. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9 to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy) -4-octadecene-3-ol (above 14) ((2S, 3R, 4E) -2-tert-Butyloxycarbonylamino-1-tert-butyl-dimethyl-silyloxy) -4-octadecene -3-ol: 58 mg, 57%, E form only). IR, 1 H NMR, and 13 C NMR data for (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy) -4-octadecene-3-ol (14) above. It is shown below.

IR( NaCl, Neat ) = 3449, 2928, 1715, 1497, 1173, 839 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.75 ( dtd, J= 15.4, 6.8, 1.2 Hz, 1H ), 5.50 ( ddt, J= 15.4, 5.6, 1.5 Hz, 1H ), 5.23 ( brm, 1H ), 4.27 ( m, 1H ), 3.93 ( dd, J= 10.2, 2.9 Hz, 1H ), 3.75 ( dd, J= 10.5, 2.4 Hz, 1H ), 3.57 ( m, 1H ), 3.31 ( brm, 1H ), 2.05 ( dt, J= 7.1, 7.1 Hz, 2H ), 1.45 ( s, 9H ), 1.25 ( s, 22H ), 0.90 ( s, 9H ), 0.85 ( m, 3H ), 0.06 ( s, 6H )
13C NMR (CDCl3, 100MHz) δ: 155.4, 133.1, 129.4, 79.4, 74.6, 63.4, 54.5, 32.3, 31.9, 29.7, 29.5, 29.3, 29.2, 28.4, 28.3, 25.8, 22.7, 18.1, 14.1, -5.6 IR (NaCl, Neat) = 3449, 2928, 1715, 1497, 1173, 839 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.75 (dtd, J = 15.4, 6.8, 1.2 Hz, 1H), 5.50 (ddt, J = 15.4, 5.6, 1.5 Hz, 1H), 5.23 (brm, 1H), 4.27 (m, 1H), 3.93 (dd, J = 10.2, 2.9 Hz, 1H), 3.75 (dd, J = 10.5, 2.4 Hz, 1H), 3.57 (m, 1H), 3.31 (brm, 1H), 2.05 (dt, J = 7.1, 7.1 Hz, 2H), 1.45 (s, 9H), 1.25 (s, 22H), 0.90 (s, 9H), 0.85 (m, 3H), 0.06 (s, 6H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.4, 133.1, 129.4, 79.4, 74.6, 63.4, 54.5, 32.3, 31.9, 29.7, 29.5, 29.3, 29.2, 28.4, 28.3, 25.8, 22.7, 18.1, 14.1,- 5.6

（参考例１０）

Figure 0004825947
(Reference Example 10)
Figure 0004825947

四臭化炭素(0.375 mmol, 124 mg)のピリジン(1.3 mL)溶液に０℃で、２−ブロモエチルジメチルホスファイト（2-Bromoethyl(dimethyl)phosphite：0.056ml, 0.375mmol)を加え、続いて、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−4−オクタデセン−1,3−ジオール(上記13)（100 mg, 0.250 mmol)を加えた。徐々に室温まで昇温しながら3.5時間攪拌した。反応混合物を濾過し、2N-塩酸で酸性にした後、酢酸エチルで抽出した。有機層を2N-塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー(ヘキサンに33％〜50％の酢酸エチルを溶かしたもの)により分離・精製し、2−ブロモエチル ((2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記15)(2-Bromoethyl((2S,3R,4E)-2-tert-butyloxycarbonylamino-3-hydroxy-octadec-4-enyl)(methyl)phosphate：133mg,88.7%)を得た。2−ブロモエチル ((2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記15) のIR、1H NMR、13C NMRデータを以下に示す。 To a solution of carbon tetrabromide (0.375 mmol, 124 mg) in pyridine (1.3 mL) at 0 ° C., 2-Bromoethyl (dimethyl) phosphite (0.056 ml, 0.375 mmol) was added, followed by (2S, 3R, 4E) -2-t-butyloxycarbonylamino-4-octadecene-1,3-diol (13 above) (100 mg, 0.250 mmol) was added. The mixture was stirred for 3.5 hours while gradually warming to room temperature. The reaction mixture was filtered, acidified with 2N-hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with 2N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (33% -50% ethyl acetate dissolved in hexane), and 2-bromoethyl ((2S, 3R, 4E) -2-t-butyloxycarbonylamino-3- Hydroxyoctadeca-4-enyl) methyl phosphate (above 15) (2-Bromoethyl ((2S, 3R, 4E) -2-tert-butyloxycarbonylamino-3-hydroxy-octadec-4-enyl) (methyl) phosphate: 133 mg, 88.7%). IR, 1 H NMR and 13 C NMR data of 2-bromoethyl ((2S, 3R, 4E) -2-t-butyloxycarbonylamino-3-hydroxyoctadec-4-enyl) methyl phosphate (15 above) are shown below. Shown in

IR (NaCl neat): 3387.31, 1712.94, 1521.97, 1460.25, 1259.63, 1174.75, 1024.29 cm-1
1H NMR (CDCl3, 400 MHz) δ: 5.76 (td, J =6.8, 15.4 Hz, 1H), 5.50 (dd, J = 7.1, 15.4 Hz, 1H),5.05 (brs, 1H), 4.36-4.31 (m, 3H), 4.16 (m, 2H), 3.82 (d, J=11.2 Hz, 3/2H ), 3.82 (d, J=11.2 Hz, 3/2H), 3.79 (m, 1H), 3.55 (dd, J=6.1, 6.1 Hz, 2H), 2.04 (m, 2H), 1.44 (s, 9H), 1.26 (m, 22H), 0.88 (t, 6.8 Hz, 3H)
13C NMR (CDCl3, 100MHz) δ: 155.6, 134.9, 128.5, 79.7, 72.4, 66.9 (m, 2C), 54.7 (m, 2C), 32.3, 31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 29.1, 28.3, 22.6, 14.1. IR (NaCl neat): 3387.31, 1712.94, 1521.97, 1460.25, 1259.63, 1174.75, 1024.29 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.76 (td, J = 6.8, 15.4 Hz, 1H), 5.50 (dd, J = 7.1, 15.4 Hz, 1H), 5.05 (brs, 1H), 4.36-4.31 (m, 3H), 4.16 (m, 2H), 3.82 (d, J = 11.2 Hz, 3 / 2H), 3.82 (d, J = 11.2 Hz, 3 / 2H), 3.79 (m, 1H), 3.55 ( dd, J = 6.1, 6.1 Hz, 2H), 2.04 (m, 2H), 1.44 (s, 9H), 1.26 (m, 22H), 0.88 (t, 6.8 Hz, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.6, 134.9, 128.5, 79.7, 72.4, 66.9 (m, 2C), 54.7 (m, 2C), 32.3, 31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 29.1 , 28.3, 22.6, 14.1.

（参考例１１）

Figure 0004825947
(Reference Example 11)
Figure 0004825947

2−ブロモエチル ((2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記15)( 500 mg, 0.833 mmol )の塩化メチレン( 4.16 ml )溶液に0℃でトリフルオロ酢酸( 1.67 ml )を加え、1.5時間攪拌した。反応溶液に1N NaOH水溶液を加え、中和した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮を行った。残渣をTHF、H2O( 8.32ml, 1:1 )で溶解し、0℃で炭酸カリウム( 575 mg, 4.16 mmol )、パルミトイルクロリド( 0.28 ml, 0.916 mmol ) を順次加え、15分攪拌した。反応混合液を飽和塩化アンモニウム水溶液で中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィー(クロロホルムに０％〜10％の酢酸エチルを溶かしたもの)により分離・精製し、2−ブロモメチル((2S,3R,4E)−2−ヘキサデカノイルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記16)（2-Bromoethyl((2S,3R,4E)-2-hexadecanoylamino-3-hydroxy-octadec-4-enyl)(methyl)phosphate：522mg, 85%)を得た。2−ブロモメチル((2S,3R,4E)−2−ヘキサデカノイルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記16) のIR、1H NMR、13C NMRデータを以下に示す。 2-Bromoethyl ((2S, 3R, 4E) -2-t-butyloxycarbonylamino-3-hydroxyoctadec-4-enyl) methyl phosphate (above 15) (500 mg, 0.833 mmol) in methylene chloride (4.16 ml ) To the solution was added trifluoroacetic acid (1.67 ml) at 0 ° C. and stirred for 1.5 hours. 1N NaOH aqueous solution was added to the reaction solution to neutralize it, followed by extraction with chloroform. The organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, concentration under reduced pressure was performed. The residue was dissolved in THF and H2O (8.32 ml, 1: 1), potassium carbonate (575 mg, 4.16 mmol) and palmitoyl chloride (0.28 ml, 0.916 mmol) were added successively at 0 ° C., and the mixture was stirred for 15 minutes. The reaction mixture was neutralized with saturated aqueous ammonium chloride and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (0 to 10% ethyl acetate in chloroform) and 2-bromomethyl ((2S, 3R, 4E) -2-hexadecanoylamino-3-hydroxyocta Deca-4-enyl) methyl phosphate (16) above (2-Bromoethyl ((2S, 3R, 4E) -2-hexadecanoylamino-3-hydroxy-octadec-4-enyl) (methyl) phosphate: 522mg, 85%) Obtained. IR, 1 H NMR, and 13 C NMR data of 2-bromomethyl ((2S, 3R, 4E) -2-hexadecanoylamino-3-hydroxyoctadec-4-enyl) methyl phosphate (16 above) are shown below. .

IR (KBr disk): 3291, 2917, 1647, 1547, 1468, 1269, 1047 cm-1
1H NMR (CDCl3, 400 MHz) δ: 6.25 ( d, J =7.3 Hz, 1H), 5.75 ( td, J = 6.8, 15.1 Hz, 1H ), 5.48 ( dd, J =6.6, 15.4 Hz, 1H ), 4.33 ( m, 3H ), 4.17 ( m, 3H ), 3.81 ( d, J =11.2 Hz, 3/2H ), 3.80( d, J =11.2 Hz, 3/2H ), 3.55 ( t, J =6.1 Hz, 2H ), 2.19 ( dt, J =1.7, 7.1 Hz, 2H ), 2.03 ( td, J =7.1, 1.7 Hz, 2H ), 1.61 ( m, 2H ), 1.26 ( m, 46 H ), 0.88 ( t, J =6.6 Hz, 6 H )
13C NMR (CDCl3, 100MHz) δ: 173.6, 134.8, 128.5, 72.4, 67.2 ( m ), 66.8 ( d, JC-P = 5.0 Hz ), 54.77 ( d, JC-P = 5.8 Hz, 1/2 C ), 54.74 ( d, JC-P = 5.8 Hz, 1/2 C ), 53.7 ( d, JC-P = 5.8 Hz ), 36.7, 32.3, 31.9, 29.7, 29.5, 29.4, 29.3, 29.3, 29.1, 25.7, 22.6, 14.1 IR (KBr disk): 3291, 2917, 1647, 1547, 1468, 1269, 1047 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 6.25 (d, J = 7.3 Hz, 1H), 5.75 (td, J = 6.8, 15.1 Hz, 1H), 5.48 (dd, J = 6.6, 15.4 Hz, 1H ), 4.33 (m, 3H), 4.17 (m, 3H), 3.81 (d, J = 11.2 Hz, 3 / 2H), 3.80 (d, J = 11.2 Hz, 3 / 2H), 3.55 (t, J = 6.1 Hz, 2H), 2.19 (dt, J = 1.7, 7.1 Hz, 2H), 2.03 (td, J = 7.1, 1.7 Hz, 2H), 1.61 (m, 2H), 1.26 (m, 46 H), 0.88 (t, J = 6.6 Hz, 6 H)
13 C NMR (CDCl 3 , 100 MHz) δ: 173.6, 134.8, 128.5, 72.4, 67.2 (m), 66.8 (d, J CP = 5.0 Hz), 54.77 (d, J CP = 5.8 Hz, 1/2 C) , 54.74 (d, J CP = 5.8 Hz, 1/2 C), 53.7 (d, J CP = 5.8 Hz), 36.7, 32.3, 31.9, 29.7, 29.5, 29.4, 29.3, 29.3, 29.1, 25.7, 22.6, 14.1

（参考例１２）

Figure 0004825947
(Reference Example 12)
Figure 0004825947

2−ブロモメチル((2S,3R,4E)−2−ヘキサデカノイルアミノ−3−ヒドロキシオクタデカ−4−エニル)メチルホスフェート(上記16)（ 502 mg, 0.679 mmol ) のメタノール ( 8.36 ml )溶液に室温で無水のトリメチルアミン ( 5.40 ml ) を加え、同温で2日間攪拌した。反応混合物を水で希釈し、クロロホルム、メタノールで抽出し、有機層を減圧濃縮した。残渣をシリカゲルクロマトグラフィー(メタノール：クロロホルム＝1：9〜メタノール：クロロホルム：水＝65：25：4 )により分離・精製し、スフィンゴミエリン(上記17)を得た。スフィンゴミエリンのIR、1H NMRデータを以下に示す。 To a solution of 2-bromomethyl ((2S, 3R, 4E) -2-hexadecanoylamino-3-hydroxyoctadec-4-enyl) methyl phosphate (16 above) (502 mg, 0.679 mmol) in methanol (8.36 ml) Anhydrous trimethylamine (5.40 ml) was added at room temperature, and the mixture was stirred at the same temperature for 2 days. The reaction mixture was diluted with water, extracted with chloroform and methanol, and the organic layer was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (methanol: chloroform = 1: 9 to methanol: chloroform: water = 65: 25: 4) to obtain sphingomyelin (17 above). IR and 1 H NMR data of sphingomyelin are shown below.

IR(KBr disk): 3447, 2919, 1640, 1231, 1090 cm-1
1H NMR (CDCl3, 400MHz) δ: 5.71 (dtd, J=15.4, 6.6, 0.5Hz, 1H), 5.46 (ddt, J=15.4, 7.6, 1.5Hz, 1H), 4.28 (m, 2H), 4.14-3.88 (m, 4H), 3.63 (t, J=4.9Hz, 2H), 3.22 (s, 9H), 2.19 (m, 2H),
2.03 (dt, J=6.8, 6.8Hz, 2H), 1.59 (m, 2H), 1.29 (s, 46H), 0.90 (t, J=7.1Hz, 6H) IR (KBr disk): 3447, 2919, 1640, 1231, 1090 cm -1
1 H NMR (CDCl 3 , 400MHz) δ: 5.71 (dtd, J = 15.4, 6.6, 0.5Hz, 1H), 5.46 (ddt, J = 15.4, 7.6, 1.5Hz, 1H), 4.28 (m, 2H), 4.14-3.88 (m, 4H), 3.63 (t, J = 4.9Hz, 2H), 3.22 (s, 9H), 2.19 (m, 2H),
2.03 (dt, J = 6.8, 6.8Hz, 2H), 1.59 (m, 2H), 1.29 (s, 46H), 0.90 (t, J = 7.1Hz, 6H)

（実施例４）

Figure 0004825947
Example 4
Figure 0004825947

(2S,3R)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ペンテン−3−オール(上記18)（106 mg, 0.320 mmol )のジクロロメタン(4.79 ml )溶液に室温で1−ペンタデセン(269 mg, 1.28 mmol )を加え、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（ＩＶ）ジクロリド(8 mg, 0.00959 mmol )を加えた。反応混合物を２時間還流した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに９％〜25％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−オクタデセン−3−オール(上記14)( 118 mg, 72% )を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−オクタデセン−3−オールのIR、1H NMR、13C NMRデータを以下に示す。 To a solution of (2S, 3R) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-penten-3-ol (above 18) (106 mg, 0.320 mmol) in dichloromethane (4.79 ml) 1-Pentadecene (269 mg, 1.28 mmol) was added at room temperature, followed by tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] ( Benzylidene) ruthenium (IV) dichloride (8 mg, 0.00959 mmol) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9 to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy-4-octadecene-3-ol (above 14) (118 mg, 72%) was obtained. IR, 1 H NMR, and 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-octadecene-3-ol are shown below.

IR(NaCl,Neat) = 3449, 2928, 1715, 1497, 1173, 839 cm-1
1H NMR(CDCl3,400MHz) δ: 5.75 (dtd, J= 15.4, 6.8, 1.2 Hz, 1H), 5.50 (ddt, J= 15.4, 5.6, 1.5 Hz, 1H), 5.23 (brm, 1H), 4.27 (m, 1H), 3.93 (dd, J= 10.2, 2.9 Hz, 1H), 3.75 (dd, J= 10.5, 2.4 Hz, 1H), 3.57 (m, 1H), 3.31 (brm, 1H), 2.05 (dt, J= 7.1, 7.1 Hz, 2H), 1.45 (s, 9H), 1.25 (s, 22H), 0.90 (s, 9H), 0.85 (m, 3H), 0.06 (s, 6H)
13C NMR (CDCl3,100MHz) δ: 155.4, 133.1, 129.4, 79.4, 74.6, 63.4, 54.5, 32.3, 31.9, 29.7, 29.5, 29.3, 29.2, 28.4, 28.3, 25.8, 22.7, 18.1, 14.1, -5.6 IR (NaCl, Neat) = 3449, 2928, 1715, 1497, 1173, 839 cm -1
1 H NMR (CDCl 3 , 400 MHz) δ: 5.75 (dtd, J = 15.4, 6.8, 1.2 Hz, 1H), 5.50 (ddt, J = 15.4, 5.6, 1.5 Hz, 1H), 5.23 (brm, 1H), 4.27 (m, 1H), 3.93 (dd, J = 10.2, 2.9 Hz, 1H), 3.75 (dd, J = 10.5, 2.4 Hz, 1H), 3.57 (m, 1H), 3.31 (brm, 1H), 2.05 (dt, J = 7.1, 7.1 Hz, 2H), 1.45 (s, 9H), 1.25 (s, 22H), 0.90 (s, 9H), 0.85 (m, 3H), 0.06 (s, 6H)
13 C NMR (CDCl 3 , 100MHz) δ: 155.4, 133.1, 129.4, 79.4, 74.6, 63.4, 54.5, 32.3, 31.9, 29.7, 29.5, 29.3, 29.2, 28.4, 28.3, 25.8, 22.7, 18.1, 14.1,- 5.6

（実施例５）

Figure 0004825947
(Example 5)
Figure 0004825947

(2S,3R)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ペンテン−3−オール(上記18)（ 101 mg, 0.305 mmol )のジクロロメタン( 4.79 ml )溶液に室温で1-ノネン( 154 mg, 1.22 mmol )を加え、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（ＩＶ）ジクロリド( 8 mg, 0.00914 mmol )を加えた。反応混合物を2時間還流した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに９％〜25％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ドデセン−3−オール(上記19) ( 71 mg, 55% )を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ドデセン−3−オールのIR、1H NMR、13C NMRデータを以下に示す。 To a solution of (2S, 3R) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-penten-3-ol (above 18) (101 mg, 0.305 mmol) in dichloromethane (4.79 ml) 1-Nonene (154 mg, 1.22 mmol) was added at room temperature followed by tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] ( Benzylidene) ruthenium (IV) dichloride (8 mg, 0.00914 mmol) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9 to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy-4-dodecen-3-ol (19 above) (71 mg, 55%) was obtained. IR, 1 H NMR, and 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-dodecene-3-ol are shown below.

IR(NaCl,Neat) = 3449, 2930, 1715, 1499, 1173, 837 cm-1
1H NMR (CDCl3,400MHz) δ: 5.75 (dtd, J= 15.4, 6.6, 1.2 Hz, 1H), 5.51 (dd, J= 15.4, 5.6 Hz, 1H), 4.19 (m, 1H), 3.93 (dd, J= 10.3, 2.9 Hz, 1H), 3.75 (m, 1H), 3.56 (m, 1H), 3.25-3.34 (brm, 1H), 2.05 (dt, J= 14.2, 6.8 Hz, 2H), 1.44 (s, 9H), 1.25 (s, 10H), 0.90 (s, 9H), 0.88 (t, J= 7.1 Hz, 3H)
13C NMR (CDCl3,100MHz) δ: 155.8, 133.0, 129.4, 79.4, 74.5, 63.4, 54.5, 32.3, 31.8, 29.14, 29.10, 28.3, 25.8, 25.7, 22.6, 18.1, 14.0, -5.65, -5.68 IR (NaCl, Neat) = 3449, 2930, 1715, 1499, 1173, 837 cm -1
1 H NMR (CDCl 3 , 400MHz) δ: 5.75 (dtd, J = 15.4, 6.6, 1.2 Hz, 1H), 5.51 (dd, J = 15.4, 5.6 Hz, 1H), 4.19 (m, 1H), 3.93 ( dd, J = 10.3, 2.9 Hz, 1H), 3.75 (m, 1H), 3.56 (m, 1H), 3.25-3.34 (brm, 1H), 2.05 (dt, J = 14.2, 6.8 Hz, 2H), 1.44 (s, 9H), 1.25 (s, 10H), 0.90 (s, 9H), 0.88 (t, J = 7.1 Hz, 3H)
13 C NMR (CDCl 3 , 100MHz) δ: 155.8, 133.0, 129.4, 79.4, 74.5, 63.4, 54.5, 32.3, 31.8, 29.14, 29.10, 28.3, 25.8, 25.7, 22.6, 18.1, 14.0, -5.65, -5.68

（実施例６）

Figure 0004825947
(Example 6)
Figure 0004825947

(2S,3R)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ペンテン−3−オール(上記18)（ 114 mg, 0.344 mmol )のジクロロメタン( 5.16 ml )溶液に室温でスチレン157 mg, 1.38 mmol )を加え、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（ＩＶ）ジクロリド( 9 mg, 0.0103 mmol )を加えた。反応混合物を２時間還流した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに９％〜25％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−5−フェニル−4−ペンテン−3−オール(上記20) ( 99 mg, 71% )を得た。（(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−5−フェニル−4−ペンテン−3−オールのIR、1H NMR、13C NMRデータを以下に示す。 To a solution of (2S, 3R) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-penten-3-ol (18 above) (114 mg, 0.344 mmol) in dichloromethane (5.16 ml) Styrene 157 mg, 1.38 mmol) was added at room temperature followed by tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] (benzylidene) ruthenium (IV) Dichloride (9 mg, 0.0103 mmol) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (9 to 25% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy-5-phenyl-4-penten-3-ol (20 above) (99 mg, 71%) was obtained. (IR, 1 H NMR, 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-5-phenyl-4-penten-3-ol It is shown below.

IR(NaCl,Neat) = 3451, 2932, 1717, 1499, 1254, 839 cm-1
1H NMR (CDCl3,400MHz) δ: 7.38 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1H), 6.70 (dd, J= 15.9, 1.5 Hz, 1H), 6.27 (dd, J= 15.9, 5.6 Hz, 1H), 5.32-5.22 (brm, 1H), 4.43 (m, 1H), 3.98(dd, J= 10.3, 2.9 Hz, 1H), 3.78 (dd, J= 10.5, 2.9 Hz, 1H ), 3.72 (m, 1H), 3.57-3.48 (brm, 1H), 1.43 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13C NMR (CDCl3,100MHz) δ: 155.8, 136.7, 131.1, 129.3, 128.5, 127.6, 126.5, 79.6, 74.6, 63.5, 54.6, 28.3, 25.8, 18.1, -5.6 IR (NaCl, Neat) = 3451, 2932, 1717, 1499, 1254, 839 cm -1
1 H NMR (CDCl 3 , 400MHz) δ: 7.38 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1H), 6.70 (dd, J = 15.9, 1.5 Hz, 1H), 6.27 (dd, J = 15.9, 5.6 Hz, 1H), 5.32-5.22 (brm, 1H), 4.43 (m, 1H), 3.98 (dd, J = 10.3, 2.9 Hz, 1H), 3.78 (dd, J = 10.5, 2.9 Hz , 1H), 3.72 (m, 1H), 3.57-3.48 (brm, 1H), 1.43 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13 C NMR (CDCl 3 , 100MHz) δ: 155.8, 136.7, 131.1, 129.3, 128.5, 127.6, 126.5, 79.6, 74.6, 63.5, 54.6, 28.3, 25.8, 18.1, -5.6

（実施例７）

Figure 0004825947
(Example 7)
Figure 0004825947

(2S,3R)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ペンテン−3−オール(上記18)（50 mg, 0.151 mmol)のジクロロメタン(2.26 ml)溶液に室温で１１−（４−（７−ニトロベンゾフラザニル）アミノ）−１−ウンデセン (200 mg, 0.603 mmol)を加え、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（ＩＶ）ジクロリド(4mg, 0.00452 mmol)を加えた。反応混合物を２時間還流した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに20％〜33％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−14−（4'−（7'−ニトロベンゾフラザニル）アミノ）−4−テトラデセン−3−オール(上記21) (55mg, 57%)を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−14−（4'−（7'−ニトロベンゾフラザニル）アミノ）−4−テトラデセン−3−オールのIR、1H NMR、13C NMRデータを以下に示す。 To a solution of (2S, 3R) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-penten-3-ol (above 18) (50 mg, 0.151 mmol) in dichloromethane (2.26 ml) 11- (4- (7-Nitrobenzofurazanyl) amino) -1-undecene (200 mg, 0.603 mmol) was added at room temperature followed by tricyclophosphine [1,3-bis (2,4,6- Trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] (benzylidene) ruthenium (IV) dichloride (4 mg, 0.00452 mmol) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (20% to 33% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy-14- (4 ′-(7′-nitrobenzofurazanyl) amino) -4-tetradecene-3-ol (above 21) (55 mg, 57%) was obtained. (2S, 3R, 4E) -2-t-Butyloxycarbonylamino-1-t-butyldimethylsilyloxy-14- (4 ′-(7′-nitrobenzofurazanyl) amino) -4-tetradecene-3 -IR, 1 H NMR and 13 C NMR data of all are shown below.

IR(KBr, disk) = 3414, 2928, 1586, 1258, 1173, 839 cm-1
1H NMR (CDCl3,400MHz) δ: 8.49 (d, J= 8.5 Hz, 1H), 6.58-6.48 (brm, 1H), 6.18 (d, J= 8.8 Hz, 1H), 5.75 (dt, J= 14.6, 7.3 Hz, 1H), 5.51 (dd, J= 15.4, 5.9 Hz, 1H), 5.31-5.21 (brm, 1H), 4.20 (m, 1H), 3.94 (dd, J= 10.3, 2.9 Hz, 1H), 3.76 (dm, J= 8.1 Hz, 1H), 3.57 (m, 1H), 3.50 (dt, J= 6.8, 6.8 Hz, 2H), 3.38-3.44 (brm, 1H), 2.04 (dt, J= 6.8, 6.8 Hz, 2H), 1.81 (tt, J= 7.3, 7.3 Hz, 2H), 1.44 (s, 9H), 1.34 (m, 12H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13C NMR (CDCl3,100MHz) δ: 155.8, 144.2, 144.0, 136.5, 132.9, 129.5, 98.4, 79.4, 74.7, 63.4, 54.5, 44.0, 32.2, 29.3, 29.2, 29.1, 29.0, 28.5, 28.4, 26.9, 25.8, 18.1, -5.65, -5.68 IR (KBr, disk) = 3414, 2928, 1586, 1258, 1173, 839 cm -1
1 H NMR (CDCl 3 , 400MHz) δ: 8.49 (d, J = 8.5 Hz, 1H), 6.58-6.48 (brm, 1H), 6.18 (d, J = 8.8 Hz, 1H), 5.75 (dt, J = 14.6, 7.3 Hz, 1H), 5.51 (dd, J = 15.4, 5.9 Hz, 1H), 5.31-5.21 (brm, 1H), 4.20 (m, 1H), 3.94 (dd, J = 10.3, 2.9 Hz, 1H ), 3.76 (dm, J = 8.1 Hz, 1H), 3.57 (m, 1H), 3.50 (dt, J = 6.8, 6.8 Hz, 2H), 3.38-3.44 (brm, 1H), 2.04 (dt, J = 6.8, 6.8 Hz, 2H), 1.81 (tt, J = 7.3, 7.3 Hz, 2H), 1.44 (s, 9H), 1.34 (m, 12H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.8, 144.2, 144.0, 136.5, 132.9, 129.5, 98.4, 79.4, 74.7, 63.4, 54.5, 44.0, 32.2, 29.3, 29.2, 29.1, 29.0, 28.5, 28.4, 26.9 , 25.8, 18.1, -5.65, -5.68

（実施例８）

Figure 0004825947
(Example 8)
Figure 0004825947

(2S,3R)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−ペンテン−3−オール(上記18)（50 mg, 0.151 mmol)のジクロロメタン(2.26 ml)溶液に室温で１１−ヒドロキシ−1−ウンデセン(103 mg, 0.603 mmol)を加え、続いてトリシクロホスフィン［１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾル−２−イリデン］（ベンジリデン）ルテニウム（ＩＶ）ジクロリド(4mg, 0.00452 mmol)を加えた。反応混合物を２時間還流した。反応混合物を減圧濃縮した後、シリカゲルクロマトグラフィー（ヘキサンに17％〜33％の酢酸エチルを溶かしたもの）により分離・精製し、(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−テトラデセン−3,14−ジオール(上記22) (54mg, 75%)を得た。(2S,3R,4E)−2−t−ブチルオキシカルボニルアミノ−1−t−ブチルジメチルシリルオキシ−4−テトラデセン−3,14−ジオールンの1H NMR、13C NMRデータを以下に示す。 To a solution of (2S, 3R) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-penten-3-ol (above 18) (50 mg, 0.151 mmol) in dichloromethane (2.26 ml) 11-Hydroxy-1-undecene (103 mg, 0.603 mmol) was added at room temperature followed by tricyclophosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2 -Ilidene] (benzylidene) ruthenium (IV) dichloride (4 mg, 0.00452 mmol) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel chromatography (17% to 33% ethyl acetate dissolved in hexane), and (2S, 3R, 4E) -2-t-butyloxycarbonylamino- 1-tert-butyldimethylsilyloxy-4-tetradecene-3,14-diol (22 above) (54 mg, 75%) was obtained. 1 H NMR and 13 C NMR data of (2S, 3R, 4E) -2-t-butyloxycarbonylamino-1-t-butyldimethylsilyloxy-4-tetradecene-3,14-diolone are shown below.

1H NMR (CDCl3,400MHz) δ: 8.49 (d, J= 8.8 Hz, 1H), 6.58-6.48 (brm, 1H), 6.18 (d, J= 8.8 Hz, 1H), 5.75 (dt, J= 14.6, 7.3 Hz, 1H), 5.51 (dd, J= 15.4, 5.9 Hz, 1H), 5.31-5.21 (brm, 1H), 4.20 (m, 1H), 3.94 (dd, J= 10.3, 2.9 Hz, 1H), 3.76(md, J= 8.1 Hz, 1H) 3.57 (m, 1H), 3.50 (dt, J= 6.8, 6.8 Hz, 2H), 3.44-3.38 (brm, 1H), 2.04 (dt, J= 6.8, 6.8 Hz, 2H), 1.81 (tt, J= 7.3, 7.3 Hz, 2H), 1.44 (s, 9H), 1.34 (m, 12H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13C NMR (CDCl3, 100MHz) δ: 155.8, 144.2, 144.0, 136.5, 132.9, 129.5, 98.4, 79.4, 74.7, 63.4, 54.5, 44.0, 32.2, 29.3, 29.2, 29.1, 29.00, 29.94, 28.5, 28.3, 26.9, 25.8, 18.1, -5.65, -5.68 1 H NMR (CDCl 3 , 400MHz) δ: 8.49 (d, J = 8.8 Hz, 1H), 6.58-6.48 (brm, 1H), 6.18 (d, J = 8.8 Hz, 1H), 5.75 (dt, J = 14.6, 7.3 Hz, 1H), 5.51 (dd, J = 15.4, 5.9 Hz, 1H), 5.31-5.21 (brm, 1H), 4.20 (m, 1H), 3.94 (dd, J = 10.3, 2.9 Hz, 1H ), 3.76 (md, J = 8.1 Hz, 1H) 3.57 (m, 1H), 3.50 (dt, J = 6.8, 6.8 Hz, 2H), 3.44-3.38 (brm, 1H), 2.04 (dt, J = 6.8 , 6.8 Hz, 2H), 1.81 (tt, J = 7.3, 7.3 Hz, 2H), 1.44 (s, 9H), 1.34 (m, 12H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
13 C NMR (CDCl 3 , 100 MHz) δ: 155.8, 144.2, 144.0, 136.5, 132.9, 129.5, 98.4, 79.4, 74.7, 63.4, 54.5, 44.0, 32.2, 29.3, 29.2, 29.1, 29.00, 29.94, 28.5, 28.3 , 26.9, 25.8, 18.1, -5.65, -5.68

以上のように、本発明の不飽和アミノジオール類の製造方法は、不飽和アミノジオール類とオレフィン類をメタセシス触媒存在下で反応させるため、従来の反応工程に比べて簡便で汎用性及び反応性が高く、立体選択性（Ｅ／Ｚ選択性）がよいため高い収率で目的化合物である不飽和アミノジオール類を製造することが可能である。加えて、参考例11〜13に示すように、ドラッグデリバリーシステム等に有効なスフィンゴミエリンなどの合成原料を経済的に提供することが可能である。   As described above, the method for producing unsaturated amino diols of the present invention reacts unsaturated amino diols with olefins in the presence of a metathesis catalyst, which is simpler, versatile and reactive than conventional reaction steps. Therefore, since the stereoselectivity (E / Z selectivity) is good, it is possible to produce unsaturated aminodiols that are target compounds in a high yield. In addition, as shown in Reference Examples 11 to 13, it is possible to economically provide synthetic raw materials such as sphingomyelin that are effective for drug delivery systems and the like.

Claims (3)

下記一般式（Ｉ）
Figure 0004825947
 （式中、Ｒ１およびＲ４は水素原子または水酸基の保護基であり、Ｒ２およびＲ３は水素原子またはアミノ基の保護基であり、Ｒ５は水素原子または低級アルキル基である。ただし、Ｒ 2 またはＲ 3 のいずれか一方がＲ 4 と一緒になって環を形成しているものを除く。）で表される不飽和アミノジオール類と、下記一般式（II）
Figure 0004825947
 （式中、Ｒ６は炭素数1〜２０のアルキル基である）で表されるオレフィン類をメタセシス触媒存在下で反応させて下記一般式（III）
Figure 0004825947
 （式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ６は上記と同じである。）で表される不飽和アミノジオール類を製造することを特徴とする不飽和アミノジオール類の製造方法。 The following general formula (I)
Figure 0004825947
 (In the formula, R 1 and R 4 are a hydrogen atom or a protecting group for hydroxyl group, R 2 and R 3 are a hydrogen atom or a protecting group for an amino group, R 5 is hydrogen atom or a lower alkyl group. However , R 2 or R 3 together with R 4 to form a ring. ) Unsaturated aminodiols represented by the following general formula (II)
Figure 0004825947
 (Wherein R 6 is an alkyl group having 1 to 20 carbon atoms) is reacted in the presence of a metathesis catalyst to give the following general formula (III)
Figure 0004825947
 (Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as described above), and the production of unsaturated amino diols, characterized in that Method. 前記メタセシス触媒がルテニウムカルベン錯体であることを特徴とする請求項１記載の不飽和アミノジオール類の製造方法。   The method for producing an unsaturated aminodiol according to claim 1, wherein the metathesis catalyst is a ruthenium carbene complex. 前記ルテニウムカルベン錯体が下記一般式（IＶ）
Figure 0004825947
 （式中、Ｒ７およびＲ８はアルキル基またはアリール基であり、Ｒ９はホスフィン配位子であり、Ｘはハロゲン原子である。）で表される錯体であることを特徴とする請求項２記載の不飽和アミノジオール類の製造方法。 The ruthenium carbene complex is represented by the following general formula (IV)
Figure 0004825947
 (Wherein R 7 and R 8 are an alkyl group or an aryl group, R 9 is a phosphine ligand, and X is a halogen atom). 3. A process for producing unsaturated aminodiols according to 2.
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