JP2696524B2

JP2696524B2 - New synthesis method of ganglioside GM (3)

Info

Publication number: JP2696524B2
Application number: JP63119800A
Authority: JP
Inventors: 昌明沼田; 守杉本; 祐二松崎; 秀司藤田; 正善伊藤; 田中　　誠; 智也小川
Original assignee: メクト株式会社
Priority date: 1988-05-17
Filing date: 1988-05-17
Publication date: 1998-01-14
Anticipated expiration: 2013-01-14
Also published as: JPH01290689A

Description

【発明の詳細な説明】〔産業上の利用分野〕本発明はガングリオシドGM₃の製造方法及び該方法に
用いる中間体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention [relates] The intermediates used in the production method and the method of ganglioside GM _3.

[Conventional technology]

哺乳動物細胞の糖脂質（グリコリピド）は、スフィン
ゴシンという長鎖アミノアルコールに脂肪酸がアミド結
合したセラミドという脂質構造に、グルコース、ガラク
トース、Ｎ−アセチルグルコサミン、Ｎ−アセチルガラ
クトサミン、フコース、シアル酸などの糖が種々の組み
合せでグリコシド結合したもので、いわゆるスフィンゴ
糖脂質といわれる範疇に属する。このうちシアル酸を有
するものを特にガングリオシドと称する。Glycolipids of mammalian cells (glycolipids) are composed of a long-chain amino alcohol called sphingosine and a ceramide-containing lipid structure called ceramide, and sugars such as glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, fucose, and sialic acid. Are glycosidic bonds in various combinations and belong to the so-called glycosphingolipid category. Among them, those having sialic acid are particularly called gangliosides.

これらの化合物は一般にその大部分が細胞膜２分子層
の外側分子層に局在し、最近の研究によれば細胞におけ
る識別や情報の受容と応答、レセプター機能、分化、細
胞の増殖・悪性変化・行動などにおいて重要な役割を果
たしているものと考えられている。These compounds are generally predominantly localized in the outer molecular layer of the cell membrane bilayer, and recent studies have shown that cell identification, information reception and response, receptor function, differentiation, cell proliferation, malignant changes, It is considered to play an important role in actions.

これらのガングリオシドのうち、ガングリオシドGM₃
は、脳、ヒト脾臓およびイヌの赤血球が単離され、その
構造は式（21）であることがわかっている〔ハコモリ
（1983）、ハンドブック・オブ・リピッド・リサーチ、
Vol.3、スフィンゴ脂質生化学、カンファー、ハコモリ
編、プレナム・プレス、ニューヨーク、p89−166、（Ha
ndbook of Lipid Research,Vol.3,Sphingolipid Bioche
mistry,eds.Kanfer JN,Hakomori S,Plenum Press,New Y
ork,p89−166）〕。Of these gangliosides, ganglioside GM ₃
Has isolated brain, human spleen and canine erythrocytes, the structure of which is known to be of formula (21) [Hakomori (1983), Handbook of Lipid Research,
Vol.3, Sphingolipid Biochemistry, Camphor, Hakomori, Plenum Press, New York, p89-166, (Ha
ndbook of Lipid Research, Vol.3, Sphingolipid Bioche
mistry, eds.Kanfer JN, Hakomori S, Plenum Press, New Y
ork, p89-166)].

ガングリオシドGM₃の生合成は、腸上皮組織分化およ
び細胞成長の接触阻害と相関があることがわかってい
る。繊維芽球成長要因の存在下におけるベビーハムスタ
ー腎繊維芽球細胞の成長は、外部から加えられたガング
リオシドGM₃の存在により特異的に阻害される。生体膜
の成分であるガングリオシドがこのような重要な機能を
有しており、したがってガングリオシドGM₃を立体選択
的精密合成することは、ガングリオシドの分子構造と生
物情報との相関を解明するうえで必要不可欠なことであ
る。 Biosynthesis of ganglioside GM ₃ has been found to correlate with contact inhibition of intestinal epithelial tissue differentiation and cell growth. Growth of baby hamster kidney fibroblasts mononuclear cells in the presence of fibroblast sphere growth factor, it is specifically inhibited by the presence of ganglioside GM ₃ applied externally. Gangliosides are components of biological membranes has such important functions, thus be stereoselective precisely synthesize ganglioside GM ₃ is necessary to elucidate the correlation between molecular structure and biological information gangliosides It is essential.

シャピロは、ガングリオシドGM₃の合成のためのアプ
ローチを報告している（Shapiro D（1974）、24th,Int.
Corgr.Pure Appl.Chem.2:153−66;（1976）Chem.Abstr.
85:177800）。しかし、合成ガングリオシドGM₃のＣ−2c
の立体配置は明らかにされていない。Shapiro, report an approach for the synthesis of ganglioside _{GM 3 (Shapiro D (1974)} , 24th, Int.
Corgr. Pure Appl. Chem. 2: 153-66; (1976) Chem. Abstr.
85: 177800). However, C-2c of synthetic ganglioside GM ₃
The configuration of is not disclosed.

[Problems to be solved by the invention]

本発明者らは、ガングリオシドGM₃を立体選択的に精
密合成できる方法を見い出し、既に特願昭60−123952号
（特開昭61−282393号）として特許出願している。とこ
ろが、この方法によれば、確かにガングリオシドGM₃を
立体選択的に合成できるのであるが、収率、特にグリコ
シル化反応の収率が必ずしも高くなく（約37％）、より
高収率でガングリオシドGM₃を合成できる方法の提供が
望まれていた。The present inventors have found a method for the ganglioside GM ₃ can stereoselectively precise synthesis has already filed a patent application No. Sho 60-123952 (JP 61-282393). However, according to this method, but certainly is the ganglioside GM ₃ can stereoselectively synthesized, yield, without any particular necessarily high yield of the glycosylation reaction (approximately 37%), a higher yield in gangliosides It provides a method capable of synthesizing GM ₃ has been desired.

そこで本発明の目的は、高収率でグルコシル化反応を
行うことができ、高収率でガングリオシドGM₃を製造す
ることができる方法を提供することにある。さらに本発
明の目的は、ガングリオシドGM₃合成に有用な新規な中
間体を提供することにある。It is an object of the present invention, it is possible to carry out the glycosylation reaction in a high yield, it is to provide a method capable of producing the ganglioside GM ₃ in high yield. Further object of the present invention is to provide a novel intermediates useful in the ganglioside GM ₃ synthesis.

[Means for solving the problem]

本発明は、下記一般式（Ｉ）で示される化合物（ただし、式中、R¹はアセチル基又はベンジル基であ
り、R²はメチル基であり、R³及びR⁴は独立にアセチル基
又はベンジル基であり、R⁵は−COC（CH₃）_３、又はであり、R⁶はハロゲン又はである）と（式中Bzはベンゾイル基である）とを反応させて得られ
た上記一般式（Ｉ）で示される化合物（ただし、式中、
R¹はアセチル基又はベンジル基であり、R²メチル基であ
り、R³及びR⁴は独立にアセチル基又はベンジル基であ
り、R⁵は−COC（CH₃）_３、又はであり、R⁶はである）を得、さらに脱アセチル化又は脱ベンジル化、
脱ベンゾイル化およびケン化を行う、ガングリオシドGM
₃の製造方法に関する。The present invention provides a compound represented by the following general formula (I) (Where R ¹ is an acetyl or benzyl group, R ² is a methyl group, R ³ and R ⁴ are each independently an acetyl or benzyl group, and R ⁵ is —COC (CH ₃ ) ₃ , Or And R ⁶ is halogen or Is) (Wherein Bz is a benzoyl group) and a compound represented by the above general formula (I) (wherein,
R ¹ is acetyl or benzyl, R ^{2 is} methyl, R ³ and R ⁴ are independently acetyl or benzyl, R ⁵ is —COC (CH ₃ ) ₃ , Or And R ⁶ is And further deacetylation or debenzylation,
Ganglioside GM for debenzoylation and saponification
₃ relates to the manufacturing method.

さらに、本発明は、下記一般式（Ｉ）及び（II）で示
される化合物に関する。Furthermore, the present invention relates to compounds represented by the following general formulas (I) and (II).

（式中、R¹はアセチル基又はベンジル基であり、R²はメ
チル基であり、R³及びR⁴は独立に水素、アセチル基又は
ベンジル基であり、R⁵は−COC（CH₃）_３、又はであり、R⁶は水酸基、ベンジルオキシ基、ハロゲン、又は（式中Bzはベンンゾイル基である）であり、Acはアセチ
ル基である）。 (Wherein, R ¹ is an acetyl group or a benzyl group, R ² is a methyl group, R ³ and R ⁴ are each independently hydrogen, an acetyl group or a benzyl group, and R ⁵ is —COC (CH ₃ ) ₃ , Or R ⁶ is a hydroxyl group, a benzyloxy group, a halogen, Or (Where Bz is a benzozoyl group) and Ac is an acetyl group).

（式中、R¹¹及びR¹²は水素であるか、R¹¹とR¹²が共同で
（CH₃）₂Cであり、R¹³はアセチル基又はベンジル基で
あり、R¹⁴は水素、 −COC（CH₃）_３、又はである）以下、本発明について原料化合物（１）からガングリ
オシドGM₃（21）への合成経路をスキーム１及び２に従
って説明する。 Wherein R ¹¹ and R ¹² are hydrogen, R ¹¹ and R ¹² are jointly (CH ₃ ) ₂ C, R ¹³ is an acetyl group or a benzyl group, R ¹⁴ is hydrogen, —COC (CH ₃ ) ₃ , Or Hereinafter, a synthesis route from the starting compound (1) to the ganglioside GM ₃ (21) will be described with reference to Schemes 1 and 2.

尚、本明細書においてMeはメチル基、Acはアセチル
基、Bnはベンジル基、Bzはベンゾイル基、−CO＋はピパ
ロイル基、Cerはセラミド基を表わす。In this specification, Me represents a methyl group, Ac represents an acetyl group, Bn represents a benzyl group, Bz represents a benzoyl group, -CO + represents a piperoyl group, and Cer represents a ceramide group.

一般式（II）で示される化合物の例としては、スキー
ム１に記載された化合物（８）、（９）及び（10）を挙
げることができる。化合物（８）、（９）及び（10）は
以下のように化合物（１）から合成することができる。 Examples of the compound represented by the general formula (II) include the compounds (8), (9) and (10) described in Scheme 1. Compounds (8), (9) and (10) can be synthesized from compound (1) as follows.

原料化合物（１）は、特開昭61−12692号に記載の方
法に従って合成することができる。化合物（２）は、化
合物（１）をトリス−トリフェニルホスフィンロジウム
（Ｉ）クロライド及び1,4−ジアザビシクロオクタンで
処理することにより得られ、化合物（３）は化合物
（２）と四臭化炭素とを反応させることにより得られ、
化合物（４）は、化合物（３）をnBu₄NBr、Et₃N及びBnO
Hで処理することより得ることができる。化合物（５）
は化合物（４）をNaOCH₃−メタノールにより脱アセチル
化することにより得られる。化合物（６）は化合物
（５）をBnBr（臭化ベンジル）処理によりベンジル化し
て得ることができる。化合物（７）は化合物（６）をTM
S（トリメチルシラン）トリフレートで処理することに
より得られる。The starting compound (1) can be synthesized according to the method described in JP-A-61-12692. Compound (2) is obtained by treating compound (1) with tris-triphenylphosphine rhodium (I) chloride and 1,4-diazabicyclooctane, and compound (3) is obtained by treating compound (2) with Obtained by reacting with carbonized carbon,
Compound (4) is obtained by converting compound (3) into nBu ₄ NBr, Et ₃ N and BnO.
It can be obtained by treating with H. Compound (5)
Is obtained by deacetylating compound (4) with NaOCH ₃ -methanol. Compound (6) can be obtained by benzylation of compound (5) by treatment with BnBr (benzyl bromide). Compound (7) is compound (6)
Obtained by treating with S (trimethylsilane) triflate.

化合物（８）は化合物（７）を例えば無水メタノール
−NaOCH₃で脱アセチル化することにより得ることができ
る。無水メタノール−NaOCH₃の代りにK₂CO₃−CH₃OH、Na
OH−CH₃OH−H₂O、CH₃OH−３級塩基（例えばトリエチル
アミン）等の加水分解試薬を用いることもできる。又反
応は約０〜80℃、30〜24時間の条件で行うことが好まし
い。Compound (8) can be obtained by deacetylating compound (7) for example with anhydrous methanol -NaOCH _3. Alternatively K ₂ CO _₃ -CH ₃ OH in anhydrous methanol -NaOCH _3, Na
_{_{OH-CH 3 OH-H 2}} O, may also be used hydrolysis reagents such as CH ₃ OH-3 grade base (e.g. triethylamine). The reaction is preferably carried out at about 0 to 80 ° C. for 30 to 24 hours.

化合物（９）は、化合物（８）をトリメチルアセチル
クロライド−DMAP（ジメチルアミノピリジン）で処理す
ることにより得ることができる。トリメチルアセチルク
ロライド−DMAPの代りにトリエチルアミン−ジクロロメ
チル−ピバロイルクロライドを用いることもできる。反
応は、室温〜100℃、１時間〜12時間の条件下行うこと
が好ましい。Compound (9) can be obtained by treating compound (8) with trimethylacetyl chloride-DMAP (dimethylaminopyridine). Triethylamine-dichloromethyl-pivaloyl chloride can be used instead of trimethylacetyl chloride-DMAP. The reaction is preferably carried out at room temperature to 100 ° C. for 1 hour to 12 hours.

化合物（10）は、化合物（９）をCF₃COOHで処理して
脱保護することにより得ることができる。Compound (10) can be obtained by treating compound (9) with CF ₃ COOH to remove the compound.

一般式（Ｉ）で示される化合物の例としては、スキー
ム１及び２に記載された化合物（11）、（14）、（1
5）、（16）、（17）、（18）、（19）及び（20）を挙
げることができる。尚、化合物（19）の置換基Ｘはハロ
ゲンを示し、ハロゲンとしてはフッ素、塩素、臭素を挙
げることができ、特にフッ素であることが好ましい。Examples of the compound represented by the general formula (I) include compounds (11), (14) and (1) described in Schemes 1 and 2.
5), (16), (17), (18), (19) and (20). In addition, the substituent X of the compound (19) represents a halogen, and examples of the halogen include fluorine, chlorine, and bromine, and fluorine is particularly preferable.

化合物（11）は化合物（10）とクーンの方法〔Kuhn
R.ら、（1966）Chem Ber99:611−17〕により合成される
Ｎ−アセチルノイラミン酸アセテートメチルエステル
〔化合物（22）〕とを、ジクロロメタン、1,2−ジクロ
ロエタン等の溶媒中、Hg（CN）_２、HgBr₂、モレキュラ
ーシーブ、Ag₂CO₃、AgClO₄、AgOSO₂CF₃、（CH₃）₃COSO₂
CF₃等のグリコデーション触媒存在下に、−20℃〜150℃
で１〜120時間程度反応させることにより得られる。
尚、化合物（10）と（22）の反応の際には副反応物とし
て化合物（12）及び（13）も得られる。Compound (11) is obtained by the method of Kuhn [Kuhn] with compound (10).
R., et al., (1966) N-acetylneuraminic acid acetate methyl ester [compound (22)] synthesized by Chem Ber99: 611-17] in a solvent such as dichloromethane, 1,2-dichloroethane or the like. _{CN) _2,} HgBr _2, a molecular _{_{_{sieve, Ag 2 CO 3, AgClO 4}}} , AgOSO 2 CF 3, (CH 3) 3 COSO 2
In the presence of glycolate retardation catalyst CF _3, etc., -20 ° C. to 150 DEG ° C.
For about 1 to 120 hours.
In the reaction between the compounds (10) and (22), the compounds (12) and (13) are also obtained as by-products.

化合物（14）は、化合物（11）を無水酢酸−ピリジン
で処理することにより得ることができる。化合物（15）
は、化合物（14）をPd−Ｃ触媒を用いて水素還元するこ
とにより得ることができる。化合物（16）は、化合物
（15）を無水酢酸−ピリジンで処理することにより得る
ことができる。化合物（17）は、化合物（16）とヒドラ
ジニウムアセテート（NH₂NH₂CH₃COOH）とを溶媒、例え
ばDMFの存在下、室温〜60℃で５分〜５時間反応させる
ことにより得ることができる。Compound (14) can be obtained by treating compound (11) with acetic anhydride-pyridine. Compound (15)
Can be obtained by subjecting compound (14) to hydrogen reduction using a Pd-C catalyst. Compound (16) can be obtained by treating compound (15) with acetic anhydride-pyridine. Compound (17) is obtained by reacting compound (16) with hydrazinium acetate (NH ₂ NH ₂ CH ₃ COOH) at room temperature to 60 ° C. for 5 minutes to 5 hours in the presence of a solvent such as DMF. Can be.

化合物（18）は、化合物（17）とトリクロロアセトニ
トリルをDBU（1,8−ジアザビシクロ〔5,4,0〕−７−ウ
ンデセン）の存在下０℃〜50℃で30分〜６時間程度反応
させることにより得ることができる。DBUの代りにNaH、
K₂CO₃を用いることもできる。又、反応溶媒としてジク
ロルエタン、ジクロルメタン、THF等を用いることがで
きる。Compound (18) is obtained by reacting compound (17) with trichloroacetonitrile in the presence of DBU (1,8-diazabicyclo [5,4,0] -7-undecene) at 0 ° C. to 50 ° C. for about 30 minutes to 6 hours. Can be obtained. NaH instead of DBU,
K ₂ CO ₃ can also be used. Further, dichloroethane, dichloromethane, THF or the like can be used as a reaction solvent.

化合物（19）〔ただし、式中Ｘはフッ素である〕は、
化合物（17）とDAST〔（ジエチルアミノ）サルファート
リフルオライド〕とを−30〜30℃で30分〜６時間程度反
応させることにより得ることができる。反応溶媒として
例えばジクロルエタン等を用いることができる。Compound (19) wherein X is fluorine,
It can be obtained by reacting compound (17) with DAST [(diethylamino) sulfur trifluoride] at −30 to 30 ° C. for about 30 minutes to 6 hours. As a reaction solvent, for example, dichloroethane or the like can be used.

化合物（20）は、化合物（18）又は化合物（19）とベ
ンジルセラミド（化合物（23））とをグリコシル化触媒
の存在下−20〜60℃で２〜12時間程度反応させることに
より得ることができる。グリコシル化触媒の例として
は、BF₃−Et₂O、TMSトリフレート、AlCl₃等のルイス酸
触媒を挙げることができる。尚、化合物（23）は特開昭
61−282393号に記載の方法に基いて合成することができ
る。Compound (20) can be obtained by reacting compound (18) or compound (19) with benzylceramide (compound (23)) at −20 to 60 ° C. for about 2 to 12 hours in the presence of a glycosylation catalyst. it can. Examples of glycosylation catalyst include BF ₃ -Et ₂ O, TMS triflate, a Lewis acid catalyst such as AlCl _3. Compound (23) is disclosed in
It can be synthesized based on the method described in JP-A 61-282393.

化合物（20）は、常法〔例えばNaOCH₃等を用いる脱ア
シル化反応〕により脱保護し〔ピバロイル基、アセチル
基及びセラミド基のベンゾイル基を脱離する〕、かつケ
ン化することにより、目的生産物であるガングリオシド
GM₃（化合物（21））とすることができる。Compound (20) is deprotected by a conventional method (for example, deacylation reaction using NaOCH ₃ or the like) (to remove pivaloyl group, acetyl group and benzoyl group of ceramide group) and saponified to obtain the desired compound. Ganglioside as a product
GM ₃ (compound (21)).

尚、化合物（８）から化合物（９）の合成において、
化合物（８）を、トリメチルアセチルクロライドの代り
にトリメチルベンゾイルクロライド又はメチルベンゾイ
ルクロライドと反応させるとにより一般式（Ｉ）のR⁵が及びである化合物を得ることができる。In the synthesis of compound (9) from compound (8),
By reacting compound (8) with trimethylbenzoyl chloride or methylbenzoyl chloride instead of trimethylacetyl chloride, R ⁵ of the general formula (I) is as well as Can be obtained.

以下本発明を実施例により説明する。 Hereinafter, the present invention will be described with reference to examples.

実施例１（化合物（１）→（２））Ｉ）化合物（１）5.0g（7.9mmol）をEtOH:ベンゼン:H₂O
（7:3:1）の混合溶媒300mlに溶かし、トリス−トリフェ
ニルホスフィンロジウム（Ｉ）クロライド451mg（0.481
mmol）1,4−ジアザビシクロオクタン150mg（1.65mmol）
を加え、20時間還流を行った。反応液をセライトロ過
し、留去後、80％THF（20％H₂O）100mlを加え、I₂2.5g
（11.8mmol）を加え、室温で１時間撹拌し、水を加え、
CHCl₃で抽出した。CHCl₃層をチオ硫酸ナトリウム水溶
液、水、飽和食塩水で洗浄し、無水MgSO₄乾燥後留去し
た。残渣をシリカゲルカラム（ワコーゲル、Ｃ−300、5
0g、CHCl₃:アセトン（Et₃N1％）＝4:1）で精製して化合
物（２）を得た。Example 1 (Compound (1) → (2)) I) Compound (1) 5.0 g (7.9 mmol) was added to EtOH: benzene: H ₂ O
(7: 3: 1) in a mixed solvent (300 ml) and tris-triphenylphosphine rhodium (I) chloride (451 mg, 0.481)
mmol) 1,4-diazabicyclooctane 150 mg (1.65 mmol)
And refluxed for 20 hours. The reaction mixture filtered Seraitoro was distilled off, the _{80% THF (20% H 2} O) 100ml addition, I ₂ 2.5 g
(11.8 mmol), stirred at room temperature for 1 hour, added water,
And extracted with CHCl _3. The CHCl ₃ layer was washed with an aqueous solution of sodium thiosulfate, water, and saturated saline, dried over anhydrous MgSO _{4 and} evaporated. The residue was purified on a silica gel column (Wakogel, C-300, 5
0 g, purified with CHCl ₃ : acetone (Et ₃ N 1%) = 4: 1) to obtain a compound (2).

2.81g（60％） Rf＝0.56（CCl₄:アセトン＝4:3） II）化合物（１）26g（41mmol）をEtOH:ベンゼン:H₂O
（7:3:1）の混合溶媒1.1に溶かし、トリス−トリフェ
ニルホスフィンロジウム（Ｉ）クロライド2.5g（2.666m
mol）、1,4−ジアザビシクロオクタン780mg（8.58mmo
l）を加え、20時間還流した。反応液をセライトロ過
し、留去後、90％アセトン水溶液200mlに溶かし、HgCl₂
39g（14.4mmol）、黄HgO780mg（3.6mmol）を加え、１時
間室温で撹拌した。反応液をセライトロ過し、留去後、
CHCl₃で抽出した。CHCl₃層をヨウ化カリウム水溶液ハイ
ポ、水、飽和食塩水で洗浄し、無水MgSO₄で乾燥後留去
した。残渣をシリカゲルカラム（ワコーゲル、Ｃ−30
0、2.4kg、CHCl₃:アセトン（１％Et₃N）＝4:1）で精製
して化合物（２）を得た。2.81 g (60%) Rf = 0.56 (CCl ₄ : acetone = 4: 3) II) 26 g (41 mmol) of compound (1) was added to EtOH: benzene: H ₂ O
(7: 3: 1) in a mixed solvent 1.1, and tris-triphenylphosphine rhodium (I) chloride 2.5 g (2.666 m
mol), 780 mg of 1,4-diazabicyclooctane (8.58 mmo
l) was added and refluxed for 20 hours. The reaction mixture filtered Seraitoro was distilled off, dissolved in 90% aqueous acetone solution 200 ml, HgCl ₂
39 g (14.4 mmol) and 780 mg (3.6 mmol) of yellow HgO were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite and distilled off.
And extracted with CHCl _3. The CHCl ₃ layer was washed with an aqueous solution of potassium iodide hypo, water and saturated saline, dried over anhydrous MgSO ₄ and evaporated. The residue is purified on a silica gel column (Wakogel, C-30).
0, 2.4 kg, purified with CHCl ₃ : acetone (1% Et ₃ N) = 4: 1) to obtain compound (2).

16.4g（67.5％） ▲〔α〕²⁴ _D▼＋39.4（ｃ＝1.03、CHCl₃） 2.074（s,3H,CH₃CO）,2.080（s,3H,CH₃CO）,2.085（s,3
H,CH₃CO）,2.112（s,3H,CH₃CO）,2.115（s,3H,CH₃CO）,
2.124（s,3H,CH₃CO）,2.128（s,3H,CH₃CO）,3.941（t,1
H,H−5b）,4.357（d,1H,J＝7.69,H−1bβ）,4.381（d,1
H,J＝7.69,H−1bα）,4.740（d,1H,J＝7.69,H−1aβ）,
4.822（dd,1H,J＝3.66,10.26,H−2a）,4.860（dd,1H,J
＝5.86,7.70,H−2b）,5.210（t,J＝9.53,H−3aβ）,5.3
57（d,1H,J＝3.66,H−1aα）,5.511（t,1H,J＝9.90,H−
3aα）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 95.145（Ｃ−１α）,100.260（Ｃ−２β）,100.467（Ｃ
−１β）， 169.342（Ｃ＝０）,169.979（Ｃ＝０）,170.448（Ｃ＝
０）,170.676（Ｃ＝０）,170.703（Ｃ＝０）,170.824
（Ｃ＝０）,170.857（Ｃ＝０）元素分析 C₂₄H₃₆O₁₆ 計算値 C,49.65 H,6.25 実測値 C,49.98 H,6.12 実施例２（化合物（２）→（３）） Ar gas中化合物（２）1.5g（2.531mmol）、四臭化炭
素1.679g（5.06mmol）をCH₂Cl₂20mlに溶かし、−20℃冷
却下で（Me₂N）₃P（5.06mmol）0.826gを加え、30分撹拌
後、３時間還流した。反応液に酢酸エチルを加え、酢酸
エチル層を希HClaq、水、飽和食塩水で洗浄後、無水MgS
O₄で乾燥後留去して化合物（３）を得た。16.4 g (67.5%) ▲ [α] ²⁴ _D ▼ + 39.4 (c = 1.03, CHCl ₃ ) _{2.074 (s, 3H, CH 3} CO), 2.080 (s, 3H, CH 3 CO), 2.085 (s, 3
H, CH ₃ CO), 2.112 (s, 3H, CH ₃ CO), 2.115 (s, 3H, CH ₃ CO),
_{2.124 (s, 3H, CH 3} CO), 2.128 (s, 3H, CH 3 CO), 3.941 (t, 1
H, H-5b), 4.357 (d, 1H, J = 7.69, H-1bβ), 4.381 (d, 1
H, J = 7.69, H-1bα), 4.740 (d, 1H, J = 7.69, H-1aβ),
4.822 (dd, 1H, J = 3.66, 10.26, H-2a), 4.860 (dd, 1H, J
= 5.86,7.70, H-2b), 5.210 (t, J = 9.53, H-3aβ), 5.3
57 (d, 1H, J = 3.66, H-1aα), 5.511 (t, 1H, J = 9.90, H-
3aα) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 95.145 (C-1α), 100.260 (C-2β), 100.467 (C
-1β), 169.342 (C = 0), 169.979 (C = 0), 170.448 (C =
0), 170.676 (C = 0), 170.703 (C = 0), 170.824
(C = 0), 170.857 (C = 0) Elemental analysis C ₂₄ H ₃₆ O ₁₆ Calculated C, 49.65 H, 6.25 Found C, 49.98 H, 6.12 Example 2 (Compound (2) → (3)) Ar gas in the compound (2) 1.5g (2.531mmol), dissolved carbon tetrabromide 1.679g (5.06mmol) in CH _₂ Cl ₂ 20ml, -20 ℃ under cooling with _{_{(Me 2 N) 3 P (}} 5.06mmol) 0.826 g was added and the mixture was stirred for 30 minutes and refluxed for 3 hours. Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with dilute HClaq, water and saturated saline, and then dried over anhydrous MgS
After drying over O ₄ and evaporation, compound (3) was obtained.

1.708g（TLCより1:1） Rf＝0.45（トルエン:EtOAc＝1:1）得られたサンプルの一部をトルエン:EtOAc＝1:1で精
製し500MHz NMR測定用サンプルとした。¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.322 2.080（s,3H,CH₃CO×２）,2.097（s,6H,CH₃CO）,2.121
（s,3H,CH₃CO）,2.123（s,3H,CH₃CO）,3.847（t,1H,J＝
9.52,H−4a）,4.437（α,1H,J＝7.33,H−1bβ）,4.772
（dd,1H,J＝4.03,9.89,H−2a）,4.877（dd,1H,J＝6.23,
7.33,H−2b）,5.571（t,1H,J＝9.53,H−3a）,6.541（d,
1H,J＝4.03,H−1aα）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 86.739（Ｃ−1aα）,99.978（Ｃ−1bβ）， 169.255（Ｃ＝０）,169.570（Ｃ＝０）,170.100（Ｃ＝
０）,170.402（Ｃ＝０）,170.824（Ｃ＝０）元素分析 C₂₄H₃₅O₁₅Br 計算値 C,44.80 H,5.48 実測値 C,44.50 H,5.42 実施例３（化合物（３）→（４）） Ar gas下で化合物（３）1.7gを無水CH₂Cl₂50mlに溶か
し、氷−MeOH冷却下で、nBu₄NBr203mg（0.63mmol）、Et
₃N228mg（2.25mmol）を加えて30分撹拌後、BnOH665mg
（6.2mmol）を加え、室温で10分撹拌し、60℃で一夜撹
拌した。反応液を留去し、残渣をシリカゲルカラム（ワ
コーゲル、Ｃ−300、150g、トルエン:EtOAc（１％Et
₃N）＝10:1）で精製して化合物（４）を得た。1.708 g (1: 1 from TLC) Rf = 0.45 (toluene: EtOAc = 1: 1) A part of the obtained sample was purified with toluene: EtOAc = 1: 1 to obtain a 500 MHz NMR measurement sample. ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.322 2.080 (s, 3H, CH ₃ CO × 2), 2.097 (s, 6H, CH ₃ CO), 2.121
_{(S, 3H, CH 3 CO} ), 2.123 (s, 3H, CH 3 CO), 3.847 (t, 1H, J =
9.52, H-4a), 4.437 (α, 1H, J = 7.33, H-1bβ), 4.772
(Dd, 1H, J = 4.03, 9.89, H-2a), 4.877 (dd, 1H, J = 6.23,
7.33, H-2b), 5.571 (t, 1H, J = 9.53, H-3a), 6.541 (d,
1H, J = 4.03, H-1aα) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 86.739 (C-1aα), 99.978 (C-1bβ), 169.255 (C = 0), 169.570 (C = 0), 170.100 (C =
0), 170.402 (C = 0), 170.824 (C = 0) Elemental analysis C ₂₄ H ₃₅ O ₁₅ Br Calculated C, 44.80 H, 5.48 Found C, 44.50 H, 5.42 Example 3 (Compound (3) → (4)) Ar gas under the compound (3) 1.7 g was dissolved in anhydrous CH _₂ Cl ₂ 50ml, under ice -MeOH _{cooling, nBu 4 NBr203mg (0.63mmol),} Et
₃ After adding N228mg (2.25mmol) and stirring for 30 minutes, BnOH665mg
(6.2 mmol), and the mixture was stirred at room temperature for 10 minutes and then at 60 ° C. overnight. The reaction solution was distilled off, and the residue was subjected to silica gel column (Wako gel, C-300, 150 g, toluene: EtOAc (1% Et.
_The compound was purified by 3N) = 10: 1) to obtain a compound (4).

398mg（化合物（２）から23％） Rf＝0.46（トルエン:EtOAc＝1:1） ▲〔α〕²⁰ _D▼−47.98（CHCl₃、ｃ＝0.667）元素分析 C₃₂H₄₂O₁₆ 計算値 C,56.30 H,6.20 実測値 C,56.35 H,6.33¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.340 1.792（s,3H, 2.072（s,3H,CH₃C＝０）,2.095（s,3H,CH₃C＝０）,2.09
8（s,3H,CH₃C＝０）,2.110（s,3H,CH₃C＝０）,4.237（d
d,1H,J＝2.20,7.91,H−4b）,4.507（d,1H,J＝8.06,H−1
b）,4.563（s,2H,CH₂−Ph）,4.962（dd,1H,J＝4.60,8.0
6,H−2b）,5.584（dd,J＝1.46,1.47,H−3a）,5.628（d,
1H,J＝5.13,H−1a）,7.26〜7.38（m,5H,ph）¹³ C−NMR（500MHz,77.045、CDCl₃），δ； 20.894（CH₃）,20.914（CH₃）,20.927（CH₃）,20.941
（CH₃）,20.961（CH₃）， 90.218（Ｃ−1a）,100.367（Ｃ−1b）， 127.059,127.729,128.641（ph）実施例４（化合物（４）→（５））化合物（４）3.37g（4.94mmol）を乾燥メタノール50m
lに溶かし、1NNaOCH₃5ml（5mmol）を加え、室温５時間
撹拌した。反応液を留去乾燥して化合物（５）を得た。
〔4.05g、Rf＝0.396（メタノール：クロロホルム＝1:
8）〕化合物（５）は精製することなく、そのまま次の
反応に用いた。398 mg (23% from compound (2)) Rf = 0.46 (toluene: EtOAc = 1: 1) ▲ [α] ²⁰ _D ▼ -47.98 (CHCl ₃ , c = 0.667) Elemental analysis C ₃₂ H ₄₂ O ₁₆ Calculated C , 56.30 H, 6.20 Found C, 56.35 H, 6.33 ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.340 1.792 (s, 3H, 2.072 (s, 3H, CH ₃ C = 0), 2.095 (s, 3H, CH ₃ C = 0), 2.09
_{8 (s, 3H, CH 3} C = 0), 2.110 (s, 3H, CH 3 C = 0), 4.237 (d
d, 1H, J = 2.20,7.91, H-4b), 4.507 (d, 1H, J = 8.06, H-1
b), 4.563 (s, 2H , CH 2 -Ph), 4.962 (dd, 1H, J = 4.60,8.0
6, H-2b), 5.584 (dd, J = 1.46,1.47, H-3a), 5.628 (d,
1H, J = 5.13, H-1a), 7.26 to 7.38 (m, 5H, ph) ¹³ C-NMR (500 MHz, 77.045, CDCl ₃ ), δ; 20.894 (CH ₃ ), 20.914 (CH ₃ ), 20.927 ( CH ₃ ), 20.941
(CH ₃ ), 20.961 (CH ₃ ), 90.218 (C-1a), 100.367 (C-1b), 127.059,127.729,128.641 (ph) Example 4 (Compound (4) → (5)) 3.37 g (4.94 mmol) of compound (4) was dried in 50m of methanol.
Then, 5 ml (5 mmol) of 1NNaOCH ₃ was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was evaporated to dryness to obtain a compound (5).
[4.05 g, Rf = 0.396 (methanol: chloroform = 1:
8)] Compound (5) was used for the next reaction without purification.

実施例５（化合物（５）→（６））化合物（５）4.05gを乾燥DMF60mlに溶かし、０℃で60
％NaH1.0g（24.7mmol）を少量づつ加えた後１時間撹拌
し、BnBr4.3g（2.7mmol）を加え、そのまま一夜撹拌し
た。反応液に少量のメタノールを加え、１時間撹拌後、
留去した。残渣をEtOAcで抽出し、EtOAc層を水、飽和食
塩水で洗浄後無水MgSO₄で乾燥し、留去した。残渣をシ
リカゲルカラム（ワコーゲル、Ｃ−300トルエン:EtOAc
（１％Et₃N）＝10:1）で精製して化合物（６）を得た。Example 5 (Compound (5) → (6)) Compound (5) (4.05 g) was dissolved in dry DMF (60 ml), and dissolved at 0 ° C. for 60 minutes.
% G NaH (1.0 g, 24.7 mmol) was added in small portions, and the mixture was stirred for 1 hour. 4.3 g (2.7 mmol) of BnBr was added, followed by stirring overnight. After adding a small amount of methanol to the reaction solution and stirring for 1 hour,
Distilled off. The residue was extracted with EtOAc, and the EtOAc layer was washed with water and brine, dried over anhydrous MgSO ₄ and evaporated. The residue was subjected to a silica gel column (Wakogel, C-300 toluene: EtOAc
(1% Et ₃ N) = 10: 1) to give compound (6).

4.434g（化合物（４）から86％） Rf＝0.519（トルエン:EtOAc＝5:1） ▲〔α〕²⁰ _D▼＋16.6（ｃ＝0.553、CHCl₃）元素分析 C₆₀H₆₆O₁₆ 計算値 C,69.08 H,6.38 実測値 C,68.92 H,6.37¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.313 1.747（s,3H,CH₃CO）,4.081（dd,1H,J＝2.20,5.50,H−4
b）,4.247（d,1H,8.43,H−1b）,4.423（d,1H,J＝12.09,
CH₂ph）,4.431（d,1H,J＝12.45,CH₂ph）,4.488（d,1H,J
＝12.09,CH₂ph）,4.539（s,2H,CH₂ph）,4.572（d,1H,J
＝12.09,CH₂ph）,4.604（d,1H,J＝12.08,CH₂ph）,4.690
（d,1H,J＝11.72,CH₂ph）,4.723（d,1H,J＝12.09,CH₂p
h）,4.742（d,1H,J＝11.72,CH₂ph）,5.681（d,1H,J＝5.
50,H−1a）,7.06〜7.40（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃、77.045），δ； 97.578（Ｃ−1a）,104.442（Ｃ−1b）， 127.066〜128.715（ph），実施例６（化合物（６）→（７））化合物（６）530mg（0.50mmol）を無水CH₂Cl₂5mlに溶
かし、活性化MS−4A0.8g中に加え、０℃でTMSトリフレ
ート80.4mg（0.362mmol）を加え、そのまま１時間30分
撹拌した。反応液をセライトロ過し、炭酸水素ナトリウ
ム水溶液、水、飽和食塩水で洗浄し、無水MgSO₄で乾燥
後留去した。残渣をシリカゲルカラム（ワコーゲル、Ｃ
−300、90g、トルエン:EtOAc（１％Et₃N）＝9:1）で精
製して化合物（７）を得た。4.434 g (86% from compound (4)) Rf = 0.519 (toluene: EtOAc = 5: 1) ▲ [α] ²⁰ _D ▼ + 16.6 (c = 0.553, CHCl ₃ ) Elemental analysis C ₆₀ H ₆₆ O ₁₆ calculation Value C, 69.08 H, 6.38 actual value C, 68.92 H, 6.37 ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.313 _{1.747 (s, 3H, CH 3} CO), 4.081 (dd, 1H, J = 2.20,5.50, H-4
b), 4.247 (d, 1H, 8.43, H-1b), 4.423 (d, 1H, J = 12.09,
CH ₂ ph), 4.431 (d, 1H, J = 12.45, CH ₂ ph), 4.488 (d, 1H, J
= 12.09, CH ₂ ph), 4.539 (s, 2H, CH ₂ ph), 4.572 (d, 1H, J
= 12.09, CH ₂ ph), 4.604 (d, 1H, J = 12.08, CH ₂ ph), 4.690
(D, 1H, J = 11.72, CH ₂ ph), 4.723 (d, 1H, J = 12.09, CH ₂ p
h), 4.742 (d, 1H, J = 11.72, CH ₂ ph), 5.681 (d, 1H, J = 5.
50, H-1a), 7.06 to 7.40 (m, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 97.578 (C-1a), 104.442 (C-1b), 127.066-128.715 (ph), Example 6 (Compound (6) → (7)) 530 mg (0.50 mmol) of compound (6) was dissolved in 5 ml of anhydrous CH ₂ Cl ₂ and added to 0.8 g of activated MS-4A. mg (0.362 mmol) was added, and the mixture was stirred for 1 hour and 30 minutes. The reaction solution was filtered through celite, washed with an aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous MgSO ₄ and evaporated. The residue is purified on a silica gel column (Wakogel, C
-300,90G, _{toluene: EtOAc (1% Et 3 N} ) = 9: 1) to give to compound (7) purified.

302mg（57％） Rf＝0.367（トルエン:EtOAc＝6:1） ▲〔α〕²⁸ _D▼＋1.82（ｃ＝3.40、CHCl₃）元素分析計算値Ｃ 72.53,H 6.58（2C₆H₆CH₃）実測値Ｃ 72.40,H 7.41¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.338 1.935（s,3H,CH₃C＝０）,3.341（dd,1H,J＝6.96,8.06,H
−4a）,3.832（dd,1H,J＝4.40,10.99,H−3b）,4.091（d
d,1H,J＝1.83,5.50,H−4b）,4.316（d,1H,J＝11.72,CH₂
−ph）,4.407（d,1H,J＝8.06,H−1a）,4.415（d,1H,J＝
7.69,H−1b）,4.427（d,1H,J＝12.45,CH₂−ph）,4.475
（d,1H,J＝12.73,CH₂−ph）,4.574（d,1H,J＝12.09,CH₂
−ph）,4.583（d,1H,J＝11.35,CH₂−ph）,4.591（d,1H,
J＝12.47,CH₂−ph）,4.667（d,1H,J＝11.73,CH₂−ph）,
4.791（d,1H,J＝11.72,CH₂−ph）,4.870（d,1H,J＝12.4
5,CH₂−ph）,4.885（d,1H,J＝11.36,CH₂−ph）,5.053
（dd,1H,J＝8.06,9.16,H−2a）,7.16〜7.37（m,25H,p
h）¹³ C−NMR（500MHz,CDCl₃、77.045），δ;20.948（CH₃C
O）,26.458（CH₃）,28.026（CH₃）,99.784（Ｃ−1a）,1
02.157（Ｃ−1b）,109.852 68.026（Ｃ−6a）,68.139（Ｃ−6b）実施例７（化合物（７）→（８））化合物（７）300mg（0.29mmol）を無水メタノール10m
lに溶かし、1NNaOCH₃400μ（0.4mmol）を加え、室温
で２時間撹拌後、60℃で一夜撹拌した。反応液をアンバ
ーリストIRC−50で中和後留去した。残渣をシリカゲル
カラム（ワコーゲル、Ｃ−300、30g、トルエン:EtOAc
（１％Et₃N）＝10:1）で精製して化合物（８）を得た。302 mg (57%) Rf = 0.367 (toluene: EtOAc = 6: 1) ▲ [α] ²⁸ _D ▼ + 1.82 (c = 3.40, CHCl ₃ ) Elemental analysis Calculated C 72.53, H 6.58 (2C ₆ H ₆ CH) ₃₎ Found ^{C 72.40, H 7.41 1 H-} NMR (500MHz, TMS, CDCl 3), δ; 1.338 _{1.935 (s, 3H, CH 3} C = 0), 3.341 (dd, 1H, J = 6.96,8.06, H
−4a), 3.832 (dd, 1H, J = 4.40, 10.99, H−3b), 4.091 (d
d, 1H, J = 1.83,5.50, H-4b), 4.316 (d, 1H, J = 11.72, CH ₂
−ph), 4.407 (d, 1H, J = 8.06, H-1a), 4.415 (d, 1H, J =
7.69, H-1b), 4.427 (d, 1H, J = 12.45, CH 2 -ph), 4.475
(D, 1H, J = 12.73, CH ₂ -ph), 4.574 (d, 1H, J = 12.99, CH ₂
-Ph), 4.583 (d, 1H , J = 11.35, CH 2 -ph), 4.591 (d, 1H,
_{J = 12.47, CH 2 -ph)} , 4.667 (d, 1H, J = 11.73, CH 2 -ph),
4.791 (d, 1H, J = 11.72, CH 2 -ph), 4.870 (d, 1H, J = 12.4
_{5, CH 2 -ph), 4.885} (d, 1H, J = 11.36, CH 2 -ph), 5.053
(Dd, 1H, J = 8.06, 9.16, H-2a), 7.16 to 7.37 (m, 25H, p
h) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 20.948 (CH ₃ C
_{O), 26.458 (CH 3)} , 28.026 (CH 3), 99.784 (C-1a), 1
02.157 (C-1b), 109.852 68.026 (C-6a), 68.139 (C-6b) Example 7 (Compound (7) → (8)) Compound (7) 300 mg (0.29 mmol) was added to anhydrous methanol 10m.
Then, 400 μM (0.4 mmol) of 1NNaOCH ₃ was added, and the mixture was stirred at room temperature for 2 hours and then at 60 ° C. overnight. The reaction solution was neutralized with Amberlyst IRC-50 and distilled off. The residue was purified on a silica gel column (Wakogel, C-300, 30 g, toluene: EtOAc
(1% Et ₃ N) = 10: 1) to give compound (8).

283.6mg（98％） Rf＝0.228（トルエン:EtOAc＝6:1） ▲〔α〕²⁸ _D▼−1.08（ｃ＝0.833、CHCl₃）元素分析 C₅₈H₆₄O₁₅ 計算値 C,69.58 H,6.44 実測値 C,69.38 H,6.31¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.344 3.345（dd,1H,J＝6.96,7.70,H−4a）,3.831 3.345（d
d,1H,J＝6.96,7.70,H−4a）,3.831（dd,1H,J＝4.03,10.
99,H−3b）,4.104（dd,1H,J＝1.47,5.47,H−4b）,4.363
（d,1H,J＝12.09,CH₂ph）,4.372（d,1H,J＝7.69,H−1a
又はｂ）,4.410（d,1H,J＝8.06,H−1a又はｂ）,4.427
（d,1H,J＝12.09,CH₂ph）,4.525（d,1H,J＝12.09,CH₂p
h）,4.579（d,1H,J＝12.09,CH₂ph）,4.637（d,1H,J＝1
2.09,CH₂ph）,4.665（d,1H,J＝11.72,CH₂ph）,4.722
（d,1H,J＝11.00,CH₂ph）,4.789（d,1H,J＝12.09,CH₂p
h）,4.919（d,1H,J＝12.09,CH₂ph）,4.963（d,1H,J＝1
0.09,CH₂ph）,7.25〜7.41（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ;26.478（CH
₃−）,28.033（CH₃−）,68.259（Ｃ−6a）,69.157（Ｃ
−6b）,76.845（Ｃ−4a）,79.446（Ｃ−3b）,80.706
（Ｃ−2b）,82.717（Ｃ−3a）,101.620（Ｃ−1b）,102.
022（Ｃ−1a）， 137.321 実施例８（化合物（８）→（９））化合物（８）260mg（0.26mmol）を無水ピリジン10ml
に溶かし、トリメチルアセチルクロライド62.6mg（0.52
mmol）、DMAP20mgを加え、80℃で一夜撹拌した。反応液
を留去し、EtOAcと水を加え抽出した。EtOAc層を水、飽
和食塩水で洗浄し、無水MgSO₄で乾燥留去した。残渣を
シリカゲルカラム（ワコーゲル、Ｃ−300、30g、トルエ
ン:EtOAc（１％Et₃N）＝6:1）で精製して化合物（９）
を得た。283.6 mg (98%) Rf = 0.228 (toluene: EtOAc = 6: 1) ▲ [α] ²⁸ _D ▼ -1.08 (c = 0.833, CHCl ₃ ) Elemental analysis C ₅₈ H ₆₄ O ₁₅ Calculated C, 69.58 H, 6.44 found C, 69.38 H, 6.31 ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.344 3.345 (dd, 1H, J = 6.96, 7.70, H-4a), 3.831 3.345 (d
d, 1H, J = 6.96, 7.70, H-4a), 3.831 (dd, 1H, J = 4.03, 10.
99, H-3b), 4.104 (dd, 1H, J = 1.47, 5.47, H-4b), 4.363
(D, 1H, J = 12.09, CH ₂ ph), 4.372 (d, 1H, J = 7.69, H-1a
Or b), 4.410 (d, 1H, J = 8.06, H-1a or b), 4.427
(D, 1H, J = 12.09, CH ₂ ph), 4.525 (d, 1H, J = 12.09, CH ₂ p
h), 4.579 (d, 1H, J = 12.09, CH ₂ ph), 4.637 (d, 1H, J = 1
2.09, CH ₂ ph), 4.665 (d, 1H, J = 11.72, CH ₂ ph), 4.722
(D, 1H, J = 11.00, CH ₂ ph), 4.789 (d, 1H, J = 12.99, CH ₂ p
h), 4.919 (d, 1H, J = 12.09, CH ₂ ph), 4.963 (d, 1H, J = 1
0.09, CH ₂ ph), 7.25 to 7.41 (m, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 26.478 (CH
₃₋ ), 28.033 (CH ₃ −), 68.259 (C-6a), 69.157 (C
-6b), 76.845 (C-4a), 79.446 (C-3b), 80.706
(C-2b), 82.717 (C-3a), 101.620 (C-1b), 102.
022 (C-1a), 137.321 Example 8 (Compound (8) → (9)) 260 mg (0.26 mmol) of compound (8) was added to 10 ml of anhydrous pyridine.
In 62.6 mg of trimethylacetyl chloride (0.52
mmol) and 20 mg of DMAP, and the mixture was stirred at 80 ° C. overnight. The reaction solution was evaporated, and extracted with EtOAc and water. The EtOAc layer was washed with water and saturated saline, dried over anhydrous MgSO ₄ and evaporated. The residue was purified by silica gel column (Wako gel, C-300, 30 g, toluene: EtOAc (1% Et ₃ N) = 6: 1) to give compound (9).
I got

230mg（82％） Rf＝0.437（トルエン:EtOAc＝6:1） ▲〔α〕²⁸ _D▼−51.92（ｃ＝2.60、CHCl₃）元素分析計算値Ｃ 71.17 Ｈ 6.83（＋C₆H₅CH₃）実測値Ｃ 70.83 Ｈ 6.45¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.136（s,9H,＋C
O）， 3.338（dd,1H,J＝6.96,8.06,H−4a）,3.837（dd,1H,J＝
4.39,10.99,H−3b）,4.080（dd,1H,J＝1.46,5.86,H−4
b）,4.226（d,1H,J＝12.09,CH₂ph）,4.397（d,1H,J＝1
0.99,CH₂ph）,4.405（d,1H,J＝8.06,H−1a）,4.437（d,
1H,J＝12.09,CH₂ph）,4.463（d,1H,J＝7.70,H−1b）,4.
580（d,1H,J＝12.09,CH₂ph）,4.592（d,1H,J＝12.46,CH
₂ph）,4.671（d,1H,J＝11.72,CH₂ph）,4.778（d,1H,J＝
11.72,CH₂ph）,4.867（d,1H,J＝12.09,CH₂ph）,4.898
（d,1H,J＝10.62,CH₂ph）,5.128（dd,1H,J＝8.06,9.52,
H−2a）,7.16〜7.36（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 68.171（Ｃ−6a）,69.036（Ｃ−6b）,99.884（Ｃ−1
b）,102.103（Ｃ−1a）， 127.2〜128.6（ph）,137.295 176.729（Ｃ＝０）実施例９（化合物（９）→（10））化合物（９）95mg（0.0885mmol）をCH₂Cl₂5mlに溶か
し、水冷下で90％CF₃COOH水溶液153mg（1.34mmol）を加
え、そのまま２時間30分撹拌した。反応液に水0.5mlを
加えて５分後炭酸水素ナトリウム水溶液を加えて中和
し、EtOAcで抽出した。EtOAc層を水、飽和食塩水で洗浄
後無水MgSO₄で乾燥し留去した。残渣をシリカゲルカラ
ム（ワコーゲル、Ｃ−300、10g、トルエン:EtOAc＝2:
1）で精製して化合物（10）を得た。230 mg (82%) Rf = 0.437 (toluene: EtOAc = 6: 1) ▲ [α] ²⁸ _D ▼ -51.92 (c = 2.60, CHCl ₃ ) Elemental analysis Calculated C 71.17 H 6.83 (+ C ₆ H ₅ CH ₃ ) Found C 70.83 H 6.45 ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.136 (s, 9H, + C
O), 3.338 (dd, 1H, J = 6.96, 8.06, H-4a), 3.837 (dd, 1H, J =
4.39,10.99, H-3b), 4.080 (dd, 1H, J = 1.46,5.86, H-4
b), 4.226 (d, 1H, J = 12.09, CH ₂ ph), 4.397 (d, 1H, J = 1
0.99, CH ₂ ph), 4.405 (d, 1H, J = 8.06, H-1a), 4.437 (d,
1H, J = 12.09, CH ₂ ph), 4.463 (d, 1H, J = 7.70, H-1b), 4.
580 (d, 1H, J = 12.09, CH ₂ ph), 4.592 (d, 1H, J = 12.46, CH
_{2 ph), 4.671 (d,} 1H, J = 11.72, CH 2 ph), 4.778 (d, 1H, J =
11.72, CH ₂ ph), 4.867 (d, 1H, J = 12.09, CH ₂ ph), 4.898
(D, 1H, J = 10.62, CH ₂ ph), 5.128 (dd, 1H, J = 8.06, 9.52,
H-2a), 7.16 to 7.36 (m, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 68.171 (C-6a), 69.036 (C-6b), 99.884 (C-1
b), 102.103 (C-1a), 127.2-128.6 (ph), 137.295 176.729 (C = 0) Example 9 (Compound (9) → (10)) Compound (9) (95 mg, 0.0885 mmol) was dissolved in CH ₂ Cl _{2 (} 5 ml), and 153 mg (1.34 mmol) of a 90% CF ₃ COOH aqueous solution under water cooling. ) Was added and the mixture was stirred for 2 hours and 30 minutes. 0.5 ml of water was added to the reaction solution, and after 5 minutes, an aqueous solution of sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with EtOAc. The EtOAc layer was washed with water and saturated saline, dried over anhydrous MgSO ₄ and evaporated. The residue was purified on a silica gel column (Wakogel, C-300, 10 g, toluene: EtOAc = 2:
Purification in 1) gave compound (10).

83.6mg（92％） Rf＝0.19（トルエン:EtOAc＝4:1） ▲〔α〕²⁸ _D▼−3.70（ｃ＝0.433、CHCl₃）元素分析 C₅₉H₆₈O₁₆ 計算値 C,68.59 H,6.63 実測値 C,68.31 H,6.34¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.124 3.341（t,1H,J＝5.87,H−4a）,3.850（dd,1H,J＝4.40,1
0.99,H−3b）,4.272（d,1H,J＝12.09,CH₂ph）,4.328
（d,1H,J＝11.72,CH₂ph）,4.466（d,1H,J＝12.09,CH₂p
h）,4.476（d,1H,J＝7.69,H−1a）,4.602（d,2H,J＝12.
09,CH₂ph）,4.612（d,1H,J＝12.09,CH₂ph）,4.667（d,1
H,J＝11.36,CH₂ph）,4.820（d,1H,J＝11.35,CH₂ph）,4.
872（d,1H,J＝12.09,CH₂ph）,4.970（d,1H,J＝10.99,CH
₂ph）,5.144（dd,1H,J＝7.70,9.52,H−2a）,7.04〜7.47
（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ;27.215（CH₃×
３）， 68.225（Ｃ−6a）,69.029（Ｃ−6b）,99.810（Ｃ−1
b），実施例10（化合物（10）→（11）、（12）、（13）Ｉ）活性化したMS4A1.5gにArガス下でHgBr₂212mg（0.58
mmol）、Hg（CN）₂149mg（0.58mmol）、ジクロロエタン
4mlに溶かした化合物（10）207mg（0.2mmol）を加えて3
0分撹拌し、氷−MeOH冷却下でジクロロエタン4mlに溶か
した化合物（22）153mg（0.3mmol）を少量づつ滴下後、
そのまま一夜撹拌した。反応液をセライトロ過し、留去
後シリカゲルカラム（Ｃ−300、100g、トルエン:EtOAc
＝1:1;C−300、20g、トルエン:MeOH＝10:1;LiChro prep
Si60、トルエン:MeOH＝10:1）で精製して化合物（1
1）、（12）、（13）を得た。83.6 mg (92%) Rf = 0.19 (toluene: EtOAc = 4: 1) ▲ [α] ²⁸ _D ▼ -3.70 (c = 0.433, CHCl ₃ ) Elemental analysis C ₅₉ H ₆₈ O ₁₆ Calculated C, 68.59 H, 6.63 actual value C, 68.31 H, 6.34 ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.124 3.341 (t, 1H, J = 5.87, H-4a), 3.850 (dd, 1H, J = 4.40,1
0.99, H-3b), 4.272 (d, 1H, J = 12.09, CH 2 ph), 4.328
(D, 1H, J = 11.72, CH ₂ ph), 4.466 (d, 1H, J = 12.09, CH ₂ p
h), 4.476 (d, 1H, J = 7.69, H-1a), 4.602 (d, 2H, J = 12.
09, CH ₂ ph), 4.612 (d, 1H, J = 12.09, CH ₂ ph), 4.667 (d, 1
H, J = 11.36, CH ₂ ph), 4.820 (d, 1H, J = 11.35, CH ₂ ph), 4.
872 (d, 1H, J = 12.09, CH ₂ ph), 4.970 (d, 1H, J = 10.99, CH
_{2 ph), 5.144 (dd,} 1H, J = 7.70,9.52, H-2a), 7.04~7.47
(M, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 27.215 (CH ₃ ×
3), 68.225 (C-6a), 69.029 (C-6b), 99.810 (C-1
b), Example 10 (Compound (10) → (11), (12), (13) I) HgBr ₂ 212 mg (0.58
mmol), Hg (CN) ₂ 149mg (0.58mmol), dichloroethane
Add 207 mg (0.2 mmol) of compound (10) dissolved in 4 ml and add 3
The mixture was stirred for 0 min and 153 mg (0.3 mmol) of compound (22) dissolved in 4 ml of dichloroethane was added dropwise little by little under cooling with ice-MeOH.
The mixture was stirred overnight. The reaction solution was filtered through celite, evaporated, and silica gel column (C-300, 100 g, toluene: EtOAc)
= 1: 1; C-300, 20 g, toluene: MeOH = 10: 1; LiChro prep
Purified with Si60, toluene: MeOH = 10: 1) to give compound (1
1), (12) and (13) were obtained.

化合物（13） 5mg（1.7％） Rf＝0.175（トルエン：メタノール＝10:1） ▲〔α〕²⁴ _D▼−6.910（ｃ＝0.333、CHCl₃）元素分析 C₇₈H₉₁NO₂₇ 計算値 C,63.02 H,6.17 N,0.94 実測値 C,63.12 H,6.04 N,0.92 化合物（12） 15.3mg（β;5.1％） Rf＝0.149（トルエン：メタノール＝10:1） ▲〔α〕²³ _D▼−11.67（ｃ＝0.36、CHCl₃）元素分析 C₇₉H₉₅NO₂₈ 計算値 C,62.98 H,6.39 N,0.93 実測値 C,62.84 H,6.59 N,0.79 化合物（11） 20.7mg（α;6.9％） Rf＝0.123（トルエン：メタノール＝10:1）総合計41mg（13.6％） ▲〔α〕²³ _D▼−7.12（ｃ＝0.267、CHCl₃）元素分析 C₇₉H₉₅NO₂₈ 計算値 C,62.98 H,6.39 N,0.93 実測値 C,62.97 H,6.41 N,0.92 II）Arガス下中で活性化したMS4A1.5gにTHF4mlに溶かし
た化合物（10）418mg（0.4mmol）とAgOTf600mg（2.34mm
ol）、SnCl₂300mg（1.58mmol）を加えて30分撹拌後、氷
−MeOH冷却下で、THF4mlに溶かした化合物（22）408mg
（0.8mmol）を少量づつ加え、そのまま一夜撹拌した。
反応液をセライトロ過し、留去後シリカゲルカラム（ワ
コーゲル、Ｃ−300、100g、トルエン:EtOAc＝1:1;1:2;C
−300、20g、トルエン:MeOH＝10:1）で精製した。更にS
ephadex LH−20で精製した。 Compound (13) 5 mg (1.7%) Rf = 0.175 (toluene: methanol = 10: 1) ▲ [α] ²⁴ _D ▼ -6.910 (c = 0.333, CHCl ₃ ) Elemental analysis C ₇₈ H ₉₁ NO ₂₇ Calculated value C, 63.02 H, 6.17 N, 0.94 Found C, 63.12 H, 6.04 N, 0.92 Compound (12) 15.3 mg (β; 5.1%) Rf = 0.149 (Toluene: methanol = 10: 1) ▲ [α] ²³ _D ▼- 11.67 (c = 0.36, CHCl ₃ ) Elemental analysis C ₇₉ H ₉₅ NO ₂₈ Calculated C, 62.98 H, 6.39 N, 0.93 Found C, 62.84 H, 6.59 N, 0.79 Compound (11) 20.7 mg (α; 6.9%) Rf = 0.123 (toluene: methanol = 10: 1) Total 41 mg (13.6%) ▲ [α] ²³ _D ▼ -7.12 (c = 0.267, CHCl ₃ ) Elemental analysis C ₇₉ H ₉₅ NO ₂₈ Calculated value C, 62.98 H, 6.39 N, 0.93 actual value C, 62.97 H, 6.41 N, 0.92 II) 418 mg (0.4 mmol) of compound (10) dissolved in 4 ml of THF in 1.5 g of MS4A activated under Ar gas and 600 mg of AgOTf (2.34 mm
ol) and 300 mg (1.58 mmol) of SnCl ₂ were added, and the mixture was stirred for 30 minutes. Then, under ice-MeOH cooling, 408 mg of the compound (22) dissolved in 4 ml of THF.
(0.8 mmol) was added little by little, and the mixture was stirred overnight.
The reaction solution was filtered through celite, and after distillation, a silica gel column (Wakogel, C-300, 100 g, toluene: EtOAc = 1: 1; 1: 2; C
-300, 20 g, toluene: MeOH = 10: 1). Further S
Purified with ephadex LH-20.

デヒドロ体409mg III）Arガス下中で活性化したMS4A3.0gにCH₃CN5mlに溶
かした化合物（10）517mg（0.5mmol）とSn（OSO₂CF₃）₂
458.5mg（1.1mmol）を加えて30分撹拌後、氷−MeOH冷却
下でCH₃CN5mlに溶かした化合物（22）765mg（1.5mmol）
を少量づつ加え、そのまま一夜撹拌した。反応液をセラ
イトロ過し、留去後シリカゲルカラム（ワコーゲル、Ｃ
−300、300g、トルエン:EtOAc＝2:1、1:1、1:2;C−30
0、20g、トルエン：メタノール＝10:1）で精製した。 409 mg of dehydro compound III) 517 mg (0.5 mmol) of compound (10) dissolved in 5 ml of CH ₃ CN in 3.0 g of MS4A activated under Ar gas and Sn (OSO ₂ CF ₃ ) ₂
After adding 458.5 mg (1.1 mmol) and stirring for 30 minutes, 765 mg (1.5 mmol) of the compound (22) dissolved in 5 ml of CH ₃ CN under cooling with ice-MeOH.
Was added little by little, and the mixture was stirred as it was overnight. The reaction mixture was filtered through celite, and after distillation, a silica gel column (Wakogel, C
-300, 300 g, toluene: EtOAc = 2: 1, 1: 1, 1: 2; C-30
Purified with 0, 20 g, toluene: methanol = 10: 1).

デヒドロ体611mg 化合物（13）（４位結合体）¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.131 1.830（s,3H,CH₃）,2.009（s,3H,CH₃）,2.023（s,3H,CH
₃）,2.033（s,3H,CH₃）,2.118（s,3H,CH₃）,2.483（t,1
H,J＝12.09,H−3c ax）,5.139（dd,1H,J＝8.06,9.16,H
−2a）,7.04〜7.47（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 96.921（Ｃ−2c）,99.777（Ｃ−1b）,102.270（Ｃ−1
a）,170.113（Ｃ＝０）,170.227（Ｃ＝０）,170.657
（Ｃ＝０）,170.831（Ｃ＝０）,170.844（Ｃ＝０）,17
6.783 35.996（Ｃ−3c）,49.322（Ｃ−5c）,62.749（Ｃ−9c）化合物（12）（β）¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.116 1.729（s,3H,CH₃）,1.979（s,3H,CH₃）,1.991（s,3H,CH
₃）,2.085（s,3H,CH₃）,2.110（s,3H,CH₃）,2.527（dd,
1H,J＝4.80,13.2,H−3c eq）,3.381（t,1H,J＝5.13,H−
4a）,3.644（s,3H,COOCH₃）,4.011（dd,1H,J＝7.70 12.
46,H−9c）,4.078（m,1H,H−5c）,4.135（t,1H,J＝9.1
6,H−3b）， 5.162（m,1H,H−4c）,5.193（m,1H,H−8c）,7.17〜7.47
（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 80.989（Ｃ−3a）,99.435（Ｈ−2c）,99.831（Ｈ−1
b）,102.666（Ｈ−1c）,167.881（Ｃ＝０）,170.194
（Ｃ＝０）,170.221（Ｃ＝０）,170.328（Ｃ＝０）,17
0.650（Ｃ＝０）,170.757（Ｃ＝０）， 23.240（NHCOCH₃）,35.540（Ｃ−3c）,48.786（Ｃ−5
c）， 62.809（Ｃ−9c）化合物（11）（α）¹ H−NMR（500MHz,TMS,CDCl₃），δ;1.127 1.872（s,3H,CH₃）,1.903（s,3H,CH₃）,1.978（s,3H,CH
₃）,2.014（s,3H,CH₃）,2.082（s,3H,CH₃）,2.503（dd,
1H,J＝4.40,13.19,H−3c eq）,3.381（t,1H,J＝5.13,H
−4a）,3.758（s,3H,COOCH₃）,3.959（dd,1H,J＝5.86 1
2.46,H−9c）,4.088（m,1H,H−5c）,4.244（d,1H,J＝1
1.72, 4.439（d,1H,J＝7.69,H−1a又はｂ）,4.503（d, 4.853（m,1H,H−4c）,5.097（t,1H,J＝9.16,H−2a）,5.
123（d,1H,J＝9.52,NH）,5.308（dd,1H,J＝2.20,8.06,H
−7c）,5.397（m,1H,H−8c）,4.296（dd,1H,J＝2.56,1
2.46,H−9c）,4.559（dd,1H,J＝2.20,8.43,H−6c）,7.1
6〜7.37（m,25H,ph）¹³ C−NMR（500MHz,CDCl₃,77.045），δ； 36.606（Ｃ−3c）,62.366（Ｃ−9c）,67.313（Ｃ−9
c）,68.895（Ｃ−8c）,69.184（Ｃ−7c）,72.428（Ｃ−
6c）,98.503（Ｃ−2c）,99.770（Ｃ−1b）,102.579（Ｃ
−1a）， 170.013（Ｃ＝０）,170.073（Ｃ＝０）,170.368（Ｃ＝
０）,170.663（Ｃ＝０），実施例11（化合物（11）→（14））化合物（11）289mg（0.191mmol）を無水酢酸2ml、ピ
リジン2mlにとかし、室温で24時間撹拌した。反応液を
減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィ
ーにて精製して化合物（14）を得た。SiO₂C−300 20g
３％CH₃OH−CHCl₃ 230mg77.3％ Rf 0.18 CH₃OH−イソプロピルエーテル（1:19）元素分析 C₇₇H₉₃NO₂₇ 計算値 C,62.70 H,6.30 N,0.90 実測値 C,63.33 H,6.37 N,1.16¹ H NMR δ,ppm CDCl₃（TMS） 1.842,1H,t,J＝12.5Hz H−3c ax,2.584,1H,dd,J＝4.8,1
2.8Hz H−3c eq,1.782,1.855,1.965,1.992,2.012,2.07
8,各s Ac基、3.825,3H,s,OCH₃,4.004,dd,J＝5.1,12.5H
z,H−9,4.091,q,J＝10.3Hz,H−5c,4.147,1H,d,J＝11.7H
z,ベンジル基プロトン,4.410,1H,d,J＝7.7Hz,H−1,4.71
7,1H,d,J＝7.7Hz,H−1,4.566,1H,d,J＝12.1Hz ベンジ
ル基プロトン,4.557,1H,d,J＝11.7Hz ベンジル基プロ
トン,4.834,1H,d,J＝12.1Hz,ベンジル基プロトン,5.01
5,1H,d,J＝3.7Hz,H−4b,5.332,1H,dd,J＝2.6,8.4Hz,H−
7c,5.584,1H,m,H−8. 実施例12（化合物（14）→（15））化合物（14）214mg（0.138mmol）をメタノール10mlに
溶かし、10％Pd−C100mgを加え、水素雰囲気下、24時間
撹拌した。反応液を濾過してPd−Ｃを除き、母液を減圧
濃縮して化合物（15）を得た。 Dehydro form 611 mg Compound (13) (4-position bond) ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.131 _{1.830 (s, 3H, CH 3} ), 2.009 (s, 3H, CH 3), 2.023 (s, 3H, CH
_{3), 2.033 (s, 3H} , CH 3), 2.118 (s, 3H, CH 3), 2.483 (t, 1
H, J = 12.09, H-3c ax), 5.139 (dd, 1H, J = 8.06, 9.16, H
−2a), 7.04 to 7.47 (m, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 96.921 (C-2c), 99.777 (C-1b), 102.270 (C-1
a), 170.113 (C = 0), 170.227 (C = 0), 170.657
(C = 0), 170.831 (C = 0), 170.844 (C = 0), 17
6.783 35.996 (C-3c), 49.322 (C-5c), 62.749 (C-9c) Compound (12) (β) ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.116 _{1.729 (s, 3H, CH 3} ), 1.979 (s, 3H, CH 3), 1.991 (s, 3H, CH
_{3), 2.085 (s, 3H} , CH 3), 2.110 (s, 3H, CH 3), 2.527 (dd,
1H, J = 4.80,13.2, H-3c eq), 3.381 (t, 1H, J = 5.13, H-
4a), 3.644 (s, 3H, COOCH ₃ ), 4.011 (dd, 1H, J = 7.70 12.
46, H-9c), 4.078 (m, 1H, H-5c), 4.135 (t, 1H, J = 9.1
6, H-3b), 5.162 (m, 1H, H-4c), 5.193 (m, 1H, H-8c), 7.17 ~ 7.47
(M, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 80.989 (C-3a), 99.435 (H-2c), 99.831 (H-1
b), 102.666 (H-1c), 167.881 (C = 0), 170.194.
(C = 0), 170.221 (C = 0), 170.328 (C = 0), 17
0.650 (C = 0), 170.757 (C = 0), 23.240 (NHCOCH ₃ ), 35.540 (C-3c), 48.786 (C-5
c), 62.809 (C-9c) Compound (11) (α) ¹ H-NMR (500 MHz, TMS, CDCl ₃ ), δ; 1.127 _{1.872 (s, 3H, CH 3} ), 1.903 (s, 3H, CH 3), 1.978 (s, 3H, CH
_{3), 2.014 (s, 3H} , CH 3), 2.082 (s, 3H, CH 3), 2.503 (dd,
1H, J = 4.40, 13.19, H-3c eq), 3.381 (t, 1H, J = 5.13, H
−4a), 3.758 (s, 3H, COOCH ₃ ), 3.959 (dd, 1H, J = 5.86 1
2.46, H-9c), 4.088 (m, 1H, H-5c), 4.244 (d, 1H, J = 1
1.72, 4.439 (d, 1H, J = 7.69, H-1a or b), 4.503 (d, 4.853 (m, 1H, H-4c), 5.097 (t, 1H, J = 9.16, H-2a), 5.
123 (d, 1H, J = 9.52, NH), 5.308 (dd, 1H, J = 2.20, 8.06, H
−7c), 5.397 (m, 1H, H−8c), 4.296 (dd, 1H, J = 2.56,1
2.46, H-9c), 4.559 (dd, 1H, J = 2.20,8.43, H-6c), 7.1
6-7.37 (m, 25H, ph) ¹³ C-NMR (500 MHz, CDCl ₃ , 77.045), δ; 36.606 (C-3c), 62.366 (C-9c), 67.313 (C-9
c), 68.895 (C-8c), 69.184 (C-7c), 72.428 (C-
6c), 98.503 (C-2c), 99.770 (C-1b), 102.579 (C
−1a), 170.013 (C = 0), 170.073 (C = 0), 170.368 (C =
0), 170.663 (C = 0), Example 11 (Compound (11) → (14)) Compound (11) (289 mg, 0.191 mmol) was dissolved in acetic anhydride (2 ml) and pyridine (2 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound (14). SiO ₂ C-300 20g
_{_{3% CH 3 OH-CHCl 3}} 230mg77.3% Rf 0.18 CH 3 OH- isopropyl ether (19) Elemental analysis C ₇₇ H ₉₃ NO ₂₇ Calculated C, 62.70 H, 6.30 N, 0.90 Found C, 63.33 H, 6.37 N, 1.16 ¹ H NMR δ, ppm CDCl ₃ (TMS) 1.842,1H, t, J = 12.5 Hz H-3c ax, 2.584,1H, dd, J = 4.8,1
2.8Hz H-3c eq, 1.782,1.855,1.965,1.992,2.012,2.07
8, each s Ac _{group, 3.825,3H, s, OCH 3,} 4.004, dd, J = 5.1,12.5H
z, H-9,4.091, q, J = 10.3Hz, H-5c, 4.147,1H, d, J = 11.7H
z, benzyl proton, 4.410,1H, d, J = 7.7Hz, H-1,4.71
7,1H, d, J = 7.7Hz, H-1,4.566,1H, d, J = 12.1Hz Benzyl proton, 4.557,1H, d, J = 11.7Hz Benzyl proton, 4.834,1H, d, J = 12.1 Hz, benzyl proton, 5.01
5,1H, d, J = 3.7Hz, H−4b, 5.332,1H, dd, J = 2.6,8.4Hz, H−
7c, 5.584, 1H, m, H-8. Example 12 (Compound (14) → (15)) 214 mg (0.138 mmol) of compound (14) was dissolved in 10 ml of methanol, 100 mg of 10% Pd-C was added, and a hydrogen atmosphere was added. The mixture was stirred for 24 hours. The reaction solution was filtered to remove Pd-C, and the mother liquor was concentrated under reduced pressure to obtain a compound (15).

130mg（100％） Rf 0.80（EtOAc:EtOH:H₂O、5:2:1）HPTLC ▲〔α〕²⁰ _D▼＋28.1゜ｃ＝100 CH₃OH 一部をとりメンブランフィルターを通した後減圧乾固
して元素分析 C₃₉H₅₉NO₂₅・2H₂O 計算値 C,47.90 H,6.60 N,1.43 実測値 C,48.09 H,6.28 N,1.55 実施例13（化合物（15）→（16））化合物（15）133mg（0.141mmol）を無水酢酸2ml、ピ
リジン2mlに溶かし、室温で24時間撹拌した。反応液を
減圧濃縮し、残渣をシリカゲルカラムクロマトグラフで
精製して化合物（16）を得た。SiO₂C−300、20g（３％C
H₃OH含有クロロホルム） 160mg 98％ Rf 0.29（３％CH₃OH:CHCl₃） ▲〔α〕²¹ _D▼＋15.5゜ｃ＝0.90 CHCl₃ 元素分析 C₄₉H₆₉NO₃₀ 計算値 C,51.08 H,6.04 N,1.22 実測値 C,50.21 H,5.93 N,1.21 実施例14（化合物（16）→（17））化合物（16）127mg（0.110mmol）をDMF1mlに溶かし、
50℃〜60℃で加熱撹拌しながらヒドラジニウムアセテー
ト（NH₂・NH₂・CH₃COOH）13.5mg（0.147mmol）を加えて
５分間撹拌した。反応液を酢酸エチルで希釈した後、水
洗した。さらに飽和食塩水で洗浄した後、無水流酸マグ
ネシウムで乾燥した。130 mg (100%) Rf 0.80 (EtOAc: EtOH: H ₂ O, 5: 2: 1) HPTLC ▲ [α] ²⁰ _D ▼ + 28.1 ゜ c = 100 CH ₃ OH After taking a part and passing through a membrane filter reduced pressure to dryness to elemental analysis _{_{_{C 39 H 59 NO 25 · 2H}}} 2 O calculated C, 47.90 H, 6.60 N, 1.43 Found C, 48.09 H, 6.28 N, 1.55 example 13 (compound (15) → (16 )) 133 mg (0.141 mmol) of compound (15) was dissolved in 2 ml of acetic anhydride and 2 ml of pyridine, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound (16). SiO ₂ C-300, 20 g (3% C
H ₃ OH-containing chloroform) 160 mg 98% Rf 0.29 (3% CH ₃ OH: CHCl ₃ ) ▲ [α] ²¹ _D ▼ +15.5 ゜ c = 0.90 CHCl ₃ elemental analysis C ₄₉ H ₆₉ NO ₃₀ Calculated value C, 51.08 H, 6.04 N, 1.22 found C, 50.21 H, 5.93 N, 1.21 Example 14 (Compound (16) → (17)) 127 mg (0.110 mmol) of compound (16) was dissolved in 1 ml of DMF,
While heating and stirring at 50 ° C to 60 ° C, 13.5 mg (0.147 mmol) of hydrazinium acetate (NH ₂ · NH ₂ · CH ₃ COOH) was added, and the mixture was stirred for 5 minutes. The reaction solution was diluted with ethyl acetate and washed with water. After washing with a saturated saline solution, it was dried with anhydrous magnesium sulfate.

減圧濃縮後残渣をシリカゲルカラムクロマトグラフィ
ー（３％CH₃OH:CHCl₃）で精製して、化合物（17）104mg
を得た。After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3% CH ₃ OH: CHCl ₃ ) to obtain 104 mg of compound (17).
I got

85％ Rf 0.21（３％メタノール含有クロロホルム） ▲〔α〕²² _D▼＋22.6 ｃ＝1.21 CHCl₃ 実施例15（化合物（17）→（18））化合物（17）23mg（0.021mmol）をジクロルエタン0.5
mlに溶かし、トリクロロアセトニトリル、10.5μ（0.
105mmol）、DBU4.1μ（0.027mmol）を加え、アルゴン
雰囲気下２時間撹拌した。反応液をシリカゲルカラムク
ロマトグラフィーで精製（ワコーゲル、Ｃ−300、1.0
g、EtOAc）して化合物（18）22mgを得た。85% Rf 0.21 (chloroform containing 3% methanol) ▲ [α] ²² _D ▼ + 22.6 c = 1.21 CHCl ₃ Example 15 (Compound (17) → (18)) 23 mg (0.021 mmol) of Compound (17) was converted to dichloroethane. 0.5
Dissolve in 1 ml, trichloroacetonitrile, 10.5μ (0.
105 mmol) and 4.1 µB (0.027 mmol) of DBU, and the mixture was stirred under an argon atmosphere for 2 hours. The reaction solution was purified by silica gel column chromatography (Wakogel, C-300, 1.0
g, EtOAc) to give 22 mg of compound (18).

84.6％ Rf 0.33（EtOAc、HPTLC） ▲〔α〕²³ _D▼＋32.6゜ｃ＝1.47 CHCl₃ ¹ H NMR 500MHz δ ppm CDCl₃ TMS 1.32,9H,s,tBu基,1.683,1H,t,J＝12.8Hz H−3c ax,1.85
5,2.006,2.023,2.063,2.069,2.079,2.081,2.093,2.159,
2.249 各s,COCH₃,2.582 1H,dd,J＝4.8,12.8Hz,H−3c e
q,3.634,1H,dd,J＝2.9,11.0Hz,H−6,3.847,3H,s,0CH₃,
4.240,1H,dd,J＝5.1,12.5Hz,H−9c,4.515,1H,dd,J＝3.
3,10.3Hz,H−3b,4.680,1H,d,J＝8.1Hz,H−1b,4.897,1H,
4.897,1H,dt,J＝4.8,11.2Hz,H−4c,4.965,1H,dd,J＝8.
1,10.3Hz,H−2b,5.046,1H,d,J＝9.9Hz,NH,5.059,1H,dd,
J＝3.7,10.3Hz,H−2a,5.412,1H,dd,J＝2.6,9.2Hz,H−7
c,5.504,1H,m,H−8,5.600,1H,t,J＝9.9Hz,H−3a,6.515,
1H,d,J＝3.7Hz,H−1a,8.640,1H,s,−ｓ−NH 実施例16（化合物（18）→（20））活性化したモレキュラシーブ4A200mgに化合物（18）2
2mg（0.0175mmol）、化合物（23）（Bz Cer）20mg（0.0
263mmol）をクロロホルム0.5mlに溶かして加え、アルゴ
ン雰囲気下、氷冷撹拌しながらBF₃・Et₂O3μ（0.0228
mmol）を加えて、３時間撹拌した。室温で12時間撹拌し
たのち、クロロホルムで希釈して、ろ過した。ろ液にト
リエチルアミンを加えて中和した後減圧乾固した。残渣
をシリカゲルカラムクロマトグラフィーで精製（ワコー
ゲル、Ｃ−300、1.0g CH₃OH:CHCl₃ 1:49）して化合物
（20）を21mg得た。84.6% Rf 0.33 (EtOAc, HPTLC ) ▲ [α] ²³ _D ▼ + 32.6 DEG _{^{c = 1.47 CHCl 3 1 H NMR}} 500MHz δ ppm CDCl 3 TMS 1.32,9H, s, tBu group, 1.683,1H, t, J = 12.8Hz H-3c ax, 1.85
5,2.006,2.023,2.063,2.069,2.079,2.081,2.093,2.159,
2.249 each s, COCH ₃ , 2.582 1H, dd, J = 4.8,12.8Hz, H-3c e
q, 3.634,1H, dd, J = 2.9,11.0Hz, H-6,3.847,3H, s, 0CH 3,
4.240,1H, dd, J = 5.1,12.5Hz, H-9c, 4.515,1H, dd, J = 3.
3,10.3Hz, H-3b, 4.680,1H, d, J = 8.1Hz, H-1b, 4.897,1H,
4.897,1H, dt, J = 4.8,11.2Hz, H-4c, 4.965,1H, dd, J = 8.
1,10.3Hz, H-2b, 5.046,1H, d, J = 9.9Hz, NH, 5.059,1H, dd,
J = 3.7,10.3Hz, H-2a, 5.412,1H, dd, J = 2.6,9.2Hz, H-7
c, 5.504,1H, m, H-8,5.600,1H, t, J = 9.9Hz, H-3a, 6.515,
1H, d, J = 3.7Hz, H-1a, 8.640,1H, s, -s-NH Example 16 (Compound (18) → (20)) Activated molecular sieve 4A 200 mg to compound (18) 2
2 mg (0.0175 mmol), compound (23) (Bz Cer) 20 mg (0.0
263 mmol) dissolved in 0.5 ml of chloroform and added thereto. Under an argon atmosphere, BF ₃ .Et ₂ O 3μ (0.0228
mmol) and stirred for 3 hours. After stirring at room temperature for 12 hours, the mixture was diluted with chloroform and filtered. The filtrate was neutralized by adding triethylamine, and dried under reduced pressure. The residue was purified by silica gel column chromatography (Wako gel, C-300, 1.0 g CH ₃ OH: CHCl ₃ 1:49) to obtain 21 mg of compound (20).

65％ Rf 0.41（３％CH₃OH含有CHCl₃）HPTLC ▲〔α〕²⁰ _D▼＋3.90゜ｃ＝1.39 CHCl₃ ¹ H NMR 500MHz δ ppm CDCl₃（TMS） 0.878,6H,t,J＝6.6Hz CH_3-×2,1.144,9H,s,tBu基 1.2
54,64H,s,−c1h−,1.667,1H,t,J＝12.5Hz,1.854,1.902,
2.004,2.073,2.078,2.159,2.203,s,COCH₃×10,2.568,1
H,dd,J＝4.8,12.8Hz,H−4c,3.839,3H,s,OCH₃,4.421,1H,
d,J＝8.1Hz,H−1,4.514,1H,dd,J＝3.3,10.3Hz,H−3b,4.
610,1H,d,J＝8.1Hz,H−1,5.127,1H,d,J＝10.3Hz,NH,5.2
03,1H,t,J＝9.2Hz,H−2a,5.406,1H,dd,J＝2.6,9.2Hz,H
−7c,5.457,1H,dd,J＝7.7Hz,15.4Hz,H−4 Cer,5.540,1
H,t,J＝7.3Hz,H−3a,5.506,1H,m,H−8c,5.753,1H,d,J＝
9.2Hz,NH,5.864,1H,dd,J＝8.1,15.0Hz,H−5Cer 7.430,2
H,t,J＝8.1Hz,Bz（ｍ）,7.550,1H,t,J＝7.3Hz,Bz
（ｐ）,7.995,2H,d,J＝7.0Hz,Bz（ｏ）実施例17（化合物（17）→（19））化合物（17）22.2mg（0.020mmol）をジクロロエタン
0.5mlに溶かし、ドライアイス−CCl₄浴中、アルゴン雰
囲気下撹拌しながら、DAST（（ジエチルアミノ）サルフ
ァートリフルオライド）を加え30分撹拌した。室温で２
時間撹拌した。反応液を酢酸エチルで希釈した後、飽和
重曹水、飽和食塩水で洗浄した。無水硫酸マグネシウム
で乾燥したのち減圧乾固して、残渣をシリカゲルカラム
クロマトグラフィーで精製（SiO₂、Ｃ−300、1.0g EtO
Ac）して化合物（19）（ただし式中Ｘはフッ素である）
を得た。65% Rf 0.41 (3% CH 3 OH -containing CHCl ₃₎ HPTLC ▲ [α] ²⁰ _D ▼ + 3.90 ° _{^{c = 1.39 CHCl 3 1 H NMR}} 500MHz δ ppm CDCl 3 (TMS) 0.878,6H, t, J = 6.6Hz CH _3- × 2,1.144,9H, s, tBu group 1.2
54,64H, s, −c1h−, 1.667,1H, t, J = 12.5Hz, 1.854,1.902,
2.004,2.073,2.078,2.159,2.203, s, COCH ₃ × 10,2.568,1
H, dd, J = 4.8,12.8Hz, H-4c, 3.839,3H, s, OCH 3, 4.421,1H,
d, J = 8.1Hz, H-1,4.514,1H, dd, J = 3.3,10.3Hz, H-3b, 4.
610,1H, d, J = 8.1Hz, H-1,5.127,1H, d, J = 10.3Hz, NH, 5.2
03,1H, t, J = 9.2Hz, H-2a, 5.406,1H, dd, J = 2.6,9.2Hz, H
−7c, 5.457,1H, dd, J = 7.7Hz, 15.4Hz, H−4 Cer, 5.540,1
H, t, J = 7.3Hz, H-3a, 5.506,1H, m, H-8c, 5.753,1H, d, J =
9.2Hz, NH, 5.864,1H, dd, J = 8.1,15.0Hz, H-5Cer 7.430,2
H, t, J = 8.1Hz, Bz (m), 7.550,1H, t, J = 7.3Hz, Bz
(P), 7.995, 2H, d, J = 7.0 Hz, Bz (o) Example 17 (Compound (17) → (19)) 22.2 mg (0.020 mmol) of compound (17) was treated with dichloroethane.
The solution was dissolved in 0.5 ml, and DAST ((diethylamino) sulfur trifluoride) was added thereto while stirring under an argon atmosphere in a dry ice-CCl ₄ bath, followed by stirring for 30 minutes. 2 at room temperature
Stirred for hours. After the reaction solution was diluted with ethyl acetate, it was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the residue was dried under reduced pressure and the residue was purified by silica gel column chromatography (SiO ₂ , C-300, 1.0 g EtO
Ac) to give compound (19) (where X is fluorine)
I got

17mg 76.4％ Rf 0.38 EtOAc HPTLC¹ H NMR 500MHz δ ppm CDCl₃（TMS） 1.188,1.195,s,tBu基（α，β）1.855,2.008,2.022,2.0
45,2.054,2.062,2.071,2.089,2.096,2.119,2,162 2.23
6,2.252,s,アセチル基,2.581,dd,J＝4.8,12.8Hz,H−3c
eq,3.637,1H,dd,J＝2.9,11.0Hz,H−6c,3.846,3H,s,OC
H₃,4.122,1H,q,J＝7.3Hz,H−5c,4.649,0.25H,d,J＝8.1H
z,H−1b α,4.705 0.75H,d,J＝8.1Hz,H−1b β,4.886,
1H,dt,J＝4.4,11.0Hz,5.102,1H,d,J＝10.3Hz,NH,5.198,
1H,t,J＝8.1Hz,H−3a,5.390,1H,dd,J＝2.9,9.5Hz,H−7
c,5.548,1H,m,H−8c¹³ C NMR δ,ppm CDCl₃96.85（Ｃ−2cα）,96.87（Ｃ−
2cβ）,101.00（Ｃ−1bα,J_CH164.4Hz）,101.29 Ｃ−1
bβ ′J_CH164.4Hz 103.77（Ｃ−1aα ′J_CF229.3Hz
′J_CH185.3Hz）,106,21,C−1aβ ′J_CF218.3Hz′J_CH
172.0Hz）実施例18（化合物（19）→（20））活性化したモレキュラシーブ4A200mgに化合物（19）
（ただし式中Ｘはフッ素である。16mg（0.0144mmol）、
化合物（23）15mg（0.0201mmol）をクロロホルム0.5ml
に溶かして加え、さらにスズトリフレート8.4mg（0.020
1mmol）を加えて、アルゴン雰囲気下、室温で12時間撹
拌した。さらに50℃で２時間加熱した後、クロロホルム
で希釈して濾過した。17 mg 76.4% Rf 0.38 EtOAc HPTLC ¹ H NMR 500 MHz δ ppm CDCl ₃ (TMS) 1.188,1.195, s, tBu group (α, β) 1.855,2.008,2.022,2.0
45,2.054,2.062,2.071,2.089,2.096,2.119,2,162 2.23
6,2.252, s, acetyl group, 2.581, dd, J = 4.8,12.8Hz, H-3c
eq, 3.637,1H, dd, J = 2.9,11.0Hz, H-6c, 3.846,3H, s, OC
_{H 3, 4.122,1H, q, J} = 7.3Hz, H-5c, 4.649,0.25H, d, J = 8.1H
z, H−1b α, 4.705 0.75H, d, J = 8.1Hz, H−1b β, 4.886,
1H, dt, J = 4.4,11.0Hz, 5.102,1H, d, J = 10.3Hz, NH, 5.198,
1H, t, J = 8.1Hz, H-3a, 5.390,1H, dd, J = 2.9,9.5Hz, H-7
c, 5.548,1H, m, H- 8c 13 C NMR δ, ppm CDCl 3 96.85 (C-2cα), 96.87 (C-
2cβ), 101.00 (C-1bα, J _CH 164.4Hz), 101.29 C-1
bβ 'J _CH 164.4Hz 103.77 (C-1aα' J _CF 229.3Hz
'J _CH 185.3Hz), 106,21, C-1aβ' J _CF 218.3Hz'J _CH
172.0Hz) Example 18 (Compound (19) → (20)) Compound (19) was added to 200 mg of activated molecular sieve 4A.
(Where X is fluorine. 16 mg (0.0144 mmol),
15 mg (0.0201 mmol) of compound (23) in 0.5 ml of chloroform
8.4 mg of tin triflate (0.020
1 mmol), and the mixture was stirred at room temperature for 12 hours under an argon atmosphere. After further heating at 50 ° C. for 2 hours, the mixture was diluted with chloroform and filtered.

濾液を減圧乾固し、シリカゲルカラムクロマトグラフ
ィーで精製（SiO₂C−300 1.0g CH₃OH−CHCl₃1:49）し
て生成物化合物（20）12.1mgを得た。The filtrate was evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (SiO ₂ C-300 1.0 g CH ₃ OH—CHCl ₃ 1:49) to obtain 12.1 mg of product compound (20).

この生成物は化合物（18）から得た生成物と一致し
た。This product was consistent with the product obtained from compound (18).

収率46％実施例19（化合物（20）→（21））化合物（20）18.0mg（0.010mmol）をTHF−メタノール
1:1の混合溶媒1.0mlに溶かし、Ｎ−NaOCH₃−CH₃OH溶液6
0μを滴下して室温で３時間撹拌した。Example 19 (Compound (20) → (21)) 18.0 mg (0.010 mmol) of compound (20) was dissolved in THF-methanol.
Dissolved in 1: 1 mixed solvent of _{_{1.0ml, N-NaOCH 3 -CH 3}} OH solution 6
0 μ was added dropwise and the mixture was stirred at room temperature for 3 hours.

減圧濃縮し、THF−メタノール−H₂O、1:1:1 1.5mlの
混合溶媒を加え室温でさらに12時間撹拌した。反応液を
減圧濃縮し残渣をクロロホルム−メタノール−水60:30:
4.6の混合溶媒に溶かしSephadex−LH20を用いて精製す
ることにより化合物（21）〔ガングリオシドGM₃〕（84.
8％）を得た。Concentrated under reduced pressure, THF-methanol -H ₂ O, 1: 1: was further stirred at room temperature for 12 hours was added a mixed solvent of 1 1.5 ml. The reaction solution was concentrated under reduced pressure, and the residue was chloroform-methanol-water 60:30:
The compound (21) [ganglioside GM ₃ ] (84.) was dissolved in the mixed solvent of 4.6 and purified using Sephadex-LH20.
8%).

11.0mg この物質の物理恒数は合成された物質（Glycoconjuga
te J（1985）2:5−９）と一致した。11.0mg The physical constant of this substance is the same as the synthesized substance (Glycoconjuga
te J (1985) 2: 5-9).

───────────────────────────────────────────────────── フロントページの続き (72)発明者田中誠埼玉県越谷市下間久里760―６ (72)発明者小川智也東京都武蔵野市吉祥寺北町３―６―６― ３―101 ──────────────────────────────────────────────────続き Continuing on the front page (72) Inventor Makoto Tanaka 760-6 Shimouma Kuri, Koshigaya City, Saitama Prefecture (72) Inventor Tomoya Ogawa 3-6-6-3-1, Kichijoji Kitamachi, Musashino City, Tokyo

Claims

(57) [Claims]

1. A compound represented by the following general formula (I). (Wherein, R ¹ is an acetyl group or a benzyl group, R ² is a methyl group, R ³ and R ⁴ are each independently hydrogen, an acetyl group or a benzyl group, and R ⁵ is —COC (CH ₃ ) ₃ , R ⁶ is a hydroxyl group, a benzyloxy group, a halogen, Or Wherein Bz is a benzoyl group, and Ac is an acetyl group.

2. A compound represented by the following general formula (II). (Wherein R ¹¹ and R ¹² are hydrogen, R ¹³ is an acetyl group or a benzyl group, R ¹⁴ is hydrogen, —COC (CH ₃ ) ₃ , Is).

3. The following general formula (I): (Where R ¹ is an acetyl or benzyl group, R ² is a methyl group, R ³ and R ⁴ are each independently an acetyl or benzyl group, and R ⁵ is —COC (CH ₃ ) ₃ , And R ⁶ is halogen or Is a compound represented by the formula: (Wherein Bz is a benzoyl group), wherein the compound represented by the general formula (I) (wherein R ¹
Is an acetyl or benzyl group, R ² is a methyl group, R ³ and R ⁴ are each independently an acetyl or benzyl group, and R ⁵ is And R ⁶ is And further deacetylation or debenzylation,
Ganglioside GM ₃ for debenzoylation and saponification
Manufacturing method.