JP2002060388A - Method for producing sphingofungin e and intermediate for synthesizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for the first time total synthesis of sphingofungin E having useful physioilogical activity. SOLUTION: A method for producing the sphingofungin E via a new compound of formula (I) [wherein, R1, R2 and R6 are each an OH-protecting group; A is N3, NH2 or NHCOR8 (R8 is a lower alkyl or aromatic group); and B is CH2-OR3 (R3 is an OH-protecting group) or CH=CH-X (X is a halogen)] starting from a known compound is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for stereoselectively producing a sphingosine E derivative having sphingosine biosynthesis inhibitory activity and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Sphingfungins AE are available in 1992.
Paecilomyces varioti by the group of Merck et al.
A group of compounds isolated from i, having a structure similar to Sphingosine. Initially, this compound was isolated as a compound showing strong antibacterial activity, and Merck is conducting research and development as an antibacterial agent. Furthermore, its mechanism of action is caused by a decrease in intracellular sphingolipids and glycosphingolipids by inhibiting the activity of serine palmitoyltransferase, an enzyme that catalyzes the first reaction in the biosynthetic pathway of sphingolipids and glycosphingolipids. It has attracted the attention of many researchers because it is very unique.

In recent years, ISP-1 (myriocin), which is isolated from Isaria sinclairii and has a structure very similar to Sphingofungin E, induces apoptosis of cytotoxic T cells, and as a result, has an immunosuppressive effect. It has been revealed. Its activity has been shown to be caused by a decrease in sphingolipids and glycolipids by inhibiting the activity of serine palmitoyltransferase, similar to the antibacterial activity of sphingofungins, and this ISP-1 was used as a lead compound in Wellfard,
The development of immunosuppressant FTY-720 is in progress.

[0004] Sphins having various physiological activities as described above
gofungins have four consecutive chiral centers on their polar sites,
In particular, Sphingofungin E and F have a quaternary carbon site at the second position, and when viewed synthetically, it can be said that the construction of a continuous asymmetric point is a very interesting subject. Synthetic studies have been carried out by several groups, but relatively few examples, such as the synthesis of Sphingofungin D by Mori et al., The synthesis of D by Senda et al., The synthesis of F by Trost et al. Only the synthesis of F is known.

[0005] In particular, as can be seen from the fact that the total synthesis of Sphingofungin E has not been achieved, the synthesis of E and F having a quaternary carbon at the 2-position is based on Sphingofufu, a parent of other analogs.
It is more difficult than nginB, and it is necessary to establish an efficient synthesis method for synthesizing derivatives such as the related compound Myriocin.

[0006]

The problem to be solved by the present inventors is to find a new important intermediate for efficient production of sphingfunds, especially sphingofungin E, It is to find a stereoselective manufacturing method to be used.

[0007]

Means for Solving the Problems The present inventors have made intensive efforts to solve the above problems, and as a result, starting from a known compound, protected glucose 1, a novel important intermediate represented by the formula (I) And established a new method for synthesizing sphingofundin E via the same. That is, the present invention provides a compound represented by the formula (I):

[0008]

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(Where R¹, R^TwoAnd R⁶Is the hydroxyl group
A is -N_Three, -NH_TwoOr -NHCOR⁸
(R⁸Is a lower alkyl group or an aromatic group)
B is -CH _Two-OR^Three(R^ThreeIs a hydroxyl-protecting group
A) or -CH = CH-X (X is a halogen)
Wherein the compound is

A is —N ₃ or —NH ₂ , and B is
There, B is, -CH ₂ -OR ³ (R ³ is a protective group of hydroxyl group) or -CH = CH-X (X is halogen)
Also a compound of formula (I), which is

In the present invention, A is preferably -NHCOR.
⁸ (R ⁸ is a lower alkyl group or an aromatic group), and B is -CH = CH-X (X is a halogen).

The protecting group for a hydroxyl group represented by R ¹ , R ² , R ³ and R ⁶ means a protecting group commonly used in organic synthetic chemistry. For example, when a hydroxyl group is protected as an ether bond or an ester bond. Later, it means a protecting group when easily deprotected. Examples of these protecting groups are, for example, TWGreen "Protec
tive Groups in Organic Synthesis "John Wiley & Son
s, New York 1981.

R¹, R^Two, R^ThreeAnd R⁶Ether bonded
R as a group¹O-, R^TwoO-, R ^ThreeO- and R⁶O-group
Is an alkyl ether and a substituted alkyl ether,
For example, methyl ether, methoxymethyl ether, methyl
Luthiomethyl, benzyloxymethyl, (2-trimethyl
Lucylylethoxy) methyl, (2,2,2-trichloro)
Ethoxy) methyl, t-butyl ether; aralkyle
-Tels such as benzyl ether, p-methoxybenz
Zyl ether, o, p-dimethylbenzyl ether,
Riphenyl methyl ether; silyl ethers, for example
Trimethylsilyl ether, triethylsilyl ether
, Triisopropylsilyl ether, t-butyldimethyl
Tylsilyl ether, t-butyldiphenylsilylate
Tell; and the like.

Particularly preferably, the R ¹ O-group is benzyl ether, the R ² O-group is tributyldimethylsilyl ether, R ³ O- is tributyldimethylsilyl ether and R ⁶ The O- group is 2- (2-trimethylsilylethoxy) methyl ether.

R ¹ , R ² , R ³ and R ⁶ groups as acyl groups are alkylcarbonyl or substituted alkylcarbonyls such as acetyl, methoxymethylcarbonyl, pivaloyl, 2,2,2-trichloroethoxycarbonyl;
Arylcarbonyls or substituted arylcarbonyls,
For example, benzoyl; aryloxycarbonyl; Further, sulfonyls, for example, methanesulfonyl;

The acyl group R ⁸ CO of R ⁸ is a linear or branched chain, saturated or unsaturated aliphatic group or an aromatic group.
R ⁸ is preferably a linear or branched, saturated or unsaturated aliphatic group having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, octyl and the like. it can. R ⁸ is preferably phenyl.

X representing halogen preferably denotes bromo, chloro or iodo, particularly preferably iodo.

The present invention provides a compound of the formula (IV):

[0019]

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A method for producing sphingohungin E represented by the following formula: a) Formula (Ia):

[0021]

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(R ¹ , R ² , R ³ and R ⁶ are as defined above) to obtain the corresponding amine, followed by acylation to obtain a compound of the formula (Ib):

[0023]

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(Wherein R ¹ , R ² , R ³ and R ⁶ have the same meanings as described above). B) OH group at the 6-position of the obtained compound of the formula (Ib) After selective deprotection, is oxidized to give an aldehyde, which is then reacted with a halomethylenating agent to give a compound of formula (Ic):

[0025]

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(Wherein R ¹ , R ² , R ⁶ , R ⁸ and X have the same meanings as described above). C) The obtained compound of the formula (Ic) is added with a catalyst In the presence, the following formula:

[0027]

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By reacting an alkylboron, alkylzinc or alkyltin compound having an alkyl group represented by the following formula (II):

[0029]

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Wherein R ¹ , R ² , R ⁶ and R ⁸ are as defined above, d) then removing the ketal group and deprotecting the hydroxyl protecting group. , Formula (III):

[0031]

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After obtaining a compound represented by the formula (wherein R ⁸ is as defined above), e) ring-opening of the lactone ring site and hydrolysis of the N-acyl bond are carried out to obtain the compound of the formula (IV) This is a method for obtaining sphingohungin E.

The reduction reaction in the above step (a) can be carried out using a conventional method in organic chemical synthesis.
For example, the reaction can be carried out by a hydrogenation reaction in an inert solvent in the presence of a catalyst. The acylation reaction in the step (a) can be carried out by a usual method, for example, by allowing an acylating agent to act in a solvent in the presence of a base. As the acylating agent, an acid anhydride or an acid halide corresponding to the R ⁸ group to be introduced, for example, acetic anhydride, benzoic anhydride, acetyl chloride, benzoyl chloride and the like can be used.

The selective elimination protection of the 6-hydroxyl protecting group of the compound of the formula (Ib) in the step (b) can be carried out in a usual manner, that is, by allowing a deprotecting agent to act in a solvent.
Acetic acid, trifluoroacetic acid, CSA
An organic acid such as, for example, and an inorganic acid such as hydrogen fluoride, sulfuric acid, and hydrochloric acid can be used, and a 5% sulfuric acid aqueous solution is preferable. The oxidation reaction to the aldehyde in the step (b) can be performed by a usual method, and PDC, PC
C, Jones reagent, Dess-Martin reagent, and dimethyl sulfoxide in combination with an activating agent such as oxalyl chloride and acetic anhydride can be used, and the Dess-Martin reagent is preferred. The halomethylene conversion reaction to the aldehyde in the step (b) can be carried out by a general method in synthetic organic chemistry, but halomethylating agents that can be used include halomethane such as chloroform, bromoform, iodoform and chromium dichloride, iodine. Combination reagents with metal salts having a reducing ability such as samarium bromide and titanium trichloride are exemplified.

The step (c) of the present invention is a step of reacting a compound Ic with a corresponding alkylating agent to introduce a fatty chain to obtain a compound II, which is carried out by a conventional method in organic chemical synthesis. It can be carried out. As the alkylating agent to be used, [10 ', 10'
Alkylboron, alkylzinc, alkyltin and the like having -ethylenedioxy-1 '-(2 "-(trimethylsilylethoxy) -methyloxy) hexadec-2'-en-1'-yl]. [1,1-bis (diphenylphosphino) ferrocene] palladium dichloride is preferably used as the catalyst molecule.

Step (d) of the present invention is a step of removing a ketal bond, and further reacting with a deprotecting agent to remove all protecting groups on hydroxyl groups to obtain a triol compound III. It can be done by a method. To remove the ketal bond, an organic acid such as acetic acid, trifluoroacetic acid, or CSA, or an inorganic acid such as hydrogen fluoride, sulfuric acid, or hydrochloric acid can be used. The deprotecting agent for the hydroxyl-protecting group may be selected depending on the type of the protecting group to be deprotected, for example, organic acids such as acetic acid, trifluoroacetic acid, CSA, etc .; Or a fluorine-containing compound such as hydrogen fluoride pyridine complex, hydrogen fluoride triethylamine complex, tetrabutylammonium fluoride, palladium-carbon, hydrogenation reaction in the presence of Pearlman's catalyst, or a simple metal such as lithium, sodium, or potassium , Boron trichloride, boron tribromide, 4
Lewis acids such as tin chloride can be used, DDQ,
An oxidizing agent such as CAN can also be used.

Step (e) of the present invention is a step of opening the lactone ring site of compound III and hydrolyzing the N-acyl bond, which is carried out by a conventional method of organic chemical synthesis, that is, by using a base. Is a step of obtaining sphingohungin E by the method described above.

The base used may be an alkali metal salt such as lithium hydroxide, sodium hydroxide, potassium hydroxide.

In the above-mentioned production method, the treatment after each reaction is carried out by a usual method, and if necessary, the product may be purified by a conventional method, and then may be subjected to the next reaction step. Alternatively, it may be subjected to the next reaction step.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION The production of a compound of the formula (Ia) according to the steps shown in Scheme 1 and the production of sphingfungin E from a compound of the formula (Ia) according to Scheme 2 will be described. Starting material 1 for the method for producing sphingohungin E of the present invention is a known compound and can be produced by a known method [Bull. Chem. Soc. Jpn. 65,
2643-2654, 1992].

[0041]

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[0042]

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(Wherein All means an allyl group, R ¹ ,
R ² , R ³ , R ⁴ and R ⁶ represent a protecting group for a hydroxyl group,
R ⁵ , R ⁷ and R ⁸ represent a lower alkyl group or an aromatic group, and X has the same meaning as described above and has already been described)

In the reactions of Schemes 1 and 2, the inert solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material. Preferred inert solvents are described in each step. did. In addition, the treatment after the completion of the reaction can be carried out according to a conventional method.For example, the reaction mixture is concentrated, an immiscible organic solvent such as water and ethyl acetate is added, and after washing with water, the organic layer containing the desired product is separated. After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off. The obtained compound can be purified, if necessary, by a conventional method, for example, recrystallization or silica gel column chromatography.

First Step This step is a step in which an oxidizing agent is allowed to act on starting material 1 to obtain ketone 2. The oxidizing agent used in this step is PD
C, PCC, Jones reagent, Dess-Martin reagent, oxalyl chloride, dimethyl sulfoxide in combination with an activator such as acetic anhydride, and the like, and preferably dimethyl sulfoxide in combination with an activator, It is preferably a combination of oxalyl chloride and dimethyl sulfoxide (Swern oxidation). The inert solvent used is preferably dichloromethane, 1,2,
-Halogenated hydrocarbons such as dichloroethane,
Particularly preferred is dichloromethane. Reaction temperature is -78
C. to room temperature, preferably -78 C. to 0 C. The reaction time is 30 minutes to 3 hours, preferably 1 hour to 2 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Second Step) This step is a step of reacting the ketone 2 obtained in the first step with dichloromethyllithium to obtain a tertiary alcohol 3. The method for preparing dichloromethyllithium used includes methylene chloride and metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, or alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium. And preferably alkyllithium, and particularly preferably n-butyllithium. The inert solvent used is preferably an ethereal solvent such as diethyl ether, tetrahydrofuran, tetrahydropyran, 1,2-dimethoxyethane and the like, particularly preferably tetrahydrofuran. The reaction temperature is from -120C to -78C, preferably from -100C to 78C. The reaction time is 10 minutes to 2 hours, preferably 30 minutes to 1 hour. After the reaction,
The target compound is obtained by treating with a conventional method.

(Third Step) In this step, tertiary alcohol 3
In which a base is allowed to act on the tertiary alcohol 3 in an inert solvent (third step-1), and then reacted with a metal azide salt (third step-
2) and then a step of reacting with a reducing agent (third step-3).

(Third step-1) As the base to be used, a metal amide such as lithium diisopropylamide or lithium hexamethyldisilazide, or an alkyl such as n-butyllithium, sec-butyllithium or tert-butyllithium is used. Lithium or a strong organic base such as DBU or DBN can be mentioned, and preferably DBU. The inert solvent used is preferably a highly polar organic solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphonotriamide, particularly preferably dimethylsulfoxide. Reaction temperature is -23 ° C to 50
° C, preferably between 0 ° C and room temperature. Reaction time is 30
Minutes to 5 hours, preferably 1 hour to 4 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(3rd step-2) The α-chloroepoxide obtained in the previous step is reacted with a metal azide salt to form α-chloroepoxide.
In this step, azide aldehyde is obtained. Examples of the metal azide salt used include alkali metal azide salts such as lithium azide, sodium azide, and potassium azide, with sodium azide being preferred. The inert solvent used is preferably a highly polar organic solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphonotriamide, particularly preferably hexamethylphosphonotriamide. The reaction temperature is from room temperature to 100 ° C, preferably from 60 ° C to 80 ° C. Reaction time is 3
Hours to 24 hours, preferably 15 hours to 19 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Third Step-3) Examples of the reducing agent to be used include metal hydride salts such as sodium borohydride, lithium aluminum hydride, Red-Al, DIBAL and lithium triisobutylborohydride. Is sodium borohydride. The inert solvent used is preferably an alcohol such as methanol, ethanol, propanol, isopropanol, and particularly preferably methanol. Reaction temperature is -2
The temperature is 3 ° C to 60 ° C, preferably 0 ° C to room temperature. The reaction time is 30 minutes to 2 hours, preferably 1 hour to 2 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Fourth Step) In this step, the primary alcohol 4 obtained in the third step is protected (fourth step).
1) After further removing the benzylidene acetal at the 6th and 4th positions (4th step-2), protection at the 6th position (4th step-
3) and the step of protecting the 4-position (fourth step-4).

(Step 4-1) Examples of the protecting agent to be used include silyl protecting groups such as t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and triisopropylsilyl chloride. t
-Butyldiphenylsilyl chloride. Examples of the base to be used include organic bases such as triethylamine, tributylamine, dimethylaminopyridine, pyridine and imidazole, and preferably imidazole.
The inert solvent used is preferably a halogenated organic solvent such as methylene chloride or 1,2-dichloroethane, or an amide such as dimethylformamide or dimethylacetamide, and particularly preferably dimethylformamide. is there. The reaction temperature is 0 ° C to 100 ° C, preferably room temperature to 80 ° C. The reaction time is from 4 hours to 48 hours, preferably from 7 hours to 17 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Step 4-2) Examples of the acid catalyst used include organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and CSA, and inorganic acids such as hydrochloric acid and sulfuric acid. Is CSA. The inert solvent used is preferably a mixed solvent of any one of alcohols such as methanol, ethanol, propanol and isopropanol and any one of ethers such as tetrahydrofuran, diethyl ether and dimethoxyethane. Is a mixed solvent of methanol and tetrahydrofuran (8: 5). The reaction temperature is from 0 ° C to 60 ° C, preferably from room temperature to 40 ° C. The reaction time is from 2 hours to 48 hours, preferably from 24 hours to 36 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Step 4-3) Examples of the protecting agent used include silyl-based protecting groups such as t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and triisopropylsilyl chloride. t
-Butyldimethylsilyl chloride. Examples of the base to be used include organic bases such as triethylamine, tributylamine, dimethylaminopyridine, pyridine and imidazole, and preferably imidazole. The inert solvent used is preferably methylene chloride,
A halogenated organic solvent such as 1,2-dichloroethane,
Or amides such as dimethylformamide and dimethylacetamide, and particularly preferably dimethylformamide. The reaction temperature is from -23C to 60C, preferably from 0C to room temperature. The reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(4th step-4) Benzyl bromide, benzyl chloride, p-methoxybenzyl chloride, p-methoxybenzyl bromide,
Benzyl ether protecting groups such as o, p-dimethoxybenzyl chloride are preferably p-methoxybenzyl chloride. Lithium hydride,
It is a sodium hydride metal salt such as sodium hydride and potassium hydride, but preferably sodium hydride.
The inert solvent used is preferably an amide such as dimethylformamide or dimethylacetamide, or an ether such as tetrahydrofuran, diethyl ether or dimethoxyethane, and particularly preferably dimethylformamide. The reaction temperature is from -45 ° C to room temperature, preferably from -23 ° C to 0 ° C. Reaction time is 1 hour to 8
Hours, preferably 4 to 6 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Fifth Step) In this step, the alcohol 5 is reacted with a double bond isomerizing agent in an inert solvent to give
After converting the allyl group on the hydroxyl group to the 1-propenyl group (5th step-1), the oxidizing agent is actuated (5th step-2) to selectively remove the allyl group on the 1-hydroxyl group. It is a process.

(Step 5-1) As the double bond isomerizing agent to be used, a strong base such as potassium t-butoxide, tris (triphenylphosphine) rhodium chloride,
A transition metal catalyst such as [Ir (COD) (PMePh ₂ ) ₂ ] PF ₆ may be mentioned, and preferably [Ir (COD) (PMePh ₂ ) ₂ ]
Ph ₂ ) ₂ ] PF ₆ . The inert solvent used is preferably an ether such as tetrahydrofuran, diethyl ether or dimethoxyethane, and particularly preferably tetrahydrofuran. The reaction temperature is 0 ° C to 40 ° C,
Preferably it is room temperature. The reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Fifth step-2) As the oxidizing agent used, halogens such as iodine, bromine and chlorine, or N 2
Halogen equivalents such as CS, NBS, NIS, mCP
An epoxidizing agent such as BA and peracetic acid may be mentioned, but is preferably a halogen equivalent, and more preferably NBS. The inert solvent used is preferably a mixed solvent of ethers such as tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane and water, and particularly preferably a mixed solvent of tetrahydrofuran and water (3: 1).
It is. The reaction temperature is −23 ° C. to 40 ° C., preferably 0 ° C. to room temperature. The reaction time is 30 minutes to 5 hours,
Preferably, it is 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Sixth Step) In this step, an oxidizing agent is allowed to act on alcohol 6 (sixth step-1), and then to an amide alcohol by acting with a primary amine (sixth step-2). 7 is obtained.

(Sixth step-1) Examples of the oxidizing agent used include PDC, PCC, Jones reagent, Dess-Martin reagent, and dimethyl sulfoxide combined with an activating agent such as oxalyl chloride and acetic anhydride. Is preferably the Dess-Martin reagent. The inert solvent used is preferably a halogenated organic solvent such as methylene chloride and 1,2-dichloroethane, and more preferably methylene chloride. The reaction temperature is -2
The temperature is 3 ° C to 40 ° C, preferably 0 ° C to room temperature. The reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Sixth step-2) The primary amine used is methylamine, ethylamine, propylamine,
Examples thereof include isopropylamine and aniline, and methylamine is preferred. The inert solvent used is
Preferred are alcohols such as methanol, ethanol, propanol and isopropanol, and more preferred is methanol. The reaction temperature is −23 ° C. to 40 ° C., preferably 0 ° C. to room temperature. Reaction time is 30 minutes ~
5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Seventh Step) In this step, an oxidizing agent is allowed to act on amide alcohol 7 (seventh step-1), and then an appropriate reducing agent is acted on to effect a stereoselective reduction reaction (seventh step) Step-2) is performed.

(Seventh Step-1) Examples of the oxidizing agent used include PDC, PCC, Jones reagent, Dess-Martin reagent, and dimethyl sulfoxide combined with an activating agent such as oxalyl chloride and acetic anhydride. But preferably dimethyl sulfoxide (Swern oxidation) in combination with oxalyl chloride. The inert solvent used is preferably methylene chloride, 1,2-
It is a halogenated organic solvent such as dichloroethane, and more preferably methylene chloride. Reaction temperature is -7
The temperature is from 8 ° C to 0 ° C, preferably -78 ° C. The reaction time is 30 minutes to 3 hours, preferably 1 hour to 2 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Seventh Step-2) Examples of the reducing agent used include metal hydrides such as sodium borohydride, lithium aluminum hydride, Red-Al, DIBAL and lithium triisobutylborohydride.
Preferably it is lithium triisobutyl borohydride. The inert solvent used is preferably an ether such as tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane and the like, particularly preferably tetrahydrofuran. The reaction temperature is from -100C to -45C, preferably -78C. The reaction time is 10 minutes to 2 hours, preferably 30 minutes to 1 hour. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Eighth Step) In this step, an appropriate protecting agent is allowed to act on the amide alcohol 8, and the 5-position secondary alcohol site (8th step-1) and the 1-position amide N (8th step)
This is a step of protecting step-2).

(Eighth Step-1) The protecting agents used include methoxymethyl chloride, methylthiomethyl chloride, benzyloxymethyl chloride, (2-trimethylsilylethoxy) methyl chloride, (2,2,2-trichloroethoxy) Methyl ether-based protecting groups such as methyl chloride are exemplified, and (2-trimethylsilylethoxy) methyl chloride is preferred. Examples of the base used include sodium hydride metal salts such as lithium hydride, sodium hydride and potassium hydride, and amines such as triethylamine, diisopropylethylamine, pyridine and 2,6-dimethylpyridine. Are amines, more preferably diisopropylethylamine. The inert solvent used is preferably a halogenated organic solvent such as methylene chloride and 1,2-dichloroethane, and more preferably 1,2-dichloroethane. The reaction temperature is 0 ° C to 80
° C, preferably between room temperature and 70 ° C. Reaction time is 1
Hours to 8 hours, preferably 2 hours to 6 hours.
After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Eighth Step-2) Examples of the alkylating agent used include alkyl halides such as methyl iodide, ethyl bromide and benzyl bromide, and methyl iodide is preferred. Lithium hydride,
Examples thereof include sodium hydride metal salts such as sodium hydride and potassium hydride, and preferred is sodium hydride. The inert solvent used is preferably an ether-based organic solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, or dioxane, or an amide-based organic solvent such as dimethylformamide or dimethylacetamide. Formamide. The reaction temperature is from -23C to 40C, preferably from 0C to room temperature. The reaction time is 30 minutes to 3 hours, preferably 1 hour to 2 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Ninth Step) In this step, the amide 9
This is a step of performing a 4-position selective deprotection by acting an appropriate deprotecting agent.

The deprotecting agents used are CAN, D
Oxidants such as DQ, ozone, and NBS can be mentioned, but DDQ is preferred. The inert solvent used is preferably a mixed solvent of water and a halogenated organic solvent such as methylene chloride or 1,2-dichloroethane, and more preferably a mixed solvent of methylene chloride and water (4: 1). Solvent. The reaction temperature is from -23C to 40C, preferably 0C
~ Room temperature. The reaction time is 1 hour to 8 hours, preferably 2 hours to 4 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Tenth Step) In this step, a lactone is formed by reacting an appropriate acid on amide 10 to obtain a compound of the formula (I)
This is a step of obtaining the compound of a).

Examples of the acid catalyst used include organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, CSA, pyridinium p-toluenesulfonic acid, hydrochloric acid, and the like.
Inorganic acids such as sulfuric acid can be mentioned, and preferred is p-toluenesulfonic acid pyridinium salt. The inert solvent used is preferably a hydrocarbon-based organic solvent such as benzene, toluene and hexane, and more preferably toluene. The reaction temperature is 40 ° C to 120 ° C, preferably 6 ° C.
0 ° C to 100 ° C. The reaction time is from 2 hours to 48 hours, preferably from 24 hours to 36 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Eleventh Step) In this step, the compound Ia is treated with an appropriate reducing agent to reduce the azide moiety to an amine (Eleventh step-1), and then the acylating agent is added in the presence of a base. (11th step-2) to obtain an amide Ib.

(Eleventh step-1) As a reducing agent to be used, simple metals such as zinc, magnesium, and sodium;
Or triphenylphosphine, trimethylphosphine,
Organic compounds with reducing ability such as hydrogen sulfide, palladium
A hydrogenation reaction using a catalyst such as carbon, a Lindlar catalyst, or a Perlman catalyst can be mentioned, but a hydrogenation reaction is preferable, and a hydrogenation reaction using palladium / carbon is particularly preferable. The inert solvent used is preferably an alcohol such as methanol or ethanol, or a low-polar organic solvent such as ethyl acetate, toluene or hexane, and more preferably ethyl acetate. The reaction temperature is 0
C. to 50.degree. C., preferably room temperature to 40.degree. The reaction time is 2 hours to 12 hours, preferably 3 hours to 6 hours.
Time. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Eleventh step-2) Examples of the base to be used include inorganic bases such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic tertiary amines such as triethylamine and diisopropylethylamine. Is an organic tertiary amine, particularly preferably triethylamine. Examples of the acyl agent used include acetylating agents such as acetic anhydride and acetyl chloride, trihaloacetylating agents such as trifluoroacetic anhydride and trichloroacetic anhydride, and benzoylating agents such as benzoic anhydride and benzoyl chloride. Is preferably a benzoylating agent, particularly preferably benzoyl chloride. The inert solvent used is preferably a halogenated solvent such as dichloromethane, 1,2-dichloroethane, and particularly preferably dichloromethane. The reaction temperature is from 0 ° C to 50 ° C, preferably from room temperature to 40 ° C. The reaction time is 1 hour to 5 hours, preferably 2 hours to 4 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Twelfth Step) In this step, the amide compound I
b is reacted with a deprotecting agent to selectively remove the protecting group for the hydroxyl group at the 6-position (12th step-1), and then is reacted with an oxidizing agent to form an aldehyde (12th step-2). In this step, the halomethylene derivative of the formula (Ic) is obtained by carrying out the reaction (twelfth step-3).

(Twelfth Step-1) The deprotecting agent used is an organic acid such as acetic acid, trifluoroacetic acid, CSA or the like, or an inorganic acid such as hydrogen fluoride, sulfuric acid, hydrochloric acid, etc. Is a 5% aqueous sulfuric acid solution. The inert solvent used is preferably an alcohol such as methanol or ethanol, or a hydrophilic organic solvent such as acetone or acetonitrile, and more preferably acetone. The reaction temperature is 0 ° C to 50 ° C, preferably 0 ° C to room temperature. The reaction time is 1 hour to 5 hours, preferably 2 hours to 4 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Twelfth Step-2) Examples of the oxidizing agent used include PDC, PCC, Jones reagent, Dess-Martin reagent, and dimethyl sulfoxide combined with an activating agent such as oxalyl chloride and acetic anhydride. Is preferably the Dess-Martin reagent. The inert solvent used is preferably a halogenated organic solvent such as methylene chloride and 1,2-dichloroethane, and more preferably methylene chloride. The reaction temperature is -23
0 ° C to 40 ° C, preferably 0 ° C to room temperature. The reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Twelfth Step-3) Examples of the halomethylenating agent used include halomethanes such as chloroform, bromoform and iodoform and metal salts having a reducing ability such as chromium dichloride, samarium iodide and titanium trichloride. Preferably, it is a combination of iodoform and chromium dichloride. The inert solvent used is preferably an ether organic solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and more preferably tetrahydrofuran. Reaction temperature is -23 ° C ~
The temperature is 40 ° C, preferably 0 ° C to room temperature. The reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Thirteenth Step) In this step, an alkylating agent is allowed to act on compound Ic in the presence of a suitable catalyst molecule to introduce a fatty chain to obtain compound II.

Examples of the alkylating agent used include alkyl boron, alkyl zinc,
Alkyl tin and the like are mentioned, and alkyl borons are preferable. The catalyst molecules used include tetrakistriphenylphosphine palladium, [1,1-bis (diphenylphosphino) ferrocene] palladium dichloride, [1,2-bis (diphenylphosphino) ethane] palladium dichloride, [1,3-bis (Diphenylphosphino) propane] palladium dichloride and the like, and preferably [1,1-bis (diphenylphosphino) ferrocene] palladium dichloride. The inert solvent used is preferably a mixed solvent of an ether organic solvent such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane and an amide organic solvent such as dimethylformamide or dimethylacetamide. Particularly preferred is a mixed solvent of tetrahydrofuran and dimethylformamide (1: 3). The reaction temperature is −23 ° C. to 40 ° C., preferably 0 ° C. to room temperature.
The reaction time is 30 minutes to 5 hours, preferably 1 hour to
3 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Step 14) In this step, a ketal is removed by reacting compound II with a suitable acid catalyst.
After the step-1), a 2 '
Of the protecting groups on the hydroxyl groups at the 5th and 5th positions (Step 14—
2) Then, the protecting group on the 4-position hydroxyl group is removed by the action of a suitable deprotecting agent (Step 14-3) to give Compound III
This is the step of obtaining

(14th step-1) As the acid catalyst to be used, organic acids such as acetic acid, trifluoroacetic acid, CSA, etc .;
Alternatively, it is an inorganic acid such as hydrogen fluoride, sulfuric acid, and hydrochloric acid, and particularly preferably a 5% aqueous sulfuric acid solution. The inert solvent used is preferably an alcohol such as methanol or ethanol, or a hydrophilic organic solvent such as acetone or acetonitrile, and more preferably acetone. The reaction temperature is 0 ° C to 50 ° C, preferably 0 ° C to room temperature. The reaction time is 1 hour to 5 hours, preferably 2 hours to 4 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Step 14-2) As the deprotecting agent to be used, an organic acid such as acetic acid, trifluoroacetic acid or CSA, an inorganic acid such as sulfuric acid or hydrochloric acid, a hydrogen fluoride pyridine complex, a fluoride Compounds containing fluorine, such as hydrogen triethylamine complex and tetrabutylammonium fluoride, may be mentioned, but preferred are compounds containing fluorine, and particularly preferred are hydrogen fluoride pyridine complexes. The inert solvent used is preferably an ether organic solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, etc., and more preferably tetrahydrofuran. The reaction temperature is 0
0 ° C to 50 ° C, preferably 0 ° C to room temperature. The reaction time is 1 hour to 12 hours, preferably 4 hours to 8 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Step 14-3) As the deprotecting agent to be used, a deprotecting agent usually used for cleavage of a benzyl protecting group, for example, a hydrogenation reaction in the presence of palladium on carbon or a Perlman catalyst, or Simple metals such as lithium, sodium, potassium, etc., boron trichloride, boron tribromide,
An oxidizing agent such as a Lewis acid such as tin tetrachloride or the like, DDQ, CAN or the like can be used, but a Lewis acid is preferable, and boron trichloride is particularly preferable. The inert solvent used is preferably a halogenated organic solvent such as dichloromethane or 1,2-dichloroethane, but more preferably dichloromethane. The reaction temperature is from -100 ° C to-
45 ° C., preferably from −78 ° C. to −45 ° C. The reaction time is 10 minutes to 3 hours, preferably 30 minutes to 2 hours.
Time. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

(Fifteenth Step) This step is a step in which a base is allowed to act on compound III to hydrolyze a lactone ring site and an N-acyl bond to obtain sphingohundine E.

The base to be used includes alkali metal salts such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and preferably sodium hydroxide. The inert solvent used is preferably a mixed solvent of water and an ether organic solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and dioxane.
More preferably, it is a mixed solvent of dioxane and water (1: 1). The reaction temperature is 0 ° C to 100 ° C, preferably room temperature to 80 ° C. The reaction time is 1 hour to 12 hours, preferably 4 hours to 10 hours. After completion of the reaction, the reaction product is treated by a conventional method to obtain a target compound.

The invention is further described in the following examples, which do not limit the invention in any way.

[0088]

EXAMPLES Example 1: Allyl-3-O-benzyl-4,
Preparation of 6-O-benzylidene-α-D-arabino-hexopyranoside-2-ulose

[0089]

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100 ml of methylene chloride and 13.1 ml (151 mmol) of oxalyl chloride were placed in a dry, nitrogen-purged 1-liter three-necked flask, and cooled to -78 ° C. A methylene chloride solution of 21.4 ml (301 mmol) of dimethyl sulfoxide was slowly added dropwise, and the mixture was stirred for 10 minutes. A methylene chloride solution of 30.0 g (75.3 mmol) of alcohol 1a was slowly added dropwise, and the mixture was further stirred for 1 hour. 83.4 ml of triethylamine (602 mmo
l) was slowly added dropwise, and after the temperature was raised to 0 ° C, the mixture was further stirred for 1 hour. The reaction was stopped by adding 50 ml of water, liquid separation was performed using a water-ether system, and the organic layer was collected. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of ketone 2a . 7 g were obtained. Recrystallization was performed using a mixed solvent system of hexane-ethyl acetate, and 19.6 g (49.7 mmol) of ketone 2a was taken as the first crystal, and 3.00 g of ketone 2a was taken as the second crystal from the filtrate.
(7.6 mmol) were obtained. (76%)

[Α] _D +28.65 (c 1.22, CHCl ₃ ) IR (KB
^{r) 1753 cm -1. 1 H} NMR (500 MHz, CDCl 3) δ 3.80 (t,
1 H, J = 6.8 Hz), 3.88 (t, 1 H, J = 9.8 Hz), 4.09
(dd, 1H, J = 4.9 Hz, 12.7 Hz), 4.20-4.27 (m, 2
H), 4.37 (dd, 1 H, J = 4.9 Hz, 9.8 Hz), 4.56 (d, 1
H, J = 10.7 Hz), 4.72 (d, 1 H, J = 12.7 Hz), 4.91
(d, 1 H, J = 12.7 Hz), 4.93 (d, 1 H, J = 12.7 Hz),
5.26 (d, 1 H, J = 11.7 Hz), 5.31 (d, 1 H, J = 15.
6 Hz), 5.56 (s, 1 H), 5.89 (ddt, 1 H, J = 15.6 Hz,
11.7 Hz, 5.9 Hz), 7.27-7.34 (m, 3 H), 7.36-7.
45 (m, 5 H), 7.48 -. 7.53 (m, 2 H) 13 C NMR (100 MH
z, CDCl ₃ ) δ 63.40, 68.68, 69.17, 73.51, 80.74, 82.
41, 99.98, 101.13, 118.86, 126.13 (2 C), 127.82 (2
C), 128.24 (2 C), 128.36 (2 C), 129.12, 132.67, 1
. 36.89, 137.49, 197.34 HRMS ( M + H) + 397.1651 Calculated: C ₂₃ H ₂₅ O ₆ Found: 397.1646.

Example 2 Preparation of (2R) -allyl-3-O-benzyl-4,6-O-benzylidene-2-C-dichloromethyl-α-D-arabino-hexopyranose

[0093]

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In a 200 ml three-necked flask, which had been dried and purged with nitrogen, 50 ml of tetrahydrofuran and 2.2 ml (34.3 mmol) of methylene chloride were taken and cooled to -78 ° C. 1.52M n-butyllithium / hexane solution 2
1.5 ml (32.7 mmol) was slowly added dropwise and stirred for 10 minutes. A solution of 3.24 g (8.17 mmol) of ketone 2a in tetrahydrofuran was slowly added dropwise, followed by stirring for 30 minutes. 1 ml of methanol was added, the mixture was stirred for 10 minutes, and 5 ml of a saturated aqueous solution of ammonium chloride was added to stop the reaction.
After performing liquid separation operation with a water-ether system and collecting an organic layer,
The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 4.51 g of a crude product of alcohol 3a . Purification by silica gel column chromatography (hexane: ethyl acetate = 92: 8)
2.76 g (5.7 mmol) of the purified product of 3a were obtained as a colorless oil. (70%)

[0095] [α] _{D +42.66 (c 1.09, CHCl 3} ) IR ( ^{neat) 3528 cm -1. 1 H NMR} (500 MHz, CDCl 3) δ 3.52 (s,
1H), 3.82 (t, 1 H, J = 10.3 Hz), 3.94 (dt, 1 H, J
= 9.8Hz, 4.9Hz), 4.08 (d, 1H, J = 9.8Hz), 4.13
(dd, 1 H, J = 4.9 Hz, 10.7 Hz), 4.25-4.32 (m, 2
H), 4.34 (d, 1 H, J = 9.8 Hz), 4.85 (d, 1 H, J = 1
1.7 Hz), 4.92 (d, 1 H, J = 11.7 Hz), 5.28 (s, 1
H), 5.29 (d, 1 H, J = 12.7 Hz), 5.35 (d, 1 H, J =
16.6 Hz), 5.61 (s, 1 H), 5.94 (ddt, 1 H, J = 4.9 H
z, 12.7 Hz, 16.6 Hz), 6.25 (s, 1 H), 7.28-7.33
(m, 4 H), 7.37-7.40 (m, 4 H), 7.46-7.48 (m, 2
H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 63.05, 68.76, 69.1
0, 73.14, 75.77, 78.00, 79.50, 82.45, 97.06, 101.3
0, 119.01, 126.02 (2 C), 127.69, 127.63 (2 C), 128.
19 (2 C), 128.26 (2 C), 128.93, 132.64, 137.28, 13
. 8.04 HRMS (M + H) + 481.1185 _{Calculated: C 24 H 27 Cl 2 O} 6 Found: 481.1188

Example 3: (2S) -allyl-2-azido-3-O-benzyl-4,6-O-benzylidene-2-
Deoxy-2-hydroxymethyl-α-D-arabino-
Production of hexopyranose

[0097]

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A tertiary alcohol 3a (38.9 g, 80.8 mmol) was placed in a dry, nitrogen-purged, 300 ml three-necked flask, and diluted with 100 ml of dimethyl sulfoxide. 0 ° C
After cooling, DBU (13.3 ml, 88.9 mmol)
Was slowly added and stirred for 15 minutes. The mixture was further stirred at room temperature for 3 hours, and after confirming that the raw materials had disappeared by TLC,
The reaction was stopped by adding 10 ml of water. After liquid separation was performed using a water-ether system, the organic layer was collected, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 34.3 g of a crude product of the corresponding epoxide. This product and sodium azide (52.5 g, 808 mmol) were placed in a dry, nitrogen-purged, 300 ml three-necked flask, and HM
Dissolved in 150 ml of PA. 15-crown-5 (3.2m
l, 16.2 mmol), and the mixture was heated and stirred at 60 to 70 ° C for 17 hours in an oil bath. After confirming the disappearance of the starting materials by TLC, 50 ml of water was added to stop the reaction. After liquid separation was performed using a water-ether system, the organic layer was collected, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 37.3 g of a crude product of the corresponding aldehyde. The crude product was transferred to a 200 ml eggplant flask, and diluted with 100 ml of methanol. After cooling to 0 ° C, NaBH4 (3.1 g, 80.
8 mmol) was added slowly, and the mixture was stirred for 1 hour and 30 minutes. Water 2
After 0 ml was added to stop the reaction and methanol was distilled off under reduced pressure by a rotary evaporator, liquid separation was performed with a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure by a rotary evaporator and a vacuum pump. And 35.9 g of a crude product of alcohol 4a . Silica gel column chromatography (hexane: ethyl acetate = 1
0: 90-20: 90) to give alcohol 4a
30.7 g (67.8 mmol) of the purified product were obtained as a colorless oily substance. (3 processes 84%)

[0099] [α] _{D +50.59 (c 0.96, CHCl 3} ) IR ( ^{neat) 3515, 2125 cm -1. 1} H NMR (500 MHz, CDCl 3) δ 2.5
0 (t, 1 H, J = 6.8 Hz), 3.84-3.90 (m, 2 H), 3.92
(d, 2H, J = 6.8 Hz), 4.03 (dd, 1 H, J = 5.9 Hz, 1
2.7 Hz), 3.98-4.31 (m, 4H), 4.72 (s, 1 H), 4.73
(d, 1 H, J = 12.7 Hz), 4.98 (d, 1 H, J = 11.7 Hz),
5.28 (d, 1 H, J = 11.7 Hz), 5.32 (d, 1 H, J = 15.
6 Hz), 5.65 (s, 1 H), 5.89 (ddt, 1 H, J = 15.6 Hz,
11.7 Hz, 6.8 Hz), 7.27-7.41 (m, 8 H), 7.45-7.
50 (m, 2 H). 13 C NMR (100 MHz, CDCl 3) δ 62.83, 63.
94, 68.03, 68.61, 68.70, 75.29, 76.53, 80.50, 100.
12, 101.62, 119.06, 126.00, 127.76 (2 C), 127.99
(2 C), 128.26 (2 C), 128.37 (2 C), 128.99, 132.63,
137.34,138.01.HRMS (M + H) ⁺ 454.1978 Calculated C ₂₄ H ₂₈
O ₆ N ₃ Found: 454.1956.

Example 4 Preparation of (2R) -allyl-2-azido-3-O-benzyl-2-C- (t-butyldiphenylsilyloxymethyl) -2-deoxy-α-D-arabino-hexopyranose

[0101]

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13.5 g (29.8 mmol) of alcohol 4a and 6.1 g (89.3 mmol) of imidazole were placed in a dry, nitrogen-purged 100 ml two-necked flask, and dissolved in 30 ml of dimethylformamide. TBDPSCl
After adding 8.5 ml (32.8 mmol) and stirring at room temperature for 14 hours, the mixture was heated to 60 ° C. in an oil bath and further stirred for 3 hours. After confirming that the raw materials had disappeared by TLC, 10 ml of saturated aqueous sodium hydrogen carbonate was added to stop the reaction. A liquid separation operation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a corresponding silyl ether crude product. Put this in a 300 ml eggplant flask, and add 40 ml of methanol,
THF 25 ml, camphorsulfonic acid 1.0 g (4.3
mmol) and stirred at room temperature for 26 hours. After confirming the disappearance of the raw materials by TLC, triethylamine 1
The reaction was stopped by adding 0 ml. After evaporating the solvent under reduced pressure on a rotary evaporator, water - to carry out a liquid separation operation in ether, and the organic layer was collected, the solvent was evaporated under reduced pressure on a rotary evaporator and vacuum pump, Jio <br/> Le 5a 25.0 g of a crude product were obtained. Silica gel column chromatography (hexane: ethyl acetate = 70: 3
0 to 60:40) to obtain 15.8 g (26.2 mmol) of a purified product of the diol 5a as a white crystalline solid.

[Α] _D +23.79 (c 1.63, CHCl ₃ ) IR (KB
^{r) 3411, 2128 cm -1.} 1 H NMR (500 MHz, CDCl 3) δ 1.0
6 (s, 9 H), 2.58 (brs, 1 H), 3.13 (d, 1 H, J = 3.9
Hz), 3.56 (d, 1 H, J = 8.8 Hz), 3.63 (dt, 1 H, J =
9.8 Hz, 3.9 Hz), 3.80-3.88 (m, 3 H), 3.93-4.0
0 (m, 2 H), 4.04 (dt, 1 H, J = 4.9 Hz, 9.8 Hz), 4.
22 (dd, 1 H, J = 5.9 Hz, 12.7 Hz), 4.41 (d, 1 H, J
= 11.7 Hz), 4.65 (d, 1 H, J = 11.7 Hz), 5.07 (s, 1
H), 5.19 (d, 1 H, J = 10.7 Hz), 5.26 (d, 1 H, J =
18.6 Hz), 5.86 (ddt, 1 H, J = 10.7 Hz, 18.6 Hz, 4.
9 Hz), 7.03 -7.08 (m, 2 H), 7.10-7.14 (m, 3 H),
7.35-7.41 (m, 4 H), 7.41-7.47 (m, 2 H), 7.62
(d, 2 H, J = 6.8 Hz), 7.69 (d, 2 H, J = 6.8 Hz).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 19.11, 26.65 (3C), 62.2
5, 64.28, 68.56, 69.00, 69.63,72.00, 75.75, 80.13,
97.13, 117.47, 127.66 (2 C), 127.74 (2 C), 127.7
8,127.85 (2 C), 128.30 (2 C), 129.66, 129.84, 132.
25, 132.77, 133.29, 135.47 (2 C), 135.68 (2 C), 13
7.38. HRMS (M + Na) + 626.2662 Calculated C ₃₃ H ₄₁ N ₃ O ₆ SiNa
Found: 626.2664.

Example 5: (2R) -allyl-2-azido-3-O-benzyl-6-O- (t-butyldimethylsilyl) -2-C- (t-butyldiphenylsilyloxymethyl) -2 Production of -deoxy-4-O- (p-methoxybenzyl) -α-D-arabino-hexopyranose

[0105]

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In a dry, nitrogen-purged 100 ml two-necked flask, 15.6 g (25.8 mmol) of diol 5a and 5.3 g (77.5 mmol) of imidazole were taken, and diluted with 30 ml of dimethylformamide. After cooling to 0 ° C, TB
4.1 g (27.1 mmol) of SCl was added, and the mixture was stirred for 2 hours. After confirming the disappearance of the raw materials by TLC,
The reaction was stopped by adding 10 ml of saturated aqueous sodium hydrogen carbonate. A liquid separation operation was performed with a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump.
18.5 g of crude product of the corresponding alcohol were obtained. This crude product was placed in a dry, nitrogen-purged 100 ml two-necked flask and dissolved in 30 ml of dimethylformamide. p
7.0 ml of methoxybenzyl chloride (51.6 mmol
l) was added and cooled to -23 ° C. 1.2 g (28.4 mmol) of 55 wt% sodium hydride was slowly added, and the mixture was stirred for 5 hours and 30 minutes.
The reaction was stopped by adding 0 ml. Liquid separation was performed using a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 26.2 g of a crude product of a protected alcohol group. This crude product is
In a 00 ml eggplant flask, add 25 ml of THF, 20 ml of 1N aqueous sodium hydroxide, and 50.5 ml of 15-crown.
Was added and stirred for 9 hours. After confirming complete disappearance of p-methoxybenzyl chloride by TLC, a liquid-separating operation was performed with a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump, and A crude product of the protected group 5b was obtained. Purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3-95: 5),
13.9 g (16.5 mmol) of a purified product of silyl ether 5b
l) was obtained as a colorless oil. (2 steps 64%)

[0107] [α] _{D +34.53 (c 0.64, CHCl 3} ) IR ( ^{neat) 2124 cm -1. 1 H NMR} (500 MHz, CDCl 3) δ 0.09 (s,
3H), 0.11 (s, 3H), 0.93 (s, 9H), 1.03 (s, 9H),
3.59- 3.66 (m, 2 H), 3.69 (d, 1 H, J = 10.3 Hz),
3.76-3.90 (m, 6 H, including single signal at δ 3.79),
4.23 (dd, 1 H, J = 5.1 Hz, 12.4 Hz), 4.31 (d, 1 H,
J = 11.0 Hz), 4.59 (d, 1 H, J = 12.4 Hz), 4.73
(d, 2 H, J = 11.0 Hz), 5.14 (s, 1 H), 5.18 (dd, 1
H, J = 1.5 Hz, 10.3 Hz), 5.23 (dd, 1 H, J = 1.5 H
z, 16.8 Hz), 5.86 (ddt, 1 H, J = 10.3 Hz, 16.8 Hz,
5.1 Hz), 6.86 (d, 2 H, J = 8.8 Hz), 6.98-7.10
(m, 5 H), 7.22 (d, 2 H, J = 8.1 Hz), 7.33- 7.50
(m, 6 H), 7.58-7.63 (m, 2 H), 7.66-7.72 (m, 2
H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ -5.35, -5.22, 18.2
3, 19.05, 25.83 (3 C), 26.60 (3 C), 55.20, 62.09,
65.11, 68.18, 69.77, 72.91, 74.88, 75.66, 76.33, 7
9.31, 96.35, 113.87 (2 C), 117.07, 127.64 (2 C), 1
27.73, 127.75 (2 C), 128.18 (2C), 129.58 (2 C), 12
9.63 (2 C), 129.75, 130.40, 132.35, 132.76, 133.5
0,135.49 (2 C), 135.66 (2 C), 137.29, 159.30.HRMS
(M + Na) ⁺ 860.4102 Calculated C ₄₇ H ₆₃ N ₃ O ₇ SiNa Found: 86
0.4108.

Example 6: (2R) -2-azido-3-O
-Benzyl-6-O- (t-butyldimethylsilyl)-
2-C- (t-butyldiphenylsilyloxymethyl)
-2-Deoxy-4-O- (p-methoxybenzyl)-
Production of D-arabino-hexopyranose

[0109]

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In a dry, nitrogen-purged 50 ml two-necked flask, (1,5-cyclooctadiene) bis (methyldiphenylphosphine) iridium (I) hexafluorophosphate (Ir (COD) (PmePh ₂ ) ₂ PF ₆ ) 20g (0.24m
mol) and diluted with 10 ml of tetrahydrofuran.
The inside of the reaction vessel was purged with hydrogen and stirred until the reaction solution became a transparent solution. After the inside of the system was replaced with nitrogen again, a tetrahydrofuran solution of 10.6 g (12.6 mmol) of silyl ether 5b was added dropwise using a cannula, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After confirming the disappearance of the raw materials by ¹ HNMR, the reaction solution was transferred to a 100 ml eggplant-shaped flask, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 11.1 g of a corresponding enol ether crude product. 15 ml of tetrahydrofuran and 5 ml of water were added to the crude product. After cooling to 0 ° C., 2.7 g (15.1 mmol) of NBS was added, and the mixture was stirred for 2 hours. The reaction was stopped by adding 5 ml of a saturated aqueous sodium bicarbonate solution and 5 ml of a saturated aqueous sodium thiosulfate solution. A liquid-separating operation was performed using a water-ether system, and the organic layer was collected. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump.
The crude product of 6a was obtained. Silica gel column chromatography (hexane: ethyl acetate = 93: 7-90: 1)
0) and purified 8.26 g of alcohol 6a
(10.3 mmol) was obtained as a colorless oil. (2 steps 82%)

[0111] [α] _{D +12.62 (c 1.17, CHCl 3} ) IR ( ^{neat) 3428, 2120 cm -1. 1} H NMR (500 MHz, CDCl 3) δ 0.0
8 (s, 3 H), 0.11 (s, 3 H), 0.92 (s, 9 H), 1.04 (s,
9 H), 2.72 (d, 1 H, J = 2.9 Hz), 3.69 (d, 1 H, J =
8.8 Hz), 3.71 (d, 1 H, J = 9.8 Hz), 3.76-3.82
(including single signal at m, 4 H, δ 3.78), 3.82-3.94
(m, 3 H), 4.00 (t, 1 H, J = 8.8 Hz), 5.40 (d, 1 H,
J = 3.9 Hz), 6.85 (d, 2 H, J = 8.8 Hz), 7.03-7.0
8 (m, 2 H), 7.09-7.14 (m, 3 H), 7.19-7.24 (m,
2 H), 7.34-7.48 (m, 6 H), 7.63 (d, 2 H, J = 6.8
Hz), 7.67 (d, 2H , J = 7.8 Hz). 13 C NMR (125 MHz, C
DCl ₃ ) δ -5.34, -5.17, 18.36, 19.15,25.91 (3 C), 2
6.71 (3 C), 55.22, 62.46, 65.09, 69.55, 72.94, 74.
79, 75.59, 76.36, 78.76, 92.23, 113.86 (2 C), 127.
69 (2 C), 127.71, 127.75 (2 C), 128.05 (2 C), 128.
23 (2 C), 129.60 (2 C), 129.72, 129.79, 130.44, 13
2.49, 132.75, 135.58 (2 C), 135.63 (2 C), 137.41,
159.25. HRMS (MH) ⁺ 796.3813 calcd _{C 44 H 58 N 3 O 7} Si 2
Found: 796.3824.

Embodiment 7: (2R, 3R, 4S, 5S)-
N-methyl-2-azido-3-benzyloxy-4-
Production of (p-methoxybenzyloxy) -6- (t-butyldimethylsilyloxy) -2- (t-butyldiphenylsilyloxymethyl) -5-hydroxy-hexanoic acid amide

[0113]

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In a dry, nitrogen-purged reaction vessel, add alcohol
1.87 g (2.3 mmol) of 6a was taken and diluted with 5 ml of methylene chloride. After cooling to 0 ° C, Dess-Mar
1.50 g (3.5 mmol) of tin reagent was added and stirred for 10 minutes. After stirring at room temperature for another 2 hours,
The reaction was stopped by slowly adding 5 ml of a saturated aqueous sodium thiosulfate solution. Liquid separation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 1.80 g of a crude product of the corresponding lactone. This crude product was placed in a 35 ml eggplant flask, a 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After confirming the disappearance of the raw materials by TLC, the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump, and the amide 7 was removed.
to give the crude product of a. Silica gel column chromatography (hexane: ethyl acetate = 90: 10-85: 1
5), 1.85 g of a purified product of amide 7a
(2.2 mmol) was obtained as a crystalline white solid. (2 steps 94%)

[Α]_D +35.31 (c 0.97, CHCl_Three) IR (KB
r) 3317, 2130, 1650 cm^-1.¹H NMR (500 MHz, CDCl_Three)
δ 0.06 (s, 3 H), 0.07 (s, 3 H), 0.90 (s, 9 H), 1.
03 (s, 9 H), 2.68 (d, 1 H, J = 6.6 Hz), 2.79 (d, 3
H, J = 5.1 Hz), 3.57 (dd, 1H, J = 2.2 Hz, 8.1 Hz),
 3.66-3.75 (m, 3 H), 3.79 (s, 3 H), 4.09 (s, 2
H), 4.37-4.45 (m, 3 H), 4.63 (d, 1 H, J = 10.3 H
z), 4.78 (d, 1 H, J = 11.0 Hz), 6.81-6.89 (m, 3
H), 7.09-7.26 (m, 7H), 7.34-7.47 (m, 6H), 7.6
1 (dd, 2 H, J = 1.5 Hz, 7.3 Hz), 7.66 (dd, 2 H, J
= 1.5 Hz, 8.1Hz).¹³C NMR (125 MHz, CDCl_Three) δ -5.3
7, -5.35, 18.22, 19.16, 25.87 (3 C), 26.59 (3 C), 5
5.18, 63.37, 65.73, 71.56, 73.57, 74.28, 75.33, 7
7.91, 79.69, 113.64 (2 C), 127.53, 127.63 (2 C), 12
7.74 (4 C), 128.07, 128.19 (2C), 129.42 (2C), 129.
75, 129.84, 130.53, 132.46, 132.59, 135.51 (2 C),
135.56 (2 C), 137.59, 159.10, 169.26.HRMS (M + H)⁺ 
827.4235 Calculated value C₄₅H₆₃N _FourO₇Si_Two Found: 827.4232.

Embodiment 8: (2R, 3R, 4S, 5R)-
N-methyl-2-azido-3-benzyloxy-4-
Production of (p-methoxybenzyloxy) -6- (t-butyldimethylsilyloxy) -2- (t-butyldiphenylsilyloxymethyl) -5-hydroxy-hexanoic acid amide

[0117]

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5 ml of methylene chloride and 0.1 ml of oxalyl chloride were placed in a dry, nitrogen-purged 25 ml two-necked flask.
36 ml (4.1 mmol) was taken, and after cooling to -78 ° C, 0.58 ml (8.2 mmol) of dimethyl sulfoxide was added, followed by stirring for 10 minutes. 1.68 g of amide 7a (2.
Methylene chloride solution was slowly added dropwise with a cannula, and the mixture was further stirred for 1 hour. 2.3 ml (16.4 mmol) of triethylamine are added, and
Minutes. The reaction was stopped by adding 3 ml of water. A liquid separation operation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 1.83 g of a crude product of the corresponding ketone. The obtained crude product was used for the next reaction without purification.
3 ml of tetrahydrofuran and 6.1 ml (6.1 mmol) of lithium triisobutylborohydride-tetrahydrofuran solution were placed in a dry, nitrogen-purged 25 ml two-necked flask, and cooled to -78 ° C. A tetrahydrofuran solution of the ketone (2.0 mmol) obtained in the previous reaction was slowly added dropwise using a cannula, and the mixture was stirred for 30 minutes. After confirming the disappearance of the starting materials by TLC, 2 ml of a 1 N aqueous sodium hydroxide solution was slowly added dropwise to terminate the reaction. After raising the temperature to 0 ° C, 2 ml of 40% hydrogen peroxide aqueous solution
Was slowly added dropwise. After confirming the exothermic reaction, 1 ml of a saturated aqueous solution of sodium thiosulfate was added dropwise to remove excess hydrogen peroxide, followed by liquid separation with a water-ether system.
The organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of alcohol 8a . Purification was performed by silica gel column chromatography (hexane: ethyl acetate = 90: 10-85: 15), and 1.38 g (1.66) of a purified product of alcohol 8a was purified.
mmol) as a colorless oil. (2 steps 82%)

[0119] [α] _{D +12.83 (c 0.50, CHCl 3} ) IR ( neat) 3433, 2128, 1737, 1677 cm -1. 1 H NMR (500 MHz,
CDCl ₃ ) δ 0.04 (s, 6 H), 0.89 (s, 9 H), 1.03 (s, 9
H), 2.54 (br, d, 1 H, J = 5.9 Hz), 2.82 (d, 3 H, J
= 4.9 Hz), 3.41-3.47 (m, 1 H), 3.49 (t, 1 H, J =
7.8 Hz), 3.59 (dd, 1 H, J = 5.9 Hz, 9.8 Hz), 3.76
-3.85 (m, 4H, δ 3.78 including single signal), 4.06
(d, 1 H, J = 9.8 Hz), 4.17 (d, 1 H, J = 10.7 Hz),
4.27 (d, 1 H, J = 6.8 Hz), 4.34 (d, 1 H, J = 11.7
Hz), 4.48 (d, 1 H, J = 10.7 Hz), 4.74 (d, 1 H, J =
10.7 Hz), 4.79 (d, 1 H, J = 11.7 Hz), 6.77-6.85
(m, 3 H), 7.01-7.07 (m, 2 H), 7.14 -7.22 (m, 3
H), 7.35-7.48 (m, 6 H), 7.59 (d, 2 H, J = 6.8 H
z), 7.66 (d, 2 H, J = 6.8 Hz). 13 C NMR (125 MHz, CD
Cl ₃ ) δ -5.48, -5.42, 18.08, 19.08, 25.80 (3 C), 2
6.33, 26.52 (3 C), 55.08 (2 C), 63.57, 65.56, 71.5
8,74.37, 74.56, 76.90, 80.57, 113.53 (2 C), 127.3
6, 127.42 (2 C), 127.70 (2 C), 127.71 (2 C), 128.1
1 (2 C), 129.72, 129.78 (2 C), 129.84, 130.45, 132.
26, 132.41, 135.42 (2 C), 135.51 (2 C), 137.58, 15
9.09, 169.24.HRMS (M + H) ⁺ 827.4235 Calculated C ₄₅ H ₆₃ N ₄ O
₇ Si _{2 found} : 827.4239.

Embodiment 9: (2R, 3R, 4S, 5R)-
N-methyl-2-azido-3-benzyloxy-4-
Production of (p-methoxybenzyloxy) -6- (t-butyldimethylsilyloxy) -2- (t-butyldiphenylsilyloxymethyl) -5- (2'-trimethylsilylethoxymethyloxy) -hexanoic acid amide

[0121]

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1.33 g (1.61 mmol) of alcohol 8a was placed in a dry, nitrogen-purged 25 ml two-necked flask, and diluted with 5 ml of 1,2-dichloroethane. 1.3 ml (8.0 mmol) of diisopropylethylamine, 0.85 ml (4.8 mmol) of trimethylsilylethoxymethyl chloride.
mmol), and the mixture was stirred for 4 hours while heating to 60 ° C. in an oil bath. After confirming the disappearance of the starting materials by TLC, the temperature was returned to room temperature, and 2 ml of a saturated aqueous sodium hydrogen carbonate solution was slowly added dropwise to terminate the reaction. Liquid separation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of protected alcohol group 9a . Purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10),
1.31 g of purified product of protected alcohol 9a (1.37 mm
ol) as a colorless oil. (85%)

[Α]_D -1.53 (c 0.56, CHCl_Three) IR (Knee
G) 3438, 2127, 1681, 1515, 1250 cm ^-1.¹H NMR (500
 MHz, CDCl_Three) δ 0.00 (s, 9 H), 0.06 (s, 3 H), 0.07
(s, 3H), 0.87 (m, 11H, δ 0.93 contain single signal
), 0.17 (s, 9 H), 2.86 (d, 3H, J = 4.8 Hz), 3.42
 (br, t, 1 H, J = 7.8 Hz), 3.54 (ddd, 1 H, J = 5.9
Hz, 10.3 Hz, 10.3 Hz), 3.70-3.79 (m, 4 H), 3.81
(s, 3 H), 3.90 (dd, 1H, J = 1.8 Hz, 6.6 Hz), 4.15
(d, 1 H, J = 10.5 Hz), 4.18 (d, 1 H, J = 6.6 Hz),
4.25 (d, 1 H, J = 10.5 Hz), 4.37 (d, 1 H, J = 11.7
 Hz), 4.50 (d, 1 H, J = 10.5 Hz), 4.75-4.84 (m, 3
 H), 4.88 (d, 1 H, J = 11.7 Hz), 6.81 (d, 1 H, J =
 8.5 Hz), 6.84 (q, 1 H, J = 4.8 Hz), 7.05-7.11
(m, 2 H), 7.17-7.26 (m, 5 H), 7.41-7.52 (m, 6
H), 7.65 (d, 2 H, J = 7.1 Hz), 7.72 (d, 2 H, J = 7.
8 Hz).¹³C NMR (125 MHz, CDCl_Three) δ -5.49, -5.46,-
1.44 (3 C), 18.11 (2 C), 19.19, 25.86 (3 C), 26.4
1, 26.59 (3 C), 55.17, 61.94, 65.40, 65.72, 74.25,
 74.72, 75.00, 76.10, 79.49, 79.70, 96.39, 113.49
(2 C), 127.23, 127.46 (2 C), 127.73 (2 C), 127.75
(2 C), 128.07 (2 C), 129.71, 129.85, 130.07 (2 C),
130.82, 132.51, 132.69, 135.55 (2 C), 135.60 (2
C), 138.14, 159.05, 168.58.HRMS (M + Na)⁺ 979.4869
Calculated value C₅₁H₇₆N_FourO₈Si_ThreeNa Observed: 979.4861.

Embodiment 10: (2R, 3R, 4S, 5R)
-N, N-dimethyl-2-azido-3-benzyloxy-6- (t-butyldimethylsilyloxy) -2- (t
-Butyldiphenylsilyloxymethyl) -4- (p-
Production of (methoxybenzyloxy) -5- (2'-trimethylsilylethoxymethyl-oxy) -hexanoic acid amide

[0125]

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1.56 g (1.63 mmol) of the protected alcohol 9a was placed in a dry, nitrogen-purged 25 ml two-necked flask.
And diluted with 3 ml of dimethylformamide. After adding 0.30 ml (4.8 mmol) of methyl iodide, the mixture was cooled to 0 ° C., and 87 mg (2.0 mmol) of sodium hydride was slowly added, followed by stirring for 1 hour and 30 minutes. After confirming the disappearance of the starting materials by TLC, 2 ml of a saturated aqueous ammonium chloride solution was slowly added dropwise to stop the reaction. A liquid separation operation was performed with a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump.
1.62 g of a crude product of dimethylamide 9b was obtained. Purification by silica gel column chromatography (hexane: ethyl acetate = 95: 5) gave 1.50 g (1.59 mmol) of a purified product of dimethylamide 9b as a colorless oil. (97%)

[0127] [α] _{D -10.24 (c 0.50, CHCl 3} ) IR ( ^{neat) 2111, 1633, 1616 cm -1} . 1 H NMR (500 MHz, CDCl 3)
δ 0.00 (s, 9 H), 0.05 (s, 6 H), 0.91 (s, 9 H), 1.
10 (s, 9 H), 2.93 (brs, 3 H), 3.36 (brs, 3 H), 3.55
(dt, 1 H, J = 6.0 Hz, 9.8 Hz), 3.64 (dt, 1 H, J =
2.6 Hz, 9.8 Hz), 3.69-3.83 (m, 6 H, δ 3.79 including single signal), 3.90 (dd, 1 H, J = 2.5 Hz, 5.5 H
z), 4.21 (d, 1 H, J = 10.6 Hz), 4.28 (d, 1 H, J = 1
0.6 Hz), 4.33 (d, 1 H, J = 5.5 Hz), 4.48 (d, 1 H,
J = 11.6 Hz), 4.51 (d, 1 H, J = 10.6 Hz), 4.75 (d,
1 H, J = 10.6 Hz), 4.82 (s, 2 H), 4.86 (d, 1 H, J
= 11.6 Hz), 6.81 (d, 2 H, J = 8.6 Hz), 7.13-7.18
(m, 2 H), 7.19-7.28 (m, 5 H), 7.36-7.50 (m, 6
H), 7.67 (d, 2 H, J = 6.5 Hz), 7.73 (d, 2 H, J =
^{6.7 Hz). 13 C NMR (} 125 MHz, CDCl 3) δ -5.51, -5.47,
-1.46 (3 C), 18.08, 18.09, 19.11, 25.84 (3 C), 26.
71 (3 C), 38.78, 55.10 (2 C), 62 42, 65.36, 67.46,
74.03, 75.03, 76.45, 79.55, 80.18, 96.14, 113.42
(2 C), 127.14, 127.55 (2 C), 127.71 (2 C), 127.74
(2 C), 128.02 (2 C), 129.70, 129.79 (2 C), 129.84,
131.01, 132.48,132.58, 135.55 (2 C), 135.61 (2
C), 138.33, 158.92, 168.40.HRMS (M + K) ⁺ 1009.4765
Calculated value C ₅₂ H ₇₈ N ₄ O ₈ Si ₃ K Observed value: 1009.4763.

Example 11: (1'R, 3R, 4R, 5
S) -3-Azido-4-benzyloxy-5- [2'-
(T-butyldimethylsilyloxy) -1 ′-(2 ″-
Production of (trimethylsilyl) -ethoxymethyl-oxy) ethyl] -3- (t-butyldiphenylsilyloxymethyl) -oxolan-2-one

[0129]

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1.49 g (1.53 mmol) of dimethylamide 9b was placed in a dry, nitrogen-purged 25 ml two-necked flask, and 2 ml of methylene chloride and 0.5 ml of water were added.
After cooling to 0 ° C., 0.42 g (1.84 mmo) of DDQ
l) was added slowly and stirred for 3 hours. After confirming the disappearance of the starting materials by TLC, 5 ml of a 1N aqueous sodium hydroxide solution was slowly dropped to stop the reaction. Water-
A liquid separation operation was performed using an ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 1.44 g of a crude product of a deprotected alcohol. The crude product was transferred to a dry, nitrogen-purged 25 ml two-necked flask, and diluted with 5 ml of toluene. PPTS
0.78 g (3.1 mmol) was added, and 70
Stir for 24 hours while heating to ° C. After confirming the disappearance of the starting materials by TLC, 2 ml of saturated aqueous sodium hydrogen carbonate was added to stop the reaction. A liquid separation operation was performed with a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of Iaa . Purification by silica gel column chromatography (hexane: ethyl acetate = 95: 5) gave 0.83 g (1.59 mmol) of the purified lactone Iaa as a colorless oil. (62%)

[0131] [α] _{D -6.42 (c 0.63, CHCl 3} ) IR ( ^{neat) 2120, 1785, 1616 cm -1} . 1 H NMR (500 MHz, CDCl 3)
δ 0.01 (s, 12 H), 0.04 (s, 3 H), 0.84-1.00 (m,
11 H, δ 0.87 includes single signal), 1.07 (s, 9 H),
3.57 (dt, 1 H, J = 15.6 Hz, 5.9 Hz), 3.64-3.77
(m, 4 H), 3.88 (d, 1 H, J = 8.8 Hz), 3.96 (dd, 1
H, J = 4.9 Hz, 10.7 Hz), 4.41 (d, 1 H, J = 10.7 H
z), 4.45 (d, 1 H, J = 5.9 Hz), 4.70 (d, 1 H, J = 6.
8 Hz), 4.75 (d, 1 H, J = 6.8 Hz), 4.85 (d, 1 H, J =
4.9 Hz), 4.86 (d, 1 H, J = 5.9 Hz), 7.28-7.38
(m, 5 H), 7.38-7.50 (m, 6 H), 7.60-7.70 (m, 4
^{H). 13 C NMR (125} MHz, CDCl 3) δ -5.49, -5.40, -1.4
6, 17.99, 18.26, 19.18, 25.89 (3 C), 26.70 (3 C),
55.51, 62.31, 65.33, 65.58, 69.82, 74.33, 75.65, 7
7.82, 80.14, 95.03, 114.27, 127.93 (2 C), 127.94
(2 C), 128.00 (2 C), 128.22, 128.55 (2 C), 130.14,
131 75,131.92, 131.97, 135.56 (2 C), 135.57 (2
C), 136.54, 171.69.HRMS (M + Na) ⁺ 828.3872 Calculated C
₄₂ H ₆₃ N ₃ O ₇ Si ₃ Na Found: 828.3859.

Embodiment 12: (1'R, 3R, 4R, 5
S) -3-Benzamide-4-benzyloxy-5-
[2 '-(t-butyldimethylsilyloxy) -1'-
Production of (2 "-(trimethylsilyl) -ethoxymethyloxy) ethyl] -3- (t-butyldiphenylsilyloxymethyl) -oxolan-2-one

[0133]

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0.22 g (0.27 mmol) of Iaa was placed in a dry, nitrogen-purged 25 ml two-necked flask, and diluted with 2 ml of ethyl acetate. After adding 0.22 g of 10% palladium-carbon, the system is replaced with hydrogen, and room temperature is reduced to 3%.
Stirred for hours. After confirming that the raw materials had disappeared by TLC, the mixture was filtered through celite, and the solvent was distilled off from the obtained solution under reduced pressure using a rotary evaporator and a vacuum pump to obtain 0.22 g of a crude amino compound Ida . According to ¹ HNMR, (1′R, 3R,
4S, 5R) -3-Amino-4-benzyloxy-5-
[2 '-(t-butyldimethylsilyloxy) -1'-
(2 "-(trimethylsilyl) -ethoxymethyl-oxy) ethyl] -3- (t-butyldiphenylsilyloxymethyl) -oxolan-2-one.

[0135]

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¹ H NMR (500 MHz, CDCl ₃ ) δ 0.00 (s, 12
H), O.06 (s, 3 H), O.82-0,96 (m.11 H, δ 0.89 includes single signal), 1.04 (s, 9 H), 3.54 (ddd, 1H,
J = 5.9 Hz, 9.7 Hz, 11.1 Hz), 3.64-3.70 (m, 2 H,
δ 3.68, J = 9.8 Hz including double signal), 3,75 (d
d, 1 H, J = 6.5 Hz, 10.2 Hz), 3.81 (dd, 1H, J = 4.
6Hz, 10.2 Hz), 3.84 (d, 1H, J = 9.8 Hz), 3.89-3.
93 (m, 1H), 4.38 (d.1H, J = 11.O Hz), 4.46 (d, 1H.
J = 6.8 Hz), 4.69 (d, 1H.J = 6,7 Hz), 4,74 (d, 1
H, J = 6.7 Hz), 4.75 (d, 1H, J = 11.0 Hz), 7.24-
7.46 (m, 9H), 7.61-7.66 (m, 6H).

The above crude product was placed in a 25-ml two-necked flask, and 5.0 mg of dimethylaminopyridine and 0.11 ml (0.82 mmol) of triethylamine were added, followed by dilution with 1 ml of methylene chloride. After cooling to 0 ° C., 63.4 ml (0.55 mmol) of benzoyl chloride was added and stirred for 40 minutes. The mixture was further stirred at room temperature for 30 minutes, and after confirming that the raw materials had disappeared by TLC, saturated sodium bicarbonate solution was added.
The reaction was stopped by adding 1 ml. Water - to carry out a liquid separation operation in ether, and the organic layer was collected, the solvent was evaporated under reduced pressure on a rotary evaporator and vacuum pump, amide Iba
The crude product of was obtained. Purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5),
0.21 g (0.24 mmol) of the purified amide Iba was obtained as a colorless oil. (2 steps 87%)

[0138] [α] _{D +32.50 (c 0.45, CHCl 3} ) IR ( neat) 3422, 3352, 1783, 1668 cm -1. 1 H NMR (500 MHz,
CDCl ₃ ) δ 0.00 (s, 6 H), 0.01 (s, 3 H), 0.83-0.98
(including single signal at m, 11 H, δ 0.84), 1.01 (s, 9
H), 3.65 (t, 2 H, J = 8.3 Hz), 3.69 (dd, 1 H, J =
3.9 Hz, 11.1 Hz), 3.75 (dd, 1 H, J = 3.1 Hz, 11.1
Hz), 4.06-4.09 (m, 1 H), 4.29 (d, 1 H, J = 10.0
Hz), 4.34 (d, 1 H, J = 10.0 Hz), 4.49 (d, 1 H, J =
11.3 Hz), 4.62 (d, 1 H, J = 4.3 Hz), 4.66 (d, 1 H,
J = 11.3 Hz), 4.73 (d, 1 H, J = 6.9 Hz), 4.77 (d,
1 H, J = 6.9 Hz), 4.93 (dd, 1 H, J = 4.3 Hz, 7.5 H
z), 6.77 (brs, 1 H), 7.06-7.12 (m, 2 H), 7.12-
7.18 (m, 3 H), 7.27-7.49 (m, 9 H), 7.56-7.60
(m, 2 H), 7.61 (d, 2 H, J = 6.7 Hz), 7.66 (d, 2 H,
^{. J = 7.2 Hz) 13 C} NMR (125 MHz, CDCl 3) δ -5.49, -
5.41, -1.42 (3 C), 17.95, 18.20, 19.16, 25.86 (3
C), 26.66 (3 C), 62.87, 64.07, 65.35, 66.59, 74.40,
76.07, 79.74, 82.43, 94.97, 127.01 (2 C), 127.52
(2 C), 127.70, 127.74 (2 C), 127.85 (2 C), 128.24
(2 C), 128.51 (2 C), 129.88, 129.92, 131.87, 132.0
2, 132.43, 133.56,135.49 (2 C), 135.61 (2 C), 137.
23, 167.61, 174.20.HRMS (M + H) ⁺ 884.4409 Calculated C ₄₂
H ₇₀ NO ₈ Si ₃ Found: 884.4398.

Embodiment 13: (1'S, 3R, 4R, 5
S) -3-Benzamido-4-benzyloxy-3-
(T-butyldiphenylsilyloxymethyl) -5-
[2'-hydroxy-1 '-(2 "-(trimethylsilylethoxy) -methyloxy) ethyl] -oxolane-
Production of 2-one

[0140]

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0.21 g (0.22 mmol) of amide Iba was placed in a 10 ml eggplant- shaped flask which had been dried and purged with nitrogen, and 1.2 ml of acetone and 0.2 ml of a 5% aqueous sulfuric acid solution were added. After stirring at room temperature for 3 hours, TLC confirmed that the raw materials had disappeared, and the reaction was stopped by slowly adding 0.5 ml of saturated aqueous sodium hydrogen carbonate. After acetone was distilled off under reduced pressure by a rotary evaporator, liquid separation was performed with a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump.
A crude product of Ibb was obtained. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15), and 0.15 g (0.20 mm
ol) as a colorless oil. (82%)

[0142] [α] _{D +30.27 (c 0.56, CHCl 3} ) IR ( ^{neat) 3426, 1784, 1667 cm -1} . 1 H NMR (500 MHz, CDCl 3)
δ 0.01 (s, 9 H), 0.86-1.00 (m, 2 H), 1.02 (s, 9
H), 2.78 (brs, 1 H), 3.46-3.52 (m, 1 H), 3.58-
3.70 (m, 2 H), 3.74 (ddd, 1H, J = 6.0 Hz, 11.0 H
z, 6.0 Hz), 4.08-4.11 (m, 1 H), 4.26 (d, 1 H, J =
10.3 Hz), 4.29 (d, 1 H, J = 10.3 Hz), 4.48 (d, 1
H, J = 11.1 Hz), 4.58 (d, 1 H, J = 4.1 Hz), 4.63
(d, 1 H, J = 11.1 Hz), 4.77 (d, 1 H, J = 7.0 Hz),
4.81 (d, 1 H, J = 7.0 Hz), 4.83 (dd, 1 H, J = 4.1
Hz, 8.5 Hz), 6.72 (brs, 1 H), 7.05-7.09 (m, 2
H), 7.12-7.18 (m, 3 H), 7.30-7.50 (m, 9 H), 7.
58 (d, 2 H, J = 7.9 Hz), 7.62 (d, 2 H, J = 7.9 H
z), 7.67 (d, 2H , J = 7.1 Hz). 13 C NMR (125 MHz, CD
Cl ₃ ) δ -1.47 (3 C), 18.05, 19.15, 26.66 (3 C), 62.
04, 64.29, 65.92, 66.56, 74.64, 78.53, 79.55, 81.8
9, 95.57, 127.00 (2 C), 127.77 (2 C), 127.82 (2
C), 127.87, 127.93 (2 C), 128.29 (2 C), 128.55 (2
C), 123.00, 130.04, 131.89, 131.96, 132.24, 133.3
7, 135.52 (2 C), 135.59 (2 C), 136.87, 167.53, 17
. 4.14 HRMS (M + H) + 770.3544 calcd _{C 43 H 56 N 3 O 8} Si 2 Found: 770.3542.

Embodiment 14: (2'E-1'S, 3R, 4
R, 5R) -3-Benzamido-4-benzyloxy-
3- (t-butyldiphenylsilyloxymethyl) -5
-[3'-iodo-1 '-(2 "-(trimethylsilylethoxy) -methyloxy) prop-2'-ene-1'
-Yl] -oxolan-2-one

[0144]

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80.0 mg (0.10 mmol) of alcohol Ibb was placed in a dry, nitrogen-purged 25 ml two-necked flask, and diluted with 0.5 ml of methylene chloride. After cooling to 0 ° C., 89.1 mg of Dess-Martin reagent (0.21 mm
ol) and stirred for 15 minutes. The mixture was further stirred at room temperature for 1 hour and 30 minutes. After confirming that the raw materials had disappeared by TLC, 0.5 ml of a saturated aqueous sodium bicarbonate solution and 0.2 ml of a saturated aqueous sodium thiosulfate solution were slowly added dropwise to terminate the reaction. A liquid separation operation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 88.1 mg of a crude product of the corresponding aldehyde. This crude product was used for the next reaction without purification. Chromium dichloride 7 in a dry 25 ml two-necked flask
7.4 mg (0.63 mmol) was taken and dried by igniting using a heat gun under reduced pressure. After returning to room temperature, the system was replaced with nitrogen and 0.5 ml of tetrahydrofuran was added. 0 ° C
After cooling, 88.1 mg of the crude aldehyde product obtained in the previous reaction and 0.12 g of iodoform (0.31
mmol) in tetrahydrofuran was added dropwise with a cannula. After stirring for 10 minutes, the mixture was further stirred at room temperature for 2 hours and 30 minutes. After confirming the disappearance of the raw materials by TLC, the reaction was stopped by adding 0.5 ml of saturated aqueous sodium hydrogen carbonate. A liquid separation operation was performed with a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of an iodine form Ica . Silica gel column chromatography (hexane: ethyl acetate = 100:
0 to 90:10) to obtain 48.0 mg (0.054 mmol) of a purified product of the iodine form Ica as a white solid.
(52%)

[Α] _D +29.55 (c 0.65, CHCl ₃ ) IR (KB
r) 3420, 3318, 1783, 1667 cm -1. 1 H NMR (500 MHz,
CDCl ₃ ) δ 0.02 (s, 9 H), 0.83-0.96 (m, 2 H), 1.02
(s, 9H), 3.54 (ddd, 1 H, 6.8 Hz, 10.7 Hz, 10.7 H
z), 3.70 (ddd, 1 H, J = 5.9 Hz, 10.7 Hz, 10.7 Hz),
4.27 (s, 2 H), 4.34 (d, 1 H, J = 10.7 hz), 4.45-
4.47 (m, 2 H), 4.60-4.65 (m, 2 H), 4.67 (d, 1 H,
J = 6.8 Hz), 4.69 (d, 1 H, J = 6.8 Hz), 6.31-6.
40 (m, 2 H, δ 6.37 includes double signal J = 13.6 Hz), 6.75 (s, 1 H), 7.04-7.10 (m, 2 H), 7.14-
7.19 (m, 3 H), 7.29- 7.50 (m, 9 H), 7.56 (d, 2 H,
J = 6.8 Hz), 7.61 (d, 2 H, J = 6.8 Hz), 7.66 (d, 2
H, J = 7.8 Hz). 13 C NMR (125 MHz, CDCl 3) δ -1.39
(3 C), 17.89, 19.16, 26.70 (3 C), 64.19, 65.43, 6
6.64, 74.69, 76.18, 79.50, 83.35, 83.38, 93.08, 12
7.04 (2 C), 127.41 (2 C), 127.79, 127.85 (2 C), 12
7.99, 128.11 (2 C), 128.33 (2 C), 128.58 (2 C), 13
0.04, 130.11, 131.94, 132.02,132.27, 133.28, 135.5
5 (2 C), 135.62 (2 C), 137.07, 140.37, 167.56, 17
. 4.00 HRMS (M + H) + 892.2562 calcd _{C 44 H 55 NO 7 Si 2} found: 892.2568.

Embodiment 15: (2'E-1'S, 3R, 4
R, 5S) -3-Benzamido-4-benzyloxy-
3- (t-butyldiphenylsilyloxymethyl) -5
-[10 ', 10'-ethylenedioxy-1'-(2 "
-(Trimethylsilylethoxy) -methyloxy) hexadec-2'-en-1'-yl] -oxolan-2-
On manufacture

[0148]

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A dry, nitrogen-purged 25 ml two-necked flask was charged with 9,7-ethylenedioxy-1-tridecene 90.9.
mg (0.38 mmol), and add tetrahydrofuran 0.1
Diluted in ml. 0.38 ml (0.19 mmol) of 0.5 M 9-BBN / tetrahydrofuran solution was added,
The mixture was stirred for 30 minutes. After adding 22 μl of distilled water, the mixture was stirred at room temperature for 10 minutes. Separately dried and purged with nitrogen 25ml
Iodinated form Ica 55.8mg in a two-necked flask (0.063m
mol), 1.8 mg of triphenylarsine (0.006 mmo)
l), 0.20 g (0.63 mmol) of cesium carbonate was taken and diluted with 0.2 ml of dimethylformamide. After cooling to 0 ° C., the above-mentioned alkyl-9-BBN / tetrahydrofuran solution was added dropwise using a cannula. Further, 5.0 mg (0.006 mmol) of PdCl ₂ (dppf) was added, and the mixture was stirred for 1 hour. Then, the temperature was raised to room temperature and stirred for 1 hour.
The reaction was stopped by slowly adding 0.5 ml of water dropwise. A liquid separation operation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain 88.1 mg of a crude product of IIa . Silica gel column chromatography (hexane: ethyl acetate = 10
0: 0 to 90:10), and purified product of IIa 5
9.8 mg (0.059 mmol) were obtained as a colorless oil. (94%)

[0150] [α] _{D +50.86 (c 0.34, CHCl 3} ) IR ( ^{neat) 3423, 1787, 1668 cm -1} . 1 H NMR (500 MHz, CDCl 3)
δ 0.02 (s, 9 H), 0.88 (t, 3 H, J = 6.8 Hz), 0.88
-0.96 (m, 2 H), 1.02 (s, 9 H), 1.20-1.38 (m, 10
H), 1.53-1.62 (m, 2 H), 2.00 (q, 2 H, J = 7.8 Hz),
3.54 (ddd, 1 H, J = 5.9 Hz, 9.8 Hz, 9.8 Hz), 3.79
(ddd, 1 H, J = 6.8 Hz, 9.7 Hz, 9.8 Hz), 3.92 (s,
4 H), 4.26 (d, 1 H, J = 9.8 Hz), 4.36 (d, 1 H, J =
10.7 Hz), 4.44 (d, 1 H, J = 10.7 Hz), 4.48 (d, 1 H,
J = 2.9 Hz), 4.52 (t, 1 H, J = 8.3 Hz), 4.60 (d,
1 H, J = 11.7 Hz), 4.66 (dd, 1 H, J = 2.9 Hz, 7.8 H
z), 4.69 (d, 1 H, J = 6.8 Hz), 4.73 (d, 1 H, J =
6.8 Hz), 5.28 (dd, 1 H, J = 7.8 Hz, 15.6 Hz), 5.78
(dt, 1H, J = 6.8 Hz, 15.6 Hz), 6.80 (s, 1 H), 7.0
4-7.10 (m, 2 H), 7.13-7.18 (m, 3 H), 7.30-7.
51 (m, 9 H), 7.58 (d, 1 H, J = 7.8 Hz), 7.63 (d, 2
H, J = 7.8 Hz), 7.66 (d, 2 H, J = 7.8 Hz). 13 C NMR
(125 MHz, CDCl ₃ ) δ -1.38 (3 C), 14.09, 17.92, 19.
19, 22.61, 23.78, 23.81, 26.67 (3 C), 28.96, 29.3
3, 29.61, 29.76, 31.84, 32.54, 37.14, 37.17, 63.7
3, 64.88 (2 C), 65.15, 66.88, 74 18, 74.38, 79.73,
84.65, 92.00, 111.81, 123.80, 127.06 (2 C), 127.1
8 (2 C), 127.50, 127.78 (2 C), 127.91 (2 C), 128.1
6 (2 C), 128.53 (2 C), 129.91, 129.99, 131.90, 13
2.12, 132.43, 133.52, 135.58 (2 C), 135.64 (2 C),
137.50, 138.62, 167.63, 174.32.HRMS (M + Na) ⁺ 1028.
5504 Calculated C ₅₉ H ₈₃ NO ₉ Si ₂ Na Found: 1028.5482.

Embodiment 16: (2'E-1'S, 3S, 4
R, 5R) -3-Benzamido-4-benzyloxy-
3-hydroxymethyl-5- [10'-oxo-1'-
Hydroxy-hexadec-2'-en-1'-yl]-
Production of oxolan-2-one

[0152]

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In a 25 ml eggplant flask, 23.1 mg of IIa was added.
(0.023 mmol) and diluted with 0.3 ml of acetone. 40 ml of a 5% aqueous sulfuric acid solution was added, and the mixture was stirred at room temperature for 6 hours. The reaction was stopped by adding 0.1 ml of a saturated aqueous solution of sodium bicarbonate. After acetone was distilled off under reduced pressure by a rotary evaporator, liquid separation was performed with a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure with a rotary evaporator and a vacuum pump to obtain a crude ketone body b. The product was obtained. The obtained crude product is placed in a 5 ml eggplant flask dried and replaced with nitrogen, diluted with 0.2 ml of tetrahydrofuran,
50 ml of a hydrogen fluoride-pyridine complex was added, and the mixture was stirred at room temperature for 5 hours and 30 minutes. After confirming the disappearance of the starting material by TLC, 0.5 ml of saturated aqueous sodium hydrogen carbonate was added to stop the reaction. Liquid separation was performed using a water-ether system, the organic layer was recovered, and the solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of diol IIIa .
Silica gel column chromatography (chloroform:
Purification by methanol = 100: 0 to 98: 2) gave 10.7 mg (0.018 mmol) of a purified product of diol IIIa as a colorless oil. (2 steps 78%)

[0154] [α] _{D +34.51 (c 0.18, CHCl 3} ) IR ( neat) 3364, 1777, 1710, 1656 cm -1. 1 H NMR (500 MHz,
CDCl ₃ ) δ 0.89 (t, 3 H, J = 6.8 Hz), 1.22-1.42
(m, 12 H), 1.49-1.62 (m, 4 H), 2.01-2.06 (m, 2
H), 2.38 (t, 4 H, J = 7.8 Hz), 2.69 (brs, 1 H),
3.87 (t, 1 H, J = 11.7 Hz), 4.19 (d, 1 H, J = 12.7
Hz), 4.46-4.62 (m, 4 H), 4.85 (d, 1 H, J = 3.8
Hz), 5.23 (d, 1 H, J = 9.8 Hz), 5.50 (dd, 1 H, J =
15.6 Hz, 6.8 Hz), 5.85 (dt, 1 H, J = 15.6 Hz, 6.8H
z), 7.07 (s, 1 H), 7.08-7.14 (m, 2 H), 7.18-7.
25 (m, 3 H), 7.43 (t, 2 H, J = 7.8 Hz), 7.56 (t, 1
H, J = 6.8 Hz), 7.75 (d, 2 H, J = 6.8 Hz). 13 C NM
R (125 MHz, CDCl ₃ ) δ 14.02, 22.49, 23.76, 23.85, 2
8.62, 28.91, 28.93, 28.99, 31.60, 32.28, 42.70, 4
2.83, 65.74, 68.20, 70.64, 74.74, 78.00, 84.15, 12
6.07, 127.25 (2 c), 127.81 (2 c), 128.21, 128.51 (2
c), 128.84 (2 c), 132.61, 132.78, 136.50, 136.52, 1
69.75, 173.73, 211.66.HRMS (M + Na) ⁺ 616.3250 Calculated C ₃₅ H ₄₇ NO ₇ Na Found: 616.3238.

Embodiment 17: (2'E, 1'S, 3S, 4
R, 5R) -5- [10'-oxo-1'-hydroxy-hexadec-2'-en-1'-yl] -3-benzamido-3-hydroxymethyl-4-hydroxyoxolan-2-one Manufacture

[0156]

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Diol II was placed in a dry, nitrogen-purged reaction vessel.
Take 5.8 mg (0.0098 mmol) of Ia and dilute with 0.5 ml of methylene chloride. After cooling to -78 ° C,
1.0 M 3 boron chloride-methylene chloride solution 30.
μl (0.030 mmol) was added and stirred for 1 hour. The reaction was stopped by adding 0.1 ml of a saturated aqueous solution of sodium bicarbonate. A liquid separation operation was performed using a water-ether system, and the organic layer was recovered. The solvent was distilled off under reduced pressure using a rotary evaporator and a vacuum pump to obtain a crude product of Triol IIIb . Thin layer silica gel chromatography (chloroform: methanol = 90: 1)
0) and 0.8 mg (0.0%) of triol IIIb
016 mmol). (16%)

[0158] [α] _{D +24.52 (c 0.50, CHCl 3} ) IR ( neat) 3604, 3418, 1782, 1705 , 1652 cm -1. 1 H NMR (500
MHz, CDCl ₃ ) δ 0.87 (t, 3 H, J = 6.8 Hz), 1.20-
1.36 (m, 12 H), 1.37-1.66 (m, 4 H), 2.05-2.15
(m, 2 H), 2.35 (dt, 2 H, J = 2.0 Hz, 6.8 Hz), 2.39
(t, 2 H, J = 7.8 Hz), 2.69 (br, 1 H), 3.93-4.12
(including double signal J = 10.7 Hz in m, 3H, δ 4.06),
4.57 (dd, 1 H, J = 5.9Hz, 3.9 Hz), 4.66 (t, 1 H, J
= 5.9 Hz), 4.92 (br, s, 1 H), 5.61 (dd, 1 H, J =
6.8 Hz, 15.6 Hz), 5.93 (dt, 1 H, J = 6.8 Hz, 15.6
Hz), 7.00 (s, 1H), 7.47 (t, 2 H, J = 7.8 Hz), 7.57
(t, 1 H, J = 6.8 Hz), 7.82 (d, 2 H, J = 8.8 Hz).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.02, 22.47, 23.76, 2
3.78, 25.97, 28.20, 28.37, 28.68, 28.88, 31.56, 3
1.91, 42.65, 42.77, 64.44, 67.77, 70.96, 72.34, 84.
67, 126.34, 127.35 (2 C), 128.80 (2 C), 132.44, 13
2.67, 135.60, 169.52, 173.93, 212.92.HRMS (M + Na) ⁺
Calcd _{504.2961 (C 28 H 42 NO 7} ) Found 504.2962.

Example 18: (6E, 2R, 3R, 4R,
5S) -2-Amino-2-hydroxymethyl-3,4,
Production of 5-trihydroxy-14-oxoeicosa-6-enoic acid (sphingohundin E)

[0160]

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Triol in a 10 ml eggplant flaskIIIb
Take 2.0 mg (0.00397 mmol), 0.2 ml of water,
Diluted with 0.1 ml dioxane. Sodium hydroxide2.
Add 2 mg (0.055 mmol) and bring to 60 ° C in an oil bath
Heated and stirred for 8 hours. Ion exchange after cooling to room temperature
The resin was added, the pH of the reaction solution was returned to about 7, and the reaction was stopped.
Was. The ion exchange resin is removed by Celite filtration,
After washing with knol, the filtrate was collected. Rotary
Evaporate the solvent under reduced pressure using a vaporizer and vacuum pump
AndIVThe crude product of was obtained. Silica gel column chromatography
Raffy (chloroform: methanol: water = 90: 1
0: 0 to 80:20:10), and sphingo
1.4 mg (0.0034 mmol) of Funjin E (IV)
Was. (84%)

[Α] _D -5.43 (c 0.48, MeOH) IR (KB
r) 3532, 3198, 2928, 2855, 1711, 1637 cm -1. 1 H NM
R (500 MHz, CDCl ₃ ) δ 0.90 (t, 3 H, J = 6.8 Hz), 1.
24-1.46 (m, 12 H), 1.50-1.56 (m, 4 H), 2.06
(q, 2H, J = 6.8 Hz), 2.44 (t, 2H, J = 7.3 Hz), 2.
45 (t, 2 H, J = 7.3 Hz), 3.64 (d, 1 H, J = 6.9 H
z), 3.85 (d, 1 H, J = 11.7 Hz), 3.94-4.00 (m, 2
H, δ 3.98 includes doublet J = 11.7 Hz), 4.11 (t,
1 H, J = 7.3 Hz), 5.45 (dd, 1 H, J = 7.8 Hz, 15.6H
z), 5.77 (dt, 1 H, J = 15.6 Hz, 6.8 Hz). 13 C NMR
(125 MHz, CDCl ₃ ) δ 14.37, 23.58, 24.84, 28.86, 29.
99, 30.01, 30.14, 30.16, 32.81, 33.42, 43.45, 43.4
8, 64.95, 70.03, 71.11, 75.52, 76.27, 130.14, 135.
70, 173.42, 214.34.HRMS (M + H) ⁺ Calculated 418.2805 (C
₂₁ H ₄₀ NO ₇ ) Found 418.2806.

[0163]

Industrial Applicability The present invention relates to sphingofungin E, one of sphingofungins having useful physiological activities.
This is the first total synthesis starting from a known compound and via a new intermediate compound I.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) C07C 227/22 C07C 227/32 227/32 229/30 229/30 C07D 407/06 C07D 407/06 A61K 31 / 198 // A61K 31/198 C07B 61/00 300 C07B 61/00 300 C07D 307/32 RF term (reference) 4C063 AA01 BB03 CC81 DD73 EE05 4C206 AA04 FA47 ZB07 ZB26 4H006 AA02 AC42 AC44 AC46 AC52 AC81 BA02 BN10 BR10 BS10 BS10 BU32 4H039 CA29 CA54 CA71 CB30

Claims (5)

[Claims] 1. A compound of formula (I):[Where R¹, R^TwoAnd R⁶Is a protecting group for a hydroxyl group, and A is-
N_Three, -NH_TwoOr -NHCOR⁸(R⁸Is lower alkyl
Or an aromatic group), B is -CH _Two-OR^Three
(R^ThreeIs a protecting group for a hydroxyl group) or -CH = CH-
X (X is a halogen)].
object. 2. A is —N ₃ or —NH ₂ , and B is —CH ₂ —OR ³ (R ³ is a hydroxyl protecting group) or —CH ＝ CH—X (X is , Is a halogen). 3. A is —NHCOR ⁸ (R ⁸ is a lower alkyl group or an aromatic group), and B is —C
The compound of formula (I) according to claim 1, wherein H = CH-X, wherein X is halogen. 4. A compound of formula (IV): A method for producing sphingohungin E represented by the formula: a) Formula (Ia): (R ¹ , R ² , R ³ and R ⁶ are as defined in claim 1) to obtain the corresponding amine, followed by acylation to obtain a compound of formula (Ib): Formula 4 (Wherein R ¹ , R ² , R ³ , R ⁶ and R ⁸ are as defined in claim 1), and b) the 6-OH group of the resulting formula (Ib) Is selectively deprotected and then oxidized to give an aldehyde, which is then reacted with a halomethylenating agent to give a compound of formula (Ic): Wherein R ¹ , R ² and R ⁶ are protecting groups for a hydroxyl group, R ⁸ is a lower alkyl group or an aromatic group, and X is a halogen. c) adding the resulting compound of formula (Ic) in the presence of a catalyst,
The following formula: By reacting an alkylboron, alkylzinc or alkyltin compound having an alkyl group represented by the formula (II): Wherein R ¹ , R ² , R ⁶ and R ⁸ are as defined above, d) then removing the ketal group, deprotecting the hydroxyl protecting group and obtaining the formula ( III): (Wherein R ⁸ has the same meaning as described above). E) Ring opening of the lactone ring site and hydrolysis of the N-acyl bond are carried out to obtain a sphingohungine of the formula (IV). How to get E. 5. A compound of formula (Ic): (Wherein, R ¹ , R ² , R ⁶ , R ⁸ and X are as defined in claim 1)
Is added to a compound represented by the following formula in the presence of a catalyst: By reacting an alkylboron, alkylzinc or alkyltin compound having an alkyl group represented by the formula (II): (Wherein, R ¹ , R ² , R ⁶ and R ⁸ are as defined above).