WO2009110655A1

WO2009110655A1 - Novel beta substituted morita-baylis-hillman derivatives

Info

Publication number: WO2009110655A1
Application number: PCT/KR2008/002379
Authority: WO
Inventors: Do Hyun Ryu; Geum Sook Hwang; Kun Hong Kim; Jin Hyun Park; Hwa Jin Kim
Original assignee: Sungkyunkwan University Foundation For Corporate Collaboration; Industry-Academic Cooperation Foundation, Yonsei University; Korea Basic Science Institute; Food Science Co., Ltd.
Priority date: 2008-03-06
Filing date: 2008-04-25
Publication date: 2009-09-11
Also published as: KR20090095791A; KR101512845B1

Abstract

Provided are β-substituted Morita-Baylis-Hillman (MBH) derivatives, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof. The derivatives may be prepared by preparing β-iodo-MBH esters from a variety of carbonyl compounds such as aldehydes and ketones, or imines in the presence of a Lewis acid as a basic backbone, and substituting iodide on a vinyl position with a variety of substituents. In addition, the β-substituted MBH derivatives have an excellent pharmaceutical effect in preventing and treating cancer.

Description

NOVEL BETA SUBSTITUTED MORITA-BAYLIS-HILLMAN

DERIVATIVES

[Technical field]

The present invention relates to novel β-substituted Morita-Baylis-Hillman derivatives, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, and more particularly, to novel β-substituted Morita-Baylis-Hillman derivatives prepared by preparing β-iodo-Morita-Baylis-Hillman esters from various carbonyl compounds such as aldehydes and ketones or imines in the presence of a Lewis acid as a back bone, and substituting iodide located on a vinyl group with various substituents, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, and a method of preparing the same.

[Background Art] β-branched Morita-Baylis-Hillman (MBH) esters are useful precursors for synthesizing various biologically-active compounds and natural substances. However, the esters are difficult to obtain by conventional MBH catalysis. They are generally produced by the reaction of α-methyl acrylate and aldehyde. Another effective method to obtain various β-branched MBH esters is coupling β-iodo-MBH ester with palladium or an organocuprate reaction. These reactions do not change the geometrical configuration of olefin, and thus steroselective synthesis of β-iodo-MBH ester is a key process in selectively obtaining E/Z isomeric β-branched MBH esters. Methods for synthesizing (Z)-β-iodo-MBH esters have been well established using TiCl₄/(n-Bu)₄NI, ZrCl₄/(n-Bu)₄NI, Et₂AlI and MgI₂. These methods use aldehydes as acceptors, and are generally based on multi-element coupling between α, β-acetylene ester and aldehyde. However, there is still no convenient method for synthesizing (E)-β-iodo-

MBH ester and alkyl propiolate in one step.

[Disclosure] [Technical Problem] The present invention is directed to β-substituted Morita-Baylis-Hillman derivatives prepared by using β-indo MBH ester as a back bone, which is prepared by using boron trifluoride diethyl etherate as a Lewis acid promoter and trimethylsilyl iodide as iodide, or using AlI₃, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof. The present invention is also directed to a novel method of preparing β- substituted MBH ester derivatives.

The present invention is also directed to novel β-iodo MBH ester and a method of preparing the same.

The present invention is also directed to a novel pharmaceutical use of the β- substituted MBH ester derivatives. [Technical Solution]

To accomplish said purpose, the present invention provides compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof.

Here, R_{1 a} and R^ are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom. X₁ is OR₄ or NR_5aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl.

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl. R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, and R_3a and R_3b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

Methyl-2-(l-hydroxy-2-oxopropyl)hexadeca-2-enoate is excluded from the compounds of Formula 1. Another aspect of the present invention provides a method of preparing compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, including: (a) preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a Lewis acid selected from AII₃ or trimethylsilyliodide (TMSIyBF₃ . Et₂O and a solvent; (b) preparing a compound of Formula 5 by protecting a substituent X₁ of the compound of Formula 4 with a protective group; (c) preparing a compound of Formula 6 by substituting iodine in the compound of Formula 5; and (d) preparing the compound of Formula 1 by releasing the protective group from the compound of Formula 6.

Here, R_la and R^ are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom.

X₁ is OR₄ or NR_5aR₅b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl. X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl.

R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, R_3a and R_3b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, and Y is a protective group. Another aspect of the present invention provides compounds of Formula 4 or stereoisomers thereof:

Here, R_la and R^are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom.

X₁ is OR₄ or NR_5aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl.

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl.

R₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

Another aspect of the present invention provides a method of preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a Lewis acid selected from AlI₃ or TMSI/BF₃ ^• Et₂O and a solvent:

Here, R_la and R^ are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom. X₁ is OR₄ or NR_5aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl.

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl. R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

Another aspect of the present invention provides an anti-cancer composition containing a β-substituted MBH derivative of Formula 1, a pharmaceutically acceptable salt, a hydrate, a solvate and a stereoisomer thereof as active ingredients.

[Advantageous Effects]

The present invention is effective to synthesize novel β-substituted Morita- Baylis-Hillman derivatives by using β-indo MBH ester as a back bone, which is prepared by using boron trifluoride diethyl etherate as a Lewis acid promoter, trimethylsilyl iodide as iodide, or using AlI₃ as a Lewis acid, and substituting iodide located on a vinyl group with various substituents.

Novel β-substituted Morita-Baylis-Hillman derivatives, which have various physiological activities, may be used as candidates for development of new drugs.

[Description of Drawings]

FIG. 1 is a graph showing cytotoxicity of β-substituted MBH derivatives, SE-I to SE-8 in esophageal cancer cells (HEC4) according to the present invention; FIG. 2 is a graph showing cytotoxicity of β-substituted MBH derivatives, SE-9 to SE- 12 in esophageal cancer cells (HEC4) according to the present invention; and

FIG. 3 is a graph showing cytotoxicity of 10- and 20-fold diluted β-substituted MBH derivatives, SE-3 to SE-6 and SE-Il in esophageal cancer cells (HEC4) according to the present invention.

[Best Mode]

The composition of the present invention is explained in more detail by the following.

The present invention relates to compounds of Formula 1, pharmaceutically acceptable salts, solvates or stereoisomers thereof:

Here, R_{1 a} and R_{1 b}are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom.

X₁ is OR₄ or NR_5aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and Rs_b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl.

R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, R_3a and R_3b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

Methyl-2-(l-hydroxy-2-oxypropyl)hexadeca-2-enoate is excluded from the compounds of Formula 1.

The terms used to define substituents for the compound of Formula 1 are as follows. The term "halo" refers to -F, -Cl, -Br or -I.

The term "alkyl," unless stated otherwise, is C_1-24 linear or branched saturated hydrocarbons. Examples of C^₂₄ alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl.

The term "cycloalkyl," unless stated otherwise, includes C_3-12 non-aromatic, saturated hydrocarbon rings, which include a single ring and a fused ring. Examples of C_3-12 cycloalky include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "alkenyl," unless stated otherwise, includes C_2-24 linear or branched unsaturated hydrocarbons having at least one double bond. Examples of C_2-24 alkenyl include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1- nonene, 2-nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5- decene.

The term "alkynyl," unless stated otherwise, includes C_2-24 linear or branched unsaturated hydrocarbons having at least one triple bond. Examples of C_2-24 alkynyl include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec- butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1- heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyen, 4-octyne, 1-nonyne, 2- nonyne, 3-nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne.

The term "alkoxy," unless stated otherwise, includes C_1-24 alkyls binding to an oxygen atom. Examples of Ci_-24 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.

In the compounds of Formula 1 according to the present invention, alkyl, alkenyl, alkynyl and alkoxy have preferably 1 to 18 carbons, and more preferably 1 to 14 carbons. When the alkyl, alkenyl, alkynyl or alkoxy is used as a substituent for another substituent, it preferably has 1 to 6 carbons, and more preferably 1 to 4 carbons.

The term "aryl," unless stated otherwise, includes 6 to 12-membered aromatic ring compounds. Examples of the compound include, but are not limited to, phenyl, biphenyl, naphthyl and anthracenyl.

The term "acyl," unless stated otherwise, refers to -C(O)R, wherein R is alkyl or aryl. Examples of acyl include, but are not limited to, formyl, acetyl, propionyl or benzoyl.

Each of the alkyl, alkoxy and aryl may be randomly substituted by at least one selected from the group consisting of halo, hydroxy, amino, alkyl and alkoxy. Among the substituents, alkyl and alkoxy may also be randomly substituted by at least one selected from the group consisting of halo, hydroxy and amino.

In the present invention, the term "Lewis acid" refers to a chemical entity capable of accepting a pair of electrons from a Lewis base, which is well known to those skilled in the art.

The term "electron-withdrawing group" is also well known to those skilled in the art, and denotes a functional group withdrawing electrons more strongly than hydrogen atoms. Examples of the electron-withdrawing group include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, and chloride groups. The term "electron- donating group" is a functional group withdrawing electrons less strongly than hydrogen atoms. Examples of the electron-donating group include amino and methoxy groups.

The term "protective group" refers to a temporary substituent effectively protecting a reactive functional group from undesirable chemical modification. Examples of the protective group include: substituted methyl ester, 2-substituted ethyl ester, 2,6-dialkylphenyl ester, substituted benzyl ester, silyl ester, activated ester, amide, hydrazide, boric acid and sulfonic acid for carboxylic acids; methyl ether, substituted methyl ether, substituted ethyl ether, methoxy-substituted benzyl ether, silyl ether, ester, sulfonate, sulfenate, sulf nate, carbonate and carbamate for alcohols; carbamate, substituted ethyl carbamate and various carbamates or amides capable of being eliminated by 1,6-elimination, β elimination or photoelimination for amines; and acetal and ketal for aldehydes and ketones. Protective group chemistry is further described in the literature: [Greene, T. W.; Wuts, P.G.M Protective Groups in Organic Synthesis, 2^nd ed.; Wiley: New York, 1991].

The term "substituted" used in the present invention is considered to include all available substituents for organic compounds. In a broad aspect, available substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of organic compounds. Examples of the substituents include those mentioned above. The available substituents may be at least one identical or different groups with respect to suitable organic compounds. To accomplish the object of the present invention, a heteroatom such as nitrogen may have a random substituent and/or a hydrogen substituent available for the organic compound described above, which satisfies an atomic value of the heteroatom.

A more preferable definition of the substituents of the compound of Formula 1 according to the present invention is as follows.

R_la and R^ may be independently hydrogen, C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-12 aryl, in which at least one carbon atom of the C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_1-14 alkoxy may have a double bond with an oxygen atom, and preferably the C_6-I2 aryl may be substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted C_1-6 alkyl, halogen, cyano, hydroxy, C_1-6 alkoxy and C_6-12 aryl.

Preferably, R_la and R^ are independently hydrogen, acetyl, C_1-8 alkyl, C_2-8 alkenyl or C_6-12 aryl, wherein the C_6-12 aryl may be substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted Ci-₄ alkyl, halogen, cyano, C_1-4 alkoxy and C_6-12 aryl.

Preferably, X₁ may be OR₄ or NRs_aRs_b, wherein R₄ may be hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl, C(O)R₇, or C_1-6 alkyl-substituted or unsubstituted silicon.

R_5a and R₅b may be independently hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl, C_1-14 acyl, C_1-14 alkylsulfonyl or C_6-I2 arylsulfonyl, and R₇ may be C_1-I4 alkyl or C_6-12 aryl.

More preferably, X₁ is halogen, hydroxy, formyl, acetyl, propionyl, benzoyl, C_1- ₈ alkoxy, C_6-12 aryloxy, C_1-4 alkyl-substituted or unsubstituted siloxy or tosylamino.

X₂ may be oxygen or NR₆, wherein R₆ is preferably hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_6-12 aryl, and more preferably oxygen.

R₂ may be preferably hydrogen, halo, hydroxy, C_1-14 alkyl, C_3-12 cycloalkyl, C_2- i₄ alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-12 aryl, and more preferably C_1-8 alkyl or C_1- s alkoxy.

R_3a and R₃₁, may be preferably independently hydrogen, halo, hydroxy, C_1-18 alkyl, C_3-12 cycloalkyl, C_2-18 alkenyl, C_2-18 alkynyl, C_1-18 alkoxy or C₆.₁₂ aryl, and more preferably hydrogen or C_1-14 alkyl. The most preferable compounds of those of Formula 1 include, but are not limited to, at least one selected from the group consisting of (Z)-methyl-2- (hydroxy(phenyl)methyl)hexateca-2-enoate (SE-4); (E)-methyl-2-

(hydroxy(phenyl)methyl)hexateca-2-enoate (SE-5); (E)-ethyl-2-((4- fluorophenyl)(hydroxy)methyl)hexateca-2-enoate (SE-6); (Z)-methyl-2-(l -hydroxy-2- oxopropyl)hexateca-2-enoate (SE-7); (E)-ethyl-2-(4-

(thrifluoro)methylphenyl)(hydroxy)methyl)hexateca-2-enoate (SE-8) ; (Z)-methyl-2- (hydroxy(phenyl)methyl)undeca-2-enoate (SE-9); (Z)-methyl-2-

(hydroxy(phenyl)methyl)octa-2-enoate(SE-l 0); (Z)-methyl-2-

(hydroxy(phenyl)methyl)pentadeca-2-enoate (SE-Il); and (Z)-methyl-2- (acetoxy(phenyl)methyl)pentadeca-2-enoate (SE- 12) .

The compound of Formula 1 in the present invention may be prepared in the form of a pharmaceutically acceptable salt or solvate, which may be performed using an inorganic or organic acid or a solvent generally used in the art.

For preparation of the pharmaceutically acceptable salt for the compound of Formula 1 in the present invention, examples of available inorganic or organic acids include, but are not limited to, inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, phosphoric acid or nitric acid, and organic acids such as citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, gluconic acid, succinic acid, formic acid, trifiuoroacetic acid, oxalic acid, fumaric acid, methane sulfonic acid, benzene sulfonic acid, paratoluene sulfonic acid or camphosulfonic acid.

For preparation of the solvate, any pharmaceutically acceptable solvents, which are generally used in the art, may be used. Examples of the solvents may include water and ether.

The present invention also relates to a method of preparing the compound of Formula 1, including: (a) preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a Lewis acid selected from AlI₃ or TMSI/BF₃ ^• Et₂O, and a solvent, (b) preparing a compound of Formula 5 by protecting substituent group Xl of the compound of Formula 4 with a protective group, (c) preparing a compound of Formula 6 by substituting iodine of the compound of Formula 5, and (d) preparing a compound of Formula 1 by releasing the protective group from the compound of Formula 6.

Here, R_{1 a} and R_{1 b} are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom.

R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, and R_3a and R_3b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

Y is a protective group.

Preferable examples of R_la, R₁^ Xi, X₂, R-, R3a and R₃b are the same as mentioned above.

Hereinafter, each step of the method of preparing the compound of Formula 1 according to the present invention will be described in more detail. according to the present invention will be described in more detail.

In step (a) of the preparation method according to the present invention, the compound of Formula 4 is prepared by reacting the compound of Formula 2 with the compound of Formula 3 in the presence of a Lewis acid and a solvent.

Depending on the kind of the Lewis acid used in step (a), the compound of Formula 4 having (E) or (Z) selectivity may be prepared.

For example, as shown in Reaction Scheme 1, β-iodo MBH ester having (E) selectivity represented by Formula 4 according to the present invention may be prepared by reacting ethyl propiolate with aldehyde in a dichloromethane solvent in the presence of a Lewis acid such as BF₃ and TMSI. [Reaction Scheme 1]

Alternatively, as shown in Reaction Scheme 2, β-iodo MBH ester having (Z) selectivity represented by Formula 4 according to the present invention may be prepared by reacting ethyl propiolate with aldehyde (or ketone) in a dichloromethane solvent in the presence of a Lewis acid such as AlI₃. [Reaction Scheme 2]

The solvent used in the reaction is not particularly limited, and thus may be a conventional organic solvent such as dichloromethane, THF or acetone nitrile. However, in consideration of a yield and (E) or (Z) selectivity, dichloromethane is preferable. It is preferred that step (a) may be performed at -90 to -20 ^°C . More specifically, when AlI₃ is used as the Lewis acid, the reaction is preferably performed at -60 to -90 ^°C, and when BF₃ is used as the Lewis acid, the reaction is preferably performed at -20 to -60 ^°C in terms of the yield and the (E) or (Z) selectivity.

In addition, it is preferred that a content of BF₃ ^• Et₂O added in step (a) may be 0.1 to 2 equivalent weight of the compound of Formula 1. When the equivalent weight is less than 0.1, the yield is decreased, whereas when the equivalent weight is more than 2, (E) selectivity is at risk of being decreased. Moreover, a content of AlI₃ added in step (a) may be 0.1 to 4 equivalent weight of the compound of Formula 1. When the equivalent weight is less than 0.1 or more than 4, the yield is at risk of being decreased. In step (b) of the preparation method according to the present invention, the compound of Formula 5 is prepared by protecting substituent group Xi of the compound of Formula 4 with a protective group. This step may be performed by any conventional method used in organic synthesis, for example, by preparing the compound of Formula 4 in the presence of TES-Cl and imidazole providing a protective group using a DMF solvent.

In step (c) of the preparation method according to the present invention, the compound of Formula 6 is prepared by substituting iodine of the compound of Formula 5. The substitution of β-iodo of the compound of Formula 5 is also performed by any known method used in organic synthesis, for example, by adding a Grignard reagent to substitute β-iodo with an alkyl substituent. More specifically, the compound of Formula 5 may react with alkyl magnesium bromide and LiCuBr₂ in the presence of a THF solvent, resulting in preparation of the alkyl-substituted compound of Formula 6.

In step (d) of the preparation method according to the present invention, the compound of Formula 1 is prepared by releasing the protective group from the compound of Formula 6. The release of the protective group may also be performed by any known method used in organic synthesis, for example, by reacting the compound of Formula 6 with Bu₄NF in the presence of a THF solvent.

An example of the preparation method according to the present invention is illustrated in the following Reaction Scheme 3:

[Reaction Scheme 3]

Further, using the β-iodo MBH ester derivative of the present invention as a precursor, a compound having the same diffraction characteristic as natural secokotomolide A isolated from Taiwanese Cinnamomum kotoense may be synthesized (see Reaction Scheme 4). It is reported that secokotomolide A relates to apotositic DNA damage in Human HeLa cell lines, resulting in significant induction of apoptosis of the cells. Secobutanolide including secokotomolide has an (E)-β-long chain branched MBH methyl ester structure. The β-iodo MBH ester derivative used for synthesis of secokotomolide A and its derivatives is β-iodo MBH methyl ester.

Iodine-substituted MBH ester (1) may be prepared by reacting methylpropiolate with TMS-I in a dichloromethane solvent in the presence of a Lewis aid such as BF₃ from methacrolein as a starting material.

Secondary alcohol-protected MBH ester (2) may be obtained with high yield by reacting the MBH ester (1) with TES-Cl in the presence of a DMF solvent and an imidazole reagent at room temperature. In the alcohol-protected MBH ester (2) synthesized by the above method, iodine may be substituted by a tridecane alkyl chain using the Grignard reagent. In the presence of a THF solvent, the alcohol-protected MBH ester (2) reacts with tridecane magnesium bromide and LiCuBr₂, resulting in preparation of a tridecane-substituted MBH ester (3). When the starting material, the tridecane-substituted compound (3), reacts with an ozone gas in a dichloromethane solvent at low temperature, an alcohol-protected secokotomolide A (4) may be prepared.

The alcohol-protected secokotomolide A (4) is mixed with Bu₄NF in a THF solvent at low temperature, resulting in obtaining secokotomolide A (5) with high yield. [Reaction Scheme 4]

The present invention also relates to a novel compound of Formula 4, or its stereoisomer, which is an essential intermediate for preparing the compound of Formula 1:

[Formula 4]

R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl.

The substituents of the compound of Formula 4 according to the present invention are more preferably defined as follows.

Preferably, R_la and R^ may be independently hydrogen, C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-12 aryl, wherein at least one carbon of the C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_1-14 alkoxy may be capable of having a double bond with an oxygen atom, and the C_6-12 aryl may be substituted by at least one substituent selected from the group consisting of halogen- substituted or unsubstituted C_1-6 alkyl, halogen, cyano, hydroxy, C_1-6 alkoxy and C_6-12 aryl.

More preferably, R_la and Ru, are independently hydrogen, acetyl, C_1-8 alkyl, C_2- ₈ alkenyl or C_6-12 aryl, wherein the C_6-12 aryl is substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted C_1-4 alkyl, halogen, cyano, C_1-4 alkoxy and C_6-12 aryl.

X₁ may be OR₄ or NR_5aR_5b, wherein R₄ may be hydrogen, CM₄ alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 ar yl, C(O)R₇, or C_1-6 alk yl-substituted or unsubstituted silicon, and R_5a and R_5b may be independently hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl, C_1-14 acyl, C_1-14 alkyl sulfonyl, or C_6-12 aryl sulfonyl. R₇ may be preferably Ci_-14 alkyl or Ce-n aryl- Preferably, Xi is halogen, formyl, acetyl, propionyl, benzoyl, hydroxy, Ci_-8 alkoxy, C_6-I2 aryloxy, Ci_-4 alkyl-substituted or unsubstituted siloxy, or tosylamino.

X₂ may be oxygen or NR₆, wherein R₆ may be hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_6-12 aryl, and preferably, oxygen.

R₂ may be hydrogen, halo, hydroxyl, C_1-I4 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-12 aryl, and preferably Ci_-8 alkyl or C_1-8 alkoxy.

The compound of Formula 4 may be, but is not limited to, one or more selected from the group consisting of (E)-ethyl-2-(hydroxy(phenyl)methyl)-3-iodoacrylate; (E)- methyl-2-(hydroxy(phenyl)methyl)-3-iodoacrylate; (E)-ethyl-2-(hydroxy(o- tolyl)methyl)-3-iodoacrylate; (E)-methyl-2-(hydroxy(p-tolyl)methyl)-3-iodoacrylate; (E)-ethyl-2-(hydroxy(4-biphenyl)methyl)-3-iodoacrylate; (E)-ethyl-2-((4- fluorophenyl)(hydroxy)methyl)-3-iodoacrylate; (E)-ethyl-2-((4- chlorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- bromophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- cyanophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4-

(trifluoromethyl)phenyl)(hydroxy)methyl)-3-iodoacrylate; (E)-ethyl-3-hydroxy-2-

(iodomethylene)nonanoate; (E)-ethyl-(4-methyl-3-hydroxy-2-iodomethylene)- pentanoate; (Z)-methyl-2-(hydroxy(phenyl)methyl)-3 -iodoacrylate; (Z)-ethyl-2- (hydroxy(phenyl)methyl)-3-iodoacrylate; (Z)-ethyl-2-((4- trifluoromethylphenyl(hydroxy)methyl)-3-iodoacrylate; (Z)-ethyl-2-(hydroxy(4- biphenyl)methyl)-3-iodoacrylate; (Z)-ethyl-2-(hydroxy(p-tolyl)methyl)-3-iodoacrylate; (Z)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3-iodoacrylate; (Z)-ethyl-2-((4- chlorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- bromophenyl)(hydroxy)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- cyanophenyl)(hydroxy)methyl)-3-iodoacrylate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)- 4,4-dimethylpentanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-4-methylpentanoate; (Z)-methyl-3-hydroxy-2-(iodomethylene)-4-methylpentanoate; (Z)-ethyl-3-hydroxy-2- (iodomethylene)nonanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3-phenylbutanoate; (Z)-ethyl-3-(4-trifluoromethylphenyl)-3-hydroxy-2-(iodomethylene)butanoate; (Z)- ethyl-3 -(4-methoxyphenyl)-3 -hydroxy-2-(iodomethylene)butanoate; (Z)-ethyl-3 - hydroxy-2-(iodomethylene)-3-p-tolylbutanoate; (Z)-ethyl-3-hydroxy-2-

(iodomethylene)-3 -o-tolylbutanoate; (Z)-ethyl-3 -hydroxy-2-(iodomethylene)-3 - methylbutanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3,4,4-trimethylpentanoate; and (Z)-ethyl-(3 -ethy 1-3 -hydroxy-3 -phenyl-2-iodomethylene)-propionate .

The present invention also relates to a method of preparing the compound of Formula 4 in which a compound of Formula 2 reacts with a compound of Formula 3 in the presence of a Lewis acid selected from AlI₃ or TMSIZBF₃-Et₂O and a solvent:

X₁ is OR₄ or NR₅₃R_5I,, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl. X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl.

R ₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl. T he preferable examples of the substitutents R_la, Ru₃, Xi, X₂ and R₂ are the same as mentioned above.

The present invention also relates to a pharmaceutical composition containing the compound of Formula 1, pharmaceutically acceptable salt, hydrate, solvate and stereoisomer as active ingredients.

The compound according to the present invention may be widely used as an anticancer or antiviral agent, and may also be effective in treating infectious diseases resulting from bacteria parasitic to cells such as tuberculous bacilli or Hansen's bacilli.

Particularly, the pharmaceutical composition of the present invention may be effective in treating various diseases relating to tumors, including a variety of solid tumors such as lung cancer, liver cancer, gastric cancer, colon cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, thyroid cancer and melanoma and a variety of blood cancers such as leukemia.

Carriers used in the composition according to the present invention include, but are not limited to, any carriers and vehicles generally used in medical and pharmaceutical fields, for example, ion exchange resin, alumina, aluminum stearate, recithin, serum protein (e.g., human serum albumin), buffers (e.g., various phosphorates, glycin, sorbic acid, potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids), water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and a zinc salt), colloidal silica, magnesium trisilicate, polyvinylpyrolidone, a cellulose substrate, polyethylene glycol, sodium carboxymethylcellulose, poylarylate, wax, polyethylene glycol and lanolin. The composition of the present invention may further include a lubricant, a wetting agent, an emulsifier, a suspension agent or a preservative, in addition to the above components.

The pharmaceutical composition may be formulated for oral administration or parenteral administration such as an injection.

Examples of the formulations for oral administration may include tablets, troches, lozenges, aqueous or oily suspensions, prepared powder or granules, emulsions, hard or soft capsules, syrups and elixirs. For formulation of the tablets and capsules, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, an excipient such as dicalciumphosphate, a disintegrating agent such as corn starch or sweet potato starch, or a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax may be included. For formulation of the capsules, a liquid carrier such as deep fat may be further included, in addition to the above components.

Examples of the formulation for oral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions and freeze-dried products. The non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethylolate.

In one aspect, the composition according to the present invention may be prepared in the form of an aqueous solution for parenteral administration. Preferably, it may be prepared in the form of a Hank's solution, a Ringer's solution or a buffer such as a physically-buffered salt. For aqueous injectable suspension, a substrate capable of increasing viscosity of the suspension such as sorbitol or dextran may be added.

In another aspect of the present invention, the composition may be formulated in the form of a sterile injection of a water or fat-soluble suspension. The suspension may be formulated using a suitable dispersing agent or wetting agent (e.g., twin 80) and a suspension agent using a well known method in the art. The sterile injectable formulation may be a nontoxic and parenterally-available diluting agent or a sterile injection solution or suspension in a solvent (e.g., a solution in 1,3-butanediol). A preferable vehicle and solvent may be mannitol, water, a Ringer's solution or isotonic sodium chloride. In addition, sterile non- volatile oil may be generally used as a solvent or a suspension medium. To this end, any less irradiant non- volatile oil such as synthetic mono or diglyceride can be used.

Now, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited by the examples presented below.

In the following examples, all reactions were conducted in vacuum-frame dry glassware in a dry argon atmosphere. Dichloromethane was distilled from calcium hydride. THF was distilled from sodium-benzophenone before use. DMF was distilled from MgSO₄ and then dried. Thin layer chromatography (TLC) was performed on the Merck silica gel 60 F254. Column chromatography was performed using Yamazen MPLC. ¹H and ¹³C NMR spectrums were analyzed using Varian at 300 and 75 MHz, respectively. Migration of a chemical based on an inner control, tetramethylsilane (CHCl₃: delta 7.26 ppm) having solvent resonance, was recorded by ppm. The following data were shown by chemical migration, multiplicities (s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublet, qd=quartet of doublet, br=broad and m=multiplet), coupling constant (Hz) and integration. To get IR spectrum, the Nicolet 380 was used. LRMS data was obtained by the Varian GC/MS system.

[Mode for Invention]

I. Preparation of β-iodo MBH ester having (E) selectivity

<Example 1> (E)-ethyl-2-(hydroxy(phenyl)rnethyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and benzaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. TLC R_f 0.35 (Dichloromethane) FT-IR 3504, 3063, 2982, 1697, 1589, 1449, 1309, 1224, 698 cm^"1 ¹H NMR (500 MHz, CDCl₃) δ 1.23 (t, J=7.2Hz, 3H), 4.09-4.22 (m, 2H), 5.82 (s, IH), 7.25-7.55 (m, 5H), 8.11 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.25, 62.04, 76.58, 101.21, 125.38, 127.86, 128.73, 141.43, 143.25, 163.37

LRMS calcd for C₁₂H)₃IO₃: 332

<Example 2> (E)-ethyl-2-(hydroxy(o-tolyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and o-tolualdehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 91%. TLC Rf 0.35 (Dichloromethane) FT-IR 3500, 3072, 2966, 1699, 1582, 1016, 755 cm^"1 ¹H NMR (500 MHz, CDCl₃) δ 1.28 (t, J=10.5Hz, 3H), 2.46 (s, 3H), 3.95 (d, J=I lHz, IH), 4.27-4.21 (m, 2H), 5.78 (d, J=I lHz, IH), 7.22-7.14 (m, 4H), 8.05 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.29, 20,16, 62.02, 75.20, 100.61, 126.16, 126.34, 128.63, 131.27, 137.28, 138.74, 142.84, 164.23 LRMS calcd for Ci₃H₁₅IO₃: 346

<Example 3> (E)-ethyl-2-(hydroxy(p-tolyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and p-tolualdehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 91%. TLC Rf 035 (Dichloromethane) FT-IR 3499, 1688, 1588, 1307, 1222, 1039, 809, 490 cm^'1 ¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, J=7Hz, 3H), 2.33 (s, 3H), 4.20-4.14 (m,2H), 5.79 (d, J=I IHz, IH), 7.16 (d, J=7.5Hz, 2H), 7.32 (d, 8Hz, 2H) 8.09 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.21, 21.33, 61.93, 76.51, 100.84, 125.29, 129.38, 137.48, 138.42, 143.26, 163.34 LRMS calcd for C₁₃H₁₅IO₃: 346

<Example 4> (E)-ethy l-2-(hydroxy(4-biphenyl)methyl)-3 -iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and biphenylaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 85%. TLC Rf 035 (Dichloromethane) FT-IR 3500, 2980, 1695, 1486, 1308, 1222, 1040, 858, 759 cm^"1 ¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.5Hz, 3H), 4.15-4.25 (m, 2H), 4.30 (d, J=I lHz, IH), 5.89 (d, J=I lHz, IH), 7.34-7.60 (m, 9H), 8.16 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.24, 62.05, 76.49, 101.26, 125.83, 127.31, 127.46, 127.55, 129.00, 140.47, 140.71, 141.00, 143.22, 163.36 LRMS calcd for C₁₈H₁₇IO₃: 408

<Example 5> (E)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C, BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and 4-fluorobenzaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83%.

TLC R_f 0.35 (Dichloromethane) FT-IR 3500, 2983, 1732, 1697, 1507, 1312, 1222, 1042, 494 cm^"1

¹H NMR (500 MHz, CDCl₃) δ 1.25 (t, J=6.5Hz, 3H), 4.13-4.22 (m, 2H), 4.24 (d, J=I lHz, IH), 5.78 (d, J=I lHz, IH), 7.02 (t, J=9Hz, 2H), 7.40 (dd, J=8.75, 5Hz, 2H), 8.11 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.30, 62.17, 76.24, 101.36, 115.62 (d, J=21.25Hz), 127.24 (d, J=8.25Hz), 137.27, 143.11, 161.60, 163.40

LRMS calcd for C₁₂H₁₂FIO₃: 350

<Example 6> (E)-ethyl-2-((4-chlorophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and 4-chlorobenzaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 84%. TLC R_f 0.35 (Dichloromethane)

FT-IR 3486, 2091, 1689, 1589, 1308, 1221, 1086, 806, 500 cm^"1 1H NMR (500 MHz, CDCl₃) δ 1.26 (t, J=7.5Hz, 3H), 4.13-4.21 (m, 2H), 4.22 (d, J=I 1.5Hz, IH), 5.78 (d, J=I 1.5Hz, IH), 7.31-7.38 (m, 4H), 8.13 (s, IH) 1³C NMR (125 MHz, CDCl₃) δ 14.30, 62.22, 76.21, 101.63, 126.92, 128.93,

133.74, 140.08, 142.97, 163.33

LRMS calcd for C₁₂H₁₂ClIO₃: 366

<Example 7> (E)-ethyl-2-((4-bromophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and 4-bromobenzaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 86%. TLC R_f 0.35 (Dichloromethane)

FT-IR 3492, 1696, 1588, 1485, 1309, 1223, 1008, 724, 503 cm^"1

¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, J=7.5Hz, 3H), 4.15-4.20 (m, 2H), 4.23 (d, J=I 1.5Hz. IH), 5.76 (d, J=I 1.5Hz, IH), 7.29-7.31 (m, 2H), 7.46-7.48 (m, 2H), 8.13 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.31, 62.23, 76.24, 101.71, 121.89, 127.27, 131.88, 140.62, 142.91, 163.32

LRMS calcd for C₁₂H₁₂BrIO₃: 410

<Example 8> (E)-ethyl-2-((4-cyanophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C,

BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and 4-cyanobenzaldehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5 M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 77%.

TLC Rf 0.35 (Dichloromethane)

FT-IR 3484, 2984, 1699, 1588, 1326, 1121, 1067, 861, 820 cm⁴

¹H NMR (500 MHz, CDCl₃) δ 1.24 (t, J=7Hz, 3H), 4.13-4.19 (m, 2H), 4.25 (d, J=I IHz, IH), 5.84 (d, J=I 1.5Hz, IH), 7.54 (d, J=8Hz, 2H), 7.64 (d, J=8Hz, 2H), 8.20 (d, J=IHz, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.24, 62.35, 76.10, 102.72, 111.67, 119.06, 126.14, 132.58, 142.50, 146.92, 163.08

LRMS calcd for C₁₃H₁₂NIO₃: 357

<Example 9> (E)-ethyl-2-((4-trifluoromethyl)phenyl)(hydroxy)methyl)-3 - iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C, BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and α,α,α-trifluoro-ρ- tolualdehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 76%.

TLC R_f 0.35 (Dichloromethane) FT-IR 3484, 2984, 1699, 1588, 1326, 1121, 1067, 861, 820 an ¹

¹H NMR (500 MHz, CDCl₃) δ 1.25 (t, J=7Hz, 3H), 4.13-4.22 (m, 2H), 4.28 (d, J=12Hz, IH), 5.86 (d, J=12Hz, IH), 7.55 (d, J=8.5Hz, 2H), 7.61 (d, J=8Hz, 2H), 8.18 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.30, 62.33, 76.32, 102.19, 123.40, 125.75, 125.82, 130.18 (q, J=32.4Hz), 142.86, 145.59, 163.28

LRMS calcd for C₁₃H₁₂F₃IO₃: 400

<Example 10> (E)-ethyl-3-hydroxy-2-(iodornethylene)nonanoate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -25 ^°C , BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.573 ml, 4.0 mmol) and heptaaldehyde (1.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 63%.

TLC R_f 0.35 (Dichloromethane) FT-IR 3523, 2954, 2928, 1722, 1657, 1572, 1323, 1226, 1017, 911, 733, 506 cm^'1

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6.6Hz, 3H), 1.30-1.81 (m, 13H), 3.42 (d, J=9Hz, IH), 4.24 (qd, J=6.9, 1.2Hz, 2H), 4.58 (d, J=9Hz, IH), 7.86 (s, IH)

¹³C NMR (75 MHz, CDCl₃) δ 14.35, 22.85, 25.94, 29.30, 31.98, 36.54, 61.77, 76.06, 99.16, 118.50, 143.67, 163.41

LRMS calcd for C₁₂H_2IlO₃: 340

<Example 11> (E)-ethyl-(4-methyl-3-hydroxy-2-iodomethylene)- pentanoate

A 50 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.40 ml of ethyl propiolate (3.90 mmol) and 10.0 ml of dichloromethane were added. After reducing the temperature to -45 ^"C, BF₃Et₂O (0.43 ml, 3.6 mmol), TMS-I (1.0 ml, 7.2 mmol) and methacrolein (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 60%.

TLC R_f 0.35 (Dichloromethane)

FT-IR 3477, 3075, 2924, 1698, 1587, 1450, 1371, 1309, 1218, 904 cm^'1

¹H NMR (300 MHz, CDCl₃) δ 1.31 (t, J=7.2Hz, 3H), 1.79 (s, 3H), 3.96 (d, J=I 1.4Hz, IH), 4.24 (qd, J=7.2, 1.8Hz, 2H), 4.95 (q, J=I .5Hz, IH), 5.04 (q, J=0.9Hz, IH), 8.04 (s, IH)

¹³C NMR (75 MHz, CDCl₃) δ 14.39, 19.92, 62.04, 78.21, 101.38, 111.25, 144.62, 147.53, 163.52

LRMS calcd for C₉H₁₃IO₃: 296

II. Preparation of MBH ester having (Z) selectivity

<Example 12> (Z)-ethyl-2-(hydroxy(phenyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to

-78 °C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 88%. Spectrum data of the product was the same as reported previously.

TLC R_f 0.23 (Dichloromethane)

<Example 13> (Z)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^"C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of α,α,α-trifluoro-p-tolualdehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 88%. Spectrum data of the product was the same as reported previously. TLC R_f 0.23 (Dichloromethane) <Example 14> (Z)-ethyl-2-(hydroxy(4-biphenyl)methyl)-3 -iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-biphenylaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 85%. Spectrum data of the product was the same as reported previously. TLC Rf 0.23 (Dichloromethane)

<Example 15> (Z)-ethyl-2-(hydroxy(p-tolyl)methyl)-3 -iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of p-tolualdehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 82%. Spectrum data of the product was the same as reported previously. TLC Rf 0.23 (Dichloromethane)

<Example 16> (Z)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-fluorobenzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 78%. Spectrum data of the product was the same as reported previously. TLC R_f 0.23 (Dichloromethane)

<Example 17> (Z)-ethyl-2-((4-chlorophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-chlorobenzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 88%. Spectrum data of the product was the same as reported previously.

TLC R_f 0.23 (Dichloromethane)

<Example 18> (Z)-ethyl-2-((4-bromophenyl)(hydroxy)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-bromobenzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 82%. Spectrum data of the product was the same as reported previously. TLC R_f 0.23 (Dichloromethane)

<Example 19> (Z)-ethyl-2-((4-cyanophenyl)(hydroxy)methyl)-3-iodoacrylate

-78 °C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-cyanobenzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a white solid of a desired compound was obtained with a yield of 74%. Spectrum data of the product was the same as reported previously.

TLC R_f 0.23 (Dichloromethane)

<Example 20> (Z)-ethyl-3-hydroxy-2-(iodomethylene)-4,4-dimethylpentanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of pivaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously. TLC R_f 0.23 (Dichloromethane)

<Example 21 > (Z)-ethyl-3 -hydroxy-2-(iodomethylene)-4-methylpentanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of isobutylaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously. TLC Rf 0.23 (Dichloromethane)

<Example 22> (Z)-ethyl-3-hydroxy-2-(iodomethylene)nonanoate

-78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of heptaaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using

Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 67%. Spectrum data of the product was the same as reported previously.

TLC Rf 0.23 (Dichloromethane)

<Example 23> (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3-phenylbutanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of acetophenone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 88%. Spectrum data of the product was the same as reported previously.

TLC Rf 0.23 (Dichloromethane)

<Example 24> (Z)-ethyl-3-(4-trifluoromethylphenyl)-3-hydroxy-2-

(iodomethylene)butanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-trifluoromethylacetophenon were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90%. TLC Rf 0.23 (Dichloromethane)

FT-IR 3476, 2983, 1718, 1327, 1124, 845 cm^'1

¹H NMR (500 MHz, CDCl₃) δ 7.60 (2 H, d, J = 8.0 Hz), 7.54 (2 H, d, J = 8.5 Hz), 7.24 (1 H, s), 4.17 (2 H, m), 4.08 (1 H, br s), 1.70 (3 H, s), 1.16 (3 H, t, J= 7.5 Hz) ¹³C NMR (125 MHz, CDCl₃) δ 167.74, 149.20, 148.92, 129.95 (q, J = 129.5 Hz), 125.71, 125.53, 124.26 (q, J= 540.8 Hz), 84.81, 77.89, 62.05, 28.94, 13.98 LRMS calcd for C₁₄H₁₄F₃IO₃: 414

<Example 25> (Z)-ethyl-3-(4-methoxyphenyl)-3-hydroxy-2-

(iodomethylene)butanoate

-78 ^"C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-methoxyacetophenone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90%. TLC R_f 0.23 (Dichloromethane) FT-IR 3464, 2920, 1719, 1509, 1027, 505 crn ¹

¹H NMR (500 MHz, CDCl₃) δ 7.22 (2 H, d, J= 8.7 Hz), 7.03 (1 H, s), 6.86 (2 H, d, J = 8.7 Hz), 4.12 (2 H, q, J= 6.9 Hz), 3.66 (1 H, s), 1.70 (3 H, s), 1.53 (3 H, s) 1.19 (3 H, t, J= 7.2 Hz) ¹³C NMR (125 MHz, CDCl₃) δ 168.04, 159.13, 150.59, 136.97, 130.58, 113.82, 83.26, 77.80, 61.78, 55.47, 28.94, 14.09 LRMS calcd for C₁₄H₁₇IO₄: 376

<Example 26> (Z)-ethyl-3 -hydroxy-2-(iodomethylene)-3 -p-tolylbutanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 4-methylacetophenone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 84%. TLC R_f 0.23 (Dichloromethane) FT-IR 3490, 2980, 1722, 1298, 1184, 1028, 820 cm^"1 1H NMR (500 MHz, CDCl₃) δ 7.29 (2 H, d, J = 8.4 Hz), 7.13 (2 H, d, J= 8.4

Hz), 7.04 (1 H, s), 4.16 (2 H, m), 3.74 (1 H, s), 2.33 (3 H, s), 1.69 (3 H, s), 1.18 (3 H, t, J= 7.2 Hz) ¹³C NMR (125 MHz, CDCl₃) δ 167.95, 150.39, 141.96, 137.38, 129.19, 125.26, 83.48, 77.96, 61.76, 28.91, 21.21, 14.04 LRMS calcd for Ci₄H₁₇IO₃: 360

<Example 27> (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3-o-tolylbutanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 2-methylacetophenone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 80%. TLC R_f 0.23 (Dichloromethane) FT-IR 3498, 2980, 1722, 1295, 1182, 1027, 483 cm^"1 1H NMR (500 MHz, CDCl₃) δ 7.52 (1 H, m), 7.17 (3 H, m), 6.82 (1 H, s), 4.15

(2 H, m), 3.39 (1 H, br s), 2.39 (3 H, s), 1.82 (3 H, s), 1.14 (3 H, t, J= 7.2 Hz)

¹³C NMR (125 MHz, CDCl₃) δ 167.78, 150.96, 141.63, 136.15, 132.49, 128.82, 126.05, 125.96, 81.78, 78.22, 61.52, 28.69, 21.95, 14.12 LRMS calcd for C₁₄H₁₇IO₃: 360

<Example 28> (Z)-ethyl-3-hydoxy-2-(iodomethylene)-3-methylbutanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of acetone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 72%. Spectrum data of the product was the same as reported previously.

TLC R_f 0.23 (Dichloromethane)

<Example 29> (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3,4,4- trimethylpentanoate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of 3,3-dimethylbutane-2-one were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 78%.

TLC Rf 0.23 (Dichloromethane)

FT-IR 3520, 2958, 1723, 1289, 1180, 503 cnf¹ 1H NMR (500 MHz, CDCl₃) δ 6.79 (1 H, s), 4.30 (2 H, m), 2.44 (1 H, br s) 1.45

(1 H, s), 1.37 (3 H, t, J= 7.0 Hz), 0.98 (9 H, s)

¹³C NMR (125 MHz, CDCl₃) δ 169.14, 152.41, 81.92, 81.08, 61.68, 38.98, 25.81, 24.71, 14.10

LRMS calcd for C₁₁Hi₉IO₃: 326

<Example 30> (Z)-ethy l-(3 -ethyl-3 -hydroxy- 3 -phenyl-2-iodomethylene)- propionate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C , followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of propiophenone were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83%.

TLC R_f 0.23 (Dichloromethane)

FT-IR 3489, 2978, 1721, 1299, 1185, 701 cm^"1 1H NMR (500 MHz, CDCl₃) δ 7.33 (5 H, m), 7.00 (1 H, s), 4.14 (2 H, q, J= 7.2

Hz), 3.58 (1 H, s), 2.06 (2 H, m), 1.14 (3 H, t, J- 5.8 Hz), 0.82 (3 H, t, J= 7.2 Hz)

¹³C NMR (125 MHz, CDCl₃) δ 168.20, 150.37, 142.72, 128.89, 127.62, 126.14, 83.15, 80.31, 61.77, 32.70, 14.04, 7.95

LRMS calcd for Ci₄H₁₇IO₃: 360

III. Preparation of β-iodoaza-MBH ester having (Z) selectivity

<Example 31> (Z)-ethyl-3-iodo-2-(phenyl(tosylamino)methyl)acrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of ethyl propiolate and 0.20 mmol of (Z)-phenyl-N-tosylmethane imine were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 42%.

TLC R_f 0.36 (Dichloromethane)

¹H NMR (300 MHz, CDCl₃) δ 7.68 (2 H, d, J = 8.4 Hz) 7.16, 7.36 (7 H, m), 7.02 (1 H, s), 5.74 (1 H, d, J = 9.3 Hz), 5.38 (1 H, d, J = 9.3 Hz), 4.05, 4.13 (2 H, m), 2.43 (3 H, s), 1.10 (3 H, t, J= 7.2 Hz)

LRMS calcd for C₁₉H₂₀INO₄S: 485

IV. Preparation of secokotomolide A <Example 32> Preparation of secokotomolide A

Preparation Example 1> Preparation of (E)-ethyl-3-hydroxy-2- (iodomethylene)-4-methylpent-4-eoate ( 1 )

A 50 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.68 ml of methyl propiolate (7.50 mmol) and 15.0 ml of dichloromethane were added. After reducing the temperature to -25 ^°C,

BF₃-Et₂O (0.43 ml, 3.6 mmol), TMS-I (1.7 ml, 12 mmol) and methacrolein (0.25 ml,

3.0 mmol) were sequentially added and the mixture was stirred for one day. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and water was added. 5 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 60% (583 mg). TLC R_f 0.35 (Dichloromethane)

Preparation Example 2> Preparation of (E)-ethyl-3-triethylsiloxy-2- (iodomethylene)-4-methylpent-4-eoate (2)

3.0 ml of DMF was added to (E)-ethyl-3-hydroxy-2-(iodomethylene)-4- methylpent-4-eoate (1) (0.1287 g, 0.456 mmol) and the mixture was stirred, followed by adding imidazole (0.062 g, 0.912 mmol) and TES-Cl (115 μl, 0.684 mmol) at room temperature. The mixture was stirred for 33 hours. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90% (162 mg).

TLC Rf 0.62 (Dichloromethane)

FT-IR 3076, 2955, 2875, 1738, 1717, 1434, 1222, 1108, 743 cm^"1

¹H NMR (300 MHz, CDCl₃) δ 0.61 (q, J=7.8Hz, 6H), 0.93 (t, J=7.8Hz, 9H), 1.72 (s, 3H), 3.72 (s, 3H), 4.92 (d, J=0.9Hz, IH), 5.16 (s, IH), 5.19 (s, IH), 7.78 (s, IH)

¹³C NMR (75 MHz, CDCl₃) δ 5.04, 7.10, 19.55, 52.38, 76.52, 97.18, 111.18, 144.06, 144.10, 163.81

LRMS calcd for C₈H₇IO₃: 396

Preparation Example 3> Preparation of (E)-methyl-2-(l-triethylsiloxy-2- methylaryl)hexadeca-2-enoate (SE-I; 3)

MBH ester (2) (141 mg, 0.50 mmol) in which alcohol is protected by TES was dissolved in 2.0 ml of THF, and 341 μl of a LiCuBr₂/THF solution (0.44M) was added. After reducing the temperature to -30 ^°C , 2.0M of a tridecane magnesium bromide/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 4 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83% (189 mg). TLC Rf 0.48 (EtOAc:Hexane= 1:5)

FT-IR 2924, 2854, 1711, 1462, 1255, 1091, 1062, 1006, 744, 501 cm^"1 1H NMR (300 MHz, CDCl₃) δ 0.58 (q, J=8.1Hz, 6H), 0.86-0.96 (m, 12H), 1.26

(br, 22H), 1.64 (s, 3H), 2.30-2.55 (m, 2H), 3.73 (s, 3H), 4.82 (s, IH), 5.13 (s, IH), 5.26 (s, IH), 6.87 (t, J=7.5Hz, IH)

¹³C NMR (75 MHz, CDCl₃) δ 4.99, 7.11, 14.42, 19.42, 23.01, 23.04, 28.89, 29.11, 29.73, 29.85, 29.94, 30.02, 30.04, 30.05, 31.95, 32.28, 52.01, 71.74, 109.98, 133.06, 146.02, 148.24, 168.18

LRMS calcd for C₁₃H₁₃IO₃: 452 Preparation Example 4> Preparation of (E)-methyl-2-(l-triethylsiloxy-2- oxopropyl)hexadeca-2-enoate (SE-2; 4)

4.0 ml of CH₂Cl₂ was added to (E)-methyl-2-(l-triethylsiloxy-2- methylaryl)hexadeca-2-enoate (3) (21.3 mg, 0.047 mmol), and then O₃ was bubbled at - 78 ^°C for 15 minutes. The reaction result was analyzed by TLC. 0.2 ml of Me₂S was added to terminate the reaction, and a nitrogen balloon needle was fixed on a flask septum to remove the remaining O₃ gas. The resulting product was stirred for 1 hour, and heated up to room temperature. Water was added for washing, and then 4 ml each of an organic layer was extracted five times using dichloromethane, followed by drying up the extract using Na₂SO₄. The solvent was removed under reduced pressure, and the rest of the product was purified by MPLC using a 1 : 1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 62% (13.3 mg).

TLC Rf 0.47 (EtOAc:Hexane= 1:5)

FT-IR 2956, 2851, 1724, 1465, 1243, 1119, 1024, 840, 745, 501 cm^"1

¹H NMR (300 MHz, CDCl₃) δ 0.58 (q, J=5.4Hz, 6H), 0.84-0.99 (m, 12H), 1.24 (br, 22H), 2.26 (s, 3H), 2.15-2.36 (m, 2H), 3.72 (s, 3H), 6.89 (t, J=7.5Hz, IH) ¹³C NMR (75 MHz, CDCl₃) δ 5.00, 6.09, 6.93, 7.04, 14.47, 23.03, 26.67, 28.97, 29.36, 29.70, 29.76, 29.81, 29.85, 29.99, 30.02, 32.25, 52.24, 74.30, 132.17, 147.88, 167.06, 209.97

LRMS calcd for C₁₃H₁₅IO₅: 454

Preparation Example 5> Preparation of secokotomolide A (SE-3; 5)

1.0 ml of THF was added to (E)-methyl-2-(l-triethylsiloxy-2- oxopropyl)hexadeca-2-enoate (4) (0.0504 g, 0.055 mmol) and the mixture was stirred, followed by adding 1.0M of a Bu₄NFZTHF solution (94 μl, 0.094 mmol) at -30 ^°C .

The mixture was stirred for 20 minutes. The reaction result was analyzed by TLC.

1.0 ml of ammonium chloride was added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a white solid of a desired compound was obtained with a yield of 93% (0.0174 mg).

TLC Rf 0.26 (EtOAc:Hexane= 1:5)

¹H NMR (600 MHz, CDCl₃) δ 0.83 (t, J=6.3Hz, 3H), 1.24 (br, 22H), 1.47 (q, J=7.2Hz, 2H), 2.09 (s, 3H), 2.36 (q, J=7.5Hz, 2H), 3.62 (s, 3H), 4.27 (d, J=5.1Hz, IH), 4.94 (d, J=4.8Hz, IH) 6.93 (t, J=7.8Hz, IH). ¹³C NMR (125 MHz, CDCl₃) δ 14.34, 22.88, 22.91, 25.05, 28.90, 29.93, 29.57, 29.60, 29.63, 29.72, 29.83, 29.86, 29.89, 32.14, 52.25, 73.59, 129.91, 149.37, 166.77, 206.56

V. Preparation of secokotomolide A derivatives

<Example 33> Preparation of secokotomolide A derivative (SE-4) Preparation Example 1> Preparation of (Z)-methyl-2- (hydroxy(phenyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (0.22 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^°C, followed by slowly adding 2.0 ml of dichloromethane, 0.24 mmol of methyl propiolate and 0.20 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 88%. Spectrum data of the product was the same as reported previously.

TLC R_f 0.23 (Dichloromethane) Preparation Example 2> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)-3-iodoacrylate

3.5 ml of DMF was added to (Z)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.1585g, 0.50mmol) and the mixture was stirred, followed by adding imidazol (0.0681 g, 1.0 mmol) and TES-Cl (126 μl, 0.75 mmol) at room temperature.

The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by

MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 80%.

TLC Rf 0.64 (Dichloromethane:Hexane = 5:1)

LRMS calcd for C₈H₇IO₃: 446

Preparation Example 3> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)hexadeca-2-enoate

MBH ester (2) (65.5 mg, 0.131 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 30 μl of a LiCuBr₂ATHF solution (0.44M) was added. After reducing the temperature to -30 °C, 2.0M of a tridecane magnesium bromide/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 71%.

TLC #/0.48 (EtOAc:Hexane= 1:5) LRMS calcd for C₁₃H₁₃IO₃: 502

Preparation Example 4> Preparation of secokotomolide A derivative (SE-4; 4)

1.5 ml of THF was added to (Z)-methyl-2-

(triethylsiloxy(phenyl)methyl)hexadeca-2-enoate (3) (0.047 g, 0.094 mmol) and the mixture was stirred. Subsequently, 1.0M of a BU₄NF/THF solution (159 μl, 0.159 mmol) was added at -30 ^°C , and the mixture was stirred for 3 hours. The reaction result was analyzed by TLC. 1.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane.

Then, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane.

As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 89%.

TLC RfO.16 (Dichloromethane rHexane^ 3:1)

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.2Hz, 3H), 1.25 (br, 20H), 1.50 (m, 2H), 2.36 (m, 2H), 3.68 (s, 3H), 4.22 (d, J=I 1. IHz, IH), 5.69 (d, J=I 1. IHz, IH), 7.00 (t, J=7.5Hz, IH) 7.31 (m, 5H). LRMS calcd for C₁₃H₁₃IO₃: 388

<Example 34> Preparation of secokotomolide A derivative (SE-5) <Preparation Example 1> Preparation of (E)-methyl-2- (hydroxy(phenyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of methyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C ,

BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and benzaldehyde (3.0 mmol) were sequentially added and mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5 M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. TLC Rf 0.35 (Dichloromethane)

Preparation Example 2> Preparation of (E)-methyl-2- (triethylsiloxy(phenyl)methyl)-3-iodoacrylate

3.5 ml of DMF was added to (E)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.1585 g, 0.50 mmol) and the mixture was stirred, followed by adding imidazole (0.0681 g, 1.0 mmol) and TES-Cl (126 μl, 0.75 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 82%. TLC Rf 0.64 (Dichloromethane:Hexane = 5:1)

LRMS clacd for C₈H₇IO₃: 446

Preparation Example 3> Preparation of (E)-methyl-2- (triethylsiloxy(phenyl)methyl)hexadeca-2-enoate

MBH ester (2) (65.5 mg, 0.131 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 30 μl of a LiCuBr₂/THF solution (0.44M) was added. After reducing the temperature to -30 ^°C, 2.0M of a tridecane magnesium bromide/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using Na₂SO₄. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 71%.

TLC R_f 0.48 (EtOAc:Hexane = 1:5) LRMS clacd for C₁₃H₁₃IO₃: 502

Preparation Example 4> Preparation of secokotomolide A derivative (SE-5 ;4)

1,5 ml of THF was added to (E)-methyl-2-

(triethylsiloxy(phenyl)methyl)hexadeca-2-enoate (3) (0.047 g, 0.094 mmol) and the mixture was stirred, followed by adding 1.0M of a Bu₄NFZTHF solution (159 μl, 0.159 mmol) at -30 °C . The mixture was stirred for 3 hours. The reaction result was analyzed by TLC. 1.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane.

Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 89%.

TLC RfO .16 (Dichloromethane:Hexane= 3:1)

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6.6Hz, 3H), 1.27 (br, 20H), 1.43 (m, 2H), 2.49 (q, J=7.5Hz, 2H), 3.16 (d, J=6.6Hz, IH), 3.68 (s, 3H), 5.43 (d, J=6.6Hz, IH), 6.23 (td, J_AB=7.5Hz, J_AC=0.9HZ, IH) 7.28 (m, 5H). LRMS calcd for C₁₃H₁₃IO₃: 388

<Example 35> Preparation of secokotomolide A derivative (SE-6) Preparation Example 1> (E)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3- iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C, BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and 4-fluorobenzaldehyde (3.0 mmol) were added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83%. TLC R_f 0.35 (Dichloromethane) FT-IR 3500, 2983, 1732, 1697, 1507, 1312, 1222, 1042, 494 cm^"1 ¹H NMR (500 MHz, CDCl₃) δ 1.25 (t, J=6.5Hz, 3H), 4.13-4.22 (m, 2H), 4.24 (d, J=I lHz, IH), 5.78 (d, J=I lHz, IH), 7.02 (t, J=9Hz, 2H), 7.40 (dd, J=8.75, 5Hz, 2H), 8.11 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.30, 62.17, 76.24, 101.36, 115.62 (d, J=21.25Hz), 127.24 (d, J=8.25Hz), 137.27, 143.11, 161.60, 163.40 LRMS calcd for C₁₂H₁₂FIO₃: 350

Preparation Example 2> Preparation of (E)-ethyl-2-((4- fluorophenyl)(triethylsiloxy)methyl)-3-iodoacrylate

3.5 ml of DMF was added to (E)-ethyl-2-(4-fluorophenyl)(hydroxyl)methyl)-3- iodoacrylate (1) (0.175g, 0.50 mmol) and the mixture was stirred, followed by adding imidazole (0.0681g, l.Ommol) and TES-Cl (126ul, 0.75 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane was added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1 :1 mixture of dichloromethane:hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. TLC Rf 0.64 (Dichloromethane:Hexane = 5:1) LRMS clacd for C₈H₇IO₃: 464

Preparation Example 3> Preparation of (E)-methyl-2-(triethylsiloxy(4- fluorophenly)methyl)hexadeca-2-enoate

MBH ester (2) (60 mg, 0.131 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 30 μl of a LiCuBr₂ATHF solution (0.44M) was added.

After reducing the temperature to -30 ^°C , 2.0M of a tridecane magnesium bromide/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water.

After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 71%.

TLC R_f 0.48 (EtOAc:Hexane = 1 :5)

LRMS clacd for Ci₃H₁₃IO₃: 520

<Preparation Example 4> Preparation of secokotomolide A derivative (SE-6; 4)

1.5 ml of THF was added to (E)-methyl-2-(triethylsiloxy(4- fluorophenly)methyl)hexadeca-2-enoate (3) (0.048 g, 0.094 mmol) and the mixture was stirred, followed by adding 1.0M of a Bu₄NFZTHF solution (159 μl, 0.159 mmol) at -

30 TJ . The mixture was stirred for 3 hours. The reaction result was analyzed by

TLC. 1.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 91%.

TLC Rf 0.16 (Dichloromethane:Hexane= 3:1)

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6.6Hz, 3H), 1.25 (br, 23H), 1.51 (m, 2H), 2.34 (m, 2H), 4.17 (m, 3H), 5.65 (d, J=10.5Hz, IH), 7.01 (td, J^=8.1Hz, J_AC=1 -2Hz IH), 7.33 (m, 4H).

LRMS calcd for C₁₃H₁₃IO₃: 407

<Example 36> Preparation of secokotomolide A derivative (SE-7) Preparation Example 1> Preparation of (Z)-methyl-3-hydroxy-2- (iodomethylene)-4-methylpent-4-eoate (1)

A 25 ml round-bottom flask having AlI₃ (0.55 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -78 ^"C, followed by slowly adding 5.0 ml of dichloromethane, 0.60 mmol of methyl propiolate and 0.50 mmol of methacrolein were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 3ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. TLC Rf 0.35 (Dichloromethane)

Preparation Example 2> Preparation of (Z)-methyl-3-triethylsiloxy-2-

(iodomethylene)-4-methylpent-4-eoate (2)

3.0 ml of DMF was added to (Z)-methyl-3-hydroxy-2-(iodomethylene)-4- methylpent-4-eoate (0.1287 g, 0.456 mmol) and the mixture was stirred, followed by adding imidazole (0.062 g, 0.912 mmol) and TES-Cl (115 μl, 0.684 mmol) at room temperature. The mixture was stirred for 33 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90% (162 mg).

TLC Rf 0.62 (Dichloromethane)

¹H NMR (300 MHz, CDCl₃) δ 0.60 (q, J=8.1Hz, 6H), 0.97 (t, J=7.8Hz, 9H), 2.20 (s, 3H), 3.81 (s, 3H), 4.76 (d, J=0.9Hz, IH), 7.28 (s, IH), 7.35 (s, IH), 7.36 (s, IH)

LRMS calcd for C₈H₇IO₃: 396

Preparation Example 3> Preparation of (Z)-methyl-2-(l-trimethylsiloxy-2- methylaryl)hexadeca-2-enoate (3)

MBH ester (2) (141 mg, 0.50 mmol) in which alcohol is protected by TES was dissolved in 2.0 ml of THF, and 341 μl of a LiCuBr₂/THF solution (0.44M) was added. After reducing the temperature to -30 ⁰C , 2.0M of a tridecane magnesium bromide/THF solution was slowly added. The reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 4 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83% (189 mg).

TLC iϊ/0.48 (EtOAc:Hexane= 1:5)

¹H NMR (300 MHz, CDCl₃) δ 0.56 (q, J=2.4Hz, 6H), 0.88 (t, J=6.0Hz, 9H), 0.94 (t, J=6.3Hz, 3H), 1.26 (br, 22H), 1.60 (s, 3H), 2.38 (m, 2H), 4.80 (dd, J_AB=1.5Hz, J_AC=1.2HZ, IH), 4.95 (dd, J_AB=0.9Hz, J_AC=1.2Hz, IH), 4.99 (s, IH), 6.21 (td, J_AB=7.5HZ, JA_C=1.2HZ, 1H).

LRMS calcd for C₁₃H₁₃IO₃: 452

Preparation Example 4> Preparation of (Z)-methyl-2-(l-triethylsiloxy-2- oxopropyl)hexadeca-2-enoate (4)

4.0 ml of CH₂Cl₂ was added to (Z)-methyl-2-(l-triethylsiloxy-2- methylaryl)hexadeca-2-enoate (3) (21.3 mg, 0.047 mmol), and O₃ was bubbled for 15 minutes at -78 ^°C . The reaction result was analyzed by TLC. 0.2 ml of Me₂S was added to terminate the reaction, and a nitrogen balloon needle was fixed on a flask septum to remove the remaining O₃ gas. After being stirred for 1 hour, the resulting product was heated up to room temperature. Water was added for washing, and 4 ml each of an organic layer was extracted five times using dichloromethanethe, followed by drying the extract using Na₂SO₄. The solvent was removed under reduced pressure, and then the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 62% (13.3 mg). TLC Rf 0.47 (EtOAc:Hexane= 1 :5)

LRMS calcd for C₁₃H₁₅IO₅: 454

Preparation Example 5> Preparation of secokotomolide A derivative (SE-7; 5)

1.0 ml of THF was added to (Z)-methyl-2-(triethylsiloxy-2- oxopropyl)hexadeca-2-enoate (4) (0.0504 g, 0.055 mmol) and the mixture was stirred, followed by adding 1.0M of a Bu₄NFZTHF solution (94 μl, 0.094 mmol) at -30 ^"C .

The mixture was stirred for 20 minutes. The reaction result was analyzed by TLC. 1.0 ml of ammonium chloride was added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a white solid of a desired compound was obtained with a yield of 93% (0.0174 mg).

TLC Rf 0.26 (EtOAc:Hexane= 1:5) y 1H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6.3Hz, 3H), 1.26 (br, 22H), 2.20 (s,

3H), 2.52 (m, 2H), 3.74 (s, 3H), 4.06 (s, IH) 4.54 (s, IH), 6.34 (t, J=7.5Hz, IH)

<Example 37> Preparation of secokotomolide A derivative (SE-8) Preparation Example 1> (E)-ethyl-2-((4- (trifluoromethyl)phenyl)(hydroxy)methyl)-3 -iodoacrylate

A 10 ml round-bottom flask having a stirring bar was filled with argon, and then plugged with a rubber cap. Subsequently, 0.132 ml of ethyl propiolate (1.30 mmol) and 4.0 ml of dichloromethane were added. After reducing the temperature to -40 ^°C, BF₃Et₂O (0.152 ml, 1.2 mmol), TMS-I (0.344 ml, 2.4 mmol) and α,α,α-trifluoro-p- tolualdehyde (3.0 mmol) were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. After the reaction, 0.5M of a NaOMe/methanol solvent was added to make the reaction mixture neutral, and then water was added thereto. 3ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 76%.

TLC Rf 0.35 (Dichloromethane)

FT-IR 3484, 2984, 1699, 1588, 1326, 1121, 1067, 861, 820 cm^"1 1H NMR (500 MHz, CDCl₃) δ 1.25 (t, J=7Hz, 3H), 4.13-4.22 (m, 2H), 4.28 (d,

J=12Hz, IH), 5.86 (d, J=12Hz, IH), 7.55 (d, J=8.5Hz, 2H), 7.61 (d, J=8Hz, 2H), 8.18 (s, IH)

¹³C NMR (125 MHz, CDCl₃) δ 14.30, 62.33, 76.32, 102.19, 123.40, 125.75, 125.82, 130.18 (q, J=32.4Hz), 142.86, 145.59, 163.28 LRMS calcd for C₁₃H₁₂F₃IO₃: 400

Preparation Example 2> (E)-ethyl-2-((4-

(trifluoromethyl)phenyl)(triethylsiloxy)methyl)-3-iodoacrylate

6.0 ml of DMF was added to (E)-ethyl-2-((4- (trifluoromethyl)phenyl)(hydroxy)methyl)-3-iodoacrylate (1) (0.400 g, 1.0 mmol) and the mixture was stirred, followed by adding imidazole (0.136 g, 2.0 mmol) and TES-Cl (252 μl, 1.5 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. TLC R_f 0.64 (Dichloromethane:Hexane = 5:1)

LRMS clacd for C₈H₇IO₃: 514

Preparation Example 3> Preparation of (E)-methyl-2-((4- trifluorophenyl)(triethylsiloxy)methyl)hexadeca-2-enoate

MBH ester (2) (128 mg, 0.25 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 55 μl of a LiCuBr₂ATHF solution (0.44M) was added. After reducing the temperature to -30 ^°C , 2.0M of a tridecane magnesium bromide/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83%. TLC R_f 0.48 (EtOAc:Hexane = 1:5) LRMS clacd for C₁₃H₁₃IO₃: 570

Preparation Example 4> Preparation of secokotomolide A derivative (SE-8; 4)

2.0 ml of THF was added to (E)-methyl-2-((4- trifluorophenyl)(triethylsiloxy)methyl)hexadeca-2-enoate (3) (0.102 g, 0.18 mmol) and the mixture was stirred, followed by adding 1.0M of a BU₄NF/THF solution (306 μl, 0.306 mmol) at -30 ^°C . The mixture was stirred for 3 hours. The reaction result was analyzed by TLC. 2.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane.

Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%.

TLC R_f 0.16 (Dichloromethane: Hexane = 3:1)

LRMS clacd for Ci₃H₁₃IO₃: 456

<Example 38> Preparation of secokotomolide A derivative (SE-9)

Preparation Example 1> Preparation of (Z)-methyl-2- (hydroxy(phenyl)methyl)-3-iodoacrylate

A 10 ml round-bottom flask having AlI₃ (2.2 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to -

78 ^°C, followed by slowly adding 20.0 ml of dichloromethane, 2.4 mmol of methyl propiolate and 2.0 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 20 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously.

Preparation Example 2> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)-3-iodoacrylate

6.0 ml of DMF was added to (Z)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.318 g, 1.0 mmol) was added and the mixture was stirred, followed by adding imidazole (0.136 g, 2.0 mmol) and TES-Cl (252 μl, 1.5 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1 : 1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. Spectrum data of the product was the same as reported previously.

Preparation Example 3> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)undeca-2-enoate

MBH ester (2) (97.5 mg, 0.25 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 55 μl of a LiCuBr₂ATHF solution (0.44M) was added.

After reducing the temperature to -30 ^°C, 2.0M of an octane magnesium bromine/ THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water.

After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 83%. TLC Rf 0.48 (EtOAc:Hexane= 1 :5)

¹H NMR (300 MHz, CDCl₃) δ 0.55 (q, J=8.4 Hz, 6 H), 0.87 (t, J=7.8 Hz 9 H) 0.88 (t, J=6.6 Hz, 3 H), 1.26 (br s, 10H), 1.42 (m, 2H), 2.42 (q, J=7.5 Hz, 2H), 3.64 (s, 3H), 5.56 (s, IH), 6.29 (td, J^=7.8Hz, J_AC=\ .5ΑL IH), 7.26 (m, 5H).

¹³C NMR (75 MHz, CDCl₃) δ 5,02, 7.08, 14.47, 23.01, 29.54, 29.60, 29.65, 29.73, 32.18, 51.43, 73.93, 127.20, 127.50, 128.29, 135.37, 141.12, 143.49, 167.86.

LRMS calcd for C₁₃H₁₃IO₃: 376

Preparation Example 4> Preparation of secokotomolide A derivative (SE-9; 4)

2.0 ml of THF was added to (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)undeca-2-enoate (3) (0.067 g, 0.18 mmol) and the mixture was stirred, followed by adding 1.0M of a BU₄NF/THF solution (306 μl, 0.306 mmol) at -30 ^°C . The mixture was stirred for 4 hours. The reaction result was analyzed by TLC. 2.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. TLC Rf 0.16 (Dichloromethane:Hexane= 3:1)

¹H NMR (600 MHz, CDCl₃) δ 0.97 (t, J=7.8 Hz, 3 H), 1.29 (m, 10H), 1.44 (m, 2H), 2.48 (m, 2H), 3.71 (d, J=7.2 Hz, IH), 3.68 (s, 3H), 5.43 (d, J=7.2 Hz, IH), 6.22 (t, J=7.2Hz, IH), 7.32 (m, 5H).

¹³C NMR (150 MHz, CDCl₃) δ 6.80, 14.33, 22.89, 29.39, 29.44, 29.57, 29.74, 32.07, 51.62, 75.76, 126.42, 127.71, 128.55, 133.39, 142.35, 145.25, 168.01.

LRMS calcd for C₁₃H₁₃IO₃: 304

<Example 39> Preparation of secokotomolide A derivative(SE-lO) Preparation Example 1> Preparation of (Z)-methyl-2- (hydroxy(phenyl)methyl)-3 -iodoacry late

A 10 ml round-bottom flask having AlI₃ (2.2 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to - 78 ^°C, followed by slowly adding 20.0 ml of dichloromethane, 2.4 mmol of methyl propiolate and 2.0 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 20 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously.

6.0 ml of DMF was added to (Z)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.318 g, 1.0 mmol) and the mixture was stirred, followed by adding imidazole (0.136 g, 2.0 mmol) and TES-Cl (252 μl, 1.5 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1:1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. Spectrum data of the product was the same as reported previously. Preparation Example 3> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)octa-2-enoate

MBH ester (2) (97.5 mg, 0.25 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 55 μl of a LiCuBr₂/THF solution (0.44M) was added. After reducing the temperature to -30 "C, 2.0M of a pentane magnesium bromine/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 84%. TLC R_f 0.48 (EtOAc: Hexane = 1:5) LRMS clacd for C₁₃H₁₃IO₃: 334

<Preparation Example 4> Preparation of secokotomolide A derivative (SE-IO; 4)

2.0 ml of THF was added to (Z)-methyl-2-(triehtylsiloxy(phenyl)methyl)octa-2- enoate (3) (0.060 g, 0.18 mmol) and the mixture was stirred, followed by adding l.OM of a Bu4NF/THF solution (306 μl, 0.306 mmol) at -30 ^°C . The mixture was stirred for

4 hours. The reaction result was analyzed by TLC. 2.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90%.

TLC R/0Λ6 (Dichloromethane:Hexane= 3:1)

¹H NMR (600 MHz, CDCl₃) δ 0.87 (t, J=7.8 Hz, 3 H), 1.25 (m, 4H), 1.42 (m, 2H), 2.10 (s, IH), 2.49 (m, 2H), 3.69 (s, 3H), 6.11 (t, J=7.8 Hz, IH), 6.45 (s, IH), 7.30 (m, 5H).

¹³C NMR (150 MHz, CDCl₃) δ 6.80, 14.22, 29.70, 29.92, 31.75, 51.62, 75.75, 126.43, 127.71, 128.55, 133.40, 142.35, 145.21, 168.00.

LRMS calcd for C_nH₁₃IO₃: 262

<Example 40> Preparation of secokotomolide A derivative (SE- 11 )

<Preparation Example 1> Preparation of (Z)-methyl-2- (hydroxy(phenyl)methyl)-3-iodoacrylate

78 "C , followed by slowly adding 20.0 ml of dichloromethane, 2.4 mmol of methyl propiolate and 2.0 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 20 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using

Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously.

1 6.0 ml of DMF was added to (Z)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.318 g, 1.0 mmol) and the mixture was stirred, followed by adding imidazole (0.136 g, 2.0 mmol) and TES-Cl (252 μl, 1.5 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1 : 1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. Spectrum data of the product was the same as reported previously.

Preparation Example 3> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)pentadeca-2-enoate

MBH ester (2) (108 mg, 0.25 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 55 μl of a LiCuBr₂ATHF solution (0.44M) was added. After reducing the temperature to -30 ^°C, 2.0M of a dodeca magnesium bromine/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water.

After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, sticky colorless liquid of a desired compound was obtained with a yield of 79%. TLC Rf 0.48 (EtOAc: Hexane - 1 :5)

LRMS clacd for C₁₃H₁₃IO₃: 432

Preparation Example 4> Preparation of secokotomolide A derivative (SE-Il;

4)

2.0 ml of THF was added to (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)pentadeca-2-enoate (3) (0.060 g, 0.18 mmol) and the mixture was stirred, followed by adding l.OM of a Bu₄NFZTHF solution (306 μl, 0.306 mmol) at -30 ^"C . The mixture was stirred for 4 hours. The reaction result was analyzed by TLC. 2.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90%. TLC R_f0Λ6 (Dichloromethane:Hexane= 3:1)

¹H NMR (600 MHz, CDCl₃) δ 0.97 (t, J=7.8 Hz, 3 H), 1.26 (m, 18H), 1.44 (m, 2H), 2.48 (m, 2H), 3.07 (d, J=7.8 Hz, IH), 3.68 (s, 3H), 5.44 (d, J=7.2 Hz, IH), 6.22 (t, J=7.8 Hz IH), 7.33 (m, 5H). 1³C NMR (150 MHz, CDCl₃) δ 6.02, 6.80, 14.34, 22.91, 29.40, 29.58, 29.64,

29.75, 29.79, 29.86, 29.90, 31.14, 51.61, 75.76, 126.43, 127.71, 128.55, 133.38, 142.35, 145.25, 168.00.

LRMS calcd for C₁₃H₁₃IO₃: 360

<Example 41 > Preparation of secokotomolide A derivative (SE- 12)

A 10 ml round-bottom flask having AlI₃ (2.2 mmol) and a stirring bar was filled with argon, and then plugged with a rubber cap. After reducing the temperature to - 78 ^°C , followed by slowly adding 20.0 ml of dichloromethane, 2.4 mmol of methyl propiolate and 2.0 mmol of benzaldehyde were sequentially added and the mixture was stirred. The reaction result was analyzed by TLC. At the end of the reaction, water was added to terminate the reaction. 20 ml each of the produced mixture was extracted three times using dichloromethane. After that, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and then the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 87%. Spectrum data of the product was the same as reported previously.

Preparation Example 2> Preparation of (Z)-methyl-2-

(triethylsiloxy(phenyl)methyl)-3-iodoacrylate

6.0 ml of DMF was added to (Z)-methyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate (1) (0.318 g, 1.0 mmol) and the mixture was stirred, followed by adding imidazole (0.136 g, 2.0 mmol) and TES-Cl (252 μl, 1.5 mmol) at room temperature. The mixture was stirred for 8 hours at room temperature. The reaction result was analyzed by TLC. 1.0 ml of water and 3.0 ml of dichloromethane were added to terminate the reaction, and 4 ml each of the produced mixture was extracted five times using dichloromethane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using a 1 :1 mixture of dichloromethane and hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 92%. Spectrum data of the product was the same as reported previously.

<Preparation Example 3> Preparation of (Z)-methyl-2- (triethylsiloxy(phenyl)methyl)pentadeca-2-enoate

MBH ester (2) (108 mg, 0.25 mmol) in which alcohol is protected by TES was dissolved in 1.5 ml of THF, and 55 μl of a LiCuBr₂ATHF solution (0.44M) was added. After reducing the temperature to -30 ^°C, 2.0M of a dodecane magnesium bromine/THF solution was slowly added. Reaction of the produced solution was terminated by adding 2.0 ml of a saturated ammonium chloride aqueous solution and 1.0 ml of water. After the produced solution was stirred until a water layer thereof turned blue, 2 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using hexane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 79%.

TLC R_f 0.48 (EtOAc: Hexane = 1:5) LRMS clacd for C₁₃H₁₃IO₃: 432

Preparation Example 4> Preparation of secokotomolide A derivative (SE-Il; 4)

2.0 ml of THF was added to (Z)-methyl-2-

(triethylsiloxy(phenyl)methyl)pentadeca-2-enoate (3) (0.060 g, 0.18 mmol) and the mixture was stirred, followed by adding 1.0M of a Bu₄NFZTHF solution (306 μl, 0.306 mmol) at -30 ^°C . The mixture was stirred for 4 hours. The reaction result was analyzed by TLC. 2.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane.

Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 90%.

TLC i?/0.16 (Dichloromethane:Hexane= 3:1)

¹H NMR (600 MHz, CDCl₃) δ 0.97 (t, J=7.8 Hz, 3 H), 1.26 (m, 18H), 1.44 (m, 2H), 2.48 (m, 2H), 3.07 (d, J=7.8 Hz, IH), 3.68 (s, 3H), 5.44 (d, J=7.2 Hz, IH), 6.22 (t, J=7.8 Hz IH), 7.33 (m, 5H).

¹³C NMR (150 MHz, CDCl₃) δ 6.02, 6.80, 14.34, 22.91, 29.40, 29.58, 29.64, 29.75, 29.79, 29.86, 29.90, 31.14, 51.61, 75.76, 126.43, 127.71, 128.55, 133.38, 142.35, 145.25, 168.00. LRMS calcd for C₁₃H₁₃IO₃: 360 Preparation Example 5> Preparation of secokotomolide A derivative (SE- 12; 5)

1.0 ml of pyridine was added to SE-Il (4) (0.46 mmol, 16.5 mg), and then stirred. Acetic acid anhydride (6 μl, 0.06 mmol) was added at room temperature, and the mixture was stirred for 6 hours. The reaction result was analyzed by TLC. 1.0 ml of ammonium chloride was added to terminate the reaction, and 3 ml each of the produced mixture was extracted five times using hexane. Subsequently, water was dried up using Na₂SO₄, the solvent was also removed under reduced pressure, and the rest of the product was purified by MPLC using dichloromethane. As a result, a sticky colorless liquid of a desired compound was obtained with a yield of 71%. TLC Rf 0.53 (MC)

¹H NMR (600 MHz, CDCl₃) δ 0.88 (t, J=7.8 Hz, 3 H), 1.25 (m, 18H), 1.41 (m, 2H), 2.10 (s, 3H), 2.49 (m, 2H), 3.69 (s, 3H), 6.11 (t, J=7.2 Hz, IH), 6.65 (s, IH), 7.30 (m, 5H).

¹³C NMR (150 MHz, CDCl₃) δ 14.34, 21.39, 22.88, 29.37, 29.54, 29.58, 29.61, 29.78, 29.85, 29.87, 29.90, 31.82, 32.15, 51.64, 74.74, 127.60, 128.61, 131.26, 138.70, 145.12, 166.64, 169.80. LRMS calcd for Ci₃H₁₃IO₃: 402

Novel β-substituted MBH derivatives synthesized according to the methods shown in Examples IV and V are listed in Table 1. [Table 1]

VI. Experimental Example: Anticancer effects of β-substituted MBH derivatives As a cancer cell line for an MTT assay, a human esophageal cancer cell line HEC4 was used. 8 x 10³ cells of the cancer cell line per well were plated on a 96-well plate, and then incubated for 6 hours at 37 °C . Subsequently, 2 mg each of the compounds SE-I to SE- 12 was dissolved in 80 μl of DMSO, and fracions of 1 μl each were distributed to each well, followed by incubating the cells for 24 hours at 37 ^°C . After all media were removed, each pellet was washed with 100 μl of a PBS buffer solution. 40 μl of a MTT reagent was distributed to each well and the plate was covered with an aluminum foil to block light, followed by incubating the cells for 3 hours at 37 ^°C . The MTT reagent was removed, and 100 μl of DMSO was distributed to each well. The plate was covered with an aluminum foil, and then the cells were incubated for 5 to 10 minutes at 37 ^°C . Afterwards, the cell cultures were analyzed at 570 nm by an ELISA reader, and the results thereof are shown in Tables 2 to 4, and FIGs. 1 to 3. In Table 3, * means that 1/10 of the amount of a compound was used for the analysis in comparison with other compounds, and ** means that 1/20 of the amount of a compound was used for the analysis in comparison with other compounds.

As shown in FIGs. 1 and 2, compared with SE-I and SE-2, which exhibited almost no oncolytic activity, SE-3 to 6 and SE-Il exhibited very high oncolytic activities, and thus viabilities of the cancer cells were less than 20%.

From an experiment using diluted samples of those exhibiting an excellent activity among the materials, it can be noted that even though SE-3 and SE-5 were diluted 20-fold, their viabilities of the cancer cells were about 50%, and SE-5 exhibited a little higher activity than SE-3, as shown in FIG. 3. [Table 2]

[Table 3]

[Table 4]

[Industrial Applicability]

According to the present invention, novel β-substituted MBH derivatives having various physiological activities are very effective candidates for development of new drugs to treat cancer in the pharmaceutical industry.

Claims

[CLAIMS] [Claim 1]

A compound of Formula 1, a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

where, R_la and R^ are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom,

X₁ is OR₄ or NR_5aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl,

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl,

R₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, and

R_3a and R_3b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein methyl-2-(l-hydroxy-2-oxopropyl)hexadeca-2-enoate is excluded from the compounds of Formula 1.

[Claim 2]

The compound according to claim 1, wherein R_la and R^ are independently hydrogen, C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-I2 aryl, in which at least one carbon atom of the C_1-14 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-I4 alkynyl or C_1-14 alkoxy may have a double bond with an oxygen atom, and the C_6-12 aryl is substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted C_1-6 alkyl, halogen, cyano, hydroxy, C_1-6 alkoxy and C_6-12 aryl.

[Claim 3]

The compound according to claim 1, wherein R_la and R^ are independently hydrogen, acetyl, C_1-8 alkyl, C_2-8 alkenyl or C_6-12 aryl, and the C_6-12 aryl is substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted C_1-4 alkyl, halogen, cyano, C_1-4 alkoxy and C_6-12 aryl.

[Claim 4]

The compound according to claim 1, wherein X₁ is OR₄ or NR_5aR₅b, wherein R₄ is hydrogen, Ci_-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl,

C(O)R₇, or C_1-6 alkyl-substituted or unsubstituted silicon,

R_5a and R_5b are independently hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C₆-_I2 aryl, C_1-14 acyl, Ci_-H alkylsulfonyl or C_6-12 arylsulfonyl, and

R₇ is C_1-14 alkyl or C_6-I2 aryl.

[Claim 5]

The compound according to claim 1 , wherein X₁ is halogen, hydroxy, formyl, acetyl, propionyl, benzoyl, C_1-8 alkoxy, C_6-12 aryloxy, C_1-4 alkyl-substituted or unsubstituted siloxy or tosylamino.

[Claim 6]

The compound according to claim 1, wherein X₂ is oxygen or NR₆, wherein R₆ is hydrogen, C_1-I4 alkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_6-12 aryl.

[Claim 7]

The compound according to claim 1, wherein X₂ is oxygen.

[Claim 8] The compound according to claim 1 , wherein R₂ is hydrogen, halo, hydroxy, C_1-

₁₄ alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_1-14 alkoxy or C_6-12 aryl.

[Claim 9]

The compound according to claim 1, wherein R₂ is C_1-8 alkyl or C_1-8 alkoxy.

[Claim 10]

The compound according to claim 1, wherein R_3a and R_3b are independently hydrogen, halo, hydroxy, C_1-J8 alkyl, C_3-12 cycloalkyl, C_2-18 alkenyl, C_2-18 alkynyl, C_1-18 alkoxy or C_6-12 aryl.

[Claim 11 ]

The compound according to claim 1, wherein R_3a and R_3b are independently hydrogen or C_1-14 alkyl.

[Claim 12]

The compound according to claim 1 , wherein the compound of Formula 1 is at least one selected from the group consisting of (Z)-methyl-2- (hydroxy(phenyl)methyl)hexateca-2-enoate (SE-4); (E)-methyl-2- (hydroxy(phenyl)methyl)hexateca-2-enoate (SE-5); (E)-ethyl-2-((4- fluorophenyl)(hydroxy)methyl)hexateca-2-enoate (SE-6); (Z)-methyl-2-(l -hydroxy-2- oxopropyl)hexateca-2-enoate (SE-7); (E)-ethyl-2-(4-

(thrifluoro)methylphenyl)(hydroxy)methyl)hexateca-2-enoate(SE-8); (Z)-methyl-2- (hydroxy(phenyl)methyl)undeca-2-enoate (SE-9); (Z)-methyl-2- (hydroxy(phenyl)methyl)octa-2-enoate(SE-10); (Z)-methyl-2-

(hydroxy(phenyl)methyl)pentadeca-2-enoate (SE-Il); and (Z)-methyl-2- (acetoxy(phenyl)methyl)pentadeca-2-enoate (SE- 12).

[Claim 13] A method of preparing a compound of Formula 1 , comprising:

(a) preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a Lewis acid selected from AlI₃ or TMSI/BF₃ ^• Et₂O, and a solvent;

(b) preparing a compound of Formula 5 by protecting an substituent group Xl of the compound of Formula 4 with a protective group;

(c) preparing a compound of Formula 6 by substituting iodine of the compound of Formula 5; and

(d) preparing a compound of Formula 1 by releasing the protective group from the compound of Formula 6:

where, R_la and Ru, are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of having a double bond with an oxygen or sulfur atom,

X₁ is OR₄ or NR_5aR₅b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl,

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl, R₂ is hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl,

R_3a and R₃b are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, and Y is a protective group.

[Claim 14]

The method according to claim 13, wherein the solvent in step (a) is dichloromethane.

[Claim 15]

The method according to claim 13, wherein the reaction in step (a) is performed at -90 to -20 ⁰C .

[Claim 16]

The method according to claim 13, wherein a content of BF₃ ^• Et₂O added in step (a) is 0.1 to 2 equivalent weight of the compound of Formula 1.

[Claim 17] The method according to claim 13, wherein the reaction in step (c) is performed in the presence of a Grignard reagent.

[Claim 18] The method according to claim 13, further comprising: decomposing the compound of Formula 6 prepared in step (c) using ozone.

[Claim 19] A compound of Formula 4 or a stereoisomer thereof:

where, R_la and R^ are independently hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy or aryl, wherein at least one carbon atom of the alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy is capable of forming a double bond with an oxygen or sulfur atom,

X₁ is OR₄ or NR5_aR_5b, wherein R₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or alkyl-substituted or unsubstituted silicon, and R_5a and R_5b are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, alkyl sulfonyl, or aryl sulfonyl, X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl, and

[Claim 20]

The compound according to claim 19, wherein R_la and Ri_b are independently hydrogen, Ci_-I4 alkyl, C_3-12 cycloalkyl, C_2-14 alkenyl, C_2-I4 alkynyl, C_M4 alkoxy or C_6-12 aryl, in which at least one carbon atom of the C_1-14 alkyl, C_3-I2 cycloalkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_1-14 alkoxy may have a double bond with an oxygen atom, and the C_6-U aryl is substituted by at least one substituent selected from the group consisting of halogen-substituted or unsubstituted C_1-6 alkyl, halogen, cyano, hydroxy, C_1-6 alkoxy and C_6-12 aryl.

[Claim 21 ]

The compound according to claim 19, wherein Xi is OR₄ or NR.₅aR._5b, wherein R₄ is hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl, C(O)R₇, or C_1-6 alkyl-substituted or unsubstituted silicon,

R_5a and R_5b are independently hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl, C_6-12 aryl, C_1-I4 acyl, C_1-14 alkylsulfonyl or C_6-12 arylsulfonyl, and R₇ is C_1-14 alkyl or C_6-12 aryl.

[Claim 22]

The compound according to claim 19, wherein X₂ is oxygen or NR₆, wherein R₆ is hydrogen, C_1-14 alkyl, C_2-14 alkenyl, C_2-14 alkynyl or C_6-12 aryl.

[Claim 23] The compound according to claim 19, wherein R₂ is hydrogen, halo, hydroxy,

Ci_-I4 alkyl, C₃.₁₂ cycloalkyl, C_2-I4 alkenyl, C_2-I4 alkynyl, CM₄ alkoxy or C_6-Ii aryl.

[Claim 24]

The compound according to clam 19, wherein the compound of Formual 4 is selected from the group consisting of (E)-ethyl-2-(hydroxy(phenyl)methyl)-3- iodoacrylate; (E)-methyl-2-(hydroxy(phenyl)methyl)-3 -iodoacrylate; (E)-ethyl-2- (hydroxy(o-tolyl)methyl)-3-iodoacrylate; (E)-ethyl-2-(hydroxy(p-tolyl)methyl)-3- iodoacrylate; (E)-ethyl-2-(hydroxy(4-biphenyl)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- fluorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- chlorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- bromophenyl)(hydroxy)methyl)-3 -iodoacrylate; (E)-ethyl-2-((4- cyanophenyl)(hydroxy)methyl)-3-iodoacrylate; (E)-ethyl-2-((4-

(trifluoromethyl)phenyl)(hydroxy)methyl)-3-iodoacrylate; (E)-ethyl-3-hydroxy-2- (iodomethylene)nonanoate; (E)-ethyl-(4-methyl-3-hydroxy-2-iodomethylene)- pentanoate; (Z)-methyl-2-(hydroxy(phenyl)methyl)-3 -iodoacrylate; (Z)-ethyl-2- (hydroxy(phenyl)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- fluorophenyl(hydroxy)methyl)-3-iodoacrylate; (Z)-ethyl-2-(hydroxy(4- biphenyl)methyl)-3-iodoacrylate; (Z)-ethyl-2-(hydroxy(p-tolyl)methyl)-3-iodoacrylate; (Z)-ethyl-2-((4-fluorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- chlorophenyl)(hydroxy)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- bromophenyl)(hydroxy)methyl)-3 -iodoacrylate; (Z)-ethyl-2-((4- cyanophenyl)(hydroxy)methyl)-3-iodoacrylate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)- 4,4-dimethylpentanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-4-methylpentanoate; (Z)-methyl-3-hydroxy-2-(iodomethylene)-4-methylpentanoate; (Z)-ethyl-3-hydroxy-2- (iodomethylene)nonanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3-phenylbutanoate; (Z)-ethyl-3 -(4-trifluoromethylphenyl)-3 -hydroxy-2-(iodomethylene)butanoate; (Z)- ethyl-3 -(4-methoxyphenyl)-3 -hydroxy-2-(iodomethylene)butanoate; (Z)-ethyl-3 - hydroxy-2-(iodomethylene)-3-p-tolylbutanoate; (Z)-ethyl-3-hydroxy-2- (iodomethylene)-3-o-tolylbutanoate; (Z)-ethyl-3-hydroxy-2-(iodomethylene)-3- methylbutanoate; (Z)-ethyl-3 -hydroxy-2-(iodomethylene)-3 ,4,4-trimethylpentanoate; and (Z)-ethyl-(3-ethyl-3-hydroxy-3-phenyl-2-iodomethylene)-propionate.

[Claim 25]

A method of preparing a compound of Formula 4, comprising: reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a Lewis acid selected from AlI₃ or TMSIZBF₃-Et₂O and a solvent:

X₂ is oxygen, sulfur or NR₆, wherein R₆ is hydrogen, alky, alkenyl, alkynyl or aryl, and

[Claim 26]

A pharmaceutical composition comprising a compound of Formula 1 according to claim 1 and a pharmaceutically acceptable carrier as active ingredients.