KR102144837B1 - Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution - Google Patents

Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution Download PDF

Info

Publication number
KR102144837B1
KR102144837B1 KR1020190045532A KR20190045532A KR102144837B1 KR 102144837 B1 KR102144837 B1 KR 102144837B1 KR 1020190045532 A KR1020190045532 A KR 1020190045532A KR 20190045532 A KR20190045532 A KR 20190045532A KR 102144837 B1 KR102144837 B1 KR 102144837B1
Authority
KR
South Korea
Prior art keywords
formula
compound
synthesis
synthesizing
reacting
Prior art date
Application number
KR1020190045532A
Other languages
Korean (ko)
Inventor
김지민
박새한샘
박경아
Original Assignee
전남대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 전남대학교산학협력단 filed Critical 전남대학교산학협력단
Priority to KR1020190045532A priority Critical patent/KR102144837B1/en
Application granted granted Critical
Publication of KR102144837B1 publication Critical patent/KR102144837B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

The present invention relates to a method for synthesizing gamma-lactone by an asymmetric aldol reaction through kinetic division. More particularly, by acquiring an enantiomer from a mixture as a method using a difference in speed of a racemic mixture, the present invention can be efficiently used for the synthesis of gamma-lactone and xylocolactone in terms of cost and time.

Description

속도론적 분할을 통한 비대칭 알돌반응에 의한 감마-락톤 합성방법{Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution}Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution}

본 발명은 속도론적 분할을 통한 비대칭 알돌반응에 의한 감마-락톤(gamma-lactone) 합성방법에 관한 것으로서, 더욱 상세하게는 라세믹 혼합물의 속도차이를 이용한 반응법으로서 하나의 거울상이성체(enantiomer)를 혼합물로부터 수득함으로써, 비용 및 시간적 측면에서 효율적으로 감마-락톤을 합성하는 방법에 관한 것이다.The present invention relates to a method for synthesizing gamma-lactone by an asymmetric aldol reaction through kinetic division, and more particularly, a reaction method using a difference in speed of a racemic mixture, using one enantiomer. It relates to a method for synthesizing gamma-lactone efficiently in terms of cost and time by obtaining from a mixture.

감마-부틸로락톤(g-butyrolactone)골격은 13,000여개 이상의 천연물에 존재한다. 항생제 및 항암제와 같은 중요한 생리활성을 띄는 감마락톤의 비대칭 합성법은 다양한 접근법을 통해서 오랫동안 연구되어 왔다. 특히 감마위치에 치환기를 포함하는 알파, 베타 위치의 불포화된 부틴올라이드(butenolide)의 경우는 중요한 특징만큼이나 비대칭 합성에서 다양한 카이랄 중간체로서 사용될 수 있다. 이에 카이랄성을 도입하기 위해 Os을 매개로 하여 베타, 감마 불포화 에스테르(ester)의 비대칭 디하이드록실화(dihydroxylation)를 할 수 있었다(Harcken, C.; Br

Figure 112019040023935-pat00001
ckner, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2750).The gamma-butyrolactone skeleton is present in over 13,000 natural products. The asymmetric synthesis method of gammalactone, which has important physiological activities such as antibiotics and anticancer drugs, has been studied for a long time through various approaches. In particular, the alpha- and beta-position unsaturated butenolide containing a substituent at the gamma position can be used as a variety of chiral intermediates in asymmetric synthesis as well as an important feature. Accordingly, in order to introduce chirality, asymmetric dihydroxylation of beta and gamma unsaturated esters could be performed via Os (Harcken, C.; Br;
Figure 112019040023935-pat00001
ckner, R. Angew. Chem., Int. Ed. Engl. 1997, 36 , 2750).

또한 Cu 촉매를 사용한 헤테로알릴릭 비대칭 알킬화 반응을 통해서 비대칭성을 도입할 수 있었다(Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 15572). 감마-부틸로락톤의 골격을 지닌 천연물 중에 하나인 자일로집락톤은 최근 2014년 처음으로 구조가 알려졌다(Chang, Y.-C.; Lu, C.-K.; Chiang, Y.-R.; Wang, G.-J.; Ju, Y.-M.; Kuo, Y.-H.; Lee, T.-H. J. Nat. Prod. 2014, 77, 751).In addition, asymmetry could be introduced through a heteroallylic asymmetric alkylation reaction using a Cu catalyst (Geurts, K.; Fletcher, SP; Feringa, BL J. Am. Chem. Soc. 2006, 128 , 15572). One of the natural products with a skeleton of gamma-butyrolactone, xylocolactone was recently known for the first time in 2014 (Chang, Y.-C.; Lu, C.-K.; Chiang, Y.-R. ; Wang, G.-J.; Ju, Y.-M.; Kuo, Y.-H.; Lee, T.-H. J. Nat. Prod. 2014, 77 , 751).

콩꼬투리버섯과(Xylariaceae) 계열은 온화한 지역부터 열대지역까지 널리 분포되어 있는 자낭균으로 몇몇은 중국에서 전통적으로 사용되어온 약으로 분류가 되어있고 이는 콩꼬투리버섯과 균사체가 치료제로서 개발될 수 있는 가능성을 보여준다. 2014년에 보고된 바에 의하면 네가지 새로운 테트라사이클릭 디테르펜 글리코시드(tetracyclic diterpene glycosides), 즉 소르다린(sordarins) C-F와 세가지 새로운 감마-락톤 폴리케티드(polyketides), 즉 자일로집락톤(Xylogiblactone) A-C가 소르다린과 함께 자일로투물러스 지비스포러스(Xylotumulus gibbisporus) YMJ863의 이차 대사물질들로서 얻어졌다.The Xylariaceae family is widely distributed from temperate to tropical regions, and some are classified as medicines that have been traditionally used in China, and this is the possibility that soybean pod mushrooms and mycelium can be developed as therapeutic agents. Show. Reported in 2014, four new tetracyclic diterpene glycosides, namely sordarins CF and three new gamma-lactone polyketides, namely Xylogiblactone. AC was obtained as secondary metabolites of Xylotumulus gibbisporus YMJ863 along with sordarin.

이들 천연물들은 매우 높은 항진균성을 보여주었고 향후 치료제로써 개발 가능성이 높은 천연물로 판단된다. 순수한 광학활성을 띄는 감마-락톤 천연물질은 자연에 제한된 양으로 얻어지고 천연물질로부터 유도되는 다양한 구조 역시 모두 새로운 합성방법의 개발로 이룰 수 있다.These natural products showed very high antifungal properties and are considered to be natural products with high potential for development as therapeutics in the future. The pure optically active gamma-lactone natural substance is obtained in limited amounts in nature, and various structures derived from natural substances can also be achieved through the development of new synthetic methods.

알데히드의 알돌반응(Aldol reaction)은 비대칭합성분야에서 가장 많이 연구되어진 화학 반응이다. 알데히드에 에놀레이트(Enolate)를 부가하여 3-하이드록시 카르보닐기를 생성하는 비교적 단순한 형태의 이 반응은 부분입체 선택반응으로부터 촉매비대칭 반응에 이르기까지 연구대상으로 많이 활용되었다. 또한, 결과된 입체선택의 요인에 관한 이해 증진은 궁극적으로 새로운 화학세계의 내면을 엿볼 수 있는 기회를 제공하였다. 생성물은 비교적 단순하지만 하이드록시기와 카르보닐기가 포함되어 있기 때문에 기능기 전환에 의한 유용한 화합물, 특히 천연물 및 의약품을 포함하는 생리활성물질의 합성에 많이 응용되고 있다.Aldol reaction of aldehyde is the most studied chemical reaction in the field of asymmetric synthesis. This relatively simple reaction in which a 3-hydroxycarbonyl group is generated by adding enolate to an aldehyde has been widely used for research from diasteremic selective reactions to catalytic asymmetric reactions. In addition, the increased understanding of the resulting three-dimensional selection factors ultimately provided an opportunity to glimpse the inside of the new chemical world. Although the product is relatively simple, since it contains a hydroxy group and a carbonyl group, it has been widely applied in the synthesis of useful compounds by functional group conversion, particularly physiologically active substances including natural products and pharmaceuticals.

"속도론적 분할(Kinetic resolution)"은 두 거울상이 반씩 섞여있는 라세믹 혼합물의 속도차이를 이용한 반응을 의미하고, 하나의 거울상이성체(enantiomer)를 혼합물로부터 얻을 수 있는 것은 정제를 위한 비용과 시간적인 측면에서 매우 경제적이라고 할 수 있는 접근법이다. 이는 특이성이 있는 생체내 효소작용과 유사하다. 그럼에도 불구하고 산화 및 환원반응의 소수 예에서만 그 효율성이 입증되었을 정도로 제한되어져 왔다. 따라서 효율성이 입증된 방법론의 개발은 현대화학에서 매우 긴요한 과제로 인식되고 있다."Kinetic resolution" refers to a reaction using the difference in velocity of a racemic mixture in which two mirror images are mixed in half, and obtaining one enantiomer from the mixture is cost and time for purification. This is a very economical approach. This is similar to the specific in vivo enzyme action. Nevertheless, it has been limited to the extent that its effectiveness has been demonstrated in only a few examples of oxidation and reduction reactions. Therefore, the development of a methodology with proven effectiveness is recognized as a very important task in modern chemistry.

순수한 하나의 거울상 이성체(enantiomer)의 기질을 높은 순도로 합성하는 것은 상당한 노력과 시간이 필요하며 방법론적인 제약이 많이 뒤따른다. 상대적으로 손쉽게 얻을 수 있는 라세믹 혼합물(racemic mixture)의 화학적 혹은 물리적인 분할에는 역시 많은 제약과 엄청난 비용이 필수적이다. 이에 따라 속도론적 분할법이 관심을 모으게 되었다.Synthesis of a pure single enantiomer substrate with high purity requires considerable effort and time, and is subject to many methodological limitations. The chemical or physical partitioning of a racemic mixture, which can be obtained relatively easily, also requires a number of restrictions and enormous costs. Accordingly, the kinetic division method attracted attention.

이에 본 발명자들은 라세믹 혼합물의 속도차이를 이용한 반응법으로서 하나의 거울상이성체(enantiomer)를 혼합물로부터 수득함으로써, 비용 및 시간적 측면에서 효율적으로 감마-락톤을 합성할 수 있으며, 온화한 조건에서 안전하게 합성할 수 있음을 확인하였다.Therefore, the present inventors obtained one enantiomer from the mixture as a reaction method using the difference in the rate of the racemic mixture, thereby efficiently synthesizing gamma-lactone in terms of cost and time, and can be safely synthesized under mild conditions. It was confirmed that it can be.

이에, 본 발명의 목적은 속도론적 분할(kinetic resolution)을 통한 비대칭 알돌반응에 의한 감마-락톤(gamma-lactone) 합성방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a method for synthesizing gamma-lactone by asymmetric aldol reaction through kinetic resolution.

본 발명의 또 다른 목적은 자일로집락톤(Xylogiblactone)의 합성방법을 제공하는 것이다.Another object of the present invention is to provide a method for synthesizing xylogiblactone.

본 발명은 속도론적 분할을 통한 비대칭 알돌반응에 의한 감마-락톤 합성방법에 관한 것으로, 본 발명에 따른 방법은 라세믹 혼합물의 속도차이를 이용한 반응법으로서 하나의 거울상이성체(enantiomer)를 혼합물로부터 수득함으로써, 비용 및 시간적 측면에서 효율적으로 감마-락톤을 합성하는 방법을 제공한다. The present invention relates to a method for synthesizing gamma-lactone by an asymmetric aldol reaction through kinetic partitioning, and the method according to the present invention is a reaction method using a difference in speed of a racemic mixture to obtain one enantiomer from the mixture. By doing so, it provides a method for efficiently synthesizing gamma-lactone in terms of cost and time.

본 발명자들은 효율적인 비대칭 알돌반응 조절기를 도입하여 높은 선택성으로 광학이성질체를 합성할 수 있으며, 온화한 조건에서 안전하게 합성할 수 있음을 확인하였다.The present inventors have confirmed that optical isomers can be synthesized with high selectivity by introducing an efficient asymmetric aldol reaction regulator, and can be synthesized safely under mild conditions.

특히 알돌반응과 같은 카보닐 작용기와의 부가 반응에서 속도론적 분할은 특정한 기질분자에서 특정한 알데히드와의 극소수의 예만이(현재까지 2편) 보고되었고 대부분 낮은 선택성을 보여주는 것으로 논문 검색결과 판명되었다.In particular, in addition reactions with carbonyl functional groups such as aldol reaction, only a few instances of kinetic splitting with a specific aldehyde in a specific substrate molecule (2 so far) were reported, and most of them showed low selectivity.

본 발명에서 개발한 반응은 라세믹 혼합형태의 알데히드를 사용했을 때 하나의 거울상 이성체가 빠른 속도로 반응하여 선택적인 감마부가물질을 제공하는 것으로 확인되었고 상대/절대 입체화학은 다음의 X-ray 결정구조 분석을 통해서 확인할 수 있었다. 높은 선택성은 다음의 입체장애로 인한 전이상태 에너지의 차이로 기인한 것으로 이해하고 매우 특징적으로 반주입적(anti-Cram) 선택성을 보이는 것을 확인하였다.The reaction developed in the present invention was confirmed that when a racemic mixed aldehyde was used, one enantiomer reacted at a high rate to provide a selective gamma adduct, and the relative/absolute stereochemistry was determined by the following X-ray determination. It could be confirmed through structural analysis. The high selectivity was understood to be due to the difference in the energy of the transition state due to the following steric hindrance, and it was confirmed that it exhibited very characteristic anti-Cram selectivity.

이하 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.

본 발명의 일 양태는 다음의 단계를 포함하는 속도론적 분할(kinetic resolution)을 통한 비대칭 알돌반응에 의한 감마-락톤(gamma-lactone) 합성방법을 제공하는 것이다:One aspect of the present invention is to provide a method for synthesizing gamma-lactone by asymmetric aldol reaction through kinetic resolution comprising the following steps:

화학식 3a의 화합물에 화학식 4의 화합물 및 다이이소프로필에틸아민(i-Pr2Net, 화학식 5)을 반응시킨 후 화학식 6의 화합물을 첨가하여 화학식 7a의 화합물을 얻는, 화학식 7a의 화합물 합성 단계;Synthesizing a compound of formula 7a to obtain a compound of formula 7a by reacting a compound of formula 4 and diisopropylethylamine ( i- Pr 2 Net, formula 5) with the compound of formula 3a and then adding the compound of formula 6;

<화학식 3a><Formula 3a>

Figure 112019040023935-pat00002
Figure 112019040023935-pat00002

<화학식 4><Formula 4>

Figure 112019040023935-pat00003
Figure 112019040023935-pat00003

<화학식 6><Formula 6>

Figure 112019040023935-pat00004
Figure 112019040023935-pat00004

<화학식 7a><Formula 7a>

Figure 112019040023935-pat00005
Figure 112019040023935-pat00005

상기 화학식 7a의 화합물을 클로로(트리페닐포스핀)골드(I)(ClAuPPh3, 화학식 10) 및 실버테트라플루오로보레이트(AgBF4, 화학식 11) 촉매 존재하에서 반응시켜 화학식 13a의 화합물을 얻는, 화학식 13a의 화합물 합성 단계; 및The compound of Formula 7a is reacted in the presence of a catalyst of chloro (triphenylphosphine) gold (I) (ClAuPPh 3 , Formula 10) and silver tetrafluoroborate (AgBF 4 , Formula 11) to obtain a compound of Formula 13a, Synthesis of the compound of 13a; And

<화학식 13a><Formula 13a>

Figure 112019040023935-pat00006
Figure 112019040023935-pat00006

상기 화학식 13a의 화합물에 염산(HCl, 화학식 12)을 반응시켜 화학식 14a의 화합물을 합성하는, 화학식 14a의 화합물 합성 단계Synthesis of the compound of Formula 14a by reacting the compound of Formula 13a with hydrochloric acid (HCl, Formula 12) to synthesize the compound of Formula 14a

<화학식 14a><Formula 14a>

Figure 112019040023935-pat00007
;
Figure 112019040023935-pat00007
;

상기 식에서,In the above formula,

Tol은 4-메틸페닐이고,Tol is 4-methylphenyl,

R'은 메틸(Me) 또는 에틸(Et)이고,R'is methyl (Me) or ethyl (Et),

R은 Me, 페닐(Ph), PhCH2CH2, (CH3)2CH, Me2CH 또는 MeCl이다.R is Me, phenyl (Ph), PhCH 2 CH 2 , (CH 3 ) 2 CH, Me 2 CH or MeCl.

상기 화학식 3a의 화합물은 화학식 1a의 화합물에 트리브로모보란(BBr3, 화학식 2)을 반응시켜 얻는 것일 수 있다The compound of Formula 3a may be obtained by reacting tribromoborane (BBr 3 , Formula 2) with the compound of Formula 1a.

<화학식 1a><Formula 1a>

Figure 112019040023935-pat00008
.
Figure 112019040023935-pat00008
.

상기 화학식 1a의 화합물과 트리브로모보란은 0.8 내지 1.2 : 0.8 내지 1.2의 당량비로 사용되는 것일 수 있고, 예를 들어, 1:1로 사용되는 것일 수 있으나, 이에 한정되는 것은 아니다.The compound of Formula 1a and tribromoborane may be used in an equivalent ratio of 0.8 to 1.2: 0.8 to 1.2, and for example, may be used at 1:1, but are not limited thereto.

상기 화학식 7a의 화합물 합성 단계는 화학식 3a의 화합물, 다이이소프로필에틸아민, 화학식 4의 화합물을 0.8 내지 1.2 : 1.0 내지 1.5 : 0.8 내지 1.2의 당량비로 사용하여 수행되는 것일 수 있고, 예를 들어, 1.0:1.2:1.0의 당량비로 수행되는 것일 수 있으나,이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 7a may be performed by using the compound of Formula 3a, diisopropylethylamine, and the compound of Formula 4 in an equivalent ratio of 0.8 to 1.2: 1.0 to 1.5: 0.8 to 1.2, for example, It may be performed in an equivalent ratio of 1.0:1.2:1.0, but is not limited thereto.

상기 화학식 7a의 화합물 합성 단계는 -60 내지 -40℃에서 수행되는 것일 수 있고, 예를 들어, -50℃에서 수행되는 것일 수 있으나, 이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 7a may be performed at -60 to -40°C, for example, may be performed at -50°C, but is not limited thereto.

상기 화학식 14a의 화합물 합성 단계는 HCl과 8 내지 15시간 동안 반응시켜 수행되는 것일 수 있고, 예를 들어, 12시간 동안 반응시켜 수행되는 것일 수 있으나, 이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 14a may be performed by reacting with HCl for 8 to 15 hours, for example, may be performed by reacting for 12 hours, but is not limited thereto.

본 발명의 다른 양태는 다음의 단계를 포함하는 속도론적 분할을 통한 비대칭 알돌반응에 의한 감마-락톤 합성방법이다:Another aspect of the present invention is a method for synthesizing gamma-lactone by asymmetric aldol reaction through kinetic division comprising the following steps:

화학식 3b의 화합물에 화학식 4의 화합물 및 다이이소프로필에틸아민(i-Pr2Net)을 반응시킨 후 화학식 6의 화합물을 더 첨가하여 화학식 7b의 화합물을 얻는, 화학식 7b의 화합물 합성 단계;Synthesizing a compound of formula 7b to obtain a compound of formula 7b by reacting a compound of formula 4 and diisopropylethylamine ( i- Pr 2 Net) with the compound of formula 3b and then further adding the compound of formula 6;

<화학식 3b><Formula 3b>

Figure 112019040023935-pat00009
Figure 112019040023935-pat00009

<화학식 7b><Formula 7b>

Figure 112019040023935-pat00010
Figure 112019040023935-pat00010

상기 화학식 7b의 화합물을 클로로(트리페닐포스핀)골드(I)(ClAuPPh3) 및 실버테트라플루오로보레이트(AgBF4) 촉매 존재하에서 반응시켜 화학식 13b의 화합물을 얻는, 화학식 13b의 화합물 합성 단계; 및Synthesis of the compound of Formula 13b by reacting the compound of Formula 7b in the presence of a chloro (triphenylphosphine) gold (I) (ClAuPPh 3 ) and silver tetrafluoroborate (AgBF 4 ) catalyst to obtain a compound of Formula 13b; And

<화학식 13b><Formula 13b>

Figure 112019040023935-pat00011
Figure 112019040023935-pat00011

상기 화학식 13b의 화합물에 HCl을 반응시켜 화학식 14b의 화합물을 합성하는, 화학식 14b의 화합물 합성 단계Synthesis of the compound of Formula 14b by reacting HCl with the compound of Formula 13b to synthesize the compound of Formula 14b

<화학식 14b><Formula 14b>

Figure 112019040023935-pat00012
;
Figure 112019040023935-pat00012
;

상기 식에서,In the above formula,

Tol은 4-메틸페닐이고,Tol is 4-methylphenyl,

R'은 메틸(Me) 또는 에틸(Et)이고,R'is methyl (Me) or ethyl (Et),

R은 Me, 페닐(Ph), PhCH2CH2, (CH3)2CH, Me2CH 또는 MeCl이다.R is Me, phenyl (Ph), PhCH 2 CH 2 , (CH 3 ) 2 CH, Me 2 CH or MeCl.

상기 화학식 3b의 화합물은 화학식 1b의 화합물에 트리브로모보란(BBr3)을 반응시켜 얻는 것일 수 있다The compound of Formula 3b may be obtained by reacting tribromoborane (BBr 3 ) with the compound of Formula 1b.

<화학식 1b><Formula 1b>

Figure 112019040023935-pat00013
.
Figure 112019040023935-pat00013
.

상기 화학식 1b의 화합물과 트리브로모보란은 0.8 내지 1.2 : 0.8 내지 1.2의 당량비로 사용되는 것일 수 있고, 예를 들어, 1:1로 사용되는 것일 수 있으나, 이에 한정되는 것은 아니다.The compound of Formula 1b and tribromoborane may be used in an equivalent ratio of 0.8 to 1.2: 0.8 to 1.2, and for example, may be used in a 1:1 ratio, but the present invention is not limited thereto.

상기 화학식 7b의 화합물 합성 단계는 화학식 3b의 화합물, 다이이소프로필에틸아민, 화학식 4의 화합물을 0.8 내지 1.2 : 1.0 내지 1.5 : 0.8 내지 1.2의 당량비로 사용하여 수행되는 것일 수 있고, 예를 들어, 1.0:1.2:1.0의 당량비로 수행되는 것일 수 있으나,이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 7b may be performed using the compound of Formula 3b, diisopropylethylamine, and the compound of Formula 4 in an equivalent ratio of 0.8 to 1.2: 1.0 to 1.5: 0.8 to 1.2, for example, It may be performed in an equivalent ratio of 1.0:1.2:1.0, but is not limited thereto.

상기 화학식 7b의 화합물 합성 단계는 -60 내지 -40℃에서 수행되는 것일 수 있고, 예를 들어, -50℃에서 수행되는 것일 수 있으나, 이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 7b may be performed at -60 to -40°C, for example, but may be performed at -50°C, but is not limited thereto.

상기 화학식 14b의 화합물 합성 단계는 HCl과 8 내지 15시간 동안 반응시켜 수행되는 것일 수 있고, 예를 들어, 12시간 동안 반응시켜 수행되는 것일 수 있으나, 이에 한정되는 것은 아니다.The step of synthesizing the compound of Formula 14b may be performed by reacting with HCl for 8 to 15 hours, for example, may be performed by reacting for 12 hours, but is not limited thereto.

본 발명의 다른 양태는 자일로집락톤(Xylogiblactone)의 합성방법을 제공하는 것이다.Another aspect of the present invention is to provide a method for synthesizing xylogiblactone.

항진균성을 지닌 것으로 보고된 자일로집락톤 뿐만 아니라 감마락톤 골격을 지닌 천연물은 상당히 많이 존재하며 다양한 생리활성을 지닌 것으로 보고되어 있다. 따라서 본 발명에서 개발한 속도론적 분할법을 이용한 알렌노에이트 알돌반응을 이용한다면 천연/비천연 포함 다양한 유도체들의 합성이 가능하며 이는 향후 신약개발과 관련하여 매우 중요한 합성방법 발명이라 할 수 있다.There are quite a lot of natural products with a gamma lactone skeleton as well as xylocolactone reported to have antifungal properties and are reported to have various physiological activities. Therefore, if the allennoate aldol reaction using the kinetic splitting method developed in the present invention is used, it is possible to synthesize various derivatives including natural/non-natural, which can be said to be a very important synthesis method invention in connection with the future development of new drugs.

본 발명은 속도론적 분할을 통한 비대칭 알돌반응에 의한 감마-락톤 합성방법에 관한 것으로서, 더욱 상세하게는 라세믹 혼합물의 속도차이를 이용한 반응법으로서 하나의 거울상이성체(enantiomer)를 혼합물로부터 수득함으로써, 비용 및 시간적 측면에서 효율적으로 감마-락톤 및 자일로집락톤 등의 합성에 이용할 수 있다.The present invention relates to a method for synthesizing gamma-lactone by an asymmetric aldol reaction through kinetic division, and more particularly, as a reaction method using a difference in speed of a racemic mixture, by obtaining one enantiomer from the mixture, In terms of cost and time, it can be efficiently used for synthesis of gamma-lactone and xylocolactone.

이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 "%"는 별도의 언급이 없는 경우, 고체/고체는 (중량/중량)%, 고체/액체는 (중량/부피)%, 그리고 액체/액체는 (부피/부피)%이다.Throughout this specification, "%" used to indicate the concentration of a specific substance is (weight/weight)% for solids/solids, (weight/volume)% for solids/liquids, and Liquid/liquid is (vol/vol)%.

실시예 1: 새로운 비대칭 알돌반응의 개발에 의한 6-실릴옥시-5-하이드록시-2-메틸헵타-2,3-다이에노에이트 유도체의 합성Example 1: Synthesis of 6-silyloxy-5-hydroxy-2-methylhepta-2,3-dienoate derivative by development of a new asymmetric aldol reaction

본 발명의 가장 기본적인 과제는 효율적인 비대칭반응 조절기의 도입과 보고되지 않은 부틸 알레노에이트와의 반응과 라세믹 알데히드 선택적 부가 반응조건의 확립이다.The most basic task of the present invention is the introduction of an efficient asymmetric reaction regulator and the establishment of unreported reactions with butyl allenoate and racemic aldehyde selective addition reaction conditions.

부분과 절대 입체선택성은 매우 높았다. 생성물의 핵자기공명(nuclear magnetic resonance; NMR)과 그것의 MTPA-에스테르(ester)의 NMR 분석결과 91 ~ >99% ee(Enantiomeric excess) 범위를 보여주었다. 대부분의 실시예에서 95% ee 이상의 입체선택성(Enantioselectivity)을 나타내었다.The partial and absolute stereoselectivity was very high. Nuclear magnetic resonance (NMR) of the product and NMR analysis of its MTPA-ester showed a range of 91 to >99% ee (Enantiomeric excess). In most examples, it exhibited enantioselectivity of 95% ee or more.

위치선택성의 확립에 따라 서로 다른 생성물을 얻을 수 있기 때문에, 본 발명의 일 실시예를 통해 감마 위치 선택 생성물을 높은 입체선택성으로 얻을 수 있다.Since different products can be obtained according to the establishment of regioselectivity, a gamma regioselection product can be obtained with high stereoselectivity through an embodiment of the present invention.

1-1. (R,R)-비스설폰아미딜브로모보란(화학식 3a)의 합성1-1. Synthesis of (R,R)-bissulfonamidylbromoborane (Chemical Formula 3a)

비대칭조절기인 (R,R)-비스설포닐아미드(화학식 1a)과 트리브로모보란(BBr3, 화학식 2)의 반응을 통한 (R,R)-비스설폰아미딜브로모보란(화학식 3a)의 합성을 문헌에 보고된 방법을 이용하여 수행하였다(Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495; Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112, 878).(R,R)-bissulfonamidylbromoborane (Chemical Formula 3a) through the reaction of an asymmetric regulator (R,R)-bissulfonylamide (Formula 1a) and tribromoborane (BBr 3 , Formula 2) Was performed using the method reported in the literature (Corey, EJ; Yu, C.-M.; Kim, SS J. Am. Chem. Soc. 1989, 111 , 5495; Corey, EJ; Yu, C. .-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112 , 878).

구체적으로, 오븐에서 건조된 쉬링크 플라스크(Schlenk flask)를 질소 조건하에서 식힌 다음 (R,R)-비스설폰아미드(화학식 1a, 1 당량)을 가하였다. 여기에 다이클로로메탄(CH2Cl2)을 가하여 녹여 주었다. 용액을 0℃로 낮춘 후 트리브로모보란 용액 1 당량을 천천히 가하였다. 20℃로 온도를 올려준 다음 1.5시간 동안 반응을 진행하였다. 쉬링크 플라스크의 옆가지를 이용하여 0.5 torr 진공펌프로 감압하여 공기접촉을 피하면서 증류하여 용매 등의 휘발성물질을 제거하고, 다시 다이클로로메탄을 부가하였다. 이때 화학식 1a의 화합물과 트리브로모보란의 비율은 1:1 당량이 가장 적합하였다. 생성된 (R.R)-비스설폰아미딜브로모보란(화학식 3a)은 공기중에서 매우 불안하여 분리 정제하지 않고 다음 반응을 진행하였다.Specifically, an oven-dried Schlenk flask was cooled under nitrogen conditions, and then (R,R)-bissulfonamide (Formula 1a, 1 equivalent) was added. Dichloromethane (CH 2 Cl 2 ) was added thereto to dissolve. After lowering the solution to 0°C, 1 equivalent of tribromoborane solution was slowly added. After raising the temperature to 20° C., the reaction was carried out for 1.5 hours. Using a side branch of the shrink flask, the pressure was reduced with a 0.5 torr vacuum pump and distilled while avoiding air contact to remove volatile substances such as solvents, and dichloromethane was added again. At this time, the ratio of the compound of Formula 1a and tribromoborane was the most suitable 1:1 equivalent. The resulting (RR)-bissulfonamidylbromoborane (Chemical Formula 3a) was very unstable in air, so the next reaction was carried out without separation and purification.

<반응식 1><Reaction Scheme 1>

Figure 112019040023935-pat00014
Figure 112019040023935-pat00014

1-2. 1-2. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸헵타-2,3-다이에노에이트(화학식 7, R’=R=Me; 화학식 7a-1)의 합성Synthesis of -butyldimethylsilyl)oxy)-5-hydroxy-2-methylhepta-2,3-dienoate (Chemical Formula 7, R'=R=Me; Formula 7a-1)

생성된 화학식 3a의 화합물에 다이클로로메탄을 가하여 녹이고 -50℃로 온도를 낮춘 다음, 1.2 당량의 다이이소프로필에틸아민(i-Pr2Net, 화학식 5)과 1 당량의 t-부틸 알렌노에이트(화학식 4, t-butyl allenoate 혹은 tert-butyl 2-methylbuta-2,3-dienoate)를 같이 부가하였다. t-부틸 알렌노에이트(화학식 4)는 문헌에 보고된 방법에 의하여 합성하였다(Lu, K.; Kwon, O. Org. Synth. 2009, 86, 212). 이 때 반응 시간은 20분이 가장 적합하였다.Dichloromethane was added to the resulting compound of Formula 3a to dissolve it, lowered the temperature to -50°C, and then 1.2 equivalents of diisopropylethylamine ( i- Pr 2 Net, Formula 5) and 1 equivalent of t -butyl allennoate (Formula 4, t- butyl allenoate or tert- butyl 2-methylbuta-2,3-dienoate) was added together. t -butyl allennoate (Chemical Formula 4) was synthesized according to the method reported in the literature (Lu, K.; Kwon, O. Org. Synth. 2009 , 86, 212). At this time, the reaction time was most suitable for 20 minutes.

상기 반응용액에 알데히드 화합물(화학식 6, R=Me; 화학식 6-1)를 -50℃에서 10분 동안 천천히 가하였다. 이 온도에서 1시간 동안 반응시킨 후 NaHCO3 수용액을 부가한 다음 상온으로 온도를 올려 주었다. 수용액 층을 다이클로로메탄으로 두 번 추출한 뒤 혼합 용액을 MgSO4로 건조시켰다.An aldehyde compound (Chemical Formula 6, R=Me; Formula 6-1) was slowly added to the reaction solution at -50°C for 10 minutes. After reacting at this temperature for 1 hour, NaHCO 3 aqueous solution was added and the temperature was raised to room temperature. After the aqueous layer was extracted twice with dichloromethane, the mixed solution was dried over MgSO 4 .

<화학식 6-1><Formula 6-1>

Figure 112019040023935-pat00015
Figure 112019040023935-pat00015

여과하여 고체를 제거한 다음 얻어진 생성물을 실리카젤 크로마토그래피(용매, 에틸아세테이트와 핵산 혼합용액)로 분리정제하여 화학식 7(R' = R = Me)의 생성물인 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸헵타-2,3-다이엔노에이트(화학식 7a-1)를 얻었다. 이 때에 반응 온도는 -50℃가 가장 적합하였다.After removing the solid by filtration, the obtained product was separated and purified by silica gel chromatography (solvent, ethyl acetate and nucleic acid mixture solution) to obtain tert -butyl-6-(( tert -), a product of formula 7 (R' = R = Me). Butyldimethylsilyl)oxy)-5-hydroxy-2-methylhepta-2,3-dienoate (Chemical Formula 7a-1) was obtained. At this time, the reaction temperature was most suitable -50°C.

<반응식 2><Reaction Scheme 2>

Figure 112019040023935-pat00016
Figure 112019040023935-pat00016

<화학식 7a-1><Formula 7a-1>

Figure 112019040023935-pat00017
Figure 112019040023935-pat00017

수득율: 68%(20:1 dr)Yield: 68% (20:1 dr)

[α]D 20 +30.7° (c 0.008, CHCl3)[α] D 20 +30.7° (c 0.008, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.10 (s, 6H), 0.92 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 1.46 (s, 9H), 1.87 (d, J = 2.9 Hz, 3H), 2.69 (d, J = 3.7 Hz, 1H), 3.74 (dq, J = 6.0, 6.0 Hz, 1H), 3.94 (ddd, J = 7.9, 6.0, 3.7 Hz, 1H), 5.40 (dq, J = 7.9, 2.9 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.10 (s, 6H), 0.92 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 1.46 (s, 9H), 1.87 (d, J = 2.9 Hz, 3H), 2.69 (d, J = 3.7 Hz, 1H), 3.74 (dq, J = 6.0, 6.0 Hz, 1H), 3.94 (ddd, J = 7.9, 6.0, 3.7 Hz, 1H), 5.40 (dq, J = 7.9, 2.9 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.80, -4.20, 15.0, 18.0, 19.9, 25.8, 28.1, 72.3, 74.7, 80.9, 94.2, 98.5, 166.5, 209.7 13 C NMR (125 MHz, CDCl 3 ): δ -4.80, -4.20, 15.0, 18.0, 19.9, 25.8, 28.1, 72.3, 74.7, 80.9, 94.2, 98.5, 166.5, 209.7

MS m/z (%) 343.2301 (M+H)+ MS m/z (%) 343.2301 (M+H) +

화학식 7a를 합성하는 동일한 과정을 (S,S)-비스설포닐아미드(화학식 1b)로부터 수행하면 화학식 7a의 화합물과 광학이성체인 화합식 7b의 화합물을 합성할 수 있다.If the same procedure for synthesizing Formula 7a is performed from (S,S)-bissulfonylamide (Formula 1b), the compound of Formula 7a and the compound of Formula 7b, which is an optical isomer, can be synthesized.

<반응식 3><Reaction Scheme 3>

Figure 112019040023935-pat00018
Figure 112019040023935-pat00018

1-3. 1-3. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸-6-페닐헥사-2,3-다이에노에이트(화학식 7, R' = Me, R = Ph; 이하 화학식 7a-2)의 합성-Butyldimethylsilyl)oxy)-5-hydroxy-2-methyl-6-phenylhexa-2,3-dienoate (Chemical Formula 7, R'= Me, R = Ph; hereinafter Formula 7a-2) Synthesis of

상기 1-2와 같이 수행하되, 화학식 7(R' = Me, R = Ph)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸-6-페닐헥사-2,3-다이엔노에이트(화학식 7a-2)를 얻었다.Performed as in 1-2 above, but tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-5-hydroxy-2-methyl as a product of Formula 7 (R' = Me, R = Ph) -6-phenylhexa-2,3-dienoate (Chemical Formula 7a-2) was obtained.

<화학식 7a-2><Formula 7a-2>

Figure 112019040023935-pat00019
Figure 112019040023935-pat00019

수득율: 54%(5:1 dr)Yield: 54% (5:1 dr)

[α]D 20 +94.5° (c 0.006, CHCl3)[α] D 20 +94.5° (c 0.006, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.00 (s, 3H), 0.22 (s, 3H), 1.06 (s, 9H), 1.58 (s, 9H), 1.85 (d, J = 3.0 Hz, 3H), 2.73 (d, J = 5.9 Hz, 1H), 4.45 (ddd, J = 5.9, 5.9, 5.1 Hz, 1H), 4.80 (d, J = 5.1 Hz, 1H), 5.62 (dq, J = 5.9, 3.0 Hz, 1H), 7.38-7.53 (m, 5H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.00 (s, 3H), 0.22 (s, 3H), 1.06 (s, 9H), 1.58 (s, 9H), 1.85 (d, J = 3.0 Hz, 3H ), 2.73 (d, J = 5.9 Hz, 1H), 4.45 (ddd, J = 5.9, 5.9, 5.1 Hz, 1H), 4.80 (d, J = 5.1 Hz, 1H), 5.62 (dq, J = 5.9, 3.0 Hz, 1H), 7.38-7.53 (m, 5H)

13C NMR (125 MHz, CDCl3): δ -5.04, -4.61, 14.86, 18.15, 25.77, 28.04, 73.68, 78.33, 80.67, 94.38, 99.62, 127.01, 127.86, 128.05, 140.52, 166.52, 208.77 13 C NMR (125 MHz, CDCl 3 ): δ -5.04, -4.61, 14.86, 18.15, 25.77, 28.04, 73.68, 78.33, 80.67, 94.38, 99.62, 127.01, 127.86, 128.05, 140.52, 166.52, 208.77

MS m/z (%) 405.2458 (M+H)+ MS m/z (%) 405.2458 (M+H) +

1-4. 1-4. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸-8-페닐옥타-2,3-다이에노에이트(화학식 7, R' = Me, R = PhCH-Butyldimethylsilyl)oxy)-5-hydroxy-2-methyl-8-phenylocta-2,3-dienoate (Formula 7, R'= Me, R = PhCH 22 CHCH 22 ; 이하 화학식 7a-3)의 합성; Synthesis of Formula 7a-3) below

상기 1-2와 같이 수행하되, 화학식 7(R' = Me, R = PhCH2CH2)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-5-하이드록시-2-메틸-8-페닐옥타-2,3-다이엔노에이트(화학식 7a-3)를 얻었다.Performed as in 1-2 above, but as a product of Formula 7 (R' = Me, R = PhCH 2 CH 2 ) tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-5-hydroxy- 2-methyl-8-phenylocta-2,3-dienoate (Chemical Formula 7a-3) was obtained.

<화학식 7a-3><Formula 7a-3>

Figure 112019040023935-pat00020
Figure 112019040023935-pat00020

수득율: 61%(>50:1 dr)Yield: 61% (>50:1 dr)

[α]D 20 +29.4° (c 0.018, CHCl3)[α] D 20 +29.4° (c 0.018, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.120 (s, 3H), 0.123 (s, 3H), 0.95 (s, 9H), 1.41 (s, 9H), 1.80-1.86 (m, 1H), 1.87 (d, J = 2.9 Hz, 3H), 1.96-2.07 (m, 1H), 2.47 (d, J = 6.1 Hz, 1H), 2.69 (t, J = 8.3 Hz, 2H), 3.74 (ddd, J = 5.6, 5.6, 4.6 Hz, 1H), 4.22 (ddd, J = 7.0, 6.1, 4.6 Hz, 1H ), 5.50 (dq, J = 7.0, 2.9 Hz, 1H), 7.15-7.22 (m, 3H), 7.24-7.32 (m, 2H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.120 (s, 3H), 0.123 (s, 3H), 0.95 (s, 9H), 1.41 (s, 9H), 1.80-1.86 (m, 1H), 1.87 (d, J = 2.9 Hz, 3H), 1.96-2.07 (m, 1H), 2.47 (d, J = 6.1 Hz, 1H), 2.69 (t, J = 8.3 Hz, 2H), 3.74 (ddd, J = 5.6, 5.6, 4.6 Hz, 1H), 4.22 (ddd, J = 7.0, 6.1, 4.6 Hz, 1H ), 5.50 (dq, J = 7.0, 2.9 Hz, 1H), 7.15-7.22 (m, 3H), 7.24 -7.32 (m, 2H)

13C NMR (125 MHz, CDCl3): δ -4.43, -4.25, 15.1, 18.1, 25.9, 28.0, 31.4, 35.0, 71.5, 75.2, 80.9, 95.1, 99.1, 125.8, 128.3, 128.4, 141.9, 166.5, 209.0 13 C NMR (125 MHz, CDCl 3 ): δ -4.43, -4.25, 15.1, 18.1, 25.9, 28.0, 31.4, 35.0, 71.5, 75.2, 80.9, 95.1, 99.1, 125.8, 128.3, 128.4, 141.9, 166.5, 209.0

MS m/z (%) 433.2771 (M+H)+ MS m/z (%) 433.2771 (M+H) +

1-5. 1-5. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-5-하이드록시-2,7-다이메틸옥타-2,3-다이에노에이트(화학식 7, R' = Me, R = (CH-Butyldimethylsilyl)oxy)-5-hydroxy-2,7-dimethylocta-2,3-dienoate (Formula 7, R'= Me, R = (CH 33 )) 22 CH; 이하 화학식 7a-4)의 합성CH; Synthesis of Formula 7a-4) below

상기 1-2와 같이 수행하되, 화학식 7(R' = Me, R = (CH3)2CH)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-5-하이드록시-2,7-다이메틸옥타-2,3-다이엔노에이트(화학식 7a-4)를 얻었다.Performed as in 1-2 above, but as a product of Formula 7 (R' = Me, R = (CH 3 ) 2 CH) tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-5-hydro Roxy-2,7-dimethylocta-2,3-dienoate (Chemical Formula 7a-4) was obtained.

<화학식 7a-4><Formula 7a-4>

Figure 112019040023935-pat00021
Figure 112019040023935-pat00021

수득율: 63%(>99:1 dr)Yield: 63% (>99:1 dr)

[α]D 20 +26.4° (c 0.009, CHCl3)[α] D 20 +26.4° (c 0.009, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.13 (s, 3H), 0.14 (s, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.95 (s, 9H), 0.98 (d, J = 6.9 Hz, 3H), 1.47 (s, 9H), 1.86 (d, J = 2.9 Hz, 3H), 1.94 (qqd, J = 6.9, 6.9, 3.6 Hz, 1H), 2.55 (d, J = 5.7 Hz, 1H), 3.49 (dd, J = 4.9, 3.6 Hz, 1H), 4.18 (ddd, J = 8.2, 5.7, 4.9 Hz, 1H), 5.42 (dq, J = 8.2, 2.9 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.13 (s, 3H), 0.14 (s, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.95 (s, 9H), 0.98 (d, J = 6.9 Hz, 3H), 1.47 (s, 9H), 1.86 (d, J = 2.9 Hz, 3H), 1.94 (qqd, J = 6.9, 6.9, 3.6 Hz, 1H), 2.55 (d, J = 5.7 Hz , 1H), 3.49 (dd, J = 4.9, 3.6 Hz, 1H), 4.18 (ddd, J = 8.2, 5.7, 4.9 Hz, 1H), 5.42 (dq, J = 8.2, 2.9 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.08, -3.99, 15.0, 17.1, 18.4, 19.4, 26.0, 28.1, 31.3, 70.8, 80.2, 80.7, 95.5, 98.4, 166.5, 209.3 13 C NMR (125 MHz, CDCl 3 ): δ -4.08, -3.99, 15.0, 17.1, 18.4, 19.4, 26.0, 28.1, 31.3, 70.8, 80.2, 80.7, 95.5, 98.4, 166.5, 209.3

MS m/z (%) 371.2615 (M+H)+ MS m/z (%) 371.2615 (M+H) +

1-6. 1-6. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-6-페닐헥사-2,3-다이에노에이트(화학식 7, R' = Et, R = Me; 이하 화학식 7a-5)의 합성-Butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy-6-phenylhexa-2,3-dienoate (Chemical Formula 7, R'= Et, R = Me; hereinafter Formula 7a-5) Synthesis of

상기 1-2와 같이 수행하되, 화학식 7(R' = Et, R = Me)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-6-페닐헥사-2,3-다이엔노에이트(화학식 7a-5)를 얻었다.Conducted as in 1-2 above, but tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy as a product of Formula 7 (R' = Et, R = Me) -6-phenylhexa-2,3-dienoate (Chemical Formula 7a-5) was obtained.

<화학식 7a-5><Formula 7a-5>

Figure 112019040023935-pat00022
Figure 112019040023935-pat00022

수득율: 71%(18:1 dr)Yield: 71% (18:1 dr)

[α]D 20 +25.1° (c 0.011, CHCl3)[α] D 20 +25.1° (c 0.011, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.12 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.05 (t, J = 7.4 Hz, 3H; minor diastereomer, δ 1.05, t, J = 7.4 Hz), 1.21 (d, J = 6.3 Hz, 3H; minor diastereomer, δ 1.19, d, J = 6.3 Hz), 1.46 (s, 9H), 2.20-2.28 (m, 2H), 2.67 (d, J = 3.8 Hz, 1H; minor diastereomer, δ 2.33, d, J = 5.6 Hz), 3.76 (dq, J = 6.3, 6.3 Hz, 1H), 3.95 (ddd, J = 7.8, 6.3, 3.8 Hz, 1H; minor diastereomer, δ 4.10-4.16, m), 5.50 (ddd, J = 7.8, 3.1, 3.1 Hz, 1H; minor diastereomer, δ 5.58, ddd, J = 7.5, 3.2, 3.2 Hz) 1 H NMR (500 MHz, CDCl 3 ): δ 0.12 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.05 (t, J = 7.4 Hz, 3H; minor diastereomer, δ 1.05, t, J = 7.4 Hz), 1.21 (d, J = 6.3 Hz, 3H; minor diastereomer, δ 1.19, d, J = 6.3 Hz), 1.46 (s, 9H), 2.20-2.28 (m, 2H), 2.67 (d, J = 3.8 Hz, 1H; minor diastereomer, δ 2.33, d, J = 5.6 Hz), 3.76 (dq, J = 6.3, 6.3 Hz, 1H), 3.95 (ddd, J = 7.8, 6.3, 3.8 Hz , 1H; minor diastereomer, δ 4.10-4.16, m), 5.50 (ddd, J = 7.8, 3.1, 3.1 Hz, 1H; minor diastereomer, δ 5.58, ddd, J = 7.5, 3.2, 3.2 Hz)

13C NMR (125 MHz, CDCl3): δ -4.81, -4.22, 12.54, 18.02, 19.81, 21.64, 25.79, 28.14, 72.31, 74.81, 80.83, 95.88, 105.30, 166.22, 209.23 13 C NMR (125 MHz, CDCl 3 ): δ -4.81, -4.22, 12.54, 18.02, 19.81, 21.64, 25.79, 28.14, 72.31, 74.81, 80.83, 95.88, 105.30, 166.22, 209.23

MS m/z (%) 357.2464 (M+H)+ MS m/z (%) 357.2464 (M+H) +

1-7. 1-7. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-6-페닐헥사-2,3-다이에노에이트(화학식 7, R' = Et, R = Ph; 이하 화학식 7a-6)의 합성-Butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy-6-phenylhexa-2,3-dienoate (Chemical Formula 7, R'= Et, R = Ph; hereinafter Formula 7a-6) Synthesis of

상기 1-2와 같이 수행하되, 화학식 7(R' = Et, R = Ph)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-6-페닐헥사-2,3-다이엔노에이트(화학식 7a-6)를 얻었다.Conducted as in 1-2 above, but tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy as a product of Formula 7 (R' = Et, R = Ph) -6-phenylhexa-2,3-dienoate (Chemical Formula 7a-6) was obtained.

<화학식 7a-6><Formula 7a-6>

Figure 112019040023935-pat00023
Figure 112019040023935-pat00023

수득율: 51%(1.6:1 dr)Yield: 51% (1.6:1 dr)

[α]D 20 +84.5° (c 0.009, CHCl3)[α] D 20 +84.5° (c 0.009, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ -0.08 (s, 3H), 0.07 (s, 3H), 0.92 (s, 9H), 1.02 (t, J = 7.5 Hz, 3H), 1.45 (s, 9H), 2.22 (qd, J = 7.5, 3.2 Hz, 2H), 2.25 (d, J = 5.1 Hz, 1H), 4.39 (ddd, J = 6.3, 5.1, 4.7 Hz, 1H), 4.75 (d, J = 4.7 Hz, 1H), 5.45 (ddd, J = 6.3, 3.2, 3.2 Hz, 1H), 7.31-7.39 (m, 5H) 1 H NMR (500 MHz, CDCl 3 ): δ -0.08 (s, 3H), 0.07 (s, 3H), 0.92 (s, 9H), 1.02 (t, J = 7.5 Hz, 3H), 1.45 (s, 9H), 2.22 (qd, J = 7.5, 3.2 Hz, 2H), 2.25 (d, J = 5.1 Hz, 1H), 4.39 (ddd, J = 6.3, 5.1, 4.7 Hz, 1H), 4.75 (d, J = 4.7 Hz, 1H), 5.45 (ddd, J = 6.3, 3.2, 3.2 Hz, 1H), 7.31-7.39 (m, 5H)

13C NMR (125 MHz, CDCl3): δ -5.0, -4.7, 12.6, 18.2, 21.6, 25.8, 28.1, 73.8, 78.3, 80.7, 95.8, 106.4, 127.1, 127.7, 128.0, 140.1, 166.3, 208.3 13 C NMR (125 MHz, CDCl 3 ): δ -5.0, -4.7, 12.6, 18.2, 21.6, 25.8, 28.1, 73.8, 78.3, 80.7, 95.8, 106.4, 127.1, 127.7, 128.0, 140.1, 166.3, 208.3

MS m/z (%) 419.2619 (M+H)+ MS m/z (%) 419.2619 (M+H) +

1-8. 1-8. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-8-페닐옥타-2,3-다이에노에이트(화학식 7, R' = Et, R = PhCH-Butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy-8-phenylocta-2,3-dienoate (Formula 7, R'= Et, R = PhCH 22 CHCH 22 ; 화학식 7a-7)의 합성; Synthesis of Formula 7a-7)

상기 1-2와 같이 수행하되, 화학식 7(R' = Me, R = PhCH2CH2)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-8-페닐옥타-2,3-다이엔노에이트(화학식 7a-7)를 얻었다.Performed as in 1-2 above, but tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-2-ethyl-5 as a product of Formula 7 (R' = Me, R = PhCH 2 CH 2 ) -Hydroxy-8-phenylocta-2,3-dienoate (Chemical Formula 7a-7) was obtained.

<화학식 7a-7><Formula 7a-7>

Figure 112019040023935-pat00024
Figure 112019040023935-pat00024

수득율: 58%(>50:1 dr)Yield: 58% (>50:1 dr)

[α]D 20 +34.9° (c 0.018, CHCl3)[α] D 20 +34.9° (c 0.018, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.12 (s, 6H), 0.96 (s, 9H), 1.05 (dd, J = 7.4, 7.4 Hz, 3H), 1.42 (s, 9H), 1.80-1.92 (m, 1H), 1.99-2.06 (m, 1H), 2.20-2.31 (m, 2H), 2.47 (d, J = 5.8, 1H), 2.70 (dd, J = 8.5, 8.0 Hz, 2H), 3.77 (dd, J = 10.5, 5.6 Hz, 1H), 4.23 (ddd, J = 6.6, 5.8, 5.6 Hz, 1H), 5.61 (ddd, J = 6.6, 3.1, 3.1 Hz, 1H), 7.17-7.20 (m, 3H), 7.27-7.30 (m, 2H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.12 (s, 6H), 0.96 (s, 9H), 1.05 (dd, J = 7.4, 7.4 Hz, 3H), 1.42 (s, 9H), 1.80-1.92 (m, 1H), 1.99-2.06 (m, 1H), 2.20-2.31 (m, 2H), 2.47 (d, J = 5.8, 1H), 2.70 (dd, J = 8.5, 8.0 Hz, 2H), 3.77 (dd, J = 10.5, 5.6 Hz, 1H), 4.23 (ddd, J = 6.6, 5.8, 5.6 Hz, 1H), 5.61 (ddd, J = 6.6, 3.1, 3.1 Hz, 1H), 7.17-7.20 (m , 3H), 7.27-7.30 (m, 2H)

13C NMR (125 MHz, CDCl3): δ -4.4, -4.3, 12.6, 18.1, 21.7, 25.9, 28.0, 31.3, 34.9, 71.7, 75.3, 80.8, 96.7, 105.9, 125.8, 128.3, 128.4, 141.9, 166.1, 208.5 13 C NMR (125 MHz, CDCl 3 ): δ -4.4, -4.3, 12.6, 18.1, 21.7, 25.9, 28.0, 31.3, 34.9, 71.7, 75.3, 80.8, 96.7, 105.9, 125.8, 128.3, 128.4, 141.9, 166.1, 208.5

MS m/z (%) 447.2928 (M+H)+ MS m/z (%) 447.2928 (M+H) +

1-9. 1-9. terttert -부틸-6-((-Butyl-6-(( terttert -부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-7-메틸옥타-2,3-다이에노에이트(화학식 7, R' = Et, R = Me-Butyldimethylsilyl)oxy)-2-ethyl-5-hydroxy-7-methylocta-2,3-dienoate (Formula 7, R'= Et, R = Me 22 CH; 이하 화학식 7a-8)의 합성CH; Synthesis of Formula 7a-8)

상기 1-2와 같이 수행하되, 화학식 7(R' = Et, R = Me2CH)의 생성물로 tert-부틸-6-((tert-부틸다이메틸시릴)옥시)-2-에틸-5-하이드록시-7-메틸옥타-2,3-다이엔노에이트(화학식 7a-8)를 얻었다.Performed as in 1-2 above, but as a product of Formula 7 (R' = Et, R = Me 2 CH) tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-2-ethyl-5- Hydroxy-7-methylocta-2,3-dienoate (Chemical Formula 7a-8) was obtained.

<화학식 7a-8><Formula 7a-8>

Figure 112019040023935-pat00025
Figure 112019040023935-pat00025

수득율: 61%(>99:1 dr)Yield: 61% (>99:1 dr)

[α]D 20 +26.7° (c 0.007, CHCl3)[α] D 20 +26.7° (c 0.007, CHCl 3 )

1H NMR (500 MHz, CDCl3): δ 0.12 (s, 3H), 0.14(s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.95 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 1.05 (dd, J= 7.4, 7.4 Hz, 3H), 1.46 (s, 9H), 1.95 (qqd, J = 7.0, 6.8, 3.5 Hz, 1H), 2.19-2.28 (m, 2H), 2.55 (d, J = 5.1 Hz, 1H), 3.49 (dd, J = 5.1, 3.5 Hz, 1H), 4.16 (ddd, J = 8.3, 5.1, 5.1 Hz, 1H), 5.51 (ddd, J = 8.3, 3.1, 3.1 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.12 (s, 3H), 0.14 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.95 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 1.05 (dd, J = 7.4, 7.4 Hz, 3H), 1.46 (s, 9H), 1.95 (qqd, J = 7.0, 6.8, 3.5 Hz, 1H), 2.19-2.28 (m, 2H), 2.55 (d, J = 5.1 Hz, 1H), 3.49 (dd, J = 5.1, 3.5 Hz, 1H), 4.16 (ddd, J = 8.3, 5.1, 5.1 Hz, 1H), 5.51 (ddd, J = 8.3, 3.1, 3.1 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.1, -4.0, 12.5, 17.0, 18.4, 19.5, 21.6, 26.0, 28.1, 31.2, 71.1, 80.4, 80.7, 97.0, 105.1, 166.2, 208.8 13 C NMR (125 MHz, CDCl 3 ): δ -4.1, -4.0, 12.5, 17.0, 18.4, 19.5, 21.6, 26.0, 28.1, 31.2, 71.1, 80.4, 80.7, 97.0, 105.1, 166.2, 208.8

MS m/z (%) 385.2777 (M+H)+ MS m/z (%) 385.2777 (M+H) +

실시예 2: 천연물 자일로집락톤 A(Xylogiblactone A)의 합성Example 2: Synthesis of natural product Xylogiblactone A

2-1. 자일로집락톤 A(보고된 구조)의 합성2-1. Synthesis of xylocylactone A (reported structure)

상기 1-2와 같이 수행하되, 하기 반응식 4와 같이 화학식 7(R' = Me, R = MeClCH)의 생성물로 tert-부틸-6-((tert-부틸다이메틸실릴)옥시)-7-클로로-5-하이드록시-2-메틸옥타-2,3-다이에노에이트(화학식 7a-9)를 얻었다.Conducted as in 1-2 above, but tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-7-chloro as a product of Formula 7 (R' = Me, R = MeClCH) as shown in Scheme 4 below. -5-hydroxy-2-methylocta-2,3-dienoate (Chemical Formula 7a-9) was obtained.

<반응식 4><Reaction Scheme 4>

Figure 112019040023935-pat00026
Figure 112019040023935-pat00026

<화학식 7a-9><Formula 7a-9>

Figure 112019040023935-pat00027
Figure 112019040023935-pat00027

수득율: 61%Yield: 61%

1H NMR (500 MHz, CDCl3): δ 0.18 (s, 3H), 0.22 (s, 3H), 0.95 (s, 9H), 1.46 (d, J = 6.7 Hz, 3H), 1.48 (s, 9H), 1.87 (d, J = 2.9 Hz, 3H), 2.47 (d, J = 5.2 Hz, 1H), 3.83 (dd, J = 5.5, 3.5 Hz, 1H), 4.19 (ddd, J = 8.0, 5.5, 5.2 Hz, 1H), 4.32 (qd, J = 6.7, 3.5 Hz, 1H), 5.43 (dq, J = 8.0, 2.9 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.18 (s, 3H), 0.22 (s, 3H), 0.95 (s, 9H), 1.46 (d, J = 6.7 Hz, 3H), 1.48 (s, 9H) ), 1.87 (d, J = 2.9 Hz, 3H), 2.47 (d, J = 5.2 Hz, 1H), 3.83 (dd, J = 5.5, 3.5 Hz, 1H), 4.19 (ddd, J = 8.0, 5.5, 5.2 Hz, 1H), 4.32 (qd, J = 6.7, 3.5 Hz, 1H), 5.43 (dq, J = 8.0, 2.9 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.2, -3.9, 14.9, 18.4, 19.3, 26.0, 28.1, 57.6, 71.3, 80.2, 81.2, 94.1, 99.0, 166.2, 209.4 13 C NMR (125 MHz, CDCl 3 ): δ -4.2, -3.9, 14.9, 18.4, 19.3, 26.0, 28.1, 57.6, 71.3, 80.2, 81.2, 94.1, 99.0, 166.2, 209.4

화학식 7a-9의 화합물을 상기 반응식 4와 같이 클로로(트리페닐포스핀)골드(I)(ClAuPPh3, 화학식 10)와 실버테트라플루오로보레이트(AgBF4, 화학식 11) 촉매 존재하에서 다이클로로메탄(CH2Cl2)용매를 통해 2시간 동안 상온에서 반응시킨 후 화학식 13a-9의 고리화합물((tert-부틸다이메틸실릴)옥시)-3-클로로-1-하이드록시부틸-3-메틸퓨란-2(5H)-one을 70%의 수득률로 얻었다.Dichloromethane (I) (ClAuPPh 3 , Formula 10) and silver tetrafluoroborate (AgBF 4 , Formula 11) catalyst in the presence of a compound of Formula 7a-9 as shown in Scheme 4 above. CH 2 Cl 2 ) After reacting at room temperature for 2 hours through a solvent, the cyclic compound of formula 13a-9 (( tert -butyldimethylsilyl) oxy)-3-chloro-1-hydroxybutyl-3-methylfuran- 2 (5 H) -one to give the in 70% yield.

<화학식 13a-9><Formula 13a-9>

Figure 112019040023935-pat00028
Figure 112019040023935-pat00028

수득율: 70%Yield: 70%

1H NMR (500 MHz, CDCl3): δ 0.18 (s, 3H), 0.23 (s, 3H), 0.95 (s, 9H), 1.51 (d, J = 6.7 Hz, 3H), 1.94 (dd, J = 1.4, 1.4 Hz, 3H), 2.81 (d, J = 9.4 Hz, 1H), 3.47 (dd, J = 9.4, 9.4 Hz, 1H), 4.08 (qd, J = 6.7, 5.4 Hz, 1H), 4.14 (d, J = 5.4 Hz, 1H), 4.60 (ddq, J = 9.4, 1.4, 1.4Hz, 1H), 7.33-7.37 (m, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.18 (s, 3H), 0.23 (s, 3H), 0.95 (s, 9H), 1.51 (d, J = 6.7 Hz, 3H), 1.94 (dd, J = 1.4, 1.4 Hz, 3H), 2.81 (d, J = 9.4 Hz, 1H), 3.47 (dd, J = 9.4, 9.4 Hz, 1H), 4.08 (qd, J = 6.7, 5.4 Hz, 1H), 4.14 (d, J = 5.4 Hz, 1H), 4.60 (ddq, J = 9.4, 1.4, 1.4 Hz, 1H), 7.33-7.37 (m, 1H)

13C NMR (125 MHz, CDCl3): δ -4.3, -3.8, 10.7, 18.3 20.8, 26.0, 58.3, 72.8, 74.7, 79.4, 130.3, 148.7, 173.7 13 C NMR (125 MHz, CDCl 3 ): δ -4.3, -3.8, 10.7, 18.3 20.8, 26.0, 58.3, 72.8, 74.7, 79.4, 130.3, 148.7, 173.7

MS m/z (%) 264 (M+)MS m/z (%) 264 (M+)

이후 메탄올 조건하에서 염산(HCl, 화학식 12) 수용액과 12시간 동안 반응시킨 후에 기존 문헌에 보고된 구조의 자일로집락톤 A(화학식 14a-9)를 78%의 수율로 얻었다.After reacting with an aqueous solution of hydrochloric acid (HCl, Formula 12) for 12 hours under methanol conditions, xylocolactone A (Chemical Formula 14a-9) having the structure reported in the existing literature was obtained in a yield of 78%.

<화학식 14a-9><Formula 14a-9>

Figure 112019040023935-pat00029
Figure 112019040023935-pat00029

1H NMR (500 MHz, CD3OD): δ 1.59 (d, J = 6.6 Hz, 3H), 1.90 (dd, J = 1.5, 1.5 Hz, 3H), 3.62 (dd, J = 9.2, 1.0 Hz, 1H), 3.92 (dd, J = 7.4, 1.0 Hz, 1H), 4.09 (dq, J = 9.2, 6.6 Hz, 1H), 4.85 (brs, 2H), 5.0 (ddq, J = 7.4, 1.5, 1.5 Hz, 1H), 7.46 (dq, J = 1.5, 1.5 Hz, 1H) 1 H NMR (500 MHz, CD 3 OD): δ 1.59 (d, J = 6.6 Hz, 3H), 1.90 (dd, J = 1.5, 1.5 Hz, 3H), 3.62 (dd, J = 9.2, 1.0 Hz, 1H), 3.92 (dd, J = 7.4, 1.0 Hz, 1H), 4.09 (dq, J = 9.2, 6.6 Hz, 1H), 4.85 (brs, 2H), 5.0 (ddq, J = 7.4, 1.5, 1.5 Hz , 1H), 7.46 (dq, J = 1.5, 1.5 Hz, 1H)

13C NMR (125 MHz, CD3OD): δ 10.6, 22.2, 57.1, 72.4, 76.6, 82.9, 130.9, 150.7, 176.2 13 C NMR (125 MHz, CD 3 OD): δ 10.6, 22.2, 57.1, 72.4, 76.6, 82.9, 130.9, 150.7, 176.2

2-2. 자일로집락톤 A(수정된 구조)의 합성2-2. Synthesis of xylocylactone A (modified structure)

수정된 구조인 화학식 14a-10은 상기 2-1과 같이 수행하되, 하기 반응식 5와 같이 화학식 6-2 대신 화학식 6-3의 화합물을 사용한다.Formula 14a-10, which is a modified structure, is carried out as in 2-1, but the compound of Formula 6-3 is used instead of Formula 6-2 as shown in Scheme 5 below.

<반응식 5><Reaction Scheme 5>

Figure 112019040023935-pat00030
Figure 112019040023935-pat00030

생성된 tert-부틸-6-((tert-부틸다이메틸실릴)옥시)-7-클로로-5-하이드록시-2-메틸옥타-2,3-다이에노에이트의 화합물(화학식 7a-10)은 아래와 같다.The resulting compound of tert -butyl-6-(( tert -butyldimethylsilyl)oxy)-7-chloro-5-hydroxy-2-methylocta-2,3-dienoate (Formula 7a-10) Is as follows.

<화학식 7a-10><Formula 7a-10>

Figure 112019040023935-pat00031
Figure 112019040023935-pat00031

1H NMR (500 MHz, CDCl3): δ 0.16 (s, 3H), 0.17 (s, 3H), 0.96 (s, 9H), 1.47 (s, 9H), 1.54 (d, J = 6.9 Hz, 3 H), 1.87 (d, J = 2.9 Hz, 3H), 2.22 (brs, 1H), 3.71 (dd, J = 4.1, 3.8 Hz, 1H), 4.16 (qd, J = 6.9, 3.8 Hz, 1H), 4.48 (dd, J = 7.7, 4.1 Hz, 1H), 5.42 (dq, J = 7.7, 2.9 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.16 (s, 3H), 0.17 (s, 3H), 0.96 (s, 9H), 1.47 (s, 9H), 1.54 (d, J = 6.9 Hz, 3 H), 1.87 (d, J = 2.9 Hz, 3H), 2.22 (brs, 1H), 3.71 (dd, J = 4.1, 3.8 Hz, 1H), 4.16 (qd, J = 6.9, 3.8 Hz, 1H), 4.48 (dd, J = 7.7, 4.1 Hz, 1H), 5.42 (dq, J = 7.7, 2.9 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.3, -4.1, 14.9, 18.3, 20.9, 25.9, 28.0, 58.3, 69.8, 78.4, 80.9, 95.1, 99.0, 166.4, 209.2 13 C NMR (125 MHz, CDCl 3 ): δ -4.3, -4.1, 14.9, 18.3, 20.9, 25.9, 28.0, 58.3, 69.8, 78.4, 80.9, 95.1, 99.0, 166.4, 209.2

상기 2-1과 같은 방법으로, 반응식 5에 따라 화학식 13a-10의 고리화합물인 ((tert-부틸다이메틸실릴)옥시)-3-클로로-1-하이드록시부틸-3-메틸퓨란-2(5H)-one을 66%의 수득율로 얻었다.In the same manner as in 2-1 above, according to Scheme 5, (( tert -butyldimethylsilyl)oxy)-3-chloro-1-hydroxybutyl-3-methylfuran-2 ( 5 H )-one was obtained in a yield of 66%.

<화학식 13a-10><Formula 13a-10>

Figure 112019040023935-pat00032
Figure 112019040023935-pat00032

1H NMR (500 MHz, CDCl3): δ 0.19 (s, 3H), 0.21 (s, 3H), 0.95 (s, 9H), 1.52 (d, J = 6.9 Hz, 3H), 1.96 (t, J = 1.7 Hz, 3H), 2.81 (s, 1H), 3.65 (d, J =9.2 Hz, 1H), 4.03 (qd, J = 6.9, 4.8 Hz, 1H), 4.17 (d, J = 4.8 Hz, 1H), 4.60 (ddq, J = 9.2, 1.7, 1.7 Hz, 1H), 7.34 (dq, J = 1.7, 1.7 Hz, 1H) 1 H NMR (500 MHz, CDCl 3 ): δ 0.19 (s, 3H), 0.21 (s, 3H), 0.95 (s, 9H), 1.52 (d, J = 6.9 Hz, 3H), 1.96 (t, J = 1.7 Hz, 3H), 2.81 (s, 1H), 3.65 (d, J =9.2 Hz, 1H), 4.03 (qd, J = 6.9, 4.8 Hz, 1H), 4.17 (d, J = 4.8 Hz, 1H ), 4.60 (ddq, J = 9.2, 1.7, 1.7 Hz, 1H), 7.34 (dq, J = 1.7, 1.7 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ -4.6, -4.2, 10.7, 18.1, 19.5, 25.8, 57.9, 70.8, 73.2, 79.8, 130.5, 148.4, 173.8 13 C NMR (125 MHz, CDCl 3 ): δ -4.6, -4.2, 10.7, 18.1, 19.5, 25.8, 57.9, 70.8, 73.2, 79.8, 130.5, 148.4, 173.8

이후 메탄올 조건하에서 염산(HCl) 수용액과 12시간 동안 반응시킨 후에 자일로집락톤 A(화학식 14a-10)를 75%의 수율로 얻었다.After reacting with an aqueous hydrochloric acid (HCl) solution for 12 hours under methanol conditions, xyloziplactone A (Chemical Formula 14a-10) was obtained in a 75% yield.

<화학식 14a-10><Formula 14a-10>

Figure 112019040023935-pat00033
Figure 112019040023935-pat00033

1H NMR (500 MHz, CD3OD): δ 1.52 (d, J = 6.7 Hz, 3H), 1.90 (dd, J = 1.7, 1.7 Hz, 3H), 3.69 (dd, J = 6.8, 2.3 Hz, 1H), 3.74 (dd, J = 6.4, 2.3 Hz, 1H), 4.19 (dq, J = 6.8, 6.7 Hz, 1H), 4.87 (brs, 2H), 5.05 (ddq, J = 6.4, 1.7, 1.7 Hz, 1H), 7.43 (dq, J = 1.7, 1.7 Hz, 1H) 1 H NMR (500 MHz, CD 3 OD): δ 1.52 (d, J = 6.7 Hz, 3H), 1.90 (dd, J = 1.7, 1.7 Hz, 3H), 3.69 (dd, J = 6.8, 2.3 Hz, 1H), 3.74 (dd, J = 6.4, 2.3 Hz, 1H), 4.19 (dq, J = 6.8, 6.7 Hz, 1H), 4.87 (brs, 2H), 5.05 (ddq, J = 6.4, 1.7, 1.7 Hz , 1H), 7.43 (dq, J = 1.7, 1.7 Hz, 1H)

13C NMR (125 MHz, CD3OD): δ 10.8, 21.6, 61.7, 72.8, 76.7, 83.3, 131.4, 150.3, 176.4 13 C NMR (125 MHz, CD 3 OD): δ 10.8, 21.6, 61.7, 72.8, 76.7, 83.3, 131.4, 150.3, 176.4

합성된 화학식 14a-10의 경우, 공지된 물리적 데이터(Chang, Y.-C.; Lu, C.-K.; Chiang, Y.-R.; Wang, G.-J.; Ju, Y.-M.; Kuo, Y.-H.; Lee, T.-H. J. Nat. Prod. 2014, 77, 751)와 모두 일치하는 것을 확인하였다.For the synthesized formula 14a-10, known physical data (Chang, Y.-C.; Lu, C.-K.; Chiang, Y.-R.; Wang, G.-J.; Ju, Y. -M.; Kuo, Y.-H.; Lee, T.-H. J. Nat. Prod. 2014, 77 , 751).

Claims (12)

다음의 단계를 포함하는 속도론적 분할(kinetic resolution)을 통한 비대칭 알돌반응에 의한 감마-락톤(gamma-lactone) 합성방법:
화학식 3a의 화합물에 화학식 4의 화합물 및 다이이소프로필에틸아민(i-Pr2Net)을 반응시킨 후 화학식 6의 화합물을 첨가하여 화학식 7a의 화합물을 얻는, 화학식 7a의 화합물 합성 단계;
<화학식 3a>
Figure 112019040023935-pat00034

<화학식 4>
Figure 112019040023935-pat00035

<화학식 6>
Figure 112019040023935-pat00036

<화학식 7a>
Figure 112019040023935-pat00037

상기 화학식 7a의 화합물을 클로로(트리페닐포스핀)골드(I)(ClAuPPh3) 및 실버테트라플루오로보레이트(AgBF4) 촉매 존재하에서 반응시켜 화학식 13a의 화합물을 얻는, 화학식 13a의 화합물 합성 단계; 및
<화학식 13a>
Figure 112019040023935-pat00038

상기 화학식 13a의 화합물에 HCl을 반응시켜 화학식 14a의 화합물을 합성하는, 화학식 14a의 화합물 합성 단계
<화학식 14a>
Figure 112019040023935-pat00039
;
상기 식에서,
Tol은 4-메틸페닐이고,
R'은 메틸(Me) 또는 에틸(Et)이고,
R은 Me, 페닐(Ph), PhCH2CH2, (CH3)2CH, Me2CH 또는 MeCl이다.Method for synthesizing gamma-lactone by asymmetric aldol reaction through kinetic resolution, including the following steps:
Synthesizing a compound of formula 7a to obtain a compound of formula 7a by reacting a compound of formula 4 and diisopropylethylamine ( i- Pr 2 Net) with the compound of formula 3a and then adding the compound of formula 6;
<Formula 3a>
Figure 112019040023935-pat00034

<Formula 4>
Figure 112019040023935-pat00035

<Formula 6>
Figure 112019040023935-pat00036

<Formula 7a>
Figure 112019040023935-pat00037

Synthesis of the compound of Formula 13a by reacting the compound of Formula 7a in the presence of a chloro (triphenylphosphine) gold (I) (ClAuPPh 3 ) and silver tetrafluoroborate (AgBF 4 ) catalyst to obtain a compound of Formula 13a; And
<Formula 13a>
Figure 112019040023935-pat00038

Synthesis of the compound of Formula 14a by reacting HCl with the compound of Formula 13a to synthesize the compound of Formula 14a
<Formula 14a>
Figure 112019040023935-pat00039
;
In the above formula,
Tol is 4-methylphenyl,
R'is methyl (Me) or ethyl (Et),
R is Me, phenyl (Ph), PhCH 2 CH 2 , (CH 3 ) 2 CH, Me 2 CH or MeCl. 제1항에 있어서, 상기 화학식 3a의 화합물은 화학식 1a의 화합물에 트리브로모보란(BBr3)을 반응시켜 얻는 것인, 합성방법
<화학식 1a>
Figure 112019040023935-pat00040
.The method of claim 1, wherein the compound of Formula 3a is obtained by reacting tribromoborane (BBr 3 ) with the compound of Formula 1a.
<Formula 1a>
Figure 112019040023935-pat00040
. 제2항에 있어서, 상기 화학식 1a의 화합물과 트리브로모보란은 0.8 내지 1.2 : 0.8 내지 1.2의 당량비로 사용되는 것인, 합성방법.The method of claim 2, wherein the compound of Formula 1a and tribromoborane are used in an equivalent ratio of 0.8 to 1.2: 0.8 to 1.2. 제1항에 있어서, 상기 화학식 7a의 화합물 합성 단계는 화학식 3a의 화합물, 다이이소프로필에틸아민, 화학식 4의 화합물을 0.8 내지 1.2:1.0 내지 1.5:0.8 내지 1.2의 당량비로 사용하여 수행되는 것인, 합성방법.The method of claim 1, wherein the step of synthesizing the compound of Formula 7a is performed using the compound of Formula 3a, diisopropylethylamine, and the compound of Formula 4 in an equivalent ratio of 0.8 to 1.2:1.0 to 1.5:0.8 to 1.2. , Synthesis method. 제1항에 있어서, 상기 화학식 7a의 화합물 합성 단계는 -60 내지 -40℃에서 수행되는 것인, 합성방법.The method of claim 1, wherein the step of synthesizing the compound of Formula 7a is performed at -60 to -40°C. 제1항에 있어서, 상기 화학식 14a의 화합물 합성 단계는 HCl과 8 내지 15시간 동안 반응시켜 수행되는 것인, 합성방법.The method of claim 1, wherein the step of synthesizing the compound of Formula 14a is performed by reacting with HCl for 8 to 15 hours. 다음의 단계를 포함하는 속도론적 분할(kinetic resolution)을 통한 비대칭 알돌반응에 의한 감마-락톤(gamma-lactone) 합성방법:
화학식 3b의 화합물에 화학식 4의 화합물 및 다이이소프로필에틸아민(i-Pr2Net)을 반응시킨 후 화학식 6의 화합물을 더 첨가하여 화학식 7b의 화합물을 얻는, 화학식 7b의 화합물 합성 단계;
<화학식 3b>
Figure 112019040023935-pat00041

<화학식 4>
Figure 112019040023935-pat00042

<화학식 6>
Figure 112019040023935-pat00043

<화학식 7b>
Figure 112019040023935-pat00044

상기 화학식 7b의 화합물을 클로로(트리페닐포스핀)골드(I)(ClAuPPh3) 및 실버테트라플루오로보레이트(AgBF4) 촉매 존재하에서 반응시켜 화학식 13b의 화합물을 얻는, 화학식 13b의 화합물 합성 단계; 및
<화학식 13b>
Figure 112019040023935-pat00045

상기 화학식 13b의 화합물에 HCl을 반응시켜 화학식 14b의 화합물을 합성하는, 화학식 14b의 화합물 합성 단계
<화학식 14b>
Figure 112019040023935-pat00046
;
상기 식에서,
Tol은 4-메틸페닐이고,
R'은 메틸(Me) 또는 에틸(Et)이고,
R은 Me, 페닐(Ph), PhCH2CH2, (CH3)2CH, Me2CH 또는 MeCl이다.Method for synthesizing gamma-lactone by asymmetric aldol reaction through kinetic resolution, including the following steps:
Synthesizing a compound of formula 7b to obtain a compound of formula 7b by reacting a compound of formula 4 and diisopropylethylamine ( i- Pr 2 Net) with the compound of formula 3b and then further adding the compound of formula 6;
<Formula 3b>
Figure 112019040023935-pat00041

<Formula 4>
Figure 112019040023935-pat00042

<Formula 6>
Figure 112019040023935-pat00043

<Formula 7b>
Figure 112019040023935-pat00044

Synthesis of the compound of Formula 13b by reacting the compound of Formula 7b in the presence of a chloro (triphenylphosphine) gold (I) (ClAuPPh 3 ) and silver tetrafluoroborate (AgBF 4 ) catalyst to obtain a compound of Formula 13b; And
<Formula 13b>
Figure 112019040023935-pat00045

Synthesis of the compound of Formula 14b by reacting HCl with the compound of Formula 13b to synthesize the compound of Formula 14b
<Formula 14b>
Figure 112019040023935-pat00046
;
In the above formula,
Tol is 4-methylphenyl,
R'is methyl (Me) or ethyl (Et),
R is Me, phenyl (Ph), PhCH 2 CH 2 , (CH 3 ) 2 CH, Me 2 CH or MeCl. 제7항에 있어서, 상기 화학식 3b의 화합물은 화학식 1b의 화합물에 트리브로모보란(BBr3)을 반응시켜 얻는 것인, 합성방법
<화학식 1b>
Figure 112019040023935-pat00047
.The method of claim 7, wherein the compound of Formula 3b is obtained by reacting tribromoborane (BBr 3 ) with the compound of Formula 1b.
<Formula 1b>
Figure 112019040023935-pat00047
. 제8항에 있어서, 상기 화학식 1b의 화합물과 트리브로모보란은 1:1의 당량비로 사용하는 것인, 합성방법.The method of claim 8, wherein the compound of Formula 1b and tribromoborane are used in an equivalent ratio of 1:1. 제7항에 있어서, 상기 화학식 7b의 화합물 합성 단계는 화학식 3b의 화합물, 다이이소프로필에틸아민, 화학식 4의 화합물을 0.8 내지 1.2 : 1.0 내지 1.5 : 0.8 내지 1.2의 당량비로 사용하여 수행되는 것인, 합성방법.The method of claim 7, wherein the step of synthesizing the compound of Formula 7b is performed using the compound of Formula 3b, diisopropylethylamine, and the compound of Formula 4 in an equivalent ratio of 0.8 to 1.2: 1.0 to 1.5: 0.8 to 1.2. , Synthesis method. 제7항에 있어서, 상기 화학식 7b의 화합물 합성 단계는 -60 내지 -40℃에서 수행되는 것인, 합성방법.The method of claim 7, wherein the step of synthesizing the compound of Formula 7b is performed at -60 to -40°C. 제7항에 있어서, 상기 화학식 14b의 화합물 합성 단계는 HCl과 8 내지 15시간 동안 반응시켜 수행되는 것인, 합성방법.The method of claim 7, wherein the step of synthesizing the compound of Formula 14b is performed by reacting with HCl for 8 to 15 hours.
KR1020190045532A 2019-04-18 2019-04-18 Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution KR102144837B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020190045532A KR102144837B1 (en) 2019-04-18 2019-04-18 Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020190045532A KR102144837B1 (en) 2019-04-18 2019-04-18 Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution

Publications (1)

Publication Number Publication Date
KR102144837B1 true KR102144837B1 (en) 2020-08-14

Family

ID=72050173

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020190045532A KR102144837B1 (en) 2019-04-18 2019-04-18 Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution

Country Status (1)

Country Link
KR (1) KR102144837B1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120098482A (en) * 2011-02-25 2012-09-05 성균관대학교산학협력단 Enantioselective manufacturing method of methyl 2-(1-hydroxy)-buta-2,3-dienolate derivatives and method for preparing sylvone using the same
JP2013060428A (en) * 2011-08-23 2013-04-04 Mitsubishi Chemicals Corp Method for producing gamma-butyrolactone

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120098482A (en) * 2011-02-25 2012-09-05 성균관대학교산학협력단 Enantioselective manufacturing method of methyl 2-(1-hydroxy)-buta-2,3-dienolate derivatives and method for preparing sylvone using the same
JP2013060428A (en) * 2011-08-23 2013-04-04 Mitsubishi Chemicals Corp Method for producing gamma-butyrolactone

Similar Documents

Publication Publication Date Title
Kagechika et al. Asymmetric heck reaction-anion capture process. A catalytic asymmetric synthesis of the key intermediates for the Capnellenols
Block et al. New Stereoselective Route to the Epoxyquinol Core of Manumycin-Type Natural Products. Synthesis of Enantiopure (+)-Bromoxone,(−)-LL-C10037α, and (+)-KT 8110
EP2390001A1 (en) Organoaluminium compounds and their use as catalysts in the selective cyclisation of citronellal to isopulegol
Takao et al. Total synthesis of clavilactones
Liu et al. An efficient and convenient approach to the total synthesis of sphingofungin
EP3140280A1 (en) 4-vinyl-2-cyclopenten-1-one, the production thereof, and the use of same as an antibiotic agent
JP6622315B2 (en) Synthesis of chirally rich 2,4-disubstituted tetrahydropyran-4-ol and its derivatives
KR102144837B1 (en) Method for synthesis of gamma-lactone by asymmetric aldol reaction by kinetic resolution
Johansson et al. Synthesis of (−)-pregaliellalactone, conversion of (−)-pregaliellalactone to (−)-galiellalactone by mycelia of Galiella rufa
KR101130818B1 (en) Method for preparing chiral amino acid from azlactones using bifunctional bis-cinchona alkaloid thiourea organo catalysts
Müller et al. Stereoselective total syntheses of atrochrysone, torosachrysone and related 3, 4-dihydroanthracen-1 (2 H)-ones
JP2021530427A (en) Glacillin A and homologues as immunosuppressive and neuroprotective agents
JPWO2018220888A1 (en) PGE1 core block derivative and method for producing the same
Zhou et al. Enantioselective synthesis of (2R, 13R, 8Z)-2, 13-diacetoxy-8-heptadecene, the major component of the sex pheromone of the pear leaf midge, Dasineura pyri
Komura et al. A novel approach to the synthesis of optically active poly (β-hydroxy carbonyl) s by Aldol polymerization based on Mukaiyama Aldol reaction
JP2010229097A (en) New oxazolidine derivative, new oxazolidine derivative salt and method for producing optically active compound using the oxazolidine derivative salt as asymmetric organic molecular catalyst
JP3738225B2 (en) Novel chiral copper catalyst and method for producing N-acylated amino acid derivative using the same
Xu et al. Highly enantioselective allylic alkylation of 5H-oxazol-4-ones with Morita-Baylis-Hillman carbonates
JP2013166736A (en) Novel dihydropyran compound and method for producing the same
KR102135032B1 (en) Rectangular carbon ring ketone compound and method of synthesizing thereof
JP2586607B2 (en) Production method of optically active alcohol
JP2009185015A (en) Method for producing optically active alcohol
JP2642959B2 (en) Optically active fluorine-containing α-hydroxycyclopropane compound
JP5183885B2 (en) Process for producing optically active dihydrobenzofuran derivatives and chroman derivatives
US6998495B2 (en) Method for producing optically active 3,5-dihydroxycarboxylic acid derivative

Legal Events

Date Code Title Description
E701 Decision to grant or registration of patent right
GRNT Written decision to grant