KR101111096B1

KR101111096B1 - Cinchona-alkaloid-based organic catalyst and a process of preparing chiral arylamine by using the same

Info

Publication number: KR101111096B1
Application number: KR1020090046674A
Authority: KR
Inventors: 장두옥; 김상윤
Original assignee: 연세대학교 산학협력단
Priority date: 2009-05-27
Filing date: 2009-05-27
Publication date: 2012-03-14
Also published as: KR20100128182A

Abstract

본 발명은 신코나 알칼로이드계 유기 촉매 및 이를 이용한 키랄 아릴아민의 제조방법에 관한 것으로서, 더욱 구체적으로는 본 발명의 유기 촉매는 특정한 구조를 갖는 신코나 알칼로이드계 화합물의 염의 형태를 가지며, 이를 키랄 아릴아민의 제조를 위한 리디칼 첨가반응에 사용함으로써 수율과 선택도 및 부산물의 생성억제 면에서 매우 향상될 뿐만 아니라 유기 촉매의 회수율 및 반응규모의 확장가능성면에서도 현저하게 향상된 효과를 얻을 수 있다.The present invention relates to a cinchona alkaloid-based organic catalyst and a method for producing a chiral arylamine using the same. More specifically, the organic catalyst of the present invention has a form of a salt of a cinchona alkaloid-based compound having a specific structure, and this is chiral aryl The use in the radical addition reaction for the preparation of the amine can not only greatly improve the yield, selectivity and production of by-products, but also significantly improve the recovery of the organic catalyst and the scalability of the reaction scale.

신코나 알칼로이드계 유기 촉매, 키랄 아릴아민, 라디칼 첨가반응 Synkona alkaloid organic catalyst, chiral arylamine, radical addition reaction

Description

Cinchona-alkaloid-based organic catalyst and a process of preparing chiral arylamine by using the same}

본 발명은 신코나 알칼로이드계 유기 촉매 및 이를 이용한 키랄 아릴아민의 제조방법에 관한 것이다.The present invention relates to a synacona alkaloid organic catalyst and a method for preparing chiral arylamine using the same.

많은 거대 분자들을 비롯하여 미시적인 분자들까지도 키랄성 요소를 지니고 있으며, 이것은 특히 자연계 생체 내에서의 물질간의 상호작용 및 여러 반응에 있어서의 근본이 된다. 생명 그 자체는 키랄성의 인식에 의존하게 되는데 이는 키랄 성분 간의 정확한 인식을 통하여 생물학적 기능들이 작용되기 때문이다. 예를 들어서 생체내의 모든 효소들은 각기 특수한 키랄성을 지니며 이를 이용한 분자인식을 통하여 원하는 반응체와만 반응을 하게 된다. 또한 이러한 생체 시스템들은 두 거울상 이성질체들과도 완전히 다른 형식으로 상호작용을 한다. 효소 수용체에 기질이 작용하기 위해서는 일차적으로 3차원적인 구조가 상호간에 일치해야 되기 때문에 두 가지 거울상 이성질체들 가운데 한 종류만이 유효하다. 또한 한 쌍 의 거울상 이성질체는 동일한 화학적, 물리적 특성을 가지고 있으나 키랄 환경에 놓이게 되면 서로 다른 생리학적 활성도를 나타내게 된다. 대부분의 경우에 생체조직은 한 쌍의 거울상 이성질체를 각각 다른 물질로 인식하므로 결과적으로 이 거울상 이성질체는 서로 다른 생리학적 특성을 나타내게 된다. 이들은 주로 의약품, 식품 첨가제, 농약이나 살충제 등 우리의 일상생활과 매우 밀접한 용도로 사용되고 있다.Many macromolecules, even microscopic ones, have chiral elements, which are fundamental to interactions and reactions between substances, especially in nature. Life itself depends on the recognition of chirality, because biological functions are acted through the correct recognition between chiral components. For example, all enzymes in living organisms have specific chirality and react only with the desired reactants through molecular recognition using them. These biological systems also interact in a completely different form from the two enantiomers. Only one of the two enantiomers is valid because the three-dimensional structure must first coincide with each other for the substrate to act on the enzyme receptor. In addition, a pair of enantiomers have the same chemical and physical properties, but when placed in a chiral environment, they exhibit different physiological activities. In most cases, biological tissues recognize a pair of enantiomers as different substances, and as a result, the enantiomers exhibit different physiological properties. They are mainly used for medicines, food additives, pesticides and pesticides, which are very close to our daily lives.

특히 의약품의 경우 한 쌍의 거울상 이성질체 중 한 이성질체는 효과적인 치료제로 다른 이성질체는 효과가 없거나 심각한 부작용을 일으켜 치명적이 될 수 있다. 보통 한 거울상이성질체는 다른 거울상이성질체보다 높은 생리활성을 나타낸다. 이러한 이유로 라세믹 화합물을 의학적으로 사용하는 것은 위험하다. 한 거울상이성질체만이 의학적 사용이 가능하거나 두 거울상이성질체가 모두 부작용을 나타낼 수도 있으며 두 거울상이성질체가 각각 다른 부작용을 보이기도 한다. 생리활성적인 거울상이성질체가 부작용을 갖는다면 더 심각해 질 수 있다. 신진 대사에 관여하는 효소가 키랄 물질이라면 거울상이성질체의 대사경로와 속도 또한 다르게 된다.In particular, in the case of pharmaceuticals, one of the pair of enantiomers is an effective therapeutic agent, and the other isomer may be ineffective or cause serious side effects, which can be fatal. Usually one enantiomer shows higher physiological activity than the other enantiomer. For this reason, medical use of racemic compounds is dangerous. Only one enantiomer may be available for medical use, or both enantiomers may have side effects, and the two enantiomers may have different side effects. Bioactive enantiomers can become more serious if they have side effects. If the enzyme involved in metabolism is a chiral substance, the metabolic pathways and rates of the enantiomers are also different.

예를 들면 Thalidomide는 독일에서 1960년대에 개발된 약물이다. 이 당시 의약품들은 50%의 (R)-형과 50%의 (S)-형으로 이루어져 있는 라세믹체로 판매가 되고 있었는데 이 Thalidomide의 (R)-형은 좋은 진통제로 사용되어지나 (S)-형은 임산부에게 치명적인 태아기형을 유발하여 큰 문제가 되었다. 또 다른 예로 Ethambutol의 (S,S)-이성질체는 결핵 치료제, (R,R)-이성질체는 눈의 퇴화를 야기 하여 눈을 멀게 할 수 있다.Thalidomide, for example, is a drug developed in the 1960s in Germany. At this time, drugs were sold in racemic form consisting of 50% ( R ) -type and 50% ( S ) -form. The ( R ) -form of Thalidomide is used as a good analgesic ( S ) -form. Has become a major problem because it causes fatal fetal malformations in pregnant women. In another example, the ( S, S ) -isomer of Ethambutol can be used to treat tuberculosis, and the ( R, R ) -isomer can cause blindness by causing eye degeneration.

이러한 광학활성 화합물의 이성질체가 인체에 부작용을 일으킨다는 것이 알려진 후, 이에 대한 법적 규제가 크게 강화되고 있는 추세이므로 더욱 많은 연구 개발이 활발히 진행되고 있다. 미국 식품 의약청 (FDA)은 의약품 제조 시 부작용을 우려하여 한 가지 거울상 이성질체만을 사용할 것을 요구하고 있다. 따라서 한 개의 거울상 이성질체를 얻을 수 있는 효과적인 방법의 개발은 유기합성이나 의학분야에서 아주 중요한 과제이다. 이처럼 광학활성인 이성질체를 서로 구분하여 광학적 순도가 높은 화합물을 합성하기 위한 비대칭 합성법의 연구가 활발히 진행되고 있다.Since it is known that the isomers of such optically active compounds cause side effects in the human body, more and more research and development is being actively progressed since the legal regulations on them are being greatly strengthened. The U.S. Food and Drug Administration (FDA) is concerned about the side effects of manufacturing pharmaceuticals and requires the use of only one enantiomer. Therefore, the development of an effective way to obtain one enantiomer is a very important task in organic synthesis and medicine. As described above, studies of asymmetric synthesis methods for synthesizing compounds having high optical purity by distinguishing optically active isomers from each other are being actively conducted.

지금까지 과학자들이 순수한 이성질체를 얻기 위하여 많은 노력을 기울여 왔으며, 그 대략적인 방법을 도 1에 나타내었다. 순수한 광학활성을 얻는 방법으로 사용된 물질에 따라 3가지로 나눌 수 있다. 첫째는 라세메이트를 각각으로 분리하는 방법으로 각 이성질체의 반응속도 차이를 이용한 kinetic resolution과 diastereomeric salt로 결정화시켜서 분리하는 방법이며 초기에 주로 이용되었던 방법이다. 하지만 racemate를 분리하는 방법은 분리 조건이 매우 까다로울 뿐 아니라 원하는 물질의 최대 수율이 50%이고 원하는 이성칠제를 분리하고 난 뒤 다른 이성질체의 손실이 있다는 단점을 가지고 있다.To date, scientists have put a lot of effort to obtain pure isomers, the approximate method is shown in FIG. The method of obtaining pure optical activity can be divided into three types depending on the material used. The first is to separate racemates separately, and to separate them by crystallization with kinetic resolution and diastereomeric salt using the reaction rate difference of each isomer. However, the racemate separation method is not only very difficult to separate, but also has the disadvantage that the maximum yield of the desired material is 50% and the loss of other isomers after separation of the desired isomer.

둘째는 천연물로부터 얻어지는 키랄 화합물을 이용하여 키랄성의 변환를 포함하는 합성법이다. 하지만 이 방법은 많은 양의 비싼 키랄 시약이 필요하다는 단점을 지니고 있다.The second is a synthetic method involving the conversion of chirality using chiral compounds obtained from natural products. However, this method has the disadvantage of requiring a large amount of expensive chiral reagents.

이러한 점에서 키랄 촉매를 이용하는 비대칭 촉매반응이 가장 바람직한 방법이라 할 수 있겠다. 비대칭 촉매반응은 생체 내에서 일어나는 매우 중요한 반응이다. 그와 같은 반응을 일으킨다고 알려진 대부분의 metalloenzyme은 매우 빠른 속도로 prochiral 물질을 광학 활성을 지닌 키랄 화합물로 변환시킨다. 즉 작은 양의 chiral enzyme이 prochiral 화합물로부터 enantiomerical purity를 가진 많은 양의 키랄 물질로의 합성을 유도케 한다. 효소가 대표적인 키랄 촉매로 현재까지 많이 이용되고 있으나 효소가 지닌 본질적인 난점으로 인해 더 이상의 발전이 제한을 받고 있다. 그 예로 효소는 특정한 기질에만 작용한다는 점과 그러한 반응은 적당한 온도, 중성에 가까운 pH, 수용액 하에서 이루어져야 한다는 점을 들 수 있다. 더욱이 대부분의 효소들은 값이 비싸며 불안정한 면도 가지고 있다. 이러한 효소와 같은 키랄 촉매를 대체할 수 있는 화합물을 개발이 시급한 연구과제이다.In this regard, asymmetric catalysis using chiral catalyst may be the most preferable method. Asymmetric catalysis is a very important reaction in vivo. Most metalloenzymes known to cause such reactions convert prochiral materials into optically active chiral compounds at a very high rate. That is, small amounts of chiral enzymes induce the synthesis of prochiral compounds into large amounts of chiral substances with enantiomerical purity. Although enzymes have been widely used as representative chiral catalysts to date, further developments are limited by the inherent difficulties of enzymes. For example, enzymes act only on specific substrates, and such reactions should be conducted at moderate temperatures, near neutral pH, and aqueous solutions. Moreover, most enzymes are expensive and unstable. It is an urgent task to develop a compound that can replace a chiral catalyst such as an enzyme.

한편, 라디칼은 다양한 작용기와 큰 반응속도의 차이로 반응을 하여 용매나 시약을 적절히 선택할 경우 선택적인 화학 변환을 할 수 있다. 라디칼과 라디칼간의 반응속도는 매우 빨라 조절하기가 어렵지만 반응 중 라디칼의 농도를 낮게 조절해 주면 높은 수율로 생성물을 생성할 수 있다. 이와 같은 라디칼 반응은 기존에 널리 사용되고 있는 이온 반응에 비하여 여러 가지 장점을 가지고 있다. 라디칼 반응은 중성 반응조건에서 수행할 수 있으며, 낮은 입체장애 및 낮은 극성효과를 나타내며, 원치 않는 제거반응이 일어나는 경향이 이온반응에 비하여 낮다. 또한 이온반응에서 보호기를 사용하여 보호한 후 반응을 수행해야 하는 알코올, 아 민, 케톤과 같은 작용기들을 보호기로 보호하지 않고 반응을 수행할 수 있다. 이와 같은 라디칼 반응은 라디칼은 존재가 알려진 이후 주로 고분자 합성에 이용되어 왔지만, 최근 30여 년간 라디칼 반응을 이용한 유기합성법이 많이 연구 개발되어 기존의 이온 반응으로는 합성하기 매우 어려운 복잡한 구조의 분자 및 생리활성 물질의 합성에 널리 응용되고 있다.Radicals, on the other hand, may react with various functional groups at large reaction rates and may undergo selective chemical conversion when solvents or reagents are properly selected. The reaction rate between radicals and radicals is very fast and difficult to control, but by controlling the concentration of radicals in the reaction low, the product can be produced in high yield. Such radical reactions have a number of advantages over conventional ionic reactions. The radical reaction can be carried out under neutral reaction conditions, exhibits low steric hindrance and low polarity effects, and the tendency for unwanted removal reactions to occur is lower than that of ionic reactions. In addition, the reaction may be performed without protecting the functional groups such as alcohol, amine, and ketone to be protected after using the protecting group in the ionic reaction. The radical reaction has been mainly used for the synthesis of polymers since the existence of radicals is known, but the organic synthesis method using radical reactions has been researched and developed in recent 30 years, and the complex structure of molecules and physiology which is very difficult to synthesize by conventional ionic reactions. It is widely applied to the synthesis of active substances.

라디칼 반응은 유기화학에서 중요한 위치를 점하고 있지만, 효과적으로 비대칭 합성에 응용한 예는 매우 드물다. 최근 10 여 년 동안 라디칼 반응을 이용한 비대칭 합성에 관한 연구가 활발히 진행되고 있다. 연구방향은 입체선택적인 관점에서 보면 크게 두 방향으로 나눌 수 있으며, 첫 번째는 부분입체 선택적(diastereoselective) 라디칼 반응이고 두 번째는 거울상 선택적(enantioselective) 라디칼 반응이다. 그 중 가장 많이 연구가 진행된 연구방향은 키랄 보조제(chiral auxiliary)와 루이스 산을 이용한 부분입체 선택적 라디칼 반응이며 거울상 선택적 라디칼 반응은 상대적으로 많은 연구가 되어있지 않다. Radical reactions have important positions in organic chemistry, but very few have been effectively applied to asymmetric synthesis. In recent decades, research on asymmetric synthesis using radical reactions has been actively conducted. The direction of the study can be divided into two directions from a stereoselective point of view: the first is a diastereoselective radical reaction and the second is an enantioselective radical reaction. The most studied research direction is the diastereoselective radical reaction using chiral auxiliary and Lewis acid, and the enantioselective radical reaction is relatively little studied.

부분입체 선택적 라디칼 반응을 이용한 탄소-탄소 결합형성 반응을 수행한 예를 살펴보면 다음과 같다. 우선, Sibi 그룹은 4-(디페닐메틸)-2-옥사졸리디논을 키랄 보조제로 사용하여 루이스 산 존재 하에서 라디칼 첨가반응조건을 이용하여 methyl crotonate에 높은 부분입체 선택성을 가지고 알킬기를 도입할 수 있었다. 다양한 루이스 산을 사용하였고, 사용된 루이스 산은 키랄 보조제와 출발물질의 카르보닐 산소에 배위하여 rotamer를 조절하는 역할을 하여 부분입체 선택성 을 증가시키는 역할을 한다. 사용된 루이스 산 중에서 두 자리를 배위할 수 있고 친산소성이 매우 큰 Yb(OTf)₃ 가 가장 효과적이었다. 또한, Sibi 그룹은 루이스 산 Mg(ClO₄)₂ 존재 하에서 bis-oxaxoline를 키랄 리간드로 사용하여 benzimide에 알킬기를 라디칼 첨가반응을 이용하여 부분입체 선택성이 매우 큰 벤자미도-2,4-디메틸-1-옥소펜타닐 벤조에이트 화합물을 합성하였다.An example of the carbon-carbon bond formation reaction using the diastereoselective radical reaction is as follows. First, the Sibi group was able to introduce alkyl groups with high diastereoselectivity into methyl crotonate using radical addition reaction conditions in the presence of Lewis acid using 4- (diphenylmethyl) -2-oxazolidinone as chiral adjuvant. . Various Lewis acids were used, and the Lewis acids used act to coordinate the rotamer by coordinating the carbonyl oxygen of the chiral adjuvant and starting material, thereby increasing diastereoselectivity. Among the Lewis acids used, Yb (OTf) ₃ , which can coordinate two sites and has a very high oxygen affinity, was the most effective. In addition, the Sibi group uses bis-oxaxoline as chiral ligand in the presence of Lewis acid Mg (ClO ₄ ) _2, and benzimide uses a radical addition reaction of an alkyl group to benzimido-2,4-dimethyl- with very high diastereoselectivity. A 1-oxopentanyl benzoate compound was synthesized.

다음으로 거울상 선택적 라디칼 반응에 대하여 알아보면, 거울상 선택적 라디칼 반응은 부분입체 선택적 라디칼 반응과 비교하여 상대적으로 연구가 많이 진행되어있지 않다. 그 예를 살펴보면 첫째로 라디칼 수소주게와 사슬 운반체로 키랄성을 가지는 시약을 사용하는 것이다. 이 방법은 주로 라디칼 환원 반응에 이용되었다. Metzger 그룹에서는 C₂-대칭 binaphthyl기가 붙어있는 키랄 유기주석 화합물을 합성하여 bromoester 화합물의 환원반응에 응용한 결과를 보고하였다. 생성물은 -78 ℃에서 52%의 ee 값을 보여 주었다.Next, the enantioselective radical reaction has not been studied much compared to the diastereoselective radical reaction. For example, first, use a chirality reagent as a radical hydrogen donor and chain carrier. This method was mainly used for radical reduction reactions. The Metzger group reported the results of the synthesis of chiral organotin compounds with C ₂ -symmetric binaphthyl groups and their application to the reduction of bromoester compounds. The product showed an ee value of 52% at -78 ° C.

두 번째로 키랄 리간드나 키랄 루이스 산이 기질이나 반응 중간에 생기는 라디칼 중간체에 배위하도록 반응을 고안하는 것이다. 이 분야의 연구가 가장 많이 보고 되어 있으며 그 응용 예를 살펴보면 다음과 같다. Naito 그룹은 키랄 리간드인 (4S,4'S)-2,2'-(프로판-2,2-디일)비스(4-페닐-4,5-디하이드로옥사졸)과 루이스 산을 사용하여 glyoxylate imine에 isopropyl기를 도입하는 분자 간 거울상 선택적 라디칼 반응을 수행하였다. 다양한 루이스 산 중에서 MgBr₂가 가장 효과적이었고 수율은 97%로 높은 반면 52% ee로 입체선택성은 낮았다.Second, the reaction is designed to coordinate chiral ligands or chiral Lewis acids to the substrate or radical intermediates that occur in the middle of the reaction. The research in this field is reported the most and its application is as follows. Naito group is a chiral ligand (4 S, 4 'S) -2,2' - using (propane-2,2-diyl) bis (4-phenyl-4,5-dihydro-oxazole), and a Lewis acid Intermolecular enantioselective radical reaction introducing isopropyl groups into glyoxylate imine was performed. Among the various Lewis acids, MgBr ₂ was the most effective and the yield was high at 97%, while the stereoselectivity was low at 52% ee.

Friestad 그룹은 키랄 리간드인 (4S,4'S)-2,2'-(프로판-2,2-디일)비스(4-tert-부틸-4,5-디하이드로옥사졸)과 루이스 산으로 Cu(OTf)₂을 사용하여 N-acyl hydrazone에 다양한 알킬기를 도입하여 상온에서 라디칼 첨가반응을 수행하였다. Isopropyl기인 경우가 원하는 생성물의 수율은 가장 낮았으나 95% ee로 가장 높은 거울상 선택성을 보였다.Friestad group is a chiral ligand of (4 S, 4 'S) -2,2' - the (propane-2,2-diyl) bis (4-tert- butyl-4,5-dihydro-oxazole), and a Lewis acid Cu (OTf) ₂ was used to introduce various alkyl groups into N- acyl hydrazone to carry out the radical addition reaction at room temperature. The yield of the desired product was the lowest in the case of isopropyl group, but showed the highest enantioselectivity of 95% ee.

세 번째로 Bach 그룹에서 수소결합을 이용한 거울상 선택적 라디칼 반응이 있다. 3-(ω-요오도알킬리덴)파이퍼리딘-2-온과 키랄 시약으로 (1R,5R,7S)-1,5,7-트리메틸-7-(5,6,7,8-테트라하이드로나프토[2,3-d]옥사졸-2-일)-3-아자바이사이클로[3.3.1]노난-2-온을 함께 반응용매인 toluene에서 개시제 Et₃B과 라디칼 수소주게 Bu₃SnH를 사용하여 거울상 선택적 라디칼 고리화 반응을 진행하였다. 반응은 -78 ℃에서 원하는 생성물 71% 얻었으며 79% ee를 얻었다.Third, there is an enantioselective radical reaction using hydrogen bonds in the Bach group. (1 R , 5 R , 7 S ) -1,5,7-trimethyl-7- (5,6,7,8- with 3- (ω-iodoalkylidene) piperidin-2-one and chiral reagent Tetrahydronaphtho [2,3-d] oxazol-2-yl) -3-azabicyclo [3.3.1] nonan-2-one together with initiator Et ₃ B and radical hydrogen donor Bu in toluene Enantioselective radical cyclization was carried out using ₃ SnH. The reaction gave 71% of the desired product at -78 ° C and 79% ee.

부분입체 선택적 라디칼 반응에서 최소 1 당량의 키랄 보조제가 사용되고 반응 후 다시 제거하여야 한다. 또한 알킬기를 도입하려는 목적으로 사용되는 알킬 할라이드를 과량 사용하여야 하며 rotamer를 조절하기 위하여 반드시 루이스 산을 사용하여야 하는 단점을 가지고 있다.At least one equivalent of chiral adjuvant is used in the diastereoselective radical reaction and must be removed again after the reaction. In addition, an excessive amount of alkyl halide used for the purpose of introducing an alkyl group must be used, and a Lewis acid must be used to control the rotamer.

이와 같이, 종래에 거울상 선택적 라디칼 반응이 보고된 예가 매우 적을 뿐만 아니라, 그 종래에 보고된 거울상 선택성을 높이기 위한 라디칼 반응의 연구 역시 다음과 같은 문제점을 포함하고 있다.As such, not only very few examples of conventional enantioselective radical reactions have been reported, but also studies of radical reactions to enhance the enantioselectivity reported in the related art also include the following problems.

첫째로 라디칼 수소주게와 사슬 운반체로 키랄성을 가지는 시약을 사용한 경 우를 살펴보면, 이 방법은 주로 라디칼 환원 반응에 이용되었고 라디칼 반응의 가장 일반적인 수소주게로 사용되는 금속의 장점인 좋은 반응성을 취하며 동시에 거울상 선택성을 높이기 위한 목적으로 사용되었지만, 금속이 갖는 여러 단점을 그대로 가지고 있다.First, the use of chirality reagents as radical hydrogen donors and chain carriers shows that this method is mainly used for radical reduction reactions and at the same time takes advantage of the good reactivity of the metals used as the most common hydrogen donors for radical reactions. Although used for the purpose of enhancing enantioselectivity, it has many of the disadvantages of metals.

둘째로 키랄 촉매나 루이스 산을 사용하는 경우를 살펴보면, 거울상 선택성을 높이기 위한 방법으로 키랄 리간드와 금속을 사용함으로서 입체 선택성을 높이는 방법을 취하고 있다. 이 방법은 전체적인 반응을 촉매화 할 수 있다는 가능성을 열어주었지만 금속을 이용한 한계를 벗어날 수 없다. 대부분이 금속을 포함하고 있으며 촉매의 합성이 어렵고 그 가격 또한 고가로 산업화에는 한계가 있다.Secondly, in the case of using a chiral catalyst or Lewis acid, a method of enhancing stereoselectivity is employed by using a chiral ligand and a metal as a method for enhancing enantioselectivity. This method opens up the possibility of catalyzing the overall reaction but cannot overcome metal limitations. Most of them contain metals, the synthesis of the catalyst is difficult, and the price is also expensive, there is a limit to industrialization.

이런 문제를 해결하기 위해 키랄 촉매로써 금속을 포함하고 있지 않는 유기 촉매의 연구가 활발히 진행되어지고 있다. 유기 촉매는 천연물에서 간편하게 얻을 수 있을 뿐만 아니라, 취급하기 쉽다. 금속으로부터 자유로워 인체에 유독하지 않으며 촉매로써 회수가 가능하고 재사용이 가능하다는 장점들이 있어 친환경적이라 할 수 있겠다.In order to solve this problem, researches on organic catalysts that do not contain a metal as a chiral catalyst have been actively conducted. Organic catalysts can be easily obtained from natural products and are easy to handle. It is eco-friendly because it is free from metal, it is not toxic to human body, it can be recovered as a catalyst, and can be reused.

본 발명에서는 위에서 언급한 종래 관련 기술들의 문제점을 극복하는 것을 목적으로 하고 있다. 특히, 금속을 함유한 키랄 촉매가 지니는 문제점, 예를 들어 고가의 가격, 인체 유독성, 촉매 회수의 어려움, 환경 오염 등의 문제점을 해결 하고자 한다.The present invention aims to overcome the problems of the related art mentioned above. In particular, it is intended to solve the problems of metal-containing chiral catalysts, such as high price, human toxicity, difficulty in catalyst recovery, environmental pollution, and the like.

이러한 목적을 위하여, 본 발명에서는 거울상 키랄 아릴아민을 합성함에 있어서, 여러 장점을 지니고 있는 라디칼 치환 반응을 그대로 채택할 수 있음과 동시에, 위에서 언급한 종래 관련 기술의 금속 함유 촉매의 사용에 따른 문제점을 극복할 수 있는 신코나 알칼로이드계 키랄 유기 촉매 및 이를 이용한 거울상 선택성 키랄 아릴아민의 제조방법에 대해서 개시한다.To this end, in the present invention, in synthesizing the enantiomeric chiral arylamine, the radical substitution reaction having various advantages can be adopted as it is, and at the same time, the problems associated with the use of the metal-containing catalyst of the related art mentioned above are solved. Disclosed are a cinchona alkaloid chiral organic catalyst that can be overcome, and a method for producing enantioselective chiral arylamine using the same.

일 측면에 따르면, 본 발명은 아래 화학식 1의 구조를 갖는 거울상 키랄 화합물에 관한 것이다.According to one aspect, the present invention relates to a mirror image chiral compound having the structure of formula (1) below.

상기에서 R은 벤질기, 벤조일기 및 안트라센-9-카르복실레이트기 중에서 선택된다.Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups.

다른 측면에 따르면, 본 발명은 아래 화학식 2의 구조를 갖는 거울상 키랄 라디칼 유기 촉매에 관한 것이다.According to another aspect, the present invention relates to an enantiomeric chiral radical organic catalyst having the structure of formula (2) below.

상기에서 R은 벤질기, 벤조일기 및 안트라센-9-카르복실레이트기 중에서 선택되며; X는 H₃PO₂ 및 PF₆ 중에서 선택된다.Wherein R is selected from benzyl, benzoyl and anthracene-9-carboxylate groups; X is selected from H ₃ PO ₂ and PF ₆ .

또 다른 측면에 따르면, 본 발명은 위 화학식 2의 구조를 갖는 유기 촉매를 사용하여 반응물과 알킬화제를 서로 라디칼 첨가 반응시키는 단계를 포함하는 거울상 키랄 아릴아민의 제조방법에 관한 것이다.According to another aspect, the present invention relates to a method for producing a mirror-like chiral arylamine comprising the step of radical addition reaction of the reactant and the alkylating agent using an organic catalyst having the structure of formula (2).

본 발명은 신코나 알칼로이드계 유기 촉매 및 이를 이용한 거울상 키랄 아릴아민의 제조방법에 관한 것으로서, 더욱 구체적으로는 본 발명의 유기 촉매는 특정한 구조를 갖는 신코나 알칼로이드계 화합물의 염 형태를 가지며, 이를 거울상 키랄 아릴아민을 리디칼 첨가반응에 사용함으로써 수율 및 선택도가 매우 향상될 뿐만 아니라 유기 촉매의 회수율 및 반응규모의 확장가능성면에서도 현저하게 향상된 효과를 얻을 수 있다.The present invention relates to a synacona alkaloid-based organic catalyst and a method for producing a mirror-like chiral arylamine using the same, and more particularly, the organic catalyst of the present invention has a salt form of a synacona alkaloid-based compound having a specific structure, which is a mirror image By using chiral arylamine in the radical addition reaction, not only the yield and selectivity are greatly improved, but also the remarkably improved effect in terms of recoverability of organic catalyst and scalability of reaction scale.

일 측면에 따르면, 본 발명은 거울상 키랄 라이칼 유기촉매의 제조에 유용한 아래 화학식 1의 구조를 갖는 거울상 키랄 화합물에 관한 것이다.According to one aspect, the present invention relates to a mirror-like chiral compound having a structure of formula (1) below, which is useful for the preparation of a mirror-like chiral lycal organic catalyst.

[화학식 1][Formula 1]

[화학식 2][Formula 2]

위와 같이, 본 발명의 유기 촉매는 특별한 구조를 갖는 신코나 알칼로이드로서 그 자체로 사용되는 것이 아니라 위에서 언급한 바와 같은 염의 형태로 사용함에 그 특징이 있다. 아래 실시예에서 실험적으로 뒷받침하고 있는 반응뿐만 아니라 그 이외의 반응에서도 유기 촉매를 그대로 사용하는 대신에 위 유기 촉매의 염 형태로 사용하는 경우에 본 발명의 효과를 현저하게 극대화하는데 매우 유리함을 본 발명자에 의해서 확인되었다.As described above, the organic catalyst of the present invention is characterized in that it is used in the form of a salt as mentioned above, rather than being used as a synko or alkaloid having a special structure by itself. The present inventors found that the present invention is very advantageous in maximally maximizing the effect of the present invention in the case of using the salt of the above organic catalyst instead of using the organic catalyst as it is in the reactions not supported experimentally in the following examples. It was confirmed by.

본 발명에서 반응물은 거울상 키랄 아릴아민을 생성시키기에 적합한 구조를 갖는 반응물이면 특별히 제한되지 않으나, 다만 일 구현예에 있어서 상기 반응물은 아래 화학식 3의 구조를 가지는 것이 높은 수율과 광학순도뿐만 아니라 유기 촉매의 회수용이성 및 재활용 가능성, 대규모 반응 가능성 면에서 매우 유리하다.In the present invention, the reactant is not particularly limited as long as the reactant has a structure suitable for producing enantiomeric chiral arylamine, but in one embodiment, the reactant has a structure represented by Chemical Formula 3 below as well as an organic catalyst as well as high yield and optical purity. It is very advantageous in terms of recoverability, recycling potential and large scale reaction possibility.

상기에서 R과 R1은 각각 독립적으로 벤조일기, 알킬기, 치환된 알킬기, 아릴기 및 치환된 아릴기 중에서 선택되며; 상기 치환된 알킬기는 할라이드, 니트로기, 아실기, 히드록시기, Ra-O- 및 Rb-CO-NH- 중에서 선택된 하나 이상의 치환기에 의해서 치환되고; 상기 치환된 아릴기는 할라이드, 니트로기, 아실기, 히드록시기, Ra-O-, Rb-CO-NH- 및 Rc- 중에서 선택된 하나 이상의 치환기에 의해서 치환되며; 상기 Ra, Rb, Rc는 각각 독립적으로 C₁-C₅의 저급 알킬기 또는 C₆-C₂₀의 고급 알킬기이다.R and R1 are each independently selected from a benzoyl group, an alkyl group, a substituted alkyl group, an aryl group, and a substituted aryl group; The substituted alkyl group is substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, and Rb-CO-NH-; The substituted aryl group is substituted by one or more substituents selected from halide, nitro group, acyl group, hydroxy group, Ra-O-, Rb-CO-NH- and Rc-; Ra, Rb and Rc are each independently a lower alkyl group of C ₁ -C ₅ or a higher alkyl group of C ₆ -C ₂₀ .

바람직한 구현예에 따르면, 위 화학식 3에서 R1은 벤조일기이고; 상기 R은

이며; 여기서 R'-은 수소, 할라이드, 니트로기, 아실기, 히드록시기, Ra-O-, Rb-CO-NH- 및 Rc-중에서 선택되며; 상기 Ra, Rb, Rc는 각각 독립적으로 C₁-C₅의 저급 알킬기 또는 C₆-C₂₀의 고급 알킬기이다.According to a preferred embodiment, R 1 in the formula (3) is a benzoyl group; R is

Is; Wherein R'- is selected from hydrogen, halide, nitro group, acyl group, hydroxy group, Ra-O-, Rb-CO-NH- and Rc-; Ra, Rb and Rc are each independently a lower alkyl group of C ₁ -C ₅ or a higher alkyl group of C ₆ -C ₂₀ .

즉, 상기 반응물에 페닐기를 포함하는 경우에 유기 촉매의 페닐기와 파이-파 이 스태킹을 형성하여 수율 및 광학순도를 현저하게 향상시킬 수 있으며, 특히 유기 촉매의 회수율 및 반응규모의 확장가능성면에서 현저하게 향상됨을 본 발명자에 의해서 확인되었다.That is, in the case where the reactant includes a phenyl group, the yield and optical purity of the organic catalyst can be remarkably improved by forming a phenyl group and pi-py stacking of the organic catalyst, particularly in terms of recoverability of the organic catalyst and expandability of the reaction scale. It was confirmed by the present inventors that the improvement.

다만, 본 발명에 있어서 생성물이 4차 탄소를 포함하는 거울상 선택성 아미노산인 경우는 바람직하지 않으며, 따라서 이러한 생성물이 합성되도록 하는 생성물 역시 본 발명의 범위에서 배제되는 것이 바람직하다.However, in the present invention, it is not preferable that the product is an enantioselective amino acid including quaternary carbon, and therefore, a product for allowing such a product to be synthesized is also preferably excluded from the scope of the present invention.

본 발명의 다른 구현예에 따르면, 상기 알킬화제는 아래 화학식 4의 구조를 가지는 것임을 특징으로 하는 거울상 키랄 아릴아민의 제조방법:According to another embodiment of the present invention, the alkylating agent is a method for producing a mirror chiral arylamine, characterized in that having the structure of formula (4):

R-AR-A

상기에서 R은 1차, 2차 또는 3차 알킬기이고; 상기 알킬기는 C₁-C₅의 저급 알킬기 또는 C₆-C₂₀의 고급 알킬기이며; A는 할라이드이다.R is a primary, secondary or tertiary alkyl group; The alkyl group is C ₁ -C ₅ lower alkyl group or C ₆ -C ₂₀ higher alkyl group; A is a halide.

바람직한 구현예에 따르면, 위 화학식 4에서 상기 R은 이소프로필기, 사이클로헥실기, tert-부틸기 및 1-아다만틸기 중에서 선택되며; 상기 A는 I, Cl, F 중에서 선택된다.According to a preferred embodiment, in Formula 4, R is selected from isopropyl group, cyclohexyl group, tert-butyl group, and 1-adamantyl group; A is selected from I, Cl, and F.

즉, 상기 알킬화제가 1차 알킬할라이드인 경우에도 본 발명의 범위에는 포함되나 수율 및 광학순도가 저하된다는 점에서 바람직하지 않으며, 특히 2차 또는 3차 알킬할라이드를 알킬화제로 사용하는 경우에 수율 및 광학순도의 증가 이외에 유기 촉매의 회수율 및 반응규모의 확장가능성 면에서 크게 향상됨을 본 발명자에 의해서 확인되었다.That is, even when the alkylating agent is a primary alkyl halide, it is included in the scope of the present invention, but it is not preferable in terms of lowering yield and optical purity. Particularly, when the second or tertiary alkyl halide is used as the alkylating agent, the yield and optical In addition to the increase in purity, it was confirmed by the present inventors that a significant improvement in the recoverability of the organic catalyst and the scalability of the reaction scale.

또 다른 바람직한 구현예에 따르면, 상기 라디칼 첨가 반응은 -35℃ 내지 -25℃의 반응온도에서 수행되며, 상기 반응물 1당량을 기준으로 상기 유기 촉매를 0.9~3 당량으로 사용하여 수행된다.According to another preferred embodiment, the radical addition reaction is carried out at a reaction temperature of -35 ℃ to -25 ℃, it is carried out using 0.9 to 3 equivalents of the organic catalyst based on 1 equivalent of the reactants.

실시예Example

하기의 실시예는 본 발명을 더욱 구체적으로 설명하기 위함이며, 이에 의해서 본 발명의 범위가 한정되어 해석될 수 없다.The following examples are intended to illustrate the present invention in more detail, whereby the scope of the present invention is limited and cannot be interpreted.

A. 실험재료 및 실험방법A. Experimental Materials and Methods

(1) 시약 및 기기(1) reagents and instruments

모든 실험은 아르곤 하에서 수행하였으며, 실험에 사용한 초자기구들은 120℃의 oven에서 충분히 건조시킨 다음 상온까지 식힌 후에 사용하였다. 반응에 사용한 용매는 종래 문헌의 방법에 따라 정제하여 사용하였다. 반응에 사용한 시약들은 알드리치사의 제품을 사용하였고 시약이 액체인 경우는 글래스 시린지나 마이크로시린지로 옮겨 사용하였다. TLC (thin-layer chromatography)는 알드리치사 제품의 프리코티드(precoated) 실리카겔 글래스 플레이트(실리카겔 60, F-254, layer thickness 250㎛)를 사용하였으며 컬럼 크로마토그래피 분리를 위하여 E. Merck사의 실리카겔 60 (230-240mesh)과 알드리치사의 실리카겔, Merck, Grade 9385 (230-400 mesh)를 사용하였다. TLC상에서 분리된 물질의 확인을 위하여 UV lamp (254㎚)를 이용하거나 발색시약을 spray하여 plate를 구웠다. 발색시약은 1% cerium sulfate와 molybdic acid를 포함하는 10% 황산 수용액 또는 K₂CO₃와 KMnO₄를 포함하는 수용액을 이용하였다. 고성능 액체 크로마토그라피는 Gilson GX-281를 사용하였고 비대칭 컬럼은 Daicel사의 Chiralpak IA column을 사용하였다. ¹H NMR spectrum은 Brucker Advance 400 (400MHz)를 사용하였으며 화학이동은 tetramethylsilane (TMS)을 내부표준물질로 사용하여 downfield로 ppm (δ)단위로 표시하였다. GC/MS 분석은 Hewlett-Packard 5890 GC/5970 MSD (EI, 70 eV)를 이용하였다. Specific rotation의 측정은 Schmidt Polartronic HN8 polarimeter를 이용하였으며 원소 분석은 EA1110 elemental analyzer를 이용하였다.All experiments were performed under argon, and the vitreous instruments used in the experiment were dried in an oven at 120 ° C. and then cooled to room temperature. The solvent used for reaction was refine | purified according to the method of the conventional literature. Reagents used in the reaction were manufactured by Aldrich, and when the reagent was a liquid, it was transferred to a glass syringe or a micro syringe. Thin-layer chromatography (TLC) was performed using Aldrich's precoated silica gel glass plate (silica gel 60, F-254, layer thickness 250 μm), and silica gel 60 (E. Merck) for separation of column chromatography. 230-240mesh) and Aldrich's silica gel, Merck, Grade 9385 (230-400 mesh) were used. Plates were baked using a UV lamp (254 nm) or spraying a coloring reagent to identify the material separated on the TLC. The color reagent was used as 10% sulfuric acid solution containing 1% cerium sulfate and molybdic acid or aqueous solution containing K ₂ CO ₃ and KMnO ₄ . High performance liquid chromatography used Gilson GX-281 and asymmetric column used Daicel's Chiralpak IA column. Brucker Advance 400 (400MHz) was used for the ¹ H NMR spectrum and chemical shifts were expressed in ppm (δ) downfield using tetramethylsilane (TMS) as an internal standard. GC / MS analysis was performed using Hewlett-Packard 5890 GC / 5970 MSD (EI, 70 eV). Specific rotation was measured using Schmidt Polartronic HN8 polarimeter and elemental analysis was performed by EA1110 elemental analyzer.

(2) 절대배열의 결정(2) Determination of absolute arrangement

절대배열을 결정하기 위해 1a?H₃PO₂를 이용하여 얻어낸 82% ee을 갖는 N'-(2-methyl-1-phenylpropyl)benzohydrazide (3m)를 MeOH를 반응용매로 하여 SmI₂(0.1 M THF solution)를 3당량 넣어 주고 상온에서 30분 동안 교반하여 실리카겔 컬럼 크로마토그래피로 분리 하였다. 그 결과 N-N결합을 쪼개진 2-methyl-1-phenylpropan-1-amine을 84%의 수율로 얻었다. 문헌에 보고된

값과 비교하여 절대배열이 S이성질체로 결정하였다. 동일한 조건으로 1a?HPF₆를 이용하여 얻어낸 99% ee을 갖는 N'-(2-메틸-1-페닐프로필)벤조히드라자이드 (3m)을 반응을 수행 하여 원하는 생성물을 84%의 수율로 얻었다. 문헌에 보고된

값과 비교하여 절대배열이 S이성질체로 결정하였다. N ' -(2-methyl-1-phenylpropyl) benzohydrazide ( 3m ) with 82% ee obtained using 1a -H ₃ PO ₂ to determine the absolute configuration was prepared using MeOH as the reaction solvent.SmI ₂ (0.1 M THF solution) was added to 3 equivalents and stirred for 30 minutes at room temperature, and separated by silica gel column chromatography. As a result, 2-methyl-1-phenylpropan-1-amine with NN bonds was obtained in 84% yield. Reported in the literature

The absolute configuration was determined as the S isomer compared to the value. Under the same conditions, N ' -(2-methyl-1-phenylpropyl) benzohydrazide ( 3m ) having 99% ee obtained using 1a HPF ₆ was subjected to the reaction to obtain a desired product in 84% yield. Reported in the literature

The absolute configuration was determined as the S isomer compared to the value.

B. B. NN -벤조일 히드라존의 합성Synthesis of Benzoyl Hydrazone

2구 플라스크에 aldehyde 1당량을 넣어주고 N-benzoyl hydrazones 1.2당량을 Zn(ClO₄)₂ 촉매량과 함께 MeOH (10 mL)에 녹여 2구 플라스크에 넣어었다. 상온에서 4에서 12시간 교반하였다. 반응이 완결된 후 여과한 후 diethyl ether로 씻어 주어 원하는 생성물을 90% 이상의 수율로 얻었다. One equivalent of aldehyde was added to a two-necked flask, and 1.2 equivalents of N- benzoyl hydrazones were dissolved in MeOH (10 mL) together with the amount of Zn (ClO ₄ ) ₂ catalyst. Stir at 4 to 12 hours at room temperature. After the reaction was completed, filtered and washed with diethyl ether to give the desired product in more than 90% yield.

C. 유기 촉매 키랄 암모늄 염의 제조C. Preparation of Organic Catalyzed Chiral Ammonium Salts

키랄 암모늄 염은 먼저 신코나 알칼로이드인 신코닌의 C=C 결합을 Pd/C(0.1 equiv, 10wt%)를 촉매로 이용하여 H₂(5 bar)에서 MeOH 용매 하에서 3시간 교반하여 환원하였다. 환원된 신코닌 유도체를 염기(base)와 알킬할라이드를 무수 THF를 가하고 70 ℃로 3시간 가열 환류하여 히드록실기를 알킬기로 치환된 신코닌 유도체를 얻었다. 이렇게 얻어낸 신코나 알칼로이드 유도체와 여러 가지 HX를 MeOH 용매 하에서 10분간 상온에서 교반한 후 농축하여 다양한 키랄 암모늄 염을 얻었다. 이에 관한 도식적인 절차는 아래 반응식에 나타내었으며, 더욱 구체적인 내용에 대해서도 추가로 아래에 기재하였다.The chiral ammonium salt was first reduced by stirring the C = C bond of the cinnacon alkanoid, cinnamonine, using Pd / C (0.1 equiv, 10wt%) as a catalyst in H ₂ (5 bar) under a MeOH solvent for 3 hours. The reduced synthoxy derivative was added with anhydrous THF to a base and an alkyl halide, and refluxed at 70 ° C. for 3 hours to obtain a cycinin derivative in which a hydroxyl group was substituted with an alkyl group. The synacona alkaloid derivative thus obtained and various HX were stirred at room temperature for 10 minutes in a MeOH solvent and concentrated to obtain various chiral ammonium salts. A schematic procedure for this is shown in the scheme below and further details are given below.

(1) ((One) ( 2R,4S,8R2R, 4S, 8R )-2-(()-2-(( SS )-벤질옥시(퀴놀린-4-일)메틸)-8-에틸퀴누클리딘 (1a)의 합성Synthesis of) -benzyloxy (quinolin-4-yl) methyl) -8-ethylquinuclidin (1a)

수분을 제거한 고온?고압 반응기에 (+)-cinchonine (5 g, 17 mmol)와 Pd/C (1.8 g, 1.7 mmol)을 MeOH에 함께 넣었다. 고온?고압 반응기에 H₂를 5 bar 주입하여 3 시간동안 교반하였다. Celite를 이용하여 사용하여 Pd/C를 제거한 후 용매를 감압 하에 제거해 주었다. 수분을 제거한 2구 플라스크에 아르곤 기체를 충분히 흘려준 후 n-hexane으로 씻은 NaH (1 g, 25 mmol, 60% dispersion)을 무수 THF (70 mL) 용매 하에 넣어준 후 상온에서 1시간 교반한 후 benzyl bromide (2.2 mL, 18.7 mmol)을 넣고 3시간 동안 가열 환류하였다. 반응이 완결된 후 diethyl ether로 희석시킨 후 포화 NaCl 수용액으로 씻은 다음 유기층을 무수 MgSO₄로 건조하였다. 용매를 감압 하에 제거한 다음에 silca gel 컬럼 크로마토그래피 (eluent; hexane : EtOAc = 6 : 4)로 분리하였다. 원하는 생성물 1a 86% (3.3g)의 수율로 얻었다. Yellow syrup;

= +170.4 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.78 (t, J = 6.8 Hz, 3H), 1.38-1.51 (m, 4H), 1.90-2.40 (m, 5H), 2.40-2.81 (m, 2H), 3.30-3.57 (m, 2H), 4.43 (s, 2H), 5.01-5.18 (m, 1H), 7.10-7.31 (m, 6H), 7.51 (t, J = 7.8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.84 (d, J = 3.2 Hz, 1H); ¹³C NMR (CD₃COCD₃) δ 152.3, 151.1, 149.5, 142.9, 139.9, 138.2, 130.8, 130.0, 128.8, 127.5, 127.1, 126.3, 122.3, 118.1, 116.1, 80.1, 71.9, 63.7, 59.4, 44.5, 40.9, 34.4, 28.9, 26.9, 21.3, 12.7; IR (neat) ν 3196, 2938, 1641, 1283, 1141. Anal. calcd for C₂₆H₃₀N₂O: C, 80.79; H, 7.82; N, 7.25. Found: C, 80.77 H, 7.84 N, 7.24.(+)-Cinchonine (5 g, 17 mmol) and Pd / C (1.8 g, 1.7 mmol) were added together in MeOH in a high temperature and high pressure reactor in which water was removed. 5 bar of H ₂ was injected into the high temperature and high pressure reactor, followed by stirring for 3 hours. After removing Pd / C using Celite, the solvent was removed under reduced pressure. After argon gas was sufficiently flowed into the two-necked flask without water, NaH (1 g, 25 mmol, 60% dispersion) washed with n-hexane was put in anhydrous THF (70 mL) solvent, and then stirred at room temperature for 1 hour. benzyl bromide (2.2 mL, 18.7 mmol) was added and heated to reflux for 3 hours. After completion of the reaction, the mixture was diluted with diethyl ether, washed with saturated aqueous NaCl solution, and the organic layer was dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and then separated by silca gel column chromatography (eluent; hexane: EtOAc = 6: 4). The desired product 1a obtained in a yield of 86% (3.3 g). Yellow syrup;

= +170.4 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.78 (t, J = 6.8 Hz, 3H), 1.38-1.51 (m, 4H), 1.90-2.40 (m, 5H), 2.40-2.81 (m, 2H), 3.30-3.57 (m, 2H), 4.43 (s, 2H), 5.01-5.18 (m, 1H), 7.10-7.31 (m, 6H), 7.51 (t, J = 7.8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.84 (d, J = 3.2 Hz, 1H); ¹³ C NMR (CD ₃ COCD ₃ ) δ 152.3, 151.1, 149.5, 142.9, 139.9, 138.2, 130.8, 130.0, 128.8, 127.5, 127.1, 126.3, 122.3, 118.1, 116.1, 80.1, 71.9, 63.7, 59.4, 44.5, 40.9, 34.4, 28.9, 26.9, 21.3, 12.7; IR (neat) v 3196, 2938, 1641, 1283, 1141. Anal. calcd for C ₂₆ H ₃₀ N ₂ O: C, 80.79; H, 7. 82; N, 7.25. Found: C, 80.77 H, 7.84 N, 7.24.

(2) ((2) ( SS )-(()-(( 2R,4S,5R2R, 4S, 5R )-5-에틸퀴누클리딘-2-일)(퀴놀린-4-일)메틸 벤조에이트 (1b)의 합성Synthesis of) -5-ethylquinucindin-2-yl) (quinolin-4-yl) methyl benzoate (1b)

수분을 제거한 고온?고압 반응기에 (+)-cinchonine (5 g, 17 mmol)와 Pd/C (1.8 g, 1.7 mmol)을 MeOH과 함께 넣었다. 고온?고압 반응기에 H₂를 5 bar 주입하여 3 시간동안 교반하였다. Celite를 이용하여 사용하여 Pd/C를 제거한 후 용매를 감압 하에 제거해 주었다. 수분을 제거한 2구 플라스크에 아르곤 기체를 충분히 흘려준 후 환원된 cinchonine (3 g, 10.1 mmol)과 Et₃N (10.2 mL, 101.2 mmol)을 무수 THF (80 mL) 용매 하에 넣어준 후 상온에서 20분 교반한 후 benzoyl chloride (1.8 mL, 15.2 mmol)을 넣고 24시간 동안 가열 환류 하였다. 반응이 완결된 후 diethyl ether로 희석시킨 후 포화 NaHCO₃수용액와포화 NaCl 수용액으로 씻은 다음 유기층을 무수 MgSO₄로 건조하였다. 용매를 감압 하에 제거한 다음에 실리카겔 컬럼 크로마토그래피 (eluent; hexane : EtOAc = 6 : 4)로 분리하였다. 원하는 생성물 1b 81% (3.3 g)의 수율로 얻었다. Yellow syrup;

= +161.0 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.91 (t, J = 6.8 Hz, 3H), 1.39-1.68 (m, 5H), 1.94-2.83 (m, 6H), 3.30-3.59 (m, 2H), 5.49 (s, 1H), 7.18-7.88 (m, 5H), 8.11 (d, J = 8 Hz, 1H), 8.23 (t, J = 3.6 Hz, 2H), 8.37 (d, J = 11.2 Hz, 1H), 9.01-9.19 (m, 2H); ¹³C NMR (CDCl₃) δ 165.0, 152.1, 150.7, 149.1, 129.9, 129.8, 128.1, 127.8, 126.4, 125.5, 122.1, 118.2, 70.1, 60.1, 55.7, 44.0, 40.0, 30.0, 28.6, 27.3, 20.1, 10.7; IR (neat) ν 3026, 2914, 1726, 1648, 1401. Anal. calcd for C₃₄H₃₂N₂O₂: C, 77.97; H, 7.05; N, 6.99; Found: C, 78.00; H, 7.07; N, 6.98.(+)-Cinchonine (5 g, 17 mmol) and Pd / C (1.8 g, 1.7 mmol) were added together with MeOH in a high temperature and high pressure reactor from which water was removed. 5 bar of H ₂ was injected into the high temperature and high pressure reactor, followed by stirring for 3 hours. After removing Pd / C using Celite, the solvent was removed under reduced pressure. After argon gas was sufficiently flowed into the water-reduced two-necked flask, reduced cinchonine (3 g, 10.1 mmol) and Et ₃ N (10.2 mL, 101.2 mmol) were put in anhydrous THF (80 mL) solvent, and then at room temperature. After stirring for minutes, benzoyl chloride (1.8 mL, 15.2 mmol) was added thereto, and the mixture was heated to reflux for 24 hours. After the reaction was completed, the mixture was diluted with diethyl ether, and saturated aqueous NaHCO ₃ solution was added. After washing with saturated aqueous NaCl solution, the organic layer was dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and then separated by silica gel column chromatography (eluent; hexane: EtOAc = 6: 4). The desired product 1b obtained in a yield of 81% (3.3 g). Yellow syrup;

= +161.0 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.91 (t, J = 6.8 Hz, 3H), 1.39-1.68 (m, 5H), 1.94-2.83 (m, 6H), 3.30-3.59 (m, 2H), 5.49 (s , 1H), 7.18-7.88 (m, 5H), 8.11 (d, J = 8 Hz, 1H), 8.23 (t, J = 3.6 Hz, 2H), 8.37 (d, J = 11.2 Hz, 1H), 9.01 -9.19 (m, 2 H); ¹³ C NMR (CDCl ₃ ) δ 165.0, 152.1, 150.7, 149.1, 129.9, 129.8, 128.1, 127.8, 126.4, 125.5, 122.1, 118.2, 70.1, 60.1, 55.7, 44.0, 40.0, 30.0, 28.6, 27.3, 20.1, 10.7; IR (neat) v 3026, 2914, 1726, 1648, 1401.Anal. calcd for C ₃₄ H ₃₂ N ₂ O ₂ : C, 77.97; H, 7.05; N, 6.99; Found: C, 78.00; H, 7.07; N, 6.98.

(3) ((3) ( SS )-(()-(( 2R,4S,8S2R, 4S, 8S )-8-Ethylquinuclidin-2-yl)(quinolin-4-yl)methyl anthracene-9-carboxylate (1c)의 합성Synthesis of) -8-Ethylquinuclidin-2-yl) (quinolin-4-yl) methyl anthracene-9-carboxylate (1c)

수분을 제거한 고온?고압 반응기에 (+)-cinchonine (5 g, 17 mmol)와 Pd/C (1.8 g, 1.7 mmol)을 MeOH과 함께 넣었다. 고온?고압 반응기에 H₂를 5 bar 주입하여 3 시간동안 교반하였다. Celite를 이용하여 사용하여 Pd/C를 제거한 후 용매를 감압 하에 제거해 주었다. 수분을 제거한 2구 플라스크에 아르곤 기체를 충분히 흘려준 후 환원된 cinchonine (3 g, 10.1 mmol)과 Et₃N (10.2 mL, 101.2 mmol)을 무수 THF (80 mL) 용매 하에 넣어준 후 상온에서 20분 교반한 후 anthracene-9-carbonyl chloride (3.6 g, 15.2 mmol)을 넣고 24시간 동안 가열 환류하였다. 반응이 완결된 후 diethyl ether로 희석시킨 후 포화 NaHCO₃수용액와포화 NaCl 수용액으로 씻은 다음 유기층을 무수 MgSO₄로 건조하였다. 용매를 감압 하에 제거한 다음에 실리카겔 컬럼 크로마토그래피 (eluent; hexane : EtOAc = 6 : 4)로 분리하였다. 원하는 생 성물 1c 82% (4.1 g)의 수율로 얻었다. Yellow syrup;

= +152.6 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.94 (t, J = 6.8 Hz, 3H), 1.18-1.40 (m, 4H), 1.52-2.12 (m, 6H), 2.42-2.56 (m, 1H), 2.90-3.08 (m, 2H), 5.02 (t, J = 7.2 Hz, 1H), 7.21-7.40 (m, 6H), 7.54 (t, J = 7.2 Hz, 1H), 7.82-8.01 (m, 3H), 8.22-8.40 (m, 5H); ¹³C NMR (CDCl₃) δ 167.5, 151.4, 150.7, 148.6, 143.0, 137.4, 129.9, 129.7, 129.2, 128.5, 128.3, 128.2, 126.7, 125.8, 121.4, 118.3, 71.7, 63.5, 55.7, 48.9, 40.5, 29.4, 28.6, 27.3, 19.9, 12.4; IR (neat) ν 3035, 2938, 1748, 1620, 1466. Anal. calcd for C₃₄H₃₂N₂O₂: C, 81.57; H, 6.44; N, 5.60. Found: C, 81.57 H, 6.46 N, 5.62.(+)-Cinchonine (5 g, 17 mmol) and Pd / C (1.8 g, 1.7 mmol) were added together with MeOH in a high temperature and high pressure reactor from which water was removed. 5 bar of H ₂ was injected into the high temperature and high pressure reactor, followed by stirring for 3 hours. After removing Pd / C using Celite, the solvent was removed under reduced pressure. After argon gas was sufficiently flowed into the water-reduced two-necked flask, reduced cinchonine (3 g, 10.1 mmol) and Et ₃ N (10.2 mL, 101.2 mmol) were put in anhydrous THF (80 mL) solvent, and then at room temperature. After stirring for an minute, anthracene-9-carbonyl chloride (3.6 g, 15.2 mmol) was added thereto, and the mixture was heated to reflux for 24 hours. After the reaction was completed, the mixture was diluted with diethyl ether, and saturated aqueous NaHCO ₃ solution was added. After washing with saturated aqueous NaCl solution, the organic layer was dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and then separated by silica gel column chromatography (eluent; hexane: EtOAc = 6: 4). It was obtained in a yield of the desired raw Dangerous 1c 82% (4.1 g). Yellow syrup;

= +152.6 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.94 (t, J = 6.8 Hz, 3H), 1.18-1.40 (m, 4H), 1.52-2.12 (m, 6H), 2.42-2.56 (m, 1H), 2.90-3.08 (m, 2H), 5.02 (t, J = 7.2 Hz, 1H), 7.21-7.40 (m, 6H), 7.54 (t, J = 7.2 Hz, 1H), 7.82-8.01 (m, 3H), 8.22- 8.40 (m, 5 H); ¹³ C NMR (CDCl ₃ ) δ 167.5, 151.4, 150.7, 148.6, 143.0, 137.4, 129.9, 129.7, 129.2, 128.5, 128.3, 128.2, 126.7, 125.8, 121.4, 118.3, 71.7, 63.5, 55.7, 48.9, 40.5, 29.4, 28.6, 27.3, 19.9, 12.4; IR (neat) v 3035, 2938, 1748, 1620, 1466. Anal. calcd for C ₃₄ H ₃₂ N ₂ O ₂ : C, 81.57; H, 6. 44; N, 5.60. Found: C, 81.57 H, 6.46 N, 5.62.

(4) 신코나 유도체와 hypophosphorous acid 염(1a?H(4) Cincona derivatives and hypophosphorous acid salts (1a? H ₃₃ POPO ₂₂ )의 합성) Synthesis

Cinchonine 유도체 (1 g, 2.5 mmol)와 hypophosphorus acid (0.27 mL, 2.5 mmol, 50% 수용액)를 녹인 MeOH 용액을 상온에서 10 분간 교반한 다음 농축하여 1.2 g (100%)의 1a?H₃PO₂를 얻었다: Yellow syrup;

= +107.5 (c 0.50, EtOH); ¹H NMR (CDCl₃) δ 0.99 (t, J = 6.8 Hz, 3H), 1.42-1.70 (m, 4H), 2.00-2.48 (m, 5H), 2.71-2.92 (m, 2H), 3.38-3.62 (m, 2H), 4.50 (s, 2H), 5.02-5.30 (m, 1H), 6.88 (s, 1H), 7.10-7.48 (m, 6H), 7.58 (t, J = 6.8 Hz, 1H), 7.66 (t, J = 6.8 Hz, 1H), 8.20 (t, J = 5.4 Hz, 1H), 8.35 (t, J = 5.4 Hz, 1H), 8.91 (d, J = 3.6 Hz, 1H); ¹³C NMR (DMSO) δ 152.2, 151.2, 149.7, 137.3, 129.6, 129.2, 128.5, 128.2, 126.7, 125.8, 121.4, 118.4, 80.6, 72.7, 63.5, 56.3, 45.8, 33.2, 32.5, 31.3, 28.6, 19.3, 12.7; IR (neat) ν 3120, 2912, 1648, 1117. Anal. calcd for C₂₆H₃₁F₆N₂OP C, 69.01; H, 7.35 N, 6.19. Found: C, 69.03 H, 7.38 N, 6.20.A MeOH solution of Cinchonine derivatives (1 g, 2.5 mmol) and hypophosphorus acid (0.27 mL, 2.5 mmol, 50% aqueous solution) was stirred at room temperature for 10 minutes and concentrated to give 1.2 g (100%) of 1a -H ₃ PO ₂ Obtained: Yellow syrup;

= +107.5 (c 0.50, EtOH); ¹ H NMR (CDCl ₃ ) δ 0.99 (t, J = 6.8 Hz, 3H), 1.42-1.70 (m, 4H), 2.00-2.48 (m, 5H), 2.71-2.92 (m, 2H), 3.38-3.62 (m, 2H), 4.50 (s, 2H), 5.02-5.30 (m, 1H), 6.88 (s, 1H), 7.10-7.48 (m, 6H), 7.58 (t, J = 6.8 Hz, 1H), 7.66 (t, J = 6.8 Hz, 1H), 8.20 (t, J = 5.4 Hz, 1H), 8.35 (t, J = 5.4 Hz, 1H), 8.91 (d, J = 3.6 Hz, 1H); ¹³ C NMR (DMSO) δ 152.2, 151.2, 149.7, 137.3, 129.6, 129.2, 128.5, 128.2, 126.7, 125.8, 121.4, 118.4, 80.6, 72.7, 63.5, 56.3, 45.8, 33.2, 32.5, 31.3, 28.6, 19.3 , 12.7; IR (neat) v 3120, 2912, 1648, 1117. Anal. calcd for C ₂₆ H ₃₁ F ₆ N ₂ OP C, 69.01; H, 7.35 N, 6.19. Found: C, 69.03 H, 7.38 N, 6.20.

(5) 신코나 유도체와 (5) syncona derivatives and hexafluorophosphorichexafluorophosphoric acidacid 염(1a? Salt (1a? HPFHPF ₆₆ )의 합성) Synthesis

Cinchonine 유도체 (2a) (1 g, 2.5 mmol)와 hexafluorophosphoric acid (0.34 mL, 2.5 mmol, 60% 수용액)를 녹인 MeOH 용액을 상온에서 10 분간 교반한 다음 농축하여 6 g (100%)의 신코나 유도체와 hexafluorophosphoric acid의 염 (1a?HPF₆)을 얻었다: mp 133-135 ^oC;

= +110.4 (c 0.50, EtOH); ¹H NMR (DMSO) δ 0.89 (t, J = 6.8 Hz, 3H), 1.49 (s, 3H), 2.00-2.35 (m, 5H), 2.68-2.78 (m, 2H), 3.40-3.43 (m, 2H), 4.42 (s, 2H), 4.98-5.18 (m, 1H), 7.10 (s, 1H), 7.20-7.51 (m, 6H), 7.69 (t, J = 7.6 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 8.10 (t, J = 5.4 Hz, 1H), 8.20 (t, J = 5.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H); ¹³C NMR (DMSO) δ 151.4, 150.3, 148.6, 143.0, 137.3, 130.0, 129.6, 129.2, 128.5, 128.2, 126.7, 125.8, 121.4, 118.2, 116.7, 79.7, 71.7, 63.5, 55.7, 41.7, 45.1, 39.5, 39.3, 28.6, 18.5, 12.6 IR (KBr) ν 3220, 2938, 1660, 1221, 1114. Anal. calcd for C₂₆H₃₁F₆N₂OP C, 58.64; H, 5.87; N, 5.26. Found: C, 58.65 H, 5.89 N, 5.26.MeOH solution containing Cinchonine derivative ( 2a ) (1 g, 2.5 mmol) and hexafluorophosphoric acid (0.34 mL, 2.5 mmol, 60% aqueous solution) was stirred at room temperature for 10 minutes, and then concentrated to give 6 g (100%) of cincona derivatives. And a salt of hexafluorophosphoric acid ( 1a ? HPF ₆ ) was obtained: mp 133-135 ^o C;

= +110.4 (c 0.50, EtOH); ¹ H NMR (DMSO) δ 0.89 (t, J = 6.8 Hz, 3H), 1.49 (s, 3H), 2.00-2.35 (m, 5H), 2.68-2.78 (m, 2H), 3.40-3.43 (m, 2H), 4.42 (s, 2H), 4.98-5.18 (m, 1H), 7.10 (s, 1H), 7.20-7.51 (m, 6H), 7.69 (t, J = 7.6 Hz, 1H), 7.86 (t , J = 7.6 Hz, 1H), 8.10 (t, J = 5.4 Hz, 1H), 8.20 (t, J = 5.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H); ¹³ C NMR (DMSO) δ 151.4, 150.3, 148.6, 143.0, 137.3, 130.0, 129.6, 129.2, 128.5, 128.2, 126.7, 125.8, 121.4, 118.2, 116.7, 79.7, 71.7, 63.5, 55.7, 41.7, 45.1, 39.5 , 39.3, 28.6, 18.5, 12.6 IR (KBr) ν 3220, 2938, 1660, 1221, 1114. Anal. calcd for C ₂₆ H ₃₁ F ₆ N ₂ OP C, 58.64; H, 5.87; N, 5.26. Found: C, 58.65 H, 5.89 N, 5.26.

(6) 신코나 유도체와 (6) syncona derivatives and hexafluorophosphorichexafluorophosphoric acidacid 염(1c? Salt (1c? HPFHPF ₆₆ )의 합성) Synthesis

Cinchonine 유도체 (1 g, 2.0 mmol)와 hexafluorophosphoric acid (0.27 mL, 2.0 mmol, 60% 수용액)를 녹인 MeOH 용액을 상온에서 10 분간 교반한 다음 농축하여 1.3 g (100%)의 신코나 유도체와 hexafluorophosphoric acid의 염 1c?HPF₆를 얻었다: Yellow syrup;

= +148.2 (c 0.50, EtOH); ¹H NMR (CDCl₃) δ 0.92 (t, J = 6.8 Hz, 3H), 1.19-1.38 (m, 4H), 1.51-2.10 (m, 6H), 2.41-2.56 (m, 1H), 2.90-3.08 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 7.21-7.44 (m, 6H), 7.53 (t, J = 7.6 Hz, 1H ), 7.84-8.00 (m, 3H), 8.20-8.44 (m, 5H); ¹³C NMR (CDCl₃) δ 171.1, 152.1, 151.1, 148.6, 143.2, 137.9, 130.0, 129.8, 129.2, 128.6, 128.4, 128.2, 126.8, 126.0, 121.8, 118.0, 69.8, 63.5, 55.7, 48.9, 39.0, 29.6, 28.7, 27.2, 20.2, 12.6; IR (neat) ν 3301, 3196, 2880, 1641, 1538, 1083. Anal. calcd for C₃₄H₃₃F₆N₂O₂P: C, 63.16; H, 5.14; N, 4.33. Found: C, 63.18 H, 5.17 N, 4.34.A MeOH solution of Cinchonine derivatives (1 g, 2.0 mmol) and hexafluorophosphoric acid (0.27 mL, 2.0 mmol, 60% aqueous solution) was stirred at room temperature for 10 minutes, then concentrated to give 1.3 g (100%) of the Cincona derivatives and hexafluorophosphoric acid. Salt of 1c? HPF ₆ was obtained: Yellow syrup;

= +148.2 (c 0.50, EtOH); ¹ H NMR (CDCl ₃ ) δ 0.92 (t, J = 6.8 Hz, 3H), 1.19-1.38 (m, 4H), 1.51-2.10 (m, 6H), 2.41-2.56 (m, 1H), 2.90-3.08 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 7.21-7.44 (m, 6H), 7.53 (t, J = 7.6 Hz, 1H), 7.84-8.00 ( m, 3H), 8.20-8.44 (m, 5H); ¹³ C NMR (CDCl ₃ ) δ 171.1, 152.1, 151.1, 148.6, 143.2, 137.9, 130.0, 129.8, 129.2, 128.6, 128.4, 128.2, 126.8, 126.0, 121.8, 118.0, 69.8, 63.5, 55.7, 48.9, 39.0, 29.6, 28.7, 27.2, 20.2, 12.6; IR (neat) v 3301, 3196, 2880, 1641, 1538, 1083.Anal. calcd for C ₃₄ H ₃₃ F ₆ N ₂ O ₂ P: C, 63.16; H, 5. 14; N, 4.33. Found: C, 63.18 H, 5.17 N, 4.34.

D. 신코나 유도체의 염의 유기 촉매를 사용한 라디칼 첨가 반응D. Radical Addition Reactions Using Organic Catalysts of Salts of Syncona Derivatives

(1) 신코나 유도체와 hypophosphorous acid의 염(1a?H(1) Sincona derivatives and salts of hypophosphorous acid (1a? H ₃₃ POPO ₂₂ )을 이용한 라디칼 첨가 반응Radical addition reaction using

반응용매인 CH₂Cl₂를 1시간동안 sonication 한 다음 아르곤 기체를 흘려주면서 아르곤 기체가 가득 찬 풍선 3개를 사용하여 순차적으로 degassing 하였다. 1a?H₃PO₂ (3 eqiuv), N-benzohydrazide유도체 (1 eqiuv)를 넣고 -30 ℃에서 1 시간동안 교반하였다. 1 시간이 지난 후 alkyl halide (5 eqiuv), Et₃B (1 equiv, 1 M solution in n-hexane)를 넣고 syringe pump를 통하여 무수 air를 1 시간에 20 mL씩 모두 4 시간동안 80 mL를 주입하였다. 반응이 완결된 후 농축하여 용매를 제거한 다음 실리카겔 컬럼 크로마토그래피로 분리하였다.CH ₂ Cl ₂ , a reaction solvent, was sonicated for 1 hour and then degassed using three balloons filled with argon gas while flowing argon gas. 1a H ₃ PO ₂ (3 eqiuv) and N- benzohydrazide derivative (1 eqiuv) were added thereto, and the mixture was stirred at −30 ° C. for 1 hour. After 1 hour, add alkyl halide (5 eqiuv), Et ₃ B (1 equiv, 1 M solution in n-hexane) and inject 80 mL of anhydrous air for 4 hours at 20 mL per hour through syringe pump. It was. After the reaction was completed, the resultant was concentrated to remove the solvent, and then separated by silica gel column chromatography.

(2) 신코나 유도체와 hexafluorophosphoric acid의 염 (1a?HPF(2) salts of synacona derivatives and hexafluorophosphoric acid (1a? HPF ₆₆ )을 이용한 라디칼 첨가 반응Radical addition reaction using

반응용매인 CH₂Cl₂를 1시간동안 sonication 한 다음 아르곤 기체를 흘려주면서 아르곤 기체가 가득 찬 풍선 3개를 사용하여 순차적으로 degassing 하였다. 신코나 유도체와 hexafluorophosphoric acid의 염 (1 eqiuv), benzohydrazide 유도체 (1 eqiuv)를 넣고 -30 ℃에서 1 시간동안 교반하였다. 1 시간이 지난 후 alkyl halide (1.5 eqiuv)와 Ph₂SiH₂(1 equiv), Et₃B (1 equiv, 1 M solution in n- hexane)를 넣고 syringe pump를 통하여 무수 air를 1 시간에 20 mL씩 모두 4 시간동안 80 mL를 주입하였다. 반응이 완결된 후 농축하여 용매를 제거한 다음 실리카겔 컬럼 크로마토그래피로 분리하였다.CH ₂ Cl ₂ , a reaction solvent, was sonicated for 1 hour and then degassed using three balloons filled with argon gas while flowing argon gas. A cinnacon derivative, a salt of hexafluorophosphoric acid (1 eqiuv), and a benzohydrazide derivative (1 eqiuv) were added thereto, and the mixture was stirred at −30 ° C. for 1 hour. After 1 hour, add alkyl halide (1.5 eqiuv), Ph ₂ SiH ₂ (1 equiv), Et ₃ B (1 equiv, 1 M solution in n-hexane) Inject 80 mL each for 4 hours. After the reaction was completed, the resultant was concentrated to remove the solvent, and then separated by silica gel column chromatography.

(3) 신코나 유도체와 hexafluorophosphoric acid의 염 1c?HPF(3) 1c? HPF salts of synacona derivatives and hexafluorophosphoric acid ₆₆ 를 이용한 라디칼 첨가 반응Radical addition reaction

반응용매인 C₂H₄Cl₂를 1시간동안 sonication 한 다음 아르곤 기체를 흘려주면서 아르곤 기체가 가득 찬 풍선 3개를 사용하여 순차적으로 degassing 하였다. 신코나 유도체와 hexafluorophosphoric acid의 염 1c?HPF₆(1 eqiuv), N-benzohydrazide 유도체 (1 eqiuv)를 넣고 -30 ℃에서 1 시간동안 교반하였다. 1 시간이 지난 후 alkyl halide (1.5 eqiuv)와 Ph₂SiH₂(1 equiv), Et₃B (1 equiv, 1 M solution in n-hexane)를 넣고 needle을 통해 3일 동안 air를 지속적으로 주입하였다. 반응이 완결된 후 농축하여 용매를 제거한 다음 실리카겔 컬럼 크로마토그래피로 분리하였다. 각 화합물의 합성에 관하여 이하에서 더욱 구체적으로 살펴보았다.The reaction solvent, C ₂ H ₄ Cl ₂ , was sonicated for 1 hour, and then degassed using three balloons filled with argon gas while flowing argon gas. Salt 1c of cincona derivatives and hexafluorophosphoric acid ? HPF ₆ (1 eqiuv) and N- benzohydrazide derivative (1 eqiuv) were added thereto, and the mixture was stirred at −30 ° C. for 1 hour. After 1 hour, alkyl halide (1.5 eqiuv), Ph ₂ SiH ₂ (1 equiv) and Et ₃ B (1 equiv, 1 M solution in n-hexane) were added and air was continuously injected for 3 days through a needle. . After the reaction was completed, the resultant was concentrated to remove the solvent, and then separated by silica gel column chromatography. The synthesis of each compound was described in more detail below.

(4) (4) N'N ' -(1-(4-Fluorophenyl)-2-methylpropyl)benzohydrazide (3a)-(1- (4-Fluorophenyl) -2-methylpropyl) benzohydrazide (3a)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100 mg, 0.41 mmol)²⁸, 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41mmol), ⁱ PrI (0.21 mL, 2.07 mmol) 을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3a을 118 mg (82%)를 얻었다: (eluent; hexane : EtOAc = 8 : 2): 82% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 20.9 min, t_r (minor) = 19.5 min]. mp 113-115 ^oC;

=-9.8 (c 0.11, CHCl₃); ¹H NMR (CDCl₃) δ 0.79 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 1.98-2.01 (m, 1H), 3.85 (d, J = 7.3 Hz, 1H), 5.32 (s, 1H), 7.04 (t, J = 8.6 Hz, 2H), 7.21-7.60 (m, 8H); ¹³C NMR (CD₃COCD₃) δ 167.3, 160.2, 137.8, 134.1, 132.1. 130.6, 129.1, 128.4, 115.4, 114.6, 68.6, 33.9, 20.3, 19.9; IR (KBr) ν 3231, 2869, 1736, 1666, 1160. Anal. calcd for C₁₇H₁₉FN₂O: C, 71.31; H, 6.69; N, 9.78. Found: C, 71.31; H, 6.68; N, 9.79. ( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100 mg, 0.41 mmol) ²⁸ , 1a -H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), ⁱ PrI ( 0.21 mL, 2.07 mmol) was used to give 118 mg (82%) of compound 3a : (eluent; hexane: EtOAc = 8: 2): 82% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 20.9 min, t _r (minor) = 19.5 min]. mp 113-115 ^o C;

= -9.8 (c 0.11, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 1.98-2.01 (m, 1H), 3.85 (d, J = 7.3 Hz, 1H), 5.32 (s, 1H), 7.04 (t, J = 8.6 Hz, 2H), 7.21-7.60 (m, 8H); ¹³ C NMR (CD ₃ COCD ₃ ) δ 167.3, 160.2, 137.8, 134.1, 132.1. 130.6, 129.1, 128.4, 115.4, 114.6, 68.6, 33.9, 20.3, 19.9; IR (KBr) v 3231, 2869, 1736, 1666, 1160.Anal. calcd for C ₁₇ H ₁₉ FN ₂ O: C, 71.31; H, 6.69; N, 9.78. Found: C, 71.31; H, 6.68; N, 9.79.

(5) (5) NN '-(1-(4-Fluorophenyl)propyl)benzohydrazide (3b)'-(1- (4-Fluorophenyl) propyl) benzohydrazide (3b)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100 mg, 0.41 mmol)²⁹, 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41 mmol), ⁱ PrI (0.21 mL, 2.07 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 개시제인 Et₃B에서 기인한 부생성물 3b가 10 mg (9%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): mp 106-108 ^oC;

= -7.1 (c 0.11, CHCl₃); ¹H NMR (CDCl₃) δ 0.86 (t, J = 7.4 Hz, 3H), 1.61-1.72 (m, 1H), 1.84-1.95 (m, 1H), 3.95-4.05 (m, 1H), 4.94 (s, 1H), 7.03 (t, J = 8.8 Hz, 2H), 7.28-7.70 (m, 8H); ¹³C NMR (CDCl₃) δ 166.6, 159.7, 134.6, 133.2, 131.8, 128.9, 127.0, 125.8, 114.5, 133.8, 68.5, 26.9, 14.4; IR (KBr) ν 3110, 2912, 1712, 1630, 1164. Anal. calcd for C₁₆H₁₇FN₂O: C, 70.57; H, 6.29; N, 10.29. Found: C, 70.58 H, 6.31 N, 10.32. ( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100 mg, 0.41 mmol) ²⁹ , 1a ? H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), ⁱ PrI ( 0.21 mL, 2.07 mmol) was reacted according to the general experimental method to obtain byproduct 3b resulting from the initiator Et ₃ B in a yield of 10 mg (9%): (eluent; hexane: EtOAc = 8: 2) : mp 106-108 ^o C;

= -7.1 (c 0.11, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.86 (t, J = 7.4 Hz, 3H), 1.61-1.72 (m, 1H), 1.84-1.95 (m, 1H), 3.95-4.05 (m, 1H), 4.94 (s , 1H), 7.03 (t, J = 8.8 Hz, 2H), 7.28-7.70 (m, 8H); ¹³ C NMR (CDCl ₃ ) δ 166.6, 159.7, 134.6, 133.2, 131.8, 128.9, 127.0, 125.8, 114.5, 133.8, 68.5, 26.9, 14.4; IR (KBr) ν 3110, 2912, 1712, 1630, 1164. Anal. calcd for C ₁₆ H ₁₇ FN ₂ O: C, 70.57; H, 6. 29; N, 10.29. Found: C, 70.58 H, 6.31 N, 10.32.

(6) (6) NN '-(Cyclohexyl(4-fluorophenyl)methyl)benzohydrazide (3c)'-(Cyclohexyl (4-fluorophenyl) methyl) benzohydrazide (3c)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100mg, 0.41 mmol), 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41 mmol), cyclohexyl iodide (0.27 mL, 2.07 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3c을 104 mg (77%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 84% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 19.7 min, t_r (minor) = 17.8 min]. Yellow oil;

= -24.6 (c 0.12, CHCl₃); ¹H NMR (CDCl₃) δ 0.98-2.10 (m, 11H), 3.84 (d, J = 7.2 Hz, 1H), 5.30 (s, 1H), 7.03 (t, J = 8.5 Hz, 2H), 7.20-7.75 (m, 8H); ¹³C NMR (CDCl₃) δ 167.3, 161.1, 136.7, 133.1, 130.6, 129.3, 128.7, 126.9, 115.7, 114.8, 70.9, 39.6, 28.9, 26.5, 26.2; IR (neat) ν 3325, 2981, 1710, 1656, 1325, 1168. Anal. calcd for C₂₀H₂₃FN₂O: C, 73.59; H, 7.10; N, 8.58. Found: C, 73.57 H, 7.14 N, 8.60.( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100mg, 0.41 mmol), 1a -H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), cyclohexyl iodide (0.27 mL , 2.07 mmol) was used to give Compound 3c in a yield of 104 mg (77%): (eluent; hexane: EtOAc = 8: 2): 84% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 19.7 min, t _r (minor) = 17.8 min]. Yellow oil;

= -24.6 (c 0.12, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.98-2.10 (m, 11H), 3.84 (d, J = 7.2 Hz, 1H), 5.30 (s, 1H), 7.03 (t, J = 8.5 Hz, 2H), 7.20- 7.75 (m, 8 H); ¹³ C NMR (CDCl ₃ ) δ 167.3, 161.1, 136.7, 133.1, 130.6, 129.3, 128.7, 126.9, 115.7, 114.8, 70.9, 39.6, 28.9, 26.5, 26.2; IR (neat) v 3325, 2981, 1710, 1656, 1325, 1168.Anal. calcd for C ₂₀ H ₂₃ FN ₂ O: C, 73.59; H, 7. 10; N, 8.58. Found: C, 73.57 H, 7.14 N, 8.60.

(7) (7) N'N ' -(1-(4-Fluorophenyl)-2,2-dimethylpropyl)benzohydrazide (3d)-(1- (4-Fluorophenyl) -2,2-dimethylpropyl) benzohydrazide (3d)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100 mg, 0.41 mmol), 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41 mmol), ^t butyl iodide (0.25 mL, 2.07 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3d을 83 mg (67%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 92% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 19.1 min, t_r (minor) = 17.0 min]. mp 150-152 ℃;

= -13.6 (c 0.10, CHCl₃); ¹H NMR (CDCl₃) δ 1.00 (s, 9H), 3.89 (s, 1H), 5.45 (s, 1H), 7.03 (t, J = 8.6 Hz, 2H), 7.18-7.58 (m, 8H); ¹³C NMR (CDCl₃) δ 167.2, 163.6, 137.5, 135.8, 133.1, 132.0, 130.9, 128.9, 126.9, 115.0, 114.8, 73.5, 34.5, 27.0; IR (KBr) ν 3105, 2813, 1750, 1607, 1263, 1140. Anal. calcd for C₁₈H₂₁FN₂O: C, 71.98; H, 7.05; N, 9.33. Found: C, 72.01 H, 7.08 N, 9.34. ( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100 mg, 0.41 mmol), 1a -H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), ^t butyl iodide ( 0.25 mL, 2.07 mmol) was reacted according to the general experimental method, and compound 3d was obtained in a yield of 83 mg (67%): (eluent; hexane: EtOAc = 8: 2): 92% ee as determined by HPLC [ Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 19.1 min, t _r (minor) = 17.0 min]. mp 150-152 ° C;

= -13.6 (c 0.10, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 1.00 (s, 9H), 3.89 (s, 1H), 5.45 (s, 1H), 7.03 (t, J = 8.6 Hz, 2H), 7.18-7.58 (m, 8H); ¹³ C NMR (CDCl ₃ ) δ 167.2, 163.6, 137.5, 135.8, 133.1, 132.0, 130.9, 128.9, 126.9, 115.0, 114.8, 73.5, 34.5, 27.0; IR (KBr) ν 3105, 2813, 1750, 1607, 1263, 1140.Anal. calcd for C ₁₈ H ₂₁ FN ₂ O: C, 71.98; H, 7.05; N, 9.33. Found: C, 72.01 H, 7.08 N, 9.34.

(8) (8) N'N ' -(1-(4-Fluorophenyl)adamantyl)benzohydrazide (3e)-(1- (4-Fluorophenyl) adamantyl) benzohydrazide (3e)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100 mg, 0.41 mmol), 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41 mmol), 1-adamantyl iodide (542 mg, 2.07 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3e을 110 mg (70%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 94% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 19.6 min, t_r (minor) = 16.9 min]. mp 223-225 ^oC;

= -30.1 (c 0.10, CHCl₃); ¹H NMR (CDCl₃) δ 1.10-2.12 (m, 15H), 4.11 (d, J = 7.3 Hz, 1H), 5.53 (s, 1H), 7.02-7.70 (m, 10H); ¹³C NMR (CDCl₃) δ 167.1, 161.1, 148.5, 134.9, 134.7, 133.1, 131.9, 128.8, 126.9, 114.9, 114.7, 74.4, 39.2, 37.2, 36.3, 28.6; IR (KBr) ν 3180, 2910, 1709, 1660, 1212, 1120. Anal. calcd for C₂₄H₂₇FN₂O: C, 76.16; H, 7.79; N, 7.40. Found: C, 76.17; H, 7.76; N, 7.37. ( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100 mg, 0.41 mmol), 1a -H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), 1-adamantyl iodide (542 mg, 2.07 mmol) was reacted according to the general experimental method to give compound 3e in yield of 110 mg (70%): (eluent; hexane: EtOAc = 8: 2): 94% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 19.6 min, t _r (minor) = 16.9 min]. mp 223-225 ^o C;

= -30.1 (c 0.10, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 1.10-2.12 (m, 15H), 4.11 (d, J = 7.3 Hz, 1H), 5.53 (s, 1H), 7.02-7.70 (m, 10H); ¹³ C NMR (CDCl ₃ ) δ 167.1, 161.1, 148.5, 134.9, 134.7, 133.1, 131.9, 128.8, 126.9, 114.9, 114.7, 74.4, 39.2, 37.2, 36.3, 28.6; IR (KBr) ν 3180, 2910, 1709, 1660, 1212, 1120.Anal. calcd for C ₂₄ H ₂₇ FN ₂ O: C, 76.16; H, 7.79; N, 7.40. Found: C, 76.17; H, 7.76; N, 7.37.

(9) (9) N'N ' -(1-(4-Fluorophenyl)nonyl)benzohydrazide (3f)-(1- (4-Fluorophenyl) nonyl) benzohydrazide (3f)

(E)-N'-(4-Fluorobenzylidene)benzohydrazide (100 mg, 0.41 mmol), 1a?H₃PO₂ (562 mg, 1.24 mmol), Et₃B (0.41 mL, 0.41 mmol), ⁿ octyl iodide (0.38 mL, 2.07 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3f을 61 mg (41%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 60% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH= 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 15.4 min, t_r (minor) = 14.1 min]. Yellow oil;

= -30.4 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.97 (t, J = 7.4 Hz, 3H), 1.20-1.45 (m, 10H), 1.70-1.85 (m, 2H), 1.70-1.85 (m, 2H), 4.15-4.30 (m, 1H), 5.02 (s, 1H), 7.35-7.60 (m, 6H), 7.70-7.80 (m, 3H), 7.85 -7.95 (m, 1H); ¹³C NMR (CDCl₃) δ 165.5, 154.3, 136.7, 132.9, 132.0, 128.9, 128.6, 127.0, 117.6, 116.8, 67.3, 32.6, 32.7, 31.9, 29.2, 22.7, 14.2; IR (KBr) ν 3280, 2928, 1744, 1687, 1211, 1146. Anal. calcd for C₂₂H₂₉FN₂O: C, 74.12; H, 8.20; N, 7.86. Found: C, 74.17; H, 8.17 N, 7.87.( E ) -N ' -(4-Fluorobenzylidene) benzohydrazide (100 mg, 0.41 mmol), 1a -H ₃ PO ₂ (562 mg, 1.24 mmol), Et ₃ B (0.41 mL, 0.41 mmol), ⁿ octyl iodide ( 0.38 mL, 2.07 mmol) was reacted according to the general experimental method, and compound 3f was obtained in a yield of 61 mg (41%): (eluent; hexane: EtOAc = 8: 2): 60% ee as determined by HPLC [ Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 15.4 min, t _r (minor) = 14.1 min]. Yellow oil;

= -30.4 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.97 (t, J = 7.4 Hz, 3H), 1.20-1.45 (m, 10H), 1.70-1.85 (m, 2H), 1.70-1.85 (m, 2H), 4.15-4.30 (m, 1H), 5.02 (s, 1H), 7.35-7.60 (m, 6H), 7.70-7.80 (m, 3H), 7.85-7.95 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 165.5, 154.3, 136.7, 132.9, 132.0, 128.9, 128.6, 127.0, 117.6, 116.8, 67.3, 32.6, 32.7, 31.9, 29.2, 22.7, 14.2; IR (KBr) v 3280, 2928, 1744, 1687, 1211, 1146.Anal. calcd for C ₂₂ H ₂₉ FN ₂ O: C, 74.12; H, 8. 20; N, 7.86. Found: C, 74.17; H, 8.17 N, 7.87.

(10) 10 N'N ' -(1-(4-Chlorophenyl)-2-methylpropyl)benzohydrazide (3g)-(1- (4-Chlorophenyl) -2-methylpropyl) benzohydrazide (3g)

(E)-N'-(4-Chlorobenzylidene)benzohydrazide (100 mg, 0.39 mmol)³⁰, 1a? H₃PO₂ (524 mg, 1.16 mmol), Et₃B (0.39 mL, 0.39 mmol), ⁱ PrI (0.19 mL, 1.93 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3g을 94 mg (80%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): mp 116-118 ^oC;

= -16.2 (c 0.12, CHCl₃); ¹H NMR (CDCl₃) δ 0.79 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.95-2.05 (m, 1H), 3.84 (d, J = 7.3 Hz, 1H), 5.31 (s, 1H), 7.28-7.65 (m, 10H); ¹³C NMR (CDCl₃) δ 167.3, 161.0, 136.6, 133.0, 131.9, 129.2, 127.1, 126.8, 115.6, 114.6, 70.8, 32.8, 20.0, 19.4; IR (KBr) ν 2982, 1701, 1667, 1363, 1223. Anal. calcd for C₁₇H₁₉ClN₂O: C, 67.43; H, 6.32; N, 9.25. Found: C, 67.42; H, 6.35 N, 9.25.( E ) -N ' -(4-Chlorobenzylidene) benzohydrazide (100 mg, 0.39 mmol) ³⁰ , 1a ? 94 g (80%) of compound 3g was reacted according to the general experimental method using H ₃ PO ₂ (524 mg, 1.16 mmol), Et ₃ B (0.39 mL, 0.39 mmol), ⁱ PrI (0.19 mL, 1.93 mmol). (Eluent; hexane: EtOAc = 8: 2): mp 116-118 ^° C .;

= -16.2 (c 0.12, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.95-2.05 (m, 1H), 3.84 (d, J = 7.3 Hz, 1H), 5.31 (s, 1 H), 7.28-7.65 (m, 10 H); ¹³ C NMR (CDCl ₃ ) δ 167.3, 161.0, 136.6, 133.0, 131.9, 129.2, 127.1, 126.8, 115.6, 114.6, 70.8, 32.8, 20.0, 19.4; IR (KBr) v 2982, 1701, 1667, 1363, 1223. Anal. calcd for C ₁₇ H ₁₉ ClN ₂ O: C, 67.43; H, 6. 32; N, 9.25. Found: C, 67.42; H, 6.35 N, 9.25.

(11) (11) N'N ' -(2-Methyl-1-(4-nitrophenyl)propyl)benzohydrazide (3i)-(2-Methyl-1- (4-nitrophenyl) propyl) benzohydrazide (3i)

(E)-N'-(4-Chlorobenzylidene)benzohydrazide (100 mg, 0.39 mmol), 1a?H₃PO₂ (524 mg, 1.16 mmol), Et₃B (0.39 mL, 0.39 mmol), ⁱ PrI (0.19 mL, 1.93 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3i을 94 mg (80%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 21.5 min, t_r (minor) = 19.2 min]. mp 147-149 ^oC;

= -39.7 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.82 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 1.96-2.10 (m, 1H), 4.03 (d, J = 7.3 Hz, 1H), 5.31 (s, 1H), 7.28-7.70 (m, 8H), 8.19 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃) δ 167.8, 149.0, 147.5, 132.6, 129.7, 129.3, 128.5, 127.1, 126.7, 123.7, 123.5, 71.1, 33.1, 20.0, 19.2; IR (KBr) ν 3243, 2962, 1717, 1626, 1240, 1143. Anal. calcd for C₁₇H₁₉FN₃O₃: C, 65.16; H, 6.11; N,13.41. Found: C, 65.18; H, 6.12; N, 13.40.( E ) -N ' -(4-Chlorobenzylidene) benzohydrazide (100 mg, 0.39 mmol), 1a -H ₃ PO ₂ (524 mg, 1.16 mmol), Et ₃ B (0.39 mL, 0.39 mmol), ⁱ PrI (0.19 mL, 1.93 mmol) was used and the reaction was carried out according to the general experimental method, and the compound 3i was obtained in a yield of 94 mg (80%): (eluent; hexane: EtOAc = 8: 2): 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 21.5 min, t _r (minor) = 19.2 min]. mp 147-149 ^o C;

= -39.7 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.82 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 1.96-2.10 (m, 1H), 4.03 (d, J = 7.3 Hz, 1H), 5.31 (s, 1H), 7.28-7.70 (m, 8H), 8.19 (d, J = 8.8 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 167.8, 149.0, 147.5, 132.6, 129.7, 129.3, 128.5, 127.1, 126.7, 123.7, 123.5, 71.1, 33.1, 20.0, 19.2; IR (KBr) v 3243, 2962, 1717, 1626, 1240, 1143. Anal. calcd for C ₁₇ H ₁₉ FN ₃ O ₃ : C, 65.16; H, 6. 11; N, 13.41. Found: C, 65.18; H, 6. 12; N, 13.40.

(12) (12) N'N ' -(1-(4-Acetylphenyl)-2-methylpropyl)benzohydrazide (3k)-(1- (4-Acetylphenyl) -2-methylpropyl) benzohydrazide (3k)

(E)-N'-(4-Acetylbenzylidene)benzohydrazide (100 mg, 0.38 mmol), 1a?H₃PO₂ (511 mg, 1.13 mmol), Et₃B (0.38 mL, 0.38 mmol), ⁱ PrI (0.19 mL, 1.9 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3k을 94 mg (80%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 82% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 25.1 min, t_r (minor) = 23.8 min]. mp 193-195 ^oC;

= -10.4 (c 0.10, CHCl₃); ¹H NMR (CDCl₃) δ 0.81 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.95-2.10 (m, 1H), 2.62 (s, 3H), 3.96 (d, J = 7.0 Hz, 1H), 5.36 (s, 1H), 7.15-7.67 (m, 8H), 7.95 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃) δ 198.1, 167.5, 146.8, 136.7, 132.9, 132.1, 128.9, 128.8, 128.5, 127.0, 71.1, 32.8, 26.8, 19.7, 19.1; IR (KBr) ν 2976, 1707, 1521, 1157, 1110. Anal. calcd for C₁₉H₂₂N₂O₂: C, 73.52; H, 7.14; N, 9.03. Found: C, 73.51 H, 7.18 N, 9.07.( E ) -N ' -(4-Acetylbenzylidene) benzohydrazide (100 mg, 0.38 mmol), 1a -H ₃ PO ₂ (511 mg, 1.13 mmol), Et ₃ B (0.38 mL, 0.38 mmol), ⁱ PrI (0.19 mL, 1.9 mmol) was used to give the compound 3k in 94 mg (80%) yield in the general experimental manner: (eluent; hexane: EtOAc = 8: 2): 82% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 25.1 min, t _r (minor) = 23.8 min]. mp 193-195 ^o C;

= -10.4 (c 0.10, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.81 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.95-2.10 (m, 1H), 2.62 (s, 3H), 3.96 ( d, J = 7.0 Hz, 1H), 5.36 (s, 1H), 7.15-7.67 (m, 8H), 7.95 (d, J = 8.0 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 198.1, 167.5, 146.8, 136.7, 132.9, 132.1, 128.9, 128.8, 128.5, 127.0, 71.1, 32.8, 26.8, 19.7, 19.1; IR (KBr) ν 2976, 1707, 1521, 1157, 1110. Anal. calcd for C ₁₉ H ₂₂ N ₂ O ₂ : C, 73.52; H, 7. 14; N, 9.03. Found: C, 73.51 H, 7.18 N, 9.07.

(13) (13) N'N ' -(2-Methyl-1-phenylpropyl)benzohydrazide (3m)-(2-Methyl-1-phenylpropyl) benzohydrazide (3m)

(E)-N'-Benzylidenebenzohydrazide (100 mg, 0.45 mmol), 1a?H₃PO₂ (601 mg, 1.33 mmol), Et₃B (0.45 mL, 0.45 mmol), ⁱ PrI (0.22 mL, 2.23 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3m을 97 mg (80%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 78% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH= 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 25.5 min, t_r (minor) = 24.2 min]. mp 106-108 ^oC;

= -35.1 (c 0.10, CHCl₃); ¹H NMR (CDCl₃) δ 0.79 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.92- 2.10 (m, 1H), 3.85 (m, 1H), 5.31 (s, 1H), 7.04 (t, J = 8.8 Hz, 3H), 7.17-7.68 (m, 8H); ¹³C NMR (CDCl₃) δ 167.5, 142.6, 133.2, 131.8, 129.1, 128.8, 127.9, 126.9, 114.2, 71.2, 32.8, 19.7, 19.3; IR (KBr) ν 3314, 2904, 1714, 1550, 1203, 1120. Anal. calcd for C₁₇H₂₀N₂O: C, 76.09; H, 7.51; N, 10.44. Found: C, 76.11 H, 7.56; N, 10.40. (E) -? N '-Benzylidenebenzohydrazide (100 mg, 0.45 mmol), 1a H 3 PO 2 (601 mg, 1.33 mmol), Et 3 B (0.45 mL, 0.45 mmol), i PrI (0.22 mL, 2.23 mmol) Reaction was carried out according to the general experimental method using to give compound 3m in 97 mg (80%) yield: (eluent; hexane: EtOAc = 8: 2): 78% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 25.5 min, t _r (minor) = 24.2 min]. mp 106-108 ^o C;

= -35.1 (c 0.10, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.92-2.10 (m, 1H), 3.85 (m, 1H), 5.31 ( s, 1H), 7.04 (t, J = 8.8 Hz, 3H), 7.17-7.68 (m, 8H); ¹³ C NMR (CDCl ₃ ) δ 167.5, 142.6, 133.2, 131.8, 129.1, 128.8, 127.9, 126.9, 114.2, 71.2, 32.8, 19.7, 19.3; IR (KBr) v 3314, 2904, 1714, 1550, 1203, 1120.Anal. calcd for C ₁₇ H ₂₀ N ₂ O: C, 76.09; H, 7.51; N, 10.44. Found: C, 76.11 H, 7.56; N, 10.40.

(14) (14) NN '-(1-(4-Methoxyphenyl)-2-methylpropyl)benzohydrazide (3o)'-(1- (4-Methoxyphenyl) -2-methylpropyl) benzohydrazide (3o)

(E)-N'-Benzylidenebenzohydrazide (100 mg, 0.45 mmol), 1a?H₃PO₂ (601 mg, 1.33 mmol), Et₃B (0.45 mL, 0.45 mmol), ⁱ PrI (0.22 mL, 2.23 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3o을 97 mg (80%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH= 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 16.3 min, t_r (minor) = 14.5 min]. colorless oil;

= -11.8 (c 0.12, CHCl₃); ¹H NMR (CDCl₃) δ 0.80 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.97-2.06 (m, 1H), 3.75-3.90 (m, 4H), 5.37 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.20-7.58 (m, 8H); ¹³C NMR (CDCl₃) δ 167.7, 158.2, 146.8, 136.7, 132.9, 132.1, 129.2, 128.9, 128.6, 126.8, 71.1, 55.7, 32.7, 19.7, 19.1; IR (neat) ν 3230, 2868, 1715, 1632, 1293, 1127. Anal. calcd for C₁₈H₂₂N₂O₂: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.50 H, 7.39 N, 9.41. (E) -? N '-Benzylidenebenzohydrazide (100 mg, 0.45 mmol), 1a H 3 PO 2 (601 mg, 1.33 mmol), Et 3 B (0.45 mL, 0.45 mmol), i PrI (0.22 mL, 2.23 mmol) The reaction was carried out according to the general experimental method using to give compound 3o in 97 mg (80%) yield: (eluent; hexane: EtOAc = 8: 2): 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 16.3 min, t _r (minor) = 14.5 min]. colorless oil;

= -11.8 (c 0.12, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.97-2.06 (m, 1H), 3.75-3.90 (m, 4H), 5.37 (s, 1 H), 6.90 (d, J = 8.8 Hz, 2 H), 7.20-7.58 (m, 8 H); ¹³ C NMR (CDCl ₃ ) δ 167.7, 158.2, 146.8, 136.7, 132.9, 132.1, 129.2, 128.9, 128.6, 126.8, 71.1, 55.7, 32.7, 19.7, 19.1; IR (neat) v 3230, 2868, 1715, 1632, 1293, 1127. Anal. calcd for C ₁₈ H ₂₂ N ₂ O ₂ : C, 72.46; H, 7. 43; N, 9.39. Found: C, 72.50 H, 7.39 N, 9.41.

(15) (15) NN '-(4-(1-(2-Benzoylhydrazinyl)-2-methylpropyl)phenyl)acetamide (3q)'-(4- (1- (2-Benzoylhydrazinyl) -2-methylpropyl) phenyl) acetamide (3q)

(E)-N-(4-((2-Benzoylhydrazono)methyl)phenyl)acetamide (100 mg, 0.35 mmol), 1a?H₃PO₂ (480 mg, 1.06 mmol), Et₃B (0.35 mL, 0.35 mmol), ⁱ PrI (0.18 mL, 1.8 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3q을 89 mg (77%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2); 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 18.8 min, t_r (minor) = 16.5 min]. mp 158-160 ^oC (lit., mp 155-157 ^oC);

= -3.1 (c 0.15, CHCl₃); ¹H NMR (CDCl₃) δ 0.82 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.98-2.15 (m, 1H), 2.61 (s, 3H), 3.96 (d, J = 6.8 Hz, 1H), 5.34 (s, 1H), 7.12-7.80 (m, 8H) 7.95 (d, J = 8.0 Hz, 2H), 8.91 (s, 1H); ¹³C NMR (CDCl₃) δ 168.1, 167.5, 146.8, 136.7, 132.9, 132.1, 129.1, 128.7, 128.2, 126.9, 71.1, 32.8, 22.7, 19.7, 19.1; IR (KBr) ν 3330, 2932, 1752, 1662, 1261. Anal. calcd for C₁₉H₂₃N₃O₂: C, 70.13; H, 7.12; N, 12.91. Found: C, 70.13 H, 7.15 N, 12.93. (E) - N -? ( 4 - ((2-Benzoylhydrazono) methyl) phenyl) acetamide (100 mg, 0.35 mmol), 1a H 3 PO 2 (480 mg, 1.06 mmol), Et 3 B (0.35 mL, 0.35 mmol), ⁱ PrI (0.18 mL, 1.8 mmol) to give compound 3q in yield of 89 mg (77%) according to the general experimental method: (eluent; hexane: EtOAc = 8: 2); 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 18.8 min, t _r (minor) = 16.5 min]. mp 158-160 ^o C (lit., mp 155-157 ^o C);

= -3.1 (c 0.15, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.82 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.98-2.15 (m, 1H), 2.61 (s, 3H), 3.96 ( d, J = 6.8 Hz, 1H), 5.34 (s, 1H), 7.12-7.80 (m, 8H) 7.95 (d, J = 8.0 Hz, 2H), 8.91 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 168.1, 167.5, 146.8, 136.7, 132.9, 132.1, 129.1, 128.7, 128.2, 126.9, 71.1, 32.8, 22.7, 19.7, 19.1; IR (KBr) v 3330, 2932, 1752, 1662, 1261. Anal. calcd for C ₁₉ H ₂₃ N ₃ O ₂ : C, 70.13; H, 7. 12; N, 12.91. Found: C, 70.13 H, 7.15 N, 12.93.

(16) (16) NN '-(1-(4-Ethylphenyl)-2-methylpropyl)benzohydrazide (3s)'-(1- (4-Ethylphenyl) -2-methylpropyl) benzohydrazide (3s)

(E)-N'-(4-Ethylbenzylidene)benzohydrazide (100 mg, 0.40 mmol), 1a?H₃PO₂ (541 mg, 1.2 mmol), Et₃B (0.40 mL, 0.40 mmol), ⁱ PrI (0.2 mL, 2.0 mmol)을 사용하여 일반적 실험 방법에 따라 반응시켜 화합물 3s을 93 mg (79%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2): (eluent; hexane : EtOAc = 8 : 2); 74% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 20.6 min, t_r (minor) = 19.2 min]. colorless oil;

= -1.9 (c 0.15, CHCl₃); ¹H NMR (CDCl₃) δ 0.76 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 1.90-2.02 (m, 1H), 2.55-2.65 (m, 2H), 3.76 (d, J = 7.2 Hz, 1H), 5.32 (s, 1H), 7.08-7.55 (m, 10H); ¹³C NMR (CDCl₃) δ 167.1, 143.6, 138.1, 133.3, 131.9, 128.8, 128.6, 127.9, 127.0, 71.2, 32.8, 28.7, 19.8, 19.3, 15.7; IR (neat) ν 3080, 2951, 1726, 1630, 1215. Anal. calcd for C₁₉H₂₄N₂O: C, 76.99; H, 8.16; N, 9.45. Found: C, 77.01 H, 8.17 N, 9.46.( E ) -N ' -(4-Ethylbenzylidene) benzohydrazide (100 mg, 0.40 mmol), 1a -H ₃ PO ₂ (541 mg, 1.2 mmol), Et ₃ B (0.40 mL, 0.40 mmol), ⁱ PrI (0.2 mL, 2.0 mmol) was used to give a compound 3s in 93 mg (79%) yield according to the general experimental method: (eluent; hexane: EtOAc = 8: 2): (eluent; hexane: EtOAc = 8: 2); 74% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 20.6 min, t _r (minor) = 19.2 min]. colorless oil;

= -1.9 (c 0.15, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 1.90-2.02 (m, 1H), 2.55-2.65 (m, 2H), 3.76 (d, J = 7.2 Hz, 1H), 5.32 (s, 1H), 7.08-7.55 (m, 10H); ¹³ C NMR (CDCl ₃ ) δ 167.1, 143.6, 138.1, 133.3, 131.9, 128.8, 128.6, 127.9, 127.0, 71.2, 32.8, 28.7, 19.8, 19.3, 15.7; IR (neat) v 3080, 2951, 1726, 1630, 1215.Anal. calcd for C ₁₉ H ₂₄ N ₂ O: C, 76.99; H, 8. 16; N, 9.45. Found: C, 77.01 H, 8.17 N, 9.46.

(17) (17) NN '-(1-(4-Hydroxyphenyl)-2-methylpropyl)benzohydrazide (3u)'-(1- (4-Hydroxyphenyl) -2-methylpropyl) benzohydrazide (3u)

(E)-N'-(4-Hydroxybenzylidene)benzohydrazide (100 mg, 0.42 mmol), 1a?H₃PO₂ (561 mg, 1.2 mmol), Et₃B (0.42 mL, 0.42 mmol), ⁱ PrI (0.21 mL, 2.08 mmol)을 사용하여 일반적 합성 방법에 따라 반응시켜 화합물 3u을 93 mg (78%)의 수율로 얻었다: (eluent; hexane : EtOAc = 8 : 2); 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r (major) = 20.1 min, t_r (minor) = 18.3 min]. mp 237-239 ^oC;

= -8.5 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.81 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.63 (s, 1H), 2.14-2.20 (m, 1H), 3.96 (d, J = 8.0 Hz, 1H), 5.34 (s, 1H), 7.15-7.62 (m, 8H), 7.95 (d, J = 8.4 Hz, 2H); ¹³C NMR (CDCl₃) δ 166.8, 157.8, 136.7, 133.1, 132.1, 129.0, 128.8, 128.6, 127.1, 71.0, 32.7, 19.6, 19.2; IR (KBr) ν 3312, 2904, 1701, 1687, 1203, 1114. Anal. calcd for C₁₇H₂₀N₂O₂: C, 71.81; H, 7.09; N, 9.85. Found: C, 71.80 H, 7.10 N, 9.83.( E ) -N ' -(4-Hydroxybenzylidene) benzohydrazide (100 mg, 0.42 mmol), 1a -H ₃ PO ₂ (561 mg, 1.2 mmol), Et ₃ B (0.42 mL, 0.42 mmol), ⁱ PrI (0.21 mL, 2.08 mmol) was reacted according to the general synthetic method to give compound 3u in a yield of 93 mg (78%): (eluent; hexane: EtOAc = 8: 2); 76% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 20.1 min, t _r (minor) = 18.3 min]. mp 237-239 ^o C;

= -8.5 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.81 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.63 (s, 1H), 2.14-2.20 (m, 1H), 3.96 ( d, J = 8.0 Hz, 1H), 5.34 (s, 1H), 7.15-7.62 (m, 8H), 7.95 (d, J = 8.4 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 166.8, 157.8, 136.7, 133.1, 132.1, 129.0, 128.8, 128.6, 127.1, 71.0, 32.7, 19.6, 19.2; IR (KBr) v 3312, 2904, 1701, 1687, 1203, 1114. Anal. calcd for C ₁₇ H ₂₀ N ₂ O ₂ : C, 71.81; H, 7.09; N, 9.85. Found: C, 71.80 H, 7.10 N, 9.83.

(18) (18) NN '-(2-Methyldecan-3-yl)benzohydrazide (3w)'-(2-Methyldecan-3-yl) benzohydrazide (3w)

(E)-N'-Nonylidenebenzohydrazide (100 mg, 0.40 mmol), 1a?H₃PO₂ (543 mg, 1.2 mmol), Et₃B (0.40 mL, 0.40 mmol), ⁱ PrI (0.20 mL, 2.0 mmol)을 사용하여 일반적 합성 방법에 따라 반응시켜 화합물 3w을 90 mg (76%)의 수율로 얻었다: (efluent; hexane : EtOAc = 8 : 2): 64% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH= 90 / 10, 0.5 mL / min_,λ = 254 nm, t_r(major) = 15.7 min, t_r (minor) = 14.7 min]. colorless oil;

= -7.4 (c 0.50, CHCl₃); ¹H NMR (CDCl₃) δ 0.70 (t, J = 6.8 Hz, 3H), 0.80-1.01 (m, 6H), 1.18-1.45 (m, 10H), 1.50-1.71 (m, 2H), 2.00-2.18 (m, 1H), 2.52-2.60 (m, 1H), 5.37 (s, 1H), 7.35-7.60 (m, 5H), 7.89 (t, J = 7.2 Hz, 1H), 8.09 (t, J = 12.6 Hz, 2H); ¹³C NMR (CDCl₃) δ 164.5, 133.4, 131.9, 128.7, 127.6, 71.8, 31.9, 29.2, 26.9, 22.8, 20.0, 19.4, 14.2; IR (KBr) ν 2931, 1706, 1660, 1264. Anal. calcd for C₁₈H₃₀N₂O: C, 74.44; H, 10.41; N, 9.65. Found: C, 74.48 H, 10.37 N, 9.66. (E) -? N '-Nonylidenebenzohydrazide (100 mg, 0.40 mmol), 1a H 3 PO 2 (543 mg, 1.2 mmol), Et 3 B (0.40 mL, 0.40 mmol), i PrI (0.20 mL, 2.0 mmol) The reaction was carried out according to the general synthetic method using to give compound 3w in 90 mg (76%) yield: (efluent; hexane: EtOAc = 8: 2): 64% ee as determined by HPLC [Daicel Chiralpak IA, hexane / ⁱ PrOH = 90/10, 0.5 mL / min _, λ = 254 nm, t _r (major) = 15.7 min, t _r (minor) = 14.7 min]. colorless oil;

= -7.4 (c 0.50, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 0.70 (t, J = 6.8 Hz, 3H), 0.80-1.01 (m, 6H), 1.18-1.45 (m, 10H), 1.50-1.71 (m, 2H), 2.00-2.18 (m, 1H), 2.52-2.60 (m, 1H), 5.37 (s, 1H), 7.35-7.60 (m, 5H), 7.89 (t, J = 7.2 Hz, 1H), 8.09 (t, J = 12.6 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 164.5, 133.4, 131.9, 128.7, 127.6, 71.8, 31.9, 29.2, 26.9, 22.8, 20.0, 19.4, 14.2; IR (KBr) ν 2931, 1706, 1660, 1264. Anal. calcd for C ₁₈ H ₃₀ N ₂ O: C, 74.44; H, 10.41; N, 9.65. Found: C, 74.48 H, 10.37 N, 9.66.

E. 실험 결과E. Experimental Results

(1) 1a?H(1) 1a? H ₃₃ POPO ₂₂ 의 유기 촉매를 사용한 거울상 키랄 아릴아민의 제조Of Enantiomeric Chiral Arylamines Using Organic Catalysts

탈기(degassing)한 CH₂Cl₂를 사용하고 라디칼 수소주게인 신코나 유도체와 히드로포스포러스 산(hypophosphorous acid)의 염(1a?H₃PO₂)의 당량과 반응온도를 변화시키며 반응을 수행하였다(표 1). 반응온도를 상온에서 -78 ℃으로 낮추며 반응을 수행한 결과, 원하는 생성물 3a를 얻었으며 개시제인 Et₃B에 의해 3b가 부생성물로 얻었다. 원하는 생성물 3a의 광학순도(enantiomeric excess)를 측정하였다. 그 결과 -30 ℃일 때 82%의 가장 높은 수율로 3a를 얻었으며 82% ee의 거울상 선택성을 보였다(entry 4). 온도가 낮아질수록 높은 거울상 선택성을 보였으나 원하는 생성물인 3a의 수율은 낮아졌다. 또한 개시제인 Et₃B에서 기인한 부생성물 3b가 증가하였다(entry1-8). 최적의 반응온도를 -30 ℃로 결정하고 라디칼 수소주개인 신코나 유도체와 히드로포스포러스 산의 염(1a?H₃PO₂)의 최적 당량을 알아보기 위하여 3당량에서 1당량까지 반응을 수행하였다. 그 결과 3당량일 때에 비해 2당량, 1당량일 때 각각 64%, 49%의 낮은 수율로 생성물 3a를 얻었으며 생성물 3a는 46% ee, 28% ee로 낮은 거울상 선택성을 보였다(entry 5-6). 1a?H₃PO₂의 3당량이하 일 때 원하는 생성물 3a의 거울상 선택성이 낮아짐을 따라 1a?H₃PO₂의 최적 당량을 -30 ℃일 때 3당량으로 결정하였다.The reaction was carried out using degassing CH ₂ Cl ₂ and changing the equivalent temperature and reaction temperature of the radical hydrogen donor synkona derivative and the salt of the hydrophosphorous acid ( 1a ? H ₃ PO ₂ ). (Table 1). The reaction was carried out at room temperature to -78 ° C to give the desired product 3a was obtained as a by-product 3b by the initiator Et ₃ B. The optical purity (enantiomeric excess) of the desired product 3a was measured. As a result, 3a was obtained at the highest yield of 82% at −30 ° C. and enantioselectivity of 82% ee (entry 4). Lower temperatures showed higher enantioselectivity but lower yields of the desired product 3a . There was also an increase in byproduct 3b due to the initiator Et ₃ B (entry 1-8). The reaction temperature was determined to be -30 ° C and the reaction was carried out from 3 to 1 equivalents to determine the optimal equivalents of the Cincona derivative, the radical hydrogen host, and the salts of hydrophosphoric acid ( 1a- H ₃ PO ₂ ). . As a result, the product 3 a was obtained at a lower yield of 64% and 49% at 2 equivalents and 1 equivalent, respectively, at 3 equivalents, and the product 3a was 46% ee and 28% ee having low enantioselectivity (entry 5- 6). 1a? 3 equivalents of less than one when the best equivalent of 1a? H ₃ PO ₂ in accordance with the desired enantiomer selectivity of the product becomes lower in a 3 H ₃ PO ₂ was determined with 3 equivalents when -30 ℃.

반응용매의 영향을 알아보기 위하여 표 1에서 결정한 최적 조건을 적용하여 탈기한 반응용매를 변화시켜 반응을 수행하였다(표 2). 탈기한 THF를 반응용매로 사용한 반응을 수행하여 원하는 생성물 3a를 76% 얻었으며 84% ee를 얻었다(entry 1). 다음으로 탈기한 에테르, 톨루엔, CH₃CN을 반응용매로 반응을 수행한 결과, 원하는 생성물 3a를(50～56%)의 수율로 얻을 수 있었다(entry 2-4). 반응용매로 에테르, 톨루엔, CH₃CN으로 사용한 경우 각각 72% ee, 40% ee, 80% ee의 광학순도를 얻었다. CH₂Cl₂와 THF이외 용매에서 거울상 선택성이 낮음을 확인할 수 있었다(entry 2-4). 반응용매를 톨루엔으로 사용할 경우 라디칼 수소주개인 신코나 유도체와 히드로포스포러스 산의 염(1a?H₃PO₂)의 용해도가 떨어져서 낮은 거울상 선택성을 얻었다(entry 3).In order to determine the effect of the reaction solvent, the reaction was performed by changing the degassed reaction solvent by applying the optimum conditions determined in Table 1 (Table 2). The reaction was performed using degassed THF as a reaction solvent to obtain 76% of the desired product 3a and 84% ee (entry 1). Next, degassed ether, toluene, and CH ₃ CN were reacted with a reaction solvent, and the desired product 3a was obtained in a yield of (50 to 56%) (entry 2-4). When the reaction solvent was used as ether, toluene and CH ₃ CN, optical purity of 72% ee, 40% ee and 80% ee was obtained, respectively. Low enantioselectivity was found in solvents other than CH ₂ Cl ₂ and THF (entry 2-4). When the reaction solvent was used as toluene, the solubility of the synacona derivative which is a radical hydrogen host and the salt of hydrophosphoric acid ( 1a? H ₃ PO ₂ ) was lowered to obtain low enantioselectivity (entry 3).

최적의 조건에서 1a?H₃PO₂와 다양한 알킬 할라이드를 사용하여 라디칼 첨가반응을 수행하였다(표 3). 2차 알킬 할라이드를 알킬 공급체로 한 반응은 높은 수율과 좋은 거울상 선택성을 보여주었다(entry 2). 3차 알킬 할라이드는 수율이 낮았지만 거울상 선택성이 92% ee, 94% ee로 높은 선택성을 얻을 수 있었다. 그러나 1차 알킬 할라이드인 ⁿ옥틸 요오다이드와의 반응은 반응성이 떨어져서 원하는 생성물 3f를 41%의 수율을 얻을 수 있었으며 거울상 선택성도 낮았다(entry 4).Under optimal conditions, the radical addition reaction was carried out using 1a H ₃ PO ₂ and various alkyl halides (Table 3). Reactions with secondary alkyl halides as alkyl feeders showed high yields and good enantioselectivity (entry 2). Tertiary alkyl halides had low yields but high selectivity with enantioselectivity of 92% ee and 94% ee. However, the reaction with ⁿ octyl iodide, the primary alkyl halide, was inactive , yielding 41% yield of the desired product 3f and low enantioselectivity (entry 4).

다음으로 CH₂Cl₂에서 라디칼 유기 촉매로 1a?H₃PO₂를 사용하고 위 표 4에서 높은 수율과 좋은 선택성을 보인 이소프로필 요오다이드와 출발물질인 다양한 히드라존(hydrazone) 유도체의 라디칼 반응을 통하여 라디칼 첨가반응을 수행하였다(표 4). 페닐기를 지닌 유도체가 그렇지 않은 유도체보다 좋은 거울상 선택성을 보여 주었다(entry 1-9).Next, radical reactions of isopropyl iodide and various hydrazone derivatives as starting materials using 1a ? H ₃ PO ₂ as a radical organic catalyst in CH ₂ Cl ₂ and high yield and good selectivity are shown in Table 4 above. Radical addition was carried out through (Table 4). Derivatives with phenyl groups showed better enantioselectivity than those with no phenyl group (entry 1-9).

(2) 1a?H(2) 1a? H ₃₃ POPO ₂₂ 이외에 다른 종류의 유기 촉매를 사용하여 거울상 키랄 아릴아민의 제조 Preparation of Enantiomeric Chiral Arylamines Using Other Kinds of Organic Catalysts

다음으로 HPF₆, HBF₄, p-톨루엔술폰산, 캠포설폰산, 트리플루오로메탄술폰산을 이용하여 다양한 키랄 암모늄 염을 합성하고 나서(반응식 1), 이를 유기 촉매로 사용하여 탈기한 CH₂Cl₂ 반응용매 및 -30 ℃의 조건에서 알킬 공급체인 ⁱ PrI, 개시제인 Et₃B와 Ph₂SiH₂함께 반응을 수행하였다(표 5). 라디칼 유기 촉매로서 1a?HPF₆을 3당량으로 반응을 수행한 결과, 81%의 수율로 원하는 생성물 3a 얻었으며 원하는 생성물 3a는 99% ee이상으로 높은 거울상 선택성이 높았다(entry 1). 라디칼 유기 촉매로서 산의 염(1a?HPF₆)의 최적 당량을 알아보기 위해 당량을 3당량에서 0.1당량으로 낮추며 반응을 수행한 결과, 원하는 생성물 3a의 수율은 최대 82%에서 최저 76%로 얻었으며 광학순도는 당량이 감소함에 따라 거울상 선택성이 낮아짐을 확인할 수 있었다(entry 1-8). 알킬 공급체인 ⁱ PrI의 당량을 1.5당량으로 줄여주어 반응을 수행하였다. 그 결과 원하는 생성물 3a의 수율과 거울상 선택성이 5당량과 동일하였다(entry 9). 1a?HOTs0.5당량을 라디칼 유기 촉매로 반응을 수행하는 경우 원하는 생성물 3a를 77% 얻었으며 원하는 생성물 3a의 20% ee로 그 외의 키랄 암모늄 염에 비해 낮은 거울상 선택성을 보였다(entry 9). 그 밖에 1a?HBF₄, 1a?캠포술폰산과 1a?트리플루오로메탄술폰산을 동일한 조건에서 반응을 수행하여 원하는 생성물 3a를 각 76%, 73% 수율로 얻었으며 40% ee를 얻었다(entry 10-12).Next, various chiral ammonium salts were synthesized using HPF ₆ , HBF ₄ , p -toluenesulfonic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid (Scheme 1), and then CH ₂ Cl _{2 was} degassed using the organic catalyst. The reaction was carried out together with the reaction solvent and the alkyl feeder ⁱ PrI, the initiator Et ₃ B and Ph ₂ SiH ₂ at -30 ° C (Table 5). The reaction was carried out in 3 equivalents of 1a to HPF ₆ as a radical organic catalyst, and the desired product 3a was obtained in a yield of 81%, and the desired product 3a had a high enantioselectivity higher than 99% ee (entry 1). Salt of the acid as a radical organic catalyst (1a? HPF ₆₎ After carrying out the reaction, lower equivalent weight to determine the best equivalent to 0.1 equivalents from 3 equivalents of a yield of the desired product 3a was obtained in up to 82% to a minimum 76% The optical purity was found to decrease the mirror image selectivity as the equivalent weight decreased (entry 1-8). The reaction was carried out by reducing the equivalent of ⁱ PrI, the alkyl supply source, to 1.5 equivalents. As a result, the yield and enantioselectivity of the desired product 3a were equal to 5 equivalents (entry 9). 1a ? HOTs When the reaction was carried out with 0.5 equivalents of the radical organic catalyst, 77% of the desired product 3a was obtained and 20% ee of the desired product 3a showed low enantioselectivity compared to other chiral ammonium salts (entry 9). In addition, 1a HBF ₄ , 1a camphorsulfonic acid and 1a trifluoromethanesulfonic acid were reacted under the same conditions to obtain desired product 3a in 76%, 73% yield and 40% ee (entry 10- 12).

최적의 조건에서 1a?HPF₆와 다양한 알킬 할라이드를 사용하여 라디칼 첨가반응을 수행하였다(표 6). 2차 알킬 할라이드를 알킬 공급체로 한 반응은 높은 수율과 좋은 거울상 선택성을 보여주었다(entry 1). 3차 알킬 할라이드인 tert-부틸 요오다이드와 1-아다만틸 요오다이드(1-adamantyl iodide)는 수율이 낮았지만 높은 거울상 선택성을 나타내어 99% ee의 선택성을 얻었다(entry 2-3). 그러나 1차 알킬 할라이드인 ⁿ 옥틸 요오다이드와의 반응은 반응성이 떨어져서 원하는 생성물 3f를 55%의 수율을 얻을 수 있었으며 거울상 선택성도 낮았다(entry 4).Under optimal conditions, radical addition reactions were carried out using 1a HPF ₆ and various alkyl halides (Table 6). Reactions with secondary alkyl halides as alkyl feeders showed high yields and good enantioselectivity (entry 1). Tert-butyl iodide and 1-adamantyl iodide, tertiary alkyl halides, had low yields but high enantioselectivity resulting in 99% ee selectivity (entry 2-3). However, the reaction with ⁿ octyl iodide, the primary alkyl halide, was inactive , yielding a desired product 3f of 55% and low enantioselectivity (entry 4).

표 5에서 볼 수 있듯이 1a?HPF₆는 라디칼 유기 촉매로서 높은 거울상 선택성을 보임을 알 수 있다. 다음으로 CH₂Cl₂에서 라디칼 유기 촉매로 1a?HPF₆을 이용하여 ⁱ PrI를 사용하고 다양한 벤조일히드라존 유도체에 라디칼 첨가 반응을 수행하였다(표 7). 상대적으로 반응에 참여한 양이 적음에도 불구하고 전체적으로 라디칼 유기 촉매로써 1a?HPF₆을 사용한 경우가 입체 선택성을 높게 나타남을 확인할 수 있었다. 방향족(aromatic) 그룹을 포함한 유도체인 경우 광학순도가 현재까지 수행한 반응에서 전 반응이 99% ee이상의 아주 높은 입체 선택성을 보여주었다(entry 1-9). 그러나 알킬기만 있는 경우는 수율과 거울상 선택성이 떨어짐을 확인할 수 있었다(entry 10).As shown in Table 5, it can be seen that 1a- HPF ₆ shows high enantioselectivity as a radical organic catalyst. Next, using the 1a? HPF ₆ as a catalyst in an organic radical CH ₂ Cl ₂ using an ⁱ PrI and a radical addition reaction was carried out in a variety of benzoyl hydrazone derivatives (Table 7). In spite of the relatively small amount participating in the reaction, it was confirmed that the use of 1a- HPF ₆ as the radical organic catalyst as a whole showed high stereoselectivity. Derivatives containing aromatic groups showed very high stereoselectivity of more than 99% ee in the reactions performed up to now with optical purity (entry 1-9). However, only the alkyl group was found to be inferior in yield and enantioselectivity (entry 10).

위 실시예에서 비록 명시적으로 실험 데이터를 기재하지는 않았으나, 본 명세서의 해당 부분에서 언급한 바와 같이, 유기 촉매의 회수율 및 반응규모의 확장가능성 면에서도 현저한 정도의 정량적 향상의 증가가 확인되었다.Although the experimental data were not explicitly described in the above examples, as noted in the relevant sections of the present specification, a significant increase in the quantitative improvement was observed in terms of the recovery rate of the organic catalyst and the scalability of the reaction scale.

도 1은 순수한 이성질체를 얻기 위한 종래기술에 대한 분류도Figure 1 is a classification for the prior art to obtain pure isomers

Claims

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Method for producing a mirror-like chiral arylamine comprising radical addition reaction of the reactant and the alkylating agent using an organic catalyst having a structure of formula (2) below:

[Formula 2]

Wherein R is a benzyl group or benzoyl group or RO is an anthracene-9-carboxylate group; X is selected from H ₃ PO ₂ and PF ₆ .

The method of claim 3, wherein the reactant has a structure of Formula 3 below.

(3)

In Formula 3, R 1 and R each independently represent a benzoyl group, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R is selected from alkyl groups, substituted alkyl groups, aryl groups and substituted aryl groups;

The substituted alkyl group is substituted by one or more substituents selected from halides, nitro groups, acyl groups, hydroxy groups, Ra-O-, and Rb-CO-NH-; The substituted aryl group is substituted by one or more substituents selected from halide, nitro group, acyl group, hydroxy group, Ra-O-, Rb-CO-NH- and Rc-; Ra, Rb and Rc each independently represent a lower alkyl group of C ₁ -C ₅ or a higher alkyl group of C ₆ -C ₂₀ .

5. The method of claim 4, wherein R 1 in Formula 3 is a benzoyl group. 6.

The method according to claim 4, wherein in Formula 3 R is

ego; R'- is selected from hydrogen, halide, nitro group, acyl group, hydroxy group, Ra-O-, Rb-CO-NH- and Rc-; Ra, Rb, Rc are independently a lower alkyl group of C ₁ -C ₅ or a higher alkyl group of C ₆ -C ₂₀ characterized in that the method for producing a mirror chiral arylamine.

The method of claim 3, wherein the alkylating agent has a structure of the following formula (4):

[Formula 4]

R-A

In Formula 4, R is a primary, secondary or tertiary alkyl group; The alkyl group is C ₁ -C ₅ lower alkyl group or C ₆ -C ₂₀ higher alkyl group; A represents a halide.

According to claim 7, wherein in Formula 4, R is selected from isopropyl group, cyclohexyl group, tert-butyl group and 1-adamantyl group; A is a method for producing a mirror chiral arylamine, characterized in that selected from I, Cl, F.

The method of claim 3 or 8, wherein the radical addition reaction is carried out at a reaction temperature of -35 ℃ to -25 ℃, characterized in that using the organic catalyst in 0.9 to 3 equivalents based on 1 equivalent of the reactants. Method for preparing enantiomeric chiral arylamine.