KR101114616B1 - Method for Preparation of Alpha-Amino Carbonyl Compound Using Chiral Catalyst - Google Patents

Method for Preparation of Alpha-Amino Carbonyl Compound Using Chiral Catalyst Download PDF

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KR101114616B1
KR101114616B1 KR1020080138529A KR20080138529A KR101114616B1 KR 101114616 B1 KR101114616 B1 KR 101114616B1 KR 1020080138529 A KR1020080138529 A KR 1020080138529A KR 20080138529 A KR20080138529 A KR 20080138529A KR 101114616 B1 KR101114616 B1 KR 101114616B1
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amino carbonyl
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KR20100079931A (en
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김대영
심성보
이주희
김선미
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순천향대학교 산학협력단
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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Abstract

알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매의 존재하에서, 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조하는 방법이 개시된다. 상기 제조방법은, 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다.A method of preparing an alpha-amino carbonyl compound is disclosed by reacting an alpha-cyanoketone or beta-ketoester compound with an azo compound in the presence of a chiral catalyst. In the above production method, an optically active material having high optical purity can be efficiently produced using a chiral catalyst.

키랄 촉매, 아조 화합물, 광학활성, 알파-아미노 카보닐 Chiral Catalysts, Azo Compounds, Optically Active, Alpha-Amino Carbonyl

Description

키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법{Method for Preparation of Alpha-Amino Carbonyl Compound Using Chiral Catalyst}Method for Preparation of Alpha-Amino Carbonyl Compound Using Chiral Catalyst

본 발명은 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법에 관한 것이다. The present invention relates to a method for preparing an alpha-amino carbonyl compound using a chiral catalyst.

광학이성질체들은 밀도, 녹는점, 끓는점 등 대부분의 물리적 성질이 동일하지만, 편광된 빛을 흡수하는 정도가 다르기 때문에 선형편광된 빛을 조사(照射)했을 때 편광면이 회전하게 되며, 이러한 현상을 광학활성이라고 한다. Optical isomers have the same physical properties as density, melting point and boiling point, but due to the different absorption of polarized light, the plane of polarization rotates when irradiated with linearly polarized light. It is called active.

물질의 광학활성은 편광계를 사용하여 측정한다. 광학활성은 대칭 중심, 대칭면 또는 회전축 등의 대칭 요소를 갖지 못하는 분자에서 나타나며, 이러한 분자들은 왼손 또는 오른손과 같이 좌우가 바뀌고 서로 겹쳐지지 않는 거울상체의 관계를 갖는 2 개의 이성질체로 존재할 수 있으며, 이런 성질을 가진 분자를 키랄성 화합물(chiral compound)이라고 한다. The optical activity of the material is measured using a polarimeter. Optical activity occurs in molecules that do not have symmetrical elements, such as the center of symmetry, the plane of symmetry, or the axis of rotation, and these molecules can exist as two isomers with enantiomers that do not overlap and overlap each other, such as the left or right hand. Molecules with properties are called chiral compounds.

탄소에 연결된 4 개의 원자단(原子團)이 모두 다른 비대칭(키랄중심, chiral center) 탄소를 가진 탄소화합물, 또는 두 자리 리간드를 가진 전이금속착물에서 흔히 볼 수 있다. 자연계에 존재하는 20여 종의 아미노산 중 글리신을 제외한 모 든 아미노산은 비대칭탄소를 가진 키랄성 화합물이다. All four atomic groups linked to carbon are commonly found in carbon compounds with different asymmetric (chiral center) carbons, or in transition metal complexes with bidentate ligands. Of the 20 kinds of amino acids present in nature, all amino acids except glycine are chiral compounds with asymmetric carbons.

특히, 키랄 알파-아미노 카보닐 화합물은 생명과학적으로 이용이 되고 있는 알파-아미노산으로의 전환이 가능하기 때문에 많은 연구가 진행되고 있는 분야이다. 키랄 유기촉매를 이용한 베타-케토에스테르의 비대칭 아민화 반응은 일부 알려져 있으나, 적용된 유도체 범위가 제한되어 있으며 낮은 입체선택성을 나타내고 있다. In particular, the chiral alpha-amino carbonyl compound is a field in which a lot of research is being conducted since conversion to alpha-amino acid which is used in bioscience is possible. The asymmetric amination of beta-ketoesters using chiral organic catalysts is known in part, but the range of derivatives applied is limited and shows low stereoselectivity.

본 발명에서는 이러한 낮은 입체선택성을 보완하고, 유도체의 범위를 확대할 수 있는 제조방법을 제공하고자 한다. The present invention aims to provide a preparation method that can complement such low stereoselectivity and extend the range of derivatives.

본 발명의 일실시예의 목적은 알파-아미노 카보닐 화합물의 제조방법을 제공하는 것이다.It is an object of one embodiment of the present invention to provide a method for preparing an alpha-amino carbonyl compound.

본 발명에 따른 제조방법은, 알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매의 존재하에서, 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조하는 것을 특징으로 한다. The production method according to the invention is characterized in that an alpha-cyanoketone or beta-ketoester compound is reacted with an azo compound in the presence of a chiral catalyst to produce an alpha-amino carbonyl compound.

본 발명에 따른 알파-아미노 카보닐 화합물을 제조하는 방법은, 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다. In the method for preparing an alpha-amino carbonyl compound according to the present invention, a chiral catalyst can be used to efficiently produce an optically active material having high optical purity.

본 발명의 일실시예에 따른 알파-아미노 카보닐 화합물의 제조방법은, 알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매(chiral catalyst)의 존재하에서, 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조한다. 상기 제조방법은 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다. 또 다른 일실시예에서, 상기 키랄 촉매는, 티오우레아와 아민 그룹이 결합된 키랄 양기능 유기촉매일 수 있다. 티오우레아와 아민 그룹이 결합된 키랄 양기능 유기촉매를 이용하는 비대칭 아민화 반응은, 광학적으로 순수한 키랄 알파-아미노 카보닐 화합물을 고수율로 얻을 수 있는 매우 간편하고 유용한 반 응이다.In the method for preparing an alpha-amino carbonyl compound according to an embodiment of the present invention, an alpha-cyano ketone or a beta-ketoester compound is reacted with an azo compound in the presence of a chiral catalyst to alpha-amino Prepare a carbonyl compound. The preparation method is for efficiently preparing an optically active material having high optical purity using a chiral catalyst. In another embodiment, the chiral catalyst may be a chiral bifunctional organic catalyst having a thiourea and an amine group bonded thereto. Asymmetric amination reactions using chiral bifunctional organic catalysts in which thiourea and amine groups are combined is a very simple and useful reaction that can yield optically pure chiral alpha-amino carbonyl compounds in high yield.

일실시예에서, 상기 키랄 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 0.01 내지 20 몰%이며, 보다 구체적으로는 0.2 내지 20 몰%이다. In one embodiment, the content of the chiral catalyst is 0.01 to 20 mol%, more specifically 0.2 to 20 mol%, based on the total moles of the reactants.

일실시예에서, 상기 키랄 촉매는, 하기 화학식 1로 표현될 수 있다.In one embodiment, the chiral catalyst, it may be represented by the formula (1).

Figure 112008091089021-pat00001
Figure 112008091089021-pat00001

또 다른 일실시예에서, 상기 알파-시아노케톤 화합물은 하기 화학식 2로 표현될 수 있고, 상기 베타-케토에스테르 화합물은 화학식 3으로 표현될 수 있다. In another embodiment, the alpha-cyanoketone compound may be represented by Formula 2, and the beta-ketoester compound may be represented by Formula 3.

Figure 112008091089021-pat00002
Figure 112008091089021-pat00002

Figure 112008091089021-pat00003
Figure 112008091089021-pat00003

위의 화학식 2 또는 3에서, In Formula 2 or 3 above,

상기 R1 및 R2는 C1-C40의 알킬기, 알킬렌기 또는 아릴기이고, 상호 동일하거나 상이하며, R1 및 R2 는 서로 연결되어 고리계의 일부를 형성할 수 있고, R 1 and R 2 are C 1 -C 40 alkyl, alkylene or aryl groups, the same as or different from each other, R 1 and R 2 May be connected to each other to form part of a ring system,

상기 R3는 C1-C20의 알킬기이며, R 3 is an alkyl group of C 1 -C 20 ,

상기 알킬기는 선형 또는 가지형 알킬기이다.The alkyl group is a linear or branched alkyl group.

일실시예에서, 상기 아조 화합물은 하기 화학식 4의 구조를 갖는 화합물일 수 있다. In one embodiment, the azo compound may be a compound having a structure of formula (4).

Figure 112008091089021-pat00004
Figure 112008091089021-pat00004

상기 식에서, R4는 C1-C20의 선형 또는 가지형 알킬기이다.Wherein R 4 is a C 1 -C 20 linear or branched alkyl group.

또 다른 일실시예에서, 상기 알파-아미노 카보닐 화합물은, 화학식 5 또는 6 의 구조를 갖는 화합물일 수 있다.In another embodiment, the alpha-amino carbonyl compound may be a compound having a structure of Formula 5 or 6.

Figure 112008091089021-pat00005
Figure 112008091089021-pat00005

Figure 112008091089021-pat00006
Figure 112008091089021-pat00006

위의 화학식 5 또는 6에서, In Formula 5 or 6 above,

상기 R1 및 R2는 C1-C20의 알킬기, 알킬렌기 또는 아릴기이고, 상호 동일하거나 상이하며, R1 및 R2 는 서로 연결되어 고리계의 일부를 형성할 수 있고, R 1 and R 2 are C 1 -C 20 alkyl group, alkylene group or aryl group, the same as or different from each other, R 1 and R 2 May be connected to each other to form part of a ring system,

상기 R3 및 R4는 C1-C20의 알킬기이며, R 3 and R 4 are C 1 -C 20 Alkyl group,

상기 알킬기는 선형 또는 가지형 알킬기이다. The alkyl group is a linear or branched alkyl group.

일실시예에서, 상기 아릴기는 알콕시기로 치환된 아릴기일 수 있으며, 상기 R3 및 R4는 터셔리 부틸기일 수 있다. In one embodiment, the aryl group may be an aryl group substituted with an alkoxy group, the R 3 and R 4 may be a tertiary butyl group.

이하, 본 발명의 일실시예에 따른 알파-아미노 카보닐 화합물의 제조방법에 대하여 보다 구체적으로 살펴본다. Hereinafter, a method of preparing an alpha-amino carbonyl compound according to an embodiment of the present invention will be described in more detail.

먼저, 상기 키랄 양기능 유기촉매는 하기 반응식 1의 과정을 통해 합성될 수 있다.First, the chiral bifunctional organic catalyst may be synthesized through the process of Scheme 1 below.

Figure 112008091089021-pat00007
Figure 112008091089021-pat00007

상기 반응식 1을 통해 제조된 키랄 양기능 유기촉매를 이용하여, 반응물질에 대한 아민화 반응을 유도함으로써, 알파-아미노 카보닐 화합물을 제조하게 된다. By using the chiral bifunctional organic catalyst prepared in Scheme 1, an amination reaction for the reactants is induced, thereby preparing an alpha-amino carbonyl compound.

일실시예에서, 알파-시아노케톤(1a)을 키랄 촉매의 존재하에서 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조할 수 있다. 또 다른 일실시예에서, 베타-케토에스테르(1b)를 키랄 촉매의 존재하에서 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조할 수 있다. 구체적인 반응식은 하기 반응식 2와 같다. In one embodiment, alpha-cyanoketone (la) can be reacted with an azo compound in the presence of a chiral catalyst to produce an alpha-amino carbonyl compound. In another embodiment, alpha-amino carbonyl compounds can be prepared by reacting beta-ketoester (1b) with an azo compound in the presence of a chiral catalyst. Specific reaction schemes are the same as in Scheme 2 below.

Figure 112008091089021-pat00008
Figure 112008091089021-pat00008

위 반응식 2에서 R1 내지 R4는 위에서 정의한 바와 같다.R 1 to R 4 in the above Scheme 2 are as defined above.

이하, 하기 실시예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시예 등은 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples and the like are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

[실시예1] 2-시아노-1-인다논의 아민화 생성물Example 1 Amination Product of 2-Cyano-1-indanon

플라스크에 2-시아노-1-인다논(화학식 2) 0.05 mmol을 넣고 톨루엔 0.05 mL를 넣은 후 상온에서 교반하였다. 그런 다음, 키랄 양기능 유기촉매(화학식 1) 1 mol%를 넣고 플라스크 주변을 0로 맞추어 주었다. 15 분 후에 톨루엔 0.05 mL에 녹인 터셔리-부틸 아조디카복실레이트(화학식 4) 0.075 mmol을 천천히 적가하였다. 반응 혼합물을 -20에서 2 시간 동안 교반하였다. 반응이 완료되면 용매를 감압 농축하여 컬럼크로마토그래피(SiO2, EA : Hex = 1 : 4)로 분리 정제하여 아민화 생성 물(화학식 6)을 93% 수율과 97% ee(enatiomeric excess)로 생성물을 얻었다.0.05 mmol of 2-cyano-1-indanonone (Formula 2) was added to the flask, and 0.05 mL of toluene was added thereto, followed by stirring at room temperature. Then, 1 mol% of a chiral functional organic catalyst (Formula 1) was added, and the vicinity of the flask was adjusted to zero. After 15 minutes, 0.075 mmol of tert-butyl azodicarboxylate (Formula 4) dissolved in 0.05 mL of toluene was slowly added dropwise. The reaction mixture was stirred at -20 for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, purified by column chromatography (SiO 2 , EA: Hex = 1: 4), and the amination product (Formula 6) was produced in 93% yield and 97% ee (enatiomeric excess). Got.

[a]21 D -22.5 (c 1.38, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3)δ = 7.90-7.86 (d, J = 8Hz, 1H), 7.82-7.70 (t, J = 8.1Hz, 1H), 7.56-7.43 (m, 2H), 7.09-7.01 (s, 1H), 4.07-3.87 (q, J = 10Hz, 2H), 1.62-1.22 (m, 18H); 13C NMR (50 MHz, CDCl3)δ = 192.0, 155.5, 149.3, 136.9, 136.6, 132.2, 128.6, 126.5, 123.8, 115.6, 83.0, 82.6, 68.4, 40.0, 28.2, 27.8; MS (MSI): m/z 387 [M+], 356(10), 332(70), 275(32), 232(8), 213(12), 188(7.5), 158(8); HPLC (Hexane-i-PrOH, 80:20, 254nm, 1.0 mL/min, Chiralpak AD column): t R = 5.8 min (minor), t R = 7.7 min (major).[a] 21 D -22.5 (c 1.38, CHCl 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.90-7.86 (d, J = 8 Hz, 1H), 7.82-7.70 (t, J = 8.1 Hz, 1H), 7.56-7.43 (m, 2H), 7.09- 7.01 (s, 1 H), 4.07-3.87 (q, J = 10 Hz, 2H), 1.62-1.22 (m, 18H); 13 C NMR (50 MHz, CDCl 3 ) δ = 192.0, 155.5, 149.3, 136.9, 136.6, 132.2, 128.6, 126.5, 123.8, 115.6, 83.0, 82.6, 68.4, 40.0, 28.2, 27.8; MS (MSI): m / z 387 [M + ], 356 (10), 332 (70), 275 (32), 232 (8), 213 (12), 188 (7.5), 158 (8); HPLC (Hexane- i -PrOH, 80:20, 254 nm, 1.0 mL / min, Chiralpak AD column): t R = 5.8 min (minor), t R = 7.7 min (major).

[실시예 2-15] Example 2-15

촉매량과 반응온도를 변화시킨 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 2-시아노-1-인다논의 아민화 생성물을 합성하였다. 구체적인 반응조건 및 수율 등은 하기 표 1에 나타내었다. Amination products of 2-cyano-1-indanon were synthesized in the same manner as in Example 1, except that the catalyst amount and the reaction temperature were changed. Specific reaction conditions and yields are shown in Table 1 below.

온도(℃)Temperature (℃) 촉매량 (몰%)Catalyst amount (mol%) 시간 (분)Time (min) 수득률 (%)Yield (%) 대장체 과량 (%)Colonic Excess (%) 실시예 2Example 2 rtrt 2020 10 10 9595 92 92 실시예 3Example 3 rtrt 1010 1010 9393 94 94 실시예 4Example 4 rtrt 55 1010 9494 93 93 실시예 5Example 5 rtrt 1One 1010 9393 93 93 실시예 6Example 6 rt rt 1One 1010 9393 92 92 실시예 7Example 7 rtrt 0.50.5 30 30 9292 91 91 실시예 8Example 8 rtrt 0.20.2 3030 9393 9191 실시예 9Example 9 00 1One 120120 9393 96 96 실시예 10Example 10 00 1One 9090 9292 95 95 실시예 11Example 11 0 0 1010 3030 9494 95 95 실시예 12Example 12 -20-20 1010 30 30 9595 9797 실시예 13Example 13 -20-20 1One 120120 9595 9696 실시예 14Example 14 -60-60 1010 30 30 9292 9797 실시예 15Example 15 -60-60 1One 240240 9595 9797

*표 1에서 rt는 room temperature임.* Rt in room 1 is room temperature.

[실시예 16] 2-아미네이티드-2-시아노-5-메톡시-1-인단온Example 16 2-Amineated-2-Cyano-5-methoxy-1-indanone

2-시아노-1-인다논 대신에 2-시아노-5-메톡시-1-인단온을 사용하고 촉매량(10 몰%)과 온도(-78)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-시아노-5-메톡시-1인다논을 92 %수율과 97% ee로 합성하였다.Except for using 2-cyano-5-methoxy-1-indanone instead of 2-cyano-1-indanonone and varying the amount of catalyst (10 mol%) and temperature (-78) differently 2-Amineated-2-cyano-5-methoxy-1indanon was synthesized in the same manner as in Example 1 in 92% yield and 97% ee.

[α]24 D -53.8 (c = 1.0, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3)δ = 7.8 (d, J = 8.7 Hz, 1H), 7.01-6.94 (m, 3H), 4.02-3.77 (m, 5H), 1.57-1.47 (m, 9H), 1.37-1.24 (m, 9H), 13C NMR (50 MHz, CDCl3)δ = 189.6, 166.6, 155.5, 152.3, 127.6, 125.1, 116.5, 115.8, 109.6, 84.0, 82.4, 68.7, 55.8, 40.0 (d, J = 48.2 Hz), 28, 27.7; HPLC (Hexane-i-PrOH, 90:10, 220nm, 1.0 mL/min, Chiralcel OD-H column): t R = 5.87 min (major), t R = 9.15 min (minor).[α] 24 D -53.8 (c = 1.0, CHCl 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.8 (d, J = 8.7 Hz, 1H), 7.01-6.94 (m, 3H), 4.02-3.77 (m, 5H), 1.57-1.47 (m, 9H) , 1.37-1.24 (m, 9H), 13 C NMR (50 MHz, CDCl 3 ) δ = 189.6, 166.6, 155.5, 152.3, 127.6, 125.1, 116.5, 115.8, 109.6, 84.0, 82.4, 68.7, 55.8, 40.0 ( d, J = 48.2 Hz), 28, 27.7; HPLC (Hexane- i -PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 5.87 min (major), t R = 9.15 min (minor).

[실시예 17] 2-아미네이티드-2-시아노-5,6-메톡시-1-인단온Example 17 2-Amineated-2-Cyano-5,6-methoxy-1-indanone

2-시아노-1-인다논 대신에 2-시아노-5-메톡시-1-인단온을 사용하고 촉매량(10 몰%)과 온도(-78)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-시아노-5,6-메톡시-1-인단온을 95% 수율과 98% ee로 합성하였다. Except for using 2-cyano-5-methoxy-1-indanone instead of 2-cyano-1-indanonone and varying the amount of catalyst (10 mol%) and temperature (-78) differently 2-Amineated-2-cyano-5,6-methoxy-1-indanone was synthesized in the same manner as in Example 1 in 95% yield and 98% ee.

[α]24 D -108.2 (c = 0.5, CHCl3, 98% ee); 1H NMR (200 MHz, CDCl3)δ = 7.28 (s, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 4.0-43.75 (m, 8H), 1.59-1.54 (m, 9H), 1.34-1.27 (m, 9H), 13C NMR (50 MHz, CDCl3)δ = 191.5, 157, 155.4, 150.2, 145, 124, 115.9, 107.1, 105.7, 83.9, 82.4, 68.8, 56.4, 56.1, 40.1 (d, J = 52.6 Hz), 28.1, 27.8; HPLC (Hexane-i-PrOH, 90:10, 220nm, 1.0 mL/min, Chiralcel OD-H column): t R = 7.5 min (major), t R = 14.4 min (minor).[a] 24 D -108.2 (c = 0.5, CHCl 3 , 98% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.28 (s, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 4.0-43.75 (m, 8H), 1.59-1.54 (m, 9H) , 1.34-1.27 (m, 9H), 13 C NMR (50 MHz, CDCl 3 ) δ = 191.5, 157, 155.4, 150.2, 145, 124, 115.9, 107.1, 105.7, 83.9, 82.4, 68.8, 56.4, 56.1, 40.1 (d, J = 52.6 Hz), 28.1, 27.8; HPLC (Hexane- i -PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 7.5 min (major), t R = 14.4 min (minor).

[실시예 18] 2-아미네이티드-2-시아노-1-테트라론Example 18 2-Amineated-2-Cyano-1-tetraron

2-시아노-1-인다논 대신에 2-시아노-1-테트라론을 사용하고 온도(-78)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-시아노-1-테트라론을 94% 수율과 99% ee로 합성하였다. 2-amined-in the same manner as in Example 1, except that 2-cyano-1-tetrarone was used instead of 2-cyano-1-indanon and the temperature (-78) was changed differently. 2-cyano-1-tetraron was synthesized in 94% yield and 99% ee.

1H NMR (200 MHz, CDCl3)δ = 7.56-7.13(m, 4H), 6.81-6.55(br m, 1H), 3.1-2.65(m, 2H), 2.61-1.77(m, 4H), 1.49-1.41(m, 18H); 13C NMR (50 MHz, CDCl3)δ = 197.7, 196.9, 196.3, 155.3, 153.4, 137.3, 131, 129, 128, 126, 116.6, 84.0, 83.4, 81.9, 69.1, 35.4, 34:.1, 28.0, 23.7; HPLC (Hexane-i-PrOH, 97:3, 254nm, 1.0 mL/min, Chiralpak AS column): t R = 7.63 min (major), t R = 10.15 min (minor). 1 H NMR (200 MHz, CDCl 3 ) δ = 7.56-7.13 (m, 4H), 6.81-6.55 (br m, 1H), 3.1-2.65 (m, 2H), 2.61-1.77 (m, 4H), 1.49 -1.41 (m, 18 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 197.7, 196.9, 196.3, 155.3, 153.4, 137.3, 131, 129, 128, 126, 116.6, 84.0, 83.4, 81.9, 69.1, 35.4, 34: .1, 28.0 , 23.7; HPLC (Hexane- i -PrOH, 97: 3, 254nm, 1.0 mL / min, Chiralpak AS column): t R = 7.63 min (major), t R = 10.15 min (minor).

[실시예 19] 2-아미네이티드-2-시아노-6-메톡시-1-테트라론Example 19 2-Amineated-2-Cyano-6-methoxy-1-tetraron

2-시아노-1-인다논 대신에 2-시아노-6-메톡시-1-테트라론을 사용하고 촉매량(10 몰%)과 온도(-78)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-시아노-6-메톡시-1-테트라론을 94% 수율과 99% ee로 합성하였다. Except for using 2-cyano-6-methoxy-1-tetraron instead of 2-cyano-1-indanon and changing the amount of catalyst (10 mol%) and temperature (-78) differently 2-Cyano-6-methoxy-1-tetraron was synthesized in the same manner as in Example 1 in 94% yield and 99% ee.

[α]21 D +0.0128 (c 1.0, CHCl3 , 99% ee); 1H NMR (200 MHz, CDCl3)δ = 8.08-7.92 (dd, J = 8.8 Hz, 1H), 6.89-6.85 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 7.05-6.49(br m, 1H), 3.86 (s, 3H), 3.47-2.5 (m, 4H), 1.51-1.37 (m, 18H); 13C NMR (50 MHz, CDCl3)δ = 184.6, 183.7, 164.6, 155.4, 152.8, 145.3, 131.7, 123.3, 114.3, 112.5, 84.0, 83.6, 82.9 69.7, 65.3, 55.6, 32.2, 28.1, 27.0, 26.0; HPLC (Hexane/i-PrOH=97/3, 254nm, 1.0 mL/min, CHIRALPAK OD-H column): t R = 12.3 min (major), t R = 14.9 min (minor).[α] 21 D +0.0128 (c 1.0, CHCl 3 , 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.08-7.92 (dd, J = 8.8 Hz, 1H), 6.89-6.85 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 7.05-6.49 (br m, 1 H), 3.86 (s, 3 H), 3.47-2.5 (m, 4 H), 1.51-1.37 (m, 18 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 184.6, 183.7, 164.6, 155.4, 152.8, 145.3, 131.7, 123.3, 114.3, 112.5, 84.0, 83.6, 82.9 69.7, 65.3, 55.6, 32.2, 28.1, 27.0, 26.0 ; HPLC (Hexane / i -PrOH = 97/3, 254nm, 1.0 mL / min, CHIRALPAK OD-H column): t R = 12.3 min (major), t R = 14.9 min (minor).

[실시예 20] 2-아미네이티드-2-시아노-1-벤조수베론Example 20 2-Amineated-2-Cyano-1-benzosuberon

2-시아노-1-인다논 대신에 2-시아노-1-벤조수베론을 사용하고 촉매량(10 몰%)과 온도(-30)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-시아노-1-벤조수베론을 77% 수율과 99% ee로 합성하였다. Same as Example 1, except that 2-cyano-1-benzosuberon was used instead of 2-cyano-1-indanonone and the amount of catalyst (10 mol%) and the temperature (-30) were changed differently. 2-cyano-1-benzosuberon was synthesized by the method in 77% yield and 99% ee.

1H NMR (200 MHz, CDCl3)δ = 7.56-7.13(m, 4H), 6.81-6.55(br m, 1H), 3.1-2.65(m, 2H), 2.61-1.77(m, 4H), 1.49-1.41(m, 18H); 13C NMR (50 MHz, CDCl3)δ = 197.7, 196.9, 196.3, 155.3, 153.4, 137.3, 131, 129, 128, 126, 116.6, 84.0, 83.4, 81.9, 69.1, 35.4, 34.1, 28.0, 23.7; HPLC (Hexane-i-PrOH, 97:3, 254nm, 1.0 mL/min, Chiralpak AS column): t R = 7.63 min (major), t R = 10.15 min (minor). 1 H NMR (200 MHz, CDCl 3 ) δ = 7.56-7.13 (m, 4H), 6.81-6.55 (br m, 1H), 3.1-2.65 (m, 2H), 2.61-1.77 (m, 4H), 1.49 -1.41 (m, 18 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 197.7, 196.9, 196.3, 155.3, 153.4, 137.3, 131, 129, 128, 126, 116.6, 84.0, 83.4, 81.9, 69.1, 35.4, 34.1, 28.0, 23.7; HPLC (Hexane- i -PrOH, 97: 3, 254nm, 1.0 mL / min, Chiralpak AS column): t R = 7.63 min (major), t R = 10.15 min (minor).

[실시예 21] 2-아미네이티드-2-시아노사이클로펜탄온Example 21 2-Amineated-2-Cyanocyclopentanone

2-시아노-1-인다논 대신에 2-시아노사이클로펜탄온을 사용하고 촉매량(10 몰%)과 온도(-78 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-시아노사이클로펜탄온을 94% 수율과 95% ee로 합성하였다. In the same manner as in Example 1, except that 2-cyanocyclopentanone was used instead of 2-cyano-1-indanon and the amount of catalyst (10 mol%) and the temperature (-78 degrees) were changed differently. 2-Amineated-2-cyanocyclopentanone was synthesized in 94% yield and 95% ee.

1H NMR (200 MHz, CDCl3)δ = 6.78 (s, 1H), 2.72-2.58 (m, 2H), 2.51-2.42 (m, 1H), 2.38-2.22 (m, 1H), 2.19-1.81 (m, 2H), 1.49-1.37 (d, J = 24.6 Hz, 18H); 13C NMR (50 MHz, CDCl3)δ = 202.4, 153.3, 153.0, 115.1, 84.0, 82.5, 69.3, 34.9, 34.0, 28.2, 28.0, 18,7; MS (MSI): M/z = 339 [M+], 308(6), 295(6), 283(12), 263(4), 228(28), 184(4); HPLC (Hexane-i-PrOH, 90:10, 220nm, 1.0 mL/min, Chiralpak AD column): t R = 7.38 min (minor), t R = 9.93 min (major). 1 H NMR (200 MHz, CDCl 3 ) δ = 6.78 (s, 1H), 2.72-2.58 (m, 2H), 2.51-2.42 (m, 1H), 2.38-2.22 (m, 1H), 2.19-1.81 ( m, 2H), 1.49-1.37 (d, J = 24.6 Hz, 18H); 13 C NMR (50 MHz, CDCl 3 ) δ = 202.4, 153.3, 153.0, 115.1, 84.0, 82.5, 69.3, 34.9, 34.0, 28.2, 28.0, 18,7; MS (MSI): M / z = 339 [M + ], 308 (6), 295 (6), 283 (12), 263 (4), 228 (28), 184 (4); HPLC (Hexane- i -PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralpak AD column): t R = 7.38 min (minor), t R = 9.93 min (major).

[실시예 22] 2-아미네이티드-2-시아노사이클로헥산온Example 22 2-Amineated-2-Cyanocyclohexanone

2-시아노-1-인다논 대신에 2-시아노사이클로헥산온을 사용하고 촉매량(10 몰%)과 온도(상온)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-시아노사이클로헥산온을 95% 수율과 94% ee로 합성하였다. 2-cyanocyclohexanone was used instead of 2-cyano-1-indanon and the same method as in Example 1 except that the amount of catalyst (10 mol%) and the temperature (room temperature) were changed differently. Aminated-2-cyanocyclohexanone was synthesized in 95% yield and 94% ee.

[α]24 D -15.2 (c 1.13, CHCl3 , 94% ee); 1H NMR (200 MHz, CDCl3)δ = 6.83-5.59 (brm, 1H), 3.15-2.70 (m, 1H), 2.69-2.40 (m, 2H), 2.39-2.05 (m, 2H), 2.04-1.79 (m, 3H), 1.52- 1.46 (s, 18H); 13C NMR (50 MHz, CDCl3)δ = 199.5, 155.4, 154.4, 116,4, 84.6, 82.3, 67.9, 38.1, 37.2, 28.7, 27.9, 21.1, 19.5; MS (MSI): M/z = 353 [M+], 337(12), 298(85), 291(4), 241(29), 199(5), 170(3); HPLC (Hexane-i-PrOH, 90:10, 216nm, 1.0 mL/min, (S,S)whelk-01 column): t R = 15.8 min (major), t R = 18.9 min (minor).[α] 24 D -15.2 (c 1.13, CHCl 3 , 94% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 6.83-5.59 (brm, 1H), 3.15-2.70 (m, 1H), 2.69-2.40 (m, 2H), 2.39-2.05 (m, 2H), 2.04- 1.79 (m, 3 H), 1.52- 1.46 (s, 18 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 199.5, 155.4, 154.4, 116,4, 84.6, 82.3, 67.9, 38.1, 37.2, 28.7, 27.9, 21.1, 19.5; MS (MSI): M / z = 353 [M + ], 337 (12), 298 (85), 291 (4), 241 (29), 199 (5), 170 (3); HPLC (Hexane- i -PrOH, 90:10, 216 nm, 1.0 mL / min, (S, S) whelk-01 column): t R = 15.8 min (major), t R = 18.9 min (minor).

[실시예 23] 2-아미네이티드-3-옥소-2,3-다이페닐-프로피오나이트릴Example 23 2-Amineated-3-oxo-2,3-diphenyl-propionitrile

2-시아노-1-인다논 대신에 3옥소2,3다이페닐프로피오나이트릴을 사용하고 촉매량(10 몰%)과 온도(-30 도)를 다르게 변화시킨 것을 제외하고는 실시예 1과 동일한 방법으로 2-아미네이티드-3-옥소-2,3-다이페닐-프로피오나이트릴을 94% 수율과 94% ee로 합성하였다. Same as Example 1 except for using 3-oxo2,3-diphenylpropionitrile instead of 2-cyano-1-indanon and changing the amount of catalyst (10 mol%) and the temperature (-30 degrees) differently. 2-amine-3-oxo-2,3-diphenyl-propionitrile was synthesized in 94% yield and 94% ee by the method.

[α]23 D -112 (c = 1.7, CHCl3, 94% ee); 1H NMR (200 MHz, CDCl3)δ = 7.9-7.71 (m, 2H), 7.69-7.56 (m, 2H), 7.55-7.36 (m, 4H), 7.35-7.27 (m, 2H), 6.37 (brm, 1H), 1.54-1.21 (m, 18H), 13C NMR (50 MHz, CDCl3)δ =188.9, 154.2, 133.6, 133.3, 130.6, 130.2, 129.8, 129.7, 129.5, 129.2, 128.9, 128.3, 117.4, 84.3, 82.5, 81.2, 27.9, 27.8; MS (MSI): M/z = 451 [M+], 408(4), 396(26), 352(20), 325(30), 295(28). 252(3), 225(14); HPLC (Hexane-i-PrOH, 98:2, 254nm, 1.0 mL/min, Chiralcel OD-H column): t R = 9.97 min (major), t R = 12.2 min (minor).[α] 23 D -112 (c = 1.7, CHC1 3 , 94% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.9-7.71 (m, 2H), 7.69-7.56 (m, 2H), 7.55-7.36 (m, 4H), 7.35-7.27 (m, 2H), 6.37 ( brm, 1H), 1.54-1.21 (m, 18H), 13 C NMR (50 MHz, CDCl 3 ) δ = 188.9, 154.2, 133.6, 133.3, 130.6, 130.2, 129.8, 129.7, 129.5, 129.2, 128.9, 128.3, 117.4, 84.3, 82.5, 81.2, 27.9, 27.8; MS (MSI): M / z = 451 [M + ], 408 (4), 396 (26), 352 (20), 325 (30), 295 (28). 252 (3), 225 (14); HPLC (Hexane- i -PrOH, 98: 2, 254nm, 1.0 mL / min, Chiralcel OD-H column): t R = 9.97 min (major), t R = 12.2 min (minor).

[실시예 24] 2-아미네이티드-2-벤조일-2-나프탈렌아세토나이트릴Example 24 2-Amineated-2-benzoyl-2-naphthaleneacetonitrile

2-시아노-1-인다논 대신에 2-벤조일-2-나프탈렌아세토나이트릴을 사용하고 촉매량(10 몰%)과 온도(-78 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-벤조일-2-나프탈렌아세토나이트릴을 94% 수율과 93% ee로 합성하였다. Example 1 except that 2-benzoyl-2-naphthaleneacetonitrile was used in place of 2-cyano-1-indanon and the amount of catalyst (10 mol%) and temperature (-78 degrees) were changed differently. In the same manner, 2-amined-2-benzoyl-2-naphthaleneacetonitrile was synthesized in 94% yield and 93% ee.

[α]23 D -121.9(c = 1.2, CHCl3, 93% ee); 1H NMR (200 MHz, CDCl3)δ = 8.22 (s, 1H), 7.92-7.77 (m, 5H), 7.62-7347 (m, 4H), 7.38-7.34 (m, 2H), 6.22-5.9 (brm, 1H), 1.51-1.17 (m, 18H) HPLC (Hexane-i-PrOH, 90:10, 220nm, 1.0 mL/min, Chiralcel OD-H column): t R = 5.47 min (major), t R = 6.65 min (minor).[α] 23 D -121.9 (c = 1.2, CHCl 3 , 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.22 (s, 1H), 7.92-7.77 (m, 5H), 7.62-7347 (m, 4H), 7.38-7.34 (m, 2H), 6.22-5.9 ( brm, 1H), 1.51-1.17 (m, 18H) HPLC (Hexane- i -PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 5.47 min (major), t R = 6.65 min (minor).

[실시예 25] 2-아미네이티드-3-옥소-2-(4-메톡시페닐)-3-페닐-프로피오나이트릴Example 25 2-Amineated-3-oxo-2- (4-methoxyphenyl) -3-phenyl-propionitrile

2-시아노-1-인다논 대신에 3-옥소-2-(4-메톡시페닐)-3-페닐-프로피오나이트릴 을 사용하고 촉매량(10 몰%)과 온도(-78 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-3-옥소-2-(4-메톡시페닐)-3-페닐-프로피오나이트릴을 93% 수율과 99% ee로 합성하였다. 3-oxo-2- (4-methoxyphenyl) -3-phenyl-propionitrile is used instead of 2-cyano-1-indanon and the amount of catalyst (10 mol%) and temperature (-78 degrees) are different. Except for the change, 2-amined-3-oxo-2- (4-methoxyphenyl) -3-phenyl-propionitrile was prepared in 93% yield and 99% ee in the same manner as in Example 1. Synthesized.

[α]20 D -0.1524 (c 1.0, CHCl3 , 91% ee); 1H NMR (200 MHz, CDCl3)δ = 7.82-7.73 (dd, J = 26.2, 3.8 Hz, 2H), 7.55-7.49 (m, J = 5.21 Hz, 3H), 7.40-7.329 (t, J = 4.6 Hz, 2H), 6.92-6.84 (d, J = 13.6 Hz, 2H), 6.21-5.87 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 1.48-1.29 (m, 18H); 13C NMR (50 MHz, CDCl3)δ = 186.3, 152.9, 142.7, 134.8, 129.3, 129.0, 128.9, 127.5, 127.35, 114.3, 84.4, 83.9, 82.3, 32.4, 28.2, 28.0, 26.6; HPLC (Hexane-i-PrOH, 97:3, 254nm, 1.0 mL/min, Chiralpak OD-H column): t R = 7.9 min (major), t R = 10.4 min (minor).[α] 20 D -0.1524 (c 1.0, CHCl 3 , 91% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.82-7.73 (dd, J = 26.2, 3.8 Hz, 2H), 7.55-7.49 (m, J = 5.21 Hz, 3H), 7.40-7.329 (t, J = 4.6 Hz, 2H), 6.92-6.84 (d, J = 13.6 Hz, 2H), 6.21-5.87 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 1.48-1.29 (m, 18H); 13 C NMR (50 MHz, CDCl 3 ) δ = 186.3, 152.9, 142.7, 134.8, 129.3, 129.0, 128.9, 127.5, 127.35, 114.3, 84.4, 83.9, 82.3, 32.4, 28.2, 28.0, 26.6; HPLC (Hexane- i -PrOH, 97: 3, 254 nm, 1.0 mL / min, Chiralpak OD-H column): t R = 7.9 min (major), t R = 10.4 min (minor).

[실시예 26] 2-아미네이티드-베타-옥소-알파-2-프로페닐 벤젠프로판나이트릴Example 26 2-Amineated-Beta-oxo-alpha-2-propenyl benzenepropanenitrile

2-시아노-1-인다논 대신에 베타-옥소-알파-2-프로페닐 벤젠프로판나이트릴을 사용하고 촉매량(10 몰%)과 온도(-78 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-베타-옥소-알파-2-프로페닐 벤젠프로판나이트릴을 92% 수율과 87% ee로 합성하였다. Except using beta-oxo-alpha-2-propenyl benzenepropanenitrile instead of 2-cyano-1-indanonone and varying the amount of catalyst (10 mol%) and the temperature (-78 degrees) differently, 2-Amineated-beta-oxo-alpha-2-propenyl benzenepropanenitrile was synthesized in the same manner as in Example 1 in 92% yield and 87% ee.

1H NMR (200 MHz, CDCl3)δ = 8.36-8.69 (brs, 1H), 8.68-7.81 (brm, 1H), 7.70-7.45 (m, 3H), 6.7-6.56 (brm, 1H), 6.01-5.57 (m, 1H), 5.3-5.07 (m, 2H), 3.25-2.82 (m, 2H), 1.65-1.18 (m, 18); 13C NMR (50 MHz, CDCl3)δ = 187.2, 155.8, 153.9, 133.6, 129.5, 128.9, 128.7, 128.6, 121.6, 116.7, 82.4, 74.7, 40.4, 28.2, 27.7; HPLC (Hexane-i-PrOH, 80:20, 254nm, 1.0 mL/min, Chiralpak AD-H column): t R = 16.7 min (major), t R = 8.9 min (minor). 1 H NMR (200 MHz, CDCl 3 ) δ = 8.36-8.69 (brs, 1H), 8.68-7.81 (brm, 1H), 7.70-7.45 (m, 3H), 6.7-6.56 (brm, 1H), 6.01- 5.57 (m, 1H), 5.3-5.07 (m, 2H), 3.25-2.82 (m, 2H), 1.65-1.18 (m, 18); 13 C NMR (50 MHz, CDCl 3 ) δ = 187.2, 155.8, 153.9, 133.6, 129.5, 128.9, 128.7, 128.6, 121.6, 116.7, 82.4, 74.7, 40.4, 28.2, 27.7; HPLC (Hexane- i -PrOH, 80:20, 254 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 16.7 min (major), t R = 8.9 min (minor).

[실시예 27] 2-아미네이트-2-페닐-아세토아세토나이트릴Example 27 2-Aminoate-2-phenyl-acetoacetonitrile

2-시아노-1-인다논 대신에 2-페닐-아세토아세토나이트릴을 사용하고 촉매량(10 몰%)과 온도(-78 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-2-페닐-아세토아세토나이트릴을 45% 수율과 96% ee로 합성하였다. The same method as in Example 1, except that 2-phenyl-acetoacetonitrile was used instead of 2-cyano-1-indanon and the amount of catalyst (10 mol%) and the temperature (-78 degrees) were changed differently. 2-amine-2-phenyl-acetoacetonitrile was synthesized in 45% yield and 96% ee.

1H NMR (200 MHz, CDCl3)δ = 7.74-7.53 (m, 2H), 7.45-7.42 (m, 3H), 6.18-5.86 (d, J 64 Hz, 1H), 2.42-2.37 (d, 3H), 1.62-1.30 (m, 18H); 13C NMR (50 MHz, CDCl3)δ = 186.3, 152.9, 142.7, 134.8, 129.3, 129.0, 128.9, 127.5, 127.35, 114.3, 84.4, 83.9, 82.3, 32.4, 28.2, 28.0, 26.6; HPLC (Hexane : i-PrOH, 95 : 5, 254nm, 1.0 mL/min, Chiralpak OD-H column): t R = 5.31 min (major), t R = 4.86 min (minor). 1 H NMR (200 MHz, CDCl 3 ) δ = 7.74-7.53 (m, 2H), 7.45-7.42 (m, 3H), 6.18-5.86 (d, J 64 Hz, 1H), 2.42-2.37 (d, 3H ), 1.62-1.30 (m, 18 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 186.3, 152.9, 142.7, 134.8, 129.3, 129.0, 128.9, 127.5, 127.35, 114.3, 84.4, 83.9, 82.3, 32.4, 28.2, 28.0, 26.6; HPLC (Hexane: i -PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralpak OD-H column): t R = 5.31 min (major), t R = 4.86 min (minor).

[실시예 28] 2-아미네이트-3-옥소-2-페닐-펜탄나이트릴Example 28 2-Aminoate-3-oxo-2-phenyl-pentanenitrile

2-시아노-1-인다논 대신에 3-옥소-2-페닐-펜탄나이트릴을 사용하고 촉매량(10 몰%)과 온도(-18 도)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-3-옥소-2-페닐-펜탄나이트릴을 93% 수율과 90% ee로 합성하였다. Example 1, except that 3-oxo-2-phenyl-pentanenitrile was used instead of 2-cyano-1-indanon and the catalyst amount (10 mol%) and the temperature (-18 degrees) were changed differently 2-Amineated-3-oxo-2-phenyl-pentanenitrile was synthesized in 93% yield and 90% ee in the same manner as

[α]24 D -68.3 (c = 1.04, CHCl3, 85% ee); 1H NMR (200 MHz, CDCl3)δ = 7.72-7.52 (m, 2H), 7.44-7.41 (m, 3H), 6.23-5.92 (brm, 1H), 3.14-3.01 (m, 1H), 2.76-2.49 (m, 1H), 1.52-0.98 (m, 18H) 13C NMR (50 MHz, CDCl3)δ = .(d, J = 25 Hz), 154.7, 154.2, 130.4, 130, 129.2, 129, 128.4, 127.4, 116.9, 84.1, 82.9, 81.5, 60.3, 31.8, 27.9, 7.8; HPLC (Hexane-i-PrOH, 90:10, 220nm, 1.0 mL/min, Chiralcel OD-H column): t R = 7.0 min (major), t R = 16.3 min (minor).[a] 24 D -68.3 (c = 1.04, CHC1 3 , 85% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.72-7.52 (m, 2H), 7.44-7.41 (m, 3H), 6.23-5.92 (brm, 1H), 3.14-3.01 (m, 1H), 2.76- 2.49 (m, 1H), 1.52-0.98 (m, 18H) 13 C NMR (50 MHz, CDCl 3 ) δ =. (D, J = 25 Hz), 154.7, 154.2, 130.4, 130, 129.2, 129, 128.4 , 127.4, 116.9, 84.1, 82.9, 81.5, 60.3, 31.8, 27.9, 7.8; HPLC (Hexane- i -PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 7.0 min (major), t R = 16.3 min (minor).

[실시예 29][Example 29]

플라스크에 2-옥소-1-인단온 카복실산 터셔리-부틸에스테르 0.2 mmol와 키랄 양기능 유기촉매 10 mol%를 넣고 톨루엔 0.4 mL를 넣은 후 상온에서 10 분간 교반하였다. 그런 다음, -70(또는 -30)로 냉각시키고, 톨루엔 0.3 mL에 녹인 터셔리-부틸 아조디카복실레이트 0.4 mmol을 5 분간 적가하였다. 반응 혼합물을 -70(또는 -30)에서 교반하였다. 0.2 mmol of 2-oxo-1-indanone carboxylic acid tertiary-butyl ester and 10 mol% of a chiral bifunctional organic catalyst were added to the flask, 0.4 mL of toluene was added thereto, and the mixture was stirred at room temperature for 10 minutes. Then, cooled to −70 (or −30) and 0.4 mmol of tert-butyl azodicarboxylate dissolved in 0.3 mL of toluene was added dropwise for 5 minutes. The reaction mixture was stirred at -70 (or -30).

반응이 완료되면 반응물을 상온으로 올린 뒤 용매를 감압 농축하여 컬럼 크로마토그래피(SiO2, EA : Hex = 1 : 5)로 분리 정제하여 아민화 생성물을 93%수율, 99%ee로 얻었다. When the reaction was completed, the reaction product was raised to room temperature, the solvent was concentrated under reduced pressure, purified by column chromatography (SiO 2 , EA: Hex = 1: 5), and the amination product was obtained in 93% yield and 99% ee.

[α]24 D = -60.50 (c = 0.55, CHCl3 , 99% ee); 1H NMR (200 MHz, CDCl3) δ = 1.29 (s, 9H), 1.41 (s, 9H), 1.49 (s, 9H), 3.48-4.45 (m, 2H), 6.74 (br, 1H), 7.34 (t, J = 7.0 Hz, 1H), 7.53 (d, J = 6.2 Hz, 1H), 7.60 (t, J = 7.0 Hz, 1H), 7.75(m, 1H); 13C NMR (50 MHz, CDCl3) δ = 27.6, 28.0, 37.0, 78.6, 81.2, 82.6, 83.8, 124.8, 126.2, 127.4, 133.5, 135.3, 135.8, 154.5, 154.7, 167.0, 197.1; HPLC (90:10, Hexane : EtOH, 254 nm, 0.25 mL/min) Chiralpak AD-H, tR = 22 min (major), tR = 30 min (minor)[a] 24 D = -60.50 (c = 0.55, CHC1 3 , 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 1.29 (s, 9H), 1.41 (s, 9H), 1.49 (s, 9H), 3.48-4.45 (m, 2H), 6.74 (br, 1H), 7.34 (t, J = 7.0 Hz, 1H), 7.53 (d, J = 6.2 Hz, 1H), 7.60 (t, J = 7.0 Hz, 1H), 7.75 (m, 1H); 13 C NMR (50 MHz, CDCl 3 ) δ = 27.6, 28.0, 37.0, 78.6, 81.2, 82.6, 83.8, 124.8, 126.2, 127.4, 133.5, 135.3, 135.8, 154.5, 154.7, 167.0, 197.1; HPLC (90:10, Hexane: EtOH, 254 nm, 0.25 mL / min) Chiralpak AD-H, t R = 22 min (major), t R = 30 min (minor)

[실시예 30] 2-아미네이트-2-옥소-5-메톡시인단온 카복실산 터셔리-부틸에스테르Example 30 2-Aminoate-2-oxo-5-methoxyindanone carboxylic acid tertiary butyl ester

2-옥소-1-인단온 카복실산 터셔리-부틸에스테르 대신에 2-옥소-5-메톡시인단온 카복실산 터셔리-부틸에스테르을 사용하고 온도(-30)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이트-2-옥소-5-메톡시인단온 카복실산 터셔리-부틸에스테르를 95% 수율과 98% ee로 합성하였다. Example, except that 2-oxo-5-methoxyindanone carboxylic acid tertiary-butylester was used instead of 2-oxo-1-indanone carboxylic acid tertiary-butylester and the temperature (-30) was changed differently 2-Amimate-2-oxo-5-methoxyindanone carboxylic acid tert-butyl ester was synthesized in the same manner as in 1 in 95% yield and 98% ee.

[α]22 D = -93.24 (c = 1.80, CHCl3 , 97% ee); 1H NMR (200 MHz, CDCl3)δ = 1.24 (s, 9H), 1.42 (s, 9H), 1.49 (s, 9H), 3.52-4.19 (m, 2H), 3.87 (s, 1H), 6.86 (br, 1H), 6.90 (s, 1H), 7.61-7.65 (d, J = 7.6 Hz, 2H); 13C NMR (50 MHz, CDCl3)δ= 27.3, 27.6, 27.7, 34.4, 55.8, 81.4, 81.9, 82.7, 83.2, 108.6, 115.1, 115.4, 115.6, 126.2, 154.6, 157.3, 163.3, 165.4, 192.7; HPLC (90:10, Hexane : i-PrOH, 254 nm, 1.0 mL/min) (S,S)-Whelk-01, tR = 6.5 min (major), tR = 9.2 min (minor)[a] 22 D = -93.24 (c = 1.80, CHC1 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 1.24 (s, 9H), 1.42 (s, 9H), 1.49 (s, 9H), 3.52-4.19 (m, 2H), 3.87 (s, 1H), 6.86 (br, 1 H), 6.90 (s, 1 H), 7.61-7.65 (d, J = 7.6 Hz, 2H); 13 C NMR (50 MHz, CDCl 3 ) δ = 27.3, 27.6, 27.7, 34.4, 55.8, 81.4, 81.9, 82.7, 83.2, 108.6, 115.1, 115.4, 115.6, 126.2, 154.6, 157.3, 163.3, 165.4, 192.7; HPLC (90:10, Hexane: i -PrOH, 254 nm, 1.0 mL / min) (S, S) -Whelk-01, t R = 6.5 min (major), t R = 9.2 min (minor)

[실시예 31] 2-아미네이트-2-옥소-5-테트랄론 카복실산 터셔리-부틸에스테르Example 31 2-Aminoate-2-oxo-5-tetralon carboxylic acid tertiary butyl ester

2-옥소-1-인단온 카복실산 터셔리-부틸에스테르 대신에 2-옥소-5-테트랄론 카복실산 터셔리-부틸에스테르을 사용하고 온도(-70)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이티드-3-옥소-2-페닐-펜탄나이트릴을 85% 수율과 93% ee로 합성하였다. Example 1, except that 2-oxo-5-tetralon carboxylic acid tertiary-butylester was used instead of 2-oxo-1-indanone carboxylic acid tertiary-butylester and the temperature (-70) was changed differently 2-Amineated-3-oxo-2-phenyl-pentanenitrile was synthesized in 85% yield and 93% ee by the same method as described above.

[α]23 D = -20.37 (c = 0.85, CHCl3 , 93% ee); 1H NMR (200 MHz, CDCl3)δ = 1.10 (s, 9H), 1.39 (s, 9H), 1.43 (s, 9H), 2.44-2.55 (m, 1H), 2.80-2,89 (m, 2H), 2.80-3.29 (m, 1H), 6.21 (br, 1H), 7.09-7.22 (m, 2H), 7.26-7.48 (m, 1H), 7.75-7.98 (m, 1H); 13C NMR (50 MHz, CDCl3)δ = 25.4, 25.7, 27.3, 27.7, 27.9, 80.4, 80.7, 82.4, 83.0, 126.3, 127.4, 128.4, 131.8, 133.1, 144.4, 154.0, 155.3, 167.6, 191.3; HPLC (90:10, Hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H, tR = 5.4 min (minor), tR = 7.9 min (major)[a] 23 D = -20.37 (c = 0.85, CHC1 3 , 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 1.10 (s, 9H), 1.39 (s, 9H), 1.43 (s, 9H), 2.44-2.55 (m, 1H), 2.80-2,89 (m, 2H), 2.80-3.29 (m, 1H), 6.21 (br, 1H), 7.09-7.22 (m, 2H), 7.26-7.48 (m, 1H), 7.75-7.98 (m, 1H); 13 C NMR (50 MHz, CDCl 3 ) δ = 25.4, 25.7, 27.3, 27.7, 27.9, 80.4, 80.7, 82.4, 83.0, 126.3, 127.4, 128.4, 131.8, 133.1, 144.4, 154.0, 155.3, 167.6, 191.3; HPLC (90:10, Hexane: i -PrOH, 254 nm, 1.0 mL / min) Chiralpak AD-H, t R = 5.4 min (minor), t R = 7.9 min (major)

[실시예 32] 2-아미네이트-2,3-디히드로-2-옥소-1-인덴-카복실산터셔리-부틸에스테르 Example 32 2-Aminoate-2,3-dihydro-2-oxo-1-indene-carboxylic acid tert-butyl ester

2-옥소-1-인단온 카복실산 터셔리-부틸에스테르 대신에 2,3-디히드로-2-옥소-1-인덴-카복실산 터셔리-부틸에스테르를 사용하고 온도(-30)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이트-2,3-디히드로-2-옥소-1-인덴-카복실산 터셔리-부틸에스테르를 92% 수율과 93% ee로 합성하였다. 2,3-dihydro-2-oxo-1-indene-carboxylic acid tert-butyl ester was used instead of 2-oxo-1-indanone carboxylic acid tert-butyl ester, and the temperature (-30) was changed differently. Except for the 2-amine-2,3-dihydro-2-oxo-1-indene-carboxylic acid tertiary butyl ester in the same manner as in Example 1 except that 92% yield and 93% ee.

1H NMR (200 MHz, CDCl3)δ = 0.98-1.80 (m, 27H), 3.43-3.85 (m, 2H), 7.10-7.45 (m, 4H); HPLC (90:10, Hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H, tR = 4.8 min (minor), tR = 7.8 min (major). 1 H NMR (200 MHz, CDCl 3 ) δ = 0.98-1.80 (m, 27H), 3.43-3.85 (m, 2H), 7.10-7.45 (m, 4H); HPLC (90:10, Hexane: i -PrOH, 254 nm, 1.0 mL / min) Chiralpak AD-H, t R = 4.8 min (minor), t R = 7.8 min (major).

[실시예 33] 2-아미네이트-2-옥소-사이클로펜탄카복실산 터셔리-부틸에스테르Example 33 2-Aminoate-2-oxo-cyclopentanecarboxylic acid tertiary butyl ester

2-옥소-1-인단온 카복실산 터셔리-부틸에스테르 대신에 2-옥소-사이클로펜탄카복실산 터셔리-부틸에스테르를 사용하고 온도(-30)를 다르게 변화시킨 것을 제외하고는, 실시예 1과 동일한 방법으로 2-아미네이트-2-옥소-사이클로펜탄카복실산 터셔리-부틸에스테르를 93% 수율과 97% ee로 합성하였다. Same as Example 1, except that 2-oxo-cyclopentanecarboxylic acid tertiary-butylester was used instead of 2-oxo-1-indanone carboxylic acid tertiary-butylester and the temperature (-30) was changed differently. 2-Aminoate-2-oxo-cyclopentanecarboxylic acid tertiary-butylester was synthesized by 93% yield and 97% ee by the method.

[α]25 D = -4.76 (c = 1.10, CH2Cl2 , 97% ee); 1H NMR (200 MHz, CDCl3)δ = 1.36-1.54 (m, 27H), 1.78-2.05 (m, 2H), 2.05-2.37 (m, 2H), 2.63 (m, 2H), 6.50 (br, 1H); 13C NMR (50 MHz, CDCl3)δ = 6.3, 18.6, 27.8, 28.0, 35.8, 79.6, 82.3, 82.5, 85.2, 154.5, 155.1, 167.1, 209.9; Rt HPLC (95:5, n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H, tR = 6.5 min (major), tR = 8.2 min (minor)[a] 25 D = -4.76 (c = 1.10, CH 2 Cl 2 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 1.36-1.54 (m, 27H), 1.78-2.05 (m, 2H), 2.05-2.37 (m, 2H), 2.63 (m, 2H), 6.50 (br, 1H); 13 C NMR (50 MHz, CDCl 3 ) δ = 6.3, 18.6, 27.8, 28.0, 35.8, 79.6, 82.3, 82.5, 85.2, 154.5, 155.1, 167.1, 209.9; R t HPLC (95: 5, n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H, t R = 6.5 min (major), t R = 8.2 min (minor)

Claims (9)

베타-케토에스테르 화합물을, 키랄 촉매의 존재하에서, 아조 화합물과 반응시켜 알파-아미노 카보닐 화합물을 제조하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법으로, 상기 베타-케토에스테르 화합물은 화학식 3으로 표현되는 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법.A method for preparing an alpha-amino carbonyl compound using a chiral catalyst which reacts a beta-ketoester compound with an azo compound in the presence of a chiral catalyst to produce an alpha-amino carbonyl compound, wherein the beta-ketoester compound is represented by the chemical formula Method for producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that 3. [화학식 3](3)
Figure 112011004085654-pat00013
Figure 112011004085654-pat00013
 상기 화학식 3에서, In Chemical Formula 3, 상기 R1 및 R2 는 C1-C40의 알킬기 또는 아릴기이고, 상호 동일하거나 상이하며, R1 및 R2 는 서로 연결되어 고리계의 일부를 형성할 수 있고, R 1 and R 2 may be an alkyl group or an aryl group of C 1 -C 40 , the same as or different from each other, R 1 and R 2 may be linked to each other to form a part of a ring system, 상기 R3 는 C1-C20의 알킬기이며, R 3 is an alkyl group of C 1 -C 20 , 상기 알킬기는 선형 또는 가지형 알킬기임.The alkyl group is a linear or branched alkyl group. 제 1 항에 있어서,The method of claim 1, 상기 키랄 촉매는, 티오우레아와 아민 그룹이 결합된 키랄 양기능 유기촉매인 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법.The chiral catalyst is a method for producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that a chiral bifunctional organic catalyst in which thiourea and an amine group are bonded. 제 1 항에 있어서,The method of claim 1, 상기 키랄 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 0.2 내지 20 몰%인 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법.The amount of the chiral catalyst is 0.2 to 20 mole%, based on the total moles of the reactants, a method for producing an alpha-amino carbonyl compound using a chiral catalyst. 제 1 항에 있어서,The method of claim 1, 상기 키랄 촉매는, 하기 화학식 1의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법:The chiral catalyst, the method of producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that having the structure of formula (1): [화학식 1][Formula 1]
Figure 112008091089021-pat00009
Figure 112008091089021-pat00009
 삭제delete 제 1 항에 있어서,The method of claim 1, 상기 아조 화합물은 하기 화학식 4의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법:Method for producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that the azo compound has the structure of formula (4): [화학식 4][Formula 4]
Figure 112008091089021-pat00012
Figure 112008091089021-pat00012
 상기 화학식 4에서, R4는 C1-C20의 선형 또는 가지형 알킬기임.In Chemical Formula 4, R 4 is a C 1 -C 20 linear or branched alkyl group. 제 1 항에 있어서,The method of claim 1, 상기 알파-아미노 카보닐 화합물은, 화학식 6의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법:The alpha-amino carbonyl compound has a structure of the formula (6), characterized in that for producing an alpha-amino carbonyl compound using a chiral catalyst: [화학식 6][Formula 6]
Figure 112011004085654-pat00014
Figure 112011004085654-pat00014
 상기 화학식 6에서, In Formula 6, 상기 R1 및 R2 는 C1-C40의 알킬기 또는 아릴기이고, 상호 동일하거나 상이하며, R1 및 R2 는 서로 연결되어 고리계의 일부를 형성할 수 있고, R 1 and R 2 may be an alkyl group or an aryl group of C 1 -C 40 , the same as or different from each other, R 1 and R 2 may be linked to each other to form a part of a ring system, 상기 R3 및 R4 는 C1-C20의 알킬기이며, R 3 and R 4 are C 1 -C 20 Alkyl group, 상기 알킬기는 선형 또는 가지형 알킬기임.The alkyl group is a linear or branched alkyl group. 제 1 항 또는 제 7 항에 있어서,The method according to claim 1 or 7, 상기 아릴기는 알콕시기로 치환된 아릴기인 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법.The aryl group is a method for producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that the aryl group substituted with an alkoxy group. 제 1 항 내지 제 4 항, 제 6 항 및 제 7 항 중 어느 한 항에 있어서,The method according to any one of claims 1 to 4, 6 and 7, 상기 R3 및 R4는 터셔리 부틸기인 것을 특징으로 하는 키랄 촉매를 이용한 알파-아미노 카보닐 화합물의 제조방법.R 3 and R 4 is a method for producing an alpha-amino carbonyl compound using a chiral catalyst, characterized in that the tertiary butyl group.
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