KR101082282B1 - Method for Preparation of Beta-Amino Carbonyl Compound Using Chiral Catalyst - Google Patents

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

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KR101082282B1
KR101082282B1 KR1020090054388A KR20090054388A KR101082282B1 KR 101082282 B1 KR101082282 B1 KR 101082282B1 KR 1020090054388 A KR1020090054388 A KR 1020090054388A KR 20090054388 A KR20090054388 A KR 20090054388A KR 101082282 B1 KR101082282 B1 KR 101082282B1
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김대영
심성보
강영구
이주희
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순천향대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C07D219/12—Amino-alkylamino radicals attached in position 9

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Abstract

알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매의 존재하에서, 이민과 반응시켜 베타-아미노 카보닐 화합물을 제조하는 방법이 개시된다. 상기 제조방법은, 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다.A method of preparing a beta-amino carbonyl compound is disclosed by reacting an alpha-cyanoketone or beta-ketoester compound with an imine 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, 이민, 광학활성, 베타-아미노 카보닐 화합물 Chiral catalysts, imines, optically active, beta-amino carbonyl compounds

Description

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

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

광학이성질체는 밀도, 녹는점, 끓는점 등 대부분의 물리적 성질이 동일하다. 그러나, 편광된 빛을 흡수하는 정도가 다르기 때문에 선형편광된 빛을 조사(照射)했을 때 편광면이 회전하게 되며, 이러한 현상을 광학활성이라고 한다. Optical isomers have almost the same physical properties, such as density, melting point, and boiling point. However, since the degree of absorption of polarized light is different, the polarization plane rotates when the linearly polarized light is irradiated. This phenomenon is called optical activity.

물질의 광학활성은 편광계를 사용하여 측정한다. 광학활성은 대칭 중심, 대칭면 또는 회전축 등의 대칭 요소를 갖지 못하는 분자에서 나타난다. 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 centers of symmetry, planes of symmetry, or axes of rotation. These molecules can exist as two isomers with enantiomers that change left and right and do not overlap each other, such as the left or right hand, and a molecule having this property is called a chiral compound.

키랄성 화합물은, 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 20 여 종의 아미노산 중, 글리신을 제외한 모든 아미노산은 비대칭탄소를 가진 키랄성 화합물이다. Chiral compounds are commonly found in carbon compounds having four asymmetric (chiral center) carbons, all of which are linked to carbon, or transition metal complexes having 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 베타-아미노 카보닐 화합물은, 생명과학적으로 이용이 되고 있는 베타-아미노산으로의 전환이 가능하기 때문에 많은 연구가 진행되고 있는 분야이다. 키랄 유기촉매를 이용한 베타-케토에스테르의 비대칭 만니히 반응은, 일부 알려져 있으나, 적용된 유도체 범위가 제한되어 있으며, 낮은 입체선택성을 나타내고 있다.In particular, the chiral beta-amino carbonyl compound is a field in which many studies are being conducted because conversion to beta-amino acid which is used in bioscience is possible. Asymmetric Mannich reactions of beta-ketoesters using chiral organic catalysts, although some are known, have a limited range of derivatives applied and exhibit low stereoselectivity.

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

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

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

본 발명의 일실시예에 따른 베타-아미노 카보닐 화합물의 제조방법은, 알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매(chiral catalyst)의 존재하에서, 이민 화합물과 반응시켜 베타-아미노 카보닐 화합물을 제조한다. 상기 제조방법은, 키랄 촉매를 이용하여, 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다.In the method for preparing a beta-amino carbonyl compound according to an embodiment of the present invention, an alpha-cyanoketone or beta-ketoester compound is reacted with an imine compound in the presence of a chiral catalyst to beta-amino Prepare a carbonyl compound. The above production method is for efficiently producing an optically active material having high optical purity by using a chiral catalyst.

또 다른 일실시예에서, 상기 키랄 촉매는, 유레아와 아민 그룹이 결합된 키랄 양기능 유기촉매, 또는 싸이오유레아와 아민 그룹이 결합된 양기능 유기촉매일 수 있다. 유레아와 아민 그룹이 결합된 키랄 양기능 유기촉매 또는 싸이오유레아 와 아민 그룹이 결합된 양기능 유기촉매를 이용하는 비대칭 아민화 반응은, 광학적으로 순수한 키랄 베타-아미노 카보닐 화합물을 고수율로 얻을 수 있는 매우 간편하고 유용한 반응이다.In another embodiment, the chiral catalyst may be a chiral bifunctional organic catalyst in which urea and amine groups are bonded, or a bifunctional organic catalyst in which thiourea and amine groups are combined. Asymmetric amination reactions using chiral bifunctional organic catalysts combined with urea and amine groups or bifunctional organic catalysts combined with thiourea and amine groups can yield optically pure chiral beta-amino carbonyl compounds in high yield. That is a very simple and useful reaction.

일실시예에서, 상기 키랄 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 5 내지 20 몰%, 구체적으로는 7 내지 15 몰%, 보다 구체적으로는 10 몰%이다. 상기 범위는, 광학 순도가 높은 베타-아미노 카보닐 화합물을 효율적으로 제조하기 위한 것이다. 키랄 촉매의 함량이 상기 범위보다 낮은 경우에는, 합성된 베타-아미노 카보닐 화합물의 광학 순도가 저하되고, 상기 범위보다 높은 경우에는, 촉매 첨가로 인한 효율성이 떨어질 수 있다.In one embodiment, the content of the chiral catalyst is 5 to 20 mol%, specifically 7 to 15 mol%, more specifically 10 mol%, based on the total moles of the reactants. The above range is for efficiently producing beta-amino carbonyl compounds having high optical purity. When the content of the chiral catalyst is lower than the above range, the optical purity of the synthesized beta-amino carbonyl compound is lowered, and when higher than the above range, the efficiency due to the addition of the catalyst may be lowered.

일실시예에서, 상기 키랄 촉매는, 하기 화학식 1의 구조를 갖는다.In one embodiment, the chiral catalyst, has a structure of formula (1).

Figure 112009036943413-pat00001
Figure 112009036943413-pat00001

상기 식에서, X는 O 또는 S이다.Wherein X is O or S.

또 다른 일실시예에서, 상기 알파-시아노케톤 화합물은 하기 화학식 2의 구조를 갖고, 베타-케토에스테르 화합물은 화학식 3의 구조를 갖는다. In another embodiment, the alpha-cyanoketone compound has a structure of Formula 2, and the beta-ketoester compound has a structure of Formula 3.

Figure 112009036943413-pat00002
Figure 112009036943413-pat00002

Figure 112009036943413-pat00003
Figure 112009036943413-pat00003

상기 화학식 2 또는 3에서, In Chemical Formula 2 or 3,

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 group, the same or different from each other, R 1 and R 2 may be connected to each other to form a part of the ring system,

상기 R3은 C1~C20의 알킬기이며, R 3 is a C 1 ~ C 20 Alkyl group,

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

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

Figure 112009036943413-pat00004
Figure 112009036943413-pat00004

상기 식에서,Where

R4는 아릴기, C1~C20인 알킬기, 알킬렌기 또는 알콕시 카보닐기이며,R 4 is an aryl group, C 1 -C 20 alkyl group, alkylene group or alkoxy carbonyl group,

R5는 아릴기, 헤테로 아로마틱, 포스피닐, 술포닐 또는 알콕시 카보닐기이다. R 5 is an aryl group, hetero aromatic, phosphinyl, sulfonyl or alkoxy carbonyl group.

일실시예에서, 상기 아릴기는 알콕시기, 알콕시 카보닐, 알킬 또는 할로겐으로 치환된 아릴기일 수 있다.In one embodiment, the aryl group may be an aryl group substituted with an alkoxy group, alkoxy carbonyl, alkyl or halogen.

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

Figure 112009036943413-pat00005
Figure 112009036943413-pat00005

Figure 112009036943413-pat00006
Figure 112009036943413-pat00006

상기 화학식 5 또는 6에서, In Chemical Formula 5 or 6,

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

R3는 C1~C20의 알킬기이며, R 3 is a C 1 ~ C 20 alkyl group,

상기 알킬기는 선형 또는 가지형 알킬기이고,The alkyl group is a linear or branched alkyl group,

R4는 아릴기, C1~C20의 알킬기, 알킬렌기 또는 알콕시 카보닐기이며, R 4 is an aryl group, a C 1 to C 20 alkyl group, an alkylene group or an alkoxy carbonyl group,

R5는 아릴기, 헤테로 아로마틱, 포스피닐, 술포닐 또는 알콕시 카보닐기 이다.R 5 is an aryl group, hetero aromatic, phosphinyl, sulfonyl or alkoxy carbonyl group.

일실시예에서, 상기 아릴기는 알콕시기, 알콕시 카보닐, 알킬 또는 할로겐으로 치환된 아릴기일 수 있다. In one embodiment, the aryl group may be an aryl group substituted with an alkoxy group, alkoxy carbonyl, alkyl or halogen.

이하, 본 발명의 일실시예에 따른 베타-아미노 카보닐 화합물의 제조방법에 대하여 보다 구체적으로 살펴본다. Hereinafter, a method of preparing the beta-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 112009036943413-pat00007
Figure 112009036943413-pat00007

상기 반응식 1을 통해 제조된 키랄 양기능 유기촉매를 이용하여, 반응물질에 대한 만니히 반응(Mannich reaction)을 유도함으로써, 베타-아미노 카보닐 화합물을 제조하게 된다. Using the chiral bifunctional organic catalyst prepared in Scheme 1, a Mannich reaction to the reactants is induced, thereby preparing a beta-amino carbonyl compound.

일실시예에서, 알파-시아노케톤(반응식 2의 1a)을 키랄 촉매의 존재하에서 이민 화합물과 반응시켜 베타-아미노 카보닐 화합물을 제조할 수 있다. 또 다른 일실시예에서, 베타-케토에스테르(반응식 2의 1b)를 키랄 촉매의 존재하에서 이민 화합물과 반응시켜 베타-아미노 카보닐 화합물을 제조할 수 있다. 구체적인 반응식은, 하기 반응식 2와 같다. In one embodiment, beta-amino carbonyl compounds can be prepared by reacting alpha-cyanoketone (1a in Scheme 2) with an imine compound in the presence of a chiral catalyst. In another embodiment, the beta-ketoester (1b of Scheme 2) may be reacted with an imine compound in the presence of a chiral catalyst to prepare a beta-amino carbonyl compound. The specific reaction formula is the same as the following scheme 2.

Figure 112009036943413-pat00008
Figure 112009036943413-pat00008

상기 반응식 2에서, R1 내지 R5는 위에서 정의한 바와 같다.In Scheme 2, R 1 to R 5 is 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.

[실시예 1] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노사이클로펜탄온: Example 1 ( S ) -2-[( S ) -tertiary-butoxycarbonylamino] benzyl-2-cyanocyclopentanone:

Figure 112009036943413-pat00009
Figure 112009036943413-pat00009

플라스크에 2-시아노사이클로펜탄온(화학식 2) 0.2 mmol을 넣고 톨루엔 0.4 mL를 넣은 후 상온에서 교반하였다. 그런 다음, 키랄 양기능 유레아촉매 (X = O, 화학식 1) 10 mol%를 넣고 플라스크 주변을 -78℃로 맞추어 주었다. 5 분 후에 톨루엔 0.4 mL에 녹인 N-터셔리-부톡시카보닐-벤즈알드이민 (화학식 4) 0.24 mmol을 천천히 적가하였다. 반응 혼합물을 -78℃에서 1 시간 동안 교반하였다. 반응이 완료되면 반응혼합물을 상온으로 올린 후, 용매를 감압 농축하여 컬럼크로마토그래피(SiO2, EA : Hex = 1 : 5)로 분리 정제하여 (S)-2-[(S)-터셔리부톡시카보닐아미노]벤질-2-시아노사이클로펜탄-온 (화학식 5)을 81% 수율, 부분입체이성질체 100 :0 , >99% ee로 얻었다.0.2 mmol of 2-cyanocyclopentanone (Formula 2) was added to the flask, and 0.4 mL of toluene was added thereto, followed by stirring at room temperature. Then, 10 mol% of a chiral bifunctional urea catalyst (X = O, Formula 1) was added thereto, and the vicinity of the flask was adjusted to -78 ° C. After 5 minutes, 0.24 mmol of N -tertiary-butoxycarbonyl-benzalimine (Formula 4) dissolved in 0.4 mL of toluene was slowly added dropwise. The reaction mixture was stirred at -78 ° C for 1 hour. After the reaction was completed, the reaction mixture was raised to room temperature, the solvent was concentrated under reduced pressure, purified by column chromatography (SiO 2 , EA: Hex = 1: 5), and purified by ( S ) -2-[( S ) -terminal part. Toxycarbonylamino] benzyl-2-cyanocyclopentan-one (Formula 5) was obtained in 81% yield, diastereomer 100: 0,> 99% ee.

[a]D 22 =-42.2 (c = 0.3, CHCl3, > 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.47-7.35 (m, 5H), 5.57 (br d, J = 10 Hz, 1H), 5.02 (d, J = 10 Hz, 1H), 2.80-2.55 (m, 1H), 2.53-2.30 (m, 1H), 2.24-1.98 (m, 1H), 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.5, 154.9, 136.1, 129.0, 127.6, 118.0, 80.6, 54.7, 35.8, 32.6, 28.1, 18.6; ESI-MS m/z 315.0 [M+H] +; HPLC (hexane-i-PrOH, 97:3, 220 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 33.5 min (major), t R = 36.6 min (minor).[ a ] D 22 = -42.2 ( c = 0.3, CHCl 3 ,> 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.47-7.35 (m, 5H), 5.57 (br d, J = 10 Hz, 1H), 5.02 (d, J = 10 Hz, 1H), 2.80-2.55 ( m, 1H), 2.53-2.30 (m, 1H), 2.24-1.98 (m, 1H), 1.40 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.5, 154.9, 136.1, 129.0, 127.6, 118.0, 80.6, 54.7, 35.8, 32.6, 28.1, 18.6; ESI-MS m / z 315.0 [M + H] + ; HPLC (hexane- i -PrOH, 97: 3, 220 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 33.5 min (major), t R = 36.6 min (minor).

[실시예 2-8] Example 2-8

상기 실시예 1과 동일한 방법으로, (S)-2-((S)-터셔리-부톡시카보닐아미노)벤질-2-시아노사이클로펜탄온을 합성하였다. 구체적인 반응조건 및 수율 등은 하기 표 1에 나타내었다. In the same manner as in Example 1, ( S ) -2-(( S ) -tertiary-butoxycarbonylamino) benzyl-2-cyanocyclopentanone was synthesized. Specific reaction conditions and yields are shown in Table 1 below.

용매menstruum 온도(℃)Temperature (℃) 촉매량 (몰%)Catalyst amount (mol%) 반응시간 (시간)Response time (hours) 수득률
(%)Yield
(%) 대장체
과량 (%)Colon
Excess (%) dr
(%)dr
(%) 실시예 2Example 2 DCMDCM rtrt 1010 0.30.3 8585 7474 76/2476/24 실시예 3Example 3 아세톤Acetone rtrt 1010 0.30.3 8383 59 59 50/5050/50 실시예 4Example 4 AcOEtAcOEt rtrt 1010 0.30.3 8181 53 53 55/4555/45 실시예 5Example 5 THFTHF rtrt 1010 0.30.3 8383 2323 45/5545/55 실시예 6Example 6 톨루엔toluene rtrt 1010 0.30.3 8181 8888 98/298/2 실시예 7Example 7 톨루엔toluene -40-40 1010 0.80.8 8080 88 88 100/0100/0 실시예 8Example 8 톨루엔toluene -78-78 1010 1 One 8181 >99> 99 100/0100/0

*표 1에서, rt는 상온(room temperature), dr은 부분입체 이성질체의 비율(diastereomeric ratio)을 뜻하며, DCM은 디클로로메탄(dichloromethane), THF는 테트라하이드로퓨란(tetrahydrofuran)임.In Table 1, rt is room temperature, dr is diastereomeric ratio, DCM is dichloromethane, and THF is tetrahydrofuran.

[실시예 9] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-플루오로페닐)메틸]-2-시아노사이클로펜탄온: Example 9 ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (2-fluorophenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00010
Figure 112009036943413-pat00010

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-플루오로페닐)메틸]-2-시아노사이클로펜탄온을 96% 수율, 부분입체이성질체 100 :0 , >99% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[(( S ) -tertiary-butoxycarbonylamino) (2-fluorophenyl) methyl] -2-cyanocyclopentanone was 96% Yield, diastereomer 100: 0,> 99% ee.

[a]D 20 = -57.2 (c = 1.0, CHCl3, >99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.60-7.49 (m, 1H), 7.44-7.30 (m, 1H), 7.29-7.06 (m, 2H), 5.55 (d, J = 9.2 Hz, 1H), 5.46 (d, J = 9.2 Hz, 1H), 2.84-2.61 (m, 1H), 2.54-2.02 (m, 5H), 1.41(s, 9H); 13C NMR (50 MHz, CDCl3)δ= 206.5, 160.0 (J 1 C-F= 244.5 Hz), 154.8, 130.5 (J 3 C-F= 8.4 Hz), 128.6, 125.0 (J 3 C-F= 1.75 Hz), 123.5 (J 2 C-F= 14.0 Hz), 117.7, 115.7 (J 2 C-F= 22.5 Hz), 80.7, 54.8, 48.0, 35.8, 32.6, 28.1, 18.6. ESI-MS m/z 332.9 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 17.4 min (minor), t R = 21.3 min (major).[ a ] D 20 = -57.2 ( c = 1.0, CHCl 3 ,> 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.60-7.49 (m, 1H), 7.44-7.30 (m, 1H), 7.29-7.06 (m, 2H), 5.55 (d, J = 9.2 Hz, 1H) , 5.46 (d, J = 9.2 Hz, 1 H), 2.84-2.61 (m, 1 H), 2.54-2.02 (m, 5H), 1.41 (s, 9 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.5, 160.0 ( J 1 CF = 244.5 Hz), 154.8, 130.5 ( J 3 CF = 8.4 Hz), 128.6, 125.0 ( J 3 CF = 1.75 Hz), 123.5 ( J 2 CF = 14.0 Hz), 117.7, 115.7 ( J 2 CF = 22.5 Hz), 80.7, 54.8, 48.0, 35.8, 32.6, 28.1, 18.6. ESI-MS m / z 332.9 [M + H] + ; HPLC (hexane- i -PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 17.4 min (minor), t R = 21.3 min (major).

[실시예 10] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-클로로페닐)메틸]-2-시아노사이클로펜탄온: Example 10 ( S ) -2-[(( S ) -tertiary-butoxycarbonylamino) (2-chlorophenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00011
Figure 112009036943413-pat00011

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-클로로페닐)메틸]-2-시아노사이클로펜탄온을 80% 수율, 부분입체이성질체 100 :0 , 97% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (2-chlorophenyl) methyl] -2-cyanocyclopentanone in 80% yield , Diastereomer 100: 0, 97% ee.

[a]D 20 = -60.6 (c = 1.0, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3) δ = 7.84-7.70 (m, 1H), 7.55-7.24 (m, 4H), 5.68 (br d, J = 8.6 Hz, 1H), 5.56 (d, J = 8.6 Hz, 1H), 2.88-2.63 (m, 1H), 2.58-2.20 (m, 2H), 2.21-2.05 (m, 3H), 1.39 (s, 9H); 13C NMR = (50 MHz, CDCl3): δ = 206.6, 154.5, 134.6, 133.6, 129.8, 129.6, 128.3, 127.7, 117.9, 80.6, 54.4, 49.8, 35.8, 32.4, 28.0, 19.0; ESI-MS m/z 348.9 [M+H] +; HPLC (hexane-i-PrOH, 90:10, 220 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 10.2 min (minor), t R = 14.3 min (major).[ a ] D 20 = -60.6 ( c = 1.0, CHCl 3 , 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.84-7.70 (m, 1H), 7.55-7.24 (m, 4H), 5.68 (br d, J = 8.6 Hz, 1H), 5.56 (d, J = 8.6 Hz, 1H), 2.88-2.63 (m, 1H), 2.58-2.20 (m, 2H), 2.21-2.05 (m, 3H), 1.39 (s, 9H); 13 C NMR = (50 MHz, CDCl 3 ): δ = 206.6, 154.5, 134.6, 133.6, 129.8, 129.6, 128.3, 127.7, 117.9, 80.6, 54.4, 49.8, 35.8, 32.4, 28.0, 19.0; ESI-MS m / z 348.9 [M + H] + ; HPLC (hexane- i- PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 10.2 min (minor), t R = 14.3 min (major).

[실시예 11] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-클로로페닐)메틸]-2-시아노사이클로펜탄온: Example 11 ( S ) -2-[(( S ) -tertiary-butoxycarbonylamino) (4-chlorophenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00012
Figure 112009036943413-pat00012

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-클로로페닐)메틸]-2-시아노사이클로펜탄온을 83% 수율, 부분입체이성질체 100 :0 , 98% ee 로 얻었다.In the same manner as in Example 1, ( S ) -2-[(( S ) -tertoxy-butoxycarbonylamino) (4-chlorophenyl) methyl] -2-cyanocyclopentanone in 83% yield , Diastereomer 100: 0, 98% ee.

[a]D 20 = -48.6 (c = 1.0, CHCl3, 98% ee); 1H NMR (200 MHz, CDCl3) δ = 7.38-7.36 (m, 4H), 5.54 (d, J = 8.8 Hz, 1H), 4.98 (d, J = 8.8 Hz, 1H), 2.84-2.34 (m, 2H), 2.24-1.95 (m, 4H), 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.4, 154.9, 135.0, 134.8, 129.2, 129.0, 117.7, 80.9, 54.4, 54.2, 36.0, 32.7, 29.7, 28.2, 18.7; ESI-MS m/z 348.9 [M+H] +; HPLC (hexane-i-PrOH, 90:10, 220 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 23.2 min (major), t R = 30.6 min (minor).[ a ] D 20 = -48.6 ( c = 1.0, CHCl 3 , 98% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.38-7.36 (m, 4H), 5.54 (d, J = 8.8 Hz, 1H), 4.98 (d, J = 8.8 Hz, 1H), 2.84-2.34 (m , 2H), 2.24-1.95 (m, 4H), 1.40 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.4, 154.9, 135.0, 134.8, 129.2, 129.0, 117.7, 80.9, 54.4, 54.2, 36.0, 32.7, 29.7, 28.2, 18.7; ESI-MS m / z 348.9 [M + H] + ; HPLC (hexane- i- PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 23.2 min (major), t R = 30.6 min (minor).

[실시예 12] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-메톡시페닐)메틸]-2-시아노사이클로펜탄온:Example 12 ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (4-methoxyphenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00013
Figure 112009036943413-pat00013

키랄 양기능 유기촉매로 싸이오유레아 (X = S, 화학식 1)를 사용하였다는 점을 제외하고는, 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-메톡시페닐)메틸]-2-시아노사이클로펜탄온을 88% 수율, 부분입체이성질체 100 :0 , 86% ee 로 얻었다. In the same manner as in Example 1, except that thiourea (X = S, Formula 1) was used as the chiral bifunctional organic catalyst, ( S ) -2-[(( S ) -Turiary- Butoxycarbonylamino) (4-methoxyphenyl) methyl] -2-cyanocyclopentanone was obtained in 88% yield and diastereomer 100: 0, 86% ee.

[a]D 27 = -25.8 (c = 0.3, CHCl3, 86% ee); 1H NMR (200 MHz, CDCl3) δ = 7.34 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.41 (d, J = 9.2 Hz, 1H), 4.96 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H), 2.81-2.54 (m, 1H), 2.53-2.28 (m, 1H), 2.22-1.94 (m, 4H), 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.7, 160.0, 155.0, 128.8, 128.2, 118.2, 114.4, 80.7, 55.4, 55.0, 54.3, 35.8, 32.8, 28.2, 18.6; ESI-MS m/z 345.0 [M+H] +; HPLC (hexane-i-PrOH, 90:10, 220 nm, 1.0 mL/min, Chiralcel OJ column): t R = 11.9 min (major), t R = 22.0 min (minor).[ a ] D 27 = -25.8 ( c = 0.3, CHCl 3 , 86% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.34 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.41 (d, J = 9.2 Hz, 1H), 4.96 ( d, J = 9.2 Hz, 1H), 3.81 (s, 3H), 2.81-2.54 (m, 1H), 2.53-2.28 (m, 1H), 2.22-1.94 (m, 4H), 1.40 (s, 9H) ; 13 C NMR (50 MHz, CDCl 3 ) δ = 206.7, 160.0, 155.0, 128.8, 128.2, 118.2, 114.4, 80.7, 55.4, 55.0, 54.3, 35.8, 32.8, 28.2, 18.6; ESI-MS m / z 345.0 [M + H] + ; HPLC (hexane- i- PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralcel OJ column): t R = 11.9 min (major), t R = 22.0 min (minor).

[실시예 13] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-메틸페닐)메틸]-2-시아노사이클로펜탄온:Example 13 ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (4-methylphenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00014
Figure 112009036943413-pat00014

키랄 양기능 유기촉매로 싸이오유레아 (X = S, 화학식 1)를 사용하였다는 점을 제외하고는, 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(4-메틸페닐)메틸]-2-시아노사이클로펜탄온을 88% 수율, 부분입체이성질체 100 :0 , 91% ee 로 얻었다. In the same manner as in Example 1, except that thiourea (X = S, Formula 1) was used as the chiral bifunctional organic catalyst, ( S ) -2-[(( S ) -Turiary- Butoxycarbonylamino) (4-methylphenyl) methyl] -2-cyanocyclopentanone was obtained in 88% yield, diastereomer 100: 0, 91% ee.

[a]D 20 = -53.6 (c = 1.0, CHCl3, 91% ee); 1H NMR (200 MHz, CDCl3) δ = 7.35-7.15 (m, 4H), 5.47 (d, J = 9.4 Hz, 1H), 4.98 (d, J = 9.4 Hz, 1H), 2.82-2.58 (m, 1H), 2.54-2.28 (m, 1H), 2.25-1.94 (m, 4H), 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.6, 155.0, 138.9, 133.1, 129.7, 127.4, 118.2, 80.6, 54.9, 54.5, 35.8, 32.7, 28.2, 21.1, 18.6; ESI-MS m/z 329.0 [M+H] +; HPLC (hexane-i-PrOH, 97:3, 220 nm, 1.0 mL/min, Chiralcel OD-H column): t R = 8.6 min (minor), t R = 10.3 min (major).[ a ] D 20 = -53.6 ( c = 1.0, CHCl 3 , 91% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.35-7.15 (m, 4H), 5.47 (d, J = 9.4 Hz, 1H), 4.98 (d, J = 9.4 Hz, 1H), 2.82-2.58 (m , 1H), 2.54-2.28 (m, 1H), 2.25-1.94 (m, 4H), 1.40 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.6, 155.0, 138.9, 133.1, 129.7, 127.4, 118.2, 80.6, 54.9, 54.5, 35.8, 32.7, 28.2, 21.1, 18.6; ESI-MS m / z 329.0 [M + H] + ; HPLC (hexane- i- PrOH, 97: 3, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 8.6 min (minor), t R = 10.3 min (major).

[실시예 14] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-나프틸)메틸]-2-시아노사이클로펜탄온:Example 14 ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (2-naphthyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00015
Figure 112009036943413-pat00015

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-나프틸)메틸]-2-시아노사이클로펜탄온을 90% 수율, 부분입체이성질체 100 :0 , 98% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (2-naphthyl) methyl] -2-cyanocyclopentanone in 90% yield , Diastereomer 100: 0, 98% ee.

[a]D 22 = -44.8 (c = 1.0, CHCl3, 98% ee); 1H NMR (200 MHz, CDCl3) δ = 7.96-7.81 (m, 4H), 7.62-7.49 (m, 2H), ), 5.60 (d, J = 9.2 Hz, 1H), 5.18 (d, J = 9.2 Hz, 1H), 2.90-2.32 (m, 2H), 2.29-2.01 (m, 4H), 1.42 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.5, 155.0, 133.5, 133.3, 133.1, 129.1, 128.2, 127.7, 127.2, 126.8, 124.6, 118.1, 80.8, 55.0, 54.6, 35.8, 32.8, 28.2, 18.7; ESI-MS m/z 365.1 [M+H] +; HPLC (hexane-i-PrOH, 90:10, 254 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 14.3 min (major), t R = 20.2 min (minor).[ a ] D 22 = -44.8 ( c = 1.0, CHCl 3 , 98% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.96-7.81 (m, 4H), 7.62-7.49 (m, 2H),), 5.60 (d, J = 9.2 Hz, 1H), 5.18 (d, J = 9.2 Hz, 1H), 2.90-2.32 (m, 2H), 2.29-2.01 (m, 4H), 1.42 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.5, 155.0, 133.5, 133.3, 133.1, 129.1, 128.2, 127.7, 127.2, 126.8, 124.6, 118.1, 80.8, 55.0, 54.6, 35.8, 32.8, 28.2, 18.7; ESI-MS m / z 365.1 [M + H] + ; HPLC (hexane- i- PrOH, 90:10, 254 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 14.3 min (major), t R = 20.2 min (minor).

[실시예 15] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-퓨릴)메틸]-2-시아노사이클로펜탄온:Example 15 ( S ) -2-[(( S ) -tert-butoxycarbonylamino) (2-furyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00016
Figure 112009036943413-pat00016

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-퓨릴)메틸]-2-시아노사이클로펜탄온을 90% 수율, 부분입체이성질체 100 :0 , 93% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[(( S ) -tertoxy-butoxycarbonylamino) (2-furyl) methyl] -2-cyanocyclopentanone in 90% yield, Diastereomers 100: 0, 93% ee.

[a]D 20 = -48.0 (c = 1.0, CHCl3, 93% ee); 1H NMR (200 MHz, CDCl3) δ = 7.46-7.39 (m, 1H), 6.45-6.32 (m, 1H), 5.44 (d, J = 9.8 Hz, 1H), 5.27 (d, J = 9.8 Hz, 1H), 2.79-2.39 (m, 2H), 2.39-2.96 (m, 4H), 1.44 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.2, 154.8, 148.9, 143.1, 117.7, 110.6, 108.9, 80.9, 54.1, 49.7, 35.9, 32.4, 28.1, 18.7; ESI-MS m/z 305.2 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 220 nm, 1.0 mL/min, Chiralcel OD-H column): t R = 8.6 min (minor), t R = 12.1 min (major).[ a ] D 20 = -48.0 ( c = 1.0, CHCl 3 , 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.46-7.39 (m, 1H), 6.45-6.32 (m, 1H), 5.44 (d, J = 9.8 Hz, 1H), 5.27 (d, J = 9.8 Hz , 1H), 2.79-2.39 (m, 2H), 2.39-2.96 (m, 4H), 1.44 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.2, 154.8, 148.9, 143.1, 117.7, 110.6, 108.9, 80.9, 54.1, 49.7, 35.9, 32.4, 28.1, 18.7; ESI-MS m / z 305.2 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 8.6 min (minor), t R = 12.1 min (major).

[실시예 16] (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-사이에닐)메틸]-2-시아노사이클로펜탄온:Example 16 ( S ) -2-[(( S ) -tertiary-butoxycarbonylamino) (2-cyenyl) methyl] -2-cyanocyclopentanone:

Figure 112009036943413-pat00017
Figure 112009036943413-pat00017

상기 실시예 1과 동일한 방법으로, (S)-2-[((S)-터셔리-부톡시카보닐아미노)(2-사이에닐)메틸]-2-시아노사이클로펜탄온을 99% 수율, 부분입체이성질체 100 :0 , >99% ee 로 얻었다. In the same manner as in Example 1, 99% of ( S ) -2-[(( S ) -tertiary-butoxycarbonylamino) (2-cyenyl) methyl] -2-cyanocyclopentanone Yield, diastereomer 100: 0,> 99% ee.

[a]D 22 = -40.2 (c = 1.0, CHCl3, > 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.28 (dd, J = 4.8, 4.2 Hz, 1H), 7.21-7.14 (m, 1H), 7.01 (dd, J = 4.6, 4.2 Hz, 1H), 5.43-5.33 (m, 2H), 2.75-2.52 (m, 1H), 2.51-2.40 (m, 1H), 2.39-1.96 (m, 2H), 1.41 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 206.2, 154.7, 138.5, 127.2, 126.7, 125.8, 117.9, 81.0, 55.2, 51.1, 35.9, 32.7, 28.2, 18.6; ESI-MS m/z 321.0 [M+H] +; HPLC (hexane-i-PrOH, 90:10, 220 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 13.0 min (major), t R = 14.5 min (minor).[ a ] D 22 = -40.2 ( c = 1.0, CHCl 3 ,> 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.28 (dd, J = 4.8, 4.2 Hz, 1H), 7.21-7.14 (m, 1H), 7.01 (dd, J = 4.6, 4.2 Hz, 1H), 5.43 -5.33 (m, 2H), 2.75-2.52 (m, 1H), 2.51-2.40 (m, 1H), 2.39-1.96 (m, 2H), 1.41 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.2, 154.7, 138.5, 127.2, 126.7, 125.8, 117.9, 81.0, 55.2, 51.1, 35.9, 32.7, 28.2, 18.6; ESI-MS m / z 321.0 [M + H] + ; HPLC (hexane- i- PrOH, 90:10, 220 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 13.0 min (major), t R = 14.5 min (minor).

[실시예 17] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노사이클로헥산온:Example 17 ( S ) -2-[( S ) -Turry - Butoxycarbonylamino] benzyl-2-cyanocyclohexanone:

Figure 112009036943413-pat00018
Figure 112009036943413-pat00018

상기 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노사이클로헥산온을 75% 수율, 부분입체이성질체 100 :0 , 90% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[( S ) -tertiary-butoxycarbonylamino] benzyl-2-cyanocyclohexanone was obtained in 75% yield, diastereomer 100: 0, Obtained as 90% ee.

[a]D 22 = -24.4 (c = 1.1, CHCl3, 90% ee); 1H NMR (200 MHz, CDCl3) δ = 7.43-7.28 (m, 5H), 5.48 (br d, J = 9.8 Hz, 1H), 5.35 (br d, J = 9.8 Hz, 1H), 3.04-2.55 (m, 2H), 2.16-1.72 (m, 6H), 1.37 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 202.3, 154.7, 136.2, 128.8, 127.8, 118.3, 80.6, 58.6, 55.5, 39.8, 38.6, 35.7, 28.1, 27.2, 20.7; ESI-MS m/z 329.0 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 220 nm, 1.0 mL/min, Chiralpak AD-H column): t R = 14.0 min (major), t R = 15.9 min (minor). [ a ] D 22 = -24.4 ( c = 1.1, CHCl 3 , 90% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.43-7.28 (m, 5H), 5.48 (br d, J = 9.8 Hz, 1H), 5.35 (br d, J = 9.8 Hz, 1H), 3.04-2.55 (m, 2H), 2.16-1.72 (m, 6H), 1.37 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 202.3, 154.7, 136.2, 128.8, 127.8, 118.3, 80.6, 58.6, 55.5, 39.8, 38.6, 35.7, 28.1, 27.2, 20.7; ESI-MS m / z 329.0 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 220 nm, 1.0 mL / min, Chiralpak AD-H column): t R = 14.0 min (major), t R = 15.9 min (minor).

[실시예 18] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노사이클로헵탄온:Example 18 ( S ) -2-[( S ) -Turry - Butoxycarbonylamino] benzyl-2-cyanocycloheptanone:

Figure 112009036943413-pat00019
Figure 112009036943413-pat00019

상기 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노사이클로헵탄온을 77% 수율, 부분입체이성질체 100 :0 , >99% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[( S ) -tertiary-butoxycarbonylamino] benzyl-2-cyanocycloheptanone in 77% yield, diastereomer 100: 0, > 99% ee.

[a]D 22 = -71.0 (c = 1.0, CHCl3, > 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.54-7.30 (m, 5H), 5.53 (d, J = 9.4 Hz, 1H), 5.05 (d, J = 9.4 Hz, 1H), 3.06-2.86 (m, 1H), 2.74-2.56 (m, 1H), 2.14-1.78 (m, 3H), 1.77-1.50 (m, 3H), 1.38 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 204.3, 154.8, 135.6, 128.9, 128.9, 127.9, 119.1, 80.6, 63.0, 58.2, 40.1, 39.9, 29.7, 28.1, 26.4, 24.8; ESI-MS m/z 343.0 [M+H] +; HPLC (hexane-i-PrOH, 97:3, 220 nm, 1.0 mL/min, Chiralcel OD-H column): t R = 12.2 min (major), t R = 15.9 min (minor). [ a ] D 22 = -71.0 ( c = 1.0, CHCl 3 ,> 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.54-7.30 (m, 5H), 5.53 (d, J = 9.4 Hz, 1H), 5.05 (d, J = 9.4 Hz, 1H), 3.06-2.86 (m , 1H), 2.74-2.56 (m, 1H), 2.14-1.78 (m, 3H), 1.77-1.50 (m, 3H), 1.38 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 204.3, 154.8, 135.6, 128.9, 128.9, 127.9, 119.1, 80.6, 63.0, 58.2, 40.1, 39.9, 29.7, 28.1, 26.4, 24.8; ESI-MS m / z 343.0 [M + H] + ; HPLC (hexane- i- PrOH, 97: 3, 220 nm, 1.0 mL / min, Chiralcel OD-H column): t R = 12.2 min (major), t R = 15.9 min (minor).

[실시예 19] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노-1-인단온:Example 19 ( S ) -2-[( S ) -Turry - Butoxycarbonylamino] benzyl-2-cyano-1-indanone:

Figure 112009036943413-pat00020
Figure 112009036943413-pat00020

키랄 양기능 유기촉매 (X = O, 화학식 1) 20 mol% 사용하였다는 점을 제외하고는, 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노-1-인단온을 80% 수율, 부분입체이성질체 67:33, 77% ee 로 얻었다. In the same manner as in Example 1, except that 20 mol% of a chiral cationic organic catalyst (X = O, Formula 1) was used, ( S ) -2-[( S ) -tertiary-butoxycarbo Nylamino] benzyl-2-cyano-1-indanone was obtained in 80% yield, diastereomer 67:33, 77% ee.

[a]D 16 = -8.8 (c = 0.3, CHCl3, 77% ee); 1H NMR (200 MHz, CDCl3) δ = 7.71(d, J = 7.6 Hz, 1H), 7.72-7.61 (m, 1H), 7.52-7.32 (m, 7H), 5.61 (d, J = 8.8 Hz, 1H), 4.87 (d, J= 8.8 Hz, 1H), 3.49-3.22 (m, 2H). 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 195.3, 154.8, 149.6, 137.0, 136.3, 133.4, 128.9, 127.8, 126.2, 125.7, 118.4, 80.6, 58.0, 53.0, 36.4, 28.2; ESI-MS m/z 363.0 [M+H]+; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min Chiralhyun-Leu-1 column) : t R = 53.9 min (minor), t R = 57.6 min (major). [ a ] D 16 = -8.8 ( c = 0.3, CHCl 3 , 77% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.71 (d, J = 7.6 Hz, 1H), 7.72-7.61 (m, 1H), 7.52-7.32 (m, 7H), 5.61 (d, J = 8.8 Hz , 1H), 4.87 (d, J = 8.8 Hz, 1H), 3.49-3.22 (m, 2H). 1.40 (s, 9 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 195.3, 154.8, 149.6, 137.0, 136.3, 133.4, 128.9, 127.8, 126.2, 125.7, 118.4, 80.6, 58.0, 53.0, 36.4, 28.2; ESI-MS m / z 363.0 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 254 nm, 1.0 mL / min Chiralhyun-Leu-1 column): t R = 53.9 min (minor), t R = 57.6 min (major).

[실시예 20] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-5-메톡시-2-시아노-1-인단온:[Example 20] ( S ) -2-[( S ) -tertiary - butoxycarbonylamino] benzyl-5-methoxy-2-cyano-1-indanone:

Figure 112009036943413-pat00021
Figure 112009036943413-pat00021

상기 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-5-메톡시-2-시아노-1-인단온을 75% 수율, 부분입체이성질체 99.8 : 0.2 , 94% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[( S ) -tertiary-butoxycarbonylamino] benzyl-5-methoxy-2-cyano-1-indanone in 75% yield, Diastereomer 99.8: 0.2, 94% ee.

[a]D 21 = -30.3 (c = 1.0, CHCl3, >99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.71(d, J = 8.8 Hz, 1H), 7.47-7.21(m , 5H), 6.98-6.88 (m, 1H), 6.82-6.75 (m, 1H), 5.81 (br s, 1H), 4.97 (br d, J = 8 Hz, 1H), 3.86 (s, 3H), 3.34 (br m, 2H), 1.39 (s, 9H) ); 13C NMR (50 MHz, CDCl3) δ = 193.4, 166.5, 154.8, 153.0, 137.2, 128.7, 127.7, 127.4, 126.3, 118.6, 116.8, 109.4, 80.4, 58.2, 55.8, 52.9, 36.2, 28.1; ESI-MS m/z 393.0 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min, Chiralhyun-Leu-1 column): t R = 33.6 min (minor), t R = 35.6 min (major).[ a ] D 21 = -30.3 ( c = 1.0, CHCl 3 ,> 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.71 (d, J = 8.8 Hz, 1H), 7.47-7.21 (m, 5H), 6.98-6.88 (m, 1H), 6.82-6.75 (m, 1H) , 5.81 (br s, 1 H), 4.97 (br d, J = 8 Hz, 1 H), 3.86 (s, 3 H), 3.34 (br m, 2 H), 1.39 (s, 9 H)); 13 C NMR (50 MHz, CDCl 3 ) δ = 193.4, 166.5, 154.8, 153.0, 137.2, 128.7, 127.7, 127.4, 126.3, 118.6, 116.8, 109.4, 80.4, 58.2, 55.8, 52.9, 36.2, 28.1; ESI-MS m / z 393.0 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralhyun-Leu-1 column): t R = 33.6 min (minor), t R = 35.6 min (major).

[실시예 21] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노-1-테트라론:Example 21 ( S ) -2-[( S ) -tertiary - butoxycarbonylamino] benzyl-2-cyano-1-tetraron

Figure 112009036943413-pat00022
Figure 112009036943413-pat00022

상기 실시예 1과 동일한 방법으로 (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-시아노-1-테트라론을 84% 수율, 부분입체이성질체 99 : 1 , 95% ee 로 얻었다.( S ) -2-[( S ) -tertoxy -butoxycarbonylamino] benzyl-2-cyano-1-tetraron in 84% yield, diastereomer 99: 1 in the same manner as in Example 1 above , 95% ee.

[a]D 22 = -12.8 (c = 1.0, CHCl3, 95% ee); 1H NMR (200 MHz, CDCl3) δ = 8.04 (d, J = 7.7 Hz, 1H), 7.61-7.50 (m , 3H), 7.43-7.31 (m, 4H), 7.30-7.21 (m, 1H), 5.5 (d, J = 9.2 Hz, 1H), 5.28 (d, J = 9.2 Hz, 1H), 3.36-3.14 (m, 1H), 3.10-2.90 (m, 1H), 2.56- 2.35 (m, 1H), 2.18-2.02 (m, 1H), 1.34 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 189.2, 154.5, 141.5, 134.6, 130.0, 129.0, 128.8, 127.6, 127.5, 118.2, 55.0, 54.7, 30.2, 28.1, 24.4; ESI-MS m/z 376.9 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min, Chiralcel OD-H column x 2): t R = 20.5 min (minor), t R = 34.4 min (major).[ a ] D 22 = -12.8 ( c = 1.0, CHCl 3 , 95% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.04 (d, J = 7.7 Hz, 1H), 7.61-7.50 (m, 3H), 7.43-7.31 (m, 4H), 7.30-7.21 (m, 1H) , 5.5 (d, J = 9.2 Hz, 1H), 5.28 (d, J = 9.2 Hz, 1H), 3.36-3.14 (m, 1H), 3.10-2.90 (m, 1H), 2.56- 2.35 (m, 1H ), 2.18-2.02 (m, 1 H), 1.34 (s, 9 H); 13 C NMR (50 MHz, CDCl 3 ) δ = 189.2, 154.5, 141.5, 134.6, 130.0, 129.0, 128.8, 127.6, 127.5, 118.2, 55.0, 54.7, 30.2, 28.1, 24.4; ESI-MS m / z 376.9 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralcel OD-H column x 2): t R = 20.5 min (minor), t R = 34.4 min (major).

[실시예 22] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-6-메톡시-2-시아노-1-테트라론:[Example 22] ( S ) -2-[( S ) -tertiary - butoxycarbonylamino] benzyl-6-methoxy-2-cyano-1-tetraron:

Figure 112009036943413-pat00023
Figure 112009036943413-pat00023

상기 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-6-메톡시-2-시아노-1-테트라론을 81% 수율, 부분입체이성질체 86 : 14 , 95% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[( S ) -tertiary-butoxycarbonylamino] benzyl-6-methoxy-2-cyano-1-tetraron was obtained in 81% yield, Diastereomers 86: 14, 95% ee.

[a]D 22 = -16.7 (c = 1.0, CHCl3, 95% ee); 1H NMR (200 MHz, CDCl3) δ = 8.01 (d, J = 8.6 Hz, 1H), 7.62-7.30 (m, 5H), 6.87 (dd, J = 2.0, 2.0 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 5.63 (br s, 1H), 5.28 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 3.33-3.10 (m, 1H), 3.08-2.86 (m, 1H), 2.54-5.30 (m, 1H), 2.16-1.98 (m, 1H), 1.35 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 187.7, 164.5, 154.5, 144.2, 136.7, 131.3, 128.8, 127.6, 123.2, 118.3, 114.3, 112.4, 80.2, 55.5, 55.1, 54.1, 30.0, 28.0, 24.8; ESI-MS m/z 407.0 [M+H] +; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min, Chiralcel OD-H x 2): t R = 31.8 min (minor), t R = 39.6 min (major).[ a ] D 22 = -16.7 ( c = 1.0, CHCl 3 , 95% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 8.01 (d, J = 8.6 Hz, 1H), 7.62-7.30 (m, 5H), 6.87 (dd, J = 2.0, 2.0 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 5.63 (br s, 1H), 5.28 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 3.33-3.10 (m, 1H), 3.08-2.86 (m, 1H), 2.54-5.30 (m, 1H), 2.16-1.98 (m , 1H), 1.35 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 187.7, 164.5, 154.5, 144.2, 136.7, 131.3, 128.8, 127.6, 123.2, 118.3, 114.3, 112.4, 80.2, 55.5, 55.1, 54.1, 30.0, 28.0, 24.8; ESI-MS m / z 407.0 [M + H] + ; HPLC (hexane- i- PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralcel OD-H x 2): t R = 31.8 min (minor), t R = 39.6 min (major).

[실시예 23] (S)-2-[(S)-터셔리-부톡시카보닐아미노]벤질-2-벤조일-4-펜텐나이트릴:Example 23 ( S ) -2-[( S ) -tertiary - butoxycarbonylamino] benzyl-2-benzoyl-4-pentennitrile:

Figure 112009036943413-pat00024
Figure 112009036943413-pat00024

상기 실시예 1과 동일한 방법으로, (S)-2-[(S)-터셔리-부톡시카보닐아미노 벤질]-2-벤조일-4-펜텐나이트릴을 80% 수율, 부분입체이성질체 59 : 41 , 98% ee 로 얻었다. In the same manner as in Example 1, ( S ) -2-[( S ) -tertoxy -butoxycarbonylamino benzyl] -2-benzoyl-4-pentennitrile was obtained in 80% yield, diastereomer 59: 41, 98% ee.

[a]D 21 = +6.6 (c = 0.78, CHCl3, 98% ee); 1H NMR (200 MHz, CDCl3) δ = 7.48-7.30 (m, 3H), 7.30-7.12 (m, 7H), 5.93-5.68 (m, 1H), 5.58-5.42 (m, 2H), 5.33-5.14 (m, 2H), 3.31-3.13 (m, 1H), 2.95-2.78 (m, 1H), 1.44 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 196.0, 154.9, 137.2, 137.0, 132.6, 130.6, 128.9, 128.7, 128.5, 128.0, 121.5, 120.0, 80.7, 61.0, 59.3, 42.0, 28.2; ESI-MS m/z 408.4 [M+NH3] +; HPLC (hexane-i-PrOH, 95:5, 254 nm, 1.0 mL/min, Chiralpak AD-H): t R = 16.7 min (major), t R = 19.0 min (minor).[ a ] D 21 = +6.6 ( c = 0.78, CHCl 3 , 98% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.48-7.30 (m, 3H), 7.30-7.12 (m, 7H), 5.93-5.68 (m, 1H), 5.58-5.42 (m, 2H), 5.33- 5.14 (m, 2H), 3.31-3.13 (m, 1H), 2.95-2.78 (m, 1H), 1.44 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 196.0, 154.9, 137.2, 137.0, 132.6, 130.6, 128.9, 128.7, 128.5, 128.0, 121.5, 120.0, 80.7, 61.0, 59.3, 42.0, 28.2; ESI-MS m / z 408.4 [M + NH 3 ] + ; HPLC (hexane- i- PrOH, 95: 5, 254 nm, 1.0 mL / min, Chiralpak AD-H): t R = 16.7 min (major), t R = 19.0 min (minor).

[실시예 24] 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노메틸]-2-옥소싸이클로-펜탄카복실레이트: Example 24 Methyl ( 1R ) -1-[( S ) -1-Turistry - Butoxycarbonylaminomethyl] -2-oxocyclo-pentanecarboxylate:

Figure 112009036943413-pat00025
Figure 112009036943413-pat00025

상기 실시예 1과 동일한 방법으로, 플라스크에 2-옥소-싸이클로펜탄카복실레이트 0.1 mmol와 키랄 양기능 유기촉매 (X = O, 화학식 1) 10 mol%를 넣고 톨루엔 0.8 mL를 넣은 후 상온에서 10 분간 교반하였다. 그런 다음, -78℃로 냉각시키고, 톨루엔 0.2 mL에 녹인 N-터셔리-부톡시카보닐-벤즈알드이민 0.12 mmol을 1 분간 적가하였다. 반응 혼합물을 -78℃에서 교반하였다. In the same manner as in Example 1, 0.1 mmol of 2-oxo-cyclopentanecarboxylate and 10 mol% of a chiral functional organic catalyst (X = O, Formula 1) were added to the flask, 0.8 mL of toluene was added thereto, and then 10 minutes at room temperature. Stirred. Then, cooled to −78 ° C., and 0.12 mmol of N -tertiary-butoxycarbonyl-benzaldehyde imine dissolved in 0.2 mL of toluene was added dropwise for 1 minute. The reaction mixture was stirred at -78 ° C.

반응이 완료되면 반응물을 상온으로 올린 뒤 용매를 감압 농축하여 컬럼 크로마토그래피(SiO2, EA : Hex = 1 : 3)로 분리 정제하여 만니히 생성물을 93%수율, 부분입체 이성질체 97 : 3, 99 %ee로 얻었다. After 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: 3), and the Mannich product was 93% yield, diastereomer 97: 3, 99. got as% ee.

Major diastereoisomer. [a]27 D = -56.2 (c = 0.4, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.30-7.23 (m, 5H), 5.87. (brs, 1H), 5.16 (d, J = 9.4 Hz, 1H), 3.67 (s, 3H), 2.54-2.42 (m, 1H), 2.42-2.30 (m, 2H), 2.04-1.80 (m, 3H), 1.38 (s, 9H); 13C NMR (50 MHz; CDCl3) δ = 210.8, 169.8, 155.1, 138.2, 128.3, 128.0, 127.4, 79.7, 64.8, 55.6, 52.6, 37.5, 30.5, 28.1, 18.9; MS (ESI): m/z = 348.0 [M+H]+ 120.9, 123.0, 149.9, 206.6; Rt HPLC (95 : 5 n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 13.7 min (major), tR = 38.3 (minor).Major diastereoisomer. [ a ] 27 D = -56.2 ( c = 0.4, CHCl 3, 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.30-7.23 (m, 5H), 5.87. (brs, 1H), 5.16 (d, J = 9.4 Hz, 1H), 3.67 (s, 3H), 2.54-2.42 (m, 1H), 2.42-2.30 (m, 2H), 2.04-1.80 (m, 3H ), 1.38 (s, 9 H); 13 C NMR (50 MHz; CDCl 3 ) δ = 210.8, 169.8, 155.1, 138.2, 128.3, 128.0, 127.4, 79.7, 64.8, 55.6, 52.6, 37.5, 30.5, 28.1, 18.9; MS (ESI): m / z = 348.0 [M + H] + 120.9, 123.0, 149.9, 206.6; R t HPLC (95: 5 n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 13.7 min (major), t R = 38.3 (minor).

[실시예 25] 메틸 (1R)-1-[(S)-1-터서리-부톡시카보닐아미노-푸란-2-닐-메틸]-2-옥소싸이클로펜탄카복실레이트: [Example 25] Methyl ( 1R ) -1-[( S ) -1-tersus-butoxycarbonylamino-furan-2-yl-methyl] -2-oxocyclopentanecarboxylate:

Figure 112009036943413-pat00026
Figure 112009036943413-pat00026

상기 실시예 1과 동일한 방법으로, 메틸 (1R)-1-[(S)-1-터서리-부톡시카보닐아미노-푸란-2-닐-메틸]-2-옥소싸이클로펜탄카복실레이트를 96% 수율, 부분입체 이성질체 100 : 0, 99 %ee로 얻었다. In the same manner as in Example 1, methyl ( 1R ) -1-[( S ) -1-tertoxy-butoxycarbonylamino-furan-2-yl-methyl] -2-oxocyclopentanecarboxylate 96% yield, diastereomer 100: 0, 99% ee.

Major diastereoisomer. [a]24 D = -32.4 (c = 0.4, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.30-7.29 (m, 1H) 6.31-6.29 (m, 1H), 6.22-6.21 (m, 1H), 5.63 (brs, 1H) 5.47 (d, J = 10.1 Hz, 1H), 3.73 (s, 3H), 2.66-2.54 (m, 1H), 2.39-2.32 (m, 2H), 2.12-1.92 (m, 3H) 1.41 (s, 9H), 13C NMR (50 MHz; CDCl3) δ = 210.5, 169.5, 155.0, 151.6, 141.9, 110.4, 108.0, 80.0, 64.3, 52.7, 50.5, 37.6, 30.5, 28.1, 18.9; MS (ESI): m/z = 338.5 [M+H]+ 121.0, 156.0, 212.0; Rt HPLC (97 : 3, n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 15.4 min (major), tR = 34.4 (minor).Major diastereoisomer. [ a ] 24 D = -32.4 ( c = 0.4, CHCl 3, 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.30-7.29 (m, 1H) 6.31-6.29 (m, 1H), 6.22-6.21 (m, 1H), 5.63 (brs, 1H) 5.47 (d, J = 10.1 Hz, 1H), 3.73 (s, 3H), 2.66-2.54 (m, 1H), 2.39-2.32 (m, 2H), 2.12-1.92 (m, 3H) 1.41 (s, 9H), 13 C NMR ( 50 MHz; CDCl 3 ) δ = 210.5, 169.5, 155.0, 151.6, 141.9, 110.4, 108.0, 80.0, 64.3, 52.7, 50.5, 37.6, 30.5, 28.1, 18.9; MS (ESI): m / z = 338.5 [M + H] + 121.0, 156.0, 212.0; R t HPLC (97: 3, n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 15.4 min (major), t R = 34.4 (minor).

[실시예 26] 메틸(1R)-1-[(S)-1-터셔리-부톡시카보닐아미노나프탈렌-2-닐-메틸]-2-옥소싸이클로펜탄카복실레이트:Example 26 Methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylaminonaphthalene-2-yl-methyl] -2-oxocyclopentanecarboxylate:

Figure 112009036943413-pat00027
Figure 112009036943413-pat00027

상기 실시예 1과 동일한 방법으로, 메틸(1R)-1-[(S)-1-터셔리-부톡시카보닐아미노나프탈렌-2-닐-메틸]-2-옥소싸이클로펜탄카복실레이트를 90%수율, 부분입체 이성질체 98 : 2, 98 %ee로 얻었다. In the same manner as in Example 1, methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylaminonaphthalene-2-yl-methyl] -2-oxocyclopentanecarboxylate was added to 90 % Yield, diastereomer 98: 2, 98% ee.

Major diastereoisomer. [a]25 D = -26.5 (c = 0.8, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.85-7.75 (m, 4H), 7.49-7.40 (m, 3H), 6.11 (d, J = 9.5 Hz, 1H), 5.39 (d, J = 9.5 Hz, 1H), 3.68 (s, 3H), 2.61-2.51 (m, 1H), 2.40-2.28 (m, 2H), 2.13-1.88 (m, 3H), 1.39 (s, 9H); 13C NMR (50 MHz; CDCl3) δ = 210.9, 169.9, 155.2, 135.7, 132.9, 132.7, 128.0, 128.0, 127.4, 127.3, 126.1, 126.1, 125.7, 79.8, 64.9, 55.9, 52.7, 37.4, 30.6, 28.2, 18.9; MS (ESI): m/z = 397.9 [M+H]+ 121.0, 199.9, 256.0; Rt HPLC (97 : 3, n-hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 24.8 min (minor), tR = 25.5 (major).Major diastereoisomer. [ a ] 25 D = -26.5 ( c = 0.8, CHCl 3, 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.85-7.75 (m, 4H), 7.49-7.40 (m, 3H), 6.11 (d, J = 9.5 Hz, 1H), 5.39 (d, J = 9.5 Hz , 1H), 3.68 (s, 3H), 2.61-2.51 (m, 1H), 2.40-2.28 (m, 2H), 2.13-1.88 (m, 3H), 1.39 (s, 9H); 13 C NMR (50 MHz; CDCl 3 ) δ = 210.9, 169.9, 155.2, 135.7, 132.9, 132.7, 128.0, 128.0, 127.4, 127.3, 126.1, 126.1, 125.7, 79.8, 64.9, 55.9, 52.7, 37.4, 30.6, 28.2, 18.9; MS (ESI): m / z = 397.9 [M + H] + 121.0, 199.9, 256.0; R t HPLC (97: 3, n-hexane: i- PrOH, 254 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 24.8 min (minor), t R = 25.5 (major).

[실시예 27] 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-메톡시-페닐메틸]-2-옥소싸이클로 펜탄카복실레이트:Example 27 Methyl ( 1R ) -1-[( S ) -1-tertiary-butoxycarbonylamino-4-methoxy-phenylmethyl] -2-oxocyclo pentanecarboxylate:

Figure 112009036943413-pat00028
Figure 112009036943413-pat00028

상기 실시예 1과 동일한 방법으로, 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-메톡시-페닐메틸]-2-옥소싸이클로펜탄카복실레이트를 72% 수율, 부분입체 이성질체 96 : 4, 99 %ee로 얻었다In the same manner as in Example 1, methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylamino-4-methoxy-phenylmethyl] -2-oxocyclopentanecarboxylate 72% yield, diastereoisomer 96: 4, 99% ee

Major diastereoisomer. [a]26 D = -22.0 (c = 1.2, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.22 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.90 (brs, 1H), 5.17 (d, J = 9.6 Hz, 1H), 3.76 (s, 1H), 3.68 (s, 3H), 2.58-2.45 (m, 1H), 2.39-2.20 (m, 2H), 2.08-1.85 (m, 3H), 1.38 (s, 9H); 13C NMR (50 MHz; CDCl3) δ = 211.0, 169.8, 159.0, 155.1, 129.2, 128.6, 113.6, 79.6, 65.1, 55.1, 55.1, 52.6, 37.6, 30.4, 28.2, 18.8; MS (ESI): m/z = 378.1 [M+H]+ 120.9, 179.9, 235.9; Rt HPLC (95 : 5, n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 20.4 min (major), tR = 61.0 (minor).Major diastereoisomer. [ a ] 26 D = -22.0 ( c = 1.2, CHCl 3, 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.22 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.90 (brs, 1H), 5.17 (d, J = 9.6 Hz, 1H), 3.76 (s, 1H), 3.68 (s, 3H), 2.58-2.45 (m, 1H), 2.39-2.20 (m, 2H), 2.08-1.85 (m, 3H), 1.38 (s, 9H); 13 C NMR (50 MHz; CDCl 3 ) δ = 211.0, 169.8, 159.0, 155.1, 129.2, 128.6, 113.6, 79.6, 65.1, 55.1, 55.1, 52.6, 37.6, 30.4, 28.2, 18.8; MS (ESI): m / z = 378.1 [M + H] + 120.9, 179.9, 235.9; R t HPLC (95: 5, n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 20.4 min (major), t R = 61.0 (minor).

[실시예 28] 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-메틸-페닐메틸]-2-옥소싸이클로펜탄카복실레이트:Example 28 Methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylamino-4-methyl-phenylmethyl] -2-oxocyclopentanecarboxylate:

Figure 112009036943413-pat00029
Figure 112009036943413-pat00029

상기 실시예 1과 동일한 방법으로, 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-메틸-페닐메틸]-2-옥소싸이클로펜탄카복실레이트 96% 수율, 부분입체 이성질체 99 : 1, 97 %ee로 얻었다. In the same manner as in Example 1, methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylamino-4-methyl-phenylmethyl] -2-oxocyclopentanecarboxylate 96% Yield, diastereomer 99: 1, 97% ee

Major diastereoisomer. [a]26 D = -22.0 (c = 1.2, CHCl3, 97% ee); 1H NMR (200 MHz, CDCl3) δ = 7.18 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.97 (d, J = 9.7 Hz, 1H), 5.18 (d, J = 9.7 Hz, 1H), 3.68 (s, 3H), 2.55-2.43 (m, 1H), 2.34-23.0 (m. 5H), 2.08-1.88 (m, 3H), 1.38 (s, 9H); 13C NMR (50 MHz; CDCl3) δ = 210.8, 169.7, 155.0, 137.3, 135.2, 128.9, 127.8, 79.5, 64.9, 55.3, 52.5, 37.4, 30.4, 28.1, 20.8, 18.7; MS (ESI): m/z = 362.0 [M+H]+ 121.0 164.0, 219.9; Rt HPLC (95 : 5, n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 12.5 min (major), tR = 36.7 (minor).Major diastereoisomer. [ a ] 26 D = -22.0 ( c = 1.2, CHCl 3, 97% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.18 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.97 (d, J = 9.7 Hz, 1H), 5.18 ( d, J = 9.7 Hz, 1H), 3.68 (s, 3H), 2.55-2.43 (m, 1H), 2.34-23.0 (m. 5H), 2.08-1.88 (m, 3H), 1.38 (s, 9H) ; 13 C NMR (50 MHz; CDCl 3 ) δ = 210.8, 169.7, 155.0, 137.3, 135.2, 128.9, 127.8, 79.5, 64.9, 55.3, 52.5, 37.4, 30.4, 28.1, 20.8, 18.7; MS (ESI): m / z = 362.0 [M + H] + 121.0 164.0, 219.9; R t HPLC (95: 5, n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 12.5 min (major), t R = 36.7 (minor).

[실시예 29] 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-클로로-페닐메틸]-2-옥소싸이클로펜탄카복실레이트:Example 29 Methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylamino-4-chloro-phenylmethyl] -2-oxocyclopentanecarboxylate:

Figure 112009036943413-pat00030
Figure 112009036943413-pat00030

상기 실시예 1과 동일한 방법으로, 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노-4-클로로-페닐메틸]-2-옥소싸이클로펜탄카복실레이트 89% 수율, 부분입체 이성질체 100 : 0, 99 %ee로 얻었다. In the same manner as in Example 1, methyl ( 1R ) -1-[( S ) -1-tertary-butoxycarbonylamino-4-chloro-phenylmethyl] -2-oxocyclopentanecarboxylate 89% Yield, diastereomer 100: 0, 99% ee.

Major diastereoisomer. [a]25 D = -22.3 (c = 2.6, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ = 7.30-7.20 (m, 4H), 5.88. (brs, 1H), 5.16 (d, J = 9.4 Hz, 1H), 3.68 (s, 3H), 2.55-2.48 (m, 1H), 2.37-2.25 (m, 2H), 2.04-1.85 (m, 3H), 1.38 (s, 9H); 13C NMR (50 MHz; CDCl3) δ = 210.8, 169.7, 155.1, 137.0, 133.6, 129.5, 128.5, 80.0, 64.7, 55.2, 52.8, 37.5, 30.7, 28.2, 18.9; MS (ESI): m/z = 381.9 [M+H]+ 121.0, 239.9; Rt HPLC (95 : 5 n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 13.7 min (major), tR = 38.3 (minor).Major diastereoisomer. [ a ] 25 D = -22.3 ( c = 2.6, CHCl 3, 99% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.30-7.20 (m, 4H), 5.88. (brs, 1H), 5.16 (d, J = 9.4 Hz, 1H), 3.68 (s, 3H), 2.55-2.48 (m, 1H), 2.37-2.25 (m, 2H), 2.04-1.85 (m, 3H ), 1.38 (s, 9 H); 13 C NMR (50 MHz; CDCl 3 ) δ = 210.8, 169.7, 155.1, 137.0, 133.6, 129.5, 128.5, 80.0, 64.7, 55.2, 52.8, 37.5, 30.7, 28.2, 18.9; MS (ESI): m / z = 381.9 [M + H] + 121.0, 239.9; R t HPLC (95: 5 n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 13.7 min (major), t R = 38.3 (minor).

[실시예 30] 메틸 (1R)-1-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-2-옥소-싸이클로헥산카복실레이트: Example 30 Methyl ( 1R ) -1-[( S ) -1-tertiary-butoxycarbonylaminophenylmethyl] -2-oxo-cyclohexanecarboxylate:

Figure 112009036943413-pat00031
Figure 112009036943413-pat00031

상기 실시예 6과 동일한 방법으로, 플라스크에 2-옥소-싸이클로헥산카복실레이트 0.1 mmol와 키랄 양기능 유기촉매 (X = O, 화학식 1) 10 mol%를 넣고 에테르 1.0 mL를 넣은 후 상온에서 10 분간 교반하였다. 상온에서 N-터셔리-부톡시카보닐-벤즈알드이민 0.12 mmol을 1 분간 적가하였다. 반응 혼합물을 상온에서 교반하였다. In the same manner as in Example 6, 0.1 mmol of 2-oxo-cyclohexanecarboxylate and 10 mol% of a chiral bifunctional organic catalyst (X = O, Chemical Formula 1) were added to the flask, 1.0 mL of ether was added thereto, and then at room temperature for 10 minutes. Stirred. At room temperature, 0.12 mmol of N -tertiary-butoxycarbonyl-benzalimine was added dropwise for 1 minute. The reaction mixture was stirred at room temperature.

반응이 완료되면 반응물을 상온으로 올린 뒤 용매를 감압 농축하여 컬럼 크로마토그래피(SiO2, EA : Hex = 1 : 3)로 분리 정제하여 만니히 생성물을 68%수율, 부분입체 이성질체 96 : 4, 95 %ee로 얻었다. After the reaction was completed, the reaction product was heated to room temperature, the solvent was concentrated under reduced pressure, purified by column chromatography (SiO 2 , EA: Hex = 1: 3), and the Mannich product was 68% yield, diastereomer 96: 4, 95. got as% ee.

Major diastereoisomer. [a]25 D = 2.4 (c = 1.6, CHCl3, 95% ee); 1H NMR (200 MHz, CDCl3) δ = 7.20-7.48 (m, 5H), 6.28 (d, J = 10.16, 1H), 5.25 (d, J = 10.16, 1H), 3.53 (s, 3H), 2.51-2.66 (m, 1H), 2.34-2.51 (m, 2H), 1.87-2.04 (m, 4H), 1.67-1.87 (m, 1H), 1.37 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 208.5, 169.1, 157.0, 138.4, 128.3, 128.1, 127.7, 79.7, 66.8, 57.2, 52.2, 40.5, 34.4, 28.2, 27.7, 21.6; MS (ESI): m/z = 362.0 [M+H]+ 120.9, 205.9, 240.0; Rt HPLC (97 : 3, n-hexane : i-PrOH, 220 nm, 1.0 mL/min) Chiralcel OJ column, tR = 13.8 min (major), tR = 26.4 (minor).Major diastereoisomer. [ a ] 25 D = 2.4 ( c = 1.6, CHCl 3, 95% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.20-7.48 (m, 5H), 6.28 (d, J = 10.16, 1H), 5.25 (d, J = 10.16, 1H), 3.53 (s, 3H), 2.51-2.66 (m, 1H), 2.34-2.51 (m, 2H), 1.87-2.04 (m, 4H), 1.67-1.87 (m, 1H), 1.37 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 208.5, 169.1, 157.0, 138.4, 128.3, 128.1, 127.7, 79.7, 66.8, 57.2, 52.2, 40.5, 34.4, 28.2, 27.7, 21.6; MS (ESI): m / z = 362.0 [M + H] + 120.9, 205.9, 240.0; R t HPLC (97: 3, n-hexane: i -PrOH, 220 nm, 1.0 mL / min) Chiralcel OJ column, t R = 13.8 min (major), t R = 26.4 (minor).

[실시예 31] 메틸 (2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-1-옥소-2-인단카복실레이트: Example 31 Methyl ( 2R ) -2-[( S ) -1-tertary-butoxycarbonylaminophenylmethyl] -1-oxo-2-indanecarboxylate:

Figure 112009036943413-pat00032
Figure 112009036943413-pat00032

양기능 유기촉매로 싸이오유레아 (X = S, 화학식 1)을 사용하였다는 점을 제외하고는, 실시예 6과 동일한 방법으로, 메틸 (2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-1-옥소-2-인단카복실레이트를 93%수율, 부분입체 이성질체 80 : 20, 93 %ee로 얻었다. Methyl ( 2R ) -2-[( S ) -1-ter in the same manner as in Example 6, except that thiourea (X = S, Formula 1) was used as the bifunctional organic catalyst. Sherri-butoxycarbonylaminophenylmethyl] -1-oxo-2-indanecarboxylate was obtained in 93% yield, diastereomer 80:20, 93% ee.

Major diastereoisomer. [a]25 D = -81.3 (c = 2.5, CHCl3, 93% ee); 1H NMR (200 MHz, CDCl3) δ = 7.70 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.39-7.15 (m, 7H), 5.98 (brs, 1H), 5.32 (d, J = 9.1 Hz. 1H), 3.79 (d, J = 17.4 Hz, 1H), 3.74 (s, 3H), 3.22 (d, J = 17.4 Hz, 1H), 1.39 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 198.5, 169.7, 154.0, 138.6, 135.4, 134.5, 128.3, 127.9, 127.7, 126.0, 124.9, 124.3, 79.8, 64.9, 57.9, 53.0, 34.3, 28.2; MS (ESI): m/z = 396.0 [M+H]+ 120.9, 123.0, 149.9, 205.9; Rt HPLC (97 : 3, n-hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak OD-H column, tR = 13.6 min (minor), tR = 18.3 (major).Major diastereoisomer. [ a ] 25 D = -81.3 ( c = 2.5, CHCl 3, 93% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.70 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.39-7.15 (m, 7H), 5.98 (brs, 1H ), 5.32 (d, J = 9.1 Hz.1H), 3.79 (d, J = 17.4 Hz, 1H), 3.74 (s, 3H), 3.22 (d, J = 17.4 Hz, 1H), 1.39 (s, 9H ); 13 C NMR (50 MHz, CDCl 3 ) δ = 198.5, 169.7, 154.0, 138.6, 135.4, 134.5, 128.3, 127.9, 127.7, 126.0, 124.9, 124.3, 79.8, 64.9, 57.9, 53.0, 34.3, 28.2; MS (ESI): m / z = 396.0 [M + H] + 120.9, 123.0, 149.9, 205.9; R t HPLC (97: 3, n-hexane: i -PrOH, 254 nm, 1.0 mL / min) Chiralpak OD-H column, t R = 13.6 min (minor), t R = 18.3 (major).

[실시예 32] 메틸 l-(2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-1-테트랄론-2-카복실레이트:[Example 32] Methyl l- (2 R) -2 - [(S) -1-tert-butoxycarbonylamino-methyl-phenyl] -1-Te Neutral Rhone-2-carboxylate:

Figure 112009036943413-pat00033
Figure 112009036943413-pat00033

양기능 유기촉매로 싸이오유레아 (X = S, 화학식 1)을 사용하였다는 점을 제외하고는, 실시예 6과 동일한 방법으로, 메틸 l-(2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-1-테트랄론-2-카복실레이트 88%수율, 부분입체 이성질체 99 : 13, 96% ee로 얻었다.Im ohyu a positive functional organic catalyst LEA (X = S, formula (1)), which was the the same manner as in Example 6 except that methyl l- (2 R) using -2 - [(S) -1 Tertiary-butoxycarbonylaminophenylmethyl] -1-tetralone-2-carboxylate 88% yield, diastereoisomer 99: 13, 96% ee.

Major diastereoisomer. [a]26 D = 26.2 (c = 0.8, CHCl3, 96% ee); 1H NMR (200 MHz, CDCl3) δ = 7.75 (d, J = 7.7 Hz, 1H), 7.44-7.51 (m, 3H), 7.19-7.39 (m, 5H), 5.99 (d, J = 11.4 Hz, 1H), 5.33 (d, J = 11.4 Hz, 1H), 3.48 (s, 3H), 3.08 (d, J = 6.23 Hz, 2H), 2.68-2.75 (m, 1H), 2.22-2.36 (m, 1H), 1.35 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 194.4, 170.1, 154.9, 142.2, 138.7, 133.6, 132.2, 128.6, 128.2, 128.0, 127.5, 126.6, 125.6, 79.4, 63.0, 57.6, 52.2, 30.2, 28.0, 25.7; MS (ESI): m/z = 409.8 [M+H]+ 121.0, 149.9, 206.0; Rt HPLC (90 : 10, n-hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 12.2 min (major), tR = 20.6 (minor).Major diastereoisomer. [ a ] 26 D = 26.2 ( c = 0.8, CHCl 3, 96% ee); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.75 (d, J = 7.7 Hz, 1H), 7.44-7.51 (m, 3H), 7.19-7.39 (m, 5H), 5.99 (d, J = 11.4 Hz , 1H), 5.33 (d, J = 11.4 Hz, 1H), 3.48 (s, 3H), 3.08 (d, J = 6.23 Hz, 2H), 2.68-2.75 (m, 1H), 2.22-2.36 (m, 1H), 1.35 (s, 9H); 13 C NMR (50 MHz, CDCl 3 ) δ = 194.4, 170.1, 154.9, 142.2, 138.7, 133.6, 132.2, 128.6, 128.2, 128.0, 127.5, 126.6, 125.6, 79.4, 63.0, 57.6, 52.2, 30.2, 28.0, 25.7; MS (ESI): m / z = 409.8 [M + H] + 121.0, 149.9, 206.0; R t HPLC (90:10, n-hexane: i- PrOH, 254 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 12.2 min (major), t R = 20.6 (minor).

[실시예 33] (2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-2-메틸-3-옥소부티릭 에시드 에틸 에스테르 : Example 33 ( 2R ) -2-[( S ) -1-tertary-butoxycarbonylaminophenylmethyl] -2-methyl-3-oxobutyric acid ethyl ester

Figure 112009036943413-pat00034
Figure 112009036943413-pat00034

양기능 유기촉매로 싸이오유레아 (X = S, 화학식 1)을 사용하였다는 점을 제외하고는, 실시예 6과 동일한 방법으로, (2R)-2-[(S)-1-터셔리-부톡시카보닐아미노페닐메틸]-2-메틸-3-옥소부티릭 에시드 에틸 에스테르를 83%수율, 부분입체 이성질체 63 : 27, 71 %ee로 얻었다. Except for using thiourea (X = S, Formula 1) as a bifunctional organic catalyst, in the same manner as in Example 6, ( 2R ) -2-[( S ) -1-tary -Butoxycarbonylaminophenylmethyl] -2-methyl-3-oxobutyric acid ethyl ester was obtained in 83% yield, diastereomer 63:27, 71% ee.

Inseparable 3:1.8 diastereomeric mixture. [a]24 D = -4.4 (c = 2.6, CHCl3); 1H NMR (200 MHz, CDCl3) δ = 7.31-7.25 (m, 8 H), 6.63 (d, J = 9.9 Hz, 1H), 6.11 (d, J = 9.8, 0.56H), 5.25 (d, J = 9.8 Hz, 0.56H), 5.12 (d, J = 9.9 Hz), 4.25-4.10 (m, 3.3H), 2.27 (s, 3H), 2.08 (s, 1.8H), 1.48-1.06 (m, 29H); 13C NMR (50 MHz, CDCl3) δ = 206.3, 205.8, 171.5, 171.4, 154.8, 154.7, 138.3, 137.9, 128.5, 128.1, 128.0, 127.7, 127.6, 79.5, 79.6, 64.5, 63.0, 61.7, 61.5, 58.7, 28.1, 25.3, 19.7, 18.8, 13.8, 13.7; MS (ESI): m/z = 350.0 [M+H]+ 121.0, 149.9, 206.0; Rt HPLC (97 : 3, n-hexane : i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H column, tR = 13.5 min (major), tR = 15.7 (minor), 91% ee, tR = 12.0 min (major), tR = 19.5 (minor), 71% ee.Inseparable 3: 1.8 diastereomeric mixture. [ a ] 24 D = -4.4 ( c = 2.6, CHCl 3 ); 1 H NMR (200 MHz, CDCl 3 ) δ = 7.31-7.25 (m, 8H), 6.63 (d, J = 9.9 Hz, 1H), 6.11 (d, J = 9.8, 0.56H), 5.25 (d, J = 9.8 Hz, 0.56H), 5.12 (d, J = 9.9 Hz), 4.25-4.10 (m, 3.3H), 2.27 (s, 3H), 2.08 (s, 1.8H), 1.48-1.06 (m, 29H); 13 C NMR (50 MHz, CDCl 3 ) δ = 206.3, 205.8, 171.5, 171.4, 154.8, 154.7, 138.3, 137.9, 128.5, 128.1, 128.0, 127.7, 127.6, 79.5, 79.6, 64.5, 63.0, 61.7, 61.5, 58.7, 28.1, 25.3, 19.7, 18.8, 13.8, 13.7; MS (ESI): m / z = 350.0 [M + H] + 121.0, 149.9, 206.0; R t HPLC (97: 3, n-hexane: i -PrOH, 254 nm, 1.0 mL / min) Chiralpak AD-H column, t R = 13.5 min (major), t R = 15.7 (minor), 91% ee , t R = 12.0 min (major), t R = 19.5 (minor), 71% ee.

[실시예 34] N-(1S, 2S)-2-{(R)-3,5-히드로-4H-디나프트[2,1-c:1’,2’-e]아제핀-4-일}-아미노사이클로헥실 우레아의 제조[Example 34] N - (1 S, 2 S) -2 - {(R) -3,5- dihydro-4H-Deen soft [2,1-c: 1 ', 2'-e] azepin- Preparation of 4-yl} -aminocyclohexyl urea

Figure 112009036943413-pat00035
Figure 112009036943413-pat00035

N-(1S, 2S)-2-{(R)-3,5-히드로-4H-디나프트[2,1-c:1’,2’-e]아제핀-4-일}-사이클로헥산아민 0.353 g (0.9 mmol)을 THF 4.5 mL로 녹인 후, 3,5-비스(트리플루오로메틸)페닐 이소시아네이트 0.229 g (0.9 mmol)을 넣고, 상온에서 14 시간 동안 교반하였다. 조 생성물(crude product)을 컬럼 정제하여 생성물을 83% 수율로 얻었다. N- ( 1S , 2S ) -2-{( R ) -3,5-hydro- 4H -dinaft [2,1-c: 1 ', 2'-e] azin-4-yl}- 0.353 g (0.9 mmol) of cyclohexaneamine was dissolved in 4.5 mL of THF, and then 0.229 g (0.9 mmol) of 3,5-bis (trifluoromethyl) phenyl isocyanate was added thereto, followed by stirring at room temperature for 14 hours. The crude product was column purified to give the product in 83% yield.

[a]D 28 -132.8 (c=1.0, CHCl3); 1H NMR (200 MHz, DMSO-d6) δ = 9.57 (s, 1H), 8.12-7.90 (m, 6H), 7.90-7.75 (m, 2H), 7.53-7.35 (m, 3H), 7.30-7.09 (m, 4H), 6.59 (s, 1H), 4.19-3.78 (m, 1H), 3.98 (d, J = 12.2 Hz, 2H), 3.50 (d, J = 12.2 Hz, 2H), 2.98-2.68 (m, 1H), 2.35-2.12 (m, 1H), 1.82-1.57 (m, 3H), 1.57-1.10 (m, 4H); 13C NMR (50 MHz, DMSO-d6) δ = 154.7, 142.6, 134.5, 133.9, 132.4, 130.5 (q, J C-F = 32.1 Hz), 130.5, 128.2, 126.5, 126.0, 125.7, 125.4, 123.3 (q, J C-F = 270.8 Hz), 116.9, 113.1, 66.8, 51.2, 50.7, 33.1, 26.8, 25.3, 24.3; ESI-MS m/z 647.9 [M+H] +.[ a ] D 28 -132.8 ( c = 1.0, CHCl 3 ); 1 H NMR (200 MHz, DMSO-d 6 ) δ = 9.57 (s, 1H), 8.12-7.90 (m, 6H), 7.90-7.75 (m, 2H), 7.53-7.35 (m, 3H), 7.30- 7.09 (m, 4H), 6.59 (s, 1H), 4.19-3.78 (m, 1H), 3.98 (d, J = 12.2 Hz, 2H), 3.50 (d, J = 12.2 Hz, 2H), 2.98-2.68 (m, 1H), 2.35-2.12 (m, 1H), 1.82-1.57 (m, 3H), 1.57-1.10 (m, 4H); 13 C NMR (50 MHz, DMSO-d 6 ) δ = 154.7, 142.6, 134.5, 133.9, 132.4, 130.5 (q, J CF = 32.1 Hz), 130.5, 128.2, 126.5, 126.0, 125.7, 125.4, 123.3 (q , J CF = 270.8 Hz), 116.9, 113.1, 66.8, 51.2, 50.7, 33.1, 26.8, 25.3, 24.3; ESI-MS m / z 647.9 [M + H] + .

[실시예 35] N-(1S, 2S)-2-{(R)-3,5-디히드로-4H-디나프트[2,1-c:1’,2’-e]아제핀-4-일}-아미노사이클로헥실 티오우레아의 제조Example 35 N- (1 S , 2 S ) -2-{( R ) -3,5-dihydro- 4H -dinaft [2,1-c: 1 ', 2'-e] azepine Preparation of 4-yl} -aminocyclohexyl thiourea

Figure 112009036943413-pat00036
Figure 112009036943413-pat00036

N-(1S, 2S)-2-{(R)-3,5-디히드로-4H-디나프트[2,1-c:1’,2’-e]아제핀-4-일}-사이클로헥산아민 0.353 g (0.9 mmol)을 THF(tetrahydrofuran) 4.5 mL로 녹인 후, 3,5-비스(트리플루오로메틸)페닐 이소티오시아네이트 0.244 g (0.9 mmol)을 넣고, 상온에서 14 시간 동안 교반하였다. 조 생성물(crude product)을 컬럼 정제하여 생성물을 49% 수율로 얻었다. N- (1 S , 2 S ) -2-{( R ) -3,5-dihydro- 4H -dinaft [2,1-c: 1 ', 2'-e] azin-4-yl} 0.353 g (0.9 mmol) of cyclohexanamine was dissolved in 4.5 mL of THF (tetrahydrofuran), and 0.244 g (0.9 mmol) of 3,5-bis (trifluoromethyl) phenyl isothiocyanate was added thereto. Was stirred. The crude product was column purified to give the product in 49% yield.

Mp : 151-152℃; [a]D 25 -349 (c=1.0, CHCl3); 1H NMR (200 MHz, DMSO-d6) 10.07 (br s, 1H), 8.29-8.08 (m, 2H), 8.09-7.85 (m, 4H), 7.80-7.55 (m, 3H), 7.51-7.33 (m, 2H), 7.30-7.07 (m, 4H), 4.42 (br s, 1H), 4.03-3.65 (m, 2H), 3.81 (d, J = 12.2 Hz, 2H), 3.60-3.10 (m, 1H), 3.32 (d, J = 12.2 Hz, 2H), 2.87-2.61 (m, 1H), 2.40-2.15 (m, 1H), 1.77-1.42 (m, 3H), 1.42-0.08 (m, 4H); 13C NMR (50 MHz, DMSO-d6) 179.5, 141.8, 134.3, 133.9, 132.4, 131.3, 130.5, 129.9 (q, J C-F = 32.6 Hz), 128.3, 126.5, 125.9, 125.6, 125.4, 123.2 (q, J C-F = 270.8 Hz), 121.9, 115.7, 33.4, 55.1, 50.9, 31.9, 27.1, 25.1, 24.3; ESI-HRMS : m/z calcd for C37H32F6N3S [M+H]+ : 664.2221; found 664.2212.Mp: 151-152 ° C .; [ a ] D 25 -349 ( c = 1.0, CHCl 3 ); 1 H NMR (200 MHz, DMSO-d 6 ) 10.07 (br s, 1H), 8.29-8.08 (m, 2H), 8.09-7.85 (m, 4H), 7.80-7.55 (m, 3H), 7.51-7.33 (m, 2H), 7.30-7.07 (m, 4H), 4.42 (br s, 1H), 4.03-3.65 (m, 2H), 3.81 (d, J = 12.2 Hz, 2H), 3.60-3.10 (m, 1H), 3.32 (d, J = 12.2 Hz, 2H), 2.87-2.61 (m, 1H), 2.40-2.15 (m, 1H), 1.77-1.42 (m, 3H), 1.42-0.08 (m, 4H) ; 13 C NMR (50 MHz, DMSO-d 6 ) 179.5, 141.8, 134.3, 133.9, 132.4, 131.3, 130.5, 129.9 (q, J CF = 32.6 Hz), 128.3, 126.5, 125.9, 125.6, 125.4, 123.2 (q , J CF = 270.8 Hz), 121.9, 115.7, 33.4, 55.1, 50.9, 31.9, 27.1, 25.1, 24.3; ESI-HRMS: m / z calcd for C 37 H 32 F 6 N 3 S [M + H] < + >:664.2221; found 664.2212.

Claims (7)

알파-시아노케톤 또는 베타-케토에스테르 화합물을, 키랄 촉매의 존재하에서, 이민 화합물과 반응시키는 것을 포함하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법으로,In a method for producing a beta-amino carbonyl compound using a chiral catalyst comprising reacting an alpha-cyano ketone or a beta-ketoester compound with an imine compound in the presence of a chiral catalyst, 상기 키랄 촉매는, 우레아와 아민 그룹이 결합된 키랄 양기능 유기촉매 혹은 싸이오유레아와 아민 그룹이 결합된 키랄 양기능 유기촉매이고,The chiral catalyst is a chiral bifunctional organic catalyst in which urea and amine groups are bonded or a chiral bifunctional organic catalyst in which thiourea and amine groups are bonded, 상기 알파-시아노케톤 화합물은 화학식 2의 구조를 갖고, 상기 베타-케토에스테르 화합물은 화학식 3의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법: The alpha-cyano ketone compound has a structure of Formula 2, wherein the beta-ketoester compound has a structure of Formula 3, a method for producing a beta-amino carbonyl compound using a chiral catalyst, characterized in that: [화학식 2][Formula 2]
Figure 112011033645568-pat00043
Figure 112011033645568-pat00043
 [화학식 3](3)
Figure 112011033645568-pat00044
Figure 112011033645568-pat00044
 상기 화학식 2 또는 3에서, In Chemical Formula 2 or 3, 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 are C 1 -C 40 alkyl or aryl groups, which are the same or different from each other, R 1 and R 2 may be linked to each other to form part of a ring system, 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. 삭제delete 제 1 항에 있어서,The method of claim 1, 상기 키랄 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 5 내지 20 몰%인 것을 특징으로 하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법.The content of the chiral catalyst, based on the total number of moles of the reactant, a method for producing a beta-amino carbonyl compound using a chiral catalyst, characterized in that 5 to 20 mol%. 제 1 항에 있어서,The method of claim 1, 상기 키랄 촉매는 하기 화학식 1의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법:The chiral catalyst is a method for producing a beta-amino carbonyl compound using a chiral catalyst, characterized in that having the structure of Formula 1: [화학식 1][Formula 1]
Figure 112009036943413-pat00037
Figure 112009036943413-pat00037
 상기 식에서, X는 O 또는 S임.Wherein X is O or S. 삭제delete 제 1 항에 있어서,The method of claim 1, 이민 화합물은 화학식 4의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법:Method for preparing a beta-amino carbonyl compound using a chiral catalyst, characterized in that the imine compound has a structure of Formula 4: [화학식 4][Formula 4]
Figure 112011033645568-pat00040
Figure 112011033645568-pat00040
 상기 식에서,Where R4는 C1-C20의 아릴기, 알킬기 또는 알콕시 카보닐기이며,R 4 is a C 1 -C 20 aryl group, alkyl group or alkoxy carbonyl group, R5는 C1-C40의 아릴기, 헤테로 아로마틱, 포스피닐, 술포닐 또는 알콕시 카보닐기이며,R 5 is a C 1 -C 40 aryl group, heteroaromatic, phosphinyl, sulfonyl or alkoxy carbonyl group, 상기 아릴기는 C1-C20의 알콕시기, 알콕시 카보닐, 알킬 또는 할로겐으로 치환된 아릴기임.The aryl group is an aryl group substituted with a C 1 -C 20 alkoxy group, alkoxy carbonyl, alkyl or halogen. 제 1 항에 있어서,The method of claim 1, 베타-아미노 카보닐 화합물은, 화학식 5 또는 6의 구조를 갖는 것을 특징으로 하는 키랄 촉매를 이용한 베타-아미노 카보닐 화합물의 제조방법:Beta-amino carbonyl compound, a method for producing a beta-amino carbonyl compound using a chiral catalyst, characterized in that having a structure of Formula 5 or 6: [화학식 5] [Chemical Formula 5]
Figure 112011033645568-pat00041
Figure 112011033645568-pat00041
 [화학식 6][Formula 6]
Figure 112011033645568-pat00042
Figure 112011033645568-pat00042
 상기 화학식 5 또는 6에서, In Chemical Formula 5 or 6, 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 are C 1 -C 40 alkyl or aryl groups, which are the same or different from each other, R 1 and R 2 may be linked to each other to form part of a ring system, R3 는 C1-C20의 알킬기이고, R 3 is an alkyl group of C 1 -C 20 , R4는 C1-C20의 아릴기, 알킬기 또는 알콕시 카보닐기이며,R 4 is a C 1 -C 20 aryl group, alkyl group or alkoxy carbonyl group, R5는 C1-C40의 아릴기, 헤테로 아로마틱, 포스피닐, 술포닐 또는 알콕시 카보닐기이며,R 5 is a C 1 -C 40 aryl group, heteroaromatic, phosphinyl, sulfonyl or alkoxy carbonyl group, 상기 아릴기는 C1-C20의 알콕시기, 알콕시 카보닐, 알킬 또는 할로겐으로 치환된 아릴기임.The aryl group is an aryl group substituted with a C 1 -C 20 alkoxy group, alkoxy carbonyl, alkyl or halogen.
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