JP2013166114A - HETEROARENE CARBONYLATED CINCHONA ALKALOID CATALYST AND METHOD FOR PRODUCING OPTICALLY ACTIVE β-AMINOPHOSPHONIC ACID OR β-AMINOPHOSPHINE USING THE SAME - Google Patents
HETEROARENE CARBONYLATED CINCHONA ALKALOID CATALYST AND METHOD FOR PRODUCING OPTICALLY ACTIVE β-AMINOPHOSPHONIC ACID OR β-AMINOPHOSPHINE USING THE SAME Download PDFInfo
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Abstract
Description
本発明は、ヘテロアレーンカルボニル化キナアルカロイド触媒とそれを用いる光学活性β-アミノホスホン酸またはβ-アミノホスフィンの製造方法に関するものである。 The present invention relates to a heteroarene carbonylated quinaalkaloid catalyst and a method for producing optically active β-aminophosphonic acid or β-aminophosphine using the same.
光学活性なβ-アミノホスホン酸またはβ-アミノホスフィン誘導体は、医農薬品合成の中間体や不斉配位子として広く用いられるため、その不斉合成技術は盛んに研究されてきた（非特許文献１、２）。このための有効な合成法の一つとして、近年、ニトロオレフィンへの亜リン酸エステル類の不斉共役付加反応が検討されている（非特許文献３−８）。しかしながら、この手法による合成は、主に光学活性α-モノ置換β-アミノホスホン酸を与え、光学活性α,β-ジ置換β-アミノホスホン酸の合成への展開は困難である。また、より容易なβ-アミノホスホン酸またはβ-アミノホスフィンの前駆体合成の手法の一つとして、アジリジン類のリン化合物による不斉触媒的開環反応が挙げられるが、全く報告されていない。 Since optically active β-aminophosphonic acid or β-aminophosphine derivatives are widely used as intermediates and asymmetric ligands in the synthesis of medicines and agricultural chemicals, their asymmetric synthesis techniques have been actively studied (non-patented) References 1, 2). As an effective synthesis method for this purpose, an asymmetric conjugate addition reaction of phosphites to nitroolefins has recently been studied (Non-patent Documents 3-8). However, synthesis by this method mainly gives optically active α-monosubstituted β-aminophosphonic acid, and development to synthesis of optically active α, β-disubstituted β-aminophosphonic acid is difficult. One of the easier methods for synthesizing β-aminophosphonic acid or β-aminophosphine precursors is asymmetric catalytic ring-opening reaction with phosphorus compounds of aziridines, but none has been reported.
この出願の発明が解決しようとする課題は、現状の技術では、光学活性なβ-アミノホスホン酸またはβ-アミノホスフィンへと変換ができる前駆体の簡便かつ高エナンチオ選択的合成法がない点である。
本発明は、上記点に鑑みて、新規な不斉触媒（ヘテロアレーンカルボニル化キナアルカロイド触媒）を提供することにある。本発明の他の目的は、当該不斉触媒を用いて光学活性なβ-アミノホスホン酸またはβ-アミノホスフィン誘導体の不斉触媒的製造方法を提供することにある。
The problem to be solved by the invention of this application is that, with the current technology, there is no simple and highly enantioselective synthesis method of a precursor that can be converted into optically active β-aminophosphonic acid or β-aminophosphine. is there.
In view of the above points, the present invention is to provide a novel asymmetric catalyst (heteroarenecarbonylated quinaalkaloid catalyst). Another object of the present invention is to provide an asymmetric catalytic production method of an optically active β-aminophosphonic acid or β-aminophosphine derivative using the asymmetric catalyst.
この出願の発明は、上記目的を達成するものとして、次式（１）乃至（８）で示されるヘテロアレーンカルボニル化キナアルカロイド触媒を提供する (請求項１乃至８)。 In order to achieve the above object, the invention of this application provides a heteroarenecarbonylated quinaalkaloid catalyst represented by the following formulas (1) to (8) (claims 1 to 8).
また、この出願の発明は、次式（９） In addition, the invention of this application provides the following formula (9)
（式中、R1は、環状アルキル基、鎖状アルキル基、シリル基またはアリール基を示す。Ｒ２は、環状アルキル基、鎖状アルキル基、フェニル基、シリル基またはアリール基を示す。PGはピコリノイル基、キナルジノイル基、ベンゾイル基、トシル基、ノシル基、ベンゼンスルホニル基を示す。）
で示される、種々のメソアジリジン類にアルキル亜鉛と不斉配位子存在下で亜リン酸エステルを反応させてアジリジンの不斉開環反応によりβ-アミノホスホン酸またはβ-アミノホスフィン誘導体を製造する方法を提供し（請求項９）、前記不斉配位子が前記式（１）乃至（８）に記載の触媒のうちのいずれかであることを特徴とする前記請求項９記載のβ-アミノホスホン酸またはβ-アミノホスフィン誘導体を製造する方法を提供する（請求項１０）。
(Wherein R 1 represents a cyclic alkyl group, a chain alkyl group, a silyl group or an aryl group. R 2 represents a cyclic alkyl group, a chain alkyl group, a phenyl group, a silyl group or an aryl group. PG Represents a picolinoyl group, a quinaldinoyl group, a benzoyl group, a tosyl group, a nosyl group, or a benzenesulfonyl group.)
To produce β-aminophosphonic acid or β-aminophosphine derivatives by asymmetric ring-opening reaction of aziridine by reacting various mesoaziridines with alkylzinc phosphite in the presence of an asymmetric ligand The method according to claim 9, wherein the asymmetric ligand is any one of the catalysts according to the formulas (1) to (8). A process for producing a -aminophosphonic acid or β-aminophosphine derivative is provided (claim 10).
発明者らは，アジリジンの窒素上にヘテロアレーンカルボニル基を導入し、これまでに全く報告例のない亜リン酸エステルを求核剤として用いる触媒的不斉開環反応を実施検討した。また、これまでに全く検討例のない本手法を成功させるために、これまでに使用例のないキナアルカロイド由来の9-epiアミノピコリンアミド触媒を新規不斉触媒として用い、新しい合成手法の実施検討を行った。
（第１実施形態）キナアルカロイド由来の9-epiアミノピコリンアミド触媒
次式（１０）
The inventors conducted a study on a catalytic asymmetric ring-opening reaction in which a heteroarene carbonyl group was introduced on the nitrogen of aziridine and a phosphite, which has never been reported before, was used as a nucleophile. In addition, in order to succeed this method, which has not been studied at all so far, 9-epiaminopicolinamide catalyst derived from quina alkaloids, which has not been used so far, was used as a novel asymmetric catalyst, and a new synthesis method was examined. Went.
(First Embodiment) 9-epi aminopicolinamide catalyst derived from quina alkaloids (10)
式中、ＤＩＡＤは、アゾジカルボン酸ジイソプロピルを、ＰＰｈ３は、トリフェニルホスフィンを、ＤＰＰＡは、ジフェニルホスホニルアジドを、ＴＨＦは、テトラヒドロフランを、Ｅｔ３Ｎは、トリエチルアミンを、ＤＭＡＰは、4−ジメチルアミノピリジンを、ｃａｔは、触媒量を、ＣＨ２Ｃｌ２は、ジクロロメタンを、また、ＤＣＣは、Ｎ,Ｎ’-ジシクロヘキシルカルボジイミドを示す。式（１０）は、第２実施形態で記述する反応に使用する前記式（１）乃至（８）の新規不斉触媒であるシンコナアルカロイド由来のピコリンアミドの合成法である。シンコニンを光延反応条件下において9位が立体反転したアミンとし（既知反応）、ピコリノイルクロライドと反応させることでシンコニン由来の9-エピピコリンアミド触媒が得られる。また、前記アミンとピコリン酸をジシクロヘキシルカルボジイミドなどの縮合剤を用いても合成が可能である。また、シンコニジン、キニジン、キニン及びそれら誘導体も同手法にて対応するピコリンアミド触媒が合成可能である。
前記式（１０）の合成法の実施により上記式（１）乃至（８）の新規不斉触媒の合成したことについて次の実施例１乃至８に記述する。
（実施例１）
前記式（１）の化学式で与えられる目的生成物N-(9-deoxyepicinchonin-9-yl) picolinamideを前記式（５）の合成法により次のようにして合成した。
シンコニンより既知反応にて9位が立体反転したアミンとした後、9-epiシンコニンアミン（254 mg, 0.86 mmol）、ピコリン酸（112 mg, 0.91 mmol）、ジシクロヘキシルカルボジイミド（196 mg, 0.95 mmol）と4-ジメチルアミノピリジン（11 mg, 0.086 mmol）をジクロロメタン10 mlに溶かし、1時間攪拌を行った。精製は、反応溶液をセライトでろ過した後、シリカゲルカラムクロマトグラフィー (AcOEt:MeOH = 70:30)で行い、目的生成物を278 mg (81 %)で得た。
当該目的生成物N-(9-deoxyepicinchonin-9-yl)picolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 0.90-1.10 (m, 1H), 1.20-1.40 (m, 2H), 2.25-2.40 (m, 1H), 2.95-3.15 (m, 5H), 3.20-3.35 (m, 1H), 5.10-5.20 (m, 2H), 5.60 (br, 1H), 5.87-6.00 (m, 1H), 7.38-7.42 (m, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.70-7.80 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.88 (d, J = 4.5 Hz, 1H), 9.02 (br, 1H)
LRMS (ESI, positive) m/z 399.7 [M+H]+, 421.7 [M+Na]
（実施例２）
前記式（２）の化学式で与えられるN-(9-deoxyepicinchonin-9-yl)-4-nitropicolinamideを9-epiシンコニンアミンより収率34 %で得た。
当該N-(9-deoxyepicinchonin-9-yl)-4-nitropicolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 1.00-1.10 (m, 1H), 1.21-1.37 (m, 3H), 1.54-1.69 (m, 3H), 2.31-2.36 (m, 1H), 2.91-3.08 (m, 4H), 3.22-3.30 (m, 1H), 5.11-5.19 (m, 2H), 5.62 (br, 1H), 5.89-5.99 (m, 1H), 7.50-7.51 (m, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 8.13-8.16 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.71-8.72 (m, 1H), 8.86 -8.93(m, 1H), 9.04 (br, 1H)
LRMS (ESI, positive) m/z 444.3 [M+H]+
（実施例３）
前記式（３）の化学式で与えられるN-(9-deoxyepicinchonin-9-yl)-4-methoxypicolinamideを9-epiシンコニンアミンより収率15 %で得た。
当該N-(9-deoxyepicinchonin-9-yl)-4-methoxypicolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 0.97-1.03 (m, 1H), 1.21-1.35 (m, 1H), 1.52-1.66 (m, 3H), 2.29-2.31 (m, 1H), 2.93-3.13 (m, 4H), 3.19-3.28 (m, 1H), 3.81 (s, 3H), 5.10-5.15 (m, 2H), 5.60 (br, 1H), 5.85-5.98 (m, 1H), 6.88-6.89 (m, 1H), 7.49-7.50 (m, 1H), 7.55-7.65 (m, 2H), 7.72 (t, J = 7.5 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.38 (d, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.87 (d, 1H), 9.03 (br, 1H)
LRMS (ESI, positive) m/z 429.5 [M+H]+
（実施例４）
前記式（４）の化学式で与えられるN-(9-deoxyepicinchonin-9-yl)-quinaldinamideを9-epiシンコニンアミンより収率48 %で得た。
当該N-(9-deoxyepicinchonin-9-yl)-quinaldinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 1.01-1.07 (m, 1H), 1.31-1.38 (m, 1H), 1.50-1.60 (m, 2H), 1.60-1.75 (m, 3H), 2.30-2.35 (m, 1H), 3.02-3.20 (m, 4H), 3.27-3.33 (m, 1H), 5.10-5.17 (m, 2H), 5.69 (br, 1H), 5.89-5.99 (m, 1H), 7.58-7.66 (m, 3H), 7.70-7.77 (m, 2H), 7.83-7.86 (m, 1H), 8.13-8.22 (m, 4H), 8.51 (d, J = 8.4 Hz, 1H), 8.89 (d, 1H), 9.21 (br, 1H)
LRMS (ESI, positive) m/z 449.5 [M+H]+
（実施例５）
前記式（５）の化学式で与えられるN-(9-deoxyepicinchonidin-9-yl)picolinamideを9-epiシンコニジンアミンより収率92 %で得た。
当該N-(9-deoxyepicinchonidin-9-yl)picolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 0.90-1.05 (m, 1H), 1.39-1.47 (m, 1H), 1.60-1.80 (m, 4H), 2.30-2.40 (m, 1H), 2.70-2.90 (m, 2H), 3.15-3.40 (m, 3H), 4.94-5.03 (m, 2H), 5.62 (br, 1H), 5.62-5.82 (m, 1H), 7.38-7.42 (m, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.70-7.80 (m, 2H), 8.04 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 9.04 (br, 1H)
LRMS (ESI, positive) m/z 399.9 [M+H]+
（実施例６）
前記式（６）の化学式で与えられるN-(9-deoxyepicinchonidin-9-yl)-quinaldinoyllamideを9-epiシンコニジンアミンより収率83 %で得た。
当該N-(9-deoxyepicinchonidin-9-yl)-quinaldinoylamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 0.95-1.01 (m, 1H), 1.44-1.47 (m, 1H), 1.60-1.80 (m, 5H), 2.30-2.40 (m, 1H), 2.70-2.95 (m, 2H), 3.20-3.40 (m, 3H), 4.97-5.05 (m, 2H), 5.70 (br, 1H), 5.74-5.86 (m, 1H), 7.57-7.86 (m, 6H), 8.14-8.22 (m, 4H), 8.54 (d, J = 8.4 Hz, 1H), 8.90 (d, 1H), 9.21 (br, 1H)
LRMS (ESI, positive) m/z 449.5 [M+H]+
（実施例７）
前記式（７）の化学式で与えられるN-(9-deoxyepiquinidin-9-yl)picolinamideを9-epiキニジンアミンより収率51 %で得た。
当該N-(9-deoxyepiquinidin-9-yl)picolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 1.10-1.20 (m, 1H), 1.30-1.40 (m, 1H), 1.45-1.70 (m, 4H), 2.30-2.40 (m, 1H), 3.00-3.20 (m, 3H), 3.20-3.40 (m, 1H), 3.99 (s, 3H), 5.11-5.18 (m, 2H), 5.63 (br, 1H), 5.88-5.99 (m, 1H), 7.35-7.46 (m, 3H), 7.61-7.71 (m, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.99-8.08 (m, 2H), 8.58 (d, J = 3.9 Hz, 1H), 8.73 (d, J = 4.5 Hz, 1H), 8.96 (br, 1H)
LRMS (ESI, positive) m/z 429.8 [M+H]+
（実施例８）
前記式（８）の化学式で与えられるN-(9-deoxyepiquinin-9-yl)picolinamideを9-epiキニンアミンより収率66 %で得た。
当該N-(9-deoxyepiquinin-9-yl)picolinamideのスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 0.94-1.00 (m, 1H), 1.52-1.79 (m, 5H), 2.30-2.40 (m, 1H), 2.76-2.83 (m, 2H), 3.26-3.40 (m, 3H), 3.99 (s, 3H), 4.98-5.05 (m, 2H), 5.62 (br, 1H), 5.75-5.86 (m, 1H), 7.35-7.45 (m, 3H), 7.77-7.81 (m, 2H), 8.00-8.08 (m, 2H), 8.57 (d, J = 4.8 Hz, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.88 (br, 1H)
LRMS (ESI, positive) m/z 429.8 [M+H]+
（第２実施形態）アジリジンの不斉開環反応
次式（１１）
In the formula, DIAD is diisopropyl azodicarboxylate, PPh 3 is triphenylphosphine, DPPA is diphenylphosphonyl azide, THF is tetrahydrofuran, Et 3 N is triethylamine, and DMAP is 4-dimethyl. Aminopyridine, cat represents a catalytic amount, CH 2 Cl 2 represents dichloromethane, and DCC represents N, N′-dicyclohexylcarbodiimide. Formula (10) is a method for synthesizing picolinamide derived from cinchona alkaloid, which is a novel asymmetric catalyst of formulas (1) to (8) used in the reaction described in the second embodiment. The 9-epipicolinamide catalyst derived from cinchonine is obtained by reacting cinchonine with amine which is stereo-reversed at 9-position under the Mitsunobu reaction conditions (known reaction) and reacting with picolinoyl chloride. The amine and picolinic acid can also be synthesized using a condensing agent such as dicyclohexylcarbodiimide. In addition, cinchonidine, quinidine, quinine, and derivatives thereof can also synthesize corresponding picolinamide catalysts by the same method.
The following Examples 1 to 8 describe the synthesis of novel asymmetric catalysts of the above formulas (1) to (8) by carrying out the synthesis method of the above formula (10).
Example 1
The target product N- (9-deoxyepicinchonin-9-yl) picolinamide given by the chemical formula of the formula (1) was synthesized by the synthesis method of the formula (5) as follows.
9-epi cinchonine amine (254 mg, 0.86 mmol), picolinic acid (112 mg, 0.91 mmol), dicyclohexylcarbodiimide (196 mg, 0.95 mmol) And 4-dimethylaminopyridine (11 mg, 0.086 mmol) were dissolved in 10 ml of dichloromethane and stirred for 1 hour. Purification was performed by filtering the reaction solution through celite and then performing silica gel column chromatography (AcOEt: MeOH = 70: 30) to obtain 278 mg (81%) of the desired product.
The spectrum of the target product N- (9-deoxyepicinchonin-9-yl) picolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 0.90-1.10 (m, 1H), 1.20-1.40 (m, 2H), 2.25-2.40 (m, 1H), 2.95-3.15 (m, 5H), 3.20-3.35 (m, 1H), 5.10-5.20 (m, 2H), 5.60 (br, 1H), 5.87-6.00 (m, 1H), 7.38-7.42 (m, 1H), 7.51 (d, J = 4.8 Hz, 1H ), 7.62 (t, J = 7.2 Hz, 1H), 7.70-7.80 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.47 (d , J = 8.4 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.88 (d, J = 4.5 Hz, 1H), 9.02 (br, 1H)
LRMS (ESI, positive) m / z 399.7 [M + H] + , 421.7 [M + Na]
(Example 2)
N- (9-deoxyepicinchonin-9-yl) -4-nitropicolinamide given by the chemical formula of the above formula (2) was obtained from 9-epi cinchonine amine in a yield of 34%.
The spectrum of the N- (9-deoxyepicinchonin-9-yl) -4-nitropicolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 1.00-1.10 (m, 1H), 1.21-1.37 (m, 3H), 1.54-1.69 (m, 3H), 2.31-2.36 (m, 1H), 2.91-3.08 (m, 4H), 3.22-3.30 (m, 1H), 5.11-5.19 (m, 2H), 5.62 (br, 1H), 5.89-5.99 (m, 1H), 7.50-7.51 (m, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 8.13-8.16 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.71-8.72 (m, 1H), 8.86 -8.93 (m, 1H), 9.04 (br, 1H)
LRMS (ESI, positive) m / z 444.3 [M + H] +
(Example 3)
N- (9-deoxyepicinchonin-9-yl) -4-methoxypicolinamide given by the chemical formula of the formula (3) was obtained from 9-epi cinchonine amine in a yield of 15%.
The spectrum of the N- (9-deoxyepicinchonin-9-yl) -4-methoxypicolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 0.97-1.03 (m, 1H), 1.21-1.35 (m, 1H), 1.52-1.66 (m, 3H), 2.29-2.31 (m, 1H), 2.93-3.13 (m, 4H), 3.19-3.28 (m, 1H), 3.81 (s, 3H), 5.10-5.15 (m, 2H), 5.60 (br, 1H), 5.85-5.98 (m, 1H), 6.88-6.89 (m, 1H), 7.49-7.50 (m, 1H), 7.55-7.65 (m, 2H), 7.72 (t, J = 7.5 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.38 ( d, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.87 (d, 1H), 9.03 (br, 1H)
LRMS (ESI, positive) m / z 429.5 [M + H] +
Example 4
N- (9-deoxyepicinchonin-9-yl) -quinaldinamide given by the chemical formula of the formula (4) was obtained from 9-epi cinchoninamine in a yield of 48%.
The spectrum of the N- (9-deoxyepicinchonin-9-yl) -quinaldinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 1.01-1.07 (m, 1H), 1.31-1.38 (m, 1H), 1.50-1.60 (m, 2H), 1.60-1.75 (m, 3H), 2.30-2.35 (m, 1H), 3.02-3.20 (m, 4H), 3.27-3.33 (m, 1H), 5.10-5.17 (m, 2H), 5.69 (br, 1H), 5.89-5.99 (m, 1H), 7.58 -7.66 (m, 3H), 7.70-7.77 (m, 2H), 7.83-7.86 (m, 1H), 8.13-8.22 (m, 4H), 8.51 (d, J = 8.4 Hz, 1H), 8.89 (d , 1H), 9.21 (br, 1H)
LRMS (ESI, positive) m / z 449.5 [M + H] +
(Example 5)
N- (9-deoxyepicinchonidin-9-yl) picolinamide given by the chemical formula of the formula (5) was obtained from 9-epi cinchonidine amine in a yield of 92%.
The spectrum of the N- (9-deoxyepicinchonidin-9-yl) picolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 0.90-1.05 (m, 1H), 1.39-1.47 (m, 1H), 1.60-1.80 (m, 4H), 2.30-2.40 (m, 1H), 2.70-2.90 (m, 2H), 3.15-3.40 (m, 3H), 4.94-5.03 (m, 2H), 5.62 (br, 1H), 5.62-5.82 (m, 1H), 7.38-7.42 (m, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.70-7.80 (m, 2H), 8.04 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 9.04 (br, 1H)
LRMS (ESI, positive) m / z 399.9 [M + H] +
(Example 6)
N- (9-deoxyepicinchonidin-9-yl) -quinaldinoyllamide given by the chemical formula of the above formula (6) was obtained from 9-epi cinchonidine amine in a yield of 83%.
The spectrum of the N- (9-deoxyepicinchonidin-9-yl) -quinaldinoylamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 0.95-1.01 (m, 1H), 1.44-1.47 (m, 1H), 1.60-1.80 (m, 5H), 2.30-2.40 (m, 1H), 2.70-2.95 (m, 2H), 3.20-3.40 (m, 3H), 4.97-5.05 (m, 2H), 5.70 (br, 1H), 5.74-5.86 (m, 1H), 7.57-7.86 (m, 6H), 8.14 -8.22 (m, 4H), 8.54 (d, J = 8.4 Hz, 1H), 8.90 (d, 1H), 9.21 (br, 1H)
LRMS (ESI, positive) m / z 449.5 [M + H] +
(Example 7)
N- (9-deoxyepiquinidin-9-yl) picolinamide given by the chemical formula (7) was obtained from 9-epiquinidineamine in a yield of 51%.
The spectrum of the N- (9-deoxyepiquinidin-9-yl) picolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 1.10-1.20 (m, 1H), 1.30-1.40 (m, 1H), 1.45-1.70 (m, 4H), 2.30-2.40 (m, 1H), 3.00-3.20 (m, 3H), 3.20-3.40 (m, 1H), 3.99 (s, 3H), 5.11-5.18 (m, 2H), 5.63 (br, 1H), 5.88-5.99 (m, 1H), 7.35-7.46 (m, 3H), 7.61-7.71 (m, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.99-8.08 (m, 2H), 8.58 (d, J = 3.9 Hz, 1H), 8.73 ( d, J = 4.5 Hz, 1H), 8.96 (br, 1H)
LRMS (ESI, positive) m / z 429.8 [M + H] +
(Example 8)
N- (9-deoxyepiquinin-9-yl) picolinamide given by the chemical formula (8) was obtained from 9-epiquininamine in a yield of 66%.
The spectrum of the N- (9-deoxyepiquinin-9-yl) picolinamide is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 0.94-1.00 (m, 1H), 1.52-1.79 (m, 5H), 2.30-2.40 (m, 1H), 2.76-2.83 (m, 2H), 3.26-3.40 (m, 3H), 3.99 (s, 3H), 4.98-5.05 (m, 2H), 5.62 (br, 1H), 5.75-5.86 (m, 1H), 7.35-7.45 (m, 3H), 7.77-7.81 (m, 2H), 8.00-8.08 (m, 2H), 8.57 (d, J = 4.8 Hz, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.88 (br, 1H)
LRMS (ESI, positive) m / z 429.8 [M + H] +
(Second Embodiment) Asymmetric Ring-Opening Reaction of Aziridine Formula (11)
は本発明の反応の概要である。この式（１１）のような種々のメソアジリジン類にアルキル亜鉛と不斉配位子存在下で亜リン酸エステルを反応させると、高エナンチオ選択的に生成物を与える。R1 、R2は、環状アルキル基、鎖状アルキル基、シリル基またはアリール基である。
ここで、PG（保護基）はピコリノイル基が最もよく、キナルジノイル基、ベンゾイル基、トシル基、ノシル基、ベンゼンスルホニル基でも良い。また、R2はフェニル基が最もよく、アルキルやシリル基でもよい。また、用いる不斉配位子は、第１実施形態に記述したシンコニン由来の9-epiアミノピコリンアミド触媒もしくはシンコニジン由来の9-アミノピコリンアミド触媒が最も良い。
（他の実施形態）
用いる触媒はキナアルカロイド由来のジアミンや光学活性ジアミン類を主骨格として有するピコリンアミドでも良い。また、他のキナアルカロイド由来のジアミンのキナルジノイル、ベンゾイル、トシル、ノシル、ベンゼンスルホンアミドでも良い。
（参考例１）
下記実施例で用いる次式（１２）の化学式で与えられるN-picolinoyl-7-azabicyclo [4.1.0]heptane の合成について記述する。
Is a summary of the reaction of the present invention. When various mesoaziridines such as the formula (11) are reacted with an alkylzinc phosphite in the presence of an asymmetric ligand, a product is obtained with high enantioselectivity. R 1 and R 2 are a cyclic alkyl group, a chain alkyl group, a silyl group or an aryl group.
Here, PG (protecting group) is most preferably a picolinoyl group, and may be a quinaldinoyl group, a benzoyl group, a tosyl group, a nosyl group, or a benzenesulfonyl group. R 2 is most preferably a phenyl group, and may be an alkyl or silyl group. The asymmetric ligand used is best the 9-epiaminopicolinamide catalyst derived from cinchonine or the 9-aminopicolinamide catalyst derived from cinchonidine described in the first embodiment.
(Other embodiments)
The catalyst used may be quinalkaloid-derived diamine or picolinamide having an optically active diamine as a main skeleton. Further, quinalzinoyl, benzoyl, tosyl, nosyl, and benzenesulfonamide of diamine derived from other quina alkaloids may be used.
(Reference Example 1)
The synthesis of N-picolinoyl-7-azabicyclo [4.1.0] heptane given by the chemical formula of the following formula (12) used in the following examples is described.
シクロヘキセン由来の無置換のアジリジン(970 mg, 10 mmol)、4-ジメチルアミノピリジン(110 mg, 0.10 mmol)、ジシクロヘキシルカルボジイミド(2.3 g, 11 mmol)、ピコリン酸(1.3 g, 10.5 mmol)、をジクロロメタン50 mlに溶かし、1時間攪拌を行った。精製は、反応溶液をセライトでろ過した後、シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 70:30)で行い、目的生成物を1.8 g (88 %)で得た。
このN-picolinoyl-7-azabicyclo[4.1.0]heptaneのスペクトル等は以下の通り。
m.p. 65.0-67.0 °C
1H NMR (CDCl3) δ 1.30-1.56 (m, 4H, CH2), 1.80-1.96 (m, 2H, CH2), 2.14-2.30 (m, 2H, CH2), 2.85-2.87 (m, 2H, CH), 7.36-7.44 (m, 1H, Py), 7.75-7.84 (m, 1H, Py), 8.05-8.09 (m, 1H, Py), 8.68-8.70 (m, 1H, Py)
13C NMR (CDCl3) δ 20.0, 23.7, 37.2, 123.8, 126.1, 136.5, 149.3, 151.0, 177.6
IR(KBr) 2937, 1669, 1438, 1417, 1326, 1137, 750 cm−1
LRMS (APCI, positive) m/z 203.1 [M+H]+
（実施例９、１０）
次式（１３）の化学式で与えられるDiphenyl 2-(picolinamido)cyclohexylphosphonateの合成について記述する。
Cyclohexene-derived unsubstituted aziridine (970 mg, 10 mmol), 4-dimethylaminopyridine (110 mg, 0.10 mmol), dicyclohexylcarbodiimide (2.3 g, 11 mmol), picolinic acid (1.3 g, 10.5 mmol), dichloromethane It melt | dissolved in 50 ml and stirred for 1 hour. Purification was performed by filtering the reaction solution through celite, followed by silica gel column chromatography (Hexane: AcOEt = 70: 30) to obtain 1.8 g (88%) of the desired product.
The spectrum of this N-picolinoyl-7-azabicyclo [4.1.0] heptane is as follows.
mp 65.0-67.0 ° C
1 H NMR (CDCl 3 ) δ 1.30-1.56 (m, 4H, CH 2 ), 1.80-1.96 (m, 2H, CH 2 ), 2.14-2.30 (m, 2H, CH 2 ), 2.85-2.87 (m, 2H, CH), 7.36-7.44 (m, 1H, Py), 7.75-7.84 (m, 1H, Py), 8.05-8.09 (m, 1H, Py), 8.68-8.70 (m, 1H, Py)
13 C NMR (CDCl 3 ) δ 20.0, 23.7, 37.2, 123.8, 126.1, 136.5, 149.3, 151.0, 177.6
IR (KBr) 2937, 1669, 1438, 1417, 1326, 1137, 750 cm -1
LRMS (APCI, positive) m / z 203.1 [M + H] +
(Examples 9 and 10)
The synthesis of Diphenyl 2- (picolinamido) cyclohexylphosphonate given by the chemical formula of the following formula (13) will be described.
乾燥させたフラスコにシンコニン由来の9-epiアミノピコリンアミド触媒（8.0 mg, 0.02 mmol）をトルエン0.5 mLに溶解させ、ジエチル亜鉛（20 mL, 0.02 mmol）を加え30分攪拌した。続いて、参考例1に示したN-picolinoyl-7-azabicyclo[4.1.0]heptane (40 mg, 0.2 mmol）、亜リン酸ジフェニル（58 mL, 0.3 mmol）とモレキュラーシーブス4A (40 mg)のトルエン1.0 ml溶液を0 ℃に冷却し、先の溶液を加え室温で3時間攪拌した。反応はTLC（薄層クロマトグラフィー）にて確認後、1規定塩酸1 mLを加え、塩化メチレンで抽出、無水硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去後、精製はシリカゲルカラムクロマトグラフィー（Hexane:AcOEt = 60:40）で行い(R, R)の立体化学を有する開環生成物を73 mg (84 %, 99% ee) で得た。
また、乾燥させたフラスコにシンコニジン由来の9-epiアミノピコリンアミド触媒（8.0 mg, 0.02 mmol）をベンゼン0.5 mLに溶解させ、ジエチル亜鉛（20 ml, 0.02 mmol）を加え30分攪拌した。続いて、N-picolinoyl-7-azabicyclo[4.1.0]heptane (40 mg, 0.2 mmol）、亜リン酸ジフェニル（58 ml, 0.3 mmol）とモレキュラーシーブス4A (40 mg)のベンゼン1.0 ml溶液を0 °Cに冷却し、先の溶液を加え室温で3時間攪拌した。反応はTLCにて確認後、1規定塩酸1 mLを加え、塩化メチレンで抽出、無水硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去後、精製はシリカゲルカラムクロマトグラフィー（Hexane:AcOEt = 60:40）で行い(S, S) の立体化学を有する開環生成物を70 mg (80 %, 98% ee) で得た。
用いる触媒をシンコニジン由来のピコリンアミドにすると逆の立体化学を有する開環生成物が得られる。
Diphenyl 2-(picolinamido)cyclohexylphosphonateのスペクトル等は以下の通り。
1H NMR (300 MHz, CDCl3) δ 1.25-1.60 (m, 3H), 1.60-1.95 (m, 3H), 2.20-2.55 (m, 3H), 4.35-4.50 (m, 1H), 7.00-7.22 (m, 10H), 7.27-7.36 (m, 1H), 7.76-7.81 (m, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 8.54 (d, J = 8.1 Hz, 1H)
13C NMR (75 MHz, CDCl3) δ 24.6, 25.2 (d, J = 15.4 Hz), 26.3 (d, J = 5.5 Hz), 33.6, (d, J = 13.7 Hz), 41.2 (d, J = 139.7 Hz), 48.8, (d, J = 6.0 Hz), 120.5, (d, J = 1.7 Hz), 120.6 (d, J = 2.2 Hz), 122.2, 124.8, 126.0, 129.5 (d, J = 1.7 Hz), 137.2, 148.0, 150.0, 150.3 (d, J = 3.3 Hz), 150.4 (d, J = 3.8 Hz), 163.3
31P NMR (121 MHz, CDCl3) δ 22.79
LRMS (ESI, positive) m/z 399.9 [M+H]+
HPLC (DAICEL CHIRALPAK AD3O, Hexane:iPrOH = 70:30, 1.0 mL/min, 209 nm) t(R,R)= 18.6, t(S,S) = 24.3 min
（実施例１１−２８）
N-picolinoyl-7-azabicyclo[4.1.0]heptaneの代わりに、窒素上の置換基（PG）を下式（１４）に示した種々変更したメソアジリジンを下式（１４）の反応により下表１に示す種々の不斉有機触媒（Ligand 3）を用いて行った実施例の結果を表2に示す。
Cinchonine-derived 9-epiaminopicolinamide catalyst (8.0 mg, 0.02 mmol) was dissolved in 0.5 mL of toluene in the dried flask, and diethylzinc (20 mL, 0.02 mmol) was added and stirred for 30 minutes. Subsequently, N-picolinoyl-7-azabicyclo [4.1.0] heptane (40 mg, 0.2 mmol), diphenyl phosphite (58 mL, 0.3 mmol) and Molecular Sieves 4A (40 mg) shown in Reference Example 1 The toluene 1.0 ml solution was cooled to 0 ° C., the previous solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction was confirmed by TLC (thin layer chromatography), 1N hydrochloric acid (1 mL) was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, purification was performed by silica gel column chromatography (Hexane: AcOEt = 60: 40), and 73 mg (84%, 99% ee) of the ring-opening product having the stereochemistry of (R, R) was obtained. )
Further, 9-epiaminopicolinamide catalyst derived from cinchonidine (8.0 mg, 0.02 mmol) was dissolved in 0.5 mL of benzene in the dried flask, and diethylzinc (20 ml, 0.02 mmol) was added and stirred for 30 minutes. Subsequently, a 1.0 ml benzene solution of N-picolinoyl-7-azabicyclo [4.1.0] heptane (40 mg, 0.2 mmol), diphenyl phosphite (58 ml, 0.3 mmol) and molecular sieves 4A (40 mg) After cooling to ° C, the above solution was added and stirred at room temperature for 3 hours. After confirming the reaction by TLC, 1 mL of 1N hydrochloric acid was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, purification was performed by silica gel column chromatography (Hexane: AcOEt = 60: 40). 70 mg (80%, 98% ee) of the ring-opening product having the stereochemistry of (S, S) was obtained. )
When the catalyst used is picolinamide derived from cinchonidine, a ring-opening product having the opposite stereochemistry is obtained.
The spectrum of Diphenyl 2- (picolinamido) cyclohexylphosphonate is as follows.
1 H NMR (300 MHz, CDCl 3 ) δ 1.25-1.60 (m, 3H), 1.60-1.95 (m, 3H), 2.20-2.55 (m, 3H), 4.35-4.50 (m, 1H), 7.00-7.22 (m, 10H), 7.27-7.36 (m, 1H), 7.76-7.81 (m, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 8.54 ( d, J = 8.1 Hz, 1H)
13 C NMR (75 MHz, CDCl 3 ) δ 24.6, 25.2 (d, J = 15.4 Hz), 26.3 (d, J = 5.5 Hz), 33.6, (d, J = 13.7 Hz), 41.2 (d, J = 139.7 Hz), 48.8, (d, J = 6.0 Hz), 120.5, (d, J = 1.7 Hz), 120.6 (d, J = 2.2 Hz), 122.2, 124.8, 126.0, 129.5 (d, J = 1.7 Hz ), 137.2, 148.0, 150.0, 150.3 (d, J = 3.3 Hz), 150.4 (d, J = 3.8 Hz), 163.3
31 P NMR (121 MHz, CDCl 3 ) δ 22.79
LRMS (ESI, positive) m / z 399.9 [M + H] +
HPLC (DAICEL CHIRALPAK AD3 O , Hexane: iPrOH = 70:30, 1.0 mL / min, 209 nm) t (R, R) = 18.6, t (S, S) = 24.3 min
(Examples 11-28)
In place of N-picolinoyl-7-azabicyclo [4.1.0] heptane, variously modified mesoaziridines in which the substituent (PG) on nitrogen is represented by the following formula (14) are reacted by the following formula (14). Table 2 shows the results of Examples carried out using various asymmetric organic catalysts (Ligand 3) shown in 1.
Yieldは収率を示し、Eeは、エナンチオ過剰率を示す。また、nrはno reactionすなわち反応が進行しないを表し、cpはcomplex productすなわち反応系が複雑な生成物を与えたことを示す。
上記の結果より保護基としてはピコリノイル基が最もよく、他のベンゾイル基や2-ピリジンスルホニル基では全く反応が進行しないため、アジリジン上のピコリノイル基は必須である。また触媒はシンコニン由来の9-epiピコリンアミドもしくはシンコニジン由来の9-epiピコリンアミド触媒が最も良く、触媒を使い分けることで両鏡像異性体を作り分けることが可能である。また、キニジン由来の9-epiピコリンアミドもしくはキニン由来の9-epiピコリンアミド触媒でも若干のエナンチオ選択性が得られるものの、他のシンコナアルカロイド触媒では不斉収率がほとんど得られないため、触媒上のピコリノイル基は必須である。
（実施例２９−５１）
N-picolinoyl-7-azabicyclo[4.1.0]heptaneの代わりに、様々な置換基や環構造に変更した種々のメソアジリジンを表2で示した最適な不斉有機触媒（Ligand 3gまたは3i）を用いて行った実施例の結果を表3に示す。
Yield indicates the yield, and Ee indicates the enantio excess. Nr represents no reaction, that is, the reaction does not proceed, and cp represents a complex product, that is, the reaction system gave a complex product.
From the above results, the picolinoyl group on the aziridine is indispensable because the picolinoyl group is the best protecting group and the reaction does not proceed at all with other benzoyl groups or 2-pyridinesulfonyl groups. The best catalyst is 9-epipicolinamide derived from cinchonine or 9-epipicolinamide derived from cinchonidine, and it is possible to make both enantiomers differently by using different catalysts. Although some enantioselectivity can be obtained with 9-epipicolinamide derived from quinidine or 9-epipicolinamide derived from quinine, the asymmetric yield is hardly obtained with other cinchona alkaloid catalysts. The upper picolinoyl group is essential.
(Examples 29-51)
Instead of N-picolinoyl-7-azabicyclo [4.1.0] heptane, the optimal asymmetric organic catalyst (Ligand 3g or 3i) shown in Table 2 for various mesoaziridines modified to various substituents and ring structures Table 3 shows the results of the examples used.
上記の結果より保護基のピコリノイル基の4位に置換基を導入すると、収率選択性が変化し、特にメトキシ基を導入することにより反応性が向上する（実施例９及び２９−３１）。また、環構造を変更した種々のメソアジリジンも同様に4位にメトキシ基を導入することにより反応性が向上する（実施例３２、３３及び３４、３５以下４６に於いて）。また実施例９、１０同様、触媒はシンコニン由来の9-epiピコリンアミドとシンコニジン由来の9-epiピコリンアミド触媒を使い分けることで両鏡像異性体を作り分けることが可能である（実施例３４、３５以下４６に於いて）。
以下、上記した化合物について説明する。
化合物4ga（化学式１６参照）：
Diphenyl 2-(4-methoxypicolinamido)cyclohexylphosphonateのスペクトル等
From the above results, when a substituent is introduced at the 4-position of the picolinoyl group of the protecting group, the yield selectivity is changed, and in particular, the reactivity is improved by introducing a methoxy group (Examples 9 and 29-31). Similarly, various mesoaziridines having different ring structures are also improved in reactivity by introducing a methoxy group at the 4-position (in Examples 32, 33 and 34, 35 to 46). In addition, as in Examples 9 and 10, the enantiomers can be prepared separately by properly using a 9-epipicolinamide derived from cinchonine and a 9-epi picolinamide catalyst derived from cinchonidine (Examples 34 and 35). Below 46).
Hereinafter, the above-described compounds will be described.
Compound 4ga (see Formula 16):
Diphenyl 2- (4-methoxypicolinamido) cyclohexylphosphonate spectrum, etc.
（実施例２９）：収率９１％、９６％ee
1H NMR (300 MHz, CDCl3) δ 1.20-1.55 (m, 3H), 1.60-1.95 (m, 3H), 2.20-2.55 (m, 3H), 3.87 (s, 3H), 4.35-4.50 (m, 1H), 6.85 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.06-7.21 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.55 (d, J = 7.2 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 22.78; LRMS (ESI, positive) m/z 467.6 [M+H]+H; HPLC (DAICEL CHIRALPAK IA, Hexane:iPrOH = 70:30, 1.0 mL/min, 209 nm) t(R,R) = 22.2, t(S,S)= 51.0 min
化合物4ha（化学式１7参照）：
Diphenyl 2-(4-chloropicolinamido)cyclohexylphosphonateのスペクトル等
(Example 29): Yield 91%, 96% ee
1 H NMR (300 MHz, CDCl 3 ) δ 1.20-1.55 (m, 3H), 1.60-1.95 (m, 3H), 2.20-2.55 (m, 3H), 3.87 (s, 3H), 4.35-4.50 (m , 1H), 6.85 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.06-7.21 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 5.4 Hz , 1H), 8.55 (d, J = 7.2 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 22.78; LRMS (ESI, positive) m / z 467.6 [M + H] + H; HPLC (DAICEL CHIRALPAK IA, Hexane: iPrOH = 70:30, 1.0 mL / min, 209 nm) t (R, R) = 22.2, t (S, S) = 51.0 min
Compound 4ha (see Formula 17):
Diphenyl 2- (4-chloropicolinamido) cyclohexylphosphonate spectrum, etc.
（実施例３０）：収率９４％、９９．６％ee
1H NMR (300 MHz, CDCl3) δ 1.32-1.60 (m, 3H), 1.60-1.98 (m, 3H), 2.25-2.55 (m, 3H), 4.30-4.50 (m, 1H), 7.03-7.23 (m, 10H), 7.36 (dd, J = 2.1 Hz, J = 5.4 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.45 (d, J = 8.1 Hz, 1H)31P NMR (121 MHz, CDCl3) δ 22.48; LRMS (ESI, positive) m/z 471.5 [M+H]+; HPLC (DAICEL CHIRALPAK AD-3O, Hexane:iPrOH = 70:30, 1.0 mL/min, 209 nm) t(R,R)= 18.8, t(S,S) = 39.0 min
化合物4gb（化学式１８参照）：
Diphenyl 6-(4-methoxypicolinamido)cyclohex-3-enylphosphonateのスペクトル等
(Example 30): Yield 94%, 99.6% ee
1 H NMR (300 MHz, CDCl 3 ) δ 1.32-1.60 (m, 3H), 1.60-1.98 (m, 3H), 2.25-2.55 (m, 3H), 4.30-4.50 (m, 1H), 7.03-7.23 (m, 10H), 7.36 (dd, J = 2.1 Hz, J = 5.4 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.45 (d , J = 8.1 Hz, 1H) 31 P NMR (121 MHz, CDCl 3 ) δ 22.48; LRMS (ESI, positive) m / z 471.5 [M + H] + ; HPLC (DAICEL CHIRALPAK AD-3 O , Hexane: iPrOH = 70:30, 1.0 mL / min, 209 nm) t (R, R) = 18.8, t (S, S) = 39.0 min
Compound 4gb (see Formula 18):
Diphenyl 6- (4-methoxypicolinamido) cyclohex-3-enylphosphonate spectrum, etc.
シンコニン由来のピコリンアミド3gを用いた場合（実施例３４）：収率６０％、７６％ee
シンコニジン由来のピコリンアミド3iを用いた場合（実施例３５）：収率６１％、６０％ee
1H NMR (300 MHz, CDCl3) δ 2.23 (dd, J = 7.2 Hz, J = 16.8 Hz, 1H), 2.67-2.91 (m, 4H), 3.90 (s, 3H), 4.67-4.76 (m, 1H), 5.78 (s, 2H), 6.89 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.09-7.22 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.30 (d, J = 5.4 Hz, 1H), 8.65 (d, J = 7.2 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 22.56; LRMS (ESI, positive) m/z 465.6 [M+H]+; HPLC (DAICEL CHIRALPAK OD3O, Hexane:iPrOH = 80:20, 1.0 mL/min, 209 nm) t(R,R) = 13.8, t(S,S)= 18.9 min
化合物4gc（化学式１９参照）：
Diphenyl 3-(4-methoxypicolinamido)-1,2,3,4-tetrahydronaphthalen-2-yl-2-phosphona teのスペクトル等
When 3 g of picolinamide derived from cinchonine was used (Example 34): Yield 60%, 76% ee
When cinchonidine-derived picolinamide 3i was used (Example 35): yield 61%, 60% ee
1 H NMR (300 MHz, CDCl 3 ) δ 2.23 (dd, J = 7.2 Hz, J = 16.8 Hz, 1H), 2.67-2.91 (m, 4H), 3.90 (s, 3H), 4.67-4.76 (m, 1H), 5.78 (s, 2H), 6.89 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.09-7.22 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.30 ( d, J = 5.4 Hz, 1H), 8.65 (d, J = 7.2 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 22.56; LRMS (ESI, positive) m / z 465.6 [M + H] + ; HPLC (DAICEL CHIRALPAK OD3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 209 nm) t (R, R) = 13.8, t (S, S) = 18.9 min
Compound 4gc (see Formula 19):
Spectrum of Diphenyl 3- (4-methoxypicolinamido) -1,2,3,4-tetrahydronaphthalen-2-yl-2-phosphonate
シンコニン由来のピコリンアミド3gを用いた場合（実施例３７）：収率５９％、９０％ee
シンコニジン由来のピコリンアミド3iを用いた場合（実施例３８）：収率６８％、７７％ee
1H NMR (300 MHz, CDCl3) δ 2.88-3.02 (m, 2H), 3.28-3.52 (m, 3H), 3.90 (s, 3H), 4.88-4.95 (m, 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.07-7.24 (m, 10H), 7.74 (d, J = 2.7 Hz, 1H), 8.28 (d, J = 5.7 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 22.18; LRMS (ESI, positive) m/z 515.5 [M+H]+; HPLC (DAICEL CHIRALPAK OD3O, Hexane:iPrOH = 90:10, 0.5 mL/min, 209 nm) t(R,R)= 71.5, t(S,S) = 82.3 min
化合物4gd（化学式２０参照）：
Diphenyl 3-(4-methoxypicolinamido)butane-2-ylphosphonateのスペクトル等
When 3 g of picolinamide derived from cinchonine was used (Example 37): yield 59%, 90% ee
When cinchonidine-derived picolinamide 3i was used (Example 38): yield 68%, 77% ee
1 H NMR (300 MHz, CDCl 3 ) δ 2.88-3.02 (m, 2H), 3.28-3.52 (m, 3H), 3.90 (s, 3H), 4.88-4.95 (m, 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.07-7.24 (m, 10H), 7.74 (d, J = 2.7 Hz, 1H), 8.28 (d, J = 5.7 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 22.18; LRMS (ESI, positive) m / z 515.5 [M + H] + ; HPLC (DAICEL CHIRALPAK OD3 O , Hexane: iPrOH = 90: 10, 0.5 mL / min, 209 nm) t (R, R) = 71.5, t (S, S) = 82.3 min
Compound 4gd (see Formula 20):
Diphenyl 3- (4-methoxypicolinamido) butane-2-ylphosphonate spectrum, etc.
シンコニン由来のピコリンアミド3gを用いた場合（実施例４１）：収率９２％、９９％ee
シンコニジン由来のピコリンアミド3iを用いた場合（実施例４２）：収率７７％、７２％ee
1H NMR (300 MHz, CDCl3) δ 1.45 (dd, J = 7.2 Hz, J = 19.2 Hz, 3H), 1.53 (d, J = 6.9 Hz, 3H), 2.74-2.85 (m, 1H), 3.90 (s, 3H), 4.71-4.84 (m, 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.10-7.33 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 5.7 Hz, 1H), 8.52 (d, J = 8.7 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 24.67; LRMS (ESI, positive) m/z 441.7 [M+H]+; HPLC (DAICEL CHIRALPAK OD3O, Hexane:iPrOH = 90:10, 1.0 mL/min, 209 nm) t(S,S)= 18.6, t(R,R) = 21.4 min
化合物4ge（化学式２１参照）：
Diphenyl 5-(4-methoxypicolinamido)octan-4-ylphosphonateのスペクトル等
When 3 g of picolinamide derived from cinchonine was used (Example 41): Yield 92%, 99% ee
When using cinchonidine-derived picolinamide 3i (Example 42): Yield 77%, 72% ee
1 H NMR (300 MHz, CDCl 3 ) δ 1.45 (dd, J = 7.2 Hz, J = 19.2 Hz, 3H), 1.53 (d, J = 6.9 Hz, 3H), 2.74-2.85 (m, 1H), 3.90 (s, 3H), 4.71-4.84 (m, 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.10-7.33 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 5.7 Hz, 1H), 8.52 (d, J = 8.7 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 24.67; LRMS (ESI, positive) m / z 441.7 [M + H] + ; HPLC (DAICEL CHIRALPAK OD3 O , Hexane: iPrOH = 90:10, 1.0 mL / min, 209 nm) t (S, S) = 18.6, t (R, R) = 21.4 min
Compound 4ge (see Chemical Formula 21):
Diphenyl 5- (4-methoxypicolinamido) octan-4-ylphosphonate spectrum, etc.
シンコニン由来のピコリンアミド3gを用いた場合（実施例４５）：収率６２％、６８％ee
シンコニジン由来のピコリンアミド3iを用いた場合（実施例４６）：収率５６％、３６％ee
1H NMR (300 MHz, CDCl3) δ 0.90-0.97 (m, 6H), 1.32-2.00 (m, 8H), 2.45-2.65 (m, 1H), 3.90 (s, 3H), 4.55-4.80 (m, 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.10-7.33 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 5.7 Hz, 1H), 8.75 (d, J = 8.7 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 25.09; LRMS (ESI, positive) m/z 497.2 [M+H]+; HPLC (DAICEL CHIRALPAK OZ-HO, Hexane:iPrOH = 97:3, 1.0 mL/min, 209 nm) t(R,R)= 35.0, t(S,S) = 40.1 min
（実施例４７、４８）
次式（１１）による光学活性α,β-ジ置換β-アミノホスホン酸の合成について記述する。
When 3 g of picolinamide derived from cinchonine was used (Example 45): Yield 62%, 68% ee
When cinchonidine-derived picolinamide 3i was used (Example 46): yield 56%, 36% ee
1 H NMR (300 MHz, CDCl 3 ) δ 0.90-0.97 (m, 6H), 1.32-2.00 (m, 8H), 2.45-2.65 (m, 1H), 3.90 (s, 3H), 4.55-4.80 (m , 1H), 6.90 (dd, J = 2.7 Hz, J = 5.7 Hz, 1H), 7.10-7.33 (m, 10H), 7.73 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 5.7 Hz , 1H), 8.75 (d, J = 8.7 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 25.09; LRMS (ESI, positive) m / z 497.2 [M + H] + ; HPLC (DAICEL CHIRALPAK OZ-H O , Hexane: iPrOH = 97: 3, 1.0 mL / min, 209 nm) t (R, R) = 35.0, t (S, S) = 40.1 min
(Examples 47 and 48)
The synthesis of optically active α, β-disubstituted β-aminophosphonic acid according to the following formula (11) will be described.
Diphenyl (1R,2R)-2-(picolinamido)cyclohexylphosphonate (218 mg, 0.5 mmol)とNaOMe (135 mg, 2.5 mmol) をメタノール2.5 mLに懸濁させ、2時間還流を行った。反応はTLCにて確認後、室温に冷却し、水5 mLを加え、塩化メチレンで抽出、無水硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去後、精製はシリカゲルカラムクロマトグラフィー(AcOEt:MeOH = 100:0 to 90:10)で行いDimethyl (1R,2R)-2-(picolinamido) cyclohexylphosphonateを83 %収率 で得た。
Dimethyl (1R,2R)-2-(picolinamido)cyclohexylphosphonate (62 mg, 0.2 mmol)を濃塩酸4 mL に溶解させ20時間還流を行った。室温に冷却後溶媒を留去し、残渣を温かいエタノール1 mLに溶解させプロピレンオキシド0.1 mLを氷浴下で加え3時間攪拌した。反応溶液をジエチルエーテルで希釈し、沈殿物を濾取し(1R,2R)-2-aminocyclohexylphosphonic acidを95 %収率で得た。
前記得られたDimethyl (1R,2R)-2-(picolinamido)cyclohexylphosphonateのスペクトル等は以下の通り。
1H NMR (300 MHz, CDCl3) δ 1.21-1.60 (m, 4H), 1.70-1.90 (m, 2H), 2.03-2.29 (m, 3H), 3.67 (s, 3H), 3.70 (s 3H), 4.07-4.13 (m, 1H), 7.40 (dd, J = 1.5 Hz, J = 6.9 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.42, (d, J = 6.9 Hz, 1H), 8.58 (d, J = 4.2 Hz, 1H); 31P NMR (121 MHz, CDCl3) δ 31.90; LRMS (ESI, positive) m/z 335.8 [M+Na]+
前記得られた(1R,2R)-2-aminocyclohexylphosphonic acidのスペクトル等は以下の通り。
1H NMR (300 MHz, D2O) δ 1.00-1.30 (m, 4H), 1.40-1.70 (m, 3H), 1.80-2.00 (m, 2H), 2.95-3.10 (m, 1H); 13C NMR (75 MHz, D2O) δ 23.8, 24.3 (d, J = 13.7 Hz), 25.6 (d, J = 4.4 Hz), 30.7, (d, J = 12.6 Hz), 39.4 (d, J = 131.3 Hz), 50.2, (d, J = 5.5 Hz); 31P NMR (121 MHz, D2O) δ 22.50; LRMS (ESI, negative) m/z 177.6 [M-H]-
Diphenyl (1R, 2R) -2- (picolinamido) cyclohexylphosphonate (218 mg, 0.5 mmol) and NaOMe (135 mg, 2.5 mmol) were suspended in 2.5 mL of methanol and refluxed for 2 hours. The reaction was confirmed by TLC, cooled to room temperature, added with 5 mL of water, extracted with methylene chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, purification was performed by silica gel column chromatography (AcOEt: MeOH = 100: 0 to 90:10) to obtain Dimethyl (1R, 2R) -2- (picolinamido) cyclohexylphosphonate in 83% yield. It was.
Dimethyl (1R, 2R) -2- (picolinamido) cyclohexylphosphonate (62 mg, 0.2 mmol) was dissolved in 4 mL of concentrated hydrochloric acid and refluxed for 20 hours. After cooling to room temperature, the solvent was distilled off, the residue was dissolved in 1 mL of warm ethanol, and 0.1 mL of propylene oxide was added in an ice bath and stirred for 3 hours. The reaction solution was diluted with diethyl ether, and the precipitate was collected by filtration to obtain (1R, 2R) -2-aminocyclohexylphosphonic acid in 95% yield.
The spectrum and the like of the obtained Dimethyl (1R, 2R) -2- (picolinamido) cyclohexylphosphonate are as follows.
1 H NMR (300 MHz, CDCl 3 ) δ 1.21-1.60 (m, 4H), 1.70-1.90 (m, 2H), 2.03-2.29 (m, 3H), 3.67 (s, 3H), 3.70 (s 3H) , 4.07-4.13 (m, 1H), 7.40 (dd, J = 1.5 Hz, J = 6.9 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H) , 8.42, (d, J = 6.9 Hz, 1H), 8.58 (d, J = 4.2 Hz, 1H); 31 P NMR (121 MHz, CDCl 3 ) δ 31.90; LRMS (ESI, positive) m / z 335.8 [ M + Na] +
The spectrum of the obtained (1R, 2R) -2-aminocyclohexylphosphonic acid is as follows.
1 H NMR (300 MHz, D 2 O) δ 1.00-1.30 (m, 4H), 1.40-1.70 (m, 3H), 1.80-2.00 (m, 2H), 2.95-3.10 (m, 1H); 13 C NMR (75 MHz, D 2 O) δ 23.8, 24.3 (d, J = 13.7 Hz), 25.6 (d, J = 4.4 Hz), 30.7, (d, J = 12.6 Hz), 39.4 (d, J = 131.3 Hz), 50.2, (d, J = 5.5 Hz); 31 P NMR (121 MHz, D 2 O) δ 22.50; LRMS (ESI, negative) m / z 177.6 [MH] -
Claims (10)
で示される9-エピアミノピコリンアミド触媒 The following formula (1)
9-epiaminopicolinamide catalyst represented by
で示される9-エピアミノピコリンアミド触媒 The following formula (2)
9-epiaminopicolinamide catalyst represented by
で示される9-エピアミノピコリンアミド触媒 The following formula (3)
9-epiaminopicolinamide catalyst represented by
で示される9-エピアミノピコリンアミド触媒 The following formula (4)
9-epiaminopicolinamide catalyst represented by
（式中、R1は、環状アルキル基、鎖状アルキル基、シリル基またはアリール基を示す。Ｒ２は、環状アルキル基、鎖状アルキル基、フェニル基、シリル基またはアリール基を示す。PGはピコリノイル基、ベンゾイル基、トシル基、ノシル基、ベンゼンスルホニル基を示す。）
で示される、種々のメソアジリジン類にアルキル亜鉛と不斉配位子存在下で亜リン酸エステルを反応させてアジリジンの不斉開環反応によりβ-アミノホスホン酸またはβ-アミノホスフィン誘導体を製造する方法。 Formula (9)
(Wherein R 1 represents a cyclic alkyl group, a chain alkyl group, a silyl group or an aryl group. R 2 represents a cyclic alkyl group, a chain alkyl group, a phenyl group, a silyl group or an aryl group. PG Represents a picolinoyl group, a benzoyl group, a tosyl group, a nosyl group or a benzenesulfonyl group.)
To produce β-aminophosphonic acid or β-aminophosphine derivatives by asymmetric ring-opening reaction of aziridine by reacting various mesoaziridines with alkylzinc phosphite in the presence of an asymmetric ligand how to.
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