JP2008222578A - METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-FLUOROMETHYLAMINE DERIVATIVE - Google Patents

METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-FLUOROMETHYLAMINE DERIVATIVE Download PDF

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JP2008222578A
JP2008222578A JP2007059608A JP2007059608A JP2008222578A JP 2008222578 A JP2008222578 A JP 2008222578A JP 2007059608 A JP2007059608 A JP 2007059608A JP 2007059608 A JP2007059608 A JP 2007059608A JP 2008222578 A JP2008222578 A JP 2008222578A
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JP4910148B2 (en
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Tetsuo Shibata
哲男 柴田
Takeshi Toru
健 融
Kenji Mizuta
賢志 水田
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Nagoya Institute of Technology NUC
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active α-fluoromethylamine derivative in high efficiency. <P>SOLUTION: The method for producing an α-fluoromethylamine derivative in high optical purity comprises carring out the asymmetric Mannich reaction of an α-amidosulfonic acid with a fluorobissulfonylmethane compound in a solvent in the presence of a base and an optically active phase-transfer catalyst, and, the desulfonylation of the resultant α-fluorobis(phenylsulfonyl)methyl adduct in the presence a metal as a reducing agent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は光学活性α−フルオロメチルアミン誘導体の製造法に関する。   The present invention relates to a method for producing an optically active α-fluoromethylamine derivative.

光学活性α−フルオロメチルアミン類は医薬，農薬分野における重要な合成中間体である。ラセミ体のα−フルオロメチルアミン類の製造法としては，次に示す方法が挙げられる。（１）SF4/HFの存在下，アミノアルコール類のヒドロキシ基の選択的フッ素化法（非特許文献１）（２）Et4N+F-/HFの存在下，アセトニトリル中，電気酸化法を用いたアルキルベンゼン類のフッ素化法（非特許文献２）（３）アジリジン化合物とHF/ピリジンによるアジリジンのフッ素化−開環する方法（非特許文献３，４）（４）フルオロアセトニトリルから誘導したα−フルオロメチルアミン類の合成法（非特許文献５）（５）Ｎ−フルオロベンゼンスルホンイミドを用いたイミンの求電子的フッ素化する方法（非特許文献６）（６）アミノアルコール類をＮ，Ｎ−ジエチル−α，α−ジフルオロベンジルアミンで処理することにより脱酸素−フッ素化する方法（非特許文献７）一方，光学活性α−フルオロメチルアミン誘導体の製造法においては，（７）α−フルオロアセトフェノンとp−アニシジンとで形成するイミンを光学活性りん酸触媒を用いたエチル Hantzsch エステルによる不斉還的アミノ化する方法（非特許文献８）（８）塩基存在下，（Ｒ）−（tert−ブタンスルフィニル）イミン化合物とフルオロメチルフェニルスルホンと反応し，フルオロアミン誘導体を脱スルホニル化することにより光学活性α−フルオロメチルアミン誘導体を製造する方法（非特許文献９）などが報告されている。しかしながら，前記（７）の方法では含フッ素置換基を有するイミン化合物を入手する必要がある。さらに，前記（８）の方法ではジアステレオ選択的な反応を用いるので化学量論量の光学活性不斉補助基が必要である。エナンチオ選択的フルオロメチル化反応の報告例は依然としてなく，従来法において工業的に光学活性α−フルオロメチルアミン誘導体を供給に問題がある。従って，工業的スケールで効率良く製造し得る一般式（４）に示される光学活性α−フルオロメチルアミン誘導体の製造法が望まれていた。
J.Org.Chem.,40,3808(1975) Tetrahedron Lett.,43,3799(1977) J.Fluorine Chem.,16,526(1980) J.Chem.Res.Synop.,6,210(1980) J.Org.Chem.,51,2835(1986) Org.Lett.,8,4767(2006) Synlett,11,1744(2006) J.Am.Chem.Soc.,128,84(2006) Org.Lett.,8,1693(2006) Optically active α-fluoromethylamines are important synthetic intermediates in the fields of medicine and agricultural chemicals. Examples of the method for producing racemic α-fluoromethylamines include the following methods. (1) Selective fluorination method of hydroxy group of amino alcohols in the presence of SF 4 / HF (Non-patent Document 1) (2) Electrooxidation method in acetonitrile in the presence of Et 4 N + F − / HF Method of fluorination of alkylbenzenes using benzene (Non-patent Document 2) (3) Fluorination-ring-opening of aziridine with aziridine compound and HF / pyridine (Non-patent Documents 3 and 4) (4) Derived from fluoroacetonitrile Synthesis Method of α-Fluoromethylamines (Non-patent Document 5) (5) Electrophilic fluorination of imine using N-fluorobenzenesulfonimide (Non-patent Document 6) (6) Aminoalcohols with N , N-diethyl-α, α-difluorobenzylamine is a method of deoxygenation and fluorination by treatment (Non-patent Document 7). (7) A method of asymmetrically aminating an imine formed with α-fluoroacetophenone and p-anisidine with an ethyl Hantzsch ester using an optically active phosphoric acid catalyst (Non-patent Document 8) (8) Base A method for producing an optically active α-fluoromethylamine derivative by reacting a (R)-(tert-butanesulfinyl) imine compound with fluoromethylphenylsulfone in the presence to desulfonylate the fluoroamine derivative (Non-Patent Document) 9) etc. have been reported. However, in the method (7), it is necessary to obtain an imine compound having a fluorine-containing substituent. Furthermore, since the method (8) uses a diastereoselective reaction, a stoichiometric amount of an optically active asymmetric auxiliary group is required. There are still no reports of enantioselective fluoromethylation reactions, and there is a problem in supplying optically active α-fluoromethylamine derivatives industrially in the conventional method. Therefore, a method for producing an optically active α-fluoromethylamine derivative represented by the general formula (4) that can be efficiently produced on an industrial scale has been desired.
J. Org. Chem., 40, 3808 (1975) Tetrahedron Lett., 43, 3799 (1977) J. Fluorine Chem., 16,526 (1980) J. Chem. Res. Synop., 6, 210 (1980) J. Org. Chem., 51, 2835 (1986) Org. Lett., 8, 4767 (2006) Synlett, 11, 1744 (2006) J. Am. Chem. Soc., 128, 84 (2006) Org. Lett., 8, 1693 (2006)

本発明は，上記課題を解決するためになされたものであり，その目的は，溶媒中，反応触媒として光学活性な相間移動触媒を用いて前記一般式（１）と（２）とを反応させて，工業的スケールで効率良く前記一般式（３）を製造し，簡便に（３）を変換し，前記一般式（４）示される光学活性α−フルオロメチルアミン誘導体の製造法を提供することである。
The present invention has been made to solve the above-mentioned problems, and its object is to react the above general formulas (1) and (2) in a solvent using an optically active phase transfer catalyst as a reaction catalyst. And producing the optically active α-fluoromethylamine derivative represented by the general formula (4) by efficiently producing the general formula (3) on an industrial scale, easily converting (3). It is.

本発明者らは，上記課題を解決するため鋭意研究を行った結果，溶媒中，塩基存在下，光学活性な相間移動触媒を用いて前記一般式（１）のα−アミドスルホン類と前記一般式（２）フルオロビススルホニルメタン類を反応させて，前記一般式（３）に示されるα−フルオロビス（フェニルスルホニル）メチル付加体を高い光学純度で得ることを見出した。さらに，前記一般式（３）を光学純度を低下することなく脱スルホニル化し，前記一般式（４）に示されるα−フルオロメチルアミン誘導体を得ることを見出し，本発明を完成するに至った。   As a result of intensive studies to solve the above problems, the present inventors have found that the α-amide sulfones of the general formula (1) and the general formulas are obtained using an optically active phase transfer catalyst in the presence of a base in a solvent. It has been found that α-fluorobis (phenylsulfonyl) methyl adduct represented by the general formula (3) can be obtained with high optical purity by reacting the formula (2) fluorobissulfonylmethanes. Furthermore, it has been found that the general formula (3) is desulfonylated without reducing optical purity to obtain an α-fluoromethylamine derivative represented by the general formula (4), and the present invention has been completed.

すなわち，本発明は下記の（１）〜（６）に関するものである。

（１）溶媒中，塩基と光学活性な相間移動触媒存在下，一般式（１） That is, the present invention relates to the following (1) to (6).

(1) General formula (1) in the presence of an optically active phase transfer catalyst with a base in a solvent

（式中，Ｒ１は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アシル基，アルコキシカルボニル基またはアリールオキシカルボニル基を示す。Ｒ2は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アシル基，アルコキシカルボニル基またはアリールオキシカルボニル基を示す。Ｒ３は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。）
で表せるα−アミドスルホン化合物を一般式（２） (Wherein R 1 represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group, aryl group, acyl group, alkoxycarbonyl group or aryloxycarbonyl group. R 2 represents a substituted or unsubstituted group. An alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, wherein R 3 is a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group; Or an aryl group.)
An α-amide sulfone compound represented by the general formula (2)

（式中，Ｒ４，Ｒ５はそれぞれ独立に，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。さらに，Ｒ４およびＲ５が一体となって，環状構造の一部を形成してもよい。）で示されるフルオロビススルホニルメタン類との不斉マンニッヒ型反応させることを特徴とする一般式（３）
(In the formula, R 4 and R 5 each independently represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group or aryl group. Furthermore, R 4 and R 5 together form a cyclic group. A part of the structure may be formed.) Asymmetric Mannich reaction with the fluorobissulfonylmethanes represented by the general formula (3)


（式中，Ｒ１，Ｒ２，Ｒ４，Ｒ５は前記定義に同じ。）
で示される光学活性α−フルオロビス（フェニルスルホニル）メチル付加体の製造法。
（２）前記一般式（３）で表せる光学活性α−フルオロビス（フェニルスルホニル）メチル付加体を溶媒中，還元剤として金属の存在下，脱スルホニル化させることを特徴とする一般式（４）（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性α−フルオロメチルアミン誘導体の製造法。
(In the formula, R 1 , R 2 , R 4 and R 5 are the same as defined above.)
A process for producing an optically active α-fluorobis (phenylsulfonyl) methyl adduct represented by the formula:
(2) The optically active α-fluorobis (phenylsulfonyl) methyl adduct represented by the general formula (3) is desulfonylated in a solvent in the presence of a metal as a reducing agent in the general formula (4) (Wherein R 1 and R 2 are the same as defined above), a method for producing an optically active α-fluoromethylamine derivative.


（３）前記塩基は，一般に市販されているアミン類もしくは無機塩一般式（５）から選ばれる少なくとも１種類の塩基であることを特徴とする請求項１に記載の製造法。
アミンとしては，トリエチルアミン，ジイソプロピルエチルアミン，ジメチルアミノピリジン，キヌクリジン，ＤＢＵ，ＤＡＢＣＯなどを用いることができる。無機塩は一般式（５）
（Ｘ）ｎＭ （５）
（式中，Ｍは，希土類を含む遷移金属，リチウム，ナトリウム，マグネシウム，アルミニウムから選ばれた元素，ｎは，Ｍの原子価と同数の整数を表す。Ｘはアルコシド，フルオリド，カルボネートなどのマイナスイオンを表す。）

（４）前記光学活性な相間移動触媒は，光学活性４級アンモニウム塩類から選ばれる少なくとも１種類の塩であることを特徴とする請求項１に記載の製造法。
光学活性な相間移動触媒としては，一般式（６），（７）
(3) The process according to claim 1, wherein the base is at least one base selected from amines or inorganic salts of the general formula (5) that are generally commercially available.
As the amine, triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The inorganic salt has the general formula (5)
(X) nM (5)
(In the formula, M is an element selected from transition metals including rare earths, lithium, sodium, magnesium and aluminum, n is an integer having the same number as the valence of M. X is a minus such as alkoxide, fluoride, carbonate, etc. Represents an ion.)

(4) The process according to claim 1, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
As optically active phase transfer catalysts, general formulas (6), (7)


（式中，Ｒ６は水素，置換もしくは未置換のアルキル基もしくはアルコキシ基を示す。もしくはＯＲ１０で表せるＲ１０はアルキル基を示す。Ｒ７は，エチル基もしくはビニル基を示す。Ｒ８は，水素，アルキル基，アリール基またはアシル基を示す。Ｒ９は，水素，置換もしくは未置換のアルキル基またはトリフルオロメチル基を示す。ｍは０〜２の整数を表す。Ｘは，ハロゲン原子，IO４，ClO４，OTfまたはHSO４を示す。）

（５）前記溶媒が，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，クロロホルム，ジクロロメタン，ジクロロエタン，トルエン，テトラヒドロフラン，ヘキサン，ベンゼンからなる群より選ばれる少なくとも1種である請求項１，２のいずれか１項に記載の製造法。

（６）前記金属は，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素であることを特徴とする請求項２に記載の製造法。
(In the formula, R 6 represents hydrogen, a substituted or unsubstituted alkyl group or an alkoxy group, or R 10 represented by OR 10 represents an alkyl group. R 7 represents an ethyl group or a vinyl group. R 8 represents , Hydrogen, an alkyl group, an aryl group or an acyl group, R 9 represents hydrogen, a substituted or unsubstituted alkyl group or a trifluoromethyl group, m represents an integer of 0 to 2, and X represents a halogen atom. , IO 4 , ClO 4 , OTf or HSO 4 )

(5) The solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, and benzene. The production method according to item.

(6) The production according to claim 2, wherein the metal is at least one element selected from lithium, sodium, magnesium, aluminum, zinc, tin, indium, samarium and the like including transition metals including rare earths. Law.

従来，前記一般式（４）で示される光学活性α−フルオロメチルアミン誘導体の製造法は，還元的アミノ化，またはジアステレオ選択的フルオロメチル化反応に限られている。そのため，入手が容易でない基質を製造するか，光学活性不斉補助基を用いる点が問題であった。また，エナンチオ選択的フルオロメチル化反応はほとんど報告例がない。従来法と比較して，本発明における光学活性α−フルオロメチルアミン誘導体の製造法は，塩基，光学活性な相間移動触媒存在下，前記一般式（１）と（２）とを反応して前記一般式（３）を得た後，脱スルホニル化することにより前記一般式（４）に示されるα−フルオロメチルアミン誘導体を高い光学純度で得ることが可能であり，工業的に利用価値が高い。
Conventionally, the production method of the optically active α-fluoromethylamine derivative represented by the general formula (4) is limited to reductive amination or diastereoselective fluoromethylation reaction. For this reason, it has been a problem to produce a substrate that is not easily available or to use an optically active asymmetric auxiliary group. There are few reports of enantioselective fluoromethylation reactions. Compared with the conventional method, the method for producing an optically active α-fluoromethylamine derivative in the present invention reacts with the above general formulas (1) and (2) in the presence of a base and an optically active phase transfer catalyst. It is possible to obtain the α-fluoromethylamine derivative represented by the general formula (4) with high optical purity by desulfonylation after obtaining the general formula (3), and industrially has high utility value. .

以下，本発明を詳細に説明する。本発明は塩基，光学活性な相間移動触媒存在下，前記一般式（１）と（２）とを反応して前記一般式（３）を得た後，脱スルホニル化することにより前記一般式（４）に示されるα−フルオロメチルアミン誘導体を高い光学純度で得ることを特徴とする製造法である。

前記一般式（１）中のアルキル基は，前記一般式（１）中のアルキル基は炭素数が１〜２０の枝分かれがあっても良いアルキル基または炭素数が３〜２０のシクロアルキル基が好ましく，炭素数が１〜１０のアルキル基または炭素数が３〜１０のシクロアルキル基がさらに好ましい。アルキル基はハロゲン原子，シアノ基，ニトロ基，アリール基，アシル基，アルコキシ基，アリールオキシ基，アシルオキシ基などの置換基で置換されていてもよい。

前記一般式（１）中のアルケニル基は炭素数が１〜２０の枝分かれがあっても良いアルケニル基または炭素数が３〜２０のシクロアルケニル基が好ましく，炭素数が１〜１０のアルケニル基または炭素数が３〜１０のシクロアルケニル基がさらに好ましい。アルケニル基の例としては，ビニル基，１−プロペニル基，１−ブテニル基，１−ヘキセニル基，シクロヘキセニル基，アリル基などが挙げられる。アルケニル基はハロゲン原子，シアノ基，ニトロ基，アリール基，アシル基，アルコキシ基，アリールオキシ基，アシルオキシ基などの置換基で置換されていてもよい。

前記一般式（１）中のアラルキル基は，例としてベンジル基，ペンタフルオロベンジル基，ｏ−メチルベンジル基，ｍ−メチルベンジル基，ｐ−メチルベンジル基，ｐ−ニトロベンジル基，ナフチルメチル基，フルフリル基，α−フェネチル基等が挙げられる。

前記一般式（１）中のアルキニル基は，例としてエチニル基，フェニルエチニル基，２−プロピニル基等が挙げられる。

前記一般式（１）中のアリール基は炭素数が６〜２０のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。アリール基はアルキル基，ハロゲン原子，シアノ基，ニトロ基，アシル基，アルコキシ基，アシルオキシ基などの置換基で置換されていてもよい。

前記一般式（１）中のアルコキシ基は炭素数が１〜２０のアルコキシ基が好ましく，炭素数が１〜１０のアルコキシ基がさらに好ましい。アルコキシ基の場合も上記のアルキル基の場合と同様の置換基により置換されていてもよい。

前記一般式（１）中のアリールオキシ基は炭素数が１〜２０のアリールオキシ基が好ましく，炭素数が１〜１０のアリールオキシ基がさらに好ましい。アリールオキシ基の場合も上記のアリール基の場合と同様の置換基により置換されていてもよい。 The present invention will be described in detail below. In the present invention, the above general formulas (1) and (2) are reacted in the presence of a base and an optically active phase transfer catalyst to obtain the above general formula (3), followed by desulfonylation to obtain the above general formula ( This is a production method characterized in that the α-fluoromethylamine derivative shown in 4) is obtained with high optical purity.

The alkyl group in the general formula (1) is an alkyl group in the general formula (1) that may be branched having 1 to 20 carbon atoms or a cycloalkyl group having 3 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable. The alkyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, or an acyloxy group.

The alkenyl group in the general formula (1) is preferably an alkenyl group having 1 to 20 carbon atoms which may be branched, or a cycloalkenyl group having 3 to 20 carbon atoms, and an alkenyl group having 1 to 10 carbon atoms or More preferred is a cycloalkenyl group having 3 to 10 carbon atoms. Examples of alkenyl groups include vinyl, 1-propenyl, 1-butenyl, 1-hexenyl, cyclohexenyl, allyl and the like. The alkenyl group may be substituted with a substituent such as a halogen atom, cyano group, nitro group, aryl group, acyl group, alkoxy group, aryloxy group, acyloxy group.

Examples of the aralkyl group in the general formula (1) include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, Examples include a furfuryl group and an α-phenethyl group.

Examples of the alkynyl group in the general formula (1) include an ethynyl group, a phenylethynyl group, and a 2-propynyl group.

The aryl group in the general formula (1) is preferably an aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. The aryl group may be substituted with a substituent such as an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, an alkoxy group, or an acyloxy group.

The alkoxy group in the general formula (1) is preferably an alkoxy group having 1 to 20 carbon atoms, and more preferably an alkoxy group having 1 to 10 carbon atoms. In the case of an alkoxy group, it may be substituted with the same substituent as in the case of the above alkyl group.

The aryloxy group in the general formula (1) is preferably an aryloxy group having 1 to 20 carbon atoms, and more preferably an aryloxy group having 1 to 10 carbon atoms. In the case of an aryloxy group, it may be substituted with the same substituent as in the case of the above aryl group.


前記一般式（１）中のアシル基は炭素数が１〜２０のアシル基が好ましく，炭素数が１〜１０のアシル基がさらに好ましい。特に制限するわけではないが，例としてホルミル基，アセチル基，マロニル基，ベンゾイル基，シンナモイル基等が挙げられる。

前記一般式（１）中のアルコキシカルボニル基は炭素数が２〜２０のアルコキシカルボニル基が好ましく，炭素数が２〜１０のアルコキシカルボニル基がさらに好ましい。アルコキシカルボニル基の場合も上記のアルコキシ基の場合と同様の置換基により置換されていてもよい。

前記一般式（１）中のアリールオキシカルボニル基は炭素数が７〜２０のアリールオキシカルボニル基が好ましく，炭素数が７〜１５のアリールオキシカルボニル基がさらに好ましい。アリールオキシカルボニル基の場合も上記のアリールオキシ基の場合と同様の置換基により置換されていてもよい。

前記一般式（１）中のＲ３はフェニル基，ｐ−トリル基が挙げられるが特に制限するわけではない。

前記一般式（２）中のアルキル基は，置換基を有していても良く，直鎖または分岐した炭素数が１〜２０のアルキル基または炭素数が３〜２０のシクロアルキル基が好ましく，炭素数が１〜１０のアルキル基または炭素数が３〜１０のシクロアルキル基がさらに好ましい。

前記一般式（２）中のアリール基は炭素数が６〜２０の置換または無置換のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。

前記一般式（２）中のＲ４およびＲ５を組み合わせて形成されうる前記環状構造の例としては，３員環から２０員環でなる単環，双環，またはそれ以上の多環の構造を示すことができる。

前記一般式（３）で示される光学活性α−フルオロビス（フェニルスルホニル）メチル付加体としては，tert−ブチル ２−フルオロ−１−フェニル−２,２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル ２−フルオロ−１−ナフチル−２，２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル １−（４−クロロフェニル）−２−フルオロ−２，２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル １−（3−クロロフェニル）−２−フルオロ−２,２−ビス（フェニルスルホニル）エチルカルバメート, tert−ブチル １−（2−クロロフェニル）−２−フルオロ−２,２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル ２−フルオロ−１−（４−メトキシフェニル）−２，２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル ２−フルオロ−１−（フラン−２−イル）−２，２−ビス（フェニルスルホニル）エチルカルバメート，
tert−ブチル １−フルオロ−４−フェニル−１，１−ビス（フェニルスルホニル）ブタ−２−イルカルバメート，tert−ブチル １−フルオロ−１，１−ビス（フェニルスルホニル）ノナン−２−イルカルバメート， tert−ブチル１−フルオロ−３−メチル−１，１−ビス（フェニルスルホニル）ブタン−２−イルカルバメート，tert−ブチル１−シクロヘキシル−２−フルオロ−２，２−ビス（フェニルスルホニル）エチルカルバメート，tert−ブチル１−フルオロ−３，３−ジメチル−１，１−ビス（フェニルスルホニル）ブタン−２−イルカルバメート,エチル２−（tert−ブトキシカルボニル）-3-フルオロ−３，３−ビス（フェニルスルホニル）プロパノエートなどが挙げられる。

前記一般式（４）で示されるα−フルオロメチルアミン誘導体では，tert−ブチル２−フルオロ−１−フェニルエチルカルバメート，tert−ブチル２−フルオロ−１−（ナフタレン−２イル）エチルカルバメート，tert−ブチル１−（４−クロロフェニル）−２−フルオロ−エチルカルバメート，tert−ブチル１−（３−クロロフェニル）−２−フルオロ−エチルカルバメート，tert−ブチル１−（２−クロロフェニル）−２−フルオロ−エチルカルバメート，tert−ブチル２−フルオロ−１−（４−メトキシフェニル）エチルカルバメート， tert−ブチル２−フルオロ−１−（フラン−２−イル）エチルカルバメート，tert−ブチル１−フルオロノナン−２−イルカルバメート，tert−ブチル１−フルオロ−４−フェニルブタン−２−イルカルバメート，tert−ブチル１−フルオロ−３−メチルブタン−２−イルカルバメート，tert−ブチル１−シクロヘキシル−２−フルオロエチルカルバメート，tert−ブチル１−フルオロ−３，３−ジメチルブタン−２−イルカルバメート，エチル２−（tert−ブトキシカルボニルアミノ）−３−フルオロプロパノエートなどが挙げられる。

前記塩基触媒として特に制限するわけではないが，トリエチルアミン，ジイソプロピルエチルアミン，ジメチルアミノピリジン，キヌクリジン，ＤＢＵ，ＤＡＢＣＯなどを用いることができる。なお，前記一般式（５）塩基も，特に制限するわけではないが，水酸化ナトリウム，炭酸ナトリウム，水酸化セシウム等が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。

前記光学活性な相間移動触媒として，特に制限するわけではないが，光学活性４級アンモニウム塩，光学活性チオニウム塩，光学活性オキソニオウム塩，光学活性ホスホニウム塩などが挙げられる。好ましくは，キナアルカロイドの４級アンモニウム塩が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。

前記還元剤としての金属は，特に制限するわけではないが，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。

前記一般式（６），（７）中のアルキル基は炭素数が１〜２０の枝分かれがあっても良いアルキル基が好ましく，炭素数が１〜８の枝分かれがあっても良いアルキル基がさらに好ましい。
前記一般式（６），（７）中のアリール基は炭素数が６〜２０の置換または無置換のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。

前記一般式（６），（７）中のアシル基は炭素数が１〜２０のアシル基が好ましく，炭素数が１〜１０のアシル基がさらに好ましい。特に制限するわけではないが，例としてホルミル基，アセチル基，マロニル基，ベンゾイル基，シンナモイル基等が挙げられる。

本発明の反応は，溶媒として低極性有機溶媒としては，ヘプタン，ヘキサン，キシレン，トルエン，クロロホルム，ジクロロメタン，ジイソプロピルエーテルが好ましく，クロロホルム，ジクロロメタン，トルエン，ベンゼンが好ましい。非プロトン性溶媒としては，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，テトラヒドロフラン，ジメトキシエタン，ジエチレングリコールジメチルエーテル，ヘキサメチルリン酸トリアミドが好ましく，Ｎ，Ｎ−ジメチルホルムアミド，Ｎ−メチル−２−ピロリドン，１，３−ジメチル−２−イミダゾリジノン，ジメチルスルホキシド，テトラヒドロフランがさらに好ましい。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。

反応温度は特に限定されるものではないが，通常−８０℃〜１２０℃であり，より好ましくは室温付近である。反応器は大気開放型の反応器，またはオートクレーブ等の密閉型の反応器のいずれも可能である。反応圧力は大気圧下，または加圧下のいずれも可能である。反応時間は特に限定されるものではないが，通常1日〜7日で反応は完結する。

反応後，前記一般式（３）で示されるα−フルオロビス（フェニルスルホニル）メチル付加体は一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
The acyl group in the general formula (1) is preferably an acyl group having 1 to 20 carbon atoms, and more preferably an acyl group having 1 to 10 carbon atoms. Although not particularly limited, examples include formyl group, acetyl group, malonyl group, benzoyl group, cinnamoyl group and the like.

The alkoxycarbonyl group in the general formula (1) is preferably an alkoxycarbonyl group having 2 to 20 carbon atoms, and more preferably an alkoxycarbonyl group having 2 to 10 carbon atoms. In the case of an alkoxycarbonyl group, it may be substituted with the same substituent as in the case of the above alkoxy group.

The aryloxycarbonyl group in the general formula (1) is preferably an aryloxycarbonyl group having 7 to 20 carbon atoms, and more preferably an aryloxycarbonyl group having 7 to 15 carbon atoms. In the case of an aryloxycarbonyl group, it may be substituted with the same substituent as in the case of the above aryloxy group.

R 3 in the general formula (1) includes a phenyl group and a p-tolyl group, but is not particularly limited.

The alkyl group in the general formula (2) may have a substituent, and is preferably a linear or branched alkyl group having 1 to 20 carbon atoms or a cycloalkyl group having 3 to 20 carbon atoms, An alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable.

The aryl group in the general formula (2) is preferably a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms.

Examples of the cyclic structure that can be formed by combining R 4 and R 5 in the general formula (2) include a monocyclic, bicyclic or higher polycyclic structure consisting of 3 to 20 members. Can be shown.

Examples of the optically active α-fluorobis (phenylsulfonyl) methyl adduct represented by the general formula (3) include tert-butyl 2-fluoro-1-phenyl-2,2-bis (phenylsulfonyl) ethyl carbamate, tert- Butyl 2-fluoro-1-naphthyl-2,2-bis (phenylsulfonyl) ethylcarbamate, tert-butyl 1- (4-chlorophenyl) -2-fluoro-2,2-bis (phenylsulfonyl) ethylcarbamate, tert- Butyl 1- (3-chlorophenyl) -2-fluoro-2,2-bis (phenylsulfonyl) ethylcarbamate, tert-butyl 1- (2-chlorophenyl) -2-fluoro-2,2-bis (phenylsulfonyl) ethyl Carbamate, tert-butyl 2-fluoro-1- (4-methoxyphenyl) -2,2-bis (fluoro Nirusuruhoniru) ethylcarbamate, tert- butyl 2-fluoro-1- (furan-2-yl) -2,2-bis (phenylsulfonyl) ethyl carbamate,
tert-butyl 1-fluoro-4-phenyl-1,1-bis (phenylsulfonyl) but-2-ylcarbamate, tert-butyl 1-fluoro-1,1-bis (phenylsulfonyl) nonan-2-ylcarbamate, tert-butyl 1-fluoro-3-methyl-1,1-bis (phenylsulfonyl) butan-2-ylcarbamate, tert-butyl 1-cyclohexyl-2-fluoro-2,2-bis (phenylsulfonyl) ethylcarbamate, tert-butyl 1-fluoro-3,3-dimethyl-1,1-bis (phenylsulfonyl) butan-2-ylcarbamate, ethyl 2- (tert-butoxycarbonyl) -3-fluoro-3,3-bis (phenyl) Sulfonyl) propanoate and the like.

In the α-fluoromethylamine derivative represented by the general formula (4), tert-butyl 2-fluoro-1-phenylethyl carbamate, tert-butyl 2-fluoro-1- (naphthalen-2-yl) ethyl carbamate, tert- Butyl 1- (4-chlorophenyl) -2-fluoro-ethyl carbamate, tert-butyl 1- (3-chlorophenyl) -2-fluoro-ethyl carbamate, tert-butyl 1- (2-chlorophenyl) -2-fluoro-ethyl Carbamate, tert-butyl 2-fluoro-1- (4-methoxyphenyl) ethyl carbamate, tert-butyl 2-fluoro-1- (furan-2-yl) ethyl carbamate, tert-butyl 1-fluorononan-2-yl Carbamate, tert-butyl 1-fluoro-4-phenylbutan-2-ylcarbamate tert-butyl 1-fluoro-3-methylbutan-2-ylcarbamate, tert-butyl 1-cyclohexyl-2-fluoroethylcarbamate, tert-butyl 1-fluoro-3,3-dimethylbutan-2-ylcarbamate, ethyl 2 -(Tert-butoxycarbonylamino) -3-fluoropropanoate and the like.

The base catalyst is not particularly limited, but triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The base of the general formula (5) is not particularly limited, and examples thereof include sodium hydroxide, sodium carbonate, cesium hydroxide and the like. These can be used alone or in combination of two or more.

Examples of the optically active phase transfer catalyst include, but are not limited to, optically active quaternary ammonium salts, optically active thionium salts, optically active oxonium salts, and optically active phosphonium salts. Preferably, the quaternary ammonium salt of quina alkaloid is mentioned. These can be used alone or in combination of two or more.

The metal as the reducing agent is not particularly limited, and examples thereof include at least one element selected from lithium, sodium, magnesium, aluminum, zinc, tin, indium, samarium, and the like, including rare earths. These can be used alone or in combination of two or more.

The alkyl group in the general formulas (6) and (7) is preferably an alkyl group having 1 to 20 carbon atoms which may be branched, and further having an alkyl group having 1 to 8 carbon atoms which may be branched. preferable.
The aryl group in the general formulas (6) and (7) is preferably a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms.

The acyl group in the general formulas (6) and (7) is preferably an acyl group having 1 to 20 carbon atoms, and more preferably an acyl group having 1 to 10 carbon atoms. Although not particularly limited, examples include formyl group, acetyl group, malonyl group, benzoyl group, cinnamoyl group and the like.

In the reaction of the present invention, heptane, hexane, xylene, toluene, chloroform, dichloromethane and diisopropyl ether are preferred as the low polar organic solvent, and chloroform, dichloromethane, toluene and benzene are preferred. As the aprotic solvent, N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether and hexamethylphosphoric triamide are preferable. N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1, More preferred are 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, and tetrahydrofuran. These can be used alone or in combination of two or more.

Although reaction temperature is not specifically limited, Usually, it is -80 degreeC-120 degreeC, More preferably, it is room temperature vicinity. The reactor can be either an open-air reactor or a closed reactor such as an autoclave. The reaction pressure can be either atmospheric pressure or pressurized. The reaction time is not particularly limited, but the reaction is usually completed in 1 to 7 days.

After the reaction, the α-fluorobis (phenylsulfonyl) methyl adduct represented by the general formula (3) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and then distilled. Examples thereof include purification, purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization and the like.

前記一般式（４）で示されるα−フルオロメチルアミン誘導体は，一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。

以下，実施例により本発明をさらに具体的に説明するが，本発明の範囲は下記の実施例に限定されるものではない。
The α-fluoromethylamine derivative represented by the general formula (4) can be isolated and purified from the reaction solution by a general method. For example, after concentrating the reaction solution, distillation purification or silica gel, alumina, etc. Examples include purification by column chromatography using an adsorbent, salting out, and recrystallization.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.

一般的方法：α−アミドスルホンの不斉マンニッヒ型反応
α−アミドスルホン１(0.35 mmol)をCH2Cl2に溶かし，相間移動触媒としてN-benzyl qunidinium chloride (0.018 mmol)とCsOH・H2O (0.42 mmol)を加えた。溶液は，-80℃に冷却したのちfluoro(phenylsulfonyl)methane 2 (0.37 mmol)を加えて，18時間激しく撹拌した。反応後，飽和NH4Cl水溶液にて処理し，酢酸エチルで抽出（2×5 mL）を行った。有機層はMgSO4で乾燥後，ろ過，濃縮した。残渣は，カラムクロマトグラフィーにて精製し，目的とする化合物３を得た。 General method: Asymmetric Mannich reaction of α-amidosulfone α-amidosulfone 1 (0.35 mmol) is dissolved in CH 2 Cl 2 and N-benzyl qunidinium chloride (0.018 mmol) and CsOH · H 2 O are used as phase transfer catalysts. (0.42 mmol) was added. The solution was cooled to −80 ° C., fluoro (phenylsulfonyl) methane 2 (0.37 mmol) was added, and the mixture was vigorously stirred for 18 hours. After the reaction, it was treated with a saturated aqueous NH 4 Cl solution, and extracted with ethyl acetate (2 × 5 mL). The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography to obtain the target compound 3.


General procedure for the enantioselective fluoromethylation of α-amido sulfones 2 with 1: (S)-tert-Butyl 2-fluoro-1-phenyl-2,2-bis(phenylsulfonyl)ethylcarbamate (3a)
General procedure for the enantioselective fluoromethylation of α-amido sulfones 2 with 1: (S) -tert-Butyl 2-fluoro-1-phenyl-2,2-bis (phenylsulfonyl) ethylcarbamate (3a)

To a mixture of α-amido sulfone 2a (121.6 mg, 0.35 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) and CsOH・H2O (70.5 mg, 0.42 mmol) in CH2Cl2 (1.0 mL), fluorobis(phenylsulfonyl)methane (1)(118.5 mg, 0.38 mmol) was added in one portion at -80 °C. The reaction mixture was then vigorously stirred at the same temperature. After 1d, the reaction was quenched with saturated NH4Cl, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (acetone/n-hexane = 1/5). Product 3a was obtained in 92% yield, 96% ee as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.49 (s, 9H), 5.62 (t, J = 10.4 Hz, 1H), 6.55 (d, J = 10.4 Hz, 1H), 7.08-7.64 (m, 12H), 7.73 (t, J = 7.4 Hz, 1H) 8.02 (d, J = 8.4 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -128.3 (d, J = 9.2 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 55.4 (d, J = 23.9 Hz), 80.7, 113.4 (d, J = 270.1 Hz), 127.9, 128.0, 128.3, 128.4, 128.7, 130.1, 131.0, 133.1, 134.4, 134.8, 135.0, 135.6, 153.9; IR (KBr) 3436, 3066, 2979, 2932, 1725, 1583, 1497, 1449, 1339, 1314, 1235, 1163, 1077, 1005, 898, 861, 751, 685, 601, 587, 556, 527 cm-1; MS (ESI, m/z); 542.0 (M+Na+), 558.0 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.2 mL/min, λ = 254 nm, τmin = 144 min, τmaj = 150 min); [α] D 25 = -39.6 (c = 1.0 , CHCl3) , 96% ee. The absolute configuration of 3awas determined to be (S) after chemical derivatization to the known (S)-2-fluoro-1-phenylethanaminium chloride (5a) (see, p-S-14).
The absolute configuration of 3b-e was tentatively assigned as (S) by comparing the optical rotation with that of 3a.

(S)-tert-Butyl 2-fluoro-1-(3-chlorophenyl)-2,2-bis(phenylsulfonyl)ethylcarbamate (3b)
To a mixture of α-amido sulfone 2a (121.6 mg, 0.35 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) and CsOH ・ H 2 O (70.5 mg, 0.42 mmol) in CH 2 Cl 2 (1.0 mL ), fluorobis (phenylsulfonyl) methane (1) (118.5 mg, 0.38 mmol) was added in one portion at -80 ° C. The reaction mixture was then vigorously stirred at the same temperature.After 1d, the reaction was quenched with saturated NH 4 Cl, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL) .The combined organic extracts were washed with brine, dried over MgSO 4 , and concentrated under reduced pressure.The crude product was purified by column chromatography on silica gel (acetone / n-hexane = 1/5 ). Product 3a was obtained in 92% yield, 96% ee as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.49 (s, 9H), 5.62 (t , J = 10.4 Hz, 1H), 6.55 (d, J = 10.4 Hz, 1H), 7.08-7.64 (m, 12H), 7.73 (t, J = 7.4 Hz, 1H) 8.02 (d, J = 8.4 Hz, 2H); 19 F NMR (CDCl 3, 188 MHz) δ -128.3 (d, J = 9.2 Hz, 1F); 13 C NMR (CDCl 3, 50.3 MHz) 28.5, 55.4 (d, J = 23.9 Hz), 80.7, 113.4 (d, J = 270.1 Hz), 127.9, 128.0, 128.3, 128.4, 128.7, 130.1, 131.0, 133.1, 134.4, 134.8, 135.0, 135.6, 153.9; IR (KBr) 3436, 3066, 2979, 2932, 1725, 1583, 1497, 1449, 1339, 1314, 1235, 1163, 1077, 1005, 898, 861, 751, 685, 601, 587, 556, 527 cm -1 ; MS (ESI, m / z); 542.0 (M + Na + ), 558.0 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.2 mL / min, λ = 254 nm, τ min = 144 min, τ maj = 150 min); [α] D 25 = -39.6 (c = 1.0, CHCl 3 ) , 96% ee.The absolute configuration of 3awas determined to be (S) after chemical derivatization to the known (S) -2-fluoro-1-phenylethanaminium chloride (5a) (see, pS-14).
The absolute configuration of 3b-e was tentatively assigned as (S) by comparing the optical rotation with that of 3a.

(S) -tert-Butyl 2-fluoro-1- (3-chlorophenyl) -2,2-bis (phenylsulfonyl) ethylcarbamate (3b)

Reaction of 2b (133.5 mg, 0.35 mmol), 1 (115.5 mg, 0.37 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (15.8 mg, 0.035 mmol) in CH2Cl2 (1.0 mL) at -80°C gave 3b(191.1 mg, 98%, 97% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.50 (s, 9H), 5.60 (t, J = 10.4 Hz, 1H), 6.53 (d, J = 10.4 Hz, 1H), 7.06-7.20 (m, 4H), 7.31 (d, J = 7.2 Hz, 2H), 7.39-7.64 (m, 5H), 7.74 (t, J = 7.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -129.2 (d, J = 10.4 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.4, 54.9 (d, J = 23.9 Hz), 80.9, 113.0 (d, J = 270.6 Hz), 126.0, 126.1, 128.0, 128.1, 128.3, 128.5, 129.1, 129.8, 129.9, 130.8, 130.9, 133.9, 134.7, 135.1, 135.4, 135.4; IR (KBr) 3426, 3380, 3068, 2981, 2930, 1730, 1596, 1583, 1504, 1449, 1393, 1337, 1239, 1169, 1077, 1038, 1005, 930, 883, 858, 827, 787, 751, 729, 684 cm-1; MS (ESI, m/z) = 576.0 (M+Na+), 592.0 (M+K+); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 95:5, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 27.4 min, τmin = 31.1 min); [α] D 25 = -53.1 (c = 1.0 , CHCl3) , 97% ee.

(S)-tert-Butyl 2-fluoro-1-(4-chlorophenyl)-2,2-bis(phenylsulfonyl)ethylcarbamate (3c)
Reaction of 2b (133.5 mg, 0.35 mmol), 1 (115.5 mg, 0.37 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (15.8 mg, 0.035 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C gave 3b (191.1 mg, 98%, 97% ee) as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.50 (s, 9H), 5.60 (t, J = 10.4 Hz, 1H), 6.53 (d, J = 10.4 Hz, 1H), 7.06-7.20 (m, 4H), 7.31 (d, J = 7.2 Hz, 2H), 7.39-7.64 (m, 5H), 7.74 (t, J = 7.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -129.2 (d, J = 10.4 Hz, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.4, 54.9 (d, J = 23.9 Hz), 80.9, 113.0 (d, J = 270.6 Hz), 126.0, 126.1, 128.0, 128.1, 128.3, 128.5, 129.1, 129.8, 129.9, 130.8, 130.9, 133.9, 134.7, 135.1, 135.4, 135.4; IR (KBr) 3426, 3380, 3068, 2981, 2930, 1730, 1596, 1583, 1504, 1449, 1393, 1337, 1239, 1169, 1077, 1038, 1005, 930, 883, 858, 827, 787, 751, 729, 684 cm -1 ; MS (ESI, m / z) = 576.0 (M + Na + ), 592.0 (M + K + ); The ee of the product was determined by HPLC using an OD-H column (n-hexane / i-PrOH = 95: 5, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 27.4 min, τ min = 31.1 min); [α] D 25 = -53.1 (c = 1.0, CHCl 3 ) , 97% ee.

(S) -tert-Butyl 2-fluoro-1- (4-chlorophenyl) -2,2-bis (phenylsulfonyl) ethylcarbamate (3c)

Reaction of 2c (133.5 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2 (1.0 mL) at -80°C gave 3c( 182.4 mg, 94%, 87% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.49 (s, 9H), 5.83 (t, J = 10.4 Hz, 1H), 6.52 (d, J = 10.4 Hz, 1H), 7.07-7.20 (m, 4H), 7.24-7.36 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 8.2 Hz, 3H), 7.68-7.78 (m, 1H), 8.00 (d,J = 8.4 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -129.0 (d, J = 10.4 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 55.0 (d, J = 23.9 Hz), 80.9, 113.2 (d, J = 271.2 Hz), 128.1, 128.4, 128.8, 129.2, 129.3, 130.0, 130.6, 130.9, 131.9, 134.5, 134.6, 134.7, 135.1, 135.5, 153.8; IR (KBr) 3430, 3080, 2972, 2920, 1718, 1507, 1449, 1339, 1235, 1163, 1077, 1013, 911, 819, 754, 719, 684 cm-1; MS (ESI, m/z) = 575.9 (M+Na+), 592.0 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 31.3 min, τmin = 38.2 min); [α] D 25= -27.2 (c = 1.0 , CH3OH) , 92% ee.

(S)-tert-Butyl 2-fluoro-1-(4-methoxyphenyl)-2,2-bis(phenylsulfonyl)ethylcarbamate (3d)
Reaction of 2c (133.5 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C gave 3c (182.4 mg, 94%, ee 87%) as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.49 (s, 9H), 5.83 (t, J = 10.4 Hz, 1H), 6.52 (d, J = 10.4 Hz, 1H), 7.07-7.20 (m, 4H), 7.24-7.36 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 8.2 Hz, 3H), 7.68-7.78 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -129.0 (d, J = 10.4 Hz, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 55.0 (d, J = 23.9 Hz), 80.9, 113.2 (d, J = 271.2 Hz), 128.1, 128.4, 128.8, 129.2, 129.3 , 130.0, 130.6, 130.9, 131.9, 134.5, 134.6, 134.7, 135.1, 135.5, 153.8; IR (KBr) 3430, 3080, 2972, 2920, 1718, 1507, 1449, 1339, 1235, 1163, 1077, 1013, 911 , 819, 754, 719, 684 cm -1 ; MS (ESI, m / z) = 575.9 (M + Na + ), 592.0 (M + K + ); The ee of the product was determined by HPLC using an AD- H column (n-hexane / i-PrOH = 90/10, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 31.3 min, τ min = 38.2 min); [α] D 25 = -27.2 (c = 1.0, CH 3 OH) , 92% ee.

(S) -tert-Butyl 2-fluoro-1- (4-methoxyphenyl) -2,2-bis (phenylsulfonyl) ethylcarbamate (3d)

Reaction of 2d (132.1 mg, 0.35 mmol) with 1 (118.5 mg, 0.37 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at -80°C gave 3d(169.8 mg, 88%, 95% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.49 (s, 9H), 3.74 (s, 3H), 5.81 (t, J = 10.4, 11.2 Hz, 1H), 6.49 (d, J = 9.8 Hz, 1H),6.66 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 7.21-7.61 (m, 7H), 7.71 (t, J = 7.4 Hz, 1H), 8.00 (d, J = 8.2 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -128.2 (d, J = 11.4 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 55.0 (d, J = 21.1 Hz), 55.2, 80.6, 113.4, 113.6 (d, J = 269.8 Hz), 128.2, 128.7, 129.0, 129.1, 130.0, 130.9, 134.3, 134.9, 135.0, 135.8, 153.8, 159.4; IR (KBr) 3391, 3062, 2985, 2950, 2913, 2840, 1715, 1612, 1583, 1514, 1496, 1447, 1349, 1310, 1298, 1252, 1159, 1077, 1033, 1004, 907, 856, 827, 816, 783, 761, 719, 683, 648 cm-1; MS (ESI, m/z) = 572.1 (M+Na+), 588.1 (M+K+); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 90/10, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 24.8 min, τmin = 28.0 min); [α] D 25 = -60.6 (c = 1.0 , CHCl3) , 95% ee.
(S)-tert-Butyl 2-fluoro-1-naphthyl-2,2-bis(phenylsulfonyl)ethylcarbamate (3e)
Reaction of 2d (132.1 mg, 0.35 mmol) with 1 (118.5 mg, 0.37 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C gave 3d (169.8 mg, 88%, 95% ee) as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.49 (s, 9H), 3.74 (s, 3H ), 5.81 (t, J = 10.4, 11.2 Hz, 1H), 6.49 (d, J = 9.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H ), 7.21-7.61 (m, 7H), 7.71 (t, J = 7.4 Hz, 1H), 8.00 (d, J = 8.2 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -128.2 (d , J = 11.4 Hz, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 55.0 (d, J = 21.1 Hz), 55.2, 80.6, 113.4, 113.6 (d, J = 269.8 Hz), 128.2, 128.7, 129.0, 129.1, 130.0, 130.9, 134.3, 134.9, 135.0, 135.8, 153.8, 159.4; IR (KBr) 3391, 3062, 2985, 2950, 2913, 2840, 1715, 1612, 1583, 1514, 1496, 1447, 1349, 1310, 1298, 1252, 1159, 1077, 1033, 1004, 907, 856, 827, 816, 783, 761, 719, 683, 648 cm -1 ; MS (ESI, m / z) = 572.1 (M + Na + ), 588.1 (M + K + ); The ee of the product was determined by HPLC usi ng an OD-H column (n-hexane / i-PrOH = 90/10, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 24.8 min, τ min = 28.0 min); [α] D 25 = -60.6 (c = 1.0, CHCl 3 ) , 95% ee.
(S) -tert-Butyl 2-fluoro-1-naphthyl-2,2-bis (phenylsulfonyl) ethylcarbamate (3e)

Reaction of 2e (139.1 mg, 0.35 mmol), 1 (118.5 mg, 0.37 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at-80°C gave 3e (191.3 mg, 96%, 90% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.51 (s, 9H), 5.83 (t, J = 10.4 Hz, 1H), 6.64 (d, J = 10.4 Hz, 1H), 6.91 (t, J = 7.4 Hz, 2H), 7.16-7.32 (m, 3H), 7.39-7.80 (m, 10H), 8.08 (d, J = 8.2 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -128.6 (d, J = 10.4 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.4, 55.4 (d, J = 23.9 Hz), 80.6, 116.3 (d, J = 271.0 Hz), 125.0, 125.1, 125.9, 126.2, 127.0, 127.4, 127.8, 128.6, 129.6, 130.5, 131.0, 132.5, 132.9, 134.0, 134.9, 135.0, 135.3, 153.8; IR (KBr) 3391, 3062, 3981, 2913, 1712, 1582, 1494, 1447, 1350, 1322, 1237, 1162, 1076, 1007, 860, 813, 758, 718, 683, 631 cm-1; MS (ESI, m/z) = 592.0 (M+Na+), 608.0 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm, τmaj = 20.6 min, τmin = 25.6 min); [α] D 25 = -99.1 (c = 1.0 , CHCl3), 90% ee.

tert-Butyl 2-fluoro-1-(furan-2-yl)-2,2-bis(phenylsulfonyl)ethylcarbamate (3f)
Reaction of 2e (139.1 mg, 0.35 mmol), 1 (118.5 mg, 0.37 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at-80 ° C gave 3e (191.3 mg, 96%, 90% ee) as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.51 (s, 9H), 5.83 (t, J = 10.4 Hz, 1H), 6.64 (d, J = 10.4 Hz, 1H), 6.91 (t, J = 7.4 Hz, 2H), 7.16-7.32 (m, 3H), 7.39-7.80 (m, 10H), 8.08 (d, J = 8.2 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -128.6 (d, J = 10.4 Hz, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.4, 55.4 ( d, J = 23.9 Hz), 80.6, 116.3 (d, J = 271.0 Hz), 125.0, 125.1, 125.9, 126.2, 127.0, 127.4, 127.8, 128.6, 129.6, 130.5, 131.0, 132.5, 132.9, 134.0, 134.9, 135.0, 135.3, 153.8; IR (KBr) 3391, 3062, 3981, 2913, 1712, 1582, 1494, 1447, 1350, 1322, 1237, 1162, 1076, 1007, 860, 813, 758, 718, 683, 631 cm -1 ; MS (ESI, m / z) = 592.0 (M + Na + ), 608.0 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i- PrOH = 90/10, flow rate 1.0 mL / min, λ = 254 n m, τ maj = 20.6 min, τ min = 25.6 min); [α] D 25 = -99.1 (c = 1.0, CHCl 3 ), 90% ee.

tert-Butyl 2-fluoro-1- (furan-2-yl) -2,2-bis (phenylsulfonyl) ethylcarbamate (3f)

Reaction of 2f (118.1 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at -80°C gave 3f(144.8 mg, 81%, 93% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.48 (s, 9H), 5.69 (t, J = 9.6 Hz, 1H), 6.21-6.44 (m, 3H), 7.14 (s, 1H), 7.32-7.76 (m, 8H), 7.97 (d, J = 8.2 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -130.7 (d, J = 9.6 Hz, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.4, 50.9 (d, J = 25.5 Hz), 80.8, 109.6, 110.2, 110.6, 112.3 (d, J = 270.0 Hz), 128.5, 128.7, 130.2, 130.8, 130.9, 134.6, 135.0, 135.2; IR (KBr) 3430, 3068, 2979, 2931, 1503, 1726, 1583, 1503, 1449, 1239, 1162, 1076, 1008, 951, 894, 861, 814, 753, 685 cm-1; MS (ESI, m/z) =532.0 (M+Na+), 547.9 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.5 mL/min, λ = 254 nm, τmin= 65.6 min, τmaj = 83.1 min); [α] D 25 = +20.9 (c = 1.0 , CHCl3), 91% ee.

tert-butyl 1-fluoro-4-phenyl-1,1-bis(phenylsulfonyl)butan-2-ylcarbamate (3g)
Reaction of 2f (118.1 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C gave 3f (144.8 mg, 81%, 93% ee) as a white solid. 1 H NMR (CDCl 3, 200 MHz) δ 1.48 (s, 9H), 5.69 (t, J = 9.6 Hz, 1H), 6.21-6.44 (m, 3H), 7.14 (s, 1H), 7.32-7.76 (m, 8H), 7.97 (d, J = 8.2 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -130.7 (d, J = 9.6 Hz, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.4, 50.9 (d, J = 25.5 Hz), 80.8, 109.6, 110.2, 110.6, 112.3 (d, J = 270.0 Hz), 128.5, 128.7, 130.2, 130.8, 130.9, 134.6, 135.0, 135.2; IR (KBr) 3430, 3068, 2979, 2931, 1503, 1726, 1583, 1503, 1449, 1239, 1162 , 1076, 1008, 951, 894, 861, 814, 753, 685 cm -1 ; MS (ESI, m / z) = 532.0 (M + Na + ), 547.9 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.5 mL / min, λ = 254 nm, τ min = 65.6 min, τ maj = 83.1 min); (α ] D 25 = +20.9 (c = 1.0, CHCl 3 ), 91% ee.

tert-butyl 1-fluoro-4-phenyl-1,1-bis (phenylsulfonyl) butan-2-ylcarbamate (3g)

Reaction of 2g (131.3 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at -80°C gave 3g(161.9 mg, 85%, 90% ee) as a white solid. 1H NMR (CDCl3, 200 MHz, mixture of rotamers) δ 1.06 (s, 9/4H), 1.42 (s, 27/4H), 2.29-3.14(m, 4H), 4.06 (t, J = 10.8 Hz, 1/4H), 4.32 (t, J = 10.6 Hz, 3/4), 5.19 (d, J = 10.8 Hz, 1/4H), 5.42 (d, J = 10.7 Hz, 3/4), 2.08-7.78 (m, 13H), 7.94 (d, J = 8.4 Hz, 1/2H), 8.03 (d, J = 7.8 Hz, 3/2); 19F NMR (CDCl3, 188 MHz, mixture of rotamers) δ -134.9 (s, 3/4F), -136.3 (s, 1/4F); 13C NMR (CDCl3, 50.3 MHz, mixture of rotamers) δ 28.0, 28.4, 31.6 (d, J = 18.4 Hz), 32.3, 52.7 (d, J = 18.0 Hz), 53.6 (d, J = 16.3 Hz), 79.8, 80.4, 113.0 (d, J = 267.0 Hz), 125.9, 126.1, 128.2, 128.3, 128.5, 128.8, 129.0, 129.4, 130.5, 130.9, 131.1, 133.5, 133.9, 134.9, 135.0, 135.4, 135.6, 139.5, 139.8, 140.0, 154.8; IR (KBr) 3418, 3063, 2983, 2931, 1716, 1583, 1516, 1449, 1353, 1314, 1267, 1251, 1167, 1080, 1042, 1022, 864, 753, 728, 699, 606, 575, 523 cm-1; MS (ESI, m/z) = 570.1 (M+Na+), 587.1 (M+K+); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 92.5/7.5, flow rate 0.3 mL/min, λ = 254 nm, τmin= 32.6 min, τmaj = 44.5 min); [α] D 25 = +53.8 (c = 1.0, CHCl3) , 90% ee.

tert-Butyl 1-fluoro-1,1-bis(phenylsulfonyl)nonan-2-ylcarbamate (3h)
Reaction of 2g (131.3 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C gave 3g (161.9 mg, 85%, ee 90%) as a white solid. 1 H NMR (CDCl 3, 200 MHz, mixture of rotamers) δ 1.06 (s, 9 / 4H) , 1.42 (s, 27 / 4H), 2.29-3.14 (m, 4H), 4.06 (t, J = 10.8 Hz, 1 / 4H), 4.32 (t, J = 10.6 Hz, 3/4), 5.19 (d , J = 10.8 Hz, 1 / 4H), 5.42 (d, J = 10.7 Hz, 3/4), 2.08-7.78 (m, 13H), 7.94 (d, J = 8.4 Hz, 1 / 2H), 8.03 ( d, J = 7.8 Hz, 3/2); 19 F NMR (CDCl 3 , 188 MHz, mixture of rotamers) δ -134.9 (s, 3 / 4F), -136.3 (s, 1 / 4F); 13 C NMR (CDCl 3 , 50.3 MHz, mixture of rotamers) δ 28.0, 28.4, 31.6 (d, J = 18.4 Hz), 32.3, 52.7 (d, J = 18.0 Hz), 53.6 (d, J = 16.3 Hz), 79.8, 80.4, 113.0 (d, J = 267.0 Hz), 125.9, 126.1, 128.2, 128.3, 128.5, 128.8, 129.0, 129.4, 130.5, 130.9, 131.1, 133.5, 133.9, 134.9, 135.0, 135.4, 135.6, 139.5, 139.8, 140.0, 154.8; IR (KBr) 3418, 3063, 2983, 2931, 1716, 1583, 1516, 1449, 1353, 1314 , 1267, 1251, 1167, 1080, 1042, 1022, 864, 753, 728, 699, 606, 575, 523 cm -1 ; MS (ESI, m / z) = 570.1 (M + Na + ), 587.1 (M + K + ); The ee of the product was determined by HPLC using an OD-H column (n-hexane / i-PrOH = 92.5 / 7.5, flow rate 0.3 mL / min, λ = 254 nm, τ min = 32.6 min , τ maj = 44.5 min); [α] D 25 = +53.8 (c = 1.0, CHCl 3 ) , 90% ee.

tert-Butyl 1-fluoro-1,1-bis (phenylsulfonyl) nonan-2-ylcarbamate (3h)

Reaction of 2h (129.3 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at-80°C gave 3h (180.3 mg, 95%, 95% ee) as a white solid. 1H NMR (CDCl3, 200 MHz, mixture of rotamers) δ 0.80-0.96 (m, 3H), 1.22-1.34 (m, 10H), 1.41 (s, 9H), 1.64-2.60 (m, 2H), 4.27-4.52(m, 1H), 5.10 (d, J= 10.2 Hz, 1/5H), 5.36 (d, J = 10.8 Hz, 4/5H), 7.51 (dt, J = 1.6, 8.0Hz. 4H), 7.63-7.75 (m, 2H), 7.88 (t, J = 8.0 Hz, 4H); 19F NMR (CDCl3, 188 MHz, mixture of rotamers) δ -133.4 (s, 4/5F), -134.2 (s, 1/5F); 13C NMR (CDCl3, 50.3 MHz, mixture of rotamers) δ 14.2, 22.7, 28.1, 28.3, 29.0, 29.2, 30.2, 30.6, 31.8, 53.7 (d, J = 18.4 Hz), 79.8, 80.3, 113.5 (d, J = 267.8), 128.5, 128.8, 130.5, 130.6, 134.7, 134.8, 135.1, 135.3, 154.9; IR (KBr) 3423, 3074, 2928, 2858, 1713, 1583, 1516, 1450, 1338, 1253, 1169, 1080, 1050, 998, 860, 754, 730, 714 cm-1; MS (ESI, m/z) = 564.1 (M+Na+), 580.1 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 92.5/7.5, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 15.5 min, τmin = 17.1 min); [α] D 25 = +48.5 (c = 0.82 , CHCl3) , 95% ee.

tert-Butyl 1-cyclohexyl-2-fluoro-2,2-bis(phenylsulfonyl)ethylcarbamate (3i)
Reaction of 2h (129.3 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at-80 ° C gave 3h (180.3 mg, 95%, ee 95%) as a white solid. 1 H NMR (CDCl 3, 200 MHz, mixture of rotamers) δ 0.80-0.96 (m, 3H) , 1.22-1.34 (m, 10H), 1.41 (s, 9H), 1.64-2.60 (m, 2H), 4.27-4.52 (m, 1H), 5.10 (d, J = 10.2 Hz, 1 / 5H), 5.36 (d, J = 10.8 Hz, 4 / 5H), 7.51 (dt, J = 1.6, 8.0Hz. 4H), 7.63-7.75 (m, 2H), 7.88 (t, J = 8.0 Hz, 4H); 19 F NMR (CDCl 3 , 188 MHz, mixture of rotamers) δ -133.4 (s, 4 / 5F), -134.2 (s, 1 / 5F); 13 C NMR (CDCl 3 , 50.3 MHz, mixture of rotamers) δ 14.2, 22.7, 28.1, 28.3, 29.0, 29.2, 30.2, 30.6, 31.8, 53.7 (d, J = 18.4 Hz), 79.8, 80.3, 113.5 (d, J = 267.8), 128.5, 128.8, 130.5, 130.6, 134.7, 134.8 , 135.1, 135.3, 154.9; IR (KBr) 3423, 3074, 2928, 2858, 1713, 1583, 1516, 1450, 1338, 1253, 1169, 1080, 1050, 998, 860, 754, 730, 714 cm -1 ; MS (ESI, m / z) = 564.1 (M + Na + ), 580.1 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 92.5 / 7.5, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 15.5 min, τ min = 17.1 min); α] D 25 = +48.5 (c = 0.82, CHCl 3 ) , 95% ee.

tert-Butyl 1-cyclohexyl-2-fluoro-2,2-bis (phenylsulfonyl) ethylcarbamate (3i)

Reaction of 2i (123.7 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2 (1.0 mL) at -80°C, the temperature was gradually warmed to -40°C over 2h. After stirring for 22 h at -40°C, the resulting mixture gave 3i(146.6 mg, 80%, 98% ee) as a white solid by column chromatography (acetone/n-hexane = 1/5) on silica gel. 1H NMR (CDCl3, 200 MHz) δ 0.89-2.17 (m, 11H), 1.45 (s, 9H), 4.35(ddd, J = 5.8, 6.2 , 11.2 Hz, 1H), 5.69 (d, J = 11.2 Hz, 1H), 7.45-7.97 (m, 10H) ; 19F NMR (CDCl3, 188 MHz) δ -132.7 (s, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 25.9, 26.1, 26.2, 28.3, 28.4, 32.9, 33.0, 57.2 (d, J = 21.1 Hz), 79.9, 114.7 (d, J= 271.39 Hz), 128.6, 130.61, 130.64, 130.76, 130.79, 134.4, 134.7, 135.0, 135.8, 154.8; IR (KBr) 3430, 3057, 2979, 2941, 2860, 1715, 1489, 1446, 1372, 1345, 1318, 1242, 1170, 1153, 1078, 1002, 959, 859, 794, 760, 728, 712, 688 cm-1; MS (ESI, m/z) = 548.1 (M+Na+), 565.1 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 92.5/7.5, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 17.9 min, τmin = 21.1 min); [α] D 25 = -4.80 (c = 1.0 , CHCl3) , 98% ee.

tert-Butyl 1-fluoro-3-methyl-,1,1-bis(phenylsulfonyl)butan-2-ylcarbamate (3j)
Reaction of 2i (123.7 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at -80 ° C, the temperature was gradually warmed to -40 ° C over 2h.After stirring for 22 h at -40 ° C, the resulting mixture gave 3i (146.6 mg, 80%, 98% ee) as a white solid by column chromatography ( acetone / n-hexane = 1/5) on silica gel. 1 H NMR (CDCl 3, 200 MHz) δ 0.89-2.17 (m, 11H), 1.45 (s, 9H), 4.35 (ddd, J = 5.8, 6.2, 11.2 Hz, 1H), 5.69 (d, J = 11.2 Hz, 1H), 7.45-7.97 (m, 10H); 19 F NMR (CDCl 3 , 188 MHz) δ -132.7 ( s, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 25.9, 26.1, 26.2, 28.3, 28.4, 32.9, 33.0, 57.2 (d, J = 21.1 Hz), 79.9, 114.7 (d, J = 271.39 Hz ), 128.6, 130.61, 130.64, 130.76, 130.79, 134.4, 134.7, 135.0, 135.8, 154.8; IR (KBr) 3430, 3057, 2979, 2941, 2860, 1715, 1489, 1446, 1372, 1345, 1318, 1242, 1170, 1153, 1078, 1002, 959, 859, 794, 760, 728, 712, 688 cm -1 ; MS (ESI, m / z) = 548.1 (M + Na + ), 565.1 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 92.5 / 7.5, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 17.9 min, τ min = 21.1 min); [α] D 25 = -4.80 (c = 1.0, CHCl 3 ) , 98% ee.

tert-Butyl 1-fluoro-3-methyl-, 1,1-bis (phenylsulfonyl) butan-2-ylcarbamate (3j)

Reaction of 2j (109.6 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at-80°C, the temperature was gradually warmed to -40°C over 2h. After stirring for 24 h at -40°C, the resulting mixture gave 3j (157.8 mg, 93%, 99% ee) as a white solid by column chromatography (acetone/n-hexane = 1/5) on silica gel. 1H NMR (CDCl3, 200 MHz) δ 0.84 (dd, J = 2.4, 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H), 2.38-2.57 (m, 1H), 4.33 (ddd, J = 5.8, 6.0, 11.2 Hz, 1H), 5.70 (d, J = 11.2 Hz, 1H), 7.43-7.78 (m, 6H), 7.84 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 7.8 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -132.3 (s, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 18.8, 22.4 (d, J = 5.2 Hz), 28.5, 30.0, 58.0 (d, J = 21.2 Hz), 80.2, 114.8 (d, J= 271.8 Hz), 128.66, 128.70, 130.65, 130.68, 130.89, 130.91, 134.5, 134.8, 135.1, 135.8 ; IR (KBr) 3441, 3068, 2976, 2933, 2877, 1721, 1583, 1499, 1449, 1393, 1348, 1314, 1235, 1163, 1078, 999, 916, 862, 753, 725, 686, 604, 560 cm-1; MS (ESI, m/z) = 508.1 (M+Na+), 524.0 (M+K+); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.2 mL/min, λ = 254 nm, τmaj = 42.8 min, τmin = 46.2 min); [α] D 25 = +13.1 (c = 0.5 , CH3OH) , 99% ee.

tert-Butyl 1-fluoro-3,3-dimethyl-,1,1-bis(phenylsulfonyl)butan-2-ylcarbamate (3k)
Reaction of 2j (109.6 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at-80 ° C, the temperature was gradually warmed to -40 ° C over 2h.After stirring for 24 h at -40 ° C, the resulting mixture gave 3j (157.8 mg, 93%, 99% ee) as a white solid by column chromatography ( acetone / n-hexane = 1/5) on silica gel. 1 H NMR (CDCl 3, 200 MHz) δ 0.84 (dd, J = 2.4, 6.8 Hz, 3H), 1.00 (d , J = 6.8 Hz, 3H), 1.48 (s, 9H), 2.38-2.57 (m, 1H), 4.33 (ddd, J = 5.8, 6.0, 11.2 Hz, 1H), 5.70 (d, J = 11.2 Hz, 1H), 7.43-7.78 (m, 6H), 7.84 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 7.8 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -132.3 ( s, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 18.8, 22.4 (d, J = 5.2 Hz), 28.5, 30.0, 58.0 (d, J = 21.2 Hz), 80.2, 114.8 (d, J = 271.8 Hz), 128.66, 128.70, 130.65, 130.68, 130.89, 130.91, 134.5, 134.8, 135.1, 135.8; IR (KBr) 3441, 3068, 2976, 2933, 2877, 1721, 1583, 1499, 1449, 1393, 1348, 1314, 1235 , 1163, 1078, 999, 916, 862, 753, 725, 686, 604, 560 cm -1 ; MS (ESI, m / z) = 508.1 (M + Na + ), 524.0 (M + K + ); The ee of the product was determined by HPLC using an OD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.2 mL / min, λ = 254 nm, τ maj = 42.8 min, τ min = 46.2 min ); [α] D 25 = +13.1 (c = 0.5, CH 3 OH) , 99% ee.

tert-Butyl 1-fluoro-3,3-dimethyl-, 1,1-bis (phenylsulfonyl) butan-2-ylcarbamate (3k)

Reaction of 2k (114.6 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH・H2O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH2Cl2(1.0 mL) at-80°C, the temperature was gradually warmed to -40°C over 2h. After stirring for 22 h, the resulting mixture gave 3k (121.8 mg, 70%, 96% ee) as a white solid by column chromatography (acetone/n-hexane = 1/5) on silica gel. 1H NMR (CDCl3, 200 MHz) δ 0.77 (s, 9H), 1.51 (s, 9H), 4.66 (d, J = 11.2 Hz, 1H), 6.06 (d, J = 11.2 Hz, 1H), 7.48-7.78 (m, 6H), 8.02 (d, J = 7.8 Hz, 2H), 8.09 (d, J = 7.8 Hz, 2H);19F NMR (CDCl3, 188 MHz) δ -133.0 (s, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 27.6 (d, J= 4.4 Hz), 28.5, 59.2 (d, J = 22.0 Hz), 80.1, 116.2 (d, J = 279.0 Hz), 128.4, 128.9, 131.3, 131.6, 133.2, 134.7, 135.0, 136.5, 154.8; IR (KBr) 3441, 3072, 2982, 1720, 1583, 1497, 1450, 1341, 1320, 1238, 1166, 1107, 1080, 1060, 997, 931, 906, 862, 765, 754, 712, 685 cm-1; MS (ESI, m/z) = 522.1 (M+Na+), 538.1 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.50 mL/min, λ = 254 nm, τmaj = 17.5 min, τmin = 19.6 min); [α] D 25 = -64.4 (c = 1.0 , CHCl3) , 96% ee.

Typical Procedure for the Reductive Desulfonylation of 3: (S)-tert-Butyl 2-fluoro-1phenylethylcarbamate (4a)
Reaction of 2k (114.6 mg, 0.35 mmol), 1 (118.5 mg, 0.38 mmol), CsOH ・ H 2 O (70.5 mg, 0.42 mmol), N-benzyl quinidinium chloride (7.9 mg, 0.018 mmol) in CH 2 Cl 2 (1.0 mL) at-80 ° C, the temperature was gradually warmed to -40 ° C over 2h.After stirring for 22 h, the resulting mixture gave 3k (121.8 mg, 70%, 96% ee) as a white solid by column chromatography (acetone / n-hexane = 1/5) on silica gel. 1 H NMR (CDCl 3, 200 MHz) δ 0.77 (s, 9H), 1.51 (s, 9H), 4.66 (d, J = 11.2 Hz , 1H), 6.06 (d, J = 11.2 Hz, 1H), 7.48-7.78 (m, 6H), 8.02 (d, J = 7.8 Hz, 2H), 8.09 (d, J = 7.8 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -133.0 (s, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 27.6 (d, J = 4.4 Hz), 28.5, 59.2 (d, J = 22.0 Hz) , 80.1, 116.2 (d, J = 279.0 Hz), 128.4, 128.9, 131.3, 131.6, 133.2, 134.7, 135.0, 136.5, 154.8; IR (KBr) 3441, 3072, 2982, 1720, 1583, 1497, 1450, 1341 , 1320, 1238, 1166, 1107, 1080, 1060, 997, 931, 906, 862, 765, 754, 712, 685 cm -1 ; MS (ESI, m / z) = 522.1 (M + Na + ), 538.1 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.50 mL / min, λ = 254 nm, τ maj = 17.5 min, τ min = 19.6 min) ; [α] D 25 = -64.4 (c = 1.0, CHCl 3 ) , 96% ee.

Typical Procedure for the Reductive Desulfonylation of 3: (S) -tert-Butyl 2-fluoro-1phenylethylcarbamate (4a)

Method A using Mg: Under N2 atmosphere, a flask containing Mg (145.8 mg, 6.0 mmol) was heated for drying. The flask was cooled at 0 °C, and then MeOH (0.28 mL) and 3a (96% ee, 103.7 mg, 0.20 mmol) were added. The reaction mixture was stirred for 2h. The reaction was quenched with sat. NH4Cl aq. and extracted with CH2Cl2 for three times. The combined organic phase was washed with brine, dried over MgSO4and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc/n-hexane = 1/10) to give 4a(40.2 mg) in 84% yield, 95% ee.
Method B using Na/Hg amalgam: Na/Hg amalgam (3 wt.% Na in Hg, net sodium content 1.86 mmol) was added to a test tube containing 3a (92% ee, 119.3 mg, 0.23 mmol) and Na2HPO4(263.7 mg, 1.86 mmol) in 3.0 mL of anhydrous MeOH at -20 °C under nitrogen atmosphere. The reaction mixture was stirred at -20 to -10 °C for 1h. The liquid phase was filtered through a pack of Celite, and washed with MeOH. The filtrate was concentrated under vacuum. Brine (10 mL) was added to the residue and it was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc/n-hexane = 1/10). Product 4a was obtained in 92% yield, 92% ee. A white solid, 1H NMR (CDCl3, 200 MHz) δ 1.43 (s, 9H), 4.55 (ddd, J = 5.0, 9.3, 47.1 Hz, 1H), 4.76 (ddd, J = 4.2, 9.2, 47.5 Hz, 1H), 4.68-5.22 (m, 3H), 7.28-7.36 (m, 5H); 19F NMR (CDCl3, 188 MHz) δ -223.4 - -226.0 (m, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 54.9 (br.d), 79.9, 85.0 (d, J = 175.1 Hz), 126.5, 127.7, 128.5, 138.0, 154.8; IR (KBr) 3383, 2981, 1687, 1524, 1458, 1391, 1368, 1318, 1281, 1255, 1173, 1057, 1015, 920, 867, 839, 781, 756.0, 700.0 cm-1; MS (ESI, m/z) = 262.0 (M+Na+), 278.0 (M+K+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.25 mL/min, λ = 254 nm, τmaj = 30.1 min, τmin = 32.1min); [α] D 25 = +43.1 (c = 0.40 , CHCl3) , 95% ee.

(S)-tert-Butyl 1-(3-chlorophenyl)-2-fluoroethylcarbamate (4b)
Method A using Mg: Under N 2 atmosphere, a flask containing Mg (145.8 mg, 6.0 mmol) was heated for drying.The flask was cooled at 0 ° C, and then MeOH (0.28 mL) and 3a (96% ee, 103.7 The reaction mixture was stirred for 2h.The reaction was quenched with sat.NH 4 Cl aq. and extracted with CH 2 Cl 2 for three times.The combined organic phase was washed with brine, dried over MgSO 4 and concentrated under reduced pressure.The crude product was purified by column chromatography on silica gel (EtOAc / n-hexane = 1/10) to give 4a (40.2 mg) in 84% yield, 95% ee.
Method B using Na / Hg amalgam: Na / Hg amalgam (3 wt.% Na in Hg, net sodium content 1.86 mmol) was added to a test tube containing 3a (92% ee, 119.3 mg, 0.23 mmol) and Na 2 HPO 4 (263.7 mg, 1.86 mmol) in 3.0 mL of anhydrous MeOH at -20 ° C under nitrogen atmosphere.The reaction mixture was stirred at -20 to -10 ° C for 1h.The liquid phase was filtered through a pack of Celite, The washed was MeOH.The filtrate was concentrated under vacuum.Brine (10 mL) was added to the residue and it was extracted with EtOAc.The combined organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure. was purified by column chromatography on silica gel (EtOAc / n-hexane = 1/10) .Product 4a was obtained in 92% yield, 92% ee.A white solid, 1 H NMR (CDCl 3 , 200 MHz) δ 1.43 ( s, 9H), 4.55 (ddd, J = 5.0, 9.3, 47.1 Hz, 1H), 4.76 (ddd, J = 4.2, 9.2, 47.5 Hz, 1H), 4.68-5.22 (m, 3H), 7.28-7.36 ( m, 5H); 19 F NMR (CDCl 3 , 188 MHz) δ -223.4--226.0 (m, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 54.9 (br.d), 79.9, 85.0 (d, J = 175.1 Hz), 126.5, 127.7, 128.5, 138.0, 154.8; IR (KBr) 3383, 2981, 1687, 1524, 1458, 1391, 1368, 1318, 1281, 1255, 1173, 1057, 1015, 920, 867, 839, 781, 756.0, 700.0 cm -1 ; MS (ESI, m / z) = 262.0 (M + Na + ), 278.0 (M + K + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.25 mL / min, λ = 254 nm, τ maj = 30.1 min, τ min = 32.1 min ); [α] D 25 = +43.1 (c = 0.40, CHCl 3 ) , 95% ee.

(S) -tert-Butyl 1- (3-chlorophenyl) -2-fluoroethylcarbamate (4b)

Using the procedure A, reaction of 3b (97% ee, 110.8 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4b (44.9 mg, 82%, 96% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.43 (s, 9H), 4.54 (ddd, J= 4.8, 9.3, 46.8 Hz, 1H), 4.63 (ddd, J= 4.0, 9.4, 47.3 Hz, 1H), 4.78-5.02 (m, 1H), 5.06-5.28 (m, 2H), 7.17-7.31 (m, 4H); 19F NMR (CDCl3, 188 MHz) δ -225.2 - -226.5 (m, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 54.5 (br. d), 80.3, 84.9 (d, J = 175.6 Hz), 124.8, 126.8, 127.9, 12.8, 134.4, 140.3, 155; IR (KBr) 3380, 2982, 1684, 1525, 1370, 1345, 1275, 1252, 1168, 1055, 1022, 878, 849, 789, 750, 714, 697 cm-1; MS (ESI, m/z) = 296.1 (M+Na+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.30 mL/min, λ = 254 nm, τmaj = 22.8 min, τmin = 25.6 min); [α] D 25 = +51.9 (c = 0.40 , CHCl3) , 96% ee.

(S)-tert-Butyl 1-(4-chlorophenyl)-2-fluoroethylcarbamate (4c)
Using the procedure A, reaction of 3b (97% ee, 110.8 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4b (44.9 mg, 82%, 96% ee) as a white solid. 1 H NMR (CDCl 3 , 200 MHz) δ 1.43 (s, 9H), 4.54 (ddd, J = 4.8, 9.3, 46.8 Hz, 1H), 4.63 (ddd, J = 4.0, 9.4, 47.3 Hz, 1H ), 4.78-5.02 (m, 1H), 5.06-5.28 (m, 2H), 7.17-7.31 (m, 4H); 19 F NMR (CDCl 3 , 188 MHz) δ -225.2--226.5 (m, 1F) ; 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 54.5 (br.d), 80.3, 84.9 (d, J = 175.6 Hz), 124.8, 126.8, 127.9, 12.8, 134.4, 140.3, 155; IR (KBr ) 3380, 2982, 1684, 1525, 1370, 1345, 1275, 1252, 1168, 1055, 1022, 878, 849, 789, 750, 714, 697 cm -1 ; MS (ESI, m / z) = 296.1 (M + Na + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.30 mL / min, λ = 254 nm, τ maj = 22.8 min , τ min = 25.6 min); [α] D 25 = +51.9 (c = 0.40, CHCl 3 ) , 96% ee.

(S) -tert-Butyl 1- (4-chlorophenyl) -2-fluoroethylcarbamate (4c)

Using the procedure A, reaction of 3c (87% ee, 110.8 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4c (48.1 mg, 88%, 83% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.42 (s, 9H), 4.52 (ddd, J= 4.8, 9.3, 46.9 Hz, 1H), 4.62 (ddd, J= 4.0, 9.5, 47.5 Hz, 1H), 4.75-5.02 (m, 1H), 5.03-5.30 (m, 1H), 7.24-7.26 (m, 4H); 19F NMR (CDCl3, 188 MHz) δ -225.2 - -226.4 (m, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 54.0 (br. d), 80.2, 84.9 (d, J = 175.1), 128.0, 128.7, 133.6, 136.7, 154.8; IR (KBr) 3384, 2980, 1685, 1521, 1367, 1280, 1173, 1056, 1027, 869, 827 cm-1; MS (ESI, m/z) = 296.0 (M+Na+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.30 mL/min, λ = 254 nm, τmaj = 25.4 min, τmin = 28.8 min); [α] D 25 = +47.8 (c = 0.40 , CHCl3) , 83% ee.

(S)-tert-Butyl 2-fluoro 1-(4-methoxyphenyl) ethylcarbamate (4d)
Using the procedure A, reaction of 3c (87% ee, 110.8 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4c (48.1 mg, 88%, 83% ee) as a white solid. 1 H NMR (CDCl 3 , 200 MHz) δ 1.42 (s, 9H), 4.52 (ddd, J = 4.8, 9.3, 46.9 Hz, 1H), 4.62 (ddd, J = 4.0, 9.5, 47.5 Hz, 1H ), 4.75-5.02 (m, 1H), 5.03-5.30 (m, 1H), 7.24-7.26 (m, 4H); 19 F NMR (CDCl 3 , 188 MHz) δ -225.2--226.4 (m, 1F) ; 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 54.0 (br.d), 80.2, 84.9 (d, J = 175.1), 128.0, 128.7, 133.6, 136.7, 154.8; IR (KBr) 3384, 2980, 1685, 1521, 1367, 1280, 1173, 1056, 1027, 869, 827 cm -1 ; MS (ESI, m / z) = 296.0 (M + Na + ); The ee of the product was determined by HPLC using an AD -H column (n-hexane / i-PrOH = 95/5, flow rate 0.30 mL / min, λ = 254 nm, τ maj = 25.4 min, τ min = 28.8 min); [α] D 25 = +47.8 ( c = 0.40, CHCl 3 ) , 83% ee.

(S) -tert-Butyl 2-fluoro 1- (4-methoxyphenyl) ethylcarbamate (4d)

Using the procedure A, reaction of 3d (95% ee, 109.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4d (43.1 mg, 80%, 93% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.43 (s, 9H), 3,78 (s, 3H), 4.52 (ddd, J =5.0, 9.4, 47.3 Hz, 1H), 4.60 (ddd, J = 4.2, 9.2, 47.5 Hz, 1H), 4.74-4.98 (m, 1H), 5.00-5.20 (m, 1H), 6.87 (d, J = 6.6 Hz, 2H), 7.24 (d, J = 6.6 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -224.0 - -225.8 (m, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 54.3 (br. d), 55.3, 79.9, 85.0 (d, J = 175.2 Hz), 114.0, 127.8, 130.2, 130.3, 154.8, 158.9; IR(KBr) 3382, 2979, 2834, 1685, 1517, 1368, 1249, 1173, 1011, 875, 821 cm-1; MS (ESI, m/z) = 292.1 (M+Na+); The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 95/5, flow rate 0.50 mL/min, λ = 254 nm, τmaj = 32.6 min, τmin = 35.5 min); [α] D 25 = +58.0 (c = 0.20, CHCl3) , 93% ee.

(S)-tert-Butyl 2-fluoro-1-(naphthalene-3-yl) ethylcarbamate (4e)
Using the procedure A, reaction of 3d (95% ee, 109.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4d (43.1 mg, 80%, 93% ee) as a white solid. 1 H NMR (CDCl 3 , 200 MHz) δ 1.43 (s, 9H), 3,78 (s, 3H), 4.52 (ddd, J = 5.0, 9.4, 47.3 Hz, 1H), 4.60 (ddd, J = 4.2, 9.2, 47.5 Hz, 1H), 4.74-4.98 (m, 1H), 5.00-5.20 (m, 1H), 6.87 (d, J = 6.6 Hz, 2H), 7.24 (d, J = 6.6 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -224.0--225.8 (m, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 54.3 (br.d), 55.3, 79.9, 85.0 (d, J = 175.2 Hz), 114.0, 127.8, 130.2, 130.3, 154.8, 158.9; IR (KBr) 3382, 2979, 2834, 1685, 1517, 1368, 1249, 1173, 1011, 875, 821 cm -1 ; MS (ESI, m / z) = 292.1 (M + Na + ); The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 95/5, flow rate 0.50 mL / min, λ = 254 nm, τ maj = 32.6 min, τ min = 35.5 min); [α] D 25 = +58.0 (c = 0.20, CHCl 3 ) , 93% ee.

(S) -tert-Butyl 2-fluoro-1- (naphthalene-3-yl) ethylcarbamate (4e)

Using the procedure A, reaction of 3e (90% ee, 113.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4e (49.4 mg, 85%, 89% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.43 (s, 9H), 4.53-5.42 (m, 4H), 7.35-7.53 (m, 3H), 7.72-7.88 (m, 4H); 19F NMR (CDCl3, 188 MHz) δ -224.2 - -225.5 (m, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 54.7 (br. d), 80.1, 85.0 (d, J = 175.5 Hz), 124.5, 125.6, 125.9, 126.1, 127.4, 127.7, 128.4, 132.7, 133.0, 135.46, 135.54, 154.9; IR (KBr) 3384, 2976, 2925, 1685, 1518, 1457, 1334, 1284, 1169, 1056, 1012, 825, 747 cm-1; MS (ESI, m/z) = 312.1 (M+Na+); The ee of the product was determined by HPLC using an OJ-H column (n-hexane/i-PrOH = 99/1, flow rate 0.10 mL/min, λ = 254 nm, τmaj = 85.0 min, τmin = 94.4 min); [α] D 25 = +63.0 (c = 0.60, CHCl3), 89% ee.

tert-Butyl 2-fluoro-1-(furan-2-yl) ethylcarbamate (4f)
Using the procedure A, reaction of 3e (90% ee, 113.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4e (49.4 mg, 85%, 89% ee) as a white solid. 1 H NMR (CDCl 3 , 200 MHz) δ 1.43 (s, 9H), 4.53-5.42 (m, 4H), 7.35-7.53 (m, 3H), 7.72-7.88 (m, 4H); 19 F NMR (CDCl 3 , 188 MHz) δ -224.2--225.5 (m, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 54.7 (br.d), 80.1, 85.0 (d, J = 175.5 Hz) , 124.5, 125.6, 125.9, 126.1, 127.4, 127.7, 128.4, 132.7, 133.0, 135.46, 135.54, 154.9; IR (KBr) 3384, 2976, 2925, 1685, 1518, 1457, 1334, 1284, 1169, 1056, 1012 , 825, 747 cm -1 ; MS (ESI, m / z) = 312.1 (M + Na + ); The ee of the product was determined by HPLC using an OJ-H column (n-hexane / i-PrOH = 99 / 1, flow rate 0.10 mL / min, λ = 254 nm, τ maj = 85.0 min, τ min = 94.4 min); [α] D 25 = +63.0 (c = 0.60, CHCl 3 ), 89% ee.

tert-Butyl 2-fluoro-1- (furan-2-yl) ethylcarbamate (4f)

Using the procedure A, reaction of 3f (93% ee, 101.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4f (37.1 mg, 81%, 92% ee) as a pale yellow oil. 1H NMR (CDCl3, 200 MHz) δ 1.46 (s, 9H), 4.69 (ddd, J = 4.4, 9.2, 47.3 Hz, 1H), 4.67 (ddd, J = 4.2, 9.5, 46.9 Hz, 1H), 4.87-5.16 (m, 2H), 6.25-6.36 (m, 2H), 7.34-7.38 (m, 1H); 19F NMR (CDCl3, 188 MHz) δ -227.0 (dt, J = 22.9, 45.9, 1F); 13C NMR (CDCl3, 50.3 MHz) δ28.5, 49.2 (br. d), 80.2, 83.2 (d, J = 174.8 Hz), 107.2, 110.3, 142.1, 150.8, 154.7; IR (neat) 3430, 3333, 2979, 2932, 1704, 1505, 1367, 1252, 1169, 1054, 1011, 861, 740 cm-1; MS (ESI, m/z) = 252.0 (M+Na+); The ee of the product was determined by HPLC using an OJ-H column (n-hexane/i-PrOH = 95/5, flow rate 0.30 mL/min, λ = 210 nm, τmaj = 19.2 min, τmin = 23.7 min); [α] D 25 = +44.6 (c = 0.43 , CHCl3) , 92% ee.

tert-Butyl 1-fluoro-4-phenylbutan-2-ylcarbamate (4g)
Using the procedure A, reaction of 3f (93% ee, 101.9 mg, 0.20 mmol) with Mg (145.9 mg, 6.0 mmol) in MeOH (2.8 mL) gave 4f (37.1 mg, 81%, 92% ee) as a pale yellow oil. 1 H NMR (CDCl 3 , 200 MHz) δ 1.46 (s, 9H), 4.69 (ddd, J = 4.4, 9.2, 47.3 Hz, 1H), 4.67 (ddd, J = 4.2, 9.5, 46.9 Hz, 1H), 4.87-5.16 (m, 2H), 6.25-6.36 (m, 2H), 7.34-7.38 (m, 1H); 19 F NMR (CDCl 3 , 188 MHz) δ -227.0 (dt, J = 22.9, 45.9, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ28.5, 49.2 (br.d), 80.2, 83.2 (d, J = 174.8 Hz), 107.2, 110.3, 142.1, 150.8, 154.7; IR ( neat) 3430, 3333, 2979, 2932, 1704, 1505, 1367, 1252, 1169, 1054, 1011, 861, 740 cm -1 ; MS (ESI, m / z) = 252.0 (M + Na + ); The ee of the product was determined by HPLC using an OJ-H column (n-hexane / i-PrOH = 95/5, flow rate 0.30 mL / min, λ = 210 nm, τ maj = 19.2 min, τ min = 23.7 min) ; [α] D 25 = +44.6 (c = 0.43, CHCl 3 ) , 92% ee.

tert-Butyl 1-fluoro-4-phenylbutan-2-ylcarbamate (4g)

Using the procedure A, reaction of 3g (90% ee, 80.0 mg, 0.146 mmol) with Mg (106.5 mg, 4.4 mmol) in MeOH (2.0 mL) gave 4g (33.8 mg, 87%, 90% ee) as a white solid. 1H NMR (CDCl3, 200 MHz) δ 1.46 (s, 9H), 1.75-1.97 (m, 2H), 2.70 (dt, J = 2.6, 8.0 Hz, 2H), 4.41 (dd, J= 3.4, 47.4 Hz, 2H), 4.56-4.80 (m, 1H), 7.14-7.32 (m, 5H); 19F NMR (CDCl3, 188 MHz) δ -224.2 (dt, J= 27.4, 47.0, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 28.5, 32.4, 32.9, 33.0, 50.5 (d, J 19.6 Hz), 79.6, 85.0 (d, J = 170.4 Hz, 1H), 125.8, 128.1, 128.2, 141.0, 155.1; IR (KBr) 3369, 2970, 2928, 2862, 1686, 1523, 1455, 1246, 1170, 755, 702 cm-1; MS (ESI, m/z) = 290.1 (M+Na+); The ee of the product was determined by HPLC using an OJ-H column (n-hexane/i-PrOH = 95/5, flow rate 0.50 mL/min, λ = 254 nm, τmaj = 11.6 min, τmin = 13.2 min); [α] D 25 = -5.8 (c = 0.16, CHCl3), 89% ee.

tert-Butyl 1-fluorononan-2-ylcarbamate (4h)
Using the procedure A, reaction of 3g (90% ee, 80.0 mg, 0.146 mmol) with Mg (106.5 mg, 4.4 mmol) in MeOH (2.0 mL) gave 4g (33.8 mg, 87%, 90% ee) as a white solid. 1 H NMR (CDCl 3 , 200 MHz) δ 1.46 (s, 9H), 1.75-1.97 (m, 2H), 2.70 (dt, J = 2.6, 8.0 Hz, 2H), 4.41 (dd, J = 3.4 , 47.4 Hz, 2H), 4.56-4.80 (m, 1H), 7.14-7.32 (m, 5H); 19 F NMR (CDCl 3 , 188 MHz) δ -224.2 (dt, J = 27.4, 47.0, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 28.5, 32.4, 32.9, 33.0, 50.5 (d, J 19.6 Hz), 79.6, 85.0 (d, J = 170.4 Hz, 1H), 125.8, 128.1, 128.2, 141.0, 155.1; IR (KBr) 3369, 2970, 2928, 2862, 1686, 1523, 1455, 1246, 1170, 755, 702 cm -1 ; MS (ESI, m / z) = 290.1 (M + Na + ); The ee of the product was determined by HPLC using an OJ-H column (n-hexane / i-PrOH = 95/5, flow rate 0.50 mL / min, λ = 254 nm, τ maj = 11.6 min, τ min = 13.2 min) ; [α] D 25 = -5.8 (c = 0.16, CHCl 3 ), 89% ee.

tert-Butyl 1-fluorononan-2-ylcarbamate (4h)

Using the procedure A, reaction of 3h (95% ee, 135.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4b (54.5 mg, 83 %, 96% ee) as a colorless oil. 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J = 6.8 Hz, 3H), 1.20-1.62 (m, 12H), 1.45 (s, 9H), 3.55-3.90 (m, 1H), 4.39 (dd, J = 3.2, 47.4, 2H), 4.48-4.68 (m, 1H); 19F NMR (CDCl3, 188 MHz) δ -231.2 (dt, J = 27.4, 50.0, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 14.3, 22.8, 26.1, 28.5, 29.3, 29.5, 31.2, 31.9, 50.6 (br. d), 79.5, 85.0 (d, J = 170.0 Hz), 155.1; IR (neat) 3451, 3341, 2928, 2858, 1695, 1519, 1457, 1391, 1366, 1247, 1173, 1057, 1014 cm-1; MS (ESI, m/z) = 284.2 (M+Na+); The ee of the product was determined by GC analysis (CHIRADEX G-TA , 110 °C isothermal) τmaj = 178.1 min, τmin = 179.8 min); [α]D 25 = -15.0 (c = 0.91 , CHCl3), 96% ee.

tert-Butyl 1-cyclohexyl-2-fluoroethylcarbamate (4i)
Using the procedure A, reaction of 3h (95% ee, 135.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4b (54.5 mg, 83%, 96% ee) as a colorless oil. 1 H NMR (CDCl 3 , 200 MHz) δ 0.88 (t, J = 6.8 Hz, 3H), 1.20-1.62 (m, 12H), 1.45 (s, 9H), 3.55-3.90 (m, 1H), 4.39 (dd, J = 3.2, 47.4, 2H), 4.48-4.68 (m, 1H); 19 F NMR (CDCl 3 , 188 MHz) δ -231.2 (dt, J = 27.4, 50.0, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 14.3, 22.8, 26.1, 28.5, 29.3, 29.5, 31.2, 31.9, 50.6 (br.d), 79.5, 85.0 (d, J = 170.0 Hz), 155.1; IR (neat) 3451 , 3341, 2928, 2858, 1695, 1519, 1457, 1391, 1366, 1247, 1173, 1057, 1014 cm -1 ; MS (ESI, m / z) = 284.2 (M + Na + ); The ee of the product was determined by GC analysis (CHIRADEX G-TA, 110 ° C isothermal) τ maj = 178.1 min, τ min = 179.8 min); [α] D 25 = -15.0 (c = 0.91, CHCl 3 ), 96% ee.

tert-Butyl 1-cyclohexyl-2-fluoroethylcarbamate (4i)

Using the procedure A, reaction of 3i (98% ee, 131.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4i (53.3 mg, 87 %, 98% ee) as a white solid.
1H NMR (CDCl3, 200 MHz) δ 0.97-1.90 (m, 11H), 1.45 (s, 9H), 3.38 (m, 1H), 4.39 (ddd, J = 3.4, 9.3, 47.8 Hz, 1H), 4.52 (ddd, J = 42.8, 9.4, 47.1 Hz, 1H), 4.57-4.75 (m, 3H), 19F NMR (CDCl3, 188 MHz) δ -246.08 (dt, J= 29.9, 47.0, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 26.2, 26.4, 28.5, 29.3, 29.9, 38.8, 55.2 (d, J= 18.4 Hz), 79.4, 83.5 (d, J = 169.5 Hz), 155.3; IR (KBr) 3335, 2968, 2931, 2853, 1677, 1527, 1453, 1366, 1295, 1253, 1177, 1052, 985, 889, 634 cm-1; MS (ESI, m/z) = 268.1 (M+Na+); The ee of the product was determined by GC analysis (CHIRADEX G-TA , 130 °C isothermal) τmaj = 54.1 min, τmin = 55.3 min; [α] D 25 = -17.3 (c = 0.40 , CHCl3) , 98% ee.

tert-Butyl 1-fluoro-3-methylbutan-2-ylcarbamate (4j)
Using the procedure A, reaction of 3i (98% ee, 131.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4i (53.3 mg, 87%, 98% ee) as a white solid.
1 H NMR (CDCl 3 , 200 MHz) δ 0.97-1.90 (m, 11H), 1.45 (s, 9H), 3.38 (m, 1H), 4.39 (ddd, J = 3.4, 9.3, 47.8 Hz, 1H), 4.52 (ddd, J = 42.8, 9.4, 47.1 Hz, 1H), 4.57-4.75 (m, 3H), 19 F NMR (CDCl 3 , 188 MHz) δ -246.08 (dt, J = 29.9, 47.0, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 26.2, 26.4, 28.5, 29.3, 29.9, 38.8, 55.2 (d, J = 18.4 Hz), 79.4, 83.5 (d, J = 169.5 Hz), 155.3; IR (KBr ) 3335, 2968, 2931, 2853, 1677, 1527, 1453, 1366, 1295, 1253, 1177, 1052, 985, 889, 634 cm -1 ; MS (ESI, m / z) = 268.1 (M + Na + ) ; The ee of the product was determined by GC analysis (CHIRADEX G-TA, 130 ° C isothermal) τ maj = 54.1 min, τ min = 55.3 min; [α] D 25 = -17.3 (c = 0.40, CHCl 3 ) , 98% ee.

tert-Butyl 1-fluoro-3-methylbutan-2-ylcarbamate (4j)

Using the procedure A, reaction of 3j (99% ee, 121.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4j (38.4 mg, 75%, 99%ee) as white solid. 1H NMR (CDCl3, 200 MHz) δ 0.96 (d, J = 4.2 Hz, 3H), 0.99 (d, J = 4.0 Hz, 3H), 1.45 (s, 9H), 1.73-1.97 (m, 1H), 3.37-3.68 (m, 1H), 4.39 (ddd, J = 3.6, 9.4, 47.7 Hz, 1H), 4.69 (ddd, J = 3.6, 9.4, 46.9 Hz, 1H), 4.57-4.76 (m, 1H); 19F NMR (CDCl3, 188 MHz) δ -231.1 (dt, J= 27.6, 47.0, 1F); 13C NMR (CDCl3, 50.3 MHz) δ 18.9, 19.7, 28.5, 29.4 (d, J = 3.6 Hz), 55.9 (d, J = 18.8 Hz), 79.5, 83.8 (d, J = 169.6 Hz), 155.4; IR (KBr) 3340, 2968, 2925, 1699, 1541, 1457, 1366, 1251, 1174, 1072, 867 cm-1; MS (ESI, m/z) = 228.1 (M+Na+); The ee of the product was determined by GC analysis (CP-CHIRASIL-DEX CB, 110 °C isothermal) τmaj = 21.4 min, τmin = 22.9 min; [α] D 25 = -25.1 (c = 0.33 , CHCl3) , 99% ee.

tert-Butyl 1-fluoro-3,3-dimethylbutan-2-ylcarbamate (4k)
Using the procedure A, reaction of 3j (99% ee, 121.4 mg, 0.25 mmol) with Mg (182.3 mg, 7.5 mmol) in MeOH (3.5 mL) gave 4j (38.4 mg, 75%, 99% ee) as white solid 1 H NMR (CDCl 3 , 200 MHz) δ 0.96 (d, J = 4.2 Hz, 3H), 0.99 (d, J = 4.0 Hz, 3H), 1.45 (s, 9H), 1.73-1.97 (m, 1H ), 3.37-3.68 (m, 1H), 4.39 (ddd, J = 3.6, 9.4, 47.7 Hz, 1H), 4.69 (ddd, J = 3.6, 9.4, 46.9 Hz, 1H), 4.57-4.76 (m, 1H ); 19 F NMR (CDCl 3 , 188 MHz) δ -231.1 (dt, J = 27.6, 47.0, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 18.9, 19.7, 28.5, 29.4 (d, J = 3.6 Hz), 55.9 (d, J = 18.8 Hz), 79.5, 83.8 (d, J = 169.6 Hz), 155.4; IR (KBr) 3340, 2968, 2925, 1699, 1541, 1457, 1366, 1251, 1174, 1072, 867 cm -1 ; MS (ESI, m / z) = 228.1 (M + Na + ); The ee of the product was determined by GC analysis (CP-CHIRASIL-DEX CB, 110 ° C isothermal) τ maj = 21.4 min, τ min = 22.9 min; [α] D 25 = -25.1 (c = 0.33, CHCl 3 ) , 99% ee.

tert-Butyl 1-fluoro-3,3-dimethylbutan-2-ylcarbamate (4k)

Using the procedure A, reaction of 3k (96% ee, 90.0 mg, 0.18 mmol) with Mg (131.2 mg, 5.4 mmol) in MeOH (2.5 mL) gave 4k (10.3 mg, 26 %) as a white solid and recovered 65% of starting material (58.3 mg). 1H NMR (CDCl3, 200 MHz) δ 0.97 (s, 9H), 1.45 (s, 9H), 3.40-3.72 (m, 1H), 4.33-4.87 (m, 3H); 19F NMR (CDCl3, 188 MHz) δ -228.42 (dt, J = 29.7, 47.0, 1F); 13C NMR (CDCl3, 50.3 MHz) δ27.1, 28.6, 34.2, 58.1 (d, J = 17.6 Hz), 79.4, 83.4 (d, J = 170.0 Hz), 155.5; IR (KBr) 3319, 2969, 1700, 1543, 1478, 1367, 1281, 1251, 1176, 1064, 678 cm-1; MS (ESI, m/z ) = 242.05 (M+Na+); The ee of the product was determined by GC analysis (CP-CHIRASIL-DEX CB, 110 °C isothermal) τmaj = 11.7 min, τmin = 14.0 min; [α] D 25 = -20.7 (c = 0.36 , CHCl3), 99% ee.

Determination of Absolute Stereochemistry of 4a:
(S)-2-Fluoro-1-phenylethanaminium chloride (5a)
Using the procedure A, reaction of 3k (96% ee, 90.0 mg, 0.18 mmol) with Mg (131.2 mg, 5.4 mmol) in MeOH (2.5 mL) gave 4k (10.3 mg, 26%) as a white solid and recovered 65 % of starting material (58.3 mg) . 1 H NMR (CDCl 3, 200 MHz) δ 0.97 (s, 9H), 1.45 (s, 9H), 3.40-3.72 (m, 1H), 4.33-4.87 (m, 3H ); 19 F NMR (CDCl 3 , 188 MHz) δ -228.42 (dt, J = 29.7, 47.0, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ27.1, 28.6, 34.2, 58.1 (d, J = 17.6 Hz), 79.4, 83.4 (d, J = 170.0 Hz), 155.5; IR (KBr) 3319, 2969, 1700, 1543, 1478, 1367, 1281, 1251, 1176, 1064, 678 cm -1 ; MS ( ESI, m / z) = 242.05 (M + Na + ); The ee of the product was determined by GC analysis (CP-CHIRASIL-DEX CB, 110 ° C isothermal) τ maj = 11.7 min, τ min = 14.0 min; [α] D 25 = -20.7 (c = 0.36, CHCl 3 ), 99% ee .

Determination of Absolute Stereochemistry of 4a:
(S) -2-Fluoro-1-phenylethanaminium chloride (5a)

The absolute configuration of 4a was established to (S) by deprotection under HCl/dioxane
treatment to yield the known (S)-2-fluoro-1-phenylethanaminium chloride (5a).
1173414601859_33
Procedure is as follows: A solution of HCl/dioxane (2.8 M) was added to a solution of 4a (92% ee, 40.0 mg, 0.17 mmol) in MeOH (2.0 mL) at rt. After stirring at the temperature for 1h, the reaction mixture was concentrated under reduced pressure. Ether was added to the mixture and the resulting precipitate was filtered off and washed with ether to provide pure fluoromethylamine hydrochloride 5a (28.3 mg, 95%) as colorless crystals. 1H NMR (CD3OD, 200 MHz) δ 4.42-4.80 (m, 3H), 7.26-7.35 (m, 5H); 19F NMR (CD3OD, 188 MHz) δ -221.78 (dt, J = 17.1, 44.1, 1F); MS (ESI, m/z) = 140.0 (M+-35); [α]D 25 = -27.1 (c = 0.57, CH3OH), 92% ee. The absolute configuration of 4b-e was tentatively assigned as (S) by comparing the optical rotation with that of 4a.



The absolute configuration of 4a was established to (S) by deprotection under HCl / dioxane
treatment to yield the known (S) -2-fluoro-1-phenylethanaminium chloride (5a).
1173414601859_33
Procedure is as follows: A solution of HCl / dioxane (2.8 M) was added to a solution of 4a (92% ee, 40.0 mg, 0.17 mmol) in MeOH (2.0 mL) at rt. After stirring at the temperature for 1h, the reaction mixture was concentrated under reduced pressure . Ether was added to the mixture and the resulting precipitate was filtered off and washed with ether to provide pure fluoromethylamine hydrochloride 5a (28.3 mg, 95%) as colorless crystals. 1 H NMR (CD 3 OD , 200 MHz) δ 4.42-4.80 (m, 3H), 7.26-7.35 (m, 5H); 19 F NMR (CD 3 OD, 188 MHz) δ -221.78 (dt, J = 17.1, 44.1, 1F); MS (ESI, m / z) = 140.0 (M + -35);. [α] D 25 = -27.1 (c = 0.57, CH 3 OH), 92% ee The absolute configuration of 4b-e was tentatively assigned as ( S) by comparing the optical rotation with that of 4a.



本発明の光学活性α−フルオロメチルアミン誘導体の製造法は医農薬産業に利用可能である。   The method for producing the optically active α-fluoromethylamine derivative of the present invention can be used in the medical and agrochemical industry.

Claims (6)

溶媒中，塩基と光学活性な相間移動触媒存在下，一般式（１）

（式中，Ｒ１は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アシル基，アルコキシカルボニル基またはアリールオキシカルボニル基を示す。Ｒ2は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アシル基，アルコキシカルボニル基またはアリールオキシカルボニル基を示す。Ｒ３は，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。）
で表せるα−アミドスルホン化合物を一般式（２）

（式中，Ｒ４，Ｒ５はそれぞれ独立に，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。さらに，Ｒ４およびＲ５が一体となって，環状構造の一部を形成してもよい。）で示されるフルオロビススルホニルメタン類との不斉マンニッヒ型反応させることを特徴とする一般式（３）

（式中，Ｒ１，Ｒ２，Ｒ４，Ｒ５は前記定義に同じ。）
で示される光学活性α−フルオロビス（フェニルスルホニル）メチル付加体の製造法。
General formula (1) in the presence of a base and an optically active phase transfer catalyst in a solvent

(Wherein R 1 represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group, aryl group, acyl group, alkoxycarbonyl group or aryloxycarbonyl group. R 2 represents a substituted or unsubstituted group. An alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, wherein R 3 is a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group; Or an aryl group.)
An α-amide sulfone compound represented by the general formula (2)

(In the formula, R 4 and R 5 each independently represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group or aryl group. Furthermore, R 4 and R 5 together form a cyclic group. A part of the structure may be formed.) Asymmetric Mannich reaction with the fluorobissulfonylmethanes represented by the general formula (3)

(In the formula, R 1 , R 2 , R 4 and R 5 are the same as defined above.)
A process for producing an optically active α-fluorobis (phenylsulfonyl) methyl adduct represented by the formula:
前記一般式（３）で表せる光学活性α−フルオロビス（フェニルスルホニル）メチル付加体を溶媒中，還元剤として金属の存在下，脱スルホニル化させることを特徴とする一般式（４）

（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性α−フルオロメチルアミン誘導体の製造法。
The optically active α-fluorobis (phenylsulfonyl) methyl adduct represented by the general formula (3) is desulfonylated in a solvent in the presence of a metal as a reducing agent in the general formula (4)

(Wherein R 1 and R 2 are the same as defined above), a method for producing an optically active α-fluoromethylamine derivative.
前記塩基は，一般に市販されているアミン類もしくは無機塩一般式（５）から選ばれる少なくとも１種類の塩基であることを特徴とする請求項１に記載の製造法。
アミンとしては，トリエチルアミン，ジイソプロピルエチルアミン，ジメチルアミノピリジン，キヌクリジン，ＤＢＵ，ＤＡＢＣＯなどを用いることができる。無機塩は一般式（５）
（Ｘ）ｎＭ （５）
（式中，Ｍは，希土類を含む遷移金属，リチウム，ナトリウム，マグネシウム，アルミニウムから選ばれた元素，ｎは，Ｍの原子価と同数の整数を表す。Ｘはアルコシド，フルオリド，カルボネートなどのマイナスイオンを表す。）
2. The production method according to claim 1, wherein the base is at least one base selected from commercially available amines or inorganic salt general formula (5).
As the amine, triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The inorganic salt has the general formula (5)
(X) nM (5)
(In the formula, M is an element selected from transition metals including rare earths, lithium, sodium, magnesium and aluminum, n is an integer having the same number as the valence of M. X is a minus such as alkoxide, fluoride, carbonate, etc. Represents an ion.)
前記光学活性な相間移動触媒は，光学活性４級アンモニウム塩類から選ばれる少なくとも１種類の塩であることを特徴とする請求項１に記載の製造法。
光学活性な相間移動触媒としては，一般式（６），（７）

（式中，Ｒ６は水素，置換もしくは未置換のアルキル基もしくはアルコキシ基を示す。もしくはＯＲ１０で表せるＲ１０はアルキル基を示す。Ｒ７は，エチル基もしくはビニル基を示す。Ｒ８は，水素，アルキル基，アリール基またはアシル基を示す。Ｒ９は，水素，置換もしくは未置換のアルキル基またはトリフルオロメチル基を示す。ｍは０〜２の整数を表す。Ｘは，ハロゲン原子，ＩＯ４，ＣｌＯ４，ＯＴｆまたはＨＳＯ４を示す。）

The process according to claim 1, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
As optically active phase transfer catalysts, general formulas (6), (7)

(In the formula, R 6 represents hydrogen, a substituted or unsubstituted alkyl group or an alkoxy group, or R 10 represented by OR 10 represents an alkyl group. R 7 represents an ethyl group or a vinyl group. R 8 represents , Hydrogen, an alkyl group, an aryl group or an acyl group, R 9 represents hydrogen, a substituted or unsubstituted alkyl group or a trifluoromethyl group, m represents an integer of 0 to 2, and X represents a halogen atom. , IO 4 , ClO 4 , OTf or HSO 4. )

前記溶媒が，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，クロロホルム，ジクロロメタン，ジクロロエタン，トルエン，テトラヒドロフラン，ヘキサン，ベンゼンからなる群より選ばれる少なくとも1種である請求項１，２のいずれか１項に記載の製造法。
The solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, and benzene. Manufacturing method.
前記金属は，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素であることを特徴とする請求項２に記載の製造法。 The method according to claim 2, wherein the metal is at least one element selected from lithium, sodium, magnesium, aluminum, zinc, tin, indium, samarium, and the like, including rare earths.
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CN111548298A (en) * 2020-06-18 2020-08-18 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof
CN111548298B (en) * 2020-06-18 2023-03-21 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof

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