JP6950918B2 - Asymmetric metallocene fused carbene, a method for producing the same, and a metal complex using the derivative as a ligand. - Google Patents

Description

The present invention relates to carbene that can be synthesized from a surface asymmetric iminium salt derivative and a method for producing the same. This carbene is useful as an asymmetric catalytic ligand for metal complexes used in asymmetric synthesis reactions. The present invention also relates to a metal complex for an asymmetric synthesis catalyst using the carbene as a ligand.

Nitrogen-containing heterocyclic carbene plays an important role as a ligand for organic catalysts and metal catalysts. However, it is not easy to develop an optically active nitrogen-containing heterocyclic carbene for the purpose of applying it to an asymmetric reaction. This is because the nitrogen-containing heterocyclic carbene is essentially characterized by having a planar structure which is disadvantageous as an asymmetric space. Therefore, it has been desired to develop a nitrogen-containing heterocyclic carbene having an effective asymmetric space. Known nitrogen-containing heterocyclic carbene ligands include, for example, the following Non-Patent Documents 1 to 4.

N-Heterocyclic Carbene's in Synthesis; Nolan, S. et al. P. , Ed. Wiley-VCH; Weinheim, 2006. N-Heteroccyclic Carbenes in Transition Metal Catalysis; Gloris, F. et al. , Ed. Springer; Berlin, 2007. Enders, D.I. Niemeier, O.D. Henseller, A. et al. Chem. Rev. 2007,107,5606-5655. Diez-Gonzarez, S.A. Marion, N.M. Nolan, S.M. P. Chem. Rev. 2009,109,3612-3676.

In view of the above problems, an object of the present invention is to provide a ligand for a novel nitrogen-containing heterocyclic carbene that introduces the concept of surface asymmetry that is compatible with a planar structure.

The present invention has achieved the above object by providing a carbene that can be synthesized from a surface asymmetric iminium salt derivative represented by the following general formula (1).

（上記式中、Ｒ^１〜Ｒ^９は、水素原子、置換基を有していてもよいＣ_１〜Ｃ_２０炭化水素基、置換基を有していてもよいＣ_１〜Ｃ_２０アルコキシ基、置換基を有していてもよいＣ_６〜Ｃ_２０アリールオキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいホスフィノ基、置換基を有していてもよいシリル基、置換基を有していてもよいアルキルチオ基（−ＳＹ^１、式中、Ｙ^１は置換基を有していてもよいＣ_１〜Ｃ_２０アルキル基を示す。）、置換基を有していてもよいアリールチオ基（−ＳＹ^２、式中、Ｙ^２は置換基を有していてもよいＣ_６〜Ｃ_２０アリ−ル基を示す。）、置換基を有していてもよいアルキルスルホニル基（ＳＯ_２Ｙ^３、式中、Ｙ^３は置換基を有していてもよいＣ_１〜Ｃ_２０アルキル基を示す。）、置換基を有していてもよいアリールスルホニル基（−ＳＯ_２Ｙ^４、式中、Ｙ^４は置換基を有していてもよいＣ_６〜Ｃ_２０アリール基を示す。）、水酸基又はハロゲン原子である。また、Ｒ^１〜Ｒ^９は、それぞれ互いに独立し、同一であっても異なっていてもよい。また、Ｒ^２及びＲ^３、Ｒ^３及びＲ^４、Ｒ^５及びＲ^６、Ｒ^６及びＲ^７、Ｒ^７及びＲ^８、Ｒ^８及びＲ^９、並びにＲ^９及びＲ^５は、それぞれ、互いに架橋してＣ_４〜Ｃ_１０飽和環又は不飽和環を形成してもよく、前記環の場合は、酸素原子、硫黄原子、珪素原子、スズ原子、ゲルマニウム原子、又は−Ｎ（Ｂ）−で示される基（ここでＢは水素原子又はＣ_１〜Ｃ_１０炭化水素基である。）で中断されていてもよく、かつ、置換基を有していてもよい。また、上記式中のＸは置換基を有していてもよいＣ_１〜Ｃ_４炭素原子、置換基を有していてもよい窒素原子、酸素原子、硫黄原子、またこれらヘテロ原子と置換基を有していてもよい炭素原子の任意の組み合せからなる原子団である。また、上記式中のＺはハロゲン原子、ＰＦ_６、ＢＦ_４、ＣｌＯ_４、ＢＰｈ_４を示す。また、上記式中のＭは、鉄、ルテニウムなどの遷移金属を示す。また、上記式はキラルな面性不斉化合物の２つのエナンチオマーのうちの一方を示しているが、他方のエナンチオマーでも構わない。）

(In the above formula, R ^{1 to} R ⁹ are hydrogen atoms, C _{1 to} C ₂₀ hydrocarbon groups which may have a substituent, and C _{1 to} C ₂₀ alkoxy groups which may have a substituent. C _{6 to} C ₂₀ aryloxy group which may have a substituent, an amino group which may have a substituent, a phosphino group which may have a substituent, and a phosphino group which may have a substituent. A good silyl group, an alkylthio group which may have a substituent (-SY ¹ , in the formula, Y ¹ indicates a C _{1 to} C ₂₀ alkyl group which may have a substituent), a substituent. It may have an arylthio group (-SY ² , in the formula, Y ² indicates a C _{6 to} C ₂₀ allyl group which may have a substituent), or may have a substituent. A good alkylsulfonyl group (SO ₂ Y ³ , in the formula, Y ³ _{represents a C 1 to} C ₂₀ alkyl group which may have a substituent), an arylsulfonyl group which may have a substituent (SO 2 Y 3, may have a substituent). -SO ₂ Y ⁴ , in the formula, Y ⁴ _{represents a C 6 to} C ₂₀ aryl group which may have a substituent), a hydroxyl group or a halogen atom, and R ^{1 to} R ⁹ , respectively. They may be independent of each other and may be the same or different. Also, R ² and R ³ , R ³ and R ⁴ , R ⁵ and R ⁶ , R ⁶ and R ⁷ , R ⁷ and R ⁸ , R ⁸ and R ⁹ and R ⁹ and R ⁵ may be crosslinked with each other to form a C _{4 to} C ₁₀ saturated ring or an unsaturated ring, respectively, and in the case of the ring, an oxygen atom, a sulfur atom, a silicon atom, etc. It may be interrupted by a tin atom, a germanium atom, or a group represented by −N (B) − (where B is a hydrogen atom or a C _{1 to} C ₁₀ hydrocarbon group), and the substituent is used. In addition, X in the above formula may have a C _{1 to} C ₄ carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom, a sulfur atom, and the like. Further, it is an atomic group consisting of any combination of these hetero atoms and carbon atoms which may have a substituent. In the above formula, Z is a halogen atom, PF ₆ , BF ₄ , ClO ₄ , BPh ₄ . In addition, M in the above formula indicates a transition metal such as iron and ruthenium. Further, the above formula shows one of two enantiomers of a chiral planar asymmetric compound, but the other enantiomer. But it doesn't matter.)

Further, the present invention is a preferable method for producing carbene that can be synthesized from the surface asymmetric iminium salt derivative represented by the general formula (1), and the metallocene side of the metallocene derivative represented by the following general formula (4). It is an object of the present invention to provide a method for producing a planar asymmetric carbene derivative, which comprises converting a chain and carrying out a ring closure, iminiumization, and deprotonation reaction.

（上記式中、Ｒ^１〜Ｒ^９及び、Ｍは前記の定義と同じである。また、Ｙはハロゲン原子、ホルミル基を示す。）

(In the above formula, R ^{1 to} R ⁹ and M are the same as the above definitions, and Y indicates a halogen atom and a formyl group.)

Further, the present invention provides a metal complex for an asymmetric synthesis catalyst, which comprises using the above-mentioned surface asymmetric carbene derivative as a ligand.

When the metal complex using the surface asymmetric carbene of the present invention as a ligand is used as a catalyst for asymmetric synthesis, various asymmetric reactions can proceed with high enantioselectivity and reaction activity. Further, according to the production method of the present invention, the carbene derivative of the present invention can be easily produced.

In the surface asymmetric iminium salt derivative of the present invention represented by the above general formula (1), R ^{1 to} R ⁹ may have a hydrogen atom and a substituent C _{1 to} C ₂₀ hydrocarbon groups. , C _{1 to} C ₂₀ alkoxy group which may have a substituent, C _{6 to} C ₂₀ aryloxy group which may have a substituent, an amino group which may have a substituent, and a substituent. A phosphino group which may have a substituent, a silyl group which may have a substituent, and an alkylthio group which may have a substituent (-SY ¹ , in the formula, Y ¹ has a substituent. _{C 1 to} C ₂₀ alkyl groups may be indicated), arylthio groups which may have a substituent (-SY ² , in the formula, Y ² may have a substituent C _{6 to} C). _{Indicates a 20} aryl group), an alkylsulfonyl group which may have a substituent (SO ₂ Y ³ , in the formula, Y ³ _{indicates a C 1 to} C ₂₀ alkyl group which may have a substituent. .), which may have a substituent arylsulfonyl group _(-SO 2 ^{Y 4,} in ^the formula, ^{Y 4} is a good _C 6 _{-C 20} aryl group which may have a substituent.), a hydroxyl group Or it is a halogen atom. Further, R ^{1 to} R ⁹ are independent of each other and may be the same or different from each other. In addition, R ² and R ³ , R ³ and R ⁴ , R ⁵ and R ⁶ , R ⁶ and R ⁷ , R ⁷ and R ⁸ , R ⁸ and R ⁹ , and R ^{9 and R 5} , respectively, bridge each other. C _{4 to} C ₁₀ may form a saturated ring or an unsaturated ring, and in the case of the ring, it is indicated by an oxygen atom, a sulfur atom, a silicon atom, a tin atom, a germanium atom, or -N (B)-. It may be interrupted by a group (where B is a hydrogen atom or a C _{1 to} C ₁₀ hydrocarbon group) and may have a substituent. Further, X in the above formulas may have a substituent group C ₁ -C ₄ carbon atoms, a nitrogen atom which may have a substituent, an oxygen atom, a sulfur atom, also substituent as these heteroatoms It is an atomic group consisting of any combination of carbon atoms which may have. Further, Z in the above formula represents a halogen atom, PF ₆ , BF ₄ , ClO ₄ , and BPh ₄ . Further, M in the above formula indicates a transition metal such as iron and ruthenium. Further, although the above formula shows one of the two enantiomers of the chiral asymmetric compound, the other enantiomer may be used.

Here, in the present specification and claims, the _{hydrocarbon group of "C 1 to} C ₂₀ hydrocarbon group" may be a saturated or unsaturated acyclic type, or a saturated or unsaturated ring. It may be an expression. When the C _{1 to} C ₂₀ hydrocarbon groups are acyclic, they may be linear or branched. "C _{1 to} C ₂₀ hydrocarbon groups" include C _{1 to} C ₂₀ alkyl groups, C _{2 to} C ₂₀ alkenyl groups, C _{2 to} C ₂₀ alkynyl groups, C _{4 to} C ₂₀ alkyldienyl groups, C ₆ to C. ₂₀ aryl groups, C _{6 to} C ₂₀ alkylaryl groups, C _{6 to} C ₂₀ arylalkyl groups, C _{3 to} C ₂₀ cycloalkyl groups, C _{3 to} C ₂₀ cycloalkyl groups, (C _{3 to} C ₁₀ cycloalkyl) C _{1 to} C ₂₀ Alkyl groups and the like are included.

In the present specification and claims, _"C 1 _{-C 20} alkyl group" _is preferably C 1 _{-C 10} alkyl _group, more preferably a C 1 -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, dodecanyl and the like.

In the present specification and claims, _"C 2 _{-C 20} alkenyl group" _is preferably C 2 _{-C 10} alkenyl _group, more preferably a C 2 -C ₆ alkenyl group. Examples of the alkenyl group include, but are not limited to, vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, 2-methylallyl, 2-butenyl and the like.

In the present specification and claims, _"C 2 _{-C 20} alkynyl group" _is preferably C 2 _{-C 10} alkynyl _group, more preferably a C 2 -C ₆ alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl and the like.

In the present specification and claims, _"C 4 _{-C 20} alkyldienyl group" _is preferably C 4 _{-C 10} alkadienyl _group, are C 4 -C ₆ alkadienyl group Is even more preferable. Examples of the alkyldienyl group include, but are not limited to, 1,3-butadienyl and the like.

Further, in the present specification and claims, the "C _{6 to} C ₂₀ aryl group" is _{preferably a C 6 to} C ₁₀ aryl group. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indenyl, biphenylyl, anthryl, phenanthryl and the like.

Further, in the present specification and claims, the "C _{6 to} C ₂₀ alkylaryl group" is _{preferably a C 6 to} C ₁₂ alkylaryl group. Examples of alkylaryl groups include, but are not limited to, o-tolyl, m-tolyl, p-tolyl, 2,3-kisilyl, o-cumenyl, m-cumenyl, p-cumenyl, mesityl and the like. Can be done.

In the present specification and claims, _"C 6 _{-C 20} arylalkyl _group", C 6 _{-C 12} ants - preferably a Ruarukiru group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylmethyl, 3-phenylpropyl, 4-. Phenylbutyl, 5-phenylpentyl and the like can be mentioned.

Further, in the present specification and claims, the "C _{3 to} C ₂₀ cycloalkyl group" is _{preferably a C 3 to} C ₁₀ cycloalkyl group. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Further, in the present specification and claims, the "C _{3 to} C ₂₀ cycloalkenyl group" is _{preferably a C 3 to} C ₁₀ cycloalkenyl group. Examples of the cycloalkenyl group include, but are not limited to, cyclopropenyl, cyclobutenyl, 2-cyclopentene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl and the like.

Further, in the present specification and claims, the "C _{1 to} C ₂₀ alkoxy group" is preferably a C _{1 to} C ₁₀ alkoxy group, and more preferably a C _{1 to} C ₆ alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy and the like.

Further, in the present specification and claims, the "C _{6 to} C ₂₀ aryloxy group" is preferably a C _{6 to} C ₁₀ aryloxy group. Examples of aryloxy groups include, but are not limited to, phenyloxy, naphthyloxy, biphenylyloxy and the like.

Further, in the present specification and claims, "alkylthio group (-SY ¹ , in the formula, Y ¹ _{indicates a C 1 to} C ₂₀ alkyl group which may have a substituent)" and "alkylsulfonyl". In the group (-SO ₂ Y ³ , in the formula, Y ³ _{represents a C 1 to} C ₂₀ alkyl group which may have a substituent ^{), Y 1} and Y ³ are C _{1 to} C ₁₀ alkyl. It is preferably a group, more preferably a C _{1 to} C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, dodecanyl and the like.

Further, within the scope of the present specification and patent claims, "C _{1 to} C ₂₀ hydrocarbon groups", "C _{1 to} C ₂₀ alkoxy groups" and "C _{6 to} C ₂₀ aryloxy groups" represented ^{by R 1 to} R ^{9 ".} , "Amino group", "silyl group", "alkylthio group", "arylthio group", "alkylsulfonyl group", "arylsulfonyl group" may have a substituent introduced therein. Examples of the substituent include C _{1 to} C ₁₀ hydrocarbon groups (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, trill, xsilyl, benzyl, etc.) and C _{1 to} C ₁₀ alkoxy groups (for example). , Methoxy, ethoxy, propoxy, butoxy, etc.), C _{6 to} C ₁₀ allyloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.) Amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) Or a silyl group and the like. In this case, one or more substituents may be introduced at substitutable positions, and preferably one to six substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

Further, in the present specification and claims, examples of the "amino group which may have a substituent" are not limited, but are amino, dimethylamino, methylamino, methylphenylamino, and phenyl. There are amino etc.

Further, in the present specification and claims, an example of "an atomic group consisting of an arbitrary combination of a heteroatom and a carbon atom which may have a substituent" is not limited, but -CH. _{2 -CH 2 -CH 2 -O -,} - CH 2 -S-CH 2 -, - there is CH 2 -O- and the like.

Further, in the present specification and the scope of the patent claim, examples of the "silyl group which may have a substituent" are not limited, but trimethylsilyl, triethylsilyl, trimethoxysilyl, triethoxysilyl, and the like. There are diphenylmethylsilyl, triphenylsilyl, triphenoxysilyl, dimethylmethoxysilyl, dimethylphenoxysilyl, methylmethoxyphenyl and the like.

Further, within the scope of the present specification and claims, the ^{substituents represented by R 1 to} R ⁹ may be crosslinked with each other to form a C _{4 to} C ₂₀ saturated ring or an unsaturated ring. The ring formed by these substituents is preferably a 4-membered ring to a 12-membered ring, and more preferably a 4-membered ring to a 6-membered ring. This ring may be an aromatic ring such as a benzene ring, or may be an aliphatic ring. Further, a single ring or a plurality of rings may be further formed on the ring formed by these substituents. The saturated ring or unsaturated ring is represented by an oxygen atom, a sulfur atom, a silicon atom, a tin atom, a germanium atom or -N (B)-(B is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group. ) May be interrupted. That is, the saturated ring or unsaturated ring may be a heterocycle. Moreover, it may have a substituent. The unsaturated ring may be an aromatic ring such as a benzene ring. B is preferably a hydrogen atom or a C _{1 to} C ₁₀ hydrocarbon group, more preferably a hydrogen atom or a C _{1 to} C ₇ hydrocarbon group, and B is a hydrogen atom, a C _{1 to} C ₃ alkyl group. , Phenyl group or benzyl group is even more preferable. The saturated ring or unsaturated ring may have a substituent, for example, a C _{1 to} C ₁₀ hydrocarbon group (for example, a methyl, ethyl, propyl, butyl group), a C _{1 to} C ₁₀ alkoxy group (for example, a methyl, ethyl, propyl, butyl group). For example, methoxy, ethoxy, propoxy, butoxy, etc.), C _{6 to} C ₁₀ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, etc.) Substituents such as iodine) or silyl group may be introduced.

Further, in the present specification and claims, the "aromatic ring" may include a monocyclic aromatic ring and a polycyclic aromatic ring. Examples of the "monocyclic aromatic ring" include a benzene ring and a 5- or 6-membered heterocycle. Examples of the "5- or 6-membered heterocycle" include furan, thiophene, pyrrole, pyran, thiopyran, pyridine, thiazol, imidazole, pyrimidine, 1,3,5-triazine and the like. Examples of the "polycyclic aromatic ring" include a polycyclic aromatic hydrocarbon and a polycyclic complex aromatic ring. Examples of the "polycyclic complex hydrocarbon" include biphenyl, triphenyl, naphthalene, indene, anthracene, phenanthrene and the like. Examples of the "polycyclic heteroaromatic ring" include indole, quinoline, and pudding.

Further, in the present specification and claims, X is optionally substituted C ₁ -C ₄ carbon atoms, which may have a substituent nitrogen atom, an oxygen atom, are a sulfur atom .. Further, Z represents a halogen atom, PF ₆ , BF ₄ , ClO ₄ , and BPh ₄ .

Further, in the present specification and claims, M indicates a transition metal such as iron and ruthenium.

Particularly preferred as X is −CH ₂ −CH ₂ −CH ₂ −, particularly preferred as M is iron, _{particularly preferred as C 2 to} C ₄ is hydrogen, and particularly preferred as R _{5 to} R _9. Preferred is a monovalent substituent represented by ^{R 10.} In that case, the compound according to the present invention is a carbene that can be synthesized from an iminium salt represented by the following general formula (2).

（上記式中、Ｒ^１およびＺは、前記の定義と同じであり、Ｒ^１０は一価の置換基を示す。ｎは０ないし５の整数を示す。また、上記式はキラルな面性不斉化合物の２つのエナンチオマーのうちの一方を示しているが、他方のエナンチオマーでも構わない。）

(In the above formula, R ¹ and Z are the same as the above definitions, R ¹⁰ represents a monovalent substituent, n represents an integer of 0 to 5, and the above formula is a chiral facet. Although one of the two enantiomers of the asymmetric compound is shown, the other enantiomer may be used.)

In the above general formula (2), the ^{monovalent substituent represented by R 10} is not particularly limited. Examples of R ¹⁰ include hydrogen, methyl group, phenyl group and the like.

_{Further, -CH 2-} CH _2- is particularly preferable as X, iron is particularly preferable as M, hydrogen is particularly preferable as _{C 2 to} C _{4 , and R 5 to} R ₉ are particularly preferable. Is a monovalent substituent represented by ^{R 10.} In that case, the compound according to the present invention is a carbene that can be synthesized from an iminium salt represented by the following general formula (3).

（上記式中、Ｒ^１およびＺは、前記の定義と同じであり、Ｒ^１０は一価の置換基を示す。ｎは０ないし５の整数を示す。また、上記式はキラルな面性不斉化合物の２つのエナンチオマーのうちの一方を示しているが、他方のエナンチオマーでも構わない。）

(In the above formula, R ¹ and Z are the same as the above definitions, R ¹⁰ represents a monovalent substituent, n represents an integer of 0 to 5, and the above formula is a chiral facet. Although one of the two enantiomers of the asymmetric compound is shown, the other enantiomer may be used.)

In the above general formula (3), the ^{monovalent substituent represented by R 10} is not particularly limited. Examples of R ¹⁰ include hydrogen, methyl group, phenyl group and the like.

Next, a method for producing the surface asymmetric iminium salt derivative according to the present invention will be described. First, a metallocene derivative represented by the following general formula (4), for example, ( _SP )-(-)-1-iodo-2-[(2S, 4S) -4- (methoxymethyl) -1 , 3-dioxan-2-yl] ferrocene or _{(R P) - (-)} - 1- formyl -2 - [(2S, 4S) -4- ( methoxymethyl) -1,3-dioxan-2-yl] Prepare ferrocene.

（上記式中、Ｒ^１０は前記の定義と同じである。また、Ｙはハロゲン原子、ホルミル基を示す。）

(In the above formula, R ¹⁰ is the same as the above definition, and Y indicates a halogen atom and a formyl group.)

(5) is obtained by coupling (4) with acrylamide by a Mizorogi-Heck reaction in the presence of a palladium catalyst.

Next, the ferrocene side chain of (5) was reduced with lithium aluminum hydride to obtain a primary amine (6), and then (6) was treated with hydrochloric acid to hydrolyze the chiral acetal moiety and spontaneously. (7) is obtained by causing a ring-closing reaction.

Subsequently, the obtained (7) is reacted with a nucleophile to obtain an iminium salt (2).

In addition, different methods for producing an asymmetric iminium salt derivative are also shown.

(9) is obtained by carrying out a Henry reaction on (8) having a formyl group under basic conditions.

Then, the obtained (9) is acetylated by reacting with acetic anhydride under basic conditions, and then dehydrated to convert it to (10).

Further, the ferrocene side chain of (10) is reduced with lithium aluminum hydride to obtain a primary amine (11), and then (11) is treated with hydrochloric acid to hydrolyze the chiral acetal moiety, spontaneously. (12) is obtained by causing a ring closure reaction.

Subsequently, the obtained (12) is reacted with a nucleophile to obtain an iminium salt (2).

According to the above method, there is an advantage that the surface asymmetric iminium salt derivative can be selectively synthesized as a single enantiomer. It should also be noted that various surface asymmetric iminium salt derivatives can be obtained by changing the alkylating agent or arylating agent used in the final stage.

If a base is allowed to act on the surface asymmetric iminium salt derivative of the present invention represented by the general formula (2) to generate carbene and then coordinated with a transition metal as a ligand, the asymmetric metal A complex can be obtained. This complex is useful as an asymmetric synthesis catalyst.

Hereinafter, the present invention will be described in more detail with reference to examples. However, this is merely an example and does not limit the present invention.

(Example 1)
(1) Synthesis of compound represented by the general formula (2) The following procedure is a kind of compound represented by the general formula (2) (R)-(-)-2-isopropyl-. 4,5-Dihydro-3H-ferroko [c] 2-azepinium iodine was synthesized.

A nitrogen gas atmosphere, at room _temperature, Pd in dimethylformamide (0.5 mL) solution of _{(PPh 3) 2 Cl 2 (} 69.5mg, 0.099mmol), (S P) - (-) - 1- Yo - Do-2-[(2S, 4S) -4- (methoxymethyl) -1,3-dioxane-2-yl] ferrocene (4) (219 mg, 0.495 mmol), acrylamide (106 mg, 1.48 mmol), triethylamine A mixed solution of (230 μL, 1.68 mmol) dimethylformamide (2.2 mL) was added dropwise. The reaction solution was stirred at 75 ° C. for 12 hours, water was added, and the mixture was extracted 3 times with diethyl ether. The organic layer was dried by adding sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol / triethylamine = 20/1 / 0.6). In this way, (R _p )-(-)-1-((E)-(3-amino-3-oxoprop-1-ene-1-yl)) -2-[(2S, 4S) -4- (Methoxymethyl) -1,3-dioxane-2-yl] ferrocene (5) was obtained. The yield was 177 mg and the yield was 60%.

^{1 1} H NMR (CDCl ₃ ): δ 1.48 (d, J = 13.6 Hz, 1H), 1.85 (qd, J = 13.2, 5.2 Hz, 1H), 3.38 (s, 3H) ), 3.45 (dd, J = 10.4, 3.2Hz, 1H), 3.50 (dd, J = 10.4, 7.6Hz, 1H), 3.99 (t, J = 12. 4Hz, 1H), 4.03-4.11 (m, 1H), 4.15 (s, 5H), 4.31 (d, J = 1.2Hz, 1H), 4.32 (dd, J = 12.8, 5.2Hz, 1H), 4.44 (d, J = 1.2Hz, 1H), 4.65 (t, J = 0.8Hz, 1H), 5.56 (s, 1H), 5.57 (br s, 1H), 5.95 (br s, 1H), 6.44 (d, J = 15.8Hz, 1H), 7.60 (d, J = 16.8Hz, 1H).
¹³ C NMR (CDCl ₃ ): δ 27.3, 59.3, 67.0, 69.0, 69.5, 70.1, 70.3, 75.7, 77.2, 79.0, 83 .6, 100.1, 119.4, 140.7, 168.4.
HRMS (ESI) calcd for C ₁₉ H ₂₄ FeNO ₄ (M + H) 386.1049, found 386.1045.
[α] ²³ _D = −111 (c 0.10, CHCl ₃ ).

A solution of (5) (154 mg, 0.401 mmol) in tetrahydrofuran (5 mL) was added dropwise to a suspension of _{LiAlH 4} (182 mg, 4.81 mmol) in tetrahydrofuran dimethylformamide (2 mL) at 0 ° C. under a nitrogen gas atmosphere. The reaction solution was heated to reflux for 2 hours, cooled to 0 ° C., and carefully added sodium sulfate decahydrate. By adding excess sodium sulfate, filtering, and concentrating under reduced pressure, (R _p )-(-) -1- (3-aminopropyl) -2-[(2S, 4S) -4- (methoxymethyl)) -1,3-dioxane-2-yl] ferrocene (6) was obtained. The product was used as is for the next step.

^{1 1} H NMR (CDCl ₃ ): δ 1.48 (d, J = 13.2 Hz, 1H), 1.62-1.82 (m, 3H), 2.12 (br s, 2H), 2.41 (Ddd, J = 15.2,8.8,6.4Hz, 1H), 2.58 (ddd, J = 15.2,8.8, 6.0Hz, 1H), 2.66-2.78 (M, 2H), 3.37 (s, 3H), 3.37 (dd, J = 10.4, 4.0Hz, 1H), 3.49 (dd, J = 10.0, 6.4Hz, 1H), 3.94 (td, J = 12.4, 2.8Hz, 1H), 3.98-4.03 (m, 2H), 4.04 (t, J = 2.0Hz, 1H), 4.08 (s, 5H), 4.27 (dd, J = 11.6, 4.4Hz, 1H), 4.30 (t, J = 2.0Hz, 1H), 5.49 (s, 1H) ).
¹³ C NMR (CDCl ₃ ): δ 25.6, 27.9, 34.4, 41.7, 59.2, 66.2, 66.4, 66.8, 68.9, 69.4, 75 .7, 76.0, 83.6, 87.0, 10.0.3.
HRMS (ESI) calcd for C ₁₉ H ₂₈ FeNO ₃ (M + H) 374.1413, found 374.1408.
[α] ²³ _D = -31.6 (c 0.10, CHCl ₃ ).

1M hydrochloric acid (340 μL, 0.343 mmol) was added dropwise to a solution of (6) (107 mg, 0.287 mmol) in acetone dimethylformamide (5.5 mL) at 0 ° C. under a nitrogen gas atmosphere. The reaction solution was stirred at 0 ° C. for 15 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. After extraction with dichloromethane, sodium sulfate is added to the organic layer, dried, filtered, and concentrated under reduced pressure to obtain (R)-(-)-4,5-dihydro-3H-ferroko [c] azepine (7). Obtained. The yield was 39.2 mg and the yield was 39% in two steps.

^{1 1} H NMR (CDCl ₃ ): δ 1.94-2.04 (m, 1H), 2.05-2.14 (m, 1H), 2.60 (ddd, J = 16.0, 12.0) , 4.0Hz, 1H), 2.83 (dt, J = 16.0, 3.5Hz, 1H), 3.27 (ddd, J = 12.5, 10.5, 2.0Hz, 1H), 4.11-4.20 (m, 1H), 4.17 (s, 5H), 4.31 (t, J = 2.0Hz, 1H), 4.33-4.37 (m, 1H), 4.41-4.45 (m, 1H), 8.03 (d, J = 2.0Hz, 1H).
¹³ C NMR (CDCl ₃ ): δ 26.5, 30.2, 53.7, 69.9, 71.5, 71.6, 89.7, 162.0.
HRMS (ESI) calcd for C ₁₄ H ₁₆ FeN (M + H) 254.0627, found 254.0621.
[α] ²³ _D = −567 (c 0.01, CHCl ₃ ).

Under a nitrogen gas atmosphere, a mixture of (7) (22.7 mg, 0.090 mmol) and isopropyliodide (304 mg, 180 μL, 1.50 mmol) in acetonitrile dimethylformamide (180 mL) was refluxed for 1 hour and then concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, diethyl ether was added, and the mixture was reprecipitated / filtered to obtain (R)-(-)-2-isopropyl-4,5-dihydro-3H-ferroko [c] 2-aze. Pinium iodide (2) was obtained. The yield was 29.7 mg and the yield was 69%.

^{1 1} H NMR (CDCl ₃ ): δ 1.47 (d, J = 6.4 Hz, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.85-1.98 (m, 1H) ), 2.48 (ddt, J = 15.6, 8.0, 4.0Hz, 1H), 2.69 (ddd, J = 16.8, 12.8, 4.0Hz, 1H), 2. 88 (dt, J = 16.8, 3.2 Hz, 1H), 3.29 (dd, J = 14.8, 10.8 Hz, 1H), 3.96 (dd, J = 15.2, 8. 0Hz, 1H), 4.50 (s, 5H), 4.97 (t, J = 2.8Hz, 1H), 5.02 (sept, J = 6.8Hz, 1H), 5.05-5. 08 (m, 1H), 5.30-5.34 (m, 1H), 10.0 (s, 1H).
¹³ C NMR (CDCl ₃ ): δ 20.2, 20.8, 25.2, 28.9, 50.0, 63.4, 68.2, 72.3, 77.4, 78.5, 90 .3, 169.6.
HRMS (ESI) calcd for C ₁₇ H ₂₂ FeN (MI) 296.1096, found 296.1090.
[α] ²³ _D = -447 (c 0.001, CHCl ₃ ).

(Example 2)
(2) Synthesis of the compound represented by the general formula (2) The following procedure is a kind of the compound represented by the general formula (2) (R)-(-)-2-isopropyl-. 4,5-Dihydro-3H-ferroco [c] pyridinium iodide was synthesized.

_(RP )-(-)-1-formyl-2-[(2S, 4S) -4- (methoxymethyl) -1,3-dioxane-2-yl] ferrocene (RP)-(-)-1-formyl-2-[(2S, 4S) -4- (methoxymethyl) -1,3-dioxane-2-yl] ferrocene at 0 ° C. in a nitrogen gas atmosphere. 8) An aqueous solution of potassium hydroxide (1.43 g, 16.9 mmol) in a mixture of (4.28 g, 11.3 mmol), nitromethane (3.0 mL, 56.5 mmol), methanol (20 mL), tetrahydrofuran (40 mL). (5.0 mL) was added. After stirring at 0 ° C. for 1 hour, saturated aqueous ammonium chloride was added to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over sodium sulfate. Then, it is filtered and concentrated under reduced pressure to form a diastereomeric mixture 1- (1-hydroxy-2-nitroethyl) -2-[(2S, 4S) -4- (methoxymethyl) -1,3-dioxane-2-yl). ] Ferrocene (9) was obtained. The product was used as is for the next step.

At room temperature under a nitrogen gas atmosphere, (9) (5.28 g), N, N-dimethylaminopyridine (0.31 g, 2.6 mmol, 20 mol%), triethylamine (9.0 mL, 64.4 mmol), tetrahydrofuran ( Acetic anhydride (6.1 mL, 64.4 mmol) was added to the mixture (25 mL). After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride was added to stop the reaction. After extraction with dichloromethane, the organic layer was washed with saturated brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 1/2) to ( _RP )-(-)-1-((E) -2). -Nitrovinyl) -2-[(2S, 4S) -4- (methoxymethyl) -1,3-dioxane-2-yl] ferrocene (10) was obtained. The yield was 4.3 g, and the yield was 91% in two steps.

^{1 1} H NMR (CDCl ₃ ): δ 0.99 (t, J = 7.6 Hz, 3H), 1.21 (s, 9H), 1.92 (d of quanti, J = 14.0 and 7.6 Hz) , 1H), (d of quanti, J = 14.0 and 7.6Hz, 1H), 4.25 (s, 3H), 4.54 (t, J = 7.8Hz, 1H), 4.77 ( dd, J = 7.8 and 1.6Hz, 1H), 5.49 (s, 1H), 7.35 (d, 1H), 8.33 (d, J = 7.8 and 2.1Hz, 1H) ).
¹³ C NMR (CDCl ₃ ): δ 27.7, 59.4, 66.9, 68.6, 71.0, 71.2, 72.1, 72.4, 75.4, 76.3 87. 6, 99.4, 134.0, 141.46.
ESI-HRMS Calcd for C ₁₈ H ₂₁ O ₅ NFeNa (M ⁺ + Na): 410.0661. Found: 410.0661.
[α] ²³ _D = -696.0 (c 0.001, CHCl ₃ ).

(10) (84.1 mg, 0.217 mmol) was added to a diethyl ether dimethylformamide (5.8 mL) suspension of _{LiAlH 4} (28.8 mg, 0.76 mmol) at 0 ° C. under a nitrogen gas atmosphere. .. The reaction solution was stirred at room temperature for 1 hour, cooled to 0 ° C., and carefully added sodium sulfate decahydrate. By adding excess sodium sulfate, filtering, and concentrating under reduced pressure, (R _p )-(-) -1- (3-aminoethyl) -2-[(2S, 4S) -4- (methoxymethyl)) -1,3-dioxane-2-yl] ferrocene (11) was obtained. The yield was 77.1 mg and the yield was 99%.

^{1 1} H NMR (CDCl ₃ ): δ 1.48 (d, J = 13.0 Hz, 1H), 1.75 (qd, J = 11.8, 8.0 Hz, 1H), 2.46-2.69 (M, 2H), 2.80 (brs, 2H), 3.30 (s, 3H), 3.92-4.15 (m, 4H), 4.09 (s, 5H), 4.26 ( dd, J = 11.5, 4.4Hz, 1H), 4.32 (s, 1H), 5.46 (s, 1H).
¹³ C NMR (CDCl ₃ ): δ 27.9, 28.0, 32.7, 43.3, 59.2, 66.4, 66.6, 66.8, 69.27, 69.35, 75 .5, 75.9, 84.1, 84.7, 100.2.
ESI-HRMS Calcd for C ₁₈ H ₂₅ FeNO ₃ (M ⁺ + H): 360.127. Found: 360.128.
[α] ²³ _D = -773.0 (c 0.001, CHCl ₃ ).

1M hydrochloric acid (290 μL, 0.290 mmol) was added dropwise to a solution of (11) (102.4 mg, 0.29 mmol) in acetone dimethylformamide (5.0 mL) at 0 ° C. under a nitrogen gas atmosphere. The reaction solution was stirred at 0 ° C. for 10 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. After extraction with dichloromethane, sodium sulfate was added to the organic layer, dried, filtered, and concentrated under reduced pressure. By purifying the residue by thin layer silica gel chromatography for preparative use (dichloromethane / methanol / triethylamine = 9/1 / 0.3), (R)-(-)-4,5-dihydro-3H-ferroko [ c] Pyridine (12) was obtained. The yield was 59.2 mg and the yield was 87%.

^{1 1} H NMR (CDCl ₃ ): δ 2.31 (ddd, J = 15.6, 13.8, 6.2 Hz, 1H), 2.51 (ddd, J = 15.6, 6.6, 1. 8Hz, 1H), 3.58 (dddd, J = 16.7, 13.8, 6.6, 3.0Hz, 1H), 4.08-4.16 (m, 1H), 4.18 (s) , 5H), 4.24-4.26 (m, 1H), 4.27-4.30 (m, 2H), 8.36 (d, J = 3.0Hz, 1H).
¹³ C NMR (CDCl ₃ ): δ 22.0, 49.1, 64.1, 67.3, 67.9, 69.5, 72.3, 86.2, 161.3.
ESI-HRMS Calcd for C ₁₃ H ₁₄ NFe (M ⁺ + H): 240.0470. Found: 240.0480.
[α] ²⁶ _D = -925.0 (c 0.001, CHCl ₃ ).

Under a nitrogen gas atmosphere, a mixture of (12) (19.8 mg, 0.083 mmol) and isopropyliodide (0.16 mL, 1.7 mmol) in acetonitrile dimethylformamide (0.33 mL) was refluxed for 20 minutes and then concentrated under reduced pressure. bottom. The obtained residue was dissolved in dichloromethane, diethyl ether was added, and the mixture was reprecipitated / filtered to obtain (R)-(-)-2-isopropyl-4,5-dihydro-3H-ferroco [c] pyridinium iodide. (2) was obtained. The yield was 26.1 mg and the yield was 77%.

^{1 1} H NMR (CD ₃ OD): δ 1.51 (d, J = 5.5 Hz, 6H), 2.66-2.80 (m, 1H), 2.93-3.08 (m, 1H) , 3.68-3.80 (m, 1H), 3.94-4.40 (m, 1H), 4.18-4.32 (m, 1H), 4.52 (s, 5H), 4 .93 (s, 1H), 5.02 (s, 1H), 5.07 (s, 1H), 9.26-9.38 (m, 1H).
¹³ C NMR (CD ₃ OD): δ 20.9, 22.6, 63.6, 68.2, 70.9, 72.9, 72.9, 74.7, 76.7, 87.2 170.9.
ESI-HRMS Calcd for C ₁₆ H ₂₀ FeN (M ⁺ ): 282.0940. Found: 282.0939.
[α] ²⁶ _D = -925.0 (c 0.001, CHCl ₃ ).

(Example 3)
(3) Synthesis of metal complex A copper complex was synthesized by generating carbene from a planar asymmetric iminium salt derivative represented by the above general formula (2) by the following procedure.

In a nitrogen gas atmosphere, at −78 ° C., (2) (40.0 mg, 0.090 mmol) in tetrahydrofuran (870 μL) in tetrahydrofuran (880 μL) sodium hexamethyldisilazide (24.8 mg, 0.140 mmol) in tetrahydrofuran (880 μL). The solution was added. After 10 minutes, a suspension of copper (17.9 mg, 0.18 mmol) in tetrahydrofuran (1230 μL) was added to the reaction mixture. After stirring at −78 ° C. for 1 hour, the mixture was heated to room temperature and further stirred for 10 minutes. After concentrating the reaction solution under reduced pressure, diethyl ether was added, and insoluble matter was removed using a glass filter under a nitrogen gas atmosphere. Finally, the filtrate was concentrated under reduced pressure to obtain a biscarben copper complex (13).

HRMS (ESI) calcd for C ₃₄ H ₄₂ CuFe ₂ N ₂ (M-Cl) 653.1337, found 653.1337.

(Example 4)
(4) Asymmetric addition reaction using a copper complex An asymmetric addition reaction using a copper complex represented by the above formula (13) was carried out by the following procedure.

Tetrahydrofuran (290 μL) of (13) (5.3 mg, 0.0077 mmol, 5 mol%) in a solution of bispinacolato diboron (85.8 mg, 0.338 mmol) in tetrahydrofuran (150 μL) at 0 ° C. under a nitrogen gas atmosphere. ) The solution was added. After 10 minutes, t-butyl cinnamate (14) (34.5 mg, 0.169 mmol) and methanol (10.8 mg, 0.338 mmol) were added to the reaction solution. After stirring at 0 ° C. for 1 hour, sodium peroxoborate (about 200 mg) and water (440 μL) were added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. After diluting the reaction solution with water and extracting with ethyl acetate, the organic layer was dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by thin layer silica gel chromatography for preparative use (hexane / isopropanol = 7/1) to obtain alcohol (15). The absolute configuration of the product and the enantiomeric excess were determined by comparison with previously reported values using high performance liquid chromatography. The yield was 38.6 mg, the yield was> 99%, and the enantiomeric excess was 80% ee (S).

^{1 1} H NMR: δ 1.45 (s, 9H), 2.63 (dd, J = 16.4, 4.4 Hz, 1H), 2.70 (dd, J = 16.8, 8.8 Hz, 1H) ), 3.47 (d, J = 3.6Hz, 1H), 5.08 (dt, J = 8.0, 3.6Hz, 1H), 7.25-7.29 (m, 1H), 7 .32-7.39 (m, 4H).
[α] ¹⁹ _D = -28.4 (c 0.1, CHCl ₃ ).
The enantiomeric excess of 15 was determined by HPLC analysis with chiral stability phase enantiomeric excess. Daicel Chiralcel As-H, hexane / i-PrOH = 100/1, 0.3 mL / min, t _R = 43.6 min (R), t _S = 47.9 min (S).

Claims (6)

A carbene that can be synthesized from a surface asymmetric iminium salt derivative represented by the following general formula (1).

(In the formula, ^{R 1} is, ^.R 2 to R ⁴ is also a good _C 1 _{-C 20} hydrocarbon group optionally having a hydrogen atom or a substituent, Ri Oh hydrogen ^atom, R 5 to R ⁹ is a hydrogen atom or Ru good _C 1 _{-C 20} hydrocarbon radical der may have a substituent, Further, X in the above formulas, _-CH 2 _-CH 2 -CH ₂ -. or -CH ₂ -CH ₂ -.. is also, Z in the above formula represents a halogen _{atom, PF 6, BF 4, ClO} 4 or BPh _4, also, M in the formula represents iron or ruthenium. Further, the above formula shows one of the two enantiomers of the chiral planar asymmetric compound, but the other enantiomer may also be used.) Ca Reuben according to claim 1, wherein can be synthesized from the surface of the asymmetric iminium salt derivative represented by the following general formula (2).

(In the above formula, R ¹ and Z are the same as the above definitions, and R ¹⁰ indicates a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent. N is 0 to 0 to C 20 hydrocarbon group. An integer of 5 is shown. Further, the above formula shows one of the two enantiomers of the chiral planar asymmetric compound, but the other enantiomer may also be used.) Following general formula Ca Reuben according to claim 1, wherein can be synthesized from the surface of the asymmetric iminium salt derivative represented by (3).

(In the above formula, R ¹ and Z are the same as the above definitions, and R ¹⁰ indicates a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent. N is 0 to 0 to C 20 hydrocarbon group. An integer of 5 is shown. Further, the above formula shows one of the two enantiomers of the chiral planar asymmetric compound, but the other enantiomer may also be used.) The method for producing carbene according to claim 1.
A method for producing carbene , which comprises converting the metallocene side chain of a metallocene derivative represented by the following general formula (4) to perform ring closure, iminiumization, and deprotonation reactions.

(In the above formula, R ^{1 to} R ⁹ and M are the same as the above definitions, and Y indicates a halogen atom and a formyl group.) A metal complex for an asymmetric synthesis catalyst, which comprises the carbene according to claim 1 as a ligand. A surface asymmetric iminium salt derivative represented by the following general formula (1).

(In the above formula, R ¹ May have a hydrogen atom or a substituent C ₁ ~ C ₂₀ It is a hydrocarbon group. R ² ~ R ⁴ Is a hydrogen atom and R ⁵ ~ R ⁹ May have a hydrogen atom, or a substituent C ₁ ~ C ₂₀ It is a hydrocarbon group. Further, X in the above formula is -CH. ₂ -CH ₂ -CH ₂ -Or-CH ₂ -CH ₂ -. Further, Z in the above formula is a halogen atom and PF. ₆ , BF ₄ , ClO ₄ , Or BPh ₄ Is shown. Further, M in the above formula represents iron or ruthenium. Further, although the above formula shows one of the two enantiomers of the chiral asymmetric compound, the other enantiomer may be used. )