JP2007238525A - Process for producing optically active β-hydroxyimine compound - Google Patents
Process for producing optically active β-hydroxyimine compound Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title abstract description 10
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 10
- 239000010948 rhodium Substances 0.000 claims abstract description 10
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract 2
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 150000001299 aldehydes Chemical class 0.000 claims description 13
- 150000002430 hydrocarbons Chemical group 0.000 claims description 10
- -1 glyoxylic acid ester Chemical class 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxylic acid Natural products OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000003446 ligand Substances 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- PDJQCHVMABBNQW-MIXQCLKLSA-L (1z,5z)-cycloocta-1,5-diene;rhodium;dichloride Chemical compound [Cl-].[Cl-].[Rh].[Rh].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 PDJQCHVMABBNQW-MIXQCLKLSA-L 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- HEWAMPODKFTBJZ-NSHDSACASA-N ethyl (2s)-2-hydroxy-4-oxo-4-phenylbutanoate Chemical compound CCOC(=O)[C@@H](O)CC(=O)C1=CC=CC=C1 HEWAMPODKFTBJZ-NSHDSACASA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- AMEDKBHURXXSQO-UHFFFAOYSA-N azonous acid Chemical compound ONO AMEDKBHURXXSQO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- DIKSGAPSESPUGE-ACGXKRRESA-N ethyl (2s)-2-hydroxy-3-methyl-4-oxo-4-phenylbutanoate Chemical compound CCOC(=O)[C@@H](O)C(C)C(=O)C1=CC=CC=C1 DIKSGAPSESPUGE-ACGXKRRESA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000001487 glyoxylate group Chemical group O=C([O-])C(=O)[*] 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
【課題】高ジアステレオ選択的かつ高エナンチオ選択的なエンカルバメートとアルデヒドの付加反応を行う技術を提供する。
【解決手段】下式（Ｉ）で表される化合物とロジウム錯体との存在下に、エンカルバメートとアルデヒドの付加反応を行うことを特徴とする、光学活性なβ−ヒドロキシイミン化合物の製造方法。
（式中、Ａｒは置換基を有していても良いアリール基を表し、Ｒ６及びＲ７はそれぞれ独立して水素原子もしくは置換基を有していてもよいアルキル基又はアリール基を表し、Ｒ６とＲ７は共に同一の環を形成してもよい）。
本発明は、光学活性なβ−ヒドロキシイミンを高いジアステレオ選択性と良好なエナンチオ選択性の下で製造することができる。また、反応温度が０℃付近で実施できるなど、比較的穏和な条件下で不斉反応を行うことができる。The present invention provides a technique for performing an addition reaction of an encarbamate and an aldehyde with high diastereoselectivity and high enantioselectivity.
A method for producing an optically active β-hydroxyimine compound, wherein an addition reaction of an encarbamate and an aldehyde is carried out in the presence of a compound represented by the following formula (I) and a rhodium complex.
(In the formula, Ar represents an optionally substituted aryl group, R 6 and R 7 each independently represents a hydrogen atom or an optionally substituted alkyl group or aryl group, R 6 and R 7 may form the same ring together).
The present invention can produce an optically active β-hydroxyimine with high diastereoselectivity and good enantioselectivity. Further, the asymmetric reaction can be carried out under relatively mild conditions, such as being able to be carried out at a reaction temperature of around 0 ° C.
Description
本発明は、不斉触媒を用いて選択的に光学活性なβ−ヒドロキシイミン化合物を製造する方法に関する。 The present invention relates to a method for producing an optically active β-hydroxyimine compound selectively using an asymmetric catalyst.
ジアステレオ選択的かつエナンチオ選択的な炭素−炭素結合形成反応は、合成化学分野及び医薬化学分野において重要な反応の一つであり、これまで数多くの研究がなされてきた。そのような過程に於いて、置換シリルエノールエーテルをアルデヒドに求核反応させるアルドール反応が開発されて来たが、syn体生成物、anti体生成物それぞれを高ジアステレオ選択的に合成することは困難とされてきた（特許文献１、特許文献２）。 The diastereoselective and enantioselective carbon-carbon bond formation reaction is one of important reactions in the fields of synthetic chemistry and medicinal chemistry, and many studies have been made so far. In such processes, aldol reactions have been developed in which substituted silyl enol ethers nucleophilically react with aldehydes, but syn-form products and anti-form products can be synthesized in a highly diastereoselective manner. It has been considered difficult (Patent Document 1, Patent Document 2).
近年、キラルジイミン−銅触媒存在下における置換エンカルバメートを求核剤としたエチルグリオキシレートとの不斉反応において、Z体のエンカルバメートからsyn体の生成物が、E体のエンカルバメートからanti体の生成物が、それぞれ高ジアステレオ選択的かつ高エナンチオ選択的に得られることが見出された（非特許文献３）。 In recent years, in the asymmetric reaction with ethyl glyoxylate using a substituted enecarbamate as a nucleophile in the presence of a chiral diimine-copper catalyst, the product of the Z form ene carbamate to the syn form is changed from the E form of the encarbamate to the anti form. It has been found that the following products can be obtained with high diastereoselectivity and high enantioselectivity, respectively (Non-patent Document 3).
また近年、光学活性なＰ，Ｎ−配位子を用いた不斉反応が活発に検討され（非特許文献４）、本発明者らによっても、１−フェニルホスホラン−２−カルボン酸から誘導されるキラル配位子を用いた触媒的不斉合成反応が報告されている。（非特許文献５）
本発明は、従来法とは異なる触媒を用いて、より高ジアステレオ選択的かつ高エナンチオ選択的なエンカルバメートとアルデヒドの付加反応を行う技術を提供するものである。 The present invention provides a technique for performing a higher diastereoselective and higher enantioselective encarbamate and aldehyde addition reaction using a catalyst different from the conventional method.
本発明は、光学活性な［リン、窒素］−配位子とロジウム錯体とを利用することで、より高いジアステレオ選択性かつ高いエナンチオ選択性的を伴った光学活性なβ−ヒドロキシイミン化合物を製造することが可能となることを見出したことに基づく、下記の製造方法に関する発明である。 The present invention uses an optically active [phosphorus, nitrogen] -ligand and a rhodium complex to provide an optically active β-hydroxyimine compound with higher diastereoselectivity and higher enantioselectivity. The present invention relates to the following manufacturing method based on the finding that it can be manufactured.
本発明は、光学活性なβ−ヒドロキシイミンを高いジアステレオ選択性と良好なエナンチオ選択性の下で製造することができる。また、反応温度が０℃付近で足りるなど、比較的穏和な条件下で不斉反応を行うことができる。 The present invention can produce an optically active β-hydroxyimine with high diastereoselectivity and good enantioselectivity. Also, the asymmetric reaction can be carried out under relatively mild conditions such as a reaction temperature of about 0 ° C.
また本発明の反応により製造されるβ−ヒドロキシイミン化合物は、酸加水分解によって光学活性なβ−ヒドロキシカルボニル化合物に変換することができ、あるいは水添反応を行うことによって光学活性な１，３−アミノアルコール化合物を得ることができる。従って、かかる光学活性なβ−ヒドロキシカルボニル化合物もしくは光学活性な１，３−アミノアルコール化合物を製造する工程としても重要な方法である。 The β-hydroxyimine compound produced by the reaction of the present invention can be converted into an optically active β-hydroxycarbonyl compound by acid hydrolysis, or optically active 1,3-3- An amino alcohol compound can be obtained. Therefore, it is an important method as a process for producing such an optically active β-hydroxycarbonyl compound or an optically active 1,3-aminoalcohol compound.
本発明で使用されるエンカルバメートは次式（III）で表される構造を有する化合物である。
置換基を有していてもよい炭化水素基は、無置換の炭化水素基、或いは複素環基、ハロゲン、カルボキシル基、水酸基、エステル基、ニトロ基、シアノ基、エーテル基、チオール基、アミド基、アミノ基、チオエーテル基等の置換基を１以上有していてもよい炭化水素基を意味する。 The hydrocarbon group which may have a substituent is an unsubstituted hydrocarbon group, or a heterocyclic group, a halogen, a carboxyl group, a hydroxyl group, an ester group, a nitro group, a cyano group, an ether group, a thiol group, an amide group. , A hydrocarbon group optionally having one or more substituents such as an amino group and a thioether group.
また炭化水素基としては、炭素数が１０以下の、直鎖状又は分岐状のアルキル基（例えばメチル基、エチル基、プロピル基、ｉ−プロピル基、ブチル基など）、アルケニル基（例えばエテニル基、１−プロペニル基、２−プロペニル基、イソプロペニル基、１−ブテニル基、２−ブテニル基、３−ブテニル基又は２−ペンテニル基、アルキニル基（例えばエチニル基、２−プロピニル基、２−ブチニル基、３−ブチニル基、２−メチル−３−ブチニル基、フェニルエチニル基など）、シクロアルキル基（例えばシクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基など）、またはアリール基等を挙げることができる。 The hydrocarbon group includes a linear or branched alkyl group having 10 or less carbon atoms (for example, a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, etc.), an alkenyl group (for example, an ethenyl group). 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group or 2-pentenyl group, alkynyl group (for example, ethynyl group, 2-propynyl group, 2-butynyl group) Group, 3-butynyl group, 2-methyl-3-butynyl group, phenylethynyl group, etc.), cycloalkyl group (such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or aryl group. it can.
この様なエンカルバメートは、松原らの方法（Angew. Chem. Int. Ed. 43, 3258-3260 (2004).）を参考にして、当業者が適宜作製し、あるいは入手することができる。 Such an encarbamate can be appropriately prepared or obtained by those skilled in the art with reference to the method of Matsubara et al. (Angew. Chem. Int. Ed. 43, 3258-3260 (2004).).
本発明で使用されるアルデヒドは、次式（IV）で表される構造を有する化合物である。
特に好ましいアルデヒドは、グリオキシル酸エステルである。 A particularly preferred aldehyde is glyoxylate.
本発明は、上記のエンカルバメート及びアルデヒドの付加反応を、下式（Ｉ）で表される化合物と遷移金属錯体との存在下で行うことを特徴とする。
置換基を有していてもよいアルキル基は、前記の通りの置換基を有していてもよいアルキル基であり、またＲ６とＲ７が一緒になって形成する環はＮ、Ｓ、Ｏより選ばれるヘテロ原子を含んでいてもよい５員環もしくは６員環であり、該環は前記の通りの置換基をさらに有していてもよい。 The alkyl group which may have a substituent is an alkyl group which may have a substituent as described above, and the ring formed by combining R 6 and R 7 is N, S, It is a 5-membered or 6-membered ring optionally containing a heteroatom selected from O, and the ring may further have a substituent as described above.
上記の構造を有する化合物は、いわゆる［リン、窒素］−配位子であり、これらは、前述の非特許文献５に記載の方法に従い、次式で示されるスキームに基づいて合成することができる。
上記の［リン、窒素］−配位子ならびにロジウム錯体との存在下でのエンカルバメートとアルデヒドとの付加反応は、特殊な溶媒や雰囲気下で行われることを特に必要とはせず、反応温度は−２０℃〜４０℃で反応が進行するなど、穏和な条件下で行うことができる。また、エンカルバメートとアルデヒドとの混合比はエンカルバメート１当量に対してアルデヒド０．５〜１０当量程度加えればよく、また［リン、窒素］−配位子ならびにロジウム錯体の混合量は、エンカルバメート１当量に対して０．５〜１０mol%の範囲で選択すればよい。 The addition reaction of enecarbamate and aldehyde in the presence of the above [phosphorus, nitrogen] -ligand and rhodium complex is not particularly required to be carried out in a special solvent or atmosphere. Can be carried out under mild conditions such that the reaction proceeds at -20 ° C to 40 ° C. The mixing ratio of enecarbamate and aldehyde may be about 0.5 to 10 equivalents of aldehyde with respect to 1 equivalent of enecarbamate, and the mixing amount of [phosphorus, nitrogen] -ligand and rhodium complex is enecarbamate. What is necessary is just to select in the range of 0.5-10 mol% with respect to 1 equivalent.
上記の方法によって、エンカルバメートとアルデヒドから、高ジアステレオ選択的かつ高エナンチオ選択的に、光学活性なβ−ヒドロキシイミン化合物を製造することができる。 By the above method, an optically active β-hydroxyimine compound can be produced from encarbamate and aldehyde with high diastereoselectivity and high enantioselectivity.
本発明にかかる反応では、エンカルバメートが次式（VI−Ａ）（Ｒ２は水素原子以外を表す）で表されるＥ−体であるときは、次式（VII−Ａ）（Ｘはイミノ基を示す）で表されるｓｙｎ−体のアルドール付加体が主生成物として得られる。
以下に実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.
得られた残渣をエタノール（3 ml）に溶かし、47%臭化水素酸水溶液（0.3 ml）を加え、室温下９０秒撹拌した。続いて、氷冷下飽和炭酸水素ナトリウム水溶液を加え、室温に戻した後、酢酸エチルで3回抽出した。有機相を飽和食塩水で1回洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去後、得られた残渣を分取用シリカゲル薄層クロマトグラフィー（展開溶媒： ベンゼン：アセトン = 4：1）で精製し、β−ヒドロキシカルボニル化合物である (S)-エチル 2-ヒドロキシ-4-オキソ-4-フェニルブタナート式（Ｘ）{(33.2 mg、75.8%収率、64.3% ee (S)}を得た。光学純度はキラルＨＰＬＣにより決定した。HPLC：Daicel Chiralpak ADH, hexane/ｉPrOH = 4/1, flow rate = 0.5 mL/min：tＲ = 19.9 min (S), tＲ = 22.2 min (R)
このものをエタノール(3 ml) に溶解し、47%臭化水素酸水溶液（0.3 ml）を加え、室温下９０秒間撹拌した。続いて、氷冷下飽和炭酸水素ナトリウム水溶液を加え、室温に戻した後、酢酸エチルで3回抽出した。有機相を飽和食塩水で1回洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去後、得られた残渣を分取用シリカゲル薄層クロマトグラフィー（展開溶媒：ベンゼン：アセトン = 4：1）で精製し、β−ヒドロキシカルボニル化合物である(2S)-2-ヒドロキシ-3-メチル-4-オキソ-4-フェニルブタン酸エチルエステルをジアステレオマー混合物として得た。ジアステレオマー比及び光学純度はキラルＨＰＬＣにより決定した。{(33.2 mg、76%収率、シン／アンチ＝９７／３、光学純度：64%ee(syn) }。 HPLC：Daicel Chiralpak ADH, hexane/ｉPrOH = 4/1, flow rate = 0.5 mL/min：tＲ = 19.9 min (2S,3S), tＲ = 22.2 min (2R,3R)
(2S)-2-Hydroxy-3-methyl-4-oxo-4-phenyl-butyric acid ethyl ester (5f, syn/anti mixture): １H NMR syn (CDCl３) δ = 1.26 (t, 3H, J = 7.0 Hz), 1.29 (d, 3H, J = 7.0 Hz), 3.28 (br, 1H), 3.93 (dq, 1H, J = 4.2, 7.0 Hz), 4.25 (q, 2H, J = 7.0 Hz), 4.58 (d, 1H, J = 4.2 Hz), 7.40-7.65 (m, 3H), 7.90-8.05 (m, 2H); anti (CDCl３) δ = 1.20 (t, 3H, J = 7.1 Hz), 1.36 (d, 3H, J = 7.3 Hz), 3.61 (d, 1H, J = 8.3 Hz), 3.98 (dq, 1H, J = 4.6, 7.1 Hz), 4.10-4.25 (m, 2H), 4.39 (dd, 1H, J = 4.6, 8.3 Hz), 7.40-7.65 (m, 3H); １３C NMR syn (CDCl３) δ = 12.1, 14.0, 44.3, 61.9, 71.6, 128.4, 128.7, 133.3, 135.7, 173.1, 201.6; anti (CDCl３) δ = 14.0, 14.1, 44.0, 61.5, 73.1, 128.3, 128.7, 133.4, 135.9, 173.1; IR (neat) syn 3480, 3063, 2978, 2936, 1734, 1678, 1596, 1579, 1449, 1369, 1217, 1133, 1062, 1023, 1001, 975, 952, 862, 794, 708; anti 3481, 3059, 2981, 2941, 1738, 1685, 1588, 1454, 1372, 1255, 1209, 1144, 1092, 1024, 973, 701 cm−１; HRMS (FAB); Exact mass calcd for Ｃ１３Ｈ１７Ｏ４ [M+H]＋, 237.1127. Found 237.1118.; HPLC, Daicel Chiralcel AS + ADH + AD, hexane/ｉPrOH = 4/1, flow rate = 0.5 mL/min : tＲ = 46.7 min (2S, 3S), tＲ = 50.6 min (2R, 3R), tＲ = 54.3 min (2S, 3R), tＲ = 61.9 min (2R, 3S).
This was dissolved in ethanol (3 ml), 47% aqueous hydrobromic acid solution (0.3 ml) was added, and the mixture was stirred at room temperature for 90 seconds. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling, the mixture was returned to room temperature, and extracted three times with ethyl acetate. The organic phase was washed once with saturated brine and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by preparative silica gel thin layer chromatography (developing solvent: benzene: acetone = 4: 1) to give (2S) -2-hydroxy which is a β-hydroxycarbonyl compound. -3-Methyl-4-oxo-4-phenylbutanoic acid ethyl ester was obtained as a diastereomeric mixture. The diastereomeric ratio and optical purity were determined by chiral HPLC. {(33.2 mg, 76% yield, syn / anti = 97/3, optical purity: 64% ee (syn)}. HPLC: Daicel Chiralpak ADH, hexane / i PrOH = 4/1, flow rate = 0.5 mL / min: t R = 19.9 min (2S, 3S), t R = 22.2 min (2R, 3R)
(2S) -2-Hydroxy-3-methyl-4-oxo-4-phenyl-butyric acid ethyl ester (5f, syn / anti mixture): 1 H NMR syn (CDCl 3 ) δ = 1.26 (t, 3H, J = 7.0 Hz), 1.29 (d, 3H, J = 7.0 Hz), 3.28 (br, 1H), 3.93 (dq, 1H, J = 4.2, 7.0 Hz), 4.25 (q, 2H, J = 7.0 Hz), 4.58 (d, 1H, J = 4.2 Hz), 7.40-7.65 (m, 3H), 7.90-8.05 (m, 2H); anti (CDCl 3 ) δ = 1.20 (t, 3H, J = 7.1 Hz), 1.36 (d, 3H, J = 7.3 Hz), 3.61 (d, 1H, J = 8.3 Hz), 3.98 (dq, 1H, J = 4.6, 7.1 Hz), 4.10-4.25 (m, 2H), 4.39 (dd, 1H, J = 4.6, 8.3 Hz), 7.40-7.65 (m, 3H); 13 C NMR syn (CDCl 3 ) δ = 12.1, 14.0, 44.3, 61.9, 71.6, 128.4, 128.7, 133.3, 135.7, 173.1, 201.6 ; anti (CDCl 3 ) δ = 14.0, 14.1, 44.0, 61.5, 73.1, 128.3, 128.7, 133.4, 135.9, 173.1; IR (neat) syn 3480, 3063, 2978, 2936, 1734, 1678, 1596, 1579, 1449 , 1369, 1217, 1133, 1062, 1023, 1001, 975, 952, 862, 794, 708; anti 3481, 3059, 2981, 2941, 1738, 1685, 1588, 1454, 1372, 1255, 1209, 1144, 1092, 1024, 973, 701 cm -1 ; HRMS (FAB); Exact mass calcd for C 13 H 17 O 4 [M + H] + , 237.1127. Found 237.1118 .; HPLC, Daicel Chiralcel AS + ADH + AD, hexane / i PrOH = 4/1, flow rate = 0.5 mL / min: t R = 46.7 min (2S, 3S ), t R = 50.6 min (2R, 3R), t R = 54.3 min (2S, 3R), t R = 61.9 min (2R, 3S).
Claims (6)
The production method according to claim 1, wherein the rhodium complex is bis (1,5-cyclooctadiene) -μ, μ′-dichloro dirhodium.
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| CN109503660A (en) * | 2018-12-25 | 2019-03-22 | 华东师范大学 | The chiral monophosphorus catalyst Le-Phos of a kind of cyclic phosphines skeleton and its preparation method and application of full configuration |
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| WO2005070864A1 (en) * | 2004-01-23 | 2005-08-04 | Japan Science And Technology Agency | METHOD OF ENANTIOMETRICALLY SELECTIVE NUCLEOPHILIC ADDITION REACTION TO CARBONYL OF ENAMIDE AND METHOD OF SYNTHESIZING OPTICALLY ACTIVE α-HYDROXY-Ϝ-KETO ACID ESTER AND HYDROXYDIKETONE |
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| WO2005070864A1 (en) * | 2004-01-23 | 2005-08-04 | Japan Science And Technology Agency | METHOD OF ENANTIOMETRICALLY SELECTIVE NUCLEOPHILIC ADDITION REACTION TO CARBONYL OF ENAMIDE AND METHOD OF SYNTHESIZING OPTICALLY ACTIVE α-HYDROXY-Ϝ-KETO ACID ESTER AND HYDROXYDIKETONE |
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| CN109503660A (en) * | 2018-12-25 | 2019-03-22 | 华东师范大学 | The chiral monophosphorus catalyst Le-Phos of a kind of cyclic phosphines skeleton and its preparation method and application of full configuration |
| CN109503660B (en) * | 2018-12-25 | 2020-12-22 | 华东师范大学 | A class of chiral monophosphine catalysts with cyclic phosphine skeleton Le-Phos and its preparation method and application |
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