Chiral aminated sulfoxide and preparation method thereof
阅读说明：本技术 一种手性胺化亚砜及其制备方法 (Chiral aminated sulfoxide and preparation method thereof ) 是由 何川 刘文坛 于 2020-06-12 设计创作，主要内容包括：本发明属于有机合成领域,公开了一种手性胺化亚砜,其具有通式Ⅰ的结构：<Image he="390" wi="428" file="DDA0002537332900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sup>1</Sup>和R<Sup>2</Sup>各自独立地选自以下结构之一：氢、烷基、烷氧基、酯基、三氟甲基、三氟甲氧基、三氟甲硫基、<Image he="90" wi="328" file="DDA0002537332900000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>卤素、炔基、烯基、氨基、氰基、羟基、醛基、羧基、硝基、酰胺基；苯环,且与相连的苯环稠环成萘；R<Sup>3</Sup>选自以下结构之一：苯基,任选取代的苯基,芳基,杂芳基,苯乙烯基,烷基,卤代烷基等。本发明还公开了手性胺化亚砜的制备方法,以叔丁基环戊二烯基的金属铱配合物,与修饰的手性脯氨酸形成络合物,对映选择性的诱导亚砜的C–H键活化,得到手性亚砜。本发明的合成方法收率高,对映选择性好,所得到的酰胺化亚砜可以衍生化得到手性配体。(The invention belongs to the field of organic synthesis, and disclosesA chiral aminated sulfoxide is disclosed having the structure of formula I: wherein R is 1 And R 2 Each independently selected from one of the following structures: hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and mixtures thereof, Halogen, alkynyl, alkenyl, amino, cyano, hydroxyl, aldehyde, carboxyl, nitro, amide; benzene rings, which are fused together with the connected benzene rings to form naphthalene; r 3 Selected from one of the following structures: phenyl, optionally substituted phenyl, aryl, heteroaryl, styryl, alkyl, haloalkyl, and the like. The invention also discloses a preparation method of the chiral aminated sulfoxide, which comprises the steps of forming a complex by using the metal iridium complex of the tert-butyl cyclopentadienyl and the modified chiral proline, and carrying out enantioselective induction of the C-H bond activation of the sulfoxide to obtain the chiral sulfoxide. The synthesis method has high yield and good enantioselectivity, and the obtained amidated sulfoxide can be derivatized to obtain a chiral ligand.)
1. A chiral aminated sulfoxide compound having the structure of formula i:
wherein R is 1And R2Each independently selected from one of the following structures:
hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and mixtures thereof,
benzene rings fused together with the attached benzene rings to form a naphthalene,
R3selected from one of the following structures:
a phenyl group,
an optionally substituted phenyl group, wherein the phenyl group is substituted,
an aryl group, a heteroaryl group,
(ii) a heteroaryl group, wherein,
the amount of the styryl group is,
an alkyl group, a carboxyl group,
a halogenated alkyl group,
2. a compound of claim 1, wherein R is1And R2Each independently selected from one of the following structures:
hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and mixtures thereof,
a benzene ring, and a fused ring with the attached benzene ring forms a naphthalene.
3. A compound of claim 2, wherein R is1And R2Each independently selected from one of the following structures:
hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, -CO2Me, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and any of the foregoing,Halogen;
a benzene ring, and a fused ring with the attached benzene ring forms a naphthalene.
4. A compound of claim 1, wherein R is 3Selected from one of the following structures:
a phenyl group,
alkyl, alkoxy, halogen or nitro substituted phenyl,
a naphthyl group,
a benzofuranyl group, a thienyl group,
the amount of the styryl group is,
an alkyl group, a carboxyl group,
a halogenated alkyl group,
5. a compound of claim 4, wherein R is3Selected from one of the following structures:
a phenyl group,
methyl-, methoxy-, iodo-or nitro-substituted phenyl,
a naphthyl group,
a benzofuranyl group, a thienyl group,
the amount of the styryl group is,
methyl, methyl,
6. The compound according to claim 1, characterized in that it is selected from one of the following compounds:
7. a process for the preparation of a compound according to any one of claims 1 to 6, comprising the steps of: the ligand and iridium complex are used as catalysts, silver salt is added, and the compound of the formula A and the compound of the formula B react as follows
R1、R2、R3As defined in claims 1 to 6;
the ligand is at least one of Phth, Boc or Piv protected phenylalanine, valine, leucine, isoleucine, tertiary leucine, proline, 2-methyl proline, glutamic acid, glycine, alanine, methionine, tryptophan, tyrosine, serine and threonine;
the iridium complex has a structure of
R4、R5、R6、R7、R8Each independently selected from hydrogen, methyl, isopropyl, tert-butyl, cyclohexyl.
8. The method according to claim 7, wherein the ligand is at least one selected from the group consisting of Phth, Boc, and Piv-protected phenylalanine, valine, leucine, isoleucine, tert-leucine, and proline.
9. The method of claim 8, wherein the ligand is selected from at least one of the following compounds:
the iridium complex is selected from at least one of the following compounds:
the silver salt is AgSbF6And/or AgBF4。
10. The method according to any one of claims 7 to 9, wherein the ligand is used in an amount of at least 25 mol%, the iridium complex is used in an amount of at least 5 mol%, and the silver salt is used in an amount of at least 20 mol%; acetonitrile, ethyl acetate, toluene, tetrahydrofuran, methanol, diethyl ether, dichloromethane, dichloroethane or methyl tert-butyl ether are used as solvents in the reaction; the molar ratio of the compound of formula A to the compound of formula B is 1: (1-3); the reaction temperature is room temperature, and the reaction time is at least 24 h.
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to chiral aminated sulfoxide and a preparation method thereof.
Background
Achieving enantioselective functionalization of C-H bonds is one of the most attractive targets of modern synthetic chemistry. Despite the significant advances in transition metal catalysis over the past decade, enantioselective C-H bond functionalization is still in the infancy and the design of more efficient chiral metal catalysts and the development of new reaction pathways is emerging. In these processes, higher transition metals, in particular Pd (II), Rh (III), have become customary catalysts for the enantioselective C-H bond activation.
The project organization work of the Yujinquan developed mono-protected amino acids (MPAA) and related ligands to achieve a series of Pd (II) -catalyzed enantioselective C-H functionalization reactions. Meanwhile, chiral cyclopentadienyl (Cp) coordinated group 9 d6(especially trivalent rhodium) metal catalysts have also become a powerful tool for enantioselective C-H functionalization reactions. In contrast, however, similar studies of other metals have been rarely reported.
The chiral center of sulfur atom is widely existed in biological molecules and plays an important role in chemical transformation of biological metabolism. In particular, chiral sulfoxides are critical to the function of many important pharmaceutical and biologically active compounds on the market. In addition, due to high optical stability, chiral sulfoxides are widely used as chiral auxiliaries or ligands in asymmetric catalysis. Traditional strategies for synthesizing chiral sulfoxides rely primarily on chiral resolution, diastereoselective conversion, and biocatalysis, but the scope of application and efficiency of these methods is still limited.
Therefore, there is a need to develop a novel method for synthesizing chiral sulfoxides.
Disclosure of Invention
The invention aims to provide a chiral aminated sulfoxide compound with a novel structure.
Another object of the present invention is to provide a process for the preparation of the chiral aminated sulfoxide compound.
In order to achieve one of the purposes, the invention adopts the following technical scheme:
a chiral aminated sulfoxide compound having the structure of formula i:
wherein R is1And R2Each independently selected from one of the following structures:
hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and mixtures thereof,
benzene rings fused together with the attached benzene rings to form a naphthalene, wherein the structural formula of the compound is
R1And R2The substituent of the benzene ring may be mono-substituted or poly-substituted.
R3Selected from one of the following structures:
a phenyl group,
an optionally substituted phenyl group, wherein the phenyl group is substituted,
an aryl group, a heteroaryl group,
(ii) a heteroaryl group, wherein,
the amount of the styryl group is,
an alkyl group, a carboxyl group,
a halogenated alkyl group,
further, said R1And R2Each independently selected from one of the following structures:
hydrogen, alkyl, alkoxy, ester, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and mixtures thereof,
a benzene ring, and a fused ring with the attached benzene ring forms a naphthalene.
Further, said R1And R2Each independently selected from one of the following structures:
hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, -CO2Me, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and any of the foregoing,
a benzene ring, and a fused ring with the attached benzene ring forms a naphthalene.
Further, said R1And R2Each independently selected from one of the following structures:
hydrogen, methyl, tert-butyl, methoxy, -CO2Me, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and any of the foregoing,
a benzene ring, and a fused ring with the attached benzene ring forms a naphthalene.
Further, said R3Selected from one of the following structures:
a phenyl group,
alkyl, alkoxy, halogen, nitro, alkynyl, alkenyl, phenyl, cyano, hydroxyl, aldehyde, carboxyl, ester or trifluoromethyl substituted phenyl,
a naphthyl group,
a benzofuranyl group, a thienyl group,
the amount of the styryl group is,
an alkyl group, a carboxyl group,
a halogenated alkyl group,
further, said R3Selected from one of the following structures:
a phenyl group,
alkyl, alkoxy, halogen or nitro substituted phenyl,
a naphthyl group,
a benzofuranyl group, a thienyl group,
the amount of the styryl group is,
an alkyl group, a carboxyl group,
a halogenated alkyl group,
Further, said R3Selected from one of the following structures:
a phenyl group,
methyl-, methoxy-, iodo-or nitro-substituted phenyl,
a naphthyl group,
a benzofuranyl group, a thienyl group,
the amount of the styryl group is,
methyl, methyl,
Further, the chiral aminated sulfoxide compound is selected from one of the following compounds:
a preparation method of the compound comprises the following steps: the ligand and iridium complex are used as catalysts, silver salt is added, and the compound of the formula A and the compound of the formula B react as follows
R1、R2、R3As defined above;
the ligand is at least one of Phth, Boc or Piv protected phenylalanine, valine, leucine, isoleucine, tertiary leucine, proline, 2-methyl proline, glutamic acid, glycine, alanine, methionine, tryptophan, tyrosine, serine and threonine;
the iridium complex has a structure of
R4、R5、R6、R7、R8Each independently selected from hydrogen, methyl, isopropyl, tert-butyl, cyclohexyl.
Further, the ligand is at least one of Phth, Boc or Piv protected phenylalanine, valine, leucine, isoleucine, tertiary leucine and proline.
Further, the iridium complex has a structure of
R4Selected from hydrogen or methyl, R 5Selected from hydrogen, methyl, isopropyl, tert-butyl, cyclohexyl, R6Selected from hydrogen or methyl, R7Selected from hydrogen or methyl, R8Selected from methyl or tert-butyl.
Further, the ligand is selected from at least one of the following compounds:
abbreviation N-Boc-Ile-OH;abbreviation N-Boc-Tle-OH;
the abbreviation N-Piv-Me-Pro-OH.
The iridium complex is selected from at least one of the following compounds:
the silver salt is AgSbF6And/or AgBF4。
Further, the ligand is used in an amount of at least 25 mol%, the iridium complex is used in an amount of at least 5 mol%, and the silver salt is used in an amount of at least 20 mol%. The amounts of ligand, iridium complex, silver salt are based on the amount of starting compound of formula A, for example, the amount of ligand is written as 25 mol%, meaning that 0.25mol of ligand is used per 1mol of compound of formula A; the amount of iridium complex used is written in the form of 5 mol%, meaning that 0.05mol of iridium complex is used per 1mol of compound of the formula A; the amount of silver salt used is written in the form of 20 mol%, meaning that 0.20mol of silver salt is used per 1mol of compound of the formula A.
Further, the reaction uses acetonitrile, ethyl acetate, toluene, tetrahydrofuran, methanol, diethyl ether, dichloromethane, dichloroethane or methyl tert-butyl ether as a solvent.
Further, the reaction uses dichloroethane as a solvent.
Further, the molar ratio of the compound of formula a to the compound of formula B is 1: (1-3).
Further, the molar ratio of the compound of formula a to the compound of formula B is 1: 1.1.
further, the temperature of the reaction is room temperature.
Further, the reaction time is at least 24 h.
As used herein, "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art that, for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, not readily synthesized, and/or inherently unstable.
As used herein, "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a (substituent) selected from the designated group, provided that the designated atom's normal valence is not exceeded. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to mean a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into a reagent that has at least practical use.
The "substitution" of the "substituted phenyl" as used herein is a mono-substitution or a poly-substitution, and includes the case where the substituent is an alkyl group and forms a ring. For example, "substituted phenyl" includes three possibilities: (1) the benzene ring has a substituent; (2) the benzene ring has two or more same or different substituents; (3) mechanisms in which two adjacent alkyl or hydroxy groups of the benzene ring form a ring to form a benzo-polycyclic ring, e.g.
As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.
As used herein, "alkenyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from an adjacent carbon atom of the parent alkyl group. Alkenyl groups having 2 to 20 carbon atoms are preferred, and alkenyl groups having 2 to 6 carbon atoms are more preferred. The groups may be in either the cis or trans configuration with respect to one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl.
As used herein, "alkynyl" refers to an unsaturated, branched or straight chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl group. Alkynyl groups having 2 to 20 carbon atoms are preferred, and alkynyl groups having 3 to 6 carbon atoms are more preferred. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, e.g. but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl.
As used herein, "alkoxy" refers to-O- (alkyl), wherein alkyl is defined as described herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy.
As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine.
As used herein, "hydroxy" refers to the group-OH.
As used herein, "aldehyde" refers to the group-CHO.
As used herein, "carboxy" refers to the group-COOH.
As used herein, "ester group" refers to-C (O) O (alkyl) or-C (O) O (phenyl), wherein alkyl, phenyl are as defined herein. For the ester-substituted phenyl group, it may be formed either from the phenolic hydroxyl group of the phenyl ring and a carboxylic acid, such as PhOCOCH 3PhOPiv, or from the carboxyl group of the phenyl ring with an alcohol, e.g. PhCOOCH3。
As used herein, "cyano" refers to-CN.
As used herein, "trifluoromethyl" refers to-CF3。
As used herein, "trifluoromethoxy" refers to-OCF3。
As used herein, "trifluoromethylthio" means-SCF3。
As used herein, "nitro" refers to-NO2。
As used herein, "phenyl" refers to
"naphthyl" as used herein refers to
As used herein, "amino" refers to-NH2。
As used herein, "amido" refers to the group-CONRbRcWherein R isbSelected from H hydrogen, alkyl, RcSelected from alkyl groups; or RbAnd RcAnd the nitrogen to which they are attached, form an optionally substituted 5-to 8-membered nitrogen-containing heterocycloalkyl group optionally containing 1 or 2 additional heteroatoms selected from O, N and S in the heterocycloalkyl ring. Alkyl groups are defined herein.
As used herein, "aryl" refers to a 6-membered carbocyclic aromatic ring other than phenyl, including bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane, and 1,2,3, 4-tetrahydronaphthalene; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as fluorene.
For example, aryl includes a 6-membered carbocyclic aromatic ring fused to a 5-to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused bicyclic ring systems in which only one ring is a carbocyclic aromatic ring, the point of attachment may be on the carbocyclic aromatic ring or the heterocycloalkyl ring. Divalent groups that form self-substituted benzene derivatives and have a free valence at the ring atom are referred to as substituted phenylene groups. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in a "radical" by removal of one hydrogen atom from a carbon atom having a free valence are named by adding a "ene" to the name of the corresponding monovalent radical, e.g., a naphthyl radical having two points of attachment is called naphthylene. However, aryl does not in any way include or overlap with heteroaryl, which is individually defined below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl rather than aryl, as defined herein.
As used herein, "heteroaryl" refers to:
a 5-to 7-membered aromatic monocyclic ring containing one or more (e.g., 1 to 4, or in certain embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms being carbon;
a bicyclic heterocycloalkyl ring containing one or more (e.g., 1 to 4, or in certain embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms being carbon, and wherein at least one heteroatom is present in the aromatic ring;
and tricyclic heterocycloalkyl rings containing one or more (e.g., 1 to 5, or in certain embodiments 1 to 4) heteroatoms selected from N, O and S and the remaining ring atoms are carbon, and wherein at least one heteroatom is present in the aromatic ring;
for example, heteroaryl includes a 5-to 7-membered heterocycloalkyl aromatic ring fused with a 5-to 7-membered cycloalkyl or heterocycloalkyl ring. For such fused bicyclic heteroaryl ring systems wherein only one ring contains one or more heteroatoms, the point of attachment may be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.
Examples of heteroaryl groups include, but are not limited to (numbered from the attachment position designated as position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 3-pyrazolinyl, 2, 4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, and 5,6,7, 8-tetrahydroisoquinolinyl. Divalent radicals derived from monovalent heteroaryl radicals whose name ends with "radical" by removing one hydrogen atom from the atom having a free valence are named by adding "ene" to the name of the corresponding monovalent radical, e.g., a pyridyl radical having two points of attachment is pyridylene. Heteroaryl does not include or overlap with aryl, cycloalkyl or heterocycloalkyl, as defined herein.
As used herein "Styryl group means
"haloalkyl" as used herein refers to an alkyl substituted with one or more halogens, wherein halogen, alkyl are as defined herein.
As used herein, the following words and phrases are generally intended to have the meanings as set forth below, except where the context in which they are used indicates otherwise.
The following abbreviations and terms have the indicated meanings throughout:
piv means pivaloyl; phth refers to phthalimido; boc means tert-butoxycarbonyl; ph denotes phenyl; DCE refers to dichloroethane; cy means cyclohexyl; HFIP refers to hexafluoroisopropanol; ac means acetyl.
The invention has the following beneficial effects:
1. the invention provides an effective and direct method for constructing a sulfur chiral center, which selects cyclopentadienyl metal iridium complex to form a complex with chiral amino acid, can enantioselectively induce C-H bond activation of sulfoxide, and obtains the chiral sulfoxide through asymmetric and parallel kinetic resolution. The key to the success of the highly enantioselective conversion is the use of an Ir (III) catalyst with tert-butylcyclopentadienyl and Piv protected methyl substituted proline as ligand.
2. Dibenzyl sulfoxide and bisoxazolone substrates having various substituents are compatible with this synthesis method to obtain a variety of functionalized sulfoxide compounds containing amide substituents in high yields and enantioselectivities.
3. The resulting amidated sulfoxides can be derivatized to form various types of chiral sulfoxide frameworks and used as chiral bidentate and tridentate ligands for asymmetric catalysis.
Detailed Description
All reactions were carried out under an inert atmosphere unless otherwise stated, and reagents were purchased at the highest commercial quality and used without further purification. The reaction was monitored by Thin Layer Chromatography (TLC) on pre-coated silica gel 60F254 plates,and developed using UV light (254nm) with I2Or basic KMnO4Chemical dyeing is carried out, and the silica gel column chromatography uses GENERAL-REAGENT silica gel (200-300 and 300-400 meshes). Nuclear Magnetic Resonance (NMR) spectra were recorded at ambient temperature using either a Bruker DPX 400(400MHz) or Bruker DPX 600(600MHz) instrument and calibrated using residual non-deuterated solvent as internal reference (CDCl)3：1H NMR＝7.26ppm，13C NMR 77.16 ppm). s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, m represents a multiplet, and br represents a broad peak. High Resolution Mass Spectra (HRMS) were recorded by electrospray ionization (ESI) on an Agilent technologies 6230TOF LC/MS spectrometer. HPLC analysis was carried out using Agilent1260Infinity II, chiral columns IG, IA, IC, OD-H from Daicel. Optical rotation was measured with a Rudolph automated polarimeter.