CN109293700B - Chiral diphosphine ligand, preparation method, intermediate and application thereof - Google Patents

Chiral diphosphine ligand, preparation method, intermediate and application thereof Download PDF

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CN109293700B
CN109293700B CN201811320212.2A CN201811320212A CN109293700B CN 109293700 B CN109293700 B CN 109293700B CN 201811320212 A CN201811320212 A CN 201811320212A CN 109293700 B CN109293700 B CN 109293700B
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CN109293700A (en
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汤文军
付文振
刘国都
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Shanghai Institute of Organic Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
    • B01J31/2471—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom
    • C—CHEMISTRY; METALLURGY
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a chiral diphosphine ligand, a preparation method, an intermediate and application thereof. The chiral diphosphine ligand has a structure shown in formula I. Compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.

Description

Chiral diphosphine ligand, preparation method, intermediate and application thereof
Technical Field
The invention relates to a chiral diphosphine ligand, a preparation method, an intermediate and application thereof.
Background
Transition metal-catalyzed coupling of alkynal and alkynone has become an effective method for the efficient construction of allyl alcohol derivatives in current organic chemistry. Recent developments in such reactions have greatly expanded their scope and application by the use of various transition metal catalysts, such as Ti, Ni, Rh, Ir, Ru and Pd, in combination with various coupling components and reducing or alkylating agents. Of these, the nickel-catalyzed coupling reactions of the pi system, pioneered by Mori, Montgomery and Jamison, are particularly attractive because of the wide substrate range and good functional group compatibility of the reactions developed. However, enantioselective cyclisation of these substrates, in particular with regard to the construction of enantioselective cyclisation of chiral tertiary alcohols, has been poorly reported. The synthesis of chiral tertiary alcohols is more difficult because asymmetric addition of ketones (tetra-substituted carbon synthesis) is generally more challenging than addition of aldehydes. Furthermore, nickel catalytic reactions are typically at fairly high catalytic loadings (5 to 30 mol% Ni catalyst), which makes them less "green" for the utility of nickel catalytic synthesis. Thus, the development of efficient enantioselective nickel-catalyzed reactions remains one of the major challenges for synthetic chemists.
Pyrrole and piperidine are important components in organic synthesis, and polysubstituted pyrrole and piperidine derivatives are widely present in the structure of biologically active natural products and drugs. Generally, their optically active forms can enhance their biological activity. However, methods for the efficient synthesis of chirally substituted pyrroles and piperidines remain limited. Over the last two decades, scientists have developed a number of metal-catalyzed cyclizations to construct functionalized pyrrole and piperidine derivatives. However, the catalysts for the enantioselective cyclization reaction of N-alkynone in the prior art still have the technical problems of low yield, low enantioselectivity, low catalytic efficiency, large dosage of transition metal and the like.
Disclosure of Invention
The technical problems to be solved by the invention are that the catalyst for the enantioselective cyclization reaction of N-alkynone in the prior art has low yield, low enantioselectivity, low catalytic efficiency or large use amount of transition metal, and further, the invention provides a chiral diphosphine ligand, a preparation method, an intermediate and application thereof. Compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.
The invention provides a compound shown as a formula I:
Figure BDA0001857318070000021
wherein R is1And R1’Each independently is C1-C10An alkyl group;
R2、R3、R4、R5and R6Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,
Figure BDA0001857318070000022
Or C6-C20An aryl group; or, R2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics;
R2’、R3’、R4’、R5’and R6’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,
Figure BDA0001857318070000023
Or C6-C20An aryl group; or, R2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 6-10 membered heteroaromatics;
each R10Independently is C1-C4An alkyl group; each R11Independently is C1-C4An alkyl group;
each heteroatom in the 5-10 membered heterocycle or 5-10 membered heteroaromatic ring is independently N, O or S, the number of heteroatoms being 1,2 or 3;
Figure BDA0001857318070000024
and
Figure BDA0001857318070000025
represents the relative configuration of the P (i.e., phosphorus) atom when
Figure BDA0001857318070000026
Is composed of
Figure BDA0001857318070000027
When the temperature of the water is higher than the set temperature,
Figure BDA0001857318070000028
is composed of
Figure BDA0001857318070000029
When in use
Figure BDA00018573180700000210
Is composed of
Figure BDA00018573180700000211
When the temperature of the water is higher than the set temperature,
Figure BDA00018573180700000212
is composed of
Figure BDA00018573180700000213
When said R is1And R1’Each independently is C1-C10When alkyl, said C1-C10The alkyl groups may independently be C1-C4Alkyl groups, such as tert-butyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C1-C10When alkyl, said C1-C10The alkyl groups may independently be C1-C4Alkyl groups such as methyl, ethyl, n-propyl, isopropyl or tert-butyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C1-C10At alkoxy, said C1-C10Alkoxy may independently be C1-C4Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C3-C10When, C is said3-C10Cycloalkyl may independently be C3-C6Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’When each is independently halogen, the halogen may be independently fluorine, chlorine, bromine or iodine, for example fluorine.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is C6-C20When aryl, said C6-C20Aryl may independently be C6-C12Aryl radicals, for example phenyl.
When said R is2、R3、R4、R5、R6、R2’、R3’、R4’、R5’And R6’Each independently is
Figure BDA0001857318070000031
When it is used, the
Figure BDA0001857318070000032
Can independently be
Figure BDA0001857318070000033
When each R is10Independently is C1-C4When alkyl, said C1-C4The alkyl groups may independently be methyl groups.
When each R is11Independently is C1-C4When alkyl, said C1-C4The alkyl groups may independently be methyl groups.
When said R is2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10In the case of cycloalkanes, said C5-C10The cycloalkane may be C5-C6A cycloalkane.
When said R is2、R3、R4、R5And R6When any two adjacent groups together with the carbon atoms to which they are attached form a 6-10 membered aromatic ring, the 6-10 membered aromatic ring may be a benzene ring.
When said R is2、R3、R4、R5And R6Any two adjacent groups together with the carbon atoms to which they are attached form a 5-to 10-membered heterocyclic ring, which 5-to 10-membered heterocyclic ring may be a 5-or 6-membered heterocyclic ring, for example
Figure BDA0001857318070000034
When said R is2、R3、R4、R5And R6When any two adjacent groups together with the carbon atoms to which they are attached form a 5-10 membered heteroaromatic ring, the 5-10 membered heteroaromatic ring may be a 5-or 6-membered heteroaromatic ring.
When said R is2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form C5-C10In the case of cycloalkanes, said C5-C10The cycloalkane may be C5-C6A cycloalkane.
When said R is2’、R3’、R4’、R5’And R6’When any two adjacent groups together with the carbon atoms to which they are attached form a 6-10 membered aromatic ring, the 6-10 membered aromatic ring may be a benzene ring.
When said R is2’、R3’、R4’、R5’And R6’Any two adjacent groups together with the carbon atoms to which they are attached form a 5-to 10-membered heterocyclic ring, which 5-to 10-membered heterocyclic ring may be a 5-or 6-membered heterocyclic ring, for example
Figure BDA0001857318070000035
When said R is2’、R3’、R4’、R5’And R6’Any two of them are adjacentWhen a group and the carbon atom to which it is attached together form a 5-10 membered heteroaromatic ring, the 5-10 membered heteroaromatic ring may be a 5-or 6-membered heteroaromatic ring.
In some embodiments of the invention, R is1And R1’Each independently is C1-C10An alkyl group;
said R4、R5、R6、R4’、R5’And R6’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,
Figure BDA0001857318070000041
Or C6-C20An aryl group;
said R2And R3Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,
Figure BDA0001857318070000042
Or C6-C20An aryl group; or, said R2And R3Together with the carbon atom to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics;
said R2’And R3’Each independently is hydrogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C3-C10Cycloalkyl, halogen,
Figure BDA0001857318070000043
Or C6-C20An aryl group; or, said R2And R3Together with the carbon atom to which they are attached form C5-C10Cycloalkanes, 6-10 membered aromatic rings, 5-10 membered heterocycles or 5-10 membered heteroaromatics.
In some embodiments of the invention, R is1And R1’Each independentlyIs C1-C10An alkyl group;
said R4、R5、R6、R4’、R5’And R6’Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy or
Figure BDA0001857318070000044
Said R2And R3Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy or
Figure BDA0001857318070000045
Or, said R2And R3Together with the carbon atoms to which they are attached form a benzene ring or
Figure BDA0001857318070000046
Said R2’And R3’Each independently of the others is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, isopropoxy or
Figure BDA0001857318070000047
Or, said R2’And R3’Together with the carbon atoms to which they are attached form a benzene ring or
Figure BDA0001857318070000048
In one embodiment of the present invention, in the compound represented by formula I, the compound is
Figure BDA0001857318070000049
Is composed of
Figure BDA00018573180700000410
Said
Figure BDA00018573180700000411
Is composed of
Figure BDA00018573180700000412
In one embodiment of the invention, in the compound shown in the formula I,
Figure BDA0001857318070000051
Figure BDA0001857318070000052
each independently is
Figure BDA0001857318070000053
Figure BDA0001857318070000054
In one embodiment of the invention, in the compound shown in the formula I,
Figure BDA0001857318070000055
Figure BDA0001857318070000056
the same is true.
In one embodiment of the present invention, said R is1And R1’The same is true.
In one embodiment of the present invention, said R is1And R1’Is a tert-butyl group.
In one embodiment of the invention, in the compound shown in the formula I,
R1and R1’The same;
R1and R1’Is C1-C10An alkyl group;
Figure BDA0001857318070000057
and
Figure BDA0001857318070000058
the same;
R3、R4、R5、R3’、R4’and R5’Are all hydrogen;
R2、R6、R2’and R6’Each independently is C1-C10An alkoxy group.
The compound shown in the formula I can be selected from any one of the following structures:
Figure BDA0001857318070000061
the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of a reducing agent to obtain a compound shown as a formula I;
Figure BDA0001857318070000071
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure BDA0001857318070000072
And
Figure BDA0001857318070000073
the definitions of (A) and (B) are as described above.
In the reduction reaction, the organic solvent may be a solvent conventional in the art, such as an ethereal solvent (e.g., tetrahydrofuran).
In the reduction reaction, the amount of the organic solvent used is not particularly limited as long as the reaction is not affected.
In the reduction reaction, the reducing agent may be a reducing agent conventional in the art such as an organosilane reducing agent (e.g., polymethylhydrosiloxane). The reducing agent may be used in a conventional amount.
The reduction reaction can also be added with a dehydrating agent, and the dehydrating agent can be a titanate dehydrating agent, such as titanium tetraisopropoxide.
The reaction temperature of the reduction reaction may be 20 to 100 deg.C (e.g., 20 to 30 deg.C).
The reduction reaction is generally terminated when the compound represented by the formula II is no longer reacted.
The invention also provides a compound shown as the formula II:
Figure BDA0001857318070000074
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure BDA0001857318070000075
And
Figure BDA0001857318070000076
the definitions of (A) and (B) are as described above.
In one embodiment of the present invention, the compound represented by formula II is
Figure BDA0001857318070000081
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: in an organic solvent, carrying out the Suzuki coupling reaction shown in the specification on a compound shown in a formula III and a compound shown in a formula III-a in the presence of a palladium catalyst, a phosphine ligand and alkali to obtain a compound shown in a formula II;
Figure BDA0001857318070000082
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure BDA0001857318070000083
And
Figure BDA0001857318070000084
the definitions of (A) and (B) are as described above;
and the number of the first and second electrodes,
Figure BDA0001857318070000085
and
Figure BDA0001857318070000086
the same is true.
The conditions of the Suzuki coupling reaction may be conventional in the art, and the following conditions are preferred in the present invention.
In the Suzuki coupling reaction, the organic solvent can be an ether solvent, such as dioxane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the Suzuki coupling reaction, the palladium catalyst can be Pd2(dba)3. The palladium catalyst is used in an amount conventional in the art for such reactions.
In the Suzuki coupling reaction, the phosphine ligand can be BIDIME (namely
Figure BDA0001857318070000091
). The phosphine ligand may be used in amounts conventional in the art for such reactions.
In the Suzuki coupling reaction, the base can be potassium fluoride. The base may be used in amounts conventional in the art for such reactions.
The reaction temperature of the Suzuki coupling reaction may be in the range of 80-120 ℃ (e.g. 100 ℃).
The Suzuki coupling reaction is generally terminated when the compound shown in formula III is no longer reacted.
The invention also provides a compound shown as the formula III:
Figure BDA0001857318070000092
wherein R is1、R1’、
Figure BDA0001857318070000093
And
Figure BDA0001857318070000094
the definitions of (A) and (B) are as described above.
In one embodiment of the present invention, the compound represented by formula III is
Figure BDA0001857318070000095
The invention also provides a preparation method of the compound shown in the formula III, which comprises the following steps: in an organic solvent, mixing a compound shown as a formula IV and PhNTf2(namely N-phenyl bis (trifluoromethanesulfonimide)) is subjected to coupling reaction in the presence of alkali to obtain a compound shown in a formula III;
Figure BDA0001857318070000096
wherein R is1、R1’、
Figure BDA0001857318070000097
And
Figure BDA0001857318070000098
the definitions of (A) and (B) are as described above.
The conditions of the coupling reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the coupling reaction, the organic solvent may be a chlorinated hydrocarbon solvent, such as dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the coupling reaction, the PhNTf2The molar ratio to the compound of formula IV may be 6-10:1 (e.g., 8: 1).
In the coupling reaction, the base may be a tertiary amine base, such as triethylamine. The molar ratio of the base to the compound of formula IV may be 10-20:1 (e.g., 12: 1).
The reaction temperature of the coupling reaction may be 20-30 ℃.
The coupling reaction is generally terminated when the compound of formula IV is no longer reacted.
The invention also provides a compound shown as the formula IV:
Figure BDA0001857318070000101
wherein R is1、R1’、
Figure BDA0001857318070000102
And
Figure BDA0001857318070000103
the definitions of (A) and (B) are as described above.
In one embodiment of the present invention, the compound represented by formula IV is
Figure BDA0001857318070000104
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps: in an organic solvent, a compound shown as a formula V is added in a palladium catalyst and H2Carrying out catalytic hydrogenation reaction as shown in the specification under the existing condition to obtain a compound as shown in a formula IV;
Figure BDA0001857318070000105
wherein R is1、R1’、
Figure BDA0001857318070000106
And
Figure BDA0001857318070000107
the definitions of (A) and (B) are as described above.
The conditions for the catalytic hydrogenation reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the catalytic hydrogenation reaction, the organic solvent may be an alcohol solvent, such as methanol. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the catalytic hydrogenation reaction, the palladium catalyst can be Pd/C. The palladium catalyst may be used in an amount conventional in the art for such reactions.
The reaction temperature of the catalytic hydrogenation reaction may be 20 to 30 ℃.
The catalytic hydrogenation reaction is generally terminated when the compound represented by the formula V is not reacted.
The invention also provides a compound shown as the formula V:
Figure BDA0001857318070000111
wherein R is1、R1’、
Figure BDA0001857318070000112
And
Figure BDA0001857318070000113
the definitions of (A) and (B) are as described above.
In one embodiment of the present invention, the compound represented by formula V is
Figure BDA0001857318070000114
The invention also provides a preparation method of the compound shown as the formula V, which comprises the following steps: in an organic solvent, carrying out Ullmann coupling reaction on a compound shown as a formula VI-a and a compound shown as a formula VI-b in the presence of a palladium catalyst, a phosphine ligand, diborate and alkali to obtain a compound shown as a formula V;
Figure BDA0001857318070000115
wherein R is1、R1’、
Figure BDA0001857318070000116
And
Figure BDA0001857318070000117
the definitions of (A) and (B) are as described above.
The conditions of the Ullmann coupling reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.
In the Ullmann coupling reaction, the organic solvent may be a mixed solvent of an ether solvent and water, for example, a mixed solvent of dioxane and water (the volume ratio of dioxane to water may be 3-5:1, for example, 4: 1). The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
The Ullmann coupling reactionIn addition, the palladium catalyst can be Pd (OAc)2. The palladium catalyst may be used in an amount conventional in the art for such reactions.
In the Ullmann coupling reaction, the phosphine ligand can be Sphos (namely 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl). The phosphine ligand may be used in amounts conventional in the art for such reactions.
In the Ullmann coupling reaction, the diboronate ester can be a diboronic acid pinacol ester. The diboronic acid ester may be used in amounts conventional in the art for such reactions.
In the Ullmann coupling reaction, the base may be KOAc. The base may be used in amounts conventional in the art for such reactions.
The reaction temperature of the Ullmann coupling reaction can be 20-30 ℃.
The above-mentioned production methods may be combined as desired to give a route for producing a compound represented by the formula I, II, III, IV or V (e.g., III → II → I, IV → III → II → I, V → IV → III → II, IV → III → II, etc.).
The invention also provides the application of the compound shown in the formula I as a metal ligand in the reductive cyclization reaction shown as the following steps:
Figure BDA0001857318070000121
Figure BDA0001857318070000122
the reductive cyclization reaction comprises the following steps: reacting a compound A in an organic solvent in the presence of a compound shown as a formula I, a nickel compound and a reducing agent to obtain a compound B;
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure BDA0001857318070000123
And
Figure BDA0001857318070000124
the definitions of (A) and (B) are as described above;
n is 1 or 2;
R7is substituted or unsubstituted C6-C20Aryl (e.g. C)6-C12Aryl, also for example phenyl), substituted or unsubstituted 5-20 membered heteroaryl (e.g. 5-12 membered heteroaryl, also for example phenyl)
Figure BDA0001857318070000131
) Substituted or unsubstituted C1-C20Alkyl (e.g. C)1-C10Alkyl radicals, also as C1-C4Alkyl, e.g. tert-butyl) or substituted or unsubstituted C3-C20Cycloalkyl (e.g. C)3-C10Cycloalkyl groups);
R8is C1-C20Alkyl (e.g. C)1-C10Alkyl radicals, also as C1-C4Alkyl, again, methyl or ethyl) or substituted or unsubstituted C6-C20Aryl (e.g. C)6-C12Aryl radicals, such as phenyl radicals as well);
said substituted C6-C20Aryl, substituted 5-20 membered heteroaryl, substituted C1-C20Alkyl or substituted C3-C20The substituents in cycloalkyl are each independently halogen (e.g. fluorine or chlorine), C1-C5Haloalkyl (e.g. C)1-C5Fluoroalkyl, also as trifluoromethyl) or C1-C5Alkoxy (e.g., methoxy); the number of the substituent is one or more; when the number of the substituent is more than one, the substituent is the same or different;
R9is an amino protecting group (e.g. tert-butyloxycarbonyl, trifluoromethanesulfonyl, benzyl)Or p-toluenesulfonyl, preferably p-toluenesulfonyl).
The conditions for the reductive cyclization reaction may be conventional in the art, and the following conditions are preferred in the present invention.
In the reductive cyclization reaction, the organic solvent may be an ether solvent, such as dioxane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In the reductive cyclization reaction, the molar ratio of the compound shown as the formula I to the compound A can be 0.001-0.2: 1.
In the reductive cyclization reaction, the nickel compound may be a nickel compound conventional in this type of reaction in the art. Preferred nickel compounds having a valence of 0 according to the invention, e.g. Ni (cod)2. The molar ratio of the nickel compound to the compound A may be 0.0005 to 0.2:1, preferably 0.005 to 0.1: 1.
In the reductive cyclization reaction, the reducing agent may be an organosilane reducing agent, such as triethylsilane. The molar ratio of the reducing agent to the compound a may be 2-4:1 (e.g., 3: 1).
The reaction temperature of the reductive cyclization reaction may be 20 to 100 ℃ (e.g., 60 ℃,80 ℃).
In some embodiments of the invention, compound a is selected from any of the following structures:
Figure BDA0001857318070000141
in the present invention, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon radical having the specified number of carbon atoms, such as C1-C10Alkyl refers to alkyl groups having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups are optionally substituted with one or more substituents described herein.
In the present invention, the term "haloalkyl" means an alkyl group (as defined herein) in which one or more hydrogen atoms are replaced by halogen (as defined herein), the number of which may be one or more; when the number of the halogen is plural, the halogen may be the same or different. Examples of haloalkyl include, but are not limited to, trifluoromethyl and difluoromethyl.
In the present invention, the term "alkoxy" refers to an alkyl group (as defined herein) attached to the rest of the molecule through an oxygen bridge.
In the present invention, the term "cycloalkyl" or "cycloalkane" refers to a non-aromatic, saturated or unsaturated cyclic hydrocarbon group having the specified number of ring carbon atoms, and cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic and tricyclic), may be bicyclic, spirocyclic and bridged. Cycloalkyl groups optionally contain one or more double or triple bonds therein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl also includes polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [ 4.5 ], [5,5], [5,6] or [6,6] systems or as bridged ring systems, for example, bis [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
In the present invention, the term "heterocycle" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group formed by replacing at least one ring carbon atom in a cycloalkane (as defined herein) with a heteroatom selected from N, O and S.
In the present invention, the term "aryl" or "aromatic ring" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl, or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.
In the present invention, the term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom selected from O, N and S. Heteroaryl groups may be attached to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl.
In the present invention, the term "halogen" means F, Cl, Br, I unless otherwise specified.
In the present invention, room temperature means 20 to 30 ℃.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: compared with the phosphine ligand in the prior art, the chiral diphosphine ligand is used for the enantioselective cyclization reaction of N-alkynone, and higher yield, better enantioselectivity or lower transition metal dosage are realized.
Drawings
FIG. 1 is an X-ray crystal diffraction pattern of Compound 3a in Effect example 2.
FIG. 2 is an X-ray crystal diffraction pattern of Compound 3o in Effect example 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 preparation of (S, S) -DI-BI-DIME (L4)
Figure BDA0001857318070000161
Step 1
Figure BDA0001857318070000162
To a solution of S1(2.00g, 8.84mmol, 1.0 equiv.) and imidazole (1.20g, 17.68mmol, 2.0 equiv.) in methylene chloride (25mL) under nitrogen at room temperature was added TBDPSCl (3.20g, 11.49mmol, 1.3 equiv.). After stirring at room temperature overnight, the reaction was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/MeOH 100/1) to give S2 as a white solid (4.11g, 99%). S2: [ alpha. ]]D 25＝–8.2(c＝1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.81(dd,J＝7.7,1.5Hz,2H),7.81(dd,J＝7.7,1.5Hz,2H),7.50–7.42(m,3H),7.39–7.35(m,1H),7.34–7.29(m,2H),6.90(t,J＝8.2Hz,1H),6.39(dd,J＝8.2,1.8Hz,1H),6.02(dd,J＝8.1,3.5Hz,1H),4.56(d,J＝13.7Hz,1H),4.38(dd,J＝13.2,10.8Hz,1H),1.32(d,J＝16.0Hz,9H),1.12(s,9H)；13C NMR(126MHz,CDCl3)δ166.29(d,J＝17.6Hz),157.97(d,J＝1.5Hz),135.51(d,J＝40.3Hz),135.44(d,J＝0.8Hz),132.14(d,J＝183.7Hz),130.14(d,J＝1.9Hz),128.01(d,J＝19.6Hz),113.03(d,J＝5.8Hz),106.43(d,J＝5.4Hz),104.70(d,J＝92.8Hz),65.79(d,J＝60.0Hz),34.22(d,J＝73.2Hz),26.56,24.69(d,J＝0.8Hz),19.62；31P NMR(162MHz,CDCl3) δ 63.13; HRMS (ESI) calculated value [ M + Na, C27H33NaO3PSi]+487.1829; found 487.1832.
Step 2
Figure BDA0001857318070000171
To a solution of S2(4.10g, 8.82mmol, 1.0 eq) in DCM (90mL) under nitrogen at room temperature was added NBS (1.65g, 9.27mmol, 1.05 eq). After stirring at room temperature for 4 hours, the reaction was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (S3) was carried on to the next reaction without purification.
TBAF (13.3mL, 13.24mmol, 1.5 equiv., 1.0M in THF) was added to a solution of the above crude product (S3) in THF (20mL) at 0 deg.C and stirred at 0 deg.C for 5 min. Quenched with water, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was used without further purification.
At 0 ℃ to the above residue and K2CO3(3.66g, 26.47mmol, 3.0 equiv.) in DMF (50mL) was added dropwise benzyl bromide (1.26mL, 10.59mmol, 1.2 equiv.) under nitrogen and stirred at room temperature overnight. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 50/1) to give S4(3.3g, 95%) as a light yellow solid. S4: [ alpha ]]D 25＝–41.9(c＝1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.50(d,J＝8.6Hz,1H),7.44–7.38(m,2H),7.37–7.31(m,2H),7.31–7.26(m,1H),6.44(dd,J＝8.7,4.5Hz,1H),5.13(q,J＝12.0Hz,2H),4.60(dd,J＝14.0,3.1Hz,1H),4.48(dd,J＝14.0,10.6Hz,1H),1.21(d,J＝16.6Hz,9H)；13C NMR(126MHz,CDCl3)δ162.23(d,J＝16.7Hz),159.61(d,J＝2.1Hz),138.97(d,J＝1.3Hz),135.48,128.65,128.25,127.41,106.54(d,J＝6.2Hz),105.07(d,J＝88.2Hz),98.19(d,J＝6.9Hz),70.99,66.87(d,J＝58.4Hz),34.00(d,J＝73.6Hz),24.65(d,J＝0.8Hz)；31P NMR(162MHz,CDCl3) δ 65.18; HRMS (ESI) calculated value [ M + H, C18H21BrO3P]+395.0407; found 395.0406.
Step 3
Figure BDA0001857318070000181
S4(1.30g, 3.29mmol, 1.0 eq.), Pd (OAc) was added under nitrogen protection at room temperature2(148mg, 0.66mmol, 0.2 equiv.), Sphos (567mg, 1.38mmol, 0.42 equiv.), (BPin)2(585mg, 2.30mmol, 0.7 equiv.) and KOAc (968mg, 9.87mmol, 3.0 equiv.) were dissolved in dioxane/water (15mL, 4/1) and stirred at 80 ℃ for 24 h. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 20/1) to give S5(670mg, 65%) as a light yellow solid S5: [ alpha. ]]D 25＝–32.7(c＝1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.48–7.41(m,4H),7.40–7.33(m,6H),7.33–7.27(m,2H),6.59–6.53(m,2H),5.24–5.14(m,4H),4.51–4.33(m,4H),1.24(d,J＝16.4Hz,18H)；13C NMR(126MHz,CDCl3)δ163.71(d,J＝16.5Hz),159.85(d,J＝2.0Hz),137.77,135.99,128.66,128.15,127.45,115.06(d,J＝5.7Hz),104.77(d,J＝6.2Hz),103.35(d,J＝91.2Hz),70.78,66.31(d,J＝59.3Hz),33.78(d,J＝73.7Hz),24.79；31P NMR(162MHz,CDCl3) δ 64.88; HRMS (ESI) calculated value [ M + H, C36H41O6P2]+631.2373; found 631.2377.
Step 4
Figure BDA0001857318070000182
S5(825mg, 1.31mmol, 1.00 equiv.), Pd/C (800mg, 10%) was dissolved in MeOH (15mL), and the reaction was evacuated and filled with hydrogen (1 atmosphere). The reaction mixture was stirred under hydrogen overnight, then the reaction was filtered through celite (EtOAc eluent) to give S6 as a white solid (560mg, 95%). S6: [ alpha ]]D 25＝+12.1(c＝1.0,MeOH).1H NMR(500MHz,CD3OD)δ7.34(d,J＝8.3Hz,2H),6.51(dd,J＝8.2,4.6Hz,2H),4.69(dd,J＝14.3,3.2Hz,2H),4.28(dd,J＝14.2,10.7Hz,2H),1.30(d,J＝16.6Hz,18H)；13C NMR(126MHz,CD3OD)δ165.00(d,J＝17.0Hz),160.58(d,J＝2.3Hz),139.49,114.58(d,J＝5.9Hz),108.90(d,J＝6.8Hz),101.68(d,J＝94.2Hz),66.76(d,J＝60.7Hz),34.41(d,J＝74.0Hz),24.82；31P NMR(162MHz,CD3OD) δ 69.13; HRMS (ESI) calculated value [ M + H, C22H29O6P2]+451.1434; found 451.1432.
Step 5
Figure BDA0001857318070000191
To a solution of S6(560mg, 1.31mmol, 1.0 equiv.) in DCM at room temperature were added triethylamine (2.2mL, 15.70mmol, 12.0 equiv.) and PhNTf2(3.74g, 10.47mmol, 8.0 equiv.) and stirred at room temperature overnight. The reaction was then quenched with water, extracted with DCM, washed with saturated brine, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 50/1) to give S7(735mg, 78%) as a white solid. S7: [ alpha ]]D 25＝+15.6(c＝1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.52(d,J＝8.4Hz,2H),7.13(dd,J＝8.4,3.6Hz,2H),4.58(dd,J＝14.1,1.7Hz,2H),4.48(dd,J＝13.9,10.9Hz,2H),1.26(d,J＝16.9Hz,18H)；13C NMR(126MHz,CDCl3)δ163.39(d,J＝16.5Hz),149.76,137.48,121.04(d,J＝5.1Hz),118.58(q,J＝320.8Hz),113.75(d,J＝4.7Hz),108.45(d,J＝84.8Hz),66.54(d,J＝59.1Hz),34.47(d,J＝72.1Hz),24.08；31P NMR(162MHz,CDCl3) δ 63.67; HRMS (ESI) calculated value [ M + Na, C24H26F6NaO10P2S2]+737.0239; found 737.0240.
Step 6
Figure BDA0001857318070000201
To a nitrogen blanketed solution of S7(735mg, 1.03mmol, 1.0 equiv), (2, 6-dimethoxyphenyl) boronic acid (1.85g, 8.23mmol, 8.0 equiv) and KF (657mg, 11.3mmol, 11.0 equiv) in 10mL of ultra-dry dioxane was added Pd at room temperature2(dba)3(94mg, 0.10mmol, 0.1 equiv.) and BI-DIME (75mg, 0.23mmol, 0.22 equiv.), and stirred at 100 ℃ overnight. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM/MeOH 20/1) to give S8(700mg, 98%) as a gray solid. S8: [ alpha ]]D 25＝+48.1(c＝1.0,MeOH).1H NMR(500MHz,CDCl3)δ7.61(d,J＝7.6Hz,2H),7.33(t,J＝8.4Hz,2H),6.98(dd,J＝7.6,3.6Hz,2H),6.69(d,J＝8.4Hz,2H),6.60(d,J＝8.3Hz,2H),4.46(dd,J＝13.8,0.9Hz,2H),4.36(dd,J＝13.6,10.4Hz,2H),3.82(s,6H),3.76(s,6H),0.93(d,J＝15.9Hz,18H)；13C NMR(126MHz,CDCl3)δ162.43(d,J＝19.3Hz),158.81,157.61,137.91(d,J＝5.8Hz),135.58,130.13,125.08(d,J＝9.2Hz),121.37(d,J＝6.4Hz),117.30(d,J＝1.9Hz),114.63(d,J＝91.6Hz),104.52,103.19,65.22(d,J＝60.9Hz),56.08,55.52,33.80(d,J＝71.6Hz),23.81；31P NMR(162MHz,CDCl3) δ 62.75; HRMS (ESI) calculated value [ M + H, C38H45O8P2]+691.2584; found 691.2583.
Step 9
Figure BDA0001857318070000211
To a solution of S8(680mg, 0.98mmol, 1.0 equiv.) in THF (20mL) was added polymethylhydrosiloxane PMHS (5.4g) and titanium tetraisopropoxide (2.3mL, 7.88mmol, 8.0 equiv.) at room temperature. The mixture was stirred under reflux under nitrogen for 12 hours, then most of the THF was distilled off under vacuum. Carefully add 30% degassed NaOH solution (30mL) to the residue. Gas is released during the addition. Extracting with degassed ether and extracting with anhydrous Na2SO4Dried, filtered, concentrated under vacuum, and passed through a neutral alumina column (Et)2O elution) to give the desired product (S, S) -DI-BI-DIME (L4) as a white solid (610mg, 90%). L4: [ alpha ]]D 25＝+47.1(c＝1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.54(d,J＝7.7Hz,2H),7.31(t,J＝8.3Hz,2H),6.96–6.90(m,2H),6.68(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),4.82(dd,J＝12.6,1.4Hz,2H),4.51(dd,J＝24.7,12.5Hz,2H),3.79(s,6H),3.73(s,6H),0.81(d,J＝12.0Hz,18H)；13C NMR(126MHz,CDCl3)δ160.63,158.04,157.37,137.40(d,J＝18.4Hz),132.05,129.03,125.27(d,J＝12.8Hz),123.66(d,J＝4.5Hz),120.51,120.01,104.56,103.70,70.19(d,J＝26.1Hz),55.96(d,J＝1.7Hz),55.47,31.10(d,J＝18.6Hz),26.74(d,J＝14.5Hz)；31P NMR(162MHz,CDCl3) Delta-6.93; HRMS (ESI) calculated value [ M + H, C38H45O6P2]+659.2686; found 659.2687.
EXAMPLE 2 preparation of chain N-alkynones
Figure BDA0001857318070000212
Step 1
Figure BDA0001857318070000221
tert-Butyltosylcarbamate (17.7g, 65.3mmol, 1.0 eq.) and K2CO3(13.5g, 97.9mmol, 1.5 equiv.) is dissolved in 65mL of DMF and stirred at room temperature for 4 hours. (3-Bromopropynyl benzene (14.0g, 71.8mmol, 1.1 equiv.) is then added to the above solution and stirred at room temperature for 10 h, the reaction quenched with water, extracted with EtOAc, washed with saturated brine, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was dissolved in 60mL DCM and 20mL CF3COOH and stirred at room temperature overnight. Quench with water, EtOAc extraction, brine wash, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was recrystallized from hexanes/EtOAc to give S9 as a white solid (17.5g, 94%). S9:1H NMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.32–7.27(m,3H),7.26–7.20(m,2H),7.17–7.09(m,2H),4.63(t,J＝5.8Hz,1H),4.08(d,J＝6.1Hz,2H),2.36(s,3H)；ESI-MS:m/z 286.2[M+H]+.
step 2
Figure BDA0001857318070000222
To S2(5.0g, 17.5mmol, 1.0 equiv.), 2-bromo-1-phenylethanone (3.7g, 18.4mmol, 1.05 equiv.), Bu at 0 deg.C4NI (647.2mg, 1.75mmol, 0.1 eq.) in DMF (35mL) was added K2CO3(3.6g, 26.3mmol, 1.5 equiv.) and stirred at 0 ℃ for 1 hour. The reaction was then quenched with water, extracted with EtOAc, washed with saturated brine, and dried over Na2SO4Dried, filtered, and concentrated under vacuum. The residue was recrystallized from hexanes/EtOAc to give 1a as a white solid (6.0g, 85%). 1a:1H NMR(500MHz,CDCl3)δ8.01–7.95(m,2H),7.84–7.79(m,2H),7.63–7.57(m,1H),7.51–7.45(m,2H),7.33–7.26(m,3H),7.25–7.19(m,2H),7.12–7.07(m,2H),4.81(s,2H),4.49(s,2H),2.39(s,3H)；13C NMR(126MHz,CDCl3)δ193.46,143.90,136.12,135.00,133.92,131.69,129.79,128.92,128.64,128.24,128.22,127.80,122.07,86.33,81.67,51.99,38.41,21.60；ESI-MS:m/z 404.3[M+H]+.
preparation of chain N-alkynones 1b-1p according to the same procedure
Figure BDA0001857318070000231
1b white solid, 92% yield.1H NMR(500MHz,CDCl3)δ8.01–7.95(m,2H),7.84–7.78(m,2H),7.32–7.26(m,3H),7.25–7.20(m,2H),7.13–7.07(m,2H),6.97–6.91(m,2H),4.75(s,2H),4.47(s,2H),3.87(s,3H),2.38(s,3H)；13C NMR(126MHz,CDCl3) δ 191.95,164.15,143.87,136.20,131.74,130.67,129.79,128.62,128.25,128.07,127.87,122.20,114.12,86.28,81.79,55.67,51.75,38.42, 21.63; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1244.
Figure BDA0001857318070000232
1c white solid, 80% yield.1H NMR(500MHz,CDCl3)δ8.08–8.01(m,2H),7.85–7.77(m,2H),7.33–7.21(m,5H),7.19–7.06(m,4H),4.76(s,2H),4.47(s,2H),2.39(s,3H)；13C NMR(126MHz,CDCl3) δ 192.08,166.19(d, J-256.1 Hz),144.03,135.93,131.69,131.45(d, J-3.0 Hz),131.08(d, J-9.4 Hz),129.83,128.71,128.27,127.84,122.03,116.11(d, J-22.0 Hz),86.46,81.52,52.09,38.50, 21.61; HRMS (ESI) calculated value [ M + Na, C24H20FNNaO3S]+444.1040; found 444.1042.
Figure BDA0001857318070000233
1d white solid, 73% yield.1H NMR(500MHz,CDCl3)δ7.96–7.92(m,2H),7.82–7.78(m,2H),7.47–7.42(m,2H),7.33–7.26(m,3H),7.25–7.20(m,2H),7.13–7.06(m,2H),4.74(s,2H),4.45(s,2H),2.38(s,3H)；13C NMR(126MHz,CDCl3) δ 192.57,144.07,140.45,135.88,133.33,131.71,129.86,129.77,129.28,128.74,128.29,127.85,122.01,86.52,81.48,52.19,38.53, 21.64; HRMS (ESI) calculated value [ M + Na, C24H20ClNNaO3S]+460.0745; found 460.0745.
Figure BDA0001857318070000241
1e white solid, 64% yield.1H NMR(500MHz,CDCl3)δ8.14–8.08(m,2H),7.84–7.79(m,2H),7.76–7.71(m,2H),7.35–7.21(m,5H),7.12–7.06(m,2H),4.79(s,2H),4.46(s,2H),2.40(s,3H)；13C NMR(126MHz,CDCl3) δ 193.03,144.18,137.70,135.71,135.04(q, J ═ 32.6Hz),131.68,129.90,128.80,128.75,128.30,127.85,125.96(q, J ═ 3.6Hz),123.56(d, J ═ 272.8Hz),121.91,86.66,81.35,52.58,38.63, 21.61; HRMS (ESI) calculated value [ M + Na, C25H20F3NNaO3S]+494.1008; found 494.1009.
Figure BDA0001857318070000242
1f pale yellow solid, 92% yield.1H NMR(500MHz,CDCl3)δ7.85–7.77(m,2H),7.59–7.54(m,1H),7.54–7.48(m,1H),7.41–7.36(m,1H),7.33–7.26(m,3H),7.25–7.19(m,2H),7.17–7.07(m,3H),4.79(s,2H),4.48(s,2H),3.85(s,3H),2.39(s,3H)；13C NMR(126MHz,CDCl3) δ 193.39,160.01,143.92,136.29,136.10,131.71,129.93,129.81,128.66,128.25,127.81,122.08,120.74,120.53,112.49,86.36,81.65,55.62,52.16,38.42, 21.62; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1242.
Figure BDA0001857318070000243
1g of pale yellow solid, 86% yield.1H NMR(500MHz,CDCl3)δ7.83–7.77(m,3H),7.54–7.47(m,1H),7.31–7.26(m,3H),7.25–7.20(m,2H),7.15–7.10(m,2H),7.04–6.95(m,2H),4.83(s,2H),4.51(s,2H),3.91(s,3H),2.38(s,3H)；13C NMR(126MHz,CDCl3) δ 194.97,159.14,143.54,136.72,134.67,131.65,130.99,129.60,128.51,128.23,127.76,125.52,122.36,121.05,111.67,85.83,82.38,56.11,55.73,38.43, 21.60; HRMS (ESI) calculated value [ M + Na, C25H23NNaO4S]+456.1240; found 456.1243.
Figure BDA0001857318070000251
1h pale yellow solid, 79% yield.1H NMR(500MHz,CDCl3)δ8.27–8.21(m,1H),8.06(s,1H),7.72(d,J＝8.2Hz,2H),7.27–7.20(m,3H),7.19–7.14(m,3H),7.13–7.07(m,2H),6.99–6.93(m,2H),4.42(s,2H),4.35(s,2H),3.74(s,3H),2.25(s,3H)；13C NMR(126MHz,CDCl3) δ 188.54,143.99,137.30,136.83,135.72,131.72,129.78,128.52,128.17,127.96,126.72,123.74,123.06,122.63,122.26,113.99,109.86,86.41,81.51,53.34,38.55,33.83, 21.59; HRMS (ESI) calculated value [ M + H, C27H25N2O3S]+457.1580; found 457.1582.
Figure BDA0001857318070000252
1i white solid, 79% yield.1H NMR(500MHz,CDCl3)δ7.79–7.74(m,2H),7.32–7.24(m,5H),7.17–7.12(m,2H),4.45(s,2H),4.40(s,2H),2.39(s,3H),1.18(s,9H)；13C NMR(126MHz,CDCl3) δ 208.92,143.74,136.42,131.68,129.73,128.70,128.34,127.68,122.16,86.11,81.88,49.72,43.64,37.85,26.48, 21.60; HRMS (ESI) calculated value [ M + Na, C20H25NNaO3S]+406.1447; found 406.1447.
Figure BDA0001857318070000253
1j white solid, 82% yield.1H NMR(500MHz,CDCl3)δ7.96(d,J＝7.3Hz,2H),7.77(d,J＝8.2Hz,2H),7.59(t,J＝7.4Hz,1H),7.47(t,J＝7.7Hz,2H),7.31(d,J＝8.0Hz,2H),4.74(s,2H),4.21(s,2H),2.42(s,3H),1.94(tq,J＝7.5,2.0Hz,2H),0.90(t,J＝7.5Hz,3H)；13C NMR(126MHz,CDCl3)δ193.62,143.67,136.29,135.10,133.82,129.61,128.88,128.18,127.81,88.45,71.81,51.80,38.04,21.64,13.56, 12.27; HRMS (ESI) calculated value [ M + Na, C20H21NNaO3S]+378.1134; found 378.1138.
Figure BDA0001857318070000261
1k white solid, 86% yield.1H NMR(500MHz,CDCl3)δ8.00–7.94(m,2H),7.69–7.62(m,1H),7.56–7.49(m,2H),7.42–7.27(m,5H),5.05(s,2H),4.67(s,2H)；13C NMR(126MHz,CDCl3) δ 191.55,134.50,134.20,131.96,129.22,129.18,128.53,128.09,121.64,119.91(q, J ═ 322.3Hz),87.12,80.73,52.32, 39.89; HRMS (ESI) calculated value [ M + Na, C18H14F3NNaO3S]+404.0539; found 404.0541.
Figure BDA0001857318070000262
1l white solid, 77% yield.1H NMR(500MHz,CDCl3)δ7.96–7.89(m,2H),7.53–7.47(m,1H),7.42–7.31(m,6H),7.29–7.17(m,6H),4.01(s,2H),3.78(s,2H),3.66(s,2H)；13C NMR(126MHz,CDCl3) δ 197.52,138.03,136.23,133.35,131.92,129.50,128.65,128.55,128.45,128.43,128.32,127.59,123.21,86.29,84.21,59.58,58.38, 43.46; HRMS (ESI) calculated value [ M + H, C24H22NO]+340.1696; found 340.1699.
Figure BDA0001857318070000263
1m white solid, 75% yield.1H NMR(500MHz,CDCl3)δ8.04–7.98(m,2H),7.60(t,J＝7.4Hz,1H),7.49(t,J＝7.6Hz,2H),7.31–7.22(m,5H),5.78(d,J＝8.3Hz,1H),5.56–5.48(m,1H),3.04(dd,J＝17.1,5.8Hz,1H),2.89(dd,J＝17.0,5.1Hz,1H),1.47(s,9H)；13C NMR(126MHz,CDCl3)δ197.35,155.27,134.88,133.84,131.71,128.93,128.75,128.22,128.07,123.16, 84.17, 84.12, 80.16, 53.93, 28.45, 24.75; HRMS (ESI) calculated value [ M + Na, C22H23NNaO3]+372.1570; found 372.1573.
Figure BDA0001857318070000271
1n white solid, 90% yield.1H NMR(500MHz,CDCl3)δ7.98–7.92(m,2H),7.85–7.77(m,2H),7.59–7.52(m,1H),7.48–7.40(m,2H),7.31–7.18(m,5H),7.11–7.05(m,2H),4.44(s,2H),3.71(t,J＝7.1Hz,2H),3.45(t,J＝7.1Hz,2H),2.33(s,3H)；13C NMR(126MHz,CDCl3) δ 198.10,143.65,136.47,135.61,133.42,131.53,129.61,128.68,128.45,128.13,128.07,127.83,122.11,85.58,82.31,42.82,39.01,38.57, 21.44; HRMS (ESI) calculated value [ M + H, C25H24NO3S]+418.1471; found 418.1465.
Figure BDA0001857318070000272
White solid, 80% yield 1 o.1H NMR(500MHz,CDCl3)δ7.95(dd,J＝8.3,1.1Hz,2H),7.76(d,J＝8.3Hz,2H),7.59–7.54(m,1H),7.46(t,J＝7.7Hz,2H),7.29(d,J＝8.0Hz,2H),4.15(t,J＝2.2Hz,2H),3.60(t,J＝7.3Hz,2H),3.39(t,J＝7.3Hz,2H),2.41(s,3H),1.92(qt,J＝7.5,2.2Hz,2H),0.89(t,J＝7.5Hz,3H)；13C NMR(126MHz,CDCl3) δ 198.29,143.52,136.61,135.87,133.49,129.51,128.77,128.15,127.93,87.62,72.39,42.64,38.62,38.57,21.60,13.54, 12.24; HRMS (ESI) calculated value [ M + H, C21H23NO3S]+370.1471; found 370.1472.
Figure BDA0001857318070000273
1p white solid, 93% yield.1H NMR(500MHz,CDCl3)δ8.06–7.93(m,2H),7.81(d,J＝8.2Hz,2H),7.33–7.20(m,5H),7.20–7.04(m,4H),4.42(s,2H),3.68(t,J＝7.0Hz,2H),3.43(t,J＝7.0Hz,2H),2.35(s,3H).13C NMR(126MHz,CDCl3)δ196.66,167.02,164.99,143.80,135.62,133.05(d,J＝3.0Hz),131.61,130.86(d,J＝9.4Hz),129.71,128.57,128.22,127.93,122.16,85.67,82.35,42.92,39.21,38.71,21.53；19F NMR(376MHz,CDCl3) Delta-104.62 (M), HRMS (ESI) calculated value [ M + Na, C25H22FNNaO3S]+458.1197; measured value 458.1204
Figure BDA0001857318070000281
1q white solid, 85% yield.1H NMR(400MHz,CDCl3)δ7.99(dd,J＝8.7,5.4Hz,2H),7.75(d,J＝8.2Hz,2H),7.29(d,J＝8.0Hz,2H),7.14(t,J＝8.5Hz,2H),4.14(s,2H),3.59(t,J＝7.2Hz,2H),3.37(t,J＝7.2Hz,2H),2.42(s,3H),1.93(dd,J＝15.1,7.6Hz,2H),0.90(t,J＝7.5Hz,3H)；13C NMR(126MHz,CDCl3)δ196.79,167.07,165.04,143.61,135.84,133.14(d,J＝2.9Hz),130.87(d,J＝9.3Hz),129.57,128.65(d,J＝267.4Hz),127.97,116.03,115.86,87.68,72.42,42.69,38.76,38.76,21.64,13.58,12.28；19F NMR(376MHz,CDCl3) Delta-104.69 (m); HRMS (ESI) calculated value [ M + Na, C21H22FNNaO3S]+410.1197; found 410.1201.
Effect example 1
Figure BDA0001857318070000282
The operation is as follows: in a glove box, under the protection of nitrogen, adding Ni (cod)2(2. mu. mol, 1 mol%), phosphine ligand (1. mu. mol/2. mu. mol, 0.5 mol%/1 mol%) and dioxane (0.5mL) were added to a 5mL vial with magnetic stirring. Substrate 1a (0.2mmol, 1.0 equiv.) was added to the solution in one portion, stirred for 5 minutes, and then triethylsilane (Et)3SiH，0.6mmol，3.0 equivalent). The vial was closed and the resulting mixture was stirred at 25 ℃ for 12 hours. With saturated sodium bicarbonate (NaHCO)3) Quench, extract with ethyl acetate (EtOAc), wash with saturated NaCl, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. The residue was purified by column chromatography (10% petroleum ether/EtOAc) to give compound 2 a.
By the above procedure, different phosphine ligands, amounts of phosphine ligands and Ni (cod)2The results of the reaction in amounts are shown in the following table:
TABLE 1 reaction results for different phosphine ligands
Figure BDA0001857318070000291
Effect example 2
Bisphosphine ligands L4 and Ni (cod) prepared in example 1, using Compound 1a as substrate for reductive cyclization2And (3) preparing an optically active chiral pyrrole tertiary alcohol compound 2a by using triethylsilane as a reducing agent and high ligand carrying capacity (s/c is 1000).
The operation is as follows: stirring in a glove box under the protection of nitrogen gas with Ni (cod)2N-alkynone 1a (1.0g, 2.48mmol, 1.0 equiv.) was added in one portion to a reaction flask (0.682mg, 2.48. mu. mol, 0.1 mol%) containing L4(0.816mg, 1.24. mu. mol, 0.05 mol%) as a yellow solution in dioxane (3 mL). The resulting brown solution was stirred for 15 minutes, then triethylsilane (Et) was added3SiH, 1.19mL, 7.44mmol, 3.0 equiv). The vial was sealed and the resulting mixture was stirred at 60 ℃ for 12 hours. With saturated sodium bicarbonate (NaHCO)3) Quench, extract with ethyl acetate (EtOAc), wash with saturated NaCl, over anhydrous sodium sulfate (Na)2SO4) Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (10% petroleum ether/EtOAc) to give compound 2a as a colorless oil (1.26g, 98% yield, 99:1 er).
2a colorless oil, 98% yield, 99:1er, 0.05 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate of 1mL/min at 25 ℃, n-hexane/iso-hexanePropanol 98/2,254nm,6.8min (R),10.2min (S). The absolute configuration is determined by the X-ray single crystal structure of 3a (2a desilication-based product); [ alpha ] to]D 25＝+23.6(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.0Hz,2H),7.48(d,J＝7.4Hz,2H),7.41–7.25(m,8H),7.16(d,J＝7.6Hz,2H),6.45(s,1H),4.38(d,J＝14.9Hz,1H),4.21(dd,J＝14.9,1.8Hz,1H),3.68(d,J＝9.6Hz,1H),3.44(d,J＝9.6Hz,1H),2.44(s,3H),0.91(t,J＝7.9Hz,9H),0.55(q,J＝7.7Hz,6H)；13C NMR(126MHz,CDCl3) δ 144.01,143.98,142.39,135.92,132.59,129.89,128.78,128.59,128.19,127.95,127.75,127.55,126.10,126.10,83.10,60.68,50.56,21.65,7.14, 6.25; HRMS (ESI) calculated value [ M + Na, C30H37NNaO3SSi]+542.2156; found 542.2159.
Compound 2a Synthesis of Compound 3a
Figure BDA0001857318070000301
Figure BDA0001857318070000302
TBAF (1.0M in THF, 1.5mL, 1.5 equiv.) was added to a solution of 2a (520mg, 1.0mmol, 1.0 equiv.) in THF (10mL) at 0 deg.C and stirred at 0 deg.C for 0.5 h. Quench with water, EtOAc extraction, brine wash, anhydrous Na2SO4Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (20% petroleum ether/EtOAc) to give compound 3a as a white solid (390mg, 96%). 3a: [ alpha ]]D 25＝+24.5(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.63(d,J＝8.2Hz,2H),7.39–7.32(m,2H),7.29–7.13(m,8H),7.03(d,J＝7.4Hz,2H),6.19(t,J＝2.3Hz,1H),4.40(dd,J＝15.0,2.4Hz,1H),4.16(dd,J＝15.0,2.5Hz,1H),3.47(q,J＝10.4Hz,2H),2.42(s,1H),2.32(s,3H)；13C NMR(126MHz,CDCl3)δ144.03,142.58,141.59,135.64,132.98,129.93,128.76,128.65,128.44,128.01,127.97,127.94,126.61,126.31,82.05,61.50,50.72, 21.68; HRMS (ESI) calculated value [ M + Na, C24H23NNaO3S]+428.1291; observed value 428.1292 the X-ray crystal diffraction pattern of Compound 3a is shown in FIG. 1.
Using the compound 1b-1p prepared in example 2 as a substrate for reductive cyclization, bisphosphine ligands L4 and Ni (cod)2The chiral pyrrole tertiary alcohol compound 2b-1q with optical activity is prepared by using the complex of (1) as a catalyst and triethylsilane as a reducing agent (the reaction operation is the same as that of the compound 1a in the embodiment 2).
Figure BDA0001857318070000303
2b colorless oil, 87% yield, 98:2er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,15.4min (R),24.6min (S); [ alpha ] to]D 25＝+19.1(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.0Hz,2H),7.43–7.26(m,7H),7.15(d,J＝7.5Hz,2H),6.84(d,J＝8.6Hz,2H),6.47(s,1H),4.34(d,J＝14.8Hz,1H),4.18(d,J＝14.8Hz,1H),3.82(s,3H),3.68(d,J＝9.5Hz,1H),3.39(d,J＝9.5Hz,1H),2.43(s,3H),0.90(t,J＝7.9Hz,9H),0.53(dd,J＝15.6,7.7Hz,6H)；13C NMR(126MHz,CDCl3) δ 159.01,143.91,142.39,135.96,135.70,132.73,129.87,128.76,128.60,127.89,127.68,127.47,125.53,113.49,82.70,60.30,55.35,50.33,21.64,7.14, 6.24; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2431.
Figure BDA0001857318070000311
2c colorless oil, 90% yield, 99:1er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 98/2,254nm,6.9min (R),10.6min (S); [ alpha ] to]D 25＝+11.9(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.74(d,J＝8.2Hz,2H),7.48–7.42(m,2H),7.40–7.31(m,4H),7.28(t,J＝7.4Hz,1H),7.15(d,J＝7.4Hz,2H),7.02–6.96(m,2H),6.44(t,J＝2.3Hz,1H),4.34(dd,J＝14.9,2.3Hz,1H),4.21(dd,J＝14.9,2.6Hz,1H),3.66(d,J＝9.6Hz,1H),3.40(d,J＝9.6Hz,1H),2.44(s,3H),0.89(t,J＝7.9Hz,9H),0.58–0.49(m,6H)；13C NMR(126MHz,CDCl3) δ 162.16(d, J ═ 246.4Hz),144.08,142.13,139.95(d, J ═ 3.1Hz),135.74,132.47,129.91,128.81,128.57,127.91,127.86(d, J ═ 2.0Hz),127.80,126.08,114.98(d, J ═ 21.4Hz),82.63,60.46,50.43,21.62,7.09, 6.23; HRMS (ESI) calculated value [ M + H, C30H37O3NFSSi]+538.2247; found 538.2234.
Figure BDA0001857318070000312
2d colorless oil, 74% yield, 99:1er, 0.5 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,7.2min (R),9.4min (S); [ alpha ] to]D 25＝+11.6(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.2Hz,2H),7.43–7.32(m,6H),7.31–7.25(m,3H),7.14(d,J＝7.4Hz,2H),6.41(t,J＝2.2Hz,1H),4.35(dd,J＝15.0,2.3Hz,1H),4.20(dd,J＝15.0,2.6Hz,1H),3.63(d,J＝9.7Hz,1H),3.40(d,J＝9.7Hz,1H),2.44(s,3H),0.89(t,J＝7.9Hz,9H),0.58–0.48(m,6H)；13C NMR(126MHz,CDCl3) δ 144.14,142.91,141.98,135.70,133.42,132.43,129.94,128.84,128.59,128.36,127.93,127.51,126.34,110.10,82.69,60.50,50.50,21.67,7.11, 6.25; HRMS (ESI) calculated value [ M + H, C30H37O3NClSSi]+554.1952; found 554.1935.
Figure BDA0001857318070000321
2e colorless oil, 98% yieldThe ratio of the total weight of the particles,>99:1er, 0.25 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 98/2,254nm,7.7min (R),9.0min (S); [ alpha ] to]D 25＝+13.4(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.76(d,J＝8.1Hz,2H),7.59(dd,J＝19.6,8.4Hz,4H),7.41–7.33(m,4H),7.32–7.27(m,1H),7.15(d,J＝7.5Hz,2H),6.41(s,1H),4.38(dd,J＝15.0,2.0Hz,1H),4.26(dd,J＝15.0,2.3Hz,1H),3.65(d,J＝9.8Hz,1H),3.44(d,J＝9.8Hz,1H),2.45(s,3H),0.90(t,J＝7.9Hz,9H),0.61–0.51(m,6H)；13C NMR(126MHz,CDCl3) δ 148.77,144.26,141.87,135.57,132.20,129.96,129.70(q, J ═ 32.4Hz),128.86,128.57,128.04,127.98,126.91,126.27,125.21(q, J ═ 3.7Hz),124.21(q, J ═ 272.2Hz),82.87,60.73,50.69,21.61,7.07, 6.24; HRMS (ESI) calculated value [ M + H, C31H37O3NF3SSi]+588.2210; found 588.2216.
Figure BDA0001857318070000322
2f colorless oil, 98% yield, 99:1er, 0.25 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,12.3min (S),22.3min (R); [ alpha ] to]D 25＝+34.3(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.2Hz,2H),7.41–7.31(m,4H),7.31–7.26(m,1H),7.22(t,J＝8.0Hz,1H),7.18–7.13(m,2H),7.13–7.09(m,1H),7.02–6.97(m,1H),6.84–6.80(m,1H),6.44(t,J＝2.3Hz,1H),4.40(dd,J＝14.9,2.3Hz,1H),4.21(dd,J＝14.9,2.6Hz,1H),3.81(s,3H),3.64(d,J＝9.7Hz,1H),3.46(d,J＝9.7Hz,1H),2.44(s,3H),0.91(t,J＝7.9Hz,9H),0.56(q,J＝7.6Hz,6H)；13C NMR(126MHz,CDCl3) δ 159.46,145.83,143.98,142.23,135.91,132.57,129.88,129.19,128.77,128.58,127.93,127.76,126.33,118.47,112.71,112.19,83.14,60.96,55.29,50.63,21.63,7.15, 6.26; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2432.
Figure BDA0001857318070000331
2g of a colorless oil, 98% yield, 99:1er, 0.5 mol% L4, 60 ℃. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,12.2min (S),14.9min (R); [ alpha ] to]D 25＝+27.0(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.83(dd,J＝7.7,1.7Hz,1H),7.79(d,J＝8.2Hz,2H),7.38(d,J＝8.0Hz,2H),7.33(t,J＝7.6Hz,2H),7.26–7.20(m,2H),7.08(d,J＝7.4Hz,2H),7.00(td,J＝7.6,0.8Hz,1H),6.67(d,J＝7.9Hz,1H),6.04(t,J＝2.1Hz,1H),4.63(dd,J＝14.1,2.0Hz,1H),4.03(dd,J＝14.1,2.9Hz,1H),3.55(s,2H),3.10(s,3H),2.45(s,3H),0.98(t,J＝7.9Hz,9H),0.79–0.63(m,6H)；13C NMR(126MHz,CDCl3) δ 155.26,144.43,143.70,136.67,132.92,132.06,129.62,128.86,128.71,128.49,128.31,127.45,127.33,124.48,120.36,111.05,82.94,60.39,54.33,51.97,21.65,7.30, 6.16; HRMS (ESI) calculated value [ M + H, C31H40NO4SSi]+550.2447; found 550.2433.
Figure BDA0001857318070000332
2h colorless oil, 80% yield, 99:1er, 1 mol% L4, 80 ℃. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral OD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 98/2,254nm,13.3min (S),20.5min (R); [ alpha ] to]D 25＝+25.9(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.61(d,J＝8.0Hz,1H),7.41–7.27(m,7H),7.21(t,J＝7.4Hz,1H),7.18–7.15(m,2H),7.13(d,J＝7.7Hz,2H),7.09(s,1H),6.44(t,J＝3.0Hz,1H),4.71(d,J＝3.0Hz,2H),3.84(s,3H),2.42(s,3H),1.00(t,J＝8.0Hz,9H),0.62(q,J＝8.0Hz,6H)；13C NMR(126MHz,CDCl3) δ 144.33,138.65,137.12,137.10,133.16,131.54,130.08,128.72,128.02,127.82,127.60,127.00,126.49,123.28,122.38,120.18,119.91,117.53,109.66,105.90,53.17,33.05,21.68,6.71, 5.92; HRMS (ESI) calculated value [ M-OTES, C27H25N2O2S]+441.1637; found 441.1619.
Figure BDA0001857318070000341
2i colorless oil, 94% yield,>99:1er, 1 mol% L4, 80 ℃. The er value is measured by a chiral high-pressure liquid phase to obtain a desiliconized base product 3 i; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C 1mL/min, n-hexane/isopropanol 80/20,254nm,16.3min (R),21.8min (S); [ alpha ] to]D 25＝–40.7(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.74–7.69(m,2H),7.41–7.35(m,2H),7.33–7.26(m,3H),7.18–7.14(m,2H),6.45(t,J＝2.4Hz,1H),4.26(dd,J＝14.9,2.8Hz,1H),4.05(dd,J＝14.9,2.2Hz,1H),3.82(d,J＝10.0Hz,1H),2.89(d,J＝10.0Hz,1H),2.40(s,3H),0.96(s,9H),0.81(t,J＝7.9Hz,9H),0.46–0.28(m,6H)；13C NMR(126MHz,CDCl3) δ 143.93,140.19,136.05,132.24,129.84,128.81,128.65,127.89,127.51,126.77,86.32,54.49,51.48,39.95,25.13,21.62,7.23, 6.46; HRMS (ESI) calculated value [ M + Na, C28H41NNaO3SSi]+522.2469; found 522.2465.
Figure BDA0001857318070000342
2j colorless oil, 83% yield, 92:8er, 1 mol% L4, 80 ℃. The er value is measured by a chiral high-pressure liquid phase to obtain a desiliconized base product 3 j; high-pressure liquid phase conditions: chiral OD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 85/15,230nm,14.1min (R),17.8min (S); [ alpha ] to]D 25＝+17.1(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.39–7.33(m,4H),7.30–7.22(m,3H),5.35(tt,J＝7.3,2.5Hz,1H),4.13–4.06(m,1H),3.85–3.79(m,1H),3.48–3.41(m,2H),2.46(s,3H),1.99–1.91(m,2H),0.93(t,J＝7.5Hz,3H),0.89(t,J＝7.9Hz,9H),0.53(q,J＝7.7Hz,6H)；13C NMR(126MHz,CDCl3) δ 144.24,143.87,140.76,132.58,129.80,129.08,128.05,127.95,127.24,126.15,82.18,62.86,49.59,22.77,21.68,13.23,7.15, 6.26; HRMS (ESI) calculated value [ M + H, C26H38NO3SSi]+472.2336; found 472.2338.
Figure BDA0001857318070000343
2n colorless oil, 95% yield, 90:10er, 2 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate at 25 deg.C of 1mL/min, n-hexane/isopropanol of 99/1,254nm,10.9min (R),15.5min (S); [ alpha ] to]D 25＝–14.9(c＝1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.8Hz,2H),7.41–7.32(m,4H),7.32–7.22(m,6H),7.20(d,J＝7.8Hz,2H),6.85(s,1H),4.35(d,J＝12.8Hz,1H),3.67–3.58(m,1H),3.18(d,J＝12.8Hz,1H),3.03(t,J＝10.1Hz,1H),2.67(d,J＝13.5Hz,1H),2.36(s,3H),2.17–2.07(m,1H),0.74(t,J＝7.9Hz,9H),0.39–0.18(m,6H)；13C NMR(126MHz,CDCl3) δ 143.51,141.58,138.51,136.65,133.85,129.63,129.10,128.55,128.52,128.05,127.82,127.40,127.31,127.17,77.32,45.02,43.96,37.82,21.60,7.04, 6.38; HRMS (ESI) calculated value [ M + H, C31H40NO3SSi]+534.2493; found 534.2495.
Figure BDA0001857318070000351
2o colorless oil, 95% yield, 90:10er, 2 mol% L4. The er value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: a chiral AD-H column with the flow rate of 1mL/min at 25 ℃, 99/1,254nm of normal hexane/isopropanol, 6.2min (R),8.1min (S), and the absolute configuration of the chiral AD-H column is determined by the X-ray single crystal structure of 3o (2o desilication base product); [ alpha ] to]D 25＝–18.9(c＝1.0,CHCl3)；1H NMR(500MHz,CDCl3)δ7.59(d,J＝8.2Hz,2H),7.26–7.18(m,7H),5.58(t,J＝7.4Hz,1H),3.99(d,J＝12.7Hz,1H),3.43–3.37(m,1H),3.21(d,J＝12.8Hz,1H),3.03(ddd,J＝12.1,9.3,3.1Hz,1H),2.45(ddd,J＝13.3,6.4,3.2Hz,1H),2.35(s,3H),2.11(dtd,J＝14.8,7.4,3.5Hz,2H),1.92(ddd,J＝13.2,9.1,3.9Hz,1H),0.95(t,J＝7.5Hz,3H),0.67(t,J＝7.9Hz,9H),0.29–0.13(m,6H)；13C NMR(126MHz,CDCl3) δ 143.48,142.37,135.41,134.08,129.67,129.60,128.23,127.76,127.71,127.36,77.19,44.12,43.71,38.17,21.60,20.83,14.34,7.03, 6.41; HRMS (ESI) calculated value [ M + Na, C27H39NNaO3SSi]+508.2312; found 508.2320.
Figure BDA0001857318070000352
3o (2o desilication based product) preparation of 3o reference the synthetic procedure of 3a white solid; [ alpha ] to]D 25＝–24.8(c＝1.0,CHCl3)；1H NMR(500MHz,CHCl3)δ7.68(d,J＝8.1Hz,2H),7.36–7.28(m,6H),7.28–7.24(m,1H),5.14(t,J＝7.3Hz,1H),4.16(d,J＝13.1Hz,1H),3.58(d,J＝13.1Hz,1H),3.52–3.44(m,1H),3.17(td,J＝11.7,2.8Hz,1H),2.44(s,3H),2.39–2.31(m,1H),2.17–1.99(m,2H),1.84–1.79(m,1H),1.78(s,1H),0.90(t,J＝7.5Hz,3H)；13C NMR(126MHz,CHCl3) δ 143.74,143.62,135.52,134.02,131.74,129.78,128.22,127.78,127.47,126.35,77.41,77.16,76.91,75.34,43.84,42.90,38.79,21.63,20.78, 13.96; HRMS (ESI) calculated value [ M + H, C21H26NO3S]+372.1628; found 372.1629. The X-ray crystal diffraction pattern of compound 3o is shown in figure 2.

Claims (13)

1. A compound of formula I:
Figure FDA0002817880710000011
wherein R is1And R1’Is tert-butyl;
R2、R3、R4、R5and R6Each independently is hydrogen, C1-C10Alkyl or C1-C10An alkoxy group;
R2’、R3’、R4’、R5’and R6’Each independently is hydrogen, C1-C10Alkyl or C1-C10An alkoxy group;
Figure FDA0002817880710000012
the same;
Figure FDA0002817880710000013
and
Figure FDA0002817880710000014
represents the relative configuration of the P atom when
Figure FDA0002817880710000015
Is composed of
Figure FDA0002817880710000016
When the temperature of the water is higher than the set temperature,
Figure FDA0002817880710000017
is composed of
Figure FDA0002817880710000018
When in use
Figure FDA0002817880710000019
Is composed of
Figure FDA00028178807100000110
When the temperature of the water is higher than the set temperature,
Figure FDA00028178807100000111
is composed of
Figure FDA00028178807100000112
2. A compound of formula I according to claim 1, wherein: said C1-C10Alkyl is independently C1-C4An alkyl group.
3. A compound of formula I according to claim 1, wherein: said C1-C10Alkoxy is independently C1-C4An alkoxy group.
4. A compound of formula I according to claim 1, wherein:
said C1-C10Alkyl is independently methyl, ethyl, n-propyl, isopropyl or tert-butyl.
5. A compound of formula I according to claim 1, wherein: said C1-C10Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.
6. A compound of formula I according to claim 1, wherein:
said R4、R5、R6、R4’、R5’And R6’Each independently hydrogen, methyl, ethyl, isopropyl, methoxy or isopropoxy.
7. A compound of formula I according to claim 1, wherein:
Figure FDA00028178807100000113
is composed of
Figure FDA0002817880710000021
Figure FDA0002817880710000022
8. A compound of formula I according to claim 1, wherein:
said
Figure FDA0002817880710000023
Is composed of
Figure FDA0002817880710000024
Is composed of
Figure FDA0002817880710000025
9. A compound of formula I according to claim 1, wherein:
R3、R4、R5、R3’、R4’and R5’Are all hydrogen;
R2、R6、R2’and R6’Each independently is C1-C10An alkoxy group.
10. A compound of formula I according to claim 1, wherein: the compound shown in the formula I is selected from any one of the following structures:
Figure FDA0002817880710000026
Figure FDA0002817880710000031
11. a process for the preparation of a compound of formula I as claimed in any one of claims 1 to 10, comprising the steps of: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of a reducing agent to obtain a compound shown as a formula I;
Figure FDA0002817880710000032
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure FDA0002817880710000033
And
Figure FDA0002817880710000034
as defined in any one of claims 1 to 10.
12. A compound of formula II:
Figure FDA0002817880710000035
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure FDA0002817880710000036
And
Figure FDA0002817880710000037
as defined in any one of claims 1 to 10.
13. Use of a compound of formula I according to any one of claims 1 to 10 as a metal ligand in a reductive cyclization reaction as follows:
Figure FDA0002817880710000038
Figure FDA0002817880710000041
the reductive cyclization reaction comprises the following steps: reacting a compound A in an organic solvent in the presence of a compound shown as a formula I, a nickel compound and a reducing agent to obtain a compound B;
wherein R is1、R2、R3、R4、R5、R6、R1’、R2’、R3’、R4’、R5’、R6’、
Figure FDA0002817880710000042
And
Figure FDA0002817880710000043
as defined in any one of claims 1 to 10;
n is 1 or 2;
R7is substituted or unsubstituted C6-C20Aryl, substituted or unsubstituted 5-20 membered heteroaryl, substituted or unsubstituted C1-C20Alkyl or substituted or unsubstituted C3-C20A cycloalkyl group;
R8is C1-C20Alkyl or substituted or unsubstituted C6-C20An aryl group;
said substituted C6-C20Aryl, substituted 5-20 membered heteroaryl, substituted C1-C20Alkyl or substituted C3-C20The substituents in the cycloalkyl group are each independently halogen, C1-C5Haloalkyl or C1-C5An alkoxy group; the number of the substituent is one or more; when the number of the substituent is more than one, the substituent is the same or different;
R9is an amino protecting group.
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