CN115353529A

CN115353529A - Chiral spiro compound, preparation method and application thereof

Info

Publication number: CN115353529A
Application number: CN202210520379.3A
Authority: CN
Inventors: 孙建伟; 张荣华; 戈书林
Original assignee: Hong Kong University of Science and Technology HKUST
Current assignee: Hong Kong University of Science and Technology HKUST
Priority date: 2021-05-17
Filing date: 2022-05-13
Publication date: 2022-11-18

Abstract

The invention provides a chiral spiro compound, a preparation method and application thereof. The chiral spiro compound is represented by the formula:

Description

Chiral spiro compound, preparation method and application thereof

Technical Field

The invention relates to a novel chiral spiro compound (in particular to a chiral spiro diol structure-SPHENOL), a preparation method and application thereof. Due to the special molecular shape and three-dimensional orientation, the chiral spiro compound can be used as a chiral framework for designing novel chiral ligands and asymmetric synthesis catalysts.

Background

Enantioselective catalysis is a key backbone of modern organic chemistry. Over the past several decades, multifunctional chiral catalysts have been reported, contributing to the development of catalytic asymmetric syntheses. However, most practically useful enantioselective reactions are rooted in a few privileged core structures, which are called "dominant chiral catalysts". An essential feature that makes a catalyst "dominant" is its scaffold structure (core structure). Some representative examples, such as BINOL, TADDOL and SPINOL, derivatives of which have been widely used as chiral backbones for various organic catalysts and ligands for metal complexes, have been shown to be effective in a variety of mechanically unrelated reactions. However, a large number of reactions still lack efficient chiral ligands and enantioselectivity in many reactions is substrate dependent.

The development of new effective chiral catalysts, and in particular the development of new chiral frameworks on which these catalysts are based, remains an important task in the field of asymmetric catalysis.

Disclosure of Invention

Therefore, the invention provides a novel chiral spiro compound, a preparation method and application thereof. The chiral spiro compound can be used as a framework or a support of a plurality of chiral catalysts, and has a novel chiral framework.

Specifically, the present invention provides:

a chiral spiro compound represented by the formula:

SPHENOL represents the structure represented by formula I below,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently represents optionally substituted C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, or an optionally substituted heterocyclic aryl group,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

x represents C or a heteroatom selected from N, O, S and P,

a and B each independently represent-OH, -SO ₃ H. -P, -O-, C1-C6 alkylene, heteroaryl, amino and-SO ₂ -at least one of wherein a and B may be optionally substituted with at least one substituent;

m1 and m2 are 0 or 1;

z represents-PN (R) ¹⁵ ) ₂ 、-PR ₂ ', optionally substituted with R ₂ ' substituted phenylene, B ^- ，N ⁺ 、

At least one of imino and amino, wherein Tf represents trifluoromethanesulfonyl, O (S) represents O or S;

SPHENOL-A represents an enantiomer of SPHENOL;

m ₃ and m ₄ Represents a number of 0 or 1, and,

m represents 0 or 1;

* Indicates absence or indicates a point of attachment to Z;

R ₂ ' represents hydrogen, optionally substituted aryl, optionally substituted polycyclic aromatic hydrocarbon ring group, optionally substituted heterocyclic aryl or optionally substituted C1-C6 alkyl,

R ¹⁵ represents unsubstituted C1-C6 alkylene or C1-C6 alkylene substituted by aryl;

represents a single bond or is absent.

A method for preparing a chiral spiro compound, comprising the steps of converting a ketone compound represented by the following formula II into a bisnaphthol compound represented by the following formula I in the presence of a chiral acid catalyst and a solvent:

and, and

optionally converting the bisnaphthol compound represented by formula I into a chiral spiro compound other than formula I,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently represents C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, or an optionally substituted heterocyclic aryl group,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

a and B both represent-OH;

m1 and m2 are 1;

* Indicates absence; and

x represents C or a heteroatom selected from N, O, S and P.

Use of any of the compounds described above in asymmetric catalytic reactions, intermolecular hydroacylation reactions, enantioselective spiro synthesis reactions or intramolecular desymmetrization reactions.

Use of a compound as described above as a chiral catalyst or chiral ligand.

The chiral spiro compound also has good conformation rigidity and electronic property, combines the advantages of the existing chiral catalyst, and can be used as an excellent platform for developing new chiral ligands and catalysts. In addition, the design of the core catalyst of the present invention is new and is significantly different from existing chiral catalyst backbones in terms of structural rigidity, dihedral angle, pKa, etc., which is crucial to achieving better performance.

In addition, this new chiral spiro compound is characterized by easy synthesis (3 steps), cheaper than SPINOL on the market, which is very expensive due to the cumbersome synthetic process (7 steps of synthesis and need of chiral resolution).

In addition, since the compound of the present invention has a naphthalene structure, it leads to simplification of the synthetic route thereof, which greatly reduces the synthetic cost, and thus is expected to lead to wide applications. In contrast, the cost of the prior SPINOL is too high to be truly practical despite its good performance.

Detailed Description

Embodiments of the present invention are described in detail below. The embodiments described below are exemplary only, are intended to illustrate the invention, and should not be construed as limiting the invention. The embodiments are not specified to specific techniques or conditions, according to the techniques or conditions described in the literature in the field or according to the product description. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

In addition, unless otherwise explicitly indicated, the description of "each of the methods 8230, independently" and "\8230"; independently "and" \8230, independently "and" \8230 "; independently" are used interchangeably in the present invention and are to be understood broadly, and they may mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C _1-18 Alkyl "includes methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aromatic group," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" as used herein includes aliphatic saturated hydrocarbon groups. Alkyl groups may be optionally substituted with one or more substituents described herein. In one embodiment of the present invention, the alkyl group has 1 to 100 carbon atoms (i.e., C1-100 alkyl), preferably 1 to 18 carbon atoms (i.e., C1-18 alkyl). In another embodiment, the alkyl group contains 1 to 12 carbon atoms (i.e., C1-12 alkyl); in yet another embodiment, the alkyl group contains 1 to 6 carbon atoms (i.e., C1-6 alkyl); in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms (i.e., C1-4 alkyl); in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms (i.e., C1-3 alkyl).

Examples of alkyl groups include, but are not limited to, C1-12 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like.

The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "aryl" includes groups in which 1 or 2 hydrogen atoms are removed from the aromatic ring and are directly attached to another group. Aryl includes monocyclic aryl or arylene groups in which the ring system is aromatic and contains rings of 3 to 6 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, biphenyl, and the like. The aryl group is optionally substituted with one or more substituents described herein.

The term "heterocycloaryl" refers to a group formed by replacing at least one ring-forming carbon atom of an aryl group with at least one heteroatom, such as N, O, or S.

The term "polycyclic aromatic hydrocarbon ring radical" includes bicyclic, tricyclic, or tricyclic aryl groups in which at least one ring system is aromatic and in which each ring system contains 5 to 18 atoms. Examples of the polycyclic aromatic hydrocarbon ring group may include naphthyl and anthracene, and the like. The polycyclic aromatic hydrocarbon ring group is optionally substituted with one or more substituents described herein.

In the present invention, the term "optionally substituted" means that the modified group may have no substituent or be substituted with at least one substituent group.

The substituent may be selected from at least one of a halogen atom, a hydroxyl group, an aldehyde group, a carboxyl group, an amino group, a C1-C18 alkyl group optionally substituted with one or more C6-C18 aryl groups or a heterocyclic aryl group of ring-forming carbon atoms 5 to 18, a halogen atom (particularly F), an aryl group of ring-forming carbon atoms 6 to 18, a heterocyclic aryl group of ring-forming carbon atoms 5 to 18, a mercapto group, a cyano group and a nitro group.

Examples of aryl, heterocyclic aryl and polycyclic aromatic hydrocarbon ring groups include, for example, -CF ₃ Substituted phenyl groups,

Phenyl, naphthyl, anthryl, phenanthryl, tetracenyl, pyrenyl, benzo [ c]Phenanthryl, benzophenanthryl, fluorenyl, benzofluorenyl, dibenzofluorenyl, biphenyl, terphenyl, quaterphenyl, fluoranthenyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidinyl, triazinyl, indolyl, isoindolyl, imidazolyl, furyl, benzofuryl, isobenzofuryl, dibenzofuryl, dibenzothienyl, quinolyl, isoquinolyl, quinoxalyl, carbazolyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, oxazolyl, oxadiazolyl, furazanyl, thienyl, benzothienyl, dihydroacridinyl, azacarbazolyl, quinazolinyl, and the like.

The development of effective chiral catalysts, particularly ligands with novel chiral backbones, remains an important task in the field of asymmetric catalysis. BINOL has slightly higher acidity due to the large naphthalene conjugation system, but SPINOL backbone tends to show better asymmetry induction due to greater structural rigidity. In this case, the present invention proposes a new structure (which is sometimes called a SPHENOL). This new structure is expected to inherit the excellent conformational rigidity and chemical stability of SPINOL, while having electronic properties (acidity) comparable to BINOL. The latter is sometimes very important in Brookfield acid catalysis. Furthermore, similar to BINOL and SPINOL, the introduction of two substituents at the 3,3' -position of SPHENOL is expected to allow the chirality of the C2 symmetric backbone to be adjusted. Combining the advantages of these two specific structures, SPHENOL can serve as a superior platform for the development of new chiral ligands and catalysts. Such a new framework has superior performance in mechanically unrelated reactions, demonstrating the potential of SPHENOL as a privileged framework for asymmetric synthesis.

The major difference between the SPHENOL of the present invention and the previously related inventions SPINOL and modified SPINOL is the structural extension of the conjugated system onto naphthalene. In terms of function and synthesis, SPHENOL has fundamental differences and advantages. The SPHENOL of the invention has better performance as a catalyst framework, and has lower price due to ingenious design. Naphthol is much more nucleophilic and selective than phenol in the cyclization process, which results in 3 steps and high yield of the synthesis. However, existing methods of manufacturing SPINOL do not allow for inexpensive and scalable production. This makes SPINOL impractical for large-scale applications, and our invention will fill this gap and be expected to be a new generation of catalysts.

In one aspect, there is provided a chiral spiro compound represented by the formula:

SPHENOL represents the structure represented by formula I below,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

x represents C or a heteroatom selected from N, O, S and P,

a and B each independently represent-OH, -SO ₃ H. -P, -O-, C1-C6 alkylene, heteroaryl, aminoand-SO ₂ -wherein a and B may be optionally substituted with at least one substituent;

m1 and m2 are 0 or 1;

SPHENOL-A represents an enantiomer of SPHENOL;

m ₃ and m ₄ Represents a number of 0 or 1, and,

m represents 0 or 1;

* Indicates absence or indicates a point of attachment to Z;

represents a single bond or is absent.

In the above formula, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Independently in the ortho, meta or para position on the respective aromatic ring.

In one embodiment, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently is-OR, -OH, -NH ₂ 、-NHR、-NR ¹¹ R ¹² 、-F、-Cl、-Br、-I、-SR、-PR ¹³ R ¹⁴ or-SeR, where R ¹¹ 、R ¹² Each independently hydrogen or C1-6 alkyl, R ¹³ And R ¹⁴ Each independently is carbonyl, hydroxy, hydrogen or C1-6 alkyl.

Preferably, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Are all hydrogen, and R ⁹ And R ¹⁰ Each independently is by-CF ₃ Substituted phenyl or

In particular, the chiral spiro compound may be selected from at least one of the following:

wherein R and R' each independently represent C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, an optionally substituted heterocyclic aryl group, hydrogen or a substituent having a hetero atom, X, n and O (S) are as defined above, ar represents an aryl group, and P represents phosphorus.

Preferably, two R ¹⁵ Are C1-C6 alkylene groups each substituted with an aryl group and are enantiomers of each other.

Preferably, when each group is substituted, the substituent is selected from aryl, -NR ² ', polycyclic aromatic hydrocarbon ring group, optionally substituted heterocyclic aryl group or C1-C6 alkyl group.

Preferably, the compound is selected from any one of the following:

in another aspect, the present invention provides a process for the preparation of a chiral spiro compound, comprising the steps of:

(I) Converting a ketone compound represented by the following formula II into a bis-naphthol compound represented by the formula I in the presence of a chiral acid catalyst and a solvent:

and

(II) optionally, converting the bisnaphthol compound represented by formula I into a chiral spiro compound other than formula I,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

a and B both represent-OH;

m1 and m2 are 1;

* Indicates absence; and

x represents C or a heteroatom selected from N, O, S and P.

The chiral acid catalyst may be selected from at least one of the following:

wherein R represents C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, an optionally substituted heterocyclic aryl hydrogen, or a substituent having a heteroatom.

The chiral acid catalyst is preferably an (S) -type chiral phosphoric acid that catalyzes a reaction to provide a chiral spiroglycol having an inverted configuration.

Preferably, the catalyst can be a chiral phosphoric acid with BINOL (III), 8H-BINOL (IV) or SPINOL (V) as a skeleton, wherein the 3,3' -substituent R represents a polycyclic aromatic hydrocarbon, such as substituted benzene, naphthalene, fluorene, pyrene, anthrylene or triaryl.

The temperature of the conversion reaction of step (I) may be from-20 ℃ to 120 ℃.

The solvent can be selected from chlorobenzene, phCF ₃ 、PhF、CCl ₄ 、DCM、CHCl ₃ At least one solvent selected from PhMe and DCE.

In one embodiment, the chiral spiro compound is a chiral ligand compound, and the method comprises converting the compound of formula I to the represented binaphthol compound to the chiral ligand compound represented by the formula:

SPHENOL represents a structure represented by formula I below,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

x represents C or a heteroatom selected from N, O, S and P,

a and B each independently represent-SO ₃ H. -P, -O-, C1-C6 alkylene, heteroaryl, amino and-SO ₂ -at least one of wherein a and B may be optionally substituted with at least one substituent;

m1 and m2 are 0 or 1;

z represents-PN (R) ¹⁵ ) ₂ 、-PR ₂ ', optionallyGround cover R ₂ ' substituted phenylene, B ^- ，N ⁺ 、

SPHENOL-A represents an enantiomer of SPHENOL;

m ₃ and m ₄ Represents a number of 0 or 1, and,

m represents 0 or 1;

* Indicates absence or indicates a point of attachment to Z;

represents a single bond or is absent.

In a third aspect, there is provided the use of the above compound in asymmetric catalytic reactions, intermolecular hydroacylation reactions, enantioselective spiro synthesis reactions or intramolecular desymmetrization reactions.

Preferably, the asymmetric catalytic reaction comprises an asymmetric hydrogenation of one of the following:

the intermolecular hydroacylation reaction is selected from one of the following:

and

the enantioselective spiro synthesis reaction is selected from:

the intramolecular desymmetrization reaction is selected from:

therefore, the invention provides a process for synthesizing a series of chiral spiro compounds. These compounds can also be converted into other useful compounds, such as chiral ligands and chiral catalysts, by simple chemical steps. Enantioselectivity can generally remain unaffected.

This procedure represents the first catalytic enantioselective synthetic preparation of this type of structure.

The following examples are provided to illustrate the invention and to assist those skilled in the art in understanding the invention. However, the following examples of the present invention should not be construed to unduly limit the present invention. Variations and modifications to the discussed examples may occur to those of ordinary skill in the art without departing from the scope of the discovery.

1. General procedure

1.1 materials, conditions and apparatus

Flash column chromatography was performed on silica gel (200-300 mesh) purchased from pock, qin island, china. All air or moisture sensitive reactions were carried out in glassware dried in an oven with anhydrous solvents under a nitrogen atmosphere. Anhydrous solvent composed of

And (5) purifying by using a solvent purification system. Chemicals were purchased from commercial suppliers and, unless otherwise stated, were not further purified.

¹ H、 ¹³ C、 ¹⁹ F and ³¹ p NMR spectra were collected on a Brookfield AV 400MHz NMR spectrometer using residual solvent peaks as internal standard ( ¹ H NMR：CDCl ₃ At 7.26ppm, acetone-D6 at 2.05ppm, meOD-D4 at 3.31ppm; ¹³ C NMR：CDCl ₃ at 77.00ppm, and acetone-D6 at 29.84ppm ₄ At 49.00 ppm). ¹ The H NMR data is recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; p = quintet; sept = heptaplex; m = multiplet; br = broad peak), coupling constant (Hz), integral. Mass spectra were collected on an Agilent GC/MS 5975C system, a MALDI Micro MX mass spectrometer or an API QSTAR XL system. The infrared spectra were recorded on a Brooks TENSOR 27 spectrometer and reported in units of absorption frequency (cm-1). The optical rotation was measured on a JASCO P-2000 polarimeter, [ alpha ]]D values are reported in degrees; the concentration (c) is in units of 10 mg/ml. Enantiomeric excess was determined by chiral HPLC using an Agilent 1200 LC instrument and Daicel

AD-H、

IC-HAS-

OD-H column.

1.2 Synthesis of chiral dihydric alcohols I

General procedure. Ketone II (5.0 mmol) and (S) -SPINOL-3,5- (CF) ₃ ) ₂ C ₆ H ₂ -OH (1-10 mol%) was dissolved in toluene (50 ml) and then stirred at 50 ℃ for 12 hours. Progress was monitored by thin layer chromatography. After completion (in each case for a defined time), it is removed by evaporationAnd (3) a solvent. The crude product was concentrated and the residue was filtered through a short pad of silica gel using dichloromethane as eluent to give the pure silica gel product.

Preparation of (R) -Ia

(R) -Ia, also known as (R) -SPHENOL, is composed of IIa (1.85g, 5.0mmol) and (S) -SPINOL-3,5- (CF) ₃ ) ₂ C ₆ H ₂ -OH (74 mg, 0.1 mmol) was prepared as a white solid in 89% yield (1.57g, 90% ee) as a catalyst according to the general procedure. 1.39 g (R) -Ia (90% ee) was recrystallized from hexane/dichloromethane (v/v =10,>99％ee)。

[α]D ²³ ：+268.3(c＝1.0，CH ₂ Cl ₂ ). The product was subjected to HPLC analysis: a Daicel CHIRALPAK AD-H column; 20% in hexane i-PrOH;1.0 ml/min; the retention time. 9.0 min (main peak), 13.8 min (secondary peak).

¹ H NMR(400MHz，CDCl ₃ )δ7.78(d，J＝8.9Hz，2H)，7.76-7.65(m，2H)，7.42-7.30(m，4H)，7.12-7.00(m，2H)，5.13(s，2H)，3.41-3.23(m，2H)，3.17-3.04(m，2H)，2.53-2.41(m，2H)，2.38-2.19(m，2H)。

¹³ C NMR(101MHz，CDCl ₃ )δ151.8，133.1，130.2，130.0，129.7，126.8，125.7，123.5，119.0，118.2，39.0，30.4，26.2。

IR (film) 3466, 3051, 2936, 1601, 1512, 1449, 1363, 1264, 1208, 1140, 943, 825, 754cm ^-1 。

HRMS(CI+)C ₂₅ H ₂₀ O ₂ (M ⁺ ) 352.1458, found 352.1453.

Preparation of II-2

To a solution of 2-naphthol (28.8 g, 200 mmol) and pyridine (24 ml, 300 mmol) in anhydrous dichloromethane (150 ml) was added dropwise triflic anhydride (48 ml, 300 mmol) under nitrogen at 0 ℃. The mixture was warmed to room temperature and stirred at the same temperature. After completion (about 2 hours), an aqueous hydrochloric acid solution (2.0M, 200 ml) was added dropwise to the resultant mixture at 0 ℃. The mixture was phase separated and the aqueous phase was extracted with dichloromethane (100 ml × 3). The organic layers were combined, washed with brine (200 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a red liquid. The red liquid was used directly in the next step without further purification.

To a solution of 1, 1-dichlorodimethyl ether (34.2 g, 300 mmol) in anhydrous dichloromethane (120 ml) was added dropwise TiCl under nitrogen at 0 deg.C ₄ (75.8 g, 400 mmol). The mixture was then stirred at the same temperature for 15 minutes, after which a solution of the crude product of II-1 described above in dry dichloromethane (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred at the same temperature. After completion (about 2 hours), the mixture was carefully poured into 0 ℃ aqueous hydrochloric acid (1.0M, 300 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (100 ml × 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 ml x 3) and brine (200 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a red liquid. The red oil was dissolved in absolute ethanol (200 ml) and cooled to 0 ℃, to which potassium hydroxide (28.6 g, 500 mmol) was added in portions. The mixture was then warmed to 65 ℃ and stirred vigorously. After completion (about 3 hours), the mixture was carefully poured into 0 ℃ aqueous hydrochloric acid (1.0M, 500 ml). Subsequently, the layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml × 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 ml. Times.3) and brine (200 ml) and dried over anhydrous sulfurDrying on sodium acid. The solvent was evaporated to about 80 ml and the mixture was filtered through a glass filter. The filter cake was washed with acetone (150 ml. Times.3) to afford the desired product II-2 as a pale yellow solid (12.5 g, 36% over the two steps).

¹ H NMR (400 MHz, methanol-d 4) δ 10.25 (s, 1H), 8.63 (d, J =2.5hz, 1h), 8.06 (d, J =8.1hz, 1h), 7.99 (dd, J =7.1,1.3hz, 1h), 7.84 (d, J =8.9hz, 1h), 7.45 (dd, J =8.1,7.1hz, 1h), 7.17 (dd, J =8.9,2.4hz, 1h).

¹³ C NMR (101 MHz, methanol-d 4) delta 195.6, 160.0, 139.4, 136.5, 133.6, 131.4, 131.2, 130.2, 123.0, 120.1, 107.9.

Synthesis of IIa

To a solution of potassium hydroxide (22.4 g, 400 mmol) in anhydrous ethanol (100 ml) was slowly added 7-hydroxy-1-naphthaldehyde II-2 (17.2 g, 100.0 mmol) at 0 ℃ to form an orange suspension. The mixture was stirred at 0 ℃ for a further 30 minutes. Subsequently, a solution of acetone (3.7 ml, 50 mmol) in absolute ethanol (20 ml) was added dropwise over 30 minutes via a dropping funnel. The mixture was warmed to room temperature and stirred at the same temperature. After completion (about 12 hours), the dark red mixture was carefully poured into 0 ℃ aqueous hydrochloric acid (3.0M, 200 mL). The mixture was then stirred vigorously for 10 minutes and then allowed to stand in an ice bath for 20 minutes. The mixture was then filtered through a glass frit and the red cake was washed with water (100 ml × 2) and absolute ethanol/water (100 ml × 2, v/v =1. The red solid was dried under vacuum at 60 ℃ to give dienone II-3 (16.7 g, 91% yield). The orange solid was used directly in the next step without further purification.

Next, dienone II-3 (6.0 g, 16.4 mmol) was dissolved in tetrahydrofuran (60 ml), and palladium on carbon (600 mg, 10 wt%) was added thereto. The mixture was transferred to a Parr autoclave, flushed three times with hydrogen and finally pressurized to 3 bar. The mixture was stirred at room temperature for 1.5 hours and the hydrogen was carefully released in a fume hood. The mixture was filtered through a pad of bluestone and the filter cake was washed with ethyl acetate (30 ml. Times.3). The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (eluent: hexane/acetone =5, 1 → 2).

¹ H NMR (400 MHz, methanol-d 4) δ 7.66 (d, J =8.8hz, 2h), 7.54 (d, J =7.6hz, 2h), 7.25-7.20 (m, 2H), 7.16-6.98 (m, 6H), 3.22-3.05 (m, 4H), 2.85-2.66 (m, 4H).

¹³ C NMR (101 MHz, methanol-d 4) delta 212.2,156.7,136.2,134.4,131.5,130.2,127.7,127.2,123.6,118.8,106.2,44.1,28.0.

IR(thin film)2925,2698,1625,1515,1457,1377,1257,1201,1100,830,739cm-1。

HRMS(ES+)C ₂₅ H ₂₂ NaO ₃ 393.1461, 393.1466.

3. Synthesis of chiral monophosphoryl amide ligands

The general procedure was as follows. In a dry flask equipped with a stir bar, the chiral diol I (352 mg, 1.0 mmol) was dissolved in dry tetrahydrofuran (5.0 ml) at 0 ℃. Triethylamine (1.01 g, 10.0 mmol) was added. Dimethyl phosphoroamidite chloride (3.0 mmol) was then added to the solution. After that, the reaction mixture was warmed to room temperature. Progress was monitored by thin layer chromatography. After completion, the mixture was diluted with ether (20 ml), washed with distilled water and brine, dried over sodium sulfate, and concentrated. Flash evaporating the residue with silica gel to obtain pure product VI.

(according to the general procedure (eluent: hexane/diethyl ether = 15).

[α]D ²³ ：+654.6(c＝1.0，CH ₂ Cl ₂ )。

¹ H NMR(400MHz，CDCl ₃ )δ7.83-7.67(m，4H)，7.44-7.27(m，5H)，6.97(d，J＝8.8Hz，1H)，3.54-3.35(m，2H)，3.16-2.96(m，2H)，2.48-1.98(m，10H)。

¹³ C NMR(101MHz，CDCl ₃ )δ145.7(d，J＝3.7Hz)，142.2(d，J＝4.5Hz)，136.2(d，J＝5.8Hz)，134.4(d，J＝2.0Hz)，134.2，133.8，132.3(d，J＝1.5Hz)，132.1，130.5，130.4(d，J＝2.3Hz)，128.5，127.8，126.7，126.6，125.4，125.4，125.2，124.3(d，J＝5.7Hz)，124.2，123.9，42.8，34.1，34.0，27.3，27.1。

³¹ P NMR(162MHz，CDCl3)δ115.20。

IR (film) 3049, 2924, 2357, 1596, 1446, 1366, 1313, 1266, 1197, 950, 830, 743, 685, 643, 557cm ^-1 。

HRMS(CI+)C ₂₇ H ₂₅ NO ₂ Theoretical value of P (M + H) ⁺ ) 426.1617, found 426.1617.

(R) -VIb was prepared from (R) -Ia (> 99% ee,352.0 mg, 1.0 mmol) and dimethylphosphamine chloride (516 mg, 3.0 mmol) according to the general procedure (eluent: hexane/ethyl acetate = 15) as a white foam in 80% yield (362.0 mg).

[α]D ²³ ：+551.2(c＝1.0，CH2Cl2)。

¹ H NMR(400MHz，CDCl ₃ )δ7.77(d，J＝8.7Hz， ¹ H)，7.75-7.69(m，2H)，7.66(d，J＝8.7Hz，1H)，7.42-7.24(m，5H)，7.07(d，J＝8.7Hz，1H)，3.56-3.30(M，2H)，3.17-2.98(M，2H)，2.88-2.31(M，5H)，2.29-2.18(M，1H)，2.17-1.99(M，2H)，1.00(s，6H)。

¹³ C NMR(101MHz，CDCl ₃ )δ146.2(d，J＝4.1Hz)，142.5(d，J＝4.8Hz)，136.1(d，J＝5.9Hz)，134.2，134.2，133.9，132.3，132.0，130.5(d，J＝2.5Hz)，130.3，128.4，127.4，126.6，126.6，125.6，125.4，125.3，124.7(d，J＝5.9Hz)，124.2，123.8，42.8，34.1，33.9，27.3，27.2，14.9。

³¹ P NMR(162MHz，CDCl3)δ118.86。

IR (thin film) 3051, 2968, 2927, 2358, 1596, 1504, 1449, 1264, 1198, 1024, 940, 830, 744, 679, 642cm ^-1 。

HRMS(CI+)C ₂₉ H ₂₉ NO ₂ Theoretical value of P (M + H +): 454.1930, found 454.1929.

(R, RN) -VIc was prepared from (R) -Ia (> 99% ee,352.0 mg, 1.0 mmol) and 1, 1-dichloro-N, N-bis ((R) -1-phenylethyl) phospham (975 mg, 3.0 mmol) as a white foam in 80% yield (485 mg) according to the general procedure (eluent: hexane/ethyl acetate =15 to 10.

[α]D ²³ ：+462.2(c＝1.0，CH ₂ Cl ₂ )。

¹ H NMR(400MHz，CDCl ₃ )δ7.80-7.53(m，4H)，7.46-6.61(m，16H)，4.31(s，2H)，3.47-3.23(m，2H)，3.11-3.01(m，1H)，2.95-2.86(m，1H)，2.61-2.48(m，1H)，2.18-0.97(m，9H)。

¹³ C NMR(101MHz，CDCl ₃ )δ146.6(d，J＝5.5Hz)，143.2(d，J＝5.8Hz)，135.3(d，J＝6.2Hz)，134.1，133.7，133.6(d，J＝1.8Hz)，132.2，132.1，130.8，130.20(d，J＝2.4Hz)，128.5，127.9，127.7，126.5(d，J＝15.6Hz)，125.8，125.71，125.2，124.5(d，J＝6.7Hz)，124.1，123.9，52.3，43.2，34.4，34.0，31.5，27.5，26.9，22.6，14.1。

³¹ P NMR(162MHz，CDCl ₃ )δ120.59。

IR (thin film) 3050, 2968, 2930, 2356, 1598, 1500, 1447, 1371, 1321, 1196, 939, 831, 743cm ^-1 。

HRMS(ES+)C ₄₁ H ₃₇ NO ₂ Theoretical value of P (M +): 606.2556, found: 606.2562.

(R, SN) -VId was prepared from (R) -Ia (> 99% ee,352.0 mg, 1.0 mmol) and 1, 1-dichloro-N, N-bis ((S) -1-phenylethyl) phospham (975 mg, 3.0 mmol) as a white foam in 76% yield (456 mg) according to the general procedure (eluent: hexane/ether = 15.

[α]D ²³ ：+226.7(c＝1.0，CH ₂ Cl ₂ )。

³¹ P NMR(162MHz，CDCl ₃ )δ120.59。

IR (film) 3052, 2969, 2929, 2361, 2165, 1597, 1448, 1265, 1198, 947, 830, 744, 698cm ^-1 。

HRMS(ES+)C ₄₁ H ₃₇ NO ₂ Theoretical value of P (M +): 606.2556, found: 606.2567.

4. synthesis of chiral phosphoric acid

5.1 Synthesis of (R) -VII-1

To a suspension of sodium hydride (60% dispersed in mineral oil, 430 mg, 18 mmol) in anhydrous tetrahydrofuran (20 ml) was slowly added a solution of (R) -Ia (> 99% ee,2.70 g, 7.7 mmol) in anhydrous tetrahydrofuran (50 ml) under a nitrogen atmosphere at 0 deg.C. The mixture was stirred at room temperature for 2 hours, then bromomethyl ether (1.7 ml, 18 mmol) was added in one portion at 0 ℃. The mixture was stirred at room temperature for a further 1 hour. Subsequently, the reaction mixture was cooled to 0 ℃ and quenched by dropwise addition of saturated aqueous ammonium chloride solution (20 ml) and water (20 ml). The resulting mixture was extracted with diethyl ether (20 ml x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 40) to give the product (R) -VII-1 as a white solid in 94% yield (3.20 g, 7.2 mmol).

[α]D ²³ ：+232.1(c＝1.0，CH2Cl2)。

¹ H NMR(400MHz，CDCl3)δ7.75–7.66(m,4H),7.39–7.28(m,6H),4.50(d,J＝6.7Hz,2H),4.34(d,J＝6.7Hz,2H),3.44–3.31(m,2H),3.15–3.04(m,2H),2.93(s,6H),2.66–2.54(m,2H),2.51–2.42(m,2H)。

¹³ C NMR(101MHz，CDCl ₃ )δ150.6,134.7,130.9,130.5,129.9,126.7,125.9,123.9,123.1,116.5,94.8,55.4,40.5,30.5,26.8。

IR 3048,2939,2839,2359,1594,1506 1449,1351,1246,1193,1147,1012,920,822,742,611,552cm ^-1 。

HRMS(ES+)C ₂₉ H ₂₈ NaO ₄ ⁺ (M+Na ⁺ ) Has a theoretical value of 463.1880 and an actual value of 463.1882.

5.2 Synthesis of (R) -VII-2

To a solution of (R) -VII-1 (3.0 g, 6.7 mmol), distilled N, N' -tetramethylethylenediamine (2.6 ml, 17.7 mmol), and dehydrated ether (100 ml) was added dropwise N-butyllithium (2.4M in hexane, 7.1 ml, 17.7 mmol) at 0 ℃ under a nitrogen atmosphere. After stirring for 0.5 h, the reaction was slowly warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled to-78 ℃ and a solution of iodine (5.46 g, 21.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added in one portion. The reaction mixture was slowly warmed to 0 ℃, stirred for 1 hour, and then quenched with a saturated aqueous solution of sodium sulfite (20 ml) and water (20 ml). The resulting mixture was extracted with ether (15 ml x 3) and the combined organic layers were dried over sodium sulfate and concentrated. The crude product (620 mg) was used in the next step without further purification.

To a solution of the above crude product in 1, 4-dioxane (80 mL) was added aqueous hydrochloric acid (6.0M, 30 mL). The mixture was stirred at 80 ℃ for 4 hours, then cooled to room temperature and water (100 ml) was added. The resulting mixture was extracted with dichloromethane (20 ml × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 40) to give the product (R) -VII-2 as a white solid with a yield of 60% in 2 steps (2.4 g, 3.98 mmol).

[α]D ²³ ：+261.6(c＝1.0，CH2Cl2)。

¹ H NMR(400MHz，CDCl ₃ )δ8.30(s，2H)，7.62-7.55(m，2H)，7.37-7.30(m，4H)，5.31(s，2H)，3.35-3.21(m，2H)，3.13-3.02(m，2H)，2.49-2.34(m，4H)。

¹³ C NMR(101MHz，CDCl3)δ147.7，138.1，133.4，131.0，130.0，125.6，125.4，124.0，122.0，89.4，41.1，29.8，26.1。

IR (film) 3459, 2937, 1571, 1485, 1418, 1358,1263，1195，869，753 ^cm-1 。

HRMS(ES-)C ₂₅ H ₁₇ I ₂ O ₂ ^- theoretical value of (M-H +) 602.9323, measured value 602.9323.

5.3 Synthesis of (R) -VII-3

In a 25 ml round bottom flask equipped with a stir bar were added (R) -VII-2 (188 mg, 0.3 mmol), potassium carbonate (219 mg, 1.6 mmol), 3, 5-bis (trifluoromethyl) phenylboronic acid (771 mg, 3.0 mmol), palladium acetate (1.6 mg, 7 μmol), diamantanyl butylphosphine (3.2 mg, 9 μmol), dimethoxyethane (2.0 ml) and water (2.0 ml) at room temperature. The blast furnace was evacuated and nitrogen was reinjected 5 times. The mixture was then stirred under nitrogen at 90 ℃ for 24 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction mixture, followed by extraction with dichloromethane (20 ml × 3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 40) to give the product (R) -VII-3 as a white solid in 99% yield (230 mg).

[α]D ²³ ：+159.0(c＝1.0，CH ₂ Cl ₂ )。

1H NMR (400 MHz, acetone-d 6) δ 8.12 (d, J =1.7hz, 4H), 7.98 (S, 2H), 7.94 (S, 2H), 8.85-7.75 (M, 2H), 7.44-7.30 (M, 4H), 6.57 (S, 2H), 3.50-3.30 (M, 2H), 3.11 (Dt, J =16.3,3.5hz, 2h), 2.68-2.47 (M, 4H).

¹³ C NMR (101 MHz, acetone-d 6) δ 148.4, 142.1, 134.7, 131.9 (q, J =33.2 Hz), 131.4,131.0, 130.7, 130.2, 129.7, 127.7, 126.4, 126.2, 124.7, 124.6 (q, J =273.1 Hz), 121.6 (q, J =3.4 Hz), 41.5, 31.1, 26.9.

¹⁹ F NMR (376 MHz, acetone-d 6) delta-63.3.

IR (film) 3465, 1426, 1368, 1271, 1178, 1131, 896, 755, 700cm-1.

HRMS(ES-)C ₄₁ H ₂₃ F ₁₂ O ₂ ^- 775.1511, found 775.1509.

5.4 Synthesis of (R) -VII-4

To a 25 ml round bottom flask equipped with a stir bar were added (R) -VII-2 (132 mg, 0.22 mmol), potassium carbonate (161 mg, 1.2 mmol), 1-pyrenyl boronic acid (541 mg, 2.2 mmol), palladium acetate (1.1 mg, 4.7 μmol), diamantanyl butyl phosphine (2.1 mg, 6.0 μmol), dimethoxyethane (2.0 ml) and water (2.0 ml) at room temperature. The blast furnace was evacuated and nitrogen was reinjected 5 times. The mixture was then stirred at 90 ℃ for 24 hours under nitrogen. After cooling to room temperature, a saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, followed by extraction with dichloromethane (20 ml × 3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 40) to give the product (R) -VII-4 as a white solid in 99% yield (175 mg) as a mixture of diastereomers due to axial chirality.

[α]D ²³ ：+40.9(c＝1.0，CH ₂ Cl ₂ )。

¹ H NMR(400MHz，DMSO-d6)δ8.51(dd，J＝62.1，7.7Hz，1H)，8.34(d，J＝8.7Hz，1H)，8.26-8.05(m，8H)，8.04-7.87(m，3H)，7.87-7.76(m，2H)，7.76-7.62(M，2H)，7.56-7.35(M，5H)，7.26-6.75(M，5H)，5.69(S，1H)，3.36-3.16(M，2H)，3.13-2.86(M，2H)，2.79-2.31(M，4H)。

¹³ C NMR(101MHz，DMSO-d6)δ148.7，133.9，133.87，133.82，133.7，133.5，130.93，130.87，130.8，130.6，130.5，130.3，130.2，130.19，130.13，129.6，129.5，129.2，128.84，128.75，128。6,128.5,128.3,127.7,127.6,127.5,127.3,127.2,126.4,126.2,126.1,125.9,125.7,125.5,125.3,125.2,125.0,124.7,124.4,124.2,124.1,124.08,124.00,122.5,55.0,30.0,26.3.

IR (film) 3452, 3040, 2929, 2351, 1923, 1671, 1600.1424, 1365, 1250, 1187, 1030, 841, 746cm ^-1 。

HRMS(ES+)C ₅₇ H ₃₆ NaO ₂ ⁺ Theoretical value of (M + Na +): 775.2608, found: 775.2617.

5.5 Synthesis of (R) -VIIa

Phosphorus oxychloride (7.5 mmol) was added to a solution of (R) -VII-3 (260 mg, 0.33 mmol) in pyridine (2.5 mL) at 0 deg.C under nitrogen. The mixture was heated to 90 ℃ and stirred at the same temperature for 24 hours. The mixture was then cooled to 0 ℃ followed by slow addition of water (1.0 ml) and 1, 4-dioxane (2.0 ml). Next, the mixture was heated to 90 ℃ and stirred at the same temperature for 48 hours, then cooled to room temperature, diluted with dichloromethane (10 ml), and washed with aqueous hydrochloric acid (1.0 m,20 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (10 ml x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 40). The resulting product was redissolved in dichloromethane (4.0 ml) and treated with aqueous hydrochloric acid (3.0M, 2.0 ml). The organic layer was separated, dried over sodium sulfate, and evaporated to give the desired chiral phosphoric acid (R) -VIIa as a white solid in 91% yield (255 mg).

[α]D ²³ ：+456.0(c＝1.0，CH ₂ Cl ₂ )。

¹ H NMR (400 MHz, acetone-d 6) Δ 8.24 (s, 4H), 8.14 (s, 2H), 8.05-7.89 (m, 4H), 7.60-7.39 (m, 4H), 3.60-3.40 (m, 2H), 3.15 (dd, J =17.5,3.0Hz, 2H), 2.49 (td, J =14.1,4.9Hz, 2H), 2.25-2.14(m，2H)。

¹³ C NMR (101 MHz, acetone-d 6) delta 142.2, 141.4,141.3,137.1,137.0,135.1,134.28,134.25,133.68,133.67,131.7 (q, J =33.2 Hz), 131.5,131.4,131.03,131.01,130.7,128.2,127.5,126.7,124.6 (q, J =273.1 Hz), 121.5 (q, J =3.8 Hz), 45.89,45.87,35.4,27.6.

³¹ P NMR(162MHz,acetone-d6)δ-13.1。

¹⁹ F NMR (376 MHz, acetone-d 6) delta-63.1.

IR (film) 3049,2356,1595,1506,1452,1357,1272,1185,1139,1072,1012,921,822,744cm ^-1

HRMS(ES+)C ₄₁ H ₂₃ F ₁₂ NaO ₄ P ⁺ Theoretical (M + Na +): 861.1035, found: 861.1037.

5.6 Synthesis of (R) -VIIb

Phosphorus oxychloride (7.5 mmol) was added to a solution of (R) -VII-4 (250 mg, 0.33 mmol) in pyridine (2.5 ml) at 0 degrees celsius under nitrogen. The mixture was heated to 90 ℃ and stirred at the same temperature for 24 hours. The mixture was then cooled to 0 ℃ followed by slow addition of water (1.0 ml) and 1, 4-dioxane (2.0 ml). Subsequently, the mixture was heated to 90 ℃ and stirred at the same temperature for 48 hours, then cooled to room temperature, diluted with dichloromethane (10 ml), and washed with aqueous hydrochloric acid (1.0M, 20 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (10 ml x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 40). The resulting product was redissolved in dichloromethane (4.0 ml) and treated with aqueous hydrochloric acid (3.0M, 2.0 ml). The organic layer was separated, dried over sodium sulfate, and evaporated to give the desired chiral phosphoric acid (R) -VIIb as a white solid in 74% yield (200 mg) as a mixture of diastereomers due to axial chirality.

[α]D ²³ ：+378.3(c＝0.5,CH ₂ Cl ₂ )。

¹ H NMR(400MHz，DMSO-d 6)δ8.27-7.72(m，20H)，7.72-7.36(m，6H)，3.50-3.32(m，2H)，3.28-3.06(m，2H)，2.63-2.43(m，2H)，2.34-2.16(m，2H)。

¹³ C NMR(101MHz,DMSO-D ₆ )δ142.2,135.2,134.9,131.2,133.6,132.9,130.5,130.34,130.28,129.9,129.3,129.5,128.8,128.3,127.5,127.3,126.8,126.2,125.8,125.4,125.2,125.1,124.5,123.9,123.7,123.3,44.5,44.3,35.0,29.1,26.7

³¹ P NMR(162MHz，DMSO-d ₆ )δ-12.80，-13.12，-13.59。

IR (film) 3042, 2921, 2853, 2354, 1594, 1413, 1262, 1169, 1088, 956, 841, 728, 564cm ^-1 。

HRMS(ES+)C ₅₇ H ₃₅ NaO ₄ P ⁺ Theoretical value of (M + Na +): 837.2166, found: 837.2175.

6. application of chiral monophosphoryl amide ligand and chiral phosphoric acid

6.1 Use of (R) -VIa

6.1.1 asymmetric hydrogenation of dehydroamino acid derivatives VIIIa

To a vial equipped with a magnetic stir bar, bis (1, 5-cyclooctadiene) tetrafluoroboric acid (3.5 mg, 0.01 mmol), (R) -VIa (8.5 mg, 0.02 mmol) and anhydrous dichloromethane (1.0 ml) were added under nitrogen. The mixture was stirred for 30 minutes. A solution of the chiral rhodium complex (0.1 ml) was then added to the dehydroamino acid derivative VIIIa (44.0 mg, 0.2 mmol) in dry toluene (2.0 ml). The reaction mixture was transferred to an autoclave and washed with H ₂ Gas (a)<10 bar) was backfilled three times and finally the autoclave was at 10 bar H ₂ And (4) pressing. The mixture was stirred at room temperature for 8 hours. The solution was concentrated in vacuo and sampled ¹ H NMR measurement of conversion. The residue was purified by silica gel column chromatography to give the hydrogenation product IXa as a white solid in 99% yield (43.6 mg, 99% ee).

[α]D ²³ :-57.2(c＝1.0,CH ₂ Cl ₂ ). The product was subjected to the following HPLC analysis: a Daicel CHIRALPAK AD-H column; 10% in n-hexane i-PrOH;1.0 ml/min; the retention time. 9.4 min (main peak), 13.0 min (secondary peak).

¹ H NMR(400MHz，CDCl ₃ )δ7.32-7.19(m，3H)，7.12-7.05(m，2H)，6.05(s，1H)，4.92-4.83(m，1H)，3.71(s，2H)，3.18-3.02(m，2H)，1.97(s，2H)。

¹³ C NMR(101MHz,CDCl ₃ )δ172.1,169.6,135.8,129.2,128.5,127.1,53.1,52.2,37.8,23.0。

6.1.2 asymmetric hydrogenation of dehydroamino acid derivatives VIIIb

To a vial equipped with a magnetic stir bar, bis (1, 5-cyclooctadiene) tetrafluoroboric acid (3.7 mg, 0.01 mmol), (R) -VIa (8.5 mg, 0.02 mmol), and anhydrous dichloromethane (1.0 ml) were added under nitrogen. The mixture was stirred for 30 minutes. Then a solution of the chiral rhodium complex (0.6 ml) was added to the dehydroamino acid derivative VIIIb (94.2 mg, 0.6 mmol) in dry Tol (6.0 ml). The reaction mixture was transferred to an autoclave and washed with H ₂ Gas (a)<5 bar) was backfilled three times and finally the autoclave was at 5 bar H ₂ And (4) pressing. The mixture was stirred at room temperature for 12 hours. The solution was concentrated in vacuo and sampled ¹ H NMR measures the conversion. The residue was purified by silica gel column chromatography to give the hydrogenation product IXb as a colorless oil in 99% yield (92.5 mg, 98% ee).

[α]D ²³ :-5.8(c＝1.0,CH ₂ Cl ₂ ). The product was subjected to the following HPLC analysis: daicel CHIRALCEL OD-H column; 5% i-PrOH in n-hexane; 1.0 ml/min; the retention time. 13.8 min (main peak)) 20.6 min (minor peak).

¹ H NMR(400MHz，CDCl ₃ )δ6.16(s，1H)，4.61-4.51(m，1H)，3.72(s，3H)，2.01(s，3H)，1.92-1.79(m，1H)，1.77-1.62(m，1H)，0.88(t，J＝7.5Hz，3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ173.04,169.79,53.15,52.25,25.55,23.09,9.41。

6.1.3 asymmetric hydrogenation of dehydroamino acid derivative VIIIc

To a vial equipped with a magnetic stir bar, bis (dicyclopentadiene) tetrafluoroboric acid 4 (3.7 mg, 0.01 mmol), (R) -VIa (8.5 mg, 0.02 mmol), and anhydrous dichloromethane (1.0 ml) were added under nitrogen. The mixture was stirred for 30 minutes. A solution of the chiral rhodium complex (0.4 ml) was then added to a solution of the dehydroamino acid derivative VIIIc (118 mg, 0.8 mmol) in anhydrous Tol (8.0 ml). The reaction mixture was back-filled three times with H2 gas. The mixture was stirred at room temperature under an atmosphere of H2 for 24 hours. The solution was concentrated in vacuo and sampled ¹ H NMR measures the conversion. The residue was purified by silica gel column chromatography to give the hydrogenation product IXc as a colorless oil in 99% yield (116.8 mg, 99% ee).

[α]D ²³ ：+28.2(c＝1.0,CH ₂ Cl ₂ ). The product was subjected to the following HPLC analysis: daicel CHIRALCEL OD-H column; 5% in hexane i-PrOH;1.0 ml/min; when reserving: 13.8 min (main peak), 20.6 min (minor peak).

¹ H NMR(400MHz，CDCl 3)δ6.16(s，1H)，4.61-4.51(m，1H)，3.72(s，3H)，2.01(s，3H)，1.92-1.79(m，1H)，1.77-1.62(m，1H)，0.88(t，J＝7.5Hz，3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ173.04,169.79,53.15,52.25,25.55,23.09,9.41。

6.2 Application of (R, R N, R N) -VIc

6.2.1 rhodium catalyzed intermolecular hydroacylation

(R, R N, R N) -VIc (12.1 mg, 0.02 mmol) and 1,5 cyclooctadienerhodium chloride (4.9 mg, 0.01 mmol) were dissolved in dry dichloromethane (2.0 mL) and the solution was transferred to a Schlenk tube containing potassium phosphate (4.2 mg, 0.02 mmol), salicylaldehyde Xa (22. Mu.L, 0.2 mmol) and the homoallylsulfide Xb (46. Mu.L, 0.3 mmol). The reaction mixture was stirred at 0 ℃ for 72 hours by subjecting the reaction mixture to ¹ H NMR analysis to determine the branched/linear ratio (bl)>20:1. the crude product was purified by silica gel column chromatography to give the hydrogenated product XIa as a colorless oil in 91% yield (52.4 mg, 93% ee).

[α]D ²³ ：+55.0(c＝1.0,CH ₂ Cl ₂ ). The product was subjected to HPLC analysis: daicel CHIRALCEL OD-H column; 1% in n-hexane i-PrOH;1.0 ml/min; the retention time. 9.5 min (main peak), 10.3 min (secondary peak).

¹ H NMR(400MHz，CDCl ₃ )δ12.47(s，1H)，7.77-7.70(m，1H)，7.50-7.41(m，1H)，7.35-7.22(m，4H)，7.20-7.11(m，1H)，7.02-6.95(m，1H)，3.82-3.69(m，1H)，3.04-2.88(m，2H)，2.28-2.15(m，1H)，1.84-1.71(m，1H)，1.24(D，J＝6.9Hz，3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ209.7,163.1,136.4,135.8,129.8,129.1,128.9,126.0,118.9,118.7,118.4,38.7,32.5,31.2,17.5。

6.2.2 rhodium catalyzed intermolecular hydroacylation

(R, RN, RN) -VIc (6.1 mg, 0.01 mmol) and 1,5 cyclooctadienerhodium chloride (2.5 mg, 0.005 mmol) were dissolved in dry dichloromethane (2.0 mL) and the solution was transferred toSchlenk tube containing potassium phosphate (2.1 mg, 0.01 mmol), 2-hydroxy-1-naphthaldehyde Xc (34.6 mg, 0.2 mmol) and the same allyl sulfide Xb (46. Mu.l, 0.3 mmol). The reaction mixture was stirred at room temperature for 72 hours by subjecting the reaction mixture to ¹ H NMR analysis determined the branch/linear ratio (b: l) to be 8.7. The crude product was purified by silica gel column chromatography to give the hydrogenated product XIb as a colorless oil in 95% yield (63.8 mg, 82% ee).

[α]D ²³ : +50.1 (c =1.0, ch 2cl2). The product was subjected to HPLC analysis: daicel CHIRALCEL OD-H column; 2% i-PrOH in n-hexane; 1.0 ml/min; the retention time. 32.5 min (minor peak), 34.9 min (major peak).

¹ H NMR(400MHz，CDCl3)δ11.89(s，1H)，7.93(d，J＝8.5Hz，1H)，7.87(d，J＝9.0Hz，1H)，7.79(d，J＝8.0Hz，1H)，7.58-7.50(m，1H)，7.45-7。36(m，1H)，7.26-7.08(m，6H)，4.03-3.86(m，1H)，2.86(t，J＝7.4Hz，2H)，2.25-2.12(m，1H)，1.92-1.81(m，1H)，1.32(d，J＝6.7Hz，3H)。

¹³ C NMR(101MHz，CDCl ₃ )δ211.6，161.1，136.5，135.7，131.4，129.2(2C)，128.8，128.6，127.9，76.0，124.3，123.9，119.3，115.9，3.13。

IR (film) 3058, 2972, 2357, 1677, 1512, 1264, 1177, 1091, 825, 738cm ^-1 。

HRMS (ES-) for C ₂₁ H ₁₉ O ₂ The theoretical value of S (M-) is 335.1111, and the actual value is 335.1100.

6.3 Use of (R) -VIIa

Enantioselective spiro cyclization reaction of keto substrate IIa catalyzed by (R) -VIIa for the synthesis of (S) -Ia

IIa (10.05 g, 27.1 mmol), (R) -VIe (22.4 mg, 27. Mu.mol) and 135 ml of toluene were added to a 250 ml flask with a magnetic stir bar. After completion of the reaction, the solvent was evaporated, and the residue was filtered through a short pad of silica gel (eluent: dichloromethane) to give the product (S) -Ia as a white solid in a yield of 89% (8.45 g, 93% ee).

The product was subjected to HPLC analysis: a Daicel CHIRALPAK AD-H column; 20% in n-hexane i-PrOH;1.0 ml/min; retention time: 9.2 min (minor peak), 13.9 min (major peak).

6.4 Use of (R) -VIIb

(R) -VIIb catalyze the intramolecular desymmetrization of oxirane XII.

A mixture of XII (24.3 mg, 0.1 mmol) and (R) -VIIb (8.2 mg, 0.01 mmol) in toluene (1.0 ml) was stirred at 50 ℃ for 36 h. Next, the reaction mixture was filtered through a short pad of gel (eluent: hexane/ethyl acetate =2. The filtrate was concentrated to give the desired product XIII as a white solid in 99% yield (62% ee).

[α]D ²³ ：+58.4(c＝1.0,CH ₂ Cl ₂ ). The product was subjected to HPLC analysis: daicel CHIRALPAK IC column; 30% i-PrOH in n-hexane; 1.0 ml/min; the retention time. 5.9 min (main peak), 10.5 min (secondary peak).

¹ H NMR(400MHz，CDCl ₃ )δ11.74(s，1H)，8.21(d，J＝9.4Hz，1H)，7.70(dd，J＝25.7，8.1Hz，2H)，7.46(ddd，J＝8.2，6.7，1.3Hz，1H)，7。36-7.26(m，2H)，4.64-4.49(m，2H)，4.48-4.37(m，1H)，4.01-3.89(m，1H)，3.74(dd，J＝11.7，3.4Hz，1H)，2.04(s，1H)。

¹³ C NMR(101MHz，CDCl3)δ166.5，155.1，136.7，129.9，128.7，128.3，127.0，126.3，123.6，112.5，110.8，68.6，67.2，63.8。

IR (film) 3384, 3052, 2920, 2729, 2356, 1646, 1521, 1461, 1359, 1306, 1209, 1143, 1045, 957, 872, 745cm ^-1 。

HRMS (ES-) for C ₁₄ H ₁₂ NO ₃ Theoretical value of- (M-H +) 242.0822, measured value of 242.0816.

Comparative example

When (R) -VIa is used as a ligand, the product can be obtained with more excellent enantiomeric excess (ee).

Intermolecular hydroacylation reaction:

when (R, RN, RN) -VIc is used as a ligand, the product can be obtained with more excellent yield, ee and regioselectivity.

Enantioselective spiro synthesis reaction:

in this reaction, when 1mol% of (R) -VIIa was used as a catalyst, the 95% yield and 95% ee values of the resulting product were significantly better than those of (R) -SPINOL-3,5- (CF) ₃ ) ₂ C ₆ H ₂ 83% yield and 90% ee obtained with-OH catalyst. Furthermore, when the amount of (R) -VIIa used was decreased to 0.1mol%, 89% yield and 93% ee were obtained, which was even better than those obtained when 2mol% of (R) -SPINOL-3,5- (CF 3) 2C6H2-OH was used (89% yield and 90% ee), demonstrating the superior catalytic activity and chirality induction ability of the SPHENOL skeletal chiral catalyst.

Intramolecular desymmetrization reaction:

in the reaction, compared with catalysts with BINOL and SPINOL frameworks, the catalyst (R) -VIIb with the SPHENOL framework has better catalytic activity and chiral control capability at the same time, and the SPHENOL framework chiral catalyst is proved to have the advantages of good catalytic activity of the BINOL catalyst and good chiral control capability of the SPINOL catalyst at the same time.

It is to be understood that the above embodiments are merely exemplary embodiments that have been employed to illustrate the principles of the present disclosure, which, however, is not to be taken as limiting the disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the disclosure, and these are to be considered as the scope of the disclosure.

Claims

1. A chiral spiro compound represented by the formula:

SPHENOL represents the structure represented by formula I below,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

x represents C or a heteroatom selected from N, O, S and P,

a and B each independently represent-OH, -SO ₃ H. -P, -O-, C1-C6 alkylene, heteroaryl, amino and-SO ₂ -at least one of wherein a and B may optionally be taken by at least one substituentGeneration;

m1 and m2 are 0 or 1;

SPHENOL-A represents an enantiomer of SPHENOL;

m ₃ and m ₄ Represents a number of 0 or 1, and,

m represents 0 or 1;

* Indicates absence or indicates a point of attachment to Z;

represents a single bond or is absent.

2. Chiral spiro compound according to claim 1, characterised in that R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently located ortho, meta or para to the respective aromatic ring.

3. Chiral spiro compound according to any of claims 1 to 2, characterized in that R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently is optionally substituted by-CF ₃ Substituted phenyl or

4. Chiral spiro compound according to any of claims 1 to 2, wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently is-OR, -OH, -NH ₂ 、-NHR、-NR ¹¹ R ¹² 、-F、-Cl、-Br、-I、-SR、-PR ¹³ R ¹⁴ or-SeR, where R ¹¹ 、R ¹² Each independently hydrogen or C1-6 alkyl, R ¹³ And R ¹⁴ Each independently is carbonyl, hydroxy, hydrogen or C1-6 alkyl.

5. The chiral spiro compound according to any one of claims 1 to 4, wherein said chiral spiro compound is selected from at least one of the following:

wherein R and R' each independently represent C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, an optionally substituted heterocyclic aryl hydrogen or a substituent having a hetero atom, X, n and O (S) are as defined in claim 1, ar represents an aryl group, and P represents phosphorus.

6. Chiral spiro compounds according to claim 1, characterized in that two R are ¹⁵ Are C1-C6 alkylene groups each substituted with an aryl group and are enantiomers of each other.

7. Chiral spiro-compound according to claim 1, characterized in that when each group is substituted the substituents are selected from aryl, -NR ₂ ', polycyclic aromatic hydrocarbon ring group, optionally substituted heterocyclic aryl or C1-C6 alkyl.

8. Chiral spiro compound according to any of claims 1 to 7, characterized in that the compound is selected from any of the following:

where Me represents a methyl group, et represents an ethyl group and Ph represents a phenyl group.

9. A process for preparing a chiral spiro compound, characterized by comprising the step of converting a ketone compound represented by the following formula II into a bisnaphthol compound represented by the following formula I in the presence of a chiral acid catalyst and a solvent:

，

and

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

a and B both represent-OH;

m1 and m2 are 1;

* Indicates absence; and

x represents C or a heteroatom selected from N, O, S and P.

10. The process according to claim 9, characterized in that the chiral acid catalyst is selected from at least one of the following:

11. Process according to claim 9 or 10, characterized in that the solvent is chosen from chlorobenzene, phCF ₃ 、PhF、CCl ₄ 、DCM、CHCl ₃ At least one solvent selected from PhMe and DCE.

12. The process according to claim 9 or 10, wherein the chiral spiro compound is a chiral ligand compound, and the process comprises converting the bis-naphthol compound represented by formula I into the chiral ligand compound represented by the following formula:

SPHENOL represents a structure represented by the following formula,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Each independently of the otherOptionally substituted C _1-100 An alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, or an optionally substituted heterocyclic aryl group,

n is selected from the integer of 0 to 5,

d represents a C atom or a Si atom,

x represents C or a heteroatom selected from N, O, S and P,

m1 and m2 are 0 or 1;

z represents-PN (R) ¹⁵ ) ₂ 、-PR ₂ ', optionally substituted with R ₂ ' substituted phenylene radicals, B ^- ，N ⁺ 、

SPHENOL-A represents an enantiomer of SPHENOL;

m ₃ and m ₄ Represents a number of 0 or 1, and,

m represents 0 or 1;

* Indicates absence or indicates a point of attachment to Z;

represents a single bond or is absent.

13. The process according to claim 9 or 10, characterized in that the chiral acid catalyst is a (S) -type chiral phosphoric acid, which catalyzes the reaction to provide a chiral spiroglycol having an inverted configuration.

14. Use of a compound according to any one of claims 1 to 8 in asymmetric catalytic reactions, intermolecular hydroacylation reactions, enantioselective spiro synthesis reactions or intramolecular desymmetrization reactions.

15. Use according to claim 14, characterized in that the asymmetric catalytic reaction comprises an asymmetric hydrogenation of one of the following:

16. use according to claim 14, characterized in that the intermolecular hydroacylation reaction is selected from one of the following:

and

17. use according to claim 14, characterized in that said enantioselective spiro synthesis reaction is selected from:

18. use according to claim 14, characterized in that said intramolecular desymmetrization reaction is selected from:

19. use of a compound according to any one of claims 1 to 8 as a chiral catalyst or chiral ligand.