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Title:
A NEW CHIRAL BIPHENYL DIPHOSPHINE LIGAND AND PROCESS FOR PREPARATION THEREOF
Document Type and Number:
WIPO Patent Application WO/2018/189107
Kind Code:
A1
Abstract:
The present invention is related to a new chiral biphenyl diphosphine ligand of formula (I), wherein R1, R2, and R3 are independently H, alkyl or aryl; R6 and R7 is independently a substituent; and A is independently aryl or heteroaryl, optionally substituted by one or more substituents, or a stereoisomer thereof, or a stereoisomeric mixture thereof.

Inventors:
BONRATH, Werner (Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
FENG, Zheng-Chuan (Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
MEDLOCK, Jonathan, Alan (Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
PENG, Kun (Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
ZHU, Zhibin (Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
Application Number:
EP2018/059021
Publication Date:
October 18, 2018
Filing Date:
April 09, 2018
Export Citation:
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Assignee:
DSM IP ASSETS B.V. (Het Overloon 1, 6411 TE Heerlen, 6411, NL)
International Classes:
C07F9/655; C07B53/00
Domestic Patent References:
WO1992016536A11992-10-01
Foreign References:
US20050014633A12005-01-20
US5302738A1994-04-12
EP0667350A11995-08-16
Other References:
NOYORI; TAKAYA, ACC. CHERN. RES., vol. 23, 1990, pages 345
OLKUMA ET AL., AM. CHERN. SOC., vol. 120, 1998, pages 13529
SCHMID ET AL., PURE &APPL. CHERN., vol. 68, 1996, pages 131
DAMIEN HERAULT, CHEM. SOC. REV., vol. 44, 2015, pages 2508 - 2528
CARLA S.M. PEREIRA, CHEMICAL ENGINEERING SCIENCE, vol. 64, no. 14, 15 July 2009 (2009-07-15), pages 3301 - 3310
SVENJA WERKMEISTER, ORG. PROCESS RES. DEV., vol. 18, no. 2, 2014, pages 289 - 302
Attorney, Agent or Firm:
KURT, Manfred (DSM Nutritional Products Ltd, Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
Download PDF:
Claims:
Claims

1. A compound of formula (I):

Wherein R1, R2, and R3 are independently H, alkyl or aryl;

R6 and R7 are independently a substituent; and

A is independently aryl or heteroaryl, optionally substituted by one or more substituents, or a stereoisomer thereof, or a stereoisomeric mixture thereof.

2. The compound of Claim 1, wherein R1, R2, R3, R6 and R7 are independently H or alkyl; and A is phenyl substituted by one or more substituents.

3. The compound of Claim 1 or 2, wherein A is phenyl, or

4. The compound of any one of Claims 1-3, wherein the compound of formula (I) is the following compound or mixture thereof:

5. The compound of any one of Claims 1-3, wherein the stereoisomer is an isomer of formula ilia) to (l-ld) or mixture thereof:

wherein R1, R2, R3, R6, R7 and A are defined as above.

6. The compound of any one of Claims 1-3, wherein the stereoisomer is the following isomers or mixture thereof:

Wherein R1, R2, R3, R6, R7 and A are defined as any one of claims 1-6,

or a stereoisomer thereof, or a stereoisomeric mixture thereof.

8. The compound of claim 7, wherein the stereoisomer is an isomer of formula (ll-la) to (ll-ld) or mixture thereof:

9. A process for producing the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, comprising:

Reducing the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, to produce the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof:

Wherein R1, R2, R3, R6, R7 and A are defined as any one of claims 1-6.

10. The process of claim 9, wherein the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, is produced by a process comprising:

1) Reacting the compound of formula (III) with a compound of formula HP=0(OR8)2 in a solvent, such as toluene and xylene, in the presence of a base, such as trimethylamine (Et3N), and a catalyst, preferably a Palladium catalyst such as PdCI2 and Pd(dppf)CI2, to produce the compound of formula (lll-l); and

2) Converting the compound of formula (lll-l) to the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof,

Wherein R , R , R , R and R are defined as above, and R is alkyl and X is halogen.

11. The process of claim 10, wherein the conversion of the step 2) is achieved by a Grignard reaction and a coupling reaction.

12. The process of claim 10 or 11, wherein the compound of formula (III) is produced by a process comprising:

a) Reacting the compound of formula (IV) with the compound of formula (V) to obtain a compound of formula (VI);

b) Reducing the obtained compound of formula (VI) to obtain a compound of formula (VI-1); and

(VI) (VI-1 ) c) Reacting the obtained compound of formula (VI-1) with the compound of formula (V-1) to produce the compound of formula (III),

(Ml)

Wherein R1, R2, R3, R6, R7 and X are defined as above; R4 is H, alkyl or aryl; and R5 is H.

13. The process of claim 12, wherein the compound of formula (III) is produced from the compound of formula (VI-1) by the following steps:

Step (c-1): converting the compound of formula (VI-1) into a compound of the formula (VI-2) by adding a leaving group:

(VI-1 )

Step (c-2): reacting the compound of formula (VI-2) with the compound of formula (V-1) to produce the compound of formula (III).

Wherein R1, R2, R3, R6, R7 and X are defined as above and Y is a leaving group such as toluenesulfonic (Ts) group or methanesulfonic (Ms) group.

14. A chiral transition metal catalyst containing a compound of any one of claims 1-6, and a transition metal, or an ion or a complex thereof.

15. The chiral transition metal catalyst of claim 14, wherein the transition metal is selected from the group consisting of iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium or platinum, and is especially ruthenium, rhodium or iridium.

16. A method for converting a prochiral substrate to a chiral product by using the chiral transition metal catalyst of the present invention in asymmetric reactions.

17. The method of claim 16, wherein the prochiral substrate is CAN and the chiral product is LAP.

Description:
A NEW CHIRAL BIPHENYL DIPHOSPHINE LIGAND AND PROCESS FOR PREPARATION THEREOF

Technical Field

The present invention is related to chemical products and processes for preparation thereof. In particular, the present invention is related to a new chiral biphenyl diphosphine ligand, the intermediate for the preparation of the ligand, and the processes for the preparation thereof. In addition, the present invention is also related to a chiral transition metal catalyst containing the new chiral biphenyl diphosphine ligand of the present invention and the use of the chiral transition metal catalyst of the present invention in asymmetric reactions.

Background of the present invention

Asymmetric catalysis is one of the most powerful methods for accessing a wide range of enantiomerically enriched compounds through the action of a chiral catalyst in a variety of asymmetric reactions. Highly promising candidates for asymmetric synthesis are transition metal complexes bearing chiral ligands. Despite the large number of chiral ligands employed in asymmetric synthesis, only a few have found a practical application in the manufacture of chiral molecules by the chemical and pharmaceutical industry.

Among these ligands, BINAP is one of frequently used chiral ligands. BINAP has been shown to be highly effective for many asymmetric reactions (Noyori and Takaya, Acc. Chern. Res., 1990,23,345; and Olkuma et al., Am. Chern. Soc, 1998, 120, 13529). Related axially dissymmetric ligands, such as MeO-BIPHEP and BIPHEMP have also been employed in a number of asymmetric reactions (Schmid et al., Pure &Appl. Chern., 1996,68,131; Foricher, Heiser and Schmid, U.S. Pat. No. 5,302,738; Michel, European Patent Application 0667350 Al; and Broger et al., WO 92/16536). The structures for BINAP, BIPHEMP and MeO-BIPHEP are illustrated as below.

(R)-BINAP (R)-BIPHEMP (R)-MeO-BIPHEP

Despite the extensive research in this area, there is still a variety of reactions in which only modest enantioselectivity has been achieved with these ligands. Thus, it remains highly desirable to develop novel chiral ligands that are selective and effective in a variety of asymmetric catalytic reactions, and are synthetically easily accessible.

Summary of the Invention The present invention provides a compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, which is a new chiral biphenyl diphosphine ligand:

(I)

Wherein R 1 , R 2 , and R 3 are independently H, alkyl or aryl;

R 6 and R 7 are independently a substituent; and

A is independently aryl or heteroaryl, optionally substituted by one or more substituents.

The present invention also provides a new intermediate and a process for the preparation of the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, of the present invention.

The present invention further provides a chiral transition metal catalyst containing: the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, of the present invention; and a transition metal, or an ion or a complex thereof.

The present invention additionally provides use of the chiral transition metal catalyst of the present invention in asymmetric reactions.

Detailed Description of the Invention

In the present application, the term "alkyl" refers to unsubstituted or substituted straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, cycloalkyl, alkoxy or aryl.

In the present application, the term "aryl" refers to a phenyl group, which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, cycloalkyl, halo or alkoxy.

In the present application, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteroatoms independently selected from N, 0 and S and includes thienyl, furyl, pyrrolyl, pyridyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Preferably, the heteroaryl is furyl or pyridyl. The term "cycloalkyi" refers to optionally substituted monocyclic aliphatic hydrocarbon groups of 3-6 carbon atoms, which may be substituted by one or more substituents, such as alkyl, alkoxy or halo.

The term "alkoxy" refers to alkyl-O-.

The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and iodine.

In the present application, the term "substituent(s)" refers to alkyl, cycloalkyi, alkoxy or halo.

In the first aspect, the present invention provides a compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof:

Wherein R 1 , R 2 , and R 3 are independently H, alkyl or aryl;

R 6 and R 7 are independently a substituent; and

A is independently aryl or heteroaryl, optionally substituted by one or more substituents.

Preferably, R 1 , R 2 , R 3 , R 6 and R 7 are independently H or alkyl, and more preferably, are independently H.

Preferably, A is phenyl optionally substituted by one or more substituents, and more preferably,

A is

More preferably, the compound of formula (I) is the following compound or mixture thereof:

LacBIPHEP or 3,5-t-Bu-4-MeO-LacBIPHEP

The stereoisomer of the compound of formula (I) includes enantiomers and diastereomers. For example, the stereoisomer of the compound of formula (I) is an isomer of formula (l-la) to (l-ld) or mixture thereof, due to the chiral center in the sidechain and also the axial chirality of the biphenyl system:

Wherein, R 1 , R 2 , R 3 , R 6 , R 7 and A are defined as above.

Preferably, the stereoisomer of the compound of formula (I) is the following isomers or mixture thereof:

-LacBIPHEP (S Ax ,R)-LacBIPHEP

(/¾ x ,S)-3,5-t-Bu- -MeO-LacBIPHEP (S Ax ,R)-3,5-t-Bu- -MeO-LacBIPHEP

The compounds of the present invention preferably have an optical purity of at least 85% enantiomeric excess (ee) and diastereomer excess (de), more preferably at least 95% ee and de, and most preferably at least 98% ee and de. In the second aspect, the present invention provides a new intermediate of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof:

Wherein R 1 , R 2 , R 3 , R 6 , R 7 and A are defined as above.

The stereoisomer of the compound of formula (II) includes enantiomers and diastereomers. For example, the stereoisomer of the compound of formula (II) is an isomer of formula (ll-la) to (II- ld) or mixture thereof, due to the chiral center in the sidechain and also the axial chirality of the biphenyl system:

The intermediate of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, may be used for the preparation of the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, according to the method disclosed herein.

In the third aspect, the present invention provides a process for the preparation of the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, comprising:

Reducing the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, to produce the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof:

Wherein R 1 , R 2 , R 3 , R 6 , R 7 and A are defined as above.

The above reduction may carried out as known in the art from phosphine oxides to phosphines (see Damien Herault ef. al., Chem. Soc. Rev., 2015(44), 2508-2528). In one embodiment, the compound of formula (II) is reduced with a reducing agent, such as trichlorosilane, in a solvent, such as xylene, toluene and tetrahydrofuran (TH F), in the presence of a base, such as trimethylamine and tributylamine, to provide the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof.

In the embodiment, the reducing agent may be added in an amount of from 2 moles to 20 moles, preferably from 2 moles to 10 moles, more preferably from 4 moles to 8 moles, per mole of the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof; the base may be added in a n a mount of from 2 moles to 20 moles, preferably from 2 moles to 10 moles, more preferably from 4 moles to 8 moles, per mole of the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof.

In the process, the reaction may be carried out under the temperature of from 50 °C to 200 °C, preferably from 100 °C to 160 °C, more preferably under reflux. Preferably, the reaction may be carried out under the protection of inert gases, such as nitrogen or argon .

The product of the process, i.e., the compound of the formula (I), or a stereoisomer thereof, or a stereoisomeric mixtu re thereof, may be easily purified from the reaction mixture, for example, by extraction, recrystallization and column chromatography for the further application.

In the present invention, the intermediate of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, may be produced by a process comprising:

1) Reacting the compound of formula (III) with a compound of formula H P=0(OR 8 ) 2 in a solvent, such as toluene and xylene, in the presence of a base, such as trimethylamine (Et 3 N), a nd a catalyst, preferably a Palladium cata lyst such as PdCI 2 and Pd(dppf)CI 2 , to produce the compound of formula (lll-l); and

2) Converting the compound of formula (lll-l) to the compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof.

Wherein R 1 , R 2 , R 3 , R 6 and R 7 are defined as above, and R 8 is alkyl and X is halogen.

In the step 1), the compound of formula HP=0(OR 8 ) 2 may be added in the amount of from 2 moles to 10 moles, preferably from 2 moles to 4 moles, per mole of the compound of formula (III); the solvent may be added in an amount of from 500 mL to 2000 mL, preferably from 800 mL to 1500 mL, more preferable from 1000 mL to 1200 mL, per mole of the compound of formula (III); and the base may be added in an amount of from 2 moles to 10 moles, preferably from 2 moles to 5 moles, per mole of the compound of formula (III).

In the step 1), the reaction may be carried out under the protection of inert gas such as nitrogen, the temperature of the reaction may be from 20 °C to 150 °C, preferably under reflux.

The obtained compound of formula (lll-l) may be isolated from the reaction of the step 1) by any known process such as extraction for the next step.

In the step 2), the conversion may be achieved by a Grignard reaction and a coupling reaction. In one embodiment of the step 2), the conversion includes a Grignard reaction followed by a coupling reaction as indicated below.

In another embodiment of the step 2), the conversion includes a coupling reaction followed by a Grignard reaction as indicated below.

In the above Grignard reaction, a chlorination reagent such as SOCI 2 may be added at first for chlorination reaction in a solvent, such as THF, in the presence of a catalyst, such as dimethylformamide (DMF), and then a Grignard reagent (A-MgX, A and X are defined as above) are added for Grignard reaction in a solvent, such as THF.

In the coupling reaction, a coupling reagent, such as lithium diisopropylamide (LDA) or Lithium 2,2,6,6-tetramethylpiperidide (LiTMP), may be added for reaction in a solvent, such as THF or diethyl ether (Et20), in the presence of an oxidant, such as FeCb.

Preferably, the conversion is carried out under an inert atmosphere, for example, under the protection of nitrogen or argon.

In the present invention, the compound of formula (III) may be produced by a process comprising: a) reacting the compound of formula (IV) with the compound of formula (V) to obtain a compound of formula (VI);

b) reducing the obtained compound of formula (VI) to obtain a compound of formula (Vl-l); and

(VI) (VI-1 ) c) reacting the obta ined compound of formula (VI-1) with the compound of formula (V-l) to produce the compound of formula (III)

Wherein R 1 , R 2 , R 3 , R 6 , R 7 and X are defined as above; R 4 is H, alkyl or aryl; and R 5 is H.

In the step a) of the process, the reaction may be ca rried out under Mitsunobu reaction conditions, for example, in a solvent, such as TH F or Et 2 0, in the presence of phosphine, such as triphenylphosphine (PPh 3 ), and an azo compound, such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and l,l'-(azodicarbonyl)dipiperidine (ADDP).

In the step a ) of the process, the compound of formula (V) may be added in an amount of from 1 mole to 10 moles, preferably from 1 mole to 4 moles, more preferably from 1 mole to 2 moles, per mole of the compound of formula (IV); and the phosphine may be added in an amount of from 1 mole to 10 moles, preferably from 1 mole to 4 moles, more preferably from 1 mole to 2 moles, per mole of the compound of formula (IV).

The reaction of the step a) of the process may be carried out at the temperatu re of from 0 °C to 100 °C, preferably from 20 °C to 60 °C.

The resulted product from the step a) may be used for the next step after filtration and concentration.

The compound of formula (IV) and the compound of formu la (V) are commercially available or synthesized by a method known in the art (see Carla S.M. Pereira ef. al., Chemical Engineering Science, Volume 64, Issue 14, 15 July 2009, Pages 3301-3310).

In the step b) of the process, the reduction may be carried out in the way of ester reduction methods known in the art (see Svenja Werkmeister ef. al., Org. Process Res. Dev., 2014, 18(2), pp 289-302). In one embodiment of the step b), the used reducing agent is selected from Na BH 4 and LiAI H 4 , and the reducing agent is added in an amount of from 1 mole to 10 moles, preferably from 2 moles to 8 moles, preferably from 4 moles to 6 moles, per mole of the compound of formula (VI- 1). In the case that NaBH 4 is used as reducing agent, CaCI 2 , MgCI 2 or ZnCI 2 is preferably added in an amount of from 2 moles to 4 moles, per mole of the compound of the formula (VI-1).

The reaction of the step b) of the process may be carried out at the temperature of from -10 °C to 100 °C, preferably from 0 °C to 40 °C. The resulted product of the compound of formula (VI-1) may be used for the next step after extraction and concentration.

In the step c) of the process, the reaction may be carried out under Mitsunobu reaction conditions same as step a). The resulted product of the compound of formula (III) may be used for the next step with or without purification.

Alternatively, the compound of formula (II) may be produced from the compound of formula (VI- 1) by a nucleophilic substitution reaction. As an example, the nucleophilic substitution reaction includes the following steps:

Step (c-1): converting the compound of formula (VI-1) into a compound of the formula (VI-2) by adding a leaving group:

Step (c-2): reacting the compound of formula (VI-2) with the compound of formula (V-1) to produce the compound of formula (III).

Wherein R 1 , R 2 , R 3 , R 6 , R 7 and X are defined as above and Y is a leaving group such as toluenesulfonic (Ts) group or methanesulfonic (Ms) group.

In the step (c-1), the reaction may be carried out in the presence of a base, such as Et 3 N, and a chloride of the leaving group, such as p-toluenesulfonyl chloride or methanesulfonyl chloride. In the step (c-2), the reaction may be carried out in a solvent, such as d imethyl su lphoxide (DMSO), dimethylformamide (DMF), CH 3 CN and acetone, in the presence of a base, such as K 2 C0 3 , Cs 2 C0 3 and Na 2 C0 3 .

In the fourth aspect, the present invention provides a chiral transition metal catalyst that contains: a compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof; and a transition metal, or an ion or a complex thereof:

Wherein, R 1 , R 2 , R 3 , R 6 , R 7 a nd A are defined as above.

The transition metal may be iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium or platinum, and is especially ruthenium, rhodium or iridium. Preferably, the chiral transition metal cata lyst of the present application contains the metal of rutheniu m, rhod iu m or iridium, and 1 mole to 5 moles, preferably 1 moles to 2 moles of the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, per mole of the metal.

The chiral transition meta l cata lyst of the present application may be obtained by reacting a compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, with a suitable metal salt, or a suitable metal complex of a transition metal. The chiral transition metal catalyst may be generated in situ, or it may be isolated prior to use.

The ch iral transition metal catalyst of the present invention obta inable as described herein may be employed for converting a prochiral substrate to a ch iral product under reaction conditions otherwise suitable for asymmetric induction. Accordingly, in the fifth aspect, the present invention provides a method for converting a prochiral substrate to a chiral product by using the chiral transition metal cata lyst of the present invention in asymmetric reactions.

Such asymmetric reactions include, but are not limited to, catalytic hydrogenation, hydrosilylation, hydroboration, hydroformylation, hydrocarboxylation, hyd roacylation, Heck reaction and some allylic isomerization and substitution reactions. A preferred reaction for asymmetric induction using a chiral transition metal cata lyst of the present application is catalytic hydrogenation. The chiral transition metal cata lysts of the present invention are especially effective when employed in asymmetric catalytic hydrogenation of cyclic anhydride (CAN) into L-Lactone (LAP) as shown below:

CAN LAP

The following Examples are intended to further illustrate the invention and are not to be construed as being limitations thereon.

Examples

Example 1

Step I: (fi)-methyl 2-(3-bromophenoxy)propanoate

Under nitrogen protection, to a 250 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

12.3 g ethyl L(-)-lactate (104.0mmol, 1.0 equiv.),

28.1 g triphenylphosphine (PPh 3 , 107.6 mmol, 1.03 equiv.),

18.0 g 3-bromophenol (104.0 mmol, 1.0 equiv.), and

100 mL tetrahydronfuran (THF). Then

21.0 g diisopropyl azodicarboxylate (DIAD, 104.0 mmol, 1.0 equiv.) was added dropwise into the reaction mixture at 0-10 °C, the reaction was allowed to be stirred at room temperature overnight (16h). Then THF was removed under vacuum, the remaining crude product was triturated in

200 mL petroleum ether (PE, bp = 60-90°C), triphenylphosphine oxide and diisopropyl 1,2- hydrazinedicarboxylate were filtered as white solid, the solution was concentrated giving the crude product as colorless oil without further purification (24.8 g, 87.3-93.8% yield).

Example 2

Step II: (fi)-2-(3-bromophenoxy)propan-l-ol

Under nitrogen protection, to a 500 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

10.0 g (R)-methyl 2-(3-bromophenoxy)propanoate (36.6 mmol, 1.0 equiv.),

8.2 g calcium chloride (73.5 mmol, 2.0 equiv.), and

250 mL EtOH at 0°C, then

5.5 g sodium borohydride (147.0 mmol, 4.0 equiv.) was added portion-wise in 15 min, the reaction was stirred overnight (16h) then quenched with

200 mL 1M HCI, the solvents were removed under vacuum and extracted three-times with

200 mL ethyl acetate and then dried under Na 2 S0 4 , evaporated to dryness to afford colorless oil

(8.0 g, 90-95% yield).

Example 3

Step III: (R)-l,2-bis(3-bromophenoxy)propane

Under nitrogen protection, in a 100 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

5.0 g (R)-2-(3-bromophenoxy)propan-l-ol (21.6 mmol, 1.0 equiv.),

6.3 g triphenylphosphine (24 mmol, 1.1 equiv.), and

20.0 mL THF. Then

4.0 g 3-bromophenol (23 mmol, 1.05 equiv.) and 4.6 g Diisopropyl azodicarboxylate (23 mmol, 1.05 equiv.) was added within lh, after stirring at 23 °C for additional lh, the solvent was removed under vacuum and

100 mL petrolium ether and

0.5 mL H 2 0 2 (30%) was added, after stirring for lh and filtration, colorless oil was obtained after solvent removal under vacuum (6.87 g, 82% yield).

Example 4

K 2 C0 3 , CH3CN

Step III: (R)-l,2-bis(3-bromophenoxy)propane

Under nitrogen protection, to a 100 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

9.2 g (R)-2-(3-bromophenoxy)propan-l-ol (40.0 mmol, 1.0 equiv.),

4.45 g triethylamine (44.0 mmol, 1.1 equiv.),

30.0 mL dichloromethane, and then

4.8 g methanesulfonyl chloride (42 mmol 1.05 equiv.) was added dropwise at 0 °C, the mixture was gradually warmed to room temperature and stirred for another lh, then dichloromethane was removed under vacuum, to another 500 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added :

150 mL acetonitrile,

6.9 g 3-bromophenol (40.0 mmol, 1.0 equiv.),

27.6 g potassium carbonate (200.0 mmol, 5.0 equiv.), and then refluxed for lh, the mesylate in

10.0 mL acetonitrile was added, the mixture was refluxed overnight (16h), after filtration and washed with

50.0 mL acetonitrile, the solvents was removed and residue was dissolved in

50.0 mL dichloromethane and washed with 50.0 mL 1M HCI,

50.0 mL water and then concentrated, separated via flash column to afford colorless oil (12.8 g, 81-83% yield).

Example 5

Step IV: tetraethyl (((2R)-propane-l,2-diylbis(oxy))bis(3,l-phenylene))bis(phosp honate)

Under dry nitrogen protection, to a 50 mL dry Schlenk tube equipped with a magnetic stirrer and rubber septum was added:

95.0 mg Pd(dppf)CI 2 (0.13 mmol, 0.01 equiv.),

5.0 g (R)-l,2-bis(3-bromophenoxy)propane (13.0 mmol, 1.0 equiv.),

4.0 mL diethyl phosphonate (31.1 mmol, 2.4 equiv.),

4.4 mL triethylamine (31.1 mmol, 2.4 equiv.), and

13 mL toluene. The solution was then cooled to -78°C under vacuum to remove the remaining oxygen in the solution. After warm up to room temperature under dry nitrogen protection, the solution was stirred under reflux for lOh. After cooling to room temperature,

50 mL water was added and then extracted with

50 mL dichloromethane for 3 times, the combined organic solution was washed with

100 mL brine, dried under Na 2 S0 4 and the solvent was removed under vacuum (6.1 g, 94% yield).

Example 6

Step V: (((2R)-propan-l,2-diylbis(oxy))bis(3,l-phenylene))bis(bis(3, 5-ditertbutyl-4- methoxyphenyl)phosphine oxide)

Under nitrogen protection, to a 250 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

1.0 g tetraethyl (((2fi)-propane-l,2-diylbis(oxy))bis(3,l-phenylene))bis(phos phonate) (2.0 mmol, 1.0 equiv.) in

3.0 mL thionyl chloride (40.0 mmol, 20.0 equiv.) under nitrogen was added

30.0 μΐ dimethylformamide (0.4 mmol, 0.2 equiv). The mixture was stirred under reflux for 18 h, during which time

15.0 μΐ dimethylformamide (all together 8.0 mmol, 0.3 equiv.) was added after 12h. After the solvent was evaporated, the residue was dissolve in

5.0 mL THF and concentrated in vacuo (once). The residue was used for the next step without further purification.

To a phenyl magnesium bromide solution prepared from a suspension of

0.53g magnesium turning (22.0 mmol, 11.0 equiv.) and

6.0 g 5-bromo-l,3-di-tert-butyl-2-methoxybenzene (20.0 mmol, 10.0 equiv.) in

20.0 mL THF was added dropwise to the solution of the residue prepared above under nitrogen at O °C. After stirring another 1.5h at room temperature, the mixture was quenched with

10.0 mL water at 0°C and extracted three times with

50 mL dichloromethane. The combined organic layers were dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate = 75:25, to give product as a white solid (1.94 g, 81% yield).

Example 7

Step VI: (S^R)-3,5-t-Bu-4-MeO-LacBIPHEP dioxide

Under nitrogen protection, to a 250 mL dry 3-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:

6.5 mL "BuLi (14.4 mmol, 3.6 equiv.) was added dropwise to a solution of

2.2 mL diisopropylamine (16.0 mmol, 4.0 equiv.) in dry

30 mL THF at-78 °C over a period of 15 min, whereby the temperature rose to about -50 °C and a white precipitate formed (sometimes yellow precipitate was observed). The CO^acetone cooling bath was replaced by an ice/ethanol bath and the reaction mixture was stirred at about -15 °C for a further 30 minutes, then again cooled to -78 °C. A solution of

4.8 g (((2R)-propan-l,2-diylbis(oxy))bis(3,l-phenylene))bis(bis(3, 5-ditertbutyl-4- methoxyphenyl)phosphine oxide) (4.0 mmol, 1.0 equiv.) in

12.0 mL dry tetrahydrofuran was dropwised into the above reaction mixture, whereby the temperature rose to about -68 °C and a translucent caramel-colored solution (sometimes dark green) resulted. After an additional period of 5h at -78 °C, a suspension consisting

1.9 g anhydrous FeCI 3 (12.0 mmol, 3.0 equiv.) in

30.0 ml THF was added directly in one portion to the reaction mixture. After completion of the reaction overnight (16h), the reaction was quenched with

2.0 mL of saturated ammonium hydroxide at 0 °C. After filtration, the solvent was removed on rotavapor. The oil residue was dissolved in

40 mL dichloromethane, washed with 2N HCI aq., brine, dried over anhydrous Na 2 S0 4 and concentrated. The product was isolated by flash column (petroleum ether/ethyl acetate = 75/25, 48.7-68.3% yield).

Example 8

Step VII: (S^Rj-S^-t-Bu^-MeO-LacBIPHEP

Under nitrogen protection, to a 10 mL dry Schlenk tube equipped with a magnetic stirrer and rubber septum was added:

490 mg (S , X R)--3,5-t-Bu-4-MeO-LacBIPHEP dioxide (0.41 mmol, 1.0 equiv.),

720 μΐ tributylamine (3.0 mmol, 7.4 equiv.), and

3.5 mL degassed xylene. Then

290 μΐ trichlorosilane (2.9 mol, 7.0 equiv.) was added under reflux and stirred for another 3h.

After cooling to 0 °C,

6.0 mL 30% NaOH aq was added, and the mixture was stirred at 60 °C until the organic and aqueous layers become clear. The organic product was extracted with degassed toluene

10.0 mL three times, and the combined organic layer was washed with

10.0 mL water, saturated NaCI aqueous solutions successively and dried over anhydrous Na 2 S0 4 .

The organic layer was concentrated under rotvapor evaporation and followed by vacuum distillation to give a crude product containing trace amount of tributylamine. The residue was washed with

1.0 mL cold hexane three times to give a pure product as a white powder (477 mg, 99% yield).

Example 9 Asymmetric hydrogenation of CAN to LAP

CAN LAP

A mixture of

1.25 g of CAN 2.5 mg of [lr(COD)CI] 2

9.1 mg of (S , ¾ R)--3,5-t-Bu-4-MeO-LacBIPHEP, and

10 mL of THF was added to a 35 mL autoclave, sealed then flushed with nitrogen for three times, and 80 bar of hydrogen was introduced. After heated at 70 °C with shake for 18h, then the reaction was cooled to room temperature, the end pressure is 24.1 bar.

Conversion and chemoselectivity, diastereoselectivity and enantiomeric purity were determined by HPLC. The conversion was >99% and the enantiomeric excess 95% (L).

Example 10

CAN LAP

A mixture of

600 mg of CAN

6.0 mg of [lr(COD)CI] 2

22.0 mg of (R)-BINAP, and

10 mL of THF was added to a 35 mL autoclave, sealed then flushed with nitrogen for three times, and 80 bar of hydrogen was introduced. After heated at 70°C with shake for 18h, then the reaction was cooled to room temperature, the end pressure is 24.1 bar.

Conversion and chemoselectivity, diastereoselectivity and enantiomeric purity were determined by HPLC. The conversion was >99%, 44% yield of lactone with enantiomeric excess 73.8% (D).