KR101233809B1 - A preparation method of all-carbon quaternary stereocenter compound using 2,2-disubstituted 1,3-propanediol - Google Patents

Abstract

The present invention relates to a method for preparing a quaternary carbon stereocenter compound having only carbon using 1,3-propanediol having two substituents at the 2,2 position, and more particularly, pyridine bis substituted with a butyl group as a chiral ligand. A method for preparing a quaternary stereocentered carbon compound having only carbon by catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position using a complex of oxazoline and a divalent copper compound will be.

Description

A preparation method of all-carbon quaternary stereocenter compound using 2,2-disubstituted 1,3 using 1,3-propanediol having two substituents at 2,2 position -propanediol}

The present invention relates to a method for preparing a quaternary carbon stereocenter compound having only carbon using 1,3-propanediol having two substituents at the 2,2 position, and more particularly, pyridine bis substituted with a butyl group as a chiral ligand. A method for preparing a quaternary stereocentered carbon compound having only carbon by catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position using a complex of oxazoline and a divalent copper compound will be.

Stereoselective asymmetry of symmetric molecules is an economical way of generating chirality. The method is advantageous by the differentiation of two enantio site groups and is advantageous due to the relatively easy preparation of the starting substrate. The stereogenic carbon center, the formation of a quaternary center that is directly coupled with only heteroatom or carbon is particularly difficult (Fuji, K. Chem Rev 1993, 93, 2037;..... Corey, EJ et al, Angew Chem Int. Ed . 1998 , 37 , 388; Denissova, I. et al., Tetrahedron 2003 , 59 , 10105; Cozzi, PG et al., Eur. J. Org . Chem . 2007 , 5969; Bella, M. et al., Synthesis 2009 , 1583). In order to construct a quaternary stereocenter with only carbon, one must fight the intrinsic steric hindrance. Catalytic asymmetry has been rarely applied to form such carbon stereocenters (Cefalo, DR et al., J. Am . Chem . Soc . 2001 , 123 , 3139; Teng, X. et al., J. Am . Chem Soc 2002, 124, 10779 ;.. Bocknack, BM et al, Proc Natl Acad Sci USA 2004, 101, 5421;.......... Oestreich, M. et al, Angew Chem Int Ed 2005 , 44 , 149; Liu, Q. et al., J. Am . Chem . Soc . 2006 , 128 , 2552; Honjo, T. et al., Org. Lett . 2007 , 9 , 509).

Most of the known approaches for quaternary stereocenters with only carbon have a narrow substrate range and / or low stereoselectivity (Douglas, CJ et al., Proc . Natl . Acad . Sci . USA 2004 , 101 , 5363; Trost , BM et al., Synthesis 2006 , 369). These aldol cyclization (Mukherjee, S. et al., Chem. Rev. 2007, 107, 5471), Pd- catalyzed coupling reaction (Ohshima, T. et al., J. Am. Chem. Soc. 1996 ......, 118 , 7108; Willis, MC et al, Angew Chem Int Ed 2004, 43, 1249; Takenaka, K. et al, Tetrahedron: Asymmetry 2008, 19, 2492), Diels-Alder addition reaction ring (Corey, EJ et al., J. Am . Chem . Soc . 2002 , 124 , 3808), Rh-activated CH bond insertion and cyclization reactions (Watanabe, N. et al., Synlett 1996 , 85; Davies, HML et al., Chem. Rev. 2003, 103, 2861), Cu- induced misfire Sat reaction (Demizu, Y. et al., it has been performed through the Synlett 2008, 433). Therefore, it is very important and synthetically useful to develop asymmetry methods for preparing quaternary stereocenters with increased substrate range and stereoselectivity.

Therefore, the inventors of the present invention can build a quaternary stereocenter having only carbon through the catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position during the study. Discovered and completed the present invention.

It is an object of the present invention to provide a method for preparing a quaternary stereocentered carbon compound having only carbon through catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position.

In order to solve the above problems, the present invention provides a method for producing a compound represented by the following formula (1) comprising the following steps.

Preparing a chiral ligand copper complex by reacting a compound represented by Formula 2 with a divalent copper compound (step 1); And

Preparing a compound represented by Chemical Formula 1 by reacting a compound of Chemical Formula 3 with benzoyl chloride (BzCl) in the presence of the chiral ligand copper complex (Step 2).

In Chemical Formulas 1 and 3,

R ¹ and R ² are each independently hydrogen; C _{1 -6} alkyl; Cyano; C ₆ -C ₁₀ aryl; Acetyl; Or unsubstituted or substituted by halogen, C _{1 -6} alkyl, or -COO- (C _{1 -6} alkyl) C _{2 -6} alkenyl optionally substituted with, with the proviso that R ¹ and R ² are not equal to each other; Or R ¹ and R ² form a C _{3 -6} cycloalkyl substituted with C _{1 -6} alkylene group with a carbon R ¹ and R ² are connected to each other;

* Denotes a class 4 carbon stereocenter.

Preferably, in Formulas 1 and 3, R ¹ and R ² are hydrogen; methyl; ethyl; profile; Cyano; benzyl; Phenyl; Acetyl; Or is a C _{2 -4} alkenyl unsubstituted or substituted with halogen, methyl or ethyl -COO-.

Preferably, in Formulas 1 and 3, R ¹ and R ² are connected to each other to form cyclopentyl substituted with methylene together with the carbon to which R ¹ and R ² are linked.

In the present invention, the divalent copper compound is a compound in the form of the copper metal and the base of Cu ^{2 +} state engageable use whichever and, specifically, _{CuCl 2, Cu (CF 3 SO} 3) 2 [Cu (OTf ) ₂ ], Cu (PF ₆ ) ₂ , Cu (SbF ₆ ) ₂ , CuBr ₂ , Cu (CH ₃ CO ₂ ) ₂ [Cu (OAc) ₂ ], and the like, and the like.

In the present invention, it is preferable that the molar ratio of the compound represented by the formula (2) of step 1) and the divalent copper compound is 5: 1 to 0.5: 1. If the molar ratio of the compound represented by Formula 2 and the divalent copper compound is outside the above range, there is a disadvantage in that the stereoselectivity of the reactants is inferior.

In the present invention, step 1) may be performed using a general organic solvent as a solvent, but may be performed using methylene chloride (CH ₂ Cl ₂ ), toluene, or a mixture thereof in terms of reaction efficiency.

In the present invention, step 1) is preferably performed at 0 to 25 ℃. If the reaction temperature is outside the above range, there is a disadvantage that the stereoselectivity of the reactants is poor.

In the present invention, the molar ratio of the compound of Formula 3 and BzCl in step 2) is preferably 0.5 to 5.0 equivalents. If the molar ratio of the compound of Formula 3 and BzCl is outside the above range, the reaction yield of monoalcohol decreases and the production yield of dibenzoate as a side reactant increases.

In the present invention, step 2) may be performed using both an organic base or an inorganic base as a reaction base, and generally using a tertiary amine or a carbonate-based inorganic base. Specifically, examples of the reaction base that can be used in step 2) include triethylamine (Et ₃ N) or diisopropylethylamine (( i- Pr) ₂ NEt).

In the present invention, the molar ratio of the compound of formula 3 of step 2) and Et ₃ N or ( i- Pr) ₂ NEt is preferably 0.5 to 5 equivalents. If the molar ratio of the compound of Formula 3 and Et ₃ N or ( i- Pr) ₂ NEt is outside the above range, the reaction yield of the reactants is reduced.

In the present invention, step 2) is preferably carried out at 0 to -78 ℃. If the reaction temperature is outside the above range, there is a disadvantage that the stereoselectivity of the reactants is poor.

The inventors have synthesized a quaternary stereocenter with only carbon through an asymmetric monobenzoylation reaction of 1,3-diol with readily available symmetrical and two substituents in the 2,2-position. The most effective chiral ligand is Pybox 6 with 4-phenyl and 5,5-di- n -butyl substituents, which vertically intersect the two phenyl groups and the oxazolidine plane to reserve a reserve for smaller substituents on the substrate. It was confirmed that it can be done.

In an embodiment of the present invention, another type of 1, 3-diol 11 was screen asymmetry under the conditions of asymmetrical mono benzoyl screen as described above with respect to 29 in the preparation example 9 of table 1. As shown in Table 2, significant asymmetry was achieved especially in most 2-methyl 1,3-diols. A small group within the set off, 11, 10: has been distinguished from the higher than group 1 er (Example 2). While the chiral production from vinyl diol 17 proceeds with appropriate stereoselectivity due to smaller size differences between the two appendages, the vinyl groups are bulkier than β, β-dibromovinyl ( 18 ) and α-methylvinyl ( 19 ) resulted in significantly higher% ee values (Examples 8-10). As far as 20 and 21 are concerned, the attachment of methyl substituents to the conjugated ester branch of 20 significantly increased the% ee value from 85 to 98 (Examples 11 and 12). This similar trend was observed to a lesser extent with the β-bromo substituents in allyl diols 9 and 22 (Examples 1 and 13). Examination of the experimental data revealed that the stereoselectivity was enhanced in 2-methyl diol having a second substituent with α- or β-branch (Examples 3, 5, 9, 10, 12 and 13). 2-cyano diols 16 , 27 and 28 were asymmetric with greater stereoselectivity up to 20-25% ee in toluene than in CH ₂ Cl ₂ (Examples 7, 18 and 19). In fact, a 20: 1 mixture of toluene and CH ₂ Cl ₂ was used to increase the solubility. Little difference in stereoselectivity was found between this mixture and toluene. The best stereoselectivity for cyano diols was difficult to explain in theory simply by considering the relative sizes of their substituents. Since a substantial amount (15-25%) of the corresponding dibenzoate was formed with Et ₃ N during the monobenzoylation of cyano diol, the base was changed to i- Pr ₂ NEt. Although side reactions were significantly inhibited, 4-7% of dibenzoate was still formed. To determine whether kinetic partitioning was the cause of the observed good stereoselectivity, ee values were analyzed every 4 hours from the reaction of 28 and this consistency could be ruled out. The somewhat lower material balance for cyano diols is due in part to the difficulty of separation from Pybox ligands and their higher solubility in water. As expected, asymmetry of the diols having methyl groups and two other substituents was performed with reduced stereoinduction (Examples 15-17). In addition, enantio site differentiation of 24 and 25 was found to be more effective in toluene (Examples 15 and 16). In addition, monobenzoylation of methylenylcyclopentane diol 29 was completed with a notable 85% ee value (Example 20).

The present invention has only carbon through catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position by using a complex of a pyridinebisoxazoline substituted with a butyl group and a divalent copper compound as a chiral ligand. It is possible to provide a method for producing a quaternary stereocenter carbon compound. The production method of the present invention shows high efficiency in terms of stereoselectivity and yield, and is not synthesized using chiral building blocks, thereby minimizing organic materials discarded after the reaction, and maximizing the asymmetric synthesis efficiency of the reaction with only 10 mol% of catalyst. And the variety of substrates applied to the reaction system has excellent advantages.

1 is a diagram showing the asymmetric process of 2-allyl-2-methylpropane-1,3-diol using a complex of Pybox (L ^* ) and CuCl ₂ according to substituents. At this time, I shows the three-dimensional structure of the chiral ligand complex formed by Pybox (L ^* ) and CuCl ₂ .
2 is a diagram showing the catalytic asymmetry of 1,3-propanediol having two substituents at the 2,2 position using a complex of Pybox substituted with butyl group and CuCl ₂ .

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited to the following examples.

Manufacturing example  1-9: Stereoselectivity Asymmetry  Optimal for Ligand  Research

We describe tert-alcohols (Jung, B. et al., Proc . Natl . Acad . Sci . USA 2007 , 104 , 1471; Jung, B. et al., Angew . Chem . Int . Ed . 2007 , 46 , 2616) and stereoselective asymmetry of glycerol and serineol for the synthesis of tert-alkylamines (Hong, MS et al., Chem . Eur . J. 2008 , 14 , 3290). Its stereochemical results can be theoretically explained by analyzing chelated intermediates between the Cu-catalyst and the substrate via two heteroatoms at the 1,2-position rather than the 1,3-position. In the asymmetry of 1,3-propanediol having two substituents (directly linked only by carbon) at the 2,2 position of the present invention, the substrate is separated from the catalyst via only two hydroxyl groups at the 1,3-position. Coordination can be combined. Because their prostereogenic centers are located further from chiral ligands in the 1,3-chelated complex at position 2, their asymmetry still leaves substantial synthetic difficulties. With the inherent difficulties associated with 1,3-diol, asymmetry of model substrate 9 has been extensively investigated under benzoylation reaction conditions by varying or controlling chiral ligands, bases, temperatures and the like. As a result, pyridine bisoxazoline 1 (Desimoni, G. et al. , Chem. Rev. 2003, 103, 3119) has been found to form a relatively high stereoselectivity, thus such a major skeleton structure of the frame for pre-chiral ligand It could be proposed as (Production Example 1, Table 1 and Fig. 1).

Various kinds of functionalized pyridinebisoxazolines (Pybox) were prepared and selected to investigate the optimal ligand for the asymmetry of 9 . The results of some ligands are summarized in Table 1 below and in FIG. 1.

Initially two phenyl substituents of 1 were replaced with alkyl, benzyl and 2-naphthyl. While racemic mixtures of the mono-benzoate is obtained with the (alkyl) ₂ Pybox and (Bn) ₂ Pybox, (2- naphthyl) ₂ Pybox ₂ provided a rather poor stereoselectivity compared to suitable but 1 to them (prepared Example 2).

Next, the examination of Pybox 3 and 4 with four substituents showed that both were less effective than 1 , and interestingly they had significantly different capabilities in ligand function (Preparations 3 and 4). At this point, we found that the Pybox-Cu (II) catalyst creates an octahedral complex with 1,3-diol and benzoyl chloride to deliver the benzoyl cation to the closest hydroxyl group, where the tridentate Pybox is at the equator position Benzoyl chloride was placed in the axial position, and the substrate was assumed to lie in both the equator position and the axial position. In the proposed transition state, smaller groups of substrates were expected to occupy space near the 4-phenyl substituents of the oxazoline ring when based on stereology.

Thus, the inventors speculated that they must ensure sufficient space in the space to provide smaller methyl substituents. The conjecture suggested that ineffective as a tetravalent chiral ligand could be due to the inflexible planarity of the indanyl substituent. We designed two substituents to be attached at the 5-position of the oxazoline ring to vertically push the phenyl group into the ring to allow extra space as shown in intermediate I (Table 1 and FIG. 1).

As a result of examining several substituents, the most effective chiral ligand 6 including n -butyl group was produced (Production Example 6). In addition, the solvent was changed from THF to CH ₂ Cl ₂ to increase both stereoinductive and chemical conversion (Production Example 9). On the other hand, the methyl group appeared rather small for the intended phenyl configuration, whereas the isopropyl group appeared to be too bulky by itself (preparations 5 and 7). In addition, the chloride anions worked best among the catalytic anions. When 5, 15 or 20 mol% of 6 was loaded, 10 was obtained with slightly lower ee values (88%) and slightly lower yields (95%).

Manufacturing example L ^* % Yield ^a % ee One One 64 (32) 65 2 2 60 (36) 61 3 3 62 (36) 50 4 4 45 (53) 2 5 5 66 (30) 61 6 6 80 (17) 76 7 7 47 (50) 14 8 8 54 (40) 73 9 ^b 6 98 89 NOTE: sm recovered in parentheses
b: CH ₂ Cl ₂ is used as solvent instead of THF

Example  1: 2- ( hydroxymethyl )-2- methylpent -4- enyl benzoate  Produce

Ligand compound 6 (593 mg, 1 mmole) as used in Preparation Examples 6 and 9 was dissolved in 100 ml of CH ₂ Cl ₂ , and then reacted at room temperature for 3 hours by adding CuCl ₂ (134 mg, 1 mmole). I was. 2-allyl-2-methylpropane-1,3-diol (1.30 g, 10 mmole) was added to the reaction mixture at room temperature, followed by stirring, followed by BzCl (1.74 g, 15 mmole) and Et ₃ N (1.53 g, 11 mmole) was added and reacted under stirring at −78 ° C. for 12 hours, yielding 2.3 g of the title compound as a clear liquid (yield 98%).

¹ H NMR δ 8.03 (d, J = 1.1 Hz, 1H), 8.02 (t, J = 1.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (dt, J _d = 1.6 Hz, J _t = 5.9 Hz, 7.8 Hz, 2H ), 5.82 - 5.89 (m, 1H) 5.11 (d, J = 13.6Hz, 2H), 4.20 (s, 2H), 3.42 (d, J = 11.6Hz, 1H), 3.39 (d, J = 11.5 Hz, 1H), 2.38 (br, 1H), 2.14 (dd, J = 7.5 Hz, 0.9 Hz, 2H), 0.97 (s, 3H). ¹³ C NMR δ 167.08, 133.42, 133.18, 129.91, 129.63, 128.46, 118.44, 68.19, 66.76, 39.65, 38.90, 18.66. [α] _D ²⁶ = +2.33 (1.5 in MeOH)

Example  2-20

Using the ligand compound 6 in the same manner as in Example 1 to obtain a compound of Examples 2 to 20 as shown in Table 2 and FIG.

Table 2 shows reaction times, solvents used, yields and structural confirmation data such as ¹ H-NMR, ¹³ C NMR, and [α] _D.

Experimental Example  1: Investigation of Stereoselectivity of Compounds of the Invention

Stereoselectivity was investigated for the compounds obtained in Examples 1 to 20.

Stereoselectivity was determined by HPLC analysis using a DAICEL chiral column under the conditions shown in Table 3.

Example Monobenzoate
Compound number Chiral
column Eluent (% i PrOH)
in n-hexane) Flow rate (ml / min) Retention time (minutes) One 10 AS-H 1.5 0.5 2 30 OJ-H 1.6 0.3 36.99, 40.32 3 31 OJ-H 1.3 0.7 21.27, 24.73 4 32 OF 5.0 1.0 23.72, 29.93 5 33 AS-H 5.0 1.0 29.45, 35.10 6 34 AS-H 3.0 0.8 26.82, 30.13 7 35 AD-H 4.0 0.9 29.08, 31.18 8 36 OJ-H 2.0 0.7 23.32, 26.60 9 37 OF 5.0 0.7 28.37, 33.95 10 38 OF 4.0 0.6 31.32, 47.75 11 39 OD 3.0 1.0 30.25, 35.40 12 40 acetate AS-H 2.0 1.0 9.65, 13.65 13 41 OJ-H 3.0 0.8 21.08, 23.40 14 42 OD 1.8 0.75 39.38, 43.02 15 43 AD-H 6.0 0.9 18.78, 20.88 16 44 OF 5.0 1.0 23.72, 29.93 17 45 OD 3.0 0.9 12.50, 14.01 18 46 OJ-H 4.0 0.9 17.97, 22.75 19 47 OJ-H 6.0 0.9 19.68, 22.78 20 48 AS-H 4.0 0.4 28.82, 31.48

The results are shown in Table 4 below.

Example No. % ee ^a One 89 2 84 ( R ) 3 94 ( R ) 4 95 ( R ) 5 95 ( R ) 6 83 ( R ) 7 99 ( R ) 8 54 ( R ) 9 97 ( R ) 10 96 ( R ) 11 85 ( R ) 12 98 ( R ) 13 92 14 94 15 49 ( R ) 16 84 17 51 18 98 19 98 20 86 NOTE: a: Absolute placement of the primary enantiomer in parentheses.

Through the results in Table 4, 1,3-propanediol having two substituents at the 2,2 position using a complex of a ligand compound 6 and a divalent copper compound which is a pyridinebisoxazoline substituted with a butyl group as a chiral ligand Through catalytic asymmetry, it was confirmed that quaternary stereocentered carbon compounds could be prepared with excellent stereoselectivity.

Claims (11)

Method for preparing a compound represented by the following formula (1) comprising the following steps:
Preparing a chiral ligand copper complex by reacting a compound represented by Formula 2 with a divalent copper compound (step 1); And
Preparing a compound represented by Chemical Formula 1 by reacting a compound of Chemical Formula 3 with benzoyl chloride in the presence of the chiral ligand copper complex (Step 2):
[Formula 1]

(2)

(3)

In Chemical Formulas 1 and 3,
R ¹ and R ² are each independently hydrogen; C _1-6 alkyl; Cyano; C ₆ -C ₁₀ aryl; Acetyl; Or C _2-6 alkenyl unsubstituted or substituted with halogen, C _1-6 alkyl or —COO— (C _1-6 alkyl), provided that R ¹ and R ² are not identical to each other; Or R ¹ and R ² are linked to each other to form C _3-6 cycloalkyl substituted with C _1-6 alkylene with the carbon to which R ¹ and R ² are linked;
* Denotes a class 4 carbon stereocenter.
The compound of claim 1, wherein R ¹ and R ² are hydrogen; methyl; ethyl; profile; Cyano; benzyl; Phenyl; Acetyl; Or unsubstituted or halogen, A method for producing a compound represented by the formula (1) a C _{2 -4} alkenyl optionally substituted with methyl or ethyl -COO-.
The method of claim 1, wherein R ¹ and R ² are connected to each other to form cyclopentyl substituted with methylene together with carbon to which R ¹ and R ² are linked.
The method of claim 1, wherein the divalent copper compound is selected from the group consisting of CuCl ₂ , Cu (OTf) ₂ , Cu (PF ₆ ) ₂ , Cu (SbF ₆ ) ₂ , CuBr ₂ and Cu (OAc) ₂ . Any one or more, a method for producing a compound represented by the formula (1).
The method of claim 1, wherein the molar ratio of the compound represented by the formula (2) of step 1) and the divalent copper compound is 0.5: 1 to 5: 1.
The method of claim 1, wherein step 1) is performed using at least one selected from the group consisting of methylene chloride and toluene as a solvent.
The method for preparing a compound having a quaternary carbon stereocenter having only carbon represented by Formula 1 according to claim 1, wherein step 1) is performed at 0 to 25 ° C.
The method of claim 1, wherein the molar ratio of the compound of formula 3 to benzoyl chloride in step 2) is 0.5 to 5 equivalents of benzoyl chloride based on 1 equivalent of compound of formula 3.
The method of claim 1, wherein step 2) is performed using triethylamine or diisopropylethylamine.
The method of claim 1, wherein the molar ratio of the compound of formula 3 and triethylamine or diisopropylethylamine in step 2) is 0.5 to 5 based on 1 equivalent of the compound of formula 3, triethylamine or diisopropylethylamine. Method for producing a compound represented by the formula (1) which is equivalent.
The method of claim 1, wherein step 2) is performed at 0 to −78 ° C. 7.

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