JP2518101B2 - Optically active alcohol - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel optically active alcohol having a stannyl group at the γ-position and an epoxy group in the molecule.

Problems to be Solved by the Related Art and Invention Secondary allyl alcohol is a useful compound in itself, and has been widely accepted as a useful synthetic intermediate. In particular, various physiologically active compounds containing a skeleton of secondary allyl alcohol in the molecular structure thereof have been widely known in recent years, but most of these compounds are optically active compounds, and optically active compounds of secondary allyl alcohol. Has been an industrially important issue.

In particular, when considering the synthesis of the final target compound (often containing an optically active skeleton of allyl alcohol in its molecular structure, which is a more complex compound and its stereoisomer), these compounds are favored. As an intermediate that can be synthesized, an allyl alcohol having an optical activity that allows various reaction operations to be performed very easily is desired.

For example, in the synthesis of a new type of drug, a prostaglandin compound, an optically active allyl alcohol having a halogen atom at the γ-position [ _IIIc ] (In the formula, Hal represents a halogen atom, R represents a saturated or unsaturated C 1-10 substituted or unsubstituted alkyl group, or a substituted or unsubstituted phenyl group.
As well. ) Is an optically active allyl alcohol [IV _c ] having a halogen atom at the γ-position by reversing the asymmetry on the carbon atom substituted with a hydroxyl group by the Mitsunobu reaction or the like. It is well known that the optically active allyl alcohol [IV _c ] having a halogen atom at the γ-position can be used as it is as a raw material for the ω side chain after being changed to (JWPatter).
Son, Jr. et al., J. Org. Chem., 39 , 2506 (1974)).

Further, as a raw material for the ω side chain, an optically active allyl alcohol having a stannyl group at the γ-position [IV _b ] Can also be used. (EJCorey et al., Tetrahedron L
etter, 27 , 2199 (1986)).

In addition, the following compounds (V
I) has also been reported (JG Miller, W, Kurz, J. Am. Chem. S.
oc., 96 , 6774 (1974)).

Conventionally, a method for synthesizing an optically active secondary allyl alcohol is a method by asymmetric reduction of a conjugated enone [VII] represented by the following formula (Noyori et al., J. Am. Chem. Soc., 101 , 5843 (1979)).
etc), Alternatively, a method of obtaining by asymmetric reduction of conjugated inone [VIII] represented by the following formula, hydroalumination reaction, and further halogenation (CJSih et al., J. Am. Chem. Soc., 97 857 (1975)
Etc.) and a method of hydrogenating after the asymmetric reduction of conjugated inones (Noyori et al., J. Am. Chem. Soc., 106 , 6717 (1984)) are well known.

However, these methods it is necessary to use an expensive enzyme or expensive optically active binaphthol as asymmetric sources, also the resulting compound [IV _b] [IV _c] Optical purity following the lower 95% ee of the reaction conditions However, it requires a low substrate concentration and a considerably low temperature (for example, -100 ° C), and thus has many problems as an industrial production method.

On the other hand, Kazuki and Sharpless et al. Use a kinetic optical resolution method to carry out an epoxidation reaction with a peroxide such as tertiary butyl hydroperoxide using titanium tetraalkoxide of allyl alcohol and optically active tartaric acid diester. Was extremely useful as a method for synthesizing optically active allyl alcohols (JP-A-57-122072, U).
SP-4471130, USP-4594439).

This so-called "Sharpless oxidation reaction" is superior to other methods in that an inexpensive raw material called tartaric acid diester is used as an asymmetric source. Recently, it has become clear that the amount of this asymmetric source can be reduced to the amount of catalyst, and its importance is increasing (KBSharpless et al., J.Org.C.
hem., 51 , 1922 (1986)).

However, the method of Sharpless et al. Has various problems.

That is, as a first problem, in the kinetic optical resolution in secondary allyl alcohol disclosed by Sharpless et al., A specific optically active allyl alcohol that undergoes an epoxidation reaction faster and a slower epoxidation reaction undergoes an epoxidation reaction. The corresponding rate ratio with the opposite optically active allyl alcohol is not sufficient in many cases, and for example, the racemic allyl alcohol that is the raw material for the epoxidation reaction of Sharpless et al.
% Or more epoxidized, optically pure allyl alcohol of extremely high purity cannot be obtained (KBSharpless et al., JA
m. Chem. Soc., 103 , 6237 (1981)).

This means that when trying to obtain a useful optically active secondary allyl alcohol, 60% or more of the racemic secondary allyl alcohol as a raw material is wasted, and even if this is carried out industrially, this step In that case, the yield is 40% or less, which is very disadvantageous. Furthermore, in many cases, considering that many chemical reaction operations are performed after this step to give a more complicated final product, there is a problem that the overall yield becomes very small.

The second problem is that allyl alcohol disclosed by Sharpless et al. Has a problem that the cis isomer has a very low optical resolution efficiency and is practically low as the optical resolution of the cis allyl alcohol. are doing.

A third problem is that allyl alcohol disclosed by Sharpless et al. Has a compound having an electron-withdrawing halogen atom, such as a compound having a bromine atom [IX] or an atom that is easily oxidized, such as a sulfur atom [X]. Or tin atom,
There is no example of a reaction substrate such as a compound [V _b ] having a halogen atom, and there is a possibility that the epoxidation reaction itself does not proceed, and it was not possible to be an effective optical resolution method.

The reason why the epoxidation reaction itself does not proceed is that the halo-olefin has a low electron density of double bonds, and it is generally considered that the oxidation reaction is slow, and that the oxidation of tin atom, halogen atom or sulfur atom is more difficult than the oxidation of olefin. Is likely to be fast. Another reason why the epoxy alcohols [I '] or [II'] expected as reaction products are considered to be extremely unstable is one of the reasons why these examples were not known.

Epoxy alcohol is a useful compound itself, and is also useful as a synthetic intermediate. That is, in recent years, the number of physiologically active compounds containing an optically active epoxy group in the molecular structure has increased, and compounds obtained by stereospecifically reacting an optically active epoxy group, such as optically active secondary allyl alcohol and optically active This is because 1,2-diol and optically active 1,3-diol are also useful as physiologically active compounds. However, the optically active epoxy alcohols [I '] and [II'] having an atom which can be easily converted, for example, an atom such as silicon, tin and halogen, in the γ-position have not been known so far, which is a major industrial obstacle. It was.

The present invention has been achieved by overcoming the problems of the three limitations of the reaction of Sharpless et al., And the present invention provides a novel useful optically active alcohol having a stannyl group at the γ-position. The purpose is to do.

Means for Solving the Problems The present invention has been earnestly studied to achieve the above object, and as a result, a trans-type allyl alcohol [V] having a stannyl group at the γ-position has been obtained. In the presence of titanium tetraalkoxide and optically active tartaric acid diester, the following reaction signals at a high optical resolution ratio that could not be obtained in the past, and the anti-form optically active epoxy is obtained. Alcohol [I] and optically active allyl alcohol [III] or optically active epoxy alcohol [II] and optically active allyl alcohol [IV] can be obtained. In this case, optically active epoxy alcohols [I] and [II] are novel substances. The present invention has been discovered and has led to the present invention.

Therefore, the present invention provides a compound represented by the general formula [I] And the general formula [II] (However, R represents a saturated or unsaturated alkyl group having 1 to 10 carbon atoms, and R ¹ , R ² and R ³ are the same or different from each other and have 1 to 10 carbon atoms.
10 alkyl groups are shown. ] A novel optically active alcohol having a stannyl group at the γ-position selected from the compounds represented by:

The alcohols represented by the general formulas [I] and [II] of the present invention include many stereo-regulated secondary allyl alcohols, epoxy alcohols, and 1s which have not been easily obtained by other methods than Sharpless et al. It is useful for synthesizing complex physiologically active substances containing 2,2-diol, 1,3-diol and the like in its skeleton.

That is, the novel optically active alcohol [I] of the present invention,
[II] has a stannyl group at the γ-position, and various derivations are possible by using these heteroatoms as a handhold. For example, it can be easily applied to the ω chain for prostaglandins and leukotriene B4 (LTB ₄ ).

Here, the characteristics of the production method for obtaining the novel compounds [I] and [II] of the present invention will be explained. The first is the optical resolution efficiency. That is, a secondary allyl alcohol compound (V) having a stannyl group at the γ-position (racemic or a mixture of two optical antipodes) is oxidized with hydroperoxide using titanium tetraalkoxide and an optically active tartaric acid diester. Then, according to the optical structure of the tartaric acid diester used, the racemic compound [V] of the reaction substrate used
One optical isomer undergoes an epoxidation reaction rapidly, while the opposite optical isomer undergoes an epoxidation reaction very slowly. That is, when the epoxidation reaction is completed within a practical reaction time, for example, the optical purity of the epoxy compound obtained in about 7 hours is 99% or more, while the remaining allyl alcohol optical purity is 99% or more. The high optical purity of such a product hardly changes even after a reaction time of 10 hours.

This corresponds to the optical structure of the tartaric acid diester used, and after almost all one optical isomer of the compound [V] that undergoes epoxidation reaction rapidly undergoes epoxidation reaction, It can be said that the opposite of the other optical isomer of V] begins to undergo epoxidation.

Therefore, this indicates that the reaction rate ratio of both is close to infinity.

That is, in this reaction, since the epoxidation reaction rate ratio for the optical isomers contained in the racemic compound is close to infinity,
Reaction management becomes extremely easy. When stopping the reaction by advancing the reaction rate of epoxidation to about 60% (relative to the racemic reaction substrate) as in the past, the reaction stop point is determined in order to further improve the yield of chiral allyl alcohol. There was a considerable amount of labor and loss of reactants for monitoring. However, in the above-mentioned method, the speed ratio described above is extremely large and can be said to be infinite. Therefore, it is sufficient to manage the reaction time with a considerable allowable range. This means that it is possible to reduce the amount of the oxidizing agent used to the minimum necessary amount, or conversely, to increase it in a large excess.

In addition, it becomes easy to control the reaction temperature, for example, the conventional -25
It became possible even if the reaction temperature condition that was normally -20 ℃ was about + 20 ℃. The softening of this reaction condition is a great advance industrially.

The second characteristic is that an epoxy alcohol having high optical purity can be obtained.

That is, Optically active alcohol [I] obtained by the method
And [II] can be obtained with a high optical purity of 98% or more due to the effect of the stannyl group at the γ-position. Further, the optically active alcohols [I] and [II] are further converted as they are or stereospecifically to obtain useful optically active allyl alcohol, 1,2-
It can be a diol or a 1,3-diol. For example, it can be converted into a useful optically active allyl alcohol as described below. In other words, in the usual examples of Sharpless et al., About half of the raw racemic allyl alcohol (usually 60% or more) becomes an epoxy compound,
The optical purity of the resulting epoxy alcohol is at most 90%
It is as low as ee and is poor as a chiral synthetic raw material, and it is necessary to further epoxidize optically active allyl alcohol (usually a mixture of syn-form and anti-form) in order to obtain epoxy alcohol of high optical purity. there were.

On the other hand, the optical purity of the epoxy alcohol obtained by the above reaction is as high as 95% ee or more, and almost only the anti form is obtained. Moreover, as will be described later, the obtained epoxy alcohol can be easily converted into an optically active allyl alcohol. That is, half of the compound [V] having a stannyl group at the γ-position of the raw material can be effectively used as an optically active allyl alcohol, and the other half can be effectively used as an optically active epoxy alcohol.

Another feature is that the epoxidation of compound [V] proceeds faster than in the conventional Sharpless method. On top of that, by increasing the amount of hydroperoxide used as the first feature and raising the reaction temperature,
In addition, the reaction time can be shortened to about 10 to 20 hours, which is a great improvement compared to the conventional Sharpless method which required 5 to 15 days, and it is extremely useful as an industrial process. This is an important point.

The point for obtaining this useful new optical activity [I], [II] with extremely high optical purity is to obtain a compound represented by [V], By using a secondary allyl alcohol having a stannyl group at the γ-position, the compound of the present invention can be obtained in high purity.

Further, as can be understood from the description so far, the compound of the formula [I] or [II] has the formula [III] or [I]
V] can also be synthesized.

Hereinafter, the present invention will be described in more detail.

Novel optical activity [I], [II] of the present invention: As mentioned above, R represents a saturated or unsaturated C 1-10 substituted or unsubstituted alkyl group, and specifically, methyl, ethyl, n-propyl, i-
Propyl, n-butyl, i-butyl, t-butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl,
2-methylhexyl, 2-methyl-2-hexyl, 2-
Hexyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hexa-4-yn-2-yl, hepta-
4-in-2-yl, 2,6-dimethyl-hepta-5-en-1-yl, penta-1-en-1-yl, penta-
2-en-1-yl, hexa-1-en-2-yl, 3
-Ethoxy-2-methyl-propan-2-yl, ethoxyethyl, 5-methoxyhexyl, 6-methoxy-2-
Hexyl, methyl halide, n-butyl halide,
N-pentyl halide, nonyl halide, n-pentyloxymethyl, 1-ethoxy-2-methyl-propan-2-yl, 1-butyl-cyclopropyl, 3-ethyl-cyclopentyl, 2-octenyl, 3-methoxy Carbonylpropyl, vinyl, etc. can be mentioned.

In addition, R ¹ , R ² and R ³ are alkyl groups having 1 to 10 carbon atoms, specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, Amyl, hexyl, heptyl, octyl, nonyl, decyl and the like can be mentioned. Note that R ¹ , R ² , and R ³ may be the same or different.

Next, the method for producing the novel compound according to the present invention will be described. It is preferable to obtain optically active alcohols [I] and [II] from compound [V]. For this purpose, as shown in the following formula, The optically active tartaric acid diester used is used to control the stereo configuration of the alcohol product. As the optically active tartaric acid diester used here, L-(+)-
Dimethyl tartrate, L-(+)-diethyl tartrate, L-
(+)-Diisopropyl tartrate, L-(+)-di-t-butyl tartrate, L-(+)-distearyl tartrate, L-
Examples include (+)-diphenyl tartrate and their D-(-)-forms. For example, if L-(+)-tartaric acid diester is used, Or, if D-(-)-tartaric acid diester is used, Therefore, almost no syn-form epoxy alcohol which is a stereoisomer of [I] or [II] is produced.

The amount of the tartaric acid diester used is 0.9 to 2.0 mol, and particularly 1.0 to 1.2 mol, per mol of the titanium alkoxide mentioned above.
Molar is preferred.

In the above reaction, titanium tetraalkoxide is used, but as titanium tetraalkoxide, specifically, titanium tetramethoxide, titanium tetraethoxide, titanium tetrapropoxide, titanium tetraisopropoxide, titanium. Tetrabutoxide, titanium tetra-t-butoxide, etc. may be mentioned, and one or more of them may be used. The amount used is preferably 0.05 to 1.5 mol per mol of allyl alcohol represented by [V].

As the oxidizing agent (hydroperoxide),
Usually, fatty acid hydroperoxides are used, for example, t-butyl hydroperoxide, α, α-dimethylheptyl hydroperoxide, bis-isobutyl-2,5-dihydroperoxide, 1-methylcyclohexyl hydroperoxide, Cumene hydroperoxide, cyclohexyl hydroperoxide and the like can be mentioned. The amount used is 0.5 to 3 mol, and particularly preferably 0.5 to 1.5 mol, per 1 mol of the allyl alcohol of [V].

A solvent is preferably used in the above production method, and an inert solvent, particularly a halogenated hydrocarbon solvent is preferably used as the solvent. Specifically, dichloromethane,
Dichloroethane etc. can be mentioned.

The reaction temperature is in the range of -80 ° C to 80 ° C, preferably -30 ° C to 30 ° C. The reaction time varies depending on the reaction substrate or the temperature, but is usually from 10 minutes to 100 hours.

Since the reaction system is very dislike of water, it is necessary to dehydrate the reaction solvent, reaction substrate and reaction agent as much as possible. Further, when a catalytic amount of a tartaric acid diester is used, powdered molecular sieve, calcium hydride, silica gel or the like may be allowed to coexist and react.

The trans allyl alcohol [V] used in the above method is It may be a racemate or a mixture of optically active compounds, and when optically active epoxy alcohol [I] or [II] is synthesized, the corresponding optically active allyl alcohol, that is, compound of [IV] or compound of [III] in this order respectively May be used.

Here, the compound of [V] can be synthesized by a conventional method, that is, reduction of enone with ketone, reaction of vinyl metal reagent with aldehyde, transhydrogenation of acetylene alcohol, and the like.

Next, the usefulness of the compounds [I] and [II] of the present invention will be specifically described.

The essence of the usefulness of these compounds is that they are chiral compounds and at the same time have an epoxystannyl group. The compound of the present invention having a stannyl group [I], [II]
Therefore, the optically active allyl alcohol in the cis form, which could not be obtained efficiently by the conventional methods such as Sharpless, can be obtained easily and easily.

For example, the above-mentioned [VI] used as the ω chain of prostaglandins having a halogen can be easily obtained as shown in the following reaction formula.

The novel compounds [I] and [II] of the present invention can synthesize all stereoisomers of many kinds of secondary allyl alcohols. The following reactions can be shown by giving more specific examples.

Reacting the Grignard reagent with a compound in which the hydroxyl group of the anti-epoxy alcohol represented by the general formula [I _a ] is protected, (However, R has the same meaning as described above, and R ⁴ represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an aryl group, or a derivative thereof. Indicates a group. ) Various 1,2-diols represented by the general formula [XI] can be obtained.

Then, a compound represented by the general formula [XI] can be obtained by subjecting the compound represented by the general formula [XI] to a basic Pitterson elimination reaction and an acidic Pitterson elimination reaction, respectively.

Similarly, an optically active allyl alcohol [IV _b ] can be obtained by reacting an anti-epoxy alcohol represented by the general formula [I _b ] having a stannyl group at the γ-position with an organotin lithium reagent.

Further, it has a butanyl group [I _a ] or [II _a ]
Can be converted to an unsubstituted epoxy alcohol [XII] by protecting the hydroxyl group, treating with tetrabutylammonium fluoride, and then deprotecting.

The unsubstituted epoxy alcohol [XII] is an insect pheromone, brevicomin (S. Takano et al., JCS, Chem.
Comunn., 1985 , 1759) and monosaccharides (D. Seebach et al., He
lv.Chim.Acta, 64 , 687 (1981)) and other useful compounds.

In addition, an optically active 1,3-diol can also be obtained by utilizing red-Al reduction of an optically active epoxy alcohol similar to the compound of [I] or the compound of [II].

Further, the above reaction is carried out, for example, with respect to [I] having a hydroxyl group of which the configuration is opposite to that of [II] and the configuration is restricted.
The antiepoxy alcohol having a stannyl group at the position can be carried out to obtain a compound having stereoregularity.

EFFECTS OF THE INVENTION As described above, the general formulas [I] and [I
The optically active alcohol represented by [I] is a novel compound, which is useful as an intermediate for the synthesis of various physiologically active substances, and at the same time the alcohol itself acts as a physiologically active substance.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to the following examples.

In the following examples, Bu represents a butyl group and Am represents an amyl group.

〔Example〕

Titanium tetraisopropoxide cooled to -20 ° C 0.
0.61 ml of L-(+)-diisopropyl tartrate [DIPT] was added dropwise to a solution of 18 ml of CH ₂ Cl _{2 of} 72 ml, and the mixture was stirred for 10 minutes. To this, 1- (1) 1.01 g of CH ₂ Cl ₂ 3 ml solution was added dropwise, and further 10
Stir for minutes. Subsequently, 1.07 ml of a 3.40 M CH ₂ Cl ₂ solution of t-butyl hydroperoxide [TBHP] was added dropwise, and the mixture was stirred for 4 hours. 1- (2) and 1- by thin layer chromatography
After confirming that (3) was approximately 1: 1, 0.71 ml of dimethyl sulfide was added at -20 ° C, and the mixture was stirred at the same temperature for 40 minutes. Then 25 ml of ether and 10 wt% tartaric acid aqueous solution
1 ml, NaF3g, and celite 10g were added at room temperature, and it stirred for 1 hour. The mixture was suction filtered to remove the precipitate and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography to give 1- (3) 433 mg and 1- (2) 450.
mg was obtained as an oil.

 The analytical values of the compounds 1- (2) and 1- (3) are shown below.

¹ H NMR (CCl ₄ , TMS) 69.6,58.4,48.2,33.8,32.0,29.0,27.3,25.1,22.5,13.9,
13.6,8.8 ▲ [α] ²⁵ _D ▼ -34.5 ° (C 1.10, CHCl ₃ , 88% ee) IR (neat) 3425,2920,2850,1460,1380,1250,1070,102
0,862 (cm ^-1 ) ¹ H NMR (CCl ₄ ) δ 0.76 to 1.71 (m, 39H, 4CH ₃ , 13CH ₃ , OH), 3.79 to 4.10
(M, 1H, CHOH), 5.54 to 6.40 (m, 2H, CH = OH) ▲ [α] ²⁵ _D ▼ −3.09 ° (C 1.10, chloroform) The optical purity of this product is 100% ee from the results of the reference example. You can judge that it is very close.

[Reference example] 7 ml of an ether solution of 543 mg of compound 1- (3) was cooled to 0 ° C., and 363 mg of iodine was added thereto. After stirring at 0 ° C. for 1 hour, a Na ₂ S ₂ O ₃ aqueous solution was added. The product was extracted with hexane, the extract was dried over MgSO ₄ and concentrated, and the resulting oil was purified by silica gel column chromatography to obtain 304 mg of 2- (3) as an oil. Yield 92% ¹ H NMR (CDCl ₃ ) δ 0.87 (t, J = 6.0Hz, 3H, CH ₃ ), 1.06 to 1.76 (m, 8H, C
H ₂ ), 2.45 (brs, 1H, OH), 4.03 (q, J = 6.0Hz, 1H, CHO),
5.26 (d, J = 15.6Hz, 1H, HCI), 5.55 (dd, J = 15.6Hz, 6.0H
z, 1H, IC = CH) ▲ [α] ²⁴ _D ▼ −9.86 ° (C 1.48, methanol) Literature value of 1- (3) enantiomer (R. Noyori et al.
al., J. Am. Chem. Soc., 106, (1979)) is ▲ [α] ²⁴ _D ▼ -9.87 ° (C 1.57, methanol), which is in good agreement.

The optical purity was 99.5% ee or more by the method of measuring NMR by inducing 2- (3) into an optically active ester of α-methoxy-α-trifluoromethylphenylacetic acid (Mosher ester).

Claims (1)

(57) [Claims] 1. A general formula [I]: And the general formula [II]: [In the formula, R represents a saturated or unsaturated alkyl group having 1 to 10 carbon atoms, and R ¹ , R ² and R ³ are the same or different from each other and have 1 to 10 carbon atoms.
10 alkyl groups are shown. ] An optically active alcohol having a stannyl group at the γ-position selected from the compounds represented by: