JPH032158A - New triflate and production of natural substance using the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula [R1 and R4 are H or alkyl]; R2 and R3 are alkyl; R5 is -CH2R6 (R6 is alkyl or aryl) or-SO2R6]. EXAMPLE:(4R,5R)-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolan-4-methyltr iflate. USE:Useful for the production of various natural substances or their derivatives. Especially, an aggregation pheromone of pine engravers [(+)-exo-brevicomin] can be synthesized in high efficiency. PREPARATION:The objective compound of formula can be produced by O- alkylating a hydroxyl group of a corresponding dihydric alcohol with an alkyl halide, etc., and reacting with trifluoromethane sulfonic acid anhydride to convert the remaining hydroxyl group into a triflate group.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel triflate compound and a method for synthesizing a physiologically active compound using the same.

[Prior Art] (+)-exo-previcomin, which is known as an aggregation pheromone for bark beetles, has been synthesized from D-tartrate diethyl ester in six steps, and is synthesized from 0-alkylidene- The ditosylate of threitol undergoes intermolecular and intramolecular nucleophilic reactions to form a C-〇 bond (Tetrahedr
on Letters, Vol. 23. No, 52.5
553-5554.1982).

The total yield in this method is as low as 32.3%. In addition, in this reaction, only strong alkylating agents such as alkyl copper lithium can be used (alkyl copper lithium, etc.), and therefore only limited types of alkyl can be used. There were limits to its application to the synthesis of similar compounds.

[Specific Means for Solving the Problems] In view of the problems of the prior art, the present inventors have made intensive studies and have developed a novel triflate obtained from a dihydric alcohol having an oxygen functional group at the β-position as a raw material. The present invention has been achieved by discovering that such problems can be solved by carrying out an asymmetric alkylation reaction via. That is, the present invention provides general formula RI! is reacted with an organometallic reagent, and then reacted with an organic w4 reagent to form a compound of the general formula [R1 and R4 are hydrogen or an alkyl group, R2 and R3 are an alkyl group, and R6 is -CH2R8 or -5O2R
11 (wherein R6 represents an alkyl group or an aryl group). ] and the general formula % Formula % (R1, Rz, Ra s Ra are the same as above) and the triflate represented by the general formula (R5 is -3O230R4 (R1, Rz, R3 , Ra is the same as above ++R7 and R,
is a substituent different from , and both represent an alkyl group,
) and -a triflate represented by formula (1), wherein R5 is -CH2R6
A method for producing a compound of general formula (I) by reacting a compound with an organometallic reagent, then obtaining an alcohol by hydrogen reduction, triflating this, and reacting with an organometallic reagent, and a method of producing a compound of general formula (I), and The present invention provides a method for obtaining a compound of formula -a (Ill) by reacting a triflate represented by the formula with an organometallic reagent. Furthermore, a specific compound among the compounds represented by the general formula (III), that is, a compound in which R7 is the general formula (n represents an integer of 2 to 5, and R9 and RIOlR11 represent an alkyl group), is prepared under an acid catalyst. The present invention provides a method for producing a compound represented by the formula -C (R1, R4, R8, R9, and n are the same as above) by cyclocondensation with

An alcohol having an electron-withdrawing group such as an ether at the β-position of -i cannot introduce a side chain by a coupling reaction if it is not used as is. Although a method of introducing carbon chains is known, this method limits the types of carbon chains that can be introduced due to the difficulty in preparing alkyl copper lithium.
In this issue, we describe a method to easily and efficiently introduce various side chains by reacting this type of alcohol with trifluoromethanesulfonic acid to form a triflate and then reacting it with an organometallic reagent, such as Grignard reagent. However, the present invention was made by specifically discovering a method for obtaining an asymmetric compound using a dihydric alcohol as a raw material.

The triflate represented by the general formula CI) is produced by 0-alkylating one of the hydroxyl groups of the corresponding dihydric alcohol with an alkyl halide, etc., and then reacting with trifluoromethanesulfonic anhydride to triflate the remaining hydroxyl group. Alternatively, it can be obtained by converting one of the hydroxyl groups of the corresponding dihydric alcohol into a sulfonic acid ester with an alkylsulfonyl chloride and reacting with trifluoromethanesulfonic anhydride in the same manner. O-alkylation of a hydroxyl group is carried out by a conventional method, in which an alkali halide having a desired alkyl group is reacted in a polar solvent such as DMSO in the presence of an alkali such as potassium hydroxide. In addition, alkyl sulfonic acid esterification can be performed using alkyl lithium,
For example, in the presence of an alkali such as n-butyllithium, p
-) Easily progresses by the action of an alkylsulfonyl chloride such as luenesulfonic acid chloride. After 0-alkylation or alkylsulfonic acid esterification is carried out in this manner, triflatation is carried out, but the method used in boat fishing may be used. Specifically, 0-alkylated or alkylsulfonic acid Add a solution of anhydrous trifluoromethanesulfonic acid in anhydrous methylene chloride to a solution of the esterified product in anhydrous methylene chloride and pyridine.
The reaction is carried out at approximately 5°C by dropping the solution under nitrogen atmosphere.

A triflate may be obtained from this reaction product by a conventional method, water may be removed by azeotropic distillation with toluene, and then the triflate may be subjected to the next step of reaction.

This novel triflate is useful in the synthesis of asymmetric compounds represented by general formula (III). In this synthesis method, when the triflate is an alkyl sulfonic acid ester triflate, first, an organometallic reagent is reacted with the triflate,
Introduce a side chain at the triflate site. In this case, when a strong alkylating agent such as alkyl copper lithium is used as the organometallic reagent, there is a concern that the yield will decrease because the coupling reaction also occurs competitively at the alkyl sulfonic acid ester moiety. In order to carry out the reaction more efficiently, it is preferable to use a Grignard reagent in the presence of a copper catalyst. In this method, the coupling reaction proceeds very selectively only at the triflate site. A side chain is then introduced into the alkyl sulfonic acid ester moiety, but in this case it is necessary to use a strong alkylating agent such as alkyl copper lithium as the organometallic reagent. According to this method, various alkyl groups can be efficiently introduced into the triflate moiety using a Grignard reagent, and asymmetric compounds can be synthesized extremely efficiently.

On the other hand, when the triflate contains an 0-alkylated ether, the triflate moiety is coupled with an organometallic reagent, which may be a Grignard reagent, alkyl copper lithium, alkyl copper cyanolithium, etc. The use of any strong alkylating agent is possible.

After this reaction, alcohol is produced by hydrogen reduction in the presence of a catalyst such as palladium-carbon, and triflate formation and coupling reaction are performed again.

Among the asymmetric compounds represented by the general formula (Ill) thus obtained, those in which R7 is the general formula (IV) are treated with an acid catalyst such as p-toluenesulfonic acid in a solvent such as methylene chloride. By refluxing in a nitrogen atmosphere in the presence of nitrogen, it easily undergoes cyclization and synthesizes various natural products or their derivatives in high yields, such as (+)-exo-previcomin, which is known as an aggregation pheromone for bark beetles. It is something that can be done.

In the present invention, in order to obtain the compound of general formula (n) which is a raw material for the synthesis of the compound of general formula (III), the compound of general formula (1) is used.
Another effective method is to treat alcohol, which is a precursor of a compound in which R1+ is -SO2R6, with dimethyl copper lithium or the like without triflating it, introduce a side chain into the alkyl sulfone ester moiety, and then triflate it. .

Hereinafter, the present invention will be specifically explained with reference to Examples.

The reaction schemes of Examples 1 to 9 are shown below.

Examples 1 to 5 Example 1 300 mg (1,2+mol) of (4R,5R)-4-methyloxymethyl-5-hydroxymethyl-2,2-dimethyl-1,3-dioxolane 1 and triethylamine ( 480 μl) of methylene chloride (5+
*l) Cool the solution to -15'C and add trifluoromethanesulfonic anhydride (300u 1.1.8mmol
) was added dropwise and stirred for 30 minutes. Work-up and subsequent purification by silica gel column chromatography yielded (4R,5R)-5-bensiloxymethyl-2,2-methyl- 1,3-siloxolane-4-methyltri7late 2 <444a+g
, yield 96%) was obtained. The physical properties of this material are shown below.

[αM' +8.2°(c 1.54.CHCl5
)r R(neat) 1495,1410,13
80,1240,1210.1145°1100.95
0,695.600c+a→'HN M R (CDC1
3) δ1.41 (6H, s), 3.52 (1) 1. dd
.

J=15.8, 6.2Hz), 3.73<IH, dd
, J=15.8,4.4Hz) ,4.09(2H,i
), 4.56 (2H, s), 7.32 (5H,
s) Example 2 Me2 CuCNLi2 prepared from CuCN (160 mg, 1.8 mmol) and methyllithium in THF (
5o1) The solution was the crude triflate obtained in Example 1, ? The reaction solution was added dropwise to a THF (5 ml) solution at -78°C and stirred for 30 minutes.
, 5ml) was added, filtered, concentrated, and extracted with ethyl ether. The product obtained by removing the solvent was purified by silica gel column chromatography (4R,5R)-4
-%" siloxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxolane dan-(212B, yield 71%) was obtained as a transparent oil. The physical properties of this product are shown below.

[αr I R(neat) +4.82 ° (C1,62,CHCl3)2
980.2940.2870.1500,1455,1
380°1370.1240,1215,1100.7
90,735°700 cm ('HNMR (CDC1,) 60.98 (3H, t,
J=6.8Hz), 1.40(6)1. s), 1.
61 (2H, m), 3.57 (2H, d, J = 4.4H
z), 3.7-3.9(2H,i), 4.59(2
8°s), 7.32<5)1. s) ' CN M R (CDC13) δ10.01,2
6.02, 26.97, 27.2470.72, 73.
34, 79.47, 79.65, 108.44°127
．． 40,128.13,137.89 Example 3 A mixture of 3 (430 mg, 1.72 mmol) obtained in Example 2 and 5% PdC (50+ag) was dissolved in absolute ethanol (
10+++1> and stirred at room temperature for 3 days under a hydrogen atmosphere.

The crude product obtained by filtering and concentrating the reaction solution was purified by silica gel column chromatography (eluent; hexane:diethyl ether = 1:1) to obtain (4R,5R)-4 as a transparent oil. -Humanized oxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxolane 4
(256 g, yield 93%) was obtained. The physical properties of this material are shown below.

Rf O,24 (hexane-ethyl ether, 1:1) [αF +18.7°
(c 1.88.CHCl3)IR(neat)
3440, 2950, 2900, 2850, 1450,
13701360, 1230.1205.1160.1
100.1060°1035.950,850,780
,760 crll('HN M R(CDCl3)
δ1.00(3)1. t, J=7.0Hz), 1.41
(6)1. s), 1.41-1.75 (2H, m), 2
．． 0 (18br), 3.6-3.9 (4H, m)
' CNMR (CDC13) δ9.92.25.87,
26.94, 27.18°62.27, 78.22,8
1.21,108.37 Example 4 4 obtained in Example 3 (300 mg, 1.88 mmol)
Add trifluoromethanesulfonic anhydride (48 μl) and triethylamine (780 μl) in methylene chloride at -15°C.
0 μ1.2°8 mmol) was added dropwise, the reaction solution was stirred for 30 minutes, and treated in the usual manner to obtain crude trifle) [<
4R,5R)-5-ethyl-2,2-dimethyl-1.
3-cy1oxolane-4-methyltri7late 5]
I got it. This product was used for the next reaction after adding toluene and performing azeotropic dehydration.

CuBr (54 mg, 0.4 m
2-(2,5
,5-trimethyl-1,3-51'oxan-2-yl)-ethylmac1nesium filomibi 6 (5,6m
1, 2.8 + mol) of THF solution was added, and the previously obtained shadow ether-dissolved iffl (5 ml) was added, and the mixture was heated at O''C for 3.5 ml.
Stir for hours. This product was purified by silica gel column chromatography (hexane:diethyl ether-4:1), and (4R,5R)-5-ethyl-4-[3-(2,5,5)-trimethyl -1,3-oxyoxan-2-yl)7°Rohyol]-2,2-cy1
Methyl-1,3-dioxolane (361mg,
A yield of 64% was obtained. The physical properties of this material are shown below.

Rf O, 27 (~K key ethyl ether, 4:1 >[αL' + 16
．． 8 ” (CO,80,CHCl3)IR(ne
at) 2970, 2930, 2920.2850,
1460, 1390° 1370.1360, 1250,
1230,1200,1100゜860730 cm('I(NMR(CDCl3)δ0.B3(3)1.s)
, 0.99 (3) 1. t, J: 6.9Hz), 1
．． 03 (3H, s), 137 (9B.

s), 1.4-1.8 (8H, m), 3.4-3
．． 7 (6H.

m) flCNMR (CDCl3) δ10°29, 20.08
, 20.23, 22.58° 22.91, 25.84.
27.36, 27.42.3Q, 05°33.40,3
8.55.70.38.80.57,82.12゜98
．． 92107.70 Example 5 7 obtained in Example 4 (380 mg, 1.27 mmol)
and a catalytic amount of p-toluenesulfonic acid monohydrate were added to methylene chloride (15 ml), and the mixture was refluxed for 2 hours in a nitrogen atmosphere.

After post-treatment, the product was purified by silica gel column chromatography to obtain (+)-exo-previcomin 8 (173B, yield 87%) as a colorless oil. The physical properties of this material are shown below.

Rf O,32 (~0% ethyl ether, 10:1) [crl'
+67.6 @ (c 1.0.
L460. L380.1235,1030,1000°845 c+a('HN M R(CDCl3)δ0.91(3H,t
, J=6.8)1z), 1.42(3)1. s), 1.
3-1.9 (88, m), 3.93 (LH.

t, J=6.2Hz), 4.12(IH,br)'C
NMR (CDC13) δ9.80.17.27.25
．． 08.28.03゜2g, 61.35.02.78.
25,81.12.107.61Example 6 (4R,5R)-4,5-Dihydrogenated oxymethyl-2.
2-silityl-1,3-cyoxolane 9 (10
0mg, 0.62mmol) of THF (2ml>,
n in a mixed solution of DMSO (0,5+*l) at -15°C.
-Butyllithium (1,58M).

A hexane solution (0.41 ml, 0.65 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The solution was cooled to 0°C and ρ-toluenesulfonyl chloride (120μI1
g, 0.62 mmol) of THF solution (11) was added,
Stirred at room temperature for 1 hour.

After post-treatment, it was purified by preparative TLC to obtain (4R,5R)-(5
-hydroxymethyl-1,3-4/”oxolane-4-
ylmethyl) p-toluenesulfonate Ysu(175
mg, yield 89%, colorless oil) was obtained.

The physical properties of this material are shown below.

Rf O, 42 (Si 1 ethyl ether) [αM' + 11, 3
° (c 2.70.CHCh )I R(n
eat) 3450, 2980, 2960, 28
70,1600,1370°1360.1190,11
75,975,785,760°660 c+a('HN M R(CDCl3) 61.35(3
t(,s), 1.39(3H,s).

2.36 (IH, s), 2.46 (38, s), 3.6
-4.2 (6H, m), 7.35 (28, d, J=8.
4Hz) 7.80 (IH, d, J = 8.4Hz) Example 7 10 obtained in Example 6 (165 mg, 0.52 mmol)
A solution of methylene chloride (3@1) (170 μl) was cooled to 15°C, and trifluoromethanesulfonic anhydride (130 μl, 0.0 μl) was added to the solution.
A solution of 78 mmol) in methylene chloride (1 ml) was added dropwise and stirred for 20 minutes. After post-treatment, it was purified by silica gel column chromatography to obtain (4R,5R)-(
5-p-Toluenesulfonyloxy-2,2-dimethyl, 3-dioxolane-4-ylmethyl) tri7late 11 was obtained. The physical properties of this material are shown below.

Rf O,44 (hexane diethyl ether = 1:1) [α M'
+7.6” (C1,26,CHC
l3)r R(neat) 3000,2950
．． 1600, 1420.1370, 12501210,
1190.1180.1150.1100,990゜9
50.815,785,760,660,610,55
0 cm('HNMR(CDCl3)
δ 1.37. (3H,s), 1.39(3H,s)
.

2.46 (3H, s), 4.14 (4H, a+), 4.
56 (211°+a), 7.36 (2H, d, J=8.
4Hz), 7.80 (2H.

d, J = 8.4H2) Example 8 A suspension of CuBr (15 mg, 0.1+Iaol) in diethyl ether (2+al) was added with
Tl of M (F solution, 1.1 ml, 0°55 mmol)
and diluted with diethyl ether (3 ml) obtained in Example 7.
> solution was added at 0°C and stirred at this temperature for 4 hours to carry out the reaction.Next, 3 equivalents of dimethyl copper lithium in diethyl ether (3+al> solution was added at 0°C and stirred at room temperature for 10 hours. The reaction was carried out. After post-treatment, the product was purified by silica gel column chromatography to obtain 7 (98B, yield 63%) as a colorless oil.

Example 9 Cu I (370 mg,
1.92 mmol) and methyllithium (1.56 M,
10 (100
mg, 0.32 ma+ol) of diethyl ether (3 m
l) The reaction mixture to which the solution was added was slowly warmed to 0"C and the reaction was carried out for 3 hours. Saturated NH was added to the mixture.
a A small amount of C1-aqNH3 (9:l) was added to stop the reaction, and the mixture was extracted with ether. The product obtained by removing the solvent was purified by silica gel column chromatography, and 4
(46 mg, yield 90%) was obtained as a clear oil.

[Effects of the Invention] According to the present invention, through a novel asymmetric triflate,
Various natural products or derivatives thereof can be easily obtained, and in particular, (+)-exa-previcomin, which is an aggregation pheromone for insects of the family Barkidaceae, can be efficiently synthesized.

Claims (6)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [R_1, R_4 are hydrogen or alkyl groups, R_2, R
_3 represents an alkyl group, and R_5 represents -CH_2R_6 or -SO_2R_6 (R_6 represents an alkyl group or an aryl group). ] A new triflate. (2) A new triflate represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (R_1, R_2, R_3, R_4 are the same as above). (3) General formula ▲ Numerical formula, chemical formula, characterized by reacting a triflate represented by general formula (I) with an organometallic reagent and then reacting with an organocopper reagent, There are tables, etc. ▼ (III) (R_1, R_2, R_3, R_4 are the same as above. R_
7 and R_8 are different substituents, and both represent an alkyl group. ) A method for producing a compound represented by (4) A triflate represented by the general formula (I) in which R_5 is -CH_2R_6 is reacted with an organometallic reagent, then an alcohol is obtained by reduction, this is triflated, and the compound is reacted with an organometallic reagent. A method for producing a compound represented by general formula (III), characterized by: (5) A method for producing a compound represented by general formula (III), which comprises reacting a triflate represented by general formula (II) with an organometallic reagent. (6) In general formula (III), R_7 is general formula▲mathematical formula,
There are chemical formulas, tables, etc.▼(IV) (n represents an integer from 2 to 5, R_9, R_1_0, R_
1_1 represents an alkyl group. ) with the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (R_1, R_4, R_8, R_9, n are the same as above.) Methods for making the represented compounds.