CA1167460A - Process for production of lineatin - Google Patents
Process for production of lineatinInfo
- Publication number
- CA1167460A CA1167460A CA000377720A CA377720A CA1167460A CA 1167460 A CA1167460 A CA 1167460A CA 000377720 A CA000377720 A CA 000377720A CA 377720 A CA377720 A CA 377720A CA 1167460 A CA1167460 A CA 1167460A
- Authority
- CA
- Canada
- Prior art keywords
- trimethyl
- lineatin
- oxabicyclo
- oxy
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
A process is disclosed for the production of racemic lineatin (3,3,7 trimethyl-2,9-dioxatricyclo[3.3.1.0]nonane), which is an aggregation pheromone of the striped timber-attacking bark beetle (trypodendron lineatum), of the formula:
(I) The process comprises subjecting an alcohol of the formula:
(c) in which n represents optionally substituted alkyl or benzyl, to acid catalysis.
Lineatin is suitable for luring the mentioned beetle and may therefore be used for facilitating its control.
A process is disclosed for the production of racemic lineatin (3,3,7 trimethyl-2,9-dioxatricyclo[3.3.1.0]nonane), which is an aggregation pheromone of the striped timber-attacking bark beetle (trypodendron lineatum), of the formula:
(I) The process comprises subjecting an alcohol of the formula:
(c) in which n represents optionally substituted alkyl or benzyl, to acid catalysis.
Lineatin is suitable for luring the mentioned beetle and may therefore be used for facilitating its control.
Description
6~
This invention relates to a process for the production of racemic lineatin (3,3,7-trimethyl-2,9-dioxatricyclo[3.3.1.0]nonane), which is an aggregation pheromone of the striped timber-attacking bark beetle (trypodendron lineatum), of the formula:
~ CH3 ~ ~ (I) Lineatin is suitable for luring the mentioned beetle and may therefore be used for facilitating its control.
Accordingly, the invention provides a process for the production of lineatin, which comprises subjecting an alcohol of the formula:
OR
HO ~ CH3 (c) wherein R represents alkyl or ben~yl, to acid catalysis.
~`
A particular aspect of the invention provides a process for the production of lineatin, which comprises rearranging 2~2,6-trimethyl-4-R-oxy-7~8-epoxy-3-oxabicyclo[4.1.0]heptane of the formula:
OR
~CH3 (a) H3C\
.
wherein R represents alkyl or benzyl, under the action of a.lkali halide an inert solvent under neutral conditions and at elevated temperature to form a mixture of 2,2J6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one and --7-one of the formulae:
J ~ CH3 and O ~ ~ CH3 (b) (b~) subsequently, reducing the mxiture of ketones (b) and ~b') with a complex hydride under conventional conditions to form the corresponding alcohols of the formulae:
This invention relates to a process for the production of racemic lineatin (3,3,7-trimethyl-2,9-dioxatricyclo[3.3.1.0]nonane), which is an aggregation pheromone of the striped timber-attacking bark beetle (trypodendron lineatum), of the formula:
~ CH3 ~ ~ (I) Lineatin is suitable for luring the mentioned beetle and may therefore be used for facilitating its control.
Accordingly, the invention provides a process for the production of lineatin, which comprises subjecting an alcohol of the formula:
OR
HO ~ CH3 (c) wherein R represents alkyl or ben~yl, to acid catalysis.
~`
A particular aspect of the invention provides a process for the production of lineatin, which comprises rearranging 2~2,6-trimethyl-4-R-oxy-7~8-epoxy-3-oxabicyclo[4.1.0]heptane of the formula:
OR
~CH3 (a) H3C\
.
wherein R represents alkyl or benzyl, under the action of a.lkali halide an inert solvent under neutral conditions and at elevated temperature to form a mixture of 2,2J6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one and --7-one of the formulae:
J ~ CH3 and O ~ ~ CH3 (b) (b~) subsequently, reducing the mxiture of ketones (b) and ~b') with a complex hydride under conventional conditions to form the corresponding alcohols of the formulae:
-2-~7'~
J- ~
o HO ~ CH3 and O ~ ~ CH3 H3C ~ H3C ~
(c) (c') and after separation converting alcohol (c) by means of acid catalysis to racemic lineatin.
According to a further aspect of the invention there is provided the compound 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one or 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-ol wherein R represents alkyl or benzyl.
This process can be depicted by the reaction scheme -OR ~ o (R: optionally substituted alkyl / ~ or benzyl) O / ~ ~ CH3 ~ H3C \\ v : CH3 (a) OR
O ~ - ~A3 ~ o ~ CH3 H3C ~ ~ H3C \ \
(b) (b~) , . . -, ~ 3-.
OR ¦ OR
~ C~13 ~ o ~ ~ - C~13 (c) (c ' ) I
(l) the spiro compound ~a) is rearranged to the mixture of cyclobutanones (b) and (b'), (2) the cyclobutanone (b) or the mixture of the cyclobutanones is reduced to the corresponding alcohols (c) resp. to the mixture (c)/(c') and, finally,
J- ~
o HO ~ CH3 and O ~ ~ CH3 H3C ~ H3C ~
(c) (c') and after separation converting alcohol (c) by means of acid catalysis to racemic lineatin.
According to a further aspect of the invention there is provided the compound 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one or 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-ol wherein R represents alkyl or benzyl.
This process can be depicted by the reaction scheme -OR ~ o (R: optionally substituted alkyl / ~ or benzyl) O / ~ ~ CH3 ~ H3C \\ v : CH3 (a) OR
O ~ - ~A3 ~ o ~ CH3 H3C ~ ~ H3C \ \
(b) (b~) , . . -, ~ 3-.
OR ¦ OR
~ C~13 ~ o ~ ~ - C~13 (c) (c ' ) I
(l) the spiro compound ~a) is rearranged to the mixture of cyclobutanones (b) and (b'), (2) the cyclobutanone (b) or the mixture of the cyclobutanones is reduced to the corresponding alcohols (c) resp. to the mixture (c)/(c') and, finally,
(3) the alcohol (c) is converted into lineatin (I).
The rearrangement (l) proceeds by the action of alkali halides, for example lithium bromide, in an inert solvent, for example acetonitrile, under neutral conditions, preferably with heating. The addition of lithium carbonate is of advantage. The compounds (b) and (b') are obtained in the approximate ratio of 4 : l and in high yield. They may be separated before further process-ing, for example by means of chromatography. However, it is more favourable only to carry out the separation of the alcohols (c)/(c').
For the reduction of (b)/(b') according to (2) complex hydrides, especially alkali borohydrides resp. derivatives of same are preferably employed.
They are applied in the conventional way and the obtained alcohols (c) and (c') are separated chromatographically.
In step (3)~ -~he alcohol ~c) is converted into racemic lineatin. This
The rearrangement (l) proceeds by the action of alkali halides, for example lithium bromide, in an inert solvent, for example acetonitrile, under neutral conditions, preferably with heating. The addition of lithium carbonate is of advantage. The compounds (b) and (b') are obtained in the approximate ratio of 4 : l and in high yield. They may be separated before further process-ing, for example by means of chromatography. However, it is more favourable only to carry out the separation of the alcohols (c)/(c').
For the reduction of (b)/(b') according to (2) complex hydrides, especially alkali borohydrides resp. derivatives of same are preferably employed.
They are applied in the conventional way and the obtained alcohols (c) and (c') are separated chromatographically.
In step (3)~ -~he alcohol ~c) is converted into racemic lineatin. This
- 4 -~ ~ ~ 7 ~3~
is achieved by means of a~id catalysis, for example, wi-th carboxylic acidsl such as aceti.c acid, sulfuric acid, hydrohalic acids and, especially, p-toluene-sulfonic acid.
The starting material ~a) may be obtained in the following way:
- 4a -~6~
O OH
3 CH - - ~ H3C ~ ~ - CH3 (dj (e) OR
II (e) D ~ CH3 C
(f) (R = optionally substituted alkyl or benzyl) OR X X OR
III ~ ~
H3C ~ CH3 ~ ~ 3 : CH3 CH3 X
; (g) . (g') (X means halogen) .~ -5-3C Cl OR
IV (g) + ~g ' ) ._ O/~ CH3 ~ /~\>--C~3 H3C t H3C ~\ C~H
(h) (h') J
(i) (i., Vl ~ (i') N3C ~CN3 (a) .
~7'~
Starting from the cyclic lactone of 5-hydroxy-3,5-dimethyl-3-hexeJIe carboxylic acid (d) known from the literature, -the hemiacetal ~e) is produced by reduction, preferably with complex hydrides, which can be converted by alkyl-ation resp. aralkylation into the acetal (f); R = lower alkyl is preferred. In step IIIJ there is added to the acetal a dihalogencarbene, preferably dichloro-carbene. The isomeric dihalocyclopropanes ~g) and (g') form in a ratio of approx. 2 : 1. The annelation of the dihalogen cyclopropane ring is preferably effected under phase transfer catalysis. According to the method of Kitatani [Bull. Chem. Soc. Jap. 50, 3288 (1977)] the mixture may be metalled and then methylated. For the optimum yield of the desired endo-methylation products (h) and (h') a low reaction temperature is favourable.
Organometallic bases may serve as metalli~ation reagent, preferably butyllithium. In order to obtain endo-alkyl derivatives, the chlorine and lithiwn isomers must have the chance to equilibrate.
A favourable reaction time therefor is 10 to 60 minutes, preferably 30 minutes. In s~ep V, the chloro-methyl-cyclopropane isomeric mixture (h)/(h') is mixed with a base of suitable strength, preferably potassium-tert-butylate in dimethylsulfoxide, whereby to form the corresponding methylene cyclopropanes (i) and (i') in a ratio of 3 : 1. IVhen this mixture is subjected to the reaction according to Prileschajew ~"Reaktionen der organ. Chemie", page 560;
Huthig Verlag Heidelberg 1976), the oxirane ~a) will form preponderantly, which serves as starting material for the reaction according to the invention.
In the following will be illustrated the production of the starting material and an example of the experimental performance of the reaction accord-ing to the invention.
7~
Production of the starting material:
a) 2,2,4-trimethyl-6-methoxy-5,6-dih~drc-~I-pyrane A solution of 157 g (1,1 mol) of 5-hydroxy-3,5-dimethyl-3-hexenoic acid lactone in a mixture of 200 ml of dry tetra-hydrofuran and 60 ml of ethylether is cooled to -20 to -30C.
In the course of 15 minutes a suspension of 11.2 g (0.29 mol) of lithium aluminium hydride in 320 ml of dry tetrahydrofuran is added. Then, the mixture is allowed to warm up to room temperature and after 30 minutes it is poured upon a mixture of 800 g of ice and 33 ml of conc. sulfuric acid. The etheric layer is separated and the aqueous phase extracted twice with each 200 ml of ether. The united e-theric extracts are washed with 100 ml of 5% sodium hydrogen carbonate solution and with 100 ml of saturated aqueous sodium chloride solution, then dried with sodium sulfate and evaporated in vacuo.
The concentrated reaction mixture is stirred - without purification - with 100 ml of trimethyl-ortho-formate and 4 g of ammonium nitrate in 40 ml of methanol for 12 hours at room temperature and then refluxed for 4 hours. After this period of time the mixture is poured into 300 ml of water ~`~ and extracted thrice with each 200 ml of chloroform. The extract is washed with 100 ml of saturated aqueaus sodium chloride solution, dried with magnesium sulfate and evaporated in vacuo. The concentrate is distillad under reduced pressure, whereby 102 g t5~% of theory) of the title compound are obtaine~.
Boiling point: 62 - 67C at 20 millibar.
. .
~ ~6 ~ ~3~
_ g _ b) Syn- and anti-2,2,6-trimethyl-4 methoxy-7,7-dichloro-3-oxabicyclo~4 1 O~he~tanes To a solution of lO0 g (0,64 mol) of the compound obtained under a) in 250 ml of chloroform are added 2 g (5,5 mmol) o~ cetyltrimethyl ammonium bromide and a cooled soIution of 250 g of sodiuM hydroxide in 250 ml of water. The two-phase reaction is effected while~
stirring vigorously. After 3 hours 9 the exothermic reaction, strong in the beginning, becomes more moderate and the analysis shows that the reaction has completed for approx.~ 50 %. ~ter stirring for l6 hours more, 95~ have been reacted. The ~eaction -solution is diluted with~l ltrO of waterj the chloro-- form phase is~separated and the aqueous phase extracted twice with each 300 ml of methy1ene chloride. The united extracts are washed twice with 500 ml of water under addition of a~ small quantity o~ magnesium sulfate.
The organlc~phase is drled~and eva~orated in vacuo.
After ~racti~onated distillation over ~sodium hydroxide~
pellets~the~title~compound is obtained in the ratio 2,1 : l.
Yield: 145~g (94%~of thèory).
Boiling point~`70 - 80C~(0,133 milliba~).
~ : : :: .
` c) 2j~2;6;7-Tetramethyl-4~meth~xy-7-chloro-3~oxabicyclo-4.l.~ hePta~e _ ____ ________ _ A solution of 24 g (lO0 mmol) of the mixture obtained according to b) in 300 ml of dry tetrahydrofuran is cooled to -100C. A-t this temperature a mixture of 90 ml of butyl lithium in hexane (275 molar, corres-ponding td ~5 mm~l) is added dropwise over a period of ~0 minutes~ After another 30 min. ~re added to the reactio~ mixture 3094 g (210 mmol) of ~ ~ .
.
' methyliodide, in the course of 20 minutes. In doing so, the temperature is kept in the range from 100 to -80C.
In the course of 10 to 12 hours, the temperature of the reaction mixture is allowed to rise to room temperature.
Then, the solution is diluted with 1 ltr. o~ water and extracted 3 times with 2V0 ml o~ petroleum ether ~boiling temperature 30 to 60C~. The organic phase is dried with sodium sulfate and evaporated in ~acuo. In the fractionated distillation, 17.5 g of a fraction are obtained within th~
boiling range of 55 to 60C/l,0 mbar.
It consists to a great extent of a mixture of the title compounds.
d) Syn- and anti-2,2,6-trimethyl-4-methoxy-7-methylene-3-oxabic~clo~4.1.0~he~tanes ______ ___ _____ __ ____________________________..______ To a suspension of Z0 g (178 mol) of potassium-tert.-butylate in 60 ml o~ dried dimethylsulfoxide under nitrogen are added at 90C 12 g (55 mmol~ of the isomeric mixture obtained ~nder c), in the course of 10 minutes. After 15 minute~, the reaction mixture is cooled, diluted with 500 ml of water and extracted with ~pentane continuously for 24 hours. After ~ithdrawal of the pentane, the residue is distilled off in vacuo. There are obtained 5.63 g (56% of theory) of a 3 ~ mixture of the title compounds.
boiling point: 60 to 65C/9 mbar.
e) 2,2,6-trimethyl-4-methoxy-7,8-epoxy-3-oxabicyclo-L4.1.0]he~tane ___ _____ To 12.2 g (61.6 mmol) of the isomeres obtained in line with d) in 300 ml of methylene chloride is added 1 ltr~ of a phosphate buffer (pH 6.4, 35.5 g of Na2HP04 and 34 g of HK2P04 in 1 ltr~ o~ water).
In the course of 10 minutes are added hereto while stirring ~1 g of p-nitro perbenæoic acid (98% purity, 112 mmol). The reaction mixture is stirred for 14 hours at room temperature, whereafter the oxidation agent has been consumed completely. Then, the phases are separated and the aqueous phase is washed with 100 ml of methylene chloride. The united organic solutionsare dried with magnesium sulfate, evaporated in vacuo and subjected to a vacuo distillation.
8.1 g (66% of theory~ of the title compound are obtained.
Boiling point 55 - 65C/0.5 mbar.
Exam~le a~ 2,2,6-Trimethyl-4-methoxy-3-oxabicyclot4.2.0]octan-8-one and 7-one _____________________________________________________ To 508 g (29 mmol) of the epoxide obtained under e) in 75 ml of acetonitrile are added 250 mg of lithium carbonate and 10.2 g (117 mmo~ of lithiùm bromide (dried ~or l2~hours at 125C and'used immediately3.
!
The solution i;s s-tirred in order to dissolve the lithium bromide and heated to 60C for 30 minutes. The reaction mixture is cooled to room temperature, diluted with 100 ml of water and extracted four times with each 100 ml of pentane. The united extracts are dried with magnesium sulfate and evaporated using a Vigreaux-column. The residue is distilled after addition of 10 mg of lithium carbonate and there are obtained 4,8 g (83% of theory) of a product with the boiling point of 55 to 60C at 004 mbar.
The distillation contains the title compounds in a ratio of 4 : 1.
~6~7 b) 2,2,6-Trimethyl-4-methoxy-3-oxabicycloC4.2.0~octan~
8-ole and 7-ole _ _ __ __ _ _ _ _ _ __ _ . __ __ _ __ _ .. _ _ __ _ . ___ _ _ _ . ___ __ ___ ____ _ _ To 3.2 g (16 mmol) of the 4 : l-mixture of the bicyclic ketones obtained in line with a) in 30 ml of 95~ ethanol are added 0.611 g (16 mmol) of sodium borohydride.
The mixture is stirred at room temperature over night and diluted afterwards with 150 ml of water. It is extracted with 5 portions of each 50 ml of ethylether.
The united extracts are dried with sodium sul~ate and evaporated in vacuo. 3~2 g of an oil are obtained.
The crude product is chromatographed on 200 g o~ ~ilica-gel (hexane/ethylacetate 1 : 1), process according to Still (J. Org, Chem., ~, 2923 (1978)). Fractions of 25 ml are collect~dO Fractions 20 to 22 comprlse beside impurities the desired alcohol with the 8-OH
group (R~ = 0.55, 0.468 g). The main portion of this alcohol is found in frac~io~s 23 to 2g (1.3 g, 40% of theory). The fractions 30 to 33 contain this alcohol too, beside the isomeric alcohol with the 7-OH group (R~ = 0040). ~The~8-alcohol ls charac~erized by the NM~-spectrum~
lH-NMR: 4,98 (lH, C4, t; J =~7 Hz)3 4,42 (lH, C8, m), 3,42 (3H, OCH3, s), 2,7-1,5 (6H, OH, Cl, C5, C7, m)5 1,41 (3H, CH3, s), 1,24 (3H, CH3, s), 1,16 (3H, CH3, s).
c) ~+)-3 3~7-Trimethyl-2l9-dioxatricyclo~3 3 1 0~nonane To 1.3 g (6 mmol) of 2,Z96-trimethyl-4-methoxy-3-oxa-bicyclo~4.2.0]octane-8-ole within a mixture from 20 ml of pentane and 0~5 ml of methanol are added several crystals of p-toluenesulfonic acid (approx. 1 mg).
The mixture is stirred for 1 hour at room temp~rature, filtered through neutral alumini~ oxide and evaporated in vacuo. The vacuum distillation (under addition of 2 mg of lithium carbonate) yields 0.71 g o~ lineatin (65% of theory);
boiling point 70C/16 mbar.
In line with the gas-chromatographical analysis the p~ duct has a purity degree of 98%. It is characterized by NMR.
l~-NMR: 4.91 (lH, Cl, b, s), 4~39 (lH, C5, m), 2.2-1.5 (5H, C4, C~, C81 m), 1.15 (6H, 2CH3, s) 1.11 (3H, CH3, s).
. ~ :
is achieved by means of a~id catalysis, for example, wi-th carboxylic acidsl such as aceti.c acid, sulfuric acid, hydrohalic acids and, especially, p-toluene-sulfonic acid.
The starting material ~a) may be obtained in the following way:
- 4a -~6~
O OH
3 CH - - ~ H3C ~ ~ - CH3 (dj (e) OR
II (e) D ~ CH3 C
(f) (R = optionally substituted alkyl or benzyl) OR X X OR
III ~ ~
H3C ~ CH3 ~ ~ 3 : CH3 CH3 X
; (g) . (g') (X means halogen) .~ -5-3C Cl OR
IV (g) + ~g ' ) ._ O/~ CH3 ~ /~\>--C~3 H3C t H3C ~\ C~H
(h) (h') J
(i) (i., Vl ~ (i') N3C ~CN3 (a) .
~7'~
Starting from the cyclic lactone of 5-hydroxy-3,5-dimethyl-3-hexeJIe carboxylic acid (d) known from the literature, -the hemiacetal ~e) is produced by reduction, preferably with complex hydrides, which can be converted by alkyl-ation resp. aralkylation into the acetal (f); R = lower alkyl is preferred. In step IIIJ there is added to the acetal a dihalogencarbene, preferably dichloro-carbene. The isomeric dihalocyclopropanes ~g) and (g') form in a ratio of approx. 2 : 1. The annelation of the dihalogen cyclopropane ring is preferably effected under phase transfer catalysis. According to the method of Kitatani [Bull. Chem. Soc. Jap. 50, 3288 (1977)] the mixture may be metalled and then methylated. For the optimum yield of the desired endo-methylation products (h) and (h') a low reaction temperature is favourable.
Organometallic bases may serve as metalli~ation reagent, preferably butyllithium. In order to obtain endo-alkyl derivatives, the chlorine and lithiwn isomers must have the chance to equilibrate.
A favourable reaction time therefor is 10 to 60 minutes, preferably 30 minutes. In s~ep V, the chloro-methyl-cyclopropane isomeric mixture (h)/(h') is mixed with a base of suitable strength, preferably potassium-tert-butylate in dimethylsulfoxide, whereby to form the corresponding methylene cyclopropanes (i) and (i') in a ratio of 3 : 1. IVhen this mixture is subjected to the reaction according to Prileschajew ~"Reaktionen der organ. Chemie", page 560;
Huthig Verlag Heidelberg 1976), the oxirane ~a) will form preponderantly, which serves as starting material for the reaction according to the invention.
In the following will be illustrated the production of the starting material and an example of the experimental performance of the reaction accord-ing to the invention.
7~
Production of the starting material:
a) 2,2,4-trimethyl-6-methoxy-5,6-dih~drc-~I-pyrane A solution of 157 g (1,1 mol) of 5-hydroxy-3,5-dimethyl-3-hexenoic acid lactone in a mixture of 200 ml of dry tetra-hydrofuran and 60 ml of ethylether is cooled to -20 to -30C.
In the course of 15 minutes a suspension of 11.2 g (0.29 mol) of lithium aluminium hydride in 320 ml of dry tetrahydrofuran is added. Then, the mixture is allowed to warm up to room temperature and after 30 minutes it is poured upon a mixture of 800 g of ice and 33 ml of conc. sulfuric acid. The etheric layer is separated and the aqueous phase extracted twice with each 200 ml of ether. The united e-theric extracts are washed with 100 ml of 5% sodium hydrogen carbonate solution and with 100 ml of saturated aqueous sodium chloride solution, then dried with sodium sulfate and evaporated in vacuo.
The concentrated reaction mixture is stirred - without purification - with 100 ml of trimethyl-ortho-formate and 4 g of ammonium nitrate in 40 ml of methanol for 12 hours at room temperature and then refluxed for 4 hours. After this period of time the mixture is poured into 300 ml of water ~`~ and extracted thrice with each 200 ml of chloroform. The extract is washed with 100 ml of saturated aqueaus sodium chloride solution, dried with magnesium sulfate and evaporated in vacuo. The concentrate is distillad under reduced pressure, whereby 102 g t5~% of theory) of the title compound are obtaine~.
Boiling point: 62 - 67C at 20 millibar.
. .
~ ~6 ~ ~3~
_ g _ b) Syn- and anti-2,2,6-trimethyl-4 methoxy-7,7-dichloro-3-oxabicyclo~4 1 O~he~tanes To a solution of lO0 g (0,64 mol) of the compound obtained under a) in 250 ml of chloroform are added 2 g (5,5 mmol) o~ cetyltrimethyl ammonium bromide and a cooled soIution of 250 g of sodiuM hydroxide in 250 ml of water. The two-phase reaction is effected while~
stirring vigorously. After 3 hours 9 the exothermic reaction, strong in the beginning, becomes more moderate and the analysis shows that the reaction has completed for approx.~ 50 %. ~ter stirring for l6 hours more, 95~ have been reacted. The ~eaction -solution is diluted with~l ltrO of waterj the chloro-- form phase is~separated and the aqueous phase extracted twice with each 300 ml of methy1ene chloride. The united extracts are washed twice with 500 ml of water under addition of a~ small quantity o~ magnesium sulfate.
The organlc~phase is drled~and eva~orated in vacuo.
After ~racti~onated distillation over ~sodium hydroxide~
pellets~the~title~compound is obtained in the ratio 2,1 : l.
Yield: 145~g (94%~of thèory).
Boiling point~`70 - 80C~(0,133 milliba~).
~ : : :: .
` c) 2j~2;6;7-Tetramethyl-4~meth~xy-7-chloro-3~oxabicyclo-4.l.~ hePta~e _ ____ ________ _ A solution of 24 g (lO0 mmol) of the mixture obtained according to b) in 300 ml of dry tetrahydrofuran is cooled to -100C. A-t this temperature a mixture of 90 ml of butyl lithium in hexane (275 molar, corres-ponding td ~5 mm~l) is added dropwise over a period of ~0 minutes~ After another 30 min. ~re added to the reactio~ mixture 3094 g (210 mmol) of ~ ~ .
.
' methyliodide, in the course of 20 minutes. In doing so, the temperature is kept in the range from 100 to -80C.
In the course of 10 to 12 hours, the temperature of the reaction mixture is allowed to rise to room temperature.
Then, the solution is diluted with 1 ltr. o~ water and extracted 3 times with 2V0 ml o~ petroleum ether ~boiling temperature 30 to 60C~. The organic phase is dried with sodium sulfate and evaporated in ~acuo. In the fractionated distillation, 17.5 g of a fraction are obtained within th~
boiling range of 55 to 60C/l,0 mbar.
It consists to a great extent of a mixture of the title compounds.
d) Syn- and anti-2,2,6-trimethyl-4-methoxy-7-methylene-3-oxabic~clo~4.1.0~he~tanes ______ ___ _____ __ ____________________________..______ To a suspension of Z0 g (178 mol) of potassium-tert.-butylate in 60 ml o~ dried dimethylsulfoxide under nitrogen are added at 90C 12 g (55 mmol~ of the isomeric mixture obtained ~nder c), in the course of 10 minutes. After 15 minute~, the reaction mixture is cooled, diluted with 500 ml of water and extracted with ~pentane continuously for 24 hours. After ~ithdrawal of the pentane, the residue is distilled off in vacuo. There are obtained 5.63 g (56% of theory) of a 3 ~ mixture of the title compounds.
boiling point: 60 to 65C/9 mbar.
e) 2,2,6-trimethyl-4-methoxy-7,8-epoxy-3-oxabicyclo-L4.1.0]he~tane ___ _____ To 12.2 g (61.6 mmol) of the isomeres obtained in line with d) in 300 ml of methylene chloride is added 1 ltr~ of a phosphate buffer (pH 6.4, 35.5 g of Na2HP04 and 34 g of HK2P04 in 1 ltr~ o~ water).
In the course of 10 minutes are added hereto while stirring ~1 g of p-nitro perbenæoic acid (98% purity, 112 mmol). The reaction mixture is stirred for 14 hours at room temperature, whereafter the oxidation agent has been consumed completely. Then, the phases are separated and the aqueous phase is washed with 100 ml of methylene chloride. The united organic solutionsare dried with magnesium sulfate, evaporated in vacuo and subjected to a vacuo distillation.
8.1 g (66% of theory~ of the title compound are obtained.
Boiling point 55 - 65C/0.5 mbar.
Exam~le a~ 2,2,6-Trimethyl-4-methoxy-3-oxabicyclot4.2.0]octan-8-one and 7-one _____________________________________________________ To 508 g (29 mmol) of the epoxide obtained under e) in 75 ml of acetonitrile are added 250 mg of lithium carbonate and 10.2 g (117 mmo~ of lithiùm bromide (dried ~or l2~hours at 125C and'used immediately3.
!
The solution i;s s-tirred in order to dissolve the lithium bromide and heated to 60C for 30 minutes. The reaction mixture is cooled to room temperature, diluted with 100 ml of water and extracted four times with each 100 ml of pentane. The united extracts are dried with magnesium sulfate and evaporated using a Vigreaux-column. The residue is distilled after addition of 10 mg of lithium carbonate and there are obtained 4,8 g (83% of theory) of a product with the boiling point of 55 to 60C at 004 mbar.
The distillation contains the title compounds in a ratio of 4 : 1.
~6~7 b) 2,2,6-Trimethyl-4-methoxy-3-oxabicycloC4.2.0~octan~
8-ole and 7-ole _ _ __ __ _ _ _ _ _ __ _ . __ __ _ __ _ .. _ _ __ _ . ___ _ _ _ . ___ __ ___ ____ _ _ To 3.2 g (16 mmol) of the 4 : l-mixture of the bicyclic ketones obtained in line with a) in 30 ml of 95~ ethanol are added 0.611 g (16 mmol) of sodium borohydride.
The mixture is stirred at room temperature over night and diluted afterwards with 150 ml of water. It is extracted with 5 portions of each 50 ml of ethylether.
The united extracts are dried with sodium sul~ate and evaporated in vacuo. 3~2 g of an oil are obtained.
The crude product is chromatographed on 200 g o~ ~ilica-gel (hexane/ethylacetate 1 : 1), process according to Still (J. Org, Chem., ~, 2923 (1978)). Fractions of 25 ml are collect~dO Fractions 20 to 22 comprlse beside impurities the desired alcohol with the 8-OH
group (R~ = 0.55, 0.468 g). The main portion of this alcohol is found in frac~io~s 23 to 2g (1.3 g, 40% of theory). The fractions 30 to 33 contain this alcohol too, beside the isomeric alcohol with the 7-OH group (R~ = 0040). ~The~8-alcohol ls charac~erized by the NM~-spectrum~
lH-NMR: 4,98 (lH, C4, t; J =~7 Hz)3 4,42 (lH, C8, m), 3,42 (3H, OCH3, s), 2,7-1,5 (6H, OH, Cl, C5, C7, m)5 1,41 (3H, CH3, s), 1,24 (3H, CH3, s), 1,16 (3H, CH3, s).
c) ~+)-3 3~7-Trimethyl-2l9-dioxatricyclo~3 3 1 0~nonane To 1.3 g (6 mmol) of 2,Z96-trimethyl-4-methoxy-3-oxa-bicyclo~4.2.0]octane-8-ole within a mixture from 20 ml of pentane and 0~5 ml of methanol are added several crystals of p-toluenesulfonic acid (approx. 1 mg).
The mixture is stirred for 1 hour at room temp~rature, filtered through neutral alumini~ oxide and evaporated in vacuo. The vacuum distillation (under addition of 2 mg of lithium carbonate) yields 0.71 g o~ lineatin (65% of theory);
boiling point 70C/16 mbar.
In line with the gas-chromatographical analysis the p~ duct has a purity degree of 98%. It is characterized by NMR.
l~-NMR: 4.91 (lH, Cl, b, s), 4~39 (lH, C5, m), 2.2-1.5 (5H, C4, C~, C81 m), 1.15 (6H, 2CH3, s) 1.11 (3H, CH3, s).
. ~ :
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of lineatin, which comprises subjecting an alcohol of the formula:
(c) wherein R represents alkyl or benzyl, to acid catalysis.
(c) wherein R represents alkyl or benzyl, to acid catalysis.
2. A process for the production of lineatin, which comprises rearranging 2,2,6-trimethyl-4-R-oxy-7,8-epoxy-3-oxabicyclo[4.1.0]heptane of the formula:
(a) wherein R represents alkyl or benzyl, under the action of alkali halide an inert solvent under neutral conditions and at elevated temperature to form a mixture of 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one and -7-one of the formu-lae:
and (b) (b') subsequently, reducing the mixture of ketones (b) and (b') with a complex hydride under conventional conditions to form the corresponding alcohols of the formulae:
and (c) (c') and after separation converting alcohol (c) by means of acid catalysis to racemic lineatin.
(a) wherein R represents alkyl or benzyl, under the action of alkali halide an inert solvent under neutral conditions and at elevated temperature to form a mixture of 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one and -7-one of the formu-lae:
and (b) (b') subsequently, reducing the mixture of ketones (b) and (b') with a complex hydride under conventional conditions to form the corresponding alcohols of the formulae:
and (c) (c') and after separation converting alcohol (c) by means of acid catalysis to racemic lineatin.
3. Process as claimed in claim 2, which comprises using lithium bromide for the rearrangement of compound (a).
4. Process as claimed in claim 3, which comprises using acetonitrile as solvent.
5. Process as claimed in claim 2, which comprises using sodium borohydride as agent for reduction of compounds (b) and (b').
6. Process as claimed in claim 1 or 2, which comprises using p-toluene sulfonic acid as catalyst for conversion of the alcohol (c) to lineatin.
7. The compound 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one or 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-ol wherein R represents alkyl or benzyl.
8. The compound 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-one, wherein R represents alkyl or benzyl.
9. The compound 2,2,6-trimethyl-4-R-oxy-3-oxabicyclo[4.2.0]octane-8-ol, wherein R represents alkyl or benzyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803018635 DE3018635A1 (en) | 1980-05-16 | 1980-05-16 | METHOD FOR PRODUCING LINEATIN |
| DEP3018635.7 | 1980-05-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1167460A true CA1167460A (en) | 1984-05-15 |
Family
ID=6102490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377720A Expired CA1167460A (en) | 1980-05-16 | 1981-05-15 | Process for production of lineatin |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0040353B1 (en) |
| JP (1) | JPS57154186A (en) |
| AT (1) | ATE5589T1 (en) |
| CA (1) | CA1167460A (en) |
| DE (2) | DE3018635A1 (en) |
| DK (1) | DK215981A (en) |
| IL (1) | IL62871A0 (en) |
| NO (1) | NO811664L (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1961433C3 (en) * | 1969-12-08 | 1974-06-06 | Kali Chemie Ag | S-alkoxy ^ -hydroxy-S-methyl-lOmethylene-2,9-dioxatricyclo- (4,3, l, 0 to the power of 3, to the power of 7) -decane and 8-alkoxy-4-hydroxy-3,10-dimethyl- 2,9dioxatricyclo- (4,3,1,0 to the power of 3Jioch 7) -decane and process for their preparation |
| DE2129507C3 (en) * | 1971-06-15 | 1980-02-14 | Kali-Chemie Ag, 3000 Hannover | Process for the preparation of 8-alkoxy-3halomethyl-4-acetoxy-10-methylene-2,9dioxatricyclo (43, l, 03 7) decanes |
| DE2730988A1 (en) * | 1977-07-08 | 1979-01-25 | Kali Chemie Pharma Gmbh | 3-Azido-methyl-2,9-di:oxa-tri:cyclo-decane derivs. - useful as analgesic, antipyretic and antiphlogistic agents |
-
1980
- 1980-05-16 DE DE19803018635 patent/DE3018635A1/en not_active Withdrawn
-
1981
- 1981-05-06 AT AT81103409T patent/ATE5589T1/en not_active IP Right Cessation
- 1981-05-06 EP EP81103409A patent/EP0040353B1/en not_active Expired
- 1981-05-06 DE DE8181103409T patent/DE3161626D1/en not_active Expired
- 1981-05-12 JP JP56072110A patent/JPS57154186A/en active Pending
- 1981-05-14 IL IL62871A patent/IL62871A0/en unknown
- 1981-05-14 DK DK215981A patent/DK215981A/en unknown
- 1981-05-15 CA CA000377720A patent/CA1167460A/en not_active Expired
- 1981-05-15 NO NO811664A patent/NO811664L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE5589T1 (en) | 1983-12-15 |
| IL62871A0 (en) | 1981-07-31 |
| DE3161626D1 (en) | 1984-01-19 |
| DK215981A (en) | 1981-11-17 |
| DE3018635A1 (en) | 1981-11-26 |
| EP0040353B1 (en) | 1983-12-14 |
| EP0040353A1 (en) | 1981-11-25 |
| NO811664L (en) | 1981-11-17 |
| JPS57154186A (en) | 1982-09-22 |
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