CA1192208A - Process for preparation of lineatin - Google Patents

Abstract

ABSTRACT

Synthesis of (?)-lineatin (3,3,7-trimethyl-2,9-dioxatricyclo-[3.3.1.04,7]nonane) by a four-step sequence from 2,2,4-trimethyl-5,6-dihydro-2H-pyran is disclosed. The key step involves the formation of a dichlorocyclobutanone using dichloroketene cycloaddition. Modification of the usual conditions for dichloroketene generation are necessary in order to suppress side reactions in this step. The conversion of the cycloaduct to lineatin are carried out with standard synthetic tech-niques in an overall yield of 10.12%.

Description

SPECIFICATION

This invention relates to a process for the preparation of lineatin (3,3,7-trimethyl-2,9-dioxotricyclo-[3.3.1.0',7]nonane, the aggregation pheromone of the ambrosia beetle (Trypodendron lineatum) of the formula 1, I.ineatin is useful as an attractant Eor this ambrosia beetle and is useful in its control (J.G. MacConnell; J.H. ~orden; R.M. Silverstein;
E. Stokkink. J. Chem. Ecol. (1977), Vol. 3 Pg. 5~9).

Lineatin has been synthesized by a number of processes. Most of these produce mixtures of lineatin (1) and its regioisomer isolineatin

(2), or possess steps that prevent scale up or are long and low yield.
Mor; (K. Mori; M. ~asaki, Tet. Lett. (1979) pg. 1329; Idem.
Tetrahedron, (1980) Vol. 36, pg. 2197) utili~ed a [2+2]photocycloadd;-tion to construct the bicyclo[~.2.0] carbon frame of lineatin but this synthesis leads to a predominence of isolineatin and gives an overall yield of 0.16% in twelve steps.
A subsequent synthesis by Mori (K. Mori; T. Uematsu; M. Minobe; K.
Yanagi, Tet. Lett. (1982) pg. 1921; Idem. Tetrahedron (Lg83) Vol. 3~, pg. 1735) utilizes a [2+2]cycloaddition between isoprene and dichloro-ketene this process gives a mixture of lineatin and isolineatin. This synthesis requires nine steps and gave an overall yield of 3%.
Silverstein (3.H. Borden; J.R. ~andley; B.D. Johnston; J.C.
MacConnell; R.M. Silverstein; K.~. Slessor; A.A. Swigar; D.T.W. Wong, J. Chem. Ecol. (1979) Vo]. 5, pg. 681) synthesi~ed lineatin by a [2*2]cycloaddition of dichloroketene to 1,3-dimethyl-1,3-cyclopentadiene ~;

in an eighteen step synthesis that yielded only microgram amounts of lineatin which was isolated from the final step by preparative gas chromatography.
Weiler (W.R. McKay; J. Ounsworth; P.E. Sum; L. Weiler, Can. J.
Chem. (1982) Vol. 60, pg. 872) utilized a [2~2]cycloaddition of aLlene ~o anhydromevalonolactone in a Eive step synthesis that yields lineatin and isolineatin in a 6:4 mixture in 10% overall yield.
White (J.D. White; M.A. Avery; J.P. Carter, J. Am. Chem. Soc.
(1982) Vol. 104, pg. 5486) utilized a [2+2]cycloaddition of acetylene to anhydromevalonolactone ~ollowed by hydroboration to produce lineatin by a seven step synthesis in an overall yield of 14~. This synthesis produced 10mg of lineatin and was not scaled up.
Slessor (K.N. Slessor; A.C. Oehlschlager; B.D. Johnston; H.D.
Pierce, Jr.; S.K. Grewal; L.K.G. Wickremesinghe, J. Org. Chem. (1980) Vol. 45, pg. 2290) synthesized lineatin by ring expansion of an oxaspiropentane derivative of 5-hydroxy-3,5-dimethyl-3-hexenoic acid lactone, This synthesis gave reasonably pure lineatin after nine steps in 2.8% overall yield. This synthesis contains a low temperature step that hinders scale up.
Skattebol (L. Skattebol; Y. Stenstrom, Tet. Lett. (1983) pg. 3021) synthesized lineatin by thermal [2~2]cycloaddition of an allenic con-jugated ketone. This synthesis involves six steps and proceeds in 30-35% overall yield. The drawback to this process is that it requires a narrow temperature range to conduct the cycloaddition.
The process, according to the present invention, is characterized in that, according to the reaction se4uence -f~

~ CI
~<i X~?~

a b ~\
~/~

c ~b ~---' lineatin is produced in good yield by a small number oE steps, free of contamination by isolineatin and without resort to complicated apparatus or extreme conditions.
According to the process (1) the cyclic allylic ether (a) is reacted with zinc and trichloro-acetyl chloride to form the dichlorocyclobutanone (b);(2) (b) is converted to the cyclobutanone (c);

(3) (c) is oxidized to the lactone-cyclobutanone (d);
t4) (d) is converted to lineatin I.
The reaction (1) of (a) is effected by zinc dehalogenation of tri-chloroacetyl chloride to produce dichloroketene Ln situ. The reaction yields less than 10% of theoretical of (h) unless 1,2-dimethoxyethalle is added to complex with the zinc dichloride produced in the reaction.
Optimum conditions are four to six equivalents of dimethoxyethane for each equivalent of trichloroacetyl chloride when the reaction is carried out in refluxing ether over a four- to five-day period. Under these conditions, the reaction (1) yields 50-60% of theoretical of (b~.

.--In the absence of 1,2-dimethoxyethane as a reaction constituent, the reaction of (a) with zinc and trichloroacetyl chloride yields struc-ture (e) as the major product (26% of theoretical).

~
~7c,\~, e The conversion of (b) to (c), according to (2), is preferably effected inthe conventional way with zinc in methyl alcohol which is saturated with ammonium chloride.
The conversion of (c) to (d), according to (3), is preferably effected with ruthenium trichloride in a two phase mixture oE carbon tetrachloride and water containing sodium periodate, according to the procedure of Smith and Scarborough, Syn. Commun. (1980), Vol. 10, pg. 205.
In accordance with (4)~ the lactone cyclobutanone is converted to racemic lineatin. This conversion is efEected by reduction of (d) with diisobutylaluminum hydride in ether, according to conventional methods.
This reduction is followed by acidification of the reduction reaction product with an acid such as a carboxylic acid, tartaric acid, sulfuric acid, a hydrohalic acid or a sulfonic acid.
The starting compound (a) may be made by the following reaction sequence:

~ L ~ ~0~

i, Dialcohol (g) is produced by reduction of the k~own cyclic lactone of 5-hydroxy-3,5-dimethyl-3-hexene carboxylic acid (f), preferably with a complex hydride. The dialcohol (g) is converted to (a) by acidifica-tion of the reduction reaction with an acid such as a carboxylic acid, hypohalic acid or especially sulfuric acid.
The following examples illustrate the preparation of the starting material as well as the performance of the reaction according to the invention.
Preparation of ~he Starting Material (a) 2,2,4-Trimethyl-5,6-dihydro-2H-pyran A suspension of 52 g (1.4 mol) of lithium tetrahydroaluminate in 2 L of ether was cooled to 0. Over a period of 1 h, 265 g of 5-hydroxy-3,5-dimethyl-3-hexenoic acid lactone was added. Then, the reaction was allowed to warm to room temperature and remain at room temperature for 16 h. The reaction mixture was carefully poured into 3 L of ice-cold 2 M sulfuric acid and the two-phase mixture was stirred for 1 h. The ether phase was separated and the aqueous phase was extracted twice with two 500 mL portions of ether. The combined ether extracts were washed with 300 mL of a saturated aqueous sodium bicarbon-ate solution and then dried with magnesium sulfate and concentrated by distillation of the ether through a Vigreaux column at stmospheric pressure. The concentrate was distilled at atmospheric pressure, where-by 197 g (83~ of theory) of the title compound were obtained. Boiling point: 130-133C at 760 millibar.
Example 2 (b) 7,7-Dichloro-2,2,6-trimethyl-3-oxabicyclo[4.2.0]octan-8-one 100 g (1.5 mol) of zinc copper couple, prepared by the method of Krepski and Hassner in J. Org. Chem. (1978), Vol. 43, pg. 2879, was add-ed to a stirred mixture of 2 L of anhydrous ether and 500 mL anhydrous 1,2-dimethoxyethane. This mixture was maintained under a nitrogen atmosphere while 126 g (1 mol) of (a) was added, followed by dropwise addition of 250 g (1.4 mol) of trichloroacetyl chloride over a period of 1 h. The reaction was refluxed for 48 hg then 500 mL of 1,2-dimethoxy-ethane and 100 g of zinc copper couple were added. This was followed by dropwise addition of 250 g of trichloroacetyl chloride over a period of 1 h. Refluxing was continued for a further 48 h after this addition was completed.
The reaction was terminated by filtration and concentration to a volume of 350 mL in vacuo. The residue was poured in a thin stream into 3 L of petroleum ether (having a ~oiling range of 30-60C). The insolu-ble material was removed by suction filtration and the petroleum ether solution was then stirred with 1.5 I. of an aqueous, saturated solution of sodium bicarbonate for 1 h. The petroleum ether phase was separated and washed sequentially with 1 L of aqueous saturated sodium bicarbon-atel two 500 mL portions of water and 500 mL of an aqueous, saturated sodium chloride solution. The petroleum ether phase was separated and dried with magnesium sulfate and then concentrated in vacuo. The con-centrate was distilled under reduced pressure, whereby 141 g (85% pure by gas chromatographic analysis, hence 50% of theory) of the title com-pound were obtained. Boiling point: 70-85~C at 0.1 millibar. rne title compound was characterized by the following N~ spectra: lH NM~
(400 MHz, CDC13) o 3.74 (lH, CL,H, ddd, Jgem = 12~ Jcis ~ 5~
Jtrans = 2.2 Hz), 3.68 (lH, C4H , dt, Jgem = Jtrans - 12~ Jci 1.8 Hz), 3.24 (lH, ClH, d, J15 ~ 1.9 Hz), 1.84 (lH, C~H, m, Jgem = 15, Jtrans = 12, Jcis = 5 Hz), 1.66 (lH, CsH', dq, Jgem = 15, Jtrans ~ Jc ~ Jl5 ~ 2 Hz), 1.59 (3H, Ctl3, d, J = 0.8 Hz), 1.49 (3H, CH3, s), 1.21 (3U, CH3, s).
(c) 2,2,6-Trimethyl-3-oxabicyclo[4.2.01Octan-8-one A mixture of 125 g (1.74 mol) of zinc powder in 1 L of methyl alcohol saturated with am~onium chloride was prepared. To ~his was , ~ ,, ?~
~ ' added 1~0 g (0.59 mol) of (b) as prepared above (85% pure) dropwise at a rate to maintain a re~lux. After approximately 2 h, the addition was complete and then the reaction was maintained at reflux for an addition-al 4.5 h by heating. Then, the reaction was cooled to room temperature and filtered. The methyl alcohol filtrate was concentrated in vacuo to give a semi-crysta]line residue. The residue was shaken with 1.5 L of ethyl ether and 300 mL of 2 M aqueous sulfuric acid until the remaining zinc salts dissolved in the aqueous layer. After the zinc salts dis-solved, the ether phase was separa~ed and the aqueous phase was extract-ed twice with 300 mL portions of ether. The combined ether phase extracts were washed with 500 mL of an aqueous, saturated sodium bicarbonate solution and then 500 mL of water. The ether phase was dried with anhydrous magnesium sulfate and concentrated in vacuo. The concentrate was distilled under reduced pressure, whereby 58 g (58% oE
theory, 90% pure by gas chromatographic analysis) of the title compound were obtained. Boiling point: 55-60~C at 0.3 mill-ibar.
The title compound was characterized by the following NMR spectra:
H NMR (400 MHz, CDC13) o 3.70 (2H, C4H, m), 2.76 (lH, C7H, dd, Jgem =
16, Jl 7 = 1.5 Hz), 2.67 (lH, ClH, brs), 2.60 (lH, C7H, dd, Jgem =
16, Jl 7 = 1.5 Hz), 1.80 (lH, CsH, dm, Jgem = 14.5 Hz), 1.63 (lH, C5H', m~, 1.49 (3H, CH3, s), 1.44 (3H, CH3, s), 1.22 (3H, CH3, s).

(d) 2,2,6-Trimethyl-3-oxabicyclo[4.2.0] octan-4,8-dione A mixture of 32 g (190 mmol) of (c) in 400 mL of carbon tetrachlor-ide and 1 L of water containing 120 g (560 mmol) of sodium periodate was stirred at room temperature while 1.5 g (5.7 mmol) of ruthenium tri-chloride-trihydrate was added in one portion. The reaction was s~irred at room temperature for 18 h, after which time the organic phase remain~
ed yellow instead of black. This was judged to signal completion of the reaction. The reaction suspension was suction filtered and the phases separated. The aqueous phase was extracted three times with 250 mL each of methylene dichloride. The organic extracts were combined and treated with 5 mL of isopropyl alcohol to destroy remaining ruthenium tetrox-ide. The organic phase was concentrated in vacuo and the concentrate was dissolved in 1.2 L of ether which was washed with 300 mL of an aqueous, saturated sodium bicarbonate solution. The black colloidal ruthenium dioxide remained in the aqueous phase aEter shaking -Eor 10 min. The organic phase was separated and washed with 100 mL of water, dried with magnesium sulfate and concentrated in vacuo. The con-centrate was semi-crystalline and gave 21 g (61% of theory) of the title compound as a crystalline solid (m.p. 97-98C) after recrystallization from hexane:ethyl acetate (4:1). The title compound has been prepared by Skattebol and Stenstrom, Tetrahedron Letters (1983), pg. 3021, and is reported to have a melting point of 99-100C. The title compound was additionally characterized by the following NMR spectrum: lH NMR
(400 MHz, CDC13) o 2.97 (lH, ClH, s), 2.90 (2H, C5H, m), 2.84 (lH, C7H, d, Jgem = 16.8 Hz), 2.73 (lH, C7H, d, J~em = 16-8 Hz)~ 1-54 (3H~
CH3, s), 1.53 (3H, CH3, s), 1.41 (3H, CH3, s).

(e) 3,3,7-Trimethyl-2,9-dioxatricyclo[3.3.1.0!~7]nonane A solution of 38 g (0.21 mol) of (d) in 500 mL of dry ether was cooled to 0C. This solution was added dropwise over 1.5 h to a 500 mL
(0.5 mol) of a 1 M solution of diisobutylaluminum hydride in hexane while the temperature was maintained at 5-7C. lhe reaction was stirred an additional 0.5 h at 5C after addition was completed then the reac-tion mixture was poured slowly into 800 mL of an aqueous 10% tartaric acid solution which had been previously cooled to 0C. This two-phase mixture was stirred until a clean separation into two layers occurred (approximately 45 min). The organic phase was separated and the aqueous phase was extracted twice with 100 mL portions of ether. The combined ether extracts and hexane phase were combined and washed sequentially with 100 mL aqueous, saturated sodium bicarbonate, 100 mL water and 100 mL aqueous, saturated sodium chloride. The organic phase was then separated and dried with magnesium sulfate and then concentrated by distillation of the solvent through a 30 cTn Vigreaux column. The con-centrate was distilled under reduced pressure, whereby 2~.6 g (70~ of theory) of the title compound were obtained. Boiling point: 61C at 2.5 millibar.
The title compound was 98~ pure by gas chromatographic analysis and was additionally characterized by comparison of the 111 NMR spectra with data reported previously by the work cited above.

Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. The process for the preparation of lineatin which comprises sub-jecting 2,2,4-trimethyl-5,6-dihydro-2H-pyran of the formula to reaction with zinc and trihaloacetyl halide in the presence of a zinc sequestering agent of the 1,2-dioxaethane class in neutral conditions at slightly elevated temperatures, to form 7,7-dichloro-2,2,6-trimethyl-3-oxabicyclo[4.2.0]octau-8-one of the formula reducing the dichlorocyclobutanone with zinc in methyl alcohol and ammonium chloride to form the corresponding cyclobutanone of the formula oxidizing the cyclobutanone with ruthenium trichloride and sodium periodate to the lactone-cyclobutanone (d) of the following structure reducing the lactone-cyclobutanone with a complex hydride under conven-tional conditions and converting the reduction reaction product into racemic lineatin by acid catalysis.

2. The process of claim 1, where the trihaloacetyl halide is tri-chloroacetyl chloride.

3. The process of claim 1, where the zinc sequestering agent is 1,2-dimethoxyethane.

4. The process of claim 1, where the complex hydride is diisobutyl aluminum hydride.

5. The process of claim 4, where the acid catalyst used for conversion of the reduction product of (d) into lineatin is tartaric acid.