Synthesis based on cyclohexadienes Part 36: 1 an efficient methodology for the construction of spiro[4.5]decanes: a formal synthesis of acorone

An efficient strategy for the contruction of spiro[4.5]decanes is described and involves a bridgehead substitution of a methoxyl group by a methyl group followed by an oxidative cleavage of the tricyclo[5.2.2.0 1,5 ]undecane 25 to produce the spiro[4.5]decanes 31 & 32 which are intermediates in the synthesis of acorone. A novel one-pot conversion of α -methoxy carboxylic acid to α -methyl carboxylic acid is described.


Introduction
A large number of sesquiterpenes, possessing the spiro [4.5]decane framework, have been isolated 2 from natural sources.Among them, the acoranes and the enantiomerically isomeric alaskanes constitute a major group in the spiro [4.5]decanes.These compounds are represented by acorone 1, isoacorone 2 and acorenone 3, isolated from the oil of sweet flag, 3 Acorus calamus L., acorenone B 4 4, α-acoradiene 5 5, β-acoradiene 6 6, γ-acoradiene 7 (α-alaskene) 7, and δacoradiene (β-alaskene) 7 8.The absolute stereochemistry of acorone 3 was assigned on the basis of X-ray study of a derivative and also on the basis of ORD studies.Because of their structural simplicity and commercial importance, these spirocyclic sesquiterpenes attracted 8 the attention of many synthetic groups and in particular several syntheses 9 of acorone 1 and its congeners have been reported in the literature.The main challenges towards the synthesis of this class of natural products are i) stereospecific construction of the spiro quaternary carbon relative to the chiral centers, and ii) arranging the relative stereochemistry of isopropyl and methyl groups in the cyclopentane ring.The methoxycyclohexadienes, readily available from the Birch reduction of anisole derivatives are versatile intermediates in organic synthesis. 10We have extensively employed them for the synthesis of several bicyclic and tricyclic structures, which culminated in the total synthesis of several natural terpenoids. 11As part of our continued interest on the use of dihydrobenzenes in organic synthesis, we describe herein an efficient strategy for the construction of spiro [4.5] formal synthesis of acorone.The intermediates, 4,8-dimethylspiro [4.5]dec-7-en-1-one 31a and 4isopropyl-8-methylspiro [4.5]dec-7-en-1-one 31b have been identified as the targets for the synthesis of acorone and acoradienes and a detailed account of the preparation of these synthons is presented in this paper.A preliminary account 12 of this work has been reported.

Results and Discussion
We envisioned that the spiro [4.5]decane 9 can be readily generated by the oxidative cleavage of the C 5 -C 6 double bond of the tricyclo[5.2.2.0 1,5 ]undecene 10, a strategy adopted 13 by us for the total synthesis of (±) hinesol 11 from 9-hydroxytricyclo[7.2.1.0 1,6]dodec-6-ene-8-one 13 through the intermediate 12.The advantage of this oxidative cleavage method will be the stereospecific generation of the spirocentre, which scores over other synthetic strategies towards spiro compounds.Thus, oxidative cleavage of the tricyclic ketone 25a should result in the formation of the desired spiro [4.5]decane having a well defined geometry at the spiro center that can be readily converted into acorone 1 and isoacorone 2. The retrosynthetic analysis of the spiro [4.5]decanes, exemplified for acorone 1, as shown in Scheme 1, indicated that the ketone 30 can be obtained from the spiro-hydroxyacid 29, which in turn can be prepared from the tricyclic ketone 25 through an oxidative cleavage of the C 5 -C 6 double bond.The tricyclic ketone 25 can be obtained from the corresponding ketone 21 by replacing the methoxyl group with the methyl group by the strategy developed 14,15 in our laboratory.The tricyclic ketones 21 can be prepared from the corresponding indanes 18 by the Birch reduction and Diels-Alder reaction protocol.Thus, the indanes 18 have been identified as the starting materials.

Preparation of the tricyclic ketones (21a) & (21b)
The tricyclic ketone 21a was prepared from 5-methoxyindane 18a according to the reported procedure 16 and was obtained in very good yield.The tricyclic ketone 21b was obtained from 1isopropyl-6-methoxyindane 18b which was in turn made from 4-methoxyisobutyrophenone 14.Thus, reaction of anisole with isobutyroyl chloride in the presence of anhydrous AlCl 3 afforded 4-methoxyisobutyrophenone 14.Reformatsky reaction of 14 with ethyl bromoacetate followed by dehydration gave the cinnamate ester 15a, which was hydrolyzed to the acid 15b, and reduced with sodium in liquid ammonia to the acid 16 in good yield.Cyclization of the acid 16 with SOCl 2 /AlCl 3 afforded the indanone 17, which was subjected to Wolf-Kishner reduction to give 1-isopropyl-5-methoxyindane 18b.Birch reduction of the indane 18b with Li and liquid ammonia in the presence of absolute ethanol afforded 1-isopropyl-5-methoxy-4,7-dihydroindane 19 in quantitative yield.The diene 19b had the absorption bands at 1690 and 1650cm -1 characteristic of an unconjugated diene system.The 1 H NMR spectrum showed a broad singlet at δ 2.70 for the C 4 and C 7 methylene protons and a broad singlet at δ 4.64 for the olefinic proton of the enol ether, and did not show any absorption beyond δ 5 indicating absence of aromatic protons.Cycloaddition of 1-isopropyl-5-methoxy-4,7-dihydroindane 19 with 2-chloroacrylonitrile in refluxing benzene gave after chromatographic purification, the adduct 20, as a colourless liquid.The structure of the adduct 20 was deduced from its IR and 1 H NMR spectra.Hydrolysis of the adduct 20 with aq.KOH in dimethyl sulphoxide 17 at 55 °C furnished the tricyclic ketone 21b in 72% yield, whose structure was deduced from its spectral data.
We have described earlier 15 a method for substituting the methoxyl group by a methyl group at the bridgehead position in bi-and tricyclic systems.The same strategy was now adopted for the conversion of the ketones 21a and 21b into 25a and 25b, respectively.Thus, acid catalysed rearrangement of the ketone 21a in presence of BF 3 -MeOH in dry methylene chloride, furnished a 8:1 mixture of methoxy-enone 22a and the hydroxy-enone 23a in 94% yield.
However reaction of 21a with PTSA gave a 3:1 mixture of 22a and 23a.This mixture was easily separated by column chromatography on silica gel and the structures of the enones were deduced from their spectral characteristics.Treatment of the enone 22a with methyllithium furnished the allylic alcohol 24a whose IR spectrum showed the presence of a hydroxyl group.Acid catalyzed rearrangement of the alcohol 24a in the presence of perchloric acid afforded exclusively the ketone 25a.At this juncture it was envisaged that the spirodiketone 27 could be obtained from the tricyclic ketone 25 through an oxidative cleavage of the double bond, followed by decarboxylation of the resulting β-ketocarboxylic acid 28.A chemoselective reduction of the six membered ketone should result in the alcohol, which can be easily converted to (±)-acorone.However, ozonolysis of 25 followed by oxidative workup did not provide the diketone.Reduction of 25a with DIBALH afforded a 1:10 mixture of exo and endo alcohols 28a, which was separated by chromatography and characterised.Ozonolysis of this mixture 28a followed by oxidative work up with hydrogen peroxide afforded the spirohydroxy acid 29a as a colourless low melting solid, characterized as its methyl ester 30a.Several attempts 18 to convert the spirohydroxyacid 29a into the spiroketones 31a and 32a through a dehydrative-decarboxylative elimination reaction failed.The attempted methods were essentially heating the acid 29a with In all these cases extensive decomposition of the product was noticed.However, treatment of the spirohydroxy acid 29a with Ph 3 P/DEAD 19 in anhydrous THF afforded the desired ketones 31a and 32a as a 1:1 epimeric mixture.The structure of the ketones was deduced from their spectra data and finally by comparison 20 with an authentic sample, kindly provided by Professor Marx.The ketone 31a has been converted 20 earlier into acorone and other related compounds, thus completing a formal synthesis of these spiro [4.5]decane sesquiterpenes.
We have previously identified the spiroketones 31b and 32b as the precursors for the synthesis of acoradienes, 5, 6, 7 and 8.The spiroketones 31b and 32b have been synthesized from the tricyclic ketones 21b and 25b by essentially iterating the same reaction sequence described for 31a and 32a.Thus, treatment of ketone 21b with BF 3 .MeOH in dry CH 2 Cl 2 , gave a 8:1 mixture of enones 22b and 23b, which was readily separated by chromatography.Reaction of 22b with MeLi gave the allylic alchohol 24b, which smoothly rearranged to the tricyclic ketone 25b upon treatment with a catalytic amount of perchloric acid.Reduction of the ketone 25b with DIBALH afforded a 10:1 mixture of endo and exo alchohols 28b, which was separated by chromatography.This mixture 28b was subjected to ozonolytic cleavage followed by an oxidative workup with H 2 O 2 in aqueous glacial acetic acid to afford the spirohydroxy acid 29b, which was characterized as its methyl ester 30b.Reaction of the acid 29b with PPh 3 /DEAD in anhydrous THF afforded a 1:1 epimeric mixture of the spiro-ketones 31b and 32b in 53% yield.These spiroketones are useful intermediates for the synthesis of acoradienes.
In an alternative approach 21 to the synthesis of the spiroketones 31a and 32a, the tricyclic ketone 21a was reduced with sodium borohydride to give a 1:1 mixture of endo and exo alchohols 33, which was benzylated with sodium hydride and benzyl bromide to the product 34.Ozonolysis of 34 followed by oxidative work up with Jones reagent afforded the spiro acid 35 characterized as its methyl ester 36.Several methods have been investigated to convert the methoxycarboxylic acid 35 into the methylcarboxylic acid 29a.However, the best method appears to be a new one pot reductive cleavage 22 of the methoxyl group of an α-methoxycarboxylic acid with metal-ammonia solutions, followed by quenching the intermediate with methyl iodide to afford the desired product having the tertiary methyl group.Thus, reaction of the acid 35 with sodium in liquid ammonia followed by quenching the enolate with methyl iodide afforded the acid 29a whose methyl ester 30a showed identical spectral data with the same compound obtained through the bridgehead substitution strategy.
In conclusion, we have demonstrated an efficient method for the construction of the spiro [4.5]decane from readily available cyclohexadienes, which includes the synthetic exploitation of bridgehead substitution strategy and oxidative cleavage of the tricyclo[5.2.2.0 1,5 ]undecane system.During the course of the synthesis we have developed a novel method for the conversion of α-methoxy carboxylic acid to α-methyl carboxylic acid.

Experimental Section
General Procedures.Mps were recorded on a Mettler FP1 instrument and are uncorrected.IR spectra were recorded as neat liquids or in nujol mull for solids on a Perkin 780 and JASCO FT/IR-410 spectrophoto-meters.NMR spectra were recorded in CDCl 3 solution using TMS as internal standard, on a JEOL FX 90Q, Brucker ACF-200 and JEOL JNM λ-300 spectrometers.Mass spectra were recorded on a JEOL MS-DX 303 with direct-inlet system, and relative intensities of the ions are given in parenthesis.Microanalysis was carried out using a Carlo Erba 1106 instrument.Analytical and preparative TLC were performed on glass plates coated with Acme silica gel G containing 13% calcium sulphate as the binder.Spot visualization was accomplished by exposure to iodine vapour.Acme's silica gel (60-120) mesh was used for column chromatography.Liquid ammonia was distilled over sodamide before use.All reactions were performed under a blanket of nitrogen or argon filled balloons.
decanes, which led to the or i-C 3 H 7 Scheme 1 -dimethylformamide dimethyl acetal, to form the β-lactone for initiating the elimination process.