A versatile kinetic alkylation-ozonolysis route for the synthesis of lactones: chiral γ -lactones and racemic δ -lactones

A robust and versatile kinetic alkylation-ozonolysis procedure, previously used for the synthesis of 2-alkyl-2-cyclopenten-1-ones and racemic γ -substituted- γ -lactones, has now been applied to the synthesis of chiral γ -substituted- γ -lactones and δ -substituted- δ -lactones. In addition to the synthesis of lactones with simple alkyl substituents, the method allows terminal ester and halogen groups, and an alkyne bond to be incorporated into the side chain.


Introduction
Lactones are ubiquitous.They are commonly encountered as subunits in natural products and many simple lactones are of importance as they function as insect pheromones, antibacterial and anti-fungal agents, or flavour and aroma components, and can be found in the essential oils of many plants 1 .The largest sub-group by far consists of γ-lactones with a side-chain in the γposition which varies both in its length and functionalization.As would be expected, the precise biological activity of these lactones is often crucially dependent on the stereochemistry of the chiral γ-carbon.Reflecting their importance, a wide range of methods has been developed for their synthesis 2 , but many of these are not generally applicable being specific to particular γsubstituted γ-lactones, and others are not amenable to scale-up because of the nature of the starting materials or reagents used.Although less common, δ-substituted δ-lactones are also found as structural subunits in a variety of natural products, and simple members of the group function as pheromones for a variety of insects.All of the issues raised above in relation to γlactones and their synthesis 2 apply to δ-lactones as well.The structural motif of an alkyl chain, often functionalised, attached to a five-membered ring is repeated in 2-alkyl-2-cyclopenten-1ones.Although a number of these compounds are naturally occurring and are of importance as perfumery materials, it is their potential as starting materials for the synthesis of more complex materials such as prostaglandins which has resulted in the development of a large number of methods for their preparation 3 .Many of these methods suffer from the disadvantages discussed above in relation to the synthesis of lactones.We have developed a versatile procedure (Scheme 1) which can be adapted to the synthesis of all these materials and have previously reported on its application to the synthesis of 2-alkyl-2-cyclopenten-1-ones 4 and racemic γ-substituted γlactones 5 .We now report on its use for the synthesis of chiral γ-substituted γ-lactones and racemic δ-substituted δ-lactones.

Scheme 1
The previously reported work demonstrates that the method possesses a number of attractive features for the synthesis of 2-cyclopenten-1-ones and γ-lactones.In the context of the key kinetic alkylation-ozonolysis sequence, the cheap and readily available starting material, 6methyl-5-hepten-2-one 1, behaves as a half-protected 1,4-dicarbonyl compound.Once the required alkyl group has been introduced by regiospecific alkylation of the imine or hydrazone derivative of 6-methyl-5-hepten-2-one, ozonolysis of the alkene, followed by cleavage of the ozonide in the appropriate way, produces either a 1,4-ketoaldehyde or 1,4-ketoester which can be cyclized to a cyclopentenone and a γ-lactone, respectively.If the alkylation step involves the hydrazone and the introduction of a simple alkyl group, then the ketone can be regenerated and the alkene simultaneously cleaved to the aldehyde using ozone and subsequent reductive cleavage of the ozonide using dimethyl sulfide, or hydrogen and Lindlar catalyst.Although it did not prove possible to selectively ozonize a hydrazone in the presence of an alkyne, it was possible to combine reduction of the ozonide from 2f (Scheme 2) with selective hydrogenation of the triple bond to the corresponding Z-alkene.A further advantage of the approach derives from the fact that the purification of the products does not in general require chromatography as kugelrohr distillation alone gives purities in excess of 95% (GC).These considerations suggested that we consider the possibility of applying the method to the synthesis of chiral γsubstituted-γ-lactones and δ-substituted-δ-lactones.

Results and Discussion
Chiral γ-substituted-γ-lactones The kinetic alkylation of the cyclohexylimine of commercially available 6-methyl-5-hepten-2one 1 (Scheme 2) using alkyl halides under standard conditions proceeds regiospecifically giving, after acid hydrolysis, the γ,δ-unsaturated ketones 2a-e in high yield (Table 1).As before simple kugelrohr distillation gives the products in purities which are in excess of 90%.Many naturally occurring γ-lactones possess unsaturated side-chains and so with a view to their synthesis 2-methyldodec-2-en-9-yn-6-one 2f was prepared in good yield using 1-bromopent-2yne.The dienone 2g was prepared in 91% yield and through ozonolysis in NaOH/MeOH can be used to prepare compounds with a terminal ester group in the side-chain.The more direct route to compounds of this type involves alkylation with ω-haloalkanoates a reaction which proceeds in only modest yield as indicated by the preparation of methyl 13-methyl-9-oxotetradec-12enoate 2h.

Scheme 2
The precursors to γ-lactones with a terminal bromine in the side-chain can be obtained by alkylation of 6-methyl-5-hepten-2-one N,N-dimethylhydrazone with α,ω-dibromoalkanes.Such an alkylation with 1,4-dibromobutane, followed by periodate cleavage of the hydrazone, gives 2i in good yield (Table 1).It had previously been shown 6 that alkylation of the corresponding imine produces a complex mixture in which the product resulting from substitution of both bromine atoms predominates.The compound 2i, together with the compound 3i derived from it, and the analogous materials 6h, 7h and 9h prepared as part of the δ-lactone work described below, were found to be thermally unstable.Yield and purity of product after kugelrohr distillation.Analytically pure samples were obtained where required by chromatography or further distillation.b Prepared from 6-methyl-5hepten-2-one N,N-dimethylhydrazone.
The ozonolytic cleavage in methanolic sodium hydroxide 9 of the alkene bond in 2a-f, 2h and 2i leads to the direct formation of the γ-ketoesters 3a-f, 3h and 3i, respectively.The ozonolyis of the dienone 2g under the same conditions gives the diester 3j.Once again the products are obtained in good to excellent yields, with kugelrohr distillation alone giving a level of purity which was adequate for further reaction.The ozonolyis of 2-methyldodec-2-en-9-yne-6-one 2f was particularly carefully monitored by GC to ensure that the alkyne bond remained intact.In general terms this particular combination of kinetic alkylation and ozonolyis constitutes an attractive method of preparing γ-ketoesters which are useful starting materials for the synthesis of a variety of carbocyclic and heterocyclic systems 7 .
The completion of the synthesis of γ-substituted γ-lactones involves the asymmetric reduction of the 4-oxo group in the ketoesters 3.There is an obvious structural relationship between these γ-ketoesters and β-ketoesters which have been selectively and efficiently reduced using baker's yeast, Saccharomyces cerevisiae 10 .Indeed this method has also been applied to a range of γ-ketoacids giving, after acid catalysed lactonization, the corresponding γ-substituted γlactones in 13-79% yield (R = n-alkyl: C 1 -C 5 , C 8 , C 11 and C 13 ) and with enantiomeric excesses which were consistently greater than 98% 11 .Immobilized baker's yeast on κ-carrageenan beads has also been used to carry out this asymmetric reduction 12 .A recent study 13 of a series of yeasts has shown that baker's yeast is the most versatile and selective for the microbial bioreduction of γand δ-ketoacids and their ethyl esters.The reduction of the γ-ketoesters 3 was carried out using fresh baker's yeast and following the removal of the yeast residues, etc., the crude product was heated in refluxing benzene containing p-toluenesulfonic acid.Standard workup and chromatography gave the required γ-lactones (2(3H)-furanones) 4 (Table 2).Although the enantiomeric excesses and the purity of the lactones were in general good, the chemical yields obtained were disappointingly low.It is possible that hydrolysis of the ester group, and loss of the acid thus formed during work-up, may be responsible for the modest yields of lactone obtained.The use of larger amounts of yeast, the addition of extra yeast in the course of the reaction, or the use of dried yeast failed to improve the yield, and no reaction occurred when fresh or dried yeast in petroleum spirit 14 , or alginate immobilized yeast 15 were used.The γ-ketoesters 3h and 3i, which have terminal ester groups on the alkyl chains, were recovered unchanged after treatment with baker's yeast under the standard conditions, and 3j, which has a terminal bromine atom, gave a mixture containing some unreacted starting material but none of the expected lactone.Although the absolute configuration of the lactone 4f is unknown, its α D suggests that the stereochemistry of the yeast reduction of 3f may be significantly different to that of the other γ-ketoesters considered.

δ-Substituted-δ-lactones
The commercial availability and low cost of the starting material 6-methyl-5-hepten-2-one 1 is a key element in the attractiveness of the kinetic alkylation-ozonolysis route for the synthesis of γsubstituted-γ-lactones 5 and 2-alkylcyclopent-2-enones 4 .The availability of a suitable δ,εunsaturated ketone such as 6-hepten-2-one 5 is a prerequisite in the extension of this kinetic alkylation-ozonolysis approach to the synthesis of δ-substituted-δ-lactones.Two methods for the synthesis of 5 were developed in the course of this work (Scheme 3).
3-(Methylthio)-2-butanone was reacted with allyl magnesium bromide to give 3-methyl-2-(methylsulfanyl)-5-hexen-3-ol as a 76:24 mixture of diastereomers.Periodate oxidation followed by thermolysis in the presence of calcium carbonate gave 3-methyl-1,5-hexadien-3-ol, which on treatment with potassium hydride and 18-crown-6 gave the unsaturated ketone 5 in an overall yield of 60%.The ketone was also prepared using a modification of a previously published method 20 which involved the selective C-alkylation of ethyl acetoacetate with 4iodobut-1-ene followed by dealkoxycarbonylation.The overall yield in this case was 44%.6-Hepten-2-one cyclohexylimine was prepared in the standard way and alkylated with a range of alkyl halides to give the unsaturated ketones 6a-h (Scheme 3) (Table 3).The ketone 6b was also prepared from acetone cyclohexylimine in a one-pot double alkylation procedure involving 4bromobut-1-ene and 1-bromopentane.The overall yield (from acetone) in this case was 50% which, when compared with the overall yield of 44% obtained using the route which begins with 3-(methylthio)-2-butanone, suggests that the former is the method of choice for the preparation of the unsaturated ketones 6.
The ω-bromoenone 6h was prepared via the N,Ndimethylhydrazone of 6-hepten-2-one which had been prepared from the parent ketone or acetone N,N-dimethylhydrazone.The conversion of the unsaturated ketones 6 to the δ-ketoesters 7 (Table 3) was accomplished in the usual way by ozonolyis at -78º in methanolic sodium hydroxide.The purification of 6 and 7 involved only kugelrohr distillation and again resulted in purities which were generally in excess of 90%.Although the reduction of γ-ketoesters using sodium borohydride in methanol containing sodium hydrogenphosphate gives the corresponding γ-lactones directly 5 , the δ-ketoesters 7 under the same conditions give the corresponding δ-hydroxyesters 8, or at best a mixture of the hydroxyesters and the corresponding δ-lactones 9 (Table 4).Treatment of this mixture, or the pure δ-hydroxyester, with p-toluenesulfonic acid in refluxing benzene gives the δ-lactone 9 (Table 4).Despite the fact that the conversion of the δ-ketoesters 7 to the δ-lactones 9 proceeds in some cases in modest yields, this kinetic alkylation-ozonolysis based approach to the synthesis of δ-substituted-δ-lactones is competitive with most of those currently available in the literature, and the fact the method can also be applied to the preparation of chiral and racemic γ-substituted γ-lactones 5 and 2-substituted 2-cyclopenten-2-ones 4 , emphasizes the synthetic utility of this combination of reactions.
The solution was maintained at -78º during the addition and the solution was stirred at this temperature for a further 1.5h.A solution of the alkylating agent (0.012mol) and HMPA (2ml) in THF (5ml) was added over 30min.The reaction mixture was then stirred at -78º for a further 30min before being allowed to rise to room temperature overnight.10% HCl (100ml) was added and the mixture was refluxed and vigorously stirred for approximately 12h, during which time the progress of the hydrolysis was monitored by IR and GC.After cooling, the mixture was extracted with ether (3 x 50ml) and the combined organic extracts were washed with 5% NaHCO 3 before being dried over MgSO 4 .Removal of the solvent gave the products 2a-i as yellow oils which were purified by kugelrohr distillation.

11-Bromo-2-methyl-2-undecen-6-one (2i).
The ketone 2i was prepared from 6-methyl-5hepten-2-one dimethylhydrazone 33 using a modified version of the procedure outlined above.A solution of the hydrazone in THF was added to the LDA at 0ºand the resulting solution was stirred at this temperature for 15h.After cooling to -70º, 1,4-dibromobutane is added and the solution is stirred for 1h, warmed to 0º and stirred for a further hour.The usual workup gives the alkylated hydrazone which is added to phosphate buffer (15ml, prepared by the addition of 1M sodium dihydrogen phosphate to 1M sodium hydrogen phosphate to give a pH of 7) and methanol (75ml γ-Ketoesters 3a-f and 3h-j.General ozonolysis procedure The unsaturated ketone 2 (0.011mol) was dissolved in dry dichloromethane (100ml), methanolic NaOH (2.5M, 21.5ml, 0.054mol) was added, and the solution was cooled to -78º.Ozone was passed into the solution using a gas dispersion tube, initially turning it yellow.At the end of the reaction, after approximately 1h, the solution becomes clear or, in some cases, turns blue.In the case of the alkyne 2f the ozonolysis was monitored by GC.The reaction flask was then placed in an ice-water bath and water (75ml) and ether (75ml) were added.The mixture was stirred for 1h at 0º, the layers were separated and the aqueous layer was extracted with ether (3 x 50ml).The combined ether extracts were dried over MgSO 4 and after the removal of the solvent kugelrohr distillation gave the ester 3 as a clear, fruity smelling, oil.γ-Lactones (4a-f).General procedure for yeast reduction and lactonization α-Glucose (31g, 0.17mol) potassium dihydrogen phosphate (0.07g, 0.5mmol) and magnesium phosphate (0.04g, 0.3mmol) were dissolved in boiled water.The flask was equilibrated at 32º and fresh baker's yeast (Saccharomyces cerevisiae) (28g) was added.Once the mixture was fermenting vigorously, the γ-ketoester 3 (5.4mmol)and 1M KOH (10ml) were added followed by boiled water (90ml).After adjusting the solution's pH to 6-7 using more 1M KOH, it was stirred at 32º for approximately 60h, the pH being maintained at 6-7 by the addition of further portions of 1M KOH.Glucose test paper was used during this period to indicate when further α-glucose (10g) was required and the reaction was terminated when uptake of α-glucose ceased.
The mixture was then cooled to 0º and celite (40g) was added.After stirring for 4h at this temperature, the celite was removed by filtration and washed with ether (200ml), and the filtrate was continuously extracted with ether (500ml) for 24h.The combined organic extracts were dried over magnesium sulfate.After removal of the solvent the residue was dissolved in dry benzene (20ml) containing p-toluenesulfonic acid (0.1g) and the solution was refluxed for 24h.Ether (50ml) was added, the solution was washed with brine (30ml) and 10% NaHCO 3 (30ml), and was dried over MgSO 4 .Following removal of the solvent the crude product was chromatographed on silica (petroleum ether/ether, 95:5) to give the γ-lactones (dihydro-5-alkyl-2(3H)-furanones) 4 as colourless liquids whose spectroscopic data were in agreement with literature data.The enantiomeric excesses of the products were obtained by chiral GC on a Restek Rt-βDEXcst (30m, 0.32mm, 0.25µm) column.

Synthesis of 6-hepten-2-one (5). Method A. (i) Preparation of 3-methyl-2-(methylsulfanyl)-5-hexen-3-ol.
A solution of allyl bromide (15.72g, 0.13mol) in dry ether (20ml) was added over 1h to a mixture of magnesium (8.86g, 0.86mol) and dry ether (80ml) containing a few crystals of iodine.The resulting mixture was stirred vigorously for 7h and then heated to reflux for a brief period.After cooling in ice-water, the excess magnesium was removed by filtration and 3-(methylthio)-2-butanone (10.64g, 0.09mol) in dry ether (40ml) was added at 0-4º over 1h to the solution of allylmagnesium bromide which was then refluxed for 20h.Chilled 10% HCl (50ml) was them added, the aqueous layer was extracted with ether and having been washed with washed with 5% NaHCO 3 (2 x 50ml), the combined ether extracts were dried over MgSO 4 .

Table 2 .
Preparation of γ-substituted γ-lactones 4 a Yield and purity of product after chromatography.b Determined by chiral GC using a Restek Rt-βDEXcst (30m, 0.32mm, 0.25µm) column.c Double the standard amount of fresh baker's yeast.d Additional yeast added during the reaction.e Dried baker's yeast.f Fresh baker's yeast in petroleum spirit.g Alginate immobilized baker's yeast.h Immobilized baker's yeast in petroleum spirit.

Table 3 .
Preparation of δ,ε-unsaturated ketones 6 and δ-ketoester 7 a Yield and purity of the product after kugelrohr distillation.Analytically pure samples were obtained where required by chromatography or further distillation.b Prepared in a one-pot procedure from acetone cyclohexylimine; product purification involved chromatography on silica.c Prepared from 6-hepten-2-one N,N-dimethylhydrazone.d Unstable on GC.

Table 4 .
Preparation of δ-hydroxyesters 8 and δ-lactones 9 cThe reaction gives a mixture of δ-hydroxyester 8 and δ-lactone 9; conversion to the lactone was completed by treatment with pTsOH.d Unstable on GC.