Synthesis of enantiomericaly pure γ -lactones from 2,3-O - isopropylidene-D-or L-erythrose

Conventional synthetic transformations such as Wittig olefination, catalytic hydrogenation and lactonization reactions were used to obtain enantiomerically pure ( R )- γ -caprolactone and ( S )- japonilure, pheromones of the beetle Trogoderma and the Osaka beetle Anomala osakana , respectively, as well as the hydroxylated γ -lactone L-factor from 2,3-O -isopropylidene- D - or L - erythrose.


Introduction
Many natural products with important biological activities have the structure of a chiral γlactone. 1A number of such lactones have been isolated from insects and are part of their intriguing communication systems.(R)-γ-Caprolactone 1 is a component of the pheromone secreted by the female dermestid beetle Trogoderma glabrum and Trogoderma granarium 2 (Figure 1).These beetles are among the worst insect pests infecting nearly all forms of stored products, including grain, meat, dairy products, carpets and clothing.(4R,5Z)-4-Hydroxy-5tetradecenoic acid γ-lactone 3 ent-2 4 or (R)-japonilure is a pheromone of the Japanese beetle Popillia japonica, a notorious pest of a variety of trees, grasses, ornamentals and cultivated crops, whereas (S)-japonilure 5 2 is the pheromone of the Osaka beetle Anomala osakana.These two pheromones act as strong behavioral antagonists for the allospecific receiver, 6 a fact that increases the demand for enantiomerically pure (R)-or (S)-japonilure.
(4S,5R)-4,5-Dihydroxydecanoic acid γ-lactone or L-factor 7 3 and (4R,5R)-4,5dihydroxyheptadecanoic acid γ-lactone or (-)-muricatacin 8 4 have closely related structures possessing an additional hydroxyl group with respective erythro-and threo-relative configurations differing also in the length of the carbon chains.The first of them, produced by Streptomyces griseus, was initially proposed to be an autoregulator of anthracycline biosynthesis, whereas muricatacin isolated from the tropical fruit, Annona muricata is an anticancer agent.The synthesis of the above γ-lactones and related compounds has became the subject of intensive work and a number of publications towards their enantioselective syntheses have been reported in the literature, [9][10][11][12] including both asymmetric synthesis and chiral pool.In addition, enantiomerically pure γ-lactones are valuable chiral synthetic intermediates, useful for further transformations. 13Our continuing interest in the synthesis of pheromones and natural products with a lactonic structure using inexpensive commercially available carbohydrates, 14 prompted us to investigate the synthesis of enantiomerically pure γ-lactones, such as those depicted in Figure 1.

Results and Discussion
Protected D-or L-erythrose were the starting material of choice, since both enantiomers are easily prepared either from the respective inexpensive commercial D-or L-arabinose, 15 or from D-ribose 16 or isoascorbic acid. 17This fact has the advantage of allowing the possibility to prepare both enantiomers of the target molecule, simply by selecting the other starting enantiomer of erythrose.In our hands, protected D-and L-erythrose (5 and ent-5, respectively) were repeatedly prepared from the respective D-and L-arabinose, 15 in 90% yield.
A 2:5 mixture of E-/Z-6 (Scheme 1) in 90% yield was prepared by Wittig olefination of 5 with the stable ylide Ph 3 P=CHCO 2 Me.It has been reported, 17a that this reaction yields exclusively the E-6.However, the given 1 H and 13 C NMR data 17a were consistent to those of Z-6 we obtained (J cis = 11.6 Hz, J trans = 16.1 Hz).It is also well known that the presence of a 4-OH at an aldehyde (open form of 5) favors the formation of Z-alkenes in Wittig reactions with stable ylides. 18Subsequent catalytic hydrogenation over Raney Ni of this mixture gave 70% yield of the saturated ester 7. 14b After some experimentation, 19 the desired iodide 8 was prepared in 90% yield from 7 by careful balancing the ratio of reactants (1.1 equiv.I 2 , 1.0 equiv.imidazole, 2.0 equiv.Ph 3 P, toluene, reflux, 2h).
The overall yield was 43% from 2,3-O-isopropylidene-D-erythrose 5 in five steps or 39% from D-arabinose in seven steps.Compared to other syntheses of (R)-γ-caprolactone 1 from chiral pool components, 9 our method is the most highly yielding and one of the shortest synthetic approaches.
Methyl (4S,5R)-4,5-O-isopropylidene-4,5,6-trihydroxy-hexanoate 7, intermediately prepared in the synthesis of (R)-γ-caprolactone 1, could also be used for the easy access to (S)-japonilure 2 (Scheme 2).Treatment of 7 with a catalytic amount of p-toluenesulfonic acid afforded the known dihydroxy γ-caprolactone 10 10g,22 in 45% yield, which upon periodate cleavage can afford aldehyde 11, a reaction already applied for the preparation of ent-11 from ent-10.22b The final step of its conversion to the desired (S)-japonilure 2 is known in the literature to proceed by a simple Wittig reaction.10h The last natural product we pursued was L-Factor 3 (Scheme 3).This compound has the structure of (S)-γ-decanolactone possessing an additional hydroxyl group at α-position relative to the lactone moiety with erythro-stereochemistry. L-Erythrose ent-5 was the starting material and the terminal aliphatic chain was introduced by a Wittig reaction with the proper phosphorus ylide in 94% yield.(Z)-12 was thus produced contaminated by 9% (E)-12, as shown by integration of the easily discerned H-3 proton signals in their 1 H NMR spectra.The primary hydroxyl group was then subjected to Swern oxidation following by a second Wittig olefination with the stable ylide Ph 3 P=CHCO 2 Et.The ratio of geometric isomers obtained was of no importance and the product was hydrogenated over catalytic Raney Ni to give the known ester 13 in 37% yield (three steps).The data of this compound were generally in agreement with those reported in the literature, except for the [α] D values.11c For this reason, we proceeded in the next step and treatment of 13 with catalytic p-toluenesulfonic acid 11c led to the formation of L-Factor 3 in 59% yield, whose analytical data was in good agreement with the reported data.The enantiomer of L-Factor ent-3 can also be prepared by the same route starting from protected D-erythrose 5.In addition, their diastereoisomers with threo relative configuration could also be prepared by a Mitsunobu inversion of the free secondary hydroxyl group. 12urthermore, this method could be used for the synthesis of any analogous γ-lactone stereoisomer, differing also in the length of the carbon chains.In fact, the synthesis of epimuricatacin by this procedure from protected D-erythrose 5 was reported by Scharf and coworkers.17a

Conclusions
In conclusion, easily accessible protected D-or L-erythrose obtained from the respective enantiomer of inexpensive commercial arabinose was used for the synthesis of enantiomerically pure γ-lactones, applying conventional synthetic transformations such as Wittig olefination, catalytic hydrogenation and lactonization reactions.The possibility of using either D-or Lerythrose is a great advantage, since both enantiomers of a chiral γ-lactone could be prepared.This was exemplified by the synthesis of pheromones (R)-γ-caprolactone and (S)-japonilure, as well as the natural γ-lactone L-factor in enantiomerically pure form, reported here.In addition, several compounds prepared, such as 7-13, could prove valuable chiral synthetic intermediates.

Experimental Section
General Procedures.All reagents are commercially available and were used without further purification.Solvents were dried by standard methods.Raney Ni was purchased from Aldrich.The reactions' progress was checked by thin layer chromatography (TLC) on Merck silica gel 60F 254 glass plates (0.25 mm).The spots were visualised by heat staining with anisaldehyde in ethanol/sulfuric acid.Column chromatography was performed with Merck silica gel 60 (0.063-0.200 mm).Melting points were determined on a Kofler hot-stage microscope and are uncorrected.Optical rotations were determined at room temperature on an A. Krüss P3000 Automatic Digital Polarimeter.The 1 H-and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively, on a Bruker 300 AM spectrometer, with tetramethylsilane (TMS) as internal standard.IR spectra were recorded on a Perkin Elmer FT-IR 1650 instrument as indicated.Highresolution mass spectra (HRMS) were obtained on a 7 T APEX II mass spectrometer by electro spray technique, positive mode.(S)-5-Vinyldihydrofuran-2(3H)-one (9).To a solution of 8 (588 mg, 1.80 mmol) in MeOH (20 mL), was added activated Zn 20a (580 mg, 9 mmol) and the mixture was refluxed for 2 h with stirring.Then, the solids were removed by filtration through Celite®, the solvent was evaporated and the residue chromatographed on a silica gel column with hexane/EtOAc (3:1) as the eluent to give 9 (245 mg, 95%) as a thick oil with 1 H and 13 C NMR were identical to those reported in the literature. 22 (R)-5-Ethyldihydrofuran-2(3H)-one (1).To a solution of 9 (258 mg, 1.8 mmol) in methanol (8 mL) catalytic amount of Raney Ni was added and the mixture was stirred under hydrogen atmosphere (1 atm) for 2 h at room temperature.Then, the solids were removed by filtration through Celite®, the solvent was evaporated and the residue chromatographed on a silica gel column with hexane/EtOAc (4:1) as the eluent to give 1 (209 mg, 80%) as a thick oil with 1 H and C NMR were identical to those reported in the literature. 9[α] D 25 +50.

(S)-5-((R)-1,2-Dihydroxyethyl)dihydrofuran-2(3H)-one (10).
A solution of 7 (272 mg, 1.24 mmol) and TsOH•H 2 O (15 mg) in MeOH (30 mL) was stirred at room temperature for 2 h.Saturated aqueous NaHCO 3 (10 mL) was added, the mixture was extracted with ethyl acetate (3x60 mL) and the organic phase was washed with brine and dried over Na 2 SO 4 .After evaporation of the solvent, the residue was chromatographed on a silica gel column with hexane/EtOAc (1:1) as the eluent to give 10 (82 mg, 45%  (10 mL) containing catalytic amount of 12-crown-4 was cooled at -60 ºC and n-BuLi 2.34 M in hexanes (7 mL, 16.42 mmol) was added dropwise under argon atmosphere.The solution became orange-reddish, then protected Lerythrose ent-5 (536 mg, 3.35 mmol) in THF (5 mL) was added at the same temperature and the mixture was allowed overnight to warm at room temperature before being quenched with saturated aqueous NH 4 Cl.The mixture was subsequently extracted with CH 2 Cl 2 (3x60 mL), the organic layer was washed with H 2 O (60 mL) and dried over Na 2 SO 4 .The solvent was then evaporated and the residue chromatographed on a silica gel column with hexane/EtOAc (5:1) as the eluent to give 12 (628 mg, 94%, Z/E = 91:9) as a thick oil: [ Ethyl (4S,5R)-4,5-isopropylidenedioxydecanoate (13).A solution of (COCl) 2 (0.95 mL, 10.9 mmol) in dry CH 2 Cl 2 (12.5 ml) was cooled to -60 ºC and DMSO (1.5 mL, 20.0 mmol) in dry CH 2 Cl 2 (7.5 ml) was added dropwise.Alcohol 12 (500 mg, 2.5 mmol) dissolved in dry CH 2 Cl 2 (30 ml) was subsequently added, dropwise as well.After stirring for 20 min at the same temperature, Et 3 N (5.95 mL, 40 mmol) was added and stirring was continued for 30 min.Then, the mixture was allowed to warm to room temperature, poured into water and the organic phase was washed with brine (3×30 ml).The aqueous layer was extracted with CH 2 Cl 2 (3×50 ml).The combined organic phases were dried and concentrated in vacuum.The resulting aldehyde was dissolved in EtOH (50 mL), Ph 3 P=CHCO 2 Et (1.305 g, 3.75 mmol) was added and the mixture was allowed to stir overnight.The solvent was subsequently evaporated and the residue chromatographed on a silica gel column with hexane/EtOAc (10:1) as the eluent to give a thick oil, which was dissolved in MeOH (50 mL), catalytic amount of Raney Ni was added and the mixture was stirred under a hydrogen atmosphere (1 atm) for 24 h at room temperature.Then, the solids were removed by filtration through Celite®, the solvent was evaporated and the residue chromatographed on a silica gel column with hexane/EtOAc (15:1) as the eluent to give 13 (252 mg, overall 37%) as a thick oil with 1 H and 13 C NMR identical to those reported in the literature: 11   (5 mL) was added, the mixture was extracted with ethyl acetate (2x20 mL) and the organic phase was washed with brine and dried over Na 2 SO 4 .After evaporation of the solvent, the residue was chromatographed on a silica gel column with hexane/EtOAc (3:1) as the eluent to give L-factor 3 (44 mg, 59%) with 1 H and 13 C NMR identical to those reported in the literature.