A New Approach to the Synthesis of ( ± )-Methyl Jasmonate and ( ± )-Baclofen via Conjugated Addition of Oxazoline Cyanocuprate to Michael Acceptors

Introduction of a synthon equivalent to a carboxymethyl anion to enones and nitroalkenes, through a 1,4-addition reaction of 2,4,4-trimethyl-2-oxazoline cyanocuprate 3, proved to be an interesting methodology for the synthesis of natural products such as (±)-methyl jasmonate (1) and (±)-baclofen (2).


Introduction
Conjugated addition of functionalized carbanions to the b position of a a,b-unsaturated systems have vast utility in synthetic organic chemistry, and several different variants have been developed for this purpose 1 .Among them, carboxymethyl anion equivalents such as silylketene acetals 2 , were tacitly designed to depress the inherent nature of 1,2-carbonyl addition for naked ester enolates 3 .
Recently, we developed the preparation and use of oxazoline cyanocuprate 3 in reactions with enones 4 and nitroalkenes 5 , in which a nucleophilic addition allow the introduction of a carboxymethyl anion equivalent to those Michael acceptors.Application of this methodology in the synthesis of natural products is illustrated here, having (±)-methyl jasmonate (1) and (±)-baclofen (2) as target molecules.The retrosynthetic pathway that illustrate our approach to prepare both compounds is shown in Scheme 1, employing 2-cyclopenten-1-one and p-chloro-bnitrostyrene as starting material.
Jasmonates induce genes encoding proteinase inhibitors, antifungal proteins, and enzymes involved in the biosynthesis of defensive secondary metabolites 6 .Thus, in addition to their well-established function as plant growth regulators and development 7 , jasmonates play a key role as phytohormones or signal transducers in the defense signaling systems of plants.While there is a high degree of chemical diversity among the primary elicitors, defensive signaling in plants seems to rely on at least one common group of signal transducers.For a large number of species from different plant families, it has been shown that recognition of the primary elicitors eventually induces the biosynthesis of jasmonic acid or methyl jasmonate 8 .
The g-aminobutyric acid (GABA) is known as the major inhibitory neurotransmitter in the central nervous system, and its b-substituted derivatives play an important role in a number of central nervous system functions 9,10 .Baclofen (2) 11 (commercially available as Lioresal Ò , 3-(p-chlorophenyl)g-aminobutyric acid), a lipophilic derivative of GABA, is used in the treatment of spasticity caused by disease of the spinal cord 12 , particularly traumatic lesions.While earlier studies were mainly concentrate on baclofen, recent literature indicate renewed interest in the biological activities of b-phenyl-GABA.These include anticonvulsant 13 , antiepileptic 14 , antistress 15 , antiamnesic and antihypoxic 16 , antihypertensive 17 , and analgesic activities 18 .Because of its biological and pharmacological importance, several methodologies have been described focusing the total synthesis of baclofen 19,20 .
We have previously established the one-pot conditions (MeOH/H 2 SO 4 ) for the conversion of the oxazoline function to the respective methyl ester, which was carried out by using a mixture of compound 6 with propargyl alcohol, as a model system, to check the stability of the triple bond in this reaction.Under this condition, the keto-oxazolines 4 and 5 were converted to the desired esters 8 and 9, respectively.
The success of this methodology relies on the exchange of the copper enolate by tin enolate, as described by Itoh et al. 21, using sequential vicinal double alkylation via stannyl enolate trapping in a tandem double addition on the 2-cyclopenten-1-one moiety.This methodology was employed to prevent the formation of C,O-dialkylation product, C,C-dialkylation product, O-alkylation product, among others, since the stannyl enolate trapping inhibits the equilibration of the enolates 22 .
The g-nitrooxazoline 11 was submitted to several reduction conditions (LiAlH  25 , H 2 /Pd-C 26 and H 2 /Raney-Ni 27 ) aiming the selective reduction of the nitro group.All the attempts resulted in a mixture of several non-identified products, none of them holding the oxazoline ring.
An alternative approach to (±)-baclofen was then employed where the oxazoline group was first converted to the corresponding ester.The resulting nitroester 12 was submitted to reduction with H 2 /Raney-Ni affording a mixture of aminoester 13 and the lactam 14.This mixture was refluxed in o-xylene to provide lactam 14 as a single product.Hydrolysis of lactam 14 produced (±)-baclofen (2) as its hydrochloric salt in 39 % overall yield from pchloro-b-nitrostyrene (Scheme 3).

Conclusion
The use of oxazoline cyanocuprate to introduce a carboxymethyl synthon to the b position of a a,bunsaturated systems has shown to be a versatile methodology for the synthesis of natural products, and its chiral version is now been applied using optically active oxazolines.

General
Reagents and solvents were purified and dried using standard methods.Reactions involving organometallic reagents were carried out under argon in oven-dried glassware.Hydrogenations were carried out using a Parr Ò apparatus or a balloon filled with hydrogen.Reactions were monitored by thin-layer chromatography (TLC; glass plates 7x21 cm) and gas chromatography (GC) using a Varian Ò model 3800 (flame ionization detector (FID, 30 m x 0.25 mm VA-5: 5%-phenyl-methylpolysiloxane) or (FID, 30 m x 0.25 mm VA-WAX: Polyethylene Glycol).GC-EIMS (70 eV) analysis were carried out on a Varian Ò Saturn 2000 GC-MS spectrometer in a split injector model with an Ion Trap technology (30 m x 0.25 mm VA-5: 5%-phenylmethylpolysiloxane).Conventional and flash column chromatographies were carried out with 70-230 and 230-400 mesh silica gel (E.Merck), respectively.IR spectra were recorded on a Bomem MB100 spectrometer with internal calibration. 1H NMR were recorded on CDCl 3 solutions using Bruker AC-80, Bruker ARX-400, Bruker ARX-200 or Varian Ò Gemini 300 spectrometer.Chemical shifts (d) are given in ppm and coupling constants (J) in Hz.Deuterated solvents were used as lock and reference signal ( 1 H NMR reference signal relative to the proton resonance resulting from TMS signal: d 0.00 ppm). 13C NMR spectra were determined as solutions in CDCl 3 with the spectrometers described above.The chemical shifts (d) are reported in ppm relative to the center peak of CDCl 3 (d 77.0 ppm).

4-(4-Chloro-phenyl)-pyrrolidin-2-one (14)
The nitroester 12 (0.150 g, 0.55 mmol) was dissolved in EtOH (7.5 cm 3 ) and a suspension of methanol wet Raney-Ni (0.037 g) was added at room temperature and stirred for 8 h under (50 psi) of H 2 pressure in a Parr ® apparatus.The mixture was suction filtered on Celite, and the residue was washed several times with ethanol.The solvent was evaporated and the residue, purified by flash chromatography using AcOEt, affording 0.045 g of lactam 14 and 0.056 g of the corresponding ethyl 3-(4-chlorophenyl)-4aminobutanoate 13.This mixture was refluxed in o-xylene affording 14 (0.081g, 75%) as a single product.;IR n max /cm -