Asymmetric synthesis of glutamate derivatives

Analogs of glutamic acid were synthesized through the asymmetric Michael reaction using chiral acyclic  -enaminoesters and various Michael acceptors. The influence of the alkoxy group of the enaminoesters and also the nature of the olefins in the presence or not of zinc chloride on yield and enantioselectivity are explored.


Introduction
Glutamic acid (1) (Glu, Figure 1) is the major excitatory neurotransmitter in the central nervous system where it is involved in many biological processes by means of two types of receptors: the ionotropic ones (iGluR) and metabotropic ones (mGluR).Those receptors, in particular mGluR, are thought to interesting targets for the treatment of different pathologies such as Parkinson's disease 1,2 or epilepsy. 3So developing synthesis of non natural analogs of glutamic acid appears to be of interest to access new ligands of mGluR.Asymmetric Michael reaction involving acyclic chiral β-enaminoesters appears to be a tool of choice and can easily afford new precursors of glutamic acid analogs like compound 2 (Figure 1).Indeed, the Michael reaction is known to be one of the simplest and most efficient methods for the construction of quaternary carbon centers.Use of an asymmetric variant of this reaction with chiral imines/enamines is proved to give an easy access to molecules presenting an asymmetric quaternary center, generally with a high degree of regio-and enantio-selectivity.][14][15][16][17][18] In this paper, we explore the Michael reaction between acyclic chiral β-enaminoesters exhibiting various alkoxy groups and various olefins, the effect of Lewis acid on the reactivity and the enantioselectivity of this reaction will be explored.

Scheme 1
Synthesis of ketoesters of types 4 and 5 bearing differentiated ester groups, e.g. an easily cleavable benzylic, appears to be of interest in the elaboration of a new variety of molecules with acid functions.In previous works, we observed that the nature of the ester group carried by the quaternary carbon center could induce a decrease of the enantioselectivity into the final Michael compounds. 21Indeed, the asymmetric Michael reaction between cyclic benzyl β-enaminoester 6b and methyl acrylate furnished the corresponding adduct 7b with a disappointing ee (55%) compared to the ee of its methyl analog 7a which was ≥ 95%.Firstly, the erosion of the enantioselectivity was attributed to the presence of benzyl ester group, but compared to the result obtained with Michael adduct 8b (ee = 94%) formed by condensation of the acyclic benzyl enaminoester 3b with phenyl vinyl sulfone, other factors should be implicated (Scheme 2).ii: AcOH 10%

Scheme 2
In the asymmetric Michael reaction, the acrylate 9 approaches on the less hindered -face of enaminoester 3 (anti to the bulky phenyl group of the chiral amine moiety) with an endo-arrangement in which the electron withdrawing group of the olefin faces the nitrogen atom of enaminoester 3.Besides the related six membered aza-ene-synthesis-like transition state, the transfer of the proton of the enaminoester to the vinylic centre of acceptor 9, induced the control of the tertiary stereogenic centre in intermediate imines 10.It could be considered that using a benzylic enaminoester can modify the usual approach of the two reactants due to the steric hindrance caused by the benzylic group (Scheme 3).

Scheme 3
3][24] The energy difference is in favour of the Reapproach in which the benzyl group of 6b is pushed away from the methyl acrylate face approach.Consequently, using a benzyl enaminoester does not disturb the asymmetric Michael mechanism.
In our aim to synthetize final chiral compounds with differentiated ester functions and to understand the influence of the alkoxy groups of the enaminoesters in the asymmetric Michael reaction, acyclic methyl and benzyl enamines 3a and 3b were condensed to various mono-substitued acrylates in neutral conditions and with the presence of zinc chloride as activator.
At first, it can be noted that β-ketoester 11c is commercially available and inexpensive, contrary to 11a and 11b which must be prepared by methylation of their corresponding acetoacetates, and separation of the methylate adducts from the starting materials is demanding due to very close polarity.In a first step, in order to have sufficient material available, we proved equivalence between methylic enamine 3a and ethylic enamine 3c toward certain monosubstituted Michael acceptors.(Scheme 4)

Scheme 4
Chiral β-enaminoesters 3a-c were easily and quantitatively prepared by condensation between pure (S)-1phenylethylamine and respectively methyl, ethyl and benzyl 2-methylacetoacetates 11, in refluxing toluene in the presence of a catalytic quantity of p-toluenesulfonic acid.These enaminoesters were of pure Z geometry secured by an intramolecular hydrogen bonding between the hydrogen atom carrying by nitrogen of the enaminoesters and the carbonyl group of the ester.3a-c can be used as it is and no further purification is necessary.These crude enamines were first condensed, under neutral condition in refluxing THF, to various monosubstitued olefins.Thus, addition of 3a and 3c, in refluxing anhydrous THF, to methylacrylate, acrylonitrile and phenyl vinyl sulfone furnished, after hydrolytic work-up, the expected compounds.In all cases, the Michael adducts were obtained with similar yields and excellent ee's (Table 1; entries 1, 2, 4, 5, 7 and 8) and demonstrated the equal reactivity of methyl and ethyl enaminoesters.Then, all these results were compared with those obtained with benzylic enaminoester 1b, and to extend our comparative study the t-butyl and benzyl acrylates were also used.All the results are summarized in Table 1.The ethyl β-enaminoester 3c is able to react with all olefins, as the expected yield is higher with phenyl vinyl sulfone (Table 1, entry 8); and acrylonitrile (Table 1, Entry 5) or acrylate with an ester function (Table 1, entries 10 and 12), yields are around 40%.Generally, ee's are at least equal to 95% except for 15c derived from benzyl acrylate which was obtained with 85% ee.Concerning benzylic enaminoester 3b, this revealed another intrinsic reactivity.Indeed, 3b exhibited a great reactivity with phenylvinylsulfone and benzylic acrylate (Table 1, entries 9 and 13) which furnished corresponding adducts with 80% yield over three steps,but very poor results were obtained with other acrylates (Table 1, entries 3, 6 and 11).Enaminoester 3b seems to be reactive only with acrylates bearing a phenyl group, these results could implicate interactions between the aromatic groups of both partners.In case of the other acceptors, even after several days of reaction, considerable starting ketoester 11b was recovered after the hydrolytic work-up, showing the lack of reactivity of 3b toward them.In the first part of our study, we have thus confirmed that the asymmetric Michael reaction could be extended to ethylic and benzylic β-enaminoesters and various electrophilic mono-substituted alkenes.Final adducts were generally obtained in three steps with good stereocontrol of the quaternary carbon center.A decrease of the e.e. was observed when using benzyl acrylate.
Asymmetric Michael reactions using β-enaminoesters are generally performed with Lewis acid as Michael acceptor activator, [4][5][6][7][8][9][10][11] so the preceding reactions were repeated in the presence of zinc chloride (1.4 equivalents) in order to study the influence of this catalyst on both reactivity and selectivity.The results are summarized in Table 2.We observed that the addition of zinc chloride caused, in general, an improvement in term of yields.However, an exception was noted in the case of the reaction between β-enaminoester 3c and methyl acrylate, in which the expected Michael adduct 12c was isolated in lower yield when using zinc chloride (Table 2, entry 1 versus table 1, entry 1).In fact, the overall yield is good, but in this case a by-product was formed in 50% yield and was characterized as the cyclohexenone 15 (ee and de ≥ 95%) (Scheme 5). 3 This process was not observed when t-butyl acrylate was used instead of methyl acrylate (

Scheme 5
In the presence of zinc chloride, reactivity of acrylonitrile and ter-butyl acrylate are enhanced and can react with benzylic enamine 3b.With t-butyl acrylate, 3c and 3b furnished the corresponding adducts 14c and 14b with excellent yield and ee's (Table 2, entries 6 and 7).If the addition of ethylic enaminoester 3c with acrylonitrile furnished adduct 13c with good optical purity, an erosion was observed using 3b (Table 2, entries 2 and 3).Similarly, both enamines react very well with phenyl vinyl sulfone but a great decrease of enantioselectivity is observed in the case of the benzyl enamine: ee = 55% (Table 2, entries 4 and 5).
In order to have access to precursors of functionalized analogs of glutamic acid, β-enaminoesters used previously were condensed with different α-substituted acrylates (Scheme 6).Thin layer chromatographies of crude reactions using methyl acetoxy-and methyl acetamido-acrylate in presence of zinc chloride showed the formation of many side-products.Performed without catalyst, the Michael reaction led to expected adducts with good overall yields., mentioned for comparison.
In order to determine relative configurations, compounds 4a-c and 5a-c were cyclised in the presence of ammonia.All ketoesters 4 lead in quantitative yield to the hemiacetal 17, and compounds 5 furnish the pyrrolidine 18 in quantitative yields (Scheme 7).Both cyclic adducts were crystallized. 19

Conclusions
In conclusion, we have demonstrated that the asymmetric Michael reaction can be successfully extended to acyclic β-enaminoesters leading to β-ketoesters with different ester groups.
The ethyl enaminoester 3c reacted with monosubstitued olefins and furnished Michael adducts with excellent optical purity and good global yields with or without the use of a Lewis acid.The intrinsic reactivity of the benzyl analogue 3b is different.Indeed, in neutral conditions, enaminoester 3b reacted very well with Michael acceptor bearing a phenyl group and poor results were obtained with acrylonitrile or ter-butyl acrylate; an activation with zinc chloride is necessary.When using benzyl acrylate, final compounds were obtained with low ee.
Moreover, a decrease of the enantioselectivity was observed with benzyl enaminoester 3b depending of the nature of the acrylate and the presence or absence of zinc chloride.
The Michael adducts obtained by the condensation between the acyclic β-enaminoesters and methyl acetoxy-and methyl acetamidoacrylate are polyfunctionalized and bear differentiated ester functions.Their transformation into diacid and pharmacomodulation are in process.

Experimental Section
General.Commercial reagents were used without purification.Prior to use, THF was freshly distilled from sodium-benzophenone, Methanol was dried over magnesium and distilled under a nitrogen atmosphere.All anhydrous reactions were carried out under nitrogen atmosphere.Analytical thin layer chromatography was performed on SDS silica gel 60F254 aluminium plates (0.2 mm layer) and was revealed by UV-light or Kägi-Misher reagent.All flash chromatography separations were performed with SDS silica gel 60.Melting points were recorded on a Kofler bench and were uncorrected.Infrared (IR) spectra were obtained as neat films and were recorded on Bruker Vector 22 spectrophotometer. 1 H and 13 C spectra were recorded respectively either on a Bruker AC 200 P or a Bruker Avance 300 at 200 or 300 MHz and 50 or 75 MHz, respectively.CDCl3 was used as internal reference.Specific rotations []D were measured on a Optical Activity Limited AA-10R polarimeter with sodium (589 nm) lamp at specified temperature in a 1 dm-cell.Elemental analyses were performed by the Service de Microanalyse, Centre d'Etudes Pharmaceutiques, Châtenay-Malabry, France, with a Perkin-Elmer 2400 analyser.Enantiomeric excesses (ee's) were evaluated either by 1 H NMR spectroscopy using Eu(hfc)3 as chiral shift reagent or by chiral HPLC on a Spectrasystem P1000XR with a Spectraseries UV100 spectrophotometer and a chiral column Chiralcel AD.HPLC spectra were obtained by using Azur program.

Table 1 .
Asymmetric Michael reaction in neutral conditionsEven if the Michael adduct 8b, formed by the condensation of 3b with phenyl vinyl sulfone, was obtained with 94% ee's (Table1, entry 9); a reduction in the stereoselectivity was however observed when benzylic acrylate was used (84%; Table1, Entry 13).
a (a) determined by 1 H NMR with Eu(hfc)3 as chiral shift reagent; (b) determined by chiral HPLC; (c) reaction already published (entries 7 and 9) 21 , mentioned for comparison .

Table 2 .
Asymmetric Michael reaction in presence of zinc chloride

Table 2 ,
entries 6 and 7).It implied that this cyclization is dependent on the steric hindrance of the ester function in the acrylate.

Table 3 .
Asymmetric Michael reaction in neutral conditions b (a) determined by 1 H NMR with Eu(hfc)3 as chiral shift reagent; (b) determined by chiral HPLC; (c) reaction already published (entries 1 and 4)