Enantioselective Michael reactions promoted by recoverable dimeric anthryl-derived Cinchona phase-transfer catalysts

Dimeric cinchonidine and cinchonine-derived ammonium salts have been used as phase transfer catalysts in the Michael addition reaction of N -(diphenylmethylene)glycine tert -butyl ester to electron-poor olefins. The enantioselectivity of the reaction (up to 97% ee ) was dependent of the counter-anion present in the ammonium salt, and the catalysts could be recovered by precipitation.


Introduction
The synthesis of optically active α-amino acids still remains as an important synthetic challenge which has boosted the development of many methodologies. 1 Amongst all of them, the easily scalable phase-transfer catalysis (PTC), 2 has been applied profusely, especially for the asymmetric alkylation of glycine and alanine Schiff bases.1n,o,2g-i Thus, the pioneering works of O'Donnell 3 on the use of quaternized Cinchona alkaloids, 4 such as the cinchonidine-derived ammonium salt 1, as chiral PTC catalysts for the enantioselective alkylation of benzophenone imine glycinates, were improved independently by Lygo (2a) 5 and Corey (2b), 6 achieving high degrees of enantioselection using a very simple procedure.In addition, dimeric, 7 trimeric, 8 dendrimeric 9 Cinchona alkaloid-derived catalysts, and even polymer-supported, 10 have been employed for this type of PTC alkylations. 10Other non-Cinchona-derived catalysts such as spiro ammonium 11 and phosphonium salts, 12 TADDOL 13a,b and other tartaric derivatives, 13c,d guanidinium salts, 13e binaphthyl-derived amines 13b,14 and salen-metal complexes 15 have also been used.
On the contrary of all the extensive work devoted to the PTC-promoted asymmetric synthesis of α-amino acids through alkylation reactions, only some efforts have been devoted to the use of the asymmetric PTC preparation of amino acid derivatives through such an important process as the Michael addition reaction.Thus, Corey's cinchonidine-derived ammonium salt 2b has been used in the conjugate addition reaction of benzophenone imine tert-butyl glycinate to different Michael acceptors achieving high enantioselectivities, 16 the same catalyst being employed in the asymmetric synthesis of (S)-ornithine, 17 (ε-13 C,ε-15 N)-enriched lysine 18 and solid-phase bounded glycinates. 19In addition, asymmetric PTC Michael addition reactions have been performed using other chiral ammonium salts derived from L-tartrate 20 and (S)-BINOL, 21 both achieving moderate enantioselectivities.Moreover, chiral guanidines from (R)-1phenylethanamine have also been used although achieving low ee's, 22 much better results being achieved using guanidines from C 2 -symmetric 1,2-diphenylethane-1,2-diamines 23 or even a chiral crown ether from chiro-inositol. 24e have recently prepared dimeric ammonium salts derived from cinchonidine or cinchonine and a bridging (anthracen-9,10-yl)dimethyl moiety, 3a,d and 4a,d respectively, which have shown good enantioselection as catalysts in the PTC alkylation of benzophenone imine glycinates.7c These ammonium salts present a unique effect of the accompanying counteranion in the enantioselectivity of the alkylation reaction. 25Thus, the tetrafluoroborate or hexafluorophosphate anions in cinchonidine-derived salts 3b,e and 3c,f and in cinchoninederived salts 4b,e and 4c,f gave generally place to higher ee's compared to the chloride or bromide anions in 3a,d or 4a,d The more noticeable differences and higher ee's were generally observed when the O-allylated dimeric catalysts 3d,e,f and 4d,e,f were employed.With these antecedents we decide to continue the study of the behavior of these dimeric O-allylated Cinchona-derived dimeric ammonium salts as PTC catalysts.Here we describe the enantioselective Michael addition reaction of benzophenone imine-derived tert-butyl glycinate with electron poor olefins.

Results and Discussion
The chiral PTC cinchonidinium-derived catalysts were prepared starting from dimeric chloride salt 3a, which was obtained by reaction of 9,10-di(chloromethyl)anthracene with cinchonidine as described (Scheme 1).7c O-Allylation of ammonium salt 3a gave place to the dimeric cinchonidinium salt 3d, and further exchange of the bromide anions by the tetrafluoroborate and the hexafluorophosphate anions after reaction with sodium tetrafluoroborate or potassium hexafluorophosphate afforded salts 3e and 3f, respectively. 25imilarly, we prepared their O-allylated cinchoninium counterparts 4d, 4e and 4f, which can be considered as pseudoenantiomers of the formers, therefore driving to an opposite enantioselection.4f All this array of dimeric ammonium salts bearing different counter-anions were employed as chiral PTC catalysts (5 mol%) in the Michael addition reaction of tert-butyl N-(diphenylmethylene)glycinate ( 5) to different electron-deficient olefins (Scheme 2, Table 1).The aqueous base selected for these PTC reaction was 50% KOH whereas the solvent employed was a mixture of toluene/chloroform (7/3 v/v), these reaction conditions being the previously found as more appropriate when working with these dimeric PTC catalysts.7c, 25 The reactions were monitored by GLC, an their enantioselectivity was measured by chiral GLC analysis 26 of the corresponding N-trifluoroacetamide esters from 6 or 7, 27 whereas the absolute configuration was determined by comparison of the retention times obtained by chiral HPLC analysis of the final products with those of the literature. 23The catalysts could be recovered by precipitation with ether when the reaction was finished and reused, 25  The Michael addition reaction of glycinate 5 with methyl acrylate under the above mentioned conditions and employing the dimeric bromide 3d as PTC catalysts gave a 26% ee of the corresponding adduct (S)-6a when the reaction was carried out at -55 ºC, a value which experienced no increment when the temperature was lowered to -78 ºC (Table 1, entries 1 and 2).The anion-interchanged tetrafluoroborate and hexafluorophosphate dimeric salts 3e and 3f gave even lower ee's working at -55 ºC, the reaction time being increased considerably, especially in the case of using the hexafluorophosphate 3f as catalyst, which also gave the lowest enantioselectivity (Table 1, entries 3 and 4).We expected that increasing the steric bulkiness of the Michael acceptor would drive to higher enantioselectivities, therefore we employed tert-butyl acrylate as electron-deficient olefin for the conjugate addition.Disappointingly, when cinchonidine-derived bromide 3d was used as PTC catalyst, the corresponding adduct (S)-6b was obtained in only 20% ee, which is a lower value than when using methyl acrylate (Table 1, entry 5).The use of the tetrafluoroborate dimeric salt 3e improved slightly the enantioselection up to 30% but with low yield, whereas the hexafluorophosphate 3f again performed poorly, with very long reaction times, low yield and only 16% ee of (S)-6b (Table 1, entries 6 and 7).Other Michael acceptor such as methyl vinyl ketone also gave very low ee's of the corresponding adduct (S)-6c with all the cinchonidine-derived catalysts (Table 1, entries 8-10), catalyst 3f affording higher ee.However, when a low sterically demanding olefin such as acrylonitrile was employed in the conjugate addition, a 41% ee of the adduct (S)-6d was obtained using bromide 3d as PTC catalysts and working at 0 ºC, this enantioselectivity being increased up to 72% ee when the temperature was lowered to -35 ºC (Table 1, entries 11 and 12).When the ammonium tetrafluoroborate salt 3e was used as catalyst, the enantioselection for (S)-6d rose to 80% ee (Table 1, entry 13), whereas now the hexafluorophosphate 3f performed the best as catalyst, allowing the enantioselectivity to reach to 88% ee (Table 1, entry 14).Lowering the temperature to -55 ºC did not give a higher ee, but a low yield and extremely long reaction time (Table 1, entry 15).As expected, when the cinchonine derived bromide 4d was used as PTC catalyst, the enantioselectivity for the Michael adduct was the opposite, and a 60% ee of (R)-6d was obtained (Table 1, entry 16), whereas hexafluorophosphate 4f gave a higher ee and tetrafluoroborate 4e a very low enantioselection (Table 1, entries 17 and 18).
When we employed as Michael acceptor a cyclic electron-deficient olefin such as 2cyclohexenone, performing the reaction with the dimeric bromide 3d as PTC catalyst at -35 ºC, the adducts 7 were obtained in a 70% de, the major diastereomer (2S,3S)-7 being obtained in 92% ee and being assigned according to the literature, 16 whereas the minor diastereomer was obtained in 50% ee (Table 1, entry 19).The use of the cinchonidinium-derived tetrafluoroborate 3e gave place to a similar de of 7, although to lower ee's for both diastereomers (Table 1, entry 20).As in the case of using acrylonitrile as Michael acceptor, the hexafluorophosphate salt 3f gave rise, not only to the higher distereoselection (86% de) for 7, but also to the higher enantioselection for (2S,3S)-7 (97% ee), although in a long reaction time (Table 1, entry 21).In addition, in the cinchonine-derived series 4, the major diastereomer was the same than in the cinchonidine series 3 but the enantioselectivity was opposite as expected, bromide 4d giving place to almost identical enantioselection than its pseudoenantiomer 3d, allowing to obtain (2R,R)-7 in a 90% ee (Table 1, entry 22).The hexafluorophosphate 4f gave similar results than 3f, whereas the cinchonine-derived tetrafluoroborate 4e gave better results than its counterpart 3e (table 1, entries 23 and 24).acrylonitrile using hexafluorophosphate-containing ammonium salts as catalysts, cinchonidinium and cinchoninium giving place to products with opposite configuration.The enantioselection was higher when cyclohexenone was used as Michael acceptor, ee's up to 97% being achieved.The dimeric catalysts could be separated from the reaction medium by precipitation and reused.

Experimental Section
General Procedures.All the reagents and solvents employed were of the best grade available and were used without further purification.IR data were collected on a Nicolet Impact 400D-FT spectrometer and only diagnostic bands are given.The 1 H and 13 C NMR spectra were recorded on a Bruker AC-300 at 300 MHz and 75 MHz, respectively, using CDCl 3 as solvent and TMS as internal standard and the coupling constants are given in Hz.The enantiomeric excesses of products 6 and 7 were determined by GLC analyses (Crownpack Chirasil-L-Val column, 25 m x 0.25 mm i.d.Conditions: P = 85 kPa, 1 min 85ºC, 2ºC/min to 180ºC) of their corresponding Ntrifluoroacetamide esters, obtained after 15% aq citric acid hydrolysis of the imines 6 or 7 and further reaction with trifluoroacetic anhydride. 26GLC reference racemic samples were prepared from the corresponding racemic 6 and 7, which were obtained using n-tetrabutylammonium bromide as phase-transfer catalyst.HPLC determinations were performed using a Chiralcel OD column (Conditions: n-hexane/isopropanol 100:1, flow rate: 1.0 mL min -1 , detection: 254 nm).
Asymmetric Michael addition reactions under PTC conditions.General procedure A mixture of 5 (74 mg, 0.25 mmol), the corresponding olefin (1.25 mmol) and the catalyst 3d,e,f or 4d,e,f (0.013 mmol) in toluene/CHCl 3 (7/3 v/v, 1.5 mL) was cooled (see Table 1) and aqueous 50% solution of KOH (0.37 mL) was added.The mixture was vigorously stirred and monitored by GLC.When the reaction was finished, ether (2 mL) was added and the mixture was filtered for recovering the solid calalysts.Water (10 mL) was added to the filtrate and the mixture was extracted with EtOAc (3 x 10 mL).The organics were dried (Na 2 SO 4 ) and evaporated in vacuo, affording crude products, which were analyzed by 1 H NMR.

7 H
We can conclude that dimeric cinchonidinium and cinchoninium-derived ammonium salts bearing different counter-anions can be employed as chiral phase-transfer catalysts in the asymmetric Michael addition reaction of a benzophenone imine-derived glycinate with electronpoor olefins.The best enantioselectivity in open chain Michael acceptors was achieved for

Table 1 .
Asymmetric Michael addition reactions under PTC reaction conditions 1 Configuration of the major isomer (HPLC, Chiralcel OD).b Crude yield determined by1H NMR (300 MHz).c Determined by chiral GLC from the corresponding trifluoroacetamides (see text).d In parenthesis, diastereomeric excess.e Ee of the major diastereomer.f Ee of the minor diastereomer.