Polymer-supported Cinchona Alkaloid-derived Ammonium Salts as Recoverable Phase-transfer Catalysts for the Asymmetric Synthesis of Α-amino Acids †

Alkaloids such as cinchonidine, quinine and N-methylephedrine have been N-alkylated using polymeric benzyl halides or co-polymerized and then N-alkylated, thus affording a series of polymer-supported chiral ammonium salts which have been employed as phase-transfer catalysts in the asymmetric benzylation of an N-(diphenylmethylene)glycine ester. These new polymeric catalysts can be easily recovered by simple filtration after the reaction and reused. The best ee's were achieved when Merrifield resin-anchored cinchonidinium ammonium salts were employed.

Attaching the chiral catalyst to a solid support can be considered a next step in the development of the PTC methodology due to the resulting ease of separation and possible recycling.As a result, the preparation and uses of all kind of supported reagents is considered nowadays a fast developing topic [16].Polymeric Cinchona alkaloids have been previously used as catalysts [3] in other processes such as asymmetric Michael addition [17], dihydroxylation [18] and aminohydroxylation [19] reactions.However, the use of polymeric Cinchona alkaloid-derived ammonium salts as PTC catalysts for the asymmetric synthesis of α-amino acid derivatives is very recent and limited.Thus, N-supported Merrifield resin-derived ammonium salts 2 (n = 1, R = H, X = Cl [20]; n = 4, 6 or 8, R = H, OMe, X = I [21]) from cinchonidine and quinine (R = OMe) have been prepared, as well O-supported polymeric derivatives such as 3 [22]  In this context, and as part of our ongoing studies towards the synthesis of easily recoverable and reusable PTC catalysts for the asymmetric synthesis of α-amino acids [8b,10,20c], we describe in this paper the preparation of a series of ammonium salts derived from alkaloids such as cinchonidine (6), quinine (7) and N-methylephedrine (8), supported mainly at the nitrogen to an array of commercially available or easily prepared polymers, as well as their use as chiral catalysts in the model asymmetric benzylation reaction of a N-(diphenylmethylene)glycine ester under PTC conditions.

Results and Discussion
Polymer-supported ammonium salt 2a was obtained as previously reported [20c] by N-alkylation of cinchonidine (6) with the Merrifield resin (Fluka, polystyrene crosslinked with 1% divinylbenzene, 1.7 meq Cl/g resin) in refluxing toluene, and is included in this study for comparison.When the N-alkylation reaction was carried out on O-allyl cinchonidine [5a] using Merrifield resin the O-allylated polymer 2b was obtained, whereas resin 2c was prepared similarly to resin 2a, but using quinine (7) instead of cinchonidine.Moreover, we also prepared in the same way the (1R,2S)-Nmethylephedrine (8)-supported resin 9, which has been previously used in the PTC ethylation of α-cyanotoluene giving rather low ee's [24], although its use in the alkylation of glycinimides was never attempted.
After the preparation of all these supported ammonium salts from commercially available polymers, we thought of the synthesis of an anchored cinchonidinium-derived ammonium salt incorporating a 9-anthrylmethyl moiety, which has shown its efficiency as an enantioselectivity-increasing group in Cinchona-derived PTC catalysts [5,6].Thus, we prepared the mercapto resin 15 by treatment of the Merrifield resin ( 14) with thiourea and subsequent hydrolysis (Scheme 1) [25].This resin was deprotonated with sodium hydride and reacted with 9,10-dichloromethylanthracene [26] (2 equiv) and subsequently with cinchonidine (6), affording polymeric salt 16.

Scheme 1.
The incorporation of the alkaloid in all these obtained catalysts was demosntrated by the presence of new bands in the IR spectra attributable to the alkaloid structure, and also by the increase in the initial resin weight and also the elemental analysis, which also allowed the determination of the loading.

18
Polymers 2, 9-13 as well as 16 and 18 were used as insoluble PTC catalysts (0.1 eq) in the model triphase benzylation reaction of glycine-derived N-(diphenylmethylene)glycine isopropyl ester 19 [28] with benzyl bromide in an organic solvent and using an aqueous base (Scheme 3).The isopropyl ester 19 was chosen, instead of the tert-butyl derivative usually employed in asymmetric PTC alkylations, From the results shown in Table 1 it can be observed that the Merrifield-anchored cinchonidinederived ammonium salt 2a afforded the higher ee at 0ºC (90%, Table 1, entry 2), and lowering the reaction temperature further did not produce an increase in the ee (entries 3 and 4).However, its allylated counterpart 2b gave place to considerably lower ee values, both at r.t.(entry 5) or 0ºC (entry 6).The analogous polymeric quinine derivative 2c was clearly less effective as an asymmetric PTC catalyst than its structurally similar cinchonidine-derivative 2a, giving very low ee's (Table 1, entries 7 and 8).Moreover, the (1R,2S)-N-methylephedrine-derived resin 9 gave a low yield of an almost racemic 20 (Table 1, entry 9).
The polymeric trityl-anchored cinchonidine salt 10a gave a 44% ee of 20 working at r.t.(Table 1, entry 10), which was raised to 70% ee when the temperature was lowered to 0ºC (Table 1, entry 11), but showed no further increment when the reaction was carried out at -20ºC (Table 1, entry 12).Similarly to 2a, when the benzylation reaction was carried out with the O-allylated trityl-supported resin 10b resin, the ee dropped remarkably (Table 1, entry 13).In addition, the JandaJel TM  After the benzylation reaction, the polymeric catalysts were filtered off from the reaction mixture and were reused up to three times without any loss of effectivity.

Conclusions
We have prepared chiral polymeric ammonium salts by anchoring a number of alkaloids, mainly from Cinchona, to different commercially available halogenated polymers and to a prepared anthrylcontaining polystyrene.In addition, we have also obtained a cinchonidinium salt-acrylonitrile copolymer.All these polymeric ammonium salts have been employed as solid-supported chiral PTC catalysts for the asymmetric benzylation of N-(diphenylmethylene)glycine isopropyl ester achieving moderate enantioselectivities.The best results were obtained using a Merrifield resin-supported cinchonidinium salt, the use quinine or ephedrine-derived ammonium salts affording poor results.In all cases higher ee's were obtained when a hydroxyl group was present in the alkaloid moiety, their Oallylated counterparts giving lower enantioselectivities. Lowering the reaction temperature usually resulted in higher ee's, although temperatures below 0 ºC generally did not affected remarkably the degree of asymmetric induction.All the supported catalysts could be separated from the reaction mixture by simple filtration and recycled.

General
Reagents and solvents from commercial suppliers were of the best grade available and used as provided unless otherwise stated.IR spectra were recorded with a Nicolet 510 P-FT.NMR spectra were measured with a Bruker AC-300 at 300 MHz for 1 H-and 75 MHz for 13 C-using TMS as internal standard.Elemental analyses were carried out by the Microanalytical Service at the Research Technical Services of the University of Alicante.Chiral GLC analysis were performed using a Chirasil-L-Val column (Chrompack), 1 min 85º, 2º/min to 180º.
General procedure for the preparation of the polymeric ammonium salts 2 and 9-13.
The corresponding halogenated polymer (1 meq) was added to a suspension of the alkaloid 6, 7 or 8 (2 mmol) in toluene (10 mL) and the mixture was stirred under reflux for 24 h.The reaction mixture was cooled to r.t. and the solid was filtered, washed with AcOEt (3 x 15 mL) and dried in vacuo, affording the polymer-supported ammonium salts 2a, 2c, 9, 10a, 11, 12

Table 1 .
-anchored cinchonidine ammonium salt 11 gave a 62% ee of 20 at r.t.(Table1, entry 14) and a slightly lower 56% ee at 0ºC, with an observed increase of the reaction time (Table1, entry 15), whereas the Wangsupported cinchonidinium salt 12 gave ca.55% ee, both at r.t. or 0ºC (Table 1, entries 16 and 17).Moreover, ArgoGel TM -supported cinchonidinium salt 13a afforded up to 68% ee from r.t. to -20ºC (Table 1, entries 18-20) and again a tremendous drop in the ee was observed using its O-allylated counterpart 13b (Table 1, entry 21).Furthermore, when the N-substituted 9-anthrylmethyl derivative 16 was used as PTC catalyst, up to 74% ee of 20 was obtained working at -20ºC (Table 1, entry 23).The use of the co-polymeric cinchonidinium ammonium salt 18 with an anthrylmethyl group at the N gave a 44% ee when working at r.t.(Table 1, entry 25), which increased to 70% ee, almost independently of reductions in the temperature to 0ºC or -20ºC (Table 1, entries 26 and 27).Enantioselective PTC benzylation of glycine derivative 19 using polymeric chiral catalysts and 13a.The O-allylated polymeric ammonium salts 2b, 10b and 13b were obtained following the same procedure, but starting from O-allyl cinchonidine [5a].