Asymmetric Synthesis of Î±-Amino Acids Using Polymer-Supported

Chapter 16

Downloaded by EAST CAROLINA UNIV on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch016

Asymmetric Synthesis of α-Amino Acids Using Polymer-Supported Cinchona Ammonium Salts as Phase-Transfer Catalysts Rafael Chinchílla* and Carmen Nájera* Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Sintesis Orgánica (ISO), Universidad de Alicante, P.O. Box 99, 03080 Alicante, Spain

Cinchona ammonium salts from cinchonine, cinchonidine, quinine and quinidine alkaloids have been anchored to polymers and used as phase-transfer catalysts in the enantioselective alkylation of N-diphenylmethylene glycine esters to afford enantioenriched α-amino acid derivatives. These supported catalysts can be separated from the reaction medium and reused, being promising from an industrial viewpoint.

Introduction Quaternary ammonium salts derived from Cinchona alkaloids have evolved as economic and readily available chiral catalysts in several enantioselective processes (/) performed using the mild, simple and easily scalable phase-transfer catalysis (PTC) methodology (2). Especially, intensive studies have been performed on their use in the enantioselective alkylation of jV-diphenylmethylene glycine esters 1, which afford α-alkylated derivatives 2 thus driving to a variety of natural and of non-natural α-amino acids after hydrolysis (Figure 1) (J). Both enantiomers of 2 can be obtained by using as catalysts cinchonine/quinidinederived salts [driving generally to (R)-2] or cinchonidine/quinine-derived salts © 2009 American Chemical Society

In Asymmetric Synthesis and Application of -Amino Acids; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

251

252


[driving generally to (S)-2], these alkaloids being considered as pseudoenantiomers. Although small amounts of these not too expensive solution phase catalyst are consumed working under PTC conditions, reusable polymer supported catalysts might have more advantages in a large scale production from both practical and economical viewpoints (4). This article presents a revision of the use of polymer-anchored ammonium salts from Cinchona alkaloids as recyclable catalysts for the enantioselective alkylation of glycinates 1 under PTC conditions.

Ο

PTC-catalyst*

Ο

N

pv -A)R> Τ Ph

p

„

R

2

H

f

•

v -AORn

Τ Ph

base, solvent 1

Τ2

R 2

υ

κ

Figure 1. Enantioselective a-alkylation ofglycine imines under PTC conditions.

Polymer-Supported Cinchona-derived salts Based on the connection site to the polymer, the supported Cinchonaderived ammonium salts can be classified into four categories (Figure 2). These anchored systems are employed as PTC catalysts in the enantioselective benzylation reaction of glycinates 1 to give enantioenriched phenylalanine derivatives 3 (Figure 3), this reaction being always carried out as a model for testing the performance of the PTC catalyst.

iV-Anchored Ammonium Salts The attachment of a Cinchona alkaloid to a polymer through the nitrogen atom of the quinuclidine system is the most direct way for creating a chiral supported ammonium salt. Thus, the first enantioselective PTC-promoted alkylation of glycinate la using a polymer-bound Cinchona ammonium salt was performed back in 1998 using cinchonine and quinine-derived ammonium salts 4a and 5c (Figure 4), obtained by treating the alkaloid with the Merrifield resin (5). However, the achieved enantioselections were very low under the employed reaction conditions (10 mol% of catalyst, CH C1 , 50% aq NaOH, 20 °C). Thus, when using the cinchonine-derived salt 4a as PTC catalyst, only a 9% ee of the corresponding alkylated product (R)-3 was obtained in the benzylation reaction 2

2


253 (C-l l)-anchoring (?)—[SPACER (?)—1 SPACER (0-6')-anchoring N-anchoring


SPACER)—(?) SPACER|—(p) (09)-anchoring Figure 2. Options for the attachment of ammonium derivatives of Cinchona alkaloids to polymers.

Ο v

^

Ο OR

Ph

PTC-catalyst* base, solvent

| Ph

Τ

° Ph

la: R = r-Bu lb.R = iPr

3

Figure 3. Model enantioselective benzylation ofglycinates 1.

of la (Figure 3), whereas a 6% ee of its enantiomer (5)-3 was obtained using the quinine derivative 5c (5). These enantioselections could be improved slightly under the same reaction conditions using the cinchonine derivative 4a as well as its pseudoenantiomeric cinchonidine derivative 5a (Figure 4) up to 12 and 27% ee, respectively, by increasing the amount of catalysts up to 100 mol% (Table 1, entries 1 and 4) (6). These supported catalysts were reused up to three times. The poor enantioselections obtained using these Merrifield-derived PTC catalysts were dramatically improved by changing the reaction conditions and the starting glycinate 1 (7). Thus, when the benzylation reaction (10 mol% of catalyst, toluene, 25% aq NaOH, 0 °C) was carried out on the isopropyl glycinate lb using the cinchonine salt 4a as PTC catalyst, a 40% ee of (R)-3 could be obtained, whereas a 90% ee of (5)-3 was obtained using the supported cinchonidine salt 5a (Table 1, entries 2 and 6). Other substituted benzyl bromides, as well as allyl and propargyl halides were used as electrophiles achieving ee's in the range 24-66%. In addition, yields were much higher and reaction times considerably shorter than when using the previous procedure, something probably related to the less strict sterical requirements imposed to the



254

1

PS = crosslinked polystyrene

2

5c: R =OMe, R = H , X = C1 5d: R = H, R = 4 - 0 N C H C O , X = CI 1

2

2

6

4

Figure 4. Merrifield N-anchored Cinchona ammonium salts.

polymeric catalyst by the isopropyl group in 1 when compared to the ter/-butyl group. In fact, only a 58% ee for (S)-3 was obtained starting from the terf-butyl derivative la in 36 h reaction time. When the 0-allylated ammonium salts 4b and 5b were used as catalysts under this reaction conditions, lower enantioselections were achieved (Table 1, entries 3 and 7), as well as when using the quinine-derived salt 5c (Table 1, entry 8) (8). In addition, a Merrifield-supported p-nitrobenzoate (0-9)-esterified cinchonidine salt 5d has afforded also a very low enantioselection in the

Table 1. Enantioselective benzylation of glycinates 1 using catalysts 4 and 5 Ent. 1 2 3 4 5 6 7 8 9 10

/

la lb lb la la lb lb la lb la

Cat.

Solvent

4a 4a 4b 5a 5a 5a 5b 5c 5c 5d

CH C1 PhMe PhMe CH C1 PhMe PhMe PhMe CH CI PhMe CH CI 2

2

2

2

2

2

2

2

Base 50% aq KOH 25% aq NaOH 25% aq NaOH 50% aq NaOH 25% aq NaOH 25% aq NaOH 25% aq NaOH 50% aq NaOH 25% aq NaOH 50% aq KOH

Τ (°C) 20 0 0 20 25 0 0 20 0 0

w 48 24 24 48 36 17 140 20 96 24

Yield (%) 55 85 45 48 80 90 23 48 81 27

ee (%) 12 (Λ) 40 (Λ) 32 (R) 27(5) 58(5) 90(5) 50(5) 9(5) 20(5) 3(R)



255 benzylation ofteri-butylglycinate la (Table 1, entry 10), this result being raised up to 18% ee for (R)~3 when working in the absence of an organic solvent (9). Moreover, it is interesting than when an ^/-cinchonidine derivative similar to 4a but with opposed C-9 stereochemistry was employed as PTC catalyst, a very low enantioselection (8% ee) was obtained but also in favour of (S)-3 (8). Other supported jV-benzylated ammonium salts 6-9 were prepared by Nalkylation of cinchonidine using different commercial halogenated polymers (70) (Figure 5), such as crosslinked polystyrene-bound triphenylchloromethane (affording 6), chloromethylated l-[4-(4-vinylphenoxy)butoxy]-4-vinylbenzenecrosslinked polystyrene (JandaJel™-Cl) (affording 7), Wang-Br resin (affording 8) and chloromethylated polyethylene glycol-polystyrene copolymer (ArgoGel™-Cl) (affording 9). In addition, the 9-anthracenylmethylated polymeric cinchonidine derivative 10 was prepared. All these polymer-bound cinchonidine ammonium salts were used in the benzylation of isopropyl glycinate lb giving rise to enantioselections in the range 2-70% ee for the (S)-3 enantiomer (Figure 5), and could be separated by filtration and reused. Cinchonidine and cinchonine were also N-quaternized using chloromethylated polystyrene-grafted polypropylene (chloromethylated Synphase™ lanterns) (8). These derivatized Lanterns 11 and 12 were added to the reaction flask, being employed as PTC catalysts in the benzylation of lb. Thus, when the cinchonidine-supported lantern 11 was used under the above reaction conditions (10 mol% catalyst, toluene, 25% aq NaOH, 0 °C) but working at room temperature, the final (S)-3 was obtained with identical enantioselectivity than when using its Merrifield resin-attached counterpart 5a (66% ee, 83% yield in 24 h), although lowering the reaction temperature also lowered the ee and increased considerably the reaction time (8). These lanternattached ammonium salts have been tweezers-separated after the reaction and reused up to three times, observing just a 3% lowering in yield and ee between first and third run. The role of the spacer between the N-quaternization moiety and the Cinchona alkaloid in the enantioselectivity of the PTC alkylation of glycinate la (10 mol% catalyst, toluene, 50% aq KOH, 0 °C) has been investigated preparing a series of Ν-attached cinchonine (13a) (11-13), quinidine (13b) (11,13), cinchonidine (14a) (11,13) and quinine-derived (14b) (11,13) polymeric salts (n = 4, 6, 8) (Figure 7). The best result (81% ee, 60% yield in 27 h) was achieved using the cinchoninium iodide bound to polystyrene with a four-carbon spacer 13a (n = 4) (11-13). Surprisingly, the same enantiomer (R)-3 was always obtained irrespective of the catalyst used (//), thus revealing the strong influence of the 'superstructure' of the polymer in the sense of the enantioselectivity. The use of other activated or inactivated halides as electrophiles gave lower enantioselectivities, and recycling of the catalyst gave rise to longer reaction times and lower enantioselections (75).



256

10 (32 h, 94%, 70% ee)

JJ = JandaJel™ AG = ArgoGel™ Figure 5. Supported cinchonidine-derived salts. In parenthesis, reaction times, yields and enantioselectivities for (S)-3 achieved when used as PTC catalysts in the benzylation of lb (10 mol% catalyst, toluene, 25% aq NaOH, 0 °C).



13a: R = H 13: R = OMe

η = 4, 6, 8

14a: R = Η 14b: R = OMe

Figure 7. Cinchona-derived ammonium salts attached to differently spaced crosslinkedpolystyrene beads.

The nature of the support in these anchored supported catalysts has also been changed using a poly(ethylene glycol) (PEG) non-crosslinked matrix type, thus attempting an increase in the solubilising properties in different solvents. Thus, MeO-PEG-OH ( M 5000) has been used as polymeric phase for the synthesis of the ammonium saltsfromcinchonidine 15a (13-15) and quinine 15b (13,14) (Figure 8), including the O-substituted surrogates 15c and 15d (14). The pseudoenantiomeric cinchonine and quinidine counterparts were also obtained (13,14). These PEG-anchored ammonium salts have been used as PTC catalysts in the model benzylation reaction of la, the cinchonidine-derived system being more efficient. Thus, when the PEG-supported cinchonidine salt 15a was employed as catalyst at 20 °C, a moderate enantiosectivity for (S)-4 was observed (56% ee) (75), being considerably improved when working at 0 °C (81% ee) (13,14) (Figure 8). These polymers could be separated after the reaction by precipitation with ether, although reusing gave slightly lower yields and ee's (15). w


258 1

15a: R 15b: R 15c: R 15d: R

1

1

1

2

= R = H [(S>3: 84%, 81% ee, 0 °C] = OMe, R = H [(S)-3: 78%, 33% ee, 0 °C] = H, R = Allyl [(S)-3: 83%, 73% ee, 20 °C] = H, R = Bn [(S>3: 78%, 57% ee, 20 °C] 2

2

2

OPEG ooOMe


50

Figure 8. N-PEG-supported Cinchona quaternized salts. In brackets, yields and enantioselectivities achieved when used as PTC catalysts in the benzylation of la (10 mol% catalyst, toluene, 50% aq KOH).

Dimeric PEG-supported Cinchona ammonium salts from cinchonidine and quinine 16a and 16b, respectively, have been prepared by reaction of the alkaloid with diacetamido-PEG2000 chloride (Figure 9). The linking PEG group acts as a surfactant which can mix the organic components in water, thus allowing the enantioselective alkylation of la in 1M KOH at room temperature and in the absence of any organic solvent in only 6 h (16). The quinine derivative 16b has performed better than its cinchonidine counterpart in the model benzylation reaction of la and has been used as catalysts in the alkylation reaction of la using different benzyl, allyl and alkyl halides in high yields and with very good enantioselectivities of the corresponding (S)-2 in the range 8297% ee. The related dimeric cinchonine derivative has also been prepared and gave rise to a slightly lower enantioselection for the /^-enantiomer. The catalysts could be recovered by precipitation with ether and reused without loss of activity.

(0-9)-Anchored Ammonium Salts As Cinchona ammonium salts have allowed to obtain very high enantioselectivities in the PTC-promoted enantioselective alkylation of glycinate la when the jV-quaternization moiety is a 9-anthracenylmethyl group (5), keeping this structural area intact by attaching the polymer to the alkaloid in other position was a logical reasoning. Thus, the free C-9 hydroxyl group in the alkaloid can be easily deprotonated with a base such as sodium hydride and can react with the Merrifield resin to afford the corresponding (3: 98%, 83% ee] Figure 9. Dimeric PEG-supported cinchonidine and quinine-derived ammonium salts. In brackets, yields and enantioselectivities achieved when used as PTC catalysts in the benzylation of la (10 mol% catalyst, 1M KOH, rt, 6 h).

derivatives gave much lower enantioselections (23-36%), the pseudoenantiomeric effect being observed. Recycling of the catalyst resulted in a certain loss of activity after the third run (13). This polymer deterioration was avoided by 0-linking the ammonium salt to Synphase™ lanterns, which allowed a higher stability, although with lower enantioselectivities (up to 78% ee) (13). In addition, CMinking the cinchonidinium moiety to polystyrene through a 4-carbon spacer to give the polymeric salt 17b did not improve the results, and a 81% ee of (S)-3 was obtained under the same reaction conditions than when using 17a (13). Very good enantioselectivities have been achieved using the (0-9)Merrifield supported dihydrocinchonidine-derived ammonium salts 18 which have been quaternized with benzyl systems containing hydrogen bond-inducing groups (Figure 10) (77). The jV-oxy derivative 18c showed the highest enantioselectivity for (S)-3 (18a, 91% ee; 18b, 93% ee; 18c, 95% ee) with yields in the range 81-88% and working under solid-liquid PTC conditions (20 mol% catalyst, toluene, 50% aq KOH, 0 °C). The alkylation of l a has also been performed using 18c as PTC catalyst with other benzyl, allyl and alkyl halides, affording the corresponding (5)-amino acid derivatives with 76-96% ee. The supported catalyst 18c could be recovered by filtration and reused five times with no decrease in the enantioselectivity. The ether linkage of the Cinchona ammonium salt to the polymer has been changed by an ester by grafting the cinchonidinium salt to a cross-linked carboxypolystyrene resin to afford the (0-9)-anchored species 19a (Figure 11) (13). In addition, soluble non-crosslinked homopolymeric polystyrene-supported



260

Figure 10. (0-9)-Crosslinkedpolystyrene-bonded cinchonidine and dihydrocinchonidine-derived ammonium salts.

ammonium salts from dihydrogenated cinchonidine (19b) and quinine (19c) have been prepared by polymerization of the dihydro alkaloid 0-9-(4-vinylbenzoate) and further quaternization (13). When all these ammonium salts were used as PTC catalysts in the benzylation of la (10 mol% catalyst, toluene, 50% aq KOH, 0 °C), long reaction times were observed (120 h) for the insoluble catalyst 19a and only 30% ee for (S)-3. The soluble analogues were more efficient, with reaction completed in 24 h, and more enantioselective (19b, 85% ee; 19c, 45% ee). The pseudoenantiomeric counterparts from cinchonine, dihydrocinchonine and dihydroquinidine have also been prepared, the highest enantioselectivity for (R)-3 being achieved with the dihydroquinidine-derived salt (67% ee). However, attempts to reuse these catalysts failed to give good conversions, indicating strong degradation of the catalyst structure. Moreover, the use of a PEG support to get soluble catalysts, as the case of the (

Asymmetric Synthesis of Î±-Amino Acids Using Polymer-Supported

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