Asymmetric Synthesis of α-Amino Acids via Cinchona Alkaloid-Catalyzed Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides

Abstract

Acyl-transfer reactions use cheap reagents to transform readily available starting materials into useful and easily purified products. These characteristics, in combination with high enantioselectivity, enable acyl-transfer reactions catalyzed by enzymes such as lipases and esterases to become highly valuable methods for asymmetric synthesis. 1 The development of synthetic catalysts to mimic lipases/esterases with the goal of further expanding the scope of asymmetric acyl transfer catalysis is of both conceptual and practical significance for asymmetric catalysis. 2 Although effective phosphorus and nitrogen synthetic catalysts for the kinetic resolution of racemic alcohols have emerged, 3,4 efforts to develop small molecule-catalyzed kinetic resolutions of racemic carbonyl derivatives have met with limited success despite their great potential in asymmetric synthesis. 5 We report here an exceedingly general and highly enantioselective kinetic resolution of urethane-protected R-amino acid N-carboxyanhydrides (UNCA) that generates optically active R-amino acid derivatives suitable for further synthetic elaboration such as peptide synthesis.Encouraged by our discovery of modified cinchona alkaloids as efficient catalysts for asymmetric alcoholysis of meso and racemic cyclic anhydrides, 6-8 we became interested in the kinetic resolution of urethane-protected R-amino acid N-carboxyanhydrides (UNCA, 2) via cinchona alkaloid-catalyzed alcoholysis (Scheme 1). UNCAs (2) can be easily prepared from the readily available racemic amino acids (1). 9 Their alcoholysis generates the carbamate-protected amino ester 3 and CO 2 . When suitably protected, amino ester 3 will not interfere with the cinchona alkaloid-catalyzed alcoholysis. Furthermore, the unreacted enantiomerically enriched UNCA (2) can be hydrolyzed to protected amino acid (4) (Scheme 1). The resulting mixture of the basic amine catalyst, the acidic amino acid (4) and the neutral amino ester (3), can be separated using simple extractive procedures to give 3, 4, and the recovered amine catalyst in desired chemical and optical purity. We initially utilized racemic N-Cbz-phenylalanine NCA (2a) as a model substrate. Reaction of 2a with methanol (0.55 equiv) in ether at room temperature with (DHQD) 2 AQN (10 mol %) and molecular sieves (4 Å) afforded ester 3a in 80% ee at 42% conversion, corresponding to a selectivity factor (s) of 16 for the kinetic resolution (entry 1, Table 1). Importantly, the enantioselectivity of the kinetic resolution could be dramatically improved at low temperature and, at -60°C, reached a level (s ) 79, entry 2, Table 1) comparable to that of an enzyme-catalyzed resolution. Further catalyst screening studies revealed that (DHQD) 2 AQN is the most effective catalyst. Notably, high enantioselectivity is also achieved with the monocinchona alkaloids, DHQD-PHN, and quinidine (entries 3, 4, Table 1). Interestingly, under the same conditions, other related amines such as (DHQD) 2 PYR, (DHQD) 2 -PHAL, DHQD-MEQ, DHQD-CLB, and quinuclidine afforded o...

Elucidation of the active conformation of cinchona alkaloid catalyst and chemical mechanism of alcoholysis of meso anhydrides

“…The reaction first showed a first-order dependence on methanol, which turned to a zero-order dependence as an excess amount of methanol was employed. These kinetic results are consistent with a general base catalysis mechanism (Scheme 1) in which the cinchona alkaloid first forms an aminealcohol hydrogen-bonding complex (8). The alcohol, associated with and activated by the chiral amine, reacts selectively with one of the enantiotopic carbonyl groups of 1a.…”

Asymmetric Synthesis of Chiral Aldehydes by Conjugate Additions with Bifunctional Organocatalysis by Cinchona Alkaloids

“…We were pleased to find that, in stark contrast to DABCO, quinuclidine, and bisocupreidine, 6'-OH cinchona alkaloids 1 a-c did not promote the polymerization of 3 a. These and previous results [10,11] indicate that 6'-cinchona alkaloids 1 a-c were effective general base catalysts but poor nucleophilic catalysts. We therefore suspected that 1 a-c might efficiently promote conjugate additions of carbonyl donors to 3 a without provoking polymerizations of the latter.…”

“…On the other hand, mechanistic studies by us established that cinchona alkaloids, such as dihydroquinidine 9-O-(9-phenanthryl) ether (DHQD-PHN), as a chiral hydrogen-bond donor functioned as a general base catalyst rather than a nucleophilic catalyst for the highly enantioselective alcoholysis of N-carboxyanhydrides. [10] More recent mechanistic studies from our laboratories indicated that 6'-OH cinchona alkaloids 1 a-c (Scheme 2) were able to promote a variety of efficient enantioselective conjugate additions [11] as acid-base bifunctional organic catalysts from their ability to interact with the nucleophiles and electrophiles as hydrogenbond acceptors and donors, respectively. We were pleased to find that, in stark contrast to DABCO, quinuclidine, and bisocupreidine, 6'-OH cinchona alkaloids 1 a-c did not promote the polymerization of 3 a.…”

Efficiency in Nonenzymatic Kinetic Resolution

“…A related example of this type is the catalytic methanolysis of oxazolidinediones described by Deng and co-workers (illustrated in the reaction of rac-144 to (S)-144; Table 10). [94] With some substrates, this method is selective enough to produce both the product (R)-145 and the unreacted (S)-144 in high ee. Because (S)-144 is easily hydrolyzed to (S)-146, both enantiomers of the amino acid can be obtained with > 90 % ee.…”