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Synthesis of α-Amino Acids and Derivatives

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The use of visible light and a silane reductant enables a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. A Brønsted acid-mediated formation of a ketiminium species is followed by rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide).
J. H. Blackwell, R. Kumar, M. J. Gaunt, J. Am. Chem. Soc., 2021, 143, 1598-1609.

A chiral catalyst based on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a wide variety of alkylzinc reagents to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups.
Z.-P. Yang, D. J. Freas, G. C. Fu, J. Am. Chem. Soc., 2021, 143, 8614-8618.

Diethyl N-Boc-iminomalonate, prepared on multi-gram scale, served as a stable and highly reactive electrophilic glycine equivalent which reacted with organomagnesium compounds affording substituted aryl N-Boc-aminomalonates. Subsequent hydrolysis produced arylglycines.
P. Cali, M. Begtrup, Synthesis, 2002, 63-64.

The use of catalytic loadings of picolinaldehyde and Ni(II) salts in catalytic α-allylation of unprotected amino acid esters induces preferential reactivity at the enolizable α-carbon over the free nitrogen with electrophilic palladium π-allyl complexes to produce α-quaternary α-allyl amino acid esters. Additionally, the use of chiral ligands to access enantioenriched α-quaternary amino acid esters from racemic precursors is demonstrated.
P. Fang, M. R. Chaulagian, Z. D. Aron, Org. Lett., 2012, 14, 2130-2133.

A direct catalytic enantioselective allylation of acyclic α-ketiminoesters provides α-allyl-α-aryl and α-allyl-α-trifluoromethyl amino esters in excellent isolated yield and with high optical purity in the presence of catalytic amounts of indium(I) iodide and commercially available BOX-type ligands. The allylated products are easily converted to enantiomerically enriched α-substituted proline derivatives.
U. Bhakta, P. V. Kattamuri, J. H. Siitonen, L. B. Alemany, L. Kürti, Org. Lett., 2019, 21, 9208-9211.

The combination of dirhodium(II)/Xantphos catalyzes a three-component reaction of readily accessible amines, diazo compounds, and allylic compounds to afford various architecturally complex and functionally diverse α-quaternary α-amino acid derivatives in good yields with high atom and step economy.
B. Lu, X. Liang, J. Zhang, Z. Wang, Q. Peng, X. Wang, J. Am. Chem. Soc., 2021, 143, 11799-11810.

A Xantphos-containing dinuclear palladium complex catalyzes a geminal aminoallylation of diazocarbonyl compounds to provide a range of quaternary α-amino esters. Direct N-H insertion, allylic alkylation of amino nucleophiles, and diene formation were not observed under standard conditions.
P. Ou, L. Zhu, Y. Yu, L. Ma, X. Huang, Org. Lett., 2022, 24, 4109-4113.

A chiral phase-transfer catalyst enables an asymmetric Pd-catalyzed allylation of a tert-butyl glycinate-benzophenone Schiff base with various allylic acetates to give the allylated products in good yields and high enantioselectivity without any chiral ligands.
M. Nakoji, T. Kanayama, T. Okino, Y. Takemoto, Org. Lett., 2001, 3, 3329-3331.

In a catalyst- and additive-free α-alkylation reactions of glycine derivatives with diacyl peroxides, the diacyl peroxide substrate acts as both alkylation agent and oxidizing agent. This atom-economical method was applied to various glycine derivatives, dipeptides, and a 3,4-dihydroquinoxalin-2(1H)-one derivative and could be carried out on a gram scale.
H. Tian, W. Xu, Y. Liu, Q. Wang, Org. Lett., 2020, 22, 5005-5008.

A general Pd-catalyzed, enantioselective three-component synthesis using readily available sulfonamides, glyoxylic acid derivatives, and boronic acids provides a broad range of α-arylglycines in high yields and excellent levels of enantioselectivity. Incorporation of Pbf-amides gives a racemization-free access to N-unprotected α-arylglycines.
T. Beisel, A. M. Diehl, G. Manolikakes, Org. Lett., 2016, 18, 4032-4035.

A protocol for Pd(II)-catalyzed asymmetric arylation of N-aryl imino esters affords a practical and direct access to chiral arylglycine derivatives in good yields and with high enantioselectivities.
J. Chen, X. Lu, W. Lou, Y. Ye, H. Jiang, W. Zeng, J. Org. Chem., 2012, 77, 8541-8548.

A Pd-catalyzed α-arylation of esters and protected amino acids provides a short, general route to α-aryl carboxylic acids and α-aryl amino acids in good yields. Glycinates are activated for direct coupling by unsaturated amine protecting groups.
S. Lee, N. A. Beare, J. F. Hartwig, J. Am. Chem. Soc., 2001, 123, 8410-8411.

Blue light mediates an α-C-H benzylation of readily available N-phenyl glycine ester with benzyl oxalates as a coupling partner under mild conditions to provide α-amino phenylpropanoids in good yields. The utility of this methodology is underlined by its application to the late-state modification of natural products.
L. Wang, K. Li, T. Ye, L. Huang, H. Wu, J. Zhang, H. Xie, Y. Liu, J. Zeng, P. Cheng, J. Org. Chem., 2023, 88, 11924-11934.

Global Diastereoconvergence in the Ireland-Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids
T. J. Fulton, A. Q. Cusumano, E. J. Alexy, Y. E. Du, H Zhang, K. N. Houk, B. M. Stoltz, J. Am. Chem. Soc., 2020, 142, 21938-21947.

Ru/Cu dual catalysis enables a Z-retentive asymmetric allylic substitution reactions of aldimine esters to provide chiral Z-olefins in high yields and with excellent enantioselectivity under mild conditions. The reaction systems converts also trisubstituted linear and branched allylic electrophiles affording stereoretentive products in either Z- or E-form.
H. Song, M. Li, S.-L. You, J. Am. Chem. Soc., 2024, 146, 4333-4339.

A synergistic Pd and Cu catalysis enables stereodivergent coupling reactions between 1,3-dienes and aldimine esters with wide substrate scope and good functional group tolerance. By using different enantiomers of the two metal catalysts, all four stereoisomers of the coupling products could be accessed with high diastereo- and enantioselectivity.
Q. Zhang, H. Yu, L. Shen, T. Tang, D. Dong, W. Chai, W. Zi, J. Am. Chem. Soc., 2019, 141, 14554-14559.

A new method for the Rh(I)-catalyzed addition of arylboronic acids to chiral N-tert-butanesulfinyl imino esters allows the asymmetric synthesis of arylglycine derivatives in high yields and diastereoselectivities for various functionalized arylboronic acids.
M. A. Beenen, D. J. Weix, J. A. Ellman, J. Am. Chem. Soc., 2006, 128, 6304-6305.

A cationic palladium-complex catalyzes the addition of arylboronic acids to N-tert-butanesulfinyl iminoacetates to yield optically active arylglycine derivatives with good yield and high diastereoselectivity. This reaction provides a convenient and efficient method for the synthesis of arylglycine derivatives.
H. Dai, X. Lu, Org. Lett., 2007, 9, 3077-3080.

An efficient method for the asymmetric synthesis of anti-β-hydroxy-α-amino acid derivatives is based on highly enantio- and diastereoselective aldol reactions of the silicon enolate derived from N-trifluoroacetylglycinate with aldehydes using a chiral zirconium catalyst.
J. Kobayashi, M. Nakamura, Y. Mori, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 9192-9193.

A straightforward three-component reaction of preformed aromatic or in situ generated benzylic organozinc reagents with amines and ethyl glyoxylate allows the synthesis of a range of α-amino esters in very good yields. The procedure, which is characterized by its simplicity, allows the concise synthesis of esters bearing a phenylglycine or a phenylalanine scaffold.
C. Haurena, E. Le Gall, S. Sengmany, T. Martens, M. Troupel, J. Org. Chem., 2010, 75, 2645-2650.

C. Haurena, E. Le Gall, S. Sengmany, T. Martens, M. Troupel, J. Org. Chem., 2010, 75, 2645-2650.

A copper(I)-catalyzed direct three-component coupling of ethyl glyoxylate, p-anisidine, and terminal alkynes provides β,γ-alkynyl α-amino acid derivatives in good yields.
Z. Shao, A. S. C. Chan, Synthesis, 2008, 2868-2870.

In systematic investigations to develop an efficient enantioselective synthetic method for α-alkyl-alanine by catalytic phase-transfer alkylation, the alkylation of 2-naphthyl aldimine tert-butyl ester in the presence of RbOH and O(9)-allyl-N-2‘,3‘,4‘-trifluorobenzylhydrocinchonidinium bromide as catalyst at -35°C showed the highest enantioselectivities.
S.-s. Jew, B.-S. Jeong, J.-H. Lee, M.-S. Yoo, Y.-J. Lee, B.-s. Park, M. G. Kim, H.-g. Park, J. Org. Chem., 2003, 68, 4514-4516.

A Ir/Cu-catalyzed α-allylation of readily available imine esters enables a fully stereodivergent synthesis of a range of α,α-disubstituted α-amino acids. Importantly, the two chiral catalysts allow for full control over the configuration of the stereocenters, affording all stereoisomers of the desired products.
X. Huo, J. Zhang, J. Fu, R. He, W. Zhang, J. Am. Chem. Soc., 2018, 140, 2080-2084.

The regioselective opening of Bn₂N-α-methylserine-β-lactone with organocuprates gave enantiopure α-methyl amino acids in excellent yields.
N. D. Smith, A. M. Wohlrab, M. Goodman, Org. Lett., 2005, 7, 255-258.

The Hf(OTf)₄-catalyzed Mannich-type reaction of an enol silyl ether or a ketene silyl acetal with an N,O-acetal allows the preparation of amino acid derivatives. In particular, use of the N,O-acetal having a bis(trimethylsilyl)amino group directly produced N-unprotected aspartic acid derivatives after a standard aqueous workup.
N. Sakai, A. Sato, T. Konakahara, Synlett, 2009, 1449-1452.

An efficient α-arylation of imino amides with arylboronic acids provides an alternative approach for the synthesis of α-functionalized glycine derivatives. Different substrates were examined for this arylation reaction.
L. Zhao, X. Liao, C.-J. Li, Synlett, 2009, 2953-2956.

In the presence of a catalytic amount of Cu(OTf)₂ and a chiral diamine ligand, various N-acylimino esters reacted smoothly with silyl enol ethers and alkyl vinyl ethers to afford the corresponding Mannich-type adducts in high yields with high diastereo- and enantioselectivities. The reaction mechanism is discussed.
S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M. Sugiura, J. Am. Chem. Soc., 2003, 125, 2507-2515.

Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the Mannich-type reactions of aldehydes with α-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities.
H. Zhang, S. Mitsumori, N. Utsumi, M. Imia, N. Garcia-Delgado, M. Mifsud, K. Albertshofer, P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2008, 130, 875-886.

Direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and α-imino esters using 5-10 mol % of (R)-3-pyrrolidinecarboxylic acid or (R)-β-proline as catalyst in 2-PrOH at room temperature gave products in good yields with high diastereo- and enantioselectivities.
H. Zhang, M. Mifsud, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 9630-9631.

Proline-catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified ketones provided functionalized α-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol.
A. Cordova, W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas, J. Am. Chem. Soc., 2002, 124, 1842-1843.

Proline-catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified aliphatic aldehydes provided functionalized α-amino acids in high yields with excellent enantioselectivities. The diastereoselectivity of the reaction increased with the bulkiness of the substituents of the aldehyde donor.
A. Cordova, W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas, J. Am. Chem. Soc., 2002, 124, 1866-1867.

A direct highly anti-selective and enantioselective asymmetric Mannich reaction using a novel axially chiral amino trifluoromethanesulfonamide has been developed. Reactions between aldehydes and N-PMP-protected α-imino ethyl glyoxylate proceed smoothly to give β-amino aldehydes with high anti/syn ratio and enantioselectivity.
T. Kano, Y. Yamaguchi, O. Tokuda, K. Maruoka, J. Am. Chem. Soc., 2005, 127, 16408-16409.

(3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid as catalyst for Mannich-type reactions afforded anti-products in good yields with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings.
S. Mitsumori, H. Zhang, P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 1040-1041.

Chelated amino acid ester enolates are excellent nucleophiles for allylic alkylations. With these enolates, even terminal π-allyl palladium complexes react without significant isomerization.
K. Krämer, U. Kazmaier, J. Org. Chem., 2006, 71, 8950-8953.

A Lewis acid-catalyzed three-component, mild, highly atom econocial, direct-type Mannich reaction of simple aromatic and enolizable aliphatic aldehydes, secondary amines, and glycine derivatives affords various synthetically important anti-α,β-diamino ester derivatives in high yields with high diastereoselectivities.
M. M. Salter, J. Kobayashi, Y. Shimizu, S. Kobayashi, Org. Lett., 2006, 8, 3533-3536.

The AgOAc/ThioClickFerrophos complex effectively catalyzed a conjugate addition of glycine imino esters to arylidene and alkylidene malonates, furnishing the corresponding adducts in good yields with high enantioselectivities. The complex also catalyzed a highly enantioselective, conjugate addition to α-enones in the presence of 1,4-diazabicyclo[2.2.2]octane.
T. Konno, S. Watanabe, T. Takahashi, Y. Tokoro, S.-i. Fukuzawa, Org. Lett., 2013, 15, 4418-4421.

Chiral complexes of calcium promote asymmetric 1,4-addition reactions and [3+2] cycloaddition reactions of α-amino acid derivatives with α,β-unsaturated carbonyl compounds. The reactions proceeded smoothly in the presence of 5-10 mol % of the chiral calcium catalyst to afford the desired adducts in high yields with high diastereo- and enantioselectivities.
S. Saito, T. Tsubogo, S. Kobayashi, J. Am. Chem. Soc., 2007, 129, 5364-5365.

Homoallylic α-amino esters and amines were prepared via a Pd(II)-catalyzed coupling of 1,2-nonadiene and boronic acids with ethyl iminoacetate or aliphatic, aromatic, and heteroaromatic imines.
C. D. Hopkins, H. C. Malinakova, Org. Lett., 2006, 8, 5971-5974.

Related

Chiral diaminodioxaphosphonium salts can be used in catalytic amounts in a highly enantioselective protonation of α-amino acid-derived ketene disilyl acetals in the presence of 2,6-dimethylphenol as stoichiometric proton source.
D. Uraguchi, N. Kinoshita, T. Ooi, J. Am. Chem. Soc., 2010, 132, 12240-12242.