Organic Chemistry Portal
Reactions >> Name Reactions

Further Information

Related Reactions
Synthesis of α-amino acids

O'Donnell Amino Acid Synthesis

The O'Donnell Amino Acid Synthesis enables the construction of natural or unnatural α-amino acids via alkylation of benzophenone imines of glycine alkyl esters often under biphasic, basic conditions using a phase transfer catalyst or mediator.

Alternatively, a sequence of deprotonation with a strong base such as LDA at low temperatures under anhydrous conditions followed by alkylation can also be used.

Mechanism of the O'Donnell Amino Acid Synthesis

Use of the stable benzophenone imines of glycine alkyl esters offers two important advantages for the synthesis of monoalkylated amino acid derivatives. Since the monoalkylated Schiff base products are considerably less acidic than the starting material, selective monoalkylation can be achieved. Additionally, and beneficial for later developed enantioselective syntheses, subsequent product racemization does not occur under the standard reaction conditions for phase transfer catalysis:

The Schiff base esters can be conveniently prepared by a room temperature transimination:

The Schiff base esters are then alkylated with alkyl, benzyl, or allyl halides in the presence of an aqueous or solid base and a phase transfer catalyst or mediator - often a quarternary ammonium salt. An early publication shows an interesting scope of electrophiles already:

M. J. O'Donnell, J. M. Boniece, S. E. Earp, Tetrahedron Lett., 1978, 19, 2641-2644.

Early methodologies tried to avoid saponification of the ethyl ester. This is circumvented in later reactions using the tBu ester instead.

During the amino acid synthesis by phase transfer catalysis, deprotonation occurs at the interface between the organic and aqueous phases. The Schiff base anion subsequently ion pairs with the quaternary ammonium salt and then reacts with the electrophile in the organic phase:

The use of chiral quaternary ammonium phase transfer catalysts derived from the Cinchona alkaloids in the enantioselective alkylation of indanones, prompted Martin O'Donnell to use such catalysts for the alkylation of the Schiff base esters (J. Am. Chem. Soc., 1989, 111, 2353. DOI: 10.1021/ja00188a089). The cinchonidine-derived first generation catalyst shown gives, on benzylation, the natural (S) enantiomers of phenylalanine and other amino acids while the diastereomeric cinchonine-derived catalysts (not shown) lead to the (R) enantiomers. A second generation of catalysts resulted in higher enantioselectivites while further improvement was reported simultaneously from the Corey and Lygo groups in 1997.

The enantioselectivity is strongly influenced by the choice of solvent, the ester group and the leaving group of the electrophile. Although the early enantioselectivities were moderate, recrystallization often yielded enantiomerically pure α-amino acids. Further details and subsequent developments are featured in a review by O'Donnell (Acc. Chem. Res. 2004, 37, 506. DOI: 10.1021/ar0300625). Some newer publications are shown in the recent literature section.

For the synthesis of α,α-disubstituted amino acids from monoalkylated Schiff bases, more basic conditions can be achieved without water for example using solid bases in organic solvents. Here the phase transfer catalyst mediates between the solid and the liquid phase.

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.

In addition to reactions with alkyl, benzyl or allyl halides as electrophiles, reactions with enones (Michael reactions), aldehydes (aldol reactions), or imines (Mannich reactions) have also been reported.

T. Ooi, M. Kameda, M. Taniguchi, K. Maruoka, J. Am. Chem. Soc., 2004, 126, 9685-9694.

The resulting products can by hydrolyzed using mildly acidic conditions to provide the amino esters:

Recent Literature

Synthesis of Novel Chiral Phase-Transfer Catalysts and Their Application to Asymmetric Synthesis of α-Amino Acid Derivatives
W. He, Q. Wang, Q. Wang, B. Zhang, X. Sun, S. Zhang, Synlett, 2009, 1311-1314.

Practical Stereoselective Synthesis of β-Branched α-Amino Acids through Efficient Kinetic Resolution in the Phase-Transfer-Catalyzed Asymmetric Alkylations
T. Ooi, D. Kato, K. Inamura, K. Ohmatsu, K. Maruoka, Org. Lett., 2007, 9, 3945-3948.

Practical Catalytic Enantioselective Synthesis of α,α-Dialkyl-α-amino Acids by Chiral Phase-Transfer Catalysis
T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem. Soc., 2000, 122, 5228-5229.

Chiral Phosphine-Free Pd-Mediated Asymmetric Allylation of Prochiral Enolate with a Chiral Phase-Transfer Catalyst
M. Nakoji, T. Kanayama, T. Okino, Y. Takemoto, Org. Lett., 2001, 3, 3329-3331.

Phase-Transfer Catalysis via a Proton Sponge: A Bifunctional Role for Biscyclopropenimine
L. Belding, P. Stoyanov, T. Dudding, J. Org. Chem., 2016, 81, 553-558.

Cyclopropenimine-Catalyzed Enantioselective Mannich Reactions of tert-Butyl Glycinates with N-Boc-Imines
J. S. Bandar, T. H. Lambert, J. Am. Chem. Soc., 2013, 135, 11799-11802.