Practical Synthesis of Enantiomerically Pure β²-Amino Acids via Proline-Catalyzed Diastereoselective Aminomethylation of Aldehydes

Abstract

Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion, generated from a readily prepared precursor, provides alpha-substituted-beta-amino aldehydes with 85:15 to 90:10 dr. The alpha-substituted-beta-amino aldehydes can be reduced to beta-substituted-gamma-amino alcohols, the major diastereomer of which can be isolated via crystallization or column chromatography. The amino alcohols are efficiently transformed to protected beta2-amino acids, which are valuable building blocks for beta-peptides, natural products, and other interesting molecules. Because conditions for the aminomethylation and subsequent reactions are mild, beta2-amino acid derivatives with protected functional groups in the side chain, such as beta2-homoglutamic acid, beta2-homotyrosine, and beta2-homolysine, can be prepared in this way. The synthetic route is short, and purifications are simple; therefore, this method enables the preparation of protected beta2-amino acids in useful quantities.

Comparison of design strategies for α-helix backbone modification in a protein tertiary fold

“…1D) to ascertain the effect of β-residue side-chain placement on folded stability of helix-modified GB1 variants. Derivatives of β 2 -Ala and β 2 -Lys suitable for use in solid-phase synthesis were prepared by reported routes, 15 and a new protected form of β 2 -Asn was prepared by adaptation of known methods (Scheme S1). 16 We synthesized proteins 3–5 by standard Fmoc solid phase methods and purified each by HPLC and ion exchange chromatography (Fig.…”

Aminomethylation of chiral silyl enol ethers: access to β2-homotryptophane and β2-homolysine derivatives

“…16 Recently, the same group reported an organocatalytic aminomethylation reaction as a new route to b 2 -amino acids. 17 In the reported methodology, good yields and selectivities are obtained when amino acids with hydrocarbonic side chains are involved. However, if the selectivity remains high in the case of functionalized b 2 -amino acids, such as b 2 -homolysine, a drop of the yield is observed.…”

Enantiopure β3-neopentylglycine: synthesis and resolution

“…More 'classical' approaches towards b-amino acids and their derivatives involve syntheses with, for example, chiral Lewis acids and chiral auxiliaries. [20][21][22][23][24][25][26][27][28][29] The majority of these routes suffer from long synthetic sequences, expensive chemicals, long reaction times and protecting groups that are difficult to remove. Despite all efforts, there have until now been no general routes found for large-scale preparations of b-amino acids.…”