Towards Functionalized Silicon‐Containing α‐Amino Acids: Asymmetric Syntheses of Sila Analogs of Homoserine and Homomethionine

Abstract

Dedicated to Dr. G¸nther Ohloff on the occasion of his 80th birthdayThe homoserine and homomethionine sila analogs, (R)-HOSi(Me 2 )CH 2 CH(NH 2 )CO 2 H ((R)-21) and (R)-MeSCH 2 Si(Me 2 )CH 2 CH(NH 2 )CO 2 H ((R)-24), respectively, were each synthesized in nine steps and in 30 and 23% overall yield, respectively, from commercially available ClSiMe 2 CH 2 Cl. The key step of both syntheses was the asymmetric a-bromination of an Evans amide to introduce the stereogenic center of the amino acids with defined absolute configuration. While the preparation of the homomethionine analog (R)-24 followed the expected pathway, the sila analog of homoserine, (R)-21, was unexpectedly formed during the catalytic hydrogenation of an N 3 CH 2 -substituted silane derivative.Introduction. ± Nonproteinogenic and unnatural amino acids are important building blocks for peptide chemistry [1 ± 3], and, among such compounds, sila amino acids are of increasing interest [3 ± 13]. With their large hydrophobic groups, they are expected and have been shown to offer several advantages over classical amino acids when incorporated into peptides, such as prevention of hydrophobic-pocket collapse, higher lipophilicity, and enhanced stability towards proteolytic enzymatic degradation Alternatively, the amino acids were prepared by stereoselective a-amination of bsilylated carboxylic acids [7] [12]. While most of the previous studies targeted rather simple trialkyl-or trialkyl/triarylsilanes, Tacke et al. reported the first enantioselective synthesis of Si-containing amino acids that are hetero-functionalized at a Si-containing side chain [10]. However, the hetero group, an amino function, was introduced early in the synthetic scheme, limiting the versatility of the method. In continuation of our investigations [6] [7] [13], we were looking for a more flexible route to functionalized sila amino acids, considering halogenomethyl-substituted silanes such as 4 as precursors.

Designing Silylated l‐Amino Acids using a Wittig Strategy: Synthesis of Peptide Derivatives and 18F‐Labelling

“…Finally, dipeptide 18a was quantitatively hydrogenated in MeOH in the presence of Pd/C as catalyst to give the corresponding saturated methoxysilane 20a ; under the same conditions, compound 18c led to a mixture of silanol 20b and methoxysilane 20c in a 2:3 ratio (Scheme ). It is interesting to note that silanol amino acids and peptides have only rarely been described in the literature to date , …”

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

“…α-Azido-N-acyl oxazolidinone 79 allowed the formation of homomethionine (R)-38t and homoserine (R)-38u in greater than 90% yields and with enantiomeric excesses above 99% (Scheme 20). 45 In all the asymmetric syntheses described above, the need to use chiral auxiliaries in stoichiometric amounts, and the low In 1996, Tanaka and co-workers 51 published the first biotransformation for preparation of enantiopure silicon-containing amino acids. Enantiopure TMSAla was obtained by enzymatic resolution of racemic acetyl derivatives.…”

Synthesis and applications of silicon-containing α-amino acids

“…Electrophilic addition of amine equivalents to molecules already containing the silicon group can also be used to access b-silyl amino acids. 31,32 N-Acyl oxazolidinones 43a-d are readily synthesised in high yields from b-silyl propionic acids 42a-d (Scheme 10). Azide introduction via the bromides 33 proceeds with high diastereoselectivities in good chemical yields (65-87%) for compounds 44a-c.…”