1. 2,3-Diaminopropanols Obtained from d-Serine as Intermediates in the Synthesis of Protected 2,3-l-Diaminopropanoic Acid (l-Dap) Methyl Esters
Andrea Temperini, Donatella Aiello, Fabio Mazzotti, Constantinos M Athanassopoulos, Pierantonio De Luca, Carlo Siciliano Molecules. 2020 Mar 13;25(6):1313. doi: 10.3390/molecules25061313.
A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the p-toluensulfonyl (tosyl, Ts) or acid-labile tert-butyloxycarbonyl (Boc) moieties. The synthetic approach to protected l-Dap methyl esters uses appropriately masked 2,3-diaminopropanols, which are obtained via reductive amination of an aldehyde prepared from the commercial amino acid Nα-Fmoc-O-tert-butyl-d-serine, used as the starting material. Reductive amination is carried out with primary amines and sulfonamides, and the process is assisted by the Lewis acid Ti(OiPr)4. The required carboxyl group is installed by oxidizing the alcoholic function of 2,3-diaminopropanols bearing the tosyl or benzyl protecting group on the 3-NH2 site. The procedure can easily be applied using the crude product obtained after each step, minimizing the need for chromatographic purifications. Chirality of the carbon atom of the starting d-serine template is preserved throughout all synthetic steps.
2. Studies of peptide antibiotics. XLIII. Syntheses of gramicidin S analogs containing D-serine or dehydroalanine in place of D-phenylalanine and asymmetric hydrogenation of the dehydroalanine residue
S Ando, H Aoyagi, M Waki, T Kato, N Izumiya Int J Pept Protein Res. 1983 Mar;21(3):313-21.
Gramicidin S (GS) analogs, [D-Ser4,4']-GS and its precursor [O-benzyl-D-Ser4,4']-GS, were synthesized by the conventional method in order to evaluate the role of the hydroxymethyl side chains in D-Ser at 4,4' positions on the biological activity. Another analog [L-Orn(delta-Boc)2,2',delta Ala4,D-Ser4']-GS was prepared from [D-Ser4,4']-GS by t-butyloxycarbonylation and successive dehydration using dicyclohexylcarbodiimide-CuCl as dehydrating reagent. The delta Ala residue was asymmetrically hydrogenated to D-Ala in the presence of Pd-black. On the microbial assays, [O-benzyl-D-Ser4,4']-GS showed high antimicrobial activity as natural GS, but [D-Ser4,4']-GS showed low activity; the structure-activity relationships of the analogs were discussed.
3. Design and Use of an Oxazolidine Silyl Enol Ether as a New Homoalanine Carbanion Equivalent for the Synthesis of Carbon-Linked Isosteres of O-Glycosyl Serine and N-Glycosyl Asparagine
Alessandro Dondoni, Alberto Marra, Alessandro Massi J Org Chem. 1999 Feb 5;64(3):933-944. doi: 10.1021/jo981861h.
A trimethylsilyl enol ether carrying the N-Boc 2,2-dimethyloxazolidine ring was designed to serve as a synthetic equivalent of the homoalanine carbanion for the introduction of the alpha-amino acid side chain at the anomeric carbon of sugars. This new functionalized silyl enol ether was prepared in multigram scale and high enantiomeric purity starting from methyl N-Boc-L-threoninate (six steps, 49% yield). This reagent was employed in two synthetic approaches to C-glycosyl amino acids. In one approach, the BF(3).Et(2)O-promoted coupling with tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate afforded the alpha-linked C-glycoside as main product (30% isolated yield), which upon treatment with tert-butyllithium was converted into the beta-linked isomer. Deoxygenation of these compounds by the Barton-McCombie method and unmasking of the glycyl moiety from the oxazolidine ring by oxidative cleavage with the Jones reagent gave the C-glycosyl serine isosteres alpha- and beta-Gal-CH(2)()-Ser. In a similar way were prepared alpha- and beta-Glc-CH(2)()-Ser starting from tetra-O-benzyl-D-glucopyranosyl trichloroacetimidate. In a second approach, the same oxazolidine silyl enol ether was condensed with formyl tetra-O-benzyl-beta-D-C-galactopyranoside in the presence of BF(3).Et(2)O to give the beta-linked C-glycoside in 78% yield without any anomerization. The deoxygenation of this product and the cleavage of the oxazolidine ring as described above afforded the glycosyl asparagine isostere beta-Gal-(CH(2)())(2)()-Asn. The same reaction sequence was applied to convert formyl tetra-O-benzyl-beta-D-C-glucopyranoside and mannopyranoside into the C-glycosyl amino acids beta-Glc-(CH(2)())(2)()-Asn and beta-Man-(CH(2)())(2)()-Asn, respectively.
