Large-Scale Syntheses of FMOC-Protected Non-Proteogenic Amino Acids:  Useful Building Blocks for Combinatorial Libraries

Abstract

Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarboxylic acid were converted into their corresponding FMOC-derivatives in excellent yields without the need for an extractive workup. In addition, FMOC-cis-β-amino acids were also prepared, employing a [2 + 2]-cycloaddition strategy between a cyclic olefin and N-chlorosulfonyl isocyanate (CSI).The resulting N-chlorosulfonyl β-lactams were reduced to the parent β-lactams with sodium sulfite and then converted to the cis-β-amino acid hydrochlorides by exposure to aqueous hydrochloric acid. The resulting cis-β-amino acids were converted to their FMOC-derivatives under conditions similar to those developed for the commercially available amino acids. Differences in the conditions employed between these β-amino acids and the commercial derivatives were observed, primarily in the nature of the base required for the reaction. A possible rationale for the differences in behavior is described. These FMOC-amino acid derivatives are valuable intermediates for the solid-phase synthesis of combinatorial libraries.

A New Class of Dengue and West Nile Virus Protease Inhibitors with Submicromolar Activity in Reporter Gene DENV-2 Protease and Viral Replication Assays

“…All final compounds and intermediates were obtained by solid-phase peptide synthesis according to the Fmoc protocol. The 4-benzyloxyphenylglycine derivatives ( 59 – 67 ) were obtained by O-alkylation of the corresponding 4-hydroxyphenylglycine as previously described. , Phenylglycine derivatives were N -Fmoc protected (compounds 68 – 76 ) as described by Dener et al Peptide coupling reactions were performed with COMU/TMP (on resin) or HATU / TMP (in solution) since it was shown that under those conditions, the α-carbon racemization of the phenylglycine derivative can be minimized to a negligible extent . As further detailed below, stereochemical purity was verified for the compounds presented here.…”

“…1 H NMR (500 MHz, CD 3 OD) δ 8.69 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.41−7.24 (m, 7H), 7.18 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 5.35 (s, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 2.28 (t, J = 7.5 Hz, 2H), 1.62 (p, J = 7.1 Hz, 2H), 1.37−1.27 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). 13 (22). 22 was synthesized according to the general procedure for guanidinylation from 14 (10 mg, 0.02 mmol), N,N′-di-Boc-1H-pyrazole-1-carboxamidine (10 mg, 0.03 mmol), DMAP (1 mg, 0.01 mmol), and DIPEA (0.004 mL, 0.02 mmol).…”

Identification of Fmoc‐β‐Ala‐OH and Fmoc‐β‐Ala‐amino acid‐OH as new impurities in Fmoc‐protected amino acid derivatives*

“…The appearance of β‐Ala in Fmoc‐Ala‐OH prompted an investigation of other Fmoc‐amino acids, in order to determine whether similar impurity problems in the drug substance could arise. It is possible that the β‐Ala‐related impurities arise in the raw materials according to the method of producing the Fmoc‐protected amino acids (2,3) and residual, unacknowledged amounts remain after their purification. Fmoc‐Arg(Pbf)‐OH was found to be the next amino acid derivative with a high content of β‐Ala‐related material.…”

Hydrolysis of a Ni-Schiff-Base Complex Using Conditions Suitable for Retention of Acid-labile Protecting Groups

“…We then subjected this solution to a standard aqueous Fmoc protection. 8 After reaction completion and work-up, we determined the reaction afforded a 25% yield of Fmoc-protected glycine. This percent yield is not surprising considering the dilute concentration of the reaction and suggests that the presence of Ni 2+ ions and EDTA do not interfere with a standard Fmoc protection reaction.…”

“…With evidence supporting that each individual component of our methodology (hydrolysis, isolation of free amino acid, and Fmoc protection) is feasible, we performed a proof-of-concept experiment using Ni-PBP-Gly. We assessed the viability of the hydrolysis conditions described above and subsequent Fmoc protection using a standard protocol 8 to afford an Fmoc-protected amino acid in reasonable yield. To a stirred solution of Ni-PBP-Gly (404 mg, 0.971 mmol, 1 equiv) in 40 mL DMF at room temperature was added 0.2 M EDTA solution at pH 4.5 (65 mL, 13 mmol, 13 equiv).…”