Francesca Perri

A preparation of N-Fmoc-N-methyl-α-amino acids and N-nosyl-N-methyl-α-amino acids

A convenient route for the synthesis of lipophilic N-Fmoc-N-methyl-α-amino acids and N-nosyl-N-methyl-α-amino acids, interesting building blocks to be used for the preparation of N-methylated peptides, is presented. Both nosyl- and Fmoc-protected monomers are accessible, so these compounds can be used in solution as well as in solid phase peptide synthesis. The methodology is based on the use of benzhydryl group to protect temporarily the carboxyl function of N-nosyl-α-amino acids and on the subsequent methylation of the N-nosyl-α-amino acid benzhydryl esters with diazomethane. The benzhydryl esters offer several beneficial features such as simple preparation, stability to methylation and selective deprotection under mild conditions. The overall procedure is highly efficient in that the adopted conditions keep the chiral integrity of amino acid precursors and the process does not require chromatographic purification of the methylated products.

A new non-natural arginine-like amino acid derivative with a sulfamoyl group in the side-chain

Sulfamoylation of the l-ornithine methyl ester side-chain generates a non-natural arginine isostere which can be coupled with N-Fmoc-l-proline to synthesize analogues which maintain the structural characteristics of the biologically important Pro-Arg dipeptide sequence. As a probe of its biological importance, the sulfamoylated amino acid derivative was also incorporated as P1 residue in tripeptide structures matching the C-terminal subsequence of fibrinogen. The reported results demonstrate that the functionalization of l-ornithine side-chain with a neutral sulfamoyl group can generate an arginine bioisostere which can be used for the synthesis of prototypes of a new class of human thrombin inhibitors.

An Efficient Preparation of N-Methyl-α-amino Acids from N-Nosyl-α-amino Acid Phenacyl Esters

In this paper we describe a simple and efficient solution-phase synthesis of N-methyl-N-nosyl-alpha-amino acids and N-Fmoc-N-methyl-alpha-amino acids. This represents a very important application in peptide synthesis to obtain N-methylated peptides in both solution and solid phase. The developed methodology involves the use of N-nosyl-alpha-amino acids with the carboxyl function protected as a phenacyl ester and the methylating reagent diazomethane. An important aspect of this synthetic strategy is the possibility to selectively deprotect the carboxyl function or alternatively both amino and carboxyl moieties by using the same reagent with a different molar excess and under mild conditions. Furthermore, the adopted procedure keeps unchanged the acid-sensitive side chain protecting groups used in Fmoc-based synthetic strategies.

Methylation of α-Amino Acids and Derivatives Using Trimethylsilyldiazomethane

A study of the methylation of N‐nosyl‐α‐amino acids and derivatives with trimethylsilyldiazomethane is here reported. Trimethylsilyldiazomethane allows the chemo‐specific methylation of the carboxyl function of N‐nosyl‐α‐amino acids in high yields and purity. This method provides a practical route to N‐methyl‐α‐amino acids avoiding the use of the more toxic and explosive diazomethane. This simple and safe methylation methodology of α‐amino acids and derivatives is not limited to organic synthesis and involves the use of a commercially available reagent as well.

Transformations of 3-hydroxy steroids with lewis and anhydrous protic acids: the case of pregn-4-en-3β,17α,20β-triol.

The acid‐catalyzed dehydration is one of the most important processes, which transforms 3‐hydroxy steroids into their corresponding unsaturated derivatives. This reaction is of great importance because it can produce molecules that play a key role in the understanding of the natural metabolism of steroids. Sterol dehydration is generally performed with aqueous acidic systems, and the treatment often affords low yields of the desired compounds and/or complex mixtures of by‐products. In this paper, we report the results obtained from the study of the structural and stereochemical effects of the acid‐induced reaction of pregn‐4‐en‐3β,17α,20β‐triol in anhydrous systems. In particular, the treatment of this trihydroxy steroid model with Lewis acids leads to the corresponding Δ3,5‐steradiene as the only product and in very high yields. With Lewis acids, no modifications of the 1,2‐diol function on the D‐ring are observed, even when the reactions are performed at high temperatures. Protic acid catalysis in non‐aqueous organic solvents causes the formation of an epimeric mixture of the corresponding Δ3,5‐steradiene derivatives by a partial stereochemical inversion of the asymmetric C‐17. The reactivity of the 17α,20β‐diolic residue is also evaluated by exposing pregn‐4‐en‐3β,17α,20β‐triol and the corresponding Δ3,5‐steradiene to the prolonged action of anhydrous protic acid systems under thermal conditions.

D-homoannulation of 17α,21-dihydroxy-20-keto steroids (corticosteroids)

Synthetic corticosteroids are widely used as anti-inflammatory agents. Mechanisms of their degradation continue to be studied. D-ring homoannulation is a well-known metabolic pathway for steroids in vivo. The rearrangement with aluminium trichloride of the commercial anti-inflammatory drugs hydrocortisone, cortisone and dexamethasone is here presented. The structures of the corresponding 17a-keto-17-hydroxy-D-homosteroids are established by mono- and two-dimensional NMR analysis. Inversion of the α-configuration of C-16 is observed in the Lewis acid assisted D-homoannulation of dexamethasone.

Site-selective methylation of N(beta)-nosyl hydrazides of N-nosyl protected alpha-amino acids.

The methylation reaction of N(beta)-nosyl hydrazides of N-nosyl protected alpha-amino acids by using diazomethane shows a controlled regiochemical trend and makes it possible to obtain the corresponding products methylated at specific positions depending on the amount of diazomethane used. The observed selectivity is closely connected with the different acidity of sulfonyl hydrazide, sulfonamide, and acyl hydrazine protons present in the analyzed substrates. The reactivity order of these three diverse reactive sites is supported by theoretical calculations. The hydrazine derivatives considered in this work belong to a class of compounds with interesting biological activity and of great interest in organic synthesis.

Steroidal seven-membered A-ring epoxy lactones by oxidation of the corresponding Δ4-3-ketosteroids

Treatment of Delta 4-3-ketosteroids with m-chloroperbenzoic acid at 0 degrees C produced the corresponding steroidal seven-membered A-ring epoxy lactones. The adopted procedure allowed for efficient recovery and separation of the products with definite stereochemistry.

Synthesis of Chiral Nitrones from N‐Fmoc Amino Acids and N‐Fmoc Dipeptides

Abstract In this work is presented a synthetic procedure for the preparation of chiral nitrones from N‐Fmoc protected amino acids and dipeptides. The nitrone functional group can replace the carboxyl unit of amino acid and peptide systems and can be inserted into the peptide chain. The introduction of the 1,3‐dipole in peptide segments can improve the solubility and the stability toward enzymatic degradation.