Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Synthèse Organique et Méthodologie - LSOM

Stereoselective Syntheses of Amino Acids and AminoPhosphonic Acids : Application for the Synthesis of Bioactive CycloPeptides

We were interested, few years ago, by the stereoselective synthesis of natural and unnatural cyclic amino acids with constrained conformations as well as by their amino phosphonic analogues. These compounds, except for their interesting biological activities, they present valuable building-blocks for the synthesis of peptide mimetics with restricted conformation.

I. Enantioselective synthesis of methanoamino acids and aminophosphonic analogues

The cyclopropane amino acids constitute a unique shape of natural and unnatural amino acids with constrained conformation. They have many biological activities such as enzyme inhibitors, antifeeding, or plant growth regulators.

In the course of our work, we have developed a convenient and rapid way for the synthesis of such previously unknown amino acids. This method should be realized from the cyclopropanone acetals, which were easily accessible in our Laboratory.

I.a. Cyclopropane Amino Acids (A. Fadel, A. Khesrani, 3 publications)

Thus for this study, we have developed an efficient one-pot asymmetric Strecker reaction starting from cyclopropanone acetals and proceeding, in three steps, via amino nitriles to prepare such amino acids: Aminocyclopropanecarboxylic acid (ACC) (Tetrahedron 1991, 47, 6265), (S)- and (R)-methanovalines (herbicide) (Synlett 1993, 503) and enantiopure allo-norcoronamic and allo-coronamic acids in excellent yields and excellent enantiomeric excesses (Tetrahedron: Asymmetry 1998, 9, 305).

I.b. Synthesis of aminocyclopropanephosphonic acids (A. Fadel, N. Tesson)

We applied the same methodology for the synthesis of cyclic aminophosphonic acids of potential therapeutic interests. The aminocyclopropanephosphonic acids, in which the tetrahedral phosphorus moiety acts as transition-state analogue of peptide bond cleavage, constitute an interesting bioactive molecules (antibacterial, fungicide, peptidase and proteinase inhibitors). However, very few examples of aminocylopropanephosphonic acids have been previously reported.

We have developed for the first time a simple and convenient synthesis of aminocyclopropane-phosphonic acids, in three steps, starting from cyclopropanone hemi-acetals and proceeding via aminophosphonates. This key-step was occurred by a stereoselective nucleophilic addition of phosphite to the iminium species as intermediate.

This one-pot reaction under various conditions, involving the formation of the iminium intermediates with various chiral amines and the nucleophilic addition with different phosphites, gave the aminophosphonates with good selectivities. Subsequent hydrogenolysis of the benzyl group and hydrolysis of phosphonate functions were accomplished with good yields and excellent enantiomeric excesses. Furthermore, the selectivity of this reaction was increased with the steric hindrance of R groups and with the steric hindrance and nucleophilicity of phosphites (R= t-Butyl, or tri-isopropyl phosphite, ds > 97: 3) (J.O.C.1999, 64, 4953; Eur. J. O. C. 2000, 2153; Tet: Asy 2000, 11, 2023; Tet: Asy 2002, 13, 2267).

II. Synthesis of enantiopure aminocyclobutane-carboxylic acids

Amino acids from cyclobutane series have been investigated very little. Although, among these amino acids few have been detected in natural sources. The biological activities of 1-amino-cyclobutanecarboxylic acid derivatives have been well documented as N-methyl-D-aspartate (NMDA) receptor agonists or antagonists. Moreover, a few methods for the synthesis of 2-substituted 1-aminocyclobutanecarboxylic acids have been described in recent years for the racemic form and rarely for the optically active compounds. Application of our methodology for the synthesis of cyclobutane amino acids could be interesting too.

II.a. Synthesis of 2-alkylated cyclobutane amino acids (M. Truong, A. Fadel )

Despite the biological interests of these molecules, very few examples of aminocyclobutanecarboxylic acids have been previously reported. We have studied the selectivity of the one-pot Strecker reaction with the nucleophilic addition of cyanide anion on the iminium species A and B, which are formed in situ from the racemic or optically active cyclobutanones with chiral amines. The amino nitriles were obtained with excellent stereoselectivities. Subsequent transformation of these nitriles provided, for the first time, opticaly active 2-alkylated cyclobutanecarboxylic acids (Tet: Asy 2003, 14, 1063).

II.b. Synthesis of 2-hydroxyaminocyclobutane-carboxylic acid, sérine derivative (D. Hazelard, A. Fadel, C. Girard)

Serine analogues that incorporate the cyclobutane skeleton (c4Ser) have very recently been synthetized by a selective Michael-aldol reaction, but in racemic form.

Likewise, we have studied the selectivity of such one-pot asymmetric Strecker reaction, starting from benzyloxycyclobutanone. These optically active ketones were prepared by enantioselective enzymatic transesterification (A. Fadel, D. Hazelard, G. Morgant Tetrahedron: Asymmetry 2004, 15, 1711). Thus, by changing the Strecker reaction control, each amino nitrile can be separately obtained as a major product and isolated on silica gel as a pure compound.

Hydrogenolysis and hydrolysis of the resulting nitriles were optimized to provide, new optically active 1-amino-2-hydroxycyclobutanecarboxylic acids. The absolute configuration has been established by X-ray analysis of the corresponding cis-amino nitrile (Tetrahedron: Asymmetry 2006, 17, 1457).

III. Synthesis of heterocyclic amino acids and aminophosphonic analogues (N. Rabasso, N. Louaisil, A. Fadel)

Several modifications on the amino acids have been developed in the literature, to improve biological activities and increase their stabilities in the cellular medium. Among these modifications, the introduction of cyclic or heterocyclic rings into the molecular skeleton can increase its rigidity and modify electronic effects. In addition, the replacement of carbon atom by various heteroatoms (N, S, O…) seems to be very efficient.

III.a. Synthesis of heterocyclic aminophosphonic acids (N. Rabasso, N. Louaisil, A. Fadel, Tetrahedron 2006, 62, 7445; Synthesis, 2007, 289)

For this study, we have applied our methodology (one-pot reaction), starting from 4- heterocyclohexanones. Subsequent transformation of the resulting a-aminophosphonates gave, in three step sequence from ketones, new 4-heterocyclohexyl-phosphonic acids (X = O, N, S).

The same methodology was also applied for the synthesis of optically active 3-heterocyclohexyl-phosphonic acids via phosphite addition to iminium ions formed with chiral amines.

IV. Synthesis of enantiomerically pure (R)-Pipecolic acid and (S)-Proline (Fadel, Lahrache JOC 2007, 72, 1780)

We have developed an easy and efficient four step synthesis of enantiopure (+)-pipecolic acid and (S)-proline, starting from dihydropyran and dihydrofuran. These amino acids were obtained from amino nitriles, which were prepared by asymmetric Strecker reaction in aqueous medium with excellent selectivity. The final products can be obtained in any configuration in very high enantiomeric purity (>99% ee).

Prospects and Projects

A. Synthesis of heterocyclic compounds and bioactive alkaloids

We have very recently reported a new and efficient synthesis of cyclic amino acids from cyclic enol ethers. We will apply this methodoloy as key-step for the synthesis of alkaloids such as pumiliotoxin C, conicein (antitumoral) and tetraporenin (frog skin extracts) and others alkaloids. The obtention of piperidinone derivatives by other methods would be investigated too.

B. From Amino Acids to CycloPeptides

Cyclic peptides containing the sequence RGD attract today intense interest, due to their ability to inhibit integrins selectively. Taking this lead, our project targets the preparation of original cyclic amino acids, particularly designed to bridge RGD sequences, with a view to discovering hitherto unknown integrin binding profiles. These new amino acids will be cyclic or heterocyclic in themeselves and host aminophosphonates moieties.