Practical Synthesis of Phosphinic Dipeptides by Tandem Esterification of Aminophosphinic and Acrylic Acids under Silylating Conditions

Abstract

In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type 5 is presented. These compounds serve as valuable building blocks for the development of highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases. The proposed method is based on the tandem esterification of α-aminophosphinic and acrylic acids under silylating conditions in order to subsequently participate in a P-Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also compatible with the reaction conditions. Based on the above, we expect that the practicality of the proposed protocol will facilitate the discovery of pharmacologically useful bioactive phosphinic peptides.

Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases

“…Another major concern that must be taken under consideration is that optimization opportunities strongly depend on synthetic advances in the field, ,,, as highlighted by the application of combinatorial chemistry principles in the discovery of selective inhibitors of several Zn-metalloproteases ,,, or the successful preparation of capricious sequences which allowed the synthesis of RXPA380 , or inhibitors of aminopeptidase A. , Finally, the transformation of phosphinic inhibitors of MMPs to molecular probes has set the basis for similar studies with other pharmacologically important Zn-metalloproteases, expanding the range of applications of this privileged class of tool compounds. Future development of novel, improved tool compounds or probes thereof will be largely accelerated by addressing unmet challenges such as stereoselective synthetic strategies, late-stage diversification approaches, or synthesis of unusual, conformationally constrained analogues. − …”

Organophosphorus Chemistry 2021

“…A synthetic protocol for the preparation of novel phosphinic dipeptides was presented by Georgiadis and co-workers [ 2 ]. These compounds serve as valuable building blocks for developing highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases.…”

Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction

“…We found that the use of a phenyl-isoxazole-substituted acrylic derivative leads to the respective PDI 5a with a 5.1:1 dr, while replacement of ethyl with benzyl ester further increases the observed dr to 6.0:1, as demonstrated in the case of PDI 5b . Moreover, we produced a common derivative from known PDI 4a and newly synthesized isoxazole PDI 5a , and after comparison by 31 P NMR, we confirmed that the S stereochemical configuration at position P 1 ′ is favored (see the Supporting Information), in accord with previous reports. , Strikingly, the dr for 5b was dramatically increased to 10:1 when CH 2 Cl 2 was replaced by a polar aprotic solvent (MeCN or DMF) and to 18:1 when the reaction mixture was stirred first at 4 °C for 24 h and then at room temperature for 48 h. Next, we evaluated the effect of a carboxylic ester moiety on the observed diastereoselectivity, as depicted in Scheme B. In general, benzyl type esters 5c – h were generated with improved diastereoselectivities in all cases compared to that of reference ester 5b (20–25:1 vs 18:1).…”