Preparation of Oxazolidine‐Containing Peptides: Unusual effects in Rh^III‐catalyzed acetalizations of aldehydes with urethane‐protected serine and threonine esters and with dipeptides containing serine or threonine residues at the N‐terminus

Abstract

The cyclization reaction of aldehydes with Z-and Boc-protectedB -hydroxyamino-acid esters (Tables 1 and 2), or of dipeptides containing serine or threonine at the N-terminus (Table 3), to give oxazolidine derivatives, occurs in the presence of isopropyl orthoformate and catalytic amounts of [Rh(MeCN)3(triphos)](CF3S03)3. The reaction may be carried out under kinetic or under thermodynamic control, so that the ratio of the two possible epimeric products can be changed. The protecting group can be removed from the 3-position of the oxazolidine ring, and the resulting NH group can be coupled with another amino acid. Thus, a new method for the preparation of peptides containing B -hydroxy-amino acid-derived oxazolidines ('pseudo-prolines') is available. N-Neopentyl-substituted tripeptides are also described.Serine-Derived Oxazolidines and Transition-Metal Acetalization Catalysts. -Oxazolidines, prepared from the j3 -hydroxyamino acids serine and threonine, have found multiple uses in stereoselective syntheses [l-lo]. They have been employed by one of our groups to synthesize a-branched analogs of serine and threonine, as well as other synthetically interesting building blocks [ 1 1-14], applying the principle of self-regeneration of stereogenic centers [15-171. Not only have these amino acids shown themselves as useful building blocks in diastereoselective syntheses, but the concomitant mechanistic and structural investigations have led to better understanding of the role amide groups play in modern organic synthesis, as discussed in a recently published review article [18]. Following a totally different line of work, Mutter et al. showed that the solubility problems often encountered both in solid and solution-phase peptide synthesis can be overcome by incorporating serines, as oxazolidine derivatives ('pseudo-prolines'), thus preventing the formation of poorly solublej3 -strands [ 191. For this purpose, the pivalaldehyde acetal of serine methyl ester was used as a building block in an otherwise conventional peptide synthesis.Recent work on transition-metal-catalyzed acetalization indicated that it might be possible to obtain oxazolidines directly from a given peptide. For over a decade, a ') Part of the projected Ph. D. theses of T. S. and of J. Q., ETH-Zurich. The authors gratefully acknowledge a stipend given to T. S. by the Verband der Chemisehen Industrrr (D-Frankfurt).

Synthesis of Constrained Peptidomimetics Containing 2‐Oxo‐1,3‐oxazolidine‐4‐carboxylic Acids

“…Finally, to demonstrate the usefulness of Oxd-peptides as conformationally defined peptidomimetics containing a pseudo-proline, [6] an analogue of the endogenous opioid peptide endomophin-1 (EM1), H-Tyr-Pro-Trp-PheNH 2 was prepared. Among the different natural or synthetic opioid peptides, [23] EM1 is unique for high receptor affinity and selectivity towards the μ-opioid receptor (MOR).…”

“…[6] In some cases, they have been utilized as prodrugs [7] or as intermediates for the preparation of other peptidomimetics. [8] In medicinal chemistry, the oxazolidinone ring is present in some bioactive peptides or mimetics, such as the GPIIb/IIIa integrin antagonists, which are based on the (oxo-oxazolidinyl)-methyl scaffold, [9] or the HIV-1 protease inhibitors, which incorporate an oxo-N-phenyloxazolidine-5-carboxylic acid moiety, that are designed to improve the cellular antiviral potency.…”

From?-lactams to?- and?-amino acid derived peptides

“…Due to the importance of a-methyl fl-alkylserines for the study and design of new bioactive targets (Altmann and Mutter, 1988;Seebach and Venanci, 1994;Wohr and Mutter, 1995), we have also developed the above approach…”

Peptide Backbone Modifications

“…Seebach and Venanzi et al described the formation of so-called pseudo-proline containing dipeptides by a Rh-catalyzed ([Rh(MeCN) 2 (triphos)](CF 3 SO 3 ) 3 ) acetalization of serine-Xaa or threonine-Xaa dipeptides with aldehydes [20]. Seebach and Venanzi et al described the formation of so-called pseudo-proline containing dipeptides by a Rh-catalyzed ([Rh(MeCN) 2 (triphos)](CF 3 SO 3 ) 3 ) acetalization of serine-Xaa or threonine-Xaa dipeptides with aldehydes [20].…”