Pseudoproline derivatives

The protecting groups of hydroxy moieties can be classified into three different types, namely alkyl ethers, carbonic acid esters, and sUyl ethers (Scheme 1). Pseudoprolines derived from serine and threonine have also been suggested as a form of temporary protection for both of these amino acids. 

However, it can be difficult to couple to the hindered Hmb-protected amino acids so in cases where the peptide chain contains Ser or Thr, oxazolidine dipeptide derivatives 3 have been employed (Scheme 7). These pseudoproline derivatives induce a turn in the peptide chain disrupting P-sheet formation. 

Like morphiceptin and PL017, cisltrans isomerization occurs around the Tyr-Pro amide bond in endomorphin-1, with similar populations (75%trans, 25%cis) found for the two conformations (819). Based on structural comparison of the cis and trans conformations of endomorphin-1 to other /x- and 8-selective opioid peptides, Podlogar et al. proposed that the trans conformation was the bioactive form (819). Recently, Schiller and coworkers reported endomorphin-2 and morphiceptin analogs containing a pseudoproline derivative in... 

Note 4-Thiaproline is also named as pseudoproline, Cys(WPro), 169 whereby the related disubstituted derivatives at the C5 position of the proline ring are defined as... 

Scheme 14 Serine (Oxa), Threonine [Oxa(5-Me)], and Cysteine (Thz) Derived Pseudoprolines[82 851...

Studies on host-guest peptides have shown that incorporation of a proline residue into peptides which have a high tendency to fold into ordered secondary structures disrupts the onset of helical as well as P-sheet conformations and increases solubility and coupling rates.f Based on this observation, serine- and threonine-derived oxazolidine, and cysteine-derived thiazolidine derivatives (pseudoprolines) were proposed as valuable tools for combining protection of their side-chain functions with the simultaneous solubilization of the peptide chain. Due to the induction of kink conformations in the peptide backbone, originating from the preference of these pseudoproline residues to adopt the cis-imide bond configuration, insertion of such derivatives into peptides prevents self-association and P-structure formation. 

Mutter and co-workers have defined oxa- and thiaproline derivatives of serine, threonine, and cysteine with Ser( PPro), Thr( PPro), and Cys-( Pro), respectively, where the abbreviation PPro indicates the relationship to proline (with heteroatomic ring substitution in position 4). Pseudoprolines with substitution in position 2 of the proline ring are named Ser/Thr/Cys( Pro). 

Fig. 11.13 (A) Synthesis of pseudoprolines ( / Pro) by condensation reaction of aldehydes or ketones with Xaa (Ser, Thr, or Cys). (B) Direct insertion ( post-insertion ) of f Pro systems into dipeptide derivatives for use in peptide synthesis [153-161].

Fig. 11.15 The concept of pseudoprolines (IFPro) The temporary insertion of a Ser-, Thr-, or Cys-derived PPro system results in a kink-conformation, giving access to a number of applications in peptide synthesis and bioorganic chemistry.

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