α‐Aminoxy acids as building blocks for the oxime and hydroxylamine pseudopeptide links. Application to the synthesis of human elastase inhibitors

Abstract

The aminoxy acids NH2-O-C(alpha)HR-CO2H are much more easily obtained in the enantiomerically pure form than the analogous hydrazino acids NH2-NH-C(alpha)HR-CO2H, and it has been shown that the isosteric amidoxy psi[CO-NH-O] and hydrazide psi[CO-NH-NH] amide surrogates Induce two quite similar gamma-like folded structures. An aminoxy acid can also be N-coupled to a peptide aldehyde to give the aldoxime psi[CH = N-O] link or to a peptide ketone to form the ketoxime psi[CR= N-O] link. The former can be further reduced into the hydroxylamine psi[CH2-NH-O] link which gives rise to reduced amidoxy peptides. The structural properties Induced by these amide surrogates were studied, using IR and NMR spectroscopy, paying particular attention to the Z/E-isomerism of the oxime link. In order to investigate their inhibitory potency, the three amide surrogates were introduced in the Pro3-Val4 and Val4-Ala5 position of Z-Ala1-Ala2-Pro3-Val4-Ala5-Ala6-NHiPr, a substrate which is cleaved in the Val4-Ala5 position by human leukocyte elastase (HLE). The [Val4psi[CO-NH-O]Ala5] analogue was still a substrate, while the [Pro3psi[CO-NH-O]Val4] and [Val4psi[CH = N-O]Ala5] pseudopeptides acted as HLE competitive inhibitors.

Weinreb Amide as Secondary Station for the Dibenzo‐24‐crown‐8 in a Molecular Shuttle

“…A second reductive amination was carried out in methanol between the aldehyde 2 and the commercial O ‐methylhydroxylamine hydrochloride in the presence of triethylamine. Noteworthy, the reduction of the O ‐methyloxime intermediate turned out to be difficult, as already reported by Vanderesse et al Whereas hydrogenation using palladium catalyst or reduction using sodium borohydride (NaBH 4 ) were inefficient, the use of an excess of sodium cyanoborohydride (NaBH 3 CN, 15 equiv.) at pH 5–6 gave satisfactory results and provided the methoxyamine compound 3 in a 71 % overall yield.…”

2-[(tert-Butoxycarbonylamino)oxy]acetic acid

“…Data collection: SMART (Siemens, 1996); cell refinement: SAINT (Siemens, 1996); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL. (Vandersse et al, 2003;Deroo et al, 2003). As a contribution in this filed, we report here the crystal structure of the title compound.…”

“…For applications and structural studies of N-Boc-O-(carboxymethyl)hydroxylamine, see: Vandersse et al (2003); Deroo et al, 2003.…”

Expanding the Versatility of Microbial Transglutaminase Using α‐Effect Nucleophiles as Noncanonical Substrates

“…[9] Theu nique chemical and structural properties of these pseudopeptide linkages can contribute to enhanced proteolytic stability, hence their application in peptidomimetics. [10] Thes tability improvement associated with these "a-effect" pseudopeptide linkages thus prompted us to explore whether the isopeptide bond analogues formed from the a-effect amine substrates (Table 1) may confer as imilar protective ability against proteolysis,specifically by mTG itself.Although TG is known for its bond-forming reaction, it is also able to catalyze the reverse reaction. [11] In the absence of excess amine substrates, the enzyme can hydrolyze the isopeptide linkage,t hereby irreversibly converting the original Gln residue to aglutamic acid.…”