Synthesis of Deuterium‐Labelled 3‐Hydroxy‐L‐arginine: Comparative Studies on Different Protecting‐Group Strategies

Abstract

The β‐hydroxy‐α‐amino acid 3‐hydroxy‐L‐arginine is an important intermediate in biosynthetic pathways involving 2‐oxoglutarate (2‐OG) dependent FeII oxygenases. It also plays an essential role in post‐translational modifications of ribosomal proteins. For profound studies on arginine‐hydroxylating enzymes, synthetic reference compounds are of utmost importance. However, the synthesis of β‐hydroxy‐α‐amino acids is often not trivial. In particular, the preparation of a densely functionalized compound such as 3‐hydroxy‐L‐arginine poses a challenge in terms of a protecting‐group strategy. We have previously established a concise synthesis of 3‐hydroxy‐L‐arginine that is suitable for the preparation of both 3‐epimers of this β‐hydroxy‐α‐amino acid. However, we have since observed a remarkable isomerization reaction upon removal of the hydrogenolytically cleavable protecting groups, thus limiting the reliability of our previously described route. In this paper, we report a comparative study of protecting‐group strategies for this synthetic route, including a newly developed, more robust pathway to the target amino acid. The versatility of this improved route is demonstrated by the synthesis of the deuterium‐labelled derivatives (3R)‐ and (3S)‐3‐hydroxy‐[5‐2H]‐L‐arginine. These new isotope‐labelled arginine derivatives represent important tools for the elucidation of biosynthetic pathways, such as the formation of the arginine‐derived amino acid epicapreomycidine in the biosynthesis of muraymycin nucleoside antibiotics.

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

“…It cannot be ruled out that an epimerisation reaction might be involved in the biosynthesis of 108 , in particular with respect to other epimerisation steps in bacterial biosynthetic pathways [ 122 ]. Consequently, synthetic routes towards both 3-epimers of 3-hydroxy-L-arginine have been developed which would also enable the preparation of isotopically labelled congeners for biosynthetic studies [ 123 – 124 ]. It should also be noted that a biomimetic domino guanidinylation–aza-Michael-addition reaction for the synthesis of the capreomycidine scaffold has been developed, which only furnished the target structures as stereoisomeric mixtures though [ 125 ].…”