Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal Diazirines and ¹⁵N₂-Diazirines and Their Application as Hyperpolarized Markers

Abstract

A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDAmediated transformation occurs via three consecutive reactions and involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it is operationally simple, and it can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that this transformation could be applied to dipeptides without racemization. Furthermore, 14 N 2 and 15 N 2 isotopomers can be obtained, emphasizing a key trans-imination step when using 15 NH 3 . In addition, we report the first experimental observation of 14 N/ 15 N isotopomers directly creating an asymmetric carbon. Finally, the 15 N 2 -diazirine from L-tyrosine was hyperpolarized by a parahydrogen-based method (SABRE-SHEATH), demonstrating the products' utility as hyperpolarized molecular tag.

N−N Bond Formation Using an Iodonitrene as an Umpolung of Ammonia: Straightforward and Chemoselective Synthesis of Hydrazinium Salts

“…[12] This electrophilic N ‐species is able to react with sulfur compounds providing several iminated derivatives such as sulfoximines, [12,13] sulfonimidates and sulfonamides, [14] and sulfonimidamides [15] (Scheme 2). Reboul reported recently an elegant synthesis of 1,2‐diazirine starting from α‐aminoacids, using a combination of PhI(OAc) 2 and an excess of NH 3 [16] . Diaziridine A resulting from the addition of an iodonitrene to an imine (Scheme 2), was proposed as an intermediate.…”

Terminal Diazirines Enable Reverse Polarization Transfer from 15N2 Singlets

“…[10] Isotopically enriched diazirines were readily created using 15 N-ammonia and 15 N-labeled amino acids or unlabeled ones,where diazirines bearing astereogenic center (asymmetric sulfur of the sulfoxide group) were synthesized from cysteine and methionine.T hese "terminal" diazirines replace methyl groups,o ne of the most commonly encountered chemical groups in biochemistry and beyond. [10] Isotopically enriched diazirines were readily created using 15 N-ammonia and 15 N-labeled amino acids or unlabeled ones,where diazirines bearing astereogenic center (asymmetric sulfur of the sulfoxide group) were synthesized from cysteine and methionine.T hese "terminal" diazirines replace methyl groups,o ne of the most commonly encountered chemical groups in biochemistry and beyond.…”

“…[18][19][20][21][22][23][24][25] In this article,wefocus on terminal diazirines as SABRE targets.T he terminal diazirines depicted in Table 1w ere chosen to probe various molecular motifs.I nm olecule (1) at erminal diazirine moiety is directly attached to an aryl group with as imple structure and J-coupling network. [10] Diazirines (4,5) have as tereogenic center, which makes it possible to probe hyperpolarized long-lived singlet states and to permit transfer to 1 H. In the following,wewill demonstrate astrategy to store polarization in hyperpolarized 15 N 2 singlets and then convert the polarization from 15 Nsinglet order into 1 Hm agnetization for more sensitive detection. [10] Diazirines (4,5) have as tereogenic center, which makes it possible to probe hyperpolarized long-lived singlet states and to permit transfer to 1 H. In the following,wewill demonstrate astrategy to store polarization in hyperpolarized 15 N 2 singlets and then convert the polarization from 15 Nsinglet order into 1 Hm agnetization for more sensitive detection.…”

“…An ew approach yielding terminal diazirines (-CHN 2 )i n only one step from a-amino acids has recently been demonstrated. [10] Isotopically enriched diazirines were readily created using 15 N-ammonia and 15 N-labeled amino acids or unlabeled ones,where diazirines bearing astereogenic center (asymmetric sulfur of the sulfoxide group) were synthesized from cysteine and methionine.T hese "terminal" diazirines replace methyl groups,o ne of the most commonly encountered chemical groups in biochemistry and beyond.…”

“…The tyrosine and histidine derivatives (2,3) represent non-chiral examples that were effectively synthesized with high yields. [10] Diazirines (4,5) have as tereogenic center, which makes it possible to probe hyperpolarized long-lived singlet states and to permit transfer to 1 H. In the following,wewill demonstrate astrategy to store polarization in hyperpolarized 15 N 2 singlets and then convert the polarization from 15 Nsinglet order into 1 Hm agnetization for more sensitive detection. Furthermore, we show that polarization is transferred from 15 Ns inglets to 1 Hp airs creating hyperpolarized 1 Hs inglet states,w hich exhibit significantly increased relaxation times.…”