A rapid and highly enantioselective C–¹¹C bond formation of l-[¹¹C]phenylalanine via chiral phase-transfer catalysis

Abstract

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq μmol of the enantiomerically pure [C]phenylalanine, showing that the process is robust and amenable to broad use in PET.

Stereoselective 11C Labeling of a “Native” Tetrapeptide by Using Asymmetric Phase‐Transfer Catalyzed Alkylation Reactions

“…[17] On the basis of the results of our enantioselective synthesis of L-[ 11 C]phenylalanine, [16] initial experiments for the [ 11 Table 1), and further screening revealed an optimal concentration of 7 of >30 mM (Table 1, entries 7-9). The three-step, one-pot synthesis involved an initial Grignard reaction with [ 11 C]CO 2 to yield a [ 11 C]benzoic acid, which was further reduced and iodinated to [ 11 C]BnI, according to our previous report.…”

“…[3,10] The presence Figure 1. [12][13][14] Previously, we reported the highly stereoselective synthesis of L/D-[ 11 C]alanine [15] and L/D-[ 11 C]phenylalanine [16] by using a commercially available quaternary ammonium salt phase-transfer catalyst (PTC) with [ 11 C]methyl iodide or [ 11 C]benzyl iodide ([ 11 C]BnI). of carbon in all AAs and peptides makes carbon-11 (99 % + , 0.96 MeV) an ideal radionuclide for the synthesis of isotopologues of peptides.…”

Stereocontrolled [11C]Alkylation of N‐Terminal Glycine Schiff Bases To Obtain Dipeptides

“…To summarize, (S,S)-Cat8 yielded high diastereoselectivities with precursors 3 and 4, whereas with (R,R)-Cat9 better results were obtained with D-dipeptide precursors 7 and 8. The presented work was focused on the development of the radiochemistry method, and the molar activity is dependent upon the starting alkylation agent and provided by previous studies determined to be 50 [12] to 153 Gbq μmol -1 [13] of tracer ready for biological studies As soon as an authentic PET tracer candidate is achieved by implementing this methodology, the molar activity will be determined. Nonetheless, these catalysts are favorable for good enantioselectivities owing to strengthened internal hydrogen bonding by the F atoms with water, which leads to more rigid conformations of the catalysts.…”

Efficient Synthesis of 11C‐Acrylesters, 11C‐Acrylamides and Their Application in Michael Addition Reactions for PET Tracer Development

“…The second approach implemented here is a Pdmediated carbonylation reaction with [ 11 C]CO to obtain acrylester 3 and acrylamide 4. To date, this methodology has been successfully described in radiosyntheses of [ 11 C]alanine [15] and [ 11 C]phenylalanine, [16] as well as for dipeptides [17] and tetrapeptides. The more widespread application of [ 11 C]CO became possible in 2013 when Eriksson et al published a simplified procedure for the transfer of [ 11 C]CO making use of xenon gas and Dahl et al introduced xantphos as trapping support agent, which caused a major breakthrough.…”

“…The asymmetric radiolabeling approach with highly specialized chiral catalysts is unique and highly valuable to radiolabeled chiral compounds. To date, this methodology has been successfully described in radiosyntheses of [ 11 C]alanine [15] and [ 11 C]phenylalanine, [16] as well as for dipeptides [17] and tetrapeptides. [18] In addition, the asymmetric Michael addition [19,20] has been explored in 12 C-organic chemistry; however, this challenging radiosynthesis method is unprecedented in radiochemistry thus far.…”