Alternative One-Pot Synthesis of (Trifluoromethyl)phenyldiazirines from Tosyloxime Derivatives: Application for New Synthesis of Optically Pure Diazirinylphenylalanines for Photoaffinity Labelingby Lei Wang, Yuta Murai, Takuma Yoshida, Akiko Ishida, Katsuyoshi Masuda, Yasuko Sakihama, Yasuyuki Hashidoko, Yasumaru Hatanaka, Makoto Hashimoto

Org. Lett.


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Alternative One-Pot Synthesis of (Trifluoromethyl)phenyldiazirines from Tosyloxime Derivatives: Application for New Synthesis of

Optically Pure Diazirinylphenylalanines for Photoaffinity Labeling

Lei Wang,† Yuta Murai,†,∥ Takuma Yoshida,† Akiko Ishida,† Katsuyoshi Masuda,‡ Yasuko Sakihama,†

Yasuyuki Hashidoko,† Yasumaru Hatanaka,§ and Makoto Hashimoto*,† †Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-ku, Sapporo 060-8589,

Japan ‡Suntory Institute for Bioorganic Research, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan §Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan *S Supporting Information

ABSTRACT: Alternative one-pot synthesis of 3-(trifluoromethyl)-3-phenyldiazirine derivatives from corresponding tosyloximes is developed. The deprotonation of intermediate diaziridine by NH2 − is a new approach for construction of diazirine. Moreover, a novel synthesis of optically pure (trifluoromethyl)diazirinylphenylalanine derivatives was attempted involving these methods. 3-(Trifluoromethyl)-3-phenyldiazirine (TPD)1 has emerged as the most effective photoreactive group in photoaffinity labeling2 because of its relatively small size, long activation wavelength (approximately 360 nm), thermal and chemical stability, low rate of rearrangement, and high reactivity of its intermediate.3

Nevertheless, compared to the other commonly used photoreactive groups in photoaffinity labeling (aryl azides2b and benzophenones4), the tedious synthetic procedure of TPD derivatives is a major consideration for researchers. In the past decades, the formation of diaziridines from tosyloxime derivatives is the crucial step to further construct TPD (Scheme 1, I). Generally, liquid NH3 was used to construct diaziridines from tosyloximes (Scheme 1, I, step 1). Despite its wide use, long reaction time and low yields were reported.5 To further construct TPD derivatives by oxidation6 (Scheme 1, I, step 2), the inevitable isolation of diaziridines, preparation of fresh oxidant,6b and post-treatment after oxidation were also time-consuming and yield-diminishing. In light of the importance of TPD derivatives, a convenient method to prepare TPD derivatives from tosyloximes can not only decrease the cost and waste but also minimize the synthetic cycles of TPD-containing probes in photoaffinity labeling.

Optically pure (trifluoromethyl)diazirinylphenylalanine ((Tmd)Phe) has been used as important building block for investigation of peptides, proteins, and other biomacromolecule.7 One widely used method to prepare optically pure (Tmd)Phe derivatives involved the concatenation of halogenated TPD and α-amino acids followed by the enzymatic resolution of N-acylamino acids7e,8 or the use of amino acid oxidase to afford the relative configuration.9 Asymmetric syntheses were achieved through treatment of halogenated

TPD with the chiral Ni complex10 or cinchonidine-based asymmetric catalyst.7b By combination of p-diodobenzene and

L-serine, Fillion et al. prepared Fmoc-L-(4-Tmd)Phe with a 14% overall yield via 10 steps.7c However, although the preparation were successful, all of the above-mentioned methods generally could not circumvent tedious enzymatic procedure, low yields, complicated preparation of chiral complex, or a limited configuration of the desired products. Herein, for the first time, we developed a one-pot synthesis of TPD derivatives from the corresponding tosyloximes (Scheme 1, II). For further application, direct construction of the Tmd group on optically pure phenylalanines for preparation of (Tmd)Phe derivatives was first reported.

During the synthesis of diaziridines with liquid NH3, we found that the corresponding TPD derivatives were sometimes generated in small amounts, possibly derived from diaziridines.

To confirm our hypothesis, initial studies were performed using

Received: December 16, 2014

Published: January 14, 2015

Scheme 1. Construction of TPD Derivatives from the

Corresponding Tosyloximes

Letter © 2015 American Chemical Society 616 DOI: 10.1021/ol503630z

Org. Lett. 2015, 17, 616−619 tosyloxime 1a as the model substrate. It was found that formation of TPD 3a, at room temperature, was dependent on reaction time to a great extent (Table 1, entries 1−3).

Temperature optimization indicated that 80 °C was clearly ideal for the reaction (Table 1, entries 4 and 5). However, reaction at 100 °C resulted in decomposition of the diazirine ring within 1 h (Figure S1, Supporting Information). No decomposition of diazirine and high isolated yield of 3a (Table 1, entry 5) indicated the viability of this strategy. Other solvents also worked well, although reactions did not improve (Table 1, entries 6 and 7). An attempt to perform the reaction in the absence of solvent was successful (Table 1, entry 8), which was beneficial for the tosyloximes with low solubility in common organic solvents. To confirm the species responsible for the formation of 3a, tosyloxime 1a was directly treated with gaseous NH3 at 80 °C (Table 1, entry 9). Diaziridine 2 was detected as the sole product without 3a, indicating liquid NH3 was essential for the formation of 3a. On the basis of these results, we postulated that the NH2 − species generated from liquid NH3 11 may be responsible for the formation of TPD 3a, despite liquid NH3 having a low self-ionization constant (pKa = 27.6 at 25 °C).12 A control experiment with NH4Cl as an ion counter for inhibiting the self-ionization of liquid NH3 also confirmed this hypothesis (Table 1, entry 10). Inspired by these results, a series of experiments with alkali amide as NH2 − supplier in liquid NH3 were carried out at low temperature.

Initially, lithium amide was tested, but the reaction at −78 °C afforded 2 in 100% yield without 3a after 12 h (Table 1, entry 11). To our delight, reaction at 0 °C provided 3a in 100% yield within 10 h (Table 1, entry 12). The reaction was completed within 4 h at room temperature (Table 1, entry 13). Sodium amide and sodium hydride afforded to no desired product due to the ammonolysis of ester (Table 1, entries 14 and 15), but diazirine ring was formed. Further investigation indicated that both reagents were suitable for synthesis of TPD without substituent (Table S1, Supporting Information). Compared to sodium amide, lithium amide displays low solubility in liquid