Angewandte
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the donor in the presence of imidazole, thus achieving yields
Conflict of interest
of up to 95% for these reactions when run for 24 hours (see
the Supporting Information). We also confirmed the enzy-
matic Fries product of 4b into 2b on a semi-preparative scale
[46% yield (isolated), Scheme 2]. It is worth mentioning, that
the catalyst loading in comparison to the substrate was just
0.05 mol%.
The authors declare no conflict of interest.
Keywords: acylation · arenes · biocatalysis · enzymes ·
rearrangements
We examined the ability of ATase to transfer acyl groups
other than acetyl by testing the propanoyl analogues of
MAPG (2a) and DAPG (3a). Di- and monopropanoylphlor-
oglucinol (DPPG/MPPG, 15 mm) were readily accepted as
donors for the transformation of 1b (10 mm), thus yielding the
respective C-monopropanoylated product 6b with 69% (for
DPPG) and 50% (for MPPG) conversion after 18 hours
(Scheme 1b). Employing vinyl propionate as donor for the
C-acylation of 1b, using the same reaction conditions as with
IPEA/Im, resulted in the formation of 14% of 6b within
18 hours. However, larger acyl groups (like n-butanoyl) were
not transferred by this transferase.
Summarizing, the regioselective C-acylation of resorcinol
derivatives has been demonstrated using a biocatalyst and
readily available IPEA in buffer. The presented biocatalytic
Friedel–Crafts acylation method and, to the best of our
knowledge, the first preparative biocatalytic equivalent to the
Fries rearrangement[19] may open an avenue for the extension
ˇ
[1] S. Grucarevic, V. Merz, Chem. Ber. 1873, 6, 60.
[2] C. Friedel, J. M. Crafts, C. R. Hebd. Seances Acad. Sci. 1877, 84,
1450 – 1454.
[3] a) G. A. Olah, Friedel – Crafts chemistry, Wiley, New York, 1973;
b) M. B. Smith, J. March, Marchꢀs Advanced Organic Chemistry,
Ed. 6, Wiley, New Jersey, 2007.
[4] Examples include Lewis acids (AlCl3, BF3), Brønsted acids (HF,
H2SO4), palladium, trimethylsilyl polyphosphate, and recyclable
solid catalysts (zeolites, Nafionꢁ, metal oxides, heteropoly acids,
etc.). See for instance: a) F. Mo, L. J. Trzepkowski, G. Dong,
´
[5] L. A. Wessjohann, H. F. Schreckenbach, G. N. Kaluderovic in
¯
Science of Synthesis: Biocatalysis in Organic Synthesis, Vol. 2
(Eds.: K. Faber, W.-D. Fessner, N. J. Turner), Thieme, Stuttgart,
2015, pp. 177 – 211.
À
of the biocatalytic toolbox for C C bond formation meth-
ods[20,21] to be applied in organic synthesis and biotechnology.
[6] a) M. Tengg, H. Stecher, L. Offner, K. Plasch, F. Anderl, H.
Experimental Section
General procedure for the Friedel–Crafts bioacetylations of 1b–h
and 1j on semi-preparative scale: The acceptor 1b–h or 1j (10 mm
final concentration) was dissolved in potassium phosphate buffer
(50 mm, pH 7.5) in a baffled shaking flask. Imidazole (100 mm, added
from a 1m stock solution prepared in the reaction buffer) was
subsequently added. The mixture was preheated to 358C for
10 minutes. Meanwhile, cell-free extract containing the PpATaseCH
(165 U, 3.1 mm) was thawed at 218C, followed by a short preheating
period (358C, 10 min). The enzyme solution was added to the reaction
mixture and the bioacetylation was started by adding IPEA (100 mm
final concentration). The bioacetylation (100 mL total volume, final
pH 8.30) was run at 358C and 140 rpm for 24 h. The reaction was
aborted by acidification (pH ꢀ 1.0) with aq. HCl (6 n) and shaking
was continued for further 10 minutes to precipitate protein. The
resulting suspension was extracted with CH2Cl2 (3 ꢀ 50 mL). The
organic layers which still contained imidazolium salt and/or protein
precipitate were centrifuged (15 min, 14000 rpm) to remove the
remaining solids. The cleared organic layers were pooled in a sepa-
ration funnel, washed with brine (2 ꢀ 40 mL), dried over anhydrous
Na2SO4 and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography. Compounds
were characterized by 1H and 13C NMR spectroscopy and GC-MS,
and the chemical identity was confirmed by comparison to literature
data (see the Supporting Information).
[8] I. Drienovskꢂ, A. Rioz-Martꢃnez, A. Draksharapu, G. Roelfes,
[9] V. P. Reddy, G. K. S. Prakash in The Chemistry of Phenols, Vol. 1
(Ed.: Z. Rappoport), Wiley-VCH, Weinheim, 2003, p. 605.
[10] a) J. Sun, C. Lin, X. Qin, X. Dong, Z. Tu, F. Tang, C. Chen, J.
27, 393 – 416; c) J. H. P. Tyman, Synthetic and Natural Phenols,
Elsevier, New York, 1996.
[11] a) A. Hayashi, H. Saitou, T. Mori, I. Matano, H. Sugisaki, K.
[12] a) M. G. Bangera, L. S. Thomashow, J. Bacteriol. 1999, 181,
3155 – 3163; b) J. Achkar, M. Xian, H. Zhao, J. W. Frost, J. Am.
[14] E. Angov, C. J. Hillier, R. L. Kincaid, J. A. Lyon, PLoS One
4284; b) A. Gerecs in Friedel – Crafts and Related Reactions,
Vol. 3, Part 1 (Ed.: G. A. Olah), Wiley, London, 1964, p. 449.
[16] The Fries rearrangement may also take place intermolecular-
[17] a) A. S. de Miranda, L. S. M. Miranda, R. O. M. A. de Souza,
d) U. T. Bornscheuer, R. J. Kazlauskas, Hydrolases in Organic
Synthesis: Regio- and Stereoselective Biotransformations,
2nd Ed., Wiley-VCH, Weinheim, 2006.
Acknowledgments
This study was financed by the Austrian FFG, BMWFJ,
BMVIT, SFG, Standortagentur Tirol and ZIT through the
Austrian FFG-COMET- Funding Program. COST Action
CM1303 “Systems Biocatalysis” is acknowledged.
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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