UPDATES
Total Synthesis of Capsaicin Analogues from Lignin-Derived Compounds
novation Systems (VINNOVA). Dr. Luca Deiana is acknowl-
edged for initially providing Pd-controlled pore glass nano-
particles.
Experimental Section
Typical Procedure for the Synthesis of Nonivamide
(7b) from Vanillyl Alcohol (1a)
Step 1: An oven-dried microwave vial was loaded with va-
nillyl alcohol (1a) (46.3 mg, 0.3 mmol, 1.0 equiv.) and Pd(0)
nanocatalyst [Pd(0)-AmP-MCF, 20.1 mg, 0.015 mmol,
8 wt%] or [Pd(0)-AmP-CPG, 500 ꢂ, 90.0 mg, 0.015 mmol,
166 mmol/g] followed by addition of toluene (0.6 mL). Next,
the vial was sealed and a balloon filled with O2 was connect-
ed to it and the reaction mixture was stirred at 708C. After
3 h [when Pd(0)-AmP-MCF was used] or 2 h [when Pd(0)-
CPG, 500 ꢂ was used] the conversion had reached >99% to
vanillin (2a).
References
[1] E. K. Nelson, J. Am. Chem. Soc. 1919, 41, 1115–1121.
[2] D. J. Bennett, G. W. Kirby, J. Chem. Soc. C 1968, 442–
446.
[3] K. Iwai, T. Suzuki, H. Fujiwake, Agric. Biol. Chem.
1979, 43, 2493–2498.
[4] T. Kawada, T. Watanabe, K. Katsura, H. Takami, K.
Step 2: Vanillin (2a) (99.3 mg, 0.65 mmol, 1.0 equiv.) was
dissolved in DMSO (1.31 mL). d-Glucose (352.8 mg,
1.96 mmol, 3.0 equiv.), l-alanine (290.8 mg, 3.26 mmol,
5.0 equiv.) and ammonium chloride (104.8 mg, 1.96 mmol,
3.0 equiv.) were dissolved in 50 mM HEPES buffer (6 mL)
in a 50-mL falcon tube, the vanillin solution was added and
the pH was adjusted to 8.2 at 378C (1M NaOH). NADH
(9.55 mg, 0.013 mmol, 0.02 equiv.), glucose dehydrogenase
(GDH) (0.65 mg, 130.6 U) and amine transaminase (ATA)
(20.9 mg) were dissolved in 50 mM HEPES buffer (pH 8.2
at 378C) and added to the reaction tube, along with l-ala-
nine dehydrogenase (l-ADH) (20 mL, 91.4 U). More
HEPES buffer (50 mM, pH 8.2 at 378C) was added to give
a final volume of 13.06 mL and final concentrations 250 mM
L-alanine, 50 mM vanillin, 150 mM ammonium chloride,
150 mM d-glucose, 1 mM NADH and 10% DMSO v/v, to-
gether with 1.9 mg/mL ATA, 7 U/mL L-ADH and 10 U/mL
GDH. The reaction was performed in 378C and darkness
Iwai, J. Chromatogr. 1985, 329, 99–105.
[5] A. Kobayashi, T. Osaka, Y. Namba, S. Inoue, T. H. Lee,
S. Kimura, Am. J. Physiol. Regul. Integr. Comp. Physi-
ol. 1998, 275, R92–R98.
[6] T. Watanabe, T. Kawada, T. Kato, T. Harada, K. Iwai,
Life Sciences 1994, 54, 369–374.
[7] K. Kim, T. Kawada, K. Ishihara, K. Inoue, T. Fushiki,
Biosci. Biotechnol. Biochem. 1997, 61, 1718–1723.
[8] T. Kawada, K. Hagihara, K. Iwai, J. Nutr. 1986, 116,
1272–1278.
[9] a) K. Bley, G. Boorman, B. Mohammad, D. McKenzie,
S. Babbar, Toxicol. Pathol. 2012, 40, 847–873; b) Y.
Surh, J. Natl. Cancer Inst. 2002, 94, 1263–1265; c) A.
Oyagbemi, A. Saba, O. Azeez, Indian J. Cancer 2010,
47, 53–58.
[10] E. K. Nelson, J. Am. Chem. Soc. 1919, 41, 2121–2130.
[11] K. Abiraj, D. C. Gowda, J. Chem. Res. (S) 2003, 6, 332–
334.
[12] a) P. M. Gannett, D. L. Nagel, P. J. Reilly, T. Lawson, J.
Sharpe, B. Toth, J. Org. Chem. 1988, 53, 1064–1071;
b) H. Kaga, M. Miura, K. Orito, J. Org. Chem. 1989,
54, 3477–3478.
with no stirring. After 22 h the conversion to vanillylACHTUNTRGNEUNGamine
(4a) had reached 94% as determined by HPLC analysis. The
pH of the solution was adjusted to 12 (1M NaOH), and the
reaction mixture was freeze-dried, in order to remove the
water.
[13] B. Wang, F. Yang, Y. Shan, W. Qiu, J. Tang, Tetrahedron
2009, 65, 5409–5412.
Step 3: The dried crude reaction mixture from the previ-
ous step (containing vanillylamine 94 mg, 0.62 mmol,
1.00 equiv.) was dissolved in 2-methyl-2-butanol (31 mL,
20 mM). To the reaction was added 4ꢂ molecular sieves
(2 g), compound 5b (98.7 mg, 0.62 mmol, 1.00 equiv.) and
lipase (1.9 g, 20 mg/mL). The reaction was stirred at 458C
for 48 h. Afterwards the reaction was cooled to room tem-
perature and filtered. The solvent was removed under re-
duced pressure and the crude material was purified by chro-
matography to afford nonivamide (7b) as a light yellow oil;
isolated yield: 52%.
[14] a) K. Kobata, K. Yoshikawa, M. Kohashi, T. Watanabe,
Tetrahedron Lett. 1996, 37, 2789–2790; b) K. Kobata,
M. Toyoshima, M. Kawamura, T. Watanabe, Biotech-
nol. Lett. 1998, 20, 781–783; c) M. Koreishi, D. Zhang,
H. Imanaka, K. Imamura, S. Adachi, R. Matsuno, K.
Nakanishi, J. Agric. Food Chem. 2006, 54, 72–78; d) E.
Castillo, A. Torres-Gavilꢃn, P. Severiano, N. Arturo, A.
Lꢀpez-Munguꢄa, Food Chem. 2007, 100, 1202–1208.
[15] That vanillin is produced from wood in 1,500 tonnes
every year by Borregaard. Life-Cycle Assessment
proves that wood-derived vanillin has a 90% smaller
CO2 footprint as compared to mineral oil-based vanil-
nillin-extracted-from-wood-at-borregaard/).
More details and information about other procedures can
be found in the Supporting Information.
[16] S. R. Collinson, W. Thielemans, Coord. Chem. Rev.
2010, 254, 1854–1870.
[17] a) S. F. Mayer, W. Kroutil, K. Faber, Chem. Soc. Rev.
2001, 30, 332–339; b) Z. Du, Z. Shao, Chem. Soc. Rev.
2013, 42, 1337–1378; c) C. A. Denard, J. F. Hartwig, H.
Zhao, ACS Catal. 2013, 3, 2856–2864.
[18] P. Berglund, M. S. Humble, C. Branneby, in: Compre-
hensive Chirality, (Eds.: E. M. Carreira, H. Yamamoto),
Elsevier, Amsterdam, 2012, Vol. 7, pp 390–401.
Acknowledgements
We gratefully acknowledge financial support from KTH
Royal Institute of Technology for an excellence PhD student
position to MA, the European Union Structural Funds, Mid
Sweden University and the Swedish National Research Coun-
cil (VR). The Berzelii Center EXSELENT is financially sup-
ported by VR and the Swedish Governmental Agency for In-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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