relatively poor yield of the product (entry 3). From these obser-
vations it is clear that the oxidation step is facilitated by the
synergistic combination of air and palladium hydroxide (entries
E. Benfenati and G. Icardi, Carbohydr. Res., 1988, 184, 67;
(
1
f) R. J. Kerns, T. Tpoida and R. J. Linhardt, J. Carbohydr. Chem., 1996,
5, 581; (g) J. Rohovec, J. Kotek, J. A. Peters and T. Maschmeyer,
Eur. J. Org. Chem., 2001, 3899; (h) M. J. Lacey, M. S. Allen,
R. L. N. Harris and W. V. Brown, J. Enol. Viticul., 1991, 42, 103;
2
and 3). Running the entire reaction sequence under an atmos-
(i) M. S. Allen, M. J. Lacey and S. J. Boyd, J. Agric. Food Chem., 1995,
phere of hydrogen led to no detectable product (entry 4).
43, 769; ( j) A. Adams and N. de Kimpe, Food Chem., 2009, 115, 1417.
4
(a) B. R. Moser, J. Nat. Prod., 2008, 71, 487; (b) S. Lee, T. G. LaCour
and P. Fuchs, Chem. Rev., 2009, 109, 2275.
Conclusions
5
6
L. Chill, M. Aknin and Y. Kashman, Org. Lett., 2003, 14, 2433.
(a) R. Durán, E. Zubía, M. J. Ortega, S. Naranjo and J. Salvá, Tetrahe-
dron, 1999, 55, 13225; (b) R. Saito, M. Tokita, K. Uda, C. Ishikawa and
M. Satoh, Tetrahedron, 2009, 65, 3019.
In conclusion, we have investigated the proposed biomimetic
dimerization of amino acid-derived α-amino aldehydes into
natural 2,5-disubstituted pyrazines. Whilst Boc- and Fmoc-val-
inals 25a and 25b were not viable substrates for this biomimetic
transformation, Cbz-valinal 25c underwent hydrogenolysis,
dimerization and oxidation to the natural product 2,5-diisopro-
pylpyrazine 10 in a one-pot operation. This route was success-
fully extended to the biomimetic synthesis of 2,5-bis(3-
indolylmethyl)pyrazine 11 and actinopolymorphol C 12. The
biomimetic synthesis of the three natural products 10, 11 and 12
clearly demonstrates the viability of this recently proposed,
alternative biosynthetic route to 2,5-disubstituted pyrazines in
7 (a) G. Dunn, G. T. Newbold and F. S. Spring, J. Chem. Soc., 1949, 2586;
b) T. Yokotsuka, M. Sasaki, K. Kikuchi, Y. Asao and A. Nobuhara,
(
Nippon Nogeikagaku Kaishi, 1967, 41, 32; (c) M. Sasaki, Y. Asao and
T. Yokotsuka, Nippon Nogeikagaku Kaishi, 1968, 42, 288;
(d) K. Tatsuka, S. Tsuchiya and S. Umeyawa, J. Antibiot., 1972, 25, 674;
(e) K. Tatsuka, K. Fujimoto, M. Yamashita, T. Tsuchiya, S. Umeyawa and
H. Umeyawa, J. Antibiot., 1973, 26, 606.
W. Yong, J. B. Gloer, J. A. Scott and D. Malloch, J. Nat. Prod., 1995, 58,
8
93.
9 (a) J. F. Bousquet, H. B. de Franqueville, A. Kollmann and R. Fritz,
Can. J. Bot., 1980, 58, 2575; (b) M. Devys, M. Barbier, A. Kollmann
and J.-F. Bousquet, Tetrahedron Lett., 1982, 23, 5409.
1
0 (a) B. W. Zilkowski, R. J. Bartelt, D. Blumberg, D. G. James and D.
K. Weaver, J. Chem. Ecol., 1999, 25, 229; . The previous syntheses of 10
suffer from poor yield and selectivity: (b) S. Schulz, J. Fuhlendorff and
H. Reichenbach, Tetrahedron, 2004, 60, 3863; (c) J. S. Dickschat,
H. Reichenbach, I. Wagner Döbler and S. Schulz, Eur. J. Org. Chem.,
2005, 4141.
36
nature. It is envisaged the methodology reported herein will
provide a useful alternative to existing pyrazine syntheses.
Experimental
11 M. Shaaban, R. P. Maskey, I. Wagner-Döbler and H. Laatsch, J. Nat.
Full experimental details are included in the ESI.†
Prod., 2002, 65, 1660.
2 S.-X. Huang, E. Powell, S. R. Rajski, L.-X. Zhao, C.-L. Jiang, Y. Duan,
1
W. Xu and B. Shen, Org. Lett., 2010, 12, 3525.
Acknowledgements
13 For reviews on the biogenesis of pyrazines, see: (a) J. J. Brophy and
G. W. K. Cavill, Heterocycles, 1980, 14, 477; (b) G. P. Rizzi, Food Rev.
Int., 1988, 4, 375; (c) G. P. Rizzi, in Heteroaromatic Aroma Compounds,
ed. G. A. Reineccius and T. A. Reineccius, ACS, Washington, 2002, vol.
We thank Professor Hartmut Laatsch (Göttingen University) for
insightful discussions and for providing the original spectra of
826, p. 132.The synthesis of pyrazines generally relies on reactions out-
2
,5-bis(3-indolylmethyl)pyrazine 11. We are indebted to Pro-
lined in references 14–16.
fessor Stefan Schulz (TU Braunschweig) for valuable sugges-
tions during the preparation of the manuscript.
14 Condensation of a 1,2-dicarbonyl with a 1,2-diamine: S. Mahboobi,
A. Sellmer, T. Burgemeister, A. Lyssenko and D. Schollmeyer, Monatsh.
Chem., 2004, 135, 333.
1
5 Self-condensation of
(
(
a
non-amino acid derived 2-aminoketone:
a) A. B. Charette and T. Focken, Org. Lett., 2006, 8, 2985;
b) M. Montserrat Martínez, L. Sarandeses and J. Pérez Sestelo, Tetrahe-
Notes and references
1
(a) R. Mondal, S. Ko and Z. Bao, J. Mater. Chem., 2010, 20, 10568;
b) R. Saito, Y. Matsumura, S. Suzuki and N. Okazaki, Tetrahedron,
010, 66, 8273; (c) M. Wriedt, I. Jess and C. Näther, Eur. J. Inorg.
Chem., 2009, 363; (d) H.-Y. Liu, H. Wu, J.-F. Ma, J. Yang and Y.-Y. Liu,
Dalton Trans., 2009, 38, 7957; (e) M. A. S. Gother, B. Bitschnau,
B. Sodin, C. Gspan and F. A. Mautner, J. Mol. Struct., 2008, 886, 32;
dron Lett., 2007, 48, 8536; (c) M. Peña-López, M. Montserrat Martínez,
L. A. Sarandeses and J. Pérez Sestelo, Org. Lett., 2010, 12, 852.
(
2
16 Modification (metallation or cross-coupling) of a pre-constructed pyra-
zine: (a) C. Fruit, A. Turck, N. Plé, L. Mojovic and G. Quéguiner, Tetra-
hedron, 2001, 57, 9429; (b) F. Buron, N. Plé, A. Turck and G. Queguiner,
J. Org. Chem., 2005, 70, 2616; (c) R. Saito, M. Tokita, K. Uda,
C. Ishikawa and M. Satoh, Tetrahedron, 2009, 65, 3019.
(
f) S.-Y. Chang, J. Kavitha, S.-W. Li, C.-S. Hsu, Y. Chi, Y.-S. Yeh, P.-
T. Chou, G.-H. Lee, A. J. Carty, Y.-T. Tao and C.-H. Chien, Inorg.
Chem., 2006, 45, 137; (g) C. H. Chang, M. H. Yun and W. J. Choi,
Synth. Met., 2004, 145, 1.
17 (a) Y. Okada, H. Taguchi and T. Yokoi, Tetrahedron Lett., 1996, 37,
2249; (b) Y. Okada, H. Taguchi and T. Yokoi, Chem. Pharm. Bull., 1996,
44, 2259.
2
(a) M. Bobek and A. Bloch, J. Med. Chem., 1972, 15, 164;
18 (a) F. Buron, A. Turck, N. Plé, L. Bischoff and F. Marsais, Tetrahedron
Lett., 2007, 48, 4327; (b) For a biomimetic approach to bis-steroidal pyra-
zines: E. Haak and E. Winterfeldt, Synlett, 2004, 1414.
(b) L. J. Street, R. Baker, T. Book, A. J. Reeve, J. Saunders, T. Willson,
R. S. Marwood, S. Patel and S. B. Freedman, J. Med. Chem., 1992, 35,
2
2
95; (c) L. E. Seitz, W. J. Suling and R. C. Reynolds, J. Med. Chem.,
002, 45, 5604; (d) I. Niculescu-Duvaz, E. Roman, S. R. Whittaker,
19 S. Badrinarayanan and J. Sperry, Synlett, 2011, 2339.
20 T. Nawrath, J. S. Dickschat, B. Kunze and S. Schulz, Chem. Biodiv.,
2010, 7, 2129.
21 (a) A. Gallois, A. Kergomard and J. Adda, Food Chem., 1988, 28, 299;
(b) T.-B. Cheng, G. A. Reineccius, J. A. Bjorklund and E. Leete,
J. Agric. Food Chem., 1991, 39, 1009.
22 (a) A. Ohta, Chem. Pharm. Bull., 1964, 12, 125; (b) A. Ohta, Chem.
Pharm. Bull., 1968, 16, 1160; (c) A. Ohta and S. Fuji, Chem. Pharm.
Bull., 1969, 17, 851; (d) A. Ohta, Y. Akita, K. Takizawa, M. Kurihara,
S. Masano and T. Watanabe, Chem. Pharm. Bull., 1978, 26, 2046;
(e) A. Ohta, Y. Aoyagi, Y. Kurihara, K. Yuasa and M. Shimazaki, Hetero-
cycles, 1987, 26, 3181; (f) A. Ohta, Y. Aoyagi, Y. Kurihara, A. Kojima,
K. Yuasa and M. Shimazaki, Heterocycles, 1988, 27, 437; (g) A. Ohta,
A. Kojima and Y. Aoyagi, Heterocycles, 1990, 31, 1655; (h) A. Ohta,
A. Kojima, T. Saito, K. Kobayashi, H. Saito, K. Wakabayashi, S. Honma,
F. Friedlos, R. Kirk, I. J. Scanlon, L. C. Davies, D. Niculescu-Duvaz,
R. Marais and C. J. Springer, J. Med. Chem., 2008, 51, 3261; (e) X.-
C. Cheng, X.-Y. Liu, W.-F. Xu, X.-L. Guo, N. Zhang and Y.-N. Song,
Bioorg. Med. Chem., 2009, 17, 3018; (f) J. Zitko, M. Dolezai,
M. Svobodova, M. Vejsova, R. Kucera and P. Jilek, Bioorg. Med. Chem.,
2
011, 19, 1471; (g) M. L. N. Dubuisson, J.-F. Rees and J. Merchand-Bry-
naert, Mini-Rev. Med. Chem., 2004, 4, 421.
(a) J. A. Maga and C. E. Sizer, J. Agric. Food Chem., 1973, 21, 22;
3
(b) A. Arnoldi, C. Arnoldi, O. Baldi and A. Griffini, J. Agric. Food
Chem., 1988, 36, 988; (c) K. Sumoto, M. Irie, N. Mibu, S. Miyano,
Y. Nakashima, K. Watanabe and T. Yamaguchi, Chem. Pharm. Bull.,
1
991, 39, 792; (d) S. J. Eitelman and M. S. Feather, Carbohydr. Res.,
979, 77, 205; (e) G. Candiano, G. M. Ghiggeri, R. Gusmano, L. Zetta,
1
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