Biomimetic synthesis of 2,5-Bis(indol-3-ylmethyl)pyrazine via intermolecular amino aldehyde cyclization

Article abstract of DOI:10.1055/s-0030-1260310

The biomimetic synthesis of the natural product 2,5-bis(3-indolylmethyl) pyrazine (11) is described. The 2,5-disubstituted pyrazine was constructed by the novel biomimetic cyclization of a tryptophan-derived amino aldehyde. The synthesis validates a recen

Full text of DOI:10.1055/s-0030-1260310

LETTER
2339
Biomimetic Synthesis of 2,5-Bis(indol-3-ylmethyl)pyrazine via Intermolecular
Amino Aldehyde Cyclization
B
iomimetic Sy
a
nthesis of
nd
hpyrazine ya Badrinarayanan, Jonathan Sperry*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax +64(9)3737422; E-mail: j.sperry@auckland.ac.nz
Received 14 June 2011
natural 2,5-disubstituted pyrazines. Herein, we provide
Abstract: The biomimetic synthesis of the natural product 2,5-
bis(3-indolylmethyl)pyrazine (11) is described. The 2,5-disubstitut-
ed pyrazine was constructed by the novel biomimetic cyclization of
a tryptophan-derived amino aldehyde. The synthesis validates a re-
strong support for the biosynthesis of 2,5-disubstituted
pyrazines via path B with the total synthesis of the natural
product 2,5-bis(3-indolylmethyl)pyrazine (11) using the
cently proposed, alternative biosynthetic pathway into the construc- biomimetic cyclization of a tryptophan-derived amino al-
tion of 2,5-disubstituted pyrazine natural products.
dehyde. This novel intermolecular cyclization proceeds
under mild conditions, providing new insight into the bio-
synthesis of amino acid derived, 2,5-disubstituted pyra-
zines in nature.
Key words: pyrazine, biomimetic, alkaloid, cyclization
Compounds containing the pyrazine heterocycle have
widespread application in the science of food,1 materials2
and medicinal chemistry3 but are not commonly observed
as natural products. Although the bis-steroidal cephalost-
atins and ritterazines4 are arguably the most well-known
examples, the majority of pyrazine natural products are
derived from amino acids. Selected examples include bar-
renazines A (1) and B (2),5 botryllazines A (3) and B (4),6
flavacol (5),7 deoxymutaaspergillic acid (6),7 deoxy-
aspergillic acid (7),7 terezine A (8),8 septorine (9),9 acti-
N
HN
R
R
NH
N
barrenazine A, R = (CH2)3Me 1
barrenazine B, R = (CH2)2CH=CH2
2
OH
N
O
N
N
O
O
OH
nopolymorphol
C
(10),10 2,5-bis(3-indolylmethyl)-
N
pyrazine (11)11 and 2,5-diisopropylpyrazine (12)12
(Figure 1). Despite being small in number, the synthesis
of natural pyrazines has received widespread attention.
Generally speaking, construction of the pyrazine hetero-
cycle is achieved by the condensation of a 1,2-dicarbonyl
with a 1,2-diamine component,13 metalation of a pre-con-
structed pyrazine14 or the self-condensation of a non-
amino acid derived 2-aminoketone.15
OH
OH
botryllazine A
botryllazine B
3
4
OH
N
N
MeO
N
N
R
OH
OH
flavacol
R = CH2CH(Me)2
deoxymuta-aspergillic acid,
R = CH(Me)2
OH
5
Our interest in the aforementioned natural products is fo-
cused on their biomimetic synthesis and in particular
pyrazines possessing a 2,5-disubstitution pattern (i.e. 10–
12). Pyrazines have long been thought to originate in na-
ture from the reduction and aromatization of diketopiper-
azines (Scheme 1, Path A), a postulate that is highly
plausible when considering the oxygenation patterns ob-
served in the tri- and tetrasubstituted pyrazines 5–9.16 In a
fascinating recent development, labeling studies into the
biosynthesis of 2,5-diisopropylpyrazine (12) have cast
doubt into the validity of path A, instead pointing to a
pathway in which the amino acid (valine) is first reduced
to the amino aldehyde which then undergoes cyclization
(Scheme 1, Path B).17 It is attractive to imagine this alter-
native biosynthetic pathway is potentially operating for all
(–)-terezine A
8
6
deoxyaspergillic acid
R = CH(Me)CH2Me 7
MeO
HO
N
N
OH
HO
N
5
O
(+)-septorine
2
9
N
OH
actinopolymorphol C
(tyrosine-derived)
10
N
5
2
N
N
5
N
NH
2
N
H
2,5-diisopropylpyrazine
(valine-derived)
12
2,5-bis(3-indolylmethyl)pyrazine
(tryptophan-derived)
SYNLETT 2011, No. 16, pp 2339–2342
Advanced online publication: 13.09.2011
x
x
.x
x
.2
0
1
1
11
DOI: 10.1055/s-0030-1260310; Art ID: D18911ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Selected amino acid derived pyrazines

2340
S. Badrinarayanan, J. Sperry
LETTER
Thus, a scalable synthesis of the key biomimetic cycliza-
tion precursor 14 was sought. Commercially available
Cbz-L-tryptophan underwent straightforward HATU-me-
diated amide coupling with N,O-dimethylhydroxylamine
hydrochloride furnishing the known Weinreb amide 15.20
Treatment of 15 with lithium aluminum hydride delivered
aldehyde 14,21,22 the masked amino aldehyde substrate for
the proposed biomimetic cyclization, in excellent overall
yield (Scheme 3).
O
O
NH
OH
NH2
cyclization
path A
R
R
R
HN
O
amino
acid
diketopiperazine
reduction
then
reduction
path B
aromatization
cyclization
then
aromatization
O
N
H
2
R
5
R
OMe
O
R
N
NH2
amino
aldehyde
N
CO2H
pyrazine
Me
HNMe(OMe)
HATU, Et3N
CH2Cl2
NHCbz
NHCbz
Scheme 1 Proposed biosyntheses of 2,5-disubstituted pyrazines
N
100%
N
H
H
The natural product 2,5-bis(3-indolylmethyl)pyrazine
(11) was isolated in 2002 from the bacterial strain Cyto-
phaga sp. AM13.1 obtained from the North sea. As allud-
ed to previously, the pyrazine ring present in 11 is
potentially constructed biosynthetically by the intermo-
lecular cyclization of an amino aldehyde (Scheme 1, path
B) and is not derived from the corresponding diketopiper-
azine.18 We set out to test this hypothesis and instigated a
biomimetic synthesis of 11 based on this recently pro-
posed alternative biosynthetic pathway17 and the retrosyn-
thesis of 11 is shown in Scheme 2. In the key biomimetic
step, the pyrazine core of 11 was to be obtained from the
intermolecular cyclization of the amino aldehyde 13. Due
to the stability issues often associated with a-amino alde-
hydes, we sought to unmask 13 by the hydrogenolysis19 of
the Cbz-derivative 14.
Cbz-L-tryptophan
15
LiAlH4
Et2O
90%
CHO
CHO
NH2
H2
Pd(OH)2
MeOH–CH2Cl2–
AcOH
NHCbz
2 x
N
H
N
H
13
14
N
N
remove H2
and stir
under air
NH
73%
from 14
N
11
H
Scheme 3 Biomimetic synthesis of 2,5-bis(3-indolylmethyl)pyrazine
(11)
N
With multigram quantities of 14 to hand, we were keen to
attempt the key biomimetic cyclization. Upon subjecting
14 to an atmosphere of hydrogen over Pd(OH)2 (Pearl-
man’s catalyst), TLC analysis of the reaction mixture in-
dicated the formation of a polar product, assumed to be
the amino aldehyde 13. At this point the hydrogen gas was
immediately removed (to avoid the hydrogenation of any
imine intermediates) and the reaction mixture was stirred
at room temperature under air. Upon purification, the sole
product isolated was gratifyingly confirmed as 11, as de-
termined by the excellent agreement between the spectro-
scopic data of our synthetic material23,24 and those of the
natural product11 (Scheme 3, Table 1).
N
NH
N
H
11
biomimetic
[O]
amino aldehyde
cyclization
H2N
CHO
NH2
OHC
NH
13
N
H
remove
Cbz
In conclusion, we have achieved a biomimetic synthesis
of the natural product 2,5-bis(3-indolylmethyl)pyrazine
(11). The 2,5-disubstituted pyrazine was constructed in a
single pot by a novel biomimetic cyclization of a tryp-
tophan-derived amino aldehyde. The synthesis validates a
recently proposed alternative biosynthetic pathway into
the construction of 2,5-disubstituted pyrazines in nature.
Synthetic studies towards the biomimetic synthesis of fur-
ther 2,5-disubstituted pyrazines is in progress and will be
reported in due course.
CHO
NHCbz
14
N
H
Scheme 2 Retrosynthesis of 2,5-bis(3-indolylmethyl)pyrazine (11)
Synlett 2011, No. 16, 2339–2342 © Thieme Stuttgart · New York

LETTER
Biomimetic Synthesis of 2,5-Bis(indol-3-ylmethyl)pyrazine
2341
Table 1 NMR Data of Synthetic and Natural 2,5-Bis(3-indolylmethyl)pyrazine (11)
1
N
6
8''
2
5
3''
2''
1''
NH
8'
3'
4'
7'
3
N
4
3a''
3a'
7a'
5'
6'
4''
5''
7a''
2'
N 1'
7''
H
6''
Atom no.
Natural 2,5-bis(3-indolylmethyl)pyrazine11
Synthetic 2,5-bis(3-indolylmethyl)pyrazine23,24
1H NMR (d)
(300 MHz, CDCl3)
13C NMR (d)
1H NMR (d)
13C NMR (d)
(100 MHz, DMSO-d6)
(75 MHz, DMSO-d6) (400 MHz, CDCl3)
C2, C5
153.7
153.7
142.9
C3, C6
8.43 (s, 2 H)
142.9
8.44 (s, 2 H)
N1¢, N1¢¢
C2¢, C2¢¢
C3¢, C3¢¢
C3a¢, C3a¢¢
C4¢, C4¢
C5¢, C5¢¢
C6¢, C6¢¢
C7¢, C7¢¢
C7a¢, C7a¢¢
C8¢, C8¢¢
8.05 (br s, 2 H)
8.03 (br s, 2 H)
7.05 (d, J = 0.8 Hz, 2 H)
123.4
111.6
126.8
121.0
118.4a
118.4a
111.4
136.2
30.8
7.06 (d, J = 0.8 Hz, 2 H)
123.4
111.5
126.8
120.9
118.4a
118.4a
111.3
136.2
30.8
7.35 (dd, J = 8.3, 1.1 Hz, 2 H)
7.07 (dt, J = 7.2 1.1 Hz, 2 H)
7.18 (dt, J = 7.2, 1.2 Hz, 2 H)
7.53 (dd, J = 7.9, 1.1 Hz, 2 H)
7.35 (d, J = 8.4 Hz, 2 H)
7.08 (dt, J = 7.0, 1.1 Hz, 2 H)
7.18 (dt, J = 8.4, 1.2 Hz, 2 H)
7.53 (dd, J = 8.0, 0.8 Hz, 2 H)
4.26 (s, 4 H)
4.26 (s, 4 H)
a The peaks corresponding to the chemical shift of the carbons at C5¢, C5¢¢, C6¢¢ and C6¢¢ overlap in 13C NMR spectrum of both the natural and
synthetic samples.
Bitschnau, B.; Sodin, B.; Gspan, C.; Mautner, F. A. J. Mol.
Supporting Information for this article is available online at
Struct. 2008, 886, 32. (f) Chang, S.-Y.; Kavitha, J.; Li,
S.-W.; Hsu, C.-S.; Chi, Y.; Yeh, Y.-S.; Chou, P.-T.; Lee,
G.-H.; Carty, A. J.; Tao, Y.-T.; Chien, C.-H. Inorg. Chem.
2006, 45, 137. (g) Chang, C. H.; Yun, M. H.; Choi, W. J.
Synth. Met. 2004, 145, 1.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are indebted to Professor Hartmut Laatsch (Göttingen Univer-
sity) for insightful discussions and for providing the original spectra
of 2,5-bis(3-indolylmethyl)pyrazine.
(3) For selected examples, see: (a) Bobek, M.; Bloch, A.
J. Med. Chem. 1972, 15, 164. (b) Street, L. J.; Baker, R.;
Book, T.; Reeve, A. J.; Saunders, J.; Willson, T.; Marwood,
R. S.; Patel, S.; Freedman, S. B. J. Med. Chem. 1992, 35,
295. (c) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med.
Chem. 2002, 45, 5604. (d) Niculescu-Duvaz, I.; Roman, E.;
Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I. J.;
Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer,
C. J. J. Med. Chem. 2008, 51, 3261. (e) Cheng, X.-C.; Liu,
X.-Y.; Xu, W.-F.; Guo, X.-L.; Zhang, N.; Song, Y.-N.
Bioorg. Med. Chem. 2009, 17, 3018. (f) Zitko, J.; Dolezai,
M.; Svobodova, M.; Vejsova, M.; Kucera, R.; Jilek, P.
Bioorg. Med. Chem. 2011, 19, 1471. (g) Dubuisson, M. L.
N.; Rees, J.-F.; Brynaert-Merchand, J. Mini-Rev. Med.
Chem. 2004, 4, 159.
(4) (a) Moser, B. R. J. Nat. Prod. 2008, 71, 487. (b) Lee, S.;
LaCour, T. G.; Fuchs, P. Chem. Rev. 2009, 109, 2275.
(5) Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 14, 2433.
(6) (a) Durán, R.; Zubía, E.; Ortega, M. J.; Naranjo, S.; Salvá, J.
Tetrahedron 1999, 55, 13225. (b) Saito, R.; Tokita, M.;
Uda, K.; Ishikawa, C.; Satoh, M. Tetrahedron 2009, 65,
3019.
References and Notes
(1) (a) Maga, J. A.; Sizer, C. E. J. Agric. Food Chem. 1973, 21,
22. (b) Arnoldi, A.; Arnoldi, C.; Baldi, O.; Griffini, A.
J. Agric. Food Chem. 1988, 36, 988. (c) Sumoto, K.; Irie,
M.; Mibu, N.; Miyano, S.; Nakashima, Y.; Watanabe, K.;
Yamaguchi, T. Chem. Pharm. Bull. 1991, 39, 792.
(d) Eitelman, S. J.; Feather, M. S. Carbohydr. Res. 1979, 77,
205. (e) Candiano, G.; Ghiggeri, G. M.; Gusmano, R.; Zetta,
L.; Benfenati, E.; Icardi, G. Carbohydr. Res. 1988, 184, 67.
(f) Kerns, R. J.; Tpoida, T.; Linhardt, R. J. J. Carbohyr.
Chem. 1996, 15, 581. (g) Rohovec, J.; Kotek, J.; Peters, J.
A.; Maschmeyer, T. Eur. J. Org. Chem. 2001, 3299.
(2) For recent examples, see: (a) Mondal, R.; Ko, S.; Bao, Z.
J. Mater. Chem. 2010, 20, 10568. (b) Saito, R.; Matsumura,
Y.; Suzuki, S.; Okazaki, N. Tetrahedron 2010, 66, 8273.
(c) Wriedt, M.; Jeß, I.; Näther, C. Eur. J. Inorg. Chem. 2009,
363. (d) Liu, H.-Y.; Wu, H.; Ma, J.-F.; Yang, J.; Liu, Y.-Y.
Dalton Trans. 2009, 38, 7957. (e) Goher, M. A. S.;
Synlett 2011, No. 16, 2339–2342 © Thieme Stuttgart · New York

2342
S. Badrinarayanan, J. Sperry
LETTER
(7) (a) Dunn, G.; Newbold, G. T.; Spring, F. S. J. Chem. Soc.
1949, 2586. (b) Yokotsuka, T.; Sasaki, M.; Kikuchi, K.;
Asao, Y.; Nobuhara, A. Nippon Nogeikagaku Kaishi 1967,
41, 32. (c) Sasaki, M.; Asao, Y.; Yokotsuka, T. Nippon
Nogeikagaku Kaishi 1968, 42, 288. (d) Tatsuka, K.;
Tsuchiya, S. J. Antibiot. 1972, 25, 674. (e) Tatsuka, K.;
Fujimoto, K.; Yamashita, M.; Tsuchiya, T.; Umeyama, S.;
Umeyama, H. J. Antibiot. 1973, 26, 606.
(20) (a) Rodriguez, M.; Lignon, M.-L.; Galas, M.-C.; Fulcrand,
P.; Mendre, C.; Aumelas, A.; Laur, J.; Martinez, J. J. Med.
Chem. 1987, 30, 1366. (b) Shao, Y. M.; Yang, W.-B.; Peng,
H.-P.; Hsu, M.-F.; Tsai, K.-C.; Kuo, T.-H.; Wang, A. H.-J.;
Liang, P.-H.; Lin, C.-H.; Yang, A.-S.; Wong, C.-H.
ChemBioChem 2007, 8, 1654.
(21) Aldehyde 14 has been employed as an intermediate in
alkaloid syntheses, but has not been characterized due to its
poor stability. See: (a) Dyke, H.; Steel, P. G.; Thomas, E. J.
J. Chem. Soc., Perkin Trans. 1 1989, 525. (b) Herranz, R.;
Vinuesa, S.; Pérez, C.; García-López, M. T.; De Ceballos,
M. L.; del Rio, J. J. Chem. Soc., Perkin Trans. 1 1991, 2749.
(c) In our hands, 14 was stable at 0 °C under argon for 2
weeks.
(8) Yong, W.; Gloer, J. B.; Scott, J. A.; Malloch, D. J. Nat. Prod.
1995, 58, 93.
(9) (a) Bousquet, J. F.; Belhomme de Franqueville, H.;
Kollmann, A.; Fritz, R. Can. J. Bot. 1980, 58, 2575.
(b) Devys, M.; Barbier, M.; Kollmann, A.; Bousquet, J.-F.
Tetrahedron Lett. 1982, 23, 5409.
(10) Huang, S.-X.; Powell, E.; Rajski, S. R.; Zhao, L.-X.; Jiang,
C.-L.; Duan, Y.; Xu, W.; Shen, B. Org. Lett. 2010, 12, 3525.
(11) Shaaban, M.; Maskey, R. P.; Wagner-Döbler, I.; Laatsch, H.
J. Nat. Prod. 2002, 65, 1660.
(12) Beck, H. C.; Hansen, A. M.; Lauritsen, F. R. FEMS
Microbiol. Lett. 2003, 220, 67.
(13) Mahboobi, S.; Sellmer, A.; Burgemeister, T.; Lyssenko, A.;
Schollmeyer, D. Monatsh. Chem. 2004, 135, 333.
(14) (a) Fruit, C.; Turck, A.; Plé, N.; Mojovic, L.; Quéguiner, G.
Tetrahedron 2001, 57, 9429. (b) Buron, F.; Plé, N.; Turck,
A.; Queguiner, G. J. Org. Chem. 2005, 70, 2616.
(15) (a) Charette, A. B.; Focken, T. Org. Lett. 2006, 8, 2985.
(b) Montserrat Martínez, M.; Sarandeses, L. A.;
(22) (S)-Benzyl 1-(indol-3-yl)-3-oxopropan-2-ylcarbamate
(14):21 To a stirred solution of Weinreb amide 15 (416 mg,
1.1 mmol) in Et2O (60 mL) was added LiAlH4 (209 mg, 5.5
mmol) at 0 °C and the reaction mixture was stirred for 2 h at
this temperature. The reaction mixture was quenched with
H2O (10 mL), filtered through Celite® and the cake was
washed with H2O (40 mL) and then with Et2O (20 mL). The
filtrate was extracted with Et2O (3 × 30 mL) and the
combined organic layers were washed with HCl acid (1 M,
3 × 30 mL), sat. NaHCO3 solution (3 × 30 mL), brine (30
mL), dried (MgSO4), filtered and concentrated in vacuo.
Purification by flash chromatography using EtOAc–hexanes
(1:1, Rf 0.5) as eluent gave the title compound (320 mg, 0.99
mmol, 90%) as a yellow oil; [a]D21 +30.1 (c = 1.0, CH2Cl2).
IR (neat): 3347, 2924, 1704, 1456, 1513, 1373, 1341, 1244,
1045, 845, 744, 698 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 2.91 (m, 1 H, CHbHbCHa), 3.21 (m, 1 H, CHbHbCHa),
4.25 (s, 1 H, CHa), 5.03 (m, 2 H, CH2Ph), 6.96 (t, J = 6.8 Hz,
1 H, ArH), 7.08 (m, 1 H, ArH), 7.16 (s, 1 H, ArH), 7.33 (m,
6 H, ArH), 7.54 (d, J = 8.0 Hz, 1 H, ArH), 7.73 (d, J = 7.6
Pérez Sestelo, J. Tetrahedron Lett. 2007, 48, 8536.
(c) Peña-López, M.; Montserrat Martínez, M.; Sarandeses,
L. A.; Pérez Sestelo, J. Org. Lett. 2010, 12, 852.
(16) For biomimetic synthetic studies towards tri- and
tetrasubstituted pyrazines, see: (a) Okada, Y.; Taguchi, H.;
Yokoi, T. Tetrahedron Lett. 1996, 37, 2249. (b) Okada, Y.;
Taguchi, H.; Yokoi, T. Chem. Pharm. Bull. 1996, 44, 2259.
(c) Buron, F.; Turck, A.; Plé, N.; Bischoff, L.; Marsais, F.
Tetrahedron Lett. 2007, 48, 4327. Several syntheses of
pyrazines from diketopiperazines also exist: (d) Ohta, A.;
Kojima, A.; Saito, T.; Kobayashi, K.; Saito, H.;
Hz, 1 H, NH), 9.59 (s, 1 H, CHO), 10.86 (s, 1 H, NH). 13
C
NMR (100 MHz, DMSO-d6): d = 23.7 (CH2), 60.4 (CH),
65.5 (CH2), 109.5 (C), 111.3 (CH), 118.1 (CH), 118.3 (CH),
120.9 (CH), 123.7 (CH), 127.6 (CH), 127.7 (2 × CH), 128.2
(CH), 128.3 (2 × CH), 136.1 (C), 136.8 (C), 156.1 (CONH),
201.2 (CHO). MS: m/z (ESI+, %) = 323 (30) [M + H]+, 305
(65), 261 (30), 130 (10), 91 (3). HRMS: m/z [M + H]+ calcd
for C19H18N2O3 + H: 323.1380; found: 323.1383.
Wakabayashi, K.; Honma, S.; Sakuma, C.; Aoyagi, Y.
Heterocycles 1991, 32, 923. (e) Ohta, A.; Kojima, A.;
Aoyagi, Y. Heterocycles 1990, 31, 1665. (f) Candelon, N.;
Shinkaruk, S.; Bennetau, B.; Bennetau-Pelissero, B.;
Dumartin, M.-L.; Deguil, M.; Babin, P. Tetrahedron 2010,
66, 2463. (g) Chaignaud, M.; Gillaizeau, I.; Ouhamou, N.;
Coudert, G. Tetrahedron 2008, 64, 8059.
(23) 2,5-Bis(indol-3-ylmethyl)pyrazine (11):11,24 To a solution of
aldehyde 14 (85 mg, 0.26 mmol) in MeOH–CH2Cl2–AcOH
(2:2:1, 5 mL) was added Pearlman’s catalyst [Pd(OH)2, 20%
on carbon, ca.10 mg] and the reaction mixture was stirred
under an atmosphere of hydrogen for 2 h. The hydrogen
balloon was removed and the reaction mixture was stirred
for a further 15 h while open to the air, filtered through
Celite® and the filtrate was concentrated in vacuo.
(17) Nawrath, T.; Dickschat, J. S.; Kunze, B.; Schulz, S. Chem.
Biodiv. 2010, 7, 2129.
(18) Tryptophan diketopiperazine is a known natural product
called fellutanine A: Kozlovsky, A. G.; Vinokurova, N. G.;
Adanin, V. M.; Burkhardt, H.-M. D.; Gräfe, U. J. Nat. Prod.
2000, 63, 698.
(19) We employed the Cbz-derivative 14 as the Cbz protecting
group can be removed under mild conditions, whereas it was
found the acid or base needed to remove either the tert-
butyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl
(Fmoc) protecting groups degraded the unmasked amino
aldehyde 13. Full details will be reported in due course.
Purification by flash chromatography using EtOAc–hexanes
(1:1, Rf 0.46) as eluent gave the title compound (32 mg,
0.095 mmol, 73%) as a colorless oil. IR (neat): 3223, 2955,
2912, 2850, 1659, 1493, 1458, 1375, 1343, 1259, 1095,
1044, 970, 922, 797, 732, 589 cm–1. For 1H NMR and 13
C
NMR data see, Table 1. MS: m/z (ESI+, %) = 339 (100)
[M + H]+, 282 (20), 242 (15), 157 (2). HRMS: m/z [M + H]+
calcd for C22H18N4 + H: 339.1604; found: 339.1593.
(24) See Supplementary Information for 1H NMR and 13C NMR
spectra of synthetic 11.
Synlett 2011, No. 16, 2339–2342 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.