Diversity-oriented silver(i)-mediated synthesis of spiro-2-aminoimidazoles

Article abstract of DOI:10.1055/s-0030-1260012

A diversity-oriented protocol giving access to a novel class of spiro-cyclic guanidine derivatives is described. The copper(I)-catalyzed, three-component coupling of a ketone, an alkyne and a primary amine (KA ²-coupling) provides the required secondary propargylamines and assures the generation of diversity. The key step of the protocol, a silver(I)-mediated tandem guanylation of secondary propargylamines followed by an intramolecular heterocyclization, provides the target bis-Boc-protected-2- iminoimidazolines spiro-fused with a five-, six- or seven-membered (heterocyclic) ring, which could, in most cases, be further deprotected to the spiro-2-aminoimidazoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260012

PAPER
1587
Diversity-Oriented Silver(I)-Mediated Synthesis of Spiro-2-aminoimidazoles
S
ynthesisof Spiro
l
-
2-amin
g
oimidazole
s
a P. Pereshivko,a Vsevolod A. Peshkov,a Denis S. Ermolat’ev,*a Sofie Van Hove,a Kristof Van Hecke,b
Luc Van Meervelt,b Erik V. Van der Eycken*a
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: denis.ermolatev@chem.kuleuven.be; E-mail: erik.vandereycken@chem.kuleuven.be
Biomolecular Architecture, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
b
Received 21 February 2011; revised 24 March 2011
membered ring.16 These complex molecules are still a
Abstract: A diversity-oriented protocol giving access to a novel
challenge for the synthetic organic chemist.17
class of spiro-cyclic guanidine derivatives is described. The cop-
per(I)-catalyzed, three-component coupling of a ketone, an alkyne
and a primary amine (KA2-coupling) provides the required second-
ary propargylamines and assures the generation of diversity. The
key step of the protocol, a silver(I)-mediated tandem guanylation of
secondary propargylamines followed by an intramolecular hetero-
cyclization, provides the target bis-Boc-protected-2-iminoimidazo-
Propargylamines have proven to be convenient starting
materials for the synthesis of variously substituted 2-ami-
noimidazoles. Looper and co-workers have reported an
efficient synthesis of polysubstituted 2-dialkylaminoimi-
dazoles through von Braun cyanation of tertiary propargyl-
amines followed by lanthanide-mediated hydroamination
of propargyl cyanamides.18
lines spiro-fused with
a five-, six- or seven-membered
(heterocyclic) ring, which could, in most cases, be further depro-
tected to the spiro-2-aminoimidazoles.
As a result of our ongoing efforts on the synthesis of var-
iously substituted 2-aminoimidazoles,19 we have recently
described a rapid and highly efficient silver(I)-mediated
synthesis of 1,4,5-trisubstituted 2-aminoimidazoles start-
ing from secondary propargyl amines.20–22 This procedure
was successfully applied for the total synthesis of 1,4,5-
trisubstituted imidazole alkaloids of the naamine family.
Key words: 2-aminoimidazoles, spiro compounds, tandem reac-
tion, ring closure, silver
2-Aminoimidazoles and guanidine derivatives are found
as structural elements in a growing number of complex
natural products and biologically active compounds.1 In
particular, 2-aminoimidazole derivatives have been re-
ported as potent modulators of the formation and disper-
sion of bacterial biofilms,2 human b-secretase (BACE1)
inhibitors,3 and tubulin-binding agents.4 Marine sponges
have proven to be a rich source of 2-aminoimidazole alka-
loids with diverse biological activities.5 Chemical investi-
gation of genus Leucetta sponges resulted in the isolation
of a wide range of imidazole alkaloids, such as
naamines,6–8 isonaamines,7–9 naamidines8,10 and calcar-
idines.11 Of particular interest are alkaloids containing a
We now disclose a synthetic approach towards a structur-
ally interesting class of heterocycles containing a spirocy-
clic guanidine unit (Scheme 1). The sequence starts with
our previously described KA2-coupling,23 a condensation
of a ketone, an alkyne and a primary amine, providing a
secondary propargylamine. Next, these propargylamines
are subjected to our recently developed silver(I)-mediated
procedure for the synthesis of 2-aminoimidazoles.20 Gua-
nylation of these propargylamines followed by intramo-
lecular 5-exo-dig heterocyclization24 provides the desired
bis-Boc-protected spiro-2-iminoimidazolines, which
spiro-cyclic guanidine unit (Figure 1). Palau’amine,12
a
representative of the oroidin family,13 possesses a spiro-
cyclopentyl-2-aminoimidazole system. Considerable ef-
forts to elaborate a general method for the construction of
5-imidazolones spiro-fused with a five-membered ring
applying oxidative reactions of tetrahydrobenzimidazoles
have been made by Lovely and co-workers.14 Tubastrin-
doles A–C (Figure 1), isolated from a stony coral, Tubas-
traea sp., are dimeric bisindole alkaloids containing a
cyclic guanidine unit spiro-fused with a six-membered
ring.15 Dragmacidin E (Figure 1), originally isolated from
the marine sponges Dragmacidon sp. and Spongosorites
sp., is a structurally complex bisindole alkaloid containing
an aminoimidazole unit spiro-fused with a seven-
NH2
NH2
HN
H2N
Cl
HN
NH
NH
OH
NH
N
H
N
NH2
H
O
Br
H
N
O
NH
N
H
H
N
N
dragmacidin E
HO
H
Me
N
R
palau'amine
NH
O
tubastrindole A
X = NH, R = Br
tubastrindole B
X = NH, R = H
tubastrindole C
X = O, R = H
NMe
NMe
NH
X
N
H
N
O
Me
SYNTHESIS 2011, No. 10, pp 1587–1594
Advanced online publication: 19.04.2011
DOI: 10.1055/s-0030-1260012; Art ID: Z21611SS
x
x.
x
x
.
2
0
1
1
Figure 1 Examples of marine sponge alkaloids containing a spiro-
cyclic guanidine unit
© Georg Thieme Verlag Stuttgart · New York

1588
O. P. Pereshivko et al.
PAPER
one-pot
R2
R2
R1 NH2
+
R2
Boc
AgI
H
N
N
H+
CuI
R2
H2N
BocN
SMe
+
N
N
NH
BocN
NHBoc
R1
R1
R1
O
R2
+ Ag+
Ag+
cat.
BocHN
N
R1
– AgSMe
NBoc
Scheme 1 Synthetic approach towards spiro-2-aminoimidazoles
could be further deprotectected to give spiro-2-aminoimi- aminoimidazoles 6a–n and 6p as trifluoroacetic acid salts
dazoles.
in high yields (Table 2, entries 1–14 and 16). However, in
the case of 5o, which contains an additional Boc-protec-
tive group, complete decomposition was observed
(Table 2, entry 15). The deprotected 2-aminoimidazole 6q
spiro-fused with a five-membered ring also undergoes in-
tensive decomposition during workup, thus making isola-
tion and characterization impossible (Table 2, entry 17). It
is worth mentioning that other spiro-2-aminoimidazole
trifluoroacetic acid salts 6a–n and 6p were found to be
considerably more stable than 6q, although, for some of
them, traces of decomposition were also observed during
long-term storage under air atmosphere.
For the generation of a small library of secondary propar-
gylamines 4, a variety of ketones, primary amines, and
alkynes were evaluated in the microwave-assisted KA2-
coupling reaction (Table 1).23 The couplings worked nota-
bly well with six-membered (hetero)cyclic ketones. When
cyclohexanone was used, the desired compounds 4a–l
were obtained in 46–89% yield. When N-protected pipe-
ridinones were used, yields between 61 and 82% were ob-
tained. However, when cycloheptanone was used, the
yield dropped to 21%. Analogously, a low yield of 20%
was observed for reaction with cyclopentanone. It seems
that conformational factors play a crucial role in this pro- All the final spiro-2-aminoimidazole trifluoroacetic acid
cess, and that the ketimines from six-membered (hete- salts 6a–n and 6p could be purified by column chroma-
ro)cyclic ketones are probably more accessible for copper tography over silica gel, and their structures were con-
1
acetylide attack than imines from other ketones.25 Re- firmed by H and 13C NMR spectroscopy and HRMS
markably, the reaction with acetone also resulted in a low analysis.27 In addition, the structure of 6d was determined
yield of 30%. The application of the less active aliphatic by X-ray crystallographic analysis (Figure 2).28 This com-
octyne afforded the target compound 4e only in low yield, pound crystallized in the space group P1, with the asym-
even when two equivalents of alkyne were used.
We then investigated the silver(I)-mediated tandem gua-
nylation, intramolecular cyclization reaction of the gener-
ated propargylamines 4. When the reactions with
propargylamines 4a–q were run for one hour at room tem-
perature with protected S-methylisothiourea (1.25 equiv)
in the presence of silver nitrate (1.4 equiv) and triethyl-
amine (2 equiv) in acetonitrile, the corresponding protect-
ed spiro-2-iminoimidazolines 5a–q were obtained in high
yields ranging from 66 to 96% (Table 2). In most cases,
the reaction proceeded regio- and stereoselectively as a 5-
exo-dig heterocyclization process, providing exclusively
the five-memberred imidazoline with Z-configuration of
the exocyclic double bond. However, in the case of the
secondary propargylamines 4b, 4e and 4g, the formation
of a considerable amount of the six-memberred spiro-
guanidines 5b¢, 5e¢ and 5g¢ (minor product)26 was ob-
served (Table 2, entries 2, 5 and 7).
The Boc-deprotection of 5a–n and 5p was achieved using
trifluoroacetic acid in dichloromethane (1:2) at room tem-
perature in only one to three hours, delivering the spiro-2-
Figure
2
X-ray crystallographic structure of compound 6d,
showing the hydrogen bond network around a crystallographic inver-
sion center
Synthesis 2011, No. 10, 1587–1594 © Thieme Stuttgart · New York

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Synthesis of Spiro-2-aminoimidazoles
1589
Table 1 Microwave-Assisted Synthesis of Secondary Propargylamines via KA2-Couplinga
R2
CuI (20 mol%)
NH
R1 NH2
R2
+
+
O
100 °C, 25 min
MW, neat
R1
3
1
2
4a–r
Entry Product
Yield
(%)
Entry Product
Yield
(%)
Entry Product
Yield
(%)
NAc
1
2
3
4a
4b
4c
76
75
64
7
8
9
4g
4h
4i
89
61
77
13
14
15
4m
4n
4o
64
82
61
Ph
4-AmOC6H4
Ph
NH
NH
NH
PMB
PMB
PMB
NCOOEt
Ph
PMP
F
Ph
Ph
NH
NH
NH
NH
NH
PMB
Hex
PMB
PMB
NBoc
Ph
NH
NH
Oct
PMB
4
5
4d
4e
75
10
11
4j
46
62
16
17
4p
4q
21
Ph
Ph
Ph
S
NH
NH
NH
PMB
cHep
PMB
PMB
31b
4k
20b,c
Ph
Ph
Hex
NH
NH
PMB
OMe
Ph
6
4f
74
12
4l
68
18
4r
30
4-HepC6H4
OMe
OMe
NH
NH
NH
PMB
PMB
a Reaction conditions: amine 1 (1.0 mmol), alkyne 2 (1.2 mmol), ketone 3 (1.2 mmol), CuI (20 mol%), 100 °C (80 W), 25 min.
b Alkyne (2 mmol) was used.
c The reaction was run under conventional heating at 100 °C for 20 h because the same reaction under MW-assisted conditions resulted in the
formation of multiple inseparable byproducts with only traces of 4q.
metric unit containing two spiro-2-aminoimidazole directly used in the next Boc-deprotection step, delivering
molecules. A hydrogen-bond network is formed around compound 6r in 44% overall yield (Scheme 2).
the crystallographic inversion centers between the oxygen
In conclusion, we have prepared a small library of vari-
atoms of the trifluoroacetate units and the hydrogen atoms
ously substituted spiro-2-aminoimidazoles, starting from
of the 2-aminoimidazoles, for both molecules in the asym-
readily available primary amines, ketones, and alkynes.
metric unit (Figure 2).
The key step of this protocol, a silver(I)-mediated tandem
To expand the applicability of our protocol, the silver(I)- guanylation, intramolecular cyclization of secondary pro-
mediated tandem guanylation, intramolecular cyclization pargylamines, proved to be a powerful synthetic tool for
of propargylamine 4r was investigated. After cyclization, the construction of spirocyclic guanidine systems.
the crude bis-Boc-protected 2-iminoimidazoline 5r was
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1590
O. P. Pereshivko et al.
PAPER
SMe
NHBoc
CF3COO–
Ph
Ph
Boc
H
N
BocN
TFA–CH2Cl2
+
N
(1:2)
(1.25 equiv)
H2N
Ph
BocN
r.t., 2 h
N
NH
AgNO3 (1.4 equiv)
Et3N (2 equiv)
MeCN, 1 h, r.t., dark
N
PMB
PMB
4r
PMB
6r, 44%
5r
(yield over two steps)
Scheme 2 Synthesis of 2-aminoimidazole 6q
Table 2 Silver(I)-Mediated Synthesis of Bis-Boc-spiro-2-iminoimidazolines 5 Followed by Deprotection to Spiro-2-aminoimidazoles 6
SMe
R2
R2
CF3COO–
H2N
Boc
H
N
BocN
NHBoc
TFA–CH2Cl2
(1:2)
+
N
(1.25 equiv)
R2
BocN
AgNO3 (1.4 equiv)
Et3N (2 equiv)
MeCN, 1 h, r.t., dark
r.t., 1–3 h
N
N
NH
6
R1
R1
5
R1
4
Entry Propargylamine 4
5
Yield (%)a
85
6
Yield (%)a
99
Ph
Ph
Boc
N
CF3COO–
H2N
H
N
+
1
2
4a
4b
5a
6a
BocN
N
N
PMB
PMB
PMP
PMB
Boc
CF3COO–
H
+
N
N
5b
87
9
6b
97
BocN
H2N
N
N
PMB
PMB
Boc
N
PMB
5b¢
BocN
N
PMB
F
F
Boc
CF3COO–
H2N
3
4c
5c
95
91
6c
H
99
+
N
N
BocN
N
N
PMB
PMB
S
S
Boc
CF3COO–
H
N
4
5
4d
4e
5d
6d
6e
92
65
+
N
H2N
BocN
BocN
N
N
PMB
PMB
Hex
Hex
CF3COO–
H2N
Boc
H
+
N
N
5e
77
19
N
N
PMB
PMB
Boc
Hex
N
N
5e¢
BocN
PMB
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Synthesis of Spiro-2-aminoimidazoles
1591
Table 2 Silver(I)-Mediated Synthesis of Bis-Boc-spiro-2-iminoimidazolines 5 Followed by Deprotection to Spiro-2-aminoimidazoles 6
(continued)
SMe
R2
R2
CF3COO–
H2N
Boc
H
N
BocN
NHBoc
TFA–CH2Cl2
(1:2)
+
N
(1.25 equiv)
R2
BocN
AgNO3 (1.4 equiv)
Et3N (2 equiv)
MeCN, 1 h, r.t., dark
r.t., 1–3 h
N
N
NH
6
R1
R1
5
R1
4
Entry Propargylamine 4
5
Yield (%)a
87
6
Yield (%)a
99
C6H4(4-Hep)
C6H4(4-OAm)
C6H4(4-OAm)
C6H4(4-Hep)
Boc
CF3COO–
H
N
+
N
6
7
4f
5f
6f
BocN
H2N
N
N
PMB
PMB
C6H4(4-OAm)
CF3COO–
Boc
H
N
+
N
4g
5g
75
20
95
96
90
77
6g
99
H2N
BocN
N
N
PMB
PMB
Boc
N
5g¢
5h
5i
BocN
N
PMB
Ph
Ph
Ph
Ph
CF3COO–
Boc
H
N
+
N
8
9
4h
4i
6h
6i
92
90
95
83
H2N
BocN
BocN
BocN
N
N
Hex
Hex
Ph
Boc
CF3COO–
H2N
H
N
+
N
N
N
Oct
Oct
Ph
Boc
CF3COO–
H
+
N
N
10
11
4j
5j
6j
H2N
N
N
cHep
cHep
Ph
Ph
Ph
CF3COO–
Boc
N
H
N
+
4k
5k
6k
BocN
MeO
H2N
MeO
N
N
Ph
Boc
CF3COO–
H2N
H
N
+
N
BocN
N
N
12
4l
5l
87
6l
85
OMe
OMe
MeO
MeO
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1592
O. P. Pereshivko et al.
PAPER
Table 2 Silver(I)-Mediated Synthesis of Bis-Boc-spiro-2-iminoimidazolines 5 Followed by Deprotection to Spiro-2-aminoimidazoles 6
(continued)
SMe
R2
R2
CF3COO–
H2N
Boc
H
N
BocN
NHBoc
TFA–CH2Cl2
(1:2)
+
N
(1.25 equiv)
R2
BocN
AgNO3 (1.4 equiv)
Et3N (2 equiv)
MeCN, 1 h, r.t., dark
r.t., 1–3 h
N
N
NH
6
R1
R1
5
R1
4
Entry Propargylamine 4
5
Yield (%)a
67
6
Yield (%)a
92
Ph
Ph
Ph
CF3COO–
Boc
H
N
+
N
13
14
4m
4n
5m
6m
6n
BocN
H2N
N
N
NAc
NAc
PMB
PMB
Ph
Boc
CF3COO–
H2N
H
+
N
N
5n
66
82
95
BocN
N
N
NCOOEt
NCOOEt
PMB
PMB
Ph
N
Ph
Boc
N
CF3COO–
H2N
H
+
N
15
4o
5o
6o
0b
BocN
N
N
PMB
PMB
N
H
Boc
Ph
Ph
CF3COO–
H2N
Boc
N
H
+
N
16
17
4p
4q
5p
76
77
6p
6q
75
BocN
N
N
PMB
PMB
CF3COO–
Ph
Ph
Boc
H
+
N
N
c
5q
–
BocN
N
H2N
N
PMB
PMB
a Isolated yield.
b Complete decomposition was observed.
c Intensive decomposition of 6q during workup prevented isolation and complete characterization.
The 1H and 13C NMR chemical shifts are reported in parts per mil-
lion (ppm) relative to tetramethylsilane (TMS) using the residual
solvent signal as internal reference. High-resolution mass spectra
(EI) were recorded with a resolution of 10000; the ion source tem-
perature was 150–250 °C, as required. All microwave irradiation
experiments were carried out with a dedicated CEM-Discover
monomode microwave apparatus, operating at a frequency of
2.45 GHz, with continuous irradiation power from 0 to 300 W, us-
ing the standard absorbance level of 300 W maximum power. The
reactions were carried out in 10-mL glass tubes, sealed with Teflon
septa and placed in the microwave cavity. The reactions were irra-
diated at a required ceiling temperature using maximum power for
the stipulated time, then cooled to ambient temperature with air-jet
cooling.
the cavity of a CEM-Discover microwave reactor at a ceiling tem-
perature of 100 °C and a maximum power of 80 W for 25 min.
Upon completion of the reaction, the vial was cooled with a stream
of air. The resulting reaction mixture was directly purified by col-
umn chromatography over silica gel (EtOAc–heptanes, 10–30%) to
afford the corresponding propargylamine.
N-(4-Methoxybenzyl)-1-(2-phenylethynyl)cyclohexanamine
(4a)
Yield: 243 mg (76%).
1H NMR (300 MHz, CDCl3): d = 7.59–7.41 (m, 2 H), 7.40–7.25 (m,
5 H), 6.86 (d, J = 8.6 Hz, 2 H), 3.91 (s, 2 H), 3.78 (s, 3 H), 2.10–
1.90 (m, 2 H), 1.82–1.16 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 158.6, 133.2, 131.6, 129.6, 128.2,
127.7, 123.7, 113.8, 93.6, 84.7, 55.25, 55.22, 47.4, 38.2, 25.9, 23.0.
Synthesis of Secondary Propargylamines 4; General Procedure
To a microwave vial equipped with a magnetic stir bar, primary
amine (1 mmol), ketone (1.2 mmol), acetylene (1.2 mmol), and CuI
(38 mg, 20 mol%) were added. The mixture was degassed and
flushed with argon. The reaction vessel was sealed and irradiated in
HRMS (EI): m/z [M]+ calcd for C22H25ON: 319.1936; found:
319.1936.
Synthesis 2011, No. 10, 1587–1594 © Thieme Stuttgart · New York

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Synthesis of Spiro-2-aminoimidazoles
1593
Ag(I)-Mediated Tandem Guanylation, Intramolecular Cycliza-
tion; General Procedure
References
(1) (a) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva,
A. E.; Romminger, S.; Morais, R. P.; Bandeira, K.; Mizuno,
C. M. Nat. Prod. Rep. 2010, 27, 1871. (b) Berlinck, R. G.
S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep.
2008, 25, 919. (c) Berlinck, R. G. S.; Kossuga, M. H. Nat.
Prod. Rep. 2005, 22, 516. (d) Berlinck, R. G. S. Nat. Prod.
Rep. 2002, 19, 617; and references cited therein.
(2) For anti-biofilm activity of 2-aminoimidazoles, see:
(a) Huigens, R. W.; Richards, J. J.; Parise, G.; Ballard, T. E.;
Zeng, W.; Deora, R.; Melander, C. J. Am. Chem. Soc. 2007,
129, 6966. (b) Rogers, S. A.; Melander, C. Angew. Chem.
Int. Ed. 2008, 47, 5229; Angew. Chem. 2008, 120, 5307.
(c) Ballard, T. E.; Richards, J. J.; Wolf, A. L.; Melander, C.
Chem. Eur. J. 2008, 14, 10745.
To a solution of the respective propargylamine 4 (0.5 mmol) and
N,N¢-di-Boc-S-methylisothiourea (181 mg, 0.625 mmol) in MeCN
(2.5 mL), Et3N (101 mg, 1 mmol) was added under an argon atmo-
sphere. After dissolution, silver nitrate (119 mg, 0.7 mmol) was
added and the heterogeneous reaction mixture was vigorously
stirred for 1 h. The reaction mixture was filtered through Celite and
the filtrate was concentrated under vacuum to afford an oily sub-
stance. The crude product was loaded onto a silica gel column for
chromatography (EtOAc–heptanes, 20–100%) providing the target
bis-Boc-protected-2-iminoimidazoline 5 as an amorphous white
foam.
Compound 5a
Yield: 239 mg (85%).
(3) (a) Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu,
Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.;
Jacobsen, S.; Magolda, R. L.; Pangalos, M.; Robichaud, A.
J. J. Med. Chem. 2010, 53, 1146. (b) Malamas, M. S.; Erdei,
J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.;
Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.;
Robichaud, A. J. J. Med. Chem. 2009, 52, 6314.
1H NMR (300 MHz, CDCl3): d = 7.63–7.54 (m, 2 H), 7.34–7.30 (m,
2 H), 7.28–7.18 (m, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.33 (s, 1 H),
4.6 (s, 2 H), 3.77 (s, 3 H), 1.80–1.43 (m, 19 H), 1.02 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 160.1, 158.7, 152.0, 148.5, 138.7,
136.2, 130.2, 129.0, 128.6, 128.2, 127.3, 116.7, 113.8, 82.7, 79.1,
64.8, 55.2, 43.1, 31.9, 28.2, 27.3, 24.9, 23.0.
(4) (a) Coleman, R. S.; Campbell, E. L.; Carper, D. J. Org. Lett.
2009, 11, 2133. (b) Nodwell, M.; Pereira, A.; Riffell, J. L.;
Zimmermann, C.; Patrick, B. O.; Roberge, M.; Andersen, R.
J. J. Org. Chem. 2009, 74, 995.
(5) (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 584. (b) Jin, Z. Nat.
Prod. Rep. 2005, 22, 196. (c) Jin, Z. Nat. Prod. Rep. 2006,
23, 464. (d) Jin, Z. Nat. Prod. Rep. 2009, 26, 382.
(e) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931.
(f) Sullivan, J. D.; Giles, R. L.; Looper, R. E. Curr. Bioact.
Compd. 2009, 5, 39. (g) Hoffmann, H.; Lindel, T. Synthesis
2003, 175. (h) Koswatta, P. B.; Lovely, C. J. Nat. Prod. Rep.
2010, 28, 511; and references cited therein.
MS (ESI): m/z = 562.3 [M + H]+.
Boc-Deprotection of Bis-Boc-2-iminoimidazolines 5 to Spiro-2-
aminoimidazoles 6; General Procedure
The respective bis-Boc-protected-2-iminoimidazoline 5 (0.3 mmol)
was dissolved in CH2Cl2 (4 mL) and TFA (2 mL) was added. The
reaction mixture was stirred at r.t. for 1–3 h. After completion of the
reaction, the solvent was evaporated under reduced pressure and the
residue was subjected to flash chromatography over silica gel
(MeOH–CH2Cl2, 5–10%) to give the spiro-2-aminoimidazoles 6 as
trifluoroacetic acid salts.
(6) (a) Dunbar, D. C.; Rimoldi, J. M.; Clark, A. M.; Kelly, M.;
Hamann, M. T. Tetrahedron 2000, 56, 8795. (b) Crews, P.;
Clark, D. P.; Tenney, K. J. Nat. Prod. 2003, 66, 177.
(c) Hassan, W.; Edrada, R.; Ebel, R.; Wray, V.; Berg, A.;
Van Soest, R.; Wiryowidagdo, S.; Proksch, P. J. Nat. Prod.
2004, 67, 817.
(7) (a) Fu, X.; Barnes, J. R.; Do, T.; Schmitz, F. J. J. Nat. Prod.
1997, 60, 497. (b) Gross, H.; Kehraus, S.; König, G. M.;
Woerheide, G.; Wright, A. D. J. Nat. Prod. 2002, 65, 1190.
(8) (a) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1987, 28,
3003. (b) Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron
1989, 45, 2193.
Compound 6a
Yield: 141 mg (99%).
1H NMR (300 MHz, CDCl3): d = 7.37–7.30 (m, 4 H), 7.25–7.17 (m,
1 H), 7.13 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.94 (s,
1 H), 4.60 (s, 2 H), 3.76 (s, 3 H), 1.92–1.66 (m, 9 H), 1.34–1.17 (m,
1 H).
13C NMR (75 MHz, CDCl3): d = 159.4, 156.3, 140.5, 134.1, 128.9,
127.9, 127.6, 126.9, 126.5, 114.5, 104.4, 68.5, 55.3, 43.1, 33.8,
23.9, 20.8.
HRMS (EI): m/z [M]+ calcd for C23H27ON3: 361.2154; found:
361.2171.
(9) Fu, X.; Schmitz, F. J.; Tanner, R. S.; Kelly-Borges, M.
J. Nat. Prod. 1998, 61, 384.
(10) (a) Akee, R. K.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P.
J.; Stout, T. J.; Clardy, J. J. Org. Chem. 1990, 55, 1944.
(b) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem.
1993, 46, 1229. (c) Mancini, I.; Guella, G.; Debitus, C.;
Pietra, F. Helv. Chim. Acta 1995, 78, 1178. (d) Plubrukarn,
A.; Smith, D.; Cramer, R.; Davidson, B. J. Nat. Prod. 1997,
60, 712.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of NMR spectra and X-ray crystallographic data.
Acknowledgment
Support was provided by the Research Fund of the Katholieke Uni-
versiteit Leuven. V.A.P. is grateful to the EMECW (Triple I) for ob-
taining a doctoral scholarship. D.S.E. is grateful to the Fund for
Scientific Research - Flanders (F.W.O.-Vlaanderen) for obtaining a
postdoctoral fellowship. The authors thank Ir. B. Demarsin for va-
luable help with HRMS.
(11) Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod. 2003,
66, 939.
(12) For original isolation, see: (a) Kinnel, R. B.; Gehrken, H. P.;
Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376.
(b) Kinnel, R. B.; Gehrken, H. P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281. (c) For
structural reassignment, see: Buchanan, M. S.; Carroll, A.
R.; Quinn, R. J. Tetrahedron Lett. 2007, 48, 4573. (d) For
total synthesis, see: Seiple, I. B.; Su, S.; Young, I. S.; Lewis,
C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed.
2010, 49, 1095; and references cited therein.
Synthesis 2011, No. 10, 1587–1594 © Thieme Stuttgart · New York

1594
O. P. Pereshivko et al.
PAPER
(20) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.;
(13) For a review on the synthesis of alkaloids from the Oroidin
family, see: Arndt, H. D.; Riedrich, M. Angew. Chem. Int.
Ed. 2008, 47, 4785.
De Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew.
Chem. Int. Ed. 2010, 49, 9465.
(14) (a) Sivappa, R.; Koswatta, P.; Lovely, C. J. Tetrahedron
Lett. 2007, 48, 5771. (b) Sivappa, R.; Hernandez, N. M.; He,
Y.; Lovely, C. J. Org. Lett. 2007, 9, 3861. (c) Lovely, C. J.;
Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6, 735.
(15) Iwagawa, T.; Miyazaki, M.; Okamura, H.; Nakatani, M.;
Doe, M.; Takemura, K. Tetrahedron Lett. 2003, 44, 2533.
(16) Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A.
T. R.; Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J. Nat.
Prod. 1998, 61, 660.
(17) For synthetic efforts towards dragmacidin E, see:
(a) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2005, 7,
5449. (b) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8,
4775. (c) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2010,
12, 4502.
(21) Ermolat’ev, D. S. PhD Thesis; Katholieke Universiteit
Leuven: Belgium, 2008.
(22) For the synthesis of secondary propargylamines, see:
Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V.
Chem. Eur. J. 2010, 16, 3281.
(23) For a description of the KA2-coupling, see: Pereshivko, O.
P.; Peshkov, V. A.; Van der Eycken, E. V. Org. Lett. 2010,
12, 2638.
(24) During the preparation of this manuscript, the rhodium(II)-
catalyzed 6-endo-dig-selective hydroamination of
propargylguanidines was reported, see: Gainer, M. J.;
Bennett, N. R.; Takahashi, Y.; Looper, R. E. Angew. Chem.
Int. Ed. 2011, 50, 684.
(25) For the addition of lithium acetylides and n-BuLi to six-
membered ketimines, see: Ma, Y.; Lobkovsky, E.; Collum,
D. B. J. Org. Chem. 2005, 70, 2335.
(18) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E.
Angew. Chem. Int. Ed. 2009, 48, 3116.
(19) (a) Ermolat’ev, D. S.; Babaev, E. V.; Van der Eycken, E. V.
Org. Lett. 2006, 8, 5781. (b) Ermolat’ev, D. S.; Alifanov, V.
L.; Rybakov, V. B.; Babaev, E. V.; Van der Eycken, E. V.
Synthesis 2008, 2083. (c) Ermolat’ev, D. S.;
(26) Differences in Rf values allow both minor and major
products to be isolated through gradient-elution column
chromatography.
(27) See Supporting Information for details.
(28) CCDC-801762 contains the supplementary crystallographic
data for this paper and can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax:+44(1223)336033; or
deposit@ccdc.cam.ac.uk).
Van der Eycken, E. V. J. Org. Chem. 2008, 73, 6691.
(d) Ermolat’ev, D. S.; Svidritzky, E. P.; Babaev, E. V.;
Van der Eycken, E. Tetrahedron Lett. 2009, 50, 5218.
(e) Modha, S. G.; Mehta, V. P.; Ermolat’ev, D. S.; Balzarini,
J.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E.
Mol. Diversity 2010, 14, 767.
Synthesis 2011, No. 10, 1587–1594 © Thieme Stuttgart · New York