Stereoselective synthesis of (Z)-axino- and (Z)-debromoaxinohydantoin

Article abstract of DOI:10.1016/j.tet.2008.12.053

(Z)-Axinohydantoin and (Z)-debromoaxinohydantoin, two pyrrole-imidazole alkaloids isolated from different marine sponges, possess moderate activities in inhibiting the progress of the cell cycle at different phases. A stereoselective synthesis of both nat

Full text of DOI:10.1016/j.tet.2008.12.053

Tetrahedron 65 (2009) 2372–2376
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Tetrahedron
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Stereoselective synthesis of (Z)-axino- and (Z)-debromoaxinohydantoin
*
Federico Tutino, Helena Posteri, Daniela Borghi, Francesca Quartieri, Nicola Mongelli, Gianluca Papeo
Department of Chemistry, BU-Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 October 2008
Received in revised form 21 November 2008
Accepted 11 December 2008
Available online 24 December 2008
(Z)-Axinohydantoin and (Z)-debromoaxinohydantoin, two pyrrole–imidazole alkaloids isolated from
different marine sponges, possess moderate activities in inhibiting the progress of the cell cycle at dif-
ferent phases. A stereoselective synthesis of both natural products was achieved. The key step in the
synthetic pathway was the installation of the hydantoin northern ring by using 1-benzoyl-2-methyl-
sulfanyl-1,5-dihydroimidazol-4-one.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Natural products
Isomerization
Kinetics
1. Introduction
H
H
The increasing number of papers published in the last decade,
dealing with the isolation and total synthesis of marine pyrrole–
imidazole alkaloids, witnesses the restless attention that this family
of alkaloids deserves.1 The synthetic challenge, sometimes hidden
behind apparently simple structures, associated with promising
biological activities, justifies this interest. The role of pyrrole–im-
idazole alkaloids in the sponge economy is far from being com-
pletely understood. While the fish feeding deterrent properties of
the parent oroidin (1, Fig. 1) and some other derivatives2 have been
established, the reasons for the existence of the vast majority of
these alkaloids are still obscure. Also their biosynthesis is an open
question. Although a number of hypotheses exists,3,1a only one
experiment on sponge cells culture concerning the incorporation of
14C-labelled amino acids into stevensine biosynthesis has been
reported by Kerr et al.4
Six different modes of cyclization, seven modes of dimerization
1b and one mode of tetramerization5 of the basic skeleton of oroidin
have been discovered so far, but a number of potential other
architectures is probably waiting to be unveiled.1a The growing
complexity of the members of this family culminated in the breath-
taking structure of palau’amine (2, Fig. 1) that has been recently
revised.6,3e,5b Among the cyclized structures arising from oroidin,
hymenialdisines (only (Z)-hymenialdisine (3, Fig. 1) is depicted for
better clarity), and their close analogues, axinohydantoins (4–7,
Fig. 1), represent the tricyclic core most commonly found in
H
N
N
N
NH
OH
H
NH
O
NH
Br
N
H
N
H
NH
NH
Cl
Br
NH2
N
H
N
H
O
H2N
2 Palau'amine
1 Oroidin
O
13
HN
12
14
N
H2N
Br
O
NH
15
10
11
4
HN
9
O
3
8
2
1
6
NH
NH
7
R
5
N
N
H
H
O
O
3 (Z)-Hymenialdisine
4 (E)-Axinohydantoin R=Br
5 (E)-Debromoaxinohydantoin R=H
H
N
O
O
HN
NH
R
N
H
O
6 (Z)-Axinohydantoin R=Br
7 (Z)-Debromoaxinohydantoin R=H
* Corresponding author. Tel.: þ39 0331 581537; fax: þ39 0331 581347.
E-mail address: gianluca.papeo@nervianoms.com (G. Papeo).
Figure 1. Pyrrole–imidazole alkaloids.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.053

F. Tutino et al. / Tetrahedron 65 (2009) 2372–2376
2373
sponges.1a,7 Moreover, along with agelastatin A,8 they are the only
1) NH2(CH2)2CO2Et·HCl
TEA, CH3CN, rt
O
pyrrole–imidazole alkaloids possessing a single bromine atom at 2-
position of the pyrrole ring. Incorporation of the halogen atom is
supposed to be catalyzed by a specific pair of haloperoxidase/hal-
ogenase enzymes.9
2) NaOH 2 N then HCl , rt
3) PPA, P2O5 120 °C
CCl3
NH
N
H
Y = 78%
N
H
O
over three steps
O
(E)-Axinohydantoin 4 (from the sponge Axinella sp.)10 and (E)-
debromoaxinohydantoin 5 (from the sponge Monanchora pertain-
ing to the genera Hymeniacidon)11 were the first alkaloids of the
quartet to be isolated by Pettit et al. Subsequently, (Z)-axinohy-
dantoin 6 and (Z)-debromoaxinohydantoin 7 were isolated from
the sponge Stylotella aurantium12 and later, christened with the
name of spongiacidins D and C, respectively, from Hymeniacidon
species.13 Biogenetically, axinohydantoins could arise from differ-
ent linear precursors.10,14 (E)-Axinohydantoin 4 was only margin-
ally active on murine P388 lymphocytic leukemia (PS system) with
9
1) NH2(CH2)2CO2Et·HCl
TEA, CH3CN, rt
Y = 42%
over four steps
2) NBS, CH3OH/THF (1 : 2)
0 °C to rt
3) NaOH 1 N then HCl, rt
4) (i) (COCl)2, DMF cat. DCE, rt.
(ii) AlCl3, rt.
O
an ED50 of 18
(Z)-debromoaxinohydantoin 7 showed micromolar activities on
protein kinase C with IC50 values of 9 and 22
M, respectively.12,15
m
g/mL.10 On the other hand, (Z)-axinohydantoin 6 and
NH
Br
N
H
O
m
10
Furthermore, (Z)-axinohydantoin 6 displayed inhibitory activities
on a number of kinases in the micromolar range as well (glycogen
Scheme 2. Synthesis of 9 and 10.
synthase kinase-3
IC50¼4 M; casein kinase 1, IC50¼4.5
5/p25, IC50¼7
M).16 However, an exhaustive investigation of the
b
, IC50¼3
m
M; cyclin dependent kinase 1/cyclin B,
m
mM; cyclin dependent kinase
m
brominated precursor 10 was also prepared from the same
starting material (Scheme 2).
potential bioactivities of axinohydantoins is far from being ach-
ieved. Despite having been isolated more than a decade ago, axi-
nohydantoins 4–7 did not significantly raise the interest of the
synthetic community. Only a single communication on the syn-
thesis of debromoaxinohydantoins 5 and 7 appeared in 2002 by
Horne et al.14 As a result of this indifference, to date no syntheses of
However, cyclization of 2-bromopyrrole acid intermediate in the
presence of PPA/P2O5 suffered from a protic acid-mediated halogen
dance on the pyrrole ring, delivering a nearly 1:1 hardly separable
mixture of 10 and its corresponding 3-bromo regioisomer.18 The
bromine atom scrambling was effectively suppressed by the use of
AlCl3.17 The yield in this last step was increased up to 69%, de-
livering 10 with an optimized 42% overall yield.19 Aldisine 9 and 2-
bromoaldisine 10 were subsequently reacted, in the presence of
TiCl4 and pyridine, with excess 8,17 prepared from hyppuric acid in
two steps with an improved 47% overall yield (Scheme 3).
(Z)-axinohydantoin
6 and (E)-axinohydantoin 4 have been
accomplished.
2. Results and discussion
Previous work in our laboratory demonstrated the un-
precedented 1-benzoyl-2-methylsulfanyl-1,5-dihydroimidazol-4-
one 8 as an effective tool for the construction of the northern ring in
(Z)-hymenialdisines.17 In order to test its versatility, we envisioned
the chance to capitalize on this reagent to prepare (Z)-axinohy-
dantoins 6 and 7. Herein, the results of our efforts are reported. The
planned synthetic strategy towards these alkaloids is depicted in
Scheme 1.
Advanced precursors aldisine 9 and 2-bromoaldisine 10 de-
liver intermediates (11a or 11b) and (12a or 12b) upon reaction
with 8. Conversion of the 2-methylthiodihydroimidazolone ring
into the corresponding hydantoin, removal of the N-benzoyl
protecting group and double bond isomerization (in the case of
intermediates 11a and 12a) should afford, respectively, (Z)-
debromoaxinohydantoin 7 and (Z)-axinohydantoin 6. The prep-
aration of aldisine 9 was routinely achieved on a multi-gram
scale (Scheme 2). Starting from 2-trichloroacetylpyrrole, 9 was
rapidly obtained in a optimized 78% yield over three steps,
without the need of any chromatographic purification.17 The
Due to its poor solubility in THF, 2-bromoaldisine 10 required
dichloromethane as the solvent for the reaction to proceed. The
crude reaction intermediates, whose endo-regiochemistry (11a and
12a) or exo-regiochemistry (11b and 12b, Scheme 1) was not de-
termined at this stage, were rapidly worked-up and submitted to
the next step without any further purification that, as previously
investigated,17 resulted in extensive decomposition. Thus, by ex-
posing the condensation products to aqueous 2 N HCl in THF at
room temperature, the corresponding hydantoins 13 and 14 were
isolated in, respectively, 40 and 34% yield over two steps along
with, in the case of the brominated substrate 12a, a small amount
(8%) of side-product 15 (Scheme 3). The observed endocyclic po-
sitioning of the double bond in compounds 13 and 14 allowed us to
infer the correct structure of their precursors 11a and 12a. The last
steps, namely the N-benzoyl-protecting group removal and the
endocyclic/exocyclic double bond isomerization, were tentatively
performed in one pot, in analogy with the synthesis of hyme-
nialdisine,17 by exposing both 13 and 14 to 7 N ammonia in meth-
anol. However, the reactions proved to be sluggish and poorly
N
MeS
Ph
O
H
N
N
N
N
MeS
Ph
O
MeS
Ph
O
R
O
O
O
O
8
N
N
HN
O
or
O
O
NH
R
N
H
NH
NH
NH
R
R
O
N
H
N
H
N
H
O
O
9
R=H
11a R=H
7 R=H
11b R=H
12b R=Br
10 R=Br
12a R=Br
6 R=Br
Scheme 1. Synthetic strategy.

2374
F. Tutino et al. / Tetrahedron 65 (2009) 2372–2376
O
OH
Ph
N
H
O
1) NH4SCN, Ac2O, AcOH
60°C to 100 °C
2) NaH, MeI, DMF, rt
Y = 47% over two steps
O
N
O
MeS
N
SMe
MeS
Ph
H
N
O
N
O
O
O
O
O
NH
O
H
N
2N HCl,
THF rt
8
Ph
Ph
N
Ph
N
O
+
O
O
O
TiCl4, Pyridine
THF (DCM for 10)
-10 °C to rt
NH
R
N
H
NH
NH
NH
Br
R
R
O
N
N
N
H
H
H
O
9
R=H
13 R=H (Y = 40% over two steps)
14 R=Br (Y = 34% over two steps)
11a R=H
12a R=Br
15 (Y = 8%)
10 R=Br
Scheme 3. Northern ring installation.
O
H
N
H
N
H
N
O
O
O
O
O
O
O
HN
O
NH
.
NH2NH2 H2O
HN
Ph
N
HN
MeOH, rt
+
O
R
NH
NH
O
NH
NH
R
R
R
N
N
H
N
H
N
H
H
O
O
13 R=H
16 R=H
R=H Y = 82% overall (7/5 ratio:90/10)
14 R=Br
17 R=Br
R=Br Y = 67% overall (6/4 ratio:80/20)
Scheme 4. Benzoyl removal and double bond isomerization.
productive. We then turned to NH2NH2$H2O, which has been
reported to cleave N-acetyl protecting group on spirohydantoins.20
Thus, compounds 13 and 14 were reacted with excess of
NH2NH2$H2O in methanol (Scheme 4), delivering debromoax-
inohydantoins (82% overall yield, 7/5 ratio: 90:10) and axinohy-
dantoins (67% overall yield, 6/4 ratio: 80:20), respectively (Scheme
4). (Z) and (E) isomers were easily separated by reverse phase flash
chromatography.
In both cases the protecting group removal/double bond
isomerization proceeded stepwise, as judged by changing in the
HPLC retention times/UV profiles of same molecular mass peaks
over time (see Supplementary data). Detachment of the benzoyl
group took place first, affording fast-eluting 16 and 17, which
upon standing in a basic environment, equilibrate towards axi-
nohydantoins (Scheme 4). Endocyclic/exocyclic double bond
isomerization could be reasonably justified in terms of shift to-
wards a tetra-substituted and more extensively conjugated al-
kene. On the other hand, the stereochemical outcome of the last
step was anticipated by semiempirical calculations.14 To experi-
mentally consolidate the predicted14 different stability of (Z) and
(E) isomers, the isomerization kinetics of axinohydantoins 4 and 6
was monitored at room temperature in MeOH-d4 through NMR
spectroscopy. (Z)-Axinohydantoin 6 equilibrated at less than half
of the velocity of its (E)-isomer 4 (Fig. 2). These data were ten-
tatively rationalized capitalizing on (E)-axinohydantoin 4 crystal
100
95
90
85
80
75
70
65
100
95
90
85
80
75
70
65
60
60
4 in MeOH-d4
4 in DMSO-d6
55
55
50
6 in DMSO-d6
6 in MeOH-d4
50
0
10
20
days
30
40
0
10
20
days
30
40
Figure 2. Isomerization of 6 and 4 in MeOH-d4.
Figure 3. Isomerization of 6 and 4 in DMSO-d6.

F. Tutino et al. / Tetrahedron 65 (2009) 2372–2376
2375
100
95
90
85
80
75
70
65
60
55
50
were obtained on a Waters Q-Tof Ultima directly connected with
micro HPLC 1100 Agilent.21
4.2. Experimental procedures
4.2.1. 1-Benzoyl-5-(8-oxo-1,6,7,8-tetrahydro-pyrrolo[2,3-c]azepin-
4-yl)-imidazolidine-2,4-dione (13)
A solution of 1 M TiCl4 in CH2Cl2 (7.32 mL, 7.32 mmol) was
added to dry THF (30 mL) at ꢁ10 ꢀC. Compounds 9 (300 mg,
1.83 mmol) and 8 (864 mg, 3.66 mmol) were subsequently added,
the temperature was raised to 0 ꢀC and the mixture stirred for
20 min. After dropwise addition of dry pyridine (1.18 mL,
14.64 mmol) in 30 min, the mixture was stirred at 0 ꢀC for 2 h and
at room temperature for additional 2 h. The reaction was quenched
with NH4Cl (30 mL, saturated solution) and stirred for 10 min. After
extraction with CH2Cl2 (3ꢂ60 mL), the organic phases were com-
bined, washed with water and brine, dried over anhydrous Na2SO4
and concentrated under vacuum. The obtained intermediate was
dissolved as crude in THF (35 mL) and treated with aqueous 2 N HCl
(10 mL). The solution was stirred overnight at room temperature
until HPLC revealed the disappearance of the starting material.
Filtration and washing with water of the precipitate afforded the
product as a white solid (240 mg, 40% over two steps). 1H NMR
5 in DMSO-d6
7 in DMSO-d6
0
10
20
days
30
40
Figure 4. Isomerization of 7 and 5 in DMSO-d6.
structure, which revealed the C12 carbonyl group being tilted out
of the plane of the pyrrole ring by 10ꢀ to relieve the steric in-
teraction between O-12 and CH-3.10 This lack of coplanarity, by
preventing the participation of the aforementioned C12 carbonyl
group in the conjugated system, may account, along with steric
factors, for the lower stability of 4 in MeOH. Surprisingly, how-
ever, similar experiments performed in a different solvent (DMSO-
d6) showed the two isomers moving towards each other at the
same velocity, mainly due to an increased stability of 4 (Fig. 3). If
a solvent effect could then be invoked at this stage, data collected
(499.75 MHz, DMSO-d6) d 3.34–3.38 (signal obscured by water, 1H,
CHH-8), 3.44 (ddd, J¼5.1, 6.6, 15.0 Hz, 1H, CHH-8), 5.56 (br s, 1H, H-
11), 6.08 (t, J¼6.6 Hz, 1H, H-9), 6.34 (br s, 1H, H-3), 7.05 (t, J¼2.6 Hz,
1H, H-2), 7.40–7.43 (m, 2H, m-Ar–H), 7.52–7.55 (m, 3H, o- and p-Ar–
H), 7.64 (t, J¼5.1 Hz, 1H, NH-7), 11.83 (s, 1H, NH-1). 13C NMR
(125.7 MHz, DMSO-d6)
d 37.4, 63.5, 106.2, 122.2, 122.5, 123.1, 126.1,
127.7, 128.8, 1321.9, 133.2, 163.3, 167.7. HRMS calcd for C18H14N4O4
[MþHþ] 351.1088, found 351.1089.
4.2.2. (Z)-2-Debromoaxinohydantoin (7) and (E)-2-
debromoaxinohydantoin (5)
for
(Z)-debromoaxinohydantoin
7
and
(E)-debromoax-
inohydantoin 5 isomerization in DMSO-d6 demonstrated also
a meaningful negative role of the bromine atom on the stability of
the (Z)-isomers (Fig. 4). Thus, a complex and elusive to be ratio-
nalized interplay of factors seems to govern axinohydantoins
isomerization behaviour.
To a suspension of compound 13 (240 mg, 0.69 mmol) in
methanol (3.6 mL), NH2NH2$H2O (0.21 mL, 4.14 mmol) was added.
The mixture was stirred at room temperature for 48 h yielding the
desired products, which precipitated as a white solid. Filtration
afforded a mixture of Z/E isomers (140 mg, 82% overall yield, ratio
9:1 determined by NMR). Purification by reverse phase flash
chromatography (eluant 0.1% trifluoroacetic acid in H2O/acetoni-
trile 95:5 as mobile phase A and acetonitrile as mobile phase B),
afforded 7 (110 mg, 65%) and 5 (10 mg, 6%) as white solids. The
separation was performed using a rapid gradient increasing from
0 to 25% B in 15 min followed by a hold at 100% B for 3 min at a flow
3. Conclusions
In summary, the first total synthesis of (Z)-axinohydantoin 6 has
been accomplished in a stereoselective fashion, through a seven-
step sequence (8% overall). Alongside, (Z)-debromoaxinohydantoin
7 was stereoselectively prepared in six steps, with an overall yield
of 23%. These achievements demonstrated the versatility of our 1-
benzoyl-2-methylsulfanyl-1,5-dihydroimidazol-4-one reagent 8.
The synthesis of both (Z)-axinohydantoins 6 and 7 proved to be
robust and scalable, thus allowing access to the larger amount of
materials required to draw a more complete picture of their
bioactivities.
rate of 20 mL/min. Compound 7: IR (neat)
n
3269, 3175, 3130, 1744,
3.21–3.25 (m,
1708, 1618 cmꢁ1. 1H NMR (499.75 MHz, DMSO-d6)
d
2H, CH2-9), 3.29–3.32 (m, 2H, CH2-8), 6.54 (t, J¼2.3 Hz, 1H, H-3),
6.98 (t, J¼2.9 Hz, 1H, H-2), 7.91 (t, J¼4.5 Hz, 1H, NH-7), 9.45 (s, 1H,
H-13), 11.05 (br s, 1H, H-15), 11.81 (br s, 1H, H-1). 13C NMR
(125.7 MHz, DMSO-d6)
d 30.3, 40.2, 110.0, 121.5, 122.2, 122.4, 122.8,
125.6, 154.2, 162.9, 165.5. HRMS calcd for C11H10N4O3 [MþHþ]
247.0826, found 247.0824. Compound 5: 1H NMR (499.75 MHz,
DMSO-d6)
d 2.69–2.71 (m, 2H, CH2-9), 3.19–3.23 (m, 2H, CH2-8),
4. Experimental
4.1. General
6.71 (t, J¼2.5 Hz, 1H, H-3), 6.84 (t, J¼2.8 Hz, 1H, H-2), 7.84 (t,
J¼5.6 Hz, 1H, NH-7), 9.79 (s, 1H, NH-15), 10.87 (br s, 1H, NH-13),
11.59 (br s, 1H, NH-1). 13C NMR (125.7 MHz, DMSO-d6)
d 35.4, 38.1,
112.7,119.7,120.8,122.1,124.8,125.0,154.0,162.8,164.4. HRMS calcd
IR spectra were recorded on a ThermoNicolet Avatar 360 FTIR.
NMR spectra (1D, 2D homo H–H and hetero H–C correlated) were
recorded at 25 ꢀC in DMSO-d6 on a Varian Inova 500 spectrometer
equipped with a triple resonance cold probe. Residual solvent sig-
for C11H10N4O3 [MþHþ] 247.0826, found 247.0821.
4.2.3. 1-Benzoyl-5-(2-bromo-8-oxo-1,6,7,8-tetrahydro pyrrolo[2,3-
c]azepin-4-yl)-imidazolidine-2,4-dione (14)
nal was used as reference; chemical shifts are reported in
d
units
A solution of 1 M TiCl4 in CH2Cl2 (4.96 mL, 4.96 mmol) was
added to dry CH2Cl2 (30 mL) at ꢁ10 ꢀC. Compounds 10 (300 mg,
1.24 mmol) and 8 (584 mg, 2.5 mmol) were subsequently added,
the temperature was raised to 0 ꢀC and the mixture stirred for
(ppm). 13C assignments were made using the standard two-di-
mensional sequences provided by Varian (gradient-enhanced
HSQC and HMBC). ESI(þ) high-resolution mass spectra (HRMS)

2376
F. Tutino et al. / Tetrahedron 65 (2009) 2372–2376
20 min. After dropwise addition of dry pyridine (0.82 mL,
9.92 mmol) in 30 min, the mixture was stirred at 0 ꢀC for 2 h and at
room temperature for additional 2 h. The reaction was quenched
with NH4Cl (22 mL, saturated solution) and stirred for 10 min. After
extraction with CH2Cl2 (3ꢂ60 mL), the organic phases were com-
bined, washed with water and brine, dried over anhydrous Na2SO4
and concentrated. The obtained intermediate was dissolved in THF
(18 mL), treated with aqueous 2 N HCl (8 mL) and stirred overnight
at room temperature until disappearance of the starting material
according to HPLC trace. Filtration and washing with water of the
precipitate afforded a first aliquot of product 14 as a pale yellow
solid. The filtrate was concentrated and purified on silica gel (eluant
CH2Cl2/MeOH 9:1) yielding a further aliquot of 14 and compound
15 as side product (42 mg, 8%); 175 mg of final compound 14 was
recovered (34% over two steps). Compound 14: 1H NMR
DMSO-d6) d 2.66–2.68 (m, 2H, CH2-9), 3.18–3.22 (m, 2H, CH2-8),
6.66 (s, 1H, H-3), 7.92 (t, J¼4.7 Hz, 1H, NH-7), 9.85 (s, 1H, NH-15),
10.94 (s, 1H, NH-13), 12.38 (s, 1H, NH-1). 13C NMR (125.7 MHz,
DMSO-d6)
d 36.2, 38.4, 101.6, 114.4, 120.1, 121.3, 125.6, 126.6, 153.8,
162.9, 163.5. HRMS calcd for C11H9BrN4O3 [MþHþ] 324.9931, found
324.9943.
Acknowledgements
This work was supported by a Nerviano Medical Sciences Grant
to F.T.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.12.053.
(499.75 MHz, DMSO-d6)
d
3.36 (ddd, J¼4.8, 6.7, 15.0 Hz, 1H, CHH-8),
3.45 (ddd, J¼4.8, 6.7, 15.0 Hz, 1H, CHH-8), 5.66 (s, 1H, H-11), 6.18 (t,
J¼6.7 Hz, 1H, H-9), 6.39 (br s, 1H, H-3), 7.44–7.47 (m, 2H, m-Ar–H),
7.57–7.60 (m, 1H, p-Ar–H), 7.62–7.64 (m, 2H, o-Ar–H), 7.74 (t,
J¼4.8 Hz, 1H, NH-7), 11.73 (s, 1H, NH-13), 12.71 (s, 1H, NH-1). 13C
References and notes
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d 37.4, 62.1, 104.1, 123.6, 124.1, 127.8,
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3. (a) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237; (b) Linington, R. G.;
Williams, D. E.; Tahir, A.; van Soest, R.; Andersen, R. J. Org. Lett. 2003, 5, 2735;
(c) Travert, N.; Al-Mourabit, A. J. Am. Chem. Soc. 2004, 126, 10252; (d) Baran, P.
S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int. Ed. 2004, 48, 2674; (e) Kock,
M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem., Int. Ed. 2007, 46, 6586.
4. Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G. Tetrahedron Lett. 1999, 40,
4775.
128.1, 128.9, 131.9, 132.6, 154.0, 162.1, 167.3, 170.5. HRMS calcd for
C18H13BrN4O4 [MþHþ] 429.0193, found 429.0208. Compound 15: IR
(neat)
d6)
n
1625, 1474, 1421, 1196 cmꢁ1. 1H NMR (499.75 MHz, DMSO-
2.22 (s, 3H, SCH3), 3.46 (dd, J¼5.1, 6.7 Hz, 2H, CH2-8), 5.60 (d,
d
J¼7.2 Hz, 1H, NHCHCO), 5.82 (t, J¼6.7 Hz, 1H, H-9), 6.26 (s, 1H, H-3),
7.45–7.47 (m, 2H, m-Ar–H), 7.53–7.56 (m, 1H, p-Ar–H), 7.73 (t,
J¼5.1 Hz, 1H, NH-7), 7.87–7.89 (m, 2H, o-Ar–H), 8.94 (d, J¼7.2 Hz,
1H, CONHCH), 11.72 (br s, 1H, CONHCO), 12.60 (br s, 1H, NH-1). 13C
NMR (125.7 MHz, DMSO-d6)
d 11.6, 37.4, 56.3, 104.0, 108.5, 123.2,
5. (a) Grube, A.; Kock, M. Org. Lett. 2006, 8, 4675; (b) Buchanan, M. S.; Carroll, A.
R.; Addepalli, R.; Avery, V. M.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 2007, 72,
2309.
123.7, 125.3, 127.8, 128.4, 131.7, 133.6, 162.4, 166.7, 169.7, 170.3.
HRMS calcd for C19H17BrN4O4S [MþHþ] 477.0227, found 477.0215.
6. Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett. 2007, 48, 4573.
7. Note: other examples are cyclooroidin (Fattorusso, E.; Taglialatela-Scafati, O.
Tetrahedron Lett. 2000, 41, 9917); and latonduines (Linington, R. G.; Williams, D.
E.; Tahir, A.; Van Soest, R.; Andersen, R. J. Org. Lett. 2003, 5, 2735).
8. D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.; Pusset, J.; Leroy, S.; Pietra,
F. J. Chem. Soc., Chem. Commun. 1993, 1305.
4.2.4. (Z)-Axinohydantoin (6) and (E)-axinohydantoin (4)
To a suspension of compound 14 (175 mg, 0.41 mmol) in
methanol (2.6 mL), NH2NH2$H2O (0.1 mL, 2.05 mmol) was added.
Removal of benzoyl group followed by two days of endo/exo
isomerization yielded the desired product, which precipitated as
a yellow solid. Filtration afforded a mixture of Z/E isomers (90 mg,
67% overall yield, ratio 8:2 determined by 1H NMR). Purification by
reverse phase flash chromatography (eluant 0.1% trifluoroacetic
acid in H2O/acetonitrile 95:5 as mobile phase A and acetonitrile as
mobile phase B) afforded 6 (60 mg, 45%) and 4 (10 mg, 8%) as yel-
low solids. The separation was performed using a rapid gradient
increasing from 0 to 30% B in 20 min followed by a hold at 100% B
9. Van Pee, K. H. Arch. Microbiol. 2001, 175, 250.
10. Pettit, G. R.; Herald, C. L.; Leet, J. E.; Gupta, R.; Schaufelberger, D. E.; Bates, R. B.;
Clewlow, P. J.; Doubek, D. L.; Manfredi, K. P.; Rutzler, K.; Schmidt, J. M.; Tackett,
L. P.; Ward, F. B.; Bruck, M.; Camou, F. Can. J. Chem. 1990, 68, 1621.
11. Groszek, G.; Kantoci, D.; Pettit, G. R. Liebigs Ann. 1995, 715.
12. Patil, A. D.; Freyer, A. J.; Killmer, L.; Hofmann, G.; Johnson, R. K. Nat. Prod. Lett.
1997, 9, 201.
13. Inaba, K.; Sato, H.; Tsuda, M.; Kobayashi, J. J. Nat. Prod. 1998, 61, 693.
14. Barrios Sosa, A. C.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 2002, 67, 4498.
15. Nakao, Y.; Fusetani, N. J. Nat. Prod. 2007, 70, 689.
16. Meijer, L.; Thunnissen, A. M. W. H.; White, A. W.; Garnier, M.; Nikolic, M.; Tsai,
L. H.; Walter, J.; Cleverley, K. E.; Salinas, P. C.; Wu, Y. Z.; Biernat, J.; Mandelkow,
E. M.; Kim, S. H.; Pettit, G. R. Chem. Biol. 2000, 7, 51.
17. Papeo, G.; Posteri, H.; Borghi, D.; Varasi, M. Org. Lett. 2005, 7, 5641.
18. Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36, 413.
19. Note: 2-bromoaldisine 10 is now commercially available on gram-scale from
Fulcrum Scientific Ltd.
for 3 min at a flow rate of 20 mL/min. Compound 6: IR (neat)
1732, 1616, 1481, 1442, 1371 cmꢁ1. 1H NMR (499.75 MHz, DMSO-d6)
3.18–3.27 (m, 4H, CH2-8 and CH2-9), 6.53 (d, J¼1.7 Hz, 1H, H-3),
7.96 (t, J¼4.5 Hz,1H, NH-7), 9.61 (s, 1H, NH-15), 11.09 (s, 1H, NH-13),
11.58 (br s, 1H, NH-1). 13C NMR (125.7 MHz, DMSO-d6)
31.2, 39.7,
n 1749,
d
d
20. Santoyo Gonzalez, F.; Robles Diaz, R.; Garcia Calvo-Flores, F. A.; Vargas Beren-
guel, A.; Gimenez Martinez, J. J. Synthesis 1992, 7, 631.
21. Colombo, M.; Riccardi Sirtori, F.; Rizzo, V. Rapid Commun. Mass Spectrom. 2004,
18, 511–517.
104.4,111.6, 121.3, 123.0, 123.7, 127.2, 155.0, 163.7, 165.6. HRMS calcd
for C11H9BrN4O3 [MþHþ] 324.9931, found 324.9931. Compound 4:
IR (neat)
n .
1748, 1707, 1613, 1368 cmꢁ1 1H NMR (499.75 MHz,