Synthesis of wilsoniamines A and B

Article abstract of DOI:10.1016/j.tetlet.2013.03.122

A two-step synthesis of marine origin brominated alkaloids wilsoniamines A (1) and B (2), isolated from Australian bryozoan Amathia wilsoni Kirkpatrick, possessing a novel hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one ring system is described. The core hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one ring systems is constructed through a condensation reaction between (2,4,6-tribromo-3- methoxyphenyl)acetaldehyde and (S)-N-methylpyrrolidine-2-carboxamide as key steps. The orientation of substituted benzyl side-chain in the two epimeric natural products was controlled by carrying out the key condensation reaction under kinetic or thermodynamic conditions.

Full text of DOI:10.1016/j.tetlet.2013.03.122

Tetrahedron Letters 54 (2013) 2996–2998
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Tetrahedron Letters
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Synthesis of wilsoniamines A and B
Faiz Ahmed Khan a, , Saeed Ahmad b
⇑
a Department of Chemistry, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram 502205, India
b Department of Chemistry, Indian Institute of Technology Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step synthesis of marine origin brominated alkaloids wilsoniamines A (1) and B (2), isolated from
Australian bryozoan Amathia wilsoni Kirkpatrick, possessing a novel hexahydro-1H-pyrrolo[1,2-c]imida-
zol-1-one ring system is described. The core hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one ring systems is
constructed through a condensation reaction between (2,4,6-tribromo-3-methoxyphenyl)acetaldehyde
and (S)-N-methylpyrrolidine-2-carboxamide as key steps. The orientation of substituted benzyl side-
chain in the two epimeric natural products was controlled by carrying out the key condensation reaction
under kinetic or thermodynamic conditions.
Received 13 February 2013
Revised 27 March 2013
Accepted 29 March 2013
Available online 8 April 2013
Keywords:
Wilsoniamine
Amathia wilsoni
Condensation
Quaternization
Ó 2013 Elsevier Ltd. All rights reserved.
Among the natural products isolated from marine sources in the
recent years, considerable percentage belongs to organohalogens.
Most of the organohalogen compounds found in marine organisms
are produced for the chemical defenses or other specific purposes.1
Amathia wilsoni Kirkpatrick is a marine bryozoan from which a ser-
ies of brominated alkaloids, amathamides A–F, were isolated in the
last decades.2 Recently, Carroll et al. isolated two new alkaloids
wilsoniamines A (1) and B (2) from the same species (Fig. 1).3 Both
molecules possess a novel and very unique hexahydro-1H-pyrrolo
[1,2-c]imidazol-1-one ring system. Their structures were estab-
lished by extensive NMR experiments. Interestingly, hexahydro-
1H-pyrrolo[1,2-c]imidazol-1-one skeleton was not detected in
nature previously, with a sole exception of (ꢀ)-dysibetaine PP
(3). The dipeptidyl betaine (ꢀ)-dysibetaine PP (3) also has the same
core ring skeleton and was isolated by Sakai et al. from the marine
sponge Dysidea herbacea.4 The total synthesis of (ꢀ)-dysibetaine PP
(3) was achieved by the diastereoselective tandem cyclization
strategy.5 The N,N-acetal moiety in 3 was constructed employing
a tandem cyclization leading, initially, to a fused bicyclic five and
six membered ring system. Later, the pyrrolidine unit of hexahy-
dro-1H-pyrrolo[1,2-c]imidazol-1-one ring system was obtained
by intramolecular reductive amination. Various hexahydro-1H-
pyrrolo[1,2-c]imidazol-1-one frameworks were prepared and used
as chiral ligands in asymmetric reactions.6 In an extensive and in-
depth study of prolinamide catalyzed aldol reactions, hexahydro-
1H-pyrrolo[1,2-c]imidazol-1-one intermediates were obtained
and it was suggested that these intermediates may influence the
reaction rate and the enantioselectivity.7
We recently described a synthesis of convolutamine F, where
(2,4,6-tribromo-3-methoxyphenyl)acetaldehyde (6) was used.8
We anticipated that aldehyde 6 would be an ideal precursor for a
straightforward synthesis of wilsoniamines A (1) and B (2). A retro-
synthetic analysis as depicted in Scheme 1 revealed that both wil-
soniamines A (1) and B (2), which are epimeric with regard to
substituted benzyl side-chain, could be obtained by kinetically
and thermodynamically controlled conditions, respectively. The
desired absolute configuration for the natural products could be
obtained by employing (S)-N-methylpyrrolidine-2-carboxamide 7.
Br
Br
OMe
Br
OMe
Br
Br
Br
Me
Me
N
N
Me
Me
O
O
N
N
H
H
1 wilsoniamine A
2 wilsoniamine B
H
CO2
Me
N
N
O
H
3 (−)-dysibetaine PP
Figure 1. Structure of marine alkaloids containing hexahydro-1H-pyrrolo[1,2-
c]imidazol-1-one ring system.
⇑
Corresponding author. Tel.: +91 40 23016084.
E-mail address: faiz@iith.ac.in (F.A. Khan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.122

F. A. Khan, S. Ahmad / Tetrahedron Letters 54 (2013) 2996–2998
2997
Br
Br
OMe
Br
OMe
Br
Kinetically
controlled
OMe
Br
O
Br
Br
Br
H
Me
N
H
Me
O
NHMe
Br
N
HN
H
Me
O
N
N
CHO
H
7
6
4
1
No steric hindrance
More stable transition state
Br
Br
OMe
OMe
Br
Thermodynamically
controlled
Br
Br
Me
Br
6
7
Me
HN
H
N
Me
N
O
O
N
H
H
5
2
Steric hindrance
Less stable transition state
Scheme 1. Retrosynthetic analysis for wilsoniamines A and B.
Condensation of (2,4,6-tribromo-3-methoxyphenyl)acetalde-
hyde 6 with (S)-N-methylpyrrolidine-2-carboxamide 7 at a lower
temperature is expected to give a more stable (sterically less hin-
dered) iminium ion intermediate 4 which upon cyclization would
yield imidazolidinone product with substituted benzyl side-chain
disposed in sterically demanding endo-face (Scheme 1). At rela-
tively higher temperature, a thermodynamically more stable imi-
dazolidinone product with substituted benzyl side-chain
disposed on sterically comfortable exo-face is expected to prevail
albeit through a congested iminium ion intermediate 5.7
starting material). Stereoselective methyl quaternization of com-
pound
8
by using trimethyloxonium tetrafluoroborate
(Me3OBF4)10 in acetonitrile at 0ꢀ5 °C gave compound
1
(Scheme 2). Synthetic 1 thus obtained was confirmed to be iden-
tical to natural wilsoniamine A by H and 13C NMR data and high-
1
resolution mass spectrometry.
Aldehyde 6 on treatment with amide 7 in anhydrous toluene/
TFA11 under reflux condition, gave product 9 in 52% yield
(Scheme 3). While employing p-TsOH (10 mol %) in place of TFA,
in benzene or toluene under reflux condition gave a trace amount
of product. Stereoselective methyl quaternization of compound 9
using trimethyloxonium tetrafluoroborate (Me3OBF4) in acetoni-
trile at 0ꢀ5 oC gave compound 2 in 85% yield.14 Synthetic 2 was
confirmed to be identical to natural wilsoniamine B by 1H and
13C NMR data and high-resolution mass spectrometry. The struc-
ture of wilsoniamine B (2) was further confirmed by single crystal
X-ray analysis12,13 (Fig. 2). Further, upfield shift of the endo-
methine protons at the newly created stereocenters in 9 and 214
compared to the corresponding signals in 8 and 114 corroborates
the assigned relative configurations and is consistent with the
trend reported for related imidazolidinones.7
Our initial attempts to synthesize imidazolidinone 8 from
(2,4,6-tribromo-3-methoxyphenyl)acetaldehyde
6
and (S)-N-
methylpyrrolidine-2-carboxamide 79 were not fruitful under var-
ious conditions such as CHCl3, DMSO, DMF, CHCl3/4 Å molecular
sieves, and toluene/TFA (0 °C to room temperature). They led
either to an intractable reaction mixture or furnished a very poor
yield of compound 8. Finally, stirring the reaction mixture in
anhydrous methanol without any additive at 0–30 °C for 12 days
furnished chromatographically separable imidazolidinone 8 and 9
in 55% and 10% isolated yields, respectively, (67% conversion, 81%
and 14% yields of 8 and 9, respectively, based on recovered
Br
Br
OMe
OMe
O
TFA, toluene
O
MeOH
0 to 30 ο
12 d
C
N
H
reflux, 30 h
52%
N
H
Br
Br
Br
Br
Br
NHMe
NHMe
CHO
CHO
7
6
6
7
Br
Br
Br
Br
OMe
OMe
OMe
Br
OMe
Me3OBF4
CH3CN
Me3OBF4
CH3CN
Br
Br
Br
Br
Me
Br
1
Br
Me
Me
Me
(from 8)
N
N
N
N
0 to 5 ο
C
0 to 5 οC, 1h
85%
Me
O
O
O
H
N
N
N
O
N
3 h, 78%
H
H
BF4
H
2
9
8
9
10%
55%
Scheme 2. Synthesis of wilsoniamine A (1).
Scheme 3. Synthesis of wilsoniamine B (2).

2998
F. A. Khan, S. Ahmad / Tetrahedron Letters 54 (2013) 2996–2998
8. Khan, F. A.; Ahmad, S. J. Org. Chem. 2012, 77, 2389–2397.
9. (a) Elliott, R. L.; Kopecka, H.; Lin, N. H.; He, Y.; Garvey, D. S. Synthesis 1995, 7,
772–774; (b) Chang, J. K.; Sievertsson, H.; Currie, B.; Folkers, K. J. Med. Chem.
1971, 14, 484–487.
10. Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31–33.
11. Moss, W. O.; Jones, A. C.; Wisedale, R.; Mohan, M. F.; Molloy, K. C.; Bradbury, R.
H.; Hales, N. J.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1992, 2615–2624.
12. Wilsoniamine B (2) was isolated as a colorless gum when counter ion was TFA
anion.3 We synthesized wilsoniamine
B
with BF4 as counter anion and
ꢀ
obtained a crystalline solid. We thought of performing a single crystal X-ray
analysis as a further confirmation of the natural product structure.
13. Crystallographic data for the structure 2 have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
924045. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
14. Experimental section, compound 8: To a cooled (0 °C) solution of aldehyde 6
(387 mg, 1.0 mmol) in anhydrous MeOH (10 mL) was added prolinamide 7
(128 mg, 1.0 mmol), then reaction was allowed to warm to 30 °C and stirred for
12 days. All volatiles were removed under reduced pressure and the residue
was purified over silica gel column chromatography (15–90% EtOAc/Hexane
and then 1–6% MeOH/EtOAc) to give 6 (126.9 mg, 33%), compound 8 (272 mg,
55%) as a colorless oil and compound 9 as a red brown oil (48.4 mg, 10%). [a 26
]
D
+26.3 (c 0.97, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.82 (s, 1H), 5.14 (dd, 1H,
J = 7.6, 4.9 Hz), 3.89 (s, 3H), 3.70 (dd, 1H, J = 9.2, 4.5 Hz), 3.62 (dd, 1H, J = 14.4,
7.9 Hz), 3.48 (dd, 1H, J = 14.4, 4.9 Hz), 3.16 (t, 1H, J = 7.3 Hz), 2.78ꢀ2.72 (m, 1H),
2.67 (s, 3H), 2.20ꢀ2.16 (m, 1H), 2.10ꢀ2.07 (m, 1H), 1.92ꢀ1.86 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 177.5, 154.6, 136.8, 136.2, 122.6, 120.4, 117.3, 65.6,
60.6, 47.8, 37.9, 28.3, 25.8, 25.1; IR (neat) 2966, 2840, 1702, 1451, 1108,
Figure 2. X-ray crystal structure (ORTEP) of wilsoniamine B (2).
938 cmꢀ1
; HRMS (ESI) calcd for C15H18Br3N2O2 (M+H), 494.8918; found,
In summary, a straightforward two-step synthesis of wilsoni-
amines A and B was achieved through a condensation reaction be-
tween (2,4,6-tribromo-3-methoxyphenyl)acetaldehyde and (S)-N-
methylpyrrolidine-2-carboxamide followed by quaternization of
ring junction nitrogen (overall yield of 43% and 44%, respectively).
The structure of wilsoniamine B was further confirmed by single
crystal X-ray analysis.
494.8915. Compound 9: To a solution of prolinamide 7 (128 mg, 1.0 mmol)
in anhydrous toluene (3.5 mL) were added aldehyde 6 (503 mg, 1.3 mmol) and
trifluoroacetic acid (171 mg, 1.5 mmol). The reaction was refluxed for 30 h
with azeotropic removal of water through Dean–Stark condenser, after that all
volatiles were removed under reduced pressure and the residue was taken in
CH2Cl2 (40 mL). The organic phase was washed with saturated aqueous
NaHCO3 solution (7 mL), brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified over silica gel column
chromatography (1–8% MeOH/CH2Cl2) to give 9 (258 mg, 52%) as a red brown
oil. ½a 2D5
ꢁ
ꢀ22.3 (c 0.74, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.77 (s, 1H), 4.46
Acknowledgments
(dd, 1H, J = 8.7, 4.4 Hz), 3.90 (dd, 1H, J = 9.2, 4.6 Hz), 3.86 (s, 3H), 3.37 (dd, 1H,
J = 13.2, 4.6 Hz), 3.17 (dd, 1H, J = 13.2, 8.9 Hz), 2.83 (s, 3H), 2.82ꢀ2.80 (m,
partially merged with –NMe, 1H), 2.37ꢀ2.32 (m, 1H), 2.10ꢀ2.04 (m, 1H),
1.96ꢀ1.92 (m, 1H), 1.68ꢀ1.62 (m, 2H); 13C NMR (125 MHz, CDCl3) d 175.5,
154.0, 137.2, 135.5, 122.8, 121.1, 116.6, 80.8, 63.8, 60.7, 56.0, 41.8, 28.0, 27.4,
F.A.K. gratefully acknowledges CSIR for financial support. S.A.
thanks CSIR for fellowship.
25.3; IR (neat) 2936, 1698, 1451, 1263, 732 cmꢀ1
15H18Br3N2O2 (M+H), 494.8918; found, 494.8911.
; HRMS (ESI) calcd for
C
Supplementary data
Wilsoniamine A (1): To a cooled (0 °C) solution of compound 8 (145.2 mg,
0.29 mmol) in anhydrous acetonitrile (3 mL) was added Me3OBF4 (64.8 mg,
0.44 mmol). The reaction was stirred for 1 h at 0–5 °C, and then the solvent was
evaporated in vacuo. The residue was purified over silica gel column
chromatography (5–30% MeOH/CH2Cl2) to give 8 (12.8 mg) and 1 (136 mg,
Supplementary data (1H and 13C NMR spectra) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.03.122.
78%) as a white solid. Mp 196–198 °C; ½a D26
ꢁ
+23.0 (c 1.0, DMSO); 1H NMR
(500 MHz, DMSO-d6) d 8.16 (s, 1H), 5.73 (dd, 1H, J = 8.7, 3.2 Hz), 4.66 (d, 1H,
J = 9.2 Hz), 3.93ꢀ3.80 (m, 3H, partially merged with –OMe), 3.80 (s, 3H), 3.69
(dd, 1H, J = 15.0, 8.8 Hz), 3.31 (s, 3H), 2.60 (s, 3H), 2.47ꢀ2.40 (m, 2H),
2.24ꢀ2.14 (m, 3H); 13C NMR (125 MHz, DMSO-d6) d 169.4, 154.8, 136.9, 134.2,
123.0, 121.2, 118.6, 81.7, 74.8, 61.1, 59.6, 47.7, 35.3, 28.6, 24.6, 22.2; IR (KBr)
References and notes
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609.
3422, 2937, 1724, 1454, 1265, 1058 cmꢀ1
16H20BBr3F4N2NaO2 (M+Na), 618.9002; found, 618.8998.
;
HRMS (ESI) calcd for
C
Wilsoniamine B (2): Experimental procedure is similar to that for compound 1.
After column purification the compound 9 (14.6 mg) was recovered and
compound 2 (126 mg, 85%) was obtained as a white crystalline solid. Mp 238–
240 °C (decomposed); ½a D25
ꢁ
+17.0 (c 1.0, DMSO); 1H NMR (500 MHz, DMSO-d6)
4. Sakai, R.; Suzuki, K.; Shimamoto, K.; Kamiya, H. J. Org. Chem. 2004, 69, 1180–
1185.
d 8.13 (s, 1H), 5.48 (dd, 1H, J = 10.7, 3.4 Hz), 5.09 (d, 1H, J = 8.2 Hz), 3.95 (t, 1H,
J = 9.2 Hz), 3.78 (s, 3H), 3.75ꢀ3.67 (m, 3H), 2.39 (m, 1H), 2.31 (m, 1H), 2.26 (s,
3H), 2.22 (m, 1H), 2.05ꢀ2.03 (m, 1H); 13C NMR (125 MHz, DMSO-d6) d 167.6,
154.6, 136.5, 133.9, 123.2, 121.3 118.7, 81.2, 71.7, 66.3, 61.1, 44.8, 38.9, 30.8,
24.1, 21.4; IR (KBr) 3423, 2947, 1714, 1478, 1072 cmꢀ1; HRMS (ESI) calcd for
5. Ijzendoorn, D. R.; Botman, P. N. M.; Blaauw, R. H. Org. Lett. 2006, 8, 239–242.
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C
16H20Br3N2O2 (MꢀBF4), 508.9069; found, 508.9073.