Preparation of an ABC tricyclic model of the cylindrospermopsin alkaloids via a biomimetically inspired pathway

Article abstract of DOI:10.1039/c4ra03031a

Two tricyclic guanidine model compounds 28 and 29 have been prepared in 12 steps from 1,5-pentanediol using a biomimetic synthetic approach. The pivotal reaction in the sequence is a tethered Biginelli condensation between 21/22 and β-keto esters 23 and 24. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03031a

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PAPER
Preparation of an ABC tricyclic model of the
cylindrospermopsin alkaloids via a biomimetically
inspired pathway†
Cite this: RSC Adv., 2014, 4, 20744
a
b
b
a
*
Daniel. M. Evans, Peter N. Horton, Michael B. Hursthouse and Patrick. J. Murphy
Received 4th April 2014
Accepted 28th April 2014
Two tricyclic guanidine model compounds 28 and 29 have been prepared in 12 steps from 1,5-pentanediol
using a biomimetic synthetic approach. The pivotal reaction in the sequence is a tethered Biginelli
condensation between 21/22 and b-keto esters 23 and 24.
DOI: 10.1039/c4ra03031a
www.rsc.org/advances
been the subject of considerable synthetic interest, resulting in
four total syntheses11 and several general methodological
approaches.12 These approaches generally rely upon the initial
construction of either the A or B rings of the toxin, with the
tricyclic core being completed by the installation of the C ring at
a later stage.
Introduction
The cylindrospermopsin alkaloids are a family of polyketide
derived marine natural products currently known to be
produced by 12 different species of cyanobacteria.1 Cylin-
drospermopsin 1 was rst isolated from the cyanobacteria
cylindrospermopsis raciborskii in 1992 (ref. 1a) and retrospec-
tively identied as the causative agent in an outbreak of hep-
atoenteritis which affected 148 residents of Great Palm Island
Australia.2 Subsequent to the discovery of cylindrospermopsin,
two further metabolites were isolated and characterised,
Recent advances have led to the characterisation of the gene
cluster responsible for the biosynthesis of cylindrospermopsin
in C. raciborskii strain AWT205.13 As previously indicated the
starter unit for the polyketide chain is guanidinoacetate 4 which
has been shown to be derived from a novel L-arginine–glycine
amidinotransferase enzyme.14 It is believed that the tricyclic
guanidinium core of this family of natural products is con-
structed in a modular fashion from 4, with sequential polyke-
tide extensions and Michael type ring closures generating in
turn the C ring (5 / 6), the A ring (7 / 8) and the B ring (9 /
10) (Scheme 1).
Using this biosynthesis as a guide for our synthetic investi-
gations we envisioned a strategy in which cylindrospermopsin
could be separated into two distinct fragments consisting of the
uracil D ring and the tricyclic ABC guanidinium core. Initially
we concentrated on a preparing a simplied version of the
namely the related diastereomer 7-epi-cylindrospemropsin3
2
and the C-7 deoxygenated biosynthetic intermediate 7-deoxy-
cylindrospermopsin4 3. Cylindrospermopsin has been shown to
display hepatotoxic,5 cytotoxic,6 neurotoxic7 and carcinogenic
effects,8 which are shared with its equally toxic diastereoisomer
7-epicylindrospemropsin9 2, however the deoxygenated
analogue 7-deoxycylindrospermopsin 3 has been shown to be
devoid of toxicity in vivo10 (Fig. 1). These alkaloids have also
Fig. 1 The cylindrospermopsin alkaloids.
aSchool of Chemistry, Bangor University, Bangor, Gwynedd, LL57 2UW, UK. E-mail:
chs027@bangor.ac.uk; Fax: +44 (0)1248 370528; Tel: +44 (0)1248 382375
bChemistry, University of Southampton, Southampton, SO17 1BJ, UK
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra03031a
Scheme 1 Proposed biosynthesis of the cylindrospermopsin alkaloids.
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Fig. 2 Retrosynthetic analysis of cylindrospermopsin.
tricyclic guanidinium moiety anticipating that the stereo-
chemistry generated during the formation of the initial C ring
juncture would dictate the stereochemistry generated during
the closure of the A and B rings (Fig. 2).12d,15
Scheme 2 Reagents and conditions: (a) TBSCl, NaH, THF, 2 h, 61%; (b)
oxalyl chloride, DMSO, NEt3, CH2Cl2, ꢀ78 ꢁC, 3 h, 89%; (c) MeNO2,
DIPEA, CH2Cl2, 36 h, 81%; (d) NiCl2$6H2O, NaBH4, MeOH, NEt3, 0 ꢁC, 3
h; (e) 14, 48 h, 78% (2 steps from 13); (f) PPh3, I2, imidazole, CH2Cl2,
ꢀ20 ꢁC, 1 h, 96%; (g) TBAF, THF, 0 ꢁC to rt, 24 h, 99%; (h) Dess–Martin
periodinane, pyridine, CH2Cl2, 24 h, 96%; (i) LiCl, DIPEA, 19, CH3CN, 48
h, 86%; (j) TFA–CH2Cl2 (1 : 1), 2 h; (k) NEt3, CH2Cl2, 48 h, 70% (2 steps
from 20).
Results and discussion
To test this approach we began with the simple diol, 1,5-pen-
tanediol 11 which was monosilylated in 61% yield by treatment
with TBSCl16 followed by oxidation of the remaining alcohol
function under Swern conditions to furnish aldehyde 12 in 89%
yield. The b-nitro alcohol 13 was then prepared in 81% yield via
the nitro-aldol (Henry) reaction between 12 and nitromethane.
The nitro functionality of 13 was then reduced with the NiCl2–
NaBH4 system followed by the guanylation of the primary amine
formed with 14 which gave the protected guanidine 15 in 78%
yield.17 Subsequently a Mitsunobu type cyclodehydration gave
the required C-ring heterocycle 16 in 96% yield.18 The alkyl
chain of 16 was then elaborated by removing the TBS protecting
group with TBAF followed by oxidation of alcohol 17 with Dess–
Martin periodinane to generate aldehyde 18. Aldehyde 18 then
underwent a Horner–Wadsworth–Emmons reaction with the
simple phosphonate 19 to give the model substrate, enone 20 in
86% yield. It was attempted to cyclise enone 20 under a variety
of conditions; however the only isolated material was repre-
sentative of bicyclic guanidine 21 which displays an anti-
conguration between the two bridging methine groups as
conrmed by X-ray crystallography (Fig. 3). Efforts were made to
epimerise this material under both basic and acidic conditions
via retro-Michael addition of the guanidine, however all
attempts proved unsuccessful (Scheme 2).19
Being unable to elaborate enone 20 into a suitable tricycle
guanidine, the initial synthetic approach was revised utilising
the previously prepared aldehyde 18. Thus the Boc-protecting
groups of 18 were removed to give a mixture of hemiaminal 22
and N-acyliminium species 23. The resulting mixture was then
immediately condensed with allyl acetoacetate 24 in the pres-
ence of morpholinium acetate under a variety of conditions
based on the work of Aaron and Overman.20 This tethered
Biginelli protocol successfully generated tricyclic guanidine 26
the relative stereochemistry of which was determined by 2D
NOESY NMR where a strong nOe correlation was observed
Fig. 3 X-ray crystal structure of bicyclic guanidine 21.
Scheme 3 Reagents and conditions: (a) see Table 1.
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Table 1 Optimisation of reaction conditionsa
Entry
R
Deprotection
b-Keto ester (eqv.)
Morpholinium acetate (eqv.)
T
Reaction time
Yield
1
2
3
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
TFA
TFA
TFA
TFA
3
2
1
3
5
5
5
8
5
5
1.0
1.5
1.0
1.0
2.5
2.5
2.5
4.0
0d
60 ꢁ
60 ꢁ
60 ꢁ
60 ꢁ
C
C
C
C
48 h
72 h
96 h
96 h
12 d
12 d
6 d
12 d
12 d
12 d
4%
8%
10%
12%
21%
36–43%b
26%
37%
0%
5
TFA
70 ꢁC
6
AcOH
AcOH
AcOH
AcOH
AcOH
70 ꢁ
C
C
C
C
C
7c
8c
9
100 ꢁ
100 ꢁ
70 ꢁ
70 ꢁ
10
2.5
26%
a
b
All reactions were performed on an ꢂ0.5 mmol scale in 2,2,2-triuoroethanol (1.5 mL) in the presence of sodium sulphate (1 g). Over 12
c
d
reactions. Reactions performed in a sealed tube. N-Methylmorpholine (2.5 eqv.) and AcOH (2.5 eqv.) were added to the reaction as a solution
in 2,2,2-triuoroethanol.
between the two piperidine methine protons conrming the
desired all syn relationship (Scheme 3 and Table 1).
No other tricyclic products were apparent, however, with the
hope of further increasing the reaction yield it was attempted to
Initial investigations were conducted using TFA for the recycle bicyclic intermediates isolated during purication by re-
deprotection of aldehyde 18 followed by condensation of the subjecting them to the reaction conditions. Interestingly even
resultant material with varying equivalents of 24, in the pres- though the reaction conditions employed are equilibrating21 no
ence of morpholinium acetate and Na2SO4 at 60 ꢁC (entries 1–4). further tricyclic material could be generated suggesting that the
An incremental increase in the reaction time from 48 h to 96 h addition of the b-keto ester to the N-acyliminium ion 23 occurs
allowed for an appreciable increase in the yield from 4% to 10%, through an irreversible pathway. Another reaction product iso-
with an excess of b-keto ester 24 generating a further 2% lated in low yields was the b-keto ester 28 which is formed from
increase in the isolated yield (entries 1–4). Because of the the reaction of 24 with morpholine. No tricyclic material con-
progressive increase in yield observed with increased reaction taining morpholine derived esters were observed during any of
time the reaction was allowed to proceed over a 12 day period at the reactions run. In an attempt to negate this side reaction
ꢁ
a slightly higher temperature of 70 C (entry 5). Using such a which consumes the b-keto ester, N-methylmorpholine was
prolonged reaction time had the greatest observed effect on the used as the base in the reaction (entry 9). However under these
isolated yield of guanidine 26 which increased to a more conditions no tricyclic material was isolated.
acceptable 21%. Further signicant improvements to the yield
With tricyclic guanidines 26 and 27 in hand deallylation/
were also observed when all the anionic species involved in the decarboxylation was undertaken by treatment with Pd(PPh3)4
reaction were of the same nature. Under such condition the TFA followed by treating the resulting material with NaBH3CN in a
used in the initial deprotection step was replaced with AcOH, 1 : 1 mixture of AcOH–MeOH to give saturated tricyclic guani-
which gave an increase in the isolated yield of between 36% and dines 29 and 30 in 57% and 53% yield respectively over two
43% (entry 6). The use of more forcing conditions were also steps (Scheme 4).22 Again 2D NOESY NMR spectroscopy was
investigated were the reaction was performed at 100 ꢁC in a utilised to conrm that tricyclic guanidines 29 and 30 displayed
sealed tube, however, no improvement in the isolated yield was the correct relatively stereochemistry representative of the ABC
observed (entries 7–8). The condensation was also attempted core of the cylindrospermopsin alkaloids.
using b-keto ester, 25 which under the best conditions gave the
corresponding tricyclic guanidine 27 in an unoptimised 26%
yield (entry 10). The relative stereochemistry of this tricyclic
Conclusions
material was assigned by 2D NOESY NMR spectroscopy.
In conclusion we have demonstrated the use of a nitro-aldol
reaction, intramolecular SN2 cyclisation and tethered Biginelli
condensation to produce two model tricyclic guanidinium
species which possess the correct relative syn-geometry found in
the cylindrospermopsin alkaloids. During our initial investiga-
tion of the key tethered Biginelli condensation the desired
tricyclic dihydropyrimidine could only be generated in an
initially low yield of 4%, this could be improved to between 36%
and 43% employing optimised reaction conditions. The simple
Scheme 4 Reagents and conditions: (a) Pd(PPh3)4, pyrrolidine, THF–
MeOH, 1.5–2 h; (b) NaBH3CN, AcOH–MeOH, 0 ꢁC to rt, 16 h, 57% (29),
53% (30) (2 steps).
biologically inspired approach that we have demonstrated in
combination with key tethered Biginelli condensation
a
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hopefully demonstrates the potential of this methodology for
the synthesis of 1–3 which we will report in due course.
6-(tert-Butyl-dimethyl-silanyloxy)-1-nitro-pentan-2-ol (13). To
a stirred solution of aldehyde 12 (4.93 g, 22.7 mmol) in CH2Cl2
(80 mL) at rt was added nitromethane (73.7 mL, 1.36 mol) and
the mixture cooled (0 ꢁC) and DIPEA (9.90 mL, 56.9 mmol)
added. Reaction progress was monitored via TLC and aer 5
days the reaction was quenched with an ammonium chloride
solution (sat, 200 mL), separated and the aqueous layer
extracted with chloroform (3 ꢃ 100 mL). The combined organic
extracts were washed with brine (100 mL), dried over anhydrous
magnesium sulfate and puried by ash column chromatog-
raphy on silica gel using ethyl acetate–petroleum ether (10 : 90,
30 : 70). Fractions eluting in 10 : 90 ethyl acetate–petroleum
ether gave 13 as a pale yellow oil (5.11 g, 18.4 mmol, 81%). Rf ¼
0.29 (20% ethyl acetate in petrol); nmax (chloroform)/cmꢀ1 3418,
2953, 2931, 2858, 1556, 1471, 1463, 1421, 1385 and 1361; dH (500
MHz; CDCl3) 0.04 (s, 6H), 0.88 (s, 9H), 1.43–1.59 (m, 6H), 2.87
(br s, 1H), 3.62 (t, J ¼ 5.9 Hz, 2H), 4.30–4.34 (m, 1H), 4.37 (dd, J ¼
12.6, 8.5 Hz, 1H) and 4.42 (dd, J ¼ 12.6, 3.1 Hz, 1H); dC (125
MHz; CDCl3) ꢀ5.4, 18.3, 21.6, 25.9, 32.1, 33.4, 62.8, 68.6 and
80.6; LRMS, CI, m/z 295 ([M + NH3]+, 3%), 278 ([M + H]+, 9%),
235 (5), 234 (30), 219 (7), 218 (20), 217 (100), 176 (5), 159 (8), 132
(6), 102 (3), 91 (6) and 85 (6); HRMS, ESI, m/z C12H28NO4Si,
requires 287.1782, found 287.1784 [M + H]+.
N,N0-bis-(tert-Butyloxycarbonyl)-N00-(6-(tert-butyldimethylsi-
lyloxy)-2-hydroxyhexyl)-guanidine (15). To a vigorously stirred,
cooled (0 ꢁC) solution of nickel(II) chloride hexahydrate (8.67 g,
36.5 mmol) in methanol (50 mL) was added NaBH4 (4.10 g, 109.4
mmol) and stirring continued for 30 min. To the resultant black
suspension was added nitro-alcohol 13 (3.38 g, 12.2 mmol) in
methanol (20 mL), followed by the portion-wise addition of
further NaBH4 (9.23 g, 246.8 mmol). The reaction mixture was
stirred for a further 2 h at rt and then ltered through a pad of
Celite® (ca. 5 cm) and washed with methanol (3 ꢃ 50 mL). NEt3
(149 mL, 1.07 mol) was added and aer stirring for 45 min, the
guanylating agent 14 (4.14 g, 13.4 mmol) dissolved in methanol
(15 mL) was also added. Aer 48 h the reaction was diluted with
water (400 mL) and extracted with ethyl acetate (3 ꢃ 250 mL).
The combined organic extracts were dried over magnesium
sulfate, evaporated and the resultant reaction material puried
by ash column chromatography on silica gel using ethyl
acetate–petroleum ether (5 : 95, 25 : 75). Fractions eluting in
10 : 90 ethyl acetate–petroleum ether gave 15 as a clear oil (4.66
g, 9.5 mmol, 78%). Rf ¼ 0.34 (40% ether in petrol); nmax (chlo-
roform)/cmꢀ1 3330, 3291, 3156, 2982, 2933, 2859, 1724, 1618,
1601, 1577, 1472, 1460, 1411, 1394, 1368 and 1335; dH (500 MHz;
CDCl3) 0.04 (s, 6H), 0.88 (s, 9H), 1.34–1.62 (m, 6H), 1.47 (s, 9H,
Boc), 1.49 (s, 9H, Boc), 3.33–3.39 (m, 1H), 3.54 (ddd, J ¼ 14.2, 6.3,
2.2 Hz, 1H), 3.61 (t, J ¼ 6.3 Hz, 2H), 3.71–3.80 (br m, 1H), 4.58 (br
s, 1H), 8.64–8.69 (br m, 1H) and 11.47 (s, 1H); dC (125 MHz;
CDCl3) ꢀ5.3, 18.4, 21.8, 26.0, 28.0, 28.2, 32.7, 34.9, 47.6, 63.1,
71.8, 79.5, 83.4, 153.1, 157.4 and 162.9; LRMS, CI, m/z 491 ([M +
H]+, 40%), 434 (4), 390 (3), 373 (4), 370 (1), 320 (2), 275 (3), 274
(9), 273 (14), 248 (6), 232 (11), 231 (44), 217 (100), 204 (11), 175
(4), 174 (5), 160 (15) 159 (21), 145 (20), 132 (16), 104 (18), 92 (18),
60 (30), 58 (49) and 45 (71); HRMS, ESI, m/z C23H48N3O6Si,
requires 490.3307, found 490.3312 [M + H]+.
Experimental section
General information
Column chromatography was carried out on silica gel (particle
size 40–63 mm) and thin layer chromatography conducted on
precoated Kieselgel 60 F254 (Art. 5554; Merck) with the eluent
specied in each case. All anhydrous reactions were conducted
in oven-dried apparatus under a static atmosphere of argon.
THF and dichloromethane were dried on a Pure Solv MD-3
solvent purication system. Chemical shis are reported in d
values relative to chloroform (7.27/77.0 ppm) or methanol
(3.31/49.00 ppm) as an internal standard. NMR spectra were
recorded on a Bruker Avance 400/500 spectrometer unless
otherwise stated. Mass spectra data were obtained at the EPSRC
Mass Spectrometry Service Centre at the University of Wales,
Swansea.
5-(tert-Butyl-dimethyl-silanyloxy)-pentan-1-ol (16). To a stir-
red suspension of NaH (3.86 g, 100 mmol) in anhydrous THF
(100 mL) was added pentane-1,5-diol (10.52 mL, 100 mmol),
aer 1 h TBSCl (15.07 g, 100 mol) was added and vigorous
stirring continued for a further hour. The reaction mixture was
then diluted with diethyl ether (600 mL), washed with potas-
sium carbonate (aq. 10%, 200 mL), brine (200 mL) and the
organic extracts dried over magnesium sulfate. Aer purica-
tion by ash column chromatography on silica gel using ethyl
acetate–petroleum ether (10 : 90, 40 : 60), the title compound
was obtained as a clear oil (14.7 g, 67.1 mmol, 67%). Rf ¼ 0.36
(20% ethyl acetate in petrol); nmax (chloroform)/cmꢀ1 3417,
2932, 2858, 1471, 1389 and 1361; dH (500 MHz; CDCl3) ꢀ0.01
(s, 6H), 0.84 (s, 9H), 1.30–1.36 (m, 2H), 1.46–1.54 (m, 4H), 2.74
(br s, 1H) and 3.53–3.57 (m, 4H); dC (125 MHz; CDCl3) ꢀ5.4,
18.2, 21.9, 25.9, 32.3, 32.4, 62.4 and 63.1.
5-(tert-Butyl-dimethyl-silanyloxy)-pentanal (12).23 To a cooled
ꢁ
(ꢀ78 C) and stirred solution of oxalyl chloride (3.98 mL, 46.4
mmol) in anhydrous CH2Cl2 (120 mL) was added anhydrous
DMSO (5.96 mL, 84.0 mmol). Aer 20 min a solution of alcohol
11 (6.34 g, 29.0 mmol) in anhydrous CH2Cl2 (50 mL) was added
to the reaction mixture. Aer a further 20 min NEt3 (24.2 mL,
173.9 mmol) was also added. Aer 3 h TLC analysis indicated
the complete consumption of 11 and the reaction was diluted
with brine (100 mL) and warmed to rt. Aer separation the
organic layer was washed with brine (2 ꢃ 100 mL), HCl (0.25 M,
3 ꢃ 100 mL) and water (3 ꢃ 100 mL). Aer drying and evapo-
ration the resulting yellow oil was dissolved in petroleum ether
(50 mL) and passed through a plug of silica (ca. 1 cm) eluting
with further petroleum ether (200 mL). Aer evaporation 12 was
obtained as a pale yellow oil (5.57 g, 25.7 mmol, 89%) which was
used without further purication. Rf ¼ 0.62 (20% ethyl acetate
in petrol); nmax (chloroform)/cmꢀ1 2954, 2930, 2857, 1728, 1472,
1388 and 1361; dH (500 MHz; CDCl3) 0.01 (s, 6H), 0.85 (s, 9H),
1.49–1.54 (m, 2H), 1.64–1.70 (m, 2H), 2.42 (td, J ¼ 7.4, 1.7 Hz,
2H), 3.59 (t, J ¼ 6.2 Hz, 2H) and 9.73 (t, J ¼ 1.7 Hz, 1H); dC (125
MHz; CDCl3) ꢀ5.4, 18.2, 18.6, 25.9, 32.0, 43.5, 62.5 and 202.4.
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through a tight plug of cotton wool, diluted with chloroform (20
mL) and washed with NaHCO3 (sat, 3 ꢃ 10 mL). Residual pyri-
dine was removed by azeotropic evaporation with toluene (3 ꢃ
10 mL) to give 18 as a clear oil (249 mg, 0.70 mmol, 96%) which
was used immediately without further purication. Rf ¼ 0.30
(1% methanol in ethyl acetate); nmax (chloroform)/cmꢀ1 3336,
2987, 2942, 2882, 1758, 1710, 1656, 1609, 1536, 1482, 1443, 1374
and 1320; dH (500 MHz; CDCl3) 1.42 (s, 9H), 1.47 (s, 9H), 1.51–
1.63 (m, 4H), 2.44 (td, J ¼ 6.7, 1.0 Hz, 2H), 3.44 (dd, J ¼ 12.6, 3.2
Hz, 1H), 3.80 (dd, J ¼ 12.6, 9.3 Hz, 1H), 4.05–4.09 (m, 1H) and
9.71 (s, 1H); dC (125 MHz; CDCl3) 16.6, 27.9, 28.0, 33.0, 43.2,
55.9, 55.9, 80.6, 83.1 and 201.2, three quaternary carbon signals
were not detected; LRMS, ESI, m/z 414 (15), 388 ([M + MeOH +
H]+, 100%), 356 ([M + H]+, 15%), 332 (6), 316 (12), 300 (10), 260
(14), 214 (12), 182 (10) and 164 (4); HRMS, ESI, m/z C17H30N3O5,
requires 356.2180, found 356.2186 [M + H]+.
tert-Butyl-2-(tert-butoxycarbonylimino)-5-((E)-6-oxohept-4-
enyl)imidazolidine-1-carboxylate (20). To a stirred suspension
of lithium chloride (28.2 mg, 0.65 mmol) in anhydrous aceto-
nitrile (3 mL) was added phosphonate 19 (75 mL, 0.54 mmol).
Aer 10 min, DIPEA (0.11 mL, 0.65 mmol) was then added and
the mixture stirred for a further 10 min. At this point aldehyde
18 (192 mg, 0.54 mmol) dissolved in acetonitrile (2 mL) was
added and the mixture stirred for 48 h. The reaction was diluted
with water (15 mL) and extracted with diethyl ether (3 ꢃ 15 mL)
and the combined organic extracts washed with brine (10 mL)
and dried over magnesium sulfate. Aer evaporation, enone 20
(183 mg, 0.46 mmol, 86%) was obtained as a pale yellow oil and
used without further purication. Rf ¼ 0.22 (100% ethyl
acetate); nmax (chloroform)/cmꢀ1 3320, 2980, 2933, 2860, 1764,
1707, 1678, 1650, 1605, 1532, 1374 and 1327; dH (500 MHz;
CDCl3) 1.34–1.45 (m, 2H), 1.47 (s, 9H), 1.51 (s, 9H), 1.59–1.71
(m, 4H), 2.23 (s, 3H), 3.40–3.54 (br m, 1H), 3.72–3.88 (m, 1H),
4.09–4.20 (br m, 1H), 6.07 (d, J ¼ 15.8 Hz, 1H) and 6.74 (dt, J ¼
15.8, 7.0 Hz, 1H); dC (125 MHz; CDCl3) 22.7, 27.0, 28.1, 28.1,
32.1, 33.3, 56.1, 56.1, 80.8, 83.1, 131.7, 146.9 and 198.3, three
quaternary carbon signals were not detected; LRMS, ESI, m/z
791 ([2M + H]+, 79%), 762 (7), 708 (3), 692 (6), 593 (7), 448 (12),
430 (17), 412 (49), 396 ([M + H]+, 100%), 374 (2), 356 (13), 340
(27), 296 (10), 279 (19), 256 (6), 240 (23), 212 (3) and 196 (17);
HRMS, ESI, m/z C20H34N3O5, requires 396.2493, found 396.2497
[M + H]+.
tert-Butyl-2-((tert-butoxycarbonyl)imino)-5-(4-((tert-butyldi-
methylsilyl)oxy)butyl)imidazolidine-1-carboxylate (16). A stirred
solution of alcohol 15 (7.79 g, 15.9 mmol) in CH2Cl2 (150 mL)
was cooled (ꢀ20 C) and PPh3 (9.59 g, 36.6 mmol), imidazole
ꢁ
(4.22 g, 62.0 mmol, 3.9 eqv.) and I2 (7.48 g, 31.8 mmol, 2 eqv.)
were added. Reaction progress was monitored by TLC and aer
stirring for 2 h 30 min the reaction mixture was diluted with
chloroform (150 mL), washed with an ammonium chloride
solution (sat, 150 mL) and then brine (150 mL). Aer drying over
magnesium sulfate and evaporation, the reaction material was
puried by ash column chromatography on silica gel using
ethyl acetate–petroleum ether (10 : 90, 40 : 60). Fractions
eluting in 30 : 70 ethyl acetate–petroleum ether gave 16 as a pale
yellow oil (7.31 g, 15.5 mmol, 98%). Rf ¼ 0.18 (40% ethyl acetate
in petrol); nmax (chloroform)/cmꢀ1 3313, 2954, 2930, 2858, 1760,
1703, 1651, 1604, 1532, 1473, 1460, 1438 and 1368; dH (500 MHz;
CDCl3) 0.02 (s, 6H), 0.87 (s, 9H), 1.28–1.39 (m, 2H), 1.44–1.67
(m, 4H), 1.47 (s, 9H), 1.50 (s, 9H), 3.35–3.50 (br m, 1H), 3.58 (t, J
¼ 6.5 Hz, 2H), 3.73–3.86 (br m, 1H) and 4.03–4.15 (br m, 1H); dC
(125 MHz; CDCl3) ꢀ5.3, 18.3, 20.7, 25.9, 28.1, 28.1, 32.6, 33.6,
56.4, 56.4, 62.7 and 82.8, four quaternary carbon signals were
not detected; LRMS, CI, m/z 473 ([M + H]+, 100%), 430 (2), 416
(20), 372 (76), 357 (35), 330 (2), 316 (16), 302 (12), 272 (18), 257
(31), 243 (7), 214 (8), 184 (15), 159 (6), 148 (13), 132 (29), 116 (11),
84 (57), 69 (37), 58 (96) and 45 (44); HRMS, ESI, m/z
C
23H46N3O5Si, requires 472.3201, found 472.3201 [M + H]+.
2-tert-Butoxycarbonylimido-4-(4-hydroxy-butyl)-imidazoli-
dine-1-carboxylic acid tert-butyl ester (17). To a stirred solution
of guanidine heterocycle 16 (72.4 mg, 0.154 mmol) in THF
(2 mL) at 0 ꢁC was added a solution of TBAF in THF (1 M, 0.16
mL, 0.16 mmol). Reaction progress was monitored by TLC and
aer 24 h the reaction was quenched with an ammonium
chloride solution (sat, 2 mL) and extracted with chloroform (3 ꢃ
5 mL). The combined organic extracts were then washed with
brine (5 mL) and dried over magnesium sulfate. Aer evapora-
tion, purication was achieved by ash column chromatog-
raphy on silica gel using ethyl acetate–petroleum ether (80 : 20
to 100 : 0) and ethyl acetate–methanol (90 : 10). Fractions
eluting in ethyl acetate gave 17 as a clear oil (54.4 mg, 0.152
mmol, 99%). Rf ¼ 0.03 (100% ethyl acetate); nmax (chloroform)/
cmꢀ1 3318, 2981, 2932, 2865, 1745, 1701, 1649, 1602, 1532,
1476, 1457 and 1370; dH (500 MHz; CDCl3) 1.20–1.27 (m, 2H),
1.36 (s, 9H), 1.40 (s, 9H), 1.42–1.58 (m, 4H), 3.24–3.43 (br m,
1H), 3.50 (t, J ¼ 6.3 Hz, 2H), 3.62–3.77 (br m, 1H) and 3.93–4.08
(br m, 1H); dC (125 MHz; CDCl3) 20.2, 27.8, 27.8, 32.0, 33.2, 56.0,
56.0, 61.8, 80.2 and 82.6, three quaternary carbon signals were
not detected; LRMS, CI, m/z 358 ([M + H]+, 55%), 319 (5), 302
(36), 279 (7), 258 (29), 243 (18), 211 (5), 202 (30), 186 (13), 156 (8),
133 (40), 116 (29), 98 (20), 79 (48), 69 (53), 58 (100) and 45 (54);
HRMS, ESI, m/z C17H31N3O5, requires 358.2336, found 358.2335
[M + H]+.
(5S,8aS)-5-(2-Oxopropyl)hexahydroimidazo[1,5-a]pyridin-
3(2H)-iminium triuoroacetate (21). To a stirred solution of
enone 20 (162 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) was added
triuoroacetic acid (1.5 mL) and the mixture stirred at rt for
24 h. Aer evaporation under reduced pressure, residual tri-
uoroacetic acid was removed by azeotropic evaporation with
chloroform (3 ꢃ 15 mL) and the residue dried under high
vacuum for 4 h. The resultant guanidinium salt was dissolved in
CH2Cl2 (4 mL) and triethylamine (70 mL, 0.45 mmol) was added
and the mixture stirred at rt for 48 h. Aer evaporation, puri-
cation by ash column chromatography on silica gel using
methanol–chloroform (0 : 100 to 14 : 86 in 1% increments) gave
198 (89 mg, 0.28 mmol, 70%) as a viscous oil. An analytical
sample was obtained by slow crystallisation from ethyl acetate.
Rf ¼ 0.08 (10% methanol in chloroform); m.p. 149–153 ꢁC (dec.);
tert-Butyl 2-(tert-butoxycarbonylimino)-5-(4-oxobutyl)imida-
zolidine-1-carboxylate (18). To a solution of alcohol 17 (260 mg,
0.73 mmol) in CH2Cl2 (2 mL) at rt was added pyridine (0.18 mL,
2.19 mmol) and Dess–Martin periodinane (310 mg, 0.73 mmol)
and the mixture stirred for 24 h. The reaction was then ltered
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nmax (chloroform)/cmꢀ1 3400, 2953, 2875, 1714, 1682, 1579, 7.2 Hz, 1H), 3.85–3.93 (m, 1H), 4.37 (d, J ¼ 5.4 Hz, 2H), 4.53 (dd,
1530, 1482, 1430, 1367 and 1320; dH (500 MHz; CDCl3) 1.43 (qd, J ¼ 11.1, 2.7 Hz, 1H), 4.93–5.03 (m, 2H), 5.50–5.57 (m, 1H) and
J ¼ 13.6, 3.2 Hz, 1H), 1.50–1.59 (m, 1H), 1.63 (d, J ¼ 13.6 Hz, 1H), 7.30–7.36 (m, 5H); dC (125 MHz; CDCl3) 21.3, 29.6 31.3, 48.2,
1.71–1.75 (m, 1H) 1.80 (dt, J ¼ 13.6, 3.2 Hz, 1H), 1.92 (dd, J ¼ 53.4, 58.0, 65.3, 103.5, 118.3, 128.1, 128.4, 130.2, 131.2, 133.2,
12.8, 3.0 Hz, 1H), 2.20 (s, 3H), 2.54 (dd, J ¼ 18.3, 3.2 Hz, 1H), 144.5, 153.5 and 164.8; LRMS, positive ESI, m/z 422 ([M +
3.05 (dd, J ¼ 18.3, 9.3 Hz, 1H), 3.23 (dd, J ¼ 9.5, 7.3 Hz, 1H), 3.77 2AcOH]+, 5%), 390 (6), 382 ([M + AcOH]+, 9%), 342 (13), 324 ([M +
(t, J ¼ 9.5 Hz, 1H), 3.86 (app td, J ¼ 11.5, 3.6 Hz, 1H), 4.36–4.43 H]+, 100%), 316 (69), 290 (12) and 276 (8); LRMS, negative ESI m/
(m, 1H) and 9.75 (s, 1H, NH); dC (125 MHz; CDCl3) 18.2, 28.9, z 121 (4) 113 (3) 77 (18), 59 ([M ꢀ H]ꢀ, 100%), 46 (3) and 45 (12);
30.1, 31.0, 44.3, 45.4, 47.6, 53.7, 157.9 and 206.7; LRMS, positive HRMS, ESI, m/z C19H22N3O2, requires 324.1707, found 324.1705
ESI, m/z 391 ([2M + H]+, 22%), 196 ([M + H]+, 100%), 138 (5) and [M + H]+.
130 (8); LRMS, negative ESI m/z 227 ([2M ꢀ H]ꢀ, 44%), and 113
1-Morpholinobutane-1,3-dione (28). Following the general
([M ꢀ H]ꢀ, 100%); HRMS, ESI, m/z C10H18N3O, requires procedure outlined above amide 28 was isolated as a pale yellow
196.1444, found 196.1441 [M + H]+.
oil (13% (based on 23)). Rf ¼ 0.39 (10% methanol in chloro-
General procedure for tethered Biginelli condensations. A form); dH (500 MHz; CDCl3) 2.24 (s, 3H), 3.38 (t, J ¼ 4.8 Hz, 2H),
solution of aldehyde 18 (ꢂ0.5 mmol) in glacial acetic acid (3 mL) 3.53 (s, 2H) 3.58–3.60 (m, 2H) and 3.62–3.65 (m, 4H); dC (125
was stirred at rt for 24 h. Aer evaporation under reduced MHz; CDCl3) 30.2, 42.1, 46.7, 49.7, 66.5, 66.6, 165.0 and 202.0;
pressure, residual acetic acid was removed by co-evaporation LRMS, positive EI, m/z 172 ([M + H]+, 34%), 171 (M+, 54%), 128
with chloroform (3 ꢃ 15 mL) and the residue dried under high (77), 87 (30), 86 (96), 85 (30), 57 (68), 56 (52) and 43 (100).
vacuum for 4 h. The resultant salts where then dissolved in
General procedure for deallylation/decarboxylation of di-
triuoroethanol (1.5 mL) and morpholine acetate (2.5 eqv.), hydropyrimidines. To a stirred solution of tricyclic guanidine
anhydrous sodium sulfate (1 g) and the relevant b-keto ester (5 (ꢂ0.1 mmol) in a mixture of anhydrous methanol (1 mL) and
ꢁ
eqv.) added and the mixture stirred at 70 C for 12 days. Aer anhydrous THF (1 mL) was added tetrakis(triphenylphosphine)-
cooling to rt and evaporation, purication was achieved by ash palladium(0) (0.02 eqv.) and pyrrolidine (1.2 eqv.). The reaction
column chromatography on silica gel using methanol–chloro- was stirred at rt and progress monitored by TLC. Aer 1.5–2 h
form (stepwise gradient of 0.5% increments 0 : 100 to 4 : 96) the solvent was removed under reduced pressure and the
containing 1% acetic acid.
(5aR,8aS)-5-((Allyloxy)carbonyl)-4-methyl-3,5a,6,7,8,8a-hexa- cooled (0 ꢁC), whereupon NaBH3CN (5 eqv.) was added and the
hydro-1H-2,2a1,3-triazaacenaphthylen-2-ium
acetate (26). mixture stirred to rt over 16 h. Aer evaporation, the reaction
residue dissolved in methanol (1 mL) and acetic acid (1 mL) and
Following the general procedure outlined above tricyclic material was puried by ash column chromatography on silica
guanidine 26 was obtained as a tan oil in yields of 36–43%. gel using methanol–chloroform (stepwise gradient of 1%
Upon standing or in a methanol solution the acetate counterion increments 0 : 100 to 10 : 90) containing 1% acetic acid.
was slowly converted to the corresponding carbonate by atmo-
(4S,5aR,8aS)-4-Methyl-3,4,5,5a,6,7,8,8a-octahydro-1H-2,2a1,3-
spheric CO2. Rf ¼ 0.26 (10% methanol in chloroform); nmax triazaacenaphthylen-2-ium acetate (29). Following the general
(chloroform)/cmꢀ1 3400, 2949, 2932, 2905, 2862, 1696, 1679, procedure outlined above guanidine 29 was obtained as a pale
1637, 1605, 1449, 1407, 1391 and 1337; dH (500 MHz; CDCl3) yellow oil in a 57% yield aer chromatography. Upon standing
1.32–1.40 (m, 1H), 1.51–1.66 (m, 2H), 1.70 (dd, J ¼ 12.9, 3.2 Hz, or in methanol solution the acetate counterion is slowly con-
1H) 1.87 (dt, J ¼ 13.3, 2.9 Hz, 1H), 1.96 (dd, J ¼ 13.1, 3.0 Hz, 1H) verted to the carbonate by atmospheric CO2. Rf ¼ 0.15 (10%
2.00 (s, 3H), 2.36 (s, 3H), 3.39 (dd, J ¼ 10.4, 1.9 Hz, 1H), 3.75 methanol in chloroform); nmax (chloroform)/cmꢀ1 3145, 2924,
(t, J ¼ 9.5 Hz, 1H), 3.89–3.93 (m, 1H), 4.41 (dd, J ¼ 2.8, 11.4 Hz, 2853, 1666, 1445, 1338 and 1332; dH (500 MHz; CDCl3) 1.11–1.19
1H), 4.63–4.64 (m, 2H), 5.23–5.32 (m, 2H) and 5.89–5.97 (m, (m, 1H), 1.27–1.49 (m, 4H), 1.33 (d, J ¼ 6.3 Hz, 3H), 1.90–2.05
1H); dC (125 MHz; CDCl3) 18.6, 21.3, 24.0, 29.5, 31.3, 48.0, 52.6, (m, 2H), 1.98 (s, 3H), 2.11 (app dt, J ¼ 13.4, 3.6 Hz, 1H), 3.18–
57.9, 65.0, 101.5, 118.2, 132.2, 146.7, 154.6, 165.1 and 179.5; 3.27 (m, 2H), 3.50–3.58 (m, 1H), 3.62–3.69 (m, 1H) and 3.77–3.84
LRMS, positive ESI, m/z 523 ([2M + H]+, 5%), 402 (4), 314 (15), (m, 1H); dC (125 MHz; CDCl3) 20.6, 22.2, 24.5, 29.7, 31.1, 37.1,
304 (6), 262 ([M + H]+, 100) and 222 (2); LRMS, negative ESI m/z 45.5, 48.5, 50.1, 56.8 and 155.4; LRMS, positive ESI, m/z 395 (5),
165 (6) 113 (20) 77 (100), 75 (62), 60 ([CO3]2ꢀ, 37%) and 59 ([M ꢀ 239 (2) and 180 ([M + H]+, 100%); LRMS, negative ESI m/z 113
H]ꢀ, 68%); HRMS, ESI, m/z C14H20N3O2, requires 262.1550, (7), 77 (100), 75 (7), 60 ([CO3]2ꢀ, 30%), 59 ([M ꢀ H]ꢀ, 12%), 45
found 262.1548 [M + H]+.
(14), 35 (6) and 33 (3); HRMS, ESI, m/z C10H18N3, requires
(5aR,8aS)-5-((Allyloxy)carbonyl)-4-phenyl-3,5a,6,7,8,8a-hexa- 180.1495, found 180.1492 [M + H]+.
hydro-1H-2,2a1,3-triazaacenaphthylen-2-ium
(5aR,8aS)-5-((Allyloxy)carbonyl)-4-phenyl-3,5a,6,7,8,8a-hexahy-
acetate
(27).
(4R,5aR,8aS)-4-Phenyl-3,4,5,5a,6,7,8,8a-octahydro-1H-2,2a1,3-
triazaacenaphthylen-2-iumacetate (30). Following the general
dro-1H-2,2a1,3-triazaacenaphthylen-2-ium acetate (27) was procedure outlined above guanidine 30 was obtained as a pale
prepared following the general procedure outlined above giving yellow oil in 53% yield aer chromatography. Upon standing or
tricyclic guanidine 27 as a tan oil in 26% yield aer chroma- in methanol solution the acetate counter-ion is slowly converted
tography. Rf ¼ 0.24 (10% methanol in chloroform); nmax (chlo- to the carbonate by atmospheric CO2. Rf ¼ 0.08 (10% methanol
roform)/cmꢀ1 3338, 2926, 2859, 1693, 1668, 1648, 1606, 1493, in chloroform); nmax (chloroform)/cmꢀ1 3156, 2942, 2928, 2863,
1448 and 1375; dH (500 MHz; CDCl3) 1.50–1.71 (m, 4H) 1.81– 1671, 1607, 1556, 1455 and 1379; dH (500 MHz; CD3OD) 1.22–
1.88 (m, 1H), 1.98–2.05 (m, 1H), 3.15–3.23 (m, 1H), 3.62 (t, J ¼ 1.29 (m, 1H), 1.35–1.45 (m, 1H), 1.50–1.59 (m, 1H), 1.80
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(app dt, J ¼ 13.5, 11.5, 11.0 Hz, 1H), 1.96–2.02 (m, 2H), 2.09–2.14
(m, 1H), 2.36 (app dt, J ¼ 13.5, 3.3, 3.3 Hz, 1H), 3.25–3.29 (m,
1H), 3.52 (app tt, J ¼ 11.3, 11.0, 4.0, 3.3 Hz, 1H), 3.82–3.89 (m,
2H), 4.62 (dd, J ¼ 11.5, 3.3 Hz, 1H) and 7.31–7.45 (m, 5H); dC
(125 MHz; CDCl3) 22.2, 23.0, 29.5, 30.9, 38.7, 48.6, 50.4, 54.0,
57.1, 126.1, 128.5, 129.1, 139.1, 155.9 and 174.0; LRMS, positive
ESI, m/z 483 ([2M + H]+, 6%), 284 (4) and 242 ([M + H]+, 100%);
LRMS, negative ESI m/z 120 (10), 92 (12), 76 (42), 75 (100), 59
([M ꢀ H]ꢀ, 18%), 45 (16) and 32 (5); HRMS, ESI, m/z C15H20N3,
requires 242.1648, found 242.1652 [M + H]+.
6 A. R. Humpage, F. Fontaine, S. Froscio, P. Burcham and
I. R. Falconer, J. Toxicol. Environ. Health, Part A, 2005, 68, 739.
7 T. Kiss, A. Vehovszky, L. Hiripi, A. Kovacs and L. Voros,
Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol., 2002,
131, 167.
8 I. R. Falconer and A. R. Humpage, Environ. Toxicol., 2001, 16,
192.
9 (a) R. Banker, B. Teltsch, A. Sukenik and S. Carmeli, J. Nat.
Prod., 2000, 63, 387; (b) R. Banker, S. Carmeli, M. Werman,
B. Teltsch, R. Porat and A. Sukenik, J. Toxicol. Environ.
Health, Part A, 2001, 62, 281.
10 R. L. Norris, G. K. Eaglesham, G. Pierens, G. R. Shaw,
M. J. Smith, R. K. Chiswell, A. A. Seawright and
M. R. Moore, Environ. Toxicol., 1999, 14, 163.
Acknowledgements
We gratefully acknowledge the EPSRC (EP/J01821X/1) and
Bangor University for their nancial support. We also thank the 11 (a) C. Xie, M. T. C. Runnegar and B. B. Snider, J. Am. Chem.
EPSRC National Mass Spectrometry Facility at Swansea, the
EPSRC X-Ray crystallography service at Southampton, Professor
Soc., 2000, 122, 5017; (b) G. R. Heintzelman, W. Fang,
S. P. Keen, G. A. Wallace and S. M. Weinreb, J. Am. Chem.
Soc., 2001, 123, 851; (c) G. R. Heintzelman, W. Fang,
S. P. Keen, G. A. Wallace and S. M. Weinreb, J. Am. Chem.
Soc., 2002, 124, 3939; (d) J. D. White and J. D. Hansen,
J. Am. Chem. Soc., 2002, 124, 4950; (e) J. D. White and
J. D. Hansen, J. Org. Chem., 2005, 70, 1963; (f) R. E. Looper
and R. M. Williams, Angew. Chem., Int. Ed., 2004, 43, 2930;
(g) R. E. Looper, M. T. C. Runnegar and R. M. Williams,
Tetrahedron, 2006, 62, 4549.
¯
Omura of Kitasato University for useful information and Jackie
Hollinshead for NMR studies. The contributions of previous co-
workers in the group, Andrew Thornhill, Alan Molyneux, Steven
´
P Williams and Louise Jones (nee Hall) are also acknowledged.
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