An efficient 1,2,4-triazine-based route to the louisianin alkaloids

Article abstract of DOI:10.1016/j.tetlet.2008.03.026

A new, short and efficient route to louisianins C and D is described in which the pyridine ring is constructed from a disubstituted 1,2,4-triazine by an inverse-electron-demand Diels-Alder/retro-Diels-Alder/aromatisation cascade sequence. This eight-step

Full text of DOI:10.1016/j.tetlet.2008.03.026

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Tetrahedron Letters 49 (2008) 2865–2868
An efficient 1,2,4-triazine-based route to the louisianin alkaloids
Nicola Catozzi, Pierre Wasnaire, Richard J. K. Taylor *
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 22 January 2008; revised 19 February 2008; accepted 6 March 2008
Available online 10 March 2008
Abstract
A new, short and efficient route to louisianins C and D is described in which the pyridine ring is constructed from a disubstituted
1,2,4-triazine by an inverse-electron-demand Diels–Alder/retro-Diels–Alder/aromatisation cascade sequence. This eight-step route
produces louisianin C in 16% overall yield from the commercially available 5-chloropent-1-yne.
Ó 2008 Elsevier Ltd. All rights reserved.
OH
OH
Louisianins A–D (1–4) are a family of alkaloids
reported in 1995, which were isolated from a Streptomyces
sp. obtained from a soil sample collected in Louisiana
(USA).1 Louisianin A proved to be a potent inhibitor of
testosterone-responsive carcinoma SC115, while louisia-
nins C and D were potent suppressors of cultured vascular
endothelial cells in vitro (Fig. 1).2,3
N
N
N
N
O
OH
O
O
Louisianin A (1)
Louisianin B (2)
Louisianin C (3)
Louisianin D (4)
The chemical interconversion of louisianins has been
described,3 but it was not until 2003 that Kelly’s group
published the first total synthesis of louisianin C 3.4 This
was achieved in 9 steps (11% overall yield) starting from
3,5-dibromopyridine; the key cyclopentane-forming step
utilised an intramolecular, fluoride-induced silylpyridine
to aldehyde cyclisation. Then, in 2006, Chang et al.
reported the first total synthesis of louisianin A 1 in 7 steps
(24% overall yield) starting from 2-chloro-4-cyanopyr-
idine.5 In this route, the cyclopentane construction was
achieved using a Dieckmann–Thorpe cyclisation. Both
the routes mentioned started from the commercially avail-
able pyridine derivatives, and the substituents were intro-
duced in a stepwise manner performing the annulation at
a late stage of the synthesis. Recently, however, Chen
et al. prepared louisianin D starting from ethyl cyclopen-
tene-1-carboxylate and using a [3+3] annulation strategy
Fig. 1. The louisianin alkaloids.
to construct the heterocyclic ring.6 The complete route
involved 10 steps (20% overall yield).
We have recently reported several triazine-based routes
to highly substituted pyridines.7 The most straightforward
procedure (Scheme 1) involves the in situ enamine genera-
tion from ketone 6 and pyrrolidine using Boger’s proce-
dure8 followed by a tandem inverse-electron-demand
Diels–Alder/retro-Diels–Alder sequence; the resulting
dihydropyridine then undergoes in situ aromatisation to
give pyridine 7 expedited by the presence of silica gel.9
O
4
1
1
3
R
R
5
R
R
5
4
R
R
6
N
N
N
N
2
2
R
R
Pyrrolidine
3
R
PhMe, Δ, SiO
2 - 10 h
R
2
*
7
5
Corresponding author. Tel.: +44 (0)1904 432606; fax: +44 (0)1904
50 - 99%
434523.
Scheme 1.
E-mail address: rjkt1@york.ac.uk (R. J. K. Taylor).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.026

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N. Catozzi et al. / Tetrahedron Letters 49 (2008) 2865–2868
OH
OH
N
N
O
OH
O
CO Et
2
CO Et
2
2
1
N
N
N
N
Pyrrolidine
R
R
N
N
8
9
O
O
4
3
Scheme 2.
The louisianin alkaloids, with their pyridine-based core
and promising anti-androgenic properties, represent attrac-
tive targets to validate this triazine methodology. We there-
fore designed the unified route to the louisianins shown in
Scheme 2; the ester group was included at position 3 of the
triazine ring in order to enhance its reactivity in the inverse-
electron-demand Diels–Alder reaction and also to provide
a ‘handle’ to ensure the regioselectivity of the subsequent
pyridone formation.
Thus, the thermolysis of triazine 14 with cyclopentanone
and pyrrolidine followed by silica-mediated aromatisation
gave pyridine 15 in a gratifying 89% yield.14,15 The decarb-
oxyethylation of the pyridine ester 15 proved impossible
using standard conditions.16 Success was achieved, how-
ever, by the treatment of pyridine ester 15 with very dilute
aqueous hydrochloric acid in a microwave reactor (CEM
DiscoverÒ) giving pyridine 16 in 85% yield after a basic
work-up. To the best of our knowledge, this is the first
example of the direct decarboxyalkylation of a pyridine
ester using microwave acceleration.
The recent publications in this area4–6 prompt us to
present a preliminary report describing a triazine-based
synthesis of louisianin C 3, together with its isomerisation
to louisianin D 4.
Next, regioselective cyclopentane hydroxylation was
required in order to prepare alcohol 17. We first investi-
gated the LiHMDS/O2 procedure developed by Chen
et al.6 Unfortunately, on substrate 16, this procedure gave
a mixture of two inseparable compounds (2:1 ratio, NMR)
and recovered starting material. Eventually, using an
observation made by Corey and Ensley,17 we found that
the addition of triethylphosphite to the benzylic anion gen-
erated using LiHMDS under kinetic conditions, and then
oxidation gave the required alcohol 17 as the only product
in 79% yield. At this stage, the alkene was revealed by
chemoselective sulfide oxidation (m-CPBA in CH2Cl2 at
ꢀ78 °C) followed by thermolysis in xylene, in the presence
of CaCO3. The resulting alkene 18 (76% yield from 17) was
obtained without contamination by the isomerised conju-
gated alkene. The final step in order to obtain louisianin
C 3 involved the oxidation of the benzylic alcohol but this
proved to be surprisingly difficult. Several standard oxi-
3-Ethoxycarbonyl-5-(30-phenylthiopropyl)-1,2,4-triazine
14 was chosen as the starting material in order to have a
masked propenyl unit at position 6.10 This novel triazine
was prepared by the route shown in Scheme 3. Thus, the
commercially available 5-chloropent-1-yne 10 was oxidised
using phenyliodine(III) bis(trifluoroacetate) (PIFA)11 to
produce a-hydroxy ketone 11. Without purification, ketone
11 was treated with potassium thiophenolate, prepared
in situ, to give sulfide 12 in 60% isolated yield after column
chromatography over the two steps. Next, utilising our
recently described procedure for preparing 3,6-disubsti-
tuted triazines,7c a-hydroxy ketone 12 was first condensed
with the ethyl oxalamidrazonate 1312 and the product oxi-
dised with MnO2 producing triazine 14 in 75% overall
yield.13
Having the key triazine 14 in hand, we were in a position
to investigate the crucial Diels–Alder cascade, producing
the required annulated pyridine 15 containing the complete
carbon skeleton of the louisianin alkaloids (Scheme 4).
3
dants (including CrO3 ) gave only low to moderate yields
of the ketone; however, PCC supported on basic alumina
gave the desired louisianin C 3 in 80% yield. Louisianin
CO Et
2
OH
OH
O
N
N
N
O
iii
i
ii
CO Et
2
Cl
PhS
Cl
PhS
14
H N
2
N
NH
2
10
11
12
13
Scheme 3. Reagents and conditions: (i) PIFA (1.2 equiv), CH2Cl2/CH3CN/H2O (8:2:1), 50 °C, 5 h, then satd aq NaHCO3, rt, 2 h; (ii) PhSH (1.1 equiv),
KOH (1.1 equiv), H2O/THF (50:1), 80 °C; 2 h, 60% from 10; (iii) THF, 80 °C, 4 h, then MnO2 (5 equiv), toluene, 120 °C, 18 h, 75%.

N. Catozzi et al. / Tetrahedron Letters 49 (2008) 2865–2868
2867
CO Et
2
CO Et
2
i
ii
iii
N
N
N
N
N
PhS
PhS
PhS
16
14
15
H
a
N
N
N
N
vi
v
iv
O
OH
OH
O
PhS
18
17
Louisianin C (3)
Louisianin D (4)
Scheme 4. Reagents and conditions: (i) cyclopentanone (1.2 equiv), pyrrolidine (1.2 equiv), xylene, 160 °C, 10 h, then silica, 18 h, 89%; (ii) concd HCl/H2O
(1:50), 185 °C, MW, 1 h then aq K2CO3, 85%; (iii) (a) LiHMDS (10 equiv), THF, ꢀ5 °C, 45 min; (b) P(OEt)3 (2.2 equiv), 15 min; (c) O2, 8 h, 79%; (iv) (a)
m-CPBA (1.2 equiv), CH2Cl2, ꢀ78 °C, 1 h; (b) CaCO3 (5 equiv), xylene, 160 °C, 18 h, 76%; (v) PCC supported on basic alumina (2 equiv), CH2Cl2, rt, 3 h,
80%; (vi) MTBD (1.2 equiv), toluene, 80 °C, 6 h, 78%.
C (3) was fully characterised18 and gave consistent data to
those published [e.g., dC (CDCl3) 208.0 (C@O); dH (CDCl3)
5. Chang, C.-Y.; Liu, H.-M.; Chow, T. J. J. Org. Chem. 2006, 71, 6302.
6. Chen, H.-W.; Hsu, R.-T.; Chang, M.-Y.; Chang, N.-C. Org. Lett.
2006, 8, 3033.
8.76 (1H, s, Ha); lit.2 dC (CDCl3) 207.3 (C@O); dH (CDCl3)
7. (a) Raw, S. A.; Taylor, R. J. K. Chem. Commun. 2004, 508; (b)
8.75 (1H, s, Ha)]. Treatment of louisianin C in toluene in
the presence of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-
ene (MTBD) gave clean alkene isomerisation producing
louisianin D (4) in 78% isolated yield.3,19 The authenticity
of louisianin D (4) was confirmed spectroscopically20 and
by comparison with the published data (mp 83–85 °C;
lit.3 mp 83–86 °C).
In summary, a new route to louisianins C and D has
been developed in which the pyridine ring is constructed
from a disubstituted 1,2,4-triazine by an inverse-electron-
demand Diels–Alder/retro-Diels–Alder/aromatisation cas-
cade sequence. This route is short, efficient (only 5 steps
and 37% overall yield of louisianin C from triazine 14)
and ideal for analogue synthesis. We are currently prepar-
ing novel louisianin analogues and extending this route to
prepare the other members of the louisianin family.
´
Fernandez Sainz, Y.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem. 2005,
´
70, 10086; (c) Laphookhieo, S.; Jones, S.; Raw, S. A.; Fernandez
Sainz, Y.; Taylor, R. J. K. Tetrahedron Lett. 2006, 47, 3865.
8. Boger, D. L. Chem. Rev. 1986, 86, 781 and references cited therein.
For recent references to the use of 1,2,4-triazines to prepare
substituted pyridines see: Lawecka, J.; Olender, E.; Piszcz, P.;
Rykowski, A. Tetrahedron Lett. 2008, 49, 723; Hajbi, Y.; Suzenet,
F.; Khouili, M.; Lazar, S.; Guillaumet, G. Tetrahedron 2007, 63, 8286;
Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O. V.;
Rusinov, V. L.; Chupakhin, O. N. Tetrahedron Lett. 2005, 46, 1521;
Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O. V.;
Rusinov, V. L.; Chupakhin, O. N. Tetrahedron Lett. 2005, 46, 1791;
Altuna-Urquijo, M.; Stanforth, S. P.; Tarbit, B. Tetrahedron Lett.
2005, 46, 6111.
9. Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.; Taylor, R. J.
K. Synlett 2007, 2217.
10. All novel compounds were fully characterised spectroscopically and
by HRMS.
11. Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. Tetrahedron Lett.
1985, 26, 3837.
12. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1993, VIII, 597.
13. A solution of 1-hydroxy-5-(phenylthio)pentan-2-one 12 (1.47 g,
7.00 mmol) and ethyl oxalamidrazonate 13 (1.10 g, 8.40 mmol) in
anhydrous THF (30 mL) was stirred at 80 °C for 4 h, then cooled
down and concentrated to half volume. The yellow solution thus
obtained was diluted with toluene (70 mL), MnO2 (3.04 g,
35.00 mmol) was added and the mixture was heated up to 120 °C
for 18 h. The reaction mixture was then cooled down to ca. 60 °C, and
filtered through a pad of Celite, which was washed with EtOAc–
MeOH (2:1). The combined organic fractions were concentrated in
vacuo and the residue was purified by silica gel chromatography
(petroleum ether–ethyl acetate, 2:3) to give ethyl 6-(3-(phenylthio)pro-
pyl)-1,2,4-triazine-3-carboxylate 14 (1.59 g, 75%) as a yellow oil, 1H
NMR (400 MHz, CDCl3) 8.64 (1H, s), 7.37–7.26 (4H, m), 7.24–7.18
(1H, m), 4.59 (2H, q, J 7.2 Hz), 3.25 (2H, t, J 7.6 Hz), 3.04 (2H, t, J
7.0 Hz), 2.21 (2H, tt, J 7.6, 7.0 Hz), 1.49 (3H, t, J 7.2 Hz); 13C NMR
(100 MHz, CDCl3) 162.9, 162.7, 155.8, 149.8, 135.6, 129.9, 129.2,
126.6, 63.0, 32.7, 31.8, 27.3, 13.7; IR mmax(film)/cmꢀ1 3059, 2982,
2935, 1745, 1619, 1584, 1481, 1440, 1311, 1234, 1180; MS (ESI, m/z):
304 (MH+, 100%), 326 (MNa+, 54); HMRS (ESI): found: 326.0930;
C15H17N3O2SNa requires: 326.0934 (1.09 ppm error).
Acknowledgements
We thank the E.P.S.R.C. (N.C.) and the Fond Special
de Recherche, Universite Catholique de Louvain (P.W.),
for postdoctoral support. We are also grateful to Dr. S.
A. Raw and Mr. W. J. Bromley for helpful discussions
and encouragement.
´
References and notes
1. Komiyama, K.; Takamatsu, S.; Kim, Y.-P.; Matsumoto, A.; Taka-
hashi, Y.; Hayashi, M.; Woodruff, H. B.; Omura, S. J. Antibiot. 1995,
48, 1086.
2. Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Furuhata, H. T.; Komi-
yama, K.; Woodruff, H. B.; Omura, S. J. Antibiot. 1995, 48, 1090.
3. Sunazuka, T.; Zhi-Ming, T.; Harigaya, Y.; Takamatsu, S.; Hayashi,
M.; Komiyama, K.; Omura, S. J. Antibiot. 1997, 50, 274.
4. Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T. R.
J. Org. Chem. 2003, 68, 4970.

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N. Catozzi et al. / Tetrahedron Letters 49 (2008) 2865–2868
14. A solution of triazine 14 (2.00 g, 6.59 mmol), pyrrolidine (660 lL,
7.91 mmol) and cyclopentanone (700 lL, 7.91 mmol) in xylene
(32 mL) was heated at 160 °C in a sealed tube (Ace pressure tube)
for 10 h. The reaction mixture was cooled to rt, silica (2.00 g, Fluka,
flash chromatography Silica Gel 60, 220–440 mesh) was added and
the yellow suspension obtained heated to reflux for an additional 18 h.
The mixture was then cooled to rt, filtered through a Celite pad,
concentrated and the residue obtained was purified by silica gel
chromatography (petroleum ether–ethyl acetate, 1:1) to give pyridine
15 (2.00 g, 89%) as a pale yellow oil, 1H NMR (400 MHz, CDCl3)
8.34 (1H, s), 7.36–7.25 (4H, m), 7.23–7.17 (1H, m), 4.46 (2H, q, J
7.2 Hz), 3.33 (2H, t, J 7.6 Hz), 2.94 (2H, t, J 7.0 Hz), 2.87 (2H, t, J
7.7 Hz), 2.80 (2H, t, J 7.6 Hz), 2.10 (2H, tt, J 7.7, 7,6 Hz), 1.97–1.87
(2H, m), 1.44 (3H, t, J 7.2 Hz); 13C NMR (100 MHz, CDCl3) 166.3,
154.8, 147.9, 143.4, 142.0, 136.5, 136.1, 129.7, 129.2, 126.4, 61.2, 32.9,
32.6, 30.5, 29.5, 28.4, 23.9, 14.0; IR mmax(film)/cmꢀ1 3056, 2977, 2955,
1729, 1714, 1618, 1583, 1480, 1438, 1298, 1231, 1176; MS (ESI, m/z):
342 (MH+, 100%), 364 (MNa+, 14); HMRS (ESI): found: 342.1518;
C20H24NO2S requires: 342.1522 (1.26 ppm error).
16. (a) Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2002,
43, 6015; (b) Streef, J. W.; den Hertog, H. J.; van der Plas, H. C. J.
Heterocycl. Chem. 1985, 22, 985; (c) Cohen, T.; Schambach, R. A. J.
Am. Chem. Soc. 1970, 92, 3189.
17. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
18. Louisianin C (3): pale yellow oil, 1H NMR (400 MHz, CDCl3) 8.76
(1H, s), 8.47 (1H, s), 5.98 (1H, ddt, J 16.2, 9.6, 6.6 Hz), 5.11–5.04 (2H,
m), 3.80 (2H, d, J 6.6 Hz), 3.16 (2H, dd, J 5.9, 6.0 Hz ), 2.74–2.67 (2H,
m); 13C NMR (100 MHz, CDCl3) 208.0, 149.4, 148.5, 148.2, 140.0,
135.7, 133.3, 117.0, 36.3, 32.4, 22.9; IR mmax(film)/cmꢀ1 3078, 2978,
2925, 1716, 1637, 1586, 1463, 1418, 1285, 1189, 1048, 917; MS (ESI,
m/z): 174 (MH+); HMRS (ESI): found: 174.0913, calculated for
C11H12NO: 174.2191 (1.32 ppm error).
19. Surprisingly, the use of polystyrene-bound 1,5,7-triazabicyclo[4.4.0]-
dec-5-ene in toluene at reflux gave louisianin D (4) in only 10% yield.
20. Louisianin D (4): white solid, mp 83–85 °C (petroleum ether); 1H
NMR (400 MHz, CDCl3) 8.78 (1H, s), 8.67 (1H, s), 7.40 (1H, dd, J
1.8, 16.0 Hz), 6.55 (1H, dq, J 6.8, 16.0 Hz), 3.13 (2H, dd, J 6.0,
5.9 Hz), 2.73–2.69 (2H, m), 1.98 (3H, dd, J 1.8, 6.8 Hz); 13C NMR
(100 MHz, CDCl3) 208.2, 147.9, 145.3, 145.2, 137.5, 132.6, 131.1,
123.9, 36.2, 22.72, 18.7; MS (ESI, m/z): 174 (MH+); HMRS (ESI):
found: 174.0913, calculated for C11H12NO: 174.2191 (2.28 ppm
error).
15. Pyridine 14 can also be prepared using our microwave procedure7b in
comparable yields. On a small scale (250 mg), the MW procedure is
preferred in view of the short reaction time (1 h). However, the silica-
procedure is favoured for larger scale reactions.