Studies toward the total synthesis of the variolins: Rapid entry to the core structure

Article abstract of DOI:10.1016/S0040-4039(00)01772-X

The pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine core structure of the variolins has been synthesized in three steps from commercially available materials. The key reaction involves the deoxygenation and concomitant cyclization of a triarylmethanol using the

Full text of DOI:10.1016/S0040-4039(00)01772-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 311–313
Studies toward the total synthesis of the variolins: rapid entry to
the core structure
Regan J. Anderson and Jonathan C. Morris*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Received 30 September 2000; accepted 11 October 2000
Abstract—The pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine core structure of the variolins has been synthesized in three steps from
commercially available materials. The key reaction involves the deoxygenation and concomitant cyclization of a triarylmethanol
using the combination of triethylsilane and trifluoroacetic acid. Introduction of amine functionality as required for the natural
products has been achieved in two steps. © 2000 Elsevier Science Ltd. All rights reserved.
The variolins are a new class of marine alkaloids iso-
lated from the rare, difficult to access Antarctic sponge
Kirkpatricka varialosa, with variolin B being a typical
Our retrosynthetic strategy for the 5-substituted core
structure 2 is outlined in Fig. 1. The extreme polarity of
the variolins makes them difficult to handle so
thiomethyl substituents have been used as synthetic
equivalents for the amino groups.5 Triarylmethane 4
should be obtained upon deoxygenation of the tertiary
alcohol 5, which in turn should be readily available
from the reaction of the lithio species 6 with acid
chloride 7. The synthesis of the deoxy system 2 (R=H)
was investigated initially as the starting material re-
quired, 2-chloronicotinoyl chloride (7, R=H), is com-
mercially available.
example.1 All of the variolins contain
a fused
pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine core 1, with ei-
ther a heterocyclic or ester group attached at the 5-posi-
tion. The variolins display interesting biological
activity, but further investigation has been hampered by
the limited availability of natural material.
The synthesis of triarylmethanol 5 (R=H) is detailed
in Scheme 1.† As the lithiation of commercially avail-
able 4-chloro-2-thiomethylpyrimidine 8 is reported to
be a difficult process, the chloride was converted to the
iodide 9 by the literature method in 80% yield.6 Addi-
tion of a pre-cooled (−95°C) solution of 7 (R=H) in
THF to 3 equiv. of the lithio species 6, generated by
iodine-lithium exchange using n-butyllithium in THF at
−95°C, gave the triarylmethanol 5 (R=H) in 52%
yield.
While there has been no report to date on the total
synthesis of the variolins, Alvarez and co-workers have
published two reports2 on the synthesis of bicyclic
fragments of the variolin tricyclic core. More recently, a
nine-step synthesis of 9-amino-7-ethoxycarbonyl-4-
Efficient functionalization of the tertiary alcohol
proved difficult, which meant that attempts to deoxy-
genate the triarylmethanol 5 (R=H) using such
methodologies were unproductive. Numerous methods
were investigated for the direct conversion of the ter-
tiary alcohol to the triarylmethane, but these resulted in
either no reaction occurring or complete destruction of
methoxypyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine
has
been reported by the group of Fresneda and Molina.3
This work has prompted us to report our efforts to-
wards the synthesis of the variolin core structure and in
this paper we present a short route to the 5-substituted
core skeleton of the variolins.4
Keywords: alkaloids; pyridines; pyrimidines; deoxygenation; cycliza-
tion.
* Corresponding author. Fax: 64-3-3642110; e-mail: jmorris@
canterbury.ac.nz
† All new compounds were characterized by 1H and 13C NMR, IR,
and mass spectrometry. Yields are for isolated, chromatographically
purified products.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01772-X

312
R. J. Anderson, J. C. Morris / Tetrahedron Letters 42 (2001) 311–313
Figure 1. Retrosynthetic analysis of 5-substituted core 2 .
the starting material.7 However, ionic hydrogenation of
triarylmethanol 5 (R=H) with 1.2 equiv. of triethylsi-
lane in trifluoroacetic acid (TFA) at reflux led to com-
plete consumption of starting material and the
generation of several products.8 While examination of
1
the crude material by H NMR spectroscopy indicated
that the desired triarylmethane 4 (R=H) was not
present, we were encouraged to find that one of the
reaction products had the desired core structure 3 (R=
H).9 It would appear that upon deoxygenation, triaryl-
methane 4 (R=H) is readily cyclized under the
Scheme 1. (a) 55% HI solution, 48 h, 80%; (b) n-BuLi, THF,
−95°C, 30 min then 7 (R=H), −95°C, 3.5 h, 52%.
reaction
conditions
to
afford
the
fused
pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine skeleton.
Other products from the triethylsilane/TFA reaction
have been identified and are shown in Fig. 2. These
products had not been deoxygenated, which leads to
the conclusion that they were the result of rearrange-
ments, most likely triggered by TFA. Indeed, when
triarylmethanol 5 (R=H) was refluxed in neat TFA,
compounds 10, 11, and 12 were formed in the ratio of
14:1:4.
Figure 2. Side-products from Et3SiH/TFA reaction with 5
(R=H).
The propensity of triarylmethanol 5 (R=H) to rear-
range in acid made it difficult to optimize the formation
of 3 (R=H). However, decreasing the amount of TFA
present in the reaction mixture had a significant effect
on the yield of the core structure 3 (R=H), as summa-
rized in Table 1. Any further reduction in the quantity
of TFA used beyond that in entry 4 of the Table 1 did
not lead to further improvement in the yield.
core structure 3 (R=H) was treated with meta-
chloroperbenzoic acid and the resulting material heated
at 85°C in neat 4-methoxybenzylamine, the desired
diamine 13 was obtained in 55% yield for the two
steps.10
Preliminary investigations into the conversion of the
thiomethyl groups into amines were undertaken so as
to ensure that they were appropriate synthetic equiva-
lents. This is commonly achieved by the oxidation of
the thiomethyl group to either the sulfoxide or sulfone,
followed by displacement with an amine.5 Indeed, when

R. J. Anderson, J. C. Morris / Tetrahedron Letters 42 (2001) 311–313
313
Table 1. Optimization of the reaction conditions for the
synthesis of 3 (R=H)a
Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.;
Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994, 50,
3993–4000.
Entry
Equivalents of
Et3SiH
Equivalents of
TFA
Yield of 3
(R=H)
´
2. (a) Alvarez, M.; Ferna´ndez, D.; Joule, J. A. Synthesis
´
1999, 615–620. (b) Alvarez, M.; Ferna´ndez, D.; Joule, J.
A. J. Chem. Soc., Perkin Trans. 1 1999, 249–255.
3. Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777–4780.
1
2
3
4
5
2.0
4.0
8.0
8.1
7.8
8.3
8.2
8.2
4.3
2.0
15
18
22
34
33
´
4. Professor Alvarez and co-workers have recently com-
pleted a synthesis of the model compound deoxyvariolin
´
B. See: Alvarez, M.; Ferna´ndez; D.; Joule, J. A. Tetra-
a Reactions were performed at reflux under an atmosphere of argon
using 1.3 mmol of 5 (R=H). All yields refer to isolated pure
products.
hedron Lett. 2001, 42, 315.
5. Converting a thiomethyl group into an amino group is a
common procedure. For a recent example see: Adlington,
R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J.
Chem. Soc., Perkin Trans. 1 1999, 855–866.
In conclusion, the synthesis of the 5-substituted
pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine skeleton of the
variolins has been completed in only three steps, start-
ing from commercially available materials. The key step
in the synthesis was the one-pot deoxygenation/cycliza-
tion of triarylmethanol 5 (R=H). Introduction of
amine functionality as required for the natural products
has been achieved using an oxidation/substitution pro-
cedure. Efforts are currently focussed on adapting this
strategy so that the total synthesis of the variolins can
be completed.
6. Majeed, A. J.; Antonsen, Ø.; Benneche, T.; Undheim, K.
Tetrahedron 1989, 45, 993–1006.
7. Some of the reagent systems investigated include
Me3SiCl/NaI/MeCN,NaCNBH3/ZnI2,Pd–C/AlCl3/cyclo-
hexene, P/I2/HI, H2/Pd–C, LiAlH4/AlCl3, NaBH4/TFA,
and H2/Adams’ catalyst/TFA.
8. For a review of ionic hydrogenation see: Kursanov, D.
N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633–651.
1
9. Selected spectroscopic data for compound 3 (R=H): H
NMR (300 MHz, CDCl3): l 2.68 (s, 3H), 2.73 (s, 3H),
7.34 (d, J=5.4 Hz, 1H), 7.51 (dd, J=4.6, 8.1 Hz, 1H),
7.82 (d, J=6.3 Hz, 1H), 8.06 (d, J=6.3 Hz, 1H), 8.51 (d,
J=5.4 Hz, 1H), 8.60 (dd, J=1.7, 4.6 Hz, 1H), 8.64 (dd,
J=1.7, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): l 14.3,
14.9, 101.5, 108.4, 113.0, 120.8, 120.9, 128.1, 137.6, 140.0,
141.9, 143.1, 155.2, 156.7, 161.0, 172.5; HRMS: calcd for
C16H13N352S2 (M+) 339.0612, found 339.0617.
Acknowledgements
We thank PharmaMar SA, Tres Cantos for financial
assistance, Professor M. H. G. Munro and Professor J.
W. Blunt for their support of this work, Professor P. J.
Steel for helpful discussions and Mr. B. Clark for mass
spectrometry experiments.
1
10. Selected spectroscopic data for 13: H NMR (300 MHz,
CDCl3): l 3.80 (s, 3H), 3.81 (s, 3H), 4.69 (d, J=5.9 Hz,
2H), 4.89 (d, J=5.4 Hz, 2H), 5.52 (br, exchangeable,
1H), 6.89–6.93 (m, 4H), 6.98 (d, J=5.4 Hz, 1H), 7.33–
7.42 (m, 6H), 7.63 (d, J=6.8 Hz, 1H), 8.27 (dd, J=1.0,
5.2 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.56 (br d, J=7.8
Hz, 1H), 10.36 (br t, non-exchangeable, J=5.4 Hz, 1H);
13C NMR (75 MHz, CDCl3): l 44.3, 45.1, 55.3 (2×CH3),
100.6, 101.5, 107.9, 113.9, 114.0, 120.0, 121.9, 128.4,
128.6, 128.8, 130.3, 131.4, 138.4, 139.5, 143.0, 143.4,
149.0, 157.4, 158.7, 158.9, 162.1, 162.2; HRMS: calcd for
C30H27N7O2 (M+) 517.2226, found 517.2242.
References
1. (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.;
Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron
1994, 50, 3987–3992. (b) Trimurtulu, G.; Faulkner, D. J.;
.