Total synthesis of variolin B

Article abstract of DOI:10.1016/S0040-4039(01)01881-0

The total synthesis of the marine alkaloid variolin B has been achieved in eight steps, starting from commercially available 4-chloro-2-methylthiopyrimidine. The key reaction involves the tandem deoxygenation and cyclization of a triarylmethanol using a c

Full text of DOI:10.1016/S0040-4039(01)01881-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8697–8699
Total synthesis of variolin B
Regan J. Anderson and Jonathan C. Morris*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Received 28 August 2001; revised 25 September 2001; accepted 5 October 2001
Abstract—The total synthesis of the marine alkaloid variolin B has been achieved in eight steps, starting from commercially
available 4-chloro-2-methylthiopyrimidine. The key reaction involves the tandem deoxygenation and cyclization of a triaryl-
methanol using a combination of triethylsilane and trifluoroacetic acid. © 2001 Elsevier Science Ltd. All rights reserved.
Marine organisms have provided a tremendous array of
functionally diverse and biologically interesting struc-
tures.1 In 1994, Blunt and Munro reported the struc-
tural elucidation of the variolins, a class of novel
alkaloids isolated from the rare, difficult to access
Antarctic sponge Kirkpatricka varialosa.2,3 The vari-
work7 on the variolin core structure has indicated that
3 could be generated by a tandem deoxygenation/
cyclization of triarylmethanol 4. In this Letter, we
present the successful application of this strategy to the
first reported total synthesis of variolin B.
olins contain
a
fused pyrido[3%,2%:4,5]pyrrolo[1,2-
In our synthesis of the variolin core,7 we prepared the
necessary tertiary alcohol by reaction of 4-lithio-2-
methylthiopyrimidine (5) with 2-chloronicotinoyl chlo-
ride. Adaptation of this strategy to the synthesis of
triaryl alcohol 4 is detailed in Scheme 2. Acid chloride
6 was generated in 97% yield from the acid 78 by
reaction with oxalyl chloride. However, the addition of
the lithio species 59 to the acid chloride 6 proved to be
a low yielding process, with the desired triaryl alcohol 4
being obtained in poor yields (5–15%). Extensive efforts
to optimize this reaction were hampered by the instabil-
ity of lithiated pyrimidine 5 above −95°C. The equiva-
lent Grignard reagent is reported to be stable at 0°C,10
but all attempts to react this reagent with acid chloride
6 failed to yield any trace of 4. The unacceptably low
yield of this reaction meant that an alternative
approach to triaryl alcohol 4 had to be developed
(Scheme 2).
c]pyrimidine core 1, with either a heterocyclic aromatic
ring or ester group attached at C5. Recently, variolin B
(2) has attracted considerable interest as a synthetic
target because of its potent anti-tumor activity, and
because it is no longer possible to collect the original
sponge source. A variety of strategies4–7 have been
developed to synthesize the pyrido[3%,2%:4,5]pyrrolo[1,2-
c]pyrimidine core of the variolins, with the majority of
these syntheses employing conventional heterocyclic
chemistry.
Reaction of lithio species 5 with 0.5 equiv. of diethyl
carbonate at −95°C gave the symmetric ketone 8 in 53%
yield.† Addition of 8 to a solution of lithiated pyridine
derivative 911 in THF at −78°C resulted in the forma-
tion of the desired triaryl alcohol 4 in 76% yield.
Our retrosynthetic strategy for variolin B 2 is outlined
in Scheme 1, with the key compound being the core
structure 3, which contains the appropriate functional-
ity to introduce the highly polar amines.7 Examination
of 3 reveals a hidden symmetry element, which leads to
the disconnection indicated in Scheme 1. Our previous
With triaryl alcohol 4 available, attention could now be
focused on the conversion of 4 into the core structure 3
using our tandem deoxygenation/cyclization protocol.7
* Corresponding author. Fax: 64-3-3642110; e-mail: j.morris@
chem.canterbury.ac.nz
† Yields are for purified compounds. All new compounds were fully
characterized by 1H NMR, 13C NMR, IR and HRMS.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01881-0

8698
R. J. Anderson, J. C. Morris / Tetrahedron Letters 42 (2001) 8697–8699
Scheme 1. Retrosynthetic strategy for the synthesis of 2.
Scheme 2. (a) (COCl)2/cat. DMF/CH2Cl2 (97%); (b) 3 equiv. 5/THF/−95°C (5–15%); (c) 0.5 equiv. (EtO)2CO/THF/−95°C–rt
(53%); (d) THF/−78°C (76%); (e) 8 equiv. Et3SiH/2 equiv. TFA/1,2-dichloroethane/100°C (47%); (f) 2 equiv. m-CPBA/CHCl3/−
35°C; (g) 10 equiv. p-methoxybenzylamine/85°C (78% from 3); (h) 10 equiv. NaSEt/DMF/55°C (95%); (i) TfOH/rt [PMB=p-
methoxybenzyl].
which may arise from attack of the hydroxyl group
onto one of the pyrimidine rings and subsequent CꢀC
bond cleavage. Careful optimization of this reaction
established that the best conditions involved carrying
out the reaction in a sealed tube at 100°C with 8
Reaction of 4 under our previously reported conditions
[8 equiv. triethylsilane (TES) and equiv. tri-
fluoroacetic acid (TFA)/70°C] afforded the desired core
structure 3 in a disappointing 10% yield. The major
product from this reaction was ether 10 (54% yield),
4

R. J. Anderson, J. C. Morris / Tetrahedron Letters 42 (2001) 8697–8699
8699
equiv. of TES and 2 equiv. of TFA, with 1,2-
dichloroethane as solvent. With these adjustments, 3 was
isolated in a much improved 47% yield.
assistance, Professors M. H. G. Munro and J. W. Blunt
for their support of this work, Professors P. J. Steel and
A. J. Phillips for helpful discussions and Mr. Bruce Clark
for mass spectrometry experiments.
Oxidation of 3 with 2 equiv. of m-chloroperbenzoic acid
in chloroform at −35°C proceeded smoothly to give the
disulfoxide 11, which was heated in the presence of
p-methoxybenzylamine at 85°C to give the bisprotected-
amine 12 in 78% yield for the two steps, starting from
3. To remove the methoxy protecting group, 12 was
treated with an excess of sodium ethanethiolate in dry
DMF at 55°C for 7 h to give the pyridinol 13 in 95% yield.
References
1. Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1–49.
2. Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.;
Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron
1994, 50, 3987–3992.
Finally, the p-methoxybenzyl protecting groups on the
amines were quantitatively removed by stirring 13 in neat
triflic acid at room temperature. After neutralization with
aqueous ammonia solution, the crude material was
purified using reverse-phase silica flash chromatography
(eluting with 70% methanol/water with 0.5% TFA added)
to give variolin B 2 as the conveniently handled tri-
fluoroacetate salt.2 To obtain the sparingly soluble free
base, the salt was neutralized with concentrated ammo-
nia solution to give material that was identical in all
respects with the natural product.
3. Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati,
L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G.;
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9. Lithio species 5 is generated by iodine–lithium exchange
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In summary, the first total synthesis of variolin B has
been completed in eight steps from commercially avail-
able materials. Highlights of our synthesis include the
tandem deoxygenation/cyclization to form the core var-
iolin skeleton and the straightforward functional group
manipulation required to introduce the necessary func-
tionality of variolin B. This synthetic strategy is readily
amenable to the production of analogs and will provide
material to allow further investigation of the biological
properties.
Acknowledgements
We thank PharmaMar SA, Tres Cantos for financial