Synthesis of deoxyvariolin B

Article abstract of DOI:10.1016/S0040-4039(00)01916-X

A synthesis of deoxyvariolin B (5) is described. The tricyclic pyridopyrrolopyrimidone (11) was prepared from 7-azaindole via lithiation at C-2, introduction of an aminoethyl side-chain, then closure of the third ring. A heteroaryl palladium(0)-catalysed coupling reaction was used to introduce a pyrimidine substituent at C-5.

Full text of DOI:10.1016/S0040-4039(00)01916-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 315–317
Synthesis of deoxyvariolin B
a,
a
b
´
Mercedes Alvarez, * David Ferna´ndez and John A. Joule
aLaboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, E 08028 Barcelona, Spain
bChemistry Department, The University of Manchester, Manchester M13 9PL, UK
Received 20 September 2000; accepted 30 October 2000
Abstract—A synthesis of deoxyvariolin B (5) is described. The tricyclic pyridopyrrolopyrimidone (11) was prepared from
7-azaindole via lithiation at C-2, introduction of an aminoethyl side-chain, then closure of the third ring. A heteroaryl
palladium(0)-catalysed coupling reaction was used to introduce a pyrimidine substituent at C-5. © 2000 Elsevier Science Ltd. All
rights reserved.
Variolin A (1), variolin B (2), variolin D (3) and
N-3%-methyl-3%,4%,5%,6%-tetrahydrovariolin B (4) comprise
a group of marine heterocyclic substances isolated from
the Antarctic sponge Kirkpatrickia varialosa in 1994.1,2
1, 2, and 4, as opposed to the 5-methoxycarbonyl
substituent in variolin D 3.
For the synthesis of deoxyvariolin B 5, a pyrido-
pyrrolopyrimidine tricycle 11 was constructed from 7-
azaindole, with a subsequent palladium(0)-catalysed
heteroaryl coupling of a 5-iodo derivative of 11 for the
introduction of a pyrimidine as the 5-substituent.
They have
a
common tricyclic skeleton,
a
pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidine, which has no
precedents in either terrestrial or marine natural prod-
ucts. There have been three previous reports3–5 of the
4,5
construction of this system. Two of these
describe
different ways for the preparation of the core tricycle of
the variolins, but in each case with an ester group at
C-7; in neither study was an appropriate substituent
introduced at C-5.
The introduction of a protected aminoethyl chain at the
2-position of 7-azaindole6 was achieved by reaction of a
2-lithio-derivative with 2-phthalimidoacetaldehyde 6.7
Although lithiation of 1-phenylsulfonyl-7-azaindole had
previously been described,8 we found that the method
described by Katritzky9 for indole 2-lithiation was also
suitable for 7-azaindole, gave superior results, and ad-
ditionally avoided N-protection and N-deprotection
steps. Thus, 2-lithiation of 7-azaindole-1-carboxylic
acid lithium salt, formed in situ, giving 7, then reaction
with aldehyde 6 afforded the alcohol 8 in 44% yield.
Protection of the alcohol as a tetrahydropyranyl ether
gave a diastereomeric mixture which was used without
attempting separation (both stereogenic centres are lost
later in the synthesis). Hydrazinolysis of the phthal-
imide protecting group yielded the amine 9 quantita-
tively, and this was converted into tetrahydropyrimi-
An important feature of these compounds is significant
bioactivity:1 variolin B is the most active, having cyto-
toxic activity against the P388 cell line, and also being
effective against Herpes simplex; it was inactive against
a range of other microorganisms. Variolin A also
showed important cytotoxic activity against the P388
cell line. N-3%-Methyl-3%,4%,5%,6%-tetrahydrovariolin B in-
hibited the growth of Sacharomyces cerevisiae and
showed in vitro activity against the HCT 116 cell line.
Variolin D was inactive in all the assays. The differen-
tial activity of these alkaloids is believed to show the
biological importance of the heterocyclic rings at C-5 in
CH3
H2N
H2N
H2N
N
+
N
N
N
NH2
N
OH
N
N
OH
N
CH3
CO2Me
OH
OH
4
O-
5
5
N
N
N
N
N
N
N
7
N
N
N
N
N
H2N
N
N
H2N
N
9
H2N
H2N
H2N
1
2
3
4
5
* Corresponding author.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01916-X

´
316
M. Al6arez et al. / Tetrahedron Letters 42 (2001) 315–317
O
N
CHO
OH
N
O
6
N
H
Li
CO2Li
i - iii
O
N
N
H
N
N
N
8
iv
7
O
5
v - vi
OTHP
viii - ix
OTHP
NH2
vii
N
N
N
H
N
N
N
N
H
N
H
O
O
11
9
10
Scheme 1. Reagents: (i) n-BuLi, THF, −78°C to rt; (ii) CO2, −78°C; (iii) t-BuLi, THF, −78°C; (iv) 6, THF, −78°C to rt (44%);
(v) DHP, HCl, benzene, CHCl3, D (87%); (vi) NH2NH2·H2O, EtOH, D (100%); (vii) (Cl3CO)2CO, DIPEA, CH2Cl2, rt (76%); (viii)
4N HCl, CH2Cl2 (100%); (ix) MsCl, TEA, CH2Cl2, 0°C (95%).
done 10 in 76% yield on treatment with triphosgene in
CH2Cl2 with diisopropyl ethylamine (DIPEA) as base.
Removal of the protecting group then dehydration via
the mesylate gave dihydropyrimidone 11,10 in six opera-
tional steps from 7-azaindole (Scheme 1). Ring closure
to the azaindole nitrogen, and not to the azaindole C-3,
hydride as base giving 12a and 12b, respectively. Halo-
genation of 12a using N-bromosuccinimide (NBS) or
iodine afforded 13a (80%) and 13b (62%), respectively,
and iodination of 12b with N-iodosuccinimide (NIS)
gave 13c (80%). The regioselectivity of halogenation
was confirmed by comparisons of 1H NMR spectra: the
H-5 singlets at l 6.41 ppm and 6.48 ppm present in the
spectra of 12a and 12b were absent in the spectra of
13a, 13b, and 13c. Treatment of 13a with n-butyl-
lithium followed by quenching with trimethyltin
chloride11 gave a complex mixture which could not be
resolved. Treatment of 13b with hexamethylditin and
Pd(PPh3)4 hoping for iodine–tin interchange afforded a
mixture of 14 and 12a in a ratio of 7:3, but isolation of
14 by column chromatography failed. Accordingly, the
coupling of the iodide 13b with the pyrimidinyl-stan-
nane 1513 was attempted.
1
was confirmed by the H NMR spectrum of 11 which
had a singlet signal at l 6.60 for the 5-hydrogen.
Based on our previous results in heteroaryl couplings of
3-halo- and 3-tributylstannyl-7-azaindoles11 and on the
halogenation of dihydropyrrolo[1,2-c]pyrimidin-1-
ones,12 the preparation and coupling of a tin derivative
such as 14 was envisaged as a means for the introduc-
tion of a pyrimidine substituent at the five-position.
N-Protection of 11 was achieved with methyl
chloromethyl ether or with tosyl chloride using sodium
MeS
SMe
N
N
N
N
X
Me3Sn
i
ii
15
11
N
N
N
N
N
N
iii
N
N
R
N
R
O
R
O
O
13a X = Br
13b X = I
13c X = I
R = MOM
R = MOM
R = Ts
12a R = MOM
12b R = Ts
16a R = MOM
16b R = H
iv - v
14 X = SnMe3 R = MOM
MeS
N
N
I
N
vi - vii
ix - x
viii
N
N
N
N
5
N
N
N
N
AcHN
18
H2N
17
19
H2N
Scheme 2. Reagents: (i) MOMCl, NaH, DMF, 0°C (87%) or TsCl, NaH, DMF, rt (40%); (ii) 13a NBS, CH2Cl2, 0°C (80%); 13b
I2, DMF, NaOH, rt (62%); 13c NIS, CHCl3, rt (80%); (iii) Pd2(dba)3, PPh3, LiCl, CuI, dioxane, D 15 (“16b 10%); (iv) TMSCl,
HMDSA, 2,6-lutidine; (v) NH3, 150°C, 60 psi (30% two steps); (vi) Ac2O, THF, rt (75%); (vii) NIS, CHCl3, rt (95%); (viii) (a)
Pd2(dba)3, PPh3, LiCl, CuI, dioxane, D 15; (b) HCl, MeOH, D (45% two steps); (ix) MCPBA, CH2Cl2, 0°C (90%); (x) aq. NH4OH,
dioxane, 80°C (90%).

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M. Al6arez et al. / Tetrahedron Letters 42 (2001) 315–317
317
Coupling between 13b and 15 under a variety of exper-
imental conditions always gave a mixture of 12a and
16a which it was impossible to separate. The situation
was only marginally improved using 13c instead of 13b
for although the deprotected tetracycle 16b was ob-
tained, the yield was only 10%.
4. Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777–4780.
5. Mendiola, J.; Minguez, J. M.; Alvarez-Builla, J.; Va-
quero, J. Org. Lett. 2000, 2, 3253–3256.
6. Lorenz, R. R.; Tullar, B. F.; Koelsch, C. F.; Archer, S. J.
Org. Chem. 1965, 30, 2531–2533.
7. 2-Phthalimidoacetaldehyde 6 was obtained in 75% yield
from 2-aminoacetaldehyde dimethyl acetal by reaction of
the amino group with phthalic anhydride at 140°C for 15
min followed by hydrolysis of the acetal group with 10%
aq. HCl at reflux, mp 114°C (hexane/CH2Cl2) (Charya, S.
B.; Dutta, S.; Sanyal, U. J. Indian Chem. Soc. 1998, 75,
46–48 gives 111–112°C (CHCl3/hexane)).
8. Desarbre, E.; Coudret, S.; Meheust, C.; Me´rour, J.-I.
Tetrahedron 1997, 53, 3637–3648.
9. Katritzky, A. R.; Akutagawa, K. J. Am. Chem. Soc.
Since, in any case, the carbonyl group in 11 would at
some stage need to be transformed into an amino
group, this step was now undertaken. O-Silylation of
11 with TMSCl and hexamethyldisilazane (HMDSA),
followed by nucleophilic substitution with ammonia14,15
gave amine 17. N-Acetylation followed by regioselec-
tive iodination of the pyrrole ring proceeded in excel-
lent yield giving 18 (Scheme 2).
The coupling between 18 and 15 using a combination of
Pd2(dba)3, PPh3, LiCl, and CuI gave a mixture of the
anticipated acetamide and its corresponding amine and
so the product mixture was not separated but immedi-
ately converted wholly into the amine, by methanolysis
with dry HCl in methanol, yielding the amine 19 in 45%
yield for the two steps. Deoxyvariolin B 516 was pre-
pared by substitution of the methylthio group of the
newly introduced pyrimidine ring for an amino group,
thus S-oxidation using m-chloroperbenzoic acid
(MCPBA) followed by substitution of the resulting
sulfone for an amino group using ammonium hydrox-
ide afforded 5 in excellent yield.17
1986, 108, 6808–6809.
10. Data for pyrido[3%,2%:4,5]pyrrolo[1,2-c]pyrimidin-1-one
11: 265–266°C (MeOH); IR (KBr) w 3424, 1721 cm−1; 1H
NMR (300 MHz, DMSO-d6) l 6.50 (d, J 7.4 Hz, 1H,
H-6), 6.60 (s, 1H, H-5), 6.97 (dd, J 7.4 and 5.3 Hz, 1H,
H-7), 7.37 (dd, J 8.0 and 4.7 Hz, 1H, H-3), 8.08 (dd, J 8.0
and 1.7 Hz, 1H, H-4), 8.39 (dd, J 4.7 and 1.7 Hz, 1H,
H-2), 10.81 (br d, J 5.3 Hz, 1H, NH); 13C NMR (75
MHz, DMSO-d6) l 94.9 (d, C-6), 98.0 (d, C-5), 119.8 (d,
C-3), 123.1 (s, C-4a), 127.5 (d, C-4), 128.0 (d, C-7), 137.0
(s, C-5a), 142.5 (d, C-2), 145.6 (s, C-10a*), 146.7 (s,
C-9*); MS (EI): 185 (M+, 15), 157 (M+−CO, 10); MS (CI,
NH4+): 204 (M+18, 12%), 186 (M+1, 100), 109 (48);
HRMS (CI): calculated for C10H7N3O: 185.0589. Found:
185.0593.
The flexible route to deoxyvariolin B 5 described here,
will be applicable not only to the synthesis of variolin B
itself, and the other variolins, with a 4-oxygenated-7-
azaindole as starting point, but also to other analogues
for the assessment of biological activities and the estab-
lishment of structure/activity relationships.
´
11. Alvarez, M.; Ferna´ndez, D.; Joule, J. A. Synthesis 1999,
615–620.
´
12. Alvarez, M.; Ferna´ndez, D.; Joule, J. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 249–255.
13. Majeed, A. J.; Antonsen, Ø.; Benneche, T.; Undheim, K.
Tetrahedron 1989, 45, 993–1006. The preparation of 15
from 4-iodo-2-methylthiopyrimidine and hexamethylditin
was improved using Pd(OAc)2 and PPh3 in THF, carry-
ing out the coupling reaction for one hour only, and by
using only one mol equivalent of TBAF.
Acknowledgements
This work was supported by grants from the Ministerio
de Educacio´n y Cultura (PB97-0871 and 2FD97-0486)
and the Comissionat per a Universitats i Recerca (Gen-
eralitat de Catalunya) (99-SGR00077 and 98XT-0049).
The help rendered by Dr. J. L. Ferna´ndez Puentes, Dr.
J. A. de la Fuente and Dra. M. D. Garc´ıa-Gra´valos
from the INSTITUTO BIOMAR S. A. is gratefully
acknowledged.
14. Vorbru¨ggen, H.; Krolikiewicz, K.; Niedballa, U. Liebigs
Ann. Chem. 1975, 988–1002.
15. Vorbru¨ggen, H.; Krolikiewicz, K. Liebigs Ann. Chem.
1976, 745–761.
16. Data for deoxyvariolin B 5: mp 161–162°C (DCM/hex-
1
ane); IR (film) w 3332, 1632, 1574, 1454, 1262 cm−1; H
NMR (300 MHz, DMSO-d6) l 6.63 (br, 1H, NH), 7.12
(d, J 5.5 Hz, 1H, H-5%), 7.64 (dd, J 8.0 and 4.4 Hz, 1H,
H-3), 7.70 (d, J 6.6 Hz, 1H, H-6), 7.76 (d, J 6.6 Hz, 1H,
H-7), 8.29 (d, J 5.5 Hz, 1H, H-6%), 8.51 (dd, J 4.4 and 1.4
Hz, 1H, H-2), 8.99 (dd, J 8.0 and 1.4 Hz, 1H, H-4); 13C
NMR (50 MHz, DMSO-d6) l 99.5 (s, C-5), 101.7 (d,
C-6), 106.8 (d, C-5%), 121.6 (s, C-4a), 120.7 (d, C-3), 129.1
(d, C-4), 138.2 (s, C-4%), 140.1 (d, C-7), 142.8 (s, C-5a),
143.8 (d, C-2), 149.7 (s, C-10a), 158.0 (d, C-6%), 161.4 (s,
C-2%*), 163.5 (s, C-9*); MS (CI; NH4+): 279 (M+2, 20%),
278 (M+1, 100), 277 (M+, 10).
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