Total Syntheses of Variolin B and Deoxyvariolin B1

Article abstract of DOI:10.1021/jo035332b

Two alternative synthetic routes have been developed for the preparation of variolin B and deoxyvariolin B. The strategy is based on the preparation of the core tricyclic ring common to all variolins, pyrido[3′,2′ :4,5]pyrrolo[1,2-c]pyrimidine, followed b

Full text of DOI:10.1021/jo035332b

Tota l Syn th eses of Va r iolin B a n d Deoxyva r iolin B1
Abderaouf Ahaidar,†,‡ David Ferna´ndez,‡ Gerardo Danelo´n,† Carmen Cuevas,§
Ignacio Manzanares,§ Fernando Albericio,†, J ohn A. J oule,| and Mercedes AÄ lvarez*,†,‡
Barcelona Biomedical Research Institute, Barcelona Scientific Park, University of Barcelona,
J osep Samitier 1-5, E 08028 Barcelona, Spain, Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, Avda. J oan XXIII s/ n, E 08028 Barcelona, Spain, Pharma Mar,
Avda Reyes Cato´licos 1, 28770 Colmenar Viejo, Madrid, Spain, Department of Organic Chemistry,
Universitat de Barcelona, Mart´ı Franque´s 1-11, E 08028 Barcelona, Spain, and Chemistry Department,
The University of Manchester, Manchester M13 9PL, United Kingdom
malvarez@pcb.ub.es
Received September 10, 2003
Two alternative synthetic routes have been developed for the preparation of variolin B and
deoxyvariolin B. The strategy is based on the preparation of the core tricyclic ring common to all
variolins, pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine, followed by a palladium-catalyzed cross-coupling
reaction to give the tetracyclic system.
Variolins 1-4 (Figure 1) comprise a group of marine
heterocyclic substances isolated from the Antarctic sponge
Kirkpatrickia variolosa.2,3 They have a common tricyclic
ring skeleton, which has no precedents in either ter-
restrial or marine natural products, namely a pyrido-
[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine; in each case the nucleus
carries a substituent at position 5. Pharmacological
evaluation of these compounds showed important anti-
viral and antiproliferative activity against P388 leu-
kaemia cells.2,3 Variolin B (2) is the most active of the
family, oxidation or reduction of the isolated D ring as
in variolin A (1) or N-3′-methyl-3′,4′,5′,6′-tetrahydrova-
riolin B (3), respectively, reduces the activity. The
biological importance of the aminopyrimidine substituent
at C5 is corroborated by the lack of activity of variolin D
(4) in which C5 carries only a methoxycarbonyl group.
Herein, total syntheses of variolin B and deoxyvariolin
B based on novel strategies are presented.4 Our approach
for the synthesis of both the natural product and non-
natural analogues is based on the construction of the
tricyclic pyridopyrrolopyrimidine core starting with a
7-azaindole 5 followed by the introduction of the C5
substituent, the D ring, by a palladium-catalyzed cross-
coupling reaction. We used two alternative procedures
for the construction of the aminopyrimidine ring C,
assembling first a 2-aminoethyl-substituted 7-azaindole,
8. For the preparation of deoxyvariolin B the cyclization
of 8a was achieved by using triphosgene [(Cl3CO)2CO]
to give tetrahydropyrimidinone 9a . The use of an inter-
mediate of this type required the transformation of the
tetrahydropyrimidone unit into a 2-aminopyrimidine
unit. To avoid the need for this transformation, a more
convergent strategy was used subsequently for the
synthesis of variolin B, thus, by employing N-tosyldi-
chloromethanimine (TsNdCCl2) as a cyclization reagent,
compound 8b could be converted in one step into the
protected aminodihydropyrimidine 14 (Scheme 1) requir-
ing only deprotections and a dehydration to form 16.
In our preliminary studies aimed at the preparation
of the tricyclic compound 11a , we attempted the cycliza-
tion of 13 anticipating intramolecular electrophilic attack
at the R position of the π-rich five-membered ring.
However, with use of a variety of conditions,5 with
different acids, no traces of the desired tricycle 11a could
be detected. The 1-substituted 7-azaindole 13 was ob-
tained by reaction of 7-azaindole with aminoacetaldehyde
dimethyl acetal, triphosgene, and diisopropylethylamine
(DIPEA), following a protocol with minor modifications
described for the preparation of simpler unsymmetrically
substituted ureas.6
* Address correspondence to this author. Phone: +34 93 403 70 86.
Fax: +34 03 403 71 26.
† Barcelona Biomedical Research Institute, Barcelona Scientific
Park, University of Barcelona.
‡ Laboratory of Organic Chemistry, Faculty of Pharmacy, University
of Barcelona.
§ Pharma Mar.
Department of Organic Chemistry, Universitat de Barcelona.
| Chemistry Department, The University of Manchester.
(1) Taken in part from the Ph.D. Thesis of David Ferna´ndez,
University of Barcelona, 2001. A preiminary report of portions of this
work was presented in: (a) AÄ lvarez, M.; Ferna´ndez, D.; J oule, J . A.
Tetrahedron Lett. 2001, 42, 315-317. (b) Ahaidar, A.; Ferna´ndez, D.;
Pe´rez, O.; Danelo´n, G.; Cuevas, C.; Manzanares, I.; Albericio, F.; J oule,
J . A.; AÄ lvarez, M. Tetrahedron Lett. 2003, 44, 6191-6194.
(2) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J . W.; Munro,
M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987-3992.
(3) Trimurtulu, G.; Faulkner, D. J .; Perry, N. B.; Ettouati, L.;
Litaudon, M.; Blunt, J . W.; Munro, M. H. G.; J ameson, G. B.
Tetrahedron 1994, 50, 3993-4000.
(4) In the literature, two syntheses of variolin B and two syntheses
of deoxyvariolin B, as well as several methods for the construction of
the common tricyclic skeleton of these compounds, have also been
reported: (a) Anderson, R. J .; Morris, J . C. Tetrahedron Lett. 2001,
42, 8697-8699. (b) Molina, P.; Fresneda, P. M.; Delgado, S. J . Org.
Chem. 2003, 68, 489-499. (c) Anderson, R. J .; Morris, J . C. Tetrahedron
Lett. 2001, 42, 311-313. (d) Capuano, L.; Schrepfer, H. J .; Mu¨ller, K.;
Roos, H. Chem. Ber. 1974, 107, 929-936. (e) Fresneda, P. M.; Molina,
P.; Delgado, S.; Bleda, J . A. Tetrahedron Lett. 2000, 41, 4777-4780.
(5) Conditions: (a) dry HCl in benzene at reflux temperature, (b)
aq 2 N HCl in benzene at reflux, (c) BBr3 in benzene at room
temperature and reflux, (d) concentrated H2SO4 at 100 °C, (e) TFA at
reflux, (f) MsOH at 100 °C.
10.1021/jo035332b CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003
10020
J . Org. Chem. 2003, 68, 10020-10029

Syntheses of Variolin B and Deoxyvariolin B
F IGURE 1. Structures of variolins 1-4.
SCHEME 1. P r ep a r a tion of 9-Am in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in es 12, 16, a n d 17a
a
Reagents and conditions: (i) (a) n-BuLi, THF, -78 °C to rt, (b) CO2, -78 °C, (c) t-BuLi, THF, -78 °C, (d) 2-phthalimidoacetaldehyde,
THF, -78 °C to rt; (ii) DHP, HCl, benzene, CHCl3, 4; (iii) NH2NH2‚H2O, EtOH, 4; (iv) (Cl3CO)2CO, DIPEA, CH2Cl2, rt; (v) 4 N HCl,
CH2Cl2; (vi) MsCl, TEA, CH2Cl2, 0 °C; (vii) TsNdC(Cl)2, DIPEA, CH2Cl2; (viii) (a) TMSCl, HMDSA, 2,6-lutidine, (b) NH3, 150 °C, 60 psi;
(ix) Ac2O, THF, rt.
Resu lts a n d Discu sion
none 11 in a one-pot deprotection/dehydration. Elimina-
tion of the phthaloyl protecting group by hydrazinolysis
gave 8a .
P r ep a r a tion of 9-Am in op yr id o[3′,2′:4,5]p yr r olo-
[1,2-c]p yr im id in es 12, 16, a n d 17. Commercially avail-
able 7-azaindole 5a was converted into a 2-lithiated
species with use of the device first described by Katritzky
for indole,7 in which the nitrogen is blocked by successive
reactions with n-BuLi, then CO2, generating NCO2Li, and
then, without isolation, in situ C-lithiation is achieved
with t-BuLi. Reaction of the lithiated species with 2-
phthalimidoacetaldehyde8 gave the alcohol 6a in 44%
The tetrahydropyrimidine 9a was obtained as a 1:1
diastereomeric mixture in 76% yield by reaction of 8a
and triphosgene and DIPEA in CH2Cl2 at room temper-
ature for a short time. A strong absorption at ν 1716 cm-1
in the IR spectrum of the product confirmed the cycliza-
tion to 9a . The diastereomeric mixture, without separa-
tion, was quantitatively O-deprotected with aq 4 N HCl
in chloroform, but disappointingly without dehydration.
The very polar 10a was isolated and characterized as its
hydrochloride, and used as such for further synthetic
steps.
Several conditions were tested for dehydration of 10a
under acidic conditions,10 but all attempts, rather sur-
prisingly, led to the recovery of the benzylic alcohol. The
required 1,2-elimination of water was finally achieved by
mesylation of the alcohol 10a with MsCl and triethyl-
amine (TEA) at 0 °C, giving the pyrimidinone 11a in a
high yield. The two coupled doublets at δ 6.50 and 6.79
ppm with a coupling constant of 7.4 Hz for the protons
at C6 and C7, replacing the ABX system of the precursor
tetrahydropyrimidine, confirmed the structure of 11a .
The 9-aminopyrimidine system of compound 12a re-
quired the conversion of the carbonyl group of 11a into
a leaving group for displacement with ammonia. The
1
yield, with characteristic signals in its H NMR spectrum
for the three protons of the aminoethanol chain consti-
tuting an ABX system at δ 3.88, 4.00, and 5.06 ppm. For
the next step, protection of the hydroxyl group was
necessary to avoid the competitive formation of an
oxazolidinone during the preparation of the tricyclic
system. We chose to use a tetrahydropyranyl ether as
the protecting group since it offered the advantages of
being orthogonal9 to the phthalimide protecting group,
and also having sufficient stability to survive the condi-
tions needed for the cyclization. Furthermore, we antici-
pated that the acidic conditions for its removal might also
lead to dehydration and thus the formation of pyrimidi-
(6) Majer, P.; Randad, R. S. J . Org. Chem. 1994, 59, 1937-1938.
(7) Katritzky, A. R.; Akutagawa, K. J . Am. Chem. Soc. 1986, 108,
6808-6809.
(8) Charya, S. B.; Dutta, S.; Sanyal, U. J . Indian Chem. Soc. 1998,
75, 46-48.
(10) Conditions: (a) concentrated H2SO4 at room temperature, (b)
TsOH in CHCl3 at reflux, (c) dry HCl in benzene with a Dean-Stark
separator.
(9) Barany, G.; Albericio, F. J . Am. Chem. Soc. 1985, 107, 4936-
4942.
J . Org. Chem, Vol. 68, No. 26, 2003 10021

Ahaidar et al.
preparation of the corresponding chloropyrimidine from
11a with use of POCl3 at room temperature or reflux,
using POCl3 and PCl5 in a solvent (CHCl3) or without a
solvent, at varying temperatures and for various times,
was unsuccessfulsstarting material 11a was quantita-
tively recovered in the milder conditions and only de-
composition products were produced at reflux, for ex-
ample, in POCl3 for 2 h. The functional group intercon-
version was finally achieved in a 30% yield for the two
steps by transformation of the pyrimidinone ring into the
O-trimethylsilylpyrimidine by reaction with hexameth-
yldisilazane (HMDSA), followed by a reaction with am-
monia at 150 °C and 60 psi in a Parr reactor following a
procedure reported by Vorbru¨ggen for the preparation of
4-amino-2-pyrimidinones.11 In the O-silylation step, we
used 2,6-lutidine as a cosolvent because 11a was not
soluble in HMDSA. Significant differences in the 1H NMR
spectra of 11a and 12a confirmed the transformation,
thus the chemical shifts for the protons at C6 and C7 of
12a were further downfield, at δ 6.72 and 7.30 ppm, and
the coupling constant was reduced to 6.6 Hz, both
features in agreement with the formation of a fully
aromatic ring.
Following a comparable sequence, the pyrimidinone
11b was obtained from 4-methoxy-7-azaindole 5b12 via
intermediates 6b, 7b, 8b, 9b, and 10b. However, the
transformation of pyrimidinone 11b into the aminopy-
rimidine 12b, using the conditions developed for the
deoxy-series, afforded a mixture of 12b and recovered 11b
in yields of 22% and 15%, respectively, for the two-step
sequence. Increasing the temperature and pressure for
the nucleophilic substitution step resulted only in a more
complex mixture, due probably to competitive and/or
additional substitution of the C4 methoxy group.
The greater reactivity of 11b in comparison with 11a
made it necessary to develop an alternative procedure
to avoid the pyrimidinone f amino-pyrimidine transfor-
mation in the methoxy series. Since it was the aim to
introduce a carbon and a nitrogen, directly, just as a
carbon and an oxygen had been introduced in the
formation of 9 using a phosgene synthon, we considered
the use of a nitrogen analogue of phosgene, OdCCl2,
namely N-tosyldichloromethanimine13 (TsNdCCl2). An
examination of the literature showed that this reagent
had been used in several situations for cyclizations
producing five-membered rings, where 1,4-related bis-
nucleophiles had been reacted to give five-membered
rings carrying TsHN on the carbon between the two
nucleophilic atoms; examples include closures with two
nitrogens,14 a nitrogen and an oxygen,15 and a nitrogen
and a carbon.16 There are no examples of six-membered-
ring formation by reaction of TsNdCCl2 with a 1,5-
diamine; however, the comparable reagent TsNdC(SMe)2
has been used to construct six-membered N-tosyl-
guanidines.17
dihydropyrimidines 14a and 14b. Reaction of 8a with
TsNdCCl2 and DIPEA in dichloromethane at room
temperature afforded 14a (60%), which was then O-
deprotected to 15a and dehydrated to 16a (74% for the
two steps) by using the conditions described above.
Similarly, in the methoxy series, 8b was converted into
16b in 44% yield for the three steps.
It was essential to have a good experimental procedure
to remove the tosyl protecting groupsalthough many
protocols for achieveing N-detosylation exist, no generally
applicable method has emerged. Using 16a , several of
the reported experimental conditions were tested for the
detosylation: treatment with aqueous HBr,18 HBr and
AcOH in phenol at reflux temperature,19 aqueous HI,
HF,20 Mg and NH4Cl in EtOH,21 Red-Al in toluene at
different temperatures,22 and NaOH in MeOH or DCM
all failed to bring about N-tosyl deprotection. Only with
Na in liquid ammonia23,24 was 12a obtained, but then
only in a 38% yield; Na-naphthalene25 in THF at -78 °C
gave the N-deprotected 12a in a 25% yield. A much better
result was obtained by using a reductive photolysis of
the tosyl group, thus irradiation with a high-pressure Hg
lamp with a Pyrex filter, NaBH4 as a reducing agent, and
1,4-dimethoxybenzene as an electron source26 allowed the
removal of the N-tosyl group from 16a in a 64% yield.
In tr od u ction of Rin g D. Now came the introduction
of ring D by a palladium-catalyzed cross-coupling reac-
tion, the procedure that had allowed us to prepare
simpler 3-aryl- and 3-heteroaryl-7-azaindoles27 and
5-arylpyrrolo[1,2-c]pyrimidin-1(2H)-ones.28 Thus, from
12a via the N-acetylated derivative 17a ,29 the 5-iodo
derivative 18a was produced in good yield (93%) with use
of N-iodosuccinimide (NIS) at low temperature in chlo-
roform for a short time. The regiochemistry of the
1
iodination of 17a was evidenced by the absence of a H
NMR C5 singlet signal (δ 6.53 ppm in 17a ) and by the
presence in the aromatic region of an ABC system for
the pyridine and an AB system for the pyrimidine
protons.
The coupling of 18a with 19,30 using a combination of
Pd2(dba)3 (18%), PPh3 (40%), LiCl, and CuI at reflux
(15) Merchan, F. L. Synthesis 1981, 965.
(16) Potts, K. T.; Murphy, P. M.; Kuehnling, W. R. J . Org. Chem.
1988, 53, 2889-2898.
(17) Houghten, R. A.; Simpson, R. A.; Hanson, R. N.; Rapoport, H.
J . Org. Chem. 1979, 44, 4536-4543.
(18) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367-
2371.
(19) Compagnone, R. S.; Rapoport, H. J . Org. Chem. 1986, 51, 1713-
1719.
(20) Andersen, K. K.; Bray, D. D.; Chumpradit, S.; Clark, M. E.;
Habgood, G. J .; Hubbard. C. D.; Young K. M. J . Org. Chem. 1991, 56,
6508-6516.
(21) Okabe, K.; Natsume, M. Tetrahedron 1991, 47, 7615-7624.
(22) Gold, E. H.; Babad, E. J . Org. Chem. 1972, 37, 2208-2210.
(23) Heathcock, C. H.; Smith, K. M.; Blumenkofpf, T. A. J . Am.
Chem. Soc. 1986, 108, 5022-5024.
(24) Schultz, A. G.; McCloskey, P. J .; Court, J . J . J . Am. Chem. Soc.
1987, 109, 6493-6502.
We were delighted to find that the reaction of TsNdCCl2
with 8a and with 8b led to the formation of 9-tosylamino
(25) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron
Lett. 1985, 26, 657-660.
(11) (a) Vorbru¨ggen, H.; Krolikiewicz, K.; Niedballa, U. Liebigs Ann.
Chem. 1975, 988-1002. (b) Vorbru¨ggen, H.; Krolikiewicz, K. Liebigs
Ann. Chem. 1976, 745-761.
(26) Hamada, T.; Nishida, A.; Yonemitsu, O. J . Am. Chem. Soc.
1986, 108, 140-145.
(27) AÄ lvarez, M.; Ferna´ndez, D.; J oule, J . A. Synthesis 1999, 615-
(12) Girgis, M. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B. J .
Heterocycl. Chem. 1989, 26, 317-325.
620.
(28) AÄ lvarez, M.; Ferna´ndez, D.; J oule, J . A. J . Chem. Soc., Perkin
Trans. 1 2002, 471-475.
(29) Protection of the 9-amino group was important because the
iodination of 12a gave an unidentified iodinated product that decom-
posed during attempted purification, presumably the result of iodine
attack at the primary amine.
(13) Ku¨hle, E.; Anders, B.; Zumach, G. Angew. Chem., Int. Ed. Engl.
1967, 6, 649-722.
(14) Merchan, F. L.; Garin, J .; Tejero, T. Synthesis 1982, 984-986.
Potts, K. T.; Kuehnling, W. R.; Murphy, P. J . Org. Chem. 1984, 49,
2404-2407.
10022 J . Org. Chem., Vol. 68, No. 26, 2003

Syntheses of Variolin B and Deoxyvariolin B
SCHEME 2. P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g Rea ction s for th e In tr od u ction of D Rin g
temperature of dioxane, gave a mixture of the anticipated
acetamide 20a and its corresponding amine 20b.31 For
convenience, the product mixture was not routinely
separated but converted completely into the amine with
dry HCl in methanol, yielding 20b in a 45% yield for the
two steps. The introduction of the new pyrimidine ring
N-tosyl variolin B 28 in a 60% yield. Application of the
photochemical N-detosylation procedure used for deoxy-
variolin, but with H2NNH2‚H2O as a reducing agent
instead of NaBH4, then gave variolin B 2 in a 30% yield.
The synthetic product had identical spectroscopic data
with those described for the natural alkaloid and showed
identical TLC and HPLC behavior as a sample of the
natural product supplied by Pharma Mar.
In conclusion, we have developed a novel synthetic
route from an azaindole for the preparation of deoxy-
variolin B via a pyrimidone functionalized C ring and for
variolin B via a protected aminopyrimidine. This ap-
proach is flexible for the preparation of analogues dif-
fering in the ring D with use of other aryl or heteroaryl
organometallics for the coupling reaction with the iodo
compounds 18 or 26. Using pyridine-ring-substituted
7-azaindoles as starting materials will provide opportuni-
ties for further diversity, producing variants with sub-
stituents in the A ring.
1
was proved by the H NMR spectrum in which there was
a new AB system at δ 7.33 and 8.48 ppm with a coupling
constant of 5.4, and also by the three-hydrogen singlet
at δ 2.68 ppm of the methylthio substituent.
For the transformation of 20b into deoxyvariolin B
there only remained the substitution of the methylthio
group with an amino group. For that purpose 20b was
S-oxidized with m-chloroperbenzoic acid (m-CPBA) to
sulfone 22. The sulfoxide 21 could be obtained in a 90%
yield by treatment of 20b with 1.8 equiv of m-CPBA at 0
°C during 30 min in CH2Cl2. Oxidation of 21 to 22 also
proceeded in good yield with m-CPBA. The substitution
of the methanesulfonyl group of 22 was effected with
ammonium hydroxide in dioxane at reflux, giving deoxy-
variolin B 23 in excellent yield.
Exp er im en ta l Section
2-(1-Hyd r oxy-2-p h th a lim id oeth yl)-7-a za in d ole (6a ). To
a cooled (-78 °C) solution of 7-azaindole 5a (7.6 g, 64 mmol)
in dry THF (150 mL) was added n-BuLi (44 mL, 1.6 M in
hexane) and the mixture was stirred for 10 min. Dry CO2 was
bubbled through the mixture for 40 min. The solvent was
evaporated and the residue was dissolved in fresh dry THF
(400 mL). The solution was cooled at -78 °C and t-BuLi (42
mL, 1.7 M in hexane) was added. The mixture was stirred for
20 min then a solution of 2-phthalimidoacetaldehyde (14 g,
71 mmol) in THF (400 mL) was added slowly. After 1.5 h the
reaction was quenched with saturated aq NH4Cl (100 mL) and
the organic solvent evaporated. The mixture was dissolved in
CH2Cl2 and washed with water, then the organic solution was
dried and evaporated. The crude product was purified by flash
column chromatography, where elution with CH2Cl2/acetone
(95/5) gave 7-azaindole 5a (3.8 g, 50%) and with CH2Cl2/MeOH
(98/2) afforded 6a (8.7 g, 44%) as a white solid. Mp 231-232
°C (CH2Cl2/MeOH). IR (KBr) ν 3200 (m, NH),1760 (s, CdO),
1704 (s, NCO), 1427 (m, C-N), 1395 (m, C-O). 1H NMR
(DMSO-d6, 200 MHz) δ 3.88 (dd, J ) 13.6 and 6.0 Hz, 1H,
H2′), 4.00 (dd, J ) 13.6 and 7.8 Hz, 1H, H2′), 5.06 (ddd, J )
7.8, 6.0, and 5.2 Hz, 1H, H1′), 5.83 (d, J ) 5.2 Hz, 1H, OH),
6.34 (d, J ) 1.8 Hz, 1H, H3), 6.99 (dd, J ) 8.0 and 4.8 Hz, 1H,
H5), 7.81-7.88 (m, 4H, Phth), 7.89 (dd, J ) 8.0 and 1.4 Hz,
1H, H4), 8.14 (dd, J ) 4.8 and 1.4 Hz, 1H, H6), 11.75 (br s,
1H, NH). 13C NMR (DMSO d6, 75 MHz) δ 43.6 (t, C2′), 64.4
(d, C1′), 96.8 (d, C3), 115.4 (d, C5), 119.8 (s, C3a), 123.0 (d,
Phth-â), 127.6 (d, C4), 131.6 (s, Phth-ipso), 134.3 (d, Phth-R),
140.8 (s, C2), 142.1 (d, C6), 148.6 (s, C7a), 167.7 (s, Phth-CO).
MS (EI) m/z 308 (6), 307 (M+, 25), 244 (8), 160 (43), 147 (100),
Finally, in the methoxy series, 18b was prepared from
12b in the same way, and with similar yields as those
found for the deoxy compounds. To make a more conver-
gent synthesis, by removing the necessity for the MeS
f NH2 interconversion, the tin derivative 24 was pre-
pared from 4-chloro-2-aminopyrimidine32 by N-protection
then halogen metal interchange by reaction with hex-
amethylditin catalyzed by Pd(PPh3)4.
The coupling reaction in the same conditions as before
between the iodo derivative 18a and the tin derivative
24 followed by treatment with aq HCl gave deoxyvariolin
B 23 in a 54% yield for the two steps. Using for the
coupling reaction the iodo compound 18b and the tin
derivative 24 gave only a 40% yield of the expected fully
protected variolin B, 25; however, using the tosyl deriva-
tive 26b and the organometallic 24 afforded 27, a fully
protected variolin B, in a satisfying 75% yield. Simulta-
neous deprotection of the methoxy and 3′N-acetyl groups
was achieved by treatment of 27 with an aqueous solution
of hydrobromic acid at reflux for 10 min to give the
(30) Majeed, A. J .; Antonsen, Φ.; Benneche, T.; Undheim, K.
Tetrahedron 1989, 45, 993-1006. The preparation of 19 was improveds
see Experimental Section.
(31) Acetamide 20a and amine 20b could be separated by column
chromatography. See Experimental Section.
(32) Sawayama, T.; Yamamoto, R.; Kinugasa, H.; Nishimura, H.
Heterocycles 1977, 8, 299-305.
J . Org. Chem, Vol. 68, No. 26, 2003 10023

Ahaidar et al.
119 (52). Anal. Calcd for C17H13N3O3: C (66.44), H (4.26), N
(13.67). Found: C (65.11), H (4.26), N (13.37).
was refluxed for 7 h. After cooling the mixture was washed
with saturated aq NaHCO3, dried, and evaporated and the
residue was purified by flash column chromatography, elution
with CH2Cl2/MeOH (97/3) giving 7a (10.8 g, 87%), a diaster-
eomeric mixture (NMR, 1:1), as a white solid. IR (film) ν 1717
(s, CdO), 1390 (m, C-O), 1026 (m, C-O). 1H NMR (CDCl3,
200 MHz) δ 1.30-1.80 (m, 6H, H3′′, H4′′, and H5′′), 3.25-3.45
(m, 2H, H2′), 3.80, 3.98, 4.22 and 4.38 (m, dd, J ) 14.0 and
4.4 Hz, dd, J ) 14.8 and 2.0 Hz, and dd, J ) 14.0 and 9.4 Hz,
2H, H6′′), 4.58 and 4.72 (dd, J ) 3.2 and 2.8 Hz, and dd, J )
3.4 and 3.0 Hz, 1H, H2′′), 5.30 and 5.39 (dd, J ) 8.4 and 5.2
Hz, and dd, J ) 9.2 and 4.0 Hz, 1H, H1′), 6.47 and 6.51 (d, J
) 1.8 Hz, and d, J ) 1.8 Hz, 1H, H3), 7.08 and 7.15 (dd, J )
8.2 and 4.8 Hz, and dd, J ) 8.2 and 5.2 Hz, 1H, H5), 7.69 (m,
2H, Phth-â), 7.86 (m, 2H, Phth-R), 7.86 (m, 1H, H4), 8.43 and
8.63 (dd, J ) 4.8 and 1.6 Hz, and dd, J ) 5.0 and 1.7 Hz, 1H,
H7), 10.8 and 12.5 (br s, 1H, NH). 13C NMR (CDCl3, 50 MHz)
δ 18.8 and 19.9 (t), 25.0 and 25.2 (t), 30.2 and 30.8 (t), 41.6
and 42.8 (t, C6′′), 61.8 and 63.6 (t, C2′), 69.3 and 71.7 (d, C1′),
95.5 and 97.9 (d, C2′′), 100.3 and 100.8 (d, C3), 115.9 (d, C5),
120.6 and 120.7 (s, C3a), 123.2 and 123.4 (d, Phth-â), 128.7
and 128.8 (d, C4), 131.8 and 132.0 (s, Phth-ipso), 133.9 and
134.0 (d, Phth-R), 136.5 and 137.8 (s, C2), 143.1 (d, C6), 148.7
and 149.2 (s, C7a), 168.1 (s, Phth-CO). MS (EI) m/z 391 (M+,1),
307 (9), 147 (38), 85 (100). Anal. Calcd for C22H21N3O4‚1/2H2O:
C (65.99), H (5.54), N (10.49). Found: C (66.02), H (5.80), N
(10.28).
2-(1-Hyd r oxy-2-p h th a lim id oeth yl)-4-m eth oxy-7-a za in -
d ole (6b). To a cooled (-78 °C) solution of 4-methoxy-7-
azaindole 5b12 (3.55 g, 24 mmol) in THF (75 mL) was added
n-BuLi (16.5 mL, 1.6 M in hexane) and the mixture was stirred
for 10 min. Dry CO2 was bubbled through the mixture for 40
min. The solvent was evaporated and the residue was dissolved
in fresh dry THF (175 mL). The solution was cooled at -78 °C
and t-BuLi (15.5 mL, 1.7 M in hexane) was added. The mixture
was stirred for 20 min. A solution of 2-phthalimidoacetalde-
hyde (5 g, 26 mmol) in THF (100 mL) was added slowly. After
1.5 h the reaction was quenched with saturated aq NH4Cl (50
mL) and the organic solvent evaporated. The residue was
dissolved in CH2Cl2 and washed with water, then the solution
was dried and evaporated to leave material that was purified
by flash column chromatography. Elution with CH2Cl2/acetone
(95/5) gave 5b (2.06 g, 58%) and with CH2Cl2/MeOH (98/2) gave
6b (3.68 g, 43%) as a white solid. Mp 225-226 °C (from CH2-
Cl2/MeOH). IR (KBr) ν 3500 (s, NH/OH), 1702 (s, CdO), 1594
(m), 1395 (m). 1H NMR (DMSO-d6, 300 MHz) δ 3.88 (s, 3H,
Me), 3.86 (dd, J ) 13.8 and 6.0 Hz, 1H, H2′), 3.95 (dd, J )
13.8 and 7.8 Hz, 1H, H2′), 5.00 (ddd, J ) 7.8, 6.0, and 5.1 Hz,
1H, H1′), 5.73 (d, J ) 5.1 Hz, 1H, OH), 6.30 (d, J ) 1.8 Hz,
1H, H3), 6.58 (d, J ) 5.4 Hz, 1H, H5), 7.83 (m, 4H, Phth),
8.02 (d, J ) 5.4 Hz, 1H, H6), 11.65 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75 MHz) δ 43.6 (t, C2′), 55.3 (q, Me), 64.2 (d, C1′),
94.0 (d, C5), 97.8 (d, C3), 109.5 (s, C3a), 123.0 (d, Phth-â), 131.6
(s, Phth-ipso), 134.3 (d, Phth-R), 138.1 (s, C2), 144.2 (d, C6),
150.3 (s, C7a), 158.5 (s, C4), 167.7 (s, Phth-CO). MS (EI) m/z
338 (4), 337 (M+, 20), 319 (44), 177 (100). Anal. Calcd for
4-Meth oxy-2-[2-ph th alim ido-1-(2,3,5,6-tetr ah ydr opyr an -
2-yl)oxyeth yl]-7-a za in d ole (7b). Following the same proce-
dure as for 7a , from 6b (3.8 g, 11 mmol) in CHCl3 (350 mL), 6
N HCl in benzene (35 mL) and 2,3-dihydropyran (10 mL, 110
mmol), 7b (3.07 g, 65%) was obtained as a diastereomeric
mixture (NMR, 1:1). IR (film) ν 1714 (s, CdO), 1392 (m, C-O),
C
18H15N3O4‚1/4H2O: C (63.25), H (4.57), N (12.29). Found: C
(63.32), H (4.54), N (12.07).
1
2-(2-Am in o-1-h yd r oxyeth yl)-7-a za in d ole. To a solution
of 6a (250 mg, 0.80 mmol) in EtOH (25 mL) was added NH2-
NH2‚H2O (40 µL, 0.80 mmol). The solution was refluxed for
2.5 h then the solvent was removed under vacuum. The residue
was dissolved in 2 N NaOH (10 mL) and the solution
continuously extracted with CH2Cl2 to give the title compound
(140 mg, 100%) as a white solid. IR (film) ν 3200 (s, NH/OH),
1593 (m, CdN), 1422 (m, C-N), 1286 (m, C-O). 1H NMR
(CDCl3, 200 MHz) δ 2.91 (br s, 2H, CH2), 4.74 (br s, 1H, CH),
6.15 (s, 1H, H3), 6.90 (dd, J ) 8.0 and 4.8 Hz, 1H, H5), 7.72
(dd, J ) 8.0 and 1.4 Hz, 1H, H4), 8.05 (dd, J ) 4.8 and 1.4 Hz,
1H, H6). 13C NMR (CDCl3, 50 MHz) δ 47.1 (t, CH2), 68.9 (d,
CH), 96.8 (d, C3), 115.6 (d, C5), 121.1 (s, C4a), 128.8 (d, C4),
140.9 (s, C2), 141.6 (d, C6), 147.8 (s, C7a). MS (EI) m/z 177
(M+, 1), 148 (100), 119 (67).
2-[2-Oxo-1,3-oxa zolid in -5-yl]-7-a za in d ole. A solution of
triphosgene (32 mg, 0.10 mmol) in CH2Cl2 (2 mL) was added
at room temperature to a solution of 2-(2-amino-1-hydroxy-
ethyl)-7-azaindole (50 mg, 0.27 mmol) and DIPEA (107 µL, 0.60
mmol) in CH2Cl2 (5 mL). After being stirred for 1 h the mixture
was quenched with saturated aq NH4Cl (10 mL), the organic
layer was separated, and the aqueous layer was extracted
three times with CH2Cl2. The combined and dried organic
solutions were evaporated and the residue was purified by
flash column chromatography, elution with CH2Cl2/MeOH (98/
2) giving the title compound (13 mg, 25%) and elution with
CH2Cl2/MeOH (9/1) giving 10a (11 mg, 20%). Spectroscopic
data for 2-[2-oxo-1,3-oxazolidin-5-yl]-7-azaindole: IR (film) ν
3244 (m, NH), 1740 (s, CdO), 1298 (m, C-O). 1H NMR (CDCl3,
200 MHz) δ 3.97 (dd, J ) 10.5 and 4.8 Hz, 1H, H4′), 4.48 (dd,
J ) 10.5 and 8.7 Hz, 1H, H4′), 6.18 (dd, J ) 8.7 and 4.8 Hz,
1H, H5′), 6.80 (s, 1H, H3), 7.25 (dd, J ) 7.8 and 4.5 Hz, 1H,
H3), 7.88 (dd, J ) 7.8 and 1.5 Hz, 1H, H4), 8.48 (dd, J ) 4.5
and 1.5 Hz, 1H, H4), 11.80 (br s, 1H, NH). MS (EI) m/z 203
(M+, 4), 180 (100).
1026 (m, C-O). H NMR (CDCl3, 300 MHz) δ 1.30-1.80 (m,
6H, H3′′, H4′′, and H5′′), 3.25-3.45 (m, 2H, H2′), 3.99 and 4.01
(s, 3H, OMe), 3.96, 4.08, 4.28 and 4.39 (dd, J ) 13.5 and 3.9
Hz, dd, J ) 13.8 and 4.6 Hz, dd, J ) 13.8 and 8.5 Hz, and dd,
J ) 13.5 and 9.6 Hz, 2H, H6′′), 4.57 and 4.73 (br t, J ) 3.2 Hz,
and br t, J ) 3.4 Hz, 1H, H2′′), 5.25 and 5.33 (dd, J ) 6.9 and
2.4 Hz, and dd, J ) 9.9 and 4.1 Hz, 1H, H1′), 6.54 and 6.58
(br s and br s, 1H, H3), 6.56 and 6.62 (d, J ) 5.7 Hz, and d, J
) 5.7 Hz, 1H, H5), 7.68 (m, 2H, Phth-â), 7.83 (m, 2H, Phth-
R), 8.38 and 8.57 (d, J ) 5.7 Hz, and d, J ) 5.7 Hz, 1H, H7),
11.7 (br s, 1H, NH). 13C NMR (CDCl3, 50 MHz) δ 18.9 and
19.5 (t), 25.0 and 25.3 (t), 30.2 and 30.7 (t), 42.0 and 43.0 (t,
C6′′), 55.4 (q, MeO), 61.7 and 62.9 (t, C2′), 69.4 and 71.5 (d,
C1′), 94.4 and 95.3 (d, C2′′), 97.7 (d, C5), 97.8 and 100.1 (d,
C3), 110.5 (s, C3a), 123.1 and 123.2 (d, Phth-â), 132.1 and 132.1
(s, Phth-ipso), 133.8 and 133.9 (d, Phth-R), 134.0 and 135.2
(s, C2), 144.9 and 145.1 (d, C6), 150.6 and 151.1 (s, C7a), 159.8
(s, C4), 168.1 (s, Phth-CO). MS (EI) m/z 422 (2), 421 (M+, 4),
337 (15), 177 (100). M calculated for C23H23N3O5 421.1637;
HRMS found (M+) 421.1625.
2-[2-Am in o-1-(2,3,5,6-tetr a h yd r op yr a n -2-yl)oxyeth yl]-
7-a za in d ole (8a ). To a solution of 7a (10.2 g, 26 mmol) in
EtOH (630 mL) was added NH2NH2‚H2O (1.53 mL, 31 mmol).
The mixture was refluxed for 3 h, then the solvent was
evaporated and the residue dissolved in CH2Cl2 and washed
with saturated aq NaHCO3. The aqueous layer was extracted
three times with CH2Cl2 and the combined organic solutions
were evaporated to obtain 8a (6.72 g, 100%), a light orange
solid, as a diastereomeric mixture (NMR, 1:1). IR (film) ν 3200
(m, NH), 1421 (m, C-N), 1022 (m, C-O). 1H NMR (CDCl3,
200 MHz) δ 1.40-1.90 (m, 6H, H3′′, H4′′, and H5′′), 3.20 (m,
2H, H2′), 3.48 and 3.90 (m, 1H, H6′′), 4.60 and 4.85 (br t, J )
3.5 Hz, and m, 1H, H2′′), 4.85 and 4.97 (m and br t, J ) 5.7
Hz, 1H, H1′), 6.32 and 6.43 (s, 1H, H3), 7.03 and 7.07 (dd, J )
6.6 and 4.8 Hz, and dd, J ) 6.6 and 5.0 Hz, 1H, H5), 7.85 and
7.90 (dd, J ) 6.6 and 1.4 Hz, 1H, H4), 8.29 and 8.36 (dd, J )
4.8 and 1.4 Hz, and dd, J ) 5.0 and 1.4 Hz, 1H, H7), 10.9 and
12.5 (br s, NH). 13C NMR (CDCl3, 75 MHz) δ 19.7 and 20.0 (t),
25.1 and 25.3 (t), 30.6 and 30.9 (t), 45.3 and 47.3 (t, C6′′), 62.9
2-[2-P h th a lim id o-1-(2,3,5,6-tetr a h yd r op yr a n -2-yl)oxy-
eth yl]-7-a za in d ole (7a ). To a solution of 6a (10.2 g, 33 mmol)
in CHCl3 (1 L) were added 6 N HCl in dry benzene (180 mL)
and then 2,3-dihydropyran (46 mL, 330 mmol). The mixture
10024 J . Org. Chem., Vol. 68, No. 26, 2003

Syntheses of Variolin B and Deoxyvariolin B
and 63.5 (t, C2′), 73.4 and 75.5 (d, C1′), 96.1 and 97.3 (d, C2′′),
99.8 and 99.9 (d, C3), 115.6 (d, C5), 120.7 (s, C3a), 128.4 and
128.5 (d, C4), 138.3 and 139.0 (s, C2), 142.2 and 142.3 (d, C6),
148.5 and 149.0 (s, C7a). MS (CI, CH4) m/z 263 (15), 262 (M+,
100). M + H calculated for C14H19N3O2 + H 262.1555; HRMS
found (M + H)+ 262.1557.
and C5), 130.9 (s, C5a), 147.3 and 147.7 (d, C2), 149.9 and
150.3 (s, C10a or C4), 159.7 (s, C9). MS (EI) m/z 318 (2), 317
(M+, 28), 233 (22), 217 (66), 216 (65), 177 (100), 85 (100). M
calculated for
317.1383.
C
16H19N3O4 317.1376; HRMS found (M+)
6,7,8,9-Tet r a h yd r o-6-h yd r oxyp yr id o[3′,2′:4,5]p yr r olo-
[1,2-c]p yr im id in -9-on e (10a ). To a solution of 9a (6 g, 21
mmol) in CH2Cl2 (400 mL) was added 4 N aq HCl (400 mL).
After 45 min of stirring at room temperature the two layers
were separated and the organic layer re-extracted with 4 N
aq HCl. The combined aqueous solutions were filtered and
evaporated to obtain 10a hydrochloride (5 g, 100%) as a light
orange solid. IR (KBr) ν 3500 (s, OH), 1721 (s, CdO), 1638
(m, CdC), 1503 (m, CdN). 1H NMR (CD3OD, 300 MHz) δ 3.61
(dd, J ) 13.0 and 5.0 Hz, 1H, H7), 3.77 (dd, J ) 13.0 and 4.0
Hz, 1H, H7), 5.23 (dd, J ) 5.0 and 4.0 Hz, 1H, H6), 7.05 (s,
1H, H5), 7.86 (dd, J ) 8.0 and 6.0 Hz, 1H, H3), 8.56 (dd, J )
6.0 and 1.2 Hz, 1H, H2), 8.86 (dd, J ) 8.0 and 1.2 Hz, 1H,
H4). 13C NMR (CD3OD, 75 MHz) δ 45.8 (t, C7), 59.6 (d, C6),
101.9 (d, C5), 119.0 (d, C3), 127.1 (s, C4a), 124.3 (d, C4), 137.4
(s, C5a), 139.4 (d, C2), 141.9 (s, C10a), 149.0 (s, C9). MS (CI,
NH3) m/z 205 (3), 204 (M+, 4), 180 (100), 163 (50), 130 (90). M
2-[2-Am in o-1-(2,3,5,6-tetr a h yd r op yr a n -2-yl)oxyeth yl]-
4-m eth oxy-7-a za in d ole (8b). Following the same procedure
as for 8a , from 7b (2.9 g, 10 mmol) in EtOH (100 mL) and
NH2NH2‚H2O (420 µL, 15 mmol), after a reaction time of 3 h,
8b (1.9 g, 95%) orange foam was obtained as a diastereomeric
mixture (NMR, 1:1). IR (film) ν 3150 (m, NH), 1590 (m, Cd
C), 1329 (m, C-N), 1114 (m, C-O). 1H NMR (CDCl3, 200 MHz)
δ 1.40-1.90 (m, 6H, H3′′-H5′′), 3.19 (m, 2H, H2′), 3.48 and
3.90 (m, 1H, H6′′), 3.99 and 4.00 (s, 3H, MeO), 4.60 and 4.85
(m, 1H, H2′′), 4.85 and 4.97 (m and br t, J ) 5.7 Hz, 1H, H1′),
6.42 and 6.51 (s, 1H, H3), 6.51 and 6.55 (d, J ) 5.4 Hz, 1H,
H5), 8.23 and 8.30 (d, J ) 5.4 Hz, 1H, H7). 13C NMR (CDCl3,
75 MHz) δ 20.0 (t), 25.2 and 25.4 (t), 30.7 and 30.9 (t), 45.4
and 47.4 (t, C6′′), 55.4 and 55.5 (q, MeO), 62.9 and 63.4 (t,
C2′), 73.5 and 75.5 (d, C1′), 94.7 and 96.1 (d), 97.1 and 99.6
(d, C3), 97.6 (d, C5), 110.5 (s, C3a), 135.8 and 136.5 (s, C2),
144.3 and 144.4 (d, C6), 150.3 and 151.3 (s), 159.4 and 159.5
(s). MS (CI, CH4) m/z 291 (M+, 2), 262 (12), 190 (8), 177 (100).
M calculated for C15H21N3O3 291.1582; HRMS found M+
291.1571.
6,7,8,9-Tetr a h yd r o-6-(2,3,5,6-tetr a h yd r op yr a n -2-yl)oxy-
p yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in -9-on e (9a ). A so-
lution of 8a (7.4 g, 28 mmol) and DIPEA (5 mL, 28 mmol) in
CH2Cl2 (300 mL) was slowly added to a solution of triphosgene
(2.82 g, 10 mmol) in CH2Cl2 (740 mL), and the mixture was
stirred at room temperature for 30 min. The mixture was
washed with saturated aq NH4Cl and then with water, dried,
and evaporated to give 9a (6.06 g, 76%), a yellow foam, as a
diastereomeric mixture (NMR, 1:1). IR (KBr) ν 3252 (m, NH),
1716 (s, CdO), 1407 (m, C-N), 1302 (m, C-O). 1H NMR
(CDCl3, 200 MHz) δ 1.40-1.80 (m, 6H, H3′, H4′, and H5′),
3.45-4.00 (m, 2H, H7 and H6′), 3.90 (m, 2H, H7 and H6′),
4.71 and 4.94 (m, 1H, H2′), 5.04 and 5.10 (dd, J ) 3.2 and 3.0
Hz, and t, J ) 4.4 Hz, 1H, H6), 6.56 and 6.59 (s, 1H, H5), 6.79
and 7.00 (br s, 1H, NH), 7.20 and 7.22 (dd, J ) 7.6 and 4.8
Hz, and dd, J ) 8.0 and 4.8 Hz, 1H, H3), 7.89 and 7.93 (dd, J
) 7.6 and 1.8 Hz, and dd, J ) 8.0 and 1.8 Hz, 1H, H4), 8.54
and 8.57 (dd, J ) 4.8 and 1.8 Hz, and dd, J ) 4.8 and 1.4 Hz,
1H, H2). 13C NMR (CDCl3, 50 MHz) δ 18.9 and 19.3 (t, C4′),
25.3 and 25.4 (t, C5′), 30.1 and 30.4 (t, C3′), 43.5 and 45.3 (t,
C6′), 62.2 and 62.6 (t, C7), 63.2 and 64.3 (d, C6), 95.7 and 96.7
(d, C2′), 102.3 and 103.7 (d, C5), 118.6 (d, C3), 121.3 and 121.7
(s, C4a), 129.1 and 129.2 (d, C4), 133.5 and 136.1 (s, C5a), 145.2
and 145.6 (d, C2), 148.0 and 148.1 (s, C10a), 149.8 and 150.2
(s, C9). MS (CI, CH4) m/z 289 (6), 288 (M+, 25), 204 (23), 85
(100). M + H calculated for C15H17N3O3 + H 288.1348; HRMS
found (M + H)+ 288.1352.
calculated for
204.0772.
C
10H10N3O3 204.0773; HRMS found (M+)
A solution of 10a hydrochloride in saturated aq Na2CO3 was
continuously extracted with CH2Cl2 to give the free base. IR
(KBr) ν 3400 (m, NH/OH), 1707 (s, CdO), 1468 (m, C-N), 1408
(m, C-N), 1297 (m, C-O). 1H NMR (DMSO-d6, 300 MHz) δ
3.27 (m, 1H, H7), 3.42 (m, 1H, H7), 4.90 (dd, J ) 9.3 and 5.1
Hz, 1H, H6), 5.88 (d, J ) 5.1 Hz, 1H, OH), 6.54 (s, 1H, H5),
7.21 (dd, J ) 7.4 and 4.2 Hz, 1H, H3), 7.88 (br s, 1H, NH),
7.99 (br d, J ) 7.4 Hz, 1H, H2), 8.30 (br d, J ) 4.2 Hz, 1H,
H4). 13C NMR (DMSO-d6, 75 MHz) δ 41.0 (t, C7), 55.7 (d, C6),
95.4 (d, C5), 113.8 (d, C3), 116.7 (s, C4a), 124.2 (d, C4), 135.4
(s, C5a), 139.3 (d, C2), 142.9 (s, C10a), 143.8 (s, C9).
6,7,8,9-Tet r a h yd r o-6-h yd r oxy-4-m et h oxyp yr id o[3′,2′:
4,5]p yr r olo[1,2-c]p yr im id in -9-on e (10b). To a solution of
9b (25 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 4 N aq
HCl (5 mL) and the mixture was stirred at room temperature
for 45 min. The organic layer was separated and re-extracted
with 4 N aq HCl. The combined aqueous solutions were filtered
and evaporated to obtain 10b hydrochloride (20 mg, 95%) as
a light orange solid. IR (film) ν 3244 (m, NH), 1718 (s, CdO),
1627 (s, NCO), 1505 (m, CdN), 1298 (m, C-O). 1H NMR (CD3-
OD, 200 MHz) δ 3.56 (dd, J ) 13.6 and 4.8 Hz, 1H, H7), 3.71
(dd, J ) 13.6 and 3.6 Hz, 1H, H7), 4.29 (s, 3H, MeO), 5.11 (dd,
J ) 4.8 and 3.6 Hz, 1H, H6), 6.91 (s, 1H, H5), 7.40 (d, J ) 6.9
Hz, 1H, H3), 8.42 (d, J ) 6.9 Hz, 1H, H2). 13C NMR (CD3OD,
75 MHz) δ 48.9 (t, C7), 60.5 (q, Me), 62.3 (d, C6), 101.7 (d,
C5), 105.5 (d, C3), 117.4 (s, C4a), 137.0 (s, C5a), 140.6 (d, C2),
141.4 (s, C10a), 151.9 (s, C9), 169.0 (s, C4). MS (EI) m/z 234
(12), 233 (M+, 77), 215 (17), 55 (100). M calculated for
C
11H11N3O3 233.0800; HRMS found (M+) 233.0813.
6,7,8,9-Tet r a h yd r o-6-(2,3,5,6-t et r a h yd r op yr a n -2-yl)-
oxy-4-m e t h oxy-p yr id o[3′,2′:4,5]-p yr r olo[1,2-c]p yr im i-
d in -9-on e (9b). Following the same procedure as for 9a , 9b
was obtained from triphosgene (20 mg, 0.07 mmol) in CH2Cl2
(3 mL), 8b (58 mg, 0.20 mmol), and DIPEA (34 µL, 0.20 mmol)
in CH2Cl2 (3 mL), with a reaction time of 30 min at room
temperature. The crude product was purified by flash column
chromatography, elution with CH2Cl2/MeOH (98/2) giving 9b
yellow foam (40 mg, 63%) as a diastereomeric mixture (NMR,
1:1). IR (KBr) ν 3258 (m, NH), 1714 (s, CdO), 1566 (m, CdN),
8,9-Dih yd r op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in -9-
on e (11a ). To a cooled solution of 10a (1 g, 4.2 mmol) and
TEA (1.74 mL, 13 mmol) in CH2Cl2 (200 mL) at 0 °C was added
MsCl (320 µL, 4.2 mmol) dropwise. The reaction mixture was
stirred for 30 min at 0 °C then the organic solution was washed
with saturated aq NH4Cl and with water. The organic solution
was dried and evaporated to obtain 11a (730 mg, 95%) as a
white solid pure enough to use without further purification;
mp 265-266 °C (from MeOH). IR (KBr) ν 3424 (m, NH), 1721
(s, CdO), 1691 (m, NCO), 1633 (m, CdC), 1408 (m, CdN), 1380
(m), 1303 (m). 1H NMR (DMSO-d6, 300 MHz) δ 6.50 (d, J )
7.4 Hz, 1H, H6), 6.60 (s, 1H, H5), 6.97 (dd, J ) 7.4 and 5.3
Hz, 1H, H7), 7.37 (dd, J ) 8.0 and 4.7 Hz, 1H, H3), 8.08 (dd,
J ) 8.0 and 1.7 Hz, 1H, H4), 8.39 (dd, J ) 4.7 and 1.7 Hz, 1H,
H2), 10.81 (br d, J ) 5.3 Hz, 1H, NH). 13C NMR (DMSO-d6,
75 MHz) δ 94.9 (d, C5), 98.0 (d, C6), 119.8 (d, C3), 123.1 (s,
C4a), 127.5 (d, C4), 128.0 (d, C7), 137.0 (s, C5a), 142.5 (d, C2),
145.6 (s, C10a), 146.7 (s, C9). MS (EI) m/z 186 (18), 185 (M+,
15), 157 (M - CO, 10). MS (CI, NH3) m/z 204 (M + 18, 12),
1
1290 (m, C-O). H NMR (CDCl3, 200 MHz) δ 1.40-1.80 (m,
6H, H3′, H4′, and H5′), 3.45 and 3.95 (m, 2H, H6′), 3.65 and
3.75 (m, 2H, H7), 4.00 (s, 3H, MeO), 4.67 and 4.94 (m, 1H,
H2′), 4.99 and 5.07 (m, 1H, H6), 6.20 and 6.30 (br s, 1H, NH),
6.65 and 6.66 (s, 1H, H5), 6.69 (d, J ) 5.9 Hz, 1H, H3), 8.44
and 8.46 (d, J ) 5.9 Hz, 1H, H2). 13C NMR (CDCl3, 50 MHz)
δ 18.7 and 19.4 (t, C4′), 25.3 and 25.4 (t, C5′), 30.1 and 30.3 (t,
C3′), 43.5 and 45.3 (t, C6′), 61.9 and 62.6 (t, C7), 62.9 and 63.9
(d, C6), 95.5 and 96.2 (d, C2′), 99.6, 100.6 and 101.1 (d, C3
J . Org. Chem, Vol. 68, No. 26, 2003 10025

Ahaidar et al.
187 (14), 186 (M + 1, 100), 109 (48). M calculated for C10H7N3O
200 MHz) δ 3.47 (s, 6H, 2 × OMe), 3.68 (t, J ) 5.7 Hz, 2H,
CH2), 4.61 (t, J ) 5.7 Hz, 1H, CH), 6.53 (d, J ) 4.2 Hz, 1H,
H3), 7.19 (dd, J ) 8.2 and 5.2 Hz, 1H, H5), 7.94 (dd, J ) 8.2
and 1.4 Hz, 1H, H4), 7.99 (d, J ) 4.2 Hz, 1H, H2), 8.31 (dd, J
) 5.2 and 1.4 Hz, 1H, H6), 9.90 (br s, 1H, NH). 13C NMR
(CDCl3, 50 MHz) δ 41.9 (t, CH2), 54.4 (q, OMe), 102.8 (d, CH),
103.0 (d, C3), 117.9 (d, C5), 123.4 (s, C3a), 126.1 (d, C2), 129.8
(d, C4), 142.4 (d, C6), 146.6 (s, C7a), 151.7 (s, CO). MS (EI)
m/z 249 (M+, 1), 234 (1), 218 (3), 174 (4), 118 (46). Anal. Calcd
185.0589; HRMS found (M+) 185.0593.
8,9-Dih yd r o-4-m et h oxyp yr id o[3′,2′:4,5]p yr r olo[1,2-c]-
p yr im id in -9-on e (11b). Following the same procedure as for
11a , from 10b (113 mg, 0.42 mmol), TEA (195 µL, 1.25 mmol),
and MsCl (32 µL, 0.42 mmol) in CH2Cl2 (20 mL) with a reaction
time of 30 min, 11b (74 mg, 85%) was obtained as a white
solid requiring no further purification. IR (KBr) ν 3380 (m,
NH), 1721 (s, CdO), 1693 (m, NCO), 1633 (m, CdC), 1500 (m,
1
for C12H15N3O3: C (57.82), H (6.07), N (16.86). Found:
(57.46), H (6.75), N (16.63).
C
CdN), 1294 (m, C-O). H NMR (DMSO-d6, 500 MHz) δ 3.98
(s, 3H, Me), 6.44 (d, J ) 7.5 Hz, 1H, H6), 6.54 (s, 1H, H5),
6.89 (dd, J ) 7.5 and 2.0 Hz, 1H, H7), 6.96 (d, J ) 5.5 Hz, 1H,
H3), 8.26 (d, J ) 5.5 Hz, 1H, H2). 13C NMR (DMSO-d6, 75
MHz) δ 55.5 (q, Me), 92.6 (d, C5), 98.9 (d, C6), 101.0 (d, C3),
124.7 (d, C7), 114.0 (s, C4a), 134.1 (s, C5a), 144.9 (d, C2), 146.5
(s, C9), 147.7 (s, C10a), 159.1 (s, C4). MS (EI) m/z 216 (17),
215 (M+, 100), 214 (11), 200 (59), 172 (48). M calculated for
6,7-Dih yd r o-6-(2,3,5,6-t e t r a h yd r op yr a n -2-yl)oxy-9-
tosylam in opyr ido[3′,2′:4,5]pyr r olo[1,2-c]pyr im idin e (14a).
A solution of 8a (1.0 g, 3.83 mmol) and DIPEA (2 mL, 11.5
mmol) in CH2Cl2 (50 mL) was added slowly to a solution of
13
TsNdCCl2 (1.15 g, 4.6 mmol) in CH2Cl2 (50 mL). The
resulting mixture was stirred for 90 min and was washed with
H2O. The organic solution was dried and evaporated to give a
crude product that was purified by flash column chromatog-
raphy. Elution with CH2Cl2/MeOH (99/1) gave 14a (1.18 g,
71%) as a pale orange solid. IR (film) ν 3312 (m, NH),1634 (s,
C
11H9N3O2 215.0694; HRMS found (M+) 215.0690.
9-Am in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (12a ).
TMSCl (400 µL, 2.70 mmol) was added to a solution of 11a
(500 mg, 2.70 mmol) in 2,6-lutidine (40 mL) and HMDSA (60
mL) and the mixture was refluxed for 15 h. TMSTf (100 µL,
0.27 mmol) was added and NH3 was bubbled through the
mixture for 15 min at 0 °C. The mixture was enclosed in a
sealed steel reactor and heated at 150 °C for 8 h. (60 psi). The
solvent was evaporated and the crude product purified by flash
column chromatography. Elution with CH2Cl2/MeOH (98/2)
gave 12a (150 mg, 30%) as a light yellow solid. Mp 214-215
°C dec (from CH2Cl2/hexane). IR (KBr) ν 3452 (m, NH), 3304
(m, NH), 1654 (m, CdC), 1618 (m, CdC), 1570 (m, CdN), 1403
1
CdN), 1589 (s, CdN), 1472 (s, SO2), 1134 (s, SO2 ). H NMR
(CDCl3, 300 MHz) δ 1.50-1.85 (m, 6H, H3′, H4′, and H5′), 2.37
(s, 3H, Me), 3.40-3.85 (m, 4H, H6′ and H7), 4.67 and 4.90 (2dd,
J ) 3.9 and 3.3 Hz and 3.0 and 2.4 Hz, 1H, H2′), 5.00-5.07
(m, 1H, H6), 6.59 and 6.61 (2s, 1H, H5), 7.20 (dd, J ) 7.8 and
4.8 Hz, 1H, H3), 7.26 (d, J ) 8.4 Hz, 2H, Ts), 7.85 and 7.84
(2dd, J ) 7.8 and 1.5 Hz, 1H, H4), 8.12 (d, J ) 8.4 Hz, 2H,
Ts), 8.40 (br s, 1H, NH), 8.51 and 8.50 (2dd, J ) 4.8 and 1.5
Hz, 1H, H2). 13C NMR (CDCl3, 75 MHz) δ 18.7, 19.1 (t), 21.5
(q), 25.2, 25.3 (t), 29.9, 30.2 (d), 43.1 and 44.7 (t), 62.2 and
63.7 (t), 62.5 (d), 95.6 and 96.8 (d), 104.0 and 105.5 (d), 119.2
(d), 121.5 (s), 126.4 (d), 129.2 (d), 131.9 (s), 133.7 (s), 140.0 (s),
142.5 (s), 145.5 and 145.8 (d), 148.1 (s). MS (CI) m/z 0.441 (M
+ 1, 2), 440 (M, 1), 339 (M - OTHP, 5), 185 (54), 85 (100). M
+ H calculated for C22H25N4O4S + H 441.1596; HRMS found
(M + H)+ 441.1591.
1
(m, C-N). H NMR (DMSO-d6, 300 MHz) δ 6.49 (s, 1H, H5),
6.72 (d, J ) 6.6 Hz, 1H, H6), 6.80 (br s, 1H, NH), 7.30 (d, J )
6.6 Hz, 1H, H7), 7.42 (dd, J ) 7.8 and 4.6 Hz, 1H, H3), 8.14
(dd, J ) 7.8 and 1.5 Hz, 1H, H4), 8.33 (dd, J ) 4.6 and 1.5 Hz,
1H, H2), 8.60 (br s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ
88.8 (d, C5), 101.0 (d, C6), 119.6 (d, C3), 122.9 (s, C4a), 127.5
(d, C4), 136.8 (s, C5a), 138.9 (d, C2), 139.4 (d, C7), 141.8 (s,
C10a), 148.8 (s, C9). MS (EI) m/z 185(15), 184 (M+, 100), 183
(7). M calculated for C10H8N4 184.0749; HRMS found (M+)
184.0747.
6,7-Dih ydr o-6-(2,3,5,6-tetr ah ydr opyr an -2-yl)oxy-4-m eth -
oxy-9-t osyla m in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im i-
d in e (14b). A solution of 8b (1.0 g, 3.44 mmol) and DIPEA
(1.9 mL, 10.9 mmol) in CH2Cl2 (50 mL) was slowly added to a
solution of TsNdCCl2 (952 mg, 3.78 mmol) in CH2Cl2 (50 mL).
The resulting mixture was stirred for 30 min then washed with
H2O. The organic solution was dried and evaporated to give
material that was purified by flash column chromatography,
eluting with CH2Cl2/MeOH (99/1) giving 14b (1.05 g, 65%) as
a pale orange solid. IR (KBr) ν 3312 (m, NH), 1625 (s, CdN),
1587 (s, SO2), 1293 (s, SO2). 1H NMR (CDCl3, 200 MHz) δ
1.18-1.82 (m, 6H, H3′, H4′, and H5′), 2.38 (s, 3H, CMe), 3.40-
3.60 (m, 2H, H6′), 3.64-3.80 (m, 2H, H-7), 3.97 (s, 3H, OMe),
4.41 and 4.90 (2dd, J ) 3.2 and 3.4 Hz and 2.6 and 1.9 Hz,
1H, H2′), 4.90-5.05 (m, 1H, H6), 6.67 and 6.69 (2s, 1H, H5),
7.26 (d, J ) 8.4 Hz, 2H, Ts), 8.10 (d, J ) 8.4 Hz, 2H, Ts), 8.40
(d, J ) 2.8 Hz, 1H, H3), 8.42 (d, J ) 2.8 Hz, 1H, H2). 13C NMR
(CDCl3, 75 MHz) δ 18.6, 19.3 (t), 21.6 (q), 25.2, 25.3 (t), 30.0,
30.2 (d), 43.3 and 44.9 (t), 55.6 (q), 61.9 and 62.3 (t), 62.7 and
63.5 (d), 95.5 and 96.4 (d), 101.3 and 101.4 (d), 102.9 (d), 111.9
(s), 126.2 (s), 126.4 (d), 129.2 (d), 129.3 (s), 132.2 (s), 142.5 (s),
147.6 and 150.0 (d), 159.7 (s). MS (CI) m/z 471 (M + 1, 3), 369
(M - OTHP, 11), 214 (25), 198 (89). M + H calculated for
9-Am in o-4-m eth oxyp yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr i-
m id in e (12b). Following the same procedure as for 12a , 11b
(60 mg, 0.27 mmol) was reacted with HMDSA (30 mL), 2,6-
lutidine (15 mL), and TMSCl (36 µL, 0.27 mmol) at reflux for
15 h. TMSTf (12 µL, 0.06 mmol) was added and NH3 was
bubbled through the mixture for 15 min at 0 °C then the
mixture heated at 150 °C for 8 h in a sealed steel reactor (60
psi). The solvent was evaporated and the crude material
purified by flash column chromatography, eluting with CH2-
Cl2/MeOH (99/1) giving 12b (13 mg, 22%) and with CH2Cl2/
MeOH (95/5) giving 11b (9 mg, 15%). Data for 12b: 1H NMR
(CDCl3 + CD3OD, 300 MHz) δ 4.01 (s, 3H, OMe), 6.45 (s, 1H,
H5), 6.61 (d, J ) 6.6 Hz, 1H, H6), 6.75 (d, J ) 5.6 Hz, 1H,
H3), 7.14 (d, J ) 6.6 Hz, 1H, H7), 8.18 (d, J ) 5.6 Hz, 1H,
H2). 13C NMR (CDCl3 + CD3OD, 75 MHz) δ 55.6 (q, Me), 87.5
(d, C5), 100.6 (d, C6), 102.2 (d, C3), 114.3 (s, C4a), 134.4 (s,
C5a), 136.0 (d, C2), 141.7 (d, C7), 142.8 (s, C10a), 149.0 (s,
C9), 158.8 (s, C4). MS (EI) m/z 215 (7), 214 (M+, 36), 213 (6),
199 (36), 57 (100). (ES+) m/z 216 (20), 215 (M + 1, 100).
1-[N-(2,2-Dim eth oxyeth yl)ca r ba m oyl]-7-a za in d ole (13).
To a cooled solution of triphosgene (503 mg, 1.7 mmol) in CH2-
Cl2 (5 mL) at 0 °C was added slowly (1 h) 7-azaindole 5a (500
mg, 4.2 mmol) in CH2Cl2 (10 mL). A solution of aminoacetal-
dehyde dimethyl acetal (508 µL, 4.7 mmol) and DIPEA (1.6
mL, 9.3 mmol) in CH2Cl2 (5 mL) was added and the reaction
mixture was stirred for 10 min at room temperature. The
solution was washed twice with a 0.25 M HCl solution, and
twice with a saturated NaHCO3 solution, dried, and evapo-
rated, and the residue was purified by flash column chroma-
tography. Elution with hexane/CH2Cl2 (1/1) gave 13 (483 mg,
46%) as a white solid. IR (film) ν 3200 (m, NH), 1710 (s, CdO),
1556 (m), 1418 (m, C-N), 1271 (m, C-O). 1H NMR (CDCl3,
C
23H27N4O5S + H 471.1702; HRMS found (M + H)+ 471.1699.
6,7-Dih yd r o-6-h yd r oxy-9-t osyla m in op yr id o[3′,2′:4,5]-
p yr r olo[1,2-c]p yr im id in e (15a ). To a solution of 14a (2 g,
4.54 mmol) in CH2Cl2 (50 mL) was added HCl (4 N, 50 mL)
and the mixture was stirred for 90 min. The aqueous solution
was basified with aq Na2CO3 to pH 9 and product extracted
into CH2Cl2. The organic layer was dried and evaporated
yielding 15a (1.32 g, 82%) as a light yellow foam. IR (film) ν
3315 (m, NH), 1624 (s, CdN), 1589 (s, CdN), 1473 (s, SO2),
1135 (s, SO2 ). 1H NMR (CD3OD, 300 MHz) δ 2.35 (s, 3H, Me),
3.42-3.55 (m, 1H, H7), 3.70-3.84 (m, 1H, H7), 5.04 (m, 1H,
H6), 6.55 (s, 1H, H5), 7.01 (dd, J ) 5.2 and 3.2 Hz, H3), 7.24
10026 J . Org. Chem., Vol. 68, No. 26, 2003

Syntheses of Variolin B and Deoxyvariolin B
(d, J ) 8.6 Hz, 2H, Ts), 7.72 (br d, J ) 5.2 Hz, H4), 8.04 (d, J
) 8.6 Hz, 2H, Ts), 8.27 (dd, J ) 3.2 and 1.0 Hz, H2), 8.42 (br
, 1H, NH). 13C NMR (CDCl3, 75 MHz) δ 21.5 (q, Me), 45.8 (t,
C7), 60.4 (d, C6), 103.7 (d, C5), 119.1 (d, C3), 126.5 (d, Ts),
129.2 (d, Ts), 129.4 (d, C4), 136.7 (s), 139.6 (s), 142.6 (s), 144.9
(d, C2), 148.5(s). MS (EI) m/z 356 (M+, 3), 201 (M - Ts, 10). M
NH), 1708 (s, CdO), 1626 (m, NCO). 1H NMR (CDCl3, 300
MHz) δ 2.63 (s, 3H, CMe), 6.53 (s, 1H, H5), 6.97 (d, J ) 6.6
Hz, 1H, H6), 7.41 (dd, J ) 8.0 and 4.8 Hz, 1H, H3), 7.51 (d, J
) 6.6 Hz, 1H, H7), 8.10 (dd, J ) 8.0 and 1.5 Hz, 1H, H4), 8.41
(dd, J ) 4.8 and 1.5 Hz, 1H, H2). 13C NMR (CDCl3, 75 MHz)
δ 26.2 (q, Me), 90.5 (d, C5), 107.2 (d, C6), 119.6 (d, C3), 122.8
(s, C4a), 128.4 (d, C4), 136.0 (s, C5a), 136.5 (d, C2), 139.6 (d,
C7), 141.3 (s, C10a), 142.3 (s, C9), 170.0 (s, CO). MS (EI) m/z
227 (3), 226 (M+, 18), 184 (100). M calculated for C12H10N4O
226.0855; HRMS found (M+) 226.0852. Anal. Calcd for
calculated for
356.0956.
C
17H16N4O3S 356.0943; HRMS found (M+)
6,7-Dih ydr o-6-h ydr oxy-4-m eth oxy-9-tosylam in opyr ido-
[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (15b). To a solution of
14b (8 g, 17 mmol) in CH2Cl2 (150 mL) was added HCl (4 N,
150 mL) and the mixture was stirred for 90 min. The aqueous
solution was made basic with aq Na2CO3 to pH 9 and product
extracted into CH2Cl2. The organic layer was dried and
evaporated yielding 15b (5.25 g, 80%) as a light yellow foam.
IR (film) ν 3317 (s, OH), 1627 (m, CdN), 1294 (s, SO2). 1H NMR
(CDCl3, 200 MHz) δ 2.35 (s, 3H, Me), 3.35 (dm, J ) 13.1 Hz,
1H, C7), 3.74 (dm, J ) 13.1 Hz, 1H, C7), 5.00 (m, 1H, H6),
6.42 (d, J ) 5.8 Hz, 1H, H3), 6.51 (s, 1H, H5), 7.23 (d, J ) 8.2
Hz, 2H, Ts), 8.04 (d, J ) 8.2 Hz, 2H, Ts), 8.09 (d, J ) 5.8 Hz,
1H, H2). 13C NMR (CDCl3, 75 MHz) δ 21.5 (q, Me), 44.9 (t,
C7), 55.6 (q, OMe), 60.1 (d, C6), 100.1 (d, C5), 101.3 (d, C3),
112.2 (s), 126.6 (d, Ts), 129.3 (d, Ts), 134.3 (s), 139.5 (s), 142.7
(s), 146.7 (s), 148.6 (s), 148.7 (d, C2), 159.6 (s). MS (CI) m/z
387 (M + 1, 1), 386 (M, 1), 231 (M - Ts, 2), 216 (12). M
C
12H10N4O: C (63.71), H (4.46), N (24.77). Found: C (63.65),
H (4.59), N (24.80).
9-Acet yla m in o-4-m et h oxyp yr id o[3′,2′:4,5]p yr r olo[1,2-
c]p yr im id in e (17b). Acetic anhydride (5 µL, 0.05 mmol) was
added to a solution of 12b (8 mg, 0.04 mmol) in THF (1 mL)
and the mixture was stirred at room temperature for 20 h.
The solvent was removed and the residue was taken up in CH2-
Cl2. The solution was washed with saturated aq NaHCO3,
dried, and evaporated, giving 17b (8.5 mg, 82%), which was
used without any further purification. 1H NMR (CDCl3, 300
MHz) δ 2.60 (s, 3H, Me), 4.07 (s, 3H, Me), 6.60 (s, 1H, H5),
6.82 (d, J ) 5.7 Hz, 1H, H3), 6.96 (d, J ) 6.6 Hz, 1H, H6),
7.47 (d, J ) 6.6 Hz, 1H, H7), 8.29 (d, J ) 5.7 Hz, 1H, H2). 13C
NMR (CDCl3, 75 MHz) δ 26.3 (q, Me), 55.8 (q, Me), 88.1 (d,
C5), 100.7 (d, C6), 107.7 (d, C3), 114.1 (s, C4a), 134.5 (s, C5a),
135.9 (d, C2), 142.1 (d, C7), 159.5 (s, C4), 170.1 (s, CO). MS
(ES+) m/z 258 (30), 257 (M + 1, 100). M calculated for
calculated for
386.1096.
C
18H18N4O4S 386.1049; HRMS found (M+)
C
13H12N4O2 256.0960; HRMS found (M+) 256.0970.
9-Tosyla m in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im i-
d in e (16a ). As in the preparation of 11a , but starting from
15a (1.85 g, 5.19 mmol), TEA (1.44 mL, 0.92 mmol), and MsCl
(1.32 mL, 5.30 mmol) in CH2Cl2 (80 mL), a crude product was
obtained and purified by flash column chromatography. Elu-
tion with CH2Cl2/MeOH (98/2) gave 16a (1.22 g, 70%) as a
yellow solid. IR (film) ν 3266 (m, NH), 1652 (s, CdN), 1573 (s,
CdN), 1399 (s, SO2), 1141 (s, SO2). 1H NMR (CD3OD, 300 MHz)
δ 2.37 (s, 3H, Me), 6.69 (s, 1H, H5), 6.74 (d, J ) 7.5 Hz, 1H,
H6), 7.04 (d, J ) 7.5 Hz, 1H, H7), 7.31 (d, J ) 8.4 Hz, 2H, Ts),
7.44 (dd, J ) 7.8 and 4.8 Hz, 1H, H3), 8.00(d, J ) 8.4 Hz, 2H,
Ts), 8.14 (br d, J ) 7.8 Hz, 1H, H4), 8.47 (dd, J ) 4.8 and 1.5
Hz, 1H, H2). 13C NMR (DMSO, 75 MHz) δ 21.1 (q, Me), 96.3
(d, C5), 101.6 (d, C6), 120.1 (s), 120.4 (d, C3), 123.6 (s), 126.1
(d, C4), 128.5 (d, C7), 129.48 (d, Ts), 129.54 (d, Ts), 134.5 (s),
138.4 (s), 142.5 (s), 143.0 (d, C2). MS (EI) m/z 338 (M+, 19),
183 (67). M calculated for C17H14N4O2S 338.0837; HRMS found
(M+) 338.0841.
9-Acetyla m in o-5-iod op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p y-
r im id in e (18a ). NIS (100 mg, 0.44 mmol) was added portion-
wise to a solution of 17a (100 mg, 0.44 mmol) in CH2Cl2 (20
mL) at 0 °C. After being stirred for 15 min, the solution was
diluted with CH2Cl2 (50 mL) and washed twice with water.
The organic layer was dried and evaporated to obtain 18a (142
mg, 93%) as a bright yellow solid. Mp 163-164 °C dec (CH2-
Cl2/hexane). IR (KBr) ν 3050 (m, NH), 1694 (m, CdO), 1573
(m, CdN). 1H NMR (CDCl3, 200 MHz) δ 2.63 (s, 3H, CMe),
6.94 (d, J ) 6.4 Hz, 1H, H6), 7.47 (dd, J ) 8.2 and 4.8 Hz, 1H,
H3), 7.61 (d, J ) 6.4 Hz, 1H, H7), 7.93 (dd, J ) 8.2 and 1.6
Hz, 1H, H4), 8.40 (dd, J ) 4.8 and 1.6 Hz, 1H, H2). 13C NMR
(CDCl3, 75 MHz) δ 26.4 (q, Me), 46.7 (s, C5), 107.0 (d, C6),
120.6 (d, C3), 125.2 (s, C4a), 128.8 (d, C4), 136.9 (s, C5a), 138.6
(d, C7), 140.9 (d, C2), 141.5 (s, C10a), 142.7 (s, C9), 170.2 (s,
CO). MS (EI) m/z 353 (3), 352 (M+, 22), 310 (100). M calculated
for C12H9IN4O 351.9821; HRMS found (M+) 351.9821. Anal.
Calcd for C12H9IN4O: C (40.93), H (2.58), N (15.91). Found:
C (40.91), H (2.64), N (15.79).
4-Meth oxy-9-tosyla m in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]-
p yr im id in e (16b). In a way analogous to the synthesis of 11a ,
but starting from 15b (170 mg, 0.46 mmol), product 16b was
purified by flash column chromatography. Elution with CH2-
Cl2/MeOH (98/2) gave 16b (126 mg, 78%) as a yellow solid. IR
9-Acetylam in o-5-iodo-4-m eth oxypyr ido[3′,2′:4,5]pyr r olo-
[1,2-c]p yr im id in e (18b). NIS (6.5 mg, 0.03 mmol) was added
portionwise to a solution of 17b (8 mg, 0.03 mmol) in CH2Cl2
(5 mL) at 0 °C. The mixture was stirred for 15 min then diluted
with CH2Cl2 (50 mL) and washed twice with water. The
organic layer was dried and evaporated to obtain 18b (8.4 mg,
71%) as a yellow gum. IR (film) ν 3261 (S, NH), 1694 (m, Cd
1
(film) ν 3266 (m, NH), 1293 (s, SO2 ), 1603 (s, CdN). H NMR
(CD3OD, 200 MHz) δ 2.38 (s, 3H, CMe), 4.08 (s, 3H, OMe),
6.68 (s, 1H, H5), 6.72 (d, J ) 7.4 Hz, 1H, H6), 7.02 (d, J ) 7.4
Hz, 1H, H7), 7.03(d, J ) 5.4 Hz, 1H, H3), 7.31 (d, J ) 8.2 Hz,
2H, Ar), 7.98 (d, J ) 8.2 Hz, 2H, Ar), 8.35 (d, J ) 5.4 Hz, 1H,
H2), 11.05 (br s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ
20.8 (q, Me), 55.9 (q, OMe), 92.6 (d, C5), 102.1 (d, C6), 113.9
(s), 120.0 (s), 124.2 (d, C3), 126.0 (d, Ts), 129.3 (d, Ts), 132.6
(s), 142.2 (s), 144.0 (s), 145.1 (d, C7), 158.4 (d, C2). MS (EI)
m/z 369 (7), 368 (M+, 32), 303 (100), 213 (63), 198 (46). M
calculated for C18H116N4O3S 368.0943; HRMS found (M+)
368.0941.
1
O), 1604 (m, CdN). H NMR (CDCl3, 200 MHz) δ 2.61 (s, 3H,
Me), 4.08 (s, 3H, Me), 6.84 (d, J ) 5.7 Hz, 1H, H3), 6.97 (d, J
) 6.6 Hz, 1H, H6), 7.57 (d, J ) 6.6 Hz, 1H, H7), 8.31 (d, J )
5.7 Hz, 1H, H2). 13C NMR (CDCl3, 75 MHz) δ 26.3 (q, Me),
55.8 (q, Me), 101.2 (d, C6), 107.7 (d, C3), 114.1 (s, C4a), 133.5
(s, C5a), 137.7 (d, C2), 142.5 (d, C7), 142.6 (s, C10a), 151.8 (s,
C9), 170.4 (s, C4), 176.8 (s, CO). MS (ES+) m/z 384 (15), 383
(M + 1, 100), 192 (M + 22+, 50), 191 (M2+, 22).
9-Ace t yla m in op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im i-
d in e (17a ). Acetic anhydride (200 µL, 2.04 mmol) was added
to a solution of 12a (250 mg, 1.36 mmol) in THF (20 mL) and
the mixture was stirred at room temperature for 20 h. The
solvent was removed and the residue was taken up in CH2-
Cl2. The solution was washed with saturated aq NaHCO3. The
organic layer was dried and evaporated. The crude was
purified by flash column chromatography. Elution with CH2-
Cl2/MeOH (99/1) gave 17a (225 mg, 75%) as a bright yellow
solid. Mp 160-161 °C (CH2Cl2/hexane). IR (KBr) ν 3150 (m,
2-Meth a n esu lfa n yl-4-tr im eth ylsta n n ylp yr im id in e (19).
TBAF (5 mL, 1 M in THF) was added dropwise to a solution
of 4-iodo-2-methanesulfanylpyrimidine38 (800 mg, 3.2 mmol),
hexamethylditin (1 mL, 4.8 mmol), Pd(OAc)2 (45 mg, 0.31
mmol), and PPh3 (90 mg, 0.62 mmol) in THF (10 mL). The
mixture was stirred at room temperature for 1.5 h. The solvent
was removed under vacuum and the residue purified by
neutral alumina column chromatography. Elution with hex-
ane/AcOEt (99/1) yielded 19 (585 mg, 65%) as a colorless oil.
1
IR (film) ν 1539 (m, CdN), 1402 (m), 1306 (m), 1196 (m). H
J . Org. Chem, Vol. 68, No. 26, 2003 10027

Ahaidar et al.
NMR (CDCl3, 300 MHz) δ 0.34 (s, 9H, Me3Sn), 2.54 (s, 3H,
SMe), 7.08 (d, J ) 4.5 Hz, 1H, H5), 8.26 (d, J ) 4.5 Hz, 1H,
H6). 13C NMR (CDCl3, 75 MHz) δ -9.5 (q, Me), 14.0 (q, Me),
124.5 (d, C5), 153.6 (d, C6), 171.4 (s, C2). MS (EI) m/z 291
(d, C4), 140.0 (s, C5a), 140.8 (d, C2), 143.8 (s, C10a), 144.6 (d,
C7), 150.0 (s, C9), 157.3 (d, C6′), 162.6 (s, C4′), 173.5 (s, C2′).
MS (EI) m/z 324 (M+, 47), 261 (100), MS (ES+) m/z 326 (20),
325 (M + 1, 100).
9-Am in o-5-(2-m eth a n esu lfon ylp yr im id in -4-yl)p yr id o-
[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (22). Meth od A: To a
solution of 21 (50 mg, 0.16 mmol) in CH2Cl2 (15 mL) was added
m-CPBA (88 mg, 0.36 mmol) at room temperature. After the
solution was stirred for 2 h, a saturated aq Na2S2O3 solution
(1 mL) was added and the mixture was basified with saturated
aq Na2CO3. The organic layer was separated and the aqueous
layer re-extracted with CH2Cl2. The combined, dried extracts
were evaporated giving 22 (50 mg, 91%) as a light orange solid.
(
120SnM+, 50), 276 (120SnM - Me, 100). M calculated for
C8H14N2S120Sn 290.9977; HRMS found (M+) 290.9973.
9-Acet yla m in o-5-(2-m et h a n esu lfa n ylp yr im id in -4-yl)-
p yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e
(20a )
a n d
9-Am in o-5-(2-m e t h a n e su lfa n ylp yr im id in -4-yl)p yr id o-
[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (20b). A solution of 18a
(130 mg, 0.37 mmol), 19 (93 mg, 1.10 mmol), Pd2(dba)3 (76 mg,
0.07 mmol), PPh3 (39 mg, 0.15 mmol), LiCl (47 mg, 1.10 mmol),
and CuI (14 mg, 0.07 mmol) in dioxane (10 mL) was refluxed
for 1.5 h. The organic solvent was removed and the resulting
oil dissolved in CH2Cl2 and extracted four times with 4 N HCl,
the aqueous solution was basified with solid Na2CO3, then the
product was extracted with CH2Cl2. The extract was evapo-
rated and the residue purified by flash column chromatography
eluting with CH2Cl2/MeOH (99/1) giving 20a (21 mg, 16%) as
a yellow solid, mp 160-162 °C (from CH2Cl2/hexane). IR (KBr)
ν 1704 (s, CdO), 1620 (m, CdC), 1556 (m), 1536 (m, CdN),
1517 (m), 1502 (m), 1476 (m, C-N), 1265 (m). 1H NMR (CDCl3,
200 MHz) δ 2.67 (s, 3H, CMe), 2.69 (s, 3H, SMe), 7.36 (d, J )
5.2 Hz, 1H, H5′), 7.58 (dd, J ) 8.2 and 4.8 Hz, 1H, H3), 7.83
(d, J ) 6.6 Hz, 1H, H7), 7.93 (d, J ) 6.6 Hz, 1H, H6), 8.52 (dd,
J ) 4.8 and 1.4 Hz, 1H, H2), 8.54 (d, J ) 5.2 Hz, 1H, H6′),
8.77 (dd, J ) 8.2 and 1.4 Hz, 1H, H4). 13C NMR (CDCl3, 75
MHz) δ 14.4 (q, CMe), 26.4 (q, SMe), 104.5 (s, C5), 107.4 (d,
C6), 113.0 (d, C5′), 121.1 (d, C3), 121.6 (s, C4a), 129.5 (d, C4),
137.7 (s, C5a), 141.0 (d, C2), 141.1 (d, C7), 142.5 (s, C10a),
143.3 (s, C9), 156.8 (d, C6′), 160.7 (s, C4′), 170.2 (s, C2′), 172.7
(s, CO). MS (EI) m/z 351 (M + 1, 3), 350 (M+, 33), 308 (M -
Ac, 100). M calculated for C17H14N6OS 350.0949; HRMS found
(M+) 350.0940. UV (MeOH) λ 255 (25 480), 400 (17 710).
Elution with CH2Cl2/MeOH (95/5) gave 20b (30 mg, 26%) as a
yellow solid, mp 223-224 °C (from CH2Cl2/hexane). IR (KBr)
ν 3390 (m, NH), 1632 (m, CdC), 1557 (m, CdN), 1517 (m),
Meth od B: To a solution of 20b (200 mg, 0.65 mmol) in
CH2Cl2 (50 mL) was added m-CPBA (320 mg, 1.30 mmol). The
mixture was stirred for 2 h at room temperature then
saturated aq Na2S2O3 solution was added (5 mL) and the
mixture basified with saturated aq Na2CO3. The organic layer
was separated and the aqueous layer re-extracted with CH2-
Cl2. The combined organic extracts were dried and evaporated
to give 22 (201 mg, 91%). Mp 118-189 °C (CH2Cl2/hexane).
IR (film) ν 3340 (m, NH), 1569 (m, CdC), 1517 (m), 1462 (m),
1
1262 (s, SO2). H NMR (CDCl3, 300 MHz) δ 3.41 (s, 3H, Me),
7.56 (dd, J ) 8.1 and 4.8 Hz, 1H, H3), 7.69 (d, J ) 6.6 Hz, 1H,
H7), 7.78 (d, J ) 5.7 Hz, 1H, H5′), 7.80 (d, J ) 6.6 Hz, 1H,
H6), 8.44 (dd, J ) 4.8 and 1.5 Hz, 1H, H2), 8.75 (d, J ) 5.7
Hz, 1H, H6′), 8.84 (dd, J ) 8.1 and 1.5 Hz, 1H, H4). 13C NMR
(DMSO-d6, 50 MHz) δ 39.8 (q, Me), 97.4 (s, C5), 101.0 (d, C6),
118.4 (d, C5′), 121.0 (s, C4a), 121.2 (d, C3), 128.6 (d, C4), 130.3
(s, C5a), 140.5 (d, C2), 143.3 (s, C10a), 146.8 (d, C7), 149.9 (s,
C9), 157.5 (d, C6′), 161.5 (s, C4′), 165.2 (s, C2′). MS (CI, NH3)
m/z 342 (M + 2, 6), 341 (M + 1, 20), 340 (M+, 100), 309 (M -
O2, 5), 263 (M - SO2Me, 25). M calculated for C15H12N3O2S
340.0742; HRMS found (M+) 340.0740.
9-Am in o-5-(2-a m in op yr im id in -4-yl)p yr id o[3′,2′:4,5]p yr -
r olo[1,2-c]p yr im id in e (d eoxyva r iolin B, 23). Meth od A:
A solution of 22 (25 mg, 0.04 mmol) in dioxane (3 mL) and
23% aq NH3 (5 mL) was heated in a sealed steel vessel at 80
°C for 6 h. The mixture was cooled and the solvent removed
leaving a residue that was dissolved in saturated aq Na2CO3
and extracted with CH2Cl2 several times. The organic extracts
were dried and evaporated and the crude product thus
obtained was purified by flash column chromatography. Elu-
tion with CH2Cl2/MeOH (97/3) gave 23 (18 mg, 90%) as a
yellow solid.
1
1464 (m, C-N), 1265 (m). H NMR (CDCl3, 300 MHz) δ 2.68
(s, 3H, Me), 7.33 (d, J ) 5.4 Hz, 1H, H5′), 7.49 (dd, J ) 8.4
and 4.8 Hz, 1H, H3), 7.58 (d, J ) 6.6 Hz, 1H, H7), 7.68 (d, J
) 6.6 Hz, 1H, H6), 8.40 (dd, J ) 4.8 and 1.6 Hz, 1H, H2), 8.48
(d, J ) 5.4 Hz, 1H, H6′), 8.73 (dd, J ) 8.4 and 1.6 Hz, 1H,
H4). 13C NMR (CDCl3, 50 MHz) δ 14.4 (q, SMe), 100.3 (s, C5),
102.1 (d, C6), 112.6 (d, C5′), 120.7 (d, C3), 122.0 (s, C4a), 128.6
(d, C4), 138.7 (s, C5a), 140.3 (d, C2), 142.1 (s, C10a), 143.4 (d,
C7), 149.8 (s, C9), 156.5 (d, C6′), 161.2 (s, C4′), 172.3 (s, C2′).
MS (EI) m/z 309 (7), 308 (M+, 33). M calculated for C15H12N6S
308.0844; HRMS found (M+) 308.0839. UV (MeOH) λmax 217
(16 324), 252 (21 415), 400 (11 692). A solution of 20a (15 mg,
0.043 mmol) in 5 N HCl/MeOH (5 mL) was refluxed for 1 h.
The solvent was removed and the residue dissolved in satu-
rated aq Na2CO3. The solution was extracted with CH2Cl2. The
organic solvent was evaporated giving 20b (12 mg, 90%).
Meth od B: A solution of 18a (120 mg, 0.36 mmol), 24 (200
mg, 0.72 mmol), Pd2(dba)3 (75 mg, 0.06 mmol), PPh3 (35 mg,
0.14 mmol), LiCl (42 mg, 1.10 mmol), and CuI (12 mg, 0.06
mmol) in dioxane (4 mL) was refluxed for 1.5 h. The organic
solvent was removed and the oil dissolved in HCl/MeOH and
the resulting solution refluxed for 1 h. The solvent was
evaporated and the residue dissolved in CH2Cl2. The organic
solution was extracted with aq 4 N HCl four times then the
combined aqueous extracts basified with solid Na2CO3 and
extracted with CH2Cl2. After evaporation of the solvent the
product was purified by flash column chromatography. Elution
with CH2Cl2/MeOH (95/5) gave 23 (50 mg, 54%) as a yellow
solid. Mp 160-162 °C (from CH2Cl2/hexane). IR (film) ν 3332
(m, NH), 1632 (m, CdC), 1574 (m, CdN), 1454 (m, C-N), 1262
When the reaction was repeated and the HCl/MeOH treat-
ment carried out before purification, 20b (45%) was obtained
as the only product.
9-Am in o-5-(2-m et h a n esu lfin ylp yr im id in -4-yl)p yr id o-
[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (21). To a solution of 20
(20 mg, 0.07 mmol) in CH2Cl2 (5 mL) cooled to 0 °C was added
m-CPBA (32 mg, 0.13 mmol). The mixture was stirred for 30
min then saturated aq Na2S2O3 (1 mL) was added and the
mixture was basified with saturated aq Na2CO3. The organic
layer was separated and the aqueous layer re-extracted with
CH2Cl2. The combined organic extracts were dried and evapo-
rated to give 21 (20 mg, 90%) as an orange foam. IR (film) ν
3388 (m, NH), 1635 (m, CdC), 1569 (m), 1519 (m, CdN), 1467
1
(m). H NMR (DMSO-d6, 500 MHz) δ 6.55 (br s, 2H, 2′NH2),
7.05 (d, J ) 5.5 Hz, 1H, H5′), 7.57 (d, J ) 8.0 and 4.4 Hz, 1H,
H3), 7.62 (d, J ) 6.6 Hz, 1H, H7), 7.68 (d, J ) 6.6 Hz, 1H,
H6), 8.21 (d, J ) 5.5 Hz, 1H, H6′), 8.44 (dd, J ) 4.4 and 1.4
Hz, 1H, H2), 8.55 (br s, 1H, 9NH), 8.91 (dd, J ) 8.0 and 1.4
Hz, 1H, H4), 9.35 (br s, 1H, 9NH). 13C NMR (DMSO-d6, 50
MHz) δ 99.5 (s, C5), 101.7 (d, C6), 106.8 (d, C5′), 120.7 (d, C3),
121.6 (s, C4a), 129.1 (d, C4), 138.2 (s, C5a), 140.1 (d, C2), 142.8
(s, C10a), 143.8 (d, C7), 149.7 (s, C9), 158.0 (d, C6′), 161.4 (s,
C4′), 163.5 (s, C2′). MS (ES+) m/z 279 (20), 278 (M + 1, 100),
277 (M+, 10). M calculated for C15H11N7 277.1075; HRMS found
(M+) 277.1071. UV (MeOH) λmax 225 (36 010), 250 (34 126),
350 (20 942), 400 (26 481).
1
(m), 1267 (s, SdO). H NMR (CDCl3, 200 MHz) δ 3.03 (s, 3H,
Me), 7.53 (dd, J ) 8.2 and 4.8 Hz, 1H, H3), 7.63-7.78 (m, 3H,
H7, H6, and H5′), 8.42 (dd, J ) 4.8 and 1.4 Hz, 1H, H2), 8.73
(d, J ) 5.4 Hz, 1H, H6′), 8.84 (dd, J ) 8.2 and 1.4 Hz, 1H,
H4). 13C NMR (CDCl3, 50 MHz) δ 40.3 (q, Me), 99.5 (s, C5),
102.2 (d, C6), 116.5 (d, C5′), 121.3 (d, C3), 121.9 (s, C4a), 129.1
10028 J . Org. Chem., Vol. 68, No. 26, 2003

Syntheses of Variolin B and Deoxyvariolin B
2-Acetyla m in o-4-ch lor op yr im id in e a n d 4-Ch lor o-2-d i-
a cet yla m in op yr im id in e. A solution of 2-amino-4-chloro-
pyrimidine (500 mg, 3.9 mmol) in acetic anhydride (20 mL)
was refluxed for 30 min. The solvent was removed under
vacuum and the remaining oil was dissolved in saturated aq
Na2CO3 and extracted with CH2Cl2. The organic solution was
dried and evaporated to give an oil that was purified by flash
column chromatography. Elution with CH2Cl2/hexane (2/1)
gave 4-chloro-2-diacetylaminopyrimidine (122 mg, 16%) as a
white solid. Mp 142-143 °C. 1H NMR (CDCl3, 200 MHz) δ 2.51
(s, 6H, 2Me), 7.04 (d, J ) 5.2 Hz, 1H, H5), 8.47 (d, J ) 5.2 Hz,
1H, H6). 13C NMR (CDCl3, 50 MHz) δ 25.3 (q, Me), 116.0 (d,
C5), 157.5 (d, C6), 159.2 (s, C4), 161.8 (s, C2). MS (CI, CH4)
m/z 215 (37ClM, 1), 214 (3), 213 (35ClM, 1), 212 (5), 174 (32),
172 (35ClM-Ac, 100). M + H calculated for C8H8N3O2Cl + H
214.0383; HRMS found (M + H)+ 214.0388. Elution with CH2-
Cl2 yielded 2-acetylamino-4-chloropyrimidine (270 mg, 45%)
142.6 (s), 143.4 (s), 145.1(d, C2), 159.0 (s). MS (EI) m/z 495
(7), 494 (M+, 31), 368 (12), 303 (58), 212 (100). M calculated
for C18H15N4O3SI 493.9909; HRMS found (M+) 493.9890.
5-(2-Acetylam in opyr im idin -4-yl)-4-m eth oxy-9-tosylam i-
n op yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (27). A solu-
tion of 26b (295 mg, 0.60 mmol), 24 (258 mg, 0.86 mmol),
Pd2(dba)3 (120 mg, 0.13 mmol), PPh3 (60 mg, 0.23 mmol), LiCl
(74 mg, 1.8 mmol), and CuI (23 mg, 0.12 mmol) in dioxane (25
mL) was stirred at reflux temperature for 1 h. The solvent
was then evaporated and the crude product dissolved in CH2-
Cl2. The organic solution was washed with aq 4 N HCl, and
the aqueous solution was basified with solid NaHCO3 and
extracted with CH2Cl2. The organic solution was dried and
evaporated giving a crude material that was purified by flash
column chromatography. Elution with CH2Cl2/MeOH (99/1)
gave 26b (61.5 mg, 28%) and with CH2Cl2/MeOH (9/1) gave
27 (213 mg, 71%) as a yellow solid. IR (film) ν 3379 (s, NH),
1592 (s, CdO), 1519 (m, CdN), 1474 (s, SO2). 1H NMR (CDCl3,
400 MHz) δ 2.40 (s, 3H, Me), 2.45 (s, 3H, Me), 4.05 (s, 3H,
OMe), 6.92 (d, J ) 5.2 Hz, 1H, H3), 7.30 (d, J ) 8.4 Hz, 2H,
Ts), 7.43 (d, J ) 5.2 Hz, 1H, H5′), 7.56 (d, J ) 6.8 Hz, 1H,
H7), 7.95 (br s, 1H, H6), 8.13 (d, J ) 8.4 Hz, 2H, Ts), 8.32 (d,
J ) 5.2 Hz, 1H, H6′), 8.49 (d, J ) 5.2 Hz, 1H, H2), 8.69 (br s,
1H, NH), 13.28 (br s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
21.9 (q), 25.3 (q), 56.2 (q), 93.9 (s), 94.1 (s), 102.5 (d, C3), 107.8
(d, C6), 117.3 (d, C5′), 129.0 (d, Ts), 129.5 (d, Ts), 136.3 (s),
136.5 (s), 140.1 (d, C7), 141.9 (s), 142.9 (d, C6′), 143.5 (s), 144.9
(s), 156.9 (d, 2), 158.5 (s), 160.4 (s), 162.0 (s). MS (ES+) m/z
505 (33), 504 (M + 1, 100). M calculated for C24H22N7O4S
504.1453; HRMS found (M+) 504.1445.
5-(2-Am in op yr im id in -4-yl)-4-h yd r oxy-9-tosyla m in op y-
r id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (28). A solution of
27 (200 mg, 0.4 mmol) in aq HBr (48%, 30 mL) was stirred at
reflux for 20 min. After this time the solution was basified
with Na2CO3 and extracted with CH2Cl2. The organic layer
was dried and evaporated to give 220 mg of a yellow solid.
Purification by flash column chromatography and elution with
CH2Cl2/MeOH (95/5) gave 28 (107 mg, 60%) as a yellow solid.
1H NMR (CDCl3-CD3OD, 400 MHz) δ 2.40 (s, 3H, Me), 6.81
(d, J ) 7.0 Hz, 1H, H-6), 7.05-7.09 (m, 2H, H-3 and H-5′),
7.28 (d, J ) 8.0 Hz, 2H, Ts), 7.71 (d, J ) 6.2 Hz, 1H, H-6′),
8.03 (d, J ) 8.0 Hz, 2H, Ts), 8.09 (d, J ) 7.0 Hz, 1H, H-7),
8.29 (d, J ) 5.6 Hz, 1H, H-2). 13C NMR (CDCl3-CD3OD, 100
MHz) 20.1 (q), 101.8 (d, C3), 103.9 (s), 105.0 (s), 106.0 (d, C6),
110.1 (d, C5′), 123.5 (s), 128.0 (d, Ts), 128.9 (d, Ts), 129.3 (d,
C7), 134.3 (d, C6′), 138.3 (s), 139.0 (s), 142.9 (s), 143.1 (s), 156.2
(s), 159.0 (s), 160.7 (d, C2). MS (ES+) m/z 448 (8), 447 (M+,
78), 368 (10), 292 (100), 213 (68). M calculated for C21H18N7O3S
448.1192; HRMS found (M+) 448.1189.
1
as a white solid. Mp 155-156 °C. H NMR (CDCl3, 200 MHz)
δ 2.32 (s, 3H, Me), 7.45 (d, J ) 5.3 Hz, 1H, H5), 8.76 (d, J )
5.3 Hz, 1H, H6). 13C NMR (CDCl3, 50 MHz) δ 26.3 (q, Me),
121.2 (d, C5), 160.0 (s, C4), 163.1 (d, C6), 171.6 (s, C2). MS
(EI) m/z 173 (37ClM, 5), 171 (35ClM, 16), 131 (32), 129 (100). M
calculated for C6H6N3OCl 173.0170; HRMS found (M+) 173.0163.
2-Acet yla m in o-4-t r im et h ylst a n n ylp yr im id in e (24). A
solution of 2-acetylamino-4-chloropyrimidine (170 mg, 1.0
mmol), hexamethylditin (400 µL, 1.8 mmol), and Pd(PPh3)4 (40
mg, 0.03 mmol) in dioxane (6 mL) was refluxed for 1 h. The
solvent was removed under vacuum and the residue purified
by neutral alumina column chromatography. Elution with
hexane/AcOEt (7/3) gave 24 (240 mg, 80%) as a white solid.
1H NMR (CDCl3, 300 MHz) δ 0.36 (s, 9H, 3Me), 2.53 (s, 3H,
Me), 7.13 (d, J ) 4.8 Hz, 1H, H5), 8.35 (d, J ) 4.8 Hz, 1H,
H6), 8.81 (br s, 1H, NH). 13C NMR (CDCl3, 75 MHz) δ -9.5 (q,
3Me), 25.3 (q, Me), 124.4 (d, C5), 128.5 (s, C4), 154.7 (d, C6),
155.4 (s, C2), 186.4 (s, CO). MS (EI) m/z 300 (120SnM+, 1), 285
(34), 255 (120SnM-3Me, 6), 244 (30), 136 (M - SnMe3, 100). M
calculated for C9H15N3OSn 301.0237; HRMS found (M+)
301.0236.
9-Acetylam in o-5-(2-acetylam in opyr im idin -4-yl)-4-m eth -
oxyp yr id o[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (25). A solu-
tion of 18b (7 mg, 0.018 mmol), 24 (11 mg, 0.037 mmol),
Pd2(dba)3 (4 mg, 0.004 mmol), PPh3 (2 mg, 0.007 mmol), LiCl
(2.5 mg, 0.055 mmol), and CuI (1 mg, 0.004 mmol) in dioxane
(1 mL) was refluxed for 2 h. The solvent was evaporated and
the residue dissolved in CH2Cl2. The organic solution was
extracted with 4 N HCl four times and the aqueous solution
basified with solid Na2CO3 then extracted with CH2Cl2. After
evaporation of the CH2Cl2 the residue was purified by flash
column chromatography. Elution with CH2Cl2/MeOH (95/5)
gave 25 (2 mg, 40%). IR (KBR) ν 3216 (m, ΝΗ), 1676 (s, Cd
5-(2-Am in op yr im id in -4-yl)-4-h yd r oxy-9-a m in op yr id o-
[3′,2′:4,5]p yr r olo[1,2-c]p yr im id in e (Va r iolin B, 2). A solu-
tion of 28 (100 mg, 0.22 mmol), 1,4-dimethoxybenzene (60 mg,
0.43 mmol), and NH2NH2‚H2O (0.45 mL, 9.27 mmol) in MeOH
(80 mL) was irradiated under Ar with a high-pressure Hg lamp
for 36 h. After that time the solvent was removed under
vacuum and the residue was purified by preparative HPLC
(Symetry C8, µm, 30 × 100 mm, using a gradient of MeCN-
H2O between 25:72 and 55:45 during 30 min) to give variolin
B 2 (19.7 mg, 30%). Analytical HPLC analysis was identical
with a natural sample supplied by Pharma Mar, tr 6.2 min
(Symetry C8, gradient of MeCN-H2O between 20:80 and 90:
10 during 25 min).
1
O), 1580 (m, CdN). H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H,
Me), 2.60 (s, 3H, Me), 4.07 (s, 3H, Me), 6.97 (d, J ) 5.4 Hz,
1H, H3), 7.26 (d, J ) 6.6 Hz, 1H, H6), 7.48 (d, J ) 5.4 Hz, 1H,
H5′), 7.76 (d, J ) 6.6 Hz, 1H, H7), 8.40 (d, J ) 5.4 Hz, 1H,
H2), 8.52 (d, J ) 5.4 Hz, 1H, H6′). MS (ES+) m/z 392 (M + 1,
40), 350 (55). M calculated for C19H17N7O3 391.1393; HRMS
found (M+) 391.1392.
5-Iodo-4-m eth oxy-9-tosyla m in opyr ido[3′,2′:4,5]pyr r olo-
[1,2-c]p yr im id in e (26b). To a solution of 16b (250 mg, 0.68
mmol) in CH2Cl2 (5 mL) cooled at -30 °C was added NIS (153
mg, 0.68 mmol) slowly and the mixture was stirred for 5 min
at the same temperature. Then, the organic solution was
washed with H2O, dried, and evaporated yielding 26b (319 mg,
95%) as a yellow solid, which was used without further
purification. IR (film) ν 3259 (m, NH), 1604 (m, CdN), 1495
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (Project BQU2000-0235), Biomar S. A.
(Leo´n), and Pharma Mar S. L. (Madrid) is gratefully
acknowledged.
1
(s, SO2), 1294 (s, SO2). H NMR (DMSO-d6, 200 MHz) δ 2.36
(s, 3H, CH3), 3.97 (s, 3H, OCH3), 6.62 (d, J ) 7.8 Hz, 1H, H6),
7.06 (d, J ) 5.4 Hz, 1H, H3), 7.18 (d, J ) 7.8 Hz, 1H, H7),
7.34 (d, J ) 8.2 Hz, 2H, Ar), 8.02 (d, J ) 8.2 Hz, 1H, Ar), 8.41
(d, J ) 5.4 Hz, 1H, H2), 11.17 (br s, 1H, NH). 13C NMR (DMSO-
d6, 75 MHz) δ 21.0 (q, Me), 56.1 (q, OMe), 81.2 (s, C5), 102.6
(d, C6), 113.9 (s), 126.1 (d, C3), 129.4 (4d, Ts), 134.0 (d, C7),
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O035332B
J . Org. Chem, Vol. 68, No. 26, 2003 10029