Synthesis and antimycobacterial activity of agelasine E and analogs

Article abstract of DOI:10.1039/b417471b

Agelasine E, previously isolated from the marine sponge Agelas nakamurai, has been synthesized for the first time, together with analogs with various terpenoid side chains. Treatment of N⁶-methoxy-9-methyl-9H-purin-6- amine with allylic bromides gave the desired 7,9-dialkylpurinium salts together with minor amounts of the N⁶-alkylated isomer. The N ⁶-methoxy group was finally removed reductively. ¹H- ¹⁵N HMBC and ¹H-¹⁵N HSQC NMR spectroscopy gave additional information on tautomerism and charge delocalization in the purine derivatives studied. The heterocyclic products were screened for activity against Mycobacterium tuberculosis and agelasine analogs carrying a relatively long terpenoid substituent in the purine 7-position and a methoxy group at N-6 were potent inhibitors of bacterial growth. Since agelasine analogs with the geranylgeranyl chain at N-7 exhibited antimicrobial activity, several strategies for synthesis of geometrically pure (2E,6E,10E)-geranylgeranyl bromide from geranyllinalool were evaluated. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b417471b

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Synthesis and antimycobacterial activity of agelasine E and analogs
Anne Kristin Bakkestuen, Lise-Lotte Gundersen,* Dirk Petersen, Bibigul T. Utenova and
Anders Vik
Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, N-0315, Oslo, Norway.
E-mail: l.l.gundersen@kjemi.uio.no; Fax: +4722855507; Tel: +4722857019
Received 18th November 2004, Accepted 20th January 2005
First published as an Advance Article on the web 9th February 2005
Agelasine E, previously isolated from the marine sponge Agelas nakamurai, has been synthesized for the first time,
together with analogs with various terpenoid side chains. Treatment of N6-methoxy-9-methyl-9H-purin-6-amine with
allylic bromides gave the desired 7,9-dialkylpurinium salts together with minor amounts of the N6-alkylated isomer.
The N6-methoxy group was finally removed reductively. 1H–15N HMBC and 1H–15N HSQC NMR spectroscopy gave
additional information on tautomerism and charge delocalization in the purine derivatives studied. The heterocyclic
products were screened for activity against Mycobacterium tuberculosis and agelasine analogs carrying a relatively
long terpenoid substituent in the purine 7-position and a methoxy group at N-6 were potent inhibitors of bacterial
growth. Since agelasine analogs with the geranylgeranyl chain at N-7 exhibited antimicrobial activity, several
strategies for synthesis of geometrically pure (2E,6E,10E)-geranylgeranyl bromide from geranyllinalool were
evaluated.
Introduction
Agelasines are 7,9-dialkylpurinium salts isolated from marine
sponges (Agelas sp.). At the present time a total of eleven 9-
methyladeninium salts, agelasine A–I, epiagelasine C and agelin
B, are known.1–7 All compounds carry a diterpenoid side chain
in the adenine 7-position. Until recently, only (−)-agelasine A,8
(−)-agelasine B,9 and ( )-agelasine F10 had been synthesized
and we have just completed the synthesis of (+)-agelasine D11
from (+)-manool.
Agelasines are associated with bioactivities such as antimi-
crobial and cytotoxic effects, as well as contractive responses of
smooth muscles and inhibition of Na/K-ATPases. Furthermore,
in vitro activity against Mycobacterium tuberculosis is reported
for agelasine F (Fig. 1).12 Tuberculosis (TB) is caused by M.
tuberculosis and TB is the major cause of death from a single
infectious agent among adults in developing countries and there
has been an unfortunate revival of TB in the industrialized
Fig. 1 Structure of (−)-agelasine F, (−)-agelasine E and (+)-trixagol.
world. Human immunodeficiency virus (HIV) infections have
further increased TB morbidity and mortality. Multidrug-
resistant tuberculosis (MDR-TB), defined as resistance to the
two most important drugs isoniazid (INH) and rifampicin
(RMP), is a growing problem among HIV-infected patients.
It has been estimated that ca. 30 million people will die from
tuberculosis in about 10 years.13 There is an urgent need for new
antimycobacterial agents, but no new chemotherapeutic agents
directed specifically against TB have been introduced for the last
30 years.
We recently published the first synthesis of (+)-trixagol
(Fig. 1) as well as the enantiomer which corresponds to the
terpenoid side chain of (−)-agelasine E.14 We herein report the
first synthesis of (−)-agelasine E from ent-trixagol and a study of
antimycobacterial activity of agelasine E and agelasine analogs.
Scheme 1 Reagents and conditions: i) PBr3, Et2O, 0 ◦C.
Results and discussion
The non-commercially available allylic halides required for the
introduction the N-7 substituent in agelasine E and agelasine
analogs were generated by reaction of the corresponding allylic
alcohols with PBr3 (Scheme 1).
Geranylgeraniol 1e is much more expensive than the isomer
geranyllinalool. Hence, we investigated the alternative synthesis
of the primary allylic bromides 2d (R = Me) and 2e from tertiary
allylic alcohols 3. The same set of reaction conditions as used in
the bromination of primary alchohols 1 gave E/Z-mixtures of
the product (ratio ca. 7 : 3) (Scheme 2, Table 1). Various other
procedures for halogenation of the alchohols 3 or corresponding
acetates 4 employing boron trichloride,15 boron tribromide or
zinc iodide and TMS–bromide16 were employed and the results
are summarized in Table 1. In the reactions with ZnI2–TMSBr
minor amounts of the cyclization product 6 were also formed.
Improved selectivity was obtained with BCl3, but the allylic
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3
1 0 2 5
©

View Article Online
Scheme 2 Reagents and conditions: i) PBr3, Et2O; ii) BBr3, hexane; iii) BCl3, hexane; iv) Ac2O, DMAP, CH2Cl2; v) ZnI2, TMS–Br, Et2O, −78 ◦C; vi)
PdCl2(MeCN)2, THF; vii) K2CO3, MeOH.
Table 1 Conversion of tertiary allylic alcohols 3 or acetates 4 to primary allylic halides
Starting material
Reagents
Solvent
Temp./◦C
Time
Conversion (%)a
E : Z comp. 2
Yield 6 (%)a
b
3a
3b
3a
3b
3a
3b
3a
4a
4a
4b
PBr3
PBr3
PBr3, pyridine
PBr3, pyridine
BCl3
BCl3
BBr3
ZnI2, TMSBr
ZnI2, TMSBr
ZnI2, TMSBr
Et2O
Et2O
Et2O
Et2O
Hexane
Hexane
Hexane
CH2Cl2
Et2O
0
0
−35
−35
20
20
20
RT
−15
−15
3 h
3 h
1 h
1 h
10 min
40 min
10 min
4 h
35 min
20 min
96
99
86
86
80
70 : 30
72 : 28
71 : 29
70 : 30
83 : 17
85 : 15
55 : 45
n.d.
—
—
—
—
—
—
—
b
b
b
b
b
95
b
100
__c
100
100
n.d.
13
86 : 14
74 : 26
Et2O
4–10d
a From 1H NMR of crude compound. b Not detected by 1H NMR. c No known products could be detected. d Sensitive to the rate of TMSBr addition.
chlorides formed were not reactive enough for introduction of
the N-7 substituent in the target agelasine analogs.
was substantially improved, but purification of the products was
more complicated.
Palladium(II)-catalyzed rearrangement of tertiary allylic ac-
etates are reported to give primary acetates with high E-
selectivities17 and when the geranyllinalyl acetate 4b was treated
with PdCl2(MeCN)2 geranylgeranyl acetate 5 with 87% E-
selectivity was formed. Pure (E)-geranylgeraniol 1e was obtained
after ester hydrolysis and chromatographic purification of the
alcohol.
If the allylic substituent that was introduced was relatively
short (9a–c) the salts could be separated by selective crystalliza-
tion from EtOAc, although the more lipophilic salts 9d–h had to
be separated from their isomers 11d–h by flash chromatography.
After elution with a basic eluent the betaines 10 were isolated
and could be converted to the purinium chlorides 9 by treatment
with Amberlite–Cl. Finally, the methoxy directing group in
compounds 9 were removed reductively to give the agelasine
analogs 12a–f, agelasine E 12g and ent-agelasine E 12h.
Detailed information regarding the structures of compound
8 and the simple agelasine analogs 9a, 10a and 12a could
be found from 1H, 13C and 15N NMR spectroscopy. The 6-
methoxyaminopurine 8 existed as an 8 : 2 mixture of two
tautomers in DMSO-d6 solution. The minor isomer was the
amino tautomer 8a (Scheme 3) as judged by 1H and 13C NMR,
as well as HMBC and HMQC. The chemical shifts for the
Synthesis of agelasines requires regioselective alkylation of
an adenine derivative to give a 7,9-dialkylated purinium salt.
However, alkylation of 9-substituted adenine gives mainly 1,9-
dialkyl derivatives and when 7-alkyladenines are reacted with
alkyl halides, the second N-substituent is preferably introduced
at N-3.18 In contrast, treatment of N-methoxy-9-methyl-9H-
purin-6-amine19 with alkylating agents gives the desired alkylat-
ing pattern.18 In our hands, synthesis of the N6-methoxyamine 8
from the 6-chloropurine 7 (Scheme 3) was more successful than
the rearrangement of 1-methoxyadenine reported previously.19
When the adenine derivative 8 was alkylated with allylic
bromides 2 the desired purinium salt 9 or betaine form 10
were formed, together with the isomer 11 (Table 2). When
E/Z mixtures of bromides 2 were used, the same E/Z ratios
were found in the products and separation of stereoisomers
was tedious. Attempts to alkylate compound 8 with the allylic
chloride 2j were met with little success. When the alkylating
agent was activated by the addition of sodium iodide conversion
1
nitrogens in the major compound could be assigned from H–
15N HMBC20 and it was determined that the NH was situated
in the purine 1-position and, hence, that the major tautomer
had the structure 8b. These findings were in accordance with
1
previous tautomeric studies on compound 8 by H NMR and
UV.21 The imines in Fig. 2 are presented in their most probable
double bond configuration.21 For compounds 9a, 10a, 12a and
13 only one tautomer could be detected and these are shown
in Fig. 2 together with their 15N NMR shifts. Similar to other
1 0 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3

View Article Online
Scheme 3 Reagents and conditions: i) MeONH2·HCl, Et3N, n-BuOH, D; ii) R–Br 2, DMA, 50 ◦C; iii) EtOAc, MeOH, NH3(aq.), SiO2; iv)
Amberlite–Cl, MeOH, H2O; v) Zn, AcOH, MeOH, H2O; vi) NaCl(aq.).
Table 2 Yields of compounds 9, 11 and 12
Yield 9 (%)
Yield 11 (%)
Yield 12 (%)
63, 9a
40, 9b
54, 9c
51, 9d
49, 9e
50, 9f
48, 9g
44, 9h
28, 11a
23, 11b
37, 11c
28, 11d
35, 11e
24, 11f
32, 11g
26, 11h
52, 12a
74, 12b
82, 12c
71, 12d
72, 12e
69, 12f
52, 12g
89, 12h
purine derivatives described previously,22 in the neutral purine
8b the N-7 has an azine like shift and the alkylated N-9 a pyrrole
like shift, but in the purinium cation 9a the N-7 shift is moved
towards the shift for N-9 while only small changes are observed
for the other nitrogen resonances. The nearly identical shifts for
the imidazolium nitrogens indicate an almost even distribution
of the positive charge. The nitrogen shifts found for compound
9a are also quite close to the chemical shifts reported for the
nitrogen in compound 14.23 The negative charge in the betaine
10a could, in theory, be stabilized over N-6, N-1 and N-3 but the
spectroscopic data obtained indicated a high degree of negative
charge at N-1. The purine resonances in the NMR spectra of
9b–h, 10b–h and 12b–h are very close to those described for the
simple allyl derivatives shown in Fig. 2, a strong indication that
the same tautomers dominate regardless of the identity of the
N-7 substituent.
Adenine derivatives 8–13 were screened for antibacterial
activity against Mycobacterium tuberculosis H37Rv at 6.25 lg
mL−1.24 For compounds displaying at least 90% inhibition of
bacterial growth in the initial screening, minimum inhibitory
concentrations (MICs) against M. tuberculosis were determined.
MIC is defined as the minimum concentration of compound
required to give 90% inhibition of bacterial growth. The results
are summarized in Table 3.
Fig. 2 15N NMR shifts (rel. to MeNO2), deduced from 1H–15N HMBC,
for the neutral purines 8 and 13 the betaine 10a and the purinium cations
9a and 12a. The shifts for compound 14 are taken from ref. 23 and
converted to the MeNO2 scale. *Not observed in 1H–15N HMBC, weak
correlation found in 1H–15N HSQC.
of the agelasine analogs still carrying the MeO-directing group
at N-6 were highly potent inhibitors. A relatively long N-7 side
chain was required for significant activity. M. tuberculosis has an
extremely thick and waxy cell wall, which is an effective barrier
for many chemicals. Hence, effective drugs should have a reason-
able lipophilicity in order to penetrate this wall. This may explain
why the more polar compounds 12 were less efficient than the
synthetic intermediates 9 or 10 and also why compounds 9e–h
Much to our surprise, and in contrast with what has been
reported for agelasine F,12 we found only modest antimycobac-
terial activity for agelasine E and agelasine analogs with free
NH2 in the purine 6-position (compounds 12). However, many
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3
1 0 2 7

View Article Online
Table 3 Antimycobacterial activity against Mycobacterium tuberculo-
sis for adenine derivatives 8–9 and 11–13, as well as the positive control
rifampicin. Structures are shown in Scheme 2 and Scheme 3
deuterated solvent in ratio 9 : 1). MS spectra under electron
impact conditions were recorded with a VG Prospec instrument
at 70 eV ionizing voltage and are presented as m/z (% rel.
int.). CH4 was employed as the ionization gas for chemical
ionization (CI). Electrospray MS spectra were recorded with
a Bruker Apex 47e FT-ICR mass spectrometer. Analysis on
GC were performed on a HP 6890 GC equipped with a DB5
micropor 0.53 i.d. capillary column. Elemental analyses were
performed by Ilse Beetz Mikroanalytisches Laboratorium,
Kronach, Germany. Melting points are uncorrected. Silica
gel for flash chromatography was purchased from Merck,
Darmstadt, Germany (Merck No. 9385). Analytical thin layer
chromatography was performed with E. Merck silica gel 60F254
0.25 mm plates (Merck No. 1.05554). Amberlite–Cl was treated
with sat. aq. NaCl over night and washed with water and
MeOH–water (2 : 1) prior to use. DMA was distilled from BaO,
diethyl ether from Na–benzophenone and dichloromethane
from CaH2. Dry hexane was obtained from distilled hexane
Compound No.
Inhibition at 6.25 lg mL−1 (%)
MIC/lg mL−1
8
8
27
11
35
27
100
99
100
99
0
17
30
41
86
92
63
2
n.d.
n.d.
n.d.
n.d.
n.d.
3.13
1.56
3.13
3.13
n.d.
n.d.
n.d.
n.d.
n.d.
6.25
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
6.25
0.25
9a
9b
9c
9d
9e
9f
9g
9h
11a
11b
11c
11d
11e
11g
11h
12a
12c
12d
12e
12f
12g
12h
13
˚
stored over molecular sieves (3 A). Allyl bromide 3a, prenyl
bromide 3b, cinnamyl bromide 3c, geranyl bromide 3d and
linalyl actetate 4a were commercially available. The following
compounds were prepared by literature methods: (2E,6E)-
9-Cyclohexyl-3,7-dimethyl-2,6-nonadien-1-ol 1f,14 (R)-(−)-
(2E,6E)-9-(2,2-dimethyl-6-methylenecyclohexyl)-3,7-dimethyl-
2,6-nonadien-1-ol (ent-trixagol) 1g,14 (S)-(+)-(2E,6E)-9-(2,2-
dimethyl-6-methylenecyclohexyl)-3,7-dimethyl-2,6-nonadien-1-ol
(trixagol) 1h,14 6-chloro-9-methyl-9H-purine 726 and 9-methyl-
adenine 13.27
0
2
38
21
30
38
94a
>90
Rifampicin
a At 12.5 lg mL−1
.
(2E,6E,10E)-Geranylgeraniol (1e). A mixture of geranylger-
anyl acetate 5 (0.88 g, 2.66 mmol) in a 3% solution of K2CO3
in methanol (30 mL) was stirred at ambient temperature over
night. The mixture was evaporated in vacuo and the residue
was transferred to a separation funnel using water (50 mL) and
diethyl ether (50 mL). The organic layer was separated and the
aqueous phase was extracted with diethyl ether (2 × 40 mL) and
hexane (2 × 40 mL). The combined organic layers were washed
with sat. aq. NaCl (20 mL), dried (MgSO4) and evaporated, to
give 0.67 g of residue containing both the (2E)- and (2Z)-isomer.
The E-isomer was isolated by flash chromatography on silica gel
using hexane : EtOAc : EtOH (220 : 20 : 4) (Rf 0.13); yield 0.44 g
and 10e–h were more potent antimycobacterials when compared
to compounds 9a–d or 10a–d. The reason for the large difference
in activity previously found for agelasine F,12 and for agelasine
E 12g, ent-agelasine E 12h and the related cyclohexyl analog 12f
in this study, is however not clear to us.
Even for some of the N6-alkylated isomers 11, formed
as by-products in the alkylating step (Scheme 3), significant
activities were found when the terpenoid side chain was relatively
large (compounds 10e, 10g and 10h). Furthermore, while
the methoxyadenine 8 was essentially inactive, the simple 9-
methyladenine 13 actually exhibited a MIC against M. tuber-
culosis at 6.25 mg mL−1. Reasonable antimycobacterial activity
has also been reported for some simple 9-benzyladenines.25
1
(57%). H NMR (CDCl3, 200 MHz) d 1.58 (s, 9H, CH3), 1.66
(s, 6H, CH3), 1.9–2.2 (m, 12H, CH2), 4.12 (d, J = 6.9 Hz, 2H,
CH2), 5.09 (m, 3H, CH) and 5.40 (t, J = 6.9 Hz, 1H, CH).
(2E,6E,10E)-Geranylgeranyl bromide (2e). Phosphorus tri-
bromide (0.016 mL, 0.17 mmol) was added dropwise to a stirred
solution of geranylgeraniol (100 mg, 0.34 mmol) in dry diethyl
ether (2 mL) at 0 ◦C under N2. The resulting mixture was stirred
in the dark at 0 ◦C for 3 h, diluted with diethyl ether and washed
with sat. aq. NaHCO3 (2 × 10 mL). The aqueous phase was
extracted with diethyl ether and the combined organic extracts
were dried (MgSO4) and evaporated in vacuo to give crude
compound 2e (100 mg, 82%) which was used directly in the
synthesis of compound 9e. 1H NMR (CDCl3, 200 MHz) d 1.67
(s, 6H, CH3), 1.72 (s, 3H, CH3), 1.76 (s, 3H, CH3), 1.77 (s, 3H,
CH3), 2.05 (m, 12 H, CH2), 4.06 (d, J = 8.4 Hz, 2H, CH2Br), 5.14
Experimental
General
1
The H NMR spectra were acquired on a Bruker Avance AV
600 spectrometer, a Bruker Avance DRX 500 spectrometer, a
Bruker Avance DPX 300 spectrometer or a Bruker Avance DPX
200 spectrometer at 600, 500, 300 or 200 MHz respectively.
The 1H decoupled 13C NMR spectra were recorded at 150,
125, 75 or 50 MHz using the above mentioned spectrometers.
Assignments of H and 13C resonances are inferred from 1D
1
1H NMR, 1D 13C NMR, APT, DEPT and/or from 2D NMR
(gs-COSY, gs-HMQC, gs-HMBC, NOESY) spectral data. 15N
NMR data were acquired at 50 MHz on the Bruker Avance
DRX 500 with a 5 mm TXI (1H/13C,15N–2H) Triple Resonance
Inverse probe, equipped with Z-gradient coil, by applying
2D NMR experiments based on gradient pulse selection
and inverse detection methods: gs-[1H,15N] HSQC, optimized
for 1J 15N/1H-couplings of 80 Hz (Bruker pulse program:
invietgpsi, 15N-pulses via F2-channel, relaxation delay: 1.5 s,
acquisition time: 0.17 s) and gs-[1H,15N] HMBC, optimized
for 2J/3J 15N/1H-couplings of 10 Hz (Bruker pulse program:
inv4gplplrndqf, 15N-pulses via F2-channel, relaxation delay:
1.5 s, acquisition time: 0.17 s, delay for evolution of long range
couplings: 0.1 s). 15N chemical shifts are reported relative to
external Me15NO2 at 0 ppm (MeNO2 dissolved in the respective
=
=
(m, 3H, CH C), 5.57 (t, J = 8.4 Hz, 1H, CH C). Alternatively
the same procedure could be employed on geranyllinalol 3b; for
yield see Table 1.
(2E,6E)-9-Cyclohexyl-3,7-dimethyl-2,6-nonadien-1-yl bromide
(2f). (2E,6E)-9-Cyclohexyl-3,7-dimethyl-1-tetrahydro-2-pyra-
nyloxy)-2,6-nonadien-1-ol (100 mg, 0.399 mmol) was reacted
with phosphorous tribromide (0.019 mL, 0.20 mmol) as
described for the synthesis of compound 2e above; yield 114 mg
(91%) pale yellow liquid, which was used directly without
1
further purification. H NMR (CDCl3, 500 MHz) d 0.85 (m,
2H), 1.16 (m, 6H), 1.56 (s, 3H, CH3, H-7ꢀ), 1.65 (m, 5H), 1.71
(s, 3H, CH3, H-3ꢀ), 1.94 (dd, J = 7.8 Hz, 2H, H-8), 2.07 (m,
4H, H-4 and H-5), 4.01 (d, J = 8.4 Hz, 2H, H-1), 5.05 (m, 1H,
1 0 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3

View Article Online
H-6), 5.51 (m, 1H, H-2); 13C NMR (125 MHz, CDCl3) d 15.97
(CH3), 16.02 (CH3), 26.1 (C-4 or C-5), 26.4 (CH2), 26.7 (C-11
or C-12), 29.7 (CH2Br), 33.4 (CH2), 35.8 (CH2), 36.9 (C-8), 37.4
(C-10), 39.5 (C-4 or C-5), 120.5 (C-2), 122.9 (C-6), 136.4 (C-7),
143.7 (C-3); MS (EI) m/z (rel. %) 233 (M+–Br, 8), 109 (63), 97
(22), 95 (79), 93 (38), 83 (62), 81 (96), 69 (36), 68 (27), 67 (54),
55 (100), 41 (65).
give crude allylic bromide; yield 606 mg (98%, E/Z; 85 : 15, cont.
5% starting material) clear oil. H NMR (CDCl3, 200 MHz) d
1.5–1.8 (m, 15H, 5 × CH3), 1.9–2.2 (m, 12H, 6 × CH2), 4.14 (d,
J = 7.7 Hz, 2H, H-1), 5.16 (m, 3H, H-6, H-10 and H-14), 5.47
(t, J = 7.7 Hz, 1H, H-2).
1
General procedure for converting tertiary allylic acetates 4 to
allylic bromides 2
(R)-(+)-(2E,6E)-9-(2,2-Dimethyl-6-methylenecyclohexyl)-3,7-
dimethyl-2,6-nonadien-1-yl bromide (2g). ent-Trixagol (120 mg,
0.41 mmol) was reacted with phosphorous tribromide
(0.019 mL, 0.20 mmol) as described for the synthesis of
compound 2e above; yield 139 mg (96%) pale yellow liquid,
which was used directly without further purification. 1H NMR
(CDCl3, 500 MHz) d 0.81 (s, 3H, CH3), 0.89 (s, 3H, CH3),
1.38–1.52 (m, 7H), 1.57 (s, 3H, CH3), 1.65–1.69 (m, 1H), 1.71
(s, 3H, CH3), 1.91–1.98 (m, 2H), 2.04–2.10 (m, 5H), 4.01 (d,
Allylic acetate 4 (0.90 mmol) and zinc iodide (0.135 mmol) were
dissolved in dry diethyl ether (6 mL) under N2 at −15 ◦C. A
solution of bromotrimethylsilane (1.35 mmol) in diethyl ether
(3 mL) was added dropwise over 15 min and the mixture was
allowed to stir for 20 min at −15 ◦C. The reaction mixture was
diluted with diethyl ether (60 mL) and washed with sat. aq.
NaHCO3 (20 mL). The organic layer was dried (MgSO4) and
evaporated in vacuo at ambient temperature to give crude allylic
bromides (for yields, see Table 1).
=
J = 8.4 Hz, 2H, CH2Br), 4.51 (d, J = 2.0 Hz, 1H, CH), 4.80
=
=
(br s, 1H, CH), 5.04 (br t, J = 4.6 Hz, 1H, CH), 5.51 (br t,
(2E,6E,10E)-Geranylgeranyl acetate (5). Geranyllinalyl
acetate 4b (1.62 g, 4.87 mmol) was dissolved dry
THF. PdCl2(CH3CN)2 (0.063 g, 0.24 mmol) was added and
the mixture was stirred under N2 for 40 h. Additional
PdCl2(CH3CN)2 (2 × 0.24 mmol) was added after 18 h and
28 h. The mixture was evaporated in vacuo and the residue was
purified by flash chromatography on silica gel using hexane :
EtOAc (20 : 1) as eluent; yield 1.29 g (80%), pale yellow oil.
J = 8.4 Hz, 1H, CH); 13C NMR (150 MHz, CDCl3) d 16.0
=
(CH3), 16.1 (CH3), 23.7 (CH2), 24.8 (CH2), 26.1 (CH2), 28.4
(CH3), 29.7 (CH2Br), 32.6 (CH2), 34.9 (CH3), 36.4 (CH2), 38.2
=
=
(CH2), 39.6 (CH2), 53.6 (CH), 108.8 ( CH2), 120.6 ( CH),
=
=
=
=
123.1 ( CH), 136.3 ( C), 143.6 ( C), 149.4 ( C).
(S)-(−)-(2E,6E)-9-(2,2-Dimethyl-6-methylenecyclohexyl)-3,7-
dimethyl-2,6-nonadien-1-yl bromide (2h). Trixagol (124 mg,
0.43 mmol) was reacted with phosphorous tribromide (0.02 ml,
0.2 mmol) as described for the synthesis of compound 2e above;
yield 124 mg (82%) pale yellow liquid, which was used directly
without further purification. For spectral data, see 2g.
1
Analysis on GC showed an E/Z ratio of 87 : 13. H NMR
(CDCl3, 200 MHz) d 1.63 (s, 9H, CH3), 1.68 (s, 3H, CH3), 1.73
(s, 3H, CH3), 1.9–2.2 (m, 14H, 6 × CH2 and OCH3), 4.56 (d, J =
7.1 Hz, 2H, CH2), 5.10 (m, 3H, CH), 5.32 (t, J = 7.1 Hz, CH).
N-Methoxy-9-methyl-9H-purin-6-amine (8). A mixture of
6-chloro-9-methyl-9H-purine 7 (842 mg, 5.00 mmol), O-
methylhydroxylamine hydrochloride (2.09 g, 25.0 mmol), tri-
ethylamine (7.6 mL, 55 mmol) and n-butanol (40 mL) was heated
at reflux under a N2 atmosphere for 17 h and evaporated in vacuo.
Methanol (45 mL) was added and the mixture was stirred at
50 ◦C until all solid material was dissolved, before cooling to
−45 ◦C for 5 min. The resulting mixture was filtered and the
product was washed with cold (−45 ◦C) MeOH (20 mL) and
cold (−45 ◦C) Et2O (40 mL); yield 643 mg (72%), mp 239–
241 ◦C (lit.19 239 ◦C), pale yellow solid. Both tautomers 8a and
8b were present in a ca. 2 : 8 ratio in DMSO-d6 according to
Geranyllinalyl acetate (4b). Geranyllinalool (1.77 g,
6.1 mmol) and DMAP (1.49 g, 12.2 mmol) were dissolved in dry
dichloromethane (12 mL) under N2. and stirred at 0 ◦C. Acetic
anhydride (1.15 mL, 12.2 mmol) was added and the reactiom
mixture was stirred at 0 ◦C for 1 h and then at ambient
temperature for 21 h. The mixture was diluted with CH2Cl2
(150 mL) and extracted with sat. aq. CuSO4 (4 × 50 ml), sat.
aq. NaHCO3 (2 × 50 ml) and sat. aq. NaCl (50 mL), dried with
MgSO4 and evaporated in vacuo. The residue was purified by
flash chromatography on silica gel using EtOAc : hexane 1 : 9
1
as eluent; yield 1.64 g (81%) colorless oil. H NMR (CDCl3,
200 MHz) d 1.52 (s, 3 H, CH3), 1,57 (s, 9 H, CH3), 1.65 (s, 3 H,
CH3), 1.98 (s, 3 H, CH3CO), 1.9–2.2 (m, 12 H, CH2), 5.04–5.07
1
NMR. Comp. 8a: H NMR (DMSO-d6, 500 MHz) d 3.73 (s,
3H, CH3), 3.76 (s, 3H, CH3), 8.18 (s, 1H, H-8), 8.29 (s, 1H,
=
=
(m, 5H, CH C), 5.95 (dd, J = 10.9 and 17.5 Hz, 1H, CH C).
1
H-2), 10.87 (br s, 1H, NH); Comp. 8b: H NMR (DMSO-d6,
(E)-Geranyl chloride (2i). Linalool (5.0 mmol, 0.77 g) was
dissolved in dry hexane (20 mL) and stirred under N2 at
10 ◦C. Boron trichloride (6.3 mmol, 6.3 mL, 1 M in hexane)
was added dropwise over 10 min. The resulting mixture was
stirred at ambient temperature for 10 min, before water (13 mL)
was added and the mixture stirred for additional 10 min. The
phases were separated and the organic layer was washed with
aq. NaCl (10 mL, 20% sol.) The aqueous layers were extracted
with hexane (10 mL) and the combined hexane layers were dried
(MgSO4) and evaporated to give crude allylic bromide; yield
720 mg (E/Z; 83 : 17, cont. 20% starting material), colorless oil.
1H NMR (CDCl3, 200 MHz) d 1.62 (3H, CH3), 1.70 (3H, CH3),
1.74 (3H, CH3), 2.0–2.2 (m, 4H, CH2), 4.12 (d, J = 7.9 Hz, 2H,
CH2), 5.46 (t, J = 7.9 Hz, 1H, CH).
(2E,6E,10E)-Geranylgeranyl chloride (2j). Geranyllinalool
(581 mg, 2.00 mmol) was dissolved in dry hexane (20 mL) and
stirred under N2 at 10 ◦C. Boron trichloride (2.8 mL of an 1 M
hexane solution, 2.80 mmol) was added dropwise over 10 min.
The resulting mixture was stirred at ambient temperature for
40 min, before water (10 mL) was added and the mixture stirred
for additional 5 min. The phases were separated and the organic
layer was washed with aq. NaCl (2 × 10 mL, 20% sol.). The
aqueous layers were extracted with hexane (10 mL) and the
combined hexane layers were dried (MgSO4) and evaporated to
500 MHz) d 3.62 (s, 3H, CH3), 3.73 (s, 3H, CH3), 7.56 (d, J =
3.6 Hz, 1H, H-2), 7.77 (s, 1 H, H-8), 11.17 (br s, 1H, NH);
13C NMR (125 MHz, DMSO-d6, 8a and 8b) d 29.4 (CH3), 29.5
(CH3), 60.9 (CH3), 63.5 (CH3), 117.4, 117.9, 138.9, 141.1, 141.6,
142.7, 143.9; MS (EI) m/z (rel. %) 179 (M+, 60), 164 (8), 150 (7),
149 (100), 148 (18), 122 (38), 107 (35), 94 (11), 80 (9).
General procedure for the synthesis of the 7-alkyl-9-methyl
purinium halides (9) and the 6-alkylamino purines (11)
A mixture of N-methoxy-9-methyl-9H-purin-6-amine 8 (90 mg,
0.5 mmol) and allylic bromide 2 (1–5 eq.) in DMA (4 mL) was
◦
stirred at 50 C under a N2 atmosphere for 21 h. Work up for
9a–c and 11a–c: EtOAc (10 mL) was added and the mixture was
stored in the refrigerator for precipitation of compound 9 which
was isolated by centrifugation and, if necessary, purified by
crystallization. The supernatant was evaporated and compound
11 was isolated by flash chromatography on silica gel. Work up
for 9d–h and 11d–h: The reaction mixture was evaporated in
vacuo and the products were separated by flash chromatography
on silica gel eluting with CH2Cl2, EtOAc : EtOH : NH3(aq.) (160 :
5 : 2), EtOAc : EtOH : NH3(aq.) (40 : 10 : 1), and CH2Cl2 :
MeOH : NH3(aq.) (35 : 5 : 1) to give compound 11 and the
betaine 10. Compound 10 was dissolved in MeOH (10 mL) and
water (5 mL) and eluted through a column with Amberlite–Cl
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3
1 0 2 9

View Article Online
(ca. 1.5 mL). The amberlite was washed with MeOH–water (2 :
1), ca. 25 mL, and the combined eluents were evaporated in
vacuo to give the purinium chloride 9.
3H, CH3O), 5.17 (d, J = 6.5 Hz, 2H, CH2N), 6.47 (dd, J = 15.9
and 6.5 Hz, 1H, H-2ꢀ), 6.80 (d, J = 15.9 Hz, 1H, H-3ꢀ), 7.30 (m,
1H, H-7ꢀ), 7.36 (m, 2H, Ph), 7.47 (d, J = 7.4 Hz, 2H, Ph), 7.86
(d, J = 3.8 Hz, 1H, H-2), 9.45 (s, 1H, H-8), 12.16 (d, J = 3.4 Hz,
1H, NH); 13C NMR (DMSO-d6, 125 MHz) d 31.7 (CH3N), 51.0
7-(Allyl)-6-(methoxyamino)-9-methyl-7H-purinium bromide
(9a). 5 Eq. ◦of allyl bromide 2a were used; yield 95 mg (63%),
=
(CH2N), 62.0 (CH3O), 109.9 (C-5), 122.0 ( CH), 126.7 (CH in
1
mp 251–252 C (dec.) colorless crystals. H NMR (DMSO-d6,
=
Ph), 128.5 ( CH), 128.8 (CH and Ph), 135.3 (CH in Ph), 135.5
500 MHz) d 3.81 (s, 3H, CH3), 3.83 (s, 3H, CH3), 5.01 (d, J =
5.6 Hz, 2H, H-1ꢀ), 5.33 (d, J = 17.3 Hz, H-3ꢀ), 5.37 (d, J =
10.3 Hz, H-3ꢀ), 6.05 (m, 1H, H-2ꢀ), 7.85 (d, J = 3.6 Hz, H-2),
9.39 (s, 1H, H-8), 12.15 (br s, 1H, NH); 13C NMR (DMSO-d6,
50 MHz) 31.7(CH3N), 51.2 (CH2N), 61.9 (CH3O), 109.9 (C-5),
(C in Ph), 136.7 (C-6), 137.9 (C-8), 141.2 (C-4), 148.6 (C-2);
MS (electrospray) m/z (rel. %): 296 (M+, 100), 264 (4), 192 (4);
HRMS: found 296.1495, calcd for C16H18N5O+ 296.1505. Anal.:
found: C, 50.99; H, 4.77; N, 18.27%. C16H18N5OBr requires C,
51.08; H, 4.82; N, 18.61%.
=
=
120.3 ( CH2), 131.3 ( CH), 136.6 (C-6), 138.0 (C-8), 141.2
(C-4), 148.7 (C-2); MS (electrospray) m/z (rel. %) 220 (M+,
100), 189 (12), 188 (16), 179 (16), 174 (33), 162 (5); HRMS:
found 220.1201, calcd for C10H14N5OBr+ 220.1192. Anal.:
found: C, 39.82; H, 4.59; N, 23.42%. C10H14N5OBr requires C,
40.01; H, 4.70; N, 23.33%.
(E)-N-Methoxy-9-methyl-N-(3-phenyl-2-propenyl)-9H-purin-
6-amine (11c). 1.0 Eq. of cinnamyl bromide 2c were used and
the product was purified by flash chromatography eluting with
EtOAc : EtOH : NH3(aq.) (160 : 5 : 2); yield 55 mg (37%), mp
75–78 ◦C (dec.) colorless crystals. 1H NMR (CDCl3, 500 MHz)
d 3.82 (s, 3H, CH3N), 3.96 (s, 3H, CH3O), 4.90 (dd, J = 6.3 and
N-(Allyl)-N-methoxy-9-methyl-9H-purin-6-amine (11a). 5 Eq.
of allyl bromide 2a were used and the product was purified
by flash chromatography eluting with EtOAc : EtOH : NH3(aq.)
(160 : 5 : 2); yield 31 mg (28%), colorless oil. 1H NMR (CD3OD,
500 MHz) d 3.84 (s, 3H, CH3N), 3.86 (s, 3H, CH3O), 4.76 (d,
J = 5.9 Hz, 2H, CH2N), 5.18 (dd, J = 1.3 and 10.3 Hz, 1H,
H-3ꢀ), 5.30 (dd, J = 1.3 and 17.1 Hz, 1H, H-3ꢀ), 5.97 (m, 1H,
H-2ꢀ), 8.16 (s, 1H, H-2/H-8), 8.36 (s, 1H, H-2/H-8); 13C NMR
(CD3OD, 50 MHz) d 30.3 (CH3N), 53.4 (CH2N), 62.5 (CH3O),
=
0.9 Hz, 2H, CH2N), 6.38 (m, 1H, CH ), 6.66 (d, J 15.9 Hz,
1H, CH ), 7.18 (m, 1H, Ph), 7.25 (m, 2H, Ph), 7.33 (m, 2H,
=
Ph), 7.82 (s, 1H, H-8), 8.49 (s, 1H, H-2); 13C NMR (CDCl3,
125 MHz) d 29.8 (CH3N), 52.5 (CH2N), 62.6 (CH3O), 119.2
=
(C-5), 123.8 ( CH), 126.4 (CH in Ph), 127.6 (CH in Ph), 128.4
=
(CH in Ph), 133.6 ( CH), 136.7 (C in Ph), 141.1 (C-8), 151.8
(C-4), 152.3 (C-2), 155.8 (C-6); MS (EI) m/z (rel. %) 295 (M+,
31), 264 (94), 174 (14), 133 (13), 118 (12), 117 (100), 116 (12),
115 (69), 91 (21); HRMS: found 295.1421, calcd for C15H17N5O
295.1433.
=
=
118.9 ( CH2), 119.5 (C-5), 133.6 ( CH), 144.0 (C-8), 152.7 (C-
4), 152.8 (C-2), 156.4 (C-6); MS (EI) m/z (rel. %) 219 (M+, 21),
189 (17), 188 (100), 174 (18), 134 (11), 133 (28), 107 (10); HRMS:
found 219.1126, calcd for C10H13N5O 219.1120. Anal.: found: C,
54.90; H, 5.84; N, 32.31%. C10H13N5O requires C, 54.78; H, 5.98;
N, 31.94%.
(E)-6-(Methoxyamino)-9-methyl-7-(3,7-dimethyl-2,6-octadi-
enyl)-7H-purinium chloride (9d). 0.67 mmole purine 8 and 2
eq. of geranyl bromide 2d were used; yield 120 mg (51%). Data
for the betaine 10d: mp 173–176 ◦C (dec.) colorless crystals.
1H NMR (DMSO-d6, 500 MHz) d 1.53 (s, 3H, CH3), 1.60 (s,
3H, CH3), 1.78 (s, 3H, CH3, H-10ꢀ), 2.01 (m, 2H, H-4ꢀ), 2.07
(m, 2H, H-5ꢀ), 3.56 (s, 3H, CH3O), 3.64 (s, 3H, CH3N), 5.01 (d,
J = 7.2 Hz, 2H, H-1ꢀ), 5.05 (m, 1H, H-6ꢀ), 5.49 (m, 1H, H-2ꢀ),
7.53 (s, 1H, H-2), 8.83 (s, 1H, H-8); 13C NMR (DMSO-d6,
125 MHz) d 16.5 (CH3), 17.6 (CH3), 25.5 (CH3), 25.7 (CH2),
30.6 (CH3N), 38.9 (C-4ꢀ), 46.5 (CH2, C-1ꢀ), 60.2 (CH3O), 107.7
(C-5), 118.3 (C-2ꢀ), 123.7 (C-6ꢀ), 131.2 (C-7ꢀ), 132.7 (C-8), 141.8
(C-3ꢀ), 144.9 (C-4), 148.3 (C-6), 155.9 (C-2); anal.: found: C,
64.95; H, 7.98%. C17H25N5O requires C, 64.73; H, 7.99%. Data
for the purinium chloride 9d: mp 189–191 ◦C colorless crystals.
1H NMR (CDCl3, 300 MHz) d 1.53 (s, 3H, CH3), 1.60 (s, 3H,
CH3), 1.82 (s, 3H, CH3), 2.05 (m, 4H, CH2), 3.84 (s, 3H, OCH3),
3.97 (s, 3H, NCH3), 5.00 (m, 1H, CH), 5.02 (d, J = 5.6 Hz,
2H, CH2), 5.43 (m, 1H, CH), 7.99 (s, 1H, H-2), 10.09 (s, 1H,
H-8), 11.98 (s, 1H, NH); 13C NMR (CDCl3, 75 MHz) d 17.1,
17.7, 25.6, 26.0, 32.1, 39.6, 48.2, 62.3, 110.5, 115.8, 123.3, 132.1,
136.1, 137.3, 141.4, 145.7, 149.5; MS (electrospray) m/z (rel.
%) 316 (M+, 8), 181 (9), 180 (100), 149 (16); HRMS: found
316.2124, calcd for C17H26N5O+ 316.2131.
6-(Methoxyamino)-9-methyl-7-(3-methyl-2-butenyl)-7H-purinium
bromide (9b)9b. 3.4 Eq. of prenyl bromide 2b were used and
the product was purified by crystallisation from isopropanol;
yield 66 mg (40%), mp 202–203 ◦C (dec.) colorless crystals. 1H
NMR (DMSO-d6, 500 MHz) d 1.76 (s, 3H, CH3), 1.79 (s, 3H,
CH3), 3.79 (s, 3H, CH3N), 3.83 (s, 3H, CH3O), 4.96 (d, J =
7.0 Hz, 2H, CH2N), 5.41 (m, 1H, H-2ꢀ), 7.84 (d, J = 3.0 Hz,
1H, H-2), 9.41 (s, 1H, H-8), 12.12 (br s, 1H, NH); 13C NMR
(DMSO-d6, 125 MHz) d 18.2 (CH3,), 25.5 (CH3), 31.7 (CH3N),
=
47.3 (CH2N), 61.8 (CH3O), 109.7 (C-5), 116.8 ( CH), 136.8
(C-4/C-6), 137.6 (C-8), 140.4 (C-3ꢀ), 141.4 (C-4/C-6), 148.5
(C-2); MS (electrospray) m/z (rel. %) 248 (M+, 12), 227 (9), 193
(8), 180 (100), 179 (16), 149 (13); HRMS: found 248.1493, calcd
for C12H18N5O+ 248.1505. Anal.: found: C, 44.02; H, 5.36%.
C12H18N5OBr requires C, 43.91; H, 5.53%.
N-Methoxy-9-methyl-N-(3-methyl-2-butenyl)-9H-purin-6-amine
(11b). 3.4 Eq. of prenyl bromide 2b were used and the
product was purified by flash chromatography eluting with
CH2Cl2–MeOH (30 : 1); yield 28 mg (23%), mp 121–123 ◦C
1
(dec.) colorless crystals. H NMR (CDCl3, 500 MHz) d 1.70
(s, 3H, CH3), 1.75 (s, 3H, CH3), 3.81 (s, 3H, CH3N), 3.91 (s,
3H, CH3O), 4.71 (d, J = 6.8 Hz, 2H, CH2N), 5.39 (m, 1H,
H-2ꢀ), 7.80 (s, 1H, H-2/H-8), 8.47 (s, 1H, H-2/H-8); 13C NMR
(CDCl3, 125 MHz) d 18.1 (CH3), 25.8 (CH3), 29.8 (CH3N), 48.2
(E)-N-(3,7-Dimethyl-2,6-octadienyl)-N-methoxy-9-methyl-9H-
purin-6-amine (11d). 0.43 mmole purine 8 and 1.5 eq. of
geranyl bromide 2d were used, yield 38 mg (28%), pale yellow
1
oil. H NMR (CDCl3, 500 MHz) d 1.43 (bs, 3H, CH3), 1.53
ꢀ
ꢀ
=
(CH2N), 62.4 (CH3O), 118.6 ( CH), 119.2 (C-1 ), 137.1 (C-3 ),
141.0 (C-8), 151.7 (C-4), 152.2 (C-2), 155.8 (C-6); MS (EI) m/z
(rel. %) 247 (M+, 25), 216 (100), 179 (49), 149 (38), 134 (32),
133 (21), 122 (22), 107 (15), 69 (21), 41 (31); HRMS: found
247.143447, calcd for C12H17N5O 247.143310. Anal.: found: C,
57.43; H, 6.93; N, 27.89%. C12H17N5O requires C, 58.28; H,
6.93; N, 28.32%.
(bs, 3H, CH3), 1.69 (bs, 3H, CH3), 1.92 (m, 2H), 2.00 (m, 2H),
3.74 (s, 3H, CH3N), 3.85 (s, 3H, CH3O), 4.66 (d, J = 6.9 Hz,
2H, CH2N), 4.95 (m, 1H, H-6ꢀ), 5.35 (m, 1H, H-2ꢀ), 7.73 (s, 1H,
H-8), 8.39 (s, 1H, H-2); 13C NMR (CDCl3, 125 MHz) d 16.3
(CH3), 17.5 (CH3), 25.4 (CH3), 26.1 (CH2), 29.6 (CH3N), 39.4
(CH2), 48.1 (CH2N), 62.3 (CH3O), 118.3 (C-2ꢀ), 119.1 (C-5),
123.8 (C-6ꢀ), 131.3 (C-7ꢀ), 140.2 (C-3ꢀ), 140.8 (C-8), 151.5 (C-4),
152.1 (C-2), 155.8 (C-6); MS (EI) m/z (rel. %) 315 (M+, 3), 247
(14), 246 (100), 216 (18), 215 (19), 179 (32), 174 (11), 150 (12),
133 (12), 69 (24), 41 (19); HRMS: found 315.2059, calcd for
C17H25N5O 315.2059.
(E)-6-(Methoxyamino)-9-methyl-7-(3-phenyl-2-propenyl)-7H-
purinium bromide (9c). 1.0 Eq. of cinnamyl bromide 2c were
used; yield 91 mg (54%), mp 225–227 ◦C (dec.) colorless crystals.
1H NMR (DMSO-d6, 500 MHz) d 3.81 (s, 3H, CH3N), 3.86 (s,
1 0 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3

View Article Online
(2ꢀE,6ꢀE,10ꢀE)-6-(Methoxyamino)-9-methyl-7-(3,7,11,15-tetra-
methyl-2,6,10,14-hexadecatetraenyl)-7H-purinium chloride (9e).
0.24 mmole purine 8 and 1.2 eq. of the allylic bromide 2e were
used; yield 62 mg (57%) of betaine, 5◦7 mg (49%) of chloride.
Data for the betaine 10e: mp 168–173 C, pale yellow solid. 1H
NMR (CDCl3, 500 MHz) d 1.52 (s, 6H, 2 × CH3), 1.54 (s, 3H,
CH3), 1.60 (s, 3H, CH3), 1.74 (s, 3H, CH3, H-20ꢀ), 1.91 (m, 4H),
1.98 (m, 4H), 2.06 (m, 4H, H-4ꢀ, H-5ꢀ), 3.68 (s, 3H, CH3N),
3.76 (s, 3H, CH3O), 5.01 (m, 5H, H-1ꢀ, H-6ꢀ, H-10ꢀ and H-14ꢀ),
5.37 (m, 1H, H-2ꢀ), 7.70 (s, 1H, H-2), 7.82 (s, 1H, H-8); 13C
NMR (CDCl3, 50 MHz) d 15.9 (CH3), 16.0 (CH3), 16.7 (CH3,
C-20ꢀ), 17.6 (CH3), 25.6 (CH3), 26.0 (CH2), 26.5 (CH2), 26.6
(CH2), 30.9 (CH3N), 39.4 (CH2), 39.57 (CH2), 39.61 (CH2),
47.5 (NCH2), 61.3 (CH3O), 109.2 (C-5), 116.0 (C-2ꢀ), 123.1
(CH2), 26.7 (CH2), 31.4 (CH3N), 33.3 (2 × CH2), 35.8 (CH2),
37.0 (CH2), 37.4 (CH), 39.5 (CH2), 47.9 (CH2N), 61.8 (CH3O),
ꢀ
ꢀ
=
=
110.0 (C-5), 115.6 ( CH, C-2 ), 122.7 ( CH, C-6 ), 130.8 (C-8),
=
=
136.7 ( C), 144.2 (C-4), 146.2 ( C), 155.0 (C-2), C-6 was
hidden; MS (electrospray) m/z (rel. %) 412 (100, M+), 182 (14);
HRMS: found 412.3089, calcd for C24H38N5O+ 412.3070.
(2ꢀE,6ꢀE)-N-(9-Cyclohexyl-3,7-dimethyl-2,6-nonadien-1-yl)-
N-methoxy-9-methyl-9H-purin-6-amine (11f). 0.27 mmole
purine 8 and ca. 1.2 eq. of crude (2ꢀE,6ꢀE)-9-cyclohexyl-3,7-
dimethyl-2,6-nonadien-1-yl bromide 2f were used; yield 23 mg
1
(24%), colorless oil. H NMR (CDCl3, 500 MHz) d 0.82 (m,
2H), 1.15 (m, 6H), 1.52 (s, 3H, CH3), 1.63 (m, 5H), 1.75 (br s,
3H, CH3), 1.88 (m, 2H), 1.99 (m, 2H), 2.04 (m, 2H), 3.80 (s,
3H, CH3N), 3.90 (s, 3H, CH3O), 4.71 (d, J = 6.8 Hz, 2H), 5.03
=
=
=
=
( CH), 123.8 ( CH), 124.2 ( CH), 128.9 (C-8), 131.2 ( C),
(m, 1H), 5.42 (m, 1H), 7.79 (s, 1H, H-8), 8.45 (s, 1H, H-2); 13
C
=
=
=
=
135.0 ( C), 135.8 ( C), 145.0 ( C), 145.3 ( C), 148.0 (C-6),
157.0 (C-2). Data for the purinium chloride 9e: colorless solid.
1H NMR (CDCl3, 500 MHz) d 1.56 (s, 6H, 2 × CH3), 1.57 (s,
3H, CH3), 1.64 (s, 3H, CH3), 1.79 (s, 3H, CH3), 1.91–196 (m,
4H), 2.00–2.05 (m, 4H), 2.10 (m, 4H), 3.79 (s, 3H, CH3N), 3.81
(s, 3H, CH3O), 5.05 (m, 5H, H-1ꢀ, H-6ꢀ, H-10ꢀ and H-14ꢀ), 5.42
(br t, J 7.2 Hz, 1H, H-2ꢀ), 7.81 (s, 1H, H-2), 8.35 (s, 1H, H-8);
13C NMR (CDCl3, 50 MHz) d 16.0 (CH3), 16.1 (CH3), 16.9
(CH3), 17.6 (CH3), 25.7 (CH3), 26.0 (CH2), 26.6 (CH2), 26.7
NMR (CDCl3, 125 MHz) d 15.9 (CH3), 16.5 (CH3), 26.3 (CH2),
26.4 (CH2), 26.7 (CH2), 29.8 (CH3N), 33.3 (CH2), 35.8 (CH2),
36.9 (CH2), 37.3 (CH), 39.7 (CH2), 48.2 (CH2), 62.5 (CH3O),
118.4 (CH), 119.2 (C-5), 123.4 (C-6ꢀ), 135.9 (C-7ꢀ), 140.5 (C-3ꢀ),
140.9 (C-8), 151.7 (C-4), 152.3 (C-2), 155.9 (C-6); MS (EI) m/z
(rel. %) 411 (M+, 3), 380 (27), 247 (13), 246 (100), 216 (35), 215
(16), 179 (34), 150 (11), 149 (14); HRMS: found 411.2993, calcd
for C24H37N5O+ 411.2998.
(CH2), 31.2 (CH3N), 39.5 (CH2), 39.67 (CH2), 39.70 (CH2), 47.8
(R)-(2ꢀE,6ꢀE)-6-(Methoxyamino)-9-methyl-7-[2,2-dimethyl-6-
methylenecyclohexyl)-3,7-dimethyl-2,6-nonadien-1-yl]-7H-puri-
nium chloride (9g). 0.32 mmole purine 8 and ca. 1.2 eq. of crude
(R)-(−)-(2E,6E)-9-(2,2-dimethyl-6-methylenecyclohexyl)-3,7-
dimethyl-2,6-nonadien-1-yl bromide 2g were used; yield 75 mg
ꢀ
=
(NCH2), 61.6 (CH3O), 109.8 (C-5), 115.9 ( CH, C-2 ), 123.2
=
=
=
=
( CH), 123.9 ( CH), 124.3 ( CH), 130.6 (C-8), 131.3 ( C),
=
=
135.1 ( C), 135.9 ( C), 144.4 (C-4), 145.5 (C-6), 155.6 (C-2);
MS (electrospray) m/z (rel. %) 452 (M+, 100), 180 (11); HRMS:
found 452.3399, calcd for C27H42N5O+ 452.3383.
1
(48%) of chloride. Data for the betaine 10g: colorless wax. H
(2ꢀE,6ꢀE,10ꢀE)-N-(3,7,11,15-Tetramethyl-2,6,10,14-hexadeca-
tetraenyl)-N-methoxy-9-methyl-9H-purin-6-amine (11e). 0.24
mmole purine 8 and 1.2 eq. of the allylic bromide 2e were used;
yield 41 mg (29%), colorless oil. 1H NMR (CDCl3, 500 MHz) d
1.54 (bs, 6H, 2 × CH3), 1.56 (bs, 3H, CH3), 1.64 (bs, 3H, CH3),
1.75 (bs, 3H, CH3), 1.92 (m, 4H), 2.03 (m, 8H), 3.80 (s, 3H,
CH3N), 3.90 (s, 3H, CH3O), 4.71 (d, J = 6.8 Hz, 2H, CH2N),
5.05 (t, J = 6.5 Hz, 3H), 5.41 (m, 1H, H-2ꢀ), 7.79 (s, 1H, H-8),
8.45 (s, 1H, H-2); 13C NMR (CDCl3, 50 MHz) d 16.0 (CH3),
16.5 (CH3), 17.6 (CH3), 25.7 (CH3), 26.3 (CH2), 26.6 (CH2),
26.7 (CH2), 29.7 (CH3N), 39.6 (CH2), 39.7 (CH2), 48.2 (CH2N),
62.5 (CH3O), 118.4 (CH, C-2ꢀ), 119.2 (C-5), 123.9 (CH), 124.2
(CH), 124.3 (CH), 131.2 (C), 134.9 (C), 135.2 (C), 140.5 (C-3ꢀ),
140.9 (C-8), 151.7 (C-4), 152.3 (C-2), 156.0 (C-6), 2 sign. were
hidden; MS (EI) m/z (rel. %) 451 (M+, 2), 247 (14), 246 (100),
216 (79), 215 (19), 179 (31), 162 (16), 150 (20), 149 (19), 69 (29),
41 (13); HRMS: found 451.3329, calcd for C27H41N5O 451.3311.
(2ꢀE,6ꢀE)-6-(Methoxyamino)-9-methyl-7-(9-cyclohexyl-3,7-
dimethyl-2,6-nonadien-1-yl)-7H-purinium chloride (9f). 0.27
mmole purine 7 and ca. 1.2 eq. of crude (2ꢀE,6ꢀE)-9-cyclohexyl-
3,7-dimethyl-2,6-nonadien-1-yl bromide 2f were used; 52 mg
(50%) of chloride. Data for the betaine 10f: mp 175–178 ◦C
(dec.) colorless crystals. 1H NMR (CDCl3, 500 MHz) d 0.82 (m,
2H), 1.14 (m, 6H), 1.53 (s, 3H, CH3), 1.62 (m, 5H), 1.75 (s, 3H,
CH3), 1.90 (m, 2H), 2.07 (br s, 4H), 3.70 (s, 3H, CH3N), 3.78 (s,
3H), 5.01 (m, 1H, H-6ꢀ), 5.01 (d, J = 7.3 Hz, 2H, CH2N), 5.38
(t, J = 7.3 Hz, 1H, H-2ꢀ), 7.73 (s, 1H, H-2), 7.78 (s, 1H, H-8);
13C NMR (CDCl3, 125 MHz) d 16.0 (CH3), 16.7 (CH3), 26.6
(CH2), 26.3 (CH2), 26.6 (CH2), 31.0 (CH3N), 33.2 (CH2), 35.7
(CH2), 37.0 (CH2), 37.3 (CH), 39.4 (CH2), 47.6 (CH2N), 61.4
(CH3O), 109.3 (C-5), 115.9 (C-2ꢀ), 122.6 (C-6ꢀ), 128.7 (C-8),
136.6 (C-7ꢀ), 145.1 (C-4), 145.5 (C-3ꢀ), 148.0 (C-6), 157.1 (C-2).
Data for the purinium chloride 9f: wax. 1H NMR (CDCl3,
500 MHz) d 0.81–0.87 (m, 2H), 1.06–1.24 (m, 6H), 1.50 (s, 3H,
CH3), 1.60–1.70 (m, 5H), 1.81 (s, 3H, CH3), 1.92–1.97 (m, 2H),
2.12 (br s, 4H), 3.80 (s, 3H, CH3N), 3.84 (s, 3H, CH3O), 5.04
(m, 1H, H-6ꢀ), 5.08 (d, J = 7.5 Hz, 2H, CH2N), 5.43 (t, J =
7.3 Hz, 1H, H-2ꢀ), 7.83 (s, 1H, H-2), 8.39 (s, 1H, H-8); 13C NMR
(CDCl3, 125 MHz) d 16.1 (CH3), 16.9 (CH3), 26.0 (CH2), 26.4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3
1 0 3 1

View Article Online
7-dimethyl-2,6-nonadien-1-yl bromide 2h were used; 62 mg (44%),
colorless wax. [a]2D0 +4.3 (c 1.2, CHCl3); for spectral data, see 9g.
(2ꢀE,6ꢀE,10ꢀE)-6-Amino-9-methyl-7-(3,7,11,15-tetramethyl-2,
6,10,14-hexadecatetraenyl)-7H-purinium chloride (12e). The
compound was prepared by reduction of compound 9e (34 mg,
0.070 mmol); yield 23◦mg (72%) pale yellow waxy solid, mp
155–158 (lit.9 158–162 C). 1H NMR (CDCl3, 500 MHz) d 1.52
(s, 3H, CH3), 1.54 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.64 (s, 3H,
CH3), 1.80 (s, 3H, CH3), 1.87–1.94 (m, 4H), 1.95–2.02 (m, 4H),
(S)-(2ꢀE,6ꢀE)-N-[2,2-Dimethyl-6-methylenecyclohexyl)-3,7-di-
methyl-2,6-nonadien-1-yl]-N-methoxy-9-methyl-9H-purin-6-amine
(11h). 0.32 mmole purine 8 and ca. 1.2 eq. of crude (S)-
(2E,6E)-9-(2,2-dimethyl-6-methylenecyclohexyl)-3,7-dimethyl-
2,6-nonadien-1-yl bromide 2h were used; 37 mg (26%), colorless
oil. [a]2D0 +4.9 (c 0.66, CHCl3); for spectral data, see 11g.
=
2.04 (br s, 4H), 4.06 (s, 3H, NCH3), 5.00 (m, 1H, CH), 5.04
=
=
(m, 2H, CH), 5.45 (br t, J = 6.5 Hz, 1H, CH), 5.55 (d, J
6.5 = Hz, 2H, NCH2), 6.88 (br s, 2H, NH2), 8.42 (s, 1H, H-2),
10.12 (s, 1H, H-8); 13C NMR (CDCl3, 125 MHz) d 16.0 (CH3),
16.1 (CH3), 17.4 CH3), 17.7 CH3), 25.7 CH3), 26.1 (CH2), 26.6
(CH2), 26.7 (CH2), 32.1 (NCH3), 39.5 (CH2), 39.6 (CH2), 39.7
General procedure for the synthesis of compounds 12
A mixture of compound 9 (0.9 mmol) and Zn powder (9.0 mmol)
in MeOH (25 mL), water (5 mL) and conc. acetic acid (0.62 mL)
was stirred under a N2 atmosphere at 60 ◦C for 15 h. After
cooling to ambient temperature, the mixture was filtered and the
solid washed with 25 mL MeOH. The filtrate was mixed with
MeOH (20 mL), sat. aq. NaCl (2.5 mL) and water (20 mL) and
the mixture was stirred for 1 h before evaporation. The residue
was dissolved in sat. aq. NaCl (5 mL) and water (5 mL), extracted
with CH2Cl2 (5 × 25 mL), dried (MgSO4) and evaporated.
The product was purified by flash chromatography on silica
gel eluting with CH2Cl2 followed by CH2Cl2 : MeOH (80 : 1),
CH2Cl2 : MeOH (30 : 1), and CH2Cl2 : MeOH (4 : 1).
=
=
(CH2), 48.7 (NCH2), 109.8 (C-8), 116.0 ( CH), 123.1 ( CH),
=
=
=
=
124.0 ( CH), 124.3 ( CH), 131.2 ( C), 135.1 ( C), 136.0
=
=
( C), 141.6 (C-8), 146.3 ( C), 149.5 (C-4), 152.2 (C-6), 155.9
(C-2); MS (ESI) m/z (rel.%): 422 (100, M+), 294 (5), 224 (8),
150 (8).
(2ꢀE,6ꢀE)-6-Amino-9-methyl-7-(9-cyclohexyl-3,7-dimethyl-2,6-
nonadien-1-yl)-7H-purinium chloride (12f). The compound
was prepared by reduction of compound 9f (31 mg, 0.069 mmol);
1
yield 20 mg (69%), colorless waxy material. H NMR (CDCl3,
500 MHz) d 0.77–0.84 (m, 2H), 1.05–1.22 (m, 6H), 1.50 (s,
3H, CH3), 1.58–1.64 (m, 5H), 1.80 (s, 3H, CH3), 1.86 (m, 2H),
7-(Allyl)-6-amino-9-methyl-7H-purinium chloride (12a).
Yield 122 mg (52%), mp 227–230 ◦C (dec.) colorless crystals. 1H
NMR (DMSO-d6, 500 MHz) d 3.88 (s, 3H, CH3), 5.24 (d, J =
17.2 Hz, H-3ꢀ), 5.31 (d, J = 10.4 Hz, H-3ꢀ), 5.36 (br s, 2H, H-1ꢀ),
6.07 (m, 1H, H-2ꢀ), 7.92 (br s, 2H, NH2), 8.41 (s, 1H, H-2), 9.89
(s, 1H, H-8); 13C NMR (DMSO-d6, 75 MHz): d 31.6 (CH3),
=
2.03 (br s, 4H), 4.06 (NCH3), 4.97 (m, 1H, CH), 5.45 (br t,
=
J = 6.2 Hz, 1H, CH), 5.57 (d, J = 6.2 Hz, 2H, NCH2), 6.95
(br s, 2H, NH2), 8.42 (s, 1H, H-2), 10.19 (s, 1H, H-8); 13C NMR
(CDCl3, 125 MHz) d 16.0 (CH3), 17.4 (CH3), 26.1 (CH2), 26.3
(2 × CH2), 26.7 (CH2), 32.2 (NCH3), 33.3 (2 × CH2), 35.8
(CH2), 36.9 (CH2), 37.4 (CH), 39.5 (CH2), 48.7 (NCH2), 109.8
=
=
50.5 (NCH2), 108.9 (C-5), 119.4 ( CH2), 131.8 (CH ), 142.0
(C-8), 149.0 (C-4), 152.0 (C-6), 155.9 (C-2); MS (ESI) m/z (rel.
%) 190 (M+, 74), 181 (100), 163 (60), 156 (57), 149 (11); HRMS:
=
=
=
(C-5), 116.0 ( CH), 122.6 ( CH), 136.6 ( C), 141.6 (C-8),
=
146.4 ( C), 149.5 (C-4), 152.3 (C-6), 155.9 (C-2); MS (ESI)
+
found 190.1083, calcd for C9H12N5 190.1087.
m/z (rel.%): 382 (100, M+), 205 (1), 150 (6), 141 (2); HRMS:
found 382.2961, calcd. for C23H36N5 382.2965.
+
6-Amino-9-methyl-7-(3-methyl-2-butenyl)-7H-purinium chlo-
ride (12b). The compound was prepared by reduction of
com◦pound 9c (56 mg,◦0.17 mmol); yield 32 mg (74%), mp 161–
(R)-(2ꢀE,6ꢀE)-6-Amino-9-methyl-7-[2,2-dimethyl-6-methylene-
cyclohexyl)-3,7-dimethyl-2,6-nonadien-1-yl]-7H-purinium chlo-
ride (12g), agelasine E. The compound was prepared by
reduction of compou◦nd 9g (40 mg, 0.082 mmol); yield 24 mg
(52%), mp 176–178 C colorless crystals (lit.2 180–182 ◦C);
[a]D −2.1 (c 0.36, CHCl3); (lit.2 [a]D20 −17.1 (c 1.88, CH3OH)).
1H NMR (CDCl3, 500 MHz) d 0.78 (s, 3H, CH3), 0.87 (s, 3H,
CH3), 1.36–1.49 (m, 7H), 1.52 (s, 3H, CH3), 1.61–1.64 (m, 1H),
1.81 (s, 3H, CH3), 1.94–2.15 (m, 7H), 4.06 (s, 3H, NCH3), 4.48
1
165 C (lit.9 164–169 C). H NMR (CDCl3, 300 MHz) d 3.88
(s, 3H, CH3), 5.27 (d, J = 6.4 Hz, 2H, NCH2), 5.43 (br t, J =
=
6.4 Hz, 1H, CH), 7.00 (br s, 2H, NH2), 8.48 (s, 1H, H-2), 9.76
(s, 1H, H-8).
(E)-6-Amino-9-methyl-7-(3-phenyl-2-propenyl)-7H-purinium
chloride (12c). The compound was prepared by reduction
of compound 9c (76 mg, 0.20 mmol); yield 50 mg (82%), mp
◦
1
181–185 C (dec.). H NMR (DMSO-d6, 500 MHz) d 3.90 (s,
3H, CH3), 5.50 (d, J = 5.8 Hz, 2H, NCH2), 6.48–6.54 (m, 1H,
=
=
(d, J = 2.4 Hz, 1H, CH), 4.71 (br s, 1H, CH), 4.98 (m, 1H,
=
=
CH), 5.49 (d, J = 6.3 Hz, 1H, CH), 5.56 (d, J = 6.3 Hz,
=
=
CH), 6.76 (d, J = 16.0 Hz, 1H, CH), 7.28 (m, 1H, Ph), 7.35
1H, NCH2), 6.79 (br s, 2H, NH2), 8.43 (s, 1H, H-2), 10.2 (s,
1H, H-8); 13C NMR (CDCl3, 125 MHz) d 16.1 (CH3), 17.3
(CH3), 23.7 (CH2), 24.7 (CH2), 26.1 (CH2), 28.4 (CH3), 32.1
(CH3), 32.3 (CH2), 32.4 (NCH3), 36.2 (CH2), 38.2 (CH2), 39.5
(m, 2H, Ph), 7.44 (d, J = 7.4 Hz, 2H, Ph), 8.02 (br s, 2H, NH2),
8.45 (s, 1H, H-2), 9.97 (s, 1H, H-8); 13C NMR (DMSO-d6,
75 MHz) d 31.4 (CH3), 50.3 (NCH2), 109.0 (C-5), 122.6 ( CH),
126.7 (CH in Ph), 128.4 (CH in Ph), 128.7 (CH in Ph), 134.2
=
=
(CH2), 48.7 (CH2), 53.6 (CH), 108.9 ( CH2), 109.9 (C-5), 116.1
=
( CH), 135.6 (C in Ph), 142.0 (C-8), 149.0 (C-4), 152.0 (C-6),
=
=
=
=
( CH), 122.8 ( CH), 136.7 ( C), 142.0 (C-8), 146.6 ( C),
155.5 (C-2); MS (ESI) m/z (rel. %) 266 (M+, 100), 214 (7),
=
=
149.3 ( C/C-4), 149.5 ( C/C-4), 152.2 (C-6), 156.0 (C-2), MS
182 (7), 158 (12), 159 (13), 141 (6), 117 (60); HRMS: found
(ESI) m/z (rel. %) 422 (M+, 100).
+
266.1387, calcd for C15H15N5 266.1400.
(E)-6-Amino-9-methyl-7-(3,7-dimethyl-2,6-octadienyl)-)-7H-
purinium chloride (12d). The compound was prepared by
reduction of compo◦und 9d (59 mg, 0.168 mmol); yield 40 mg
(S)-(2ꢀE,6ꢀE)-6-Amino-9-methyl-7-[2,2-dimethyl-6-methylene-
cyclohexyl)-3,7-dimethyl-2,6-nonadien-1-yl]-7H-purinium chlo-
ride (12h). The compound was prepared by reduction of
compound 9h (45 mg, 0.092 mmol); yield 34 mg (89%), mp
◦
1
(71%), mp 144–146 C colorless crystals (lit.9 145–150 C). H
NMR (CDCl3, 300 MHz) d 1.53 (s, 3H, CH3), 1.60 (s, 3H,
CH3), 1.80 (s, 3H, CH3), 2.07 (m, 4H, CH2), 4.17 (s, 3H, OCH3),
4.99 (m, 1H, CH), 5.57 (m, 3H, CH2 and CH), 6.69 (br s, 2H,
NH2), 8.44 (s, 1H, H-2), 9.92 (s, 1H, H-8); 13C NMR (CDCl3,
75 MHz) d 17.7 (CH3), 18.1 (CH3), 26.0 (CH3), 26.4 (CH2), 32.5
◦
176–179 C, colorless crystals [a]2D0 +2.2 (c 0.68, CHCl3). For
spectral data, see 12g.
Activity against Mycobacterium tuberculosis
=
(CH3), 39.8 (CH2), 49.1 (NCH2), 110.2 (C-5), 116.5 ( CH),
The primary screening against Mycobacterium tuberculosis
H37Rv (ATCC 27294) was conducted at 6.25 lg mL−1 in
BACTEC 12B medium using the Microplate Alamar Blue Assay
(MABA) as described.24 Compounds exhibiting fluorescence
were tested in the BACTEC 460-radiometric system24 and
=
=
=
123.6 ( CH), 132.7 ( C), 142.0 (C-8), 146.9 ( C), 149.9 (C-4),
152.8 (C-6), 156.4 (C-2); MS (ESI) m/z (rel. %) 286 (M+, 100),
151 (6), 150 (50); HRMS: found 286.2032, calcd for C16H24N5
+
286.2026.
1 0 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3

View Article Online
compounds demonstrating at least 90% inhibition in the pri-
mary screen were retested at lower concentrations against M.
tuberculosis H37Rv to determine the actual minimum inhibitory
concentration (MIC) in the MABA. MIC for rifampicin was
0.25 lg mL−1.
9 (a) E. Piers and J. Y. Roberge, Tetrahedron Lett., 1992, 33, 6923; (b) H.
Iio, K. Asao and T. Tokoroyama, J. Chem. Soc., Chem. Commun.,
1985, 774.
10 K. Asao, H. Iio and T. Tokoroyama, Tetrahedron Lett., 1989, 30,
6401.
11 B. T. Utenova and L.-L. Gundersen, Tetrahedron Lett., 2004, 45,
4233.
12 G. C. Mangalindan, M. T. Talaue, L. J. Cruz, S. G. Franzblau, L. B.
Adams, A. D. Richardson, C. M. Ireland and G. P. Conception,
Planta Med., 2000, 66, 364.
Acknowledgements
The Norwegian Research Council is greatly acknowledged for
scholarship to BTU and AV, as well as for partial financing of
the Bruker Avance instruments used in this study. Antimycobac-
terial data were provided by the Tuberculosis Antimicrobial
Acquisition and Coordinating Facility (TAACF) through a
research and development contract with the US National
Institute of Allergy and Infectious Diseases; we are grateful for
all help provided by Dr. Cecil Kwong and his co-workers.
13 K. Duncan, Chem. Ind., 1997, 861.
14 A. K. Bakkestuen and L.-L. Gundersen, Tetrahedron, 2003, 59, 115.
15 S.-Y. Chou, C.-L. Tseng and S.-F. Chen, Tetrahedron Lett., 2000, 41,
3895.
16 H. H. Seltzman, M. A. Moody and M. K. Begum, Tetrahedron Lett.,
1992, 33, 3443.
17 See for example: P. Basabe, A. Diego, S. Delgado, D. Dies, I. S.
Marcos and J. G. Urones, Tetrahedron, 2003, 59, 9173.
18 T. Fujii and T. Itaya, Heterocycles, 1999, 51, 393, and references
therein.
References
19 T. Fujii, T. Itaya, C. C. Wu and F. Tanaka, Tetrahedron, 1971, 27,
1 H. Nakamura, H. Wu, Y. Ohizumi and Y. Hirata, Tetrahedron Lett.,
1984, 25, 2989.
2 H. Wu, H. Nakamura, J. Kobayashi and Y. Ohizumi, Tetrahedron
Lett., 1984, 25, 3719.
2415.
20 G. E. Martin and C. E. Hadden, J. Nat. Prod., 2000, 63, 543.
21 T. Fujii, T. Saito, T. Itaya, K. Kizu, Y. Kumazawa and S. Nakajima,
Chem. Pharm. Bull., 1987, 35, 4482.
3 R. J. Capon and D. J. Faulkner, J. Am. Chem. Soc., 1984, 106, 1819.
4 H. Wu, H. Nakamura, J. Kobayashi, M. Kobayashi, Y. Ohizumi and
Y. H i r at a , Bull. Chem. Soc. Jpn., 1986, 59, 2495.
5 K. Ishida, M. Ishibashi, H. Shigemori, T. Sasaki and J. Kobayashi,
Chem. Pharm. Bull., 1992, 40, 766.
6 T. Hattori, K. Adachi and Y. Shizuri, J. Nat. Prod., 1997, 60, 411.
7 X. Fu, F. J. Schmitz, R. S. Tanner and M. Kelly-Borges, J. Nat. Prod.,
1998, 61, 548.
22 G. Remaud, J. Kjellberg, H. Bazin, N. G. Johansson and J.
Chattopadhaya, Tetrahedron, 1986, 42, 5073.
23 D. Pappo and Y. Kashman, Tetrahedron, 2003, 59, 6493.
24 L. Collins and S. G. Franzblau, Antimicrob. Agents Chemother., 1997,
41, 1004; http://www.taacf.org/.
25 E. Alksnis, D. Korneeva and E. Lukevics, Chem. Heterocycl. Comp.,
2001, 37, 743.
26 G. B. Barlin and N. B. Chapman, J. Chem. Soc., 1965, 3017.
27 K. K. Ogilvie, S. L. Beaucage and M. F. Gillen, Tetrahedron Lett.,
1978, 35, 3203.
8 E. Piers, M. L. Livain, Y. Han, G. L. Plourde, L. Guy and W.-L. Yeh,
J. Chem. Soc., Perkin Trans. 1, 1995, 963.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 2 5 – 1 0 3 3
1 0 3 3