Synthesis of (+)-agelasine C. A structural revision

Article abstract of DOI:10.1016/j.tet.2005.09.049

An efficient synthesis of (+)-agelasine C has been achieved from ent-halimic acid. The structure and absolute configuration of the natural product (-)-agelasine C was established and a structure for epi-agelasine C, is proposed.

Full text of DOI:10.1016/j.tet.2005.09.049

Tetrahedron 61 (2005) 11672–11678
Synthesis of (C)-agelasine C. A structural revision
*
´
I. S. Marcos, N. Garcıa, M. J. Sexmero, P. Basabe, D. Dıez and J. G. Urones
´
´
´
´
Departamento de Quımica Organica, Universidad de Salamanca, Plaza de los Caıdos 1-5, 37008 Salamanca, Spain
Received 18 July 2005; revised 14 September 2005; accepted 15 September 2005
Available online 10 October 2005
Abstract—An efficient synthesis of (C)-agelasine C has been achieved from ent-halimic acid. The structure and absolute configuration of
the natural product (K)-agelasine C was established and a structure for epi-agelasine C, is proposed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Epi-agelasine C8 was isolated in 1997 for Hattori et al. from
the marine sponge Agelas mauritiana as an antifouling
substance active against macroalgae. The structure of this
substance was elucidated by spectral means. The stereo-
estructure of epi-agelasine C was established by its NOE
difference spectrum. The absolute configuration still is not
known, Hattori et al. presented the structural formula 2 for
epi-agelasine C (Fig. 1).
Agelasines are a diterpene-alkaloid group, 7,9-dialkylpurine
salts, isolated from marine sponges of the genus Agelas sp.1
Until now only 11 natural products have been described,
wearing all of them a diterpene side chain in position 7
of the adenine. Until now only (K)-agelasine A,2
(K)-agelasine B,3 (G)-agelasine F4 and (C)-agelasine D5
have been synthesized.
Due to the interest of epi-agelasine C as antifouling agent9
and having the possibility of establish the absolute
configuration of this compound the synthesis of 19, has
been carried out in this work.
Agelasines are associated with biological activities with
antimicrobial and cytotoxic effects, as well as contractive
response of smooth muscles and inhibition of Na,K-
ATPase, strong activity against Mycobacterium tubercu-
losis and antifouling agent for macroalgae.6 Agelasine C is
one of the first four known agelasines isolated by Nakamura
et al. in 1984,7 from Okinawan sea sponge Agelas sp.
Agelasine C showed powerful inhibitory effects on Na,K-
ATPase and antimicrobial activities (Fig. 1).
The union of the diterpenic part with the halimane skeleton
(rearranged labdane skeleton) to the nitrogen atom at 70
position of the 90-methyladeninium group, was fixed
spectroscopically. The configuration at C-8 and C-9 was
established by chemical correlation as it was done with
agelasine A, being perfectly established the relative cis
configuration for the methyls at C-8 and C-9. The
configuration at C-5 and so the absolute configuration was
tentatively determined by circular dichroism and spectro-
scopical studies of a ketone. Nakamura et al. have presented
the structural formula 1 for agelasine C.
Keywords: Agelasine C; Epi-agelasine C; Diterpenes alkaloids; Ent-halimic
acid.
*
Corresponding author. Tel.: C34 923 294474; fax: C34 923294574;
e-mail: ismarcos@usal.es
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.049

I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
11673
2. Results and discussion
transformation required the reduction of the methoxy-
carbonyl at C-18 to a methyl group and substitution of the
alcohol in C-15 for bromine (Scheme 3).
The synthesis of 19 was planned following an analogue
scheme to the one for other agelasines, this is coupling of
the terpenic fragment with the corresponding purine as 4
(Scheme 1).
In order to reduce C-18 (Scheme 3) is necessary to protect
previously C-15 as tetrahydropyrane derivative. The
reaction of 3 with DHP15 in p-TsOH gives 11 that by
reduction with LAH lead to the hydroxyderivative 12. The
reaction of 12 with CS2 followed by treatment with MeI in
alkaline media led to the xantogenate 13, that by reduction
with Bu3SnH in presence of AIBN gave the reduction
product 15 in a modest yield.16 This yield was increased
when aldehyde 14, obtained by oxidation of 12 with TPAP,
was reduced using Huang–Minlon methodology.17 Depro-
tection of the primary hydroxy group followed by the
As starting material for the terpenic part, ent-halimic acid
methyl ester 3, duly transformed its functional groups into
the bromoderivative 5, will contribute the necessary
stereogenic centres. Ent-halimic acid is a known natural
product used already for the synthesis of chettaphanin I and
II,10 ent-halimanolides11 and sesterterpenolides.12
The synthesis of 19 is carried out in a convergent way,
synthesis of the purine fragment and the diterpenic part.
18
treatment of the hydroxyderivative 16 with CBr4 in
presence of PPh3 gave the required bromoderivative 5.
The purinic fragment 4 was done following the method-
ology of Fujii13 from adenine (Scheme 2).
Once the two fragments were obtained the synthesis was
continued. Alkylation of methoxyadenine 4 with the
bromoderivative 5 (Scheme 4) gives a mixture of 17 and
18.19 Compound 18 is the required one and 17 is the isomer
corresponding to the alkylation of the N in C-6 (Scheme 4).
The separation of these compounds is very difficult and was
achieved using polar solvents as CH2Cl2/MeOH/NH4OH in
silica gel column chromatography.
Oxidation of adenine with peracetic acid14 gives oxide 6
that by methylation produce the iodohydrate 7 that lead to 8
when pass through an amberlite column. The N-methyl
oxide 8 was selectively methylated in 9 position by
treatment with MeI in DMA (dimethyl acetamide) giving
compound 9 from which, imine 10 is obtained when passed
through an amberlite column. When compound 10 is heated
in refluxing water the required compound 4 is obtained.
Finally reduction of 18 with Zn/AcOH gives compound 19.
The physical properties of 19 are very different to the
natural product epi-agelasine C, whose proposed structure 2,
(Fig. 1) should be revised. By contrary when compared the
The second part of the synthesis is the transformation of ent-
halimic acid methyl ester 3 into the bromoderivative 5. This
Scheme 1.
Scheme 2. (a) AcOOH, AcOH, 10%, 24 h (31%); (b) MeI, DMA, 20 h; (c) Amberlite IRA-402 (HCOK3 ), H2O (44%); (d) H2O, reflux, 90 min, (77%).

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I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
Scheme 3. (a) DHP, p-TsOH, C6H6, 15 min, rt, (98%); (b) LAH, Et2O, 0 8C and then rt, 4 h, (99%); (c) nBuLi, THF, K78 8C/0 8C, 30 min then CS2, 2 h, rt
then MeI, 1 h, rt, (98%); (d) nBu3SnH, AIBN, toluene, 120 8C, 20 min, (31%); (e) TPAP, NMO, sieves, DCM, Ar, 45 min, (94%); (f) diethylene glycol,
NH2–NH2$H2O, KOH, 175 8C/230 8C, 18 h, (81%); (g) p-TsOH, MeOH, 30 min, (81%); (h) CBr4, PPh3, DCM, 3 h, (76%).
Scheme 4. (a) DMA, 50 8C, 16 h, (17: 47%; 18: 36%); (b) Zn, MeOH, H2O, AcOH, argon, 60 8C, 2 days, (18: 47%; 19: 36%).
13C NMR spectra of 19 with agelasine C, structure proposed
25.0) allow us to propose for the natural compound the
absolute configuration of 21 (Fig. 2), considering the sign
and the contribution to the aD value of the stereogenic
centre C-8, that can be deduced by comparison of the
epimers compounds of cladocorane skeleton, already
mentioned.
1
1, showed to be identical, as their H NMR, although the
rotation for 19 ([a]D22C36.7) and agelasine C ([a]2D5K55.1)
have different sign. So it should be concluded that the
structure for (K)-agelasine C should be corrected to
structure 20, enantiomer of the synthesis product 19 (C)-
agelasine C (Fig. 2).
Considering the spectroscopical properties of epi-agelasine
C (C-5 and C-9 configurations were unequivocally
established by NOE experiments)8 and by comparison
with the ones of some derivatives with the same decaline as
the sesterterpenes with cladocorane skeleton,20 can be
concluded that when methyls Me-17 and Me-20 (ent-
halimane skeleton) or Me-24 and Me-25 (cladocorane
skeleton) are in disposition cis, Me-20 or its equivalent
Me-25 is always more shielded than in compounds with a
trans disposition of these methyls. This is the case for 19
1
and epi-agelasine C, in 19, the signal for Me-20 in the H
NMR spectrum appears at 0.96 ppm while in epi-agelasine
C the signal for Me-20 appears at 1.06 ppm and
consequently in the last compound Me-20 and Me-17
should be trans, as in 21.
Figure 2. Structure revised for (K)-agelasine C and proposed for epi-
agelasine C.
Rotation for epi-agelasine C ([a]2D5C33.9) and 19 ([a]D22C

I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
11675
3. Conclusions
140.6 (C-2), 156.3 (C-4), 118.9 (C-5), 146.9 (C-6), 155.7
(C-8), 68.1 (MeO–); ESIMS: 166 (MCC1, 100), 152 (20),
135 (85); ESIHRMS: calcd for C6H8N5O (M)C 166.0723;
found (M)C 166.0721.
From the present results, the structure of agelasine C is
clearly indicated in 20 and for the natural product epi-
agelasine C is proposed as 21.
4.3. Reaction of 8 with MeI: 10
4. Experimental
A mixture of 8 (7.0 g, 41.42 mmol), MeI (6.51 mL,
103.48 mmol) and AcNMe2 (56 mL) was stirred at room
temperature for 23 h. The resultant precipitates were filtered
off, washed with EtOH to give a white solid 9. A solution of
9 in H2O (250 mL) was passed through a column (Ø: 1 cm)
of amberlite IRA-402 (100 mL) in which previously, a
saturated aqueous solution of NaHCO3 and then H2O until
pH: 7, was passed. Slowly elution of the solution with water
(300 mL) and evaporation of the eluent in vacuo left 10
(5.0 g, 68%).
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used
without further purification. IR spectra were recorded on a
MATTSON-GENESIS II FT-IR spectrophotometer. 1H and
13C NMR spectra were performed in deuterochloroform
and referenced to the residual peak of CHCl3 at d 7.26 ppm
1
and d 77.0 ppm, for H and 13C, respectively, at a Bruker
WP-200 SY and a Bruker DRX 400 MHz. Chemical shifts
are reported in d ppm and coupling constants (J) are given in
Hz. MS were performed at a VG-TS 250 spectrometer at
70 eV ionizing voltage. Mass spectra are presented as m/z
(% rel int). HRMS were recorded on a VG Platform (Fisons)
spectrometer using chemical ionization (ammonia as gas).
Optical rotations were determined on a digital ADP 220
polarimeter in 1 dm cells. Diethyl ether, THF and benzene
were distilled from sodium, and pyridine and dichloro-
methane were distilled from calcium hydride under an Ar
atmosphere.
4.3.1. 1-Methoxy-9-methyladenine (10). Mp 172 8C.
4.4. Reaction of 10 with H2O/110 8C: 4
Compound 10 (900 mg, 5.06 mmol) was treated with
boiling water for 1.5 h. The mixture was cooled, evaporated
in vacuo and crystallized in H2O obtaining 4 (634 mg,
77%).
4.4.1. 6-Methoxyamine-9-methylpurine. (N-methoxy-9-
methyl-9H-purin-6-amine) (4). Mp 236 8C; UV (EtOH
95% aq): 268 nm; H RMN (D2O) d: 7.65 and 7.61 (1H, s
4.1. Reaction of adenine with AcOOH: 6
1
Adenine (10.0 g, 74.07 mmol) was solved in softly hot
AcOH (69 mL). To this solution, AcOOH 35% in AcOH
(28 mL) was added at room temperature. As result, a
solution of AcOOH in AcOH 10% was formed. After 24 h
stirring a substancial proportion of precipitated product was
formed, filtered off and washed with a little acetic acid.
Crystallization of adenine oxide from boiling water yielded
filamentous crystals 6 (3.5 g, 31%).
each, H-2, H-8), 3.79 (3H, s, MeO–), 3.56 (3H, s, N–Me);
13C RMN (D2O) d: 146.1 (C-2), 145.8 (C-4), 116.6 (C-5),
145.9 (C-6), 140.9 (C-8), 62.0 (MeO–), 23.9 (N–Me);
ESIMS: 180 (MCC1, 100), 150 (30), 149 (95), 145 (20),
132 (30), 127 (10), 113 (70); ESIHRMS: calcd for
C7H10N5O (M)C 180.0879; found (M)C180.0880.
4.5. Reaction of 3 with DHP: 11
4.1.1. Adenine N-oxide (6). Mp 300–301 8C; UV (H2O):
231, 262 nm; 1H RMN (D2O) d: 8.52 and 8.23 (1H, s each,
H-2, H-8); ESIMS: 152 (MCC1, 100), 135 (20);
ESIHRMS: calcd for C5H6N5O (M)C152.0567; found
(M)C152.0577.
To a solution of 3 (2.1 g, 6.23 mmol) in C6H6 (25 mL),
p-TsOH (237 mg, 1.25 mmol) and DHP (1.75 mL,
18.68 mmol) was added. After stirring 15 min at room
temperature, K2CO3 (200 mg) was added. The reaction
mixture was stirred for an additional 30 min, filtered off and
extracted with AcOEt. The combined organic extracts were
washed with Na2CO3 6%, brine and H2O. After drying over
Na2SO4, the solvent was evaporated in vacuo and the
residue was chromatographed over silica gel to give 11
(2.5 g, 98%).
4.2. Reaction of 6 with MeI: 8
A mixture of 6 (3.5 g, 20.83 mmol), MeI (3.23 mL,
52.07 mmol) and AcNMe2 (28 mL) was stirred at room
temperature for 20 h. The resultant precipitates were filtered
off, washed with a small amount of EtOH and evaporated in
vacuo. The residue was recrystallized from 70% EtOH/H2O
and filtered off in vacuo obtaining 7 (Mp 222 8C). The
hydriodide 7 was dissolved in H2O (97 mL) and the solution
was passed trough a column (Ø: 1 cm) of Amberlite IRA-
402 (29 mL) in which previously, a saturated aqueous
solution of NaHCO3 and then H2O till pH: 7, was passed.
Slowly elution with water (200 mL) and evaporation of the
eluate in vacuo left 8 (1.3 g, 44%).
4.5.1. Methyl-15-tetrahydropyranyloxy-ent-halima-
1(10),13E-dien-18-oate (11). [a]2D2C24.5 (c 0.4, CHCl3);
IR (film): 2940, 1732, 1456, 1256, 1200, 1117, 1024 cmK1
;
1H NMR d: 5.35–5.31 (2H, m, H-1, H-14), 4.98–4.93 and
4.66–4.60 (1H, m each, H-10), 4.23 (1H, dd, JZ12.1,
6.4 Hz, H-15A), 4.00 (1H, dd, JZ12.1, 7.5 Hz, H-15B),
3.93–3.88 (1H, m, H-50), 3.66 (3H, s, –COOMe), 3.58–3.53
(1H, m, H-50), 2.72–2.55 (1H, m, H-5), 2.15–1.00 (19H, m),
1.69 (3H, s, Me-16), 1.11 (3H, s, Me-19), 0.91 (3H, s,
Me-20), 0.80 (3H, d, JZ7.0 Hz, Me-17); 13C NMR d: 119.6
(C-1), 22.9 (C-2), 30.7 (C-3), 44.9 (C-4), 38.4 (C-5), 22.9
(C-6), 28.3 (C-7), 38.4 (C-8), 42.8 (C-9), 141.3 (C-10), 37.7
(C-11), 34.0 (C-12), 141.3 (C-13), 120.1 (C-14), 63.8
4.2.1. 1-Methoxyadenine (8). Mp 255–257 8C; UV (EtOH):
201, 227, 273 nm; H RMN (D2O) d: 8.54 and 8.03 (1H, s
1
each, H-2, H-8), 4.18 (3H, s, MeO–); 13C RMN (D2O) d:

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I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
(C-15), 16.7 (C-16), 15.5 (C-17), 178.4 (C-18), 19.6 (C-19),
22.4 (C-20), 51.6 (–COOMe), 97.9 (C-10), 30.7 (C-20), 25.5
(C-30), 19.7 (C-40), 62.2 (C-50); EIMS: 418 (MC, 1), 235
(35), 175 (35), 137 (15), 85 (100); EIHRMS: calcd for
C26H42O4 (MC) 418.3083; found (MC) 418.3090.
EIMS: 447 (MCK33, 3), 331 (15), 270 (15), 189 (70), 85
(100).
4.8. Reaction of 13 with nBu3SnH: 15
To a solution of 13 (373 mg, 0.78 mmol) in toluene
(10 mL), AIBN (13 mg, 0.08 mmol) and nBu3SnH
(0.52 mL, 1.94 mmol) were added and the mixture was
stirred at 120 8C for 20 min. The reaction was filtered
through a column of silica and eluted with hexane/AcOEt
98:2 to yield 15 (91 mg, 31%).
4.6. Reaction of 11 with LiAlH4: 12
A solution of methoxy ether 11 (3.5 g, 8.37 mmol) in ether
(80 mL) was reduced with LiAlH4 (477 mg, 12.50 mmol) at
0 8C for 4 h. Then aqueous AcOEt was added and after
filtration, the solvent was evaporated to yield alcohol 12
(3.2 g, 99%).
4.8.1. 15-Tetrahydropyranyloxy-ent-halima-1(10),13E-
diene (15). IR (film): 2940, 2870, 1653, 1454, 1379,
4.6.1. 15-Tetrahydropyranyloxy-ent-halima-1(10),13E-
dien-18-ol (12). [a]D22C36.2 (c 0.8, CHCl3); IR (film):
1200, 1132, 1117, 1042, 907, 870 cmK1 1H RMN d:
;
5.34–5.30 (2H, m, H-1, H-14), 4.63–4.58 (1H, m, H-10),
4.20 (1H, dd, JZ11.8, 6.5 Hz, H-15A), 3.97 (1H, dd, JZ
11.8, 7.5 Hz, H-15B), 3.90–3.85 (1H, m, H-50), 3.53–3.47
(1H, m, H-50), 2.15–1.00 (20H, m), 1.66 (3H, s, Me-16),
0.89 (3H, s, Me-20), 0.87 (3H, s, Me-19), 0.82 (3H, s,
Me-18), 0.80 (3H, d, JZ7.0 Hz, Me-17); 13C RMN d: 119.8
(C-1), 23.4 (C-2), 33.5 (C-3), 31.6 (C-4), 43.6 (C-5), 23.9
(C-6), 29.4 (C-7), 39.4 (C-8), 43.1 (C-9), 141.7 (C-10),
37.7 (C-11), 34.5 (C-12), 141.4 (C-13), 120.2 (C-14), 63.9
(C-15), 16.9 (C-16), 15.9 (C-17), 26.3 (C-18), 28.40(C-19),
22.6 (C-20), 97.9 (C-10), 31.0 (C-20), 25.8 (C-3 ), 19.9
(C-40), 62.3 (C-50); EIMS: 374 (MC, 8), 272 (15), 191 (90),
121 (14), 85 (100); EIHRMS: calcd for C25H42O2 (M)C
374.3185; found (M)C 374.3178.
3468, 2940, 1454, 1379, 1117, 1022 cmK1; H RMN d:
1
5.35–5.31 (2H, m, H-1, H-14), 4.63–4.58 (1H, m, H-10),
4.23 (1H, dd, JZ11.8, 6.5 Hz, H-15A), 3.97 (1H, dd, JZ
11.8, 7.5 Hz, H-15B), 3.90–3.85 (1H, m, H-50), 3.53–3.47
(1H, m, H-50), 3.47 (1H, d, JZ10.8 Hz, H-18A), 3.24 (1H,
d, JZ10.8 Hz, H-18B), 2.10–1.10 (20H, m), 1.64 (3H, s,
Me-16), 0.88 (3H, s, Me-19), 0.83 (3H, s, Me-20), 0.79 (3H,
d, JZ7.0 Hz, Me-17); 13C RMN d: 120.0 (C-1), 22.6 (C-2),
29.0 (C-3), 36.5 (C-4), 37.8 (C-5), 23.3 (C-6), 28.6 (C-7),
39.0 (C-8), 43.0 (C-9), 141.5 (C-10), 37.5 (C-11), 34.4
(C-12), 141.2 (C-13), 120.2 (C-14), 63.8 (C-15), 16.6
(C-16), 150.6 (C-17), 69.6 (C-18), 20.6 (C-19), 22.30(C-20),
97.9 (C-1 ), 30.7 (C-20), 25.5 (C-30), 19.6 (C-4 ), 62.2
(C-50); EIMS: 390 (MC, 1), 257 (25), 207 (40), 177 (25),
149 (10), 85 (100); EIHRMS: calcd for C25H42O3 (M)C
390.3133; found (M)C 390.3140.
4.9. Reaction of 12 with TPAP: 14
To a mixture of 12 (3.3 g, 8.46 mmol), N-methylmorpholine
N-oxide (1.7 g, 12.69 mmol) and molecular sieves (4.2 g) in
anhydrous DCM (40 mL), under argon and at room
temperature, TPAP (148 mg, 0.42 mmol) was added. The
reaction mixture was stirred for 45 min and then filtered off
on silica gel and celite (EtOAc), the organic layer was
evaporated to yield the expected compound 14 (3.1 g, 94%).
4.7. Reaction of 12 with CS2/MeI: 13
To a solution of 12 (33 mg, 0.09 mmol) in THF (2 mL)
cooled at K78 8C under argon atmosphere, a solution of
nBuLi 1.6 M in hexane (0.06 mL, 0.10 mmol) was added.
The mixture was allowed to stir for 30 min at 0 8C and then
CS2 (0.05 mL, 0.85 mmol) was added. The mixture was
stirred for 2 h more at room temperature and then MeI
(0.02 mL, 0.25 mmol) was added. After 1 h, ice was added.
The mixture was extracted with AcOEt and the combined
organic extracts were washed with HCl 0.5 M, H2O and
brine. After drying over Na2SO4, the solvent was evaporated
in vacuo to yield 13 (40 mg, 98%).
4.9.1. 15-Tetrahydropyranyloxy-ent-halima-1(10),13E-
dien-18-al (14). IR (film): 2940, 2872, 1724, 1672, 1456,
1
1381, 1123, 1024 cmK1; H RMN d: 9.43 (1H, s, H-18),
5.45–5.25 (2H, m, H-1, H-14), 4.65–4.55 (1H, m, H-10),
4.20 (1H, dd, JZ11.8, 6.5 Hz, H-15A), 3.97 (1H, dd, JZ
11.8, 7.5 Hz, H-15B), 3.90–3.80 (1H, m, H-50), 3.55–3.40
(1H, m, H-50), 2.50–2.35 (1H, m, H-5), 2.20–1.20 (19H, m),
1.66 (3H, s, Me-16), 0.95 (3H, s, Me-19), 0.90 (3H, s,
Me-20), 0.79 (3H, d, JZ7.0 Hz, Me-17); 13C RMN d: 120.4
(C-1), 22.6 (C-2), 28.7 (C-3), 48.0 (C-4), 36.2 (C-5), 23.2
(C-6), 27.9 (C-7), 38.9 (C-8), 43.2 (C-9), 141.2 (C-10), 37.6
(C-11), 34.4 (C-12), 141.1 (C-13), 120.3 (C-14), 63.9
(C-15), 16.9 (C-16), 15.8 (C-17), 205.9 (C-18), 17.60(C-19),
22.50 (C-20), 97.09 (C-10), 30.9 (C-20), 25.8 (C-3 ), 19.9
(C-4 ), 62.3 (C-5 ).
4.7.1. Methyl-15-tetrahydropyranyloxy-ent-halima-
1(10),13E-dien-18-xantogenate (13). [a]2D2C38.0 (c 0.3,
CHCl3); IR (film): 1464, 1380, 1215, 1069, 1023, 666 cmK1
;
1H RMN d: 5.37–5.30 (2H, m, H-1, H-14), 4.63–4.58 (1H,
m, H-10), 4.42 (1H, d, JZ10.6 Hz, H-18A), 4.26 (1H, d, JZ
10.6 Hz, H-18B), 4.18 (1H, dd, JZ11.8, 7.2 Hz, H-15A),
3.98 (1H, dd, JZ11.8, 7.4 Hz, H-15B), 3.94–3.83 (1H, m,
H-50), 3.56–3.45 (1H, m, H-50), 2.54 (3H, s, MeS–), 2.26–
1.11 (20H, m), 1.66 (3H, s, Me-16), 0.95 and 0.91 (3H, s
each, Me-19, Me-20), 0.81 (3H, d, JZ7.0 Hz, Me-17);
13C RMN d: 120.1 (C-1), 23.5 (C-2), 29.0 (C-3), 35.9 (C-4),
38.4 (C-5), 22.7 (C-6), 29.1 (C-7), 39.4 (C-8), 43.2 (C-9),
141.3 (C-10), 37.2 (C-11), 34.3 (C-12), 141.1 (C-13), 120.2
(C-14), 63.9 (C-15), 17.0 (C-16), 15.80 (C-17), 80.5 0(C-18),
21.60 (C-19), 22.5 (C-20), 908.0 (C-1 ), 30.9 (C-2 ), 25.7
(C-3 ), 19.8 (C-40), 62.3 (C-5 ), 215.9 (–CS2), 19.0 (MeS–);
4.10. Reaction Huang–Minlon of 14: 15
To a solution of 14 (1.76 g, 4.53 mmol) in diethylene glycol
(40 mL), KOH (1.6 g, 26.6 mmol) and hydrazine hydrate
25% (6 mL, 120.0 mmol) were added. The reaction was
heated at 175 8C for 18 h, the condenser was removed for
15 min and after putting back the condenser, the heat raised

I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
11677
to 230 8C. After 4 h stirring at that temperature, the reaction
was cooled and H2O (25 mL) and HCl 6 M (25 mL) were
added. Extraction with Et2O followed by washing with H2O,
dried and evaporation of the organic layer, yield a crude,
which was chromatographed over silica (63 g) and eluted
with hexane/AcOEt 98:2 to yield 15 (1.37 g, 81%).
then with CH2Cl2/MeOH/NH3 35:5:1 to obtain 17 (26 mg,
47%) and 18 (20 mg, 36%).
4.11.1. N-[15-ent-halima-1(10),13E-dienyl]-N-methoxy-
9-methyl-9H-purin-6-amine (17). [a]2D2C44.3 (c 0.8,
CHCl3); IR (film): 1578, 1453, 1378, 1327, 1296,
1
6440cmK1; H RMN d: 8.48 (1H, s, H-20), 7.81 (1H, s,
4.10.1. Reaction of 15 with p-TsOH and CBr4/PPh3: 5. To
a solution of 15 (8 mg, 0.02 mmol) in MeOH (0.5 mL),
p-TsOH (2 mg, 0.01 mmol) was added. After 30 min
stirring, the reaction mixture was diluted with AcOEt and
washed successively with a 6% aqueous solution of
NaHCO3 and water. The organic layer was dried and
evaporated to give a crude, which was chromatographed on
silica gel (hexane/AcOEt 95:5/9:1) to yield (5 mg, 81%)
of ent-halima-1(10),13E-dien-15-ol. [a]2D2C83.0 (c 0.9,
CHCl3); IR (film): 3327, 3048, 2918, 2870, 1669, 1456,
H-8 ), 5.40 (1H, t, JZ7.1 Hz, H-14), 5.27 (1H, t, JZ3.3 Hz,
H-1), 4.73 (2H, d, JZ6.8 Hz, H-15), 3.93 (3H, s, MeO–),
3.83 (3H, s, MeN–), 2.10–1.95 (2H, m, H-6), 2.05–1.87 (1H,
m, H-7), 2.00–1.90 (1H, m, H-11), 1.90–1.80 (1H, m, H-12),
1.77–1.63 (1H, m, H-12), 1.76 (3H, s, Me-16), 1.75–1.65
(2H, m, H-2), 1.71–1.60 (1H, m, H-5), 1.59–1.50 (1H, m,
H-8), 1.41–1.34 (1H, m, H-3), 1.40–1.25 (1H, m, H-7),
1.30–1.18 (1H, m, H-11), 1.21–1.05 (1H, m, H-3), 0.87 (3H,
s, Me-20), 0.84 (3H, s, Me-19), 0.81 (3H, s, Me-18), 0.79
(3H, d, JZ7.0 Hz, Me-17); 13C RMN d: 119.6 (C-1), 23.5
(C-2), 33.3 (C-3), 31.3 (C-4), 43.3 (C-5), 23.0 (C-6), 29.1
(C-7), 39.0 (C-8), 42.8 (C-9), 141.7 (C-10), 37.4 (C-11),
34.3 (C-12), 141.6 (C-13), 117.7 (C-14), 48.2 (C-15), 16.7
(C-16), 15.5 (C-17), 25.9 (C-18), 28.1 (C-19), 22.2 (C-20),
152.3 (C-20), 151.7 (C-40), 119.2 (C-50), 155.9 (C-60), 140.8
(C-80), 62.5 (MeO–), 29.7 (MeN–); EIMS: 451 (MC, 3), 420
(20), 277 (25), 205 (50), 149 (45); EIHRMS: calcd for
C27H41ON5 (M)C 451.3311; found (M)C 451.3308.
1
1379, 1364, 1001, 851 cmK1; H RMN d: 5.38 (1H, t, JZ
7.0 Hz, H-14), 5.31 (1H, t, JZ3.2 Hz, H-1), 4.13 (2H, d, JZ
7.0 Hz, H-15), 2.05–1.98 (2H, m, H-6), 2.00–1.95 (1H, m,
H-11), 1.98–1.95 (1H, m, H-7), 1.84 (1H, dt, JZ14.8,
5.2 Hz, H-12), 1.70 (1H, dt, JZ14.8, 4.8 Hz, H-12), 1.69–
1.63 (1H, m, H-5), 1.66 (3H, s, Me-16), 1.54–1.50 (1H, m,
H-8), 1.35–1.30 (3H, m), 1.25–1.21 (1H, m, H-11), 1.15–
1.08 (2H, m, H-3), 0.90 (3H, s, Me-20), 0.88 (3H, s, Me-19),
0.83 (3H, s, Me-18), 0.81 (3H, d, JZ7.0 Hz, Me-17); 13C
RMN d: 119.8 (C-1), 23.6 (C-2), 33.4 (C-3), 31.4 (C-4), 43.4
(C-5), 23.1 (C-6), 29.1 (C-7), 39.1 (C-8), 42.9 (C-9), 141.7
(C-10), 37.7 (C-11), 34.2 (C-12), 141.2 (C-13), 122.8
(C-14), 59.4 (C-15), 16.4 (C-16), 15.6 (C-17), 25.9 (C-18),
28.2 (C-19), 22.3 (C-20); EIMS: 290 (MC, 1), 192 (100),
129 (17), 107 (15), 91 (16), 77 (22); EIHRMS: calcd for
C20H34O (M)C 290.2609; found (M)C 290.2607.
4.11.2. Compound (18). [a]2D2C22.8 (c 0.5, CHCl3); IR
(film): 3402, 1655, 1578, 1458, 1057, 644 cmK1; 1H RMN
d: 9.73 (1H, s, H-80), 7.96 (1H, s, H-20), 5.42 (1H, br s,
H-14), 5.29 (1H, br s, H-1), 5.08 (2H, d, JZ7.2 Hz, H-15),
3.99 (3H, s, MeN–), 3.89 (3H, s, MeO–), 2.11–1.93 (2H, m,
H-6), 2.04–1.93 (1H, m, H-11), 2.02–1.90 (1H, m, H-12),
1.95–1.90 (1H, m, H-7), 1.86 (3H, s, Me-16), 1.79–1.65
(1H, m, H-12), 1.75–1.65 (2H, m, H-2), 1.68–1.56 (1H, m,
H-5), 1.58–1.46 (1H, m, H-8), 1.39–1.25 (1H, m, H-7),
1.30–1.20 (1H, m, H-11), 1.18–1.02 (2H, m, H-3), 0.89 (3H,
s, Me-20), 0.86 (3H, s, Me-19), 0.82 (3H, s, Me-18), 0.79
(3H, d, JZ7.0 Hz, Me-17); 13C RMN d: 120.0 (C-1), 23.5
(C-2), 33.2 (C-3), 31.4 (C-4), 43.4 (C-5), 23.0 (C-6), 29.1
(C-7), 39.0 (C-8), 42.9 (C-9), 141.3 (C-10), 37.1 (C-11),
34.4 (C-12), 147.6 (C-13), 114.9 (C-14), 48.4 (C-15), 17.4
(C-16), 15.6 (C-17), 25.9 (C-18), 28.3 (C-19), 22.3 (C-20),
148.7 (C-20), 141.2 (C-40), 110.4 (C-50), 135.9 (C-60), 137.2
(C-80), 62.4 (MeO–), 32.2 (MeN–); EIMS: 451 (MC, 1), 386
(10), 256 (20), 191 (10), 149 (30); EIHRMS: calcd for
C27H41ON5 (M)C 451.3311; found (M)C 451.3318.
To a solution of ent-halima-1(10),13E-dien-15-ol (160 mg,
0.55 mmol) in DCM (6 mL), PPh3 (307 mg, 1.17 mmol) and
CBr4 (387 mg, 1.16 mmol) were added. The reaction was
allowed to stir under argon atmosphere for 3 h and then the
solvent was removed. The different solubility in hexane
allowed to separate 5 (148 mg, 76%).
4.10.2. 15-Bromide of ent-halima-1(10),13E-dienyl (5).
IR (film): 2924, 1653, 1456, 1379, 1200, 1119, 851 cmK1
;
1H RMN d: 5.49 (1H, t, JZ7.5 Hz, H-14), 5.30 (1H, t, JZ
3.8 Hz, H-1), 4.01 (2H, d, JZ7.5 Hz, H-15), 2.10–1.05
(14H, m), 1.71 (3H, s, Me-16), 0.89 (3H, s, Me-20), 0.88
(3H, s, Me-19), 0.83 (3H, s, Me-18), 0.81 (3H, d, JZ7.0 Hz,
Me-17); 13C RMN d: 120.0 (C-1), 23.1 (C-2), 33.4 (C-3),
31.4 (C-4), 43.5 (C-5), 23.6 (C-6), 29.1 (C-7), 39.1 (C-8),
42.9 (C-9), 141.5 (C-10), 37.3 (C-11), 34.4 (C-12), 145.0
(C-13), 120.0 (C-14), 29.7 (C-15), 16.1 (C-16), 15.6 (C-17),
25.8 (C-18), 28.3 (C-19), 22.2 (C-20); EIMS: 273 (MCK
Br, 10), 191 (100), 135 (12), 95 (12), 81 (13).
4.12. Reaction of 18 with AcOH/Zn: 19
A mixture of the betaine 18 (36 mg, 0.08 mmol) and Zn
powder (48 mg, 0.73 mmol) in MeOH (1.3 mL), water
(0.26 mL), and acetic acid (0.05 mL) was stirred under
argon atmosphere at 60 8C for 2 days. After cooling, the
mixture was filtered and the solid washed with a big amount
of MeOH. The filtrate was evaporated and mixed with
MeOH (8.5 mL), saturated aqueous NaCl (0.34 mL), and
water (2.5 mL) and stirred for 1 h before evaporation. The
residue was dissolved in saturated aqueous NaCl (1.27 mL)
and water (1.27 mL), extracted several times with CH2Cl2,
dried and evaporated. The product (32 mg) was purified by
flash chromatography on silica gel (2.0 g) eluting with
CH2Cl2/MeOH 16:1, to obtain 18 (17 mg, 47%) and 19
(12 mg, 36%).
4.11. Reaction of 5 with 6-methoxyamine-9-methyl-
purine 4: 17, 18
To a mixture of 5 (43 mg, 0.12 mmol) and 6-methoxy-
amine-9-methyl-purine 4 (26 mg, 0.16 mmol) under argon
atmosphere, DMA (2 mL) was added and the reaction was
stirred and heated at 50 8C for 16 h. After evaporation of
DMA the crude was chromatographed over flash silica
eluting first with AcOEt/EtOH/NH3 160:5:2/40:10:1) and

11678
I. S. Marcos et al. / Tetrahedron 61 (2005) 11672–11678
´
Basabe, P.; Pedrero, A. B.; Garcıa, N.; Sanz, F.; Urones, J. G.
4.12.1. Chloride of 7-[ent-halima-1(10),13E-dien-15-yl]-
9-methyl-adenonium (19). [a]2D2C36.7 (c 0.1, CHCl3);
[a]2D2C25.0 (c 0.2, MeOH); IR (film): 3308, 3070, 1646,
1609, 1455, 1362, 1295, 1175 666 cmK1; 1H RMN (CDCl3)
d: 11.1 (1H, s, H-80), 8.53 (1H, s, H-20), 6.47 (2H, br s,
–NH2), 5.63 (2H, br s, H-15), 5.41 (1H, br s, H-14), 5.31
(1H, t, JZ3.2 Hz, H-1), 4.10 (3H, br s, MeN–), 2.00–1.00
(14H, m), 1.86 (3H, s, Me-16), 0.88 (3H, s, Me-20), 0.85
(3H, s, Me-18), 0.83 (3H, s, Me-19), 0.80 (3H, d, JZ6.8 Hz,
Me-17); 1H RMN (CD3OD) d: 8.46 (1H, s, H-20), 5.19 (2H,
d, JZ7.1 Hz, H-15), 5.52 (1H, tq, JZ7.1, 1.2 Hz H-14),
5.39 (1H, t, JZ3.2 Hz, H-1), 3.97 (3H, s, MeN–), 2.18–1.85
(5H, m), 1.86 (3H, d, JZ1.2 Hz, Me-16), 1.75–1.55 (3H,
m), 1.40–1.05 (6H, m), 0.96 (3H, s, Me-20), 0.89 (3H, s,
Me-18), 0.84 (3H, s, Me-19), 0.85 (3H, d, JZ6.7 Hz, Me-
17); 13C RMN (CD3OD) d: 121.4 (C-1), 24.8 (C-2), 34.3
(C-3), 32.4 (C-4), 44.9 (C-5), 24.1 (C-6), 30.2 (C-7), 40.6
(C-8), 44.1 (C-9), 142.7 (C-10), 38.4 (C-11), 35.7 (C-12),
150.1 (C-13), 115.2 (C-14), 48.9 (C-15), 17.1 (C-16), 160.0
(C-17), 26.4 (C-18), 28.8 (C-19), 22.8 0(C-20), 157.20(C-2 ),
150.9 (C-40), 109.4 (C-50), 153.7 (C-6 ), 142.2 (C-8 ), 32.0
(MeN–); ESIHRMS: calcd for C26H40N5 (MCH)C
422.3278; found (MCH)C 422.3283.
Tetrahedron Lett. 2002, 43, 1243. (b) Marcos, I. S.;
´ ´
Hernandez, F. A.; Sexmero, M. J.; Dıez, D.; Basabe, P.;
´
Pedrero, A. B.; Garcıa, N.; Urones, J. G. Tetrahedron 2003, 60,
685.
´
11. (a) Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Dıez, D.;
´
Basabe, P.; Hernandez, F. A.; Urones, J. G. Tetrahedron Lett.
2003, 44, 369. (b) Hara, N.; Asaki, H.; Fujimoto, Y.; Gupta,
Y. K.; Singh, A. K.; Sahai, M. Phytochemistry 1995, 38, 189.
´
12. (a) Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Dıez, D.;
´
Basabe, P.; Hernandez, F. A.; Broughton, H. B.; Urones, J. G.
Synlett 2002, 105. (b) Marcos, I. S.; Pedrero, A. B.; Sexmero,
´
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M. J.; Dıez, D.; Basabe, P.; Garcıa, N.; Moro, R. F.;
Broughton, H. B.; Mollinedo, F.; Urones, J. G. J. Org.
Chem. 2003, 68, 7496.
13. (a) Fujii, T.; Itaya, T. Tetrahedron 1971, 27, 351. (b) Fujii, T.;
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Acknowledgements
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The authors are grateful to Drs. A. Lithgow, Cesar Raposo,
Servicio General de R.M.N., Servicio General de E.M.,
respectively, and to the MEC (CTQ2005-04406) for
financial support.
16. (a) Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 739. (b) Barton, D. H. R.;
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