A concise synthesis of siphonodictidine

Article abstract of DOI:10.1021/np0400860

Siphonodictidine (1) has been synthesized for the first time in a concise and regiocontrolled manner by using 2-(tert-butyldimethylsiloxy)-3-methylfuran (6) as the crucial building block. The silver trifluoro-acetate-induced alkylation of 6 with Ω-bromogeranyl acetate 7 gave the key γ-lactone intermediate 8, which on subsequent reduction, conversion of the hydroxyl into the amino group, and amidination afforded siphonodictidine (1) in an overall yield of 25.7% from 6.

Full text of DOI:10.1021/np0400860

J . Nat. Prod. 2004, 67, 1383-1386
1383
A Con cise Syn th esis of Sip h on od ictid in e†
Charles W. J efford,* J ean-Claude Rossier, J ohn Boukouvalas, Adam W. Sledeski, and Ping-Zhong Huang
Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, 1211 Geneva 4, Switzerland
Received March 30, 2004
Siphonodictidine (1) has been synthesized for the first time in a concise and regiocontrolled manner by
using 2-(tert-butyldimethylsiloxy)-3-methylfuran (6) as the crucial building block. The silver trifluoro-
acetate-induced alkylation of 6 with ω-bromogeranyl acetate 7 gave the key γ-lactone intermediate 8,
which on subsequent reduction, conversion of the hydroxyl into the amino group, and amidination afforded
siphonodictidine (1) in an overall yield of 25.7% from 6.
Sch em e 1
Siphonodictidine (1) is the secondary metabolite of an
Indo-Pacific sponge Siphonodictyon sp.,1 which burrows
into living coral. It belongs to an extensive family of
naturally occurring sesquiterpenes, which are character-
ized by a 2(5H)-furanone ring bearing a methyl group and
an allylic attachment at the C3 and C5 positions, respec-
tively. Among the members of this class discovered so far,2,3
siphonodictidine is remarkable for its biological action.1 It
inhibits growth of the coral and appears to be deployed by
the sponge to kill coral polyps in its immediate vicinity.
Apart from this specific function, which is essential for the
survival of the sponge, siphonodictidine exhibits significant
antifungal and antimicrobial activity against Gram-positive
and Gram-negative bacteria. Consequently, these poten-
tially valuable properties and the fact that siphonodictidine
(1) is only obtainable in minute amounts from undepend-
able natural sources make it a suitable synthetic target.4
Sch em e 2a
a
(i) RhCl3‚3H2O, EtOH, 100 °C, 3 h; (ii) TBDMSOTf, Et3N, Et2O, 0 to
23 °C, 24 h.
Resu lts a n d Discu ssion
amine furnished 6 in 88.5% yield (Scheme 2). Unlike
3-methyl-2-trimethylsiloxyfuran,13 6 is virtually impervious
to moisture and can be easily purified by distillation or
chromatography over silica gel.
An appropriate reagent for synthon 3 is ω-bromogeranyl
acetate (7), a known compound obtainable from geranyl
acetate by ω-hydroxylation and subsequent bromination.14
At first sight, nucleophilic displacement could occur at
either of the allylic positions.15 But it will be seen shortly
that activation with silver salt provides the desired selec-
tivity.
Having the essential reagents 6 and 7 in hand, the next
step is to put them together to create the carbon framework
of siphonodictidine (1). Coupling was achieved by treatment
with a stoichiometric amount of silver trifluoroacetate
(Scheme 3). In keeping with previous findings,10,11 alkyla-
tion occurred with high regioselectivity, giving the key
intermediate furanone 8 in 86.0% yield. It was discovered
that the reaction temperature was critical for such an
alkylation, especially when adding 7. The temperature had
to be kept below -70 °C to prevent the formation of
unwanted byproducts. Next, the furanone part of 8 was
modified. Reduction with an excess of diisobutylaluminum
hydride16 followed by hydrolysis with aqueous hydrochloric
acid generated the desired furan entity and simultaneously
liberated the alcohol function by furnishing 9 in 86.2%
yield.
Despite the apparently simple structure of such fura-
nosesquiterpenes, little attention has been paid to their
synthesis.5 Inspection of the farnesene backbone of 1
suggests that it could be conveniently assembled by
coupling the C-5 carbanion 2 of 3-methyl-2(5H)-furanone
(5) with the terminal cation 3 of geranyl acetate. Once the
carbon skeleton is put in place, subsequent modification
of the lactone ring and conversion of the acetate group into
the guanidine entity would furnish 1 (Scheme 1). Unfor-
tunately, the behavior of 2-furanolate ions is inconsistent.
For example, the lithium enolate obtained from 5 on
alkylation with various allyl bromides gives both C-3- and
C-5-substituted products, with the former predominating.6
However, we and others have already demonstrated that
the desired C-5 regioselectivity can be conferred by recourse
to 2-(trialkylsiloxy)furans, which behave as the equivalent
of the localized C-5 carbanion of the 2(5H)-furanone entity.
Applications involving vinylogous Mannich reactions, aldol-
type coupling, and alkylation are well documented.7-10
In the present instance, the reagent of choice for synthon
2 is 2-(tert-butyldimethylsiloxy)-3-methylfuran (6).11 The
starting material selected for 6 is the commercially avail-
able R-methylene-γ-butyrolactone (4). Isomerization with
rhodium chloride trihydrate afforded 3-methyl-2(5H)-fura-
none (5) in 86.6% yield.12 Treatment of 5 with tert-bu-
tyldimethylsilyl trifluoromethanesulfonate and triethyl-
† Dedicated to the late Dr. D. J ohn Faulkner (Scripps) and the late Dr.
Paul J . Scheuer (Hawaii) for their pioneering work on bioactive marine
natural products.
* To whom correspondence should be addressed. Tel: +41-22-776-3693.
Fax: +41-22-776-3601. E-mail: Charles.J efford@chiorg.unige.ch.
Conversion of 9 to the final guanidine group via the
corresponding amine did not proceed as originally planned.
Usually, an allylic alcohol is converted into its azide and
then reduced to the primary amine.17 The standard practice
10.1021/np0400860 CCC: $27.50
© 2004 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/14/2004

1384 J ournal of Natural Products, 2004, Vol. 67, No. 8
J efford et al.
Sch em e 3a
Sch em e 4
alcohol 9 is a versatile intermediate that could be used for
preparing other related furanosesquiterpenes. For example,
the hydroquinone 13, isolated from the Australian soft coral
Sinularia lochmodes,28 and marislin (14), found in Chro-
modoris marislae,2 should be equally accessible by ap-
propriate modification of the terminal hydroxyl group
(Scheme 4). The present route to 9 also constitutes a formal
synthesis of pleraplysillin-2 (15), a metabolite of the
Mediterranean sponge Pleraplysilla spinifera,29 since the
final steps have already been described.3
a
(i) AgOCOCF3; (ii) DIBAH; (iii) 1 M HCl; (iv) HN3, 2Ph3P, DIPAD.
is catalytic hydrogenation over Lindlar catalyst18 or reduc-
tion with zinc powder.19 However, when the allylic azide
10 was treated with Lindlar catalyst under 1 atm of
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points (un-
corrected) were determined on a Reichert hot stage microscope.
Infrared spectra (IR): Perkin-Elmer-681 spectrometer or FT-M
1
hydrogen, IR and H NMR analyses of the resulting product
1
Polaris, as solutions in a KBr cell. H NMR: Varian XL-200
indicated that the azide group underwent hydrogenation
as expected, but that the adjacent allylic double bond had
been reduced as well. Disappointingly, treatment of 10 with
zinc powder in aqueous hydrochloric acid led to a similar
result, namely, concomitant reduction of the azide group
and furan ring.
(200 MHz) and Bruker-AMX-400 (400 MHz) spectrometers; 13
C
NMR: Varian XL-200 (50 MHz) or Bruker AMX-400 (100
MHz); chemical shifts (δ) are in ppm with reference to TMS
()0.00 ppm) as internal standard. Finnigan GC/MS-4023
instrument with the INCOS data system; electron impact, 70
eV. High-resolution MS: VG-7070E (resolution 5000-7000).
Elemental analyses were performed by H. Eder, Service de
Microchimie, Department of Pharmaceutical Chemistry, Uni-
versity of Geneva. All solvents were distilled prior to use. THF
and Et2O were dried over Na-K alloy/benzophenone and
freshly distilled before use. CH2C12 was dried over NaHCO3,
distilled, and stored over molecular sieves (Union Carbide Type
4 Å). HMPA was distilled from CaH2 and stored over molecular
sieves (Union Carbide Type 4 Å). Anhydrous EtOH was
distilled from Mg turnings and a small amount of iodine. TLC
was performed on plastic precoated silica gel 60 F254 plates
(Merck, layer thickness 0.20 mm). Column chromatography
(CC) (flash):30 Merck silica gel 60 (230-400 mesh). R-Methyl-
ene-γ-butyrolactone was purchased from Fluka Chemie Sarl,
9471 Buchs, SG, Switzerland.
3-Meth yl-2(5H)-fu r a n on e (5). Procedure l: A mixture of
R-methylene-γ-butyrolactone (4) (5.60 g, 57.1 mmol) and
RhC13‚aq (0.27 g, 1.14 mmol) in absolute EtOH (3 mL) was
heated at 100 °C in a sealed tube for 3 h under an atmosphere
of N2. The solvent was evaporated and the residue chromato-
graphed on a column (SiO2, Et2O-pentane, 3:1) to give 5 (4.40
g, 78.46%, Rf ) 0.34) and ethyl (E)-2-methylbut-2-enate (0.89
g, 12.2%, Rf ) 0.87). Procedure-2: RhC13‚aq (0.27 g, 1.14
mmol) was placed in a 50 mL round-bottomed flask. The flask
was sealed with a rubber stopper, connected to a vacuum line
(0.2 mmHg), pumped dry, and then filled with Ar. This
procedure was repeated three times. To the flask was added
4 (5.60 g, 57.1 mmol) and absolute EtOH (3 mL) by syringe.
The mixture was heated with stirring at 100 °C for 3 h. The
workup according to procedure l gave ethyl (E)-2-methylbut-
2-enate (0.50 g, 6.84%) and 5 (4.85 g, 86.6%): IR (CHC13) νmax
3630, 3500, 3020, 2930, 2870, 1750, 1660, 1450, 1380, 1345,
1210, 1085, 1055, 825 cm- 1; 1H NMR (CDCl3) δ 7.14 (1H, m),
4.75 (2H, m), 1.92 (3H, m); LREIMS m/z 98 [M]+ (71), 69 [M
- CHO]+ (100), 53 (8.3), 50 (8.3).
Apart from preventing over-reduction, another prereq-
uisite for preparing allylamines is control of regioselectiv-
ity. Allylic azides are liable to rearrange.20,21 Consequently,
reduction might give both allylic amines. A way of avoiding
this possibility is to convert the azide to the iminophos-
phorane, the so-called Staudinger intermediate,22 by reac-
tion with triphenylphosphine. Such a procedure has been
used to advantage for converting bromides23 and alcohols24
to amines. In the present instance, submission of 9 to
the Mitsunobu reaction,25 namely, treatment with hydra-
zoic acid in the presence of diisopropyl azodicarboxylate
(DIPAD) and a 2-fold excess of triphenylphoshine,26 was
entirely successful (Scheme 3). Initially, the azide 10 was
formed. The surplus PPh3 in situ then produced, after
expulsion of nitrogen, the nonisolated Staudinger inter-
mediate 11, which on hydrolysis with aqueous hydrochloric
acid delivered the amine hydrochloride 12 in 45.7% yield.
None of the allylically rearranged amine was observed,
thereby indicating that only the terminal azide 10, and not
its sterically hindered allylic isomer, had undergone reac-
tion with PPh3. Finally, reaction of 12 with 3,5-dimeth-
ylpyrazole-l-carboxamidine nitrate27 in the presence of
triethylamine converted the amino to the guanidine group,
thereby providing siphonodictidine (1) in 75.2% yield. The
sample of synthetic 1 so obtained exhibited spectral data
(1H and 13C NMR and MS) in complete agreement with
those reported for the naturally occurring substance.1
In conclusion, the present synthetic route to 1 is opera-
tionally simple, requiring only seven steps to assemble the
product from commonly available starting materials. More-
over, the synthesis is practical, giving 1 in 27.5% yield from
6. It also demonstrates that 2-(tert-butyldimethylsiloxy)-
3-methylfuran is an ideal reagent for preparing terpenes
bearing the 4-methyl-2-furyl entity. It should be noted that
2-(ter t-Bu tyld im eth ylsiloxy)-3-m eth ylfu r a n (6). To a
stirred solution of 5 (4.00 g, 40.8 mmol) and Et3N (5.34 g, 53.0

A Concise Synthesis of Siphonodictidine
J ournal of Natural Products, 2004, Vol. 67, No. 8 1385
mmol) in dry Et2O (30 mL) was added tert-butyldimethylsilyl
triflate (12.9 g, 48.9 mmol) under N2 at 0 °C. The reaction
mixture was stirred at 0 °C for 3 h until no starting material
was left (as monitored by 1H NMR). After separation of the
Et2O layer, the residue was extracted with Et2O (30 mL). The
combined Et2O solutions were washed with cold aqueous
saturated NaHCO3 solution (2 × 20 mL), the solvent was
evaporated, and the residue was distilled under reduced
pressure to give a colorless oil (6) (78-80 °C/10 mmHg, 7.14
g, 88.5%): 1H NMR (CDC13) δ 6.73 (1H, d, J ) 2.5 Hz), 6.07
temperature for a further 4 h. Evaporation of the solvent gave
a residue, which on CC (SiO2, Rf ) 0.17, pentane-benzene,
6:1) gave 10 as a colorless oil (240 mg, 86.6%): IR (CHC13)
ν
max 2980, 2930, 2880, 2105, 1550, 1448, 1255, 1115, 950, 873,
1
805 cm-1; H NMR (CDCl3) δ 7.06 (1H, quintet, J ) 1.0 Hz),
5.87 (1H, s), 5.33 (1H, tm, J ) 7.0 Hz), 5.20 (1H, m), 3.76 (2H,
d, J ) 7.0 Hz), 3.22 (2H, s), 2.09-2.22 (4H, m), 1.98 (3H, d, J
) 1.0 Hz), 1.70 (3H, s), 1.60 (3H, s).
Hyd r ogen a tion of 10. Method A: A solution of 10 (25.9
mg, 0.1 mmol) in EtOH (2 mL) was stirred with Lindlar
catalyst (6.2 mg, 5% Pd/CaCO3) under 1 atm of H2 at room
temperature until TLC analysis indicated that all 10 had
reacted (about 5 h). The catalyst was removed by filtration.
(1H, d, J ) 2.5 Hz), 1.83 (3H, s), 0.99 (9H, s), 0.23 (6H, s); 13
C
NMR (CDCl3) δ 152.8 (qC), 131.1 (CH), 113.5 (CH), 92.1 (qC),
25.7 (CH3), 25.4 (CH3), 17.9 (qC), -4.6 (CH3); anal. calcd for
1
C
11H20O2Si (212.37), C 62.13%, H 9.76%, found C 62.21%, H
Evaporation of the solvent gave an oil (24 mg). H NMR (60
9.94%.
[2E,6E]-8-Acetoxy-2,6-d im eth yl-2,6-octa d ien yl br om id e
MHz) analysis revealed that both the N3 group and the allylic
double bond had been hydrogenated. Method B: A mixture of
10 (25.9 mg, 0.1 mmol), Zn powder (26 mg, 0.4 mmol), and
aqueous HCl (6 M, 2 mL) was stirred under N2 at 80 °C until
TLC analysis indicated that all the azide had reacted (2 h).
The reaction mixture was washed with Et2O (2 × 2 mL); the
aqueous layer was treated with aqueous NaOH (3 N), extracted
with CH2Cl2 (3 × 5 mL), and dried (K2CO3). Evaporation of
the solvent gave an oil (20 mg). The IR spectrum of the
resulting product showed that the peak at 2105 cm-1 charac-
(7). The bromide 7 was prepared from geranyl acetate.14
[2′E,6′E]-5-[8′-Acet oxy-2′,6′-d im et h yloct a -2′,6′-d ien yl]-
3-m eth yI-2(5H)-fu r a n on e (8). To a stirred suspension of
silver trifluoroacetate (2.2 g, 10 mmol) in dry CH2C12 (20
mL) under Ar at -78 °C first was added 6 (1.88 g, 0.94 mmol)
and then slowly dropwise a solution of 7 (2.5 g, 0.90 mmol) in
CH2C12 (2 mL). The stirred reaction mixture was gradually
allowed to warm to 10 °C over 4 h, filtered through Celite,
and washed with Et2O (4 × 20 mL). The Et2O solution was
washed with H2O (20 mL), aqueous saturated NaHCO3 solu-
tion (20 mL), H2O (20 mL), and brine (30 mL) and dried
(MgSO4). The solvent was evaporated under reduced pressure
and the residual oil purified by CC (SiO2, Rf ) 0.25, Et2O-
pentane, 3:4) to give 8 (2.3 g, 86.0%) as a light yellow oil: IR
(CHC13) νmax 3020, 2980, 2930, 2860, 1750, 1449, 1378, 1360,
1
teristic of the N3 group had disappeared. H NMR (60 MHz)
analysis also revealed hydrogenation of the furan ring.
[2E,6E]-3,7-Dim eth yl-8-(4′-m eth yl-2′-fu r a n yl)-2,6-octa -
d ien yla m in e (12). To a stirred solution of 9 (247 mg, 1.06
mmol) in anhydrous THF (10 mL) was added a solution of HN3
(1.2 mL, 1 M in benzene, 1.2 mmol), followed by a solution of
diisopropyl azodicarboxylate (247 mg, 95%, 1.1 mmol) in THF
(2 mL). To the resulting mixture was slowly added dropwise
a solution of PPh3 (630 mg, 2.32 mmol) in THF (5 mL) at
20-30 °C. After stirring at room temperature for 2 h and
heating the mixture under reflux for 6 h, H2O (2 mL) was
added followed by heating for another 3 h. The solvent was
evaporated under reduced pressure and the residue partitioned
between CH2C12 (15 mL) and aqueous HC1 (1 M, 15 mL). The
aqueous layer was extracted with CH2C12 (2 × 15 mL). The
combined organic phases were washed with brine and dried
(MgSO4). Evaporation of the solvent gave a residue, which on
purification by CC (SiO2, CH2C12-MeOH, 10:1) afforded a
light yellow solid (130 mg, 45.7%). Crystallization gave the
amine hydrochloride 12 (THF-n-hexane, 1:1): mp 132-134
°C; IR (CHC13) νmax 2930, 2870, 1440, 1380, 1260, 1110, 1020,
1232, 1100, 1060, 1020 cm-1 1H NMR (CDC13) δ 7.02 (1H,
;
quintet, J ) 1.6 Hz), 5.32 (1H, br t, J ) 7.0 Hz), 5.20 (1H, br
t, J ) 7.0 Hz), 4.94 (1H, tt, J ) 7.2 Hz), 4.56 (1H, d, J ) 7.0
Hz), 2.17-2.43 (2H, m), 2.04-2.16 (4H, m), 2.03 (3H, s), 1.89
(3H, t, J ) 4.0 Hz), 1.68 (3H, s), 1.66 (3H, s); 13C NMR (CDC13)
δ 174.07 (qC), 170.95 (qC), 148.71 (CH), 141.61 (qC), 129.74
(qC), 129.70 (qC), 128.18 (CH), 118.50 (CH), 79.93 (CH), 61.22
(CH2), 43.34 (CH2), 39.01 (CH2), 26.02 (CH2), 20.94 (CH3). 16.62
(CH3), 16.31 (CH3), 10.55 (CH3); LREIMS m/z 292 [M]+ (0),
249 [M - CH3CO]+ (1.30), 232 (0.81) 165 (0.93) 135 (21.87)
107 (30.71), 98 (34.18), 97 (100), 3 (60.08), 85 (23.51), 69
(35.93), 68 (44.74), 67 (39.24), 55 (31.54), 53 (32.39).
[2E,6E]-3,7-Dim eth yl-8-(4′-m eth yl-2′-fu r a n yl)-2,6-octa -
d ien ol (9). To a stirred solution of 8 (672 mg, 2.3 mmol) in
anhydrous THF (30 mL) was added dropwise a solution of
DIBAH (9.2 mL, 1 M in THF, 9.2 mmol) under Ar at -78 °C.
The mixture was stirred at -78 °C for 3 h, and aqueous HC1
(1 M, 45 mL) added dropwise with warming to -30 °C. The
stirred reaction mixture was allowed to gradually warm to 5
°C over 2 h, poured into ice-water (100 mL), and extracted
with Et2O (4 × 30 mL). The Et2O extracts were washed with
H2O (30 mL), aqueous saturated NaHCO3 solution (30 mL),
H2O (30 mL), and brine (30 mL) and dried (Na2SO4). Evapora-
tion of the solvent and chromatography of the residue (SiO2,
Rf ) 0.20. Et2O-pentane, 1:2) gave 9 (464 mg, 86.2%) as a
colorless oil: IR (CHC13) νmax 3620, 2530, 2860, 1445, 1388,
1
940, 860, 800 cm-1; H NMR (CDC13) δ 8.28 (2H, br s), 7.06
(1H, s), 5.85 (1H, s), 5.34 (1H, br t, J ) 7.0 Hz), 5.18 (1H, m),
3.55 (2H, br d, J ) 7.0 Hz), 3.21 (2H, s), 2.08 (4H, m), 1.97
(3H, s), 1.71 (3H, s), 1.57 (3H, s); 13C NMR (CDCl3) δ 154.17
(qC), 144.64 (qC), 137.65 (CH), 132.39 (qC), 125.65 (CH),
120.41 (qC), 115.23 (CH), 108.76 (CH), 39.30 (CH2), 38.37
(CH2), 37.28 (CH2), 26.28 (CH2), 16.61 (CH3), 15.85 (CH3), 9.76
(CH3); HREIMS m/z 233.1782 (calcd for C15H23NO, 233.1786).
[2E,6E]-3,7-Dim eth yl-8-(4′m eth yl-2′-fu r a n yl)-2,6-octa d i-
en ylgu a n id in e (Registr y Nu m ber 88316-91-0) (Sip h on od -
ictid in e (1)). To a stirred solution of 3,5-dimethylpyrazole-l-
carboxamidine nitrate (55.3 mg, 0.27 mmol) and 12 (64 mg,
0.24 mmol) in EtOH (3 mL) was added Et3N to bring the pH
to 9-10. The reaction mixture was heated under reflux for 6
h under an Ar atmosphere. The solvent was evaporated under
reduced pressure, and the residue extracted with dry Et2O (3
× 2 mL) to remove 3,5-dimethylpyrazole and unreacted 12.
To remove Et3NHNO3, the crude product was treated with an
aqueous solution of NaOH (1 M, 10 mL), extracted with
CH2C12 (3 × 15 mL), and dried (MgSO4). Evaporation of
the solvent gave a residue, which on purification by CC (SiO2,
CH2C12-MeOH, 10:1) (TLC, Rf ) 0.37, CH2C12-MeOH, 4:1)
gave 1 (49 mg, 75.2%): IR (CHC13) νmax 3060, 1630, 1620, 1590
1
1115, 990, 900 cm-1; H NMR (CDC13) δ 7.06 (1H, quintet, J
) 1.0 Hz), 5.87 (1H, s), 5.40 (1H, tm; J ) 7.0 Hz), 5.20 (1H,
tm, J ) 7.0 Hz), 4.13 (2H, d, J ) 7.0 Hz), 3.23 (2H, s), 2.13
(2H, m), 2.06 (2H, m), 1.98 (3H, d, J ) 0.8 Hz), 1.67 (3H, s),
1.60 (3H, s); 13C NMR (CDCl3) δ 154.36 (qC), 139.31 (qC),
137.68 (CH), 132.13 (qC), 126.12 (CH), 123.72 (CH), 120.49
(qC), 108.77 (CH), 59.31 (CH2), 39.23 (CH2), 38.42 (CH2), 26.31
(CH2), 16.15 (CH3), 15.85 (CH3), 9.71 (CH3); LREIMS m/z 234
[M]+ (1.22), 216 [M - 18]+ (9.50), 201 (2.91), 148 (38.85), 131
(59.25), 121 (35.49), 105 (49.80), 95 (74.17), 93 (90.9), 91(100),
81(28.06), 79 (64.42), 77 (62.14), 67 (57.24), 57 (39.86), 55
(78.05), 53 (68.07).
cm-1
(1H, s), 5.18 (2H, m), 3.76 (2H, d, J ) 6.0 Hz), 3.22 (2H, s),
2.00-2.20 (4H, m), 1.97 (3H, s), 1.68 (3H, s), 1.58 (3H, s); 13
;
1H NMR (CDC13) δ 7.80 (1H, br s), 7.06 (1H, s), 5.86
[2E,6E]-3,7-Dim eth yl-8-(4′-m eth yl-2′-fu r a n yl)-2,6-octa -
d ien yl Azid e (10). To a stirred solution of 9 (250 mg, 1.07
mmol), HN3 (1.10 mL, 1 M in benzene), and diisopropyl
azodicarboxylate (234.8 mg, 1.2 mmol) in anhydrous THF (10
mL) was added a solution of PPh3 (309.2 mg, 1.2 mmol) in THF
(5 mL) under N2 at 20-30 °C. The mixture was stirred at room
C
NMR (CDC13) δ 158.02 (qC), 154.25 (qC), 141.62 (qC), 137.72
(CH), 132.57 (qC), 125.72 (CH), 120.54 (qC), 118.22 (CH),
108.89 (CH), 39.67 (CH2), 39.18 (CH2), 38.42 (CH2), 26.34
(CH2), 16.48 (CH3), 15.92 (CH3), 9.75 (CH3); HREIMS m/z 275

1386 J ournal of Natural Products, 2004, Vol. 67, No. 8
J efford et al.
[M]+ (3.2), 216 [M - guanyl]+ (2.4), 148.0874 (22.6) (calcd for
C10H12O, 148.0888), 126.1035 (100) (calcd for C6H12N3, 126.1031),
105 (10.4), 84 (27.4), 60 [guanyl + H]+ (16.9).
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Ack n ow led gm en t. We thank A. Pinto and J . P. Saulnier
for determining the NMR spectra, A. Buchs and F. Gu¨lac¸ar
for the mass spectral measurements, and C. Dey for technical
assistance. We are grateful to the Swiss National Science
Foundation for financial support (Grant No. 20-27’966.89).
(19) Murahashi, S. I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J . Org. Chem.
1989, 54, 3292-3303.
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