The first synthesis of ent-agelasine F

Article abstract of DOI:10.1016/j.tet.2008.10.081

Agelasine F has previously been isolated from marine sponges (Agelas sp.) and has been associated with various bioactivities including inhibitory activity on Mycobacterium tuberculosis. No total synthesis of this natural product has been reported. ent-Age

Full text of DOI:10.1016/j.tet.2008.10.081

Tetrahedron 65 (2009) 194–199
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Tetrahedron
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The first synthesis of ent-agelasine F
a
b
,
,
*
Agnes Proszenyak , Morten Brændvang y, Colin Charnock c, Lise-Lotte Gundersen a
´
´
a Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
b Research and Development, Pronova BioPharma Norge AS, PO Box 2109, N-3202 Sandefjord, Norway
c Faculty of Health Sciences, Oslo University College, PO Box 4, St. Olavs Plass, N-0130 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2008
Received in revised form 6 October 2008
Accepted 23 October 2008
Available online 29 October 2008
Agelasine F has previously been isolated from marine sponges (Agelas sp.) and has been associated with
various bioactivities including inhibitory activity on Mycobacterium tuberculosis. No total synthesis of this
natural product has been reported. ent-Agelasine F has now been synthesized for the first time, starting
from (R)-pulegone. The synthesis is considerably more efficient than a previously reported route to rac-
agelasine F. ent-Agelasine F is found to exhibit antimicrobial activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Agelasine
Antimicrobial
Natural product synthesis
Pulegone
1. Introduction
TiCl4 gave a mixture of the diastereomeric sulfides 5 and 6 in a high
total yield, and with the desired isomer 5 as the major product. The
Agelasine F (Fig. 1), sometimes also referred to as ageline A,1 has
been isolated from marine sponges (Agelas sp.).1–5 Antibacterial
activity,1 including activity against Mycobacterium tuberculosis,6
antifungal activity,1,5 and inhibitory effects on Na,K-ATPase2 are
reported for this natural product. Only racemic agelasine F has been
synthesized.7 Our group has previously reported the first total
syntheses of agelasine D8 and E (Fig. 1),9 as well as several ana-
logs,8–10 and explored their generally potent activities against
pathogenic microorganisms and cancer cell lines, as well as the
ability to act as antifouling agents.11 We envisaged that agelasine F
would be available from the monoterpene (S)-pulegone (Fig. 1). In
order to test this hypothesis, we have performed the synthesis of
ent-agelasine F from the less expensive (R)-pulegone.
sulfides were easily oxidized to the corresponding sulfones 7 and 8,
and the stereochemistry of the sulfides and sulfones were proven
by X-ray crystallography of the sulfone 8. Compound 8 crystallized
as two crystallographically independent molecules as shown in
Figure 2. Methylmagnesium iodide was added to the ketone 7 and,
after formic acid-mediated regioselective water elimination, the
desired sulfone 9 was isolated in high yield. The use of other acids
(TFA, oxalic acid, H2SO4, H3PO4) in the elimination step resulted in
formation of the isomeric product with an exocyclic double bond, in
various amounts. In the Grignard addition, diethyl ether was su-
perior to THF as solvent. The best total yield of compound 9 was
obtained when the Grignard addition/water elimination was per-
formed after oxidizing the sulfide 5 to sulfone 7. When the sulfide 5
was reacted subsequently with methylmagnesium iodide and for-
mic acid, the yield was only ca. 40%. The sulfone 9 was at first
treated with n-butyllithium followed by the tosylate 10a according
to the procedures previously used for coupling the two mono-
terpene parts in the agelasine E side chain13 and in the side chain of
an agelasine analog.10b However, the reaction between lithiated
sulfone 9 and the tosylate 10a was sluggish and only minor
amounts of the desired compound 11 were formed. This is probably
a result of increased steric hindrance in 9 compared to sulfones
related to the previously used tosylate 10a (Fig. 3). Hence, we in-
vestigated the reaction between the lithiated sulfone 9 and the
potentially, more reactive geraniol derivatives 10b and 10c. When
the bromide 10b14 was used, a slight improvement in conversion
was observed, but the best results were obtained when the sulfone
2. Results and discussion
(R)-Pulegone 1 was converted into a diastereomeric mixture of
(2R,3R)- and (2S,3R)-2,3-dimethylcyclohexanone 3 by a modified
literature procedure,12 and the cyclohexanone 3 was transformed
into the thermodynamic silyl enol ether 4 (Scheme 1). Alkylation of
compound 4 with chloromethyl phenyl sulfide in the presence of
* Corresponding author. Tel.: þ47 22857019; fax: þ47 22855507.
E-mail address: l.l.gundersen@kjemi.uio.no (L.-L. Gundersen).
y
The contribution from the author was made independently from his position at
Pronova BioPharma.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.081

´
´
A. Proszenyak et al. / Tetrahedron 65 (2009) 194–199
195
Figure 1. Structure of agelasine D, E, and F and retrosynthetic analysis of agelasine F.
Scheme 1. (a) (1) LDA, (2) MeI, THF, ꢀ78 to 0 ꢁC; (b) KOH(aq), MeOH,
D
; (c) TMSCl, Et3N, DMF, 130 ꢁC; (d) PhSCH2Cl, TiCl4, CH2Cl2, ꢀ23 ꢁC; (e) oxone, MeOH, H2O; (f) (1) MeMgI,
Et2O, 0 ꢁC–rt, (2) HCO2H, 80 ꢁC; (g) (1) n-BuLi, (2) compd 10c, THF, 50 ꢁC; (h) Na, Na2HPO4, EtOH, THF; (i) PPTS, EtOH, 55 ꢁC; (j) PBr3, Et2O, 0 ꢁC.
was lithiated and reacted with the iodide 10c. The coupling product
11 was converted into the alkylating agent 14 by reductive removal
of the sulfone, protecting group cleavage, and finally bromination of
the alcohol 13 (Scheme 1). The optically active bromide 14 was
synthesized in 10 steps from commercially available (R)-pulegone,
whereas the previously reported method for the synthesis of rac-14
is ca. 13 steps from a non-commercially available racemic cyclo-
hexane derivative.7 The sulfone 9 may also be a useful building
block for other natural products and some examples are shown in
Figure 4.
The adenine derivative 15 was reacted with the allyl bromide 14,
in analogy with our previously reported agelasine D synthesis
(Scheme 2).8b Although the alkylation was not completely regio-
selective, the desired product 16a was formed in a good yield and
converted to ent-agelasine F (17) by reductive removal of the tert-
butoxy group. Preliminary results show that ent-agelasine F (17)
exhibits antimicrobial activity; MIC Staphylococcus aureus 2
mg/mL
and MIC Escherichia coli 16 g/mL. The synthesis of agelasine F, as
m
well as an in-depth study of bioactivities for both enantiomers and
analogs, will be published in due course.
3. Experimental
3.1. General
The 1H NMR spectra were recorded at 300 MHz with a Bruker
Avance DPX 300 instrument or at 200 MHz with a Bruker Avance
DPX 200 instrument. The decoupled 13C NMR spectra were recor-
ded at 75 or 50 MHz using instruments mentioned above, or at
150 MHz with AVII600 instrument equipped with TCI cryo probe.
Assignments of 1H and 13C resonances are inferred from 1D 1H
NMR, 1D 13C NMR, DEPT and/or from 2D NMR (gs-COSY, gs-HMQC,

´
´
196
A. Proszenyak et al. / Tetrahedron 65 (2009) 194–199
O51
C58
C51
C64
C52
O52
C65
C56
C63
C54
C59
C53
C60
C57
C55
C62
S51
O53
C61
Figure 4. Selected natural products with structural resemblance to sulfone 9.
O03
parameters; H atoms were positioned geometrically and allowed to
ride and rotate (for the CH3 group) on their carrier atoms, with C–H
bond lengths of 0.95 (aromatic C–H), 0.99 (CH2) or 0.98 Å (CH3) and
with Uiso(H)¼1.2Ueq(C) for CH2 and aromatic C–H or 1.5Ueq(C) for
CH3. Crystallographic data (excluding structure factors) for the
structure 8 in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC 692906. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
C15
C09
S01
C07
C14
C13
O02
C05
C06
C10
C11
C01
C08
O01
C12
C04
C03
C02
3.2.1. Crystal data for C18H15ClN4O2
8
Figure 2. The two molecules in the asymmetric unit of sulfone 8, showing the atom-
numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
M¼280.37, monoclinic, P2(1), a¼9.7883 (2) Å, b¼10.7792 (3) Å,
c¼13.8013 (3) Å,
b
¼101.9320 (10)ꢁ, V¼1424.71 (6) Å3, Z¼4,
Dx¼1.307 Mg mꢀ3
,
m
¼0.23 mmꢀ1, T¼105(2) K, measured 18,991
reflections in 2
q
range 3.0–68.6ꢁ, Rint¼0.021. Three hundred and
forty-four parameters refined against 11,249 F2, R¼0.03 for 10,382
I>2s(I) and 0.0342 for all 11,249 data. Absolute structure was
determined.
3.2.2. (3R)-2,3-Dimethylcyclohexanone (3)12
Figure 3. Sulfones previously coupled successfully with the tosylate 10a.9,10b
(R)-Pulegone 1 (10.0 g, 65.8 mmol) was treated with LDA [gen-
erated in situ from n-BuLi (1.6 M in hexane, 50 mL, 80 mmol) and
diisopropylamine (5.0 mL, 71 mmol) in dry THF (80 mL)] at ꢀ78 ꢁC
for 1 h. Methyl iodide (14.4 mL, 116 mmol) was added and the
mixture was stirred for 1 h at ꢀ78 ꢁC and at 0 ꢁC for 1 h. After satd
aq NH4Cl (40 mL) and Et2O (200 mL) were added, the phases were
separated, and the aqueous phase was extracted with Et2O
(2ꢂ200 mL). The combined organic extracts were dried (MgSO4)
and evaporated in vacuo. The residue was partly purified by flash
chromatography eluting with hexane–EtOAc (30:1); yield 11.0 g
mainly compound 2. This material was treated with KOH (128 g) in
water (320 mL) and MeOH (83 mL) under reflux for 38 h. The
mixture was extracted with Et2O (3ꢂ150 mL) and the combined
extracts were washed with aq HCl (1 M, 30 mL) and brine (45 mL),
dried (MgSO4), and evaporated in vacuo. The residue was distilled
under reduced pressure; yield 4.78 g (57%), mixture of isomers,
colorless liquid, bp 60–62 ꢁC/8 mmHg. 1H NMR (CDCl3, 200 MHz)
gs-HMBC, NOESY) spectroscopical data. Mass spectra under elec-
tron impact conditions were recorded with a VG Prospec in-
strument at 70 eV ionizing voltage and are presented as m/z (% rel
int.). Melting points were determined with a C. Reichert melting
point apparatus and are uncorrected. Optical rotations were de-
termined with a Perkin–Elmer 341 polarimeter. DMA was distilled
from BaO and stored over molecular sieves (3 Å). Triethylamine,
DMF, and CH2Cl2 were distilled from CaH2 and stored over molec-
ular sieves (3 Å). THF and diethyl ether were distilled from Na/
benzophenone. Silica gel for flash chromatography was purchased
from Merck, Darmstadt, Germany (Merck No. 09385). All other
reagents were commercially available and used as received. Anti-
microbial activities were determined as described before.8b
3.2. X-ray crystallographic analysis for compound 8
d
1.01 (d, J¼6.5 Hz, 3H, CH3), 1.04 (d, J¼6.0 Hz, 3H, CH3), 1.39–1.50
(m, 2H), 1.52–1.63 (m, 1H), 1.85–1.91 (m, 2H), 1.96–2.06 (m, 2H),
Crystals of 8 suitable for X-ray crystallography were obtained
from acetone–hexane (1:3) at ambient temperature. X-ray data
were collected on a Siemens SMART CCD diffractometer15 using
2.16–2.36 (m, 1H); 13C NMR (CDCl3, 50 MHz)
d 12.2, 21.2, 26.5, 34.7,
41.6, 42.0, 52.3, 213.7 (C]O).
graphite monochromated Mo K
a
radiation (
l
¼0.71073 Å). Data
3.2.3. (R)-(2,3-Dimethylcyclohex-1-enyloxy)trimethylsilane (4)
TMSCl (9.5 mL, 76 mmol) was added dropwise to a solution of
(R)-2,3-dimethylcyclohexanone 3 (4.78 g, 38 mmol) in dry Et3N
(10.4 mL, 76.0 mmol) and dry DMF (24 mL). The mixture was
heated at 130 ꢁC and was stirred overnight. After cooling, Et2O
(70 mL) was added and the mixture washed with cold satd aq
NaHCO3 solution (70 mL). The aqueous phase was extracted with
collection method:
u
-scan, step 0.3ꢁ, crystal to detector distance
5 cm. Data reduction and cell determination were carried out with
the SAINT and XPREP programs.15 Absorption corrections were
applied by the use of the SADABS program.16 The structure was
determined and refined using the SHELX program package.17 The
non-hydrogen atoms were refined with isotropic thermal

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A. Proszenyak et al. / Tetrahedron 65 (2009) 194–199
197
Scheme 2. (a) Compd 14, DMA, 50 ꢁC; (b) Zn, AcOH, MeOH, H2O, 75 ꢁC.
cold Et2O (3ꢂ70 mL) and the combined organic extracts were
3.2.5. (2S,3R)-2,3-Dimethyl-2-(phenylsulfonylmethyl)
cyclohexanone (7)
washed rapidly with cold 0.5 M aq HCl (90 mL), cold satd aq
NaHCO3 (2ꢂ70 mL), and cold brine (70 mL). The organic layer was
dried (MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography eluting with hexane–EtOAc (100:1); yield
A solution of oxone (3.69 g, 4.00 mmol) in water (15 mL) was
added to a stirring solution of sulfide 5 (992 mg, 6.00 mmol) in
methanol (15 mL) at 0 ꢁC. The cooling bath was removed and the
reaction mixture was stirred for 19 h at ambient temperature be-
fore Et2O (200 mL) was added and the resulting mixture was
washed with water (40 mL) and brine (20 mL), dried (MgSO4), and
evaporated in vacuo. The residue was purified by flash chroma-
6.40 g (85%), pale yellow oil. 1H NMR (CDCl3, 300 MHz)
d 0.20 (s, 9H,
TMS), 1.00 (d, J¼6.9 Hz, 3H, CH3), 1.28–1.33 (m, 2H), 1.58 (q,
J¼0.6 Hz, 3H), 1.66–1.73 (m, 2H), 1.99–2.03 (m, 2H), 2.10–2.16 (m,
1H); 13C NMR (CDCl3, 75 MHz)
d 0.7 (TMS), 14.2, 19.9, 20.4, 30.5,
31.2, 33.6, 116.4, 143.2; MS (EI) m/z (rel %) 198 (13, Mþ), 185 (5), 184
tography eluting with hexane–acetone (3:1); yield 976 mg (87%),
20
(16), 155 (10), 84 (4), 75 (17).
colorless crystals, mp 95–97 ꢁC. [
a
]
D
ꢀ77.3 (c 1.5, CHCl3). 1H NMR
(CDCl3, 300 MHz)
d
1.04 (s, 3H, CH3), 1.06 (d, J¼6.8 Hz, 3H, CH3),
3.2.4. (2S,3R)-2,3-Dimethyl-(2-phenylthiomethyl)cyclohexanone
(5) and (2R,3R)-2,3-dimethyl-(2-phenylthiomethyl)
cyclohexanone (6)
1.51–1.63 (m, 1H), 1.73–1.75 (m, 1H), 1.78–1.92 (m, 2H, CH2), 2.40–
2.52 (m, 2H, CH2), 2.68–2.72 (m, 1H), 3.23 (d, J¼14.0 Hz, 1H, Ha in
CH2S), 3.93 (d, J¼14.0 Hz, 1H, Hb in CH2S), 7.51–7.60 (m, 3H, Ph),
A solution of TiCl4 in CH2Cl2 (10.2 mL, 1.0 M, 10.2 mmol) was
added to a stirring solution of (R)-(2,3-dimethylcyclohex-1-eny-
loxy)trimethylsilane 4 (1.85 g, 9.30 mmol) and chloromethyl phe-
nyl sulfide (1.7 mL, 13 mmol) in CH2Cl2 (9 mL), at ꢀ23 ꢁC under N2
atmosphere. After 1 h, the resulting deep red solution was poured
into satd aq NaHCO3 (45 mL) and extracted with Et2O (2ꢂ85 mL).
The combined organic extracts were dried (MgSO4) and evaporated
in vacuo. The products were separated by flash chromatography
eluting with hexane–EtOAc (15:1); yield 1.32 g (57%) of 5 and
7.93–7.96 (m, 2H, Ph); 13C NMR (CDCl3, 75 MHz)
d 16.1 (CH3), 18.7
(CH3), 23.3 (C-5), 29.2 (C-4), 36.6 (C-3), 37.6 (C-6), 52.3 (C-2), 60.9
(CH2S), 127.6 (2ꢂCH in Ph), 129.1 (2ꢂCH in Ph), 133.3 (CH in Ph),
142.0 (C in Ph), 211.6 (C]O); MS (EI) m/z (rel %) 280 (1, Mþ), 139
(100), 121 (19), 97 (19), 95 (20), 83 (25), 77 (20); HRMS (EI) found
280.1123, C15H20O3S requires 280.1133.
3.2.6. (2R,3R)-2,3-Dimethyl-2-(phenylsulfonylmethyl)
cyclohexanone (8)
0.774 g (33%) of 6.
Compound 5: colorless oil. [
(CDCl3, 300 MHz)
Sulfide 6 (1.00 mmol) was oxidized with oxone as described for
the synthesis of sulfone 7 above; yield 161 mg (85%), colorless crys-
20
a
]
ꢀ1.1 (c 1.32, CHCl3). 1H NMR
D
20
d
0.81 (d, J¼6.8 Hz, 3H, CH3), 1.09 (s, 3H, CH3),
tals, mp 110–112 ꢁC. [
a]
D
ꢀ9.4 (c 1.45, CHCl3). 1H NMR (CDCl3,
1.47–1.61 (m, 1H), 1.61–1.79 (m, 2H), 1.89–1.98 (m, 1H), 2.18–2.30
(m, 1H), 2.31–2.48 (m, 2H), 2.97 (d, J¼12.5 Hz, 1H, Ha in CH2S), 3.37
(d, J¼12.5 Hz, 1H, Hb in CH2S), 7.14–7.17 (m, 1H, Ph), 7.21–7.27 (m,
300 MHz)
d
0.96 (d, J¼7.0 Hz, 3H, CH3), 1.43 (s, 3H, CH3), 1.44–1.59
(m,1H),1.70–1.80 (m,1H),1.81–2.03 (m, 2H), 2.14–2.21 (m,1H), 2.46–
2.56 (m, 2H, CH2), 3.25 (d, J¼14.6 Hz, 1H, Ha in CH2S), 3.56 (d,
J¼14.6 Hz, 1H, Hb in CH2S), 7.52–7.63 (m, 3H, Ph), 7.86–7.89 (m, 2H,
2H, Ph), 7.37–7.40 (m, 2H, Ph); 13C NMR (CDCl3, 75 MHz)
d 15.5
(CH3), 18.6 (CH3), 24.2 (C-5), 29.1 (C-4), 37.7 (C-3), 38.0 (C-6), 41.1
(CH2S), 53.7 (C-2),126.1 (CH in Ph),128.8 (2ꢂCH in Ph),130.1 (2ꢂCH
in Ph),138.1 (C in Ph), 213.6 (C]O); MS (EI) m/z (rel %) 248 (86, Mþ),
139 (63), 125 (21), 124 (15), 123 (100), 110 (28), 109 (19); HRMS (EI)
found 248.1237, C15H20OS requires 248.1235.
Compound 6: colorless oil. [
(CDCl3, 300 MHz)
1.53–1.61 (m, 1H), 1.61–1.73 (m, 1H), 1.73–1.87 (m, 1H), 1.88–1.97
(m, 2H), 2.28–2.42 (m, 2H, CH2), 3.08 (d, J¼12.0 Hz, 1H, Ha in
CH2S), 3.24 (d, J¼12.0 Hz, 1H, Hb in CH2S), 7.14–7.17 (m, 1H, Ph),
7.21–7.26 (m, 2H, Ph), 7.31–7.34 (m, 2H, Ph); 13C NMR (CDCl3,
Ph); 13C NMR (CDCl3, 75 MHz)
d 15.9 (CH3), 21.4 (CH3), 24.7 (C-5), 28.4
(C-4), 37.8 (C-6), 43.3 (C-3), 52.2 (C-2), 59.5 (CH2S), 127.7 (2ꢂCH in
Ph),129.3 (2ꢂCH in Ph),133.7 (CH in Ph),141.3 (C in Ph), 212.1 (C]O);
MS (EI) m/z (rel %) 280 (1, Mþ),139 (100),121 (19), 97 (19), 95 (21), 83
(22), 77(27);HRMS(EI)found280.1132, C15H20O3Srequires280.1133.
20
a
]
ꢀ65.8 (c 1.3, CHCl3). 1H NMR
D
d
0.96 (d, J¼6.9 Hz, 3H, CH3), 1.25 (s, 3H, CH3),
3.2.7. 1-{[(1S,6R)-1,2,6-Trimethylcyclohex-2-enyl]
methylsulfonyl}benzene (9)
To a solution of ketone 7 (958 mg, 3.40 mmol) in dry Et2O
(60 mL) was added MeMgI in Et2O (3.8 mL, 1.0 M, 3.8 mmol) at 0 ꢁC.
The reaction mixture was stirred at 0 ꢁC for 1 h and then at ambient
temperature for 16 h. After cooling to 0 ꢁC, satd aq NH4Cl (10 mL)
was added. The mixture was diluted with Et2O (10 mL) and the
phases separated. The aqueous phase was extracted with Et2O
(60 mL), the combined organic extracts were dried (MgSO4), and
concentrated in vacuo. The residue was stirred in concd formic acid
(2 mL) at 80 ꢁC for 2 h before the mixture was concentrated in
75 MHz)
d 15.7 (CH3), 21.1 (CH3), 24.7 (C-5), 28.9 (C-4), 38.3 (C-
6), 38.8 (CH2S), 42.2 (C-3), 52.7 (C-2), 126.1 (CH in Ph), 128.9
(2ꢂCH in Ph), 129.7 (2ꢂCH in Ph), 137.1 (C in Ph), 214.1 (C]O);
MS (EI) m/z (rel %) 248 (81, Mþ), 139 (71), 124 (12), 123 (100), 110
(20), 109 (118); HRMS (EI) found 248.1235, C15H20OS requires
248.1235.

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A. Proszenyak et al. / Tetrahedron 65 (2009) 194–199
198
vacuo. The residue was purified by flash chromatography eluting
with hexane–acetone (5:1); yield 809 mg (85%), pale yellow oil.
140.2 (C]); MS (EI) m/z (rel %) 374 (0.4, Mþ), 124 (32), 123 (100),
109 (23), 95 (22), 85 (96), 81 (36); HRMS (EI) found 374.3167,
C25H42O2 requires 374.3185.
20
[
a]
ꢀ47.9 (c 1.17, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 0.83 (d,
589
J¼6.9 Hz, 3H, CH3), 1.05 (s, 3H, CH3), 1.35–1.46 (m,1H), 1.57–1.65 (m,
1H), 1.62 (q, J¼1.8 Hz, 3H, CH3), 1.95–2.02 (m, 2H, CH2), 2.55–2.61
(m, 1H), 3.19 (d, J¼14.6 Hz, 1H, Ha in CH2S), 3.30 (d, J¼14.6 Hz, 1H,
Hb in CH2S), 5.39 (m, 1H, CH]), 7.48–7.62 (m, 3H, Ph), 7.87–7.90 (m,
3.2.10. (2E,6E)-3,7-Dimethyl-9-[(1S,6R)-1,2,6-trimethylcyclohex-2-
enyl]nona-2,6-dien-1-ol (13)
A mixture of compound 12 (374 mg, 1.00 mmol) and pyridinium
p-toluenesulfonate (PPTS) (58 mg, 0.23 mmol) in ethanol (12 mL)
was stirred at 55 ꢁC under N2 atmosphere for 17 h, before the
mixture was evaporated in vacuo and the residue was purified by
2H, Ph); 13C NMR (CDCl3, 75 MHz)
d 15.7 (CH3), 19.2 (CH3), 21.3
(CH3), 23.8 (C-4), 26.3 (C-5), 33.3 (C-6), 42.2 (C-1), 61.9 (CH2S),124.6
(C-3),127.5 (2ꢂCH in Ph),129.1 (2ꢂCH in Ph),133.3 (CH in Ph),136.2
(C-2), 142.0 (C in Ph); MS (EI) m/z (rel %) 278 (4, Mþ), 137 (38), 136
(100), 121 (44), 107 (77), 95 (45), 94 (65), 93 (36); HRMS (EI) found
278.1350, C16H22O2S requires 278.1341.
flash chromatography eluting with hexane–acetone (15:1); yield
20
237 mg (82%), pale yellow oil. [
(CDCl3, 300 MHz)
a]
þ26.4 (c 1.18, CHCl3). 1H NMR
D
d
0.83 (s, 3H, CH3 on C-1 in cyclohexene), 0.83 (d,
J¼6.9 Hz, 3H, CH3 on C-6 in cyclohexene), 1.37–1.47 (m, 4H, 2ꢂCH2,
H-4 in cyclohexene, H-5 in cyclohexene), 1.58 (s, 6H, CH3 on C-7,
CH3 on C-2 in cyclohexene), 1.61–1.72 (m, 1H, H-6 in cyclohexene),
1.62 (s, 3H, CH3 on C-3), 1.87–2.09 (m, 8H, 4ꢂCH2, H-4, H-5, H-8, H-
9), 4.12 (d, J¼6.9 Hz, 2H, H-1), 5.07 (t, J¼6.2 Hz, 1H, H-6), 5.36–5.40
3.2.8. 2-[(2E,6E)-8-Iodo-3,7-dimethylocta-2,6-
dienyloxy]tetrahydro-2H-pyrane (10c)
To a stirred solution of (2E,6E)-2,6-dimethyl-8-(tetrahydro-2H-
pyran-2-yloxy)octa-2,6-dien-1-ol13 (508 mg, 2 mmol), Ph3P
(788 mg, 3.00 mmol), and imidazole (204 mg, 3.00 mmol) in
a mixture of CH3CN (3 mL) and Et2O (5 mL) was added iodine
(760 mg, 3.00 mmol) portionwise at 0 ꢁC over 10 min. The reaction
mixture was stirred for another 20 min, diluted with Et2O (40 mL),
washed with satd aq Na2S2O3 (10 mL), water (10 mL), and brine
(10 mL), dried (MgSO4), and evaporated in vacuo. The residue was
filtered through a plug of silica eluting with hexane–EtOAc (15:1);
yield 604 mg (ca. 83%), pale yellow liquid used immediately in the
(m, 2H, H-2, H-3 in cyclohexene); 13C NMR (CDCl3, 75 MHz)
d 15.8
(CH3 on C-6 in cyclohexene), 16.2 (CH3 on C-7), 16.3 (CH3 on C-3),
19.2 (CH3 on C-2 in cyclohexene), 21.0 (CH3 on C-1 in cyclohexene),
25.5 (C-5), 26.3 (C-9), 27.0 (C-4 in cyclohexene), 33.1 (C-6 in
cyclohexene), 34.2 (C-4), 35.2 (C-5 in cyclohexene), 39.5 (C-8), 40.3
(C-1 in cyclohexene), 59.4 (C-1), 123.1 (C-6), 123.3 (C-2), 124.0 (C-3
in cyclohexene), 136.4 (C-7), 139.7 (C-2 in cyclohexene),139.8 (C-3);
MS (EI) m/z (rel %) 290 (1, Mþ), 124 (44), 123 (100), 109 (29), 95 (20),
81 (38); HRMS (EI) found 290.2600, C20H34O requires 290.2610.
next step. 1H NMR (CDCl3, 200 MHz)
d 1.43–1.65 (m, 6H), 1.65 (s,
3H), 1.75 (s, 3H), 2.02–2.15 (m, 4H), 3.45–3.54 (m, 1H), 3.89 (d,
J¼7.8 Hz, 2H), 3.99–4.08 (m, 1H), 4.11–4.27 (m, 1H), 4.60 (t,
J¼3.4 Hz, 1H), 5.37 (t, J¼6.4 Hz, 2H), 5.57–5.69 (m, 1H); 13C NMR
3.2.11. (5R,6R)-6-[(3E,7E)-9-Bromo-3,7-dimethylnona-3,7-dienyl]-
1,5,6-trimethylcyclohex-1-ene (14)
(C6D6, 75 MHz)
d
15.3 (CH3), 16.2 (CH2), 16.3 (CH3), 19.6 (CH2), 26.0
The alcohol 13 (237 mg, 0.82 mmol) was dissolved in dry Et2O
(3 mL) under N2 atmosphere at 0 ꢁC. PBr3 (0.065 mL, 0.82 mmol)
was added and the mixture was stirred at 0 ꢁC for 3 h. The mixture
was diluted with Et2O (18 mL) and washed with 10% aq NaHCO3
(6 mL). The aqueous phase was extracted with Et2O (6 mL) and the
combined organic extracts were dried (MgSO4), and evaporated in
vacuo; yield 0.267 g (93%), pale yellow oil, which was used directly
in the next step without further purification. 1H NMR (CDCl3,
(CH2), 27.0 (CH2), 31.1 (CH2), 38.6 (CH2), 61.5 (CH2), 63.6 (CH2), 97.5
(OCHO), 122.4 (CH]), 129.2 (CH]), 133.3 (C]), 138.3 (C]).
3.2.9. 2-[(2E,6E)-3,7-Dimethyl-9-[(1S,6R)-1,2,6-trimethylcyclohex-
2-enyl]nona-2,6-dienyloxy]-tetrahydro-2H-pyran (12)
n-BuLi (8.56 mL, 1.44 M, 8.60 mmol) was added dropwise to
a stirring solution of sulfone 9 (1.19 g, 4.30 mmol) in dry THF
(20 mL) at 0 ꢁC under N2 atmosphere and the resulting mixture was
stirred at 50 ꢁC for 40 min before a solution of crude iodide 10c
(3.18 g, 8.60 mmol) in THF (20 mL) was added. The reaction was
stirred for 3 h at 50 ꢁC. The mixture was diluted with Et2O (120 mL),
washed with satd aq NH4Cl (40 mL), water (3ꢂ40 mL), and brine
(40 mL), and evaporated in vacuo. The product 11 was partially
purified by flash chromatography eluting with hexane–acetone
(11:1); yield 2.20 g, pale yellow oil. A mixture of compound 11
(2.20 g), Na2HPO4 (19.0 g, 134 mmol), sodium (4.30 mg, 187 mmol),
and ethanol (16 mL) in THF (330 mL) was stirred at ambient tem-
perature for 16 h, before the mixture was filtered and the filtrate
was diluted with Et2O (430 mL). The resulting mixture was washed
with water (300 mL), satd aq NH4Cl (220 mL), and brine (220 mL),
dried (MgSO4), and evaporated in vacuo. The product was purified
by flash chromatography eluting with hexane–EtOAc (23:1); yield
1.61 g (54% from compound 9), pale yellow oil. 1H NMR (CDCl3,
300 MHz)
d
0.83 (s, 3H), 0.84 (d, J¼6.8 Hz, 3H), 1.26–1.45 (m, 4H),
1.54–1.61 (m, 1H), 1.58 (s, 3H), 1.61–2.12 (m, 8H), 4.00 (d, J¼9.9 Hz,
2H), 4.99–5.05 (m, 1H), 5.39 (s, 1H), 5.51 (t, J¼8.4 Hz, 1H); 13C NMR
(CDCl3, 75 MHz)
d 15.8, 16.0, 16.3, 19.2, 21.1, 25.5, 26.1, 27.0, 29.7,
33.2, 34.2, 35.2, 39.5, 40.4, 120.6, 122.7, 124.0, 136.7, 136.7, 139.8,
143.7; MS (EI) m/z (rel %) 352 (0.7, Mþ), 124 (46), 123 (100), 109 (21),
95 (17), 81 (31); HRMS (EI) found 352.1778, C20H33Br requires
352.1766.
3.2.12. 7-{(20E,60E)-3,7-Dimethyl-9-[(1R,6S)-1,2,6-trimethyl
cyclohex-2-enyl]nona-2,6-dienyl}-6-tert-butoxyamino-9-methyl-
7H-purinum (16a) and N6-{(20E,60E)-3,7-dimethyl-9-[(1R,6S)-1,2,6-
trimethylcyclohex-2-enyl]nona-2,6-dienyl}-
N6-tert-butoxy-9-methyl-9H-purin-6-amine (16b)
A mixture of purine 158b (111 mg, 0.50 mmol) and allylic bro-
mide 14 (182 mg, 0.52 mmol) in DMA (4.5 mL) was stirred at 50 ꢁC
under N2 atmosphere for 21 h and evaporated in vacuo. The residue
was purified by flash chromatography eluting with CH2Cl2–MeOH
satd with NH3 (12:1 then 9:1); yield (16a) 188 mg (76%). The frac-
tions containing isomer 16b were combined, evaporated, and
purified by flash chromatography eluting with hexane–EtOAc (1:1);
300 MHz)
d
0.83 (s, 3H, CH3), 0.84 (d, J¼6.8 Hz, 3H, CH3), 1.23–1.62
(m, 8H, 4ꢂCH2), 1.58 (s, 6H, 2ꢂCH3), 1.64–1.78 (m, 3H, CH2 in THP
and H-6a in cyclohexene), 1.80–2.11 (m, 8H, 4ꢂCH2), 3.45–3.52 (m,
1H, H-6a in THP), 3.84–3.91 (m, 1H, H-6b in cyclohexene), 3.97–4.03
(m, 1H, Ha in CH2O), 4.17–4.24 (m, 1H, Hb in CH2O), 4.60 (t, J¼5.6 Hz,
1H, H-2 in THP), 5.07 (t, J¼6.8 Hz, CH]), 5.35 (t, J¼6.4 Hz, 1H,
yield (16b) 28 mg (11%).
20
CH]), 5.37 (br s, 1H, CH]); 13C NMR (CDCl3, 75 MHz)
d
15.8 (CH3),
Compound 16a: mp 149–150 ꢁC, yellow crystals. [
a]
þ14.3 (c
D
16.2 (CH3 on C-7), 16.4 (CH3), 19.2 (CH3 on C-2), 19.6 (CH2), 21.0
(CH3), 25.5 (2ꢂCH2), 26.3 (CH2), 27.0 (CH2), 30.7 (CH2), 33.2 (C-6 in
cyclohexene), 34.2 (CH2), 35.2 (CH2), 39.6 (CH2), 40.4 (C-1 in
cyclohexene), 62.3 (C-6 in THP), 63.6 (OCH2), 97.7 (C-2 in THP),
120.6 (CH]), 123.2 (CH]), 124.0 (CH]), 136.3 (C]), 139.8 (C]),
0.52, CHCl3). 1H NMR (CDCl3, 300 MHz)
d 0.81 (s, 3H, CH3 on C-1 in
cyclohexene), 0.82 (d, J¼6.8 Hz, 3H, CH3 on C-6 in cyclohexene),
1.31 (s, 9H, t-Bu), 1.35–1.45 (m, 4H), 1.51 (s, 6H, CH3 on C-70 and CH3
on C-2 in cyclohexene), 1.60–1.64 (m, 2H), 1.82 (s, 3H, CH3 on C-30),
1.83–1.91 (m, 3H), 2.07–2.09 (m, 4H), 3.97 (s, 3H, NCH3), 5.02–5.08

´
´
A. Proszenyak et al. / Tetrahedron 65 (2009) 194–199
199
(m, 3H, NCH2 and H-60), 5.37 (s, 1H, H-3 in cyclohexene), 5.53 (t,
(br s, 1H, H-3 in cyclohexene), 5.63 (br s, 2H, NCH2), 7.15 (br s, 2H,
NH2), 8.43 (1H, H-2), 10.43 (s, 1H, H-8); 13C NMR (CDCl3, 75 MHz)
d
15.8 (CH3 on C-6 in cyclohexene), 16.3 (CH3 on C-70), 17.4 (CH3 on
J¼7.2 Hz, 1H, H-20), 7.91 (s, 1H, H-2), 9.99 (s, 1H, H-8); 13C NMR
(CDCl3, 75 MHz)
d
15.8 (CH3 on C-6 in cyclohexene), 16.2 (CH3 on C-
70), 17.3 (CH3 on C-30), 19.2 (CH3 on C-2 in cyclohexene), 21.0 (CH3
on C-1 in cyclohexene), 25.5 (C-50), 26.1 (C-90), 27.0 (C-4 in cylo-
hexene), 27.5 (3ꢂCH3 in t-Bu), 32.1 (NCH3), 33.2 (C-6 in cyclo-
hexene), 34.2 (CH2), 35.1 (CH2), 39.5 (CH2), 40.3 (C-1 in
cyclohexene), 48.1 (NCH2), 79.7 (C in t-Bu), 111.2 (C-5), 115.5 (C-20),
122.6 (C-60), 124.1 (C-3 in cyclohexene), 136.0 (C-2 in cyclohexene),
136.6 (C-8), 136.8 (C-30), 139.6 (C-6), 141.2 (C-4), 146.1 (C-70), 149.3
(C-2); MS (EI) m/z (rel %) 493 (10, Mþ), 216 (33), 166 (18), 165 (100),
135 (37), 123 (61), 81 (31); HRMS (EI) found 493.3763, C30H47N5O
C-30), 19.2 (CH3 on C-2 in cyclohexene), 21.0 (CH3 on C-1 in cyclo-
hexene), 25.5 (CH2), 26.2 (C-4 in cyclohexene), 27.0 (CH2), 32.2
(NCH3), 33.2 (C-6 in cyclohexene), 34.2 (CH2), 35.1 (CH2), 39.5 (CH2),
40.3 (C-1 in cyclohexene), 48.8 (NCH2), 109.9 (C-5), 115.8 (C-20),
122.5 (C-60), 124.1 (C-3 in cyclohexene), 137.0 (C]), 139.6 (C]),
141.9 (C-8), 146.8 (C]), 149.5 (C-4), 152.1 (C-6), 155.4 (C-2); MS (EI)
m/z (rel %) 421 (1, Mþ), 149 (48), 124 (32), 123 (100), 122 (17), 109
(20), 81 (31); HRMS (EI) found 421.3190, C26H39N5 requires
421.3205. Spectroscopical data were in good accordance with those
reported for agelasine F1–4 and rac-agelasine F7 before.
requires 493.3780.
20
Compound 16b: colorless oil. [
a
]
þ17.1 (c 0.52, CHCl3). 1H NMR
D
(CDCl3, 300 MHz)
d
0.80 (s, 3H, CH3 on C-1 in cyclohexene), 0.81 (d,
Acknowledgements
J¼6.8 Hz, 3H, CH3 on C-6 in cyclohexene), 1.30–1.41 (m, 4H), 1.38 (s,
9H, t-Bu), 1.49 (s, 3H, CH3 on C-70), 1.52–1.57 (m, 1H), 1.55 (q,
J¼1.5 Hz, 3H, CH3 on C-2 in cyclohexene), 1.65 (s, 3H, CH3 on C-30),
1.76–1.94 (m, 8H), 3.81 (s, 3H, NCH3), 4.20 (br s, 1H, Ha in NCH2),
4.97 (t, J¼6.7 Hz, 1H, H-60), 5.30 (t, J¼6.4 Hz, 1H, H-20), 5.37 (m, 2H,
H-3 in cyclohexene and Hb in NCH2), 7.78 (s, 1H, H-8), 8.52 (s, 1H, H-
The Norwegian Research Council is greatly acknowledged for
a scholarship to A.P. (grant 171323/V30) and for financing of the
Bruker Avance DPX 200, DPX 300, and AVII600 instruments used in
this study. We thank Dr. Osamu Sekiguchi, Department of Chem-
istry, University of Oslo for the single-crystal data collection and
initial refinement.
2); 13C NMR (CDCl3, 150 MHz)
d 15.8 (CH3 on C-6 in cyclohexene),
16.1 (CH3 on C-70), 16.6 (CH3 on C-30), 19.2 (CH3 on C-2 in cyclo-
hexene), 21.0 (CH3 on C-1 in cyclohexene), 25.5 (CH2), 26.4 (CH2),
27.0 (CH2), 27.2 (3ꢂCH3 in t-Bu), 29.8 (NCH3), 33.1 (C-6 in cyclo-
hexene), 34.1 (CH2), 35.1 (CH2), 39.6 (CH2), 40.3 (C-1 in cyclo-
hexene), 53.8 (NCH2), 82.6 (C in t-Bu), 118.7 (C-20), 119.9 (C-5), 123.3
(C-60), 123.9 (C-3 in cyclohexene), 136.0 (C-70), 139.5 (C-8), 139.8 (C-
2 in cyclohexene), 140.8 (C-30), 151.5 (C-2), 151.6 (C-4), 158.9 (C-6);
MS (EI) m/z (rel %) 493 (0.6, Mþ), 437 (50), 314 (34), 216 (17), 166
(31), 165 (100), 135 (20); HRMS (EI) found 493.3780, C30H47N5O
requires 493.3780.
References and notes
1. Capon, R. J.; Faulkner, D. J. J. Am. Chem. Soc. 1984, 106, 1819–1922.
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3.2.13. ent-Agelasine F (17)
A mixture of compound 16a (174 mg, 0.35 mmol), Zn (287 mg,
4.39 mmol), and AcOH (0.35 mL) in MeOH (18 mL) and water
(1.8 mL) was stirred vigorously at 75 ꢁC for 19 h. The mixture was
filtered and the solid washed with MeOH (18 mL). Satd aq NaCl
(9 mL) and water (9 mL) were added to the MeOH solution, and the
mixture was stirred for 1 h at ambient temperature and evaporated
in vacuo. The residue was transferred to a separatory funnel using
satd aq NaCl (37 mL) and CHCl3 (42 mL). The phases were separated
and the aqueous phase was extracted with CHCl3 (3ꢂ42 mL). The
combined organic layers were dried (MgSO4) and evaporated in
vacuo. The residue was purified by flash chromatography eluting
9. Bakkestuen, A. K.; Gundersen, L.-L.; Petersen, D.; Utenova, B. T.; Vik, A. Org. Biol.
Chem. 2005, 3, 1025–1033.
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Bohlin, L.; Gundersen, L.-L. Bioorg. Med. Chem. 2007, 15, 4016–4037; (b) Pros-
´
´
zenyak, A.; Charnock, C.; Hedner, E.; Larsson, R.; Bohlin, L.; Gundersen, L.-L.
Arch. Pharm. Chem. Life Sci. 2007, 340, 625–634; (c) Roggen, H.; Gundersen, L.-L.
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12. Tori, M.; Uchida, N.; Sumida, A.; Furuta, H.; Asakawa, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 1513–1517.
13. Bakkestuen, A. K.; Gundersen, L.-L. Tetrahedron 2003, 59, 115–121.
14. Chen, A. P.-C.; Chen, Y.-H.; Liu, H.-P.; Li, Y.-C.; Chen, C.-T.; Liang, P.-H. J. Am.
Chem. Soc. 2002, 124, 15217–15224.
15. SMART (Version 5.625) and SAINTþ (Version 6.02). Area-Detector Control and
Integration Software; Bruker Analytical X-ray Instruments: Madison, WI, 1998.
16. Sheldrick, G. M. SADABS. Program for Empirical Correction of Area Detector Data;
University of Go¨ttingen: Go¨ttingen, Germany, 1996.
with CH2Cl2–MeOH (6:1); yield 161 mg (48%), colorless crystals, mp
20
99–100 ꢁC. [
3.0, CHCl3);1
300 MHz)
a
]
D
þ12.2 (c 0.64, CHCl3); [lit. agelasine F [ D ꢀ8.4 (c
a
]
25
[a
]
ꢀ5.5 (c 2.45, MeOH3)2]. 1H NMR (CDCl3,
D
d
0.81 (s, 3H, CH3 on C-1 in cyclohexene), 0.81 (d,
J¼6.7 Hz, 3H, CH3 on C-6 in cyclohexene), 1.21–1.44 (m, 5H), 1.53 (s,
3H, CH3 on C-70), 1.54 (s, 3H, CH3 on C-2 in cyclohexene), 1.59–1.69
(m, 1H), 1.78–1.83 (m, 1H), 1.82 (s, 3H, CH3 on C-30), 1.87–1.97 (m,
2H), 2.01–2.08 (m, 4H), 4.06 (s, 3H, NCH3), 4.93 (br s, 1H, H-60), 5.37
17. Sheldrick, G. M. SHELXL (release 97-2). Programs for Crystal Structure Analysis
Structure; University of Go¨ttingen: Go¨ttingen, Germany, 1997.