The First Synthesis of (–)-Agelasine F; an Antimycobacterial Natural Product Found in Marine Sponges in the Agelas Genus

Article abstract of DOI:10.1002/ejoc.202000202

(–)-Agelasine F (also known as ageline A) is a diterpene-adenine hybrid natural product isolated from marine sponges (Agelas species) and this compound is known to display cytotoxic activity against a variety of cancer cell lines as well as microorganisms. We herein report the first total synthesis of (–)-agelasine F. The commercially available and inexpensive monoterpenoid (S)-carvone was found to be a highly suitable starting material for the construction of the terpenoid part of the desired agelasine and controlling the stereochemistry of the target compound. Two alternative strategies from (S)-carvone were evaluated. Key-intermediates in the (–)-agelasine F synthesis are believed also to be valuable starting materials for total syntheses of other bioactive marine sponge metabolites. The synthetic route to (–)-agelasine F described herein is more efficient than previously published syntheses of racemic or ent-agelasine F.

Full text of DOI:10.1002/ejoc.202000202

A Journal of
Accepted Article
Title: The first synthesis of (–)-agelasine F; an antimycobacterial
natural product found in marine sponges in the Agelas genus
Authors: Britt Paulsen and Lise-Lotte Gundersen
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
The first synthesis of (–)-agelasine F; an antimycobacterial
natural product found in marine sponges in the Agelas genus
Britt Paulsen,[a] and Lise-Lotte Gundersen*[a]
[a]
Ms B. Paulsen, Prof. L.-L. Gundersen
Department of Chemistry, University of Oslo
P. O. Box 1033, Blindern, N-0315 Oslo, Norway
E-mail: l.l.gundersen@kjemi.uio.no
https://www.mn.uio.no/kjemi/personer/vit/llotte/index.html
Supporting information for this article is given via a link at the end of the document.
Abstract: (–)-Agelasine F (also known as ageline A) is a diterpene-
adenine hybrid natural product isolated from marine sponges
(Agelas species) and this compound is known to display cytotoxic
It was clear to us that the synthetic strategy for racemic
agelasine F could not readily be modified for synthesis of the (–
)- or (+)-isomers. Previously we searched for readily available
enantiopure monoterpenes as a starting point and we have
synthesized ent-agelasine F [(+)-agelasine F] from commercially
available (R)-pulegone (7).7 Some steps in the synthesis of the
desired enantiomer of the key-intermediate 5 are shown in
Scheme 2. As a continuance of our work directed to synthesis of
agelasines and analogs7,8 and evaluation of their biological
activities,7-9 we herein present the first total synthesis of the
naturally occurring (–)-agelasine F.
activity against
a variety of cancer cell lines as well as
microorganisms. We herein report the first total synthesis of (–)-
agelasine F. The commercially available and inexpensive
monoterpenoid (S)-carvone was found to be a highly suitable
starting material for the construction of the terpenoid part of the
desired agelasine and controlling the stereochemistry of the target
compound. Two alternative strategies from (S)-carvone were
evaluated. Key-intermediates in the (–)-agelasine F synthesis are
believed also to be valuable starting materials for total syntheses of
other bioactive marine sponge metabolites. The synthetic route to (–
)-agelasine F described herein is more efficient than previously
published syntheses of racemic or ent-agelasine F.
O
O
OSiMe3
O
SPh
1) !-methylation
2) retro aldol
(R)-Pulegone (7)
(3R) 8
(R) 9
(2S,3R) 10
SO2Ph
Introduction
2 steps
4 steps
Br
(1S,6R) 11
(5R,6S) 5
Agelasines are bioactive purine-terpene hybrides isolated from
marine sponges (Agelas sp.).1 Agelasine F (also called ageline
A) was reported isolated independently by two different research
groups in 19842 and has been re-isolated on several
occations.1e,3 Agelasine F is found to display cytotoxicity against
a variety of cancer cell lines1e,3d and microorganisms1e,2a,3
Scheme 2. Literature synthesis of the key compound 5 for the preparation of
ent-agelasine F.7
Results and Discussion
including
profound
activity
against
Mycobacterium
tuberculosis.3b
A
reverse docking study has revealed
Since (S)-pulegone is substantially more expensive compared to
the R-enantiomer, we searched for a more convenient starting
point for the preparation of (–)-agelasine F, and we herein report
the first total synthesis of this natural product from (S)-(+)-
carvone.10 Conjugate addition of Me2CuLi to the enone 12 gave
the ketone 13 with excellent diastereoselectivity, the minor
isomer most probably epi at C-2,11 and compound 13 was
converted to the dimethylketone 8 by ozonolysis followed by Fe-
and Cu-mediated fragmentation12 and finally catalytic
hydrogenation (Scheme 3).11 When the reduction was performed
in Et2O substantial epimerization at C-2 in ketone 8 was
observed, but when the solvent was changed to pentane, the
epimerization was minimized. In our hands, Pd/C was a superior
catalyst compared to Rh/C. Ketone 8 was converted to the silyl
enol ether 9 which was alkylated with ClCH2SPh as described
for the enatiomer of 9 before.7 At its best the silyl enol ether 9
was isolated in 92% yield containing 6% of the unwanted
regioisomer 16, but these results turned out to be not completely
reproducible with respect to total yield and regioselectivity.
Compound 11 was available in two steps from ketone 10
following the published procedures for synthesis of ent-11.7
mycobacterial enoyl recuctase and 7,8-diaminopelargonic acid
synthase as a possible enzyme target,4 but generally the
mechanism(s) of action for agelasines are poorly understood.
Racemic agelasine F (6) was synthesized ca. 30 years ago5 with
the cyclization of aldehyde 2 to give the cyclohexanol 36 as a
key-step (Scheme 1).
OH
10 steps
acid
O
BnO
O
SiMe3
1
2
(±) 3
I
3 steps
9 steps
2 steps
Br
(±) 5
(±) 4
Cl
N
N
H2N
N
(±)-Agelasine F (6)
N
Scheme 1. Literature synthesis of (±)-agelasine F.5,6
1
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
O
O
O
O
sulfone 21 the yield was low, probably due to side reactions on
the propenyl substituent, but compound 21 could be converted
to the dimethylketone 18 by ozonolysis etc. followed by catalytic
hydrogenation. When the removal of the propenyl group was
carried out before the S-oxidation, conversion of the sulfide to
the corresponding sulfoxides 24 and 25 took place. As reported
for other sulfides before,16 the ozone mediated oxidation
stopped at the sulfoxide level at the low temperature required for
the removal of the propenyl group. The crude product was
oxidized further to sulfones 22 and 23 by treatment with oxone.
The ratio between the isomers 22 and 23 was ca. 87:13
(a)
(b)
(c)
+
(S,S,S) 13
97%, dr 99%
(S,S) 14 (S,S) 15
Tot. yield 72%, 14:15 60:40
(S)-(+)-Carvone (12)
O
SPh
O
SPh
OSiMe3
OSiMe3
O
(d)
(e)
+
+
(S,S) 8 93%
(S) 9 (S,S) 16
Tot. yield 92%, 9:16 94:6
(2R,3S) 10 52%
(S,S) 17 37%
O
SO2Ph
(g)
SO2Ph
1
according the H NMR, but in this case it was only possible to
(f)
isolate the sulfone 22 in pure form.
(2R,3S) 18
94% from 10
(1R,6S) 11 95%
Table 1. Table Caption. Alkylation of silyl enol ether 9
Scheme 3. (a) 1. MeLi, CuI, CH2(OEt)2, Et2O, -78 oC → -30 oC, 2. Phenyl
salicylate, -78 oC → r.t.; (b) 1. O3, MeOH, -40 → -10 oC, 2. Cu(OAc)2. -20 oC, 3.
FeSO4•7H2O, -20 oC → r.t.; (c) H2, Pd/C, pentane; (d) Et3N, TMSCl, DMF, 130
oC; (e) TiCl4, PhSCH2Cl, CH2Cl2, -23 °C; (f) oxone, MeOH, H2O, 0 oC → r.t.; (g)
1. MeMgBr, Et2O, 0 oC → r.t, 2. HCO2H, 80 oC.
Lewis acid
TiCl4
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/toluene
THF
Temp.]
RT
Time
30 min
1 h
Ratio 10:17[a]
1.82:1
TiCl4
0 °C
1.79:1
TiCl4
-23 °C
-78 °C
0 °C
1 h
1.82:1
As reported before,7 TiCl4 mediated alkylation of the silyl enol
ether 9 gave only a modest selectivity for the desired isomer 10.
Rac- or (R)-enol ether 9 has previously been reacted with other
electrophiles (activated alkenes, acetals) in the presence of a
Lewis acid to give 2-substituted 2,3-dimethylcyclohexanones
with high diastereoselectivity,13 and this has been rationalized by
attack of the electrophile on the least hindered side of the most
stable conformer B of the silyl enol ether (Fig. 1).13a Thus, we
were somewhat surprised and disappointed to find that
alkylation of compound 9 with ClCH2SPh under standard
conditions for reactions between silyl enol ethers and alkyl
halides (TiCl4, CH2Cl2)14 took place with only a moderate
selectivity (dr ca. 1.8:1). The isomeric ratio was virtually
unaffected by temperature and changing the Lewis acid to zinc
halides gave only a fair improvement; dr ca. 3.9:1 (Table 1).
TiCl4
1h 20 min
20 min
4 h
1.96:1
Et2AlCl
ZnBr2
ZnBr2
ZnI2
1.96:1
RT
3.85:1
THF
-78 °C → RT
RT
21 h
3.85:1
THF
3 h
3.57:1
ZnCl2
THF
RT
3 h
3.33:1
[a] Determined by crude product 1H NMR.
O
O
SOPh
O
SOPh
+
E
12
(5S,6R) 24
(5S,6R) 25
H
E
H
(b)
(c)
(a)
Me
Me
Me
Me3SiO
Me
Me
B
Me3SiO
Me
O
A
O
SPh
O
SO2Ph
(c)
O
SO2Ph
O
SO2Ph
(d)
(b)
Figure 1. Attack of an electrophile on the least hindered side of the most
stable conformer B of the silyl enol ether 9 (adapted from ref. 13a).
(2R,3S,5S) 19
54%
(2R,3S,5S) 21
21%
(5S,6R) 22
(2R,3S) 18 85%
+
+
O
SO2Ph
O
SPh
Due to difficulties in reproducing the synthesis of silyl enol ether
9 in high yields and the relatively poor stereoselectivity in the
alkylation of this compound with ClCH2SPh, we also evaluated
an alternative synthesis of ketone 18 from (S)-carvone (12)
(Scheme 4). It is worth noting that the enolate of ketone 8 has
been reacted with an allyl iodide to give the α-alkylated product
with a dr of ca. 3.8:1. However, this reaction required the use of
toxic HMPA.15 Instead, the enolate generated from 1,4-addition
of methyl cuprate to carvone was trapped directly with
ClCH2SPh. The ratio between the isomers 19 and (what is
believed to be) 20 was ca. 3:1 which was an improvement
compared the alkylation of silyl enol ether 9, but the desired
isomer 19 was, due to tedious chromatographic separation, only
isolated in 54% which was comparable to the yield of sulfide 10
(Scheme 3). When sulfide 19 was oxidized to the corresponding
ratio 19/20
in crude prod. 3:1
(5S,6R) 23
Tot. yield 56% from 21, 22:23 60:40
Tot. yield 64% (22) in two steps from 19 via 24 and 25
(S,S,S) 20
Scheme 4. (a) 1. MeMgI, CuI, LiCl, THF, -40 oC, 2. ClCH2SPh, Δ; (b) oxone,
MeOH, H2O, 0 oC → r.t.; (c) 1. O3, MeOH, -78 oC, 2. Cu(OAc)2. -78 oC, 3.
FeSO4•7H2O -78 oC → r.t.; (d) H2, Pd/C, Et2O.
Having obtained an efficient synthesis of the sulfone (1R,6S) 11
(Schemes 3 and 4), we completed the synthesis of (–)-agelasine
F (6) (Scheme 5). Sulfone (1R,6S) 11 was lithiated and reacted
with the iodide 26 before the sulfone group in compound 27 was
reductively removed. The iodide 26 was synthesized from the
corresponding alcohol17 by a modified literature7 procedure.
2
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
THP-ether 28 was converted to the corresponding bromide
(5S,6R) 5 over two steps. Finally, N6-tert-butoxy-9-methyl-9H-
purin-6-amine8c was alkylated quite selectively on N-7 by
treatment with the allyl bromide 5 under neutral conditions and
the tert-butoxy directing group was removed under reductive
conditions to give the target (–)-agelasine F (6).
Experimental Section
General remarks: 1H NMR spectra were recorded at 800 MHz with a
Bruker AVIII HD 800, at 600 MHz with a Bruker AVI 600 or Bruker AVII
600, or at 400 MHz with a Bruker AVIII HD 400 or Bruker AVII 400
instrument. The 13C NMR spectra were recorded at 200, 150 or 100 MHz
using the above-mentioned spectrometers. Mass spectrometry was
performed using electrospray (ESI) with either a Bruker Maxis II ETD or a
Micromass Q-TOF-2 instrument. Melting points were determined on a
Büchi Melting Point B-545 apparatus. Optical rotations were determined
on a Perkin Elmer Model 341 Polarimeter. Ozone was generated with a
BOC MK II ozonizer. GC analyses were carried out with a GC 8000 Top
gas chromatograph with H2 as carrier gas. All reactions were performed
in thoroughly dried glassware. CH2Cl2, Et2O, MeCN and THF were
collected from an MB-SPS 800 solvent purifying system. DMA was
distilled over BaO and stored over 3 Å molecular sieves. MeOH and
toluene were dried over 3 Å molecular sieves. TMSCl and Et3N were
distilled over CaH2 before use. LiCl, ZnCl2, ZnBr2 and ZnI2 were dried by
SO2Ph
(a)
(b)
(d)
OTHP
I
OTHP
26
27
(c)
(e)
OTHP
OH
28 55% over two steps
29 75%
Br
N
heating with
a heat gun under vacuum. All other reagents were
N
N
(5S,6R) 5 90%
commercially available and used as received. Compounds available by
ButO
N
30 78%
N
literature
methods:
(2E,6E)-2,6-Dimethyl-8-(tetrahydro-2H-pyran-2-
yloxy)octa-2,6-dien-1-ol,17 N6-tert-butoxy-9-methyl-9H-purin-6-amine.8c
Cl
N
(f)
N
N
H2N
(S,S,S)-2,3-Dimethyl-5-(2-propen-2-yl)-cyclohexanone (13): MeLi (5.5
mL, 15 mmol, 3.0 M solution in diethoxymethane) was added dropwise at
-20 ˚C to a stirring suspension of CuI (1.437 g, 7.545 mmol) in Et2O (30
mL) under Ar. The resulting clear solution was stirred at -20 ˚C for 5 min
and cooled to -78 ˚C before (S)-carvone (12) (0.78 mL, 5.0 mmol) in Et2O
(10 mL) was added dropwise. The mixture was warmed to -30 ˚C for 1 h,
cooled to -78 ˚C and transferred via a cannula to a stirring solution of
phenyl salicylate (4.285 g, 20.00 mmol) in Et2O (30 mL) at -78 ˚C. The
mixture was warmed to ambient temperature, and acetic acid (1.15 mL,
20.0 mmol) was added. The resulting mixture was filtered, washed with
sat. aq. NaHCO3 (30 mL), dried (MgSO4) and evaporated in vacuo. The
product was isolated by flash chromatography on silica gel eluting with
(–)-Agelasine F (6) 46%
N
Scheme 5. (a) 1. n-BuLi, 2. comp. 11, THF, 50 oC; (b) Na, Na2HPO4, EtOH,
THF; (c) PPTS, EtOH, 55 oC; (d) PBr3, Et2O, 0 oC; (e) N6-tert-butoxy-9-methyl-
9H-purin-6-amine, DMA, 50 oC; (f) Zn, AcOH, MeOH, H2O, 75 oC.
Conclusion
We have performed the first synthesis of the bioactive marine
natural product (–)-agelasine F. Commercially available and
inexpensive (S)-carvone was found to be a highly suitable
starting material for the construction of the terpenoid part of the
target molecule. Two different routes from (S)-carvone to the
key-intermediate 11 were evaluated. All though the total yields in
both reactions sequences were almost identical, we consider the
route depicted in Scheme 4 more robust since the method
developed for generation of the desired silyl enol ether 9
(Scheme 3) was not completely reliable and ketones 8, 14 and
15 were somewhat difficult to handle due to volatility. We depict
that the chemistry described herein may also be applied in
syntheses of other natural products, i.e. (–)-agelasidine C and
D,18 (–)-isoagelasidine B,1g (–)-axistatin 33d and 10-hydro-9-
hydroxyagelasine F1e (Fig. 2). These are all bioactive
compounds isolated from marine sponges (Agelas sp.), but none
of them have been prepared by chemical synthesis.
CH2Cl2-pentane (1:1) to give 13 (803 mg, 97%) as a colorless liquid. The
diastereomeric ratio was determined by GC to be 99%. ! = + 24 (c
!"
!
0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.83 (d, J = 7.2 Hz, 3 H, Me at
C-3), 0.99 (d, J = 6.6 Hz, 3 H, Me at C-2), 1.74 (s, 3 H, Me in propenyl),
1.78-1.93 (m, 2 H, 4-H), 2.21-2.42 (m, 3 H, 6-H, 3-H), 2.55-2.65 (m, 2 H,
5-H, 2-H), 4.74 (s, 1 H, Ha in =CH2), 4.77 (s, 1 H, Hb in =CH2) ppm. 13C
NMR (100 MHz, CDCl3): δ 12.1 (Me at C-2), 14.1 (Me at C-3), 20.7 (Me
in propenyl), 36.4 (C-3), 37.9 (C-4), 41.2 (C-5), 46.8 (C-6), 48.6 (C-2),
109.9 (=CH2), 147.8 (C=), 213.0 (CO) ppm. HRMS (ESI) found 189.1249,
calcd. for C11H18NaO+ 189.1250.
(S,S)-5,6-Dimethyl-2-cyclohexenone (14) and (S,S)-5,6-dimethyl-3-
cyclohexenone (15): Ozone was passed through
a solution of
compound 13 (593 mg, 3.57 mmol) in dry MeOH (10 mL) for 1.5 h
starting at -40 ˚C and gradually letting the temperature increase to -10 ˚C.
The solution was then purged with O2 for 10 min followed by N2 for 15
min before Cu(OAc)2 (1.600 g, 8.014 mmol) was added whilst stirring at -
20 ˚C. After 15 min, FeSO4•7H2O (1.333 g, 4.795 mmol) was added, and
the mixture was warmed slowly to ambient temperature. After stirring for
18 h, water (5 mL) was added and the mixture was extracted with Et2O (5
× 7 mL). The combined organic phases were washed with sat. aq.
NaHCO3 (5 mL), sat. aq. NaCl (5 mL) and water (5 mL), dried (MgSO4)
and evaporated in vacuo (on ice bath). The crude product was purified by
flash chromatography on silica gel eluting with Et2O-pentane (1:10) to
give 14 and 15 in a ratio of 1:0.7 (320 mg, 72%) as a colorless liquid.
HRMS (ESI) found 147.0780, calcd. for C8H12ONa+ 147.0780. The
isomers could be isolated in pure form, albeit in low yields, by further
purification by flash chromatography on silica gel eluting with Et2O-
pentane (1:10).
R
O
X
N
N
R =
H
N
H
H
N
N
NH2
NH
S
R =
(–)-Axistatin 3
N
N
O
O
X = H: (–)-Agelasidine C
X = OH: (–)-Agelasidine D
HN
Cl
R =
OH
O
O
N
NH2
N
H
S
H2N
N
R =
N
(–)-10-Hydro-9-hydroxyagelasine F
(–)-Isoagelasidine B
(S,S)-5,6-Dimethyl-2-cyclohexenone (14): 1H NMR (400 MHz, CDCl3):
δ 0.96 (d, J = 7.0 Hz, 3 H, Me at C-5), 1.05 (d, J = 7.0 Hz, 3 H, Me at C-
6), 2.08-2.56 (m, 4 H, 4-H, 5-H, 6-H), 5.95 (dt, J = 10.0, 2.0 Hz, 1 H, 2-H),
Figure 2. Natural products with structural resemblance to (–)-agelasine F.
3
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
6.84 (dt, J = 10.0, 4.3 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ
10.9 (Me at C-6), 15.9 (Me at C-5), 32.0 (C-4), 33.6 (C-5), 46.5 (C-6),
128.8 (C-2), 148.3 (C-3), 203.5 (CO) ppm.
(2S,3S)-2,3-Dimethyl-2-[(phenylthio)methyl]cyclohexan-1-one (17):
Colorless oil, ! = + 51.0 (c 1.5, CHCl3). 1H NMR (600 MHz, CDCl3): δ
!"
!
0.97 (d, J = 6.9 Hz, 3 H, Me at C-3), 1.27 (s, 3 H, Me at C-2), 1.55-1.66
(m, 1 H, 4-Ha), 1.66-1.77 (m, 1 H, 5-Ha), 1.78-1.89 (m, 1 H, 4-Hb), 1.90-
2.00 (m, 2 H, 5-Hb and 3-H), 2.30-2.46 (m, 2 H, 6-H), 3.10 (d, J = 12.0 Hz,
1 H, Ha in CH2S), 3.26 (d, J = 12.0 Hz, 1 H, Hb in CH2S), 7.13-7.19 (m, 1
H, Ph), 7.23-7.28 (m, 2 H, Ph), 7.32-7.36 (m, 2 H, Ph) ppm. 13C NMR
(150 MHz, CDCl3): δ 15.8 (Me at C-3), 21.3 (Me at C-2), 24.9 (C-5), 29.1
(C-4), 38.4 (C-6), 39.0 (CH2S), 42.3 (C-3), 52.9 (C-2), 126.3 (CH in Ph),
129.0 (2 × CH in Ph), 129.8 (2 × CH in Ph), 137.2 (C in Ph), 214.2 (CO)
ppm. HRMS (EI) found 248.1234, calcd. for C15H20OS+ 248.1235.
(S,S)-5,6-Dimethyl-3-cyclohexenone (15): 1H NMR (400 MHz, CDCl3):
δ 0.87 (d, J = 6.9 Hz, 3 H, Me at C-5), 1.05 (d, J = 6.9 Hz, 3 H, Me at C-
6), 2.64-2.94 (m, 4 H, 2-H, 5-H, 6-H), 5.67 (dt, J = 9.6, 3.5 Hz, 1 H, 3-H),
5.89-5.99 (m, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ 11.2 (Me at
C-6), 15.7 (Me at C-5), 37.8 (C-5), 40.3 (C-2), 47.4 (C-6), 123.0 (C-3),
133.8 (C-4), 211.9 (CO) ppm.
(S,S)-2,3-Dimethylcyclohexanone (8): A stirring solution of compounds
14 and 15 (647 mg, 5.21 mmol) in pentane (30 mL) was treated with
palladium on charcoal (100 mg, 10%) and H2-gas at ambient pressure for
20 h. The catalyst was filtered off and the solvent was removed in vacuo
(on ice bath) to give 8 (612 mg, 93%) as a colorless liquid. 1H NMR
(2R,3S)-2,3-Dimethyl-2-(phenylsulfonylmethyl)-cyclohexanone (18).
Method A: A solution of oxone (2.273 g, 3.700 mmol) in water (7 mL)
was added to a stirring solution of sulfide 10 (459 mg, 1.85 mmol) in
MeOH (7 mL) at 0 °C under Ar. The cooling bath was removed and the
reaction mixture was stirred for 18 h, at ambient temperature before Et2O
(150 mL) was added and the resulting mixture was washed with water
(40 mL) and sat. aq. NaCl (30 mL), dried (MgSO4), and evaporated in
vacuo. The residue was purified by flash chromatography on silica gel
eluting with acetone-hexane (1:4) to give 18 (488 mg, 94%) as colorless
crystals.
indicated that ca. 6% of an isomer, probably epi at C-2, was present.
!"
!
!
= + 73.0 (c 1.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.84 (d, J =
7.1 Hz, 3 H, Me at C-3), 0.99 (d, J = 7.0 Hz, 3 H, Me at C-2), 1.62-1.68
(m, 1 H, 4-Ha), 1.80-1.94 (m, 3 H, 5-H, 4-Hb), 2.19-2.29 (m, 2 H, 3-H, 6-
Ha), 2.31-2.39 (m, 1 H, 6-Hb), 2.55-2.61 (m, 1 H, 2-H) ppm. 13C NMR
(100 MHz, CDCl3): δ 12.0 (Me at C-2), 14.7 (Me at C-3), 23.5 (C-5), 31.3
(C-4), 37.5 (C-3), 40.8 (C-6), 49.5 (C-2), 214.5 (CO) ppm. HRMS (ESI)
found 149.0936, calcd. for C8H14ONa+ 149.0937.
Method B: A 1:0.16 mixture of sulfones 22 and 23 (295 mg, 1.13 mmol)
in Et2O (25 mL) was treated with palladium on charcoal (68 mg, 10%)
and hydrogenated at atmospheric pressure for 20 h. Additional catalyst
(32 mg) was added after 16 h. The mixture was filtered and the solvent
(S)-(2,3-Dimethylcyclohex-1-enyloxy)trimethylsilane (9): TMSCl (1.10
mL, 8.66 mmol) was added dropwise to a stirring solution of compound 8
(545 mg, 4.33 mmol) in dry Et3N (1.21 mL, 8.66 mmol) and dry DMF (5
mL) under Ar. The mixture was heated to 130 °C and stirred for 16 h.
After cooling, Et2O (7 mL) was added and the mixture washed with cold
sat. aq. NaHCO3 (7 mL). The aqueous phase was extracted with cold
Et2O (3 × 7 mL) and the combined organic extracts were washed rapidly
with cold 0.5 M aq. HCl (9 mL), cold sat. aq. NaHCO3 (2 × 7 mL), and
cold sat. aq. NaCl (7 mL). The organic layer was dried (MgSO4) and
evaporated in vacuo. The residue was purified by flash chromatography
on silica gel eluting with EtOAc-hexane (1:100) to give 9 (785 mg, 92%)
as a colorless oil containing ca. 6% of the isomer 16. 1H NMR (300 MHz,
CDCl3): δ 0.16 (s, 9 H, SiMe3), 0.99 (d, J = 6.9 Hz, 3 H, Me at C-3), 1.25-
1.30 (m, 1 H, 4-Ha), 1.52-1.58 (m, 4 H, Me at C-2, 5-Ha), 1.64-1.74 (m, 2
H, 4-Hb, 5-Hb) 1.98-2.01 (m, 2 H, H-6), 2.09-2.12 (m, 1 H, 3-H) ppm. 13C
NMR (150 MHz, CDCl3): δ 0.8 (SiMe3), 14.4 (Me at C-2), 20.1 (Me at C-
3), 20.6 (C-5), 30.7 (C-6), 31.5 (C-4), 33.7 (C-3), 116.6 (C-2), 143.4 (C-1)
ppm. HRMS (ESI) found 221.1332, calcd. for C11H22OSiNa+ 221.1334.
was removed in vacuo to give 18 (267 mg, 85%) as colorless crystals,
!"
!
m.p. 99-100 ºC.
!
= + 89.1 (c 1.1, CHCl3). 1H NMR (600 MHz,
CDCl3): δ 1.06 (s, 3 H, Me at C-2), 1.09 (d, J = 6.8 Hz, 3 H, Me at C-3),
1.55-1.64 (m, 1 H, 4-Ha), 1.76-1.83 (m, 1 H, 4-Hb), 1.85-1.99 (m, 2 H, 5-
H), 2.39-2.58 (m, 2 H, 6-H), 2.69-2.78 (m, 1 H, 3-H), 3.25 (d, J = 14.0 Hz,
1 H, Ha in CH2S), 3.96 (d, J = 14.0 Hz, 1 H, Hb in CH2S), 7.54-7.58 (m, 2
H, Ph), 7.61-7.65 (m, 1 H, Ph), 7.96-7.98 (m, 2 H, Ph) ppm. 13C NMR
(150 MHz, CDCl3): δ 16.3 (Me at C-3), 18.9 (Me at C-2), 23.5 (C-5), 29.4
(C-4), 36.7 (C-3), 37.8 (C-6), 52.5 (C-2), 61.0 (CH2S), 127.8 (2 × CH in
Ph), 129.3 (2 × CH in Ph), 133.5 (CH in Ph), 142.1 (C in Ph), 211.9 (CO)
ppm. HRMS (ESI) found 303.1025, calcd. for C15H20O3SNa+ 303.1025.
1-{[(1S,6S)-1,2,6-Trimethylcyclohex-2-enyl]methylsulfonyl}benzene
(11): To a stirring solution of ketone 18 (205 mg, 0.732 mmol) in dry Et2O
(13 mL) under Ar was added MeMgBr (0.34 mL, 2.4 M in Et2O, 0.82
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and at
ambient temperature for 16 h. After cooling to 0 °C, sat. aq. NH4Cl (4 mL)
was added. The mixture was diluted with Et2O (5 mL) and the phases
were separated. The aqueous phase was extracted with Et2O (10 mL),
the combined organic extracts were dried (MgSO4), and concentrated in
vacuo. The residue was stirred in conc. formic acid (2 mL) at 80 °C for 2
h before the mixture was concentrated in vacuo. The residue was purified
(2R,3S)-2,3-Dimethyl-2-[(phenylthio)methyl]cyclohexan-1-one
and (2S,3S)-2,3-dimethyl-2-[(phenylthio)methyl]cyclohexan-1-one
(17): A solution of TiCl4 (4.0 mL, 1.0 M in CH2Cl2, 4.0 mmol) was added
to stirring solution of compound (704 mg, 3.55 mmol) and
(10)
a
9
chloromethyl phenyl sulfide (0.66 mL, 5.0 mmol) in CH2Cl2 (3.5 mL) at -
23 °C under Ar. After 1 h, the resulting deep red solution was poured into
sat. aq. NaHCO3 (20 mL) and extracted with Et2O (2 × 30 mL). The
combined organic extracts were dried (MgSO4) and evaporated in vacuo.
The products were separated by flash chromatography on silica gel
eluting with EtOAc-hexane (1:15) to give 10 (455 mg, 52%) and 17 (329
mg, 37%).
by flash chromatography on silica gel eluting with acetone-hexane (1:5)
!"
!
to give 11 (190 mg, 94%) as a colorless oil, ! = + 31.4 (c 1.2, CHCl3).
1H NMR (600 MHz, CDCl3): δ 0.94 (d, J = 6.8 Hz, 3 H, Me at C-6), 1.07
(s, 3 H, Me at C-1), 1.38-1.48 (m, 1 H, 5-Ha), 1.57-1.65 (m, 1 H, 5-Hb),
1.66-1.69 (m, 3 H, Me at C-2), 1.94-2.08 (m, 2 H, 4-H), 2.57-2.65 (m, 1 H,
6-H), 3.21 (d, J = 14.6 Hz, 1 H, Ha in CH2S), 3.33 (d, J = 14.6 Hz, 1 H, Hb
in CH2S), 5.42 (m, 1 H, 3-H), 7.52-7.56 (m, 2 H, Ph), 7.61-7.64 (m, 1 H,
Ph), 7.90-7.93 (m, 2 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ 15.9 (Me
at C-6), 19.7 (Me at C-2), 21.5 (Me at C-1), 24.0 (C-4), 26.4 (C-5), 33.4
(C-6), 42.4 (C-1), 62.0 (CH2S), 124.8 (C-3), 127.7 (2 × CH in Ph), 129.3
(2 × CH in Ph), 133.5 (CH in Ph), 136.4 (C-2), 142.2 (C in Ph) ppm.
HRMS (ESI) found 303.1234, calcd. for C16H22O2SNa+ 303.1233.
(2R,3S)-2,3-Dimethyl-2-[(phenylthio)methyl]cyclohexan-1-one (10):
Colorless oil, ! = + 0.4 (c 1.5, CHCl3). 1H NMR (600 MHz, CDCl3): δ
!"
!
0.86 (d, J = 6.8 Hz, 3 H, Me at C-3), 1.11 (s, 3 H, Me at C-2), 1.51-1.61
(m, 1 H, 4-Ha), 1.63-1.80 (m, 2 H, 4-Hb, 5-Ha), 1.90-2.00 (m, 1 H, 5-Hb),
2.21-2.31 (m, 1 H, 3-H), 2.32-2.48 (m, 2 H, 6-H), 2.98 (d, J = 12.5 Hz, 1
H, Ha in CH2S), 3.39 (d, J = 12.5 Hz, 1 H, Hb in CH2S), 7.14-7.19 (m, 1 H,
Ph), 7.23-7.29 (m, 2 H, Ph), 7.38-7.42 (m, 2 H, Ph) ppm. 13C NMR (150
MHz, CDCl3): δ 15.7 (Me at C-3) 18.7 (Me at C-2), 24.4 (C-5), 29.3 (C-4),
37.8 (C-3), 38.2 (C-6), 41.2 (CH2S), 53.9 (C-2), 126.2 (CH in Ph), 128.9
(2 × CH in Ph), 130.3 (2 × CH in Ph), 138.2 (C in Ph), 213.8 (CO) ppm.
HRMS (EI) found 248.1235, calcd. for C15H20OS+ 248.1235.
(2R,3S,5S)-2,3-Dimethyl-2-[(phenylthio)methyl]-5-(prop-1-en-2-
yl)cyclohexan-1-one (19): LiCl (33 mg, 0.79 mmol) and CuI (75 mg,
0.39 mmol) was dissolved in dry THF (24 mL) under Ar and stirred for 15
minutes at ambient temperature before cooling to -40 ºC. (S)-Carvone
(12) (590 mg, 3.93 mmol) in dry THF (5.3 mL) was added and the
resulting mixture was stirred for 10 min before a solution of MeMgI (1.9
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
mL, 2.5 M in Et2O, 4.7 mmol) was added dropwise, and the resulting
mixture was stirred for 1 h at -40 ºC. The reaction mixture was allowed to
reach ambient temperature before chloromethyl phenyl sulfide (1.0 mL,
7.5 mmol) was added and the resulting mixture was heated at reflux for
18 h. After cooling to ambient temperature sat. aq. NH4Cl (20 mL) was
added and the mixture was extracted with Et2O (3 × 25 mL). The
combined organic layers were dried (MgSO4) and concentrated in vacuo.
1H NMR showed the isomers 19 and (what is presumed to be) 20 to be
present in ca. 3:1 ratio. Further purification by flash chromatography on
2.18-2.24 (m, 1 H, 4-Ha), 2.42-2.47 (m, 1 H, 4-Hb), 3.09-3.14 (m, 1 H, 5-
H), 3.20 (d, J = 14.0 Hz, 1 H, Ha in CH2S), 4.09 (d, J = 14.0 Hz, 1 H, Hb in
CH2S), 6.10 (dd, J = 10.0, 2.3 Hz, 1 H, 2-H), 6.95 (ddd, J = 10.0, 5.9, 2.3
Hz, 1 H, 3-H), 7.53-7.57 (m, 2 H, Ph), 7.62-7.66 (m, 1 H, Ph), 7.95-7.96
(m, 2 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ 15.7 (Me at C-5), 17.7
(Me at C-6), 31.5 (C-4), 33.3 (C-5), 49.6 (C-6), 60.1 (CH2S), 127.8 (2 ×
CH in Ph), 128.1 (C-2), 129.3 (2 × CH in Ph), 133.6 (CH in Ph), 141.8 (C
in Ph), 148.8 (C-3), 200.1 (CO) ppm. HRMS (ESI) found 301.0869, calcd.
for C15H18O3SNa+ 301.0869.
silica gel twice eluting with EtOAc-hexane (1:30) gave 19 (598 mg, 54%)
as a colorless oil,
!
= −82.9 (c 1.1, CHCl3). 1H NMR (600 MHz,
!"
!
(5S,6R)-5,6-Dimethyl-6-[(phenylsulfonyl)methyl]cyclohex-3-en-1-one
(23): Colorless oil,
!
= + 22.2 (c 1.9, CHCl3). 1H NMR (600 MHz,
!"
CDCl3): δ 0.89 (d, J = 7.2 Hz, 3 H, Me at C-3), 1.12 (s, 3 H, Me at C-2),
1.64-1.69 (m, 1 H, 4-Ha), 1.72 (s, 3 H, Me in propenyl), 1.94 (m, 1 H, 4-
Hb), 2.32 (m, 1 H, 3-H), 2.39 (ddd, J = 14.2, 5.2, 1.0 Hz, 1 H, 6-Ha), 2.47
(dd, J = 14.2, 9.8 Hz, 1 H, 6-Hb), 2.55-2.60 (m, 1 H, 5-H), 3.18 (d, J =
12.3 Hz, 1 H, Ha in CH2S), 3.32 (d, J = 12.3 Hz, 1 H, Hb in CH2S), 4.70 (s,
1 H, Ha in =CH2), 4.82 (s, 1 H, Hb in =CH2), 7.19 (m, 1 H, Ph), 7.26-7.28
(m, 2 H, Ph), 7.37-7.39 (m, 2 H, Ph) ppm. 13C NMR (150 MHz, CDCl3): δ
16.0 (Me at C-3), 19.2 (Me at C-2), 21.2 (Me in propenyl), 32.8 (C-4),
36.1 (C-3), 40.5 (C-5), 42.8 (C-6), 42.8 (CH2S), 53.1 (C-2), 110.9 (=CH2),
126.5 (CH in Ph), 129.1 (2 × CH in Ph), 130.5 (2 × CH in Ph), 137.3 (C in
Ph), 147.2 (C=), 213.5 (CO) ppm. HRMS (ESI) found 311.1440, calcd. for
C18H24OSNa+ 311.1440.
!
CDCl3): δ 1.09 (d, J = 7.2 Hz, 3 H, Me at C-5), 1.15 (s, 3 H, Me at C-6),
2.97-3.00 (m, 1 H, 2-Ha), 3.09-3.18 (m, 2 H, 2-Hb and 5-H), 3.49 (d, J =
14.3 Hz, 1 H, Ha in CH2S), 3.72 (d, J = 14.3 Hz, 1 H, Hb in CH2S), 5.66-
5.68 (m, 1 H, 4-H), 5.75-5.78 (m, 1 H, 3-H), 7.55-7.58 (m, 2 H, Ph), 7.63-
7.66 (m, 1 H, Ph), 7.92-7.94 (m, 2 H, Ph) ppm. 13C NMR (150 MHz,
CDCl3): δ 15.4 (Me at C-5), 18.4 (Me at C-6), 38.5 (C-5), 38.6 (C-2), 50.6
(C-6), 61.5 (CH2S), 122.9 (C-3), 127.8 (2 × CH in Ph), 129.4 (2 × CH in
Ph), 132.3 (C-4), 133.7 (CH in Ph), 141.6 (C in Ph), 209.9 (CO) ppm.
HRMS (ESI) found 301.0867, calcd. for C15H18O3SNa+ 301.0869.
(5S,6R)-5,6-Dimethyl-6-[(phenylsulfonyl)methyl]cyclohex-2-en-1-one
(22): Ozone was passed through a solution of sulfide 19 (564 mg, 1.96
mmol) in dry MeOH (100 mL) for 1.5 h at -78 ˚C. The solution was then
purged with O2 for 10 min followed by Ar for 10 min before Cu(OAc)2
(781 mg, 3.91 mmol) was added whilst stirring. After 15 min,
FeSO4•7H2O (652 mg, 2.35 mmol) was added, and the mixture was
warmed slowly to ambient temperature. After stirring for 18 h, water (40
mL) was added, before the mixture was concentrated to approx. ¼ of its
volume. The mixture was extracted with Et2O (3 × 100 mL), the combined
organic phases were washed with sat. aq. NaHCO3 (30 mL), water (30
mL) and sat. aq. NaCl (30 mL), dried (MgSO4) and evaporated in vacuo.
The crude product contained a mixture of the sulfoxides 24 and 25 (356
mg). HRMS (ESI) found 285.0919, calcd. for C15H18OSNa+ 285.0920.
Parts of this mixture was used directly in the next step: A solution of
oxone (1.404 g, 2.287 mmol) in water (5.4 mL) was added to a stirring
solution of sulfoxides 24 and 25 (300 mg, 1.14 mmol) in MeOH (5.4 mL)
at 0 ºC under Ar. The reaction mixture was stirred at 0 ºC for 3.5 h before
heating to ambient temperature. Et2O (70 mL) was added and the
resulting mixture was washed with water (15 mL) and sat. aq. NaCl (10
mL), dried (MgSO4) and evaporated in vacuo. The product was purified
by flash chromatography eluting with acetone-hexane (1:5) to give 22
(295 mg, 64% from compound 19) as a colorless oil. Data, see above.
(2R,3S,5S)-2,3-Dimethyl-2-[(phenylsulfonyl)methyl]-5-(prop-1-en-2-
yl)cyclohexan-1-one (21): A solution of oxone (894 mg, 1.46 mmol) in
water (4 mL) was added to a stirring solution of sulfide 19 (200 mg, 0.728
mmol) in MeOH (4 mL) at 0 ºC under Ar. The cooling bath was removed
and the reaction mixture was stirred for 2.5 h at ambient temperature
before Et2O (40 mL) was added. The resulting mixture was washed with
water (10 mL) and sat. aq. NaCl (5 mL), dried (MgSO4) and evaporated
in vacuo. The residue was purified by flash chromatography on silica gel
eluting with acetone-hexane (1:5) to give 21 (48 mg, 21%) as a colorless
oil, ! = + 2.8 (c 1.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.04 (d, J
!"
!
= 6.9 Hz, 3 H, Me at C-3), 1.11 (s, 3 H, Me at C-2), 1.70-1.78 (m, 1 H, 4-
Ha), 1.76 (s, 3 H, Me in propenyl), 1.89 (ddd, J = 13.4, 8.0, 5.3 Hz, 1 H, 4-
Hb), 2.48 (dd, J = 14.5, 4.6 Hz, 1 H, 6-Ha), 2.55-2.63 (m, 1 H, 5-H), 2.71
(ddd, J = 9.0, 6.9, 5.3 Hz, 1 H, 3-H), 2.82 (dd, J = 14.5, 10.6 Hz, 1 H, 6-
Hb), 3.36 (d, J = 14.2 Hz, 1 H, Ha in CH2S), 3.73 (d, J = 14.2 Hz, 1 H, Hb
in CH2S), 4.76 (s, 1 H, Ha in =CH2), 4.83 (s, 1 H, Hb in =CH2), 7.54-7.58
(m, 2 H, Ph), 7.62-7.66 (m, 1 H, Ph), 7.90-7.93 (m, 2 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ 15.8 (Me at C-3), 19.0 (Me at C-2), 20.8 (Me
in propenyl), 32.8 (C-4), 34.0 (C-3), 39.2 (C-5), 42.2 (C-6), 51.1 (C-2),
62.3 (CH2S), 111.0 (=CH2), 127.8 (2 × CH in Ph), 129.4 (2 × CH in Ph),
133.7 (CH in Ph), 141.6 (C in Ph), 146.9 (C=), 212.5 (CO) ppm. HRMS
(ESI) found 343.1338, calcd. for C18H24O3SNa+ 343.1338.
2-{[(2E,6E)-8-Iodo-3,7-dimethylocta-2,6-dien-1-yl]oxy}tetrahydro-2H-
pyran (26): To a stirring solution of (2E,6E)-2,6-dimethyl-8-(tetrahydro-
2H-pyran-2-yloxy)octa-2,6-dien-1-ol17 (200 mg, 0.786 mmol), Ph3P (310
mg, 1.18 mmol), and imidazole (72 mg, 1.2 mmol) in a mixture of MeCN
(1 mL) and Et2O (2 mL) under Ar was added I2 (298 mg, 1.18 mmol)
portion wise at 0 ºC over 10 min. The reaction mixture was stirred for
another 20 min, diluted with Et2O (17 mL), washed with sat. aq. Na2S2O3
(4 mL), water (4 mL), and sat. aq. NaCl (4 mL), dried (MgSO4), and
evaporated in vacuo. Et2O (1.5 mL) was added to the residue, the
mixture was and filtered and the filtrate was evaporated in vacuo to give
26 (228 mg, ca. 80%, cont. ca. 8% POPh3) as a pale yellow liquid used
immediately in the next step. 1H NMR (800 MHz, CDCl3): δ 1.49-1.62 (m,
4 H, CH2 in THP), 1.67 (s, 3 H, Me at C-6), 1.69-1.75 (m, 1 H, CH2 in
THP), 1.77 (s, 3 H, Me at C-2), 1.80-1.87 (m, 1 H, CH2 in THP), 2.05-2.12
(m, 4 H, H-4 and H-5), 3.50-3.53 (m, 1 H, CH2 in THP), 3.88-3.91 (m, 1 H,
CH2 in THP), 3.93 (s, 2 H, 1-H), 4.01-4.04 (dd, J = 12.0, 7.0 Hz, 1 H, H-
8a), 4.23-4.25 (dd, J = 12.0, 7.0 Hz, 1 H, H-8b), 4.62 (t, J = 3.7 Hz, 1 H,
CH in THP), 5.36 (t, J = 7.0 Hz, 1 H, H-7), 5.66 (t, J = 7.0 Hz, 1 H, H-3)
ppm. 13C NMR (200 MHz, CDCl3): δ 15.6 (Me at C-2), 16.5 (Me at C-6),
16.8 (C-1), 19.8 (CH2 in THP), 25.7 (CH2 in THP), 27.0 (C-4), 30.9 (CH2
in THP), 38.6 (C-5), 62.5 (CH2 in THP), 63.8 (C-8), 98.1 (CH in THP),
121.4 (C-7), 129.4 (C-3), 133.3 (C-2), 139.4 (C-6) ppm. The spectral data
were in good agreement with those reported before.7
(5S,6R)-5,6-Dimethyl-6-[(phenylsulfonyl)methyl]cyclohex-2-en-1-one
(22) and (5S,6R)-5,6-dimethyl-6-[(phenylsulfonyl)methyl]cyclohex-3-
en-1-one (23): Ozone was passed through a solution of sulfone 21 (40
mg, 0.13 mmol) in dry MeOH (15 mL) for 1.3 h whilst cooling at -78 ˚C.
The solution was purged with O2 for 10 min followed by Ar for 10 min
before Cu(OAc)2 (54 mg, 0.27 mmol) was added to the stirring mixture.
After 15 min, FeSO4•7H2O (45 mg, 0.16 mmol) was added, and the
mixture was warmed slowly to ambient temperature. After stirring for 18 h,
the solution was concentrated to approx. ¼ of its volume, and water (5
mL) was added. The mixture was extracted with Et2O (5 × 10 mL). The
combined organic phases were washed with sat. aq. NaHCO3 (5 mL),
water (5 mL) and sat. aq. NaCl (5 mL), dried (MgSO4) and evaporated in
vacuo. The crude product was purified by flash chromatography on silica
gel eluting with acetone-hexane (1:5) to give 22 and 23 in a ratio of 1:0.7
(21 mg, 56%). The isomers could be isolated in pure form, albeit in low
yields, by further purification by flash chromatography on silica gel eluting
with acetone-hexane (1:5).
(5S,6R)-5,6-Dimethyl-6-[(phenylsulfonyl)methyl]cyclohex-2-en-1-one
(22): Colorless oil, ! = + 36.3 (c 2.34, CHCl3). 1H NMR (600 MHz,
!!
!
CDCl3): δ 0.99 (s, 3 H, Me at C-6), 1.19 (d, J = 6.8 Hz, 3 H, Me at C-5),
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
2-{(2E,6E)-3,7-Dimethyl-9-[(1R,6S)-1,2,6-trimethylcyclohex-2-en-1-
yl]nona-2,6-dien-1-yloxy}tetrahydro-2H-pyran (28): n-BuLi (0.9 mL,
2.2 M in hexanes, 2 mmol) was added dropwise to a stirring solution of
sulfone 11 (250 mg, 0.898 mmol) in dry THF (4.2 mL) at 0 ºC under Ar
and the resulting mixture was stirred at 50 ºC for 40 min before a solution
of iodide 26 (741 mg, 2.04 mmol) in THF (4.2 mL) was added. The
mixture was stirred for further 3 h at 50 ºC. Et2O (24 mL) was added and
the mixture was washed with sat. aq. NH4Cl (10 mL), water (3 × 10 mL)
and sat. aq. NaCl (10 mL), and evaporated in vacuo. The crude product
was partially purified by flash chromatography eluting with acetone-
hexane (1:11) to give 27 (450 mg) as a pale yellow oil. A mixture of
compound 27 (450 mg), Na2HPO4 (3.80 g, 26.8 mmol), Na (860 mg, 37.4
mmol), and abs. EtOH (3.2 mL) in THF (66 mL) was stirred at ambient
temperature for 17 h under Ar, before the mixture was filtered and the
filtrate was diluted with Et2O (80 mL). The resulting mixture was washed
with water (60 mL), sat. aq. NH4Cl (45 mL) and sat. aq. NaCl (45 mL),
dried (MgSO4), and evaporated in vacuo. The product was purified by
flash chromatography eluting with EtOAc-hexane (1:23) to give 28 (186
mg, 55% from compound 11) as a pale yellow oil. 1H NMR (600 MHz,
CDCl3): δ 0.85 (s, 3 H, Me at C-1'), 0.86 (d, J = 6.7 Hz, 3 H, Me at C-6'),
1.40-1.55 (m, 6 H, 1 H in THP, 3 H in cyclohexene, 9-H), 1.57-1.64 (m, 8
H, Me at C-7, Me at C-2', 8-Ha, 1 H in THP), 1.67 (s, 3 H, Me at C-3),
1.69-1.74 (m, 2 H, 1 H in THP, 6'-H), 1.80-2.02 (m, 4 H, 3 H in THP, 8-
Hb), 2.02-2.05 (m, 2 H, 4-H), 2.08-2.12 (m, 2 H, 5-H), 3.49-3.53 (m, 1 H,
Ha in OCH2 in THP), 3.87-3.91 (m, 1 H, Hb in OCH2 in THP), 4.02 (dd, J =
11.8, 7.5 Hz, 1 H, 1-Ha), 4.22 (dd, J = 11.8, 6.5 Hz, 1 H, 1-Hb), 4.62 (t, J =
3.8 Hz, 1 H, CH in THP), 5.09 (t, J = 6.8 Hz, 1 H, 6-H), 5.33-5.38 (m, 1 H,
2-H), 5.41 (br s, 1 H, 3'-H) ppm. 13C NMR (150 MHz, CDCl3): δ 16.0 (Me
at C-6'), 16.4 (Me at C-7), 16.6 (Me at C-3), 19.4 (Me at C-2'), 19.8 (CH2
in THP), 21.2 (Me at C-1'), 25.7 (C-4'), 25.7 (CH2 in THP), 26.4 (C-5),
27.2 (C-5'), 33.3 (C-6'), 34.4 (C-8), 35.3 (C-9), 39.8 (C-4), 40.5 (C-1'),
62.2 (OCH2 in THP), 63.8 (C-1), 97.9 (CH in THP), 120.7 (C-2), 123.4 (C-
6), 124.2 (C-3'), 136.4 (C-7), 139.9 (C-2'), 140.4 (C-3) ppm. HRMS (ESI)
found 397.3077, calcd. for C25H42O2Na+ 397.3077.
(CH), 34.3 (CH2), 35.3 (CH2), 39.7 (CH2), 40.5 (C-1'), 120.7 (C-2), 122.8
(CH=), 124.2 (CH=), 136.8 (C=), 139.9 (C-1'), 143.8 (C-3) ppm. HRMS
(ESI) found 375.1658, calcd. for C20H3379BrNa+ 375.1658.
7-{(2’E,6’E)-3,7-Dimethyl-9-[(1R,6S)-1,2,6-trimethylcyclohex-2-
enyl]nona-2,6-dienyl}-6-tert-butoxyamino-9-methyl-7H-purinum (30):
A mixture of N6-tert-butoxy-9-methyl-9H-purin-6-amine8c (57 mg, 0.26
mmol) and bromide 5 (108 mg, 0.306 mmol) in dry DMA (2.5 mL) was
stirred at 50 ºC for 21 h under Ar and evaporated in vacuo. The residue
was purified by flash chromatography eluting with CH2Cl2-MeOH
saturated with NH3 (12:1 followed by 9:1) to give 30 (99 mg, 78%) as
yellow crystals, m.p. 134-136 ºC, ! = − 5.6 (c 1.0, CHCl3). 1H NMR
!"
!
(800 MHz, CDCl3): δ 0.85 (s, 3 H, Me at C-1'), 0.86 (d, J = 6.8 Hz, 3 H,
Me at C-6'), 1.33 (s, 9 H, t-Bu), 1.41-1.47 (m, 4 H, 8-Ha or 9-H, 5'-H), 1.59
(s, 6 H, Me at C-7, Me at C-2') 1.60-1.64 (m, 1 H, 8-Ha or 9-H), 1.69-1.72
(m, 1 H, 6'-H), 1.84 (s, 3 H, Me at C-3), 1.88-1.96 (m, 3 H, 8-Hb, 4'-H),
2.11-2.14 (m, 4 H, 4-H, 5-H), 3.90 (s, 3 H, NMe) 5.06 (br s, 1 H, 6-H),
5.10 (d, J = 7.6 Hz, 2 H, 1-H), 5.41 (br s, 1 H, 3'-H), 5.47 (t, J = 7.6 Hz, 1
H, 2-H), 7.84 (s, 1 H, H-2 in purine), 9.20 (s, 1 H, H-8 in purine) ppm. 13
C
NMR (200 MHz, CDCl3): δ 16.0 (Me at C-6'), 16.4 (Me at C-7), 17.2 (Me
at C-3), 19.3 (Me at C-2'), 21.2 (Me at C-1'), 25.7 (C-4'), 26.3 (C-5), 27.2
(C-5'), 27.8 (3 × Me in t-Bu) 31.8 (NMe), 33.4 (C-6'), 34.5 (C-8), 35.4 (C-
9), 39.7 (C-4), 40.6 (C-1'), 48.1 (C-1), 78.6 (C in t-Bu), 111.2 (C-5 in
purine), 116.0 (C-2), 122.8 (C-6), 124.3 (C-3'), 133.0 (C-8 in purine),
137.1 (C-7), 139.8 (C-2'), 140.8 (C-6 in purine), 143.2 (C-4 in purine),
145.9 (C-3), 153.0 (C-2 in purine) ppm. HRMS (ESI) found 494.3853,
calcd. for C30H48O+ 494.3853.
(–)-Agelasine F (6): A mixture of compound 30 (83 mg, 0.17 mmol), Zn
(142 mg, 2.10 mmol), and AcOH (0.17 mL) in MeOH (9 mL) and water
(0.9 mL) was stirred vigorously at 75 ºC for 20 h under Ar. The mixture
was filtered and the solid washed with MeOH (9 mL). Sat. aq. NaCl (5
mL) and water (5 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 sat. aq. NaCl (20
mL) and CHCl3 (20 mL). The phases were separated and the aqueous
phase was extracted with CHCl3 (150 mL). The combined organic layers
were dried (MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography eluting with MeOH-CH2Cl2 (1:9→1:6). The
(2E,6E)-3,7-Dimethyl-9-[(1R,6S)-1,2,6-trimethylcyclohex-2-en-1-
yl]nona-2,6-dien-1-ol (29): Compound 28 (173 mg, 0.462 mmol) was
dissolved in abs. EtOH (6 mL) before pyridinium p-toluenesulfonate (28
mg, 0.11 mmol) was added and the resulting mixture was stirred at 55 ºC
for 17 h under Ar. The mixture was evaporated in vacuo and the residue
residue was dissolved in CHCl3 and filtered, before evaporation in vacuo
!"
was purified by flash chromatography eluting with acetone-hexane (1:15)
to give 6 (38 mg, 46%) as a colorless waxy solid, ! = − 9.0 (c 1.3,
!
!"
CHCl3) [lit.2a
!
= − 8.4 (c 3.0, CHCl3)]. 1H NMR (800 MHz, CDCl3): δ
!"
!
to give 29 (105 mg, 75%) as a transparent oil,
!
= − 19.8 (c 1.3,
!
CHCl3). 1H NMR (800 MHz, CDCl3): δ 0.85 (s, 3 H, Me at C-1'), 0.86 (d, J
= 6.8 Hz, 3 H, Me at C-6'), 1.41-1.50 (m, 4 H, 9-H, 5'-H), 1.60 (s, 6 H, Me
at C-7, Me at C-2'), 1.60-1.64 (m, 1 H, 8-Ha), 1.68 (s, 3 H, Me at C-3),
1.70-1.74 (m, 1 H, 6'-H), 1.88-1.94 (m, 2 H, 8-Hb, 4'-Ha), 1.94-2.01 (m, 1
H, 4'-Hb), 2.03-2.05 (m, 2 H, 4-H), 2.09-2.12 (m, 2 H, 5-H), 4.14 (d, J =
6.8 Hz, 2 H, 1-H), 5.09 (t, J = 6.8 Hz, 1 H, 6-H), 5.40-5.41 (m, 2 H, 2-H
and 3'-H) ppm. 13C NMR (200 MHz, CDCl3): δ 16.0 (Me at C-6'), 16.38
(Me at C-3), 16.43 (Me at C-7), 19.3 (Me at C-2'), 21.2 (Me at C-1'), 25.7
(C-4'), 26.5 (C-5), 27.2 (C-5'), 33.4 (C-6'), 34.4 (C-8), 35.4 (C-9), 39.7 (C-
4), 40.6 (C-1'), 59.6 (C-1), 123.3 (C-6), 123.5 (C-2), 124.2 (C-3'), 136.6
(C-7), 139.9 (C-2'), 140.0 (C-3) ppm. HRMS (ESI) found 313.2501, calcd.
for C20H34ONa+ 313.2502.
0.83 (s, 3 H, Me at C-1'), 0.84 (d, J = 6.8 Hz, 3 H, Me at C-6'), 1.35-1.45
(m, 4 H, 8-Ha or 9-H, 5'-H), 1.55 (s, 3 H, Me at C-7), 1.57 (s, 3 H, Me at
C-2'), 1.53-1.58 (m, 1 H, 8-Ha or 9-H), 1.66-1.70 (m, 1 H, 6'-H), 1.83 (s, 3
H, Me at C-3), 1.80-1.85 (m, 1 H, 8-Hb), 1.88-1.99 (m, 2 H, 4'-H), 2.03-
2.07 (m, 4 H, 4-H, 5-H), 4.08 (s, 3 H, NMe), 5.01 (br s, 1 H, 6-H), 5.40 (br
s, 1 H, 3'-H), 5.47 (t, J = 6.8 Hz, 1 H, 2-H), 5.62 (d, J = 6.8 Hz, 2 H, 1-H),
6.91 (br s, 2 H, NH2), 8.45 (s, 1 H, H-2 in purine), 10.34 (s, 1 H, H-8 in
purine) ppm. 13C NMR (200 MHz, CDCl3): δ 16.0 (Me at C-6'), 16.4 (Me
at C-7), 17.6 (Me at C-3), 19.3 (Me at C-2'), 21.2 (Me at C-1'), 25.7 (C-4'),
26.5 (C-5), 27.2 (C-5'), 32.3 (NMe), 33.4 (C-6'), 34.4 (C-8), 35.4 (C-9),
39.7 (C-4), 40.6 (C-1'), 48.9 (C-1), 110.0 (C-5 in purine), 116.2 (C-2),
122.6 (C-6), 124.3 (C-3'), 137.2 (C-7), 139.7 (C-2'), 141.9 (C-8 in purine),
146.7 (C-3), 149.7 (C-4 in purine), 152.4 (C-6 in purine), 156.1 (C-2 in
purine) ppm. HRMS (ESI) found 422.3278, calcd. for C26H40N5+ 422.3278.
(5S,6R)-6-[(3E,7E)-9-Bromo-3,7-dimethylnona-3,7-dien-1-yl]-1,5,6-
trimethylcyclohex-1-ene (5): The alcohol 29 (99 mg, 0.34 mmol) was
dissolved in dry Et2O (1.25 mL) at 0 ºC under Ar. PBr3 (0.027 mL, 0.34
mmol) was added and the mixture was stirred at 0 ºC for 3 h. The mixture
was diluted with Et2O (8 mL) and washed with 10% aq. NaHCO3 (2 mL).
The aqueous phase was extracted with Et2O (3 mL) and the combined
organic extracts were dried (MgSO4), and evaporated in vacuo to give 5
(108 mg, 90%) as a pale yellow oil, which was used directly in the next
step without further purification. 1H NMR (400 MHz, CDCl3): δ 0.85 (s, 3
H, Me), 0.86 (d, J = 6.8 Hz, 3 H, Me), 1.39-1.52 (m, 4 H), 1.58-1.64 (m, 7
H), 1.69-1.75 (m, 5 H), 1.86-1.99 (m, 4 H), 2.05-2.12 (m, 4 H), 4.02 (d, J
= 7.9 Hz, 2 H), 5.05-5.09 (m, 1 H), 5.41 (br s, 1 H), 5.52 (t, J = 8.1 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ 16.0 (Me), 16.1 (Me), 16.5 (Me),
19.4 (Me), 21.2 (Me), 25.7 (CH2), 26.2 (CH2), 27.2 (CH2), 29.9 (C-1), 33.3
Acknowledgements
The Research Council of Norway is gratefully acknowledged for
financial support (Grant No. 209330) to BP. This work was also
partly supported by the Research Council of Norway through the
Norwegian NMR Package in 1994 and the Norwegian NMR
Platform, NNP (Grant No. 226244/F50). Additional support by
the Department of Chemistry and the Faculty of Mathematics
and Natural Sciences at University of Oslo is also acknowledged.
6
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202000202
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Natural product synthesis
O
Cl
N
N
H2N
N
(–)-Agelasine F
(S)-(+)-Carvone
N
The first total synthesis of the bioactive marine natural product (–)-agelasine F has been performed. The synthetic sequence starts
with readily available (S)-(+)- carvone which controls the stereochemistry in the target compound.
8
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