Catalytic epoxypolyene cyclization via radicals: A simple total synthesis of sclareol oxide and its 8-epimer

Article abstract of DOI:10.1055/s-2006-942406

A short synthesis of sclareol oxide from epoxyfarnesyl acetone in six steps is described. The strategy features a titanocene-catalyzed epoxypolyene cyclization for the construction of the carbocyclic core structure. The exo olefin formed during the termin

Full text of DOI:10.1055/s-2006-942406

PAPER
2151
Catalytic Epoxypolyene Cyclization via Radicals: A Simple Total Synthesis of
Sclareol Oxide and its 8-Epimer
S
ynthesisof Sclare
n
olOxide dreas Gansäuer,* Dennis Worgull, José Justicia
Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)734760; E-mail: andreas.gansaeuer@uni-bonn.de
Received 3 May 2006
Dedicated to Prof. Dieter Hoppe on the occasion of his 65th birthday
O
Abstract: A short synthesis of sclareol oxide from epoxyfarnesyl
acetone in six steps is described. The strategy features a titanocene-
catalyzed epoxypolyene cyclization for the construction of the car-
bocyclic core structure. The exo olefin formed during the termina-
tion of the cyclization is essential for the ensuing functional group
modification that results in the preparation of the dihydropyran.
O
O
8
HO
Key words: catalysis, epoxypolyene cyclization, natural products,
H
H
radicals, titanocene
O
1 and 8-epi-1
O
Sclareol oxide (1) is a constituent of the essential oils of
Salvia sclarea, a plant found in the Mediterranean region.1
It constitutes an important starting material for the semi-
synthesis of a number of important compounds, such as
ambrox®2 and ent-thallusin.3 The latter case reveals one of
the disadvantages of employing natural products as start-
ing materials, they are usually only available as one enan-
tiomer. To increase the undisputed usefulness of sclareol
oxide, we present here a total synthesis of 14 that allows
its preparation racemically or as either enantiomer from
epoxyfarnesyl acetone acetal (2) that can be readily syn-
thesized from farnesyl acetone (3) in enantiomerically
pure form via dihydroxylation.5
O
2
Scheme 1 Strategy for the synthesis of 1 from 2
acetalization step than the commonly used solvents ben-
zene or toluene. Epoxidation of 4 to yield 2 was achieved
by the classical van Tamelen procedure using NBS in
H2O–DME11 as shown in Scheme 2.
The pivotal titanocene-catalyzed epoxypolyene cycliza-
tion of 2 proceeded smoothly to yield the bicyclic alcohol
5 in 40% yield. Deoxygenation of 5 was carried out by a
Barton–McCombie reaction12 via xanthate 6. It should be
noted that the stereocenter of the epoxide controls the for-
mation of all other stereocenters in 5 and therefore in 7.
Thus, the use of enantiomerically pure 2 in either form
will lead to a synthesis of both enantiomers of 5 and there-
fore 1. This is also of some relevance for the synthesis of
other natural products, e.g. thallusin.3 From 6, the synthe-
sis of 1 and its 8-epimer were completed in just two steps
by epoxidation with MCPBA to yield 8, epoxide opening
with LiAlH4 and dihydropyran formation during acidic
work-up. Sclareol oxide (1) could be readily separated
from 8-epi-1 by column chromatography. These results
are summarized in Scheme 3.
During the last years the radical chemistry originating
from titanocene-catalyzed epoxide opening has attracted a
great deal of attention.6 Within this context the first exam-
ples of radical epoxypolyene cyclizations have recently
been reported by the group of Cuerva and Oltra.7 Their
radical tandem sequence is advantageous compared to the
classical cationic polycyclizations8 because radical gener-
ation proceeds under much milder conditions than cation
generation and the tandem cyclization can be terminated
by a b-hydride elimination. We have reported a short syn-
thesis of building blocks for the preparation of puupehedi-
one.9 These examples highlight the mildness and
functional group tolerance of the radical reactions.
Our synthetic analysis of 1 from 2 is depicted in
Scheme 1. Epoxyfarnesyl acetone acetal (2) was prepared
by a slight modification of the original procedure.10 It
turned out that farnesyl acetone acetal (4, intermediate in
Scheme 2) can be obtained from farnesyl acetone 3 in
much higher yield if dichloromethane is employed in the
O
O
1) HOCH2CH2OH,
p-TsOH, CH2Cl2,
(to acetal 4), 93%
2) NBS, DME, H2O,
K2CO3, MeOH
O
34%
O
SYNTHESIS 2006, No. 13, pp 2151–2154
Advanced online publication: 08.06.2006
x
x.
x
x
.
2
0
0
6
2
3
DOI: 10.1055/s-2006-942406; Art ID: C02506SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Improved synthesis of 2

2152
A. Gansäuer et al.
PAPER
was used as received because it is easier to isolate 5 than to separate
stereoisomers of the starting material. As it is known that cis iso-
mers do not undergo cyclization under our experimental condi-
tions,14 the yields are based on the all-trans isomer contents of the
starting mixture. Compound 2 was prepared according to known
procedure.10
O
O
Cp2TiCl2 (20 mol%),
Mn, Coll, Me3SiCl
40%
2
R
Farnesyl Acetone Acetal (4)
H
5
R = OH
To a solution of commercial farnesyl acetone (3; 10.0 g, 38.1 mmol)
in CH2Cl2 (250 mL), were added ethylene glycol (7.10 g, 114.3
mmol) and p-TsOH (728 mg, 3.81 mmol). The mixture was re-
fluxed for 24 h using a Dean–Stark apparatus. Then, the mixture
was washed with H2O and sat. aq NaHCO3, the organic layer was
separated and dried (MgSO4). The solvent was removed and the res-
idue was purified by flash chromatography (cyclohexane–EtOAc,
95:5) to give a colorless oil; yield: 10.84 g (93%).
C6F5OCSCl
Bu3SnH
6
7
R = C6F5OCSO
DMAP, 76%
AIBN, 80%
O
R = H
O
O
The 1H NMR and 13C NMR spectra are in full agreement with pre-
viously reported data.10
MCPBA
65%, dr = 80:20
H
Bicyclic Alcohol 5
8
THF (15 mL) was added to a mixture of Cp2TiCl2 (159 mg,
0.64 mmol) and Mn dust (1.36 g, 24.8 mmol) under argon and the
suspension was stirred at r.t. until it turned green (about 15 min).
Then, a solution of 2,4,6-collidine (3.01 g, 24.8 mmol), and
Me3SiCl (1.35 g, 12.4 mmol) in THF (5 mL) was added and the
mixture was stirred for 5 min. After the addition of a solution of 2
(1.00 g, 3.11 mmol) in THF (5 mL), the mixture was stirred at r.t.
overnight. Aq 2 N HCl was added, and the mixture was extracted
with t-BuOMe. The combined organic layers were dried (MgSO4)
and the solvent was removed. The residue was dissolved in THF and
1 M solution of Bu4NF in THF (3.24 g, 12.4 mmol) was added and
stirring continued for 30 min. After dilution with t-BuOMe, and
washing the solution with brine, the organic layer was dried
(MgSO4) and the solvent was removed. The residue was purified by
flash chromatography (cyclohexane–EtOAc, 9:1) to afford 5 as a
1) LiAlH4,
2) HCl
O
O
H
H
8-epi-1 13%
1
58%
Scheme 3 Synthesis of 1 and 8-epi-1 from 2
We did not attempt to optimize the diastereoselectivity of colorless oil;7a yield: 123 mg (40%); Rf = 0.13 (cyclohexane–
the epoxidation as 8-epi-1 constitutes an interesting start-
EtOAc, 80:20).
ing material for the synthesis of compounds that are inter-
esting for olfactory studies, such as isoambrox®, that has
moreover been synthesized and characterized for the first
time.
IR (neat): 3450, 2940, 1715, 1645, 1450, 1375, 1221, 1130, 1060,
1040, 945, 890, 865, 760 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.83 (dd, J = 2.4, 1.0 Hz, 1 H),
4.56 (dd, J = 2.4 Hz, 1.4 Hz, 1 H), 3.89–3.97 (m, 4 H), 3.24 (dd,
J = 11.4, 3.6 Hz, 1 H), 2.38 (ddd, J = 12.8, 4.2, 2.5 Hz, 1 H), 0.81–
2.01 (m, 13 H), 1.30 (s, 3 H), 0.98 (s, 3 H), 0.76 (s, 3 H), 0.68 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 148.05, 110.48, 107.04, 78.98,
64.75, 64.73, 56.74, 54.75, 39.54, 39.25, 38.27, 38.02, 37.22, 28.43,
28.06, 24.10, 23.93, 18.13, 15.53, 14.51.
In summary, we have devised a synthetic route to 1 and 8-
epi-1 in only six steps from commercial farnesyl acetone.
The epoxypolyene cyclization proceeded highly stereose-
lectively, and our approach can also be used for the syn-
thesis of the enantiomerically pure compounds.
HRMS-EI: m/z calcd for C20H34O3: 322.2508; found: 322.2514.
All reactions were performed in oven-dried (100 °C) glassware un-
der argon. THF was freshly distilled from K. Et2O was freshly dis-
tilled from Na/K. CH2Cl2, MeOH and benzene were freshly distilled
from CaH2. Products were purified by flash chromatography on
Merck silica gel 50. Yields refer to analytically pure samples. Iso-
mer ratios were determined by suitable 1H NMR integrals of cleanly
Xanthate 6
To a stirred solution of 5 (274 mg, 0.85 mmol) and DMAP (313 mg,
2.56 mmol) in CH2Cl2 (6 mL), was added C6F5O(CS)Cl (446 mg,
1.70 mmol) at 0 °C, and the solution was stirred for 4 h at r.t. Then,
EtOAc was added and the mixture was washed with H2O, the organ-
ic layer was separated and dried (MgSO4) and the solvent was re-
moved. The residue was purified by flash chromatography
(cyclohexane–EtOAc, 98:2) to yield 6 (356 mg, 76%) as a colorless
oil that slowly decomposed on silica gel; Rf = 0.63 (cyclohexane–
EtOAc, 75:25).
1
separated signals. NMR: Bruker AMX 300, AM 400; H NMR,
CHCl3 (7.26 ppm) in the indicated solvent as internal standard in the
same solvent; 13C NMR, CDCl3 (77.16 ppm) as internal standard in
the same solvent; integrals in accord with assignments, coupling
constants are measured in Hz and always constitute JH,H coupling
constants. IR spectra: Perkin-Elmer 1600 series FT-IR as neat films
on KBr plates. Flash chromatography was carried out according to
the procedure of Still.13
IR (neat): 755, 970, 1055, 1135, 1235, 1375, 1455, 1525, 1645,
1715, 2970 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.98 (dd, J = 12.0 Hz, 1 H), 4.87
(s, 1 H), 4.61 (s, 1 H), 3.98–3.87 (m, 4 H), 2.43 (ddd, J = 12.8, 4.0,
2.4 Hz, 1 H), 2.14–1.35 (m, 13 H), 1.31 (s, 3 H), 1.00 (s, 3 H), 0.94
(s, 3 H), 0.76 (s, 3 H).
Farnesyl acetone was purchased from Fluka in the form of a mixture
of four stereoisomers containing 31% of the all-trans isomer (GC-
MS analysis with an authentic sample as standard). This mixture
Synthesis 2006, No. 13, 2151–2154 © Thieme Stuttgart · New York

PAPER
Synthesis of Sclareol Oxide
2153
13C NMR (100 MHz, CDCl3): d = 191.85, 147.41, 110.41, 107.61,
95.24, 64.78, 64.74, 56.53, 54.82, 39.40, 38.98, 38.02, 37.97, 36.75,
28.13, 23.90, 23.75, 22.97, 18.25, 16.93, 14.60 (some signals were
not observed due to C–F coupling).
J = 13.5, 3.7Hz, 1 H), 0.81 (dd, J = 12.5, 2.3 Hz, 1 H), 0.80 (s, 3 H),
0.75 (s, 3 H), 0.72 (dm, J = 3.8 Hz, 1 H), 0.69 (s, 3 H).
13C NMR (100 MHz, C6D6): d = 148.56, 94.42, 76.16, 56.28, 52.75,
42.16, 41.65, 39.48, 36.84, 33.55, 33.24, 21.75, 20.75, 20.47, 20.01,
18.95, 18.73, 15.21.
HRMS-EI: m/z calcd for C27H33F5O4S: 548.2012; found: 584.2020.
Reduction of Xanthate 6 to Compound 7
8-epi-1
Rf = 0.19 (cyclohexane).
Xanthate 6 (473 mg, 0.86 mmol) was dissolved in benzene
(80 mL). AIBN (28 mg, 0.17 mmol) and Bu3SnH (754 mg, 2.59
mmol) were added, and the mixture was stirred at reflux for 4 h.
Then, the solvent was removed. The residue was purified by flash
chromatography (cyclohexane–EtOAc, 98:2) to yield 7 (211 mg,
80%) as a colorless oil;15 Rf = 0.63 (cyclohexane–EtOAc, 75:25).
IR (neat): 910, 960, 1075, 1120, 1160, 1385, 1460, 1710, 2935,
3445 cm–1.
1H NMR (400 MHz, C6D6): d = 4.41 (ddq, J = 6.1, 2.2, 1.1 Hz,
1 H), 2.09 (dt, J = 13.8, 2.3 Hz, 1 H), 2.04 (dt, J = 8.2, 2.3 Hz, 1 H),
1.72 (s, 3 H), 1.75–1.63 (m, 2 H), 1.59 (pseudo qt, J = 13.6, 3.4 Hz,
1 H), 1.44–1.35 (m, 4 H), 1.30 (td, J = 13.5, 4.7 Hz, 1 H), 1.18 (s,
3 H), 1.16–1.11 (m, 1 H), 1.09 (s, 3 H), 0.88 (s, 6 H), 0.71 (dd,
J = 12.2, 2.0 Hz, 1 H), 0.69 (dd, J = 13.2, 3.2 Hz, 1 H).
13C NMR (100 MHz, C6D6): d = 149.83, 95.44, 74.94, 55.57, 49.52,
42.36, 41.04, 40.54, 38.49, 33.93, 33.40, 27.05, 22.24, 20.80, 19.34,
19.04, 18.67, 13.96.
IR (neat): 2935, 1720, 1645, 1460, 1375, 1205, 1065, 890 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.81 (d, J = 1.4 Hz, 1 H), 4.55 (d,
J = 1.3 Hz, 1 H), 3.88–3.97 (m, 4 H), 2.37 (ddd, J = 12.7, 4.2, 2.4
Hz, 1 H), 0.97–2.11 (m, 15 H), 1.31 (s, 3 H), 0.86 (s, 3 H), 0.80 (s,
3 H), 0.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 148.75, 110.59, 106.61, 64.76,
64.74, 57.08, 55.69, 42.35, 39.87, 39.25, 38.48, 38.10, 33.78, 33.72,
24.59, 23.94, 21.88, 19.54, 18.05, 14.52.
HRMS-EI: m/z calcd for C18H30O: 262.2297; found: 262.2302.
HRMS-EI: m/z calcd for C20H34O2: 306.2559; found: 306.2554.
Acknowledgment
Epoxide 8
J.J. is grateful to the University of Granada and Ministerio de Edu-
cación y Ciencia for postdoctoral grants. A.G. is indebted to the
Fonds der Chemischen Industrie (research grant) for continued fi-
nancial assistance.
To a solution of 7 (206 mg, 0.68 mmol) in CH2Cl2 (12 mL), was
added MCPBA 70% (333 mg, 1.35 mmol) and the mixture was
stirred at 0 °C for 6 h. Then, CH2Cl2 was added and the solution was
washed with aq 2 N NaOH, dried (MgSO4) and the solvent was re-
moved. The residue was purified by flash chromatography (cyclo-
hexane–EtOAc, 85:15) to afford 8 as an 80:20 mixture of
diastereomers; colorless oil; yield: 139 mg (65%); Rf = 0.45 (cyclo-
hexane–EtOAc, 75:25).
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HRMS-EI: m/z calcd for C20H34O3: 322.2508; found: 322.2513.
Sclareol Oxide (1) and epi-Sclareol Oxide (8-epi-1)
To a suspension of LiAlH4 (521 mg, 13.7 mmol) in Et2O (30 mL),
was added compound 8 (138 mg, 0.428 mmol) and the mixture was
stirred at r.t. for 2 h. Then, H2O and aq 36% HCl were added, and
the mixture was extracted with t-BuOMe, the organic layer was
dried (MgSO4) and the solvent was removed. The residue was puri-
fied by flash chromatography (cyclohexane–EtOAc, 75:25) to yield
sclareol oxide (1) (65 mg, 58%) and epi-sclareol oxide (8-epi-1) (15
mg, 13%) as colorless oils.
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s, 3 H), 1.13 (ddd, J = 13.8, 12.3, 3.4 Hz, 1 H), 1.03 (pseudo td,
Synthesis 2006, No. 13, 2151–2154 © Thieme Stuttgart · New York

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Synthesis 2006, No. 13, 2151–2154 © Thieme Stuttgart · New York