A metathesis-acylation approach to the bicyclic core of polycyclic poly-prenylated acylphloroglucinols

Article abstract of DOI:10.1055/s-0034-1378380

An approach to a model compound for polycyclic polyprenylated acylphloroglucinols is developed using a ring-closing metathesis approach to give a substituted cyclooctene. This undergoes cyclization via an intramolecular acylation leading to a substituted bicyclo[3.3.1]nonan-9-one related to hyperforin, nemorosone, clusianone, garsubellin A and other members of the polyprenylated acylphloroglucinol. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0034-1378380

LETTER
▌2025
lAetteMr etathesis–Acylation Approach to the Bicyclic Core of Polycyclic Poly-
prenylated Acylphloroglucinols
Metathesis–Acylation Approach to the Bicyclic Core of PPAPs
Stefanie Schmitt,a Eva Feidt,a David Hartmann,a Volker Huch,b Johann Jauch*a
a
Institut für Organische Chemie II, Universität des Saarlandes, 66123 Saarbrücken, Germany
b
Institut für Anorganische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)30264151; E-mail: j.jauch@mx.uni-saarland.de
Received: 21.03.2014; Accepted after revision: 03.06.2014
Abstract: An approach to a model compound for polycyclic poly-
prenylated acylphloroglucinols is developed using a ring-closing
metathesis approach to give a substituted cyclooctene. This under-
goes cyclization via an intramolecular acylation leading to a substi-
tuted bicyclo[3.3.1]nonan-9-one related to hyperforin, nemorosone,
clusianone, garsubellin A and other members of the polyprenylated
acylphloroglucinol.
O
OH
O
OH
O
O
O
O
Key words: bicyclic compounds, natural products, metathesis,
alkene acylation, steric hindrance
1
2
Polycyclic polyprenylated acylphloroglucinols (PPAPs)
are a class of polyketides which contains more than 210
members having interesting bicyclo[3.3.1]nonane, bicy-
clo[3.2.1]octane or tricyclic core structures, with several
prenyl or geranyl substituents and one acyl group at vari-
ous positions.1 Prominent members of the PPAPs (Figure
1) are hyperforin (1), nemorosone (2), clusianone (3) and
garsubellin A (4). Besides their challenging structural fea-
tures, the PPAPs also show fascinating biological activi-
ties,1,2 which are compelling reasons to develop total
syntheses of these natural products.
O
HO
O
OH
O
O
O
O
O
3
4
Figure 1 Structures of hyperforin (1), nemorosone (2), clusianone
(3) and garsubellin A (4)
Synthetic endeavors and total syntheses of PPAPs have
been reviewed in several publications,1,3 whilst some
more recent total syntheses of PPAPs have also been de-
scribed.4 Furthermore methods to prepare the bicy-
clo[3.3.1]nonan-9-one core have been reviewed.5
Retrosynthetic analysis (Scheme 1) of 5 via cyclooctene
derivative 6 is straightforward. Compound 5 should be ac-
cessible through intramolecular acylation of 6. The substi-
tuted cyclooctene 6 should be formed through ring-
closing metathesis (RCM) from 7, which could be synthe-
Each synthetic approach toward the PPAPs and precur-
sors with a substituted bicyclo[3.3.1] framework pub-
lished to date starts from a six-membered-ring compound
(substituted cyclohexanones, substituted phenols, resorci-
nols or phloroglucinols), and install a suitable three-car-
bon unit to complete the bicyclo[3.3.1]nonan-9-one core
of the PPAP.
OPG
OPG
O
O
X
Our idea was to synthesize a suitably substituted cyclooc-
tene derivative and to install the bridging carbonyl group
across the cyclooctene ring. Herein, we report our initial
results along these lines.
X
5
6
O
OPG
For convenience, and as a proof-of-principle that our
strategy was feasible, we first focused our efforts on the
simpler model structure 5, which is structurally related to
compounds 1–4.
O
O
8
OMe
OMe
7
9
SYNLETT 2014, 25, 2025–2029
Advanced online publication: 23.07.2014
DOI: 10.1055/s-0034-1378380; Art ID: st-2014-b0245-l
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of model compound 5; X = Cl (ac-
id chloride) or OCOR (mixed acid anhydride); PG = protecting group
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2026
S. Schmitt et al.
LETTER
sized through aldol reaction of known compound 9 and Whereas ring closure is accelerated via the Thorpe–Ingold
commercially available 4-pentenal (8).
effect, the subsequent hydrolysis of carboxylic acid ester
12 was retarded by the steric congestion exerted by the
geminal dimethyl grouping. After trying different meth-
ods for the hydrolysis of sterically hindered esters,13 the
method of Snider et al.13c was found to work best, giving
acid 13 in 94% yield, although the reaction time was rath-
er long (ca. 4–5 days; Scheme 3). Crystallization from
chloroform gave crystals of 13 suitable for X-ray analy-
sis.14 Transformation of the acid 13 into acid chloride 6a
was straightforward using oxalyl chloride.15
Methyl hexenoate 9 was synthesized in 84% yield accord-
ing to the method of Santelli et al.,6 which involved a tita-
nium tetrachloride (TiCl4) catalyzed Sakurai reaction with
4-methyl-2-oxo-3-pentenenitrile (10).6c Aldol addition of
9 to aldehyde 8, following the procedure of Wei et al.,7
gave diene 11 as
a
mixture of diastereomers
(syn/anti = 3:1, in agreement with the results of Wei7),
which were protected as methyl ether 7 using methyl tri-
flate and Proton-sponge® as the base,8 in 93% yield
(Scheme 2). After methylation of the hydroxy group in 11, The next part of our strategy was the transannular cycliza-
the diastereomers were separated and all following reac- tion reaction of the acid chloride 6a across the eight-mem-
tions were performed with the syn diastereomer.
bered ring. Such Friedel–Crafts-like acylation reactions of
double bonds are well known,16 but are rarely applied to
natural product syntheses due to competing side reactions,
for example, polymerization of the olefin. Intramolecular
acylations for ring-closing reactions have also been pub-
lished,16 and even the transformation of cyclooct-4-ene
carboxylic acid 14 into cyclooct-4-ene carboxylic acid
chloride 15 and subsequent cyclization to give 2-chlorobi-
cyclo[3.3.1]nonan-9-one (16) have been reported.17
Hence, we began our acylation studies (Scheme 4) by re-
peating the conversion of acid chloride 15 into bicyclic
16. Whereas Kretschmar17a,b reported a reaction time of 72
hours for the uncatalyzed cyclization in 1,2-dichlo-
roethane at reflux temperature, and Kraus17d obtained sim-
ilar results after reaction for 12 hours, we found that the
cyclization was complete after seven to nine days. The
product was obtained in quantitative yield as a mixture of
diastereomers (endo/exo = 3:2, in agreement with
Kraus17d). When we used aluminum chloride (AlCl3) or
other Lewis acids as the catalyst under similar conditions,
we obtained inferior results.18 Therefore, the cyclization
of acid chloride 6a was carried out in 1,2-dichloroethane
as solvent at reflux temperature. The reaction was com-
plete after only 21 hours to give 5a as a mixture of diaste-
reomers (exo/endo = 18:1) in 40% yield after
chromatography,19 together with 9% of the elimination
product (structure not shown). Similar to the results ob-
tained in the RCM reactions (Scheme 3), this increase in
the rate of cyclization can be interpreted as a result of the
Thorpe–Ingold effect of the geminal dimethyl arrange-
ment.
O
CN
a
b
OMe
84%
89%
O
10
9
OH
OMe
O
O
c
93%
OMe
OMe
11
7
Scheme 2 Preparation of intermediate 7. Reagents and conditions:
(a) (i) TiCl4, CH2Cl2, allyl trimethylsilane, –78 °C to –30 °C; (ii)
MeOH, –30 °C to r.t.; (b) LDA, THF, –78 °C, 8; (c) Proton-sponge®,
MeOTf, CH2Cl2, r.t.
The next task was RCM of 7 to give 12. There are several
literature reports on the successful application of the RCM
for the synthesis of eight-membered rings.9 In our case,
the use of the Grubbs II catalyst, together with triphenyl-
phosphine oxide as an additive,10 led to the formation of
12 in a very good yield (Scheme 3). Important for the suc-
cess of the RCM is the presence of the quaternary carbon
with the geminal dimethyl groups (Thorpe–Ingold ef-
fect11), since RCM reactions with similar compounds12
under comparable conditions were sluggish and gave low
yields.
OMe
OMe
O
O
a
Since increasing the reactivity of the acid chloride 6a was
unsuccessful,18 we reasoned that mixed anhydride 6b
might also add across the eight-membered ring to the dou-
ble bond, resulting in the construction of the carbonyl
bridge and introduction of an oxygen next to a bridgehead
atom (similar to the arrangement in PPAPs). Mixed trifluo-
roacetic anhydrides20 have been described in the literature
and are easily prepared from carboxylic acids and trifluo-
roacetic anhydride (TFAA).20b Thus, we attempted to syn-
thesize the mixed anhydride 17 according to the
literature,20b and found that cyclization into 2-trifluoroac-
etoxybicyclo[3.3.1]nonan-9-one (18) occurred almost in-
stantaneously at room temperature (Scheme 4). The
product was obtained as a mixture of diastereomers
83%
OMe
OMe
7
12
OMe
OMe
O
O
b
c
94%
94%
OH
Cl
13
6a
Scheme 3 RCM of 7 (syn isomer only) into cyclooctene 12 and con-
version into acid chloride 6a. Reagents and conditions: (a) Grubbs II
(1.4 mol%), Ph3P=O (5 mol%), Et2O, reflux; (b) H2O, DME, LiOH
(17 equiv), reflux; (c) (COCl)2, CH2Cl2, r.t.
Synlett 2014, 25, 2025–2029
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metathesis–Acylation Approach to the Bicyclic Core of PPAPs
2027
O
O
a
b
a
b
98%
98%
OH
Cl
O
86%
60%
O
O
O
Cl
Cl
TFAO
HO
O
14
15
6a
17
16
18
19
21
OMe
OMe
OMe
OMe
OMe
O
c
a
b
Cl 40%
O
87%
64%
O
O
O
TFAO
HO
O
5a
5b
20
22
Scheme 5 Synthesis of bicyclo[3.3.1]nonandiones. Reagents and
conditions: (a) sat. aq NaHCO3, r.t.; (b) DMP, CH2Cl2, r.t.
O
O
d
98%
OH
OTFA
O
TFAO
14
18
Acknowledgment
OMe
OMe
OMe
We thank the Universität des Saarlandes for generous support and
Prof. Dr. D. Volmer and T. Dier for recording the HRMS spectra.
E.F. thanks Graduiertenförderung der Universität des Saarlandes
for a PhD scholarship.
O
O
e
98%
OTFA
OH
O
TFAO
13
6b
5b
Supporting Information for this article is available online
Scheme 4 Transannular cyclization of cyclooctenecarboxylic acid
derivatives. Reagents and conditions: (a) (COCl)2, neat, r.t.; (b) DCE,
reflux; (c) DCE, reflux; (d) TFAA, CHCl3, r.t.; (e) TFAA, CHCl3
(free of stabilizers), 0 °C.
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
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fonirtat
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References and Notes
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(Scheme 5). Compared to PPAPs, the last introduced car-
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In summary, we have developed a short and efficient syn-
thesis of a substituted bicyclo[3.3.1]nonan-9-one related
to the core structure of PPAPs. The method is based on a
ring-closing metathesis to give a cyclooctene derivative
and a simple transannular cyclization of a mixed trifluoro-
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pure form is currently underway, and the results will be
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2025–2029

2028
S. Schmitt et al.
LETTER
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OEt
OEt
OEt
OEt
i
97%
ii
36%
Scheme 6 Reagents and conditions: (i) Grubbs II (1.4 mol%),
Ph3P=O (5 mol%), Et2O, reflux, 30 min. (ii) Grubbs II (1.4
mol%), Ph3P=O (5 mol%), Et2O, reflux, 2 d.
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suitable for single crystal X-ray analysis were obtained from
CHCl3. The data were collected at 133 K on a Bruker AXS
X8Apex CCD diffractometer operating with graphite-
monochromated MoKα radiation. Frames of 0.5° oscillation
were exposed; deriving data in the θ range of 2–37° with a
completeness of ~99%. Unit cell: triclinic, P-1,
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1992, 48, 5757. See also: (b) Maier, M. E. Angew. Chem. Int.
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a = 7.1553(4) Å, b = 7.4403(4) Å, c = 11.4373(7) Å,
α = 83.096(2)°, β = 77.747(2)°, γ = 74.477(3)°,
V = 572.02(6) Å3. Structure solution and full least-squares
refinement with anisotropic thermal parameters of all non-
hydrogen atoms and free refinement of the hydrogens were
performed using SHELX.14b The final refinement resulted
in: R1 = 0.036. Crystallographic data for this structure have
Synlett 2014, 25, 2025–2029
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metathesis–Acylation Approach to the Bicyclic Core of PPAPs
2029
been deposited with the Cambridge Crystallographic Data
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(g) Cyclooct-4-ene carboxylic acid 14 was synthesized
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procedure (sat. KOH in MeOH–H2O, 9:1, reflux, 3 d). The
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(18) The elimination product, bicyclo[3.3.1]non-2-en-9-one,
became the main product and the total yield decreased. Since
acid bromides and acid iodides are more reactive than acid
chlorides, we also added tetrabutylammonium bromide or
tetrabutylammonium iodide to the reaction mixture to form
the acid bromides and acid iodides in situ, but this also led to
decreased yields of the corresponding cyclization products
and larger amounts of elimination products.
(19) Interestingly, the 1H and 13C NMR spectra of 5a before and
after chromatographic purification were identical; it seems
that either 5a decomposes to some extent during
chromatography, or is partially absorbed irreversibly.
(20) (a) Tedder, J. M. Chem. Rev. 1955, 55, 787. (b) Emmons, W.
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Figure 2 Structure representation for 13 with ellipsoids at
50% probability
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K.; Jones, N. J. Chem. Soc. (C) 1969, 1718. (c) Cantrell, T.
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