A new approach for the construction of a highly congested bicyclic system in polycyclic polyprenylated acylphloroglucinols (PPAPs)

Article abstract of DOI:10.1016/j.tetlet.2007.04.080

A highly congested bicyclo[3.3.1]nonanone core of polycyclic polyprenylated acylphloroglucinols was constructed using a stereoselective Claisen rearrangement and an intramolecular aldol reaction as the key steps. The stereochemistry of C-4 appeared to con

Full text of DOI:10.1016/j.tetlet.2007.04.080

Tetrahedron Letters 48 (2007) 4173–4177
A new approach for the construction of a highly
congested bicyclic system in polycyclic polyprenylated
acylphloroglucinols (PPAPs)
Yohei Shimizu, Akiyoshi Kuramochi, Hiroyuki Usuda,
Motomu Kanai* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 2 April 2007; revised 16 April 2007; accepted 17 April 2007
Available online 20 April 2007
Abstract—A highly congested bicyclo[3.3.1]nonanone core of polycyclic polyprenylated acylphloroglucinols was constructed using a
stereoselective Claisen rearrangement and an intramolecular aldol reaction as the key steps. The stereochemistry of C-4 appeared to
control the ground state conformation of the cyclohexenone core, which determined the diastereoselectivity in the Claisen
rearrangement.
Ó 2007 Elsevier Ltd. All rights reserved.
The polycyclic polyprenylated acylphloroglucinols
(PPAPs) are a group of naturally occurring secondary
HO
O
O
metabolites. The isolation and structural determination
of PPAPs have been studied intensively. Attention to
PPAPs as pharmaceutical leads has recently increased
due to their interesting biologic activities. In addition,
many PPAPs contain attractive chemical structures
from a synthetic viewpoint.1
2
1
O
O
O
O
O
HO
6
4
8
garsubellin A (1)
hyperforin (2)
We are especially interested in two compounds in this
group, garsubellin A (1) and hyperforin (2). Garsubellin
A was isolated from Garcinia subelliptica, and its struc-
ture was determined by Fukuyama et al.2 Garsubellin A
potently induces choline acetyltransferase (154% at
10 lM compared to negative control), and it is this
property that has led to the consideration of garsubellin
A as a pharmaceutical lead for the treatment of Alzhei-
mer’s disease. Hyperforin is extracted from St. John’s
wort, Hypericum perforatum.3 This Western herb inhib-
its serotonin uptake and has mild antidepressant activ-
ity. In vitro biologic studies suggest that hyperforin is
responsible for this activity.4 Other noteworthy proper-
ties of hyperforin are its antibacterial activity5 and its
Figure 1.
ability to repress the effectiveness of other drugs through
drug–drug interactions6 (Fig. 1).
Due to their high structural complexity, however, chem-
ical synthesis of PPAPs is extremely challenging. One of
the most difficult steps is the construction of the highly
congested bicyclo[3.3.1]nonanone system containing
two bridgehead quaternary carbons.7–9 We achieved
the first total synthesis of ( )-garsubellin A in 2005.10a
In that synthesis, we constructed the bicyclic skeleton
through stereoselective Claisen rearrangement, ring-
closing metathesis, and allylic oxidation as the key steps
(Scheme 1). Although excellent diastereoselectivity was
produced in the Claisen rearrangement, the origin of
the stereoselectivity in this key reaction was not clear.
Moreover, the realization that this approach was not
applicable to hyperforin synthesis due to the existence
Keywords: Polycyclic polyprenylated acylphloroglucinols (PPAPs);
Garsubellin A; Hyperforin; Bicyclo[3.3.1]nonanone core; Claisen
rearrangement; Intramolecular aldol reaction.
*
Corresponding authors. Fax: +81 3 5684 5206 (M.S.); e-mail:
mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.080

4174
Y. Shimizu et al. / Tetrahedron Letters 48 (2007) 4173–4177
8-deprenyl garsubellin A;8d,e the bicyclic system was
constructed through an aldol-type reaction between C-
6 and C-1 (Strategy 1 in Scheme 2). This type of intra-
molecular aldol reaction, however, did not proceed in
the synthesis of garsubellin A, probably due to the high-
er congestion at the C-6 nucleophilic center in actual
substrate 7 compared to the model substrate without a
C-8 substituent. In addition, this aldol-type reaction
between an aldehyde and a b-diketone is thermodynam-
ically unfavorable. Therefore, a slight change in the
cyclohexanone conformation caused by the C-8 substi-
tuent could destabilize the product. Based on these
results, we selected Strategy 2, which involved an aldol
reaction between C-4 and C-3. Claisen rearrangement
should reliably provide the ethylformyl group at C-6
of 9.
toluene
NaOAc
200 oC
O
O
O
8
O
4
6
7
O
O
O
O
O
O
96%
dr=>50: 1
MOMO
MOMO
4
3
1) (PhSe)2, PhIO2
pyridine
Hoveyda-Grubbs
2nd. Ru cat.
O
O
2) CSA
O
O
(20 mol %)
O
92%
70%
2 steps
MOMO
5
O
O
O
O
O
O
Based on these considerations, we began our studies of
the Claisen rearrangement with a simple substrate 13,
containing a garsubellin A substitution pattern and
without a substituent at C-4. Synthesis of 13 was
achieved through three steps from the known compound
11.10a,12 Thus, treatment of 11 with HF-py afforded the
corresponding secondary alcohol, which was oxidized
with PDC at 50 °C. The resulting b-diketone 12 was sub-
jected to selective O-allylation, giving 13 in reasonable
yield. The Claisen rearrangement of 13 proceeded by
heating a toluene solution of 13 in a sealed tube at
180 °C in the presence of N,N-diethylaniline.13 The C-
6 quaternary center was constructed in this step in high
yield. In contrast to ( )-garsubellin A synthesis (from 3
to 4 in Scheme 1 in which only one isomer was detected);
the diastereoselectivity of the Claisen rearrangement was
disappointingly low (dr = 2:1).
HO
6
Scheme 1. Construction of bicyclo[3.3.1] system in garsubellin A
synthesis (Ref. 10a).
of multiple prenyl groups in the metathesis step11 forced
us to change our synthetic strategy. In this Letter, we
describe an alternative method for constructing bicy-
clo[3.3.1]nonanone with double bridgehead quaternary
centers, which is also applicable for the synthesis of a
hyperforin system containing free prenyl groups. The
origin of the stereoselectivity in the key Claisen re-
arrangement is also proposed.
As a ‘metathesis-free’ strategy for constructing the bicy-
clic skeleton, we focused on an intramolecular aldol-
type reaction (Scheme 2). The prenyl groups should be
tolerated in this strategy. In addition, an oxygen func-
tionality can be installed at an appropriate position on
the bicyclic system through carbon–carbon bond forma-
tion. Indeed, we used this strategy in the synthesis of
To clarify the reason for this unexpected outcome, the
effect of the substituent (prenyl group) at C-4 on the ste-
reoselectivity of the Claisen rearrangement was investi-
gated. Two precursors, 16 and 19, were synthesized as
shown in Scheme 4. The potassium enolate derived from
11 was prenylated from the a-side (axial attack) stereo-
selectively, producing 15 as a single isomer. b-Prenylated
compound 18 was synthesized through epimerization at
C-4 from 15 under basic conditions. Subsequent desilyl-
ation, oxidation, and O-allylation from 15 and 18 fol-
lowing the same procedure as described in Scheme 3
Strategy 1
1
CHO
O
R
OH
O
O
R
O
6
O
OTIPS
O
O
NaHMDS
allyl iodide
HMPA
1) HF-py
pyridine
2) PDC
8
6
4
MOMO
Strategy 2
MOMO
7
8
39%
3 steps
MOMO
MOMO
toluene
N,N-diethylaniline
180 oC
3
11
12
OHC
HO
O
O
O
O
O
O
O
O
4
6
this study
81%
MOMO
MOMO
dr= 2:1
9
10
MOMO
MOMO
13
14
Scheme 2. Intramolecular aldol strategy to construct the bicyclo[3.3.1]
system.
Scheme 3. Claisen rearrangement of simple substrate.

Y. Shimizu et al. / Tetrahedron Letters 48 (2007) 4173–4177
4175
1) HF-py
pyridine
2) PDC
3) NaHMDS
allyl iodide
O
O
toluene
N,N-diethylaniline
180 oC
KHMDS
prenyl bromide
TBAI
O
OTIPS
O
O
6
4
4
H
11
H
48%
3 steps
81%
dr= ca. 6: 1
98%
MOMO
MOMO
MOMO
3.5% NOE
15
17
16
KHMDS
52%
H
O
1) HF-py
pyridine
2) PDC
3) NaHMDS
allyl iodide
O
toluene
O
OTIPS
O
O
N,N-diethylaniline
6
180 o
C
H
4
4
H
85%
dr=>33: 1
65%
3 steps
MOMO
10.7% NOE
MOMO
MOMO
3.3% NOE
20
18
19
Scheme 4. Effect of C-4 prenyl side chain on diastereoselectivity of the Claisen rearrangement.
gave Claisen rearrangement precursors 16 and 19,
respectively. The Claisen rearrangement proceeded with
high yield for both substrates. The allyl group rear-
ranged with b-selectivity (ca. 6:1) when using 16,
whereas with predominant a-selectivity (>33:1) when
using 19.14 Therefore, the rearrangement occurred from
the opposite side to the prenyl group at C-4 in both
cases. These results demonstrated that the stereochemis-
try at C-4 determines the diastereoselectivity of the Cla-
isen rearrangement, that is, the stereochemistry of the
quaternary carbon at C-6.
half-chair conformation with the C-4 prenyl group and
the C-8 substituent both at equatorial positions. The
allyl group should enter C-6 from the a-face (TS4), avoid-
ing the C-7 axial methyl group. These results suggest
that the C-4 prenyl group, rather than the C-8 substitu-
ent, determines the conformation of the cyclohexene
core, leading to the fixation of the dimethyl groups’
positions at C-7. The allyl group rearranges to C-6 from
the opposite side to the axial methyl at C-7.16 This ste-
reochemical model also explains the stereochemistry of
the Claisen rearrangement in the synthesis of garsubellin
A (3 to 4, Scheme 1).
This stereoselectivity can be explained as follows
(Scheme 5). Based on molecular modeling studies,15
the most stable ground state conformation of 16 is a
half-chair with the C-4 prenyl group at the equatorial
position. Based on this ground state conformation, Cla-
isen rearrangement should proceed from the b-face of C-
6 (TS2) to avoid steric repulsion between the C-7 axial
methyl and reacting allyl groups. A similar approach
might be applicable for the stereoselectivity of the con-
version from 19 to 20. Precursor 19 also prefers the
Further conversion of 20 to a bicyclo[3.3.1]nonanone
core of PPAPs was conducted. Terminal olefin-selective
hydroboration was accomplished using disiamylborane
followed by oxidative workup. Subsequent oxidation
of the resulting primary alcohol 21 with Dess–Martin
periodinane produced aldehyde 9. The second key
conversion, an intramolecular aldol reaction, proceeded
under basic conditions in the presence of NaOEt,
providing the bicyclic compound 22 as a diastereomix-
OMOM
OMOM
O
O
O
O
H
8
H
H
4
H
6
4
8
7
7
4
Me
iPrCO
Me
iPrCO
7
8
Me6
O
Me6
O
MOMO
MOMO
16
17
TS1
TS2
MOMO
Me
MOMO
Me
O
O
O
O
Me
Me
7
6
4
8
8
7
7
4
iPrCO
4
8
iPrCO
6
6
H
H
MOMO
O
O
MOMO
20
19
TS3
TS4
Scheme 5. Proposed model for stereochemical course of the Claisen rearrangement.

4176
Y. Shimizu et al. / Tetrahedron Letters 48 (2007) 4173–4177
5. Schempp, C. M.; Pelz, K.; Wittmer, A.; Scho¨pf, E.; Simon,
OH
O
J. C. Lancet 1999, 353, 2129.
O
O
(sia)2BH;
H2O2
6. Moore, L. B.; Goodwin, B.; Jones, S. A.; Wisely, G. B.;
Serabjit-Singh, C. J.; Willson, T. M.; Collins, J. L.;
Kliewer, S. A. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
7500.
O
NaOH aq.
7. Several synthetic studies have been reported for construc-
tion of the bicyclo[3.3.1]nonanone system of PPAPs
without double bridgehead quaternary carbons or geminal
dimethyl substitutents: (a) Mehta, G.; Bera, M. K.
Tetrahedron Lett. 2004, 45, 1113; (b) Young, D. G. J.;
Zeng, D. J. Org. Chem. 2002, 67, 3134; (c) Spessard, S. J.;
Stoltz, B. M. Org. Lett. 2002, 4, 1943; (d) Kraus, G. A.;
Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003, 44, 659; (e)
Kraus, G. A.; Dneprovskaia, E.; Nguyen, T. H.; Jeon, I.
Tetrahedron 2003, 59, 8975; (f) Abe, M.; Nakada, M.
Tetrahedron Lett. 2006, 47, 6347; (g) Takagi, R.; Nerio, T.;
Miwa, Y.; Matsumura, S.; Ohkata, K. Tetrahedron Lett.
2004, 45, 7401.
8. A synthetically useful construction of the bicyclic system
with double bridgehead quaternary carbons was achieved
in a limited number of synthetic studies: (a) Nicolaou, K.
C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem.
Soc. 1999, 121, 4724; (b) Nicolaou, K. C.; Pfefferkorn, J.
A.; Cao, G.-Q.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1,
807; (c) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V.
Angew. Chem., Int. Ed. 2005, 44, 3895; (d) Usuda, H.;
Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 859; (e)
Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2002, 43, 3621; (f) Ciochina, R.; Grossman, R. B. Org.
Lett. 2003, 5, 4619.
9. Recently, total synthesis of ( )-clusianone was achieved
using Effenberger cyclization to construct a bicyclo[3.3.1]-
nonanone core: (a) Rodeschini, V.; Ahmad, N. M.;
Simpkins, N. S. Org. Lett. 2006, 8, 5283; (b) Nuhant, P.;
David, M.; Pouplin, T.; Delpech, B.; Marazano, C. Org.
Lett. 2007, 9, 287.
10. (a) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 14200; (b)
Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006,
128, 1048.
11. In the presence of a prenyl group at C-7 in the hyperforin
system, ring-closing metathesis proceeded between the
terminal vinyl group and the prenyl group (for a repre-
sentative result, see Scheme 7), and the desired bicy-
clo[3.3.1] formation did not proceed at all. In addition,
attempts to protect the prenyl group through Mukaiyama
hydration, which was used in our garsubellin A synthesis,
failed.
MOMO
MOMO
21
20
OHC
O
O
Dess-Martin
periodinane
NaOEt, EtOH
54%
2 steps
MOMO
9
3
O
HO
O
O
O
O
Dess-Martin
periodinane
87%
2 steps
MOMO
MOMO
22
23
Scheme 6. Successful construction of bicyclo[3.3.1]nonanone core.
ture at C-3.17 The subsequent Dess–Martin oxidation
produced the important synthetic intermediate 23.
Thus, a highly congested bicyclic core of PPAPs was
constructed and the prenyl group was tolerated (Scheme
6).
In summary, we developed a new approach for con-
structing the bicyclo[3.3.1]nonanone core of PPAPs
using a Claisen rearrangement and an intramolecular
aldol reaction as the key steps. The stereochemical course
of the Claisen rearrangement of the three compounds
(13, 16, 19) revealed that the diastereoselectivity was
dependent on the conformation of the core six-mem-
bered ring, which was controlled by the stereochemistry
at C-4. Using an intramolecular aldol reaction, the bicy-
clic system was constructed while maintaining the prenyl
group, which was problematic in the former metathesis
approach. The two findings should be useful for devel-
oping an improved synthetic route for garsubellin A,
as well as for the total synthesis of hyperforin.18 These
studies are ongoing.
MeO
O
O
MeO
O
Hoveyda-Grubbs
2nd Ru cat.
O
7
References and notes
1. For a recent review, see: Ciochina, R.; Grossman, R. B.
Chem. Rev. 2006, 106, 3963.
MOMO
MOMO
2. (a) Fukuyama, Y.; Kuwayama, A.; Minami, H.
Chem. Pharm. Bull. 1997, 45, 947; (b) Fukuyama, Y.;
Minami, H.; Kuwayama, A. Phytochemistry 1998, 49,
853.
Scheme 7.
3. Gurevich, A. I.; Dobrynin, V. N.; Kolosov, M. N.;
Popravko, S. A.; Ryabova, I. D.; Chernov, B. K.;
Derbentseva, N. A.; Aizenman, B. E.; Garagulya, A. D.
Antibiotiki 1971, 6, 510.
4. Muller, W. E.; Singer, A.; Wonnemann, M.; Hafner, U.;
Rolli, M.; Schafer, C. Pharmacopsychiatry 1998, 31, 16.
12. All studies described in this paper were conducted using
racemic compounds.
13. In the absence of N,N-diethylaniline, double bond isom-
erization proceeded before Claisen rearrangement (see
Scheme 8 for a representative result).

Y. Shimizu et al. / Tetrahedron Letters 48 (2007) 4173–4177
4177
18. We developed a catalytic asymmetric Diels–Alder reaction
aiming at asymmetric total synthesis of PPAPs: Usuda,
H.; Kuramochi, A.; Kanai, M.; Shibasaki, M. Org. Lett.
2004, 6, 4387. Recent improved results were shown in
Scheme 9.
O
O
O
O
O
O
toluene
180 oC
21%
Scheme 8.
OTIPS
OTIPS
OTIPS
FeBr3 (10 mol%)
OTIPS
AgSbF6 (20 mol%)
MS 5A, CH2Cl2
R
14. Relative configurations were determined by NOE analysis.
15. A preliminary conformation search was conducted by
CONFLEX5 using an MMFF force field.
16. The model in Scheme 5 also explains the extent of
stereoselectivity (ca. 6:1 from 16 vs >33:1 from 19). There
is 1,3-diaxial repulsion between the C-8 substituent and
reacting allyl group in TS2. No such TS-destabilizing
interaction exists, however, in TS4.
R
N
O
O
O
O
N
O
N
O
N
N
(12 mol%)
OEt
O
R= Me ; 96% yield
86% ee
O
EtO
R= homoprenyl ; 93% yield
96% ee
-70 oC, 30 hr
17. Spiro bicyclic products via intramolecular aldol reaction
with the iso-propyl ketone were not detected.
Scheme 9.