The first catalytic asymmetric total synthesis of ent-hyperforin

Article abstract of DOI:10.1016/j.tet.2010.05.086

The first catalytic asymmetric total synthesis of ent-hyperforin was described here in detail. Keys to the success were a catalytic asymmetric Diels-Alder reaction, a stereoselective Clasien rearrangement, an intramolecular aldol cyclization, and a vinylogous Pummerer rearrangement. Along with the successful synthetic route, several attempted approaches toward the construction of bicyclo[3.3.1] core and the C2 oxidation were discussed.

Full text of DOI:10.1016/j.tet.2010.05.086

Tetrahedron 66 (2010) 6569e6584
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The first catalytic asymmetric total synthesis of ent-hyperforin
,
*
y
*
Yohei Shimizu, Shi-Liang Shi, Hiroyuki Usuda, Motomu Kanai , Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2010
Received in revised form 15 May 2010
Accepted 21 May 2010
Available online 31 May 2010
The first catalytic asymmetric total synthesis of ent-hyperforin was described here in detail. Keys to the
success were a catalytic asymmetric DielseAlder reaction, a stereoselective Clasien rearrangement, an
intramolecular aldol cyclization, and a vinylogous Pummerer rearrangement. Along with the successful
synthetic route, several attempted approaches toward the construction of bicyclo[3.3.1] core and the C2
oxidation were discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Steven
V. Ley on the occasion of his receipt of the
2009 Tetrahedron Prize
1. Introduction
In addition to their unique biological activities, the complex
structure of PPAPs makes them attractive synthetic targets.9 After
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are nat-
urally occurring products with a densely substituted bicyclo[3.3.1]
nonanone core (Fig. 1).1 Recent extensive studies revealed that
some PPAPs exhibit interesting biological activities: garsubellin A
(2) shows potent choline acetyltransferase inductive activity (154%
extensive synthetic studies of PPAPs, total syntheses of garsubellin
A (2),10 clusianone (3),11 and nemorosone (4)11d,f were reported by
several groups. Although biomimetic approaches using acylphlor-
oglucinols as a reactant led to rapid construction of the key bicyclo
[3.3.1]nonanone core and concise racemic total synthesis,9e,11b,e
there is only one example of asymmetric synthesis using a late
stage kinetic resolution with a stoichiometric amount of chiral
lithium amide.11c Thus, the catalytic asymmetric synthesis of
PPAPs remains a challenge. All of the synthesized PPAPs have a C8
gem-dimethyl substituent, and the necessity of stereoselective
installation of additional C8 quaternary center in hyperforin
would make its synthesis more difficult. Recently, our group
accomplished the first catalytic asymmetric total synthesis of
ent-hyperforin using a powerful catalytic asymmetric DielseAlder
reaction.12 Here, we report the details of our synthesis of
ent-hyperforin.
at 10 m
M compared to negative control)2 and clusianone (3) shows
anti-HIV activity.3 Hyperforin (1), isolated from St. John’s wort
(Hypericum perforatum) in 1971,4a is representative of the PPAP
family. Because of its inhibitory effects on the uptake of serotonin
and other neurotransmitters, hyperforin is thought to be
responsible for the antidepressant activity of St. John’s wort.5
Hyperforin also exhibits other noteworthy effects, such as its anti-
malarial activity,6 human histone deacetylase inhibitory activity,7
and the induction of CYP3A4,8 which suppresses the effectiveness
of several drugs.
2. Results and discussion
Our group previously succeeded in the total synthesis of
garsubellin
A using the Claisen rearrangementering closing
metathesis (RCM) sequence to construct the key bicyclo[3.3.1]
core.10a Based on this result, our initial synthetic plan for hyper-
forin was as follows (Scheme 1). Based on the garsubellin A
synthesis, allylic oxidation and C3-prenyl group installation by
Stille coupling to bicyclo compound 5 would lead to hyperforin.
The bicyclo[3.3.1] core of 5 could be constructed through a se-
quence of Claisen rearrangement of 7 and RCM of 6. The Claisen
rearrangement precursor 7 would be obtained from 8, a product
Figure 1. Representative PPAPs.
* Corresponding authors. E-mail address: mshibasa@mol.f.u-tokyo.ac.jp
of
a catalytic asymmetric DielseAlder reaction previously
(M. Shibasaki).
developed in our group,13 through alkylation and aldol
y
Present address: 3-14-23, Kamioosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.086

6570
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
Scheme 1. Retrosynthetic analysis.
condensation at C5 followed by dehydration. The DielseAlder
reaction between 9 and 10 was promoted by a cationic irone
pybox (11) complex, and afforded the product 8 in 93% yield and
96% ee with complete exo selectivity (dr >33:1). The product has
C7eC8 contiguous tertiary and quaternary stereocenters, which
are required for hyperforin, and because this reaction can be
routinely conducted in up to 20-g scale, it is a good starting point
for the total synthesis of complex molecules. To establish a reli-
able synthetic route toward hyperforin, a significant amount of
DielseAlder product 8 was required. Hence, we utilized chiral
pybox 11 derived from inexpensive (R)-4-hydroxyphenylglycine
for the catalytic asymmetric DielseAlder reaction, which resulted
in the synthesis of ent-hyperforin (ent-1).
other isomer decomposed a little under the same conditions.
Therefore, the ratio of the product diastereomers was enriched
to 9:1.
2.1. Claisen rearrangementering closing metathesis approach
Scheme 2. Conversion of catalytic asymmetric DielseAlder product. Reagents and
conditions: (a) EtSLi, THF, 96%. (b) LAH, THF, 99%. (c) MOMCl, TBAI, i-Pr2NEt, CH2Cl2,
94%. (d) TBAF, AcOH, THF. (e) HF$Py, pyridine, THF, 91% (two steps; dr¼1:1). (f) TMSCl,
NEt3, CH2Cl2. (g) TIPSOTf, i-Pr2NEt, CH2Cl2. (h) K2CO3, MeOH. (i) TPAP (10 mol %), NMO,
We first converted the DielseAlder adduct 8 to MOM ether 12
in three steps: addition of thiolate, reduction, and protection,
with high efficiency (Scheme 2). Because the C10 hydroxy group
was readily eliminated to give the corresponding enone under
various reaction conditions, cleavage of the two TIPS groups was
conducted by a two-step sequence, which afforded primary
alcohol 13. Although the hydrolysis of enol TIPS ether gave a 1:1
diastereomixture at C1 and the following conversions were
described from one isomer, the other isomer was also applicable
for the total synthesis with comparable efficiency. Direct oxida-
tion of 13 and subsequent addition of an isopropyl group to C10
were difficult due to the instability of the intermediate aldehyde
derived from 13. Hence, 15 was synthesized via 14, which was
produced from 13 by temporary protection of the primary alco-
hol with a TMS group, protection of the ketone as an enol silyl
ether, and selective cleavage of the TMS ether. After oxidation of
14 with TPAP14 followed by introduction of the isopropyl group
under Barbier conditions (dr¼5:1), hydrolysis of the silyl enol
ether afforded ketone 15. Multiple steps were required for the
apparently simple conversion from 13 to 15, but the overall yield
was reasonable (58% over six steps). After protection of the C10
hydroxy group of 15 with a TMS group, prenylation of the
kinetically produced lithium enolate proceeded exclusively from
ꢀ
MS 4 A, CH3CN/CH2Cl2. (j) 2-bromopropane, Li, THF (dr¼5:1). (k) TBAF, AcOH, THF, 58%
(six steps). (l) TMSCl, imidazole, DMF, 94%. (m) LDA, HMPA, prenyl bromide, THF, 89%.
The C5 quaternary center was constructed efficiently and ster-
eoselectively by aldol condensation with acetaldehyde from the
axial side, and the resulting hydroxy group was eliminated under
Martin sulfurane conditions to give 17 (Scheme 3). Subsequent
cleavage of the TMS ether, oxidation of the secondary alcohol with
DesseMartin reagent,15 and O-allylation produced 7. The stage was
set for the key Claisen rearrangement, but heating 7 in toluene to
180 ꢀC in a sealed tube equipment gave only a complex mixture.
Similar results were obtained in the garsubellin A synthesis due to
an unprotected C5 prenyl group. Although Mukaiyama hydration16
to protect the prenyl groups gave a complicated reaction mixture,
treatment with m-CPBA afforded selective epoxidation. The
obtained diepoxide 18 was a complex diastereomeric mixture, but
the subsequent Claisen rearrangement of 18, which proceeded in
moderate yield, and the critical RCM using a HoveydaeGrubbs
second generation catalyst17 successfully produced the bicyclo
[3.3.1] core. The structure was confirmed after converting the ep-
oxides to prenyl groups (VCl3(THF)3, Zn, CH2Cl2).18 Although the
construction of bicyclo[3.3.1] core was achieved via the Claisen
rearrangementeRCM sequence, the planned allylic oxidation at C2
was very difficult due to the presence of epoxides. The well-
the axial
b face at C5 to give 16. The two diastereomers derived
from the C10 stereocenter exhibited distinctly different reactivity
in this step. One isomer showed excellent reactivity, but the

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6571
established SeO2-mediated allylic oxidation and Barton’s condi-
tions,19 which was successfully applied in the total synthesis of
garsubellin A, resulted in decomposition. After the extensive
investigation, we were forced to change our strategy.
In this intramolecular aldol cyclization approach, we first fo-
cused on stereoselective construction of the C1 quaternary carbon
center. Based on the successful production of the bicyclo[3.3.1] core
discussed above, Claisen rearrangement is a reliable method for
constructing this quaternary center. In addition, our model study
clearly showed the importance of C5 stereochemistry to control the
diastereoselectivity of the Claisen rearrangement (Scheme 5); the
C5 prenyl group was a main factor in determining the conformation
during the transition state and the rearrangement proceeded from
the indicated face, avoiding steric repulsion between the pseudo
axial methyl group at C8 and the allyl group.20
Therefore, the actual substrate,
b-prenyl 16, was converted to
a-prenyl 28 before Claisen rearrangement through a deprotona-
tion/kinetic protonation sequence (Scheme 6). Cleavage of the TMS
ether, DesseMartin oxidation, and O-allylation produced 29, the
precursor of the Claisen rearrangement. Consistent with the model
study, thermal Claisen rearrangement of 29 proceeded selectively
(dr¼12:1) from the
b face. In this reaction, it was necessary to add
N,N-diethylaniline to remove the trace amount of acid that caused
irreproducible results. At this point, three contiguous stereocenters,
including two adjacent quaternary centers, were constructed with
high selectivity. The key bicyclic intermediate 31 was synthesized
uneventfully from 30 through selective hydroboration at the ter-
minal double bond using disiamylborane [(Sia)2BH], DesseMartin
oxidation, intramolecular aldol cyclization of resulting aldehyde 22,
and oxidation.
From 31, the remaining tasks were to: (1) convert the C7 MOM
ether moiety into a prenyl group, (2) oxidize C2, and (3) install
a prenyl group at C3. Of these tasks, conversion of the C7 MOM
ether to a prenyl group was conducted first. Cleavage of the MOM
ether under acidic conditions proceeded with concomitant pro-
tection of the homoprenyl group at C8 to give 32. This unplanned
selective protection was desirable because the reactive homoprenyl
group caused an undesired RCM rather than cross-metathesis at
a later stage. Swern oxidation of 32 followed by the addition of
a vinyl Grignard reagent afforded allylic alcohol 33 as a single
isomer, which was deoxygenated through acetylation and a palla-
dium-catalyzed allylic reduction.11e,21 The subsequent cross-
metathesis with isobutene using the HoveydaeGrubbs second
generation catalyst produced a third prenyl group at C7.17,22 Then,
34 was oxidized to enone 35 under the conventional palladium-
mediated conditions.23
Scheme 3. Claisen rearrangementeRCM approach toward bicyclic core. Reagents and
conditions: (a) LDA, TMEDA, acetaldehyde, THF, >99%. (b) Martin sulfurane, toluene/
CH2Cl2. (c) HF$Py, pyridine, THF, 73% (two steps). (d) DMP, CH2Cl2, 90%. (e) KHMDS,
HMPA, allyl iodide, THF, 89%. (f) m-CPBA, CH2Cl2, 74%. (g) toluene, 180 ꢀC, 46%. (h)
HoveydaeGrubbs second cat., toluene, 74%.
2.2. Claisen rearrangementeintramolecular aldol cyclization
approach
Considering the problems of the RCM approach, we next chose
an intramolecular aldol cyclization to construct the bicyclo[3.3.1]
core (Scheme 4). The intramolecular aldol reaction has two main
benefits. First, protection of the prenyl groups is not required, so the
complex diastereomixture derived from the diepoxide can be
avoided. Second, the obtained product has a C4 oxygen function,
that is, useful for further oxidation at C2.
2.3. Intermolecular approach toward C2 oxidation
The oxidation of C2 was studied next, but this task proved to
be very difficult. As a first attempt, selective epoxidation of the
electron-deficient olefin was examined using model substrate 36
Scheme 4. Aldol cyclization approach.
Scheme 5. Selectivity of Claisen rearrangement.

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Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
Scheme 6. Construction of the bicyclic core. Reagents and conditions: (a) LDA, THF; NH4Cl aq, 88% (dr >33:1). (b) HF$Py, pyridine, THF. (c) DMP, CH2Cl2, 96% (two steps). (d)
NaHMDS, allyl bromide, HMPA, THF, >99%. (e) toluene, N,N-diethylaniline, 170 ꢀC, >99% (dr¼12:1). (f) (Sia)2BH, THF; H2O2 aq, NaOH aq, EtOH, 81%. (g) DMP, CH2Cl2, 91%. (h) NaOEt,
EtOH. (i) DMP, CH2Cl2, 86% (two steps). (j) (þ)-CSA, MeOH, 66% (three cycles). (k) (COCl)2, DMSO, CH2Cl2; NEt3, 95%. (l) vinylmagnesium bromide, THF, 92% (dr >33:1). (m) Ac2O,
DMAP, i-Pr2NEt, CH2Cl2, 98%. (n) Pd(PPh3)4 (20 mol %), HCO2NH4, toluene, 95%. (o) HoveydaeGrubbs second cat. (15 mol %), 2-methyl-2-butene, CH2Cl2, >99%. (p) TMSCl, NEt3,
DMAP, CH2Cl2, 84%. (q) Pd(OAc)2, DMSO, O2, >99%.
(Table 1). Conventional conditions, such as using a base and H2O2 in
the presence or absence of a phase transfer catalyst, resulted in
decomposition of the substrate. The failure would be attributed to
the instability of the substrate or the product under rather basic
conditions. In addition, catalytic epoxidation using La-BINOLe
triphenylarsine oxide complex,24 which proceeds under milder
conditions than conventional methods and sometimes shows
special reactivity toward unreactive substrates, did not work,
possibly due to the highly congested nature of the C2-position,
which is next to the quaternary carbon center.
of silyl groups were introduced to afford b-silyl ketones 38 and 39.
Although the yields were far from satisfactory, it is noteworthy that
a proper nucleophile could be introduced at the highly congested
C2-position. With the desired
b-silyl ketones in hand, Tamaoe
Fleming oxidation was examined using H2O2 as an oxidant with
some fluoride sources or bases. These conditions gave complex
mixtures, however, and the only detectable side product was 41;
the silyl group, activated by fluoride, was removed from the
substrate before oxidation, and the resulting anion attacked the
neighboring isopropyl ketone. More reactive oxidants were not
a good choice because of the prenyl group.
Table 1
Epoxidation of enone
Entry
Conditions
Results
1
2
3
4
5
6
LiOH aq, H2O2 aq, CH3CN
NaOH aq, H2O2 aq, CH3CN
TBAF, H2O2 aq, DMSO
NaOH aq, H2O2 aq, TBAB, toluene
TBHP, Triton B, toluene
decomp.
decomp.
decomp.
decomp.
decomp.
NR
(S)-BINOL, Ph3As]O, La(OiPr)3
ꢀ
TBHP, MS4 A, THF
Scheme 7. TamaoeFleming oxidation approach.
In the second attempt, we used conjugate addition of a silyl
group followed by TamaoeFleming oxidation (Scheme 7).25 It is
well known that a silyl group can be used as a masked hydroxy
functionality, and it usually attacks electrophiles in a 1,4-addition
manner. The reaction might not be very sensitive to steric factors
due to the high nucleophilicity of a silyl anion and a large atomic
radius of a silicon atom. It was also applicable in our case; two types
2.4. Intramolecular approach toward C2 oxidation
As mentioned above, one of the reasons for the failure in C2
oxidation may have been the highly congested nature of this
position. To overcome this issue, we planned to use the C1 isopropyl
ketone as a nucleophile anchor; selective formation of an isopropyl
ketone enolate, trapping it with carbon dioxide, with the resulting

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6573
nucleophilic oxygen attacking the enone. Based on this idea, not
only carbon dioxide but also isocyanates and carbon disulfide
were examined with LHMDS as a base to generate the enolate
(Table 2). Only carbon disulfide gave the desired product in high
yield, and the other reagents did not react at all. The conversion of
sulfur to oxygen was examined next. We investigated the radical
approach, Pummerer rearrangement, and addition elimination
approaches, but none of them were successful. Though further
conversion was not accomplished, this result showed clear poten-
tial for the intramolecular approach using isopropyl ketone as the
anchor.
the addition of amines produced the desired 1,4-addition products,
but the SieN bond was too labile for further transformation in the
case of allyl amine and aniline as nucleophiles (retro-Mannich re-
action occurred). Electron deficient p-trifluoromethylaniline,
however, showed different behavior (Scheme 8). Compound 36 was
treated with LHMDS in the presence of diphenyldichlorosilane, and
after formation of enol silyl ether, p-trifluoromethylaniline and
TMSCl were added. Due to its rather low nucleophilicity, 1,4-addi-
tion did not proceed in the absence of TMSCl, but the stability of the
product was moderate and tolerated under several reaction
conditions. In this case, however, the electron deficient nature of
p-trifluoromethylaniline prevented oxidation to the imine, and
attempts toward enamine formation failed under various
conditions.
Table 2
Intramolecular approach
Entry
Electrophile
Yield
1
2
3
4
CO2
NR
NR
NR
91%
EtNCO
PhNCO
CS2
Silyl dichloride was the next candidate tether; after trapping the
enolate, addition of another nucleophile, such as water or amine,
would displace the remaining chloride and consequently add to the
enone intramolecularly. The use of water as a nucleophile gave
silanol 43 in good yield, and it was relatively stable. To induce the
oxy-Michael reaction, several amine bases, strong bases, and a Pd
catalyst were tested, but 43 did not have sufficient reactivity to
produce 44, and the harsh conditions resulted in cleavage of the
silyl group (Table 3).
Scheme 8. Intramolecular addition of silyl aniline.
2.5. Successful oxidation of C2 by vinylogous Pummerer
rearrangement and completion of the total synthesis
Finally, we planned to incorporate a sulfur atom at the C2-po-
sition and hoped that subsequent Pummerer rearrangement would
give the desired oxygen function. Because intermolecular addition
of thiols to the C2-position did not proceed at all, we chose a [3,3]-
sigmatropic rearrangement of xanthate 47, which was efficiently
produced from enone 35 (Scheme 9). Thermal rearrangement of 47
proceeded cleanly, but the expected functionalization at C2 did not
occur. Instead, dithioate 48 was obtained by a [1,3] rearrange-
ment.26 This result would be due to the rather rigid skeleton of 47,
therefore unable to form a proper conformation required for the
expected [3,3]-sigmatropic rearrangement. This finding, however,
led us to attempt a vinylogous Pummerer rearrangement for the
oxidation of C2.27 The intermediate thionium cation would be
highly electrophilic, making it possible to introduce an oxygen
functionality at the C2-position.
Table 3
Intramolecular addition of silanol
Based on this hypothesis, we studied the critical vinylogous
Pummerer rearrangement intensively using sulfoxide 54 as a model
substrate (Table 4). Treatment of 54 with trifluoroacetic anhydride
in the presence of NEt3 resulted in the vinylogous Pummerer
rearrangement and normal Pummerer rearrangement proceeding
at comparable rates, thereby affording, after hydrolysis, a 1:1.1
mixture of the desired allylic alcohol 56 and enone 57 (entry 1).
Encouraged by this result, we then optimized the reaction condi-
tions. The regioselectivity was greatly influenced by the base used.
Among the bases examined, pyridine preferentially afforded 56 in
moderate selectivity (entry 2; 56/57¼3:1). The selectivity was im-
proved by increasing the steric bulkiness of the pyridine-derived
bases. 2,6-Di-tert-butylpyridine was finally found to be the opti-
mum base, giving 56 as the major product with a selectivity of 8.3:1
(entry 4).
Entry
Conditions
Results
1
2
3
4
5
DBU (20 mol %), THF, rt
36
NR
NR
36
i-Pr2NEt (20 mol %), THF, 50 ꢀ
C
C
i-Pr2NH (20 mol %), THF, 50 ꢀ
KHMDS (20 mol %), THF, ꢁ10 ꢀC
(CH3CN)2PdCl2 (50 mol %), CH2Cl2, rt.
decomp.
The addition of nitrogen instead of oxygen is an alternative
pathway because of its higher nucleophilicity. If nitrogen is
incorporated at C2, conversion to oxygen would be possible via
enamine or imine formation followed by hydrolysis. As expected,

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Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
Scheme 9. Completion of the total synthesis. Reagents and conditions: (a) NaBH4, MeOH, 95% (dr >33:1). (b) CS2, NaH, THF; MeI, >99%. (c) toluene, 150 ꢀC. (d) EtSLi, THF; MeI, NEt3,
98% (two steps). (e) NaBO3$4H2O, AcOH (dr¼1.3:1), 95%. (f) TFAA, 2,6-di-tert-butylpyridine, CH2Cl2, ꢁ40 ꢀC; H2O, 65% (dr >33:1). (g) H2O2, HFIP, 87% (dr¼9:1). (h) DMP, CH2Cl2, 86%.
(i) Amberlyst 15DRY, toluene, 55%. (j) LiH, allyl alcohol, 67%. (k) Pd2dba3$CHCl3 (10 mol %), (S)-tol-BINAP (20 mol %), THF; Ac2O, pyridine, 50%. (l) HoveydaeGrubbs second cat.
(15 mol %), 2-methyl-2-butene, CH2Cl2, 34%. (m) K2CO3, MeOH, 94%.
presumably proceeded via a
p-allylepalladium intermediate, and
Table 4
Selectivity of the vinylogous Pummerer rearrangement
enol acetate 53 was obtained in 50% yield after O-acetylation in
a one pot reaction. It is noteworthy that thermal, microwave-
assisted, and Lewis acid-mediated Claisen rearrangement of 52
only produced a trace amount of the product (giving either complex
mixtures or no product). Finally, cross-metathesis to introduce the
prenyl group at C3, and methanolysis of the acetate under basic
conditions completed the total synthesis of ent-hyperforin (ent-1).
1H, 13C NMR, and IR spectroscopic data as well as mass spectro-
metric data were all identical with the reported values. The optical
rotation of synthesized ent-1 was opposite to that of the natural
23
isomer ([
a
]
ꢁ36.8 (c 0.38, EtOH); lit. þ41)4 (Fig. 2).
D
3. Conclusion
In conclusion, we achieved the first catalytic asymmetric total
synthesis of ent-hyperforin. The key reactions were: (1) an iron-
catalyzed asymmetric DielseAlder reaction to produce contiguous
C7 and C8 stereocenters; (2) a stereoselective Claisen rearrange-
ment to produce the bridgehead quaternary carbon atom at C1; (3)
an intramolecular aldol reaction to produce the highly substituted
bicyclic core; and (4) a vinylogous Pummerer rearrangement to
install the oxygen functionality at the C2-position. These basic
methods are applicable to the asymmetric synthesis of other PPAPs
and analogues of hyperforin. Further improvements in the
efficiency of the reactions, however, may be necessary for such
applications. Studies are ongoing and will be reported in due
course.
Entry
Solvent
Base
56:57a
1
Toluene
Toluene
CH2Cl2
CH2Cl2
Et3N
Pyridine
2,6-Lutidine
2,6-Di-tert-butylpyridine
1:1.1
3.0:1
3.6:1
8.3:1
2b
3
4c
a
Determined by 1H NMR spectroscopy.
5 equiv of TFAA were used.
3 equiv of TFAA were used.
b
c
Having optimized the vinylogous Pummerer rearrangement
with model substrate 54, we applied the conditions to the actual
substrate 49, which was synthesized from 48 through thiolysis
followed by S-methylation and S-oxidation28 (Scheme 9). As
expected, the vinylogous Pummerer rearrangement of 49 pro-
ceeded preferentially (4:1) to the normal Pummerer rearrangement
under the optimized conditions, thereby providing the desired
allylic alcohol 50 in 65% yield. The final task was to install the prenyl
group at C3. S-Oxidation using H2O2 in hexafluoroisopropanol29
followed by DesseMartin oxidation of the allylic alcohol afforded
sulfoxide 51. After deprotection of the homoprenyl group through
elimination of the methoxy group by treatment with an acidic
resin, an addition/elimination sequence using allyl alcohol afforded
allyl ether 52. The catalyzed intramolecular allyl transfer
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer. NMR spectra were recorded
on a JEOL JNM-LA500 or ECX500 spectrometer, operating at
500 MHz for 1H NMR and 125.65 MHz for 13C NMR. Chemical shifts
were reported in parts per million on the d scale relative to residual
CHCl3
(
d
¼7.26 for 1H NMR and
d
¼77.0 for 13C NMR) as an internal

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6575
Figure 2. 1H NMR of hyperforin.
reference. Optical rotations were measured on a JASCO P-1010
4.1.1. (7R,8S)-S-Ethyl
8-methyl-8-(4-methylpent-3-enyl)-9-(triiso-
polarimeter. ESI mass spectra were measured on Waters-ZQ4000 or
JEOL The AccuTOF JMS-T100LC. EI mass spectra were measured on
a JEOL JMS-BU20 GCmate. Column chromatography was performed
with silica gel Merck 60 (230e400 mesh ASTM) or silica gel 60 N
propylsilyloxy)-1-((triisopropylsilyloxy)methyl)cyclohex-1-
enecarbothioate.
(KANTO CHEMICAL, spherical, neutral, 40e100 mm). Reactions were
carried out in dry solvents under an argon atmosphere, unless
otherwise stated. Dry tetrahydrofuran (THF) was purchased from
Kanto Chemical. Co., Inc., or freshly distilled from Ph2COeNa. Other
reagents were used as received from commercial sources, unless
otherwise stated. Carbon numbering was shown in Figure 3.
To a solution of EtSH (2.1 ml, 28.5 mmol) in THF (81 ml) was
added n-BuLi (11.9 ml,19.0 mmol; 1.59 M in n-hexane) at 0 ꢀC. After
being stirred at the same temperature for 50 min, the resulting
mixture was transferred to a solution of 8 (6.18 g, 9.51 mmol) in THF
(63 ml) at 0 ꢀC. The reaction was stirred at the same temperature
for 30 min, and then quenched with saturated NH4Cl aq. The or-
ganic layer was separated and the aqueous layer was further
extracted twice with diethyl ether. The combined organic layer was
washed with water and brine, dried over Na2SO4, and concentrated
to give a yellow oil. The residue was purified by column chroma-
tography (SiO2; EtOAc/hexane¼1/50) to give thiol ester (5.68 g,
9.10 mmol, 96% yield) as a colorless oil. 1H NMR (C6D6)
d: 5.34 (t,
Figure 3. Numbering of hyperforin.
J¼6.4 Hz, C17e1H), 5.09 (d, J¼11.3 Hz, C10e1H), 4.42 (d, J¼11.3 Hz,

6576
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
23
C10e1H), 2.87 (dd, J¼2.5, 11.3 Hz, C7e1H), 2.65e2.75 (m,
SCH2CH3e2H), 2.46e2.54 (m, C5e1H), 1.87e2.19 (m, C5e1H,
C6e2H, C15e1H, 16e2H), 1.75e1.80 (m, C15e1H), 1.69 (s, C20e3H),
1.68 (s, C19e3H), 1.63 (s, C14e3H), 1.14e1.17 (m, OTIPSe21H),
1.06e1.09 (m, OTIPSe21H), 1.05 (t, J¼7.4 Hz, SCH2CH3e3H); 13C
C
35H70O4Si2 (Mþ): 610.4813, Found: 610.4808; [
CH2Cl2) (87% ee).
a
]
ꢁ25.1 (c 0.87,
D
4.1.4. (7R,8S)-1-(Hydroxymethyl)-7-((methoxymethoxy)methyl)-8-
methyl-8-(4-methylpent-3-enyl)cyclohexanone (13). To a solution of
12 (3.34 g, 5.47 mmol) and acetic acid (3.3 ml, 54.7 mmol) in THF
(60 ml) was added TBAF (27 ml, 27 mmol; 1 M in THF) at 0 ꢀC. The
resulting mixture was stirred at room temperature for 50 h. The
reaction was quenched with water, and the organic layer was
separated. The aqueous layer was further extracted twice with
EtOAc. The combined organic layer was washed with water and
brine, dried over Na2SO4, and concentrated to give a yellow oil,
which was passed through a short column chromatography (SiO2;
EtOAc/hexane¼1/1). The products were used in the next step
without further purification.
NMR (C6D6) d: 198.7, 145.8, 129.5, 124.2, 118.5, 58.1, 54.1, 39.8, 37.2,
28.7, 24.6, 23.8, 22.8, 22.2, 21.1, 17.2, 17.1, 13.8, 12.6, 11.3; IR (neat,
cmꢁ1):
n
1694; MS (EI) m/z 624 (Mþ); HRMS (EI) calcd for
C35H68O3SSi2 (Mþ): 624.4428, Found: 624.4421; [
CH2Cl2) (87% ee).
a]
25 ꢁ24.2 (c 1.30,
D
4.1.2. ((7R,8S)-8-Methyl-8-(4-methylpent-3-enyl)-9-(triisopropylsi-
lyloxy)-1-((triisopropylsilyloxy)methyl)cyclohex-1-enyl)methanol.
To a solution of the residue and pyridine (5 ml) in THF (80 ml)
was added HFePy (10 ml) slowly at 0 ꢀC. The mixture was stirred at
room temperature for 22 h. The reaction was poured into ice cooled
25% NH3 aq slowly to be neutralized. The organic layer was sepa-
rated and the aqueous layer was further extracted twice with
EtOAc. The combined organic layer was washed with water and
brine, dried over Na2SO4, and concentrated to give a yellow oil. The
residue was purified by column chromatography (SiO2; EtOAc/
A solution of thiol ester (5.68 g, 9.10 mmol) in THF (18 ml) was
added to a suspension of LAH (1.73 g, 45.5 mmol) in THF (35 ml) at
0 ꢀC. The reaction was stirred at the same temperature for 45 min,
and quenched by the successive addition of water (1.7 ml), 15%
NaOH aq (1.7 ml), and water (5.1 ml). The resulting mixture was
vigorously stirred for 30 min at room temperature. The white
suspension was filtered through a pad of Celite, washed with
CH2Cl2, and concentrated to give a pale yellow oil. The residue was
purified by column chromatography (SiO2; EtOAc/hexane¼1/15 to
1/10) to give alcohol (5.23 g, 9.22 mmol, 100% yield) as a white
hexane¼1/3) to give 13-
a
(
a
-hydroxymethyl: 742 mg, 2.49 mmol,
46% yield) and 13-b (b-hydroxymethyl: 729 mg, 2.45 mmol, 45%) as
a colorless oil.
4.1.4.1. (1S)-a-Hydroxymethyl (13-a d: 5.01 (t,
). 1H NMR (CDCl3)
J¼7.3 Hz, C17e1H), 4.56 (d, J¼6.6 Hz, OCH2OCH3e1H), 4.54 (d,
J¼6.6 Hz, OCH2OCH3e1H), 3.89 (dd, J¼9.2, 11.6 Hz, C10e1H), 3.63
(dd, J¼3.7, 9.4 Hz, C21e1H), 3.52 (dd, J¼3.2, 11.6 Hz, C10e1H), 3.29
(s, OCH2OCH3e3H), 3.20 (dd, J¼8.6, 9.4 Hz, C21e1H), 2.62 (dd,
J¼3.2, 9.2 Hz, C1e1H), 2.27e2.39 (m, C5e2H), 2.13e2.25 (m,
C6e1H, C7e1H), 2.04e2.12 (m, C16e1H), 1.89e1.97 (m, C16e1H),
1.57e1.63 (m, C6e1H, C20e3H), 1.56 (s, C19e3H), 1.40 (ddd, J¼4.9,
12.6,15.3 Hz, C15e1H),1.27 (ddd, J¼4.9,12.9,15.3 Hz, C15e1H), 0.63
solid. 1H NMR (C6D6)
d: 5.29 (t, J¼6.1 Hz, C17e1H), 5.10 (d,
J¼11.2 Hz, C10e1H), 4.42 (d, J¼11.2 Hz, C10e1H), 3.68 (dd, J¼3.4,
10.1 Hz, C21e1H), 3.21 (dd, J¼9.2, 10.1 Hz, C21e1H), 2.02e2.15 (m,
C5e1H, C7e1H, C16e2H), 1.87e2.00 (m, C5e1H, 6e1H), 1.60e1.79
(m, C6e1H, 15e2H), 1.69 (s, C20e3H), 1.63 (s, C19e3H), 1.29 (s,
C14e3H), 1.17e1.20 (m, OTIPSe21H), 1.07e1.11 (m, OTIPSe21H);
(s, C14e3H); 13C NMR (CDCl3)
d: 214.0, 130.9, 122.3, 95.5, 66.4, 56.7,
13C NMR (C6D6)
d
: 146.9, 129.4, 119.0, 61.7, 58.3, 40.9, 38.4, 36.7,
29.1, 24.7, 22.6, 22.6, 20.2, 17.4, 17.2, 16.6, 12.8, 11.4; IR (neat, cmꢁ1):
56.5, 54.1, 41.4, 40.3, 40.1, 35.5, 25.3, 24.6, 20.1, 17.4, 16.5; IR (neat,
cmꢁ1):
n
3487, 1707; MS (EI) m/z 298 (Mþ); HRMS (EI) calcd for
n
3307, 1647; MS (EI) m/z 566 (Mþ); HRMS (EI) calcd for
C17H30O4 (Mþ): 298.2144, Found: 298.2141; [
CHCl3) (96% ee).
a
]
D
14.9 (c 1.53,
23
C33H66O3Si2 (Mþ): 566.4550, Found: 566.4549; [
CH2Cl2) (87% ee).
a]
25 ꢁ25.7 (c 0.86,
D
4.1.4.2. (1R)-b-Hydroxymethyl (13-b d: 4.99 (t,
). 1H NMR (CDCl3)
4.1.3. Triisopropyl((7R,8S)-7-((methoxymethoxy)methyl)-8-methyl-
8-(4-methylpent-3-enyl)-1-((triisopropylsilyloxy)methyl)cyclohex-9-
enyloxy)silane (12). To a solution of alcohol (5.23 g, 9.2 mmol) in
CH2Cl2 (100 ml) were added i-Pr2EtN (4.88 ml, 28 mmol) and
MOMCl (2.13 ml, 28 mmol) at 0 ꢀC. The resulting mixture was
gradually warmed to room temperature, and stirred for 15.5 h. The
reaction was quenched with water, and the organic layer was
separated. The aqueous layer was further extracted twice with
diethyl ether. The combined organic layer was washed with water
and brine, dried over Na2SO4, and concentrated to give a yellow oil.
The residue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/30) to give 12 (5.29 g, 8.66 mmol, 94% yield) as a color-
J¼7.0 Hz, C17e1H), 4.66 (d, J¼6.5 Hz, OCH2OCH3e1H), 4.63 (d,
J¼6.5 Hz, OCH2OCH3e1H), 4.02 (dd, J¼9.8, 11.0 Hz, C10e1H),
3.70e3.80 (m, C21e2H), 3.57 (dd, J¼2.8, 11.0 Hz, C10e1H), 3.37 (s,
OCH2OCH3e3H), 2.58 (dd, J¼2.8, 9.8 Hz, C1e1H), 2.40e2.51 (m,
C5e1H), 2.33e2.40 (m, C5e1H), 1.94e2.10 (m, C6e2H, C7e1H),
1.76e1.92 (m, C16e2H), 1.64 (s, C20e3H), 1.55 (s, C19e3H), 1.29
(ddd, J¼5.2, 12.5, 13.8 Hz, C15e1H), 1.15 (ddd, J¼4.6, 12.5, 12.5 Hz,
15e1H), 1.09 (s, C14e3H); 13C NMR (CDCl3)
d
:213.3, 130.6, 122.6,
95.5, 65.9, 58.9, 57.3, 54.2, 40.6, 38.5, 36.4, 35.6, 24.5, 23.0, 21.2,
20.3, 16.4; IR (neat, cmꢁ1): 3446, 1704; MS (EI) m/z 298 (Mþ);
HRMS (EI) calcd for C17H30O4 (Mþ): 298.2144, Found: 298.2144;
23 21.8 (c 2.02, CHCl3) (96% ee).
n
[a]
D
less oil. 1H NMR (C6D6)
d: 5.31 (t, J¼7.0 Hz, C17e1H), 5.11 (d,
J¼11.0 Hz, C10e1H), 4.54 (d, J¼6.4 Hz, OCH2OCH3e1H), 4.51 (d,
J¼6.4 Hz, OCH2OCH3e1H), 4.44 (d, J¼11.0 Hz, C10e1H), 3.75 (dd,
J¼3.4, 9.2 Hz, C21e1H), 3.31 (dd, J¼9.2, 9.2 Hz, C21e1H), 3.21 (s,
OCH2OCH3e3H), 2.18e2.26 (m, C5e1H), 2.06e2.18 (m, C5e1H,
C6e1H, C16e2H), 1.87e2.03 (m, C6e1H, C7e1H, C15e1H),
1.77e1.84 (m, C15e1H), 1.68 (s, C20e3H), 1.63 (s, C19e3H), 1.30 (s,
C14e3H), 1.18e1.20 (m, OTIPSe21H), 1.07e1.11 (m, OTIPSe21H);
4.1.5. (1S,7R,8S)-1-(1-Hydroxy-2-methylpropyl)-7-((methoxy-
methoxy)methyl)-8-methyl-8-(4-methylpent-3-enyl)cyclohexanone
(15). To a solution of 13-a (10.4 g, 34.9 mmol) in CH2Cl2 (230 ml)
were added NEt3 (14.7 ml, 105 mmol) and TMSCl (8.9 ml,
69.8 mmol) at 0 ꢀC. The mixture was stirred at the same tempera-
ture for 30 min. The reaction was quenched with NEt3 (15 ml) and
water (60 ml). The organic layer was separated and the aqueous
layer was further extracted with diethyl ether. The combined or-
ganic layer was washed with water and brine, dried over Na2SO4,
13C NMR (C6D6)
38.5, 36.6, 29.2, 24.7, 22.7, 22.6, 20.9, 17.4, 17.2, 16.6, 12.8, 11.4; IR
(neat, cmꢁ1): 1646; MS (EI) m/z 610 (Mþ); HRMS (EI) calcd for
d:146.8, 129.4, 124.6, 119.1, 95.8, 67.5, 58.4, 38.7,
n

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6577
and concentrated to give a pale yellow oil. The obtained TMS ether
was used in next step without purification.
60.6 mmol) at 0 ꢀC. The mixture was stirred at the same tempera-
ture for 2 h, and quenched with water. The organic layer was sep-
arated, and the aqueous layer was extracted with diethyl ether. The
combined organic layer was washed twice with water and brine,
dried over Na2SO4, and concentrated to give a yellow oil. The res-
idue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/9) to give TMS ether (7.85 g, 19.0 mmol, 94% yield, a 1:5
diastereomixture derived from Ce10) as a pale yellow oil.
To a solution of the residue in CH2Cl2 (230 ml) were added
i-Pr2NEt (21.2 ml, 122 mmol) and TIPSOTf (23.5 ml, 87.3 mmol)
at ꢁ78 ꢀC over 10 min. The mixture was stirred for 15 min at the
same temperature, and additionally for 12 h at 0 ꢀC. The reaction
was quenched with NEt3 (20 ml) and water (60 ml), and the organic
layer was separated. The aqueous layer was further extracted with
diethyl ether. The combined organic layer was washed with water
and brine, dried over Na2SO4, and concentrated to give pale a yel-
low oil. The obtained TIPS enol ether was used in next step without
purification.
4.1.7. (1S,5R,7R,8S)-7-((Methoxymethoxy)methyl)-8-methyl-1-(2-
methyl-1-(trimethylsilyloxy)propyl)-5-(3-methylbut-2-enyl)-8-(4-
methylpent-3-enyl)cyclohexanone (16). To a solution of N,N-diiso-
To a solution of the residue in MeOH (350 ml) was added K2CO3
(2.41 g,17.4 mmol) at 0 ꢀC, and the mixture was stirred for 1 h at the
same temperature. Additional K2CO3 (2.41 g,17.4 mmol) was added,
and the mixture was stirred for 5.3 h. The reaction was quenched
with saturated NH4Cl aq, and the organic layer was separated. The
aqueous layer was extracted twice with diethyl ether. The combined
organic layer was washed with water and brine, dried over Na2SO4,
and concentrated to give 14 as a yellow oil. The obtained alcohol 14
was used in next step without further purification.
propylamine (659 ml, 4.70 mmol) in THF (18 ml) was added n-BuLi
(2.7 ml, 4.28 mmol; 1.5 M in n-hexane) at 0 ꢀC. The mixture was
stirred for 30 min at the same temperature. This LDA solution was
added to a solution of TMS ether (353 mg, 855 mmol) in THF (21 ml)
at ꢁ78 ꢀC. After being stirred at 0 ꢀC for 40 min, HMPA (2.23 ml,
12.8 mmol) and prenyl bromide (988 ml, 8.55 mmol) were added at
ꢁ78 ꢀC and the mixture was stirred at 0 ꢀC for 25 min. The reaction
was quenched with pH 6.9 buffer and stirred for 20 min at 0 ꢀC and
additionally for 20 min at room temperature. The organic layer was
separated, and the aqueous layer was further extracted with diethyl
ether twice. The combined organic layer was washed with water
and brine, dried over Na2SO4, and concentrated to give a yellow oil.
The residue was purified by column chromatography (SiO2; EtOAc/
ꢀ
To a solution of 14 and MS 4 A (19.4 g) in CH2Cl2 (210 ml) and
CH3CN (22 ml) were added NMO (12.3 g, 105 ml) and TPAP (1.23 g,
3.29 mmol) at 0 ꢀC. The mixture was stirred for 1 h at the same
temperature and additionally for 1.5 h at room temperature. The
mixture was filtered through a short pad silica gel, which was
washed with CH2Cl2. The collected organic layer was concentrated
to give a pale yellow oil. The obtained aldehyde was used in next
step without further purification.
hexane¼1/100 to 1/40 to 1/30) to give 16 (365 mg, 759
mmol;
89% yield, a 9:1 diastereomixture derived from Ce10) as a pale
yellow oil.
Major isomer. 1H NMR (CDCl3)
d: 5.05e5.10 (m, C27e1H),
To a solution of the residue in THF (230 ml) were added 2-
bromopropane (9.9 ml, 105 mmol) and Li wire (1.2 g, 175 mmol) at
0 ꢀC, and the mixture was stirred vigorously at the same temper-
ature. After 2.5 h, additional 2-bromopropane (1.8 ml, 19.1 mmol)
and Li wire (720 mg, 104 mmol) were added. After being stirred for
3 h, Li wire (225 mg, 32.4 mmol) was added again, and the mixture
was stirred for 30 min. The reaction was quenched with MeOH
(30 ml), stirred for 30 min at 0 ꢀC. After addition of saturated NH4Cl
aq, the organic layer was separated, washed with water and brine.
The aqueous layer was extracted twice with diethyl ether. The
combined organic layer was washed with water and brine, dried
over Na2SO4, and concentrated to give a pale yellow oil (a 1:5
diastereomixture derived from C-10). The obtained alcohol was
used in next step without further purification.
4.96e5.01 (m, C17e1H), 4.62 (d, J¼6.7 Hz, OCH2OCH3e1H), 4.60 (d,
J¼6.7 Hz, OCH2OCH3e1H), 4.21 (dd, J¼2.9, 8.0 Hz, C10e1H), 3.71
(dd, J¼3.5, 9.2 Hz, C21e1H), 3.36 (s, OCH2OCH3e3H), 3.27 (dd,
J¼9.2, 9.2 Hz, C21e1H), 2.80 (d, J¼8.0 Hz, C1e1H), 2.35e2.44 (m,
C5e1H, C11e1H), 2.15e2.24 (m, C6e1H, C7e1H), 2.04e2.10 (m,
C26e2H), 1.95e2.00 (m, C16e2H), 1.77e1.86 (m, C6e1H), 1.69 (s,
C30e3H), 1.66 (s, C20e3H), 1.64 (s, C29e3H), 1.62 (s, C19e3H),
1.39e1.49 (m, C15e1H), 1.23e1.35 (m, C15e1H), 0.93 (d, J¼6.9 Hz,
C12e3H), 0.86 (s, C14e3H), 0.79(d, J¼6.9 Hz, C13e3H), 0.15 (s,
OTMSe9H); 13C NMR (CDCl3)
d: 216.5, 133.6, 131.2, 124.3, 120.9,
96.6, 75.7, 68.0, 55.2, 54.8, 49.9, 45.1, 38.4, 38.1, 33.8, 31.5, 29.8, 25.7,
25.7, 22.3, 20.9, 18.6, 18.0, 17.7, 16.4, 1.3; IR (neat, cmꢁ1):
n 1703; MS
(ESI) m/z 503 (MþNa)þ; HRMS (ESI) calcd for C28H52O4Si (MþNa)þ:
503.3533, Found: 503.3530; [
a
]
26 ꢁ70.2(c 1.07, CHCl3) (80% ee).
D
To a solution of the residue in THF (350 ml) were added AcOH
(20.0 ml, 349 mmol) and TBAF (175 ml, 175 mmol; 1.0 M in THF) at
0 ꢀC over 30 min. The mixture was stirred for 12.5 h at the same
temperature. The reaction was quenched with water at 0 ꢀC. After
removal of organic solvent by evaporation, the aqueous layer was
extracted three times with diethyl ether. The combined organic
layer was washed with saturated NaHCO3 aq, dried over Na2SO4,
and concentrated to give a pale yellow oil. The residue was purified
by column chromatography (SiO2; EtOAc/hexane¼1/10 to 1/4) to
give 15 (6.94 g, 20.4 mmol; 58% yield for six steps, a 1:5 diaster-
eomixture derived from C-10) as a pale yellow oil.
4.1.8. (1S,5S,7R,8S)-7-Methoxymethoxymethyl-8-methyl-5-(3-
methyl-but-2-enyl)-8-(4-methyl-pent-3-enyl)-1-(2-methyl-1-trime-
thylsilanyloxy-propyl)-cyclohexanone (28). To a solution of N,N-
diisopropylamine (2.2 ml, 15.5 mmol) in THF (62.9 ml) was added
n-BuLi (9.4 ml, 14.9 mmol; 1.59 M in n-hexane) at 0 ꢀC. The mixture
was stirred for 35 min at the same temperature. The mixture was
cooled to ꢁ78 ꢀC, and then 16 (1.49 g, 3.10 mmol) in THF (20 ml)
was added over 15 min. The mixture was stirred for 80 min at 0 ꢀC.
The reaction was quenched with saturated NH4Cl aq and the or-
ganic layer was separated. The aqueous layer was further extracted
twice with EtOAc. The combined organic layer was washed with
water and brine, dried over Na2SO4, and concentrated to give a pale
yellow oil. The residue was purified by column chromatography
(SiO2; EtOAc/hexane¼1/25) to give 28 (1.31 g, 2.72 mmol; 88%
yield, a 9:1 diastereomixture) as a pale yellow oil. Major isomer. 1H
4.1.6. (1S,7R,8S)-7-((Methoxymethoxy)methyl)-8-methyl-1-(2-
methyl-1-(trimethylsilyloxy)propyl)-8-(4-methylpent-3-enyl)
cyclohexanone.
NMR (CDCl3)
d
: 5.04e5.08 (m, C17e1H, C27e1H), 4.61 (d, J¼6.4 Hz,
OCH2OCH3e1H), 4.59 (d, J¼6.4 Hz, OCH2OCH3e1H), 4.39 (dd, J¼3.7,
8.0 Hz, C10e1H), 3.72 (dd, J¼3.1, 9.5 Hz, C21e1H), 3.35 (s,
OCH2OCH3e3H), 3.17 (dd, J¼9.2, 9.5 Hz, C21e1H), 2.69 (d, J¼8.0 Hz,
C1e1H), 2.30e2.38 (m, C5e1H, C11e1H), 2.16e2.30 (m, C7e1H,
C26e2H), 2.02e2.14 (m, C16e2H), 1.93 (ddd, J¼7.4, 7.4, 14.7 Hz,
C6e1H), 1.69 (s, C30e3H), 1.66 (s, C20e3H), 1.63 (s, C29e3H), 1.59
To a solution of 15 (6.86 g, 20.2 mmol) in DMF (168 ml) were
added imidazole (6.88 g, 101 mmol) and TMSCl (7.75 ml,

6578
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
(s, C19e3H), 1.46e1.54 (m, C6e1H), 1.19e1.28 (m, C15e2H), 0.92 (d,
J¼7.0 Hz, C12e3H), 0.78(d, J¼7.0 Hz, C13e3H), 0.74 (s, C14e3H),
hexane¼1/30) to give 29 (4.10 g, 9.18 mmol; 100% yield) as a pale
yellow oil. 1H NMR (CDCl3)
: 5.85 (tdd, J¼5.8, 10.3, 17.2 Hz,
d
0.14 (s, OTMSe9H); 13C NMR (CDCl3)
d
: 214.3, 132.7, 131.0, 124.4,
OCH2CHCH2e1H), 5.20 (d, J¼17.2 Hz, OCH2CHCH2e1H), 5.09e5.31
(m, OCH2CHCH2e1H, C27e1H), 5.03e5.09 (m, C17e1H), 4.60 (d,
J¼6.9 Hz, OCH2OCH3e1H), 4.59 (d, J¼6.9 Hz, OCH2OCH3e1H), 4.19
(dd, J¼5.8, 12.6 Hz, OCH2CHCH2e1H), 3.97 (dd, J¼5.8, 12.6 Hz,
OCH2CHCH2e1H), 3.63 (dd, J¼2.9, 9.2 Hz, C21e1H), 3.33 (s,
OCH2OCH3e3H), 3.17 (dd, J¼9.2, 9.8 Hz, C21e1H), 2.75 (sep,
J¼6.9 Hz, C11e1H), 2.39e2.47(m, C1e1H), 2.27e2.34 (m, C7e1H),
1.92e2.05 (m, C6e1H, C16e1H, C26e2H4H), 1.76e1.84 (m,
C16e1H), 1.68 (s, C30e3H), 1.63 (s, C20e3H), 1.59 (s, C29e3H), 1.58
(s, C19e3H), 1.23e1.44 (m, C6e1H, C15e2H), 1.09 (d, J¼6.9 Hz,
C12e3H), 1.03 (d, J¼6.9 Hz, C13e3H), 0.94 (s, C14e3H); 13C NMR
122.0, 96.7, 75.3, 68.0, 57.0, 55.2, 51.6, 46.2, 42.5, 36.5, 34.9, 34.4,
27.7, 25.8, 25.7, 22.3, 20.0, 18.1, 17.8, 17.7, 17.4, 1.1; IR (neat, cmꢁ1):
n
1709; MS (ESI) m/z 503 (MþNa)þ; HRMS (ESI) calcd for C28H52O4Si
25
(MþNa)þ: 503.3533, Found: 503.3535; [
a
]
ꢁ45.8(c 1.24, CHCl3)
D
(80% ee).
4.1.9. (1S,5S,7R,8S)-1-Isobutyryl-7-((methoxymethoxy)methyl)-8-
methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)
cyclohexanone.
(CDCl3)
d: 212.5, 157.2, 133.8, 133.1, 133.0, 130.9, 124.7, 121.5, 117.2,
96.6, 71.8, 68.0, 55.1, 42.5, 39.6, 38.6, 37.7, 35.9, 30.2, 28.1, 25.8, 25.6,
23.4, 23.0, 18.8, 18.7, 17.9, 17.5; IR (neat, cmꢁ1):
n 1687; MS (ESI) m/z
469 (MþNa)þ; HRMS (ESI) calcd for C28H46O4 (MþNa)þ: 469.3294,
31
To a solution of 28 (5.64 g, 11.7 mmol) in THF (117 ml) was added
pyridine (11.7 ml, 145 mmol) and HFePy (23.4 ml) at 0 ꢀC. The
mixture was stirred at the same temperature for 1.5 h, and then
poured into ice cooled 25% NH3 aq to be neutralized. The organic
phase was separated and the aqueous phase was further extracted
twice with EtOAc. The combined organic layer was washed twice
with saturated NaHCO3 and brine, dried over Na2SO4, and con-
centrated to give a pale yellow oil, which was used in next step
without further purification.
Found: 469.3283; [
a]
ꢁ9.3 (c 1.01, CHCl3) (80% ee).
D
4.1.11. (1S,5S,7R,8S)-1-Allyl-1-isobutyryl-7-((methoxymethoxy)
methyl)-8-methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)
cyclohexanone (30). A solution of 29 (135 mg, 302 mol) and N,N-
m
diethylanilline (5.4 l, 30.2 mol) in toluene (600 ml) in sealed tube
m
m
was heated at 170 ꢀC for 7 h. The mixture was cooled to room
temperature and diluted with diethyl ether. The mixture was
washed with 1 M HCl aq, saturated NaHCO3 aq and brine, dried over
Na2SO4, and concentrated to give a yellow oil. The residue was
purified by column chromatography (SiO2; EtOAc/hexane¼140 to
To a solution of crude mixture in CH2Cl2 (117 ml) was added
DesseMartin periodinane (9.93 g, 23.4 mmol) at 0 ꢀC and stirred at
the same temperature. After being stirred for 35 min, DesseMartin
periodinane (993 mg, 2.34 mmol) was added again and stirred for
15 min. The reaction was quenched with Na2S2O3 aq and the or-
ganic layer was separated. The aqueous phase was further extracted
twice with diethyl ether. The combined organic layer was washed
twice with saturated NaHCO3 aq and brine, dried over Na2SO4, and
concentrated to give a pale yellow oil. The residue was purified by
column chromatography (SiO2; EtOAc/hexane¼1/15) to give dike-
tone (4.58 g, 113 mmol; 96% yield for two steps) as a pale yellow oil.
30) to give 30 (137 mg, 307
m
mol, 100% yield; dr¼12:1) as a color-
less oil. 1H NMR (CDCl3)
d: 5.13e5.25 (m, C3e1H), 5.07e5.13 (m,
C27e1H), 5.00e5.05 (m, C17e1H), 4.89e4.98 (m, C4e2H), 4.66 (d,
J¼6.7 Hz, OCH2OCH3e1H), 4.63 (d, J¼6.7 Hz, OCH2OCH3e1H), 3.72
(dd, J¼2.8, 9.2 Hz, C21e1H), 3.38 (s, OCH2OCH3e3H), 3.29e3.32 (m,
C2e1H, C21e1H), 2.99 (sep, J¼6.5 Hz, C11e1H), 2.33e2.50 (m,
C2e1H, C5e1H, C6e1H, C7e1H, C26e1H), 1.92e2.13 (m, C16e2H,
C26e1H), 1.68 (s, C30e3H), 1.66 (s, C20e3H), 1.61 (s, C29e3H), 1.59
(s, C19e3H), 1.25e1.44 (m, C6e1H, C15e2H), 1.18 (d, J¼6.5 Hz,
C12e3H), 1.08 (d, J¼6.5 Hz, C13e3H), 0.92 (s, C14e3H); 13C NMR
1H NMR (CDCl3);
d: 5.06e5.12 (m, C27e1H), 4.95e5.01 (m,
C17e1H), 4.63 (d, J¼6.4 Hz, OCH2OCH3e1H), 4.61 (d, J¼6.4 Hz,
OCH2OCH3e1H), 3.87 (s, C1e1H), 3.69 (dd, J¼3.4, 9.5 Hz, 21e1H),
3.36 (s, OCH2OCH3e3H), 3.24 (dd, J¼9.5, 9.5, C21e1H), 2.35e2.51
(m, C5e1H, C11e1H, C26e2H), 2.09e2.20 (m, C6e1H, C7e1H), 1.97
(ddd, J¼8.0, 8.0, 15.6 Hz, C16e1H), 1.75e1.84 (m, C16e1H), 1.68 (s,
C30e3H), 1.66 (s, C20e3H), 1.60 (s, C29e3H), 1.58 (s, C19e3H),
1.49e1.57 (m, C6e1H), 1.30e1.48 (m, C15e2H), 1.07 (d, J¼6.7 Hz,
C12e3H), 1.03 (d, J¼6.7 Hz, C13e3H), 1.02 (s, C14e3H); 13C NMR
(CDCl3)
d: 216.7, 211.7, 133.9, 133.6, 132.1, 124.5, 122.0, 117.8, 97.1,
75.9, 69.4, 55.7, 48.1, 45.0, 41.4, 40.7, 36.7, 36.3, 32.4, 28.0, 26.2, 26.0,
24.3, 21.9, 20.8, 19.9, 18.1, 18.0; IR (neat, cmꢁ1):
n 1709, 1690; MS
(ESI) m/z 469 (MþNa)þ; HRMS (ESI) calcd for C28H46O4 (MþNa)þ:
469.3294, Found: 469.3286; [
a]
27 þ8.59 (c 1.31, CHCl3) (80% ee).
D
4.1.12. (1S,5S,7R,8S)-1-(3-Hydroxypropyl)-1-isobutyryl-7-((methoxy-
methoxy)methyl)-8-methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-
3-enyl)cyclohexanone.
(CDCl3) d: 210.6, 209.5, 133.3, 131.9, 123.4, 121.3, 96.7, 67.4, 66.5,
55.2, 50.8, 44.6, 42.7, 41.9, 36.8, 33.1, 27.5, 25.8, 25.6, 21.9, 18.5, 18.0,
17.8, 17.6; IR (neat, cmꢁ1):
n
1724, 1703; MS (ESI) m/z 429 (MþNa)þ;
HRMS (ESI) calcd for C25H42O4 (MþNa)þ: 429.2981, Found:
25
429.2971; [
a
]
ꢁ59.6 (c 1.20, CHCl3) (80% ee).
D
4.1.10. 1-((5S,7R,8S)-2-(Allyloxy)-7-((methoxymethoxy)methyl)-8-
methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)cyclohex-1-
To a solution of BH3$THF (5.4 ml, 5.91 mmol; 1.09 M in THF) was
added 2-methyl-2-butene (1.3 ml, 11.8 mmol) at 0 ꢀC, and the
resulting mixture was stirred for 2 h to generate disiamylborane.
Freshly prepared disiamylborane was added to a solution of 30
(881 mg, 1.97 mmol) in THF (20 ml) at 0 ꢀC. The mixture was stirred
for 40 min at the same temperature. The reaction was quenched
with EtOH (6.4 ml), then 3 M NaOH aq (3.2 ml) and 30% H2O2 aq
(3.2 ml) were added carefully to the mixture. After being stirred
vigorously for 1 h at room temperature, the mixture was diluted
with EtOAc and brine. The organic layer was separated and the
aqueous layer was further extracted twice with EtOAc. The com-
bined organic layer was washed with Na2S2O3 aq, water and brine,
dried over Na2SO4, and concentrated to give a pale yellow oil. The
enyl)-11-methylpropan-10-one (29). To
a solution of diketone
(3.72 g, 9.15 mmol) were added HMPA (19.1 ml, 110 mmol) and
NaHMDS (45.8 mml, 45.8 mmol; 1.0 M in THF) at 0 ꢀC. The mixture
was stirred for 35 min at the same temperature, and then allyl
bromide (15.7 ml, 183 mmol) was added slowly. The mixture was
stirred for 10 min and additionally for 50 min at room temperature.
The reaction was quenched with pH 6.9 buffer and stirred vigor-
ously for 1 h. The organic layer was separated and the aqueous layer
was further extracted twice with diethyl ether. The combined or-
ganic layer was washed twice with water and brine, dried over
Na2SO4, and concentrated to give a yellow oil. The residue was
purified by column chromatography (neutral silica gel EtOAc/

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6579
residue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/3) to give alcohol (743 mg, 1.60 mmol, 81% yield) as
aq and brine, dried over Na2SO4, and concentrated to give a yellow
oil. The residue was purified by column chromatography (SiO2;
EtOAc/hexane¼1/15 to 1/10) to give 31 (2.38 g, 5.17 mmol; 91%
a
colorless oil. 1H NMR (CDCl3)
d: 5.08e5.12 (m, C27e1H),
4.99e5.02 (m, C17e1H), 4.62 (d, J¼6.9 Hz, OCH2OCH3e1H), 4.59 (d,
J¼6.9 Hz, OCH2OCH3e1H), 3.69 (dd, J¼3.5, 9.2 Hz, C21e1H),
3.53e3.57 (m, C4e1H), 3.22e3.51 (m, C4e1H), 3.35 (s,
OCH2OCH3e3H), 3.30 (dd, J¼9.2, 9.2 Hz, C21e1H), 2.98 (sep,
J¼6.3 Hz, C11e1H), 2.40e2.49 (m, C2e1H, C5e1H, C7e1H,
C26e1H), 2.30e2.35 (m, C6e1H), 1.82e2.11 (m, OHe1H, C2e1H,
C16e2H, C26e1H), 1.68 (s, C30e3H), 1.65 (s, C20e3H), 1.60 (s,
C29e3H), 1.59 (s, C19e3H), 1.31e1.45 (m, C6e1H, C15e2H), 1.18 (d,
J¼6.3 Hz, C12e3H), 1.05 (d, J¼6.3 Hz, C13e3H), 0.90e1.03 (m,
yield for two steps) as a pale yellow oil. 1H NMR (CDCl3)
d:
5.01e5.10 (m, C17e1H, C27e1H), 4.57 (d, J¼6.7 Hz,
OCH2OCH3e1H), 4.55 (d, J¼6.7 Hz, OCH2OCH3e1H), 3.60 (dd, J¼3.4,
9.5 Hz, C21e1H), 3.33 (s, OCH2OCH3e3H), 3.25 (dd, J¼9.5, 9.5 Hz,
C21e1H), 2.68e2.73 (m, C3e1H), 2.56 (sep, J¼6.4 Hz, C11e1H),
2.33e2.45 (m, C3e1H, C6e1H, C26e1H), 2.20e2.31 (m, C2e1H,
C7e1H, C16e1H, C26e1H), 1.84e1.93 (m, C2e1H, C16e1H),
1.50e1.70 (m, C19e3H, C20e3H, C29e3H, C30e3H, C6e1H,
C15e1H), 1.39e1.46 (m, C15e1H), 1.26 (d, J¼6.4 Hz, C12e3H), 1.18
C3e2H), 0.91 (s, C14e3H); 13C NMR (CDCl3)
d: 217.0, 212.3, 133.4,
(d, J¼6.4 Hz, C13e3H), 0.98 (s, C14e3H); 13C NMR (CDCl3)
d: 212.8,
131.2, 124.2, 121.5, 96.7, 75.5, 69.1, 62.6, 55.3, 47.0, 44.8, 41.2, 40.6,
35.7, 32.0, 28.5, 27.8, 27.5, 25.8, 25.6, 24.1, 21.7, 20.3, 19.5, 17.8, 17.6;
211.0, 210.9,135.7, 132.3, 124.4,118.4, 97.0, 70.9, 68.3, 66.1, 55.7, 48.1,
43.5, 42.0, 41.4, 39.9, 38.0, 31.6, 26.3, 26.0, 25.9, 23.4, 20.9, 20.8,18.2,
IR (neat, cmꢁ1):
n
3436, 1705, 1688; MS (ESI) m/z 487 (MþNa)þ;
18.0, 14.3; IR (neat, cmꢁ1):
n
1718, 1703; MS (ESI) m/z 483 (MþNa)þ;
HRMS (ESI) calcd for C28H48O5 (MþNa)þ: 487.3399, Found:
HRMS (ESI) calcd for C28H44O5 (MþNa)þ: 483.3086, Found:
27
22
487.3392; [
a]
ꢁ12.9 (c 1.16, CHCl3) (80% ee).
483.3080; [
a
]
ꢁ23.8 (c 1.27, CHCl3) (80% ee).
D
D
4.1.13. 3-((1S,5S,7R,8S)-1-Isobutyryl-7-((methoxymethoxy)methyl)-
8-methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-9-ox-
4.1.15. (1S,5S,7R,8S)-7-(Hydroxymethyl)-1-isobutyryl-8-(4-methoxy-
4-methylpentyl)-8-methyl-5-(3-methylbut-2-enyl)bicyclo[3.3.1]non-
ane-4,9-dione (32). To a solution of 31 (2.38 g, 5.17 mmol) in MeOH
(52 ml) was added (þ)-CSA (3.60 g, 15.5 mmol) at room tempera-
ture. The mixture was heated to 50 ꢀC and stirred for 5 h at the
same temperature. The reaction was quenched with NaHCO3 aq and
the organic layer was separated. The aqueous layer was further
extracted twice with EtOAc. The combined organic layer was
washed with water and brine, dried over Na2SO4, and concentrated
to give a yellow oil. The residue was purified by column chroma-
tography (SiO2, EtOAc/hexane¼1/3 to 1/1) to give 32 and only MOM
cleaved product. MOM cleaved product could be converted to 32
under the same condition. After two cycles of this reaction, 32
(1.53 g, 3.41 mmol, 66% yield) was obtained as a colorless oil. 1H
ocyclohexyl)propanal (22). To
532 mol) in CH2Cl2 (5.3 ml) was added DesseMartin periodinane
(338 mg, 798
mol) at 0 ꢀC. The mixture was stirred at the same
a solution of alcohol (247 mg,
m
m
temperature for 10 min, and additionally for 2 h at room temper-
ature. The reaction was quenched with Na2S2O3 aq and the organic
layer was separated. The aqueous layer was further extracted twice
with diethyl ether. The combined organic layer was washed twice
with saturated NaHCO3 aq and brine, dried over Na2SO4, and con-
centrated to give a pale yellow oil. The residue was purified by
column chromatography (neutral silica gel EtOAc/hexane¼1/10) to
give 22 (223 mg, 482
(CDCl3) : 9.65 (s, C4e1H), 5.08e5.11 (m, C27e1H), 4.99e5.03 (m,
m
mol, 91% yield) as a colorless oil. 1H NMR
d
C17e1H), 4.65 (d, J¼6.9 Hz, OCH2OCH3e1H), 4.62 (d, J¼6.9 Hz,
OCH2OCH3e1H), 3.72 (dd, J¼3.5, 9.3 Hz, C21e1H), 3.37 (s,
OCH2OCH3e3H), 3.34 (dd, J¼9.2, 9.3 Hz, C21e1H), 2.91 (sep,
J¼6.3 Hz, C11e1H), 2.64e2.72 (m, C5e1H), 2.41e2.50 (m, C7e1H,
C26e1H), 2.29e2.41 (m, C2e1H, C6e1H), 1.91e2.14 (m, C3e2H,
C16e2H, C26e1H), 1.73e1.82 (m, C2e1H), 1.69 (s, C30e3H), 1.66 (s,
C20e3H), 1.60 (s, C19e3H, C29e3H), 1.43 (dd, J¼12.6, 25.2 Hz,
C6e1H), 1.32e1.37 (m, C15e2H), 1.22 (d, J¼6.3 Hz, C12e3H), 1.07 (d,
NMR (CDCl3)
d
: 5.05e5.08 (m, C27e1H), 3.77 (dd, J¼2.9, 10.9 Hz,
C21e1H), 3.34 (dd, J¼9.2, 9.7 Hz, C21e1H), 3.15 (s, OCH3e3H), 2.70
(d, J¼11.5 Hz, C3e1H), 2.56 (sep, J¼6.9 Hz, C11e1H), 2.33e2.44 (m,
C3e1H, C6e1H, C26e1H), 2.21e2.31 (m, C2e1H, C7e1H, C26e1H),
1.74e1.80 (m, C2e1H), 1.65 (s, C30e3H), 1.57 (s, C29e3H), 1.53e1.60
(m, C6e1H, C15e1H), 1.42e1.48 (m, C15e1H), 1.35 (dd, J¼7.4,
8.6 Hz, C17e2H), 1.26 (d, J¼6.9 Hz, C13e3H), 1.18e1.23 (m,
C16e1H), 1.18 (d, J¼6.9 Hz, C12e3H), 1.13 (s, C19e3H), 1.12 (s,
C20e3H), 1.10e1.15 (m, C16e1H), 0.96 (s, C14e3H); 13C NMR
J¼6.3 Hz, C13e3H), 0.96 (s, C14e3H); 13C NMR (CDCl3)
d: 216.5,
212.5, 200.6, 133.6, 131.7, 124.0, 121.3, 96.7, 75.2, 68.9, 55.3, 47.0,
44.6, 41.1, 40.5, 40.0, 35.6, 31.5, 27.8, 25.8, 25.6, 24.1, 23.3, 21.7, 20.3,
(CDCl3)
d: 212.6, 210.7, 210.6, 135.3, 118.0, 74.5, 70.4, 65.7, 62.7, 49.1,
47.9, 45.4, 41.6, 40.6, 40.5, 39.6, 38.2, 31.2, 25.9, 25.1, 24.9, 23.0, 21.0,
19.6, 17.8, 17.6; IR (neat, cmꢁ1):
n
1725, 1706, 1689; MS (ESI) m/z 485
20.5, 20.4, 17.8, 14.2; IR (neat, cmꢁ1):
n 3425, 1717, 1701; MS (ESI) m/
(MþNa)þ; HRMS (ESI) calcd for C28H46O5 (MþNa)þ: 485.3243,
z 471 (MþNa)þ; HRMS (ESI) calcd for C27H44O5 (MþNa)þ: 471.3086,
Found: 485.3234; [
a]
25 ꢁ13.9 (c 1.01, CHCl3) (80% ee).
Found: 471.3075; [
a
]
28 ꢁ13.6 (c 1.25, CHCl3) (80% ee).
D
D
4.1.14. (1S,5S,7R,8S)-1-Isobutyryl-7-((methoxymethoxy)methyl)-8-
methyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)bicyclo
4.1.16. (1S,5S,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5-(3-methylbut-2-enyl)-4,9-dioxobicyclo[3.3.1]nonane-7-
carbaldehyde.
[3.3.1]nonane-4,9-dione (31). To
a
solution of 22 (2.62 g,
5.66 mmol) in EtOH (57 ml) was added NaOEt (193 mg, 2.83 mmol)
at 0 ꢀC. The mixture was stirred for 10 min at the same temperature
and additionally for 130 min at room temperature. The reaction was
quenched with NH4Cl aq, and the organic solvent was removed by
evaporation. The aqueous layer was extracted three times with
EtOAc. The combined organic layer was washed with water and
brine to give secondary alcohol 23 as a yellow oil, which was used
in next step without further purification.
To a solution of the crude mixture in CH2Cl2 (57 ml) was added
DesseMartin periodinane (3.60 g, 8.49 mmol) at 0 ꢀC. After being
stirred at the same temperature for 1 h, DesseMartin periodinane
(600 mg, 1.30 mmol) was added again. The reaction was stirred for
40 min, quenched with Na2S2O3 aq, and the organic layer was
separated. The aqueous layer was further extracted with diethyl
ether. The combined organic layer was washed twice with NaHCO3
To a solution of oxalyl chloride (49.9 ml, 590 mmol) in CH2Cl2 was
added a solution of DMSO (83.8
m
l, 1.18 mmol) at ꢁ78 ꢀC. The re-
action was stirred for 5 min. Then, a solution of 32 (52.8 mg,
118
m
mol) in CH2Cl2 (590
m
l) was added to the mixture at ꢁ78 ꢀC.
After 35 min, NEt3 (495
m
l, 3.54 mmol) was added at ꢁ78 ꢀC, then
warmed to room temperature and stirred for 45 min. The reaction
was quenched with water, and the organic layer was separated. The
aqueous layer was further extracted twice with EtOAc. The com-
bined organic layer was washed with water and brine, dried over

6580
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
Na2SO4, and concentrated to give a yellow oil. The residue was
(d, J¼10.7 Hz, C23e1H), 5.07 (d, J¼17.1 Hz, C23e1H), 5.02e5.05 (m,
C27e1H), 3.14 (s, OCH3e3H), 2.66 (dd, J¼4.0, 12.2 Hz, C3e1H), 2.53
(sep, J¼6.4 Hz, C11e1H), 2.37 (d, J¼7.6 Hz, C26e2H), 2.07e2.26 (m,
C2e1H, C3e1H, C6e1H, C7e1H), 2.01(s, OCOCH3e3H), 1.86 (dd,
J¼13.4, 13.5 Hz, C2e1H), 1.68 (dd, J¼4.0, 13.4 Hz, C6e1H), 1.63 (s,
C30e3H), 1.58 (s, C29e3H), 1.44e1.55 (m, C15e2H), 1.30e1.40 (m,
C16e1H, C17e2H), 1.23 (d, J¼6.4 Hz, C12e3H), 1.16(d, J¼6.4 Hz,
C13e3H),1.12 (s, C19e3H),1.11 (s, C20e3H),1.06e1.12 (m, C16e1H),
purified by column chromatography (SiO2, EtOAc/hexane¼1/4) to
give aldehyde (49.8 mg, 112 m
mol, 95% yield) as a yellow oil. 1H
NMR (CDCl3)
d
: 9.70 (d, J¼2.3 Hz, C21e1H), 5.01e5.05 (m, C27e1H),
3.11 (s, OCH3e3H), 2.68e2.71 (m, C3e1H), 2.51e2.56 (m, C7e1H,
C11e1H), 2.19e2.37 (m, C2e2H, C3e1H, C26e2H), 2.09 (dd, J¼4.0,
13.7 Hz, C6e1H), 1.92 (dd, J¼13.2, 13.7 Hz, C6e1H), 1.67e1.79 (m,
C15e1H, C16e1H),1.62 (s, C30e3H), 1.57 (s, C29e3H),1.47e1.54 (m,
C15e1H), 1.34 (dd, J¼7.5, 8.0 Hz, C17e2H), 1.23 (d, J¼6.3 Hz,
C12e3H), 1.16 (d, J¼6.9 Hz, C12e3H), 1.10 (s, C19e3H), 1.09 (s,
C20e3H), 1.08 (s, C14e3H), 1.06e1.10 (m, C16e1H); 13C NMR
0.94 (s, C14e3H); 13C NMR (CDCl3)
d: 212.0, 210.6, 209.9, 169.5,
136.0, 135.4, 117.9, 116.1, 74.4, 71.2, 70.3, 65.5, 49.0, 48.8, 45.1, 41.7,
40.4, 39.7, 38.4, 36.2, 31.4, 25.9, 25.1, 24.9, 23.0, 21.1, 20.9, 20.8, 20.4,
(CDCl3)
d: 211.8, 209.6, 209.3, 201.5, 135.8, 117.5, 74.2, 69.4, 64.6,
17.8, 14.8; IR (neat, cmꢁ1):
n 1741, 1718, 1703; MS (ESI) m/z 539
54.5, 49.0, 48.9, 41.4, 40.5, 39.5, 37.7, 36.1, 30.9, 25.9, 25.0, 24.9, 22.8,
(MþNa)þ; HRMS (ESI) calcd for C31H48O6 (MþNa)þ: 539.3349,
20.5, 20.5, 20.3, 17.8,15.8; IR (neat, cmꢁ1):
n
1718,1704; MS (ESI) m/z
Found: 539.3352; [
a
]
25 þ18.8 (c 0.61, CHCl3) (80% ee).
D
469 (MþNa)þ; HRMS (ESI) calcd for C27H42O5 (MþNa)þ: 469.2930,
Found: 469.2917; [
a]
26 ꢁ32.9 (c 1.24, CHCl3) (80% ee).
4.1.19. (1S,5S,7R,8S)-7-Allyl-1-isobutyryl-8-(4-methoxy-4-methyl-
pentyl)-8-methyl-5-(3-methylbut-2-enyl)bicyclo[3.3.1]nonane-4,9-
dione.
D
4.1.17. (1S,5S,7R,8S)-7-(1-Hydroxyallyl)-1-isobutyryl-8-(4-methoxy-
4-methylpentyl)-8-methyl-5-(3-methylbut-2-enyl)bicyclo[3.3.1]non-
ane-4,9-dione (33). To a solution of aldehyde (167 mg, 374
mmol) in
THF (3.7 ml) was added vinylmagnesium bromide (598
m
l,
598
m
mol; 1.0 M in THF) at ꢁ78 ꢀC. After being stirred for 40 min at
the same temperature, the reaction was quenched with saturated
NH4Cl aq, and the organic layer was separated. The aqueous layer
was further extracted twice with EtOAc. The combined organic
layer was washed with water and brine, dried over Na2SO4, and
concentrated to give a yellow oil. The residue was purified by col-
umn chromatography (SiO2; EtOAc/hexane¼1/5 to 1/4) to give 33
The reaction solvent toluene was degassed before the reaction.
Pd(PPh3)4 (77.9 mg, 67.4 mmol) and ammonium formate (85.1 mg,
1.35 mmol) were dissolved in toluene (4.8 ml) at room tempera-
ture. After being stirred for 10 min, a solution of the allyl acetate
(174 mg, 337 mmol) in toluene (2.4 ml) was added. The resulting
(163 mg, 343
m
mol, 92% yield) as a white solid. 1H NMR (CDCl3)
d
:
5.82 (ddd, J¼5.2,10.4,17.1 Hz, C22e1H), 5.18 (d, J¼17.1 Hz, C23e1H),
5.14 (d, J¼10.4 Hz, C23e1H), 5.02e5.06 (m, C27e1H), 4.35 (br s,
C21e1H), 3.13 (s, OCH3e3H), 2.64 (dd, J¼4.9, 13.5 Hz, C3e1H), 2.56
(sep, J¼6.4 Hz, C11e1H), 2.35 (d, J¼7.3 Hz, C26e2H), 2.17e2.24 (m,
C3e1H, C7e1H), 2.12 (dd, J¼5.5, 16.5 Hz, C6e1H), 2.03 (dd, J¼4.0,
13.4 Hz, C2e1H), 1.86 (dd, J¼13.4, 13.5 Hz, C2e1H), 1.62 (s,
C30e3H), 1.58 (s, C29e3H), 1.52e1.62 (m, C6e1H, C15e1H),
1.34e1.44 (m, C15e1H, C16e1H, C17e2H), 1.23 (d, J¼6.4 Hz,
C12e3H), 1.16 (d, J¼6.4 Hz, C13e3H), 1.17 (s, C19e3H), 1.12 (s,
C20e3H), 1.11 (s, C14e3H), 1.07e1.12 (m, C16e1H); 13C NMR
mixture was stirred at 100 ꢀC for 2.5 h. The reaction was diluted
with water and extracted three times with EtOAc. The combined
organic layer was washed with water and brine, dried over Na2SO4,
and concentrated to give a yellow oil. The residue was purified by
column chromatography (SiO2; EtOAc/hexane¼1/8) to give C7-allyl
product (146 mg, 318
(CDCl3) : 5.59e5.69 (m, C22e1H), 4.96e5.05 (m, C23e2H,
m
mol, 95% yield) as a pale yellow oil. 1H NMR
d
C27e1H), 3.13 (s, OCH3e3H), 2.64e2.69 (m, C3e1H), 2.56 (sep,
J¼6.9 Hz, C11e1H), 2.29e2.33 (m, C26e2H), 2.16e2.24 (m, C3e1H,
C6e1H, C7e1H, C21e2H), 1.62 (s, C30e3H), 1.57 (s, C29e3H),
1.46e1.66 (m, C2e2H, C6e1H, C15e1H), 1.23 (d, J¼6.9 Hz, C12e3H),
1.22e1.43 (m, C15e1H, C16e2H, C17e2H), 1.16 (d, J¼6.9 Hz,
C12e3H), 1.11 (s, C19e3H), 1.11 (s, C20e3H), 0.94 (s, C14e3H); 13C
(CDCl3)
d: 212.5, 211.0, 210.2, 141.0, 135.1, 118.1, 114.5, 74.5, 70.6,
70.0, 65.6, 49.1, 46.2, 41.7, 40.7, 39.7, 38.3, 35.5, 31.4, 25.9, 25.1, 24.9,
23.0, 21.0, 20.8, 20.4, 17.8, 15.5; IR (neat, cmꢁ1):
n 3421, 1717, 1701;
MS (ESI) m/z 497 (MþNa)þ; HRMS (ESI) calcd for C29H46O5
NMR (CDCl3)
d: 212.6, 210.7, 210.7, 136.7, 135.2, 118.1, 116.7, 74.4,
26
(MþNa)þ: 497.3243, Found: 497.3238; [
a
]
þ10.4 (c 1.60, CHCl3)
70.6, 66.0, 49.0, 48.7, 42.0, 41.9, 40.6, 39.6, 38.3, 33.6, 31.2, 25.9, 25.1,
D
(80% ee).
25.0, 23.0, 21.0, 20.6, 20.5, 17.8, 13.7; IR (neat, cmꢁ1):
n 1737, 1718,
1702; MS (ESI) m/z 481 (MþNa)þ; HRMS (ESI) calcd for C29H46O4
25
4.1.18. 21-((1S,5S,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methyl-
pentyl)-8-methyl-5-(3-methylbut-2-enyl)-4,9-dioxobicyclo[3.3.1]
nonan-7-yl)allyl acetate.
(MþNa)þ: 481.3294, Found: 481.3284; [
a]
þ2.5 (c 0.68, CHCl3)
D
(80% ee).
4.1.20. (1S,5S,7R,8S)-5-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)bicyclo[3.3.1]nonane-4,9-dione
(34). To a solution of C7-allyl compound (146 mg, 318 mmol) in
CH2Cl2 (8 ml) and 2-methyl-2-butene (8 ml) was added Hovey-
daeGrubbs second catalyst at room temperature. The resulting
mixture was stirred at 40 ꢀC for 1 h. DMSO (1.1 ml) was added to the
reaction mixture and it was stirred for 7 h at the same temperature.
The mixture was directly evaporated and purified by column
chromatography (SiO2; EtOAc/hexane¼1/15 to 1/10) to give 34
To a solution of 33 (163 mg, 343
added i-Pr2NEt (300 l, 1.72 mmol), DMAP (21.0 mg, 172
acetic anhydride (163
l, 1.72 mmol) at 0 ꢀC. The mixture was stir-
m
mol) in CH2Cl2 (3.4 ml) were
m
mmol), and
m
red at the same temperature for 30 min, and quenched with water.
The organic layer was separated and the aqueous layer was further
extracted twice with EtOAc. The combined organic layer was
washed with water and brine, dried over Na2SO4, and concentrated
to give a yellow oil. The residue was purified by column chroma-
tography (SiO2; EtOAc/hexane¼1/5) to give allyl acetate (174 mg,
(162 mg, 332 m d:
mol, 100% yield) as a white solid. 1H NMR (CDCl3)
5.02e5.05 (m, C27e1H), 4.96e4.99 (m, C22e1H), 3.13 (s,
OCH3e3H), 2.65e2.68 (m, C3e1H), 2.56 (sep, J¼6.4 Hz, C11e1H),
2.31e2.33 (m, C26e2H), 2.18e2.22 (m, C3e1H, C21e2H), 2.15 (dd,
J¼4.0, 13.5 Hz, C6e1H), 2.00e2.04 (m, C7e1H), 1.68 (s, C30e3H),
1.63 (s, C24e3H), 1.58 (s, C29e3H), 1.54 (s, C25e3H), 1.46e1.70 (m,
C2e2H, C6e1H, C15e1H), 1.24e1.42 (m, C15e1H, C16e2H,
C17e2H), 1.24 (d, J¼6.4 Hz, C12e3H), 1.16 (d, J¼6.4 Hz, C13e3H),
337
(ddd, J¼5.2, 10.7, 17.1 Hz, C22e1H), 5.45 (d, J¼5.2 Hz, C21e1H), 5.15
m d: 5.66
mol, 98% yield) as a pale yellow oil. 1H NMR (CDCl3)

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6581
1.11 (s, C19e3H), 1.11 (s, C20e3H), 0.96 (s, C14e3H); 13C NMR
(CDCl3) : 212.7, 210.9, 210.8, 135.1, 133.1, 122.5, 118.2, 74.4, 70.7,
66.1, 49.0, 48.8, 43.1, 42.3, 41.7, 40.5, 39.6, 38.4, 31.3, 27.6, 25.9, 25.8,
C
31H48O4 (MþNa)þ: 507.3450, Found: 507.3449; [
a
]
29 ꢁ14.1 (c 1.36,
D
d
CHCl3) (80% ee).
25.1, 25.0, 23.0, 21.2, 20.5, 20.4, 17.9, 17.8, 13.7; IR (neat, cmꢁ1):
n
4.1.23. (1S,5S,7R,8S)-4-Hydroxy-1-isobutyryl-8-(4-methoxy-4-meth-
ylpentyl)-8-methyl-5,7-bis(3-methylbut-2-enyl)bicyclo[3.3.1]non-2-
en-9-one.
1718, 1702; MS (ESI) m/z 509 (MþNa)þ; HRMS (ESI) calcd for
C31H50O4 (MþNa)þ: 509.3607, Found: 509.3604; [
a
]
25 ꢁ2.6 (c 1.06,
D
CHCl3) (80% ee).
4.1.21. (1S,5S,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)-4-(trimethylsilyloxy)bicyclo
[3.3.1]non-3-en-9-one.
To a solution of 35 (144 mg, 297 mmol) in MeOH (3 ml) was
added NaBH4 (56.4 mg, 1.49 mmol) at ꢁ20 ꢀC. The reaction mixture
was stirred at the same temperature for 10 min, and quenched with
water and diluted with EtOAc. The organic layer was separated, and
the aqueous layer was further extracted twice with EtOAc. The
combined organic layer was washed with water and brine, dried
over Na2SO4, and concentrated to give a pale yellow oil. The residue
was purified by column chromatography (SiO2; EtOAc/hexane¼1/4)
To a solution of 34 (1.33 g, 2.73 mmol) in CH2Cl2 (27 ml) were
added NEt3 (7.63 ml, 54.6 mmol), DMAP (667 mg, 5.46 mmol), and
TMSCl (3.49 ml, 27.3 mmol) at 0 ꢀC. The reaction mixture was
stirred at room temperature for 40 h. The reaction was quenched
with saturated NH4Cl aq at ꢁ78 ꢀC. The organic layer was sepa-
rated, and the aqueous layer was further extracted twice with
EtOAc. The combined organic layer was washed with water and
brine, dried over Na2SO4, and concentrated to give a brown oil.
The residue was purified by column chromatography (neutral
silica gel; EtOAc/hexane¼1/15 to 1/10 to 1/6) to give TMS enol
ether (1.28 g, 2.29 mmol, 84% yield) as a pale yellow oil. 1H NMR
to give alcohol (148 mg, 304
NMR (CDCl3)
: 6.10 (dd, J¼2.3, 10.3 Hz, C3e1H), 5.95 (dd, J¼1.8,
m
mol, 100% yield) as a colorless oil. 1H
d
10.3 Hz, C2e1H), 5.26e5.30 (m, C27e1H), 5.09e5.13 (m, C22e1H),
4.37 (br s, C4e1H), 3.12 (s, OCH3e3H), 2.62 (sep, J¼6.3 Hz, C11e1H),
2.41 (dd, J¼9.2,14.3 Hz, C26e1H), 2.29 (dd, J¼4.6,14.3 Hz, C26e1H),
1.98e2.14 (m, C6e1H, C7e1H, C21e2H), 1.73 (s, C30e3H), 1.70 (s,
C24e3H),1.66 (s, C29e3H),1.58 (s, C25e3H),1.55e1.66 (m, C6e1H),
1.20e1.40 (m, C15e2H, C16e2H, C17e2H), 1.09e1.10 (m, C12e3H,
C19e3H, C20e3H),1.04 (s, C14e3H),1.00 (d, J¼6.3 Hz, C13e3H); 13C
NMR (CDCl3) d: 213.2, 210.8, 135.3, 133.8, 132.6, 127.2, 123.1, 120.1,
(CDCl3)
d
: 5.04e5.12 (m, C22e1H, C27e1H), 4.99 (dd, J¼3.5, 4.0 Hz,
75.8, 74.4, 72.0, 56.4, 49.0, 47.9, 40.7, 40.1, 39.9, 37.9, 34.4, 33.4, 28.3,
C3e1H), 3.16 (s, OCH3e3H), 2.58e2.66 (m, C11e1H, C26e2H), 2.26
(dd, J¼6.9, 14.9 Hz, C21e1H), 2.20 (dd, J¼6.9, 14.9 Hz, C21e1H),
2.04e2.08 (m, C6e1H), 1.84e1.90 (m, C7e1H), 1.71e1.78 (m,
C2e2H), 1.68 (s, C30e3H), 1.67 (s, C24e3H), 1.60 (s, C29e3H), 1.57
(s, C25e3H), 1.54e1.68 (m, C6e1H, C15e1H), 1.25e1.40 (m,
C15e1H, C16e1H, C17e1H), 1.18 (d, J¼6.3 Hz, C12e3H), 1.13 (s,
C19e3H), 1.13 (s, C20e3H), 1.06 (d, J¼6.3 Hz, C13e3H), 0.88 (s,
26.1, 25.9, 25.1, 25.1, 20.9, 20.3, 19.8, 18.0, 17.9, 15.9; IR (neat, cmꢁ1):
n
1720, 1705; MS (ESI) m/z 509 (MþNa)þ; HRMS (ESI) calcd for
C31H50O4 (MþNa)þ: 509.3607, Found: 509.3604; [
a
]
28 ꢁ9.3 (c 0.99,
D
CHCl3) (80% ee).
4.1.24. O-(1S,5S,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-
8-methyl-5,7-bis(3-methylbut-2-enyl)-9-oxobicyclo[3.3.1]non-2-en-
4-yl S-methyl carbonodithioate (47). To a solution of alcohol (1.02 g,
C14e3H), 0.20 (s, OTMSe9H); 13C NMR (CDCl3)
d: 215.0, 211.4,
150.2, 132.5, 123.6, 121.1, 102.4, 74.5, 70.6, 54.8, 49.1, 47.3, 43.5,
40.5, 39.6, 39.6, 38.7, 29.8, 27.1, 26.4, 25.9, 25.8, 25.2, 25.1, 22.1,
2.10 mmol) and CS2 (761
50e72% in oil) at 0 ꢀC. The reaction mixture was stirred at the same
temperature. After being stirred for 30 min, MeI (784 l,
ml, 12.6 mmol) was added NaH (504 mg;
21.5, 20.0, 18.0, 17.8, 13.6, 0.21; IR (neat, cmꢁ1):
n
1710, 1671; MS
m
(ESI) m/z 581 (MþNa)þ; HRMS (ESI) calcd for C34H58O4Si
12.6 mmol) was added at 0 ꢀC, and the mixture was stirred for
30 min. The reaction mixture was quenched with saturated NH4Cl
aq. The organic layer was separated, and the aqueous layer was
further extracted twice with EtOAc. The combined organic layer
was washed with water and brine, dried over Na2SO4, and con-
centrated to give a yellow oil. The residue was purified by column
chromatography (SiO2; EtOAc/hexane¼1/20) to give 47 (1.24 g,
28
(MþNa)þ: 581.4002, Found: 581.4005; [
a
]
ꢁ32.5 (c 0.96, CHCl3)
D
(80% ee).
4.1.22. (1S,5S,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)bicyclo[3.3.1]non-2-ene-4,9-di-
one (35). To a solution of TMS enol ether (166 mg, 297
mmol) in
DMSO (3.0 ml) was added Pd(OAc)2 (133 mg, 594 mol) at room
m
2.15 mmol, 100% yield) as a yellow oil. 1H NMR (CDCl3)
d: 6.31 (dd,
temperature. The atmosphere in the flask was replaced with O2,
and the mixture was stirred at room temperature for 10.5 h. The
reaction mixture was directly purified by column chromatography
J¼2.9, 10.3 Hz, C3e1H), 6.22 (br s, C4e1H), 6.07 (dd, J¼1.8, 10.3 Hz,
C2e1H), 5.09e5.15 (m, C22e1H, C27e1H), 3.12 (s, OCH3e3H), 2.61
(sep, J¼6.9 Hz, C11e1H), 2.58 (s, SCH3e3H), 2.29e2.37 (m,
C26e2H), 2.08e2.13 (m, C21e2H), 1.98e2.05 (m, C6e1H), 1.72 (s,
C30e3H),1.65 (s, C24e3H),1.59 (s, C29e3H),1.56e1.68 (m, C7e1H),
1.52 (s, C25e3H), 1.17e1.43(m, C6e1H, C15e2H, C16e2H, C17e2H),
1.09e1.11 (m, C12e3H, C19e3H, C20e3H), 1.07 (s, C14e3H), 1.01 (d,
(SiO2; EtOAc/hexane¼1/10 to 1/6) to give 35 (145 mg, 299
mmol,
: 7.28 (d,
100% yield) as a pale yellow oil. 1H NMR (CDCl3)
d
J¼10.4 Hz, C2e1H), 6.55 (d, J¼10.4 Hz, C3e1H), 5.01e5.03 (m,
C27e1H), 4.91e4.95 (m, C22e1H), 3.13 (s, OCH3e3H), 2.68 (sep,
J¼6.9 Hz, C11e1H), 2.44 (d, J¼6.9 Hz, C26e2H), 1.99 (dd, J¼5.2,
13.2 Hz, C6e1H), 1.77e1.81 (m, C22e2H), 1.62e1.69 (m, C24e3H,
C25e3H, C29e3H, C30e3H), 1.17e1.44 (m, C6e1H, C7e1H,
C15e2H, C16e2H, C17e2H), 1.13 (d, J¼6.9 Hz, C12e3H), 1.11 (s,
C19e3H), 1.11 (s, C14e3H, C20e3H), 1.08 (d, J¼6.9 Hz, C13e3H); 13C
J¼6.9 Hz, C13e3H); 13C NMR (CDCl3)
d: 214.7, 212.4, 208.6, 135.0,
132.8, 129.4, 129.3, 123.2, 119.0, 83.9, 74.3, 72.1, 55.1, 49.0, 48.4, 40.7,
40.4, 40.0, 38.0, 36.6, 33.2, 27.9, 26.0, 25.9, 25.1, 21.0, 20.3, 19.9, 18.7,
18.0, 17.7, 15.5; IR (neat, cmꢁ1):
n 1723, 1712; MS (ESI) m/z 599
(MþNa)þ; HRMS (ESI) calcd for C33H52O4S2 (MþNa)þ: 599.3205,
NMR (CDCl3)
d
: 211.1, 206.4, 199.1, 146.1, 134.5, 133.5, 132.8, 122.0,
Found: 599.3214; [
a
]
32 þ31.5 (c 1.30, CHCl3) (80% ee).
D
119.3, 74.2, 73.4, 67.0, 67.0, 49.1, 47.7, 40.7, 40.7, 39.2, 38.0, 28.8, 27.8,
25.9, 25.8, 25.0, 21.0, 20.1, 19.9, 18.0, 17.9, 16.2; IR (neat, cmꢁ1):
n
4.1.25. S-(1S,5R,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-
8-methyl-5,7-bis(3-methylbut-2-enyl)-9-oxobicyclo[3.3.1]non-2-en-
1719, 1681; MS (ESI) m/z 507 (MþNa)þ; HRMS (ESI) calcd for

6582
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
4-yl S-methyl carbonodithioate (48). The solution of 47 (31.6 mg,
54.8 mol) in toluene (570
l) was stirred at 150 ꢀC (sealed tube) for
11 h. The reaction was cooled to room temperature and concen-
trated to give 48 as a yellow oil, which was used for next reaction
without purification.
yield) as a yellow oil. 1H NMR (CDCl3)
d
: 5.66 (d, J¼5.7 Hz, C3e1H),
m
m
5.13 (dd, J¼5.2, 5.7 Hz, C2e1H), 4.95e5.02 (m, C22e1H, C27e1H),
3.43 (sep, J¼6.9 Hz, C11e1H), 3.15 (s, OCH3e3H), 2.50 (dd, J¼5.7,
15.5 Hz, C26e1H), 2.26 (s, SCH3e3H), 2.26e2.30 (m, C26e1H),
1.90e2.05 (m, OHe1H, C6e1H, C21e2H), 1.68 (s, C30e3H), 1.66 (s,
C24e3H),1.63 (s, C29e3H),1.63e1.75 (m, C7e1H),1.56 (s, C25e3H),
1.23e1.49 (m, C6e1H, C15e2H, C16e2H, C17e2H), 1.13 (s, C19e3H),
1.12 (s, C20e3H), 1.11 (d, J¼6.9 Hz, C12e3H), 1.09 (d, J¼6.9 Hz,
4.1.26. (1S,5R,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)-4-(methylthio)bicyclo[3.3.1]
non-2-en-9-one.
C13e3H), 0.81 (s, C14e3H); 13C NMR (CDCl3)
d: 218.7, 208.5, 146.3,
133.1, 133.0, 122.5, 120.0, 118.9, 74.7, 74.2, 71.2, 57.2, 49.1, 47.8, 41.9,
40.0, 38.9, 38.6, 35.5, 31.5, 27.5, 25.8, 25.8, 25.3, 25.2, 21.0, 19.8, 19.5,
18.4, 18.1, 18.0, 15.2; IR (neat, cmꢁ1):
n 1720, 1685; MS (ESI) m/z 555
(MþNa)þ; HRMS (ESI) calcd for C32H52O4S (MþNa)þ: 555.3484,
28
Found: 555.3490; [
a
]
þ24.8 (c 1.37, CHCl3) (80% ee).
D
To a solution of 48 in THF (570
172
mol; 0.2 M in THF) at 0 ꢀC and stirred. After being stirred at
the same temperature for 25 min, MeI (53.5 l, 859 mol) and NEt3
(120 l, 859 mol) were added to the mixture. The resulting mix-
m
l) was added EtSLi (860
m
l,
4.1.29. (1R,5R,7R,8S)-2-Hydroxy-1-isobutyryl-8-(4-methoxy-4-
methylpentyl)-8-methyl-5,7-bis(3-methylbut-2-enyl)-4-(methyl-
sulfinyl)bicyclo[3.3.1]non-3-en-9-one.
m
m
m
m
m
ture was stirred at room temperature for 105 min. The reaction was
quenched with saturated NH4Cl aq. The organic layer was sepa-
rated, and the aqueous layer was further extracted twice with
EtOAc. The combined organic layer was washed with water and
brine, dried over Na2SO4, and concentrated to give a yellow oil. The
residue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/30 to 1/20 to 1/10) to give sulfide (27.7 mg, 53.6
mmol;
: 6.21 (dd,
To a solution of 50 (15.9 mg, 29.8
mmol) in HFIP (300 ml) was
98% yield for two steps) as a yellow oil. 1H NMR (CDCl3)
d
added 30% H2O2 aq (15 l) at room temperature. The resulting
m
J¼2.9, 10.3 Hz, C3e1H), 5.84 (dd, J¼2.3, 10.3 Hz, C2e1H), 5.21e5.25
(m, C27e1H), 5.11e5.15 (m, C22e1H), 3.51 (br s, C4e1H), 3.13 (s,
OCH3e3H), 2.65 (sep, J¼6.3 Hz, C11e1H), 2.27 (d, J¼7.5 Hz,
C26e2H), 2.18 (s, SCH3e3H), 1.98e2.12 (m, C6e1H, C21e2H), 1.72
(s, C30e3H), 1.70 (s, C24e3H), 1.65 (s, C29e3H), 1.58 (s, C25e3H),
1.55e1.62 (m, C7e1H), 1.17e1.43(m, C6e1H, C15e2H, C16e2H,
C17e2H), 1.10e1.11 (m, C12e3H, C19e3H, C20e3H), 0.99e1.02 (m,
mixture was stirred at the same temperature for 15 min. The re-
action was quenched with saturated Na2S2O3 aq. The organic layer
was separated, and the aqueous layer was further extracted twice
with EtOAc. The combined organic layer was washed with water
and brine, dried over Na2SO4, and concentrated to give a yellow oil.
The residue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/1 to 2/1) to give sulfoxide (14.2 mg, 25.9
mmol, 87% yield,
a 9:1 diastereomixture derived from S) as a pale yellow oil.
C14e3H, C13e3H); 13C NMR (CDCl3)
d: 213.1, 211.3, 134.3, 132.8,
132.5, 125.4, 123.0, 120.7, 74.3, 72.2, 55.2, 54.5, 49.0, 48.8, 40.8, 40.7,
39.9, 38.3, 38.0, 32.9, 28.0, 26.0, 25.7, 25.1, 25.1, 20.9, 20.4, 19.8, 17.9,
4.1.30. (1S,5R,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)-4-(methylsulfinyl)bicyclo[3.3.1]
non-3-ene-2,9-dione (51). To a solution of sulfoxide (504 mg,
17.7, 15.6, 15.5; IR (neat, cmꢁ1):
n 1721, 1706; MS (ESI) m/z 539
(MþNa)þ; HRMS (ESI) calcd for C32H52O3S (MþNa)þ: 539.3535,
Found: 539.3539; [
a
]
26 þ5.3 (c 0.80, CHCl3) (80% ee).
D
918 mmol) in CH2Cl2 (9.2 ml) was added DesseMaritn periodinane
(780 mg,1.84 mmol) at room temperature. After being stirred at the
same temperature for 40 min, the reaction was quenched with
Na2S2O3 aq. The organic layer was separated and the aqueous layer
was further extracted twice with ether. The combined organic layer
was washed twice with NaHCO3 aq and brine, dried over Na2SO4,
and concentrated to give a yellow oil. The residue was purified by
column chromatography (SiO2; EtOAc/hexane¼1/4) to give 51
4.1.27. (1S,5R,7R,8S)-1-Isobutyryl-8-(4-methoxy-4-methylpentyl)-8-
methyl-5,7-bis(3-methylbut-2-enyl)-4-(methylsulfinyl)bicyclo[3.3.1]
non-2-en-9-one (49). To a solution of sulfide (926 mg, 1.79 mmol)
in AcOH (17.9 ml) was added NaBO3$4H2O (826 mg, 5.37 mmol) at
room temperature. The resulting mixture was stirred at the same
temperature for 45 min. The reaction was diluted with water. The
aqueous layer was extracted twice with EtOAc. The combined or-
ganic layer was washed twice with saturated NaHCO3 aq and with
brine, dried over Na2SO4, and concentrated to give a yellow oil. The
residue was purified by column chromatography (SiO2; EtOAc/
hexane¼1/2 to 3/2) to give 49 (910 mg,1.71 mmol, 95% yield, a 1.3:1
diastereomixture derived from S) as a yellow oil.
(433 mg, 791
yellow oil.
mmol, 86% yield, a 9:1 diastereomixture) as a pale
4.1.31. (1S,5R,7R,8S)-1-Isobutyryl-8-methyl-5,7-bis(3-methylbut-2-
enyl)-8-(4-methylpent-3-enyl)-4-(methylsulfinyl)bicyclo[3.3.1]non-
3-ene-2,9-dione.
4.1.28. (1R,5R,7R,8S)-2-Hydroxy-1-isobutyryl-8-(4-methoxy-4-
methylpentyl)-8-methyl-5,7-bis(3-methylbut-2-enyl)-4-(methylthio)
bicyclo[3.3.1]non-3-en-9-one (50). To a solution of 49 (910 mg,
1.71 mmol) and 2,6-di-tert-butylpyridine (1.73 ml, 7.79 mmol) in
CH2Cl2 (17 ml) was added TFAA (712
m
l, 5.13 mmol) at ꢁ40 ꢀC. The
resulting mixture was stirred at the same temperature for 2 h. The
reaction was quenched with saturated NaHCO3 aq. The organic
layer was separated, and the aqueous layer was further extracted
twice with EtOAc. The combined organic layer was washed with
water and brine, dried over Na2SO4, and concentrated to give
a yellow oil. The residue was purified by column chromatography
(SiO2; EtOAc/hexane¼1/6 to 1/3) to give 50 (590 mg,1.11 mmol, 65%
To a solution of 51 (11.1 mg, 20.3 mmol) in toluene (200 ml) was
added Amberlyst 15DRY (11.1 mg). The resulting mixture was stir-
red at 80 ꢀC for 1.5 h. After cooling to room temperature, Amberlyst
15DRY was filtrated and the filtrate was concentrated to give
a yellow oil. The residue was purified by column chromatography

Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
6583
(SiO2; EtOAc/hexane¼1/5) to give C8-homoprenyl product (7.2 mg,
14 mol, 69% yield, a 9:1 diastereomixture) as a pale yellow oil.
To a solution of 53 (14.4 mg, 26
methyl-2-butene (650
catalyst (2.4 mg, 3.9
m
mol) in CH2Cl2 (650
m
l) and 2-
m
m
l) was added HoveydaeGrubbs second
mol). The resulting mixture was stirred at
m
4.1.32. (1S,5S,7R,8S)-4-(Allyloxy)-1-isobutyryl-8-methyl-5,7-bis(3-
methylbut-2-enyl)-8-(4-methylpent-3-enyl)bicyclo[3.3.1]non-3-ene-
40 ꢀC for 30 min, and after cooling to room temperature the solvent
was removed by evaporator. The residue was purified by column
chromatography (SiO2; EtOAc/hexane¼1/30) to give O-acetyl-ent-
2,9-dione (52). To
(120 mg, 233
a solution of C8-homoprenyl compound
m
mol) in allyl alcohol (2.3 ml) was added LiH (9.3 mg,
hyperforin (5.2 mg, 9.0
(CDCl3) d: 4.98e5.06 (m, C17e1H, C22e1H, C27e1H, C32e1H), 3.03
m
mol, 34% yield) as a colorless oil. 1H NMR
1.2
m
mol) at ꢁ40 ꢀC. The resulting mixture was stirred at the same
temperature for 39.5 h. The reaction was quenched with saturated
NH4Cl aq. The organic layer was separated, and the aqueous layer
was further extracted twice with EtOAc. The combined organic
layer was washed with water and brine, dried over Na2SO4, and
concentrated to give a yellow oil. The residue was partially purified
by column chromatography (SiO2; Hexane/toluene¼2/3 to toluene
only) to give 52 as a colorless oil, which was used for next step
without further purification.
(dd, J¼7.0, 15.0 Hz, C31e1H), 2.84 (dd, J¼7.1, 15.0 Hz, C31e1H), 2.48
(dd, J¼6.7, 15.3 Hz, C26e1H), 2.33 (dd, J¼7.0, 15.3 Hz, C26e1H), 2.23
(s, OCH3e3H), 2.06e2.13 (m, C6e1H, C21e1H), 1.93e2.01 (m,
C11e1H, C21e1H), 1.72e1.89 (m, C6e1H, C7e1H, C16e2H), 1.69 (s,
C20e3H, C30e3H), 1.67 (s, C29e3H), 1.65 (s, C19e3H), 1.64 (s,
C24e3H), 1.59 (s, C34e3H), 1.55 (s, C25e3H, C35e3H), 1.35e1.43
(m, C15e2H), 1.10 (d, J¼6.7 Hz, C12e3H), 1.00 (s, C4e3H), 0.98 (d,
J¼6.7 Hz, C13e3H); 13C NMR (CDCl3)
d: 208.5, 206.2, 193.4, 166.5,
162.7, 134.0, 132.9, 131.1, 124.7, 122.5, 119.8, 119.1, 84.4, 57.0, 49.8,
42.8, 42.2, 38.1, 36.4, 30.0, 27.1, 25.9, 25.7, 25.6, 25.0, 23.9, 21.1, 20.5,
4.1.33. (1S,5S,7R,8S)-3-Allyl-5-isobutyryl-6-methyl-1,7-bis(3-meth-
ylbut-2-enyl)-6-(4-methylpent-3-enyl)-4,9-dioxobicyclo[3.3.1]non-2-
en-2-yl acetate (53). The reaction solvent THF was degassed before
20.3, 18.1, 17.9, 17.7, 17.6, 13.5; IR (neat, cmꢁ1):
n 1777, 1732, 1657,
1634; MS (ESI) m/z 601 (MþNa)þ; HRMS (ESI) calcd for C37H54O5
(MþNa)þ: 601.3869, Found: 601.3868; [
a
]
ꢁ71.8 (c 0.44, CHCl3)
23
the reaction. Pd2dba3$CHCl3 (7.6 mg, 7.3
(10.0 mg, 14.7 mol) were dissolved into THF (490
stirred at room temperature for 30 min, a solution of 52 (37.3 mg,
73.3 mol) in THF (1.5 ml) was added to the mixture. The resulting
mixture was stirred for 2.5 h at room temperature, then Ac2O
(13.9 l, 147 mol) and pyridine (11.9 l, 147 mol) were added.
After 1 h, additional Ac2O (27.8 l, 294 mol) and pyridine (23.8 l,
294 mol) were added, and the mixture was stirred for 1.5 h. The
m
mol) and (S)-tol-BINAP
D
m
ml). After being
(80% ee).
m
4.1.35. ent-Hyperforin (ent-1). To
hyperforin (1.7 mg, 2.9 mol) in methanol (100
K2CO3 (0.9 mg, 6.5
mol) at 0 ꢀC. The resulting mixture was stirred
a
solution of O-acetyl-ent-
m
ml) was added
m
m
m
m
m
m
m
m
at the same temperature for 35 min. The reaction was quenched
with NH4Cl aq. The organic layer was separated and the aqueous
layer was further extracted twice with EtOAc. The combined or-
ganic layer was washed with water and brine, dried over Na2SO4,
and concentrated to give a pale yellow oil. The residue was purified
by column chromatography (SiO2; EtOAc/hexane¼1/5) to give ent-1
m
reaction was quenched with water. The organic layer was separated,
and the aqueous layer was further extracted twice with EtOAc. The
combined organic layer was washed with water and brine, dried
over Na2SO4, and concentrated to give an orange oil. The residue was
purified by column chromatography (SiO2; EtOAc/hexane¼1/30) to
give an inseparable mixture of 53 and unknown byproduct
(20.4 mg; 4:1 mixture) as a colorless oil. This mixture was further
purified by HPLC. HPLC purification was performed on JASCO HPLC
systems containing of following: pump, PU-980; detector, UV-970,
measured at 210 nm; column, Shiseido HPLC PACKED COLUMN, SG
80 A; mobile phase, dichloromethane/hexane¼1/1; flow rate,
(1.5 mg, 2.8 m d:
mol, 94% yield) as a colorless oil. 1H NMR (CD3OD)
5.11e5.15 (m, C32e1H), 4.97e5.07 (m, C17e1H, C22e1H, C27e1H),
3.17 (dd, J¼7.0, 14.7 Hz, C31e1H), 3.11 (dd, J¼6.7, 14.7 Hz, C31e1H),
2.54 (dd, J¼6.7, 14.1 Hz, C26e1H), 2.44 (dd, J¼7.0, 14.1 Hz, C26e1H),
1.90e2.19 (m, C6e1H, C11e1H, C16e2H, C21e1H), 1.74 (s, C30e3H),
1.72 (s, C20e3H, C29e3H), 1.69 (s, C19e3H), 1.68 (s, C24e3H),
1.66e1.79 (m, C7e1H, C15e2H, C21e1H), 1.66 (s, C34e3H), 1.62 (s,
C25e3H), 1.61 (s, C35e3H), 1.38e1.47 (m, C6e1H), 1.12 (d, J¼6.4 Hz,
C12e3H), 1.06 (d, J¼6.4 Hz, C13e3H), 1.01 (s, C14e3H); 13C NMR
5.0 mL/min. 1H NMR (CDCl3)
d: 5.66e5.75 (m, C32e1H), 4.99e5.06
(m, C17e1H, C22e1H, C27e1H, C33e2H), 3.13 (dd, J¼6.3, 15.5 Hz,
C31e1H), 2.92 (dd, J¼6.3, 15.5 Hz, C31e1H), 2.50 (dd, J¼6.9, 15.5 Hz,
C26e1H), 2.32 (dd, J¼6.9, 15.5 Hz, C26e1H), 2.24 (s, OCOCH3e3H),
2.07e2.14 (m, C6e1H, C21e1H), 2.02 (dd, J¼4.6, 14.3 Hz, C21e1H),
1.97 (sep, J¼6.9 Hz, C11e1H), 1.71e1.91 (m, C6e1H, C7e1H,
C16e2H), 1.69 (s, C20e3H, C30e3H), 1.67 (s, C29e3H), 1.64 (s,
C19e3H),1.59 (s, C24e3H),1.55 (s, C25e3H),1.36e1.42 (m, C5e2H),
1.10 (d, J¼6.9 Hz, C12e3H), 1.01 (s, C14e3H), 0.99 (d, J¼6.9 Hz,
(CDCl3) d: 135.44, 135.04, 132.63, 126.98, 124.73, 123.66, 122.82,
121.90, 43.94, 41.68, 38.81, 31.59, 29.52, 27.02, 26.90, 26.83, 26.74,
26.33, 23.43, 22.86, 22.01, 19.10, 19.01, 18.94, 18.70, 16.13; IR (neat,
cmꢁ1):
n
3336, 1724, 1601; MS (ESI) m/z 559 (MþNa)þ; HRMS (ESI)
23
calcd for C35H52O4 (MþNa)þ: 559.3763, Found: 559.3763; [
ꢁ36.8 (c 0.38, EtOH) (80% ee).
a]
D
C13e3H); 13C NMR (CDCl3)
d: 208.4, 206.0, 193.3, 166.6, 164.1, 134.2,
Acknowledgements
133.5, 132.9, 132.5, 131.2, 124.6, 122.4, 118.9, 116.4, 84.4, 57.3, 49.9,
42.9, 42.3, 38.1, 36.4, 30.0, 28.7, 27.1, 25.9, 25.7, 25.7, 25.0, 21.2, 20.6,
Financial support was provided by a Grant-in-Aid for Young
Scientists (S) and Scientific Research (S) from JSPS. Y.S. and H.U.
thank JSPS for research fellowships.
20.4, 18.1, 17.9, 17.7; IR (neat, cmꢁ1):
n 1777, 1732, 1656, 1638; MS
(ESI) m/z 573 (MþNa)þ; HRMS (ESI) calcd for C35H50O5 (MþNa)þ:
573.3556, Found: 573.3562; [
a
]
D
23 ꢁ78.8 (c 0.82, CHCl3) (80% ee).
Supplementary data
4.1.34. (1S,5S,7R,8S)-5-Isobutyryl-6-methyl-1,3,7-tris(3-methylbut-
2-enyl)-6-(4-methylpent-3-enyl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-
yl acetate.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.05.086.
References and notes
1. Review: Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963.
2. Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997, 45, 947.
3. Piccinelli, A. L.; Cuesta-Rubio, O.; Chica, M. B.; Mahmood, N.; Pagano, B.; Pav-
one, M.; Barone, V.; Rastrelli, L. Tetrahedron 2005, 61, 8206.
4. (a) 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.

6584
Y. Shimizu et al. / Tetrahedron 66 (2010) 6569e6584
Antibiotiki 1971, 16, 510; (b) Bystrov, N. S.; Chernov, B. K.; Dobrynin, V. N.;
8840; (e) Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 12682; (f) Simpkins, N.
S.; Taylor, J. D.; Weller, M. D.; Hayes, C. J. Synlett 2010, 639.
12. Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.
2010, 49, 1103.
13. Usuda, H.; Kuramochi, A.; Kanai, M.; Shibasaki, M. Org. Lett. 2004, 6, 4387.
14. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem.
Commun. 1987, 1625.
15. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
16. Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 1071.
17. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
18. Inokuchi, T.; Kawafuchi, H.; Torii, S. Synlett 1992, 510.
19. Barton, D. H. R.; Crich, D. Tetrahedron 1985, 41, 4359.
20. Shimizu, Y.; Kuramochi, A.; Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2007, 48, 4173.
Kolosov, M. N. Tetrahedron Lett. 1975, 16, 2791; (c) Brondz, I.; Greibrokk, T.;
Groth, P. A.; Aasen, A. J. Tetrahedron Lett. 1982, 23, 1299; (d) Brondz, I.;
Greibrokk, T.; Groth, P. A.; Aasen, A. J. Acta Chem. Scand. A 1983, 37, 263; (e)
Adam, P.; Arigoni, D.; Bacher, A.; Eisenreich, W. J. Med. Chem. 2002, 45,
4786.
5. Muller, W. E.; Singer, A.; Wonnemann, M.; Hafner, U.; Rolli, M.; Schafer, C.
Pharmacopsychiatry 1998, 31, 16.
6. Verotta, L.; Appendino, G.; Bombardelli, E.; Brun, R. Bioorg. Med. Chem. Lett.
2007, 17, 1544.
7. Gey, C.; Kyrylenko, S.; Henning, L.; Nguyen, L. D.; Büttner, A.; Pham, H. D.;
Giannis, A. Angew. Chem., Int. Ed. 2007, 46, 5219.
8. 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.
9. Synthetic studies of PPAPs (representative examples): (a) Nicolaou, K. C.;
Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem. Soc. 1999, 121, 4724; (b)
Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943; (c) Abe, M.; Nakada, M.
Tetrahedron Lett. 2007, 48, 4873; (d) Mehta, G.; Bera, M. K. Tetrahedron Lett.
2009, 50, 3519; (e) Couladouros, E. A.; Dakanali, M.; Demadis, K. D.; Vidali, V. P.
Org. Lett. 2009, 11, 4430.
21. Hughes, G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2, 107.
22. Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939.
23. (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011; (b) Larock, R. C.;
Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. A. Tetrahedron Lett. 1995, 36,
2423.
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; (c) Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.;
Blake, A. J. J. Org. Chem. 2007, 72, 4803.
11. (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; (c) Rodeschini, V.; Simpkins, N. S.; Wilson, C. J. Org. Chem. 2007, 72, 4265;
(d) Tsukano, C.; Siegel, D. R.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46,
24. Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2725.
25. Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
26. Taguchi, T.; Kawazoe, Y.; Nakao, M. Tetrahedron Lett. 1963, 131.
27. Feldman, K.; Fodor, M. D. J. Am. Chem. Soc. 2008, 130, 14964.
28. McKillop, A.; Tarbin, J. A. Tetrahedron Lett. 1983, 24, 1505.
29. Ravikumar, K. S.; Zhang, Y. M.; Bégué, J. P.; Bonnet-Delpon, D. Eur. J. Org. Chem.
1998, 2937.