Catalytic asymmetric total synthesis of ent-hyperforin

Article abstract of DOI:10.1002/anie.200906678

(Figure Presented) Key to success: The first catalytic asymmetric total synthesis of ent-hyperforin (see picture) was accomplished by using a Diels-Alder reaction promoted by a chiral cationic iron catalyst (A; 96% ee, d.r. >33:1), a diastereoselective Claisen rearrangement (B; 12:1 selectivity), an intramolecular aldol reaction (C), and a vinylogous Pummerer rearrangement (D) as key steps.

Full text of DOI:10.1002/anie.200906678

Angewandte
Chemie
DOI: 10.1002/anie.200906678
Total Synthesis
Catalytic Asymmetric Total Synthesis of ent-Hyperforin**
Yohei Shimizu, Shi-Liang Shi, Hiroyuki Usuda, Motomu Kanai,* and Masakatsu Shibasaki*
Naturally occurring polycyclic polyprenylated acylphloroglu-
cinols (PPAPs: Scheme 1) commonly have a highly substi-
tuted bicyclo[3.3.1]nonanone core.[1] Hyperforin (1), a repre-
providing a greater obstacle to its synthesis. We report
herein the first catalytic asymmetric total synthesis of ent-
hyperforin (5, the antipode of 1).[10]
We previously developed a catalytic asymmetric Diels–
Alder reaction between diene 7 and dienophile 8, which was
promoted by a cationic iron complex (10 mol%) derived from
pybox ligand 6 (Scheme 2).[11] Product 9, which contains
Scheme 1. Representative PPAPs.
sentative of this family, was isolated from the herb St. Johnꢀs
wort (Hypericum perforatum).[2a] Hyperforin exhibits various
biological activities, including mild antidepressant activity,[3]
antimalarial activity,[4] human histone deacetylase inhibitory
activity,[5] and CYP3A4 induction activity.[6] Enhancement of
a specific biological activity through structural modification is
an important direction in drug-discovery research, and thus
establishing a flexible, asymmetric total synthetic route is a
fundamental prerequisite.
Their structural complexity and potential utility as
pharmaceutical leads make PPAPs very attractive synthetic
targets. The total syntheses of garsubellin A (2),[7] clusianone
(3),[8] and nemorosone (4)[8d] have been accomplished.[9] The
use of elegant biomimetic approaches to construct the bicyclic
core has resulted in some of these racemic syntheses being
short and applicable for the production of structurally diverse
analogues.[8b,e,9e] The catalytic asymmetric synthesis of PPAPs,
however, remains a daunting challenge; there is only one
asymmetric synthesis of PPAPs (that of 3), which involved a
late-stage kinetic resolution using a stoichiometric amount of
chiral lithium amide.[8c] Hyperforin (1) contains an additional
chiral quaternary center at C8 compared to 2–4, thus
Scheme 2. Synthetic plan.
contiguous tertiary and quaternary stereocenters (corre-
sponding to C7 and C8 of 5), was obtained in 93% yield
and 96% ee with complete exo selectivity (d.r. > 33:1).[12] This
reaction is practical: reactions can be routinely conducted on
up to 20 g scales (average 89% ee).[13] We thus planned our
synthesis of 5 (Scheme 2) based on this powerful catalytic
asymmetric reaction.
After conversion of 9 into allyl enol ether 10, the key
bicyclic compound 12 would be constructed by a Claisen
rearrangement (10!11) and intramolecular aldol cyclization,
according to previous model studies.[14] In the model studies,
however, a simplified substrate containing geminal dimethyl
substituents at C8 was utilized. The effect of the C8
quaternary stereocenter in 10 on the reactivity and stereose-
lectivity of the Claisen rearrangement was a major concern in
this system. Moreover, the success in the construction of the
bicyclic core intimately depended on the substitution pattern
and conformation of the substrate.[15] In this sense, the C8
[*] Y. Shimizu, S.-L. Shi, Dr. H. Usuda, Dr. M. Kanai,
Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
[**] 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 the JSPS for research fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906678.
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stereocenter could also affect the intramolecular aldol
rearrangement.[14] Therefore, b-prenyl 17 was converted into
a-prenyl 18 through a deprotonation/kinetic protonation
sequence (Scheme 4). Cleavage of the TMS ether, Dess–
Martin oxidation,[18] and O-allylation produced 10, the
cyclization. From key intermediate 12, introduction of an
oxygen functionality at the extremely congested C2-position
and installation of a prenyl group at the C3-position would
lead to 5.
Based on the synthetic plan, we first converted enantio-
merically enriched oxazolidinone 9 to MOM ether 13 over
three steps with high efficiency (Scheme 3). Since the C10
Scheme 3. Conversion of the catalytic asymmetric Diels–Alder product.
Reagents and conditions: a) EtSLi, THF, 96%. b) LAH, THF, 99%.
c) MOMCl, TBAI, iPr2NEt, CH2Cl2, 94%. d) TBAF, AcOH, THF.
e) HF·py, py, THF, 91% (over 2 steps; d.r.=1:1). f) TMSCl, NEt3,
CH2Cl2. g) TIPSOTf, iPr2NEt, CH2Cl2. h) K2CO3, MeOH. i) TPAP
(10 mol%), NMO, 4ꢀ MS, CH3CN/CH2Cl2. j) 2-bromopropane, Li, THF
(d.r.=5:1). k) TBAF, AcOH, THF, 58% (over 6 steps). l) TMSCl,
imidazole, DMF, 94%. m) LDA, HMPA, prenyl bromide, THF, 89%
(d.r.>33:1). LAH=lithium aluminum hydride, MOM=methoxy-
methyl, TBAI=tetrabutylammonium iodide, TBAF=tetrabutylammo-
nium fluoride, py=pyridine, TMS=trimethylsilyl, TIPS=triisopropyl-
silyl, OTf=trifluoromethanesulfonate, TPAP=tetrapropylammonium
perruthenate, NMO=4-methylmorpholine N-oxide, HMPA=hexa-
methyl phosphoramide.
Scheme 4. Construction of the bicyclic core. Reagents and conditions:
a) LDA, THF; aq NH4Cl, 88% (d.r. >33:1). b) HF·py, py, THF. c) DMP,
CH2Cl2, 96% (over 2 steps). d) NaHMDS, allyl bromide, HMPA, THF,
>99%. e) toluene, N,N-diethylaniline, 1708C, >99% (d.r.=12:1).
f) (Sia)2BH, THF; aq H2O2, aq NaOH, EtOH, 81%. g) DMP, CH2Cl2,
91%. h) NaOEt, EtOH. i) DMP, CH2Cl2, 86% (over 2 steps). j) (+)-
CSA, MeOH, 66% (over 3 cycles). k) (COCl)2, DMSO, CH2Cl2; NEt3,
95%. l) vinylmagnesium bromide, THF, 92% (d.r.>33:1). m) Ac2O,
DMAP, iPr2EtN, CH2Cl2, 98%. n) [Pd(PPh3)4] (20 mol%), HCO2NH4,
toluene, 95%. o) Hoveyda–Grubbs 2nd generation cat. (15 mol%), 2-
methyl-2-butene, CH2Cl2, >99%. DMP=Dess–Martin periodinane,
HMDS=1,1,1,3,3,3-hexamethyldisilazane, CSA=camphorsulfonic
acid, DMAP=4-dimethylaminopyridine.
hydroxy group 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 14.[16] Direct oxidation of 14 and
subsequent addition of an isopropyl group to C10 were
difficult because of the instability of the intermediate
aldehyde derived from 14. Hence, 16 was synthesized via 15,
which was produced from 14 by temporary protection of the
primary alcohol with a TMS group, protection of the ketone
as an enol silyl ether, and selective cleavage of the TMS ether.
After oxidation of 15 with TPAP [17] followed by introduction
of the isopropyl group under Barbier conditions (d.r. = 5:1),
hydrolysis of the enol silyl ether afforded ketone 16. Although
multiple steps were required for the apparently simple
conversion from 14 into 16, the overall yield was reasonable
(58% over 6 steps). After protection of the C10 hydroxy
group of 16 with a TMS group, prenylation of the kinetically
produced lithium enolate proceeded exclusively from the
axial b face at C5 to give 17. The two diastereomers derived
from the C10 stereocenter exhibited distinctly different
reactivity in this step, and the ratio of the product diastereo-
mers was enriched to 9:1.
precursor for the key Claisen rearrangement. The thermal
Claisen rearrangement of 10 proceeded with high selectivity
(12:1) from the b face, and 11, which contains the requisite
three contiguous stereocenters (two of which are quaternary),
was obtained with high fidelity. This excellent stereoselectiv-
ity was consistent with the model studies,[14] and attributable
to the pseudoaxial methyl group at C8 blocking the a face
(19). The key bicyclic intermediate 12 was synthesized
uneventfully from 11 through a selective hydroboration at
the terminal double bond using disiamylborane [(Sia)2BH],
Dess–Martin oxidation, intramolecular aldol cyclization of
resulting aldehyde 20, and oxidation.
From 12, the remaining tasks were: 1) to 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 into a prenyl group was conducted first.
Cleavage of the MOM ether under acidic conditions pro-
Previous studies indicated that the configuration at C5
controls the approach of an allyl group to C1 in the Claisen
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ceeded with concomitant protection of the homoprenyl group
at C8 to give 21. This unplanned selective protection was
desirable because the reactive homoprenyl group caused side
reactions at a later metathesis stage. Swern oxidation of 21,
followed by the addition of a vinyl Grignard reagent produced
allylic alcohol 22 as a single isomer, which was deoxygenated
through acetylation and a palladium-catalyzed allylic reduc-
tion.[8e,19] The subsequent cross-metathesis with isobutene
using the Hoveyda–Grubbs catalyst[20] afforded 23 containing
the prenyl group at C7.
ment[23] for the oxidation of C2. The intermediate thionium
cation would be highly electrophilic, thus making it possible
to introduce an oxygen functionality at the C2-position.
Based on this hypothesis, we studied the critical vinyl-
ogous Pummerer rearrangement intensively by using sulfox-
ide 32 as a model substrate (Table 1). Treatment of 32 with
Table 1: Selectivity of vinylogous Pummerer rearrangement.
The oxidation of C2 was studied next; however, this task
proved to be extremely difficult. After the conversion of 23
into 24 under the palladium-mediated conditions
(Scheme 5),[21] inter- and intramolecular conjugate addition
of various heteronucleophiles (such as Si, O, and N reagents)
was attempted, but without success.[13a] Finally, we attempted
a [3,3] sigmatropic rearrangement of xanthate 25, which was
produced efficiently from 24. Thermal rearrangement of 25
proceeded cleanly; however, the expected functionalization
at C2 did not occur. Instead, dithioate 26 was obtained by a
[1,3] rearrangement.[22] This result again illustrated the highly
congested nature of the C2-position. This finding, however,
allowed us to attempt a vinylogous Pummerer rearrange-
Entry
Solvent
Base
34/35[a]
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
2[b]
3
4[c]
[a] Determined by 1H NMR spectroscopy. [b] 5 equiv of TFAA were used.
[c] 3 equiv of TFAA were used.
trifluoroacetic anhydride (TFAA) 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 34 and enone 35 (entry 1). Encouraged
by this result, we then optimized the reaction conditions. The
regioselectivity was greatly influenced by the base used.
Among these examined, pyridine preferentially afforded 34 in
moderate selectivity (entry 2; 34/35 = 3:1). The selectivity was
improved by increasing the steric bulkiness of the pyridine-
derived bases. 2,6-Di-tert-butylpyridine was finally found to
be the optimum base, giving 34 as the major product with a
selectivity of 8.3:1 (entry 4).
Having optimized the vinylogous Pummerer rearrange-
ment with model substrate 32, we applied the conditions to
the actual substrate 27, which was synthesized from 26
through thiolysis followed by S-methylation and S-oxida-
tion[24] (Scheme 5). As expected, the vinylogous Pummerer
rearrangement of 27 proceeded preferentially (4:1) to the
normal Pummerer rearrangement under the optimized con-
ditions, thereby providing the desired allylic alcohol 28 in
65% yield.
The final task was the installation of the prenyl group at
C3. S-Oxidation using H2O2 in hexafluoroisopropanol
(HFIP)[25] followed by Dess–Martin oxidation of the allylic
alcohol afforded sulfoxide 29. 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 30. The
catalyzed intramolecular allyl transfer presumably proceeded
Scheme 5. Completion of the total synthesis. Reagents and conditions:
a) TMSCl, NEt3, DMAP, CH2Cl2, 84%. b) Pd(OAc)2, DMSO, O2,
>99%. c) NaBH4, MeOH, 95% (d.r. >33:1). d) CS2, NaH, THF; MeI,
>99%. e) toluene, 1508C. f) EtSLi, THF; MeI, NEt3, 98% (over 2
steps). g) NaBO3·4H2O, AcOH (d.r.=1.3:1), 95%. h) TFAA, 2,6-di-tert-
butylpyridine, CH2Cl2, ꢀ408C; H2O, 65% (d.r.>33:1). i) H2O2, HFIP,
87% (d.r.=9:1). j) DMP, CH2Cl2, 86%. k) Amberlyst 15DRY, toluene,
55%. l) LiH, allyl alcohol, 67%. m) [Pd2(dba)3] CHCl3 (10 mol%), (S)-
tol-binap (20 mol%), THF; Ac2O, pyridine, 50%. n) Hoveyda–Grubbs
2nd generation cat. (15 mol%), 2-methyl-2-butene, CH2Cl2, 34%.
o) K2CO3, MeOH, 94%. dba=trans,trans-dibenzylideneacetone,
binap=2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl.
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[7] a) A. Kuramochi, H. Usuda, K. Yamatsugu, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2005, 127, 14200; b) D. R. Siegel,
S. J. Danishefsky, J. Am. Chem. Soc. 2006, 128, 1048; c) N. M.
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[10] In this study, chiral ligand 6 derived from inexpensive (R)-4-
hydroxyphenylglycine was used in the catalytic asymmetric
Diels–Alder reaction between 7 and 8, thus resulting in the
synthesis of the antipode of natural 1.
[11] H. Usuda, A. Kuramochi, M. Kanai, M. Shibasaki, Org. Lett.
2004, 6, 4387.
[12] During the scale-up studies, it was found that the enantioselec-
tivity of this catalytic Diels–Alder reaction was improved to up
to 96% ee (87% ee in Ref. [11]) by using strict temperature
control and moisture exclusion.
[13] a) See the Supporting Information for details; b) when the
catalytic asymmetric Diels–Alder reaction was conducted on
greater than 10 g scales, a decline in the ee value was observed,
probably because of the slight increase in the reaction temper-
ature during the addition of substrates.
via a p-allyl-palladium intermediate, and enol acetate 31 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 30 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 (5). 1H, 13C NMR, and IR spectroscopic data
as well as mass spectrometric data were all identical with the
reported values. The optical rotation of synthesized 5 was
opposite to that of the natural isomer (½aꢁ2D3 = ꢀ36.8 (c = 0.38,
EtOH); Lit. + 41).[2]
In conclusion, we have achieved the first catalytic
asymmetric total synthesis of ent-hyperforin. The key reac-
tions were: 1) an iron-catalyzed asymmetric Diels–Alder
reaction to produce contiguous C7 and C8 stereocenters;
2) a stereoselective Claisen rearrangement to produce the
bridgehead quaternary carbon atom at C1; 3) an intramolec-
ular 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. However, further
improvements in the efficiency of the reactions may be
necessary for such aplications. Studies are ongoing and will be
reported in due course.
Received: November 26, 2009
Published online: January 8, 2010
[14] Y. Shimizu, A. Kuramochi, H. Usuda, M. Kanai, M. Shibasaki,
Tetrahedron Lett. 2007, 48, 4173.
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[16] The hydrolysis of the enol TIPS ether provided a 1:1 mixture of
C1 isomers. Although further conversion was described from
one isomer (14) in the text, the other isomer was also utilized for
the synthesis of intermediate 10 with comparable efficiency; see
the Supporting Information for details.
Keywords: asymmetric synthesis · Claisen rearrangement ·
homogeneous catalysis · natural products · rearrangement
.
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