A chiral-pool-based approach to the core structure of (+)-hyperforin

Article abstract of DOI:10.1002/ejoc.201101629

Asymmetric entry to the bicyclic core structure of (+)-hyperforin is presented. The developed synthetic strategy features a carefully orchestrated stereochemical relay from the single chiral center residing within (-)-Wieland-Miescher ketone and an intram

Full text of DOI:10.1002/ejoc.201101629

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101629
A Chiral-Pool-Based Approach to the Core Structure of (+)-Hyperforin
Jean-Alexandre Richard[a] and David Y.-K. Chen*[b]
Keywords: Natural products / Total synthesis / Polycycles / Chiral pool
Asymmetric entry to the bicyclic core structure of (+)-hyper- and an intramolecular aldol reaction to cast the [3.3.1] bicy-
forin is presented. The developed synthetic strategy features
a carefully orchestrated stereochemical relay from the single
chiral center residing within (–)-Wieland–Miescher ketone
clic scaffold found in a diverse array of polycyclic polyprenyl-
ated acylphloroglucinols.
Introduction
Polycyclic polyprenylated acylphloroglucinols (PPAPs)
constitute a fascinating family of natural products that is
found to display a broad spectrum of biological properties.
Among them, (+)-hyperforin (1), nemorosone (2), and gar-
subellin A (3) instigated significant interest from the syn-
thetic community mainly because of their challenging mo-
lecular architecture in conjunction with their promising an-
tidepressant, antimalarial, antibacterial, antioxidant, and
antineurodegenerative activities (Figure 1).[1] Significant
progress have been made in the last decade towards the syn-
thesis of a diverse array of PPAP congeners;[2] however,
asymmetric entry to the densely functionalized bicy-
clo[3.3.1]nonane-2,4,9-trione or bicyclo[3.2.1]octane-2,4,8-
trione core of the PPAPs remains a formidable synthetic
challenge. Evidently, only four asymmetric total syntheses
of (+)- and (–)-clusianone,[3] (+)-hyperibone K,[4] and ent-
hyperforin[5] have been accomplished, together with spo-
radic reports on asymmetric model studies.[6] In particular,
the landmark total synthesis of ent-hyperforin reported in
2010 by Kanai, Shibasaki, and co-workers[5] that featured
a catalytic asymmetric Diels–Alder reaction to introduce
the C8 quaternary center further highlighted the difficulties
associated with this unique structural element that is absent
in other members of the PPAP family. Indeed, the complica-
tions encountered in connection with the introduction of
this additional quaternary center, asymmetrically, may ex-
plain the relatively few synthetic reports of hyperforin in
contrast to those available for its PPAP siblings.
Figure 1. Structures of selected PPAPs along with their biological
activities.
Results and Discussion
With an appreciation for historical synthetic studies
towards hyperforin and its related PPAPs in mind, here we
report our progress towards the synthesis of the core struc-
ture of (+)-hyperforin (1) by exploiting (–)-Wieland–
Miescher ketone (7) as a convenient source of asymmetric
information.[7] Recent reports from the laboratories of The-
odorakis,[8] Bonjoch,[9] and Hanessian[10] have beautifully
showcased the utility of optically enriched Wieland–
Miescher ketone in the preparation of highly functionalized
chiral materials for natural product synthesis. Furthermore,
the total synthesis of taxol reported by the Danishefsky
group featured ingenious use of (+)-Wieland–Miescher
ketone to rapidly access a substituted cyclohexane.[11] In-
spired by this latter report, our proposed synthesis of the
core structure of (+)-hyperforin (1) called for a late-stage
construction of the [3.3.1] bicyclic system from highly sub-
stituted and suitably functionalized cyclohexanone 4. A
critical element of the synthesis, as alluded to earlier, is the
introduction of the two quaternary centers at the C5 and
C8 positions. In this context, we envisaged that the former
could be controlled through a Claisen-type rearrangement
from stereochemically defined allylic alcohol 5, whereas the
latter could originate from (–)-Wieland–Miescher ketone (7)
derived cyclohexanone 6 (Scheme 1).
[a] Organic Chemistry @ Helios,
Institute of Chemical and Engineering Sciences (ICES),
Agency for Science, Technology and Research (A*STAR)
11 Biopolis Way, The Helios Block, #03-08
Singapore 138667
[b] Department of Chemistry, Seoul National University
Gwanak-1 Gwanak-ro, Gwanak-gu, Seoul 151-742,
South Korea
E-mail: davidchen@snu.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101629.
484
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 484–487

Chiral-Pool-Based Approach to the Core Structure of (+)-Hyperforin
However, further elaboration of TMS enol ether 11 proved
less satisfactory (25% over the two steps), and often af-
forded complicated mixtures primarily attributed to the
isomerization of 11 into more stable 12. As a precautionary
measure to facilitate our ensuring synthetic studies, alde-
hyde-ester 13 was exhaustively reduced (LiAlH4), and the
resulting hydroxy groups were guarded as benzyl ethers.
Liberation of the dioxolane moiety of 15 (pTsOH) then af-
forded ketone 16 in 70% yield over the three steps.
With trisubstituted cyclohexanone 16 efficiently prepared
with high stereochemical fidelity, the introduction of the C5
quaternary center was the next task on the agenda
(Scheme 3). In this context, functionalization of the C5
methylene carbon of ketone 16 first called for a Saegusa–Ito
oxidation [TMSOTf, NEt3; then Pd(OAc)2/O2][13] to afford
enone 17 in 75% yield over the two steps [93% based on
recovered starting material (brsm)]). After extensive optimi-
zation of the reaction conditions, conjugate addition of the
organocuprate reagent (CuBr·Me2S, TMSCl, HMPA) de-
rived from alkynyl halide 8[14] proceeded smoothly to afford
TMS enol ether 18 as a single diastereoisomer (95% brsm),
though the stereochemistry of the newly formed stereocen-
ter at C5 could not be determined at this juncture. However,
the stereochemical outcome of this alkylation process was
inconsequential due to the subsequent conversion of 18 into
enone 20 through initial enol ether hydrolysis (pTsOH) fol-
lowed by oxidative selenium chemistry (LDA, PhSeBr; then
pyridine/H2O2, 73% yield over the three steps). It is worth
noting that the direct conversion of TMS enol ether 18 into
enone 20 under enolate oxidation conditions proved less
satisfactory. Reduction of enone 20 under DIBAL-H condi-
tions afforded allylic alcohol 21 exclusively, where the newly
formed hydroxy stereocenter was crucial and indirectly vali-
dated by a later intermediate (vide infra). With allylic
alcohol 21 secured, the stage was set for the generation of
the C5 quaternary center through a Claisen-type stereo-
chemical relay (from C1). However, the fruition of this
transformation necessitated intense experimental efforts,
where the venerable Ireland–Claisen,[15] Johnson–
Claisen,[16] and selenium-mediated[17] Claisen rearrange-
ments all proved unsatisfactory. At last, implementation of
the Eschenmoser–Claisen protocol[18] (N,NЈ-dimethylacet-
amide dimethyl acetal) promoted the anticipated sigma-
tropic rearrangement with concomitant introduction of the
C5 quaternary center, as evident in product amides 22 and
23. The optimized reaction condition required microwave
irradiation at 220 °C for 1 h to afford a separable mixture
of TMS-protected alkyne 23 and terminal alkyne 22 in 37
and 41% yield, respectively, where silylation of terminal
alkyne 22 (LDA, TMSCl, 96%) permitted recycling of this
material. Next, oxygenation at the C9 position that later
represents the bridged ketone oxygen of hyperforin/PPAPs
took advantage of the iodolactonization protocol, which
proceeded in the presence of iodine in THF/H2O (3:1) to
provide lactone 24 in 90% yield. Although a stable crystal-
line derivative of iodide 24 could not be obtained for X-
ray crystallographic analysis, extensive NOESY studies of
bicyclic lactone 24 offered convincing evidence to support
Scheme 1. Retrosynthetic analysis towards the [3.3.1] bicyclic core
structure of (+)-hyperforin (1).
Our synthesis commenced with a chemoselective protec-
tion of (–)-Wieland-Miescher ketone (7) as dioxolane deriv-
ative 9,[12] and subsequent Birch reduction to provide
ketone 10 as a single stereoisomer (quant. yield over the
two steps, Scheme 2). In doing so, the C7 stereogenic center
of (+)-hyperforin was also conveniently introduced. Silyl
enol ether formation of bicyclic ketone 10 (TMSOTf, NEt3)
proceeded smoothly to afford 12 as a 9:1 mixture with its
regioisomer 11. Oxidative rupture of bicyclic silyl enol ether
12 was achieved through ozonolysis, thereby revealing sub-
stituted cyclohexane 13 upon esterification (TMSCHN2,
51% over the three steps). It is worth noting that regioisom-
eric silyl enol ether 11 could also serve as a valuable inter-
mediate to advance our hyperforin campaign forward,
where it could be obtained exclusively through Birch re-
duction of enone 9 followed by quenching with TMSCl.
Scheme 2. Synthesis of functionalized cyclohexanone 16. TMS =
trimethylsilyl, pTsOH = p-toluenesulfonic acid, Bu = butyl, OTf
= trifluoromethanesulfonate, Me = methyl, Bn = benzyl, TBAI =
tetrabutylammonium iodide.
Eur. J. Org. Chem. 2012, 484–487
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
485

J.-A. Richard, D. Y.-K. Chen
SHORT COMMUNICATION
Scheme 3. Synthesis of alkynyl ketone 27 from ketone 16. TMS = trimethylsilyl, OTf = trifluoromethanesulfonate, Ph = phenyl, Ac =
acetyl, DMSO = dimethyl sulfoxide, Bn = benzyl, LDA = lithium diisopropylamide, HMPA = hexamethylphosphoramide, pTsOH = p-
toluenesulfonic acid, DIBAL-H = diisobutylaluminum hydride, Me = methyl, MW = microwave irradiation, Et = ethyl, Bu = butyl,
DMP = Dess–Martin periodinane, brsm = based on recovered starting material.
the proposed structure and thus the indirect validation of where the latter transformation proceeded with concomi-
the stereochemical outcome of the reduction of enone 20 tant removal of the TMS group. Subsequent DMP-medi-
(Figure 2).
ated oxidation (73% over the two steps) afforded ketone 27,
in readiness for the casting of the bicyclic core structure of
(+)-hyperforin (Scheme 3).
In view of the rich repertoire of cyclization strategies
documented in the synthetic studies towards PPAPs[2] and
the synthetic versatility of alkynyl ketone 27, as a proof-of-
principal study we were first attracted to the efficiency of
the intramolecular aldol reaction that had been demon-
strated previously (Scheme 4).[5] In this context, partial re-
duction of the terminal alkyne to the corresponding alkene
was found to be capricious under a variety of conditions.
However, we soon discovered a streamlined procedure that
enabled the conversion of alkyne 27 into aldehyde 29
through initial hydrostannation [PdCl2(PPh3)2, nBu3SnH][19]
of alkyne 27. In situ generated vinyl stannane 28 was
not isolated but instead directly treated with OsO4 and
Figure 2. Proposed model for the stereoselective reduction of enone
20 and determination of the stereochemistry through key NOE cor-
relations of 24.
With the successful installation of the three crucial NMO to afford the corresponding diol, where the latter
stereogenic centers at C7, C8, and C5 of (+)-hyperforin, in compound was used in its crude form and treated with
particular the quaternary centers residing at C5 and C8, Pb(OAc)4 to furnish desired keto aldehyde 29 in 79% yield
the formation of the [3.3.1] bicyclic system was pursued in over the three steps. Gratifyingly, the proposed intramolec-
earnest. In preparation for this event, removal of the iodine ular aldol reaction proceeded smoothly under the influence
residue from 24 under standard conditions (AIBN, of NaOEt, where the so-obtained [3.3.1] bicyclic hydroxy
nBu3SnH at 80 °C) was found to be unsatisfactory, and a ketone was oxidized (DMP) to afford diketone 31 in 70%
solution was ultimately secured by performing the reaction yield over the two steps. Indeed, diketone 31 possesses the
at low temperature (i.e., –78 °C) in the presence of Et3B as key structural elements required in (+)-hyperforin and rep-
a radical initiator (79% yield). Reduction of bicyclic lactone resents a plausible intermediate to be further elaborated to
25 (LiAlH4, 95%) followed by the selective benzylation of both the naturally occurring and designed compounds in
resulting diol 26 (NaH, BnBr) took place uneventfully, view of the related synthetic work.[2]
486
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 484–487

Chiral-Pool-Based Approach to the Core Structure of (+)-Hyperforin
[2] For synthetic aspects, see: a) I. P. Singh, J. Sidana, S. B. Bhar-
ate, W. J. Foley, Nat. Prod. Rep. 2010, 27, 393–416; b) J. T.
Njardarson, Tetrahedron 2011, 67, 7631–7666.
[3] (–)-Clusianone: a) V. Rodeschini, N. S. Simpkins, C. Wilson,
J. Org. Chem. 2007, 72, 4265–4267; (+)-clusianone: b) M. R.
Garnsey, D. Lim, J. M. Yost, D. M. Coltart, Org. Lett. 2010,
12, 5234–5237; (+)- and (–)-clusianone: c) M. R. Garnsey, J. A.
Matous, J. J. Kwiek, D. M. Coltart, Bioorg. Med. Chem. Lett.
2011, 21, 2406–2409.
[4] J. Qi, A. B. Beeler, Q. Zhang, J. A. Porco Jr., J. Am. Chem. Soc.
2010, 132, 13642–13644.
[5] a) Y. Shimizu, S.-L. Shi, H. Usuda, M. Kanai, M. Shibasaki,
Angew. Chem. 2010, 122, 1121; Angew. Chem. Int. Ed. 2010,
49, 1103–1106; b) Y. Shimizu, S.-L. Shi, H. Usuda, M. Kanai,
M. Shibasaki, Tetrahedron 2010, 66, 6569–6584.
[6] a) G. Mehta, M. K. Bera, Tetrahedron Lett. 2004, 45, 1113–
1116; b) H. Usuda, A. Kuramochi, M. Kanai, M. Shibasaki,
Org. Lett. 2004, 6, 4387–4390; c) M. Abe, A. Saito, M. Nak-
ada, Tetrahedron Lett. 2010, 51, 1298–1302.
Scheme 4. Synthesis of the functionalized [3,3,1] bicyclic core of
(+)-hyperforin (1). Bn = benzyl, Bu = butyl, Ph = phenyl, Ac =
acetyl, NMO = N-methylmorpholine N-oxide, DMP = Dess–Mar-
tin periodinane.
[7] a) P. Wieland, K. Miescher, Helv. Chim. Acta 1950, 33, 2215–
2228; b) P. Buchschacher, A. Fürst, J. Gutzwiller, Organic Syn-
theses, Wiley, New York, 1990, Collect. Vol. 7, pp. 368–372; c)
T. Bui, C. F. Barbas III, Tetrahedron Lett. 2000, 41, 6951–6954.
[8] For selected examples, see: a) T. Ling, A. X. Xiang, E. A. Theo-
dorakis, Angew. Chem. 1999, 111, 3277; Angew. Chem. Int. Ed.
1999, 38, 3089–3091; b) T. Ling, C. Chowdhury, B. A. Kramer,
B. G. Vong, M. A. Palladino, E. A. Theodorakis, J. Org. Chem.
2001, 66, 8843–8853; c) T. Ling, E. Poupon, E. J. Rueden, S. H.
Kim, E. A. Theodorakis, J. Am. Chem. Soc. 2002, 124, 12261–
12267; d) T. X. Nguyen, M. Dakanali, L. Trzoss, E. A. Theo-
dorakis, Org. Lett. 2011, 13, 3308–3311; e) T. Ling, J. Xu, R.
Smith, A. Ali, C. L. Cantrell, E. A. Theodorakis, Tetrahedron
2011, 67, 3023–3029.
[9] B. Bradshaw, G. Etxebarria-Jardí, J. Bonjoch, J. Am. Chem.
Soc. 2010, 132, 5966–5967.
[10] S. Hanessian, N. Boyer, G. J. Reddy, B. Deschênes-Simard, Org.
Lett. 2009, 11, 4640–4643.
[11] a) S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B.
Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G.
Bornmann, C. A. Alaimo, C. A. Coburn, M. J. Di Grandi, J.
Am. Chem. Soc. 1996, 118, 2843–2859; b) J. J. Masters, J. T.
Link, L. B. Snyder, W. B. Young, S. J. Danishefsky, Angew.
Chem. 1995, 107, 1886; Angew. Chem. Int. Ed. Engl. 1995, 34,
1723–1726.
Conclusions
In summary, a chiral-pool approach involving the use of
(–)-Wieland–Miescher ketone (7) as a readily accessible chi-
ral building block rendered a high-yielding preparation of
the functionalized [3,3,1] bicyclic core structure of (+)-hy-
perforin (1). Key synthetic maneuvers involved oxidative
rupture of decalin 12, enone reduction/Eschenmoser–
Claisen rearrangement to cast the C5 quaternary center, a
one-pot alkyne hydrostannation/dihydroxylation to circum-
vent the troublesome alkyne partial reduction, and an ef-
ficient intramolecular aldol cyclization. Further efforts and
full account of our journey towards (+)-hyperforin (1) will
be reported in due course.
Supporting Information (see footnote on the first page of this arti-
cle): General information for the Experimental Section, experimen-
tal procedures and compound characterization, and 1H and 13C
NMR spectra for all compounds.
[12] P. Ciceri, F. W. J. Demnitz, Tetrahedron Lett. 1997, 38, 389–
390.
[13] a) Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–
1013; b) R. C. Larock, T. R. Hightower, G. A. Kraus, P. Hahn,
D. Zheng, Tetrahedron Lett. 1995, 36, 2423–2426.
[14] a) G. Lutteke, R. AlHussainy, P. J. Wrigstedt, B. T. Buu Hue,
R. de Gelder, J. H. van Maarseveen, H. Hiemstra, Eur. J. Org.
Chem. 2008, 925–933; b) L. Palais, A. Alexakis, Chem. Eur. J.
2009, 15, 10473–10485.
[15] S. Pereira, M. Srebnik, Aldrichim. Acta 1993, 26, 17–29.
[16] a) W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brock-
som, T. Li, D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc.
1970, 92, 741–743; b) K. C. Nicolaou, H. Ding, J.-A. Richard,
D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 3815–3818.
[17] R. Pitteloud, M. Petrzilka, Helv. Chim. Acta 1979, 62, 1319–
1325.
Acknowledgments
We thank Dr. Vengala Rao Ravu for early synthetic studies and
Ms. Doris Tan (ICES) for HRMS assistance. Financial support for
this work was provided by Agency for Science, Technology and
Research, Singapore.
[1] For reviews on polycyclic polyprenylated acylphloroglucinols
and phloroglucinols of natural origin along with their corre-
sponding biological activities, see: a) R. Ciochina, R. B. Gross-
man, Chem. Rev. 2006, 106, 3963–3986; b) I. P. Singh, S. B.
Bharate, Nat. Prod. Rep. 2006, 23, 558–591; for insight regard-
ing their biosynthesis, see: c) M. Dakanali, E. A. Theodorakis,
“Polyprenylated Phloroglucinols and Xanthones” in Biomime-
tic Organic Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH,
Weinheim, 2011.
[18] A. E. Wick, D. Felix, K. Steen, A. Eschenmoser, Helv. Chim.
Acta 1964, 47, 2425–2429.
[19] H. X. Zhang, F. Guilbé, G. Balavoine, J. Org. Chem. 1990, 55,
1857–1867.
Received: November 11, 2011
Published Online: December 15, 2011
Eur. J. Org. Chem. 2012, 484–487
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
487