Enantioselective total synthesis of hyperforin

Article abstract of DOI:10.1021/ja312150d

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3

Full text of DOI:10.1021/ja312150d

Communication
pubs.acs.org/JACS
Enantioselective Total Synthesis of Hyperforin
Brian A. Sparling, David C. Moebius, and Matthew D. Shair*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
Our strategy for the construction of hyperforin is shown in
Scheme 1. The synthesis can be deconstructed into the
ABSTRACT: A modular, 18-step total synthesis of
hyperforin is described. The natural product was quickly
accessed using latent symmetry elements, whereby a
group-selective, Lewis acid-catalyzed epoxide-opening
cascade cyclization was used to furnish the bicyclo[3.3.1]-
nonane core and set two key quaternary stereocenters.
Scheme 1. (A) Synthesis Strategy for Hyperforin (1) and (B)
Comparison of This Work to Hyperforin Biosynthesis
yperforin (1)1,2 was first isolated in 1971 from St. John’s
H
wort (Hypericum perforatum L.) and is now considered to
be the constituent of the medicinal herb responsible for its
antidepressant activity.3,4 Hyperforin blocks the re-uptake of a
variety of neurotransmitters through a unique mechanism of
action, possibly by selectively activating TRPC6 (classical
transient receptor potential protein).5 TRPC6 activation leads
to a cellular influx of Na+ and Ca2+, diminishing membrane
electrochemical gradient (thus indirectly inhibiting neuronal
neurotransmitter reuptake) and triggering cell differentiation.
As a selective activator of TRPC6, hyperforin is a powerful
probe of TRPC6 biology, a critical lead for the treatment of
depression and possibly other human diseases. However, the
therapeutic potential of hyperforin is severely handicapped by
its poor water solubility, facile oxidative degradation upon
exposure to light and air,6 and potent activation of pregnane X
receptor,7 leading to increased expression of many genes
involved in xenobiotic metabolism. Access to a wide variety of
hyperforin analogues is critical for mitigating these short-
comings while maintaining TRPC6 activation. While limited
semisynthetic manipulation of isolated hyperforin is feasible,8
total synthesis is the only possible means of obtaining diverse
hyperforin analogues.
Structurally, hyperforin is one of over 200 polycyclic
polyprenylated acylphloroglucinol (PPAP) natural products.9
Many PPAPs are characterized by a highly oxidized
bicyclo[3.3.1]nonane core densely substituted with terpenoid
side chains. Widespread interest in their bioactivity and
structural complexity has culminated in the total syntheses of
several PPAPs.10 While these PPAPs contain a geminal
dimethyl group at the C8 position (hyperforin numbering),
differential substitution at the hyperforin C8 position renders
these otherwise effective strategies inapplicable toward hyper-
forin total synthesis. Numerous approaches toward hyperforin11
have only resulted in one total synthesis of ent-hyperforin,
accomplished by the Shibasaki group in 2010.12 Given the
considerable length of this route (51 steps from propargyl
bromide), we set out to devise a new enantioselective approach
that would not only incorporate elements of modularity but
also exploit latent symmetry. A practical total synthesis would
enable the first full SAR study of hyperforin.
stepwise fusion of six easily obtainable chemicals (Scheme 1A).
We postulated that 1 would be accessible from alcohol 2
through bridgehead acylation at C1 and prenylations at C3 and
C7. We would access key intermediate 2 from cyclohexadiene 3
via a group-selective, Lewis acid-mediated epoxide-opening
cyclization. Cyclohexadiene 3 would be synthesized in two
steps through the regioselective coupling of 1,5-dimethoxy-1,4-
cyclohexadiene 4 with prenyl chloride 5 and known
epoxygeranyl bromide 6.13
In developing our hyperforin synthesis, we drew inspiration
from its proposed biosynthesis14 (Scheme 1B). In nature,
hyperforin is formed from alkylation of a nucleophilic,
Received: December 12, 2012
© XXXX American Chemical Society
A
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Communication
polyketide-derived acylphoroglucinol with geranyl pyrophos-
phate. Stereochemical fidelity over the course of this coupling
in the biosynthesis is governed by enzyme catalysis.
favored to yield 7 over its diastereomeric transition state TS-2,
which must adopt a boat-like conformation containing two
severe eclipsing interactions in forming 8. Additionally, a 6-
(enolendo)-tet cyclization should be favored over a 5-(enol-
endo)-tet cyclization due to geometric constraints of the
substrate.15 The contributions of these factors culminate in
(1) the formation of the hyperforin bicyclo[3.3.1]nonane
skeleton; (2) the introduction of stereochemistry at the C5
quaternary position; and (3) the creation of a stereogenic
quaternary center at C8.
Our synthesis of hyperforin is depicted in Scheme 3.
Oxymercuration followed by reductive workup of epoxygeranyl
bromide 6 and subsequent TESCl-mediated silylation gave 9.
Over the course of the synthesis, it became apparent that
formal silanolysis of the olefin present in 6 was indispensible.
Deprotonation of cyclohexadiene 4 with t-BuLi, treatment with
freshly prepared BaI2,16 and alkylation with prenyl chloride 7
yielded diene 11. In the absence of BaI2, non-regioselective
prenylation across the pentadienyl anion took place. Coupling
of 9 with the anion generated from diene 11 and s-BuLi gave
cyclization precursor 12.
We envisioned utilizing a similar bond disconnection in the
key cyclization of our synthesis, specifically one involving a
geraniol-derived fragment. While unable to exploit enzyme-
driven stereoselection, we postulated that an epoxide
functionality strategically placed in the geraniol fragment
would be an effective means of relaying stereochemical
information to the C1, C5, and C8 carbon centers, when
employed in concert with a truncated, symmetric cyclo-
hexadiene ring.
An analysis of the cyclization of 3 is depicted in Scheme 2.
Owing to the symmetry of compound 3, the quaternary carbon
Scheme 2. Transition-State Analysis of the Cyclization of 3
Gratifyingly, exposure of 12 to TMSOTf and 2,6-lutidine
gave the ketal 13 in 79% yield as the only isolated product. As
previously mentioned, the stereochemistry of two key
quaternary centers were established as a result of this
transformation: at the previously prostereogenic C5 carbon,
and at the C8 position. Aside from the construction of the
bicyclo[3.3.1]nonane framework, the formation of a cyclic
methyl ketal was an unexpected yet fortuitous outcome to this
reaction, safeguarding the C7 carbinol during the subsequent
allylic oxidation step. The efficiency of this approach was
demonstrated by our ability to easily prepare 60 g of 13.
After extensive optimization, allylic oxidation of 13 was
at C5 is prostereogenic, and the two methyl enol ethers are
diastereotopic. Exposure of 3 to Lewis acid activates the
epoxide for nucleophilic attack. While either methyl enol ether
may engage this activated epoxide, transition state TS-1 is
17
accomplished using TBHP, PhI(O2CCF3)2, and O2 to afford
a
Scheme 3. Total Synthesis of Hyperforin (1)
a
Conditions: (a) Hg(OAc)2, Me2CO/H2O; NaOH, 0 °C; NaBH4, 0 °C, 91%; (b) TESCl, imid, DMF, 97%; (c) t-BuLi, THF, −78 °C; BaI2, −78 °C;
5, −78 to −5 °C, 85%; (d) 11, s-BuLi, THF, −78 to −30 °C; 9, −78 to −40 °C, 85%; (e) TMSOTf, 2,6-lut, CH2Cl2, −78 °C, 79%; (f)
PhI(O2CCF3)2, TBHP, Cs2CO3, 4 Å MS, EtOAc, O2, −78 to 0 °C, 44%; (g) BrBMe2, NEt3, CH2Cl2, −95 °C; NEt3; sat. aq. NaHCO3, 57%; (h)
LiTMP, THF, −78 to 0 °C, 97%; (i) ClC(S)OC6F5, N-hydroxysuccinimide, pyr, PhMe, 80 °C, 82%; (j) allyl−SnBu3, BEt3, PhH, air, 72%; (k) 17, 2-
methyl-2-butene, CH2Cl2, 40 °C, 86%; (l) LiTMP, TMSCl, THF, −78 to 0 °C, 90%; (m) LiTMP, THF, −78 to 0 °C; i-PrC(O)CN, −78 to −30 °C,
49%; (n) p-TsOH·H2O, PhMe, HOAc, 2-methyl-2-butene, microwave, 100 °C, 65%; (o) LDA, THF, −78 °C; Li(2-Th)CuCN, −78 to −40 °C;
prenyl bromide, −78 to −30 °C, 98%; (p) LiCl, DMSO, 120 °C, 55%.
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Journal of the American Chemical Society
Communication
vinylogous ester 14.18 This was an exceptionally challenging
transformation given the four allylic sites present in 13 and the
steric environment surrounding the desired oxidation site.
Hydrolysis of the ketal present in 14 to yield alcohol 15 was
ACKNOWLEDGMENTS
■
We acknowledge financial support from Chemiderm, Inc.
B.A.S. acknowledges a NSF Predoctoral Fellowship.
19
performed in two steps: treatment of 14 with BrBMe2
REFERENCES
■
followed by LiTMP-mediated methanol extrusion from the
intermediate hemiketal. It was crucial to maintain the
temperature of the BrBMe2-mediated hydrolysis below −90
°C; above this temperature, elimination of the triethylsilyl ether
was observed.
After surveying a variety of methods to install the C7 prenyl
group from 15, we pursued a radical Keck allylation approach.20
A radical precursor, thionocarbonate 16, was generated from
the reaction of alcohol 15 with ClC(S)OC6F5.21 Using BEt3/air
as an initiator, radical allylation of 16 with allyl−SnBu3 afforded
a product containing a C7 allyl group as a single diastereomer.
Employing more reactive radical precursor functionality or
either photochemical or thermal radical generation conditions
gave inferior results for this coupling reaction. An ensuing
cross-metathesis with 2-methyl-2-butene catalyzed by Hovey-
da−Grubbs second-generation catalyst 1722 afforded 18
containing the requisite C7 prenyl moiety.
After silylation at the C3 position, sequential bridgehead
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noteworthy given that previously reported instances of PPAP
bridgehead acylation at the C1 position require multiple steps
involving a bridgehead iodide intermediate.10b,d,l One-pot
desilylation and elimination to give 20 was accomplished
through microwave irradiation of 19 with p-TsOH·H2O. The
final C3 prenyl group was installed utilizing a precedented
sequence23 to afford hyperforin methyl ether 21:24 (1)
deprotonation of 20 with LDA, (2) transmetalation with
Li(2-Th)CuCN,25 and (3) trapping with prenyl bromide.
Finally, hyperforin (1) was revealed by heating a DMSO
solution of 21 with LiCl.
In summary, we report an enantioselective total synthesis of
hyperforin. The synthesis is 18 steps at its longest sequence,
starting from geraniol. This approach is also highly scalable; to
date, we have prepared over 40 mg of hyperforin. Latent
symmetry elements were utilized to quickly access the
hyperforin bicyclo[3.3.1]nonane core and to set two key
quaternary stereocenters, specifically in the conversion of
epoxide 12 to ketal 13. This practical and modular route is
already being exploited to create diverse hyperforin analogues,
which we are using to further understand the SAR and
underlying mechanisms of hyperforin biological and medicinal
activity. Results from these studies will be reported in due
course.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and H and 13C
1
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
shair@chemistry.harvard.edu
Notes
The authors declare no competing financial interest.
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