Asymmetric Synthesis of the Antiviral Diterpene Wickerol A

Article abstract of DOI:10.1021/jacs.7b05046

Wickerol A (1) is an unusual diterpene with remarkable activity against the H1N1 influenza virus. Its tetracyclic skeleton contains three quaternary carbons and is marked by several syn-pentane interactions which force a six-membered ring into a twist-boat conformation. We present an asymmetric synthesis of wickerol A (1) that is based on a Jung Diels-Alder reaction, an intramolecular alkylation to complete the 6-5-6-6 ring system, and a conjugate addition, all of which overcome considerable steric strain. During the synthesis, we isolated an unexpected cyclopropane that presumably stems from a carbonium ion intermediate.

Full text of DOI:10.1021/jacs.7b05046

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Communication
Asymmetric Synthesis of the Antiviral Diterpene Wickerol A
Shu-An Liu, and Dirk Trauner
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Jun 2017
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Asymmetric Synthesis of the Antiviral Diterpene Wickerol A
ShuꢀAn Liua and Dirk Traunera,b
aDepartment of Chemistry and Center for Integrated Protein Science, LudwigꢀMaximiliansꢀUniversität Munich, Butenꢀ
andtstraße 5ꢀ13, 81377 Munich, Germany
bDepartment of Chemistry, New York University, 100 Washington Square East, New York, NY 10003, United States
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Supporting Information Placeholder
ABSTRACT: Wickerol A (1) is an unusual diterpene with
remarkable activity against H1N1 influenza virus. Its tetracyclic
skeleton contains three quaternary carbons and is marked by
several synꢀpentane interactions which force a sixꢀmembered
ring into a twistꢀboat conformation. We present an asymmetric
synthesis of wickerol A (1) that is based on a Jung Diels–Alder
reaction, an intramolecular alkylation to complete the 6ꢀ5ꢀ6ꢀ6
ring system, and a conjugate addition, all of which overcome
considerable steric strain. During the synthesis, we isolated an
unexpected cyclopropane that presumably stems from a carbonꢀ
ium ion intermediate.
Figure 1. Structure of wickerol A (1) and B (2).
Terpenes continue to challenge synthetic chemists with the
complexity of their hydrocarbon scaffolds,[1] which are often
highly strained. This strain can be photochemical in origin but
usually stems from to the ability of terpene cyclases to bend
linear cyclization precursors into highꢀenergy conformations
and promote hydride and carbonꢀcarbon bond shifts that are
otherwise unlikely to proceed.[2] A case in point are the wickꢀ
erols, two bioactive diterpenes isolated from the fungus Tricho-
derma atroviride FKIꢀ3849 by Ōmura and Shiomi (Fig. 1).[3]
Wickerol A (1) proved to be highly active against the type
A/H1N1 influenza virus with an IC50 of 0.07 ꢁg/mL, whereas
wickerol B (2), which differs from its congener only by hyꢀ
droxylation at C8, was significantly less potent (IC50 of 5.0
ꢁg/mL). Wickerol B (2) turned out to be identical with the preꢀ
viously reported natural product trichodermanine A (2).[4] Both
natural products feature a unique tetracyclic carbon skeleton
that comprises two adjacent quaternary carbons and seven steꢀ
reocenters, two of which are quaternary as well. Although the
6ꢀ5ꢀ6ꢀ6 skeleton of the wickerols contains only five and sixꢀ
membered primary rings, the molecules are remarkably strained
due to numerous synꢀpentane interactions. These primarily
involve the angular methyl group at C10a which force the Dꢀ
TBSO
intramol.
alkylation
X
O
Me
Me
Me
H
H
O
H
H
H
Me
O
OH
OTBS
Me
Diels-Alder
3
4
X = H wickerol A (1)
X = OH wickerol (2)
B
TBSO
HO
Me
Me
+
O
OTBS
O
7
5
6
Scheme 1. Retrosynthetic analysis of the wickerols.
Key intermediate 4, which contains all carbons of the wickerols
save two, could be accessed with a Diels–Alder addition[6] of
known enone 5[7] to diene 6. The latter in turn, would be deꢀ
rived from known ketone 7, which is readily accessible from
ring into
a boat conformation, as confirmed by Xꢀray
analysis.[3] The corresponding strain was estimated to be in the
range of 60ꢀ70 kJ/mol (see the Supporting Information for DFT
calculations on isomers of Wickerol A).
geraniol
via
Sharplessꢀepoxidation,
Yamamotoꢀ
rearrangement[8] and carbonyl–ene cyclization.[9]
Despite the formidable challenge posed by the wickerols, only a
single synthetic study has been disclosed to date.[5] We now
report an asymmetric synthesis of wickerol A (1) that is a tesꢀ
tament to the power of catalysis in cycloadditions and the many
pleasant and unpleasant surprises that one encounters when
working with complex, sterically congested molecules.
Our actual synthesis commenced with the Diels–Alder
addition[10] of the achiral enone 5 to the chiral diene 6, which
could be procured from 7[9] in two steps (see Supporting Inforꢀ
mation). The intermolecular cycloaddition represented a major
challenge since both partners, though electronically matched,
are sterically very hindered. Initially, we explored thermal or
high pressure conditions,[11] but all our efforts in this regard
proved to be unsuccessful.
Our synthetic strategy toward the wickerols is shown in
Scheme 1. We envisioned that both could be derived from a
diketone of type 3 via conjugate reduction and addition of a
methyl group. Disconnection of the Cꢀring would lead to a
spiro tricycle of type 4. In the forward direction, the ring would
be closed through an intramolecular alkylation.
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tions). Epimerization to the desired trans hydrindanone under a
Scheme 2. Synthesis of wickerol A (1).
variety of conditions proved unsuccessful, reflecting a thermoꢀ
dynamic preference of ca. 14 kJ/mol for the cis fusion (see
Supporting information).[17] To solve this problem, we turned to
the Grainger method, which has proven to be very useful in the
synthesis of transꢀhydrindanes.[18] Thus, we selectively reduced
one of the carbonyl groups in 8, eliminated the resultant secꢀ
ondary alcohol regioselectively using Burgess reagent,[19] and
dihydroxylated[20] the resultant alkene from the more accessible
face, which yielded diol 9. Treatment of 9 under Grainger’s[18b]
conditions indeed afforded the desired transꢀfused hyꢀ
drindanone via stereospecific hydride shift. To prevent epimeriꢀ
zation during workup, we reduced the carbonyl group in situ,
which gave alcohol 10. The desired A,Bꢀring trans junction
was confirmed by Xꢀray structure analysis of diol 21, obtained
through TBSꢀdeprotection of the primary hydroxyl group (Figꢀ
ure 2 and Supporting Information).
We then focused our attention on Lewis and Brønsted acid
activation and found that commonly used Lewis acids such as
BF3·Et2O, BCl3, TiCl4, SnCl4, Tf2NH,[12] Me2AlNTf2,[13]
Me2AlCl, Et2AlCl or AlCl3 resulted in desilylation of 6, dimeriꢀ
zation of 5 via heteroꢀDiels–Alder reaction, or Mukaiyama–
Michael addition without ring closure. However, Jung’s condiꢀ
tions, which employ a mixture of AlBr3/AlMe3 as a catalyst,
gave the desired endoꢀproduct 4 as a single diastereomer.[14]
Both the quaternary and the neopentylic stereocenters were set
with the correct simple and induced diastereoselectivity. Preꢀ
sumably, the enone approaches the diene via an endoꢀtransition
state and the methyl group provides less steric hindrance than
the silyloxy methyl moiety.
With three of the four rings of wickerol A (1) established, we
set out to prepare the requisite precursor for the intramolecular
alkylation. For that purpose, a 1,3ꢀtranspostion of the carbonyl
group in 4 was necessary, which we envisioned to achieve
through 1,2ꢀmethyl addition, elimination of the resulting terꢀ
tiary alcohol and allylic oxidation. Unfortunately, all attempts
to add an organometallic reagent[15] to 4 or perform an olefinaꢀ
tion[16] failed, presumably due to the extreme steric hindrance
of the carbonyl group or its competing enolization. We hypothꢀ
esized that establishing the correct configuration at the A,Bꢀ
ring junction would lead to a conformational change that would
make the ketone more accessible. Upon hydrolysis of Diels–
Alder product 4, however, we obtained unwanted cisꢀ
hydrindanone 8 as the sole product. Notably, the corresponding
cisꢀfused isomer of wickerol A is less stable than the transꢀ
fused isomer (see Supporting Information for DFT calculaꢀ
Having set the correct configuration at C2a, we turned to the
modification of ring D. Again, the carbonyl group at C6 proved
to be unreactive toward methyl addition or methylenation.
Therefore, we protected the secondary alcohol as a MOM ether
and reduced the resultant ketone with DIBALꢀH, which gave
alcohol 11 in excellent yield. Subsequent elimination could
only be achieved by exposure to Martin’s sulfurane.[21] This
gave alkene 12, albeit together with an inseparable side product
in a 2:1 ratio. Since all attempts at improving this ratio were
unsuccessful, we subjected the mixture to a Mn(OAc)3ꢀ
mediated allylic oxidation,[22] which provided enone 14. The
unreacted side product could be separated at this stage. It was
identified as cyclopropane 13 through NMR and Xꢀray strucꢀ
ture analysis of a derivative, diol 22 (Figure 2 and Supporting
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Information). Presumably, 13 is formed via a carbonium ion,
In summary, we have developed the first total synthesis of a
wickerol. Our convergent strategy allowed for the rapid assemꢀ
bly of the complex carbon framework but encountered probꢀ
lems with steric hindrance and unexpected thermodynamic and
kinetic preferences, which could be successfully overcome.
Salient features of our synthesis are a powerful Diels–Alder
reaction to provide most of the rings and carbons, a stereospeꢀ
cific hydride shift to install the challenging C,Dꢀring trans juncꢀ
tion, and an intramolecular alkylation to close a bond between
two neopentylic carbons. Also of note are a stereoselective
conjugate addition to a sterically hindered enone and a final
Mukaiyama hydration to establish the tertiary alcohol. The
isolation of cyclopropane 13 is another example of the unexꢀ
pected results that make the total synthesis of complex natural
products so rewarding.
which nicely corresponds to the biosynthesis of terpenoid cyꢀ
1
2
3
4
5
6
7
8
clopropanes.[23]
To set the stage for the crucial intramolecular ring closure, the
primary alcohol function in 14 was deprotected and mesylated,
giving rise to the key intermediate 15. To our delight, treatment
of 15 with KHMDS gave the desired tetracycle 16, of which a
Xꢀray crystal structure could be obtained (Fig. 2). The ease with
which this intramolecular alkylation proceeded was surprising
considering the synꢀpentane strain built up in its course and the
conformational changes that are necessary for the two ends to
meet.[24] Interestingly, the reaction showed a strong counterion
effect, with the yield significantly decreasing when NaHMDS
or LiHMDS were employed.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. The Supporting Information conꢀ
tains detailed experimental procedures, spectral data and Xꢀray
crystallography (PDF). CCDC 1550221, CCDC 1550223,
CCDC 1550222 contain the supplementary crystallographic
data for 21, 22, 16 and can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
https://www.ccdc.cam.ac.uk/structures/.
AUTHOR INFORMATION
Figure 2. Xꢀray structures of 21, 22 and 16.
Corresponding Author
With the ring system of wickerol A (1) complete, we turned to
the introduction of the missing methyl groups. The methyl
group on the D ring could be added with complete diastereoseꢀ
lectivity by exposure of 16 to methyl lithiocyanocuprate in the
presence of BF3·Et2O.[25] Given the steric hindrance at the neoꢀ
pentylic βꢀposition and the introduction of additional synꢀ
pentane strain, it is remarkable that this reaction proceeded at
all.
*Eꢀmail: dirktrauner@nyu.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Next, we attempted the removal of the carbonyl group in the
resultant ketone 17 via WolffꢀKishner[26] or Mozingo reducꢀ
tion.[27] Since these failed, we developed a reliable threeꢀstep
sequence involving hydride reduction, xanthate formation and
Barton–McCombie deoxygenation.[28] Deprotection of the
MOM ether and oxidation with DMP then afforded ketone 18.
We thank the Deutsche Forschungsgemeinschaft (SFB749) and
the Studienstiftung des Deutschen Volkes for financial support,
Dr. Bryan Matsuura for experimental help with the synthesis,
and Dr. Peter Mayer for Xꢀray analysis. Furthermore, we are
grateful to Dr. Julius R. Reyes and Dr. HongꢀDong Hao for
helpful discussions and to Dr. Giulio Volpin and Matthias
Schmid for assistance with preparing this manuscript.
The final challenge of the synthesis was provided by the methyl
addition to 18 to afford wickerol A (1). Addition of a methyl
Grignard or methyllithium species to ketone 18 gave 3ꢀepiꢀ
wickerol A (20) as the sole product. In the presence of the Lewꢀ
is acid MAD,[29] which is known to invert the stereoselectivity
of nucleophilic attacks to cyclohexanones, we obtained a 1:4
mixture of wickerol A (1) and its C3ꢀepimer. Since we were not
able to overcome the strong substrate bias with additives,[30] we
subjected ketone 18 to Wittig olefination. A subsequent Mukaiꢀ
yama hydration[31] gave wickerol A (1) together with 3ꢀepiꢀ
wickerol A (20) as an almost equimolar mixture, which could
be separated by chromatography.
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The H and 13C NMR data of our synthetic wickerol A (1) are
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neopentylic
syn-pentane
O
O
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KHMDS
OMOM
OH
OMOM
OMs
wickerol A
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