Catalytic Enantioselective Total Synthesis of the Picrotoxane Alkaloids (-)-Dendrobine, (-)-Mubironine B, and (-)-Dendroxine

Article abstract of DOI:10.1021/acs.orglett.8b01782

A concise enantioselective total synthesis of three sesquiterpenoid alkaloids - (-)-dendrobine, (-)-mubironine B, and (-)-dendroxine - is presented, which highlights the state-of-art catalytic methods, including enantioselective Diels-Alder cycloaddition, iron-catalyzed aerobic lactonization, copper-catalyzed cycloisomerization, and free-radical-initiated hydroazidation.

Full text of DOI:10.1021/acs.orglett.8b01782

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Total Synthesis of the Picrotoxane
Alkaloids (−)-Dendrobine, (−)-Mubironine B, and (−)-Dendroxine
Lei Guo, Wolfgang Frey, and Bernd Plietker*
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A concise enantioselective total synthesis of three sesquiterpenoid alkaloids(−)-dendrobine, (−)-mubironine
B, and (−)-dendroxineis presented, which highlights the state-of-art catalytic methods, including enantioselective Diels−
Alder cycloaddition, iron-catalyzed aerobic lactonization, copper-catalyzed cycloisomerization, and free-radical-initiated
hydroazidation.
he picrotoxane family of natural products can be divided
Tinto two main subfamilies, i.e., the picrotoxane
sesquiterpenes and the dendrobine sesquiterpenoid alkaloids.
Their complex molecular framework is the result of a complex
polycyclization of farnesyl pyrophosphate and subsequent ring
rearrangement to give the bicyclo[4.3.0]nonane core that is
common in all picrotoxane natural products. Site-selective
oxidation of the C-5/C-9 methyl groups and the adjacent C-2/
C-3-methylene groups delivers the tricyclic skeleton found in
the aforementioned subfamilies.1 Further site-selective late-
stage aminations lead to dendrobine sesquiterpenoid alkaloids,
such as dendrobine 4,2 mubironine 5,3 or dendroxine 64 (see
Figure 1).
achiral substrates have been published. In 2004, Corey
reported a formal total synthesis by accessing Kende’s
intermediate via a catalytic, enantioselective Diels−Alder
reaction.7c,8e While the present work was in progress, Chen
published a catalytic enantioselective formal synthesis of
dendrobine by accessing the same intermediate via an
asymmetric allylation reaction.8f Herein, we report a 10-/11-
step total synthesis of (−)-dendrobine 4, (−)-mubironine B 5,
and (−)-dendroxine 6 featuring an asymmetric catalytic Diels−
Alder reaction as an enantioselective key step (Figure 2).
In our retrosynthetic analysis (Figure 2), we envisioned
dehydropyrrolidine 7 to be a key intermediate for the final
elaboration into the three alkaloids under either reductive or
redox-neutral conditions. Disconnection of the imine in 7
would lead to amine 8, which could be realized by the
challenging direct anti-Markovnikov hydroazidation reaction
from olefin 9.9 The cyclopentane in 9 possessing a quaternary
stereocenter could be derived from lactone 11 via a conjugate
addition and catalytic cycloisomerization reaction.10 Before
lactonization of 12 to lactone 11 under catalytic aerobic
conditions,11 the introduction of chirality could be realized via
an enantioselective catalytic [4 + 2]-cycloaddition using
12−14
́
Danishefskys diene 13.
The synthesis started with a screening of enantiopure Lewis-
acid catalyst for the asymmetric Diels−Alder reaction between
diene 13 and oxazolidinone 14 (see Table 1). However,
cationic Cu2+-box complexes did not provide any product
(Table 1, entry 1),13 with cationic Fe3+ and (R,R)-Ph-pybox L1
yielded the desired product in moderate yield with high
diastereoselectivity but low enantioselectivity (Table 1, entries
Figure 1. Biosynthesis of dendroine sesquiterpenoid alkaloids.
Dendrobine 4 as the most prominent representative of the
reported sesquiterpenoid alkaloids was isolated in the 1930s
from Dendrobium nobile Lindl.2 It shows hypertensive,
antipyretic, analgesic, and anti-influenza A virus activities.5
Fifteen formal and total syntheses of this natural product have
been reported,6−8 three of which are enantioselective chiral-
pool total syntheses.6 To date, only two reports in which
chirality was introduced via enantioselective catalysis using
Received: June 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01782
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Letter
Scheme 1. Synthesis of Key Intermediate 9
Figure 2. Retrosynthesis of dendrobine sesquiterpene alkaloids.
Table 1. Asymmetric Catalytic [4 + 2] Cycloaddition
a
entry
catalyst
ligand
additive
t (°C) yield (%)/ee (%)
b
1
Cu(OTf)2
FeBr3
FeBr3
FeBr3
Yb(OTf)3
L1
L1
L1
L2
L3
AgBF4
AgBF4
AgBF4
AgBF4
DBU
−40
−40
−50
−40
0
−/−
47/0
25/17
33/−25
78/91
b
2
b
3
b
4
c
With diol 12 in hand, we envisioned Ma’s most recently
reported aerobic Fe-catalyzed oxidation of alcohols to
carboxylic acids to offer the chance for an aerobic Fe-catalyzed
oxidative lactonization.11 Indeed, upon subjecting diol 12 to
Ma’s reaction condition, a chemoselective oxidation of the
primary alcohol to the corresponding aldehyde and direct
formation of the desired lactone 11 through condensation with
the secondary alcohol at C-6, followed by hemiacetal oxidation
in 89% yield was observed (see Scheme 1). Notably, the use of
alternative oxidation conditions (TPAP/NMO, Swern-oxida-
tion, etc.) led to aromatization. With lactone 11 in hand, we set
out to install the central cyclopentane motif. Diastereoselective
conjugate addition of 4-bromo-1-trimethylsilylbut-1-yne-de-
rived cuprate, followed by methylation of the resulting copper
enolate 18 and desilylating workup led to the isolation of
stereoisomerically pure ketone 10 in 64% overall yield (see
Scheme 1).
Transformation of 10 into the corresponding TBS-enolether
19 under thermal conditions and subsequent treatment with
Ph3PAuCl/AgBF4 resulted in a clean cyclization and a clean
installation of the quaternary center in 9.10a Traditionally, the
weak nucleophilicity of ketone requires the synthesis of TBS-
enolether as a well-precedented nucleophilic species to attack
the Au+-complexed alkyne. Through application of Dixon’s
5
a
Isolated yield, the enantio excess was determined by compound 17.
b
c
The reaction was stirred at indicated temperature for 7 h. The
reaction was stirred at 0 °C for 3 h.
2 and 3).14 To our delight, Nishida’s condition with Yb-(R)-
BINUREA complex Yb-L3 delivered the product with high
diastereo- and enantioselectivity in 78% yield (Table 1, entry
5).12
With the scalable [4 + 2] cycloaddition in hand, we
attempted to use the oxazolidinone motif for a direct lactone
formation through a one-pot oxazolidinone hydrolysis with
H2O2/LiOH, and subsequent substrate-directed Rubottom-
oxidation−epoxide opening−lactonization. However, we were
not able to isolate any of the desired or intermediate
products.15 At this point, we decided to treat oxazolidinone
16 directly with LiBH4 and subsequent acidic workup to give
cyclohexenone 17 with 71% yield and an enantiomeric excess
of 91% (see Scheme 1). Cyclohexenone 17 was converted to
α-hydroxyketone 12 in a diastereoselective Rubottom
oxidation in 82% yield and with correct relative configuration
of the hydroxy group.
B
DOI: 10.1021/acs.orglett.8b01782
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most recently published method on Cu-enamine co-catalyzed
cycloisomerization, a direct conversion of 10 to 9 without the
need for the formation of an labile silylenolether was possible,
albeit at lower overall yield, compared to the two-step Au-
catalyzed sequence.10b Notably, attempts to combine the two
Cu-mediated steps in a sequential manner (1,4-addition and
subsequent cycloisomerization) were not successful. However,
at this stage, we were able to improve the enantiomeric excess
of 9 upon recrystallization to 99% with 86% yield.
accomplished in 11 or 10 steps with 6.7%, 7.8%, and 7.4%
yields, respectively. The spectroscopic data of our synthesized
alkaloids are identical to the data reported in the literature (see
Scheme 2).
In conclusion, we report here a concise catalytic
enantioselective total synthesis of (−)-dendrobine, (−)-mubir-
onine B, (−)-dendroxine overall yields of 6.7%, 7.8%, and
7.4%, respectively. The key to the efficiency of the total
syntheses is the use of an Yb-catalyzed enantioselective Diels−
Alder reaction to generate the central six-membered ring, a Fe-
catalyzed oxidative intramolecular lactonization, a Au- (or Cu-
)catalyzed cycloisomerization for the construction of the
central cyclopentane motif featuring a exocyclic methylene
group, and finally, a hydroboration-radical azidation to furnish
the C−N-bond necessary to accomplish the formation of the
pyrrolidine moiety.
With olefin 9 in hand, we set out to finish the synthesis of
the three alkaloids (see Scheme 2). Unexpectedly, the
Scheme 2. Total Synthesis of (−)-Dendrobine 4,
(−)-Mubironine B 5, and (−)-Dendroxine 6
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01782.
Experimental procedures for preparation of starting
materials and products, full characterization of all
1
reported compounds, H NMR, 13C NMR, IR, HRMS
spectra (PDF)
Accession Codes
CCDC 1831627 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernd.plietker@oc.uni-stuttgart.de.
ORCID
Lei Guo: 0000-0001-7038-8053
Bernd Plietker: 0000-0001-8423-6173
Notes
envisioned direct hydroamination of the 1,1-disubstituted
double bond proved to be troublesome, which is an
observation that might be explained by the steric hindrance
imposed by the adjacent all-carbon quaternary center.15
Consequently, a hydrozirconition/amination sequence16 or
copper-catalyzed direct hydroamination17 failed to give any
products. After several unsuccessful attempts, we decided to
make use of Renaud’s most recently published anti-
Markovnikov-type hydroazidation through hydroboration of
9 to 20 and subsequent free-radical-initiated azidation of the
C−B-bond in 20.9 This approach was successful and delivered
the desired C−N-bond with exclusive diastereoselectivity and
regioselectivity (see Scheme 2).
Azide 8 was isolated in 47% yield over two steps.
Gratifyingly, the intramolecular Staudinger-aza-Wittig reaction
of 8 led to a clean formation of dehydropyrrolidine 7,6a from
which (−)-dendrobine 4 and (−)-mubironine B 5 were
obtained under reductive conditions and N-methylation. Upon
treatment of imine 7 with 2-iodoethanol under thermal
conditions, (−)-dendroxine 6 was obtained. In summary, the
enantioselective total synthesis of 4, 5, and 6 were
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Deutsche Forschungsgemeinschaft
and the Chinese Scholarship Council (through a Ph.D. grant
for L.G.) is gratefully acknowledged. We are grateful to Dr.
Wolfgang Frey (Institut fur Organische Chemie, Universitat
̈
̈
Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart, Germany)
for X-ray structure analysis.
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DOI: 10.1021/acs.orglett.8b01782
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