Bioinspired total synthesis of bolivianine: A diels-alder/intramolecular hetero-Diels-Alder cascade approach

Article abstract of DOI:10.1021/ja4040335

We report the first total synthesis of bolivanine in a 14-step pathway involving the synthesis of onoseriolide. Our synthesis features a palladium-catalyzed intramolecular cyclopropanation involving an allylic metal carbene and a Diels-Alder/intramolecular hetero-Diels-Alder cascade, allowing the single-step assembly of a tricyclic system with proper configuration. The synthetic efforts validate our modified biogenetic hypothesis and allow us to confirm the absolute configuration of bolivianine.

Full text of DOI:10.1021/ja4040335

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Communication
Bioinspired Total Synthesis of Bolivianine: a Diels- Alder/
Intramolecular Hetero-Diels-Alder Cascade Approach
Changchun Yuan, Biao Du, Li Yang, and Bo Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4040335 • Publication Date (Web): 28 May 2013
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Bioinspired Total Synthesis of Bolivianine: a Diels- Alder/
Intramolecular Hetero-Diels-Alder Cascade Approach
Changchun Yuan,† Biao Du,† Li Yang,† and Bo Liu*,
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† ‡
† Key Laboratory of Green Chemistry & Technology of the Ministry of Education, College of Chemistry, Sichuan
University, Chengdu, Sichuan 610064, China
‡ Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Shanghai 200032,
China
Supporting Information Placeholder
bolivianine (1) (path a). Alternatively, initial oxidation of
ABSTRACT: We report the first total synthesis of bolivanine in
onoseriolide (2) could furnish 3, which could couple with 7 to
a 14-step pathway involving the synthesis of onoseriolide. Our
yield bolivianine (1), via either a Diels-Alder/intramolecular
synthesis features
a
palladium-catalyzed intramolecular
hetero-Diels-Alder pathway (DA/IMHDA, path b) or a hetero-
Diels-Alder/intramolecular Diels-Alder pathway (HDA/IMDA,
path c). Here we report our investigations into these different
pathways and describe the total synthesis of onoseriolide and
bolivianine.
cyclopropanation involving an allylic metalcarbene, and a Diels-
Alder/intramolecular hetero-Diels-Alder (DA/IMHDA) cascade,
making the single-step assembly of a tricycle system with proper
configuration. The synthetic efforts validate our modified
biogenetic hypothesis and have allowed us to confirm the
absolute configuration of bolivianine.
Scheme 1. Hypotheses for biogenesis of bolivianine
A. Proposed hypothesis by the Jullian group:
GPP
PPO
H
H
H
In 2007, the structurally complex sesterterpenoid, bolivianine,
was isolated by the Jullian group from Hedyosmum angustifolium
(Chloranthaceae), along with an artifact named isobolivianine.1
Bolivianine contains a glaring heptacyclic skeleton and nine
stereogenic centers. The complexity of this molecule has made it
an alluring biosynthetic and chemically synthetic target. The
Jullian group proposed a hypothesis for its biogenesis. As
illustrated in Scheme 1A, the enal 3 could be accessed via allylic
oxidation of onoseriolide, a lindenane-type sesquiterpenoid that
occurs together with bolivianine in H. angustifolium.2
Simultaneous hydrolysis of 3 and nucleophilic attack on
geranylpyrophosphate (GPP), followed by the double bond
migration of the geranyl moiety, could generate intermediate 4.
Subsequent ene reaction, lactonization and finally intramolecular
hetero-Diels-Alder cycloaddition could furnish bolivianine.
O
O
O
1) SN
2
R
[O]
H
H
O
O
O
CO2H
2) alkene
isomerization
H
H
O
OH
CHO
3
onoseriolide (2)
4, R = prenyl
ene
E
H
H
A
O
OH
F
B
C
O
O
hetero-
D.-A.
O
CO2H
D
G
H
H
H
CHO
O
O
5
6
bolivianine (1)
B. Proposed hypothesis by our group:
GPP
Some insights from our research group and others led us to
consider modifying this hypothesis. We discovered that β-E-
ocimene (7), a natural monoterpene generated from GPP in vivo,3
is also present in H. angustifolium.4 This raised the biosynthetic
possibility of constructing ring E of bolivianine through a Diels-
Alder cycloaddition between onoseriolide (2) or its natural
derivative(s) and β-E-ocimene (7). In fact, reaearchers have long
wondered whether lindenane-type sesquiterpenoid dimers,
isolated from the same Chloranthaceae family as bolivianine,
could be assembled biosynthetically from the corresponding
-HOPP
O
+ 7
O
Diels-Alder Rxn.
H
OH
8
-E-ocimene (7)
[O]
path a
+ 7
intramolecular
6
1
Diels-Alder Rxn.
path b
hetero-Diels-Alder
[O]
onoseriolide (2)
3
Intramolecular
Diels-Alder Rxn.
+ 7
path c
O
O
monomers through Diels-Alder cycloaddition,5 Indeed,
a
hetero-Diels-Alder
H
protracted search for Diels-Alderase led to the discovery of an
enzyme that catalyzes [4+2] cycloaddition in the biosynthesis of
spinosyn A, based on experimental data6 and computational
modeling.7
9
O
Inspired by our biogenetic hypothesis (Scheme 1B), we
expected that we could achieve sequential cycloadditions using 2
or its derivative 3 with 7 at a late stage (Scheme 2).8 This
approach is quite challenging because the desired chemo-, endo-
and diastereo- selectivities must be achieved using reactants with
different double bonds (2+7 or 3+7). We hypothesized that
Based on these insights we chose to pursue a modified
biogenetic hypothesis for bolivianine (Scheme 1B). First,
onoseriolide (2) could react with 7 to furnish compound 8, which
could be oxidized in vivo to compound 6 and ultimately yield
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o
at 40 C. Direct heating or the use of other metal catalysts led to
enantiopure onoseriolide (2) could be obtained from its furan
precursor 10,9 produced from 11 via aldol reaction. Compound 11
could be achieved through Hodgson cyclopropanation from the
epoxide 12.10 The diastereoselective epoxidation of 13 could
presumably be controlled by the substrate itself or by a chiral
catalyst (Strategy A). Alternatively, compound 11 could be
generated through metal-catalyzed carbenoid transfer via
intermediate 14 (Strategy B). Both retrosynthetic strategies point
to the allylic oxidation of compound 16. Commercially available
(+)-verbenone (17) was thus deduced to be the starting molecule
for both strategies.
1
2
3
4
5
6
7
8
lower yields. To the best of our knowledge, this is the first
successful example of intramolecular cyclopropanation of an
allyic diazo compound.
We continued by perfoming acid-catalyzed deprotection to
yield compound 11. Treating 11 with the functionalized pyruvate
25,15 followed by acid-catalyzed furan formation and DIBAL-H
reduction, furnished compound 10.16 Protecting this compound
with silyl ether, elaborating the furan ring and deprotecting
proceeded smoothly to yield onoseriolide (2), whose
characterization data were in good accord with those reported.2
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Scheme 2. Retrosynthetic analysis
Scheme 3. Enantioselective total synthesis of onoseriolide
Michael addition to (+)-verbenone using vinyl copper reagent,
followed by ring-opening of the cyclobutane, led to the enol
acetate 19 (Scheme 3).11 This was directly transformed to the 1,3-
dioxolane 20 in the presence of acid. Allylic oxidation and
subsequent Lüche reduction afforded compound 13. The next
step of metal-catalyzed selective epoxidation, however, proved
problematic. We speculated that if 13 adopted a stable chair
conformation during metal catalysis, the equatorial vinyl group
could block the approaching peroxide from the α−face of the
axial gem-substituted double bond, resulting in predominance of
the undesired 21a over the desired 21b.12 To override this
unfavorable substrate control, Sharpless asymmetric epoxidation
was attempted in an effort to achieve a catalyst-controlled effect.
Contrary to our expectations, this led to even worse
diastereoselectivity probably because of the greater bulkiness of
the catalyst complex. Although mCPBA behaved much better, it
still gave the desired 21b as the minor product in an
unsatisfactory yield.
The IMDA reaction with alkylidene-5H-furan-2-one has
proven extremely useful in natural product synthesis.17 However,
although 5-methylene-2(5H)-furanone was proved to be a suitable
substrate in the intermolecular Diels-Alder reaction,18 substituted
alkylidene-5H-furan-2-ones with dienes often lead to
unsatisfactory site-, regio-, diastereo- and endo/exo selectivities.19
To probe the feasibility of biogenetic path a (Scheme 1B), we
examined whether 2 and 7 react together.20 Since β-E-ocimene (7)
is unstable to acid,21 we focused our attention on the thermal
conditions.22 Unfortunately, we observed no reaction between 2
Armed with our insight into the importance of optimal
conformation for the metal-catalyzed epoxidation of 13, we
hypothesized that direct intramolecular cyclopropanation via an
allylic carbenoid could proceed through this conformation in
order to generate 11 (Strategy B, Scheme 2). Of the many ways to
synthesize diazo compounds are versatile,13 we considered an
approach using tosylhydrazone salt to be one of the safest and so
we used it in metal-catalyzed intramolecuar cyclopropanation.14
After carefully screening reaction conditions, we finally achieved
compound 24 as the sole isolable diastereomer in 65% yield; in
this approach, an active metalcarbene species was generated in
situ from palladium catalyst and the sodium salt of compound 23
o
and 7 even at 150 C, making us discount the possibility of the
corresponding biogenetic pathway (path a, Scheme 1B). So we
introduced an alien electron-withdrawing group into the
alkylidene-5H-furan-2-one segment of onoseriolide (2), in order
to activate the dienophile by decreasing its LUMO energy. After
reacting compound 28 with 7 in toluene at 150 oC for 5 h,15
compound 29 formed in 55% yield without other detectable site-,
regio- or diastero- isomers (Scheme 4). The relative configuration
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commercially available (+)−verbenone. Our synthetic strategy
involves dexterous assembly of 3/5/6 skeleton via
of 29 was confirmed by converting it to bolivianine (1) in five
steps.15
This success encouraged us to attempt a DA/IMHDA cascade
1
2
3
4
5
6
7
8
a
intramolecular cyclopropanation of an allylic metalcarbene
intermediate, and an ambitious DA/IMHDA cascade to elaborate
the EFG tricycle of bolivianine in one pot. Our total synthesis has
allowed us to confirm the absolute configuration of bolivianine
and provides experimental support for a modified biogenetic
pathway.
with 3 and 7. Compound 3 was prepared by IBX oxidation of 2
and then mixed with β-E-ocimene (7) in toluene and heated in a
sealed tube at 150 oC. This ambitious cascade excitingly delivered
bolivianine (1) in 52% yield with no other isomers detected
(Scheme 4). All characterization data of our synthetic 1 were
identical to the reported data, including optical rotation {synthetic
1, [α]26 -52 (c 0.1, CHCl3); natural sample: [α]25 -50 (c 0.2,
ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data, 1H NMR and 13C
NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
D
D
CHCl3)},1 which confirmed the absolute configuration of
bolivianine and its biogenetic correlation with onoseriolide. This
one-pot cascade fueled two successful chemical transformations,
generating three cycles, four C-C bonds and five stereogenic
centers with excellent selectivities. To the best of our knowledge,
such a complex DA/IMHDA cascade has not been exploited
before,23 and it may prove useful in other natural product
syntheses.
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AUTHOR INFORMATION
Corresponding Author
Scheme 4. Bioinspired synthesis of bolivianine
chembliu@scu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are also grateful for financial support from NSFC (21021001,
21172154, 21290180) and the MOST of China (973 program,
2010CB833200)..
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o
reaction, we treated 3 with the known compound 30 at 150 C for
2.5 h and observed no reaction (Scheme 5).24 This allowed us to
rule out the possibility of an alternative cascade mechanism
initiated by hetero-Diels-Alder reaction (path c, Scheme 1B). We
also found that compound 31 spontaneously turned to compound
32 after standing in ethyl acetate for two days at room
temperature,15 through an IMHDA process. These observations
lead us to suggest that the most likely biogenetic route to
bolivianene should consist of an initial oxidation of onoseriolide
(2) to 3, subsequent Diels-Alder reaction with β-E-ocimene (7),
probably catalyzed in vivo by a Diels-Alderase, and spontaneous
IMHDA reaction (path b, Scheme 1B).
Scheme 5. Probing the mechanism of the cascade
In conclusion, we completed the first total synthesis of
onoseriolide and bolivianine in 12 and 14 steps respectively from
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