Nazarov cyclization entry to chiral bicyclo[5.3.0]decanoid building blocks and its application to formal synthesis of (-)-englerin A

Article abstract of DOI:10.1021/acs.orglett.7b02428

A divergent entry to the chiral bicyclo[5.3.0]-decane skeletons relevant to sesqui- and higher terpenoids has been achieved. Its usefulness was demonstrated by formal synthesis of a guaiane sesquiterpenoid (-)-englerin A. The key reactions are (i) diaster

Full text of DOI:10.1021/acs.orglett.7b02428

Letter
pubs.acs.org/OrgLett
Nazarov Cyclization Entry to Chiral Bicyclo[5.3.0]decanoid Building
Blocks and Its Application to Formal Synthesis of (−)-Englerin A
Keisuke Morisaki,† Yusuke Sasano,† Takahiro Koseki,† Takuro Shibuta,† Naoki Kanoh,†
Wen-Hua Chiou,‡ and Yoshiharu Iwabuchi*,†
†Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
‡Department of Chemistry, National Chung Hsing University, Taichung, 40227, Taiwan
S
* Supporting Information
ABSTRACT: A divergent entry to the chiral bicyclo[5.3.0]-
decane skeletons relevant to sesqui- and higher terpenoids has
been achieved. Its usefulness was demonstrated by formal
synthesis of a guaiane sesquiterpenoid (−)-englerin A. The key
reactions are (i) diastereoselective Nazarov cyclization for
stereoselective construction of the bicyclo[5.3.0]decane
skeleton, (ii) intramolecular C−H amination for tuning an oxidation state, and (iii) introduction of an alkyl group to a β-
alkoxy ketone with a zinc(II) ate complex.
he bicyclo[5.3.0]decane (hydroazulene) skeleton is a
prevalent structural motif found in many sesqui- and
cycloheptadiene was developed previously by our group.4 As an
expedient maneuver to extend a cyclopentane ring with
synthetic functionalities, Nazarov cyclization5 of dienone 6,
which should be accessible from 5, was expected to furnish
bicyclo[5.3.0]decane scaffold 7, where the stereoelectronic bias
of 6 would impart diastereoselectivity (Scheme 1). The peculiar
T
higher terpenoids,1 serving as a versatile platform for
accommodating huge arrays of structural diversity to elicit
various biological activities, such as antitumor, antiviral, and
antimalarial activities (Figure 1). Consequently, functionalized
Scheme 1. Nazarov Cyclization Entry to
Bicyclo[5.3.0]decane Skeletons
Figure 1. Examples of bicyclo[5.3.0]decane compounds (hydro-
azulene) in natural products.
enone juxtaposition to the oxo-bridge of 7 would provide
diverse opportunities for diastereoselective functionalization
around the framework. We herein report an expedient Nazarov
cyclization entry to bicyclo[5.3.0]decane building blocks and its
application to the formal synthesis of (−)-englerin A (1),6,7
which may potentially lead to the development of antirenal
cancer agents.8
To assess the feasibility of the concept, a panel of dienones
8a−8d were prepared from 5 (see Supporting Information)
and subjected to Nazarov cyclization (Table 1). After screening
Lewis and Brønsted acids using (Z)-dienone 8a as a model
substrate, TfOH was identified as the acid of choice to give
bicyclo[5.3.0]decane product 9a, which shares a prototypical
common structure with guaianoids, as a single stereoisomer in
81% yield (entry 1). The stereochemistry of the product was
bicyclo[5.3.0]decane derivatives have in particular continuously
drawn the attention of the synthetic community in terms of the
following issues; should the cis- or trans-fused ring system be
targeted, what combination of substituents may be installed on
the periphery, and how efficiently the enantio- and diaster-
eoselectivity are secured.2 Generally, target-oriented synthesis
adopts a convergent strategy to pursue maximum efficiency,
which does not always fit with the synthesis of the derivatives of
interest. In this regard, methods that allow late-stage
incorporation of diverse functionalities onto a chiral
bicyclo[5.3.0]decane system will find promising use in
discovery-oriented ventures in chemical biology and medicinal
chemistry.3
We contemplated the development of bicyclo[5.3.0]decane-
type building blocks stemming from a chiral cycloheptanoid
building block, namely, 8-oxabicyclo[3.2.1]oct-3-en-2-one (5),
the facile entry to which in both enantiomeric forms from 1,3-
Received: August 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02428
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Letter
Table 1. Examination of Nazarov Cyclization
Scheme 3. Plausible Mechanism of Diastereoselective
Nazarov Cyclization
entry
substrate
product
yield (%)
1
2
3
4
8a (R1 = Me, R2 = H)
8b (R1 = i-Pr, R2 = H)
8c (R1 = H, R2 = H)
8d (R1 = H, R2 = Me)
9a (R3 = Me)
9b (R3 = i-Pr)
9c (R3 = H)
9a (R3 = Me)
81
64
84
83
determined on the basis of NOESY spectra. Carotane-related
product 9b equipped with an isopropyl substituent was
obtained from 8b in 62% yield under the same conditions
(entry 2). The Nazarov cyclization of vinyl ketone 8c afforded
9c in 84% yield (entry 3). It was interesting to observe that (E)-
dienone 8d gave the same product 9a as the (Z)-dienone 8a-
derived product in comparable (83%) yield (entry 4). Careful
TLC analyses of the reaction mixture indicated that Z to E
isomerization proceeded prior to the Nazarov cyclization under
the given conditions.
Encouraged by the intriguing result, we attempted a short-
step synthesis of 9a using a readily accessible mixture of 8d and
8a. Thus, the enol triflate, prepared from cycloheptenone 5 via
1,4-reduction using L-selectride followed by in situ treatment of
the corresponding enolate with Tf2NPh, was subjected to Stille-
carbonylative cross-coupling9 to furnish a mixture of dienones
8d and 8a in 40% yield (Scheme 2). On treatment with TfOH
in CH2Cl2, the mixture furnished the bicyclic enone 9a in 82%
yield as a single diastereomer.
Scheme 4. Diastereodivergent Hydrogenation of 9a
At this juncture, we set (−)-englerin A (1) as the synthetic
target to demonstrate the utility of 14. The needed set of
additional functionalities at C6, C7, C9, and C10 prompted us
to propose 1,4-diene 18 as a virtual synthon (Scheme 5). 18
Scheme 5. Synthetic Plan of (−)-Englerin A
Scheme 2. Shorter-Step Synthesis of Bicyclo[5.3.0]decane 9a
Although the reason for the perfect stereoselectivity observed
in the Nazarov cyclization is unclear, examination using a
molecular model indicated that the 8-oxabicyclo[3.2.1]-
octenone system accommodates 4π conrotatory electrocycliza-
tion in either a clockwise or counterclockwise direction
indiscriminately, which led us to assume that the deprotonation
would be the critical step in this particular case where the
bridgehead proton to be eliminated is better exposed at the
convex face in intermediate 10 than at the concave face in
intermediate 11 (Scheme 3). Calculations are underway.10
Having established the Nazarov cyclization entry to chiral
bicyclo[5.3.0]decane footholds, we turned our attention to the
use of 9a as a chiral building block for guaiane-related
sesquiterpenoids (e.g., compounds 1−4 in Figure 1). Thus,
we searched for methods that enable the divergent installation
of hydrogens onto the bridgehead alkene. It was eventually
identified that Pd/C in MeOH catalyzed hydrogenation onto
the enone 9a opposite to the C4-methyl group and afforded
ketone 14 in 93% yield (Scheme 4). On the other hand, PtO2
in AcOEt was found to give diastereomer 13 selectively. The
reversal of the diastereofacial selectivity may be due to the
coordination of the oxo-bridge moiety onto the surface of PtO2.
formulated enone 16 as a feasible key intermediate, and owing
to its structure, we adopted Christmann’s approach7a relying on
the intramolecular epoxide opening of 17. To accommodate
the gaps in the oxidation state between 14 and 16, a redox-
balancing sequence relying on an intramolecular C−H
amination11 was based on the seminal work by Du Bois and
co-workers:11e sulfamate 15 was expected to undergo a Rh-
catalyzed intramolecular C−H amination to furnish a cyclic
sulfamate, the hydrolysis of which ultimately gives rise to enone
16 via dehydration. Although a sequence of intramolecular C−
H amination of a C−H bond connected to an alkoxy group and
the substitution of the resulting N,O-acetal group using an
alkynyl zinc reagent were reported by Du Bois, unprecedented
connection to the hydrolytic generation of a ketone via the
cleavage of the N−O bond and the concomitant β-elimination
of a sulfamate posed a challenge. The subsequent synthetic
survey from 16 relying on conventional functional group
interconversions would yield Christmann’s intermediate 17.
The synthesis commenced with diastereoselective installation
of a sulfamate handhold for the projected C−H amination. On
treatment with DIBAL and n-BuLi, tricyclic ketone 14 (95%
ee) with shaping a caged structure accepted a hydride from the
B
DOI: 10.1021/acs.orglett.7b02428
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Letter
convex face to generate the corresponding alkoxide, which was
trapped in situ with ClSO2NH2 to give sulfamate 15 in 89%
yield (Scheme 6).12 Upon exposure to typical Du Bois’s C−H
87% yield. Note that a conventional Dess−Martin oxidation16
did not lead to alcohol oxidation in this particular one-pot
sequence and the alcohol was recovered. The next introduction
of the isopropyl group of the guaiane skeleton posed a
formidable challenge. For example, addition of a Grignard
reagent in the presence of CeCl3 gave a complex mixture, and
attempts in the formation of the corresponding enolate led to
the elimination of the oxygen functional group on the β-
position of the ketone to give the corresponding enone as a
major product. After considerable experimentation, we found
that a zinc(II) ate complex that was developed by Ishihara and
co-workers17 successfully induced the addition of the isopropyl
group to the ketone to afford the corresponding tertiary alcohol
in 93% yield as a single stereoisomer (its stereochemistry was
not determined). The next regioselective dehydration also
required considerable experimentation. Burgess reagent18
provided the desired trisubstituted alkene 23 in 58% yield
along with a mixture of undesired isomers in 38% yield, which
can be separated from the other isomers by column
chromatography. The spectral data of 23 were identical to
those of Hatakeyama’s intermediate7i in the total synthesis of
(−)-englerin A. Finally, completion of the total synthesis of
(−)-englerin A was achieved by a six-step sequence adopting
Hatakeyama’s procedure.7i
Scheme 6. Synthesis of Hydroxyenone 16
sulfamination conditions11c−e using PhI(OAc)2 and MgO in
the presence of cat. Rh2(esp)2 in warm (CH2Cl)2, sulfamate 15
underwent a smooth oxidative annulation to give 19, and to our
delight, the subsequent treatment of which in 1 M HCl in warm
THF furnished enone 16 in 91% yield.
With hydroxyenone 16 obtained, effort was focused on the
installation of the remaining functionalities toward the formal
synthesis of (−)-englerin A, in which we settled on
Hatakeyama’s intermediate 237i for Christmann’s approach7a
(Scheme 7). Although our attempts in hydrogenations to
In conclusion, we have developed a rapid and diastereose-
lective entry to bicyclo[5.3.0]decane skeletons 9a−c from
readily available chiral oxa-bridged cycloheptenone 5 and have
demonstrated the usefulness of 9a for synthesis by employing it
in the enantioselective formal synthesis of (−)-englerin A. The
Nazarov cyclization protocol provides useful bicyclo[5.3.0]-
decane-type chiral building blocks, which will prompt synthetic
studies of various hydroazulene-type bioactive natural products
and their analogs.
Scheme 7. Total Synthesis of (−)-Englerin A (1)
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.7b02428.
Experimental procedure, 1H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: y-iwabuchi@m.tohoku.ac.jp.
ORCID
secure the trans-fused hydroazulene juncture were unsuccessful,
we ultimately found that, after the hydrogenation without
exclusion of Pd/C, a one-pot treatment of the cis- and trans-
fused hydrogenated products with TfOH induced spontaneous
isomerization to give trans-fused hydroxyenone predominantly,
and the subsequent addition of dimethoxymethane13 gave
MOM ether 20 in 75% yield in a one-pot operation. The C14-
methyl group of the guaiane skeleton was introduced via
regioselective formation of an enol triflate and the subsequent
Negishi coupling14 to afford a trisubstituted alkene in 89% yield
in two steps. Dihydroxylation of the alkene using OsO4
proceeded diastereoselectively to give diol 21. The sequential
protection of the 1,2-diol as a carbonate, deprotection of the
MOM group with aqueous HCl, and aerobic oxidation of the
resulting secondary alcohol induced by Nor-AZADO−NOx
catalysis15 was conducted in one pot to afford ketone 22 in
Naoki Kanoh: 0000-0002-4382-3715
Wen-Hua Chiou: 0000-0003-3805-0225
Yoshiharu Iwabuchi: 0000-0002-0679-939X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysis” (No. 23105011) from MEXT,
Core to Core Program “Advanced Research Network for Asian
Cutting-Edge Organic Chemistry” from JSPS, and Life Science
Research (Platform for Drug Discovery, Informatics, and
Structural Life Science) from Japan Agency for Medical
C
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Letter
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DOI: 10.1021/acs.orglett.7b02428
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