Total syntheses of anominine and tubingensin A

Article abstract of DOI:10.1021/ja302765m

A divergent strategy for the total syntheses of the indole terpenoid anominine (1) and its natural congener tubingensin A (2) has been developed. The common intermediate 11 bearing all of the required stereogenic centers for both natural products was first assembled by employing a Ueno-Stork radical cyclization and a Sc(OTf)₃-mediated Mukaiyama aldol reaction to form the key C-C bonds in a stereocontrolled manner. The route to anominine features a radical deoxygenation followed by an efficient side-chain installation, while the path to tubingensin A exploits a CuOTf-promoted 6π-electrocyclization/ aromatization sequence to forge the central region of the pentacyclic scaffold.

Full text of DOI:10.1021/ja302765m

Communication
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Total Syntheses of Anominine and Tubingensin A
Ming Bian,†,§ Zhen Wang,†,§ Xiaochun Xiong,† Yu Sun,† Carlo Matera,‡ K. C. Nicolaou,*,‡ and Ang Li*,†
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
‡Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States, and Department of Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, La Jolla, California 92093, United States
S
* Supporting Information
of 10 may provide another path toward 2. Despite the lack of
ABSTRACT: A divergent strategy for the total syntheses
of the indole terpenoid anominine (1) and its natural
congener tubingensin A (2) has been developed. The
common intermediate 11 bearing all of the required
stereogenic centers for both natural products was first
assembled by employing a Ueno−Stork radical cyclization
and a Sc(OTf)3-mediated Mukaiyama aldol reaction to
form the key C−C bonds in a stereocontrolled manner.
The route to anominine features a radical deoxygenation
followed by an efficient side-chain installation, while the
path to tubingensin A exploits a CuOTf-promoted 6π-
electrocyclization/aromatization sequence to forge the
central region of the pentacyclic scaffold.
biochemical evidence to support it, we launched a total
synthesis program aimed at exploring the biosynthetic
speculation outlined in Scheme 1.
Inspired by the above hypothesis, we undertook a
retrosynthetic analysis involving a common intermediate as
the junction of the two approaches toward 1 and 2, as shown in
Scheme 2. To avoid the uncertainty in direct benzylic oxidation
of a sensitive indole derivative (Scheme 1), alcohol 11 was
considered as a practical and versatile intermediate. First, it
could serve as a convenient precursor for triene 12, the
substrate for the 6π-electrocyclization/aromatization reaction
proposed in Scheme 1. Second, it should readily undergo
radical or cationic deoxygenation to generate the desired
oxidation level for anominine. In addition, its lactol motif could
be used as a convenient handle to install the olefinic side chains
for both 1 and 2. Straightforward disassembly of 11 through
Grignard addition and Wittig processes would result in
hydroxyketone 13, which could be further traced back to
tricyclic ketone 14. In a forward manner, 13 was expected to be
available through an aldol reaction of 14 and formaldehyde. We
considered the next disconnection at the C20−C21 bond
(anominine numbering system) of 14; obviously, efficient
introduction of the all-carbon quaternary center at C20 was one
of the most challenging bond constructions in our plan because
of both steric and stereochemical issues. Thus, a Ueno−Stork
radical cyclization employing the corresponding iodoacetal as
the substrate was envisioned to solve the above problem. This
iodide could be readily assembled from known hydroxyenone
15 bearing the three stereogenic centers desired for both
natural products.
On the basis of the above analysis, we first investigated the
synthesis of the basic building block 14 (Scheme 3). To ensure
our material supply, the preparation of 155 was streamlined by
taking advantage of a scalable and selective Mukaiyama−
Michael addition process.6 Starting with readily available and
optically active ketone 16,7 regioselective trimethylsilyl (TMS)
enol ether formation followed by BF3·OEt2-promoted diaster-
eoselective 1,4-addition and subsequent Robinson annulation
afforded bicyclic enone 17 in 47% overall yield.6 Compound 17
was then converted into 15 in two steps.5b With 15 in hand, we
focused our attention on the formation of the C20−C21 bond.
nominine (1) is a structurally representative member of a
A
growing family of naturally occurring indole diterpenoids
that also includes tubingensin A (2), aspernomine (3),
aflavinine (4), and 10,23-dihydro-24,25-dehydroaflavinine (5)
(Scheme 1), which were initially isolated from Aspergillus spp.
by Gloer and co-workers.1 Several other members of this family
[e.g., 17-hydroxyeujindole (6) (Scheme 1)] were recently
isolated from Eupenicillium javanicum.2 Not surprisingly, these
intricate molecular architectures were found to possess
interesting biological properties, such as antiinsectant, antiviral,
and anticancer activities.1 Notably, the only total synthesis of
anominine to date was accomplished elegantly by Bonjoch and
co-workers in 2010, while the syntheses of its congers remain a
challenge.3
On the basis of the intriguing structural relationships among
them, we postulated a biosynthetic network connecting the
above-mentioned molecules to the parent natural product 1, as
shown in Scheme 1. On one hand, benzylic oxidation of 1 could
generate cationic species 7, which may then enter two different
paths: (a) elimination to form triene 8 followed by a 6π-
electrocyclization/aromatization sequence to give 2 or (b)
cationic olefin cyclization and oxidation state adjustment to
afford 5. Furthermore, the terminal CC bond of 5 may
migrate to afford its isomer 4, while a Friedel−Crafts cyclization
occurring at the indole C4 position of 5 would render 6. On the
other hand, oxidative dearomatization of the indole moiety of 1
could generate a reactive intermediate 9, which may undergo an
iminium−olefin cyclization to give tertiary carbenium ion 10
followed by a Friedel−Crafts/fragmentation sequence to
furnish 3.4 Additionally, simple dehydration and aromatization
Received: March 21, 2012
Published: April 26, 2012
© 2012 American Chemical Society
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Scheme 1. Postulated Biosynthetic Relationship among Some Members of the Anominine Family
Scheme 2. Retrosynthetic Analysis for Anominine (1) and
Tubingensin A (2)
Scheme 3. Construction of Tricyclic Ketone 14
a
Reagents and conditions: (a) TMSCl (3.0 equiv), HMDS (4.0
equiv), NaI (4.0 equiv), MeCN, 0 → 22 °C, 2 h; (b) MVK (3.0 equiv),
BF3·OEt2 (0.2 equiv), MeOH (1.0 equiv), CH3NO2, −20 °C, 1 h; (c)
NaOMe (1.5 equiv, 1.0 M in MeOH), 45 °C, 5 h, 47% (three steps);
(d) NIS (6.0 equiv), ethyl vinyl ether (8.0 equiv), CH2Cl2, −20 °C, 40
min, 98% (ca. 1:1 mixture of diastereomers); (e) AIBN (0.5 equiv), n-
Bu3SnH (2.0 equiv), toluene, 80 °C, 2 h, then ethanolic HCl (5.0
equiv, 2.0 M), CH2Cl2, 0 → 22 °C, 1 h, 65%.
conjugate addition and Sakurai reaction were both fruitless,
while treatment with a more powerful reagent such as Et2AlCN
only gave 1,4-adducts in low yield and poor diastereocontrol. In
an alternative attempt, the 1,2-adduct of allyl-MgBr to 15 was
subjected to anionic oxy-Cope conditions but remained inert at
elevated temperature.
With 14 in hand, our next challenge was to install the indole-
containing side chain and construct key intermediate 11
(Scheme 4). To our delight, selective C11 deprotonation with
lithium hexamethyldisilazide (LiHMDS) at −78 °C followed by
trapping of the resulting enolate with TMSCl afforded the
corresponding silyl enol ether, which reacted with form-
aldehyde under Sc(OTf)3-mediated aqueous Mukaiyama aldol
conditions9 to furnish hydroxyl ketone 13 with good overall
efficiency. Notably, indole-3-carboxaldehyde or its N-protected
versions proved to be unreactive under these Lewis acidic or
other basic aldol conditions. Through a sequence of silylation,
Wittig methylenation, desilylation, and oxidation with Dess−
Martin periodinane (DMP), alcohol 13 was readily converted
Iodoetherification of 15 in the presence of ethyl vinyl ether and
N-iodosuccinimide (NIS) gave 18 as a ca. 1:1 mixture of
diastereomers in 98% yield, setting the stage for the planned
radical cyclization.8 After examination of a variety of conditions
(initiator, temperature, addition protocol) for this trans-
formation, we were pleased to find that the cyclization
proceeded smoothly upon slow addition of azobis-
(isobutyronitrile) (AIBN) and n-Bu3SnH at 80 °C to afford a
mixture of tricyclic ketone 14 and its C22 epimer; treatment
with ethanolic HCl gave a single diastereomer. Thus, 14 was
obtained in 65% overall yield from 18. The above protocol was
also applied to the bromo counterpart of 18 and proved to be
equally effective; however, the preparation of the bromoacetal
under standard conditions was much less efficient. Notably, our
parallel investigation of intermolecular 1,4-addition (or its
equivalent reaction) to 15 or its hydroxyl-protected forms
turned out to be disappointing. For example, cuprate-mediated
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crystallographic analysis, indirectly confirmed the stereo-
chemical assignment of alcohol 11.
Scheme 4. Assembly of Key Intermediate 11
Having forged all of the requisite stereochemical information
into 11, we focused our attention on completion of the
anominine synthesis (Scheme 5). Thus, xanthate formation and
radical deoxygenation followed by desulfonylation with
tetrabutylammonium fluoride (TBAF) furnished 22 with
good overall efficiency,10 and 22 was smoothly converted to
lactol 23 by acidic hydrolysis. Surprisingly, 23 proved to be
highly resistant to nucleophilic attack. Under standard
conditions, a variety of Grignard, lithium, and Wittig reagents
as well as hydride sources were examined for the lactol-opening
reaction with little success, and only LiAlH4 slowly reduced 23
to the corresponding diol at ambient temperature. The unusual
stability of 23 could presumably be attributed to the
equilibrium between this lactol and its ring-opened aldehyde
form being heavily biased to the former side because of the
crowded nature of the latter. We suspected that a different
solvent might have a subtle influence on this equilibrium, and,
indeed, treatment of 23 with vinyl-MgBr in toluene at 60 °C for
5 h afforded the desired ring-opening addition product, albeit
with incomplete conversion. The diol product was taken
directly into a sequence of bisacetylation (Ac2O/Et3N) and
Tsuji reduction11 [Pd(PPh3)4 (cat.), HCO2NH4] to furnish the
monodeoxygenated product 24 with acceptable overall
efficiency. Finally, cross-metathesis between 24 and freshly
distilled 2-methyl-2-butene (25) promoted by Hoveyda−
Grubbs II catalyst (26)3a and subsequent cleavage of the acetyl
group with diisobutylaluminum hydride (DIBAL-H) afforded
anominine (1) in 83% yield over the two steps. The physical
properties, including the optical rotation of synthetic 1,
matched those reported for the natural material,1a which was
also consistent with the assignment of the absolute
a
Reagents and conditions: (a) TMSCl (2.0 equiv), LiHMDS (3.0
equiv, 1.0 M in THF), THF, −78 °C, 40 min; (b) Sc(OTf)3 (0.2
equiv), 37 wt % aq. formalin (10.0 equiv), THF, 22 °C, 40 min, 76%
(two steps); (c) TBSCl (2.0 equiv), imidazole (4.0 equiv), DMF, 22
°C, 1 h; (d) n-BuLi (2.0 equiv), Ph3P+CH3I− (2.2 equiv), THF, −78
→ 0 °C, 30 min, then 0 °C, 30 min; (e) TBAF (2.0 equiv), THF, 22
°C, 1 h, 76% (three steps); (f) DMP (1.5 equiv), CH2Cl2, 0 → 22 °C,
1 h, 84%; (g) 20 (5.0 equiv), THF, −78 °C, then 22 °C, 40 min, 11:
88%, C10 epimer of 11: 10%; (h) TsOH·H2O (0.1 equiv), CH2Cl2, 22
°C, 1 h, 99%.
to aldehyde 19 in good overall yield. Treatment of the latter
with Grignard reagent 20 provided our subtarget, alcohol 11,
together with its C10 epimer as a minor product. Interestingly,
11 underwent rapid cyclization to give polycyclic acetal 21
under acidic conditions (e.g., TsOH or HCl generated from old
chloroform). The structure of 21 (mp 184−187 °C, 1:1
EtOAc/petroleum ether), which was determined by X-ray
Scheme 5. Divergent Approaches toward Anominine and Tubingensin A
a
Reagents and conditions: (a) KHMDS (5.0 equiv, 0.5 M in toluene), CS2 (5.0 equiv), THF, −78 °C, 1 h, then MeI (5.0 equiv), −78 → 22 °C, 1 h;
(b) n-Bu3SnH (2.0 equiv), AIBN (0.5 equiv), toluene, 110 °C, 1 h, 72% (two steps); (c) TBAF (3.0 equiv, 1.0 M in THF), toluene, 110 °C, 2 h,
86%; (d) aq. HClO4 (1.0 M)/THF (1:1), 22 °C, 8 h, 76%; (e) vinyl-MgBr (10.0 equiv, 0.7 M in THF), toluene, 0 °C, then 60 °C, 5 h; (f) Ac2O
(10.0 equiv), Et3N (20 equiv), DMAP (1.0 equiv), CH2Cl2, 0 °C, then 40 °C, 5 h; (g) Pd(PPh3)4 (0.3 equiv), HCO2NH4 (10.0 equiv), toluene, 80
°C, 40 min, 54% for 24, 52% for 28 (three steps); (h) 26 (0.2 equiv), 25, 22 °C, 24 h; (i) DIBAL-H (5.0 equiv, 1.0 M in hexanes), CH2Cl2, −78 °C,
30 min, 83% (two steps); (j) MsCl (5.0 equiv), Et3N (10.0 equiv), CH2Cl2, −78 → 22 °C, 5 h, 79%; (k) (CuOTf)2·toluene (1.0 equiv), CH3CN, 22
°C, 4 h; (l) aq. HClO4 (4.0 M)/THF (1:1), 22 °C, 4 h, 70% (two steps); (m) DIBAL-H (5.0 equiv, 1.0 M in hexanes), CH2Cl2, −78 °C, 30 min,
87%; (n) 26 (0.2 equiv), 25, 22 °C, 24 h; (o) TBAF (5.0 equiv, 1.0 M in THF), toluene, 110 °C, 2 h, 78% (two steps).
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configuration of 1 by Bonjoch.3a Further confirmation of the
structure of 1 came from X-ray crystallographic analysis of
single crystals of ( )-1 (mp 178−180 °C, 1:1 EtOAc/
petroleum ether).12
Products Chemistry, and Chinese Academy of Sciences. K.C.N.
acknowledges funding from the National Science Foundation
(Grant CHE-0603217), and C.M. thanks the Universita
Studi di Milano for a fellowship.
̀
degli
Encouraged by the successful assembly of 1, we continued to
investigate the synthesis of our second target, tubingensin A
(2), from intermediate 11 via the envisioned 6π-electro-
cyclization/aromatization strategy (Scheme 5). Dehydration of
11 in the presence of mesyl chloride (MsCl) and Et3N gave
triene 12 as a single geometric isomer in 79% yield,10 the
structure of which was determined by X-ray crystallographic
analysis.12 Triene 12 was stable at ambient temperature with no
detectable electrocyclization or double-bond isomerization.
However, conventional thermal conditions failed to initiate
the desired electrocyclization of 12 but resulted in its
decomposition. Fortunately, CuOTf was found to be a very
efficient promoter of the 6π-electrocyclization on our substrate,
and the aromatization reaction spontaneously occurred in one
pot to furnish the desired pentacyclic carbazole scaffold.13
Subsequent acetal hydrolysis (aq. HClO4) afforded lactol 27 in
70% overall yield. The structure of 27 (mp 182−183 °C, 1;1
EtOAc/petroleum ether) was confirmed by X-ray crystallo-
graphic analysis (see the ORTEP in Scheme 5). With 27 in
hand, we carried out the same side-chain elongation protocols
as in the synthesis of 1 to reach tubingensin A (2) via
intermediate 28 (Scheme 5). The physical properties of our
synthetic sample were identical to those reported for the
natural product.1b The consistency of the sign and magnitude
of the optical rotation of the two samples also assigned the
absolute configuration of the naturally occurring 2.
REFERENCES
■
(1) (a) Gloer, J. B.; Rinderknecht, B. L.; Wicklow, D. T.; Dowd, P. F.
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́ ̀
(9) Kobayashi, S. Synlett 1994, 689, and references therein.
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(13) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13,
3356.
In conclusion, we have described efficient total syntheses of
anominine and tubingensin A, the latter of which has been
accomplished for the first time. A divergent strategy based on a
versatile common intermediate 11 was successfully applied in
our syntheses. A series of reactivity and selectivity problems
were encountered and overcome on the journey. These studies
are expected to facilitate the systematic synthetic and biological
investigations of the members of this indole terpenoid family.
These ongoing studies should further corroborate the
biosynthetic speculations on this family of natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kcn@scripps.edu; ali@sioc.ac.cn
■
Author Contributions
§M.B. and Z.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. James Gloer for providing the NMR spectra of
authentic 1 and 2 and Drs. D. J. Edmonds and Ross Denton
and Prof. Dawei Ma for helpful discussions. Financial support
was provided by National Natural Science Foundation of China
(2117223), Ministry of Human Resources and Social Security
of China, State Key Laboratory of Bioorganic and Natural
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