Concise Synthesis of the Tricyclic Core of Salimabromide

Article abstract of DOI:10.1021/acs.orglett.5b01231

A concise synthesis of the tricyclic core 2 of the structurally unique marine myxobacterial natural product salimabromide has been developed. Compound 2 contains the tetraline subunit including the two quaternary centers and the eight-membered ring of sal

Full text of DOI:10.1021/acs.orglett.5b01231

Letter
pubs.acs.org/OrgLett
Concise Synthesis of the Tricyclic Core of Salimabromide
Bjorn Schmalzbauer and Dirk Menche*
̈
́
Kekule-Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A concise synthesis of the tricyclic core 2 of the
structurally unique marine myxobacterial natural product salimabromide
has been developed. Compound 2 contains the tetraline subunit
including the two quaternary centers and the eight-membered ring of
salimabromide. Major features for its synthesis include a Lewis base
catalyzed Denmark-crotylation for stereoselective construction of the
highly hindered quaternary stereocenter, an innovative iodine/selectfluor induced endo-carbocylization, and a unique
chemoselective carbonylative lactonization of the eight-membered ring.
minute amounts (0.5 mg) and revealed antibiotic activity
he group of G. Konig has reported the isolation and
̈
Tstructural assignment of salimabromide from the marine toward Arthrobacter crystallopoietes. Further biological evalua-
tion was hampered by the scarce natural supply.1 Inspired by
the unique structure together with its highly limited natural
availability, we initiated a program directed toward a first total
synthesis of salimabromide. Such an approach is also of key
importance for unambiguous proof of the unusual constitution
and relative and absolute configuration. Herein, we report a
concise synthesis of the tricyclic core 2 of salimabromide by an
innovative strategy involving a Lewis base catalyzed Denmark-
crotylation for stereoselective construction of the highly
hindered quaternary stereocenter, an effective iodine/select-
fluor induced endo-carbocylization for construction of the
tetraline ring, and a unique carbonylative lactonization that
proceeds with excellent chemoselectivities.
myxobacterium Enhygromyxa salina in 2013.1 It presents one of
the first secondary metabolites isolated from a marine
myxobacterium.2 Salimabromide has a structurally novel
tetracyclic carbon skeleton with no apparent resemblance to
any known natural products. In detail, the unique architecture
comprises a dibrominated benzene ring, a butyrolactone
residue, and a cyclohexane ring that is bridged by a seven-/
eight-membered cyclic moiety (Scheme 1). It contains four
stereogenic centers including a sterically highly congested
quaternary center. Salimabromide could only be isolated in
Scheme 1. Retrosynthetic Analysis of the Tricyclic Core (2)
of Salimabromide (1)
As shown in Scheme 1 our synthetic approach to the tricyclic
core 2 relied on an adventurous carbonylative lactonization of
triflate 3 to form the eight-membered lactone ring of 2.
Construction of the tetraline core of 3 in turn was envisioned to
arise from 4 by an electrophilic cyclization reaction of the
aromatic ring to the appending terminal alkene. It was
anticipated that the two neighboring quaternary centers of
the alkene may favor an unusual endo-cyclization for steric
reasons. Finally, a suitable asymmetric crotylation by coupling
of allysilane 6 with aldehyde 5 was scheduled to set the chiral
quaternary center in a stereoselective fashion.
As starting material to build up the aromatic core 11 of
salimabromide, 4-ethylbenzoic acid (7) was chosen (Scheme
2). The acid was first transformed to the corresponding methyl
ester by using sulfuric acid in methanol, followed by
introduction of the bromides ortho to the ethyl-residue by
treatment with bromine and aluminum trichloride.3 The
desired compound could be readily purified by simple washings
of the resulting solid. DIBAL reduction of ester 8 then gave the
corresponding benzylic alcohol, which was subsequently
Received: April 27, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01231
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Scheme 2. Stereoselective Construction of the Quaternary
Chiral Center
Scheme 3. Completion of the Synthesis of Building Block 5
num.8 Finally, protection of the terminal alcohol as the
benzoate proceeded in a straightforward manner to give the
desired building block 4.
With 4 in hand, efforts could be directed toward formation of
the tetraline ring 15 (Scheme 4). Gratifyingly, cyclohexane
Scheme 4. Synthesis of the Tetralin Core 5 by an endo-
Selective Iodocylization
oxidized by means of activated manganese dioxide. Notably,
scale up of this sequence was facile, as none of these steps
needed purification by column chromatography and no
expensive chemicals were used. Therefore, large amounts of
aldehyde 5 could easily be prepared.
The required trichlorosilan 6 in turn was synthesized in five
steps starting from commercially available aldehyde 9. First, the
aldehyde was reduced using sodium borohydride followed by
protection of the resulting alcohol with TBDPSCl.4 Next, the
ester function was reduced by use of DIBALH, ensued by
transformation of the allylic alcohol to the corresponding allyl
chloride by utilizing the Corey−Kim protocol. The resulting
allyl chloride was then converted to the desired silane 6 by
usage of trichlorosilane and catalytic amounts of copper
chloride.5 Due to the reactive nature of 6 the allylsilane was
directly used in the crotylation reaction with 5. After
optimization of the original procedure developed by Denmark,5
this coupling proceeded in high yield (85%) and enantiose-
lectivity (95% ee) in the presence of the chiral bispyrrolidine-
based bisphosphoramide 10.6
As shown in Scheme 3, installation of the two methyl groups
in benzylic position was initiated by oxidation of the benzylic
alcohol 11 to the corresponding ketone by treatment with IBX
in DMSO (Scheme 3). After initial attempts to introduce both
geminal methyl groups in one step using the Reetz protocol or
other one-step procedures7 failed, we turned our attention to a
stepwise procedure. Accordingly, the first methyl group was
installed using trimethylaluminum and TMS-triflate. For
introduction of the second methyl group considerable
experimentation was required. Finally, this transformation
could be realized by first forming a six-membered sulphite
ring (13) of the neighboring hydroxyls of 12 with thionyl
chloride. Notably, only small amounts of the corresponding
benzylic chloride were formed during this transformation. The
resulting cyclic intermediate 13 was then directly converted to
the desired compound 14 by treatment with trimethylalumi-
formation could be effected smoothly by treatment of 4 with
iodine and selectfluor in acetonitrile. Importantly, this
iodocyclization proceeded with excellent endo-regioselectivity
and no traces of the exo-product 16 were observed. Also,
preparatively useful diastereoselectivities were observed (5:1),
which can be further increased by applying the same procedure
to the unprotected analog of 4 that does not bear a benzoate
group (dr > 20:1, not shown).9 Notably, to the best of our
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knowledge, this is the first example of an iodotetralin synthesis
by using iodine.10 The iodine in molecule 15 then had to be
replaced by a hydroxyl group for further functionalization. Since
compound 15 was very prone to elimination, this could not be
achieved in one step. Finally, an oxidative elimination of the
iodo group by means of mCPBA was followed by in situ
epoxidation through excess peroxybenzoic acid.11 The resulting
epoxide 17 was then opened in a regioselective fashion at the
benzylic position by using sodium cyanoborohydride and zinc
chloride to yield the homobenzylic alcohol 18 in a 1:2.3
mixture of diastereomers.12 Further elaboration by oxidation
with DMP and treatment with the Comins reagent and
NaHMDS gave the enol triflate 19.13 As a prelude for the
envisioned carbonylative lactonization (vide infra), a chemo-
Scheme 5. Carbonylative Methoxylation: Synthesis of the
Tricyclic Core of Salimabromide
selective methoxycarbonylation of 19 was then evaluated. This
14a,b
proceeded in excellent yields using Pd(PPh3)4
as the
catalyst. Alternatively, PdCl2(PPh3)14c and Pd(tBu)2 were also
active but resulted in lower yields. All investigated bi-
sphosphane ligands gave unsatisfactory results. No conversion
of the aryl bromides was observed, which further corroborated
our synthetic design.15
For homologation by an aldol approach, the terminal benzoyl
protecting group was first removed reductively by treatment
with DIBALH since ester cleavage using aqueous conditions
proved incompatible with the newly installed vinylic triflate.
The free alcohol was then oxidized with DMP to the
corresponding aldehyde. With this desired functional handle
in position, the stage was set for performing an aldol reaction
with TBS-protected hydroxyacetone. In the presence of
functionalization at the benzylic position by regioselective
opening of epoxide 17.
In summary, we have developed the first route to the tricyclic
core 2 of the structurally unique tetracyclic metabolite
Salimabromide. Notable features of our route include stereo-
selective generation of the chiral quaternary center by means of
a Denmark crotylation, an innovative highly regioselective
synthesis of the tetraline unit by means of an iodocylization
using iodine and selectfluor, and a challenging carbonylative
macrocyclization of the eight-membered ring. Efforts are now
focused on applying these tactics for realization of a first total
synthesis of salimabromide. Furthermore, our studies are
directed toward further evaluation of the general usefulness of
the reagent combination iodine/selectfluor for related cycliza-
tions and the further advancement of carbonylative lactoniza-
tions for medium and large ring systems.
titanium tetrachloride and Hunig’s base this coupling gave
̈
the desired product 22 as a single regioisomer in a 1:1.8
mixture of the diastereomers.16 The necessary protection of the
formed alcohol proved to be challenging, presumably due to
high steric hindrance exerted by the neighboring quaternary
center. Introduction of the methyl group could only be
achieved for the major diastereomer in modest yields by
Meerwein salt and proton sponge17 whereas the minor
diastereomer did not react at all. Subsequent removal of the
terminal TBS group proceeded smoothly with CSA in
methanol and gave the desired substrate 3 for the crucial
carbonylative lactonization to form the eight-membered ring of
salimabromide.
ASSOCIATED CONTENT
■
As shown in Scheme 5, the pivotal carbonylative
lactonization to form the eight-membered ring could indeed
be successfully realized to give the desired tricyclic core 2 of
salimabromide by treatment with CO in the presence of
S
* Supporting Information
Detailed experimental procedures, characterization, and copies
of 1H and 13C NMR spectra of new compounds. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01231.
catalytic amounts of Pd(PPh ) (16 mol %) and Hunig’s base
̈
3
4
(4.1 equiv) in DMF (60 °C). In accordance with our results for
the methoxycarbonylation of 19 this was the only catalyst that
provided acceptable conversion. Importantly, the reaction
proceeded again in a completely chemoselective manner, with
no activation of the aryl bromide to be observed. Finally, the
structure of 2 was unambiguously confirmed by X-ray
crystallography (see Supporting Information for details).
Noteworthy, this presents to the best of our knowledge the
first time an eight-membered lactone has been formed by this
method.18,19
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dirk.menche@uni-bonn.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
It should be noted that the reported route is flexible and
offers various late-stage options to finalize the first total
synthesis of salimabromide. These include installment of
different protective groups at the C-3-hydroxyl to effectuate
an elimination across the C-3/C-9 bond or a suitable
■
We thank Prof. G. Konig (University of Bonn) for fruitful
̈
cooperation on salimabromide, Andreas J. Schneider (Uni-
versity of Bonn) for HPLC-support, and Dr. G. Schnakenburg
(University of Bonn) for X-ray structure analysis.
C
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REFERENCES
■
(1) Felder, S.; Dreisigacker, S.; Kehraus, S.; Neu, E.; Bierbaum, G.;
Wright, P. R.; Menche, D.; Schaberle, T. F.; Konig, G. M. Chem.Eur.
̈
̈
J. 2013, 19, 9319.
(2) So far there is only one other secondary metabolite known that
was isolated from an obligate marine myxobacterium: Fudou, R.;
Iizuka, T.; Sato, S.; Ando, T.; Shimba, N.; Yamanaka, S. J. Antibiot.
2001, 54, 153.
(3) Manchand, P. S.; Townsend, J. M.; Belica, P. S.; Wong, H. S.
Synthesis 1980, 409.
(4) Roy, S.; Spilling, C. D. Org. Lett. 2010, 12, 5326.
(5) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
(b) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951. (c) Denmark, S. E.;
Fu, J.; Lawler, M. J. J. Org. Chem. 2006, 71, 1523.
(6) Bisphosphoramide 10 was readily obtained in three steps; see refs
5a and c.
(7) (a) Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985,
118, 1050. (b) Kim, C. U.; Misco, P. F.; Luh, B. Y.; Mansuri, M. M.
Tetrahedron Lett. 1994, 3017.
(8) Hartsel, J. A.; Craft, D. T.; Chen, Q.-H.; Ma, M.; Carlier, P. R. J.
Org. Chem. 2012, 77, 3127.
(9) The iodocyclization of compound 4 without a benzoyl-protecting
group may be more selective due to less sterical repulsion of the
hydroxyl and the iodide.
−
(10) Py2I+·BF4 has been used for this purpose: (a) Barluenga, J.;
Gonzal
1988, 27, 1546. (b) Appelbe, R.; Casey, M.; Dunne, A.; Pascarella, E.
Tetrahedron Lett. 2003, 44, 7641. (c) Barluenga, J.; Alvarez-Perez, M.;
Rodríguez, F.; Fananas, F. J.; Cuesta, J. A.; García-Granda, S. J. Org.
́
ez, J. M.; Campos, P. J.; Asensio, G. Angew. Chem., Int. Ed. Engl.
́
́
̃
Chem. 2003, 68, 6583. (d) Sano, Y.; Nakata, K.; Otoyama, T.; Umeda,
S.; Shiina, I. Chem. Lett. 2007, 36, 40. (e) Nakata, K.; Sano, Y.; Shiina,
I. Molecules 2010, 15, 6773.
(11) Previously, this kind of epoxidation of iodide by treatment with
mCPBA has only been observed as a side reaction: Macdonald, T. L.;
Narasimhan, N.; Burka, L. T. J. Am. Chem. Soc. 1980, 102, 1160.
(12) Finkielsztein, L. M.; Aguirre, J. M.; Lantano, B.; Alesso, E. N.;
̃
Moltrasio Iglesias, G. Y. Synth. Commun. 2004, 34, 895.
(13) (a) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc.
2006, 128, 2485. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299.
(14) (a) Malona, J. A.; Cariou, K.; Spencer, W. T., III; Frontier, A. J.
J. Org. Chem. 2012, 77, 1891. (b) Madin, A.; O’Donnel, C. J.; Oh, T.;
Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127,
18054. (c) Smalley, T. L., Jr. Synth. Commun. 2004, 34, 1973.
(15) This kind of selectivity has been observed for the
methoxycarbonlyation of aryltriflates containing also an arylbromide:
(a) Iwamoto, H.; Yukimasa, Y.; Fukazawa, Y. Tetrahedron Lett. 2002,
43, 8191. (b) Teply, F.; Stara,
́
I. G.; Stary, I.; Kollar
́
ovic,
̌ ̌
A.; Lustinec,
́
́
̌
D.; Krausova,
́
S.; Saman, D.; Fiedler, D. Eur. J. Org. Chem. 2007, 4244.
To the best of our knowledge no example for a vinyltriflate containing
an arylbromide is known.
́
(16) Esteve, J.; Jimenez, C.; Nebot, J.; Velasco, J.; Romea, P.; Urpí, F.
Tetrahedron 2011, 67, 6045.
(17) (a) Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42,
1801. (b) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S.
Tetrahedron Lett. 1994, 35, 7171. (c) Pettit, G. R.; Singh, S. B.; Herald,
D. L.; Lloyd-Williams, P.; Kantoci, D.; Burkett, D. D.; Barkoz
́
y, J.;
Hogan, F.; Wardlaw, T. R. J. Org. Chem. 1994, 59, 6287.
(18) For a review on macrolactonizations, see: Parenty, A.; Moreau,
X.; Niel, G.; Campagne, J.-M. Chem. Rev. 2013, 113, PR1.
(19) Macrolactones have been formed by cyclocarbonylation from
terminal hydroxyacetylenes (a), allenyl alcohols (b), and polymer
supported allyl bromides (c). For an alkoxycarbonylative macro-
lactonization process, see (d): (a) Setoh, M.; Yamada, O.; Ogasawara,
K. Heterocycles 1995, 40, 539. (b) Yoneda, E.; Zhang, S.-W.; Onitsuka,
K.; Takahashi, S. Tetrahedron Lett. 2001, 42, 5459. (c) Takahashi, T.;
Kusaka, S.; Doi, T.; Sunazuka, T.; Omura, S. Angew. Chem., Int. Ed.
̅
2003, 42, 5230. (d) Bai, Y.; Davis, D. C.; Dai, M. Angew. Chem., Int. Ed.
2014, 53, 6519.
D
DOI: 10.1021/acs.orglett.5b01231
Org. Lett. XXXX, XXX, XXX−XXX