Enantioselective synthesis of cyclohepta[ b ]indoles: Gram-scale synthesis of (S)-SIRT1-inhibitor IV

Article abstract of DOI:10.1021/ol4026217

An enantioselective gram-scale synthesis of one of the most potent SIRT1-inhibitors has been accomplished by an unprecedented domino reaction sequence establishing the cyclohepta[b]indole core. This method was developed for application in natural product

Full text of DOI:10.1021/ol4026217

ORGANIC
LETTERS
2
013
Vol. 15, No. 21
472–5475
Enantioselective Synthesis of
5
Cyclohepta[b]indoles: Gram-Scale
Synthesis of (S)‑SIRT1-Inhibitor IV
Philipp J. Gritsch, Erik Stempel, and Tanja Gaich*
‡
‡
Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 1,
3
0167 Hannover, Germany
tanja.gaich@oci.uni-hannover.de
Received September 11, 2013
ABSTRACT
An enantioselective gram-scale synthesis of one of the most potent SIRT1-inhibitors has been accomplished by an unprecedented domino
reaction sequence establishing the cyclohepta[b]indole core. This method was developed for application in natural product synthesis of a variety
of indole alkaloids.
The cyclohepta[b]indole core, which occurs in a variety
1
of indole alkaloids, is associated with a broad spectrum
2
of biological profiles ranging from anti-inflammation
3
4
and anti-aging to anti-tuberculosis activities (Figure 1).
Among the pharmaceutically active compounds based on
this structure motif, around two dozen patents have been
5
issued within the past decade. The SIRT1-inhibitor IV (4)
shows outstanding biological activity and is therefore
being heavily investigated. It belongs to a new class of
‡
These authors contributed equally.
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(
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Figure 1. Compounds containing the cyclohepta[b]indole core.
(
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Data shows
2
b,6
Compound 4 is one of the most potent compounds
8045.
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1
0.1021/ol4026217 r 2013 American Chemical Society
Published on Web 10/23/2013

Scheme 1. Enantioselective Cyclopropanation
8
cyclohepta[b]indole systems exist. Our method tolerates
rF ei ag ru rr ae n g2 e. mC eh ni rt a. lity transfer in the indoleÀvinylcyclopropane
a broad range of substituents at different positions of
the seven-membered ring, making it a robust and gen-
eral method to synthesize this structure motif (Figure 2).
Since the key step constitutes a [3,3]-sigmatropic re-
described, with IC50 values of 60À100 nM represent-
ing a 500-fold improvement over previously reported
inhibitors.
9
arrangement, each substituent can be introduced stereo-
specifically, which is not possible with any other method
available to date. Our strategy relies upon a divinylcy-
2
b
This compound contains a single stereocenter and so
far has only been synthesized as a racemate, which is
separated by chiral HPLC. The two enantiomers differ
10
clopropane rearrangement (DVCPR) involving the
indole moiety as a 2π-unit. This substrate type has pre-
viously not been reported in a DVCPR reaction, thus
drastically in their biological potency, with (S)-4 (IC50
=
=
6
2
3 nM) being 365-fold more potent than (R)-4 (IC50
3 μM), rendering an enantioselective access especial-
11
extending the scope of this reaction. This reaction not
only assembles the seven-membered ring, but due to or-
ly to the more potent (S)-4 enantiomer utmost impor-
2
tant.
12
bital symmetry considerations, chirality is transferred
b
stereospecifically from the cyclopropane ring to the
benzylic positions, which are very labile and therefore
difficult to access in a stereoselective way by other
methods (displayed in Figure 2).
Herein, we present an efficient, enantioselective, and
gram-scale synthesis of SIRT1-inhibitor IV (4). In contrast
2
b
to the established racemic route, which requires indivi-
dual planning for derivative synthesis, our synthetic access
is modular and therefore does not require additional steps
or a change in synthetic planning to allow derivatization.
This is crucial for library synthesis and rapid testing of
a large variety of compounds. Our synthetic route rests
upon a Wittig reaction/divinylcyclopropane rearrange-
The rearrangement can be carried out with a 2- or a
3
-indoleÀvinylcyclopropane 9 or 12. With both substrates,
dearomatization of the indole core occurs in the course of
the rearrangement, but only the 2-indoleÀvinylcyclopropane
product rearomatizes spontaneously. The rearrangement
temperatures vary with the substituents from 20 to 140 °C
7
ment cascade. To date, a few examples of racemic and
only one example of an enantioselective synthesis of
(see the Supporting Information). The transfer of chi-
rality for both 2- and 3-indoleÀvinylcyclopropanes 9
and 12 is depicted in Figure 2. In the case of 3-indoleÀ
vinylcyclopropanes 9 (series A transition state 10), it can
(
7) For application to terpenoids, see: (a) Pantke-B o€ cker, S.Pohnert,
G.; Fischer-Lui, I.; Boland, W. Tetrahedron 1995, 51, 7927. For recent
application to indole-type compounds, see: (b) Schwarzer, D. D.; Gritsch,
P. J.; Gaich, T. Angew. Chem. Int. Ed. 2012, 51, 11514.
2
be clearly seen that R and the indole C2-proton will
adopt the cis-stereorelationship on the seven-membered
ring. The relative configuration is therefore governed by
the geometry of the double bond; hence, a (Z)-double
bond will give the cis-compound, whereas the (E)-double
bond will give the trans-compound. The same holds true
(8) For the enantioselective example, see: (a) Loh, C. C. J.; Badorrek,
J.; Raabe, G.; Enders, D. Chem.;Eur. J. 2011, 17, 13409. For racemic
syntheses, see: (b) Anderson, A. G., Jr.; Richards, H. F.; Haddock, R. D.
Org. Prep. Proced. Int. 1989, 21, 649. (c) Arcadi, A.; Bianchi, G.;
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I. V. Chem. Heterocycl. Compd. (N.Y., NY, U.S.) 2010, 46, 117. (e)
Butin, A. V.; Kostyukova, O. N.; Tsiunchik, F. A.; Uchuskin, M. G.;
Serdyuk, O. V.; Trushkov, I. V. J. Heterocycl. Chem. 2011, 48, 684. (f)
Falke, H.; Bumiller, K.; Harbig, S.; Masch, A.; Wobbe, J.; Kunick, C.
Molbank 2011, M737. (g) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew.
Chem., Int. Ed. 2012, 51, 10390. (h) Joseph, B.; Alagille, D.; Merour,
J.-Y.; Leonce, S. Chem. Pharm. Bull. 2000, 48, 1872. (i) Joseph, B.;
Alagille, D.; Rousseau, C.; Merour, J.-Y. Tetrahedron 1999, 55, 4341. (j)
Joseph, B.; Cornec, O.; Merour, J.-Y. Tetrahedron 1998, 54, 7765. (k)
Kinnick, M. D.; Mihelich, E. D.; Morin, J. M., Jr.; Sall, D. J.; Sawyer,
J. S.; WO 2003/016277A1, July 29, 2003; (l) Kupai, K.; Banoczi, G.;
Hornyanszky, G.; Kolonits, P.; Novak, L. Cent. Eur. J. Chem. 2012, 10, 91.
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Chem. Soc. Rev. 1999, 28, 43. (c) Kazmaier, U. J. Indian Chem. Soc. 1999,
7
6, 631. (d) Langlois, Y. Claisen Rearrange. 2007, 301. (e) Nubbemeyer,
U. Synthesis 2003, 961.
(10) (a) Davies, H. M. L. Adv. Cycloaddit. 1999, 5, 119. (b) Hudlicky,
T.; Fan, R.; Reed, J. W.; Gadamasetti, K. G. Org. React. (N.Y.) 1992,
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64, 180. (d) Sarel, S. Acc. Chem. Res. 1978, 11, 204.
(11) For similar examples, see: (a) Fukuyama, T.; Liu, G. J. Am.
Chem. Soc. 1996, 118, 7426. (b) Shimokawa, J.; Harada, T.-A.; Yokoshima,
S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 17634. (c) Davies, H. M. L.;
Doan, B. D. J. Org. Chem. 1998, 63, 657. (d) Wender, P. A.; Eissenstat,
M. A.; Filosa, M. P. J. Am. Chem. Soc. 1979, 68, 2196.
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(
3
n) Shu, D.; Song, W.; Li, X.; Tang, W. Angew. Chem., Int. Ed. 2013, 52,
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€
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Org. Lett., Vol. 15, No. 21, 2013
5473

for 2-indoleÀvinylcyclopropanes 12 (series B, transition
state 13), but due to spontaneous aromatization in the
course of the reaction, only one stereocenter is retained
in the final product 11 (indicated with dashed line). The
absolute stereochemistry in products 8 and 11 is gov-
erned by the stereocenters of the cyclopropane ring.
Enantioselective Charette cyclopropanation of the eas-
ily accessible allylic alcohols (3 chemical operations/1
purification) 14, 15, and 16 (Scheme 1) with dioxabo-
rolane 17 furnished the desired products 18, 19, and 20
envisionedthatanenantioselectivesynthesiswouldpresent
a special challenge, since it was well-known that the only
stereocenter present in the molecule was prone to racemi-
zation, especially upon late-stage functional group inter-
conversions at the carboxylic acid group. Therefore we
decided to avoid this issue by directly introducing the
carboxamide from the beginning.
Table 2. Substrate Scope of Cyclohepta[b]indole Synthesis
(
1
3
a
with 89À92% ee.
from 3-IndoleÀVinylcyclopropyl Aldehyde)
To validate this concept and to explore the scope of the
domino sequence, a variety of olefins of type 9/12 were
tested (Tables 1 and 2). The reaction is very robust, and
tolerates a broad range of substituents (electron-rich and
-deficient), which can be introduced at any position on the
seven-membered ring. Even quaternary stereocenters are
formed (compounds 25, 31, and 32). Wittig adducts 9 and
12 cyclize in situ to deliver cyclohepta[b]indoles of type 8
and 11 in good to excellent yields.
Table 1. Substrate Scope of Cyclohepta[b]indole Synthesis
from 2-IndoleÀVinylcyclopropyl Aldehyde)
(
a
For solvent and reaction time refer to the Supporting Information.
In order to synthesize the more potent (S)-SIRT1-
inhibitor IV (4), we started our synthesis with the cyclo-
propantation using (S,S)-oxaborolane 17 (Scheme 2). Oxi-
dation of ent-19 to the corresponding aldehyde followed
by HornerÀWadsworthÀEmmons olefination with phos-
phonate 33 directly introduced the desired carboxamide
and in situ divinylcyclopropane rearrangement gave
cyclohepta[b]indole 35 in 74% yield. Hydrogenation of
the double bond and concomitant aromatization with
palladium on charcoal afforded precursor 37 in 88% yield.
Removal of the tosyl group using samarium diiodide
delivered (S)-SIRT1-inhibitor IV (4) with 92% ee and an
overall yield of 28% with complete retention of the labile
1
4,15
stereocenter.
It is important to note that even the
a
exposure of 37 to magnesium and methanol did not result
in racemization (as opposed to the treatment of the
corresponding ester). For practical purposes it is impor-
tant to note that the synthetic sequence requires only three
purification steps and can be performed on a gram scale.
For solvent and reaction time refer to the Supporting Information.
We then set out to apply our method to an enantiose-
lective synthesis of the (S)-SIRT1-inhibitor IV (4). We
(
13) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651.
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Org. Lett., Vol. 15, No. 21, 2013
5
474

Scheme 2. Enantioselective Synthesis of (S)-4
Scheme 4. Extension of Substrate Scope
Scheme 3. Aromatization of Cyclohepta[b]indoles from
IndoleÀ3-Vinylcyclopropane Adducts
demonstrates the tolerance of heteroatoms in the system,
serving as intermediates en route to methuenine (6).
Alternatively, compound 40 was deprotected, oxidized,
and olefinated to give after rearrangement and sponta-
neous aromatization cyclohepta[b]indole.
In conclusion, we have accomplished the first enantio-
selective synthesis of the (S)-SIRT1-inhibitors 4 via a novel
domino-Wittig/-divinylcyclopropane rearrangement se-
quence. Optical activity was introduced via Charette’s
asymmetric cyclopropanation and, in a divinylcyclopro-
pane rearrangement, was transferred to the cyclohepta-
The enantiomeric excess of all our products was deter-
mined via chiral HPLC and to our delight corresponded
to the optical purity of the cyclopropanation products,
indicating not only complete transfer of chirality but proof
that our method is mild enough to maintain the stereo-
integrity of the labile benzylic position.
As mentioned before, 3-indoleÀvinylcyclopropanes do
not rearomatize spontaneously. Thus, 29 was exemplarily
subjected to acidic conditions, upon which rearomatiza-
tion to indole 38 took place (Scheme 3).
[
b]indole core which is also a central structure motif of
The scope of the reaction can even be extended by using
a transition-metal-catalyzed cyclopropanation of 39 with
ethyl diazoacetate (Scheme 4). This is important for
the application of this methodology to the synthesis of
natural products depicted in Figure 1, which are currently
pursued in our laboratories. The synthesis of tricycle 43
many other natural products. The scope of this domino
process is very general, making a broad range of substi-
tuted cyclohepta[b]indoles accessible for further pharma-
cological testing.
1
6
Acknowledgment. We thank Dr. J. Fohrer, M. Rettstadt,
D. K o€ rtje, and Prof. E. Hofer for detailed 2D-NMR analysis
and Dr. G. Dr €a ger and R. Reichel for mass spectra. Financial
support was generously granted by the Alexander von
Humboldt foundation through a Sofja Kovalevskaja prize.
(
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Supporting Information Available. Experimental de-
13
1
tails, H and C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
16) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. (N.Y.)
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2
9
The authors declare no competing financial interest
Org. Lett., Vol. 15, No. 21, 2013
5475