Enantioselective Synthesis of Cyclohepta[ b]indoles via Pd-Catalyzed Cyclopropane C(sp3)-H Activation as a Key Step

Article abstract of DOI:10.1021/acs.orglett.9b02687

An enantioselective synthesis of functionalized cyclohepta[b]indoles via Pd-catalyzed cyclopropane C-H activation followed by olefination and indole-vinylcyclopropane rearrangement is reported. The design of the chiral cyclopropane precursor was such that both enantiomeric cyclohepta[b]indoles were accessed from a single compound exhibiting a "hidden" symmetry plane. The scope of the method was demonstrated by varying the substituents on the cyclopropane as well as on the heterocycle itself.

Full text of DOI:10.1021/acs.orglett.9b02687

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of Cyclohepta[b]indoles via Pd-Catalyzed
Cyclopropane C(sp3)−H Activation as a Key Step
†
†
̈
Maximilian Hafner, Yevhenii M. Sokolenko, Paul Gamerdinger, Erik Stempel, and Tanja Gaich*
̈
Department of Chemistry, University of Konstanz, Universitatsstraße 10, 78464 Konstanz, Germany
S
* Supporting Information
ABSTRACT: An enantioselective synthesis of functionalized cyclohepta[b]indoles via Pd-catalyzed cyclopropane C−H
activation followed by olefination and indole−vinylcyclopropane rearrangement is reported. The design of the chiral
cyclopropane precursor was such that both enantiomeric cyclohepta[b]indoles were accessed from a single compound
exhibiting a “hidden” symmetry plane. The scope of the method was demonstrated by varying the substituents on the
cyclopropane as well as on the heterocycle itself.
yclohepta[b]indole alkaloids represent a large group of
inhibitor IV (7) and other cyclohepta[b]indoles starting from
8 (Scheme 1).9 The key step therein was an enantioselective
C
natural products exhibiting various biological activities.1
Additionally, the cyclohepta[b]indole motif can be found in
several pharmaceutically active compounds (Figure 1).1 The
Scheme 1. Previous Work by Gaich and Co-workers
Charette cyclopropanation10 to give the cyclopropane
derivative, which was converted to 9 and concomitantly
underwent a divinylcyclopropane rearrangement (DVCPR) to
give compound 10. This was converted to cyclohepta[b]indole
11 in two steps. This methodology is limited with regard to
substitution of the cyclopropane ring caused by the Charette
cyclopropanation, which results in the formation of disub-
stituted cyclopropanes (blue dot indicated in Scheme 1).
To extend the scope of our methodology to trisubstituted
cyclopropane precursors for the DVCPR, we took an entirely
different strategic approach involving C−H activation of a
cyclopropane to accomplish the desired 1,2,3-substitution
pattern in an enantioselective way.
Figure 1. Cyclohepta[b]indole alkaloids and active compounds.
activities vary from inhibition of nitric oxide production in
BV2-microglial cells,2 sodium channel blocking,3 and anti-
cholinergic effects4 over antifungal5 and antibiotic properties6
to selective inhibition of histone deacetylase in nanomolar
concentrations.7
Thus, the cyclohepta[b]indole motif is an attractive target
for organic chemists, and numerous methodologies for its
synthesis have been developed, mostly involving cycloaddition
reactions.1,8 Nevertheless, achieving high enantioselectivity and
a high degree of functionalization in a rational manner still
remains a challenge in cyclohepta[b]indole synthesis. In 2013,
our group published an asymmetric synthesis of SIRT1-
Received: July 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The key step of our approach is the direct introduction of a
heteroaromatic compound (in most cases an indole, such as 14
in Scheme 2) to chiral cyclopropane 12 via Pd-catalyzed
chemistry and thus results in a library of cyclohepta[b]indoles
after DVCPR.
The synthesis of substrates 12 for the Pd(II)-catalyzed
C(sp3)−H activation commenced from commercially available
starting material 18 and known compound 2014 (Scheme 3).
Scheme 2. Enantiodivergency Plan toward
Cyclohepta[b]indoles
Scheme 3. Synthesis of Substrates for C(sp3)−H Activation
In the case of the synthesis of compound 19, the enantiomeric
excess of 91% was provided with the aid of fermentative
enantioselective saponification by porcine liver esterase
(PLE).15 Cyclopropylamides 21 and 22 were obtained with
98% ee, where the optical activity was introduced by
intramolecular enantioselective Cu(I)-catalyzed cyclopropana-
tion.14 The aminoquinoline moiety was subsequently intro-
duced to give the desired compounds on a decagram scale in
yields of up to 75% over the whole sequence.
With cyclopropylamides 19, 21, and 22 in hand, we
screened for the optimal conditions in the Pd-catalyzed C−
H activation. We found that the yields were highest when 19
(1 equiv) was treated with tosylated 3-iodoindole (3 equiv),
Pd(OAc)2 (10 mol %), and Ag2CO3 (1.2 equiv) in anhydrous
toluene (1 M) under an inert gas atmosphere at 110 °C
(Scheme 4). The reaction usually was complete within 3−6 h,
directing-group-mediated cyclopropane C(sp3)−H activa-
tion.11 To the best of our knowledge, previous studies on
related systems involved the introduction of iodobenzenes to
the cyclopropane in the C−H activation step.12 Iodoindoles
such as 14 have previously not been investigated as coupling
partners in this reaction. This methodology presents the
opportunity to further transform the C−H activation product
15 in a DVCPR with participation of the heteroaromatic
nucleus (Scheme 2). By contrast, benzene rings do not take
part in DVCPRs in general. The coupling product of the C−H
activation process, 15, possesses a fully cis-1,2,3-trisubstituted
cyclopropane ring. The all-cis-relationship is a direct result of
the reaction mechanism of the C−H activation process,
whereby the palladium is precoordinated to the substrate via
the aminoquinoline unit (NHQ) in intermediate 13.13 As a
consequence, the coupling of the heteroaromatic ring occurs
from the same side of the cyclopropane ring (cis fashion). If the
cyclopropane substrate already contains two cis-oriented
substituents, the C−H activation will introduce the third
substituent (the indole coupling partner 14) in an all-cis
manner to give 1,2,3-cyclopropane product 15. Subsequent
functional group transformations of the C−H activation
product 15 lead to indole-vinylcyclopropanes 16, which then
undergo the DVCPR to give the desired cyclohepta[b]indoles
17. Of the latter, both enantiomeric forms can be obtained
selectively from a single optical antipode of C−H activation
product 15. This is accomplished by either (1) transforming
the amide in 15 to the olefin, giving enantiomer (−)-16
(amide-to-olefin route; red in Scheme 2), or (2) transforming
the alcohol to the olefin, giving enantiomer (+)-16 (alcohol-to-
olefin route; green in Scheme 2).
Scheme 4. Synthesis of Cyclopropane 24
yielding 23 in 45−65% yield. The directing group was in turn
removed by imide formation (Boc protection) followed by
reduction to the corresponding alcohol 24 with an excess of
LiBH4. With compound 24 in hand, we demonstrated the use
of the “hidden symmetry” as an enantiomeric switch.
Optically pure compound 24 was synthesized on a gram
scale and converted to (−)-cyclohepta[b]indole 17 via the
“amide-to-olefin” route (Scheme 5). This was accomplished by
These two routes reveal a “hidden symmetry” (σ plane,
shown in blue in Scheme 2) in the C−H activation product 15,
which in this way acts as an “enantiomeric switch”. This spares
the need to synthesize both enantiomeric forms of 15, thus
providing a substantial synthetic asset. Our route is suited for
creating a library of chiral compounds consisting of diversely
substituted indole-vinylcyclopropanes with defined stereo-
B
DOI: 10.1021/acs.orglett.9b02687
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Scheme 5. Amide-to-Olefin Route
Scheme 7. Scope of the C−H Activation
Ley−Griffith oxidation, Wittig olefination, and DVCPR. The
rearrangement proceeded smoothly at 120 °C in toluene to
gave the desired (−)-cyclohepta[b]indoline 26 quantitatively.
Further TBDPS deprotection of compound 26 with the aid of
HF in pyridine and subsequent aromatization mediated by
pTsOH afforded the desired (−)-cyclohepta[b]indole 17.
To prove that 24 can also be converted to the opposite
enantiomer, (+)-cyclohepta[b]indole 17, we submitted it to
the alcohol-to-olefin route (Scheme 6). Piv protection and
Scheme 6. Alcohol-to-Olefin Route
a
b
c
Isolated yields are shown. PG = tert-butyldiphenylsilyl. PG =
triphenylmethyl.
typically varied between 43 and 60%. Changing the protecting
group to trityl led to an increase in the yields to 48−75%. The
nature of the substituent in 31−41 had no significant influence
on the substrate reactivity, but substitution at the indole 4-
position in 42 and 43 led to only trace amounts of product 30.
This most probably arises from steric clash during the oxidative
addition of the indole, resulting in a far slower reaction.
With the introduction of the methyl group to the
cyclopropane (in 21 and 22), the symmetry of the DVCPR
precursor is lost. As a consequence, the amide-to-olefin and
alcohol-to-olefin routes afford different groups of compounds
(45−49 and 50−54, respectively; Scheme 8) enabling further
product diversification. The latter group contains a quaternary
stereocenter, whereas the former group contains only a
trisubstituted double bond in the cyclohepta[b]indole. It was
from compound 55 in this series of substrates that we were
able to get single crystals of the primary rearrangement adduct
to unambiguously assert its structure.
To further demonstrate the broad utility of our method-
ology, we introduced different substituents in the cyclohepta-
[b]indole scaffold 57 by varying the olefination reagents
applied to cyclopropane 56 (Scheme 9). This feature allows for
the introduction of an additional stereocenter at the benzyl
position on C2 of the indole ring. The substituents vary from
esters (58) to ketone (59), vinyl (60), and aryl groups (61).
The scope of our methodology is very general, enabling rapid
access to cyclohepta[b]indole scaffolds for pharmacological
testing. To introduce optical activity into the C−H activation
precursor, we used enzyme-mediated desymmetrization and
copper-catalyzed asymmetric cyclopropanation. This stereo-
information was subsequently transferred to the cyclohepta-
TBDPS deprotection afforded alcohol 27, which was
submitted to the same sequence (Ley−Griffith oxidation,
Wittig reaction, and DVCPR) to give 29. Conversion of 29 to
(+)-cyclohepta[b]indole enantiomer 17 proceeded via aroma-
tization with pTsOH and deprotection of the Piv group by
reduction with DIBAL-H (Scheme 6). The spectra of (+)-17
and (−)-17 were identical, and most important, their optical
rotations were of opposite sign (with [α]2D3 +12 and −12,
respectively), proving the stereospecificity of the DVCPR and
the ability to obtain both enantiomers from a single precursor
24. To examine the scope of the C−H activation process, we
chose cyclopropanes 21 and 22 containing a quaternary
stereocenter at the cyclopropane ring (additional Me group in
Scheme 7). In the case of indole variation, we used different
electron-donating and electron-withdrawing groups at every
position of the indole benzene core (Scheme 7).
The results of the C−H activation experiments are depicted
in Scheme 7. With TBDPS as the protecting group, the yields
C
DOI: 10.1021/acs.orglett.9b02687
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Scheme 8. Product Diversification with Unsymmetrical
DVCPR Substrates
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.9b02687.
Experimental procedures, characterization for new
compounds and copies of NMR spectra (PDF)
Accession Codes
CCDC 1939947 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*tanja.gaich@uni-konstanz.de
ORCID
Tanja Gaich: 0000-0002-6793-1374
Author Contributions
†M.H. and Y.M.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was granted by the European Research
Council through an ERC starting grant (ANaPSyS GA
679418). We thank the NMR Department of the University
of Konstanz (A. Friemel and U. Haunz) for extensive analyses
Scheme 9. Variation of the Wittig reaction
̈
̈
and Inigo Gottker (Universitat Konstanz) for X-ray analyses.
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