Stable Bromiranium Ion Salts as Reagents for Biomimetic Indole Terpenoid Cyclizations

Article abstract of DOI:10.1021/acs.orglett.9b00259

Indole terpene alkaloids are a diverse group of natural products and show significant biological activities. To enable their biomimetic synthesis, electrophilic bromocyclization of polyenyl indole derivatives could be achieved using sterically demanding b

Full text of DOI:10.1021/acs.orglett.9b00259

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stable Bromiranium Ion Salts as Reagents for Biomimetic Indole
Terpenoid Cyclizations
Jonathan Bock,† Constantin G. Daniliuc,† and Ulrich Hennecke*,†,‡
†
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Correnssstrasse 40, 48149 Munster, Germany
‡Organic Chemistry Research Group, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan
2, 1050 Elsene, Belgium
S
* Supporting Information
ABSTRACT: Indole terpene alkaloids are a diverse group of
natural products and show significant biological activities. To
enable their biomimetic synthesis, electrophilic bromocycliza-
tion of polyenyl indole derivatives could be achieved using
sterically demanding bromiranium ion salts with the weakly
coordinating counterion BArF− as reagent. Starting from
polyenyl indole derivatives, the corresponding bromocycliza-
tion products have been obtained with very high diastereoselectivity and in good yields.
ndole terpene alkaloids are a diverse group of natural
products mostly isolated from plants or fungi.1 Quite a few
of these alkaloids have been identified in plants used in
traditional medicine including the bruceollines2 (from Brucea
mollis), polyveoline,3 or polyavolensinol4 (both from Polyalthia
suaveolens). Bruceollines such as bruceolline J (Figure 1)
complex structure and interesting biological activities, several
indole terpene alkaloids have been the target of total
syntheses.9 While most syntheses employed traditional
retrosynthetic approaches, several groups followed biomimetic
strategies. This includes several attempts to build up the
carbon skeleton of a selected indole terpene via biomimetic
polyene-type cyclizations.8,10 For example, Clark and co-
workers prepared a linear cyclization precursor for the
synthesis of emindole SB.8e One disadvantage of these
epoxide-induced polyene cyclizations is the requirement for
prefunctionalization (selective epoxidation of the terminal
alkene) of the isoprenoid chain. This is not necessary for
halenium-induced polyene cyclizations, which can be applied
directly on the linear polyenes. Furthermore, several recently
developed halogenation methods provide highly reactive
halenium equivalents, which promise higher reaction yields
than the epoxid cyclizations.11,12 Herein, we investigate
biomimetic polyene-type cyclizations of indole-based starting
materials employing a stable bromiranium ion salt as highly
reactive brominating agent.13 The results show that by using
this reagent, effective and highly diastereoseletive polyene
cyclizations to indole terpenoid mimics are possible.
I
Initially, the monocyclization of prenylated, tosyl-protected
indole 1a was investigated. When 1a was treated with common
electrophilic brominating agents such as NBS, TBCO, or
DBDMH in dichloromethane, only traces of the 5-endo
cyclization product 2a were observed as determined by gas
chromatography (Table 1, entries 1−3). Conducting the
reaction with NBS and morpholine in HFIP, as reported by
Gulder11d for related polyene-type cyclizations, produced the
product 2a in 8% yield (entry 4). The use of Snyder’s BDSB
reagent11b in nitromethane provided a similar yield (5%, entry
Figure 1. Selected indole terpene alkaloids containing prenyl-,
farnesyl-, or geranylgeranyl-based carbon skeletons.
contain a prenylated and cyclized indole core and are active
against P. falciparum, the causative agent of malaria.5
Polyveoline and polyavolensinol are more complex, containing
cyclized farnesyl side chains. These alkaloids show significant
biological acitivity against Trypanosoma and other protozoan
organisms.6 In general, the biosynthesis of indole terpene
alkaloids proceeds via alkylation of the indole core by a prenyl
transferase, followed by epoxidation and terpene-like cycliza-
tion of the side chain, generating highly complex natural
products out of simple precursor molecules.7,8 Due to their
Received: January 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00259
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the optimized reaction conditions in hand, the
cyclization of various prenylated and geranylated indoles was
investigated (Table 2).
Table 1. Optimization of Conditions for Electrophilic
Bromo Cyclization Reaction Using Precursor 1a*
Table 2. Bromonium-Induced Polyene-Type Cyclization of
Substituted Indoles*
*
Conditions: 1a (0.1 mmol, 1.0 equiv), base (1.2 equiv), CH2Cl2
a
(0.05 M). Yield determined by gas chromatography using n-
b
hexadecane as internal standard. Morpholine·2HFIP (1.4 equiv).
c
Reagent added as solution.
5). In general, gas chromatography showed that in many cases
either conversions were low or products were accompanied by
a large amount of various side products.
When 1a was treated with 1.0 equiv of [Ad2Br][BArF]13 and
HMDS, the 5-endo cyclization product 2a was obtained in
significantly improved yield (56% by GC, entry 6). Using 1.2
equiv of [Ad2Br][BarF] the yield improved slightly to 59%
(entry 7). Adding the reagent as a solution did not lead to an
improved yield (entry 8). Surprisingly, higher amounts of the
reagent such as 1.5 or 2.0 equiv of [Ad2Br][BArF] did not
result in increased yields, mostly due to the increased
formation of unidentifiable side products (entries 9 and 10).
When the base HMDS was replaced by less sterically hindered
collidine or even pyridine the yield of cyclization product 2a
dropped strongly (entries 11 and 12). However, HMDS could
be replaced by the sterically highly demanding 2,6-di(tert-
butyl)methylpyridine (DTBMP) without a significant drop in
yield (entry 13). NMR experiments confirmed that this
behavior is caused by the coordination of the smaller pyridines
to the [Ad2Br][BArF] reagent, while HMDS or DTBMP do
not coordinate. Attempts to improve the yield by the use of an
alternative N-protecting group were not successful (see the
Supporting Information for details).
*
Conditions: substrate (0.4 mmol, 1.0 equiv), HMDS (0.48 mmol,
1.2 equiv), [Ad2Br][BArF] (0.48 mmol, 1.2 equiv) in CH2Cl2 (0.05
a
b
M). Isolated yields. Determined by 1H NMR spectroscopy from the
crude reaction mixture.
On a 0.4 mmol scale, the 3-prenylated indole 1a underwent
5-endo cyclization to the product 2a in 48% isolated yield (56%
GC yield), which compares well with the reaction on a lower
scale (Table 1). For the 2-prenylated derivative 1b, the
cyclization yield was significantly lower (25%). Indole 3, the
double bond isomer of 1a, provided upon treatment with
[Ad2Br][BArF] a complex reaction mixture from which only
B
DOI: 10.1021/acs.orglett.9b00259
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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carbazole 4 could be isolated in 20% yield. Compound 4 could
be formed by a 6-endo cyclization followed by elimination and
oxidation to the carbazole. When the 3-geranyl-substituted
indole 5a was utilized, the reaction proceeded smoothly to the
corresponding bromocyclization product 6a with excellent
diastereoselectivity (95:5 dr) and very good yield (59%). 2-
Geranyl derivative 5b reacted in a very similar manner and
provided cyclization product 6b with very similar diaster-
eoselectivity (93:7 dr) and good yield (53%). This reaction
was repeated on a 1.0 mmol scale, in which case the product
was obtained with almost identical yield (51%) and
diastereoselectivity (93:7 dr). The indole core had a significant
impact on the yield of this cyclization, and starting materials
with electron-rich (5c) as well as more electron-poor indoles
(5e, 5f) led to low yielding cyclizations (16−21%).
Fluoroindole 5d gave the cyclization product in moderate
yield (31%). At the moment, it is not fully clear why electron-
donating as well as electron-withdrawing substituents have a
deleterious effect on the cyclization. However, at least for the
electron-rich indole derivative 5c, bromination of the indole
core can be suspected as a problem.
substituted indoles suggested that the cyclization of farnesyl
derivatives should also be possible (Table 3). The 3- and 2-
Table 3. Bromo Cyclization of Farnesyl Indoles 9*
*
The relative configuration of the major diastereomers of the
cyclization of geranyl indoles 6a and 6b could be established
by X-ray crystallography (6a: Scheme 1). The obtained
Conditions: substrate (0.4 mmol, 1.0 equiv), HMDS (0.48 mmol,
1.2 equiv), [Ad2Br][BArF] (0.48 mmol, 1.2 equiv) in CH2Cl2 (0.05
a
b
1
M). Isolated yields, Determined by H NMR spectroscopy of the
c
crude reaction mixture, Isolated as inseparable mixture of
diastereomers.
Scheme 1. Transition- and Solid-State Structures of 6a
farnesyl N-tosyl indoles 9a and 9b were prepared and
subjected to the standard reaction conditions. 3-Farnesyl
indole 9a underwent the bromenium-induced polyene-type
cyclization involving three C−C bond formations with a good
yield (45%) and acceptable diastereoselectivity (83:17 dr). 2-
Farnesyl indole derivative 9b also underwent the cyclization in
moderate yield, but with only low diastereoselectivity (61:39
dr). Based on the observation made for geranyl cyclization, it is
assumed that the major diastereomer results from cyclization
via a chair−chair conformation; however, no crystals for X-ray
crystallography could be obtained. The lower diastereoselec-
tivity for the farnesyl cyclizations might be due to the two
pseudo-1,3-diaxial interactions in a possible chair−chair
transition state leading also to cyclization via alternative,
energetically comparable transition states.
In conclusion, it was shown that [Ad2Br][BArF] can be
applied as an electrophilic brominating agent in bromenium-
induced polyene-type cyclization reactions of prenyl, geranyl,
and farnesyl indole derivatives. In most cases, the cyclizations
were highly diastereoselective and provided a range of
terpenoid indole type building blocks, which will be useful
for the synthesis of indole terpene alkaloids. This is especially
apparent for the polyveoline alkaloids, whose carbon skeleton
was assembled in a single bromination/cyclization step from
unfunctionalized 2-farnesyl indole.
configuration is in line with the expected configuration for a
concerted cyclization reaction via a chair conformation with
trans-additions across the alkene following the Eschenmoser−
Stork postulate (Scheme 1).14 This also suggested that a
diastereomeric product of 6a should be available by cyclization
of a neryl indole. This was confirmed by treatment of 2-neryl
indole 5g with [Ad2Br][BArF] leading to product 6g with
excellent diastereoselectivity (95:5 dr) and in good yield
(45%). The relative configuration of 6g was established by
NOE investigations to be diastereomeric to 6b as predicted.
Finally, the cyclization of N-geranyl indole 7 was investigated.
This cyclization provided the product 8 again with excellent
diastereoselectivity and a yield of 38%. Although the yield is
slightly lower than for 2- or 3-geranyl indoles, it shows that the
cyclization does not require a strongly electron-withdrawing
protecting group at the indole nitrogen.
One of the surprising results of the investigations was the
often improved cyclization yield for geranyl substituents,
involving two C−C bond-forming steps, compared to prenyl
substituents, involving only one C−C bond formation. While
this could be caused by the lower stability of 2a/2b, which
contain the bromo substituent at a five-membered ring, it
cannot be excluded that the cascade cyclization to geranyl
products 6 is proceeding via a mechanistically distinct pathway.
The good yields obtained for the cyclization of the geranyl-
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00259.
General experimental procedures, characterization data,
and details on X-ray structure determination (PDF)
C
DOI: 10.1021/acs.orglett.9b00259
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
J.; Roberts, L.; Walshe, N. Synlett 2005, 4, 697−599. (g) Uchida, R.;
Tomoda, H.; Omura, S. J. Antibiot. 2006, 59, 298−302. (h) Isaka, T.;
Hasegawa, M.; Toshima, H. Biosci., Biotechnol., Biochem. 2011, 75,
2213−2222.
(9) (a) Corsello, M. A.; Kim, J.; Garg, N. K. Chem. Sci. 2017, 8,
5836−5844. (b) Zou, Y.; Smith, A. B., III J. Antibiot. 2018, 71, 185−
204.
CCDC 1863343−1863346 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
(10) Barrett, A. G. M.; Ma, T.-K.; Mies, T. Synthesis 2019, 51, 67−
82.
(11) (a) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900−
903. (b) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48,
7899−7903. (c) Samanta, R. C.; Yamamoto, H. J. Am. Chem. Soc.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ulrich.hennecke@vub.be.
ORCID
̈
2017, 139, 1460−1463. (d) Arnold, A. M.; Pothig, A.; Drees, M.;
Gulder, T. J. J. Am. Chem. Soc. 2018, 140, 4344−4353.
(12) For a polyene cyclization of indole derivatives using a iridium
catalyst, see: Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E.
M. J. Am. Chem. Soc. 2012, 134, 20276−20278.
Ulrich Hennecke: 0000-0002-4904-6793
Notes
(13) Ascheberg, C.; Bock, J.; Buß, F.; Muck-Lichtenfeld, C.;
̈
The authors declare no competing financial interest.
Daniliuc, C. G.; Bergander, K.; Dielmann, F.; Hennecke, U. Chem. -
Eur. J. 2017, 23, 11578−11586.
ACKNOWLEDGMENTS
Financial support by the DFG (HE 6020/2-2, HE 6020/3-1
and HE6020/4-1) is gratefully acknowledged.
(14) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77,
5068−5077. (b) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D.
Helv. Chim. Acta 1955, 38, 1890−1904.
■
REFERENCES
■
(1) (a) Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349−
366. (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep.
2013, 30, 694−752. (c) Marcos, I. S.; Moro, R. F.; Costales, I.;
Basabe, P.; Diez, D. Nat. Prod. Rep. 2013, 30, 1509−1526.
(2) (a) Ouyang, Y.; Koike, K.; Ohmoto, T. Phytochemistry 1994, 37,
575−578. (b) Jordan, J. A.; Gribble, G. W.; Badenock, J. C.
Tetrahedron Lett. 2011, 52, 6772−6774. (c) Lopchuk, J. M.; Green, I.
L.; Badenock, J. C.; Gribble, G. W. Org. Lett. 2013, 15, 4485−4487.
(d) Dethe, D. H.; Kumar B, V. Org. Chem. Front. 2015, 2, 548−551.
(e) Scarpi, D.; Faggi, C.; Occhiato, E. G. J. Nat. Prod. 2017, 80,
2384−2388.
(3) (a) Hocquemiller, R.; Dubois, G.; Leboeuf, M.; Cave, A.;
Kunesch, N.; Riche, C.; Chiaroni, A. Tetrahedron Lett. 1981, 22,
5057−5060. (b) Ngantchou, I.; Nyasse, B.; Denier, C.; Blonski, C.;
Hannaert, V.; Schneider, B. Bioorg. Med. Chem. Lett. 2010, 20, 3495−
̈
3498. (c) Kouam, S. F.; Ngouonpe, A. W.; Lamshoft, M.; Talontsi, F.
M.; Bauer, J. O.; Strohmann, C.; Ngadjui, B. T.; Laatsch, H.; Spiteller,
M. Phytochemistry 2014, 105, 52−59.
(4) Okorie, D. A. Phytochemistry 1981, 20, 2575−2578.
(5) (a) Chen, H.; Bai, J.; Fang, Z.-F.; Yu, S.-S.; Ma, S.-G.; Xu, S.; Li,
Y.; Qu, H.; Ren, J.-H.; Li, L.; Si, Y.-K.; Chen, X.-G. J. Nat. Prod. 2011,
74, 2438−2445. (b) Bharati, A. K.; Singh, H. B. NeBIO 2012, 3, 26−
28.
(6) (a) Ngantchou, I.; Nyasse, B.; Denier, C.; Blonski, C.; Hannaert,
V.; Schneider, B. Bioorg. Med. Chem. Lett. 2010, 20, 3495−3498.
(b) Muganza, D. M.; Fruth, B.; Nzunzu, J. L.; Tuenter, E.; Foubert,
K.; Cos, P.; Maes, L.; Kanyanga, R. C.; Exarchou, V.; Apers, S.;
Pieters, L. J. Ethnopharmacol. 2016, 193, 510−516. (c) Simoben, C.
V.; Ntie-Kang, F.; Akone, S. H.; Sippl, W. Nat. Prod. Bioprospect.
2018, 8, 151−169.
(7) (a) Tagami, K.; Liu, C.; Minami, A.; Noike, M.; Isaka, T.; Fueki,
S.; Shichijo, Y.; Toshima, H.; Gomi, K.; Dairi, T.; Oikawa, H. J. Am.
Chem. Soc. 2013, 135, 1260−1263. (b) Li, H.; Sun, Y.; Zhang, Q.;
Zhu, Y.; Li, S.-M.; Li, A.; Zhang, C. Org. Lett. 2015, 17, 306−309.
(c) Van de Bittner, K. C.; Nicholson, M. J.; Bustamante, L. Y.;
Kessans, S. A.; Ram, A.; van Dolleweerd, C. J.; Scott, B.; Parker, E. J. J.
Am. Chem. Soc. 2018, 140, 582−585.
́
(8) (a) Mirand, C.; de Maindreville, M. D.; Levy, J. Tetrahedron Lett.
1985, 26, 3985−3988. (b) Nkunya, M. H. H.; Weenen, H.; Koyi, N. J.
Phytochemistry 1987, 26, 2402−2403. (c) Mirand, C.; de
́
Maindreville, M. D.; Cartier, D.; Levy, J. Tetrahedron Lett. 1987, 28,
3565−3568. (d) Nkunya, M. H. H.; Weenen, H. Phytochemistry 1989,
28, 2217−2218. (e) Clark, J. S.; Myatt, J.; Wilson, C.; Roberts, L.;
Walshe, N. Chem. Commun. 2003, 1546−1547. (f) Clark, J. S.; Myatt,
D
DOI: 10.1021/acs.orglett.9b00259
Org. Lett. XXXX, XXX, XXX−XXX