Sequential sonagashira and larock indole synthesis reactions in a general strategy to prepare biologically active β-carboline-containing alkaloids

Article abstract of DOI:10.1021/ol5029783

A general synthetic approach to β-carboline-containing alkaloids was developed. Two consecutive palladium-mediated processes, a Sonagashira coupling and a Larock indole annulation reaction, are central to the method. The scope of the approach was investigated and found to be amenable for constructing a variety of biologically significant natural products and also for preparing substituted analogues for optimization and analysis of their biological properties.

Full text of DOI:10.1021/ol5029783

Letter
pubs.acs.org/OrgLett
Sequential Sonagashira and Larock Indole Synthesis Reactions in a
General Strategy To Prepare Biologically Active β‑Carboline-
Containing Alkaloids
Xiaohong Pan and Thomas D. Bannister*
The Scripps Research Institute, Translational Research Institute and Department of Chemistry, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: A general synthetic approach to β-carboline-containing
alkaloids was developed. Two consecutive palladium-mediated processes, a
Sonagashira coupling and a Larock indole annulation reaction, are central to
the method. The scope of the approach was investigated and found to be
amenable for constructing a variety of biologically significant natural products
and also for preparing substituted analogues for optimization and analysis of
their biological properties.
fficient palladium-mediated reactions allow easy access to
Scheme 2. Synthesis of Indolopyridocoline Triflate
E
highly substituted heterocycles, including indoles, one of
the most significant and biologically active core structures in
natural products.1 We sought to apply Larock’s method of
indole synthesis2 to prepare 2-pyridyl-indoles 1 by the
retrosynthesis shown in Scheme 1. The required Larock
Scheme 1. Pyridyl Indole Retrosynthesis
The hydroxyethyl chain of compound 10 was originally
intended to be used for installing diverse groups in the indole
C3 side chain. Upon conversion of the alcohol 10 to a tosylate
or triflate, a yellow precipitate, tetracycle 11 (Scheme 2),
formed instantly. In retrospect this is not surprising, as Gribble
and Johnson reported an analogous cyclization of a bromide,7
substrate 3 would arise from a Sonagashira reaction.3 An
expected advantage of this approach is that each of these
consecutive coupling processes would likely tolerate significant
structural diversity, a benefit for the optimization of biological
activity.
Under optimized Sonagashira conditions butyne-1-ol 6 and
2-bromopyridine 7 give alkyne 8 in nearly quantitative yield
(Scheme 2). For the Larock indole annulation reaction the
conditions of Senanayake et al.,4 using bromoanilines rather
than iodoanilines and also using only a small excess (1.2 equiv)
of the alkyne, were generally suitable. A slight variation gave
optimal results: 2.5 mol % Pd(OAc)2, 5 mol % 1,1′-
bis(diphenylphosphino) ferrocene (dppf), 1 equiv of alkyne,
KHCO3, DMF, 110 °C, 4 h.5 Under these conditions the
desired indole 10 was obtained in 95% yield with high
regioselectivity.6
while Furstner et al. also described a similar cyclization of an
̈
aldehyde.8 Optimization of conditions gave compound 11 in
94% yield. The efficiency and ease of operation for this three-
step route to compound 11 (88% overall yield with purification
by simple filtration) was intriguing, as is the structural similarity
of product 11 to a number of biologically significant alkaloids.
11 is the dihydro analog of indolopyridocoline (12),8 a natural
product made in 90% yield from 11 through a DDQ-promoted
oxidation.
Received: October 9, 2014
Published: November 13, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Alkaloid 11 belongs to a very large family of diverse
tetracyclic and pentacyclic natural products (Figure 1)
including norketoyobyrine, rutaecarpine, deplancheine, isonau-
clefidine, javacarboline, and dihydroflavopereirine, structures
that have attracted significant synthetic interest.9
Scheme 4. Synthesis of Rutaecarpine
Figure 1. Related β-carboline-containing natural products.
While each step in Scheme 2 is well-precedented, the
sequential application of such high-yielding reactions to access
members of this class of biologically active alkaloids in a general
fashion is noteworthy, especially because it may facilitate rapid
structure−activity relationship (SAR) studies in natural product
scaffolds. Here, this approach to several members of this family
of alkaloids and their substituted analogues is outlined.
indolization gave a regioisomeric mixture favoring the expected
2-heteroaryl indole product 26. KHCO3 as a base gave an 8:1
preference for 26 in high isolated yield (82%). Tosylate
formation prompted pentacycle formation. Interestingly,
cyclization proceeded by the attack of the N1 rather than N3
nitrogen atom of the quinazoline ring, as established by an
NOE study of 28. Chloride-promoted demethylation then
quantitatively gave the pentacyclic product 29, an unknown
isomer of rutaecarpine. Cyclization of 26 using HCl/n-butanol
exhibited preference for rutaecarpine (16:1, 81% yield).
A synthesis of the pyridone-containing natural product
norketoyobyrine (Scheme 3) tested the generality of the
Scheme 3. Syntheses of Pentacycles Norketoyobyrine and
Demethoxycarbonyldihydrogambirtannine
Tetra- and pentacyclic alkaloids with a nonaromatic ring
annulated to the indole comprise a significant portion of this
extended family of natural products. Often the ring distal to the
indole is functionalized, as in deplancheine (Figure 1), which by
our methods requires a suitably substituted pyridine as a
Sonagashira substrate. As a model, the methoxybromopyridine
30 was found to undergo Sonagashira coupling to give alkyne
31 (Scheme 5). Larock annulation followed by cyclization gave
the tetracycle 33 in 88% yield for the three steps. The related
benzyl ether 34 has been converted to deplancheine (15).13
Scheme 5. Synthesis of Precursors to Deplancheine
approach. A Sonagashira reaction using isoquinolin-3-yl triflate
1910 gave alkyne 20 in nearly quantitative yield. Larock indole
synthesis cleanly gave indole isoquinoline 21 and then, upon
cyclization, pentacycle 22. Norketoyobyrine (13) was then
prepared using a mild oxidation procedure.11 The intermediate
pyridinium salt 22 was also reduced to the known semi-
saturated pentacycle 23.11
The synthesis of rutaecarpine tested whether a chloroquina-
zoline is a suitable substrate for the Sonagashira reaction and
also presented the key issue of regioselectivity in the cyclization
to a pentacycle (Scheme 4).
Methyl ether 24,12 readily prepared in two steps, under
Sonogashira conditions smoothly gave alkyne 25. Larock
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Letter
Certain alkaloids require that electron-withdrawing groups be
present in the Sonagashira substrate. This is accommodated;
tert-butyl ester substituted chloropyridine 35 and butyne-1-ol
gave alkyne 36 (Scheme 6). A Larock reaction and cyclization
Scheme 8. Route to Flavopereirines
Scheme 6. Isonauclefidine and Norepiisogeissoschizoate
Scheme 9. Formal Synthesis of Mitragynine
gave tetracycle 38, which was treated with acid to give
isonauclefidine triflate (39).14 The conversion of the
intermediate tetracycle 38 to norepiisogeissoschizoate (40)
has also been described.15
Substitution in the sp3 chain that undergoes cyclization is
tolerated. Tetracycle 44, an analog of javacarboline (17),16 was
prepared in three steps and 60% overall yield from the alkyne
4117 through hydroxyester 43 (Scheme 7).
were synthesized: indolopyridocoline, norketoyobyrine,
demethoxycarbonyl dihydrogambirtannine, rutaecarpine, and
isonauclefidine. Also shown are formal syntheses of norepi-
isogeissoschizoate and mitragynine as well as methods useful
for the synthesis of deplancheine, javacarboline, 6,7-dihydro-
flavopereirine, and flavopereirine. Key features are sequential
Pd-catalyzed coupling reactions, each with significant substrate
tolerances. Six substituted pyridine chlorides, triflates, and
bromides were suitable Sonagashira reaction substrates (7, 19,
24, 30, 35, and 45). Two bromoanilines were suitable Larock
annulation substrates (9 and 53). Substitution in the central
ring is allowed (44). The wide substrate tolerances suggest that
using these methods for the synthesis of arrays of natural
product analogs for the optimization of their biological
properties and study of their mechanisms of action is feasible
and such studies will be the subject of future reports from our
laboratory.
Scheme 7. Synthesis of an Analogue of Javacarboline
Acetyl bromopyridine 45 (Scheme 8) is also a suitable
substrate, giving in three steps a 63% yield of the tetracycle 48,
a known precursor18 to enone 49, a building block for
heteroyohimbine type alkaloids.19 The corresponding alcohol
50 has been converted to 6,7-dihydroflavopereirine and
flavopereirine.18 Presumably alcohol 50 would be easily
accessed by Larock annulation and cyclization using alcohol
52 or by the reduction of tetracycle 48. The alcohol 52 indeed
undergoes an efficient Larock indole synthesis reaction, as
shown by its reaction with the electron-rich aniline 53 to give
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis procedures and the 1H, 13C NMR spectra, IR spectra,
and HRMS data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
tetracycle 55, a precursor in four steps to mitragynine (56),20
a
natural product of interest due to its antinociceptive properties
AUTHOR INFORMATION
Corresponding Author
■
(Scheme 9).21
Herein is described a general strategy to access tetra- and
pentacyclic β-carboline-containing alkaloids, a large family of
natural products of great interest in organic synthesis and
intriguing for their biological properties. Five natural products
*E-mail: tbannist@scripps.edu.
Notes
The authors declare no competing financial interest.
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Letter
(21) Matsumoto, K.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux,
D.; Watanabe, K.; Horie, S. Life Sci. 2006, 78, 2265−2271.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Institute of Health for
funding via U54 MH084512-05-21755 and R01 DA035056-01
and thank Dr. Zhizhou Yue (U. Pittsburgh) for preparing a
useful synthetic intermediate.
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