A stereoselective michael-mannich annelation strategy for the construction of novel tetrahydrocarbazoles

Article abstract of DOI:10.1021/acs.orglett.7b02323

A novel annelation strategy has been devised for stereoselective synthesis of tetrahydrocarbazoles. The pathway features a regio-and stereocontrolled condensation of indole and its substituted derivatives with electron-deficient 1, 3-dienes via a Michael-Mannich reaction sequence. An extension of this method to include crossconjugated allenes as substrates also results in a Michael-Mannich-Michael cascade, incorporating 2 equiv of indole with increasing product complexity. The formal 4π + 2π cyclization describes a concise route to polycyclic alkaloids of this family.

Full text of DOI:10.1021/acs.orglett.7b02323

Letter
pubs.acs.org/OrgLett
A Stereoselective MichaelMannich Annelation Strategy for the
Construction of Novel Tetrahydrocarbazoles
David R. Williams,* Seth A. Bawel, and Richard N. Schaugaard
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: A novel annelation strategy has been devised for
stereoselective synthesis of tetrahydrocarbazoles. The pathway features
a regio- and stereocontrolled condensation of indole and its substituted
derivatives with electron-deficient 1,3-dienes via a Michael−Mannich
reaction sequence. An extension of this method to include cross-
conjugated allenes as substrates also results in a Michael−Mannich−
Michael cascade, incorporating 2 equiv of indole with increasing product
complexity. The formal 4π + 2π cyclization describes a concise route to
polycyclic alkaloids of this family.
arbazole and tetrahydrocarbazole ring systems are
prominent features displayed in many alkaloids. In fact,
and Matsuo16 have described stepwise [4 + 2] cycloadditions of
indoles to give useful tetrahydrocarbazole systems, and Zhang
and co-workers have recently demonstrated asymmetric
induction in the gold-catalyzed formal [4 + 2] cycloadditions
of 3-styrylindoles with N-allenamides.17
This report communicates studies leading to an efficient
synthesis of complex 2,3,4,9-tetrahydro-1H-carbazoles (1). As
illustrated in Figure 1, our investigations have explored a formal
C
heteroaromatic 9H-carbazoles are widely distributed among
plants of the family Rutaceae and are also isolated from
microorganisms.1 The tetrahydrocarbazole motif not only is
common to polycyclic alkaloids but also serves as a key
precursor to the parent carbazoles via mild dehydrogenation.
Representative examples show significant biological activity,
and as a result, there is a high level of interest in the
development of efficient methods of preparation.2 Prior art has
broadly utilized the multistep Fischer−Borsche procedure for
the synthesis of tetrahydrocarbazoles and subsequent oxida-
tions to 9H-carbazoles.3 Recent studies have described
transition-metal-catalyzed oxidative cyclizations which directly
access N-substituted carbazoles via aniline derivatives.4
Transition-metal catalysis has also facilitated the discovery of
applications of indoles in C−H activation and intramolecular
alkenylation.5 Asymmetric π-allyl metal cyclizations6 have been
utilized to afford tetrahydrocarbazoles. Noteworthy benzannu-
lations of 2-alkenyl-, 3-alkenyl-, and 2,3-divinyl-substituted
indoles have been described.7 Intense efforts have focused on
methods which employ indoles and simple indole derivatives
for convergent strategies in the construction of highly
substituted carbazoles.8,9 A recent report has described a one-
pot, three-component condensation of indoles, ketones, and
nitroalkenes, which leads directly to functionalized carbazoles
via in situ air oxidation.10 On the other hand, hydrogen-bonding
catalysis promotes asymmetric Michael reactions of nitro-
alkenes and 2-propenylindoles to yield complex tetrahydro-
carbazoles with good to excellent enantioselectivity.7a,11
Figure 1. Tetrahydrocarbazoles via condensations of 2 and 3.
[4π + 2π] annelation reaction of electron-deficient 1,3-dienes 2
with indole and substituted indole derivatives 3 to effect a
regio- and stereocontrolled cycloaddition.
These efforts have been substantially advanced by our prior
report of cross-coupling methodology for the preparation of
unsymmetrical α-linked bisenone systems.18 In this fashion, we
have readily obtained the differentiated and cross-conjugated
α,β-unsaturated dicarbonyl system 4. The anticipation of
increased reactivity of 4 via Lewis acid catalysis enhances
regioselectivity and underscores the role of the ketone carbonyl
as a preferred site of coordination. On this basis, the
condensation of indole with enone 4 (Scheme 1) in the
presence of anhydrous MgBr2 (1 equiv) at 22 °C has afforded
the tetrahydrocarbazole 7 (83% yield) as a single diaster-
eoisomer. Stereochemical assignments in 7 are based upon
extensive NOESY-NMR studies (see Supporting Information).
Cycloadditions have been employed for the synthesis of
tetrahydrocarbazoles using electron-deficient indoles as dien-
ophiles,12 and inverse electron-demand Diels−Alder reactions
of 3-chloro-indole have been described.13 One report has
documented asymmetric induction with chiral thioureas in the
Diels−Alder reactions of 3-vinylindole with several dienophiles
Received: August 1, 2017
as a route to enantioenriched tetrahydrocarbazoles.14 Backvall15
̈
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02323
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Scheme 1. Michael−Mannich Annelation of Indole with
Enone 4
of these investigations, a number of Lewis acid catalysts have
been examined, including anhydrous salts of CuBr2, ZnBr2,
Zn(OTf)2, Mg(OTf)2, Eu(fod)3, Yb(OTf)3, and Sc(OTf)3.20
Generally, all of these choices failed to induce productive
annelations whereas the use of anhydrous MgBr2 or MgI2 in
CH2Cl2 or 1,2-dichloroethane solutions selectively afforded the
desired adducts. Reactions are not observed upon the
introduction of coordinating solvents such as diethyl ether or
THF. Similarly, the use of chiral (S)-Binol21 or pybox ligand
2,2′-isopropylidene-bis(4S)-4-tert-butyl-2-oxazoline22 for Lewis
acid coordination also extinguished the anticipated reactivity.
Table 1 permits a comparison of MgBr2 and MgI2 catalysis.
Qualitatively faster reactions are observed with the use of
anhydrous MgI2 (1 equiv) as compared to anhydrous MgBr2 (1
equiv) at 22 °C. However, the nucleophilicity of the iodide
diminishes yields of the ethyl esters while producing small
amounts of side products (compare Table 1, entries 1−5).
Substitution in the starting indole 2 (R1 or R2) features the
series of 5-methyl, 5-methoxy, and 6-tert-butyldimethylsilyloxy
(OTBS) derivatives, leading to the expected products 14, 16,
and 18 (Table 1, entries 2−6). Although studies have focused
on the incorporation of a protected hydroxylmethyl substituent
(CH2OPMB), the successful inclusion of labile cyclopropyl and
trimethylsilyl groups in the 1,3-diene component (Table 1,
entries 7 and 8) is indicative of the breadth of the reaction.
These examples proceed without the need for N−H protection
of the indole. On the other hand, less reactive N-methylindole
(R3 = Me) (entries 9 and 10) has required the use of MgI2.
These experiments occur with annelation and subsequent
dealkylation of the ethyl ester to yield the complex butenolides
24 (80%) and 26 (35%) (30% of the ethyl ester of 26 is also
obtained). Two examples have detailed reactions of C-2
substituted indoles 27 and 29 (entries 11 and 12). The
annelation products 28 and 30 are isolated in modest yields
(40%), displaying a quaternary carbon at the ring fusion. The
latter attempts also introduced a number of uncharacterized
byproducts, contributing to the reduced yields.
The annelation has been extended to the series of conjugated
allenic, cyclic enones of Scheme 2. The allenic substrates are
prepared in one step via the Stille cross-coupling of the
propargylic stannanes 31 and 32 with α-iodoenones 33, 34, and
35 by direct application of our previous report.23 In this
fashion, the reactive allenic enones 36, 37, 38, and 39 are
generated in 51% to 69% yields, and subsequent condensations
with indoles occurred smoothly at 22 to 50 °C. This high-value
transformation efficiently assembles the unsaturated tetracycle
41 (72%) from 37 via the Mannich reaction of 40 (Scheme 2).
Similarly, the TMS substituent of 36 is tolerated for the
formation of 42 and 43 (Table 1, entries 13 and 14). In these
cases, reduced steric hindrance in the Mannich ring closure
leads to the isolation of diastereomers indicating cyclizations
proceeding from syn- and anti-Michael adducts. The extended
conjugation of these adducts has suggested the possibility of a
Michael−Mannich−Michael cascade. In the event, our
incorporation of excess indole, as shown in entries 16 and 17
of Table 1, provides for subsequent 1,6-conjugate addition from
the initial annelation products to yield 45 (72%) and 46 (60%),
We postulate a reaction mechanism which is initiated by the
nucleophilicity of C-3 of indole and the activated Michael
acceptor enone of 4. The production of an extended enolate 5
leads to intramolecular capture of the iminium intermediate in a
Michael−Mannich cascade.
In fact, the product 7 reflects the result of an inverse
electron-demand Diels−Alder reaction via an exo-transition
state (TS). Although an asynchronous cycloaddition19 is also
plausible, we have assumed a reaction coordinate that
progresses via an initial Michael addition. Our modeling has
indicated that a feasible orientation for cyclization is achieved in
the bonding arrangement leading to 9 versus 10. The exo-
arrangement 9 provides a half-chair TS with trans-diaxial
hydrogens at sites (a) and (b), whereas the endo-arrangement
10 reveals a boat-like TS for bond formation. DFT computa-
tional studies, optimized with B3LYP/6-31G(d), have provided
further details. These studies have indicated that the estimated
TS energy for an asynchronous TS via 10 is approximately 6.0
kcal/mol higher than the exo-arrangement. In addition, the
product 7 is 3.1 kcal/mol more stable than the corresponding
diastereomeric carbazole resulting from 10. Facile DDQ
oxidation (1 equiv) leads to the aromatic C-ring of the
carbazole alkaloids prior to removal of the PMB ether to yield
8. Additional quantities of DDQ result in cleavage of the PMB
to yield the corresponding alcohol of 8 (Scheme 1).
Experimental evidence for a stepwise rationale is suggested
from reactions of enone 11, incorporating β,β-disubstitution of
the unsaturated moiety. Utilizing similar reaction conditions, a
modest yield of the Michael adduct 12 is obtained as an
inseparable mixture of cis- and trans-diastereomers without
advancing the Mannich cyclization.
As a focused study to develop this concept for the synthesis
of targeted natural product congeners, the scope of our reaction
has been explored for a related series of polycyclic systems. A
compilation of results is summarized in Table 1. In the course
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DOI: 10.1021/acs.orglett.7b02323
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Table 1. Michael−Mannich Annelation Reactions
a
b
Isolated yields of the purified product are obtained after flash silica gel chromatography. An additional amount (15−20%) of the corresponding
c
phenol is obtained due to TBS cleavage. Less than 8% yield of the “all syn” diastereomer of 42 is identified (dr 88:12), based on the proton
integrations of NMR signals. This minor isomer coelutes with indole in the HPLC analysis and is not purified further. The “all syn” diastereomer of
43 is isolated in 16% yield (dr 70:30). The “all syn” diastereomer of 44 is also isolated in 13% yield (dr 84:16). Equal amounts of two trans-fused
d
e
f
tetrahydrodecalin diastereomers are also isolated (10% yield of each isomer).
respectively. These findings have illustrated an elegant, two-step
construction of molecular complexity from the starting α-iodo-
enones 33 and 34, resulting in diastereoselective generation of
novel polycyclic alkaloids. Unambiguous stereochemical assign-
ments of 45 have been established by a single crystal X-ray
diffraction study.24
In summary, a novel synthesis of complex tetrahydrocarba-
zoles has utilized a regio- and stereocontrolled annelation
achieved via the asynchronous [4 + 2] cycloaddition of indoles
with electron-deficient α-linked bisenone derivatives.
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02323.
■
S
(11) For related studies: Loh, C. C. J.; Raabe, G.; Enders, D. Chem. -
Eur. J. 2012, 18, 13250−13254.
(12) (a) de la Fuente, M. C.; Domínguez, D. Tetrahedron 2011, 67,
3997−4001. (b) Chretien, A.; Chataigner, I.; L’Helias, N.; Piettre, S. R.
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J. Org. Chem. 2003, 68, 7990−8002. (c) Kishbaugh, T. L. S.; Gribble,
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General information, experimental procedures and
1
characterization data, H and 13C NMR spectra (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: williamd@indiana.edu.
ORCID
(14) (a) Gioia, C. G.; Bernardi, L.; Ricci, A. Synthesis 2010, 2010,
161−170. (b) For a review: Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608−9644. (c) For a detailed study: Gioia, C.;
Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed.
2008, 47, 9236−9239.
David R. Williams: 0000-0003-1499-3333
Notes
(15) Backvall, J.-E.; Plobeck, N. A.; Juntunen, S. K. Tetrahedron Lett.
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1989, 30, 2589−2592.
The authors declare no competing financial interest.
(16) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.;
Matsuo, J.-i.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, 906−910.
(17) Wang, Y.; Zhang, P.; Liu, Y.; Xia, F.; Zhang, J. Chem. Sci. 2015,
6, 5564−5570.
ACKNOWLEDGMENTS
■
Our work was supported by the National Science Foundation
under Grant No. CHE-1362561 and was partially funded by the
Vice Provost for Research through the Research Equipment
Fund. We dedicate this paper to Professor Al Padwa on the
occasion of his 80th birthday.
(18) Williams, D. R.; Bawel, S. A. Org. Lett. 2017, 19, 1730−1733.
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Chem. Sci. 2012, 3, 1650−1655.
(20) In addition, the use of BF3, Ti(OiPr)4, and Et2AlCl led to
multiple products and decomposition, whereas Bi(OTf)3 produced
mixtures of the Michael addition products without further cyclization.
(21) Daniels, B. E.; Ni, J.; Reisman, S. E. Angew. Chem., Int. Ed. 2016,
55, 3398−3402.
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