An approach to cyclohepta[ b ]indoles through an allenamide (4 + 3) cycloaddition-grignard cyclization-chugaev elimination sequence

Article abstract of DOI:10.1021/ol5006455

A strategy for synthesizing highly functionalized cyclohepta[b]indoles through a concise (4 + 3) cycloaddition-cyclization-elimination sequence is described. The cycloaddition features nitrogen-stabilized oxyallyl cations derived from epoxidations of N-ar

Full text of DOI:10.1021/ol5006455

Letter
pubs.acs.org/OrgLett
An Approach to Cyclohepta[b]indoles through an Allenamide (4 + 3)
Cycloaddition−Grignard Cyclization−Chugaev Elimination Sequence
Shuzhong He, Richard P. Hsung,* William R. Presser, Zhi-Xiong Ma, and Bryan J. Haugen
Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison,
Wisconsin 53705, United States
S
* Supporting Information
ABSTRACT: A strategy for synthesizing highly functionalized
cyclohepta[b]indoles through a concise (4 + 3) cycloaddition−
cyclization−elimination sequence is described. The cycloaddition
features nitrogen-stabilized oxyallyl cations derived from epox-
idations of N-aryl-N-sulfonyl-substituted allenamides, while the
cyclization and elimination employed an intramolecular Grignard
addition and a one-step Chugaev process, respectively.
yclohepta[b]indoles represent a prevalent structural motif
Scheme 1. (4 + 3) Cycloaddition−Cyclization Strategy
C
among pharmaceutical entities as well as bioactive natural
products such as ervitsine,1 aristolasol,2 silicine,3 ambigune E,4
and actinophyllic acid (Figure 1).5 Cyclohepta[b]indole
Figure 1. Representative cyclohepta[b]indole compounds.
indoles 5 from N-arylallenamides 6. Thus, we envisioned that
while it would be difficult to include the indole formation
concomitant with the (4 + 3) cycloaddition, an ensuing
intramolecular cyclization from the aryl group onto the
carbonyl group in (4 + 3) cycloadducts 8 should accomplish
such a purpose, leading to tetracyclic cyclohepta[b]indoles 9.
We wish to communicate here our success in achieving a
strategy for constructing cyclohepta[b]indoles via a concise (4
+ 3) cycloaddition−cyclization−elimination sequence.
Our approach toward cyclohepta[b]indoles commenced with
a (4 + 3) cycloaddition reaction of N-aryl-N-sulfonylallenamide
10a22 as shown in Scheme 2. It is noteworthy that although we
have reported intramolecular (4 + 3) cycloaddition reactions of
N-sulfonylallenamides,23 the current attempt represents the first
derivatives have been shown to inhibit adipocyte fatty acid
binding protein (A-FABP)6 and of deacetylase SIRT1.7
Consequently, cyclohepta[b]indoles have received much
attention from the synthetic community. Previous approaches8
include Fischer indole syntheses,9 ring expansions,10 and
intramolecular cyclizations.11 Recently, (4 + 3) cycloaddition12
approaches have been developed. Wu13 reported an elegant
three-component (4 + 3) cycloaddition for constructing
cyclohepta[b]indoles, while Tang14 and Iwasawa15 envisaged
rhodium- and platinum-catalyzed (4 + 3) transformations. A
formal (4 + 3) cycloaddition reaction was a key step in Martin’s
total synthesis of actinophyllic acid.16
We became interested in cyclohepta[b]indoles because of
our long-standing program in (4 + 3) cycloaddition reactions17
employing nitrogen-stabilized oxyallyl cations (see 3)18 derived
from epoxidations of allenamides 1 (Scheme 1).19−21
Structurally, only three C−C bonds separate cyclohepta[b]-
Received: March 2, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Having succeeded in this first step, we proceeded to
complete the cyclohepta[b]indole ring system. As indicated
above, we envisioned that an intramolecular addition of aryl
anion to the carbonyl carbon should fulfill this task. To
accomplish this task, we elected to go with a strategy adopted
by Kobayashi and co-workers for constructing quinoline and
indole rings.25 By using i-PrMgCl·LiCl complex as the
magnesium−halogen exchange reagent,25,26 an intramolecular
Grignard addition could take place effectively to give the
tetracyclic alcohol 12a in 63% yield (Scheme 3). Other
Scheme 2. Cycloaddition of an N-Aryl-N-sulfonylallenamide
example in which an N-sulfonyl-substituted allenamide is used
in an intermolecular (4 + 3) cycloaddition manifold. More
significantly, allenamide 10a is an N-aryl- or aniline-substituted
allenamide. While this appears to be a minor structural
perturbation from previous allenamides, it is well known that
the stability and reactivity of allenamides are closely regulated
by the substitution pattern on the nitrogen atom, especially
when a substitution can impact on its ability to delocalize or
donate toward the allenic motif.19,24 This constitutes the first
challenge in our strategy because an N-aryl group allows the
delocalization of the nitrogen lone pair, thereby deactivating the
allenamide reactivity. However, when N-aryl-N-sulfonylsulfo-
namide 10a was subjected to standard conditions (ZnCl2,
DMDO, furan, and 4 Å MS in CH2Cl2), it reacted successfully
with furan to afford the desired cycloadduct 11a in 70% yield as
a single diastereomer (Scheme 2).
Scheme 3. Intramolecular Grignard Addition
tetracyclic alcohols 12b−l could also be obtained utilizing the
same reaction condition as shown in Figure 3, thereby
With this result in hand, the scope of (4 + 3) cycloaddition
reactions of N-aryl-N-sulfonylallenamides could be explored
(Figure 2). Allenamides with different substituents on the aryl
Figure 3. Intramolecular Grignard addition products.
demonstrating the generality of this cyclization. The structural
as well as stereochemical integrity of 12b was unambiguously
assigned through its X-ray single-crystal structure (Figure 4).
While tetracycle alcohols 12a−l represent highly function-
alized structural manifolds with multistereogenic centers that
can be useful in further transformations and evolution of
Figure 2. Scope of the (4 + 3) cycloaddition.
ring worked well to give products 11b−g in moderate to good
yields. In addition, Boc-protected pyrrole and cyclopentadiene
can also serve as suitable dienes to furnish cycloadducts 11h
and 11i, respectively. Allenamides stabilized by a carbamate
group also proved to be efficient in this reaction (see 11j and
11k), although 11k was obtained as an inseparable mixture with
a modest 3:1 diastereomeric ratio [stereochemistry of the major
isomer unassigned]. When allenamide bearing a 4-methox-
ybenzenesulfonyl substituent was used, the desired cycloadduct
11l was obtained in a relatively lower yield (11l, 38%), thereby
implying that these cycloadditions may favor allenamides with
strong electron-withdrawing groups.
Figure 4. X-ray structure of tetracyclic alcohol 12b.
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complexity, to truly complete the indole synthesis, elimination
of the tertiary alcohol should be accomplished here. We had
hoped that a simple acid-induced dehydrative elimination−
aromatization sequence should furnish the desired 14a
(Scheme 4). However, despite being stable to silica gel column
provided again only fragmentation product 17. We sub-
sequently turned our attention to transforming tetracyclic
alcohol 12a into a xanthate intermediate for a potential
Chugaev’s syn-elimination. When 12a was treated with base and
CS2, the desired cyclohepta[b]indole 14a was obtained directly
without the isolation of any xanthate intermediates (Scheme 5).
This result could be explained by a direct intramolecular
hydrogen abstraction of the xanthate anion 20. It is noteworthy
that base played an important role in this elimination reaction.
While using t-BuOK led to 100% conversion, KH could only
provide a conversion of 70%, and conversions were less than
10% when employing NaH and LiHMDS.
Scheme 4. Acid-Induced Grob-Type Fragmentation
We subsequently applied this effective one-step Chugaev
elimination to other tetracyclic alcohols 12b−l (Figure 5). This
chromatography, when tetracyclic alcohol 12a was treated with
catalytic amount of p-TsOH at 0 °C, we found complete
unraveling of the tetracycle. The only product obtained was 3-
furfurylindole 17, likely derived form an acid-induced
fragmentation process via intermediates 15 and 16.27
This fragmentation reaction is likely favored for two reasons:
(a) The perfect anti-periplanar alignments between C−OH
bond and the C−C bond and the C−C bond and the equatorial
lone pair of the bridging oxygen (all in blue) or the perfect
overlap and delocalization into the respective σ* and (b) the
formation of two aromatic systems (indole and furan) as the
thermodynamic driving force. Thus, we reasoned that if we first
functionalize the cycloheptenone double bond in 12a, we
should prevent the formation of furan and reduce the driving
force of the fragmentation. As shown in Scheme 5, when triol
Scheme 5. Successful Eliminations
Figure 5. Synthetic scope of cyclohepta[b]indoles.
reaction in general gave excellent yields to afford an array of
cyclohepta[b]indoles 14b−e,i,l. Cyclohepta[b]indoles 14f and
14g could be obtained only when using KH as the base because
t-BuOK-induced methyl ester hydrolysis in these two examples.
Cyclohepta[b]indole 14h was also prepared under the KH
conditions since t-BuOK led to complete decomposition of the
corresponding starting material 12h; we are not clear of the
rationale at this point. In addition, cyclohepta[b]indoles 14j
and 14k with indole nitrogen protected as carbamates were
obtained with slightly lower yields. These last three examples
suggest that the N-protecting groups could be important in this
elimination process.
We have developed a strategy for synthesizing highly
functionalized cyclohepta[b]indoles through an efficient
sequence of a (4 + 3) cycloaddition−cyclization−elimination.
The cycloaddition features nitrogen-stabilized oxyallyl cations
derived from epoxidations of N-aryl-N-sulfonyl-substituted
allenamides, while the cyclization and elimination employed
an intramolecular Grignard addition and a useful one-step
Chugaev process, respectively. Applications of this strategy in
natural product synthesis are currently underway.
18, which could be prepared via a simple dihydroxylation from
12a, was submitted to the same acidic condition, the
elimination product 19 was obtained in 30% yield. While this
result strongly supported our hypothesis and gave a highly
functionalized cyclohepta[b]indoles in 19, we recognized that
the overall process is not as efficient.
To be more effective in completing the construction of
cyclohepta[b]indoles, we pursued a direct elimination method
via syn-hydrogen abstraction mechanism and hoped we could
circumvent the fragmentation facilitated by the anti-periplanar
alignments. However, SeO2 did not react with tetracyclic
alcohol 12a under basic condition, while Burgess reagent
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Letter
2012, 68, 4641. (k) Kuznetsov, A.; Makarov, A.; Rubtsov, A. E.; Butin,
A. V.; Gevorgyan, V. J. Org. Chem. 2013, 78, 12144.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures as well as NMR spectra, character-
izations, and X-ray structural files. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
(12) For general reviews of oxyallyl cycloadditions, see: (a) Rigby, J.
H.; Pigge, F. C. Org. React. 2004, 351. (b) Davies, H. M. L. In Advances
in Cycloaddition; Harmata, M., Ed.; JAI: Stamford, 1999; Vol. 5, p 119.
(c) Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004,
43, 1934. (d) Battiste, M. A.; Pelphrey, P. M.; Wright, D. L. Chem.
Eur. J. 2006, 12, 3438. (e) Harmata, M. Adv. Synth. Catal. 2006, 348,
2297. (f) Harmata, M. Chem. Commun. 2010, 46, 8886. (g) Harmata,
M. Chem. Commun. 2010, 46, 8904.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rhsung@wisc.edu.
(13) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem., Int. Ed.
2012, 51, 10390.
Notes
(14) Shu, D.; Song, W.; Li, X.; Tang, W. Angew. Chem., Int. Ed. 2013,
52, 3237.
The authors declare no competing financial interest.
(15) Kusama, H.; Sogo, H.; Saito, K.; Suga, T.; Iwasawa, N. Synlett
2013, 24, 1364.
(16) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Hua, B.; Knezevic, C.
E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. J. Am. Chem. Soc.
2013, 135, 12984.
ACKNOWLEDGMENTS
■
We thank the NIH (GM066055) for financial support and Dr.
Victor Young at the University of Minnesota for X-ray
structural analysis.
(17) For a leading review, see: Lohse, A. G.; Hsung, R. P. Chem.
Eur. J. 2011, 17, 3812.
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