Overturning indolyne regioselectivities and synthesis of indolactam V

Article abstract of DOI:10.1021/ja200437g

We report the design and synthesis of an indolyne that displays a reversal in regioselectivity, in both nucleophilic addition and cycloaddition reactions, compared to typical 4,5-indolynes. Our approach utilizes simple computations to predict regioselectivity in reactions of unsymmetrical arynes. With this methodology, novel benzenoid-substituted indoles can be accessed with significant regiocontrol. Furthermore, the technology provides an unconventional tactic for the synthesis of C4-substituted indole alkaloids, as demonstrated by a synthesis of indolactam V.

Full text of DOI:10.1021/ja200437g

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pubs.acs.org/JACS
Overturning Indolyne Regioselectivities and Synthesis
of Indolactam V
Sarah M. Bronner, Adam E. Goetz, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S Supporting Information
b
ABSTRACT: We report the design and synthesis of an
indolyne that displays a reversal in regioselectivity, in both
nucleophilic addition and cycloaddition reactions, com-
pared to typical 4,5-indolynes. Our approach utilizes simple
computations to predict regioselectivity in reactions of
unsymmetrical arynes. With this methodology, novel ben-
zenoid-substituted indoles can be accessed with significant
regiocontrol. Furthermore, the technology provides an
unconventional tactic for the synthesis of C4-substituted
indole alkaloids, as demonstrated by a synthesis of indola-
ctam V.
Figure 1. C4-substituted alkaloids 1-4 and indolynes 5 and 6.
he past decades have witnessed a resurgence in the chemistry
of arynes. Whereas classical methods for aryne generation
obvious,12 simple calculations were used to validate our hypoth-
esis. Specifically, geometry optimization of bromoindolyne 6
showed that C4 possesses a larger internal angle compared to C5
(i.e., θ4 = 130° and θ5 = 124°).13 Following our distortion
model,3 the flatter, more electropositive carbon (C4) was pre-
dicted to be the preferred site of attack by nucleophiles.14
We envisioned accessing bromoindolyne 6 from a silyltriflate
precursor. Although halobenzynes have not previously been
generated by the Kobayashi method,15 we were able to synthesize
the targeted silyltriflate 11 using the route shown in Scheme 1.
Commercially available 5-benzyloxyindole (7) was elaborated to
silylcarbamate 8 using our previously reported, high-yielding
sequence.3b Subsequent C6 bromination was achieved using the
general lithiation/quenching protocol developed by Snieckus
and Hoppe to afford intermediate 9.16,17 Installation of the
triflate (9f10), followed by removal of the N-TIPS group,
furnished the desired indolyne precursor 11. The sequence is
robust and can be used to prepare gram quantities of 11. To
validate that indolyne 6 would be accessible, silyltriflate 11 was
treated with CsF in the presence of furan to generate oxabicycle
13. Of note, compound 13 possesses sites for further functiona-
lization on both the pyrrolo7,18 and benzenoid ring.19
T
are typically plagued by low yields, modern methodologies have
overcome these limitations; arynes can now be employed
efficiently in a variety of synthetic applications.1 These advances
have been accompanied by an interest in exploiting unsymme-
trical arynes as synthetic intermediates, although such studies
have been somewhat constrained by a lack of regiocontrol.2
In collaboration with Houk and co-workers, we recently
proposed that distortion in unsymmetrical arynes controls
regioselectivity, and simple computations may be used to make
selectivity predictions.3 To test this distortion model and its
predictive powers, we sought to control regioselectivity in
nucleophilic addition to indolynes,3-5 which are unsymmetrical
arynes that our laboratory has examined for their synthetic
versatility. A method for overturning indolyne regioselectivity
has not been previously established, but would provide an
invaluable tool for synthesizing both natural and unnatural
derivatives of the medicinally privileged indole scaffold.6,7
In this communication, we demonstrate that regioselectivity in
the nucleophilic addition to indolynes can be readily manipulated
using the predictive capabilities of the distortion model. The
studies provide access to unique benzenoid-substituted indoles
and offer a strategically distinct approach to C4-substituted
indole alkaloids.8 The latter notion is exemplified by a concise
synthesis of indolactam V (1, Figure 1).9
With access to bromoindolyne 6 and parent indolyne 5,3b each
from a silyltriflate precursor, a comparative regioselectivity study
was carried out with a range of trapping agents (Table 1). In each
case, the indolyne precursors were treated with CsF in the
presence of the appropriate trapping agent. When 4-t-Bu-benzoic
acid was used to trap indolyne 5,20 the reaction occurred with
significant regioselectivity favoring attack at C5 (entry 1).
As highlighted in Figure 1, we focused our efforts on 4,5-
indolynes, which could potentially be used to access 4-substi-
tuted indole derivatives, such as 1-4.8 Whereas 4,5-indolyne 5
exhibits a preference for nucleophilic attack at C5,3b we hypothe-
sized that brominated derivative 6 would be prone to undergo
attack at C4.10,11 Although the relative influence of the bromide
substituent and ring fusion on aryne distortion were not
Received: January 16, 2011
Published: February 25, 2011
r
2011 American Chemical Society
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Scheme 1
Scheme 2
Table 1. Nucleophilic Additions to Indolyne 5 and 6-Bro-
moindolyne 6a
furnish unique indolylpyrazoles (entries 9 and 10). These results
clearly indicate that bromoindolyne 6 displays a reversal in
regioselectivity compared to its nonbrominated counterpart 5
and validate the distortion model for predicting regioselectivities
in additions to unsymmetrical arynes.
To probe the utility of our findings in a complex setting, we
undertook a total synthesis of indolactam V (1), one of many
biologically active C4-substituted indoles.8,9 In nearly all pre-
vious syntheses of 1,24 the nine-membered ring is fashioned by
late-stage amide bond formation. We envisioned a strategically
distinct approach to 1, which involved initial C4 functionalization
using bromoindolyne 6, followed by ring closure at C3.25 As
shown in Scheme 2, treatment of silyltriflate 11 with peptide 14
in the presence of CsF furnished C4-aminated product 15 in 62%
yield, even though 14 possesses multiple nucleophilic sites. As
expected on the basis of our distortion model and experimental
studies (see Table 1), the transformation proceeded with high
regioselectivity.26 Subsequent debromination, followed by dehydra-
tion,27 provided unsaturated ester 16 without event. We next exa-
mined the critical cyclization at C3. After extensive experimenta-
tion, it was found that exposure of 16 to ZrCl4 in CH2Cl2
facilitated the desired annulation to give tricycle 17,28 thus
completing a formal synthesis of 1.24c,29 Interestingly, the stereo-
chemical configuration at C9 of 17 was set with complete
diastereoselectivity, albeit in the undesired sense. Nonetheless,
C9 epimerization and reduction using Nakatsuka’s protocol24c
furnished indolactam V (1). This is the first total synthesis in
which an indolyne has been exploited for its electrophilic
character.30 We expect that our approach to 1, using an umpo-
lung of typical indole reactivity, will be suitable for the synthesis
of other indole alkaloids.
a See Supporting Information for details. b Isolated yields.
In contrast, the corresponding reaction of bromoindolyne 6
displayed a preference for attack at C4 (regioselectivity = 1:13 for
attack at C5:C4). Similar trends were observed in reactions
involving aniline20 (entries 3 and 4) and an enamine derivative21
(entries 5 and 6). In the latter case, selectivity was 1:20 favoring
attack at C4 on indolyne 6. Cycloadditions were also examined,
and similar reversals in regioselectivity were observed. For
example, cycloaddition of indolyne 5 with benzyl azide22 gave
a mixture of products, favoring attack at C5 over C4 in a 2:1 ratio
(entry 7). However, the corresponding reaction with indolyne 6
led to a 1:4 mixture of products favoring attack at C4 (entry 8).
Analogous results were obtained in reactions with diazoesters2a,23 to
In summary, we have designed and synthesized an indolyne
(i.e., 6) that displays a reversal in regioselectivity in both
nucleophilic addition and cycloaddition reactions, compared to
the parent 4,5-indolyne 5. Our approach validates the aryne
distortion model3 which, in turn, utilizes simple computations13
to predict regioselectivity in reactions of unsymmetrical arynes.
With this methodology, novel benzenoid-substituted indoles can
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COMMUNICATION
be accessed with significant regiocontrol. Moreover, the technol-
ogy provides an unconventional tactic for the synthesis of C4-
substituted indole alkaloids, as demonstrated by our synthesis of
indolactam V (1). Further studies aimed at probing the aryne
distortion model in complex molecule synthesis are currently
underway in our laboratory.
264, 118–120. (d) Julia, M.; Igolen, J.; Kolb, M. C. R. Acad. Sci., Ser. C
1971, 273, 1776–1777.
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K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007–1010. (b) Tian, X.; Huters,
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(6) (a) Horton, D. A.; Bourne, G. T.; Smyth, M. L. Chem. Rev. 2003,
103, 893–930. (b) Rodrigues de Sꢀa Alves, F.; Barreiro, E. J.; Fraga,
C. A. M. Mini-Rev. Med. Chem. 2009, 9, 782–793.
’ AUTHOR INFORMATION
(7) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
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Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
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Methods); Academic Press: New York, 1996; pp 7-11. (d) Joule, J. A. In
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(8) A Beilstein/Crossfire search shows that more than 600 C4-
substituted indole-containing natural products exist and nearly 10,000
bioactive C4-substituted indoles have been reported.
(9) (a) For a pertinent review on indolactam isolation, tumor-
promoting activity, and derivatives, see: Irie, K.; Koshimizu, K. Com-
ments Agric. Food Chem. 1993, 3, 1–25. (b) For a recent report on
indolactam V’s stem cell differentiating abilities, see: Chen, S.; Borowiak,
M.; Fox, J. L.; Maehr, R.; Osafune, K.; Davidow, L.; Lam, K.; Peng, L. F.;
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Corresponding Author
neilgarg@chem.ucla.edu
’ ACKNOWLEDGMENT
The authors are grateful to the NIH-NIGMS (R01
GM090007), Boehringer Ingelheim, DuPont, Eli Lilly, the Foote
Fellowship (S.M.B.), and the University of California, Los
Angeles, for financial support. We thank the Garcia-Garibay
laboratory (UCLA) for access to instrumentation, Dr. Robert
Paton (Oxford) and Professor Ken Houk (UCLA) for helpful
discussions, Dr. John Greaves (UC Irvine) for mass spectra, and
Kyle Quasdorf (UCLA), Joshua Melamed (UCLA), and Jordan
Cisneros (UCLA) for experimental assistance.
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