Modular synthesis of candidate indole-based insulin mimics by claisen rearrangement

Article abstract of DOI:10.1021/ol800058d

A modular synthetic route to (indolyl)kojic acid anti-diabetes agents has been developed. Sonogashira coupling of a protected iodoaniline with a propargyl kojate was used to construct an (indole)methyl kojate. Its heteroaromatic Claisen rearrangement, followed by tautomerization to return the indole and pyrone rings, was used to create the biaryl C-C bond. This route should enable collections of insulin mimic drug candidates to be prepared from a few basic building blocks.

Full text of DOI:10.1021/ol800058d

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1151-1154
Modular Synthesis of Candidate
Indole-based Insulin Mimics by Claisen
Rearrangement
Xin Xiong and Michael C. Pirrung*
Department of Chemistry, UniVersity of California, RiVerside, California 92521
michael.pirrung@ucr.edu
Received January 9, 2008
ABSTRACT
A modular synthetic route to (indolyl)kojic acid anti-diabetes agents has been developed. Sonogashira coupling of a protected iodoaniline
with a propargyl kojate was used to construct an (indole)methyl kojate. Its heteroaromatic Claisen rearrangement, followed by tautomerization
to return the indole and pyrone rings, was used to create the biaryl C−C bond. This route should enable collections of insulin mimic drug
candidates to be prepared from a few basic building blocks.
A defining event in medicine occurred at the University of
Toronto in 1922, when Banting and Best and their co-
workers first successfully administered purified insulin by
injection to relieve diabetes symptoms in a patient.1 Insulin
represents the first therapeutic human protein, foreshadowing
the many protein therapeutics derived through biotechnology
that are used in medicine today. Though alternative orally
acting medicines to control blood glucose in Type 2 diabetes
have been developed,2 many Type 2 diabetics remain wedded
to daily insulin injections. For Type 1 diabetics, the only
alternative to insulin injections was inhaled insulin,3 no
longer marketed.
Figure 1. The natural product demethylasterriquinone B1 was
originally discovered as an oral insulin mimic. An analog replacing
the quinone with kojic acid was recently shown to retain insulin-
mimicking bioactivity.11
A potentially important event in diabetes therapy was the
1999 report of the natural product demethylasterriquinone
(1) Lestradet, H. Diabetes Metab. 1997, 23, 112-7. Rafuse, J. Can. Med.
Assoc. J. 1996, 155, 1306-8.
(2) Sheehan, M. T. Clin. Med. Res. 2003, 1, 189-200. Padwal, R.;
Majumdar, S. R.; Johnson, J. A.; Varney, J.; McAlister, F. A. Diabetes
Care 2005, 28, 736-44. Krentz, A. J.; Bailey, C. J. Drugs 2005, 65, 385-
411.
(3) McMahon, G. T.; Arky, R. A. N. Engl. J. Med. 2007, 356, 497-
502. Lassmann-Vague, V.; Raccah, D. Diabetes Metab. 2006, 32, 513-
22. Odegard, P. S.; Capoccia, K. L. Ann. Pharmacother. 2005, 39, 843-
53.
B1 (Figure 1), which mimics the effects of insulin in
controlling blood glucose in mouse models of diabetes and
as a small molecule is orally active.4 Significant research
following on this discovery5 identified improved agents that
reached the stage of testing in rats, dogs, and primates.6 Work
10.1021/ol800058d CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/28/2008

at Merck7 and in our laboratory8 defined structure-activity
relationships (SAR) in the asterriquinone insulin mimics and
identified the quinone and the 7-prenyl indole portions as
the pharmacophore. Subsequently, we discovered novel
substitution patterns that led to cell-based9 and orally active10
insulin mimics.
Scheme 1. Claisen Rearrangement of (Indole)methyl Kojates
The discovery of demethylasterriquinone B1 also repre-
sented one possible solution to a “grand challenge” of
medicinal chemistry: a small molecule that mimics the action
of a therapeutic protein. The virtues of traditional pharma-
ceuticals, including lower manufacturing costs, greater stabil-
ity during transportation and storage, and easier administra-
tion, would make small molecule drugs far superior to
proteins if they were available to treat the conditions currently
treated with protein therapeutics. Despite the aforementioned
attractions, new chemical entities based on the natural
product demethylasterriquinone B1 have not reached clinical
testing in humans. One concern about these compounds is
surely related to their quinone substructure. Although quino-
nes can be found in drug substances administered acutely,
as in anti-cancer and anti-infective therapies, this quinone
might be more problematic under the long-term administra-
tion required for a metabolic disease like diabetes. Further,
the protein that these compounds would replace is the natural
hormone (though administered in an unnatural way). This
fact undoubtedly raises the demands for safety of any insulin
replacement beyond those required for many investigational
new drugs.
In responding to this perceived difficulty, we recently
developed replacements for the quinone in the natural product
lead compound that maintain insulin mimicry.11 We de-
scribed a kojic acid derived demethylasterriquinone B1
analog (Figure 1) and a related pyridone that are insulin
mimics in cell-based assays. Preliminary broad-based phar-
macological screening of the (indolyl)kojic acid suggests it
does not present intrinsic safety issues. This compound
therefore constitutes a lead structure for further modification
to optimize biological activity. However, structural variation
of the indole portion was difficult because our route to these
compounds was not very versatile. Our synthetic strategy
required reexamination.
methyl kojate (Scheme 1). This transformation is on the one
hand precedented in the Claisen rearrangement of allyl
kojates12 but is on the other hand unprecedented: this reactant
is an analog of benzyl vinyl ether, for which the Claisen
rearrangement is unknown.13 However, such reactions can
occur when the benzyl fragment is part of a heteroaromatic
ring or when the reactants are electronically biased.14
Tautomerization of 2 following Claisen rearrangement brings
the indole and 4-pyrone back into conjugation, creating a
biaryl 3. A consequence of this strategy is the introduction
at the indole 2-position of a methyl group not present in the
lead structure. However, our SAR work showed that methyl
substitution at this position increases potency slightly.8
The preparation of a reactant to test this plan used known
compounds 415 and 5.16 Following alkylation of the kojic
acid, the THP group can be removed and 6 subjected to
pyrolysis (sealed reaction vessel, CEM Discover microwave
reactor, IR temperature monitoring). The (indolyl)kojic acid
7 is produced efficiently (Scheme 2). This Claisen reaction
Scheme 2. Test of Claisen Approach to (Indolyl)kojic Acids
We have now developed a synthetic route to (indolyl)-
kojic acids based on the Claisen rearrangement of an (indole)-
(4) Zhang, B.; Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.; Royo, I.;
Vilella, D.; Diez, M. T.; Pelaez, F.; Ruby, C.; Kendall, R. L.; Mao, X.;
Griffin, P.; Calaycay, J.; Zierath, J. R.; Heck, J. V.; Smith, R. G.; Moller,
D. E. Science 1999, 284, 974-977.
requires the indole nitrogen to be protected with an electron-
withdrawing group, as it is in 6. When the nitrogen is not
(5) Salituro, G. M.; Pelaez, F.; Zhang, B. B. Recent Prog. Horm. Res.
2001, 56, 107-26.
(6) Liu, K.; Xu, L.; Szalkowski, D.; Li, Z.; Ding, V.; Kwei, G.; Huskey,
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Pai, A.; Webster, N. J. G. J. Comb. Chem. 2007, 9, 844.
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C.; Webster, N. J. G. J. Pharm. Exp. Ther. 2007, 323, 579.
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(12) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956.
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(b) Costin, C. R.; Morrow, C. J.; Rapoport, H. J. Org. Chem. 1976, 41,
535-540. (c) Raucher, S.; Lui, A. S.-T. J. Am. Chem. Soc. 1978, 100, 4902.
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1885. (e) Lee, T. Tetrahedron Lett. 1979, 2297-2300. (f) Bu¨chi, G.; Vogel,
D. E. J. Org. Chem. 1983, 48, 5406. (g) Nemeto, H.; Shitara, E.; Fukumoto,
K.; Kametani, T. Heterocycles 1985, 23, 549. (h) Reinaud, O.; Capdevielle,
P.; Maumy, M. Synthesis 1988, 293.
(15) Nagarathnam, D. Synthesis 1992, 74.
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I.; Sohn, D. D.; Mueller, R. A. J. Med. Chem. 1988, 31, 1052.
1152
Org. Lett., Vol. 10, No. 6, 2008

protected, the major product from heating is the kojic acid
5 (10:1 ratio to the Claisen product). Solvolysis of the
(indole)methyl kojate presumably occurs when the carbamate
is absent, as precedented in the work of Raucher.14c
Following demonstration of the key Claisen rearrangement,
the final requirement for broad application of this synthetic
approach to insulin mimic candidates is quick access to
(indole)methyl kojates not involving halides like 4, whose
available structural diversity is limited. Compound 5 can be
efficiently converted (Scheme 3) to its propargyl derivative
with other metallic catalysts, primarily palladium18 but also
gold,19 platinum,20 copper,21 indium,22 or potassium tert-
butoxide.23 We found that 11 rapidly and efficiently cyclizes
to (indole)methyl kojate 12 on treatment with tetrabutylam-
monium fluoride (TBAF).24
The (indolyl)kojic acid 13 in which the Boc group had
been removed was obtained upon microwave heating of 12
in toluene under the conditions depicted earlier. This process
presumably occurs via initial Claisen rearrangement followed
by removal of the protecting group, since our earlier work
showed that an electron-withdrawing group on the indole
nitrogen is essential to prevent solvolysis of the (indole)-
methyl kojate. Supporting this idea is the fact that heating
12 conventionally in toluene at reflux overnight gives the
Claisen rearrangement product retaining the Boc group (not
shown). We suggest that the removal of the Boc group in
the microwave reaction occurs via initial loss of isobutylene
via a Cope elimination. Supporting this idea is the fact that
when the Boc group is exchanged for a (methoxy)carbonyl
group (not shown), this protecting group is retained following
Claisen rearrangement (87%).We then examined the influ-
Scheme 3. Modular Preparation of Claisen Substrate
Scheme 5. Boc/THP Group Removal by Extended Heating
8, which is coupled with o-iodoaniline sulfonamide by the
Sonogashira reaction. With N-methanesulfonyl protection,
the coupling product spontaneously cyclizes to the indole
and 9 is obtained in 70% yield. Its pyrolysis as before
delivers 10 (with partial removal of the THP group).
To obtain the 1H-indole goal structures for biological
testing would require a possibly challenging removal of an
indole N-sulfonamide from 10. We therefore switched to the
more easily removed Boc protecting group in further
developing the route (Scheme 4). Coupling 8 with N-Boc-
ence of reaction conditions on the Claisen rearrangement of
12. Because high temperatures are needed and we aimed to
avoid difficult-to-remove high-boiling solvents, reactions
were performed neat in an open flask, using conventional
oil bath heating. Heating 12 at 160 °C for 3 h provides 13
in 95% yield. Taking a cue from our earlier observation that
the thermal rearrangement of sulfonamide 9 partially depro-
tects the THP group, the reaction time was extended. As
THP removal is potentially reversible, free access to the
atmosphere permits the evaporation of dihydropyran or its
derived products. Prolonged heating delivers the ultimate
target of this route, 14, in excellent yield.
Scheme 4. Synthesis of (Indolyl)kojic Acid 13
With these results as a guide, a general modular route to
substituted (indolyl)kojic acids was developed (Scheme 6).
A variety of 4-substituted o-iodoanilines can be converted
to their Boc derivatives 15{n} via standard protocols.
(18) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856. Arcadi,
A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581.
(19) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610.
(20) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
(21) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277. Hiroya, K.; Itoh, S.; Sakamoto, T.
Tetrahedron 2005, 61, 10958.
o-iodoaniline provides 11. Cyclization of such aniline-derived
Sonogashira coupling products to the indoles can be spon-
taneous under the coupling conditions17 or can be performed
(22) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47,
631.
(23) Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996, 43, 2741.
(24) Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm.
Bull. 2003, 51, 1170. Yasuhara, A.; Suzuki, N.; Yoshino, T.; Takeda, Y.;
Sakamoto, T. Tetrahedron Lett. 2002, 43, 6579.
(17) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H.
Chem. Pharm. Bull. 1988, 36, 1305. Larock, R. C.; Yum, E. K. J. Am.
Chem. Soc. 1991, 113, 6689.
Org. Lett., Vol. 10, No. 6, 2008
1153

Scheme 6. Preparation of Diverse (Indolyl)kojic Acids 17
Scheme 7. Diversifying the Kojic Acid with Pyridone 18
setting the stage for a full exploration of substituent effects
on the biological properties of (indolyl)kojic acids. The
conversion of 8 to pyridone 18 can be performed by treatment
with methylamine under slightly acidic conditions. Sono-
gashira coupling with 15{1} (68% yield) and Claisen
rearrangement as before give product 19 (53%).
In sum, we have developed a modular synthetic route to
(indolyl)kojic acid derivatives that should permit the prepara-
tion of libraries of diverse structures as candidate insulin
mimics. It avoids the preparation of unstable organotin
reagents involved in our earlier syntheses of such com-
pounds.11 One limitation to the route is that it requires
iodoanilines or other similarly reactive nitrogen-substituted
arenes. Attempts to use protected o-bromoanilines in the
Sonogashira coupling have so far been unsuccessful, but
novel methods to achieve this transformation have lately
become available.25
Sonogashira reaction with 8 followed by the addition of
tetrabutylammonium fluoride directly to the reaction mixture
provides 5-substituted indoles 16{n}. Upon heating, these
materials are converted to the targets 17{n}. This process
requires only two pots and creates rather complex molecules
from simple starting materials: a Boc-iodoaniline and a
propargyl kojate, each readily prepared. Results are sum-
marized in Table 1.
Table 1. Results from Application of the Route in Scheme 6
to Substituted o-Iodoaniline Derivatives 15
Acknowledgment. Financial support from the NIH (DK-
60532) and the Diane & Paul Goldring Garrett Innovation
Seed Grant Program is gratefully acknowledged.
entry and n
R
yield of 16{n}
yield of 17{n}
1
2
3
4
5
H
55
61
60
70
69
87
73
70
63
70
4-Cl
4-CO2Me
4-CN
Supporting Information Available: NMR spectra for
new compounds and other experimental and characterization
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
4-Me
The process as described so far effectively incorporates
structural diversity into the indole portion of the targets. It
is also useful for varying the kojic acid portion (Scheme 7),
OL800058D
(25) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844.
1154
Org. Lett., Vol. 10, No. 6, 2008