Direct, regioselective, and chemoselective preparation of novel boronated tryptophans by friedel-crafts alkylation

Article abstract of DOI:10.1021/ol203216h

A facile synthetic approach to the direct preparation of various novel unnatural boronated protected tryptophans using a regio- and chemoselective electrophilic substitution of 4- and 5-boronated indoles with N-protected dehydroalanine is described. The g

Full text of DOI:10.1021/ol203216h

ORGANIC
LETTERS
2012
Vol. 14, No. 2
600–603
Direct, Regioselective, and
Chemoselective Preparation
of Novel Boronated Tryptophans by
FriedelÀCrafts Alkylation
Silvia Bartolucci, Francesca Bartoccini, Marika Righi, and Giovanni Piersanti*
Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6,
61029 Urbino (PU), Italy
giovanni.piersanti@uniurb.it
Received December 2, 2011
ABSTRACT
A facile synthetic approach to the direct preparation of various novel unnatural boronated protected tryptophans using a regio- and
chemoselective electrophilic substitution of 4- and 5-boronated indoles with N-protected dehydroalanine is described. The gram-scale
synthesis of two free tryptophan boronic acids is also reported.
In the past decade, there has been considerable interest
in functionalized amino acids bearing a hidden reactive
center such as sulfur, selenium, phosphorus, fluorine, or
boron.1 Among them, boronated amino acids have re-
ceived significant attention as potential pharmaceuticals
due to their use as enzyme inhibitors,2 as anti-HIV agents,3
and for their preferential uptake by growing tumor cells.
Hence, they have promising applications in boron neutron
capture therapy (BNCT).4 Remarkably, the recent biosyn-
thetic incorporation of a boronate-containing amino acid
into proteins allowed for selective protein modifications
and easier protein purification.5
Additionally, amino acid derivatives with an organo-
boron functionality on the side chain have been prepared
and used in Rh-, Ru-, Ni-, Cu- and Pd-catalyzed cross-
coupling reactions to prepare new alkylated or arylated
cross-linked amino acids and complex biologically active
(1) (a) Zhu, Y.; van der Donk, W. A. Org. Lett. 2001, 3, 1189. (b) Liu,
S.; Dockendorff, C.; Taylor, S. D. Org. Lett. 2001, 3, 1571. (c) Martarello,
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Chem. 2002, 45, 2250. (d) Jacob, C.; Giles, G. I.; Niroshini, M.; Sies, H.
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r
10.1021/ol203216h
Published on Web 12/30/2011
2011 American Chemical Society

cyclic peptide natural products.6 However, current prep-
arations of boronated amino acids are somewhat limited
due to the incompatibility of the boronic acid moiety/
derivatives with the reagents and catalysts used in many
synthetic methods, intermediate organometallic species,
and reagents employed in their preparation.7
In accordance with the above-reported renewed interest
in the design and synthesis of new boron-containing amino
acids as well as the central role that tryptophan plays
particularly in peptides and proteins, new, simple, and
reliable methods for the efficient synthesis of tryptophan
analogues containing boronic acids on the indole ring are
highly desirable (Figure 1). Tryptophan derivatives have
been previously synthesized by using enzymatic and chem-
ical methods.13
Tryptophan, an essential amino acid, functions asboth a
building block in protein biosynthesis and a biochemical
precursor; it plays a crucial role in a large number of
biochemical processes carried out by functional proteins.
It is abundantly found in most biologically active peptides
that exhibit various physiological properties, in particular
hormonal, antimicrobial, and anticancer activities.8 Tryp-
tophan analogues are also important building blocks for
the synthesis of peptidomimetics, natural products, and
biologically active compounds.9 Among tryptophans,
those which are substituted at the 4- and 5-positions
are particularly interesting because they might be useful
intermediates for the synthesis of naturally occurring (À)-
aurantioclavine, serotonin tryptamine, and indole alka-
loids, such as the ergot alkaloids, indolactam V, Chuang-
xinmycin, and CC-1065, and also unnatural derivatives
suchastriptans.10 Furthermore, 4-substituted tryptophans
are particularly challenging substrates for steric and elec-
tronic reasons since most electrophilic attacks prefer the
2- or 7-position of tryptophan.11 This problem has been
circumvented by a wide variety of ingenious methods, but
all suffer from low efficiency and practicability.12
Figure 1. Possible approaches to boronated tryptophanes: path
A (halogenÀmetal exchange), path B (Pd-catalyzed boronation),
and path C (Ir-catalyzed CÀH boronation).
(7) For a general overview of boronic acids, see: (a) Boronic Acids:
Preparation, Applications in Organic Synthesis and Medicine; Hall, D.,
Ed.; Wiley-VCH: 2005. For new approaches to prepare boronate with highly
reactive functionalities, see: (b) Merino, P.; Tejero, T. Angew. Chem., Int.
Ed. 2010, 49, 7164. For Miyaura cross-coupling reaction, see:
(c) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
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Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (f) Hartwig,
J. F. Chem. Soc. Rev. 2011, 40, 1992.
Based on these considerations and taking into account
the wide tolerance of the boronic acid ester, we envisioned
the Lewis acid FriedelÀCrafts alkylation of indoles with a
dehydroamino acid for the synthesis of 4- or 5-boronated
tryptophan derivatives.14
So, when we subjected the easily accessible boronated
indoles (1a,b)7c to FriedelÀCrafts conditions with N-acetyl
dehydroalanine methyl ester (2) we obtained the boron-
ated protected tryptophans 3a,b in excellent yields with
high regio- and chemoselectivity (Scheme 1).
To the best of our knowledge, this is the first reported
example of direct FriedelÀCrafts alkylation of boronated
indoles. Notably, the widely used lithiation/trap with
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Org. Lett., Vol. 14, No. 2, 2012
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(MIDA) boronates22 which were recently developed. They
are the next generation of boron synthetic intermediates that
meet the challenge of stability and reactivity for all boro-
nated compounds. Recently, Molander23 and Burke24 made
superb efforts to advance the transition-metal-catalyzed
SuzukiÀMiyaura coupling using organotrifluoroborate
salts and MIDA boronates as coupling partners.25 Using
standard conditions, compounds 5a and 6a were obtained
from boronate and boronic acid tryptophans respectively,
in almost quantitative yield after conventional flash chro-
matography on silica gel without specific precautions
(Scheme 2).26 Thus, four different protected boron-containing
tryptophans (3aÀ6a) can be obtained and employed accord-
ing to the use and purpose. In addition, 5a and 6a were
exposed to air at rt for a period of 2 months and no detectable
degradation was observed.27
Scheme 1. FriedelÀCrafts Alkylation of Boronated Indoles 1a,b
with N-Acetyl Dehydroalanine Methyl Ester 2
boron electrophiles method (Figure 1, path A) and
Pd-catalyzed Miyaura boronation (Figure 1, path B)15 failed
when applied to 4-bromotryptophan, showing the power of
this approach. Nevertheless, Ir-catalyzed direct boronation
of tryptophan (Figure 1, path C) led to a regioselective
2-boronated product in low yield.16 Therefore this method
is complementary for the synthesis of a series of boronated
tryptophans that cannot be accessed by the above-mentioned
methods, which are controlled by electronic and steric effects.
Chemoselective removal of the pinacol group of com-
pound 3a through oxidative cleavage with sodium
periodate17 provided the free tryptophan boronic acid 4a
in high yield, whereas the hydrolysis of the boron ester
through trans-boro-esterification with phenyl boronic acid
and 2 N HCl led to only a trace amount of the desired
product (Scheme 2). Thus, 4-boronic acid protected tryp-
tophan 4a is easily obtainable through this method. This is
quite important, since insomereactions, suchasthe Petasis
reaction,18 carbonÀheteroatom couplings,19 and oxidative
homocoupling reactions,20 free boronic acids have proven
tobemoreefficient. However, boronicacids are never ideal
because they exhibit several drawbacks, such as the partial
formation of dimeric and cyclic trimeric boroxines (which
depend on storage water content). Yet, in some cases,
these reagents may suffer from long-term instability and
protodeboronation. This has led to increased use of po-
tassium aryltrifluoroborates21 and N-methyliminodiacetyl
Scheme 2. Conversion of Boronated Tryptophan 3a to Boronic
Acid 4a, Trifluoroborate 5a, and MIDA Boronated 6a
We then turned our attention to preparing completely
deprotected free amino acids 9a and 9b. Whereas the ester
hydrolysis worked fine under standard conditions, the
(16) (a) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew.
Chem., Int. Ed. 2002, 41, 3056. (b) Takagi, J.; Sato, K.; Hartwig, J. F.;
Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. (c) Ishiyama,
T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924.
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(e) Tagata, T.; Nishida, M. Adv. Synth. Catal. 2004, 346, 1655. (f) Paul, S.;
Chotana, G. A.;Holmes, D.;Reichle, R. C.; Maleczka, R. E.; Smith, M. R.
J. Am. Chem. Soc. 2006, 128, 15552. (g) Kallepalli, V. A.; Shi, F.; Paul, S.;
Onyeozili, E. N.; Maleczka, R. E.; Smith, M. R. J. Org. Chem. 2009, 74,
9199. (h) Kallepalli, V. A.; Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka,
R. E., Jr.; Smith, M. R., III. J. Org. Chem. 2009, 74, 9199. (i) Robbins,
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R.; Kubo, Y.; James, T. D.; Fossey, J. S. Chem. Commun. 2011, 47, 1106.
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M. R. J. Org. Chem. 1995, 60, 3020. (b) Molander, G. A.; Figueroa, R.
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Chem., Int. Ed. 2009, 48, 9240.
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130, 466. (c) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
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2010, 49, 8860. (f) Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D.
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E. P.; Burke, M. D. Org. Lett. 2010, 12, 2314. (h) Struble, J. R.; Lee, S. J.;
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(27) For the MIDA derivatives, prolonged exposure to water and/or
moisture showed, by 1H NMR and TLC, formation of the hydrolyzed
boronic acid.
602
Org. Lett., Vol. 14, No. 2, 2012

removal of the acetyl group was difficult. N-Acetyl deriv-
atives require prolonged heating in concentrated acid or
base which is not compatible with sensitive compounds.
Different acidic and basic conditions were tested, but in all
cases protodeboronation or decomposition occurred both
from 7a,b or directly from 3a,b. Also, the use of acylase
enzymes from Aspergillus melleus under very mild condi-
tions (pH 7.4, temperature 37 °C) did not provide the
desired product (Scheme 3).13a,28
the ester into a carboxy group, which simultaneously
cyclized to the adjacent boron derivative to form the
unknown eight-membered ring 9a (Scheme 4).
Scheme 4. FriedelÀCrafts Alkylation of Boronated Indoles 1a,b
with Methyl 2-(Diphenylmethyleneamino)acrylates 7 and
Hydrolysis of Compounds 8a,b
Scheme 3. Hydrolysis of N-Acetyl Boronated Indoles 3a,b
A different dehydroamino acid was then necessary. We
sought to use the stable and readily available methyl
2-(diphenylmethyleneamino)acrylates29 in our sequence,
based on its reported good reactivity and the mild and
selective reaction conditions for the deprotection of
the amino group in the final compounds. We predicted
that the use of dehydroalanine 7 should rapidly give
access to useful quantities of boronated tryptophans
with unprecedented levels of ease and efficiency.
Dehydroamino acid 7 was then coupled to boronated
indoles 1a,b to give the boronated protected trypto-
phans 8a,b. Again, the FriedelÀCrafts reaction pro-
ceeded in excellent yield and the boronated protecting
group remained intact.
The adducts 8a,b were readily converted to free trypto-
phan boronic acids 9a,b by conventional sequences (1 N HCl
and 1 N NaOH) in one pot, two steps, and almost quantitative
overall yield, which presented a straightforward route to
4- and 5-substituted tryptophans (Scheme 4). Selective de-
protection of either the amino or the ester was possible as well.
Notably, in the case of 4-boronated derivatives the
treatment of 8a with aqueous sodium hydroxide converted
In summary, we have prepared various novel protected
boronate tryptophans (3a,bÀ8a,b) via a regio- and che-
moselective FriedelÀCrafts alkylation between boronate
indoles and N-protected dehydroalanine. Therefore, this
methodology offers an alternative approach to access
protected tryptophan boronates in cases where the
Miyaura boronation or more traditional stoichiometric
metalating reagent approaches fail and where Ir-catalyzed
boronation does not give the correct regioisomer. We are
currently in the process of investigating further applica-
tions of protected boronate tryptophans as building blocks
in the preparation of biaryl-containing peptide natural
products. The proper choice of protective groups in the
dehydroalanine enables easy and practical access to two
novel free boronic acid tryptophans 9a,b. Evaluation of
these boron-containing amino acids as BNCT agents is
currently under way.
Acknowledgment. We would like to thank Prof. Gilberto
Spadoni, University of Urbino, for useful discussions.
Supporting Information Available. Experimental pro-
cedure and spectral data for reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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