General synthesis of unnatural 4-, 5-, 6-, and 7-bromo-D-tryptophans by means of a regioselective indole alkylation

Article abstract of DOI:10.1016/j.tetlet.2020.151923

A general two-step approach to enantiopure bromotryptophans from unprotected bromoindoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with cyclic sulfamidates derived from enantiopure D-serine to form 4-, 5-, 6-, or 7-bromo-D-tryptophan and some other halogenated tryptophans in moderate yields but with complete regioselectivity. The bromotryptophan derivatives were deprotected using mild conditions.

Full text of DOI:10.1016/j.tetlet.2020.151923

Journal Pre-proofs
General Synthesis of Unnatural 4-, 5-, 6-, and 7-Bromo-D-Tryptophans by
Means of a Regioselective Indole Alkylation
Francesca Bartoccini, Fabiola Fanini, Michele Retini, Giovanni Piersanti
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DOI:
Reference:
S0040-4039(20)30366-X
https://doi.org/10.1016/j.tetlet.2020.151923
TETL 151923
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Tetrahedron Letters
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Revised Date:
Accepted Date:
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1 April 2020
7 April 2020
Please cite this article as: Bartoccini, F., Fanini, F., Retini, M., Piersanti, G., General Synthesis of Unnatural 4-,
5-, 6-, and 7-Bromo-D-Tryptophans by Means of a Regioselective Indole Alkylation, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.151923
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Tetrahedron Letters
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General Synthesis of Unnatural 4-, 5-, 6-, and 7-Bromo-D-Tryptophans by
Means of a Regioselective Indole Alkylation
Francesca Bartoccini, Fabiola Fanini, Michele Retini and Giovanni Piersanti*
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Piazza Rinascimento 6, 61029 Urbino, PU, Italy
E-mail: giovanni.piersanti@uniurb.it
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general two-step approach to enantiopure bromotryptophans from unprotected bromoindoles
has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted
with cyclic sulfamidates derived from enantiopure D-serine to form 4-, 5-, 6-, or 7-bromo-D-
tryptophan and some other halogenated tryptophans in moderate yields but with complete
regioselectivity. The bromotryptophan derivatives were deprotected using mild conditions.
Available online
Keywords:
Unnatural Amino acid
Indole
2009 Elsevier Ltd. All rights reserved.
Sulfamidate
Halotryptophans
Natural nonproteinogenic bromotryptophans and unnatural
bromotryptophan derivatives are essential starting materials for
the biosynthesis and synthesis of both indole alkaloid natural
products and pharmaceutically interesting products including
peptide analogues (Figure 1).1 The bromide functionality in
natural products and peptides not only has been demonstrated to
improve properties such as metabolic stability and bioavailability
compared to the desbromo counterparts,2 but it could offer a
unique, site-selective synthetic handle that can be utilized for a
wide range of applications, for instance, bioorthogonal reactions,
fluorescence labeling, late-stage modification, and bicyclic
tryptophan‐stapled peptides.3 By replacing tryptophan in proteins
with bromotryptophan, it has been possible to probe π–cation
interactions, which are known to be of high importance in
biological systems and are of increasing interest in medicinal
chemistry.4 Recently, it also has been reported that serum 6-
bromotryptophan is a consistent and novel risk factor for chronic
kidney disease progression.5
variety of bromoindoles.11 The synthetic routes to selective and
enantiomerically pure bromotryptophans typically require
multiple steps, the use of exclusive methodology/reagents with a
lack of generality, and a specific procedure for each regioisomer
and/or enantiomer. In view of these issues, devising
a
straightforward procedure for the chemical synthesis of
enantiomerically pure unprotected bromotryptophans is highly
desirable.
Thus, important inroads into selective synthetic strategies
yielding enantiopure bromotryptophan have been made through
chemo- and biocatalysis. Besides the standard use of chiral
auxiliaries,6 chiral pools,7 and the largely employed L-acylase-
mediated kinetic resolution approach,8 there are three other
catalytic asymmetric approaches to bromotryptophan worth
mentioning: (a) the synthesis of an appropriate dehydrotryptophan
precursor followed by Rh-catalyzed asymmetric hydrogenation;9
(b) bromination of L-tryptophan by tryptophan halogenases or a
fermentative process;10 and (c) the use of tryptophan synthase to
catalyze the formation of a C–C bond between L-serine and a

2
Tetrahedron
CO2H
O
Therefore, we chose 1H-indole (1a) and already known cyclic
N
H
N-Boc-sulfamidate (2) obtained from N-Boc-D-serine methyl
ester15 as the reaction partner for our optimization studies. We
decided to explore the preparation of the D-enantiomer of
bromotryptophan due to the increasing use of this enantiomer in
the production of pharmaceuticals and unnatural peptide-based
drugs16 and limited methods (mainly enzymatic kinetic resolution)
for their production. Obviously, the same chemistry can be applied
to the natural L-serine cyclic N-Boc-sulfamidate version.
N
Br
MeO
N
H
N
Br
N
H
Iptrochamide B
Eudistomin H
OR
O
OR
OR
O
Br
Br
N
N
H
N
O
NHR’
N
H
Tetraacetyl clionamide
R = R’ = acetyl
9-Bromotryptanthrin
As illustrated in Table 1, similar to the results obtained by
Chung,13 we observed a low yield and regioselectivity when only
the Grignard reagent was used as the base (Table 1, entry 1). Next,
we determined that it was absolutely necessary to use a
stoichiometric amount of copper salt in order to have
nucleophilicity through the C(3) position of the indolyl core, to
avoid the formation of N1-alkylated 4, as well as to obtain
reproducibility and scalability of this transformation (Table 1,
entries 2 and 3). The best combination was 1.3 equiv of MeMgCl
and 1.3 equiv of CuCl at -20 °C with a slight excess of indole (1.5
mmol). Different Grignard reagents with copper salt gave a lower
yield and/or regioselectivity (Table 1, entries 6 and 7). We
reasoned that the presence of the ester group in cyclic sulfamidate
2 in comparison with the cyclic sulfamidate reported by Chung
(Scheme 1) would increase the lability of the C-O bond involved
in the reaction. At -40 °C, a significantly decreased yield was
observed, which was probably due to the reduced reactivity of the
cuprate (Table 1, entry 5). Based on these preliminary optimization
reactions, we found that (1) the ring-opening reactions proceeded
with complete conversion of 2, and competitive β-elimination
reactions (dehydroalanine byproduct) were never observed; (2) a
prolonged reaction at -20 °C was necessary to achieve high
substrate conversions at reasonable rates and acceptable yields; (3)
the presence of the N-Boc group at the sulfamidate was critical for
the ring-opening reaction to proceed; and (4) anhydrous solvent
(dichloromethane) and triturated Grignard reagent needed to be
utilized to achieve a good yield. However, minimal formation of
the C3,N1-dialkylated byproduct (A) along with traces of a ketone
byproduct (B) arising from attack of the C-3 position onto the
methyl ester side chain of sulfamidate, also reported by others14l
were observed in the crude reaction mixture (according to LC-MS
analysis); these findings can partially justify the suboptimal yields.
Moreover, the 1H NMR of the crude reaction mixture, after work-
up procedure, showed the absence of any detectable sulfamidate 2
or derived from, and excellent conversion of indole into the
alkylated product. The excess of indole 1a employed was totally
recovered. Although not completed clarified yet, it appears that,
the yield of the isolated 3a was restrained as a result of its partial
sensitivity to the slightly acidic treatment required for the
hydrolysis of the sulfamate group during the purification step
and/or minimal retaining of the sulfamate group, which release a
water-soluble side product. Indeed, the weight of crude mixture to
be purified was marginally lower than theoretical weight.
H
NH2
NH
O
O
O
N
H
NH
NH
N
Br
N
HN
O
N
Br
H
N
H
NH
O
Br
Barettin
11-Bromoroquefortine C
O
H
N
Me
N
N
HN
N
H
H
Gly-Cys-Hyp-D-Trp-Glu-Pro-L-6-BrTrp-Cys-NH2
Bromocontryphan
O
NH
O
HN
O
Cl
H
N
HO
O
O
NH2
Cyclocinamide A
Figure 1. Representative natural products containing bromotryptophan or
derived from bromotryptophan.
As part of our research program aimed at establishing new
methods for the enantioselective synthesis of indole alkaloid
natural products and their associated analogues,12 we are interested
in developing convergent and efficient syntheses of enantiopure
bromotryptophans from simple unprotected indole starting
materials and a suitable electrophile. Inspired by the work of
Chung and collaborators13 on the synthesis of chiral tryptamines
using cyclic sulfamidates derived from chiral amino alcohols, we
sought to develop a more streamlined process for the direct
conversion of all commercially available regioisomer
bromoindoles to the corresponding enantiopure bromotryptophans
(Scheme 1). By taking advantage of the more nucleophilic/basic
C3 position of these C3-unsubstituted indoles (i.e., 3a) and the
relatively good electrophilicity of the chiral serine-derived cyclic
sulfamidate electrophile (i.e., 2), we were able to fashion a
regioselective two-step synthesis of enantiopure 4-, 5-, 6-, and 7-
bromotryptophans (Scheme 1). The premise behind this
alkylation/deprotection sequence was our recognition of cyclic
sulfamidates derived from serine (i.e., 2) as a rapidly accessible
two-carbon amino acid-containing electrophile and its high
propensity to readily undergo a regioselective ring-opening
reaction with an adequate nucleophile.14
Previous work: Chung et al. Ref. 13
R2
NH2
O
O
S
Table 1. Optimization of reaction conditionsa
O
+
NBoc
N
R1
N
H
R1
R2
H
This work:
R2 = alkyl, aryl
CO2H
NH2
O
O
S
O
+
NBoc
N
H
N
H
X
X
CO2Me
Scheme 1. Regioselective indole alkylation with a cyclic sulfamidate

CO2Me
NHBoc
CO2Me
NHBoc
Br
O
Br
Base
Addittive
O
55
S
O
NBoc
+
1
2
3
52c
DCM
temperature
18 h
N
N
H
N
H
H
N
CO2Me
H
1a
2
3a
1b
3b
CO2Me
CO2Me
NHBoc
O
S
O
Br
O
NHBo
N
O
Br
Boc
N
H
57
48
N
N
N
N
H
CO2Me
NHBoc
CO2Me
H
1c
NHBoc
3c
4
A
B
Undesired
Undesired
Undesired
C3/N1b
CO2Me
NHBo
Entry
Base
Additive
Temp.
-20 °C
-20 °C
-20 °C
-20 °C
0 °C
Yield 3ac
9%d
1
MeMgCl
MeMgCl
MeMgCl
MeMgCl
MeMgCl
MeMgCl
MeMgBr
PhMgCl
MeMgCl
-
20/80
21/79
100/0
100/0
100/0
100/0
75/25
100/0
–
N
H
Br
2e
3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
5%f
N
H
Br
1d
59%
34%
27%
38%
8%
3d
4g
5
CO2Me
NHBoc
6
-40 °C
-20 °C
-20 °C
-20 °C
N
H
4
5
46
N
Br
7
H
Br
1e
8
29%
NR
3e
9h
CO2Me
aBase (1.3 equiv) was added to a mixture of 1a (1.5 equiv) and additive
(1.3 equiv) in DCM (0.3 M), followed by 2 (1 equiv) in DCM (0.85
M). The cuprate was prepared at 0 °C, and a solution of 2 was added
NHBoc
Br
Br
N
-
H
N
b
H
at 0 °C or -20 °C. Ratio of C3/N1 alkylation was determined by
1f
c
d
HPLC analysis. Isolated yield. Undesired compound 4 was also
obtained in 33% yield and traces of undesired compounds A and B
3f
e
were observed by HPLC analysis. A catalytic amount of CuCl (0.2
aMeMgCl (1.3 equiv) was added to a mixture of 1b–f (1.5 equiv) and
CuCl (1.3 equiv) in DCM (0.3 M), followed by 2 (1 equiv) in DCM
(0.85 M). The cuprate was prepared at 0 °C, and a solution of 2 was
added at -20 °C. bIsolated yield.
f
equiv) was used. Traces of undesired compounds A and B were
observed byHPLC analysis. gThe cuprate was prepared at 0 °C for half
an hour instead of one hour. hNH sulfamidate was used instead of 2.
With optimized conditions in hand, we investigated the desired
bromoindoles. The reaction of differently substituted
bromoindoles 1b-e with N-Boc-D-sulfamidate 2 provided the
desired products 3b–e in modest yields but with complete chemo,
regio-, and enantioselectivities (Table 2). However, in the reaction
with the bromoindole bearing a bromide group at the C-2 position,
the desired product 3f was observed, but its purification proved to
be very difficult, probably due to its higher lability.17 Although the
L-forms have already been reported and used for the total synthesis
of a structurally and biologically fascinating class of alkaloid
natural products, the syntheses of compounds (R)-3b and (R)-3e
have not yet been described. The optical purity of these
compounds was confirmed by comparing the specific rotation
values reported in the literature for the enantiomers. (For example,
(R)-3e showed [α]D20 = -42 (c = 1.01, CHCl3) versus the S-form:
Fluorine- and chlorine-containing tryptophans are becoming
increasingly prominent in new drugs.18 The reaction described
herein is compatible with both chlorine and fluorine on the indole
substituents, and compounds 3g–j were obtained in modest yields
but comparable with those of the bromide-substituted indoles
(Scheme 2). Of note, 6-chloro-5-fluoro-D-tryptophan derivative 3j
is the key intermediate for the synthesis of KAE609 (cipargamin),
which was discovered recently by Novartis as a novel and potent
antimalarial agent and is now in phase 2 clinical trials with
promising prospects. The synthesis previously reported consisted
of five steps (including enzymatic kinetic resolution with L-
aminoacylase) and an overall yield of 5.5% starting from the same
6-chloro-5-fluoroindole (1j).19 The electron-withdrawing
substituents on the indole facilitate the reaction. For example,
when an electron-donating group, such as methoxy, was
introduced to the 5-position of indole, the reaction was much less
regioselective, and the coupling product was obtained in a lower
yield with some unidentified polar byproducts (data not shown).
20
Lit.8c [α]D = +37 (c = 1.0, CHCl3)). Reactions were typically
carried out using 200 – 300 mg of haloindole (1 mmol) but could
be readily scaled up to enable conversions of around 3 g of
bromoindole (see SI).
CO2Me
Table 2. Evaluation of substrate scope on bromoindolesa
O
CO2Me
CuCl (1.3 equiv)
MeMgCl (1.3 equiv)
O
NHBoc
S
O
O
CuCl (1.3 equiv)
MeMgCl (1.3 equiv)
O
+
NBoc
NHBoc
S
DCM
-20 °C - RT, 18 h
O
N
N
X
+
NBoc
X
H
H
CO2Me
DCM
-20 °C - RT, 18 h
N
N
Br
3g, X = 5-Cl
3h, X = 6-Cl
3i, X = 5-F
(44%)
(48%)
(41%)
Br
H
1g, X = 5-Cl
1h, X = 6-Cl
1i, X = 5-F
H
2
CO2Me
3b-f
1b-f
2
3j, X = 5-F, 6-Cl (49%)
1j, X = 5-F, 6-Cl
Entry
Substrate
Product
Yieldb
Scheme 2. Evaluation of substrate scope on chloro- and fluoroindoles

4
Tetrahedron
bromoindoles and chiral cyclic sulfamidates derived from D-
To complete the preparations of bromotryptophans 5b–e, only
serine. A few examples of other halotryptophans were also
obtained. These examples demonstrate that serine-derived cyclic
sulfamidates are versatile chiral building blocks with
complementary reactivity to the related beta-alanine cation
equivalents, but are not regioselective, such as aziridine
carboxylate.21 Moreover, the very common β-elimination side
reaction on the serine sulfamidate, occurring even under slightly
basic conditions, was completely prevented. Considering the
crucial importance of unnatural functionalized tryptophans and the
simplicity of the reaction conditions, we believe that this method
will find broader applications in the asymmetric synthesis of
related indole alkaloids as well as unnatural peptide‐based drugs
and chemical probes. Such efforts are ongoing in our laboratory
and will be reported in due course.
the removal of the Boc and methyl groups remained. Numerous
methods are available for removal of the Boc group with
preservation of the methyl ester functionality and vice versa.
However, there are very few simple and efficient methods for the
one-pot double-deprotection reaction with a single reagent
resulting in the formation of an optically pure free amino acid in
quantitative yield. Treatment with a large excess of HBr or BBr3
at 23 °C resulted in cleavage of both the Boc group and the methyl
ester as well as multiple other side products. On the other hand,
4% aq. KOH in dioxane proved to be a mild and highly effective
method for the selective hydrolysis of the methyl ester followed
by Boc cleavage by heating with 50% AcOH at 80 °C for 3 h to
give S-5b in 87% overall yield from S-3b.
Table 3. Deprotection of bromotryptophan derivativesa
CO2Me
NHBoc
CO2H
NH2
Declaration of Competing Interest
The authors declare no competing financial interest.
Supplementary Material
SiO2
N
N
H2O, 140 °C, 20 h
Br
Br
H
H
5b-e
3b-e
Entry
Substrate
Product
Yieldb
92%
Experimental procedures, compound characterizations, and
copies of 1H NMR and 13C NMR spectra can be found in
Supplementary Information.
CO2H
Br
NH2
1
2
3
3b
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H
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a 3b–e (0.1 mmol), SiO2 (200 mg, 60 Å), H2O (3 mL), 140 °C, 20 h.
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Graphical Abstract
Highlights
Leave this area blank for abstract info.
General Synthesis of Unnatural 4-, 5-, 6-, and
7-Bromo-D-Tryptophans by Means of a Regioselective
Indole Alkylation
Francesca Bartoccini, Fabiola Fanini, Michele Retini and Giovanni Piersanti*
CO2H
NH2
O
O
S
C3-Alkylation
O
NBoc
+
N
N
Deprotection
X
H
X
H
CO2Me
X = Br, Cl, F

6
Tetrahedron
General synthesis of enantiopure
bromotryptophans.
Regioselective C3-alkylation of (NH)-indoles.
Serine-derived cyclic sulfamidate as a suitable
source for the amino acid fragment.
One-pot double-deprotection reaction with a single
reagent.