A fast and direct iodide-catalyzed oxidative 2-selenylation of tryptophan

Article abstract of DOI:10.1039/d1cc00700a

A metal-free 2-selenylation of tryptophan derivatives is reported, where the use of iodide as the catalyst and oxone as the oxidant is key to obtain high yields. Various functional groups within the di-seleny and the indole ring are tolerated, and no racemization is generally observed.

Full text of DOI:10.1039/d1cc00700a

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A fast and direct iodide-catalyzed oxidative
2-selenylation of tryptophan†
Yu-Ting Gao,ab Shao-Dong Liu,ab Liang Cheng
Cite this: Chem. Commun., 2021,
57, 3504
ab
*
and Li Liu*ab
Received 5th February 2021,
Accepted 1st March 2021
DOI: 10.1039/d1cc00700a
rsc.li/chemcomm
A metal-free 2-selenylation of tryptophan derivatives is reported, precursor have been reported (Scheme 1). 2-Phenylselanyl product
where the use of iodide as the catalyst and oxone as the oxidant is has been prepared by treating tryptophan with moisture sensitive
key to obtain high yields. Various functional groups within the di-seleny phenylselenenyl bromide.5 In this case, trimethylamine was used as
and the indole ring are tolerated, and no racemization is generally the quencher to neutralize the generated hydroxyl bromide and the
observed.
substitution was limited in Ar–Se–X examples (Scheme 1a). Recently,
alkane seleninic acids were utilized to react with tryptophan and
L-Tryptophan, which bears an exclusive indole ring, is a unique other electron-rich aromatic rings to deliver the corresponding
building block in protein synthesis. Its biotransformation in products in good yields (Scheme 1b).6 However, the seleninic acids
living organisms contributes either to site-selective bioconjuga- were generally prepared through oxidation of diselenide with
tion with biomacromolecules in cells and tissues while keeping dimethyldioxirane, which limited its application in functionality-
this indole ring or breaking it to generate a variety of bioactive sensitive substrates. Thus, the development of new synthetic
metabolites.1 2-Selanyltryptophans are one class of non- methodologies for the selective 2-selanylation of tryptophan is
ribosomal amino acids that have been found as components highly desirable, particularly for the introduction of versatile func-
of some natural polypeptides, such as the Se-glucosinolate 1 tion moieties. In our continuous effort toward the discovery and
methylselenoneoglucobrassicin (Fig. 1), which is a natural development of facile oxidation processes involving bioactive
metabolite fraction in black mustard (Brassica nigra) seeds structures,7 we now present a mild and efficient method for the
grown in seleniferous areas and is believed to have anti- preparation of the title compounds with easily available diselenides
inflammatory activity.2
under the catalysis of iodide and promotion of oxone, an eco-
In addition to their natural analogues, synthetic 2-selanyltrypto- friendly and cost-effective oxidant (Scheme 1c). This reaction
phans also act as precursors of numerous key biologically active exhibits exceptional reaction kinetics (accomplishment in minutes)
integrates (drugs or nutritive additives) for human health. For and is able to deliver the designated products in good to excellent
example, the novel cyclic peptide 2 (Fig. 1, ITFUDLLWYYGKKK) yields without any loss of enantioselectivities.
containing a specific selenide bridge was developed as an anti-
As a starting point, we conducted the reaction of L-methyl
infective agent for parasiticides and a lead compound for tumor acetyl tryptophanate 1a with dibenzyldiselenide 2a with our
treatment,3 while the dimeric selenide 3 was able to inhibit tyrosine previously developed method (TBAI and H2O2), but the desired
kinases and the proliferation of Swiss 3T3 Mouse fibroblasts.4 These product 3a was obtained in 31% yield when CH3CN was used
compounds should be taken into account in the design of drugs (Table 1, entry 1). Changing the solvent to others resulted in
pertaining to tryptophan, as the 2-selanyl substituent may affect the much lower production (entries 2 and 3) or even totally halted
metabolism of such molecules. However, to date only two examples the coupling (entry 4, see the ESI,† for details). Satisfactorily,
for the synthesis of 2-selanyltryptophan from the amino acid
a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory
of Molecular Recognition and Function, CAS Research/Education Center for
Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China. E-mail: chengl@iccas.ac.cn, lliu@iccas.ac.cn
b University of Chinese Academy of Sciences, Beijing 100049, China
† Electronic supplementary information (ESI) available: Experimental details,
and characterization data. CCDC 2058699. For ESI and crystallographic data in
Fig. 1 Represented 2-selanyltryptophan derivatives.
CIF or other electronic format see DOI: 10.1039/d1cc00700a
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before purification, probably excluding further oxidation. It is
worth mentioning that this coupling was insensitive to moisture
or oxygen. However, it is worth mentioning that oxygen alone was
not capable of promoting this reaction (see the ESI,† for details).
The present coupling reaction proceeded efficiently using com-
mercial DMSO (without purification) under an open-air condition,
which makes a large-scale synthesis possible in the future. On the
other hand, this rapid, mild and efficient oxidative coupling has
no influence on the chirality. No enantioselectivity loss was
observed in this process. Yet the introduction of a C2-selenyl
substituent exhibited some restriction on the orientation of the
aromatic indole ring with respect to the amino and carboxyl
groups8 as demonstrated by the slight change in circular dichroism
spectra (see theESI,† for details).
We next examined the scope of the reaction with a variety of
differently diselenides 2. As shown in Scheme 2, excellent yields
were obtained in the reaction of methyl acetyl tryptophanate 1a
with several diselenides. Ortho-(3b–d), meta-(3e–f) and para-
substituted (3g–h) benzyl diselenides with either electron-
withdrawing or electron-donating substituents were suitable
substrates for this transformation. In most cases, the reaction
was furnished in 10 minutes, yielding the product 3b–h in good
to excellent amounts (72–94%). Furthermore, hyper-substituted
selenyls (3i–k) were introduced efficiently within 30 minutes.
With respect to the challenging methyl diselenide 2l, we were
able to obtain the 2-methylselenyl tryptophanate 3l in 79% yield
in 15 minutes. A longer alkyl chain was also tolerated (3m).
Additionally, various aryl diselenides 2n–u were very suitable
for this process, giving the desired products 3n–t in good to
Scheme 1 Traditional (a and b) and currently developed (c) strategies for
2-selenylation of tryptophan.
Table 1 Optimization process for the 2-selenylation of tryptophan 1a
with diselenide 2a under iodide catalysisa
Entry
[I]
[Ox]
Solvent
Rxn time
Yieldb (%)
1c
TBAI
TBAI
TBAI
TBAI
TBAI
NaI
H2O2d
H2O2d
H2O2d
H2O2
CH3CN
THF
MeOH
DMF
CH3CN
CH3CNh
CH3CNh
MeOH
H2O
24 h
24 h
24 h
24 h
1 h
1 h
1 h
15 min
1 h
20 min
20 min
8 min
31
6
d
2ce
3ce
4ce
5g
21
N. R.f
43
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
6
55
49
31
N. D.
69
7
KI
8g
TBAI
TBAI
TBAI
TBAI
TBAI
9g
10g
11g
12gi
DMF
DMSO
DMSO
85
94
a
General conditions: all the reactions were conducted with L-methyl
acetyl tryptophanate 1a (0.1 mmol, 26.0 mg), dibenzyldiselenide 2a
(0.1 mmol, 34.0 mg), catalyst (5 mol%) and oxidant (1.0 equiv.)
b
in selected solvent (1 mL) at room temperature. Isolated yields.
c
10 mol% of TBAI was used. d An aqueous solution of H2O2 (35%, m/m)
was used. e 2 equiv. of H2O2 was used. No reaction. g Solvent: 0.55 mL.
f
h Solvent: CH3CN (0.5 mL) + H2O (0.05 mL). i Quenched by saturated
Na2S2O3 solution before purification.
the use of oxone as the oxidant afforded 3a in 50% yield within
just one hour (entry 5). This result encouraged us to optimize
the process under the promotion of this oxidant. In this regard,
other iodide sources showed comparable catalytic activities
(entries 6 and 7, see the ESI,† for details), while the solvent
was proven to play an important role in this process (entries
8–11, see the ESI,† for details). The highly polar and water
miscible organic liquids DMF and DMSO were identified as
efficient solvents for this reaction, affording the product 3a in
69% and 85% yields, respectively. In both cases, the product 3a
was generated within 20 minutes. Interestingly, the yield would be
optimized to 94% when quenching the reaction after 8 minutes
Scheme 2 C-2 Selenylation of methyl acetyl tryptophanate 1a with
various diselenides. aUnless noted otherwise, all the reactions were con-
ducted with racemic methyl acetyl-tryptophanate (Æ)-1a (0.1 mmol,
26.0 mg), diselenide (0.1 mmol), TBAI (5 mol%, 0.85 mg), and oxone
(0.1 mmol, 61.5 mg) in DMSO (0.55 mL). Isolated yields were given.
b
L-methyl acetyl-tryptophanate 1a was used as the substrate.
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excellent yields (up to 89%). One exception was mesityl sub-
stituent 2u, which reacted slowly due to the steric hindrance.
Thus, the mild conditions have enabled us to introduce versa-
tile selenyl functionalities with the preservation of the parent
tryptophan, as demonstrated from the single crystal structure
analysis of the product 3j.
To prove the suitability for other tryptophan derivatives,
various substituted tryptophan derivatives 1b–i were chosen
for this coupling (Scheme 3). The direct introduction of the
benzylselenyl functionality was very efficient and overcame the
electron-donating/withdrawing substituents on the indole ring,
furnishing the designated products 4a–f in good to excellent
yields (67–98%). It also allowed the selective preparation of
2-selenyl tryptophanates with CF3CO (1h) and Fmoc (1i) Trp-
substrates. N-protected derivatives in the products 4g–h
remained untouched under the reaction conditions, indicating
that this method could be used directly in a solid-phase peptide
synthesis.9
Scheme 4 Gram-scale synthesis of the product 3a (a) and the cyclization
of product 3d (b).
The gram-scale synthesis was also demonstrated (Scheme 4a).
Product 3a could be prepared in an excellent yield (89%) with
only 1 mol% of a TBAI catalyst in 15 minutes. Besides, the
application of this method further proved that it could easily
generate the 2H-[1,3]selenazino[3,2-a]indole derivative 5 via an
intramolecular CuI-catalyzed N-arylation10 (Scheme 4b). Both of
these are great advantages in contrast to other methods that
have been reported previously. And also, for the first time, we
have developed the highly efficient synthesis of an unprece-
dented indole-based [1,3]selenazinan compound. Overall, the
advantages of this newly developed method include operational
simplicity, high kinetics, cost-effectiveness of the transforma-
tion, and good functional group compatibility for the synthesis
Scheme 5 Preliminary mechanism studies for this C-2 selenylation. a2
equiv. of n-Bu4OH was used. b2 equiv. of KHSO4 was used.
of 2-selenyl tryptophan products, as well as the highly efficient observed (Scheme 5b). While elemental iodine I2 promoted
preparation of cyclic selenyl molecules.
the coupling in an inferior efficiency (61%), no product was
Finally, the mechanism responsible for the efficient seleny- formed under TBAI3, NaIO3 or NaIO4. It has been proposed that
lation was preliminary investigated (Scheme 5). Comparable TBAI3 is in an equilibrium with I2 and TBAI in CH3CN,11
yields of the product 3a were observed when radical quencher however, its incapability in promoting this reaction, as well as
TEMPO or BHT was used as the additive (Scheme 5a), demon- the performance with hypervalent iodines, suggested that
strating that the selenylated product may be generated via iodine was one of the key intermediates in the catalytic
a radical-independent pathway. However, by changing the cycle.12 Interestingly, when the corresponding base of TBAI,
oxidant to other iodine species, a dramatic difference was tetrabutylammonium hydroxide, was used in the combination
of iodine, the coupling reaction was completely repressed,
indicating that an acidic environment was essential for this
reaction. Indeed, by adding KHSO4, the by-product generated
from oxone decomposition, a comparable yield of the product
3a was observed (76%). A re-examination of TBAI3 in the
presence of KHSO4 also showed the importance of an acid.
Although the exact mechanism behind these experiments is
not fully understood, we proposed that elemental iodine I2 was
first generated from peroxymonosulfate with the assistance of
acid (Scheme 6).13 It then reacted quickly with diselenide to
generate a highly electrophilic selenium cation intermediate
I,14 which was attacked by the nucleophile tryptophan to afford
the 2-selenyl product while releasing the selenenyl iodide II. We
speculated that I2 would be generated from acid-facilitated
oxidation of II with peroxymonosulfate and then finished the
Scheme 3 C-2 Selenylation of tryptophanates with dibenzyl diselenide.
3506 | Chem. Commun., 2021, 57, 3504–3507
catalytic cycle. We also prepared a selenenyl iodide II (RQPh)
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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by in situ condensation of diphenyldiselenide with iodine,
which was then reacted with tryptophanate 1a but only afforded
the product 3n in 28% yield. Although the significant decrease
of coupling efficiency did not rule out the possibility that
selenenyl iodide may be involved in the coupling, it clearly
indicated that it was not likely one of the key coupling partners
in this transformation (see the ESI,† for details).
In summary, we have developed a novel methodology for the
synthesis of valuable 2-selenylated tryptophan derivatives from
diselenide under the catalysis of iodide. In this method, no
additional metal15 was required and no precautions to water or
oxygen were needed. Diverse substitution patterns on the
diselenides or tryptophans were tolerated under the mild
conditions, which highlighted the synthetic potential of this
approach. In addition, this reaction represents an efficient and
rapid approach to access the title compounds in gram-scale and
thus avoids practical complications in the pharmaceutical
industry. Furthermore, a precise manipulation of the product
to afford 2H-[1,3]selenazino[3,2-a]indole compound increased
the value of this method. Further insightful studies will be
required, however, to fully elucidate the reaction mechanism.
Overall, this procedure benefits from mild reaction conditions
and will open up new areas in the preparation of selenyl
containing proteins.
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L. C. and L. L. conceived of the presented idea. Y. T. G. and
S. D. L. carried out the experiments. L. C. and L. L. wrote the
manuscript with input from all authors.
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