Synthesis of highly substituted imidazolidine-2,4-dione (Hydantoin) through Tf2O-mediated dual activation of Boc-protected dipeptidyl compounds

Article abstract of DOI:10.1021/ol502900j

Highly substituted chiral hydantoins were readily synthesized from simple dipeptides in a single step under mild conditions. This reaction proceeded through the dual activation of an amide and a tert-butyloxycarbonyl (Boc) protecting group by Tf₂O-pyridine. This method was successfully applied in the preparation of a variety of biologically active compounds, including drug analogs and natural products.

Full text of DOI:10.1021/ol502900j

Letter
pubs.acs.org/OrgLett
Synthesis of Highly Substituted Imidazolidine-2,4-dione (Hydantoin)
through Tf2O‑Mediated Dual Activation of Boc-Protected Dipeptidyl
Compounds
Hui Liu, Zhimin Yang, and Zhengying Pan*
Laboratory of Chemical Genomics, Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Shenzhen
Graduate School of Peking University, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: Highly substituted chiral hydantoins were
readily synthesized from simple dipeptides in a single step
under mild conditions. This reaction proceeded through the
dual activation of an amide and a tert-butyloxycarbonyl (Boc)
protecting group by Tf2O-pyridine. This method was successfully applied in the preparation of a variety of biologically active
compounds, including drug analogs and natural products.
ydantoin (imidazolidine-2,4-dione) is a privileged scaffold
generally involve harsh conditions and/or toxic reagents. Recent
developments for the synthesis of substituted nonchiral
hydantoins include transition-metal catalyzed reactions,10 the
Ugi condensation,11 reactions of activated carboxylic acids,12 and
an aminobarbituric acid−hydantoin rearrangement.13 The
synthesis of enantiopure hydantoins can be performed both in
the solid14 and solution15 phases from enantiopure α-amino
amides or α-amino esters with phosgene (or CDI) and
isocyanates, respectively. The use of isocyanates as a preactivated
reactant limited its applicability because they are not always
commercially available, especially chiral isocyanates, whose
preparation and handling can be problematic. Moreover, these
strategies are multistep procedures that require an additional
deprotection step.
H
of azaheterocycle found in a variety of biologically active
compounds, such as drugs and natural products (Figure 1).1 For
Inspired by elegant studies on the electrophilic activation of
amides for synthesizing diverse heterocycles,16 we reasoned that
amide activation in peptides, coupled with an intramolecular
reaction involving neighboring groups, could provide rapid
access to azaheterocycles bearing stereogenic center(s). Herein,
we demonstrate a single-step synthesis of highly substituted
chiral hydantoins from simple and unactivated substrates under
mild conditions. This reaction proceeded through the dual
activation of an amide and a tert-butyloxycarbonyl (Boc)
protecting group by trifluoromethanesulfonic anhydride17
(Tf2O) and pyridine without the additional step of Boc
deprotection.
Figure 1. Substituted hydantoins with various biological activities.
example, phenytoin sodium and ethotoin are marketed as
anticonvulsant drugs;2 nilutamide3 is an androgen receptor
antagonist for the treatment of advanced prostate cancer; BMS-
564929 is an orally active and selective androgen receptor
modulator;4 and parazoanthines (A and D)5 are chiral hydantoin
alkaloids isolated from the Mediterranean Sea anemone
Parazoanthus axinellae.
Our initial studies were performed on a simple dipeptide N-
Boc-L-Ala-L-Phe-OMe (1a). As probed by the reaction
conditions depicted in Table 1, the choice of base was found
to be crucial for obtaining the desired hydantoins. The previously
reported Tf2O/2-chloropyridine system in the electrophilic
activation of amides16,18 was not suitable for this reaction.
Although this system proceeded surprisingly fast (1a was fully
consumed within 30 min, even at −78 °C, as indicated by TLC
Substituted hydantoins are also valuable intermediates for the
synthesis of enantiomerically pure amino acids6 through dynamic
kinetic resolution. Moreover, chiral hydantoins are of consid-
erable interest in organic synthesis because of their synthetic
utility as intermediates, chiral auxiliaries,7 and metal ligands8 in
asymmetric catalysts.
Many methods have been reported in the literature1 for the
synthesis of substituted hydantoins. The classical approaches9
include the Urech method involving amino acid derivatives, the
Bucherer−Bergs multicomponent reaction,9a and the condensa-
tion of urea with dicarbonyl compounds.9b,c These reactions
Received: October 1, 2014
Published: October 30, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Synthesis of 3,5-Disubstituted or 3,5,5′-
a
Trisubstituted Chiral Hydantoins from Dipeptides
b
c
entry Tf2O
base
equiv
solvent
t (h) yield (%)
d
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
2-Cl-pyridine
2-Cl-pyridine
pyridine
1.3
4.0
1.4
2.5
2.5
3.0
3.0
3.0
DCM
0.5
2
13
DCM
42
CH3CN
CH3CN
DCM
4
59
pyridine
10
20 (71)
51 (30)
85
pyridine
10
2
d
pyridine
DCM
pyridine
DCM
2
86
2,6-lutidine
DCM
2
46 (44)
a
Conditions: 1 (0.25 mmol) in solvent (2.5 mL), base, then Tf2O, 4
b
c
°C, 5 min, then 25 °C. Isolated yield. Yields of recovered starting
material are in parentheses. Reaction temperature from −78 to 25 °C.
d
analysis), it only gave a 13% yield (entry 1). The major side
product was a Boc-deprotected free amine, which was easily
transformed to its diketopiperidine (DKP) counterpart through
intramolecular acyl transfer. This side reaction could be partially
mitigated by using excess 2-chloropyridine to obtain a higher
yield of the desired product (42%, entry 2).
a
Conditions: 1 (1 equiv), Tf2O (1.5 equiv), Py. (3.0 equiv), CH2Cl2
b
c
(0.1 M), 4 to 25 °C. Isolated yields are in parentheses. Tf2O (2.0
equiv), Py. (4.0 equiv), 4 h. 69% yield based on recovered starting
Using pyridine as the base in acetonitrile resulted in an even
higher yield (59%, entry 3). However, increasing the equivalent
of pyridine appeared to impede the reaction, affording the
desired product in just a 20% yield with 71% recovered starting
material, even by extending the reaction time to 10 h (entry 4). It
is interesting to note that the aforementioned side reaction was
virtually completely prevented and no DKP product was isolated.
Dichloromethane (DCM) was determined to be a better solvent
than CH3CN (51% yields, entries 4−5). Additionally, it was
found that a lower reaction temperature gave nearly an identical
yield (85%, entry 6), despite the appearance of a significant
amount of precipitants in the process of this reaction. The best
reaction conditions were achieved in entry 7 (1.5 equiv of Tf2O,
3.0 equiv of pyridine, CH2Cl2), where complete conversion was
reached within 2 h with an 86% isolated yield. Notably, warming
the reaction mixture to 25 °C after the addition of Tf2O at 4 °C is
necessary for complete consumption of the starting material.
Otherwise, a significant amount of 1a could be recovered when
the reaction temperature was kept below 20 °C. Finally, in
contrast to pyridine, neither 2,6-lutidine nor triethylamine was
effective in facilitating this reaction, leading to incomplete
conversion under otherwise identical reaction conditions.19
With the optimized reaction conditions in hand, we
investigated a variety of dipeptides, and the results are listed in
Scheme 1. The sequence and stereochemistry of peptides (2b,
2c) appear to have little influence on this process; several
substituted chiral hydantoins were isolated in good to excellent
yields. In all cases with at least two stereogenic centers,
hydantoins were formed as a single diastereomer, as determined
by 1H NMR, indicating that no racemization had occurred during
this process. Indeed, even using the highly epimerization-prone
L-phenylglycine derivative, satisfactory results were obtained
with a diastereomeric ratio >19:1 and an 80% yield (2d). The
literature known compound 2e could be efficiently prepared in
excellent yield (93%) with the specific rotation value [α]D27.7
−206.2 (c 0.5, acetone) that is in good agreement with the
literature reported value ([α]2D1.4 −207.8 (c 1.0, acetone)).15b
d
material.
This procedure is compatible with a range of common protecting
groups, such as methyl esters, acetyl (2f), and benzyl (2g)
protecting groups. The acid-sensitive tert-butyl ester (2c), tert-
butyl ether (2h), and silyl protecting groups (2i) could also
remain intact.
While glycine-derived dipeptides without α-substitution gave
lower yields (72−76%, 2f, 2j), a sterically congested substrate
could also undergo cyclization efficiently when a more activating
reagent and a longer reaction time were employed (2l). The
chemoselectivity can be achieved in the presence of a
carboxybenzyl (Cbz) protecting group, which survived under
these conditions (58% yield, 69% based on recovered starting
material, 2m).
The synthesis of 1,3,5-trisubstituted hydantoins proved to be
challenging, and the above conditions only afforded products in
Scheme 2. Synthesis of 1,3,5-Trisubstituted Hydantoins from
Peptides
a
a
Conditions: 3 (1 equiv), Tf2O (3.0 equiv), 2,6-lutidine (6.0 equiv),
b
c
CH3CN, 4 to 25 °C. Isolated yields are in parentheses. Tf2O (1.5
equiv), Py. (3.0 equiv), CH2Cl2, 4 to 25 °C.
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Letter
low yields. Reinvestigation of the reaction conditions revealed
that using CH3CN as the solvent was superior to CH2Cl2 for
these types of substrates. Using this approach, highly substituted
hydantoins were synthesized in good to high yields (4a−4c, 70−
84% yields, Scheme 2). These fused bicyclic (4b) and tricyclic
(4c) compounds with rigid scaffolds are important structural
motifs in many biologically active compounds.20 Notably, a six-
membered ring analog (5,6-dihydrouracil) could also be formed
from a β-amino acid derived dipeptide in a relatively lower yield
(4d, 53%).
Scheme 4. Control Experiments
Next, we turned our attention to nonpeptide substrates.
Different types of hydantoins were prepared by variation of the
R2 substituent of 5 (Scheme 3). A variety of N-alkyl (chain and
Scheme 3. Synthesis of 3,5-Disubstituted Hydantoins from
Nonpeptides
a
The thioamide 9 was hydrolyzed to its amide counterpart 10
when this reaction was performed under aqueous conditions or
quenched by water. We envisioned that this reaction might offer
an opportunity for stable-isotope 18O-labeling when it was
reacted with H218O. To our delight, the desired 18O-labeled
compound 11 was smoothly formed in 73% yield with 81% 18O-
labeling (90% labeling based on the purity of H218O).19 As
expected, the Cbz-protected amide compound 10 remained
intact with the Tf2O/pyridine system.22
A proposed reaction pathway that is consistent with the above
observations is depicted in Scheme 5. The amide bond is
Scheme 5. Plausible Reaction Pathway
a
Conditions: 5 (1 equiv), Tf2O (1.5 equiv), Py. (3.0 equiv), CH2Cl2
b
(0.1 M), 4 to 25 °C. Isolated yields are in parentheses.
activated by Tf2O directly or by Tf2O−pyridine adducts to afford
intermediate 13. Intramolecular cyclization of this intermediate,
followed by expulsion of the tert-butyl cation, would generate the
oxazolidinone23 product 15 (the isocyanate intermediate 16 is
also possible). The final step to give the hydantoin product 17
occurs possibly through a Mumm rearrangement.24 Attempts to
trap the reactive intermediate 15 or 16 by addition of an extra
nucleophile (e.g., benzylamine) failed. When using an 18O-
labeled amide as the substrate, the 18O-labeled HOTf was
observed by HRMS;19 thus, the possibility of single activation25
of a Boc-protected amine producing intermediate 16 could be
ruled out.
In summary, a new method of preparing highly substituted
hydantoins has been developed. Using this single-step protocol, a
variety of chiral hydantoins can be easily synthesized from readily
available substrates in good to high yields. In addition, a selective
procedure for stable-isotope 18O-labeling was presented, which
may have potential use in mechanistic studies of organic
reactions and mass spectrometry based proteomics.26
cyclic, 6a−6d), N-aryl (6e−6i), and N-vinyl (6j, 6k) amides
served as substrates, which easily produced the corresponding
hydantoin derivatives. The enantiomeric excess values of
representative products (6a, 6e, 6i) were determined to be
>98% by HPLC analysis with a chiral column.19 It merits
attention that ethotoin21 can be produced efficiently in a 60%
yield (6d) by using our method. When R2 is an aryl group, the
electron-donating group on the aromatic ring may facilitate this
process to give a higher yield (88%, 6f). It is also worth noting
that the 3-vinyl hydantoin derivative 6k could be considered an
analog of the natural products parazoanthines5 and may be useful
in their total synthesis.
To investigate the reaction mechanism, we performed several
control experiments, as indicated in Scheme 4. First, treatment of
the thioamide surrogate 7 with Hg salt produced the
corresponding hydantoin in an 80% yield. Mechanistically, the
activation of thioamide by Hg(OTf)2 is presumably the first step
of this reaction because of the high affinity of mercury and sulfur.
We note that no hydantoin was isolated when the Boc group was
changed to Cbz (compound 9) under identical reaction
conditions.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectra data, characterization data, and
copies of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: panzy@pkusz.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funding support from the 973 Program
(2013CB910700), the National Natural Science Foundation of
China (81373270), and the Shenzhen Science and Technology
Innovation Commission (ZDSYZ20130331145112855,
KQTD201103).
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