Application of the Ugi four-component condensation reaction for the synthesis of α,α- and α,β-dipeptides substituted with fluoroarylalkyl pendent groups

Article abstract of DOI:10.1039/b007455l

The application of the Ugi four-component condensation reaction for the synthesis of α,α- and α,β-dipeptides substituted with fluoroarylalkyl pendent groups was reported. The Ugi reaction using readily available fluorophenethyl amines was examined in the analysis. The method was applicable to the peptides containing a variety of amino acids attached to a diverse series of fluoroarylalkyl groups.

Full text of DOI:10.1039/b007455l

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Application of the Ugi four-component condensation reaction for
the synthesis of ꢀ,ꢀ- and ꢀ,ꢁ-dipeptides substituted with
fluoroarylalkyl pendent groups†
1
Norio Shibata, Biplab Kumar Das and Yoshio Takeuchi*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University,
Sugitani 2630, Toyama 930-0194, Japan. E-mail: takeuchi@ms.toyama-mpu.ac.jp
Received (in Cambridge, UK) 13th September 2000, Accepted 15th November 2000
First published as an Advance Article on the web 30th November 2000
Table 1 Synthesis of N-fluorophenethyl appended α,α-dipeptides 2
We report a single step synthesis based on the Ugi four-
component condensation of previously unknown ꢀ,ꢀ- and
ꢀ,ꢁ-dipeptides, 2 and 8, having fluoroaromatic groups
appended to the nitrogen atom.
Difluorotoluene nucleoside 1 has been developed as a nonpolar
shape mimic for natural thymidine and it has been intensively
used as a probe of the biological noncovalent interactions of
oligonucleotides.1 Unexpectedly, 1 serves as a template for
DNA synthesis even though it lacks standard polar hydrogen
bonding. These reports prompted our interest in the synthesis
of dipeptides 2 having a difluorotoluene group appended to
the nitrogen atom. In this paper, we describe a single step
synthesis of previously unknown dipeptides 2, substituted with
fluoroarylalkyl pendent groups using the Ugi four-component
condensation.
Entry
Amine 3
R
Product 2
Yield (%)a
1
2
3
4
3a
3b
3c
3d
p-Fluorophenyl
2,4-Difluorophenyl
Pentafluorophenyl
2,4-Difluoro-5-
methylphenyl
2a
2b
2c
2d
42
50
45
43
a Yields were based on the amines 3 employed.
Scheme 1 Reagents and conditions: i, Mg, DMF, THF, 0 ЊC, 45%;
ii, MeNO2, KOH–MeOH, 53%; iii, MsCl, Et3N, CH2Cl2, 61%;
iv, LiAlH4, THF–Et2O, reflux, 63%.
are incorporated into peptides. For example, the incorporation
of a fluoroaryl moiety could be expected to confer significant
changes on the secondary structure of the peptides due to the
strong stacking effects of the aromatic rings,5 now functioning
as nucleobase surrogates. Moreover, the introduction of a
fluorine atom into amino acids and peptides,6 in general, should
induce interesting new chemical and physiological properties.7
The preparation of the target compound 2 undoubtedly
could be accomplished by conventional peptide synthesis pro-
cedures. However, this would require multi-step syntheses. The
Ugi four-component coupling reaction has recently been shown
to be a powerful method for the synthesis of amino acids,
peptides and nucleobase–peptide chimeras.8,9 We applied this
method for the preparation of our dipeptides substituted with
fluorophenethyl pendent groups. We first examined the Ugi
reaction using readily available fluorophenethyl amines 3a–c.‡
N-Z-Glycine (4) was stirred with 3a–c, acetone and tert-butyl
isocyanide in methanol in the presence of molecular sieves 3 Å
at Ϫ78 ЊC for 2 h. Then the reaction mixture was allowed
to warm to room temperature over 1 h and stirred for 1 week.
The solvent was removed and the mixture was purified by silica-
gel column chromatography to furnish 2a–c in 42–50% yield
(Table 1, entry 1–3). We then performed the Ugi reaction using
In recent years the synthesis of heterocyclic substituted non-
proteinogenic amino acids,2 especially those amino acids with
nucleobases on the side chains,3 has received much attention.
This synthetic activity stems from the biological activity of such
analogues, their use as probes to study amino acid–nucleobase
interactions, and their utility as polyamide or peptidic nucleic
acids.4 Thus amino acids containing 2,4-difluorotoluene or
other fluoroaryl moieties may produce special effects when they
† Experimental procedures and data for characterization of new
compounds 2 and 8 (1H NMR and HPLC spectra) are available as
supplementary data. For direct electronic access see http://www.rsc.org/
suppdata/p1/b0/b007455l/
4234
J. Chem. Soc., Perkin Trans. 1, 2000, 4234–4236
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b007455l

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the amine 3d with a difluorotoluene moiety as a steric mimic for
thymine. The amine 3d was prepared from 5-bromo-2,4-
difluorotoluene (5) in 4 steps via formylation, nitroaldol
reaction, dehydration, and reduction in good yield (Scheme 1).
The Ugi reaction of 3d with 4, acetone and tert-butyl
isocyanide gave the target α,α-dipeptide 2d in 43% yield
(Table 1, entry 4).
We next focused our attention on the synthesis of fluoro-
arylmethyl appended α,β-dipeptides 8. This is designed based
on the structure of 2Ј,5Ј-linked isoDNA 9.10 The constituent
elements of 8 are an α-amino acid, a β-homoamino acid and a
fluoroarylmethyl unit. This arrangement was chosen because a
seven atom spacing can be found between the nucleobases in 9,
1-Isocyanocyclohexene (13) is quite useful for the Ugi
reaction because the cyclohexenamide moiety in the product
can be converted to a variety of functional groups.11 We
then used 13 in our Ugi reaction to obtain free dipeptides.
N-Boc-Glycine (14) was treated with 13, 3b, and acetone
in methanol to furnish corresponding α,α-dipeptide 2e, which
was deprotected readily by 3 M HCl in THF to give the free
dipeptide 2f in excellent yield. N-Boc-β-Homoalanine (15) was
also coupled with 13, 11b and acetone followed by hydrolysis to
give free α,β-dipeptide 8f (Scheme 3).
Scheme 3 Reagents and conditions: i, 3b, acetone, MeOH, MS 3 Å,
Ϫ78 ЊC, then rt, 45%; ii, 3 M HCl, THF, 100%; iii, 11b, acetone, MeOH,
MS 3 Å, Ϫ78 ЊC, then rt, 43%; iv, 3 M HCl, THF, 98%.
In summary, we have demonstrated single step syntheses of
α,α- and α,β-dipeptides having fluoroaromatic groups appended
to the nitrogen atom as isosteric replacements for thymine.
Of particular note regarding our method is its applicability to
those peptides containing a variety of amino acids (not only
α- and β-, but also γ-amino acids) attached to a diverse series
of fluoroarylalkyl groups. Incorporation of 2 and 8 into oligo-
peptides is now under investigation.
and because the optimal number of bonds between the nucleo-
bases and the backbone was found to be one.
The target α,β-dipeptides 8 were also synthesized in the same
manner. The Ugi condensation of the four components, N-Z-β-
homoalanine (10), fluorobenzylamine derivatives 11a–d,
acetone, and tert-butyl isocyanide, successfully produced
the dipeptides 8a–d in a single step in moderate yields. The
results are summarized in Table 2. The starting amines 11a–c
are readily available and 11d was prepared from 5 in two steps
(Scheme 2).
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan. N. S. wishes to thank the Kato
Memorial Bioscience Foundation for support.
Table 2 Synthesis of N-fluorobenzyl appended α,β-dipeptides 8
Notes and references
‡ Typical experimental procedure: the amine 3a (200 mg, 1.52 mmol)
and acetone (176 mg, 3.04 mmol) were dissolved in distilled methanol
in a flask containing 3 Å molecular sieves. The mixture was allowed
to stir for 1 h and then 4 (635 mg, 3.04 mmol) was added directly into
the flask in one portion. A solution of tert-butyl isocyanide (252 mg,
3.04 mmol) in methanol was added to the flask at Ϫ78 ЊC in one
portion. The resulting solution was allowed to stir at room temperature
for a week. When the reaction was complete by TLC (5–10% MeOH in
CH2Cl2), the reaction mixture was filtered and the solvent was removed
in vacuo. The residue was chromatographed on silica gel to give 2a
(301 mg, 42%) as colourless solid.
Entry
Amine 11
R
Product 8
Yield (%)a
1
2
3
4
11a
11b
11c
11d
p-Fluorophenyl
2,4-Difluorophenyl
Pentafluorophenyl
2,4-Difluoro-5-
methylphenyl
8a
8b
8c
8d
59
66
43
42
a Yields were based on the amines 11 employed.
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ii, BH3–THF complex, THF, reflux, 2.6 M HCl, reflux, 67%.
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