Conjugation and cyclization-two strong driving forces leading to the formation of new chromophores

Article abstract of DOI:10.1016/j.tetlet.2009.02.080

Novel chromophores formed in the solvent reactions of α-amino acids and small peptides were identified by crystal structure analysis and characterized by UV absorption. The formation of these chromophores in basic solutions was attributed to two strong dr

Full text of DOI:10.1016/j.tetlet.2009.02.080

Tetrahedron Letters 50 (2009) 3741–3745
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conjugation and cyclization—two strong driving forces leading
to the formation of new chromophores
*
Darryl D. DesMarteau , Changqing Lu, Don Vanderveer
Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel chromophores formed in the solvent reactions of a-amino acids and small peptides were identified
by crystal structure analysis and characterized by UV absorption. The formation of these chromophores in
basic solutions was attributed to two strong driving forces—conjugation and cyclization. The discussion
Received 13 December 2008
Revised 10 February 2009
Accepted 11 February 2009
Available online 15 February 2009
of possible reaction pathways could benefit the future design of
a
-amino acid-based chromophores.
Published by Elsevier Ltd.
Keywords:
Chromophores
Conjugation
Cyclization
a-Amino acids
In our early research on the trifluoroethylation of
a
-amino acids
To characterize the newly formed chromophore in compound
1(R,S), UV spectra were obtained. The two starting -amino acid
and small peptides, it was found that the trifluoroethylated N-ter-
mini of linear dipeptides retained sufficient nucleophilicity to un-
dergo intramolecular cyclization reactions to form cyclic
dipeptides (2,5-diketopiperazines, DKPs).1 This stimulated us to
explore the possibility of building N-trifluoroethylated linear pep-
a
derivatives (in acid form) were also subjected to UV measurement
under the same conditions, as shown in Figure 3. The newly formed
chromophore in compound 1(R,S) has a kmax = 265 nm and a molar
extinction coefficient
e
max = 3.46 Â 104.
tide bonds, for example, by deprotonating the trifluoroethylated
a-
The proposed rationale for the formation of compound 1 is
shown in Scheme 2. Solvent CH3CN was deprotonated by NaH.
The methylene cyanide attacked the carbonyl carbon of phenylal-
anine methyl ester to replace the methoxy moiety. Racemization
amino proton and using amino acid fluorides for the coupling reac-
a
tions.2 Further, by converting N -protected amino acids into the
corresponding acid chlorides, we were eventually able to construct
the N-1H,1H-perfluoroalkylated linear peptide bonds.3
at the a-carbon of (L)phenylalanine could occur at this stage. The
In the modification of N-1H,1H-perfluoroalkylated
a
-amino
racemic intermediate then underwent an intramolecular cycliza-
tion reaction to form a new five-membered ring intermediate. This
cyclic intermediate was deprotonated at the methylene carbon of
acids and small peptides, several compounds that resulted from
solvent reactions attracted our attention due to their unique struc-
tures. In the first example shown in Scheme 1, we attempted to re-
the ring resulting in the formation of a conjugated system contain-
a
a
place the methoxy moiety of the N -pentafluoropropylated
ing 8p
electrons. Subsequent reaction with N -phthaloyl glycine
(
L
)phenylalanine methyl ester with methylene cyanide –CH2CN
acid chloride converted the anionic intermediate into a neutral
species. Through an intramolecular proton shift, the zwitterionic
compound 1(R,S) containing 10 conjugated p electrons was
formed in situ by deprotonating the solvent acetonitrile.4 Follow-
a
ing the reaction with the N -phthaloyl-protected glycine acid chlo-
ride, the compound 1(R,S) bearing a unique chromophore was
obtained.5,9 The crystal structure of 1(R) is shown in Figure 1.
Compound 1(R,S) contains a five-membered ring. Four of the
formed.
The second example of the formation of new chromophores
from solvent reactions is shown in Scheme 3. In order to study
the N/O selectivity toward the trifluoroethylating agent
CF3CH2I(C6H5)N(SO2CF3)2, deprotonation by NaH was expected to
occur at the nitrogen of the secondary amide moiety of the starting
cyclic dipeptide. However, when the deprotonation was carried out
in DMF, both compound 2(R,S) and compound 3(R,S) were
formed.10–12
five ring atoms are in a planar conjugated system containing 10
electrons, as shown in Figure 2.
p
* Corresponding author. Tel.: +1 864 656 1251; fax: +1 864 656 2545.
E-mail address: fluorin@clemson.edu (D.D. DesMarteau).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.080

3742
D. D. DesMarteau et al. / Tetrahedron Letters 50 (2009) 3741–3745
O
H
O
O
H
N
O
N
N CH CF CF
3
H
2
2
N
MeO
Cl
O
N CH CF CF
2
2
3
N / NaH
CH C
O
O
3
O
H
60 oC, 16 h
reflux, 16 h
1 (R,S)
Scheme 1. The formation of compound 1(R,S) (24%) bearing a unique chromophore.
5
4
O
H
O
H
N
N
O
N
CH CF CF
2
2
3
O
0.10 mM
H
1 (R,S)
3
2
1
0
N
H
CH CF CF
2
2
3
HO
O
O
O
1.00 mM
1.00 mM
N
OH
O
200
225
250
275
300
325
350
375
400
Wavelength (nm)
Figure 1. The crystal structure of compound 1(R).
Figure 3. The solvent-subtracted UV absorption in EtOH of compound 1(R,S) and
the corresponding starting -amino acid derivatives (acid form).
a
H
O
H
N
dered ring methylene carbon first led to the irreversible C–C bond
formation with solvent DMF to give the aldehyde intermediate.
The conversion of the aldehyde intermediate into the alkoxide
intermediate could occur via one of two pathways: (a) hydride act-
ing as a nucleophile to attack the carbonyl carbon of the alde-
N
O
hyde;13–18 or (b) homolytic cleavage of the carbonyl
p bond,
Figure 2. The novel chromophore of compound 1(R,S).
followed by (b1) a single electron transfer (SET) from hydride an-
ion to the carbonyl oxygen radical and (b2) combination of the
resulting H radical and carbonyl C radical to form the alkoxide
intermediate.19–24 The elimination of NaOH from the alkoxide
intermediate gave compound 2(R,S). The elimination of HF by
NaH from the CF3CH2– moiety further extended the conjugated
system. The irreversible C–C bond formation with solvent DMF in
The crystal structures of compound 2(S) and compound 3(R) are
shown in Figure 4.
Compound 2(R,S) contains a conjugated system with 10p elec-
trons; while compound 3(R,S) has a conjugated system with 14
p
electrons, as shown in Figure 5.
the presence of NaH at the more sterically hindered a-carbon of
To characterize the newly formed chromophores in both com-
pound 2(R,S) and compound 3(R,S), the UV measurements were
carried out, as shown in Figure 6. The UV of the starting cyclic
dipeptide was measured under the same conditions.
phenylalanine, followed by the conversion of aldehyde into alkox-
ide intermediate, provided a nucleophile. Intramolecular attack by
alkoxide nucleophile on the difluoroenamine
p bond and elimina-
tion of NaF resulted in a fused ring system, that is, compound
From Figure 6, it is clear that increasing the number of
p
elec-
3(R,S). Racemization at the
a-carbon of the phenylalanine could oc-
trons shifts the absorption wavelength toward the visible region
(red shift).
cur in the first step.
In summary, the solvent CH3CN or DMF reacted with an
a-ami-
The proposed rationale for the formation of compounds 2 and 3
is shown in Scheme 4. In the starting cyclic dipeptide N -
no acid or a small peptide in the presence of NaH to form novel
chromophores. The formation of these chromophores in basic solu-
tions was attributed to two strong driving forces—conjugation and
cyclization.
a
CF3CH2(L)PheGly, three types of ring protons could be abstracted
by NaH. However, only proton abstraction at the less sterically hin-

D. D. DesMarteau et al. / Tetrahedron Letters 50 (2009) 3741–3745
3743
N
H
H
H
CH C N NaH
3
H N CH CF CF
3
2
2
O
MeO
N CH CF CF
2
2
3
Na CH C N
2
Na CH C N
2
O
H
reflux
Na
H
N
H
N
O
Na
H
H
O
O
N
N CH CF CF
2
2
3
N CH CF CF
2 2 3
Cl
O
O
O
H
H
O
O
H
O
H
H
H
N
N
N
N
O
O
N CH CF CF
N CH CF CF
2 2 3
2
2
3
O
O
H
H
1 (R,S)
Scheme 2. The proposed rationale for the formation of compound 1(R,S).
O
O
O
O
O
O
H
H
H
F
CF CH
F
F
3
2
N
N
N
H
NH
O
NH
F
NH
DMF / NaH
70 oC, 16 h
H
H
3 (R,S)
2 (R,S)
a
Scheme 3. The transformation of cyclic dipeptide N -CF3CH2(L)PheGly into compound 2(R,S) (39%) and compound 3(R,S) (46%) bearing novel chromophores.
Figure 4. The crystal structures of compound 2(S) (left) and compound 3(R) (right).

3744
D. D. DesMarteau et al. / Tetrahedron Letters 50 (2009) 3741–3745
4
O
O
O
1.00 mM
CF CH
O
O
H
3
2
N
N
H
N
NH
3
2
1
0
NH
O
O
O
NH
H
H
H
F
F
N
O
F
NH
O
O
H
F
Figure 5. The chromophores of compound 2(R,S) (left) and compound 3(R,S) (right).
N
O
NH
2 (R, S)
0.10 mM
0.10 mM
3 (R, S)
200
230
260
290
320
350
380
Wavelength (nm)
Figure 6. The solvent-subtracted UV absorption in EtOH of compound 2(R,S) and
compound 3(R,S) along with the starting cyclic dipeptide.
O
O
O
O
O
O
Na
H
H
CF CH
3
2
O
CF CH
H
CF CH
3 2
N
3
2
H
NH
N
H
N
H
H
H
N(CH )
3 2
NH
NaH
NH
(b)
H
O
(a)
NaH
O
O
Na
O
O
O
O
ONa
H
H
H
CF CH
CF CH
3
2
3
2
CF CH
H
N
H
N
H
H
3
2
N
H
H
NH
NH
(b1) SET
NaH
(b2)
NH
H
H
O
NaOH
O
O
O
O
H
H
O
F
F
O
F
F
F
F
N
N
N
F
NH
NH
H
N(CH )
O
NH
(a) or (b)
NaH
2NaH
3 2
H
Na
O
H
O
2 (R,S)
O
O
O
F
F
N
F
N
O
NH
NaO
H
NH
NaF
H
O
3 (R,S)
Scheme 4. The proposed rationale for the formation of compound 2(R,S) and compound 3(R,S).

D. D. DesMarteau et al. / Tetrahedron Letters 50 (2009) 3741–3745
10. Preparation of 2(R,S) and 3(R,S): Cyclic dipeptide N -CF3CH2(
3745
a
L
)PheGly1 (1.002 g,
Acknowledgment
3.50 mmol) was dissolved in 10 mL of dry DMF. NaH (95%, 0.575 mg,
22.7 mmol) was wetted with 30 mL of dry DMF. The cyclic dipeptide N -
a
Financial support of this research by the National Science Foun-
dation is gratefully acknowledged.
CF3CH2(L)PheGly solution was transferred into the NaH suspension in DMF. The
reaction mixture was heated at 70 °C for 16 h. The solvent was evaporated. The
resulting residue was partitioned between ethyl acetate and H2O. The organic
layer was separated and the solvent was evaporated. After column
chromatography with 10–40% acetone in hexanes as eluent, 2(R,S) (0.408 g,
1.37 mmol, 39.1%) and 3(R,S) (0.468 g, 1.62 mmol, 46.3%) were obtained.
Supplementary data
11. Spectral data of 2(R,S): 19F NMR (282.78 MHz, acetone-d6): d À69.51 (3F, t). 1
H
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.080.
NMR (300.53 MHz, acetone-d6): d 3.13–3.41 (2H, dd), 3.85–3.99 (1H, m), 4.50–
4.53 (1H, m), 4.53 (1H, s), 4.83–4.98 (1H, m), 4.96 (1H, s), 7.05–7.26 (5H, m).
Crystallographic description of 2(R,S): Crystal dimensions (mm):
0.31 Â 0.19 Â 0.17. C14H13F3N2O2, Mr = 298.26. T = 153(2) K. Orthorhombic,
space group P2(1)2(1)2(1); a = 8.0516(16) Å, b = 14.837(3) Å, c = 23.102(5) Å;
References and notes
V = 2759.9(10) Å3; Z = 8; Dcalc = 1.436 g/cm3;
l
= 0.124 mmÀ1; F(0 0 0) = 1232;
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R
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r
R1 = 0.0477, wR2 = 0.1185,
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H
5. Preparation of 1(R,S): N -CF3CF2CH2(
L
dissolved in 10 mL of dry CH3CN. NaH (95%, 0.197 g, 7.80 mmol) was wetted
NMR (300.53 MHz, acetone-d6): d 3.05–3.29 (2H, dd), 4.39–4.74 (2H, dd), 4.44–
4.87 (2H, d), 6.62 (1H, s), 6.99–7.26 (5H, m). Crystallographic description of
3(R,S): Crystal dimensions (mm): 0.48 Â 0.24 Â 0.12. C15H13FN2O3,
a
with 15 mL of dry CH3CN. The N -CF3CF2CH2(L)PheOMe solution was
transferred into NaH/CH3CN suspension. The reaction mixture was heated at
a
60 °C for 16 h. N -PhthGlyCl (0.805 g, 3.60 mmol)7,8 was dissolved in 10 mL of
ꢀ
Mr = 288.27. T = 153(2) K. Triclinic, space group P1; a = 10.599(2) Å,
a
dry CH3CN. The obtained solution was transferred into N -
b = 11.296(2) Å, c = 18.369(4) Å;
V = 2019.1(7) Å3; Z = 6; Dcalc = 1.422 g/cm3;
Reflections collected/unique = 13,994/7006 [R(int) = 0.0415]; refinement
method = full-matrix least-squares on F2; final
indices [I > 2(I)]
a
= 100.47(3)°, b = 96.53(3)°,
c
= 108.27(3)°;
l
= 0.110 mmÀ1
; F(0 0 0) = 900;
CF3CF2CH2(L)PheOMe/NaH/CH3CN solution. The reaction mixture was
refluxed for 16 h. The solvent was then evaporated. The resulting residue
was partitioned between ethyl acetate and H2O. The organic layer was
separated and the solvent was evaporated. After column chromatography
with 10–50% acetone in hexanes as eluent, 1(R,S) was obtained (0.365 g,
0.719 mmol, 24.0%).
R
r
R1 = 0.0749, wR2 = 0.1903,
R indices (all data) R1 = 0.1017, wR2 = 0.2204;
goodness-of-fit on F2 = 1.094; CCDC 679116.
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9. Spectral data of 1(R,S): 19F NMR (282.78 MHz, acetone-d6): d À83.74 (3F, s),
À118.2 to À118.4 (2F, octet). 1H NMR (300.53 MHz, acetone-d6): d 3.16–3.44
(2H, m), 4.16–4.32 (1H, m), 4.25 (1H, dd), 4.58–4.74 (1H, m), 4.72–4.90 (2H, q),
7.18–7.38 (5H, m), 7.67 (1H, br s), 7.83–7.89 (4H, m), 8.67 (1H, br s). MS (ESI),
MH+, found 508.1122, C24H19F5N3O4 requires 508.1295. Crystallographic
description of 1(R,S): Crystal dimensions (mm): 0.65 Â 0.12 Â 0.10.
C24H18F5N3O4, Mr = 507.42. T = 153(2) K. Monoclinic, space group P2(1)/c;
a = 7.2146(14) Å,
V = 2580.6(9) Å3; Z = 4; Dcalc = 1.455 g/cm3;
Reflections collected/unique = 19,164/4508 [R(int) = 0.0655]; refinement
method = full-matrix least-squares on F2; final
indices [I > 2(I)]
R1 = 0.0679, wR2 = 0.1698, indices (all data) R1 = 0.0892, wR2 = 0.1922;
goodness-of-fit on F2 = 1.096; CCDC 679117.
b = 14.240(3) Å,
c = 25.340(5) Å;
l
b = 97.58(3)°;
= 0.125 mmÀ1; F(0 0 0) = 1168;
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R
r
R