Synthesis of N-urethane protected α-aminoalkyl-α-cyanomethyl ketones; Application to the synthesis of 3-substituted 5-amino-1H-pyrazole tethered peptidomimetics

Article abstract of DOI:10.1055/s-0032-1316586

The preparation of N-protected amino/peptide α-cyanomethyl ketones through cyanation of the corresponding α-bromomethyl ketones is described. The utility of the resulting α-cyanomethyl ketones in the synthesis of 3-substituted-5-amino-1H-pyrazoles has also been demonstrated. In both steps a wide range of N-protected amino/peptide acids has been employed and the products are obtained in good yield. The enantiomeric purity of both the α-cyanomethyl ketones and pyrazoles were confirmed by chiral HPLC analysis of the corresponding Z-protected d- and l-Ala-OH as model substrates. The synthesis of peptide pyrazolecarboxamides is also delineated. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316586

LETTER
▌1913
lSetyternthesis of N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones;
Application to the Synthesis of 3-Substituted 5-Amino-1H-pyrazole Tethered
Peptidomimetics
N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones
M. K. Sharnabai, G. Nagendra, Vommina V. Sureshbabu*
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar
Veedhi, Bangalore 560 001, India
Received: 05.04.2012; Accepted after revision: 08.06.2012
N-Protected α-aminoalkyl-α′-halomethyl ketones9 have
Abstract: The preparation of N-protected amino/peptide α-cyano-
emerged as attractive targets for the design of peptidomi-
methyl ketones through cyanation of the corresponding α-bromo-
metics.10–12 Our group has developed a simple route for
the preparation of N-protected α-aminoalkyl-α′-halo-
methyl ketones is described. The utility of the resulting α-
cyanomethyl ketones in the synthesis of 3-substituted-5-amino-1H-
pyrazoles has also been demonstrated. In both steps a wide range of methyl ketones and employed them for the construction of
thiazole,13 selenazole,14 and triazole15 tethered peptidomi-
metics (Scheme 1).
N-protected amino/peptide acids has been employed and the prod-
ucts are obtained in good yield. The enantiomeric purity of both the
α-cyanomethyl ketones and pyrazoles were confirmed by chiral
In the present letter we describe the synthesis of N-ure-
thane protected α-aminoalkyl-α′-cyanomethyl ketones
and their utility in the synthesis of amino acid derived 3-
substituted 5-amino-1H-pyrazoles. The α-cyanomethyl
ketone is an important scaffold that is found in many phar-
maceutical compounds16 with a broad spectrum of biolog-
ical activity.17,18 Sauve et al. reported amino acid derived
α-cyanomethyl ketones and carboxy group modified di-
peptides.19 Boc/Ac-protected Phe/Leu-Phe derived cya-
nomethyl ketones were synthesized through alkylation of
Boc/Ac-amino thioamide with methyl triflate and the re-
sulting intermediate was treated with a nucleophile. N-
Acetyl protected cyanomethyl ketones have also been pre-
pared by the reaction of activated carboxylic acids and the
carbanion of tert-butyl cyanoacetate, and the resulting
enols were then subjected to hydrolysis followed by de-
carboxylation.20 α-Cyanomethyl ketones derived from
N,N′-bisbenzyl protected benzyl phenyl alaninate was
prepared by the reaction of MeCN and NaNH2.21 Some of
the above approaches either require a cumbersome proto-
col or are incompatible with the use of urethane-type pro-
tecting groups. We describe herein a convenient method
for the synthesis of urethane-protected α-cyanomethyl ke-
tones and their conversion into N-Boc/Z-protected α-ami-
noalkyl-5-amino pyrazoles. Pyrazole22 derivatives of α-
amino acids have received considerable attention because
of their diverse range of biological properties such as po-
tent angiotensin II antagonist activity both in vitro and in
vivo,23 anti-hypertensive, anti-bacterial, and anti-inflam-
matory activity,24 muscle relaxant properties, and inhibi-
tion of cyclin dependent kinases.25 They have also been
used as building blocks for the synthesis of peptidomimet-
ics.26,27
HPLC analysis of the corresponding Z-protected D- and L-Ala-OH
as model substrates. The synthesis of peptide pyrazolecarbox-
amides is also delineated.
Key words: peptidomimetics, amino acid mimics, ketones, pyr-
azole
An important aspect of peptidomimetic design involves
the use of suitable building blocks. To this end, either the
-NH2 or -COOH group of enantiopure α-amino acids are
converted into the desired functionality. Among them,
azides,1 isonitriles,2 nitriles,3 and acetylenes4 have been
generated at the amine or acid termini of α-amino acids.
Employing these key constituents, the insertion of scaf-
folds such as a tetrazole, thiazole, imidazole, triazole, and
oxadiazole in place of the peptide bond has also been a
subject of interest, particularly for studying the physio-
chemical and biological properties of peptides (Figure
1).5–8
R
R1
R
O
N
S
ZHN
OBn
CO2Me
PgHN
ZHN
N
N
N
N
N
R2
Me
Ph
N
CO2Et
Boc or Z
X = O or S
R
R
O
N
BocHN
BocHN
N
CO2Et
N
HN
N
CO2Et
Figure 1 Selected examples of N-heterocycles derived from amino
acids
The required urethane-protected α-aminoalkyl-α′-bromo-
methyl ketone precursors were prepared by using a two-
step procedure reported by our group.13 A similar ap-
proach was employed for the preparation of bromomethyl
ketones containing the Boc-protected compounds with
suitable modifications.28 In all cases, bromomethyl ke-
SYNLETT 2012, 23, 1913–1918
Advanced online publication: 23.07.2012
DOI: 10.1055/s-0032-1316586; Art ID: ST-2012-D0308-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1914
M. K. Sharnabai et al.
LETTER
R1
PgHN
Br
O
R1
R1
R1
N
X
PgHN
R2
NHBoc/Z
N
NH2
FmocHN
PgHN
N
N
COOH
O
S
N
X = S/Se
Pg = Fmoc, Boc or Z group
Pg = Fmoc, Boc or Z group
Scheme 1 Various transformations of N-protected α-aminoalkyl-α′-halomethyl ketones reported by our group
tones were obtained as stable solids without the need for confirmed the formation of 3a. The protocol was further
column purification. The resulting α-bromomethyl ke- applied to various N-protected amino/peptide α-bromo-
tones were then converted into α-cyanomethyl ketones. methyl ketones to obtain the corresponding cyanomethyl
We initially investigated the use of several cyanating re- ketones (Table 2).29 The procedure worked well even for
agents by using different solvents; the results are summa- amino acids Ser and Thr, which contain free hydroxyl
rized in Table 1. Boc-Ala-[CH2Br] 2a (Scheme 2) was groups (Table 2, entries 9, 13, and 15).
used as a model substrate to optimize the reaction condi-
Table 1 Screening of Cyanating Agents and Solvents for the Synthe-
tions, with the progress of the reaction being monitored by
TLC. Treatment of 2a with TMSCN in MeOH failed to
sis of 3aa
give 3a at room temperature (Table 1, entry 1), but under
reflux conditions the product was obtained in 20% yield
(Table 1, entry 2). We then explored the use of NaCN,
HgCN, K3Fe(CN)6 and KCN at room temperature in
MeOH (Table 1, entries 3–6). KCN turned out to be the
most useful to obtain 3a. Furthermore, we examined a
range of solvents with the aim of stabilizing the reaction
conditions and found that use of THF and CH3CN led to
the formation of 3a in moderate yield (Table 1, entries 7
and 8), DMF and DMSO gave acceptable yields of 3a (68
and 72% respectively; Table 1, entries 9 and 10), but the
use of MeOH provided an excellent yield of 3a at room
temperature (Table 1, entry 6).
Entrya
Cyanating reagent
Solvent
Temp
(°C)
Yield
(%)b
1
2
TMSCN
TMSCN
NaCN
HgCN
K3Fe(CN)6
KCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
25
60
25
25
25
25
35
25
40
40
–
20
38
49
55
91
40
45
68
72
3
4
5
6
7
KCN
8
KCN
MeCN
DMF
R1
O
1. Et3N, ECF, CH2N2
–15 °C, THF
R1
H
N
9
KCN
H
Br
N
COOH
PgHN
2. 47% aq HBr
THF, r.t., 5 min
PgHN
R2
10
KCN
DMSO
O
R2
n
O
n
a Boc-Ala-CH2Br 2a (1.0 mmol) was treated with cyanating reagent
(1.2 mmol).
2
1
R1
O
H
N
CN
b Yield of isolated product 3a after column purification.
KCN
PgHN
MeOH
30 min
R2
O
n
3
Next, we turned our attention to the synthesis of a hitherto
unreported class of Nα-Boc/Z-aminoalkyl-5-amino pyr-
azoles.30 The 3-substituted 5-amino-1H-pyrazole deriva-
tives 4 were prepared by reaction of α-cyanomethyl
ketones 3 with hydrazine hydrate under reflux in MeOH
(Scheme 3). In a typical experiment, Boc-Ala-[CH2CN]
3a was added to a solution of 99–100% hydrazine hydrate
in MeOH. The reaction mixture was heated to reflux at
40 °C for approximately two hours. After completion of
the reaction (TLC analysis), the solvent was evaporated
under reduced pressure and the residue was purified by
column chromatography to afford 4a.31 Several Boc and
Z-protected α-aminoalkyl-α′-cyanomethyl ketones were
Pg = Fmoc, Z, or BOc group
n = 0, 1
R1, R2 = amino acid side chain
Scheme 2 Synthesis of N-protected α-aminoalkyl or peptidyl cyano-
methyl ketones 3
Under the optimized conditions, reactant 2a was com-
pletely consumed, as evidenced by IR and RP-HPLC
analysis. The disappearance of the strong IR absorption
band at 1730 cm–1 for the α-bromomethyl ketone 2a and
the appearance of strong bands at 1650 and 2243 cm–1 for
the carbonyl and adjacent nitrile groups, respectively,
Synlett 2012, 23, 1913–1918
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones
1915
Table 2 List of Nα-Z/Boc-Protected α-Cyanomethyl Ketones 3a–r
converted into their respective pyrazole derivatives 4a–i
in good yield and purity (Table 3).
25
Entry Product 3
[α]D
Yield
(c 1, CHCl3) (%)a
Table 2 List of Nα-Z/Boc-Protected α-Cyanomethyl Ketones 3a–r
25
Entry Product 3
[α]D
Yield
(c 1, CHCl3) (%)a
14
15
3n
3o
–20.4
–15.7
80
82
FmocHN
CN
O
1
2
3a
3b
–14.2
–12.1
89
88
BocHN
BocHN
CN
CN
O
O
H
N
CN
ZHN
O
OH
ZHN
O
O
4
H
Ph
N
CN
16
17
3p
3q
–13.6
–16.2
84
81
BocHN
3
4
5
3c
3d
3e
–21.2
–15.3
–13.4
90
87
89
O
BocHN
BocHN
CN
O
O
H
N
CN
COOBn
CN
FmocHN
O
O
OBzl
SBn
O
H
N
CN
BocHN
CN
18
3r
–18.2
79
FmocHN
O
O
COOt-Bu
a Isolated yield.
6
3f
–16.7
90
ZHN
ZHN
ZHN
CN
O
R
R
N2H4⋅H2O
PgHN
O
CN
PgHN
NH2
CN
O
7
8
3g
3h
–18.3
+21.6
91
90
40 ºC, 2 h
N
NH
3
4
Pg = Boc or Z group
R = amino acid side chain
CN
O
Scheme 3 Synthesis of N-protected 3-substituted 5-amino-1H-pyr-
azoles 4
OH
9
10
11
3i
–22.1
–12.5
–13.9
88
80
78
Similarly, two examples of Nα-Boc/Z-protected peptidyl
3-substituted 5-amino-1H pyrazoles 4j–k were also pre-
pared (Figure 2). Both cyanomethyl ketones and pyrazole
derivatives were characterized by mass, IR and NMR
analyses.
ZHN
CN
O
FmocHN
CN
3j
3k
O
O
COOBn
NH2
NH2
NHZ
FmocHN
FmocHN
CN
H
N
NH
4
H
NH
N
N
ZHN
N
BocHN
O
O
OH
12
13
3l
–17.2
–14.8
89
79
4j
79%
[α]D25 (c 1,CHCl3) = +19.7
4k
78%
CN
O
[α]D25 (c 1,CHCl3) = –20.5
OH
Figure 2 Dipeptidyl pyrazoles synthesized
3m
FmocHN
CN
In order to gain insight into the possibility of racemiza-
tion, enantiomeric Z-protected D- and L-Ala-OH were
O
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1913–1918

1916
M. K. Sharnabai et al.
LETTER
converted into cyanomethyl ketones and pyrazoles under bilization of peptides.34 Thus, pyrazoles 4 were employed
the developed reaction conditions, and their enantiomeric to synthesize peptide-derived pyrazolecarboxamides 6.
excess was determined by chiral HPLC analysis.32 As
As a test case, a solution of Fmoc-Val-Cl35 in anhydrous
shown in Figure 3, compounds 3g and 3h showed single
THF, Boc-Ala-pyrazole amine 4a and NMM were reacted
peaks with retention times of 28.1 and 22.5 min, respec-
at 0 °C. The coupling was found to be complete in three
tively.
hours, as observed by TLC analysis (Scheme 4).
In contrast, the constituents of the racemic mixture of 3g
and 3h were separated with retention times of 27.8 and
21.9 min. Similarly, HPLC profiles for pyrazoles 4g and
4h showed retention times of 16.9 and 10.1 min, respec-
tively. Thus, these results confirm that both α-cyanometh-
yl ketones and pyrazoles were prepared in optically pure
form.
R1
R1
H
R2
NHPg2
4, Et3N
N
Cl
FmocHN
FmocHN
0 °C, 2–3 h
O
N
NH
O
5
6
Pg2 = Boc or Z group
Scheme 4 Synthesis of pyrazole-tethered peptidomimetics
Finally, the synthesis of pyrazole-linked dipeptidomimet-
ics was undertaken. Pyrazolecarboxamide derivatives are
known for their use in the treatment of pain and
inflammation33 and also play a vital role in the β-sheet sta-
The desired N,N′-orthogonally protected dipeptidomimet-
ic 6a36 was isolated in 88% after column purification. As
Table 3 Data for 3-Substituted 5-Amino-1H-pyrazole Derivatives 4a–i
4
PG
R
HRMS [M + Na]+
Calcd
Yield (%)a
[α]D25 (c 1, CHCl3)
Found
4a
Boc
Boc
Boc
Boc
Boc
Z
Me
249.1327
277.1640
325.1638
291.1793
355.1748
505.1849
359.1481
248.1241
445.1856
249.1230
277.1643
325.1640
291.1791
355.1746
253.1852
359.1484
248.1249
455.1852
85
88
92
94
92
91
90
88
87
–12.1
–15.3
–17.2
–14.5
–10.9
–29.5
–13.5
–14.9
–16.2
4b
i-Pr
4c
Bn
4d
i-Bu
4e
CH2OH
CH2COOt-Bu
Me
4f
4g
Z
4h
Z
Meb
4i
Z
CH(CH3)OH
a Isolated yield.
b Z-D-Ala-OH was used as starting compound.
Figure 3 Chiral HPLC analysis.32 Chromatograms shown are: (a) Z-L-Ala-CH2CN 3g; (b) Z-D-Ala-CH2CN 3h; (c) Prepared 1:1 mixture of 3g
and 3h; (d) Z-L-Ala-pyrazole 4g; (e) Z-D-Ala-pyrazole 4h; (f) Prepared 1:1 mixture of 4g and 4h.
Synlett 2012, 23, 1913–1918
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones
1917
Ph
H
H
H
N
N
N
FmocHN
FmocHN
FmocN
O
N
O
N
O
N
NH
NHZ
NHBoc
NHBoc
NH
NH
6a
6b
6c
OBn
ZHN
Ph
4
H
N
H
N
FmocHN
FmocHN
O
N
O
N
NH
NHBoc
NHZ
NH
6d
6e
Figure 4 List of pyrazolecarboxamide peptidomimetics 6
and Proteins; Vol. 7; Weinstein, B., Ed.; Dekker: New York,
1983, 267.
(9) (a) Reeder, M. R.; Anderson, R. M. Chem. Rev. 2006, 106,
2828. (b) Birch, P. L.; El-Obeid, H. A.; Akthar, M. Arch.
Biochem. Biophys. 1972, 148, 447. (c) Albek, A.; Persky, R.
Tetrahedron 1994, 50, 6333.
(10) Uekun, F. M.; Perrey, D. A.; Narla, R. K. Bioorg. Med.
Chem. Lett. 2000, 10, 547.
(11) (a) Beaulieu, P. L.; Wernic, D.; Duceppe, J.-S.; Guindon, Y.
Tetrahedron Lett. 1995, 36, 3317. (b) Onishi, T.; Hirose, N.;
Nakano, T.; Nakazawa, M.; Izawa, K. Tetrahedron Lett.
2001, 42, 5883.
shown in Figure 4, the same procedure was extended to
the synthesis of compounds 6b–e.
In summary, a simple and easily accessible route has been
established for the synthesis of enantiopure N-urethane-
protected amino acid/peptidyl cyanomethyl ketones. The
resulting cyanomethyl ketones were utilized for the con-
struction of amino acid derived 3-substituted-5-amino-
1H-pyrazoles. The protocol has also been extended to pre-
pare five N,N′-orthogonally protected pyrazolecarbox-
amide tethered peptidomimetics in good yield.
(12) (a) Izawa, K.; Onishi, T. Chem. Rev. 2006, 106, 2811.
(b) Beaulieu, P. L.; Lavallee, A.; Abraham, A.; Anderson, P.
C.; Boucher, C.; Bousquet, Y.; Duceppe, J.-S.; Gillard, J.;
Gorys, V.; Grand-Maitre, C.; Grenier, L.; Guindon, Y.;
Guse, I.; Plamondon, L.; Soucy, F.; Valois, S.; Wernic, D.;
Yoakim, C. J. Org. Chem. 1997, 62, 3440. (c) Goodman, M.;
Felix, A.; Moroder, L.; Toniolo, C. Houben-Weyl: Synthesis
of Peptides & Peptidomimetics; Vol. E22c; Georg Thieme
Verlag: Stuttgart, 2003, 393–395.
Acknowledgment
We thank the University Grants Commission, New Delhi [UGC,
grant No. F. No. 37-79/2009 (SR)] Govt. of India for financial assi-
stance. M.S.K. thanks the DST, Govt. of India for the award of an
INSPIRE fellowship.
(13) Narendra, N.; Vishwanatha, T. M.; Sudarshan, N. S.;
Sureshbabu, V. V. Protein Pept. Lett. 2009, 16, 1029.
(14) Lalithamba, H. S.; Narendra, N.; Shankar, A. N.;
Sureshbabu, V. V. ARKIVOC 2010, (xi), 77.
(15) (a) Narendra, N.; Vishwanatha, T. M.; Sureshbabu, V. V.
Int. J. Pept. Res. Ther. 2010, 16, 283. (b) Rotella, D. P.
Tetrahedron Lett. 1995, 36, 5453.
References and Notes
(1) (a) Rijkers, D. T. S.; Van Esse, G. W.; Merkx, R.; Brouwer,
A. J.; Jacobs, H. J. F.; Pieters, R. J.; Liskamp, R. M. J. Chem.
Commun. 2005, 4581. (b) Sureshbabu, V. V.; Shankar, A.
N.; Hemantha, H. P.; Narendra, N.; Ushati, D.; Guru Row,
T. N. J. Org. Chem. 2009, 74, 5260.
(2) (a) Ugi, I. Isonitrile Chemistry; Academic Press: New
York/London, 1971. (b) Zhu, J.; Wu, X.; Danishefsky, S. J.
Tetrahedron Lett. 2009, 50, 577. (c) Sureshbabu, V. V.;
Narendra, N.; Nagendra, G. J. Org. Chem. 2009, 74, 153.
(3) (a) Sureshbabu, V. V.; Venkataramanarao, R.; Shankar, A.
N.; Chennakrishnareddy, G. Tetrahedron Lett. 2007, 48,
7038. (b) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4,
2525.
(16) (a) Bazewicz, C. G.; Lipkin, J. S.; Lozinak, K. A.; Watson,
M. D.; Brewer, S. H. Tetrahedron Lett. 2011, 52, 6865.
(b) Rappaport, Z. The Chemistry of the Cyano Group;
Interscience Publishers: London, England, 1970.
(17) (a) Jones, G. Org. React. 1967, 15, 204. (b) Robichaud,
B. A.; Liu, K. G. Tetrahedron Lett. 2011, 52, 6935.
(18) Huff, J. R. J. Med. Chem. 1991, 34, 2305.
(19) Sauve, G.; Mansour, T. S.; Lachance, P.; Belleau, B.
Tetrahedron Lett. 1988, 29, 2295.
(20) (a) Brillon, D.; Sauve, G. J. Org. Chem. 1992, 57, 1838.
(b) Sauve, G.; Le Berre, N.; Zacharie, B. J. Org. Chem.
1990, 55, 3002.
(21) Stuk, T. L.; Haight, A. R.; Scarpetti, D.; Allen, M. S.;
Menzia, J. A.; Robbins, T. A.; Parekh, S. I.; Langridge, D.
C.; Tien, J. H. J.; Pariza, R. J.; Kerdesky, F. A. J. J. Org.
Chem. 1994, 59, 4040.
(4) Tam, A.; Arnold, U.; Soellner, M. B.; Raines, R. T. J. Am.
Chem. Soc. 2007, 129, 12670.
(5) (a) Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36,
1674. (b) Huisgen, R. 1,3-Dipolar Cycloaddition-
Introduction, Survey, Mechanism, In 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, 1–176. (c) Falorni, M.; Giacomelli, G.; Spanu,
E. Tetrahedron Lett. 1998, 39, 9241.
(6) (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3169. (b) Domling, A. Chem. Rev. 2006, 106, 17.
(7) (a) Maareseveen, J. H. V.; Horne, W. S.; Ghadiri, M. R. Org.
Lett. 2005, 7, 4503. (b) Pedersen, D. S.; Abell, A. Eur. J.
Org. Chem. 2011, 2399.
(22) Santos, F.; Sanchez-Rosello, M.; Pablo, B.; Simon-Fuentes,
A. Chem. Rev. 2011, 111, 6984.
(23) Chen, C.; Wilcoxen, K. M.; Huang, C. Q.; Xie, Y. F.;
McCarthy, J. R.; Webb, T. R.; Zhu, Y. F.; Saunders, J.; Liu,
X. J.; Chen, T. K.; Bozigian, H.; Grigoriadis, D. E. J. Med.
Chem. 2004, 47, 4787.
(8) (a) Abell, A. D. Lett. Pept. Sci. 2002, 8, 267. (b) Spatola, A.
F. In Chemistry and Biochemistry of Amino Acids, Peptides
(24) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1913–1918

1918
M. K. Sharnabai et al.
LETTER
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
was heated at reflux at 40 °C for 2 h (progress monitored by
TLC). After cooling, the solvent was removed under reduced
pressure to obtain the crude product, which was purified by
column chromatography (silica gel 100–200 mesh; CHCl3–
MeOH, 9:1).
(25) Fancelli, D.; Berta, D.; Bindi, S.; Cameron, A.; Capella, P.;
Carpinelli, P.; Catana, C.; Forte, B.; Giordano, P.; Giorgini,
M. L.; Mantegani, S.; Marsiglio, A.; Meroni, M.; Moll, J.;
Pittala, V.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.;
Tonani, R.; Varasi, M.; Vulpetti, A.; Vianello, P. J. Med.
Chem. 2005, 48, 3080.
Compound 4a: Yield: 85%; yellowish gum; [α]D25 –12.1 (c
1.0, CHCl3); Rf = 0.3 (CHCl3–MeOH, 9:1); IR (neat): 1740,
2874, 3429 cm–1; 1HNMR (CDCl3, 400 MHz): δ = 1.34 (d,
J = 8.1 Hz, 3 H), 1.40 (s, 9 H), 3.82 (m, 1 H), 5.22 (br, 2 H),
5.80 (s, 1 H), 6.21 (br, 1 H), 9.40 (br, 1 H); 13C NMR
(CDCl3, 100 MHz): δ = 19.2, 29.0, 48.3, 80.1, 96.3, 141.2,
155.1, 155.8; HRMS: m/z [M + Na]+ calcd for C10H18N4O2:
249.1430; found: 249.1427.
(26) De Luca, L.; Falorni, M.; Giacomelli, G.; Porcheddu, A.
Tetrahedron Lett. 1999, 40, 8701.
(27) Bagley, M. C.; Davis, T.; Dix, M. C.; Murziani, P. G. S.;
Rokicki, M. J.; Kipling, D. Bioorg. Med. Chem. Lett. 2008,
18, 3745.
Compound 4k: Yield: 78%; yellowish gum; [α]D25 –20.5 (c
1.0, CHCl3); Rf = 0.4 (CHCl3–MeOH, 9:1); IR (neat): 1747,
1762, 2881, 3432 cm–1; 1H NMR (CDCl3, 400 MHz): δ =
0.98 (d, J = 6.3 Hz, 6 H), 1.61–1.63 (m, 2 H), 1.70 (m, 1 H),
2.43–2.54 (s, 1 H), 4.82 (br, 2 H), 5.25 (s, 2 H), 4.50 (t, J =
5.6 Hz, 1 H), 5.34 (s, 2 H), 5.8 (s, 1 H), 6.50 (br, 1 H), 7.11–
7.23 (m, 5 H), 10.11 (br, 1 H); 13C NMR (CDCl3, 100 MHz):
δ = 19.3, 21.1, 38.9, 49.6, 52.3, 65.1, 65.9, 93.2, 125.7,
127.3, 128.2, 139.9, 142.1, 154.2, 155.8, 169.3; HRMS: m/z
[M + Na]+ calcd for C19H27N5O4: 412.1961; found: 412.1963
(32) Chiral HPLC details: Agilent 1100 series having G1311A
VWD at λ = 230 nm; flow 1.0 mL/min; Column:
(28) Preparation of Boc-Protected Bromomethyl Ketones;
Typical Procedure for 2a: To a solution of diazomethyl
ketone (1.8 mmol, 0.4 g) in THF, aq 47% HBr (2–3 mL) at
0 °C was added. The reaction mixture was stirred for another
2–3 min until the starting material was completely
consumed. The reaction mixture was diluted with excess
H2O and the precipitated solid was filtered. A simple
recrystallization (THF–H2O) led to the analytically pure
product
(29) Preparation of Boc-Ala-[CH2CN] 3a; Typical
Procedure: To a solution of Boc-Ala-CH2Br (1.8 mmol, 0.5
g) in MeOH (5 mL), KCN (3.7 mmol, 0.24 g) was added at
r.t. The reaction mixture was stirred for 3 h (reaction
followed by TLC analysis). After completion of the reaction,
the solvent was evaporated under reduced pressure and the
residue was dissolved in EtOAc (2 × 10 mL) and, to dispose
of any excess KCN, the reaction mixture was quenched with
sat. KMnO4 solution and washed with excess H2O. The
organic layer was washed with brine (10 mL) and the
solution was dried over anhydrous Na2SO4. The solvent was
filtered and evaporated under reduced pressure and the
product 3a was isolated by column chromatography
Compound 3a: Yield: 89%; brownish gum; [α]D25 –14.2 (c
1.0, CHCl3); Rf = 0.4 (EtOAc–hexane, 3:7); IR (neat): 1650,
1745, 2243 cm–1; 1H MR (CDCl3, 400 MHz): δ = 1.31 (d,
J = 6.0 Hz, 3 H), 1.35 (s, 9 H), 3.19 (s, 2 H), 4.23 (m, 1 H),
6.8 (br, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 13.6, 28.0,
28.7, 56.4, 80.1, 116.5, 155.4, 205.4; HRMS: m/z [M + Na]+
calcd for C10H16N2O3: 235.1059; found: 235.1062
Compound 3o: Yield: 82%; brownish gum; [α]D25 –15.7 (c
1.0, CHCl3); Rf = 0.4 (EtOAc–hexane, 5:5); IR (neat): 1658,
1718, 1741, 2231 cm–1; 1H NMR (CDCl3, 400 MHz): δ =
0.99 (d, J = 4.8 Hz, 6 H), 1.62 (m, 2 H), 1.78 (m, 1 H), 2.64
(s, 1 H), 3.70 (s, 2 H), 3.78 (m, 2 H), 3.84 (m, 1 H), 4.64 (m,
1 H), 5.12 (m, 2 H), 5.93 (br, 1 H), 7.12 (m, 5 H); 13C NMR
(CDCl3, 100 MHz): δ = 22.0, 22.4, 28.4, 40.4, 47.2, 57.3,
63.4, 65.1, 116.2, 127.1, 127.3, 128.3, 140.2, 155.5, 170.8,
207.2; HRMS: m/z [M + Na]+ calcd for C19H25N3O5:
398.1794; found: 398.1792
Phenominex made Lux; pore size 5 μm; Cellusole-1,
250 × 4.6 mm; n-hexane–isopropanol (85:15) in isocratic
mode in 40 min
(33) Dressen, D.; Garofalo, A. W.; Hawkinson, J.; Hom, D.;
Jagodzinski, J.; Marugg, J. L.; Neitzel, M. L.; Pleiss, M. A.;
Szoke, B.; Tung, J. S.; Wone, D. W. G.; Wu, J.; Zhang, H.
J. Med. Chem. 2007, 50, 5161.
(34) Černovská, K.; Kemter, M.; Gallmeier, H.-C.; Rzepecki, P.;
Schrader, T.; König, B. Org. Biomol. Chem. 2004, 2, 1603.
(35) Sureshbabu, V. V.; Hemantha, H. P. ARKIVOC 2008, (ii),
243.
(36) Preparation of Pyrazole-Linked Peptidomimetic 6a;
Typical Procedure: To a solution of Fmoc-Val-Cl (0.5
mmol, 0.2 g) and NMM (0.68 mmol, 0.07 mL) in THF at
0 °C, was added Cbz-protected-Ala-5-amino-pyrazole. The
reaction mixture was stirred for 2–3 h (TLC monitoring).
After completion of reaction, the solvent was removed under
reduced pressure and the residue was dissolved in EtOAc (10
mL), washed with citric acid (10%, 10 mL), aqueous
Na2CO3 (10%, 10 mL), H2O (2 × 10 mL), and brine (2 × 10
mL). The organic phase was dried over anhydrous Na2SO4
and then concentrated under reduced pressure. The residue
was purification by column chromatography (silica gel 100–
200 mesh; CHCl3–MeOH, 9:1) to afford
pyrazolecarboxamides.
Compound 6a: Yield: 78%; yellowish solid; [α]D25 +52.7 (c
1.0, CHCl3); Rf = 0.3 (CHCl3–MeOH, 9:1); IR (neat): 1659,
1766, 2886, 3423 cm–1; 1H NMR (CDCl3, 400 MHz): δ =
0.99 (m, 6 H), 1.30 (d, J = 4.5 Hz, 3 H), 2.01 (m, 1 H), 4.19
(d, J = 3.9 Hz, 1 H), 4.20 (t, J = 6.6 Hz, 1 H), 4.21 (d, J =
7.4 Hz, 2 H), 4.82 (m, 1 H), 5.01 (s, 2 H), 5.18 (m, 2 H), 5.89
(s, 1 H), 6.09 (br, 2 H), 7.25–7.77 (m, 13 H), 11.8 (br, 1 H);
13C NMR (CDCl3, 100 MHz): δ = 16.1, 20.2, 28.0, 42.4,
46.2, 47.5, 52.0, 58.1, 64.9, 66.8, 91.3, 124.6, 125.3, 126.1,
126.8, 127.0, 128.4, 136.1, 139.3, 140.2, 141.6, 143.0,
155.3, 155.5, 170.1; HRMS: m/z [M + Na]+ calcd for
C33H35N5O5: 604.2536; found: 604.2538.
(30) Goodman, M.; Felix, A.; Moroder, L.; Toniolo, C. Houben-
Weyl: Synthesis of Peptides & Peptidomimetics; Vol. E22c;
Georg Thieme Verlag: Stuttgart, New York, 2003, 663–689.
(31) Preparation of Boc-Ala-5-amino-pyrazole 4a; Typical
Procedure: To a solution of Nα-protected Boc-Ala-
[CH2CN] 3a (1.8 mmol, 0.4 g) in MeOH (5 mL), hydrazine
hydrate (14 mmol, 0.7 mL) was added. The reaction mixture
Synlett 2012, 23, 1913–1918
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.