The Overman rearrangement in carbohydrate chemistry: Stereoselective synthesis of functionalized 3-amino-3,6-dihydro-2H-pyrans and incorporation in peptide derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.11.109

A stereocontrolled synthesis of an unsaturated sugar bearing two amino groups (one of them masked as an azide), using an Overman rearrangement as key step, is described. This scaffold is used to prepare two peptides having aromatic fragments, which have s

Full text of DOI:10.1016/j.tetlet.2004.11.109

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 401–405
The Overman rearrangement in carbohydrate
chemistry: stereoselective synthesis of functionalized
3-amino-3,6-dihydro-2H-pyrans and incorporation
in peptide derivativesq
*
´
Ana Montero, Enrique Mann and Bernardo Herradon
´ ´
Instituto de Quımica Organica General, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain
Received 15 October 2004; accepted 22 November 2004
Abstract—A stereocontrolled synthesis of an unsaturated sugar bearing two amino groups (one of them masked as an azide), using
an Overman rearrangement as key step, is described. This scaffold is used to prepare two peptides having aromatic fragments, which
have shown activity as calpain inhibitors.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Additionally, the substituent on the anomeric position
offers a site for further molecular diversity and the endo-
cyclic olefinic bond provides a conformational bias to
the molecule. The target molecule A can be synthesized
from hexenopyranosides of type B, which in turn can be
prepared from readily available glycals using standard
transformations in carbohydrate chemistry. Recently,
we have reported the synthesis of compounds of type
C, using a Claisen rearrangement as key step, where
the two peptide chains have the same orientation.5 The
synthetic utility of the scaffold B may be expanded by
reversing the sense of the peptide chains (retro-pep-
tides),6 provided that a 3,6-diamino-substituted-3,6-
dihydro-2H-pyran (D) is available. In this letter, we
report the synthesis of the 3,6-dihydro-2H-pyran 1 as well
as its application to peptide derivatives of type E as
well as their activity as inhibitor of the protease calpain.
Although many peptides are biologically active, they fre-
quently suffer from inadequate in vivo efficacy as a result
of poor absorption, lack of transportation, rapid
metabolic degradation, and inability to achieve the
biologically active conformation. To overcome these
inconveniences, many peptide analogues have been pre-
pared.1 An important step in the development of drug
candidates is the use of molecular scaffolds that are de-
signed to induce conformational restraints as well as to
improve the pharmacological profile.2,3 In connection
with ongoing projects on the synthesis, structure, and
biological activity of peptidic compounds,4 we have
been interested in the preparation of new peptide deriv-
atives employing unsaturated carbohydrate as scaffolds
(peptide–carbohydrate hybrids). The generic target com-
pound A (Fig. 1) has peptide or amino acid residues
tethered to the positions 3 and 6 of an unsaturated pyra-
nose. Since the relative stereochemistry and the distance
(by changes in the nature of the groups X and Y) of the
two peptide chains can be readily controlled, the poten-
tial structural variety of compounds of type A is high.
2. Results and discussion
The synthesis of the target amine 1 is indicated in
Scheme 1. The allylic alcohol 3 was prepared in five
steps (66% overall yield) from commercial available
3,4,6-tri-O-triacetyl-D-glucal (2) as previously reported.5
Treatment of 3 with trichloroacetonitrile in presence of
DBU furnished the trichloroacetimidate 4 (95% yield),7
which, after purification, was submitted to the Overman
rearrangement8 by refluxing in xylene in the presence of
potassium carbonate,9,10 giving the corresponding
Keywords: Amino sugar; Calpain inhibitor; Enkephalin; Overman
rearrangement; Peptidomimetic.
q Taken in part from the Ph.D. thesis of AM.
*
Corresponding author. Tel.: +34 915618806; fax: +34 915644853;
e-mail: herradon@iqog.csic.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.109

402
A. Montero et al. / Tetrahedron Letters 46 (2005) 401–405
OR
X-peptide
OR
X'
O
O
R
O
peptide-Y
Y'
H
O
O
N
N
B
A (X, Y = NH, CO)
H
NH
O
C
R
O
O
O
R
R
O
H
R
O
NH2
N
H
N
N
H
N
O
H
D, R = NH2
1, R = N3
O
E
Figure 1. Structures of peptide–carbohydrate hybrids (A, C, E) and 3,6-dihydro-2H-pyran derivatives (B, D, 1).
t
t
Me2 BuSiO
t
Me2 BuSiO
Me2 BuSiO
AcO
AcO
HO
CCl3
O
O
O
c
a
b
O
O
NH
O
O
AcO
O
3
CCl3
O
NH
4
2
5
RO
N3
N3
O
d
f
g
O
O
O
O
O
CCl3
NH
NH2
CCl3
NH
1
O
O
8
6, R = H
e
7, R = SO2CH3
Scheme 1. Reagents and conditions: (a) five steps (66% yield), Ref. 5; (b) Cl3CCN, DBU, CH2Cl2, 0 °C to rt, 95%; (c) K2CO3, xylene, reflux, 77%, (d)
TBAFÆ3H2O, THF, 80%; (e) MsCl, Et3N, CH2Cl2, 0 °C; (f) NaN3, Et3N, DMF, 60 °C, 56% (two steps); (g) NaOH, EtOH, H2O, reflux, 64%.
trichloroacetamide 5 in good yield (77%) and with total
stereoselectivity.11 Compound 5 was desylilated (TBAF,
80% yield) to the alcohol 6, which, in turn, was sequen-
tially transformed to the sulfonate 7 and the azide 8
(56% yield for the combined two steps). Finally, hydro-
lysis of the trichloroacetamide 8 under basic conditions
afforded the unsaturated amino azide 1 (64% yield), that
has been used for the synthesis of peptide–carbohydrate
hybrids.
The synthesis of 11 and 12 is indicated in Scheme 2. All
the peptide bonds were formed by standard solution
methods using 1-ethyl-3-(3-(dimethylamino)propyl)-carbo-
diimide hydrochloride (EDC) and 1-hydroxybenzo-
triazole (HOBt) as coupling reagents, triethyl amine as
base, 4-(dimethylamino)pyridine (DMAP) as catalysts,
and dimethylformamide as solvent.16 Reaction of amino
azide 1 with dipeptides Ac-Leu-Phe-OH and C6F5SO2-
Met-Phe-OH gave intermediates 9 (50%) and 10 (52%),
respectively. Reduction of the azido group was achieved
by reaction with triphenylphosphine and water in reflux-
ing benzene. The resulting amines, which were used
without any purification, were coupled to 4-Biph-Tyr-
OH and Ts-Tyr(Ts)-OH employing the peptide coupling
procedure described above to furnish compounds 11
(74%) and 12 (76%), respectively.17
Our recent research on calpain,4a,12 a cysteine protease
involved in a variety of degenerative diseases,13 has
shown that peptide derivatives having hydrophobic
and aromatic amino acids are inhibitors of this enzyme.
Therefore, we chose as target the peptides 11 and 12,
which, in turn, can be considered as analogues of the
natural penta-peptides Leu-enkephalin (Leu-Phe-Gly-
Gly-Tyr) and Met-enkephalin (Leu-Phe-Gly-Gly-Tyr),
respectively, where the dihydro-2H-pyran scaffold re-
places the Gly-Gly fragment of the natural peptides.14
Although the enkephalins are potent analgesic natural
peptides acting on the opioid receptor, their pharmaco-
logical utility is limited, what makes the search for
enkephalin analogues an active research field.15
Although a detailed conformational analysis on peptides
11, 12, and related compounds is underway, we have ob-
served concentration-independent strong m (N–H) bands
at 3287 cmꢀ1 in the IR spectra (CH2Cl2) of 11 and 12,
which are indicative of the presence of intramolecular
H-bond. On the other hand, although the biological
activity of 11 and 12 as enkephalin analogues has not

A. Montero et al. / Tetrahedron Letters 46 (2005) 401–405
403
OH
O
H
N
N3
N
H
O
O
c
O
Ph
Ph
O
O
O
O
H
N
H
NH
N
NH
N
H
N
H
O
O
O
O
11
9
a
TsO
1
N3
O
S
H
b
N
CH3
F
N
H
d
O
O
O
Ph
O
F
F
O
S
O
O
F
F
Ph
O
S
O
O
F
HN
NH
H
N
F
N
NH
O
H
N
H
O
F
F
O
S
O
F
S
10
12
Scheme 2. Reagents and conditions: (a) Ac-L-Leu-L-Phe-OH, EDC, HOBt, Et3N, DMAP, DMF, rt, 50%; (b) C6F5SO2-Met-Phe-OH, EDC, HOBt,
Et3N, DMAP, DMF, rt, 55%, (c) (i) Ph3P, H2O, benzene, reflux, (ii) 4-Biph-Tyr-OH, EDC, HOBt, Et3N, DMAP, DMF, 74% (two steps); (d) Ts-
Tyr(Ts)-OH, EDC, HOBt, Et3N, DMAP, DMF, 76% (two steps).
2. For some reviews and reports, see: (a) Schneider, J. P.;
Kelly, J. W. Chem. Rev. 1995, 95, 2169–2187; (b) Nowick,
J. S.; Smith, E. M.; Pairish, M. Chem. Soc. Rev. 1996, 401–
415; (c) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T.
S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–4011; (d)
Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567–4570; (e)
Farrera-Sinfreu, J.; Zaccaro, L.; Vidal, D.; Salvatella, X.;
Giralt, E.; Pons, M.; Albericio, F.; Royo, M. J. Am.
Chem. Soc. 2004, 126, 2048–6057; (f) Belvisi, L.; Colombo,
L.; Manzoni, L.; Potenza, D.; Scolastico, C. Synlett 2004,
1449–1471.
3. For some selected references on the use of carbohydrate
derivatives as scaffolds, see: (a) Smith, A. B., Jr.; Sasho, S.;
Bari, A. B.; Sprengeler, P.; Barbosa, J.; Hirschmann, R.;
Cooperman, B. S. Bioorg. Med. Chem. Lett. 1998, 8, 3133–
3136; (b) Brittain, D. E. A.; Watterson, P. P.; Claridge, T.
D. W.; Smith, M. D.; Fleet, G. W. J. J. Chem. Soc., Perkin
Trans. 1 2000, 3655–3665; (c) Chakraborty, T. K.;
Jayaprakash, S.; Ghosh, S. Comb. Chem. High Throughput
Screening 2002, 5, 373–387; (d) Gruner, S. A. W.; Locardi,
E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491–514;
(e) Grotenberg, G. M.; Timmer, M. S. M.; Llamas-Saiz,
A. L.; Verdoes, M.; van der marel, G. A.; van Raaij, M. J.;
Overkleeft, H. S.; Overhand, M. J. Am. Chem. Soc. 2004,
126, 3444–3445.
been determined yet, we have determined their activities
as calpain inhibitors, finding that compounds 11 and 12
are moderate calpain inhibitors, with IC50 values of 17
and 78 lM, respectively.18
3. Conclusion
We have developed a totally stereoselective route for the
synthesis of the densely functionalized 3,6-dihydro-2H-
pyran 1, which presents a cis stereochemistry between
the side chains containing the nitrogenated functional-
ities. This scaffold was incorporated in peptidomimetics
that can be considered modified retro-analogues of
enkephalins, and that have shown activity as calpain
inhibitors. Work is in progress in order to determine,
by solution and computational techniques, the conform-
ational preferences induced by template 1 when intro-
duced into a peptidic chain as well as the biological
activity of the resulting enkephalin analogues.
Acknowledgements
´
4. (a) Mann, E.; Chana, A.; Sanchez-Sancho, F.; Puerta, C.;
Garcıa-Merino, A.; Herradon, B. Adv. Synth. Catal. 2002,
Financial support from Janssen-Cilag and Spanish Min-
istry of Science and Technology (project # BQU2001-
2270) is gratefully acknowledged. A.M. thanks CSIC
for an EPO-fellowship. We thank Mercedes Alonso
for computational modeling and for the measuring cal-
pain activity.
´
´
344, 855–867; (b) Mann, E.; Montero, A.; Maestro, M. A.;
´
Herradon, B. Helv. Chim. Acta 2002, 85, 3624–3638; (c)
Salgado, A.; Mann, E.; Sanchez-Sancho, F.; Herradon, B.
´
´
´
Heterocycles 2003, 60, 57–71; (d) Herradon, B.; Montero,
A.; Mann, E.; Maestro, E. CrystEngComm 2004, 6, 512–521.
´
5. Montero, A.; Mann, E.; Herradon, B. Eur. J. Org. Chem.
2004, 3063–3073.
References and notes
6. Inversion of an amide bond in a peptide chain is one of the
earliest amide modifications introduced in peptides in
order to improve their pharmacological properties, see: (a)
Goodman, M.; Chorev, M. Acc. Chem. Res. 1979, 12, 1–7;
For recent applications, see: (b) Volunterio, A.; Bellosta,
1. (a) Hruby, V. J.; Li, G.; Haskell-Luevano, M.; Shender-
ovich, M. Biopolymers 1997, 43, 219–248; (b) Lien, S.;
Lowman, H. B. Trends Biotechnol. 2003, 21, 556–562.

404
A. Montero et al. / Tetrahedron Letters 46 (2005) 401–405
S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.;
17. The analytical and spectroscopic data for 11 and 12 are
indicated below. To identify the signal assignations (that
have been done by a combination of mono- and bi-
dimensional NMR experiments), we have numbered the
atoms in the following manner: unprimed number refer to
the pyrane ring and the dipeptide fragment (including
the side chains of the amino acids), starting from the
pyranosidic oxygen; the primed number (0) indicate the
carbon and hydrogen atoms in the allyloxy fragment; and
the double-primed (00) numbers denote atoms in the
tyrosine derivative fragment (including the side chain).
Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez
de Arellano, C.; Zanda, M. Chem. Eur. J. 2003, 9, 4510–
4522, and references cited therein.
7. All the new compounds gave satisfactory analytical (C, H,
N, 0.3%) and spectroscopic (1H and 13C NMR, IR, MS)
data (for compounds 11 and 12, see Ref. 17).
8. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599;
(b) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–
2910.
9. Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org.
Chem. 1998, 63, 188–192.
1
Peptide 11: Mp: 128–130 °C; [a]D +7 (c 0.3, MeOH); H
10. Interestingly, when trichloroacetimidate 4 was subjected
without any purification to the Overman rearrangement
conditions, the allylic chloride 13 was isolated as sole
product in 50% yield instead of the expected trichloroacet-
amide 4. Remarkably, the reaction took place in a total
stereoselective way, affording exclusively the 3b-chloro
diastereoisomer; its configuration was firmly established
on the basis of NOESY experiments and the X-ray crystal
structure of a p-nitrobenzoyl derivative. As other allylic
chlorides [Jeganmohan, M.; Shanmugasundaram, M.;
Cheng, C. Org. Lett. 2003, 5, 881–884], compound 13
can be a valuable synthetic intermediate. In addition, this
compound has proved useful for the synthesis of haloge-
nated sugars and peptide–carbohydrate hybrids, [Mon-
NMR (300 MHz, 40 °C, DMSO-d6) d 9.06 (s, 1H, OH),
8.51 (d, 1H, J11,9 = 8.5, NH-11), 8.12 (t, 1H, J1 ,7 = 5.6,
00
NH-100), 7.91 (m, 2H, Harom; 1H, NH-8; 1H, NH-16), 7.80
00
00 00
(d, 1H, J4 ,2 = 8.0, NH-4 ), 7.72 (m, 4H, Harom), 7.46 (m,
3H, Harom), 7.20 (m, 5H, Harom), 7.12 (d, 2H, Jortho = 8.3,
arom-Tyr), 6.62 (d, 2H, Jortho = 8.5, Harom-Tyr), 5.91 (d,
H
1H, J5,4 = 10.5, H-5), 5.85 (C of ABCXY, 1H, H-20), 5.66
(dd, 1H, J4,5 = 10.5, J4,3 = 3.9, H-4), 5.24 (A of ABCXY,
1H, J4 ,2 = 17.1, H-40), 5.12 (B of ABCXY, 1H,
0
0
J3 ,2 = 10.5, H-30), 4.66 (m, 1H, H-9), 4.54 (m, 1H, H-
0
0
200), 4.53 (s, 1H, H-2), 4.19 (m, 1H, H-12), 4.07 (X de
ABCXY, 1H, J1 a,1 b = 13.2, J1 a,2 = 6.0, H-10a), 4.11 (X0
0
0
0
0
of A0B0X0, 1H, H-6), 4.00 (m, 1H, H-3), 3.97 (Y of
ABCXY, 1H, J1 b,1 a = 13.2, J1 a,2 = 5.6, H-10b), 3.39 (A0
of A0B0X0, 1H, J7a,7b = 12.9, J7a,6 = 6.1, H-7a), 3.20 (B0 of
A0B0X0, 1H, J7b,7a = 12.9, J7b,6 = 3.7, H-7b), 2.89 (m, 4H,
H-10, H-300), 1.82 (s, 3H, COCH3), 1.48 (m, 1H, H-14),
1.31 (m, 2H, H-13), 0.83 (d, 3H, J = 6.6, H-15), 0.78 (d,
J = 6.6, H-15); 13C NMR (75 MHz, 40 °C, DMSO-d6) d
171.9 (s, CO), 171.8 (CO), 170.5 (s, CO), 169.3 (s, CO),
165.8 (s, CO), 155.7 (s, Carom), 142.8 (s, Carom), 139.1 (s,
0
0
0
0
´
tero, A.; Benito, E.; Herradon, B., in preparation].
t
Me2 BuSiO
O
O
Cl
C
arom), 137.5 (s, Carom), 134.4 (d, C-20), 132.8 (s, Carom),
130.0(d, 2C, Carom), 129.2 (d, 2C, Carom), 129.0 (d, 2C,
13
C
C
arom), 128.6 (d, C-5), 128.4 (d, Carom), 128.1 (d, 2C,
arom), 127.9 (d, 2C, Carom), 126.8 (d, 2C, Carom), 123.2 (d,
11. For synthetic applications of related compounds, see: (a)
Takeda, K.; Kaji, E.; Konda, Y.; Sato, N.; Nakamura, H.;
Miya, N.; Morizane, A.; Yanagisawa, Y.; Akiyama, A.;
Zen, S.; Harigaya, Y. Tetrahedron Lett. 1992, 33, 7145–
7148; (b) Donohoe, T. J.; Blades, K.; Helliwell, M. Chem.
Commun. 1999, 1733–1734; (c) Blades, K.; Donohoe, T. J.;
Winter, J. J. G.; Stemp, G. Tetrahedron Lett. 2000, 41,
4701–4704; (d) Kriek, N. M. A. J.; van der Hout, E.;
Kelly, P.; van Meijgaarden, K. E.; Geluk, A.; Ottenhoff,
T. H. M.; van der Marel, G. A.; Overhand, M.; van Boom,
J. H.; Valentijn, A. R. P. M.; Overkleeft, H. S. Eur. J. Org.
Chem. 2003, 22, 2418–2427; (e) Donohoe, T. J.; Logan, J.
G.; Laffan, D. D. P. Org. Lett. 2003, 5, 4995–4998.
2C, Carom), 122.6 (d, Carom), 122.5 (d, C-4), 116.8 (t,
CH@CH2), 114.8 (d, 2C, Carom), 97.5 (d, C-2), 67.5 (t,
C-10), 66.2 (d, C-6), 55.4 (d, C-9), 53.4 (d, C-200), 51.1 (d,
C-12), 45.1 (d, C-3), 42.1 (t, C-13), 37.5 (t, C-7), 36.5 (t,
C-10 or C-300), 36.4 (t, C-300 or C-10), 24.1 (d, C-14), 22.8
(q, C-15), 23.4 (q, C-15), 21.6 (q, COCH3); IR (KBr) m
3430, 3287, 3061, 2956, 2920, 2861, 1640, 1541, 1384, 1276,
1115, 700; MS (ES+) m/z = 830 ([MꢀH]+, 100%); Anal.
Calcd for C48H55N8O8: C, 69.46; H, 6.68; N, 8.44. Found:
C, 69.46; H, 6.58; N, 8.35. Peptide 12: Mp: 150–152 °C;
[a]D +28 (c 0.25, MeOH); 1H NMR (300 MHz, 40 °C,
DMSO-d6) d 9.42 (d, 1H, J15,12 = 7.7, NH-15), 8.14 (d, 1H,
J11,9 = 7.9, NH-11), 8.06 (d, 1H, J8,3 = 8.2, NH-8), 8.01
´
12. (a) Montero, A.; Mann, E.; Chana, A.; Herradon, B.
Chem. Biodiv. 2004, 1, 442–457; (b) Montero, A.; Alonso,
(t, 1H, J1 ,7 = 5.5, NH-100), 7.96 (d, 1H, J4 ,2 = 9.1,
NH-400), 7.69 (d, 2H, Jortho = 8.4, Harom-tolyl), 7.63 (d,
2H, Jortho = 8.6, Harom-tolyl), 7.45 (d, 2H, Jortho = 8.6,
00
00 00
M.; Benito, E.; Chana, A.; Mann, E.; Navas, J. M.;
´
Herradon, B. Bioorg. Med. Chem. Lett. 2004, 14, 2753–
2757; (c) Montero, A.; Albericio, F.; Royo, M.; Herradon,
´
Harom-tolyl), 7.42 (d, 2H, Jortho = 8.4, Harom-tolyl), 7.20
B. Org. Lett. 2004, 6, 4089–4092.
(m, 5H, Harom-Phe), 7.08 (d, 2H, Jortho = 8.6, Harom-Tyr),
6.79 (d, 2H, Jortho = 8.4, Harom-tolyl), 5.89 (C of ABCXY,
1H, H-20), 5.70 (d, 1H, J5,4 = 10.2, H-5), 5.61 (dd, 1H,
J4,5 = 10.2, J4,3 = 4.4, H-4), 5.28 (A of ABCXY, 1H,
13. Goll, D. E.; Thompson, V. F.; Li, H.; Wei, W.; Cong, J.
Physiol. Rev. 2003, 83, 731–801, and literature cited in Ref.
12b.
14. Computational modeling (MMFF94 force field) on the
N,N0-bis-formyl derivative of D yields a structure that
mimics the b-turn of HC(O)-Gly-Gly-NHCH3.
15. (a) Dooley, C. T.; Houghton, R. A. Biopolym. (Pept. Sci.)
1999, 51, 379–390; (b) Alves, I.; Cowell, S.; Lee, Y. S.;
Tang, X.; Davis, P.; Porreca, F.; Hruby, V. J. Biochem.
Biophys. Res. Commun. 2004, 318, 335–340; (c) Eguchi, M.
Med. Res. Rev. 2004, 24, 182–212.
J4 ,2 = 17.2, H-40), 5.16 (B of ABCXY, 1H, J3 ,2 = 10.2,
0
0
0
0
H-30), 4.56 (m, 1H, H-9), 4.50 (s, 1H, H-2), 4.39 (m, 1H,
0
0
0
0
H-12), 4.13 (X of ABCXY, 1H, J1 a,1 b = 13.3, J1 a,2 = 5.9,
H-10a), 4.00 (m, 2H, H-3, H-10b), 3.96 (m, 1H, H-200), 3.90
(m, 1H, H-6), 3.18 (m, 1H, H-7a), 3.98 (m, 2H, H-7b, H-
10a), 2.80 (m, 2H, H-1000b, H-300a), 2.62 (m, 1H, H-300b),
2.41 (s, 3H, CH3-tolyl), 2.39 (m, 2H, H-14), 2.33 (s, 3H,
CH3-tolyl), 2.03 (s, 3H, COCH3), 1.91 (m, 2H, H-13); 13C
NMR (75 MHz, 40 °C, DMSO-d6) d 170.4 (s, 2C, CO),
169.4 (s, CO), 147.6 (s, Carom), 145.4 (m, 2C, C–F),
145.6 (s, Carom), 142.2 (s, Carom), 141.9 (m, 2C, C–F), 139.0
16. Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical
Approaches to the Synthesis of Peptides and Proteins; CRC:
Boca Raton, 1997.

A. Montero et al. / Tetrahedron Letters 46 (2005) 401–405
405
(m, 1C, C–F), 138.1 (s, Carom), 137.3 (s, Carom), 136.4
(s, Carom), 134.4 (d, C-20), 133.7 (s, Carom), 132.0 (Carom),
131.6 (d, 2C, Carom), 131.4 (d, 2C, Carom), 130.6 (d, C-5),
130.2 (Carom), 129.2 (Carom), 128.9 (d, 2C, Carom), 128.6 (d,
CH3-tolyl), 14.6 (q, CH3S); IR (KBr) m 3429, 3288,
3063, 2956, 2923, 2868, 1639, 1545, 1454, 1384, 1276,
1115, 700; MS (ES+) m/z = 1030 ([(MꢀOAllyl)Na]+,
100%); Anal. Calcd for C52H54F5N5O12S4: C, 53.64; H,
4.67; N, 6.02; S, 11.02. Found: C, 53.76; H, 4.40; N, 6.31;
S, 10.98.
2C,
Carom), 128.1 (Carom), 126.2 (Carom), 122.3 (d,
C-4), 121.4 (d, 2C, Carom), 116.8 (t, CH@CH2), 115.0
(m, C-ipso de C6F5), 97.5 (d, C-2), 67.5 (t, C-10), 66.2
(d, C-6), 57.5 (d, C-200), 53.6 (d, C-10), 52.6 (d, C-12), 45.1
(d, C-3), 37.6 (t, C-7), 36.5 (t, C-10; t, C-300), 30.8 (t,
C-13), 29.5 (t, C-14), 21.1 (q, CH3-tolyl), 20.9 (q,
18. Other peptide-scaffold hybrids (with other scaffolds than
carbohydrate) with sequence similarities to enkephalins
are also calpain inhibitors (Montero, A. Ph.D. Thesis,
´
Autonoma University, Madrid, July 2004).