Stereocontrolled Synthesis of ψ[CH(CF3)NH]Gly-Peptides

Article abstract of DOI:10.1021/ol0354730

(Matrix presented). A novel class of peptidomimetics having a stereogenic [CH(CF₃)NH] replacement for a [CONH] peptide bond has been synthesized. The new compounds have been obtained in a stereocontrolled fashion using a kinetically controlled

Full text of DOI:10.1021/ol0354730

ORGANIC
LETTERS
2
003
Vol. 5, No. 21
887-3890
Stereocontrolled Synthesis of
3
ψ[CH(CF )NH]Gly-Peptides
3
Marco Molteni, Alessandro Volonterio,* and Matteo Zanda*
C.N.R.sIstituto di Chimica del Riconoscimento Molecolare, sezione “A. Quilico”, and
Dipartimento di Chimica, Materiali ed Ingegneria Chimica “G. Natta”, Politecnico di
Milano, Via Mancinelli 7, I-20131, Milan, Italy
matteo.zanda@polimi.it
Received August 5, 2003
ABSTRACT
3
A novel class of peptidomimetics having a stereogenic [CH(CF )NH] replacement for a [CONH] peptide bond has been synthesized. The new
compounds have been obtained in a stereocontrolled fashion using a kinetically controlled aza-Michael addition of chiral r-amino acid esters
to trans-3,3,3-trifluoro-1-nitropropene. The stereoselectivity is strongly influenced by the solvent, the base, its stoichiometry, and the R side-
chain. Diastereomeric ratios higher than 11:1 were achieved using H-Val-OtBu‚HCl in toluene with 1.1 equiv of DIPEA.
Backbone modification with replacement of one or more
1
peptide bonds is a well-established strategy for (1) circum-
venting some of the pharmacological drawbacks of peptides
such as low in vivo bio-availability and adverse ADMET
2
parameters and (2) generating unnatural oligomers with a
strong tendency to adopt specific and predictable conforma-
3
tions in solution (“foldamers”).
Recently, within the frame of a broad project aimed at
the investigation of the “fluorine-effect” in peptides, we have
described the synthesis and some structural and conforma-
tional features of a new class of fluorinated retropeptides A
3
(Figure 1) having a [CH(CF )NH] unit instead of the natural
(
1) (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; B o¨ s, M.; Cook, C. M.;
3
Figure 1. Structure of natural and ψ[CH(CF )NH]Gly-peptides.
Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V.
S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.; Vincent, G. P.; Voss, M. E.
J. Med. Chem. 1993, 36, 3039-3049. (b) Gante, J. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1699-1720. (c) Leung, D.; Abbenante, G.; Fairlie, D. P. J.
Med. Chem. 2000, 43, 305-341. (d) Fletcher, M. D.; Campbell, M. M.
Chem. ReV. 1998, 98, 763-795.
4
[
CONH] peptide bond. This unit is a sort of hybrid between
a peptide bond mimic and a proteolytic transition state
analogue, as it combines some of the properties of a peptidyl
(
2) Loffet, A. J. Peptide Sci. 2002, 8, 1-7. ADMET is an acronym for
absorption, distribution, metabolism, excretion, and toxicity.
3) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015-2022.
b) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101,
219-3232. (c) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem.
ReV. 2001, 101, 3131-3152.
-
CONH- group (low NH basicity, a CH(CF
3
)-NH-CH
(
backbone angle close to 120°, a C-CF bond substantially
3
(
3
isopolar with the CdO) with properties of the tetrahedral
intermediate B (Figure 1) involved in the protease-mediated
1
0.1021/ol0354730 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/18/2003

Table 1. Results of the Aza-Michael Reaction.
R-amino
ester
major
entry
product
R
X
base, solvent, T (°C)
drb
yield (%)
b
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
L-3a
L-3a
L-3a
L-3a
L-3b
L-3b
L-3a
L-3b
L-3b
L-3b
L-3b
L-3b
L-3b
L-3b
L-3b
L-3c
L-3c
L-3d
L-3d
L-3e
D-3f
4a
4a
4a
4a
4b
4b
4a
4b
4b
4b
4b
4b
4b
4b
4b
4c
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
Me
sBu
sBu
Bn
Bn
Bn
Bn
Bn
tBu
tBu
Bn
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
Me
tBu
Me
NaHCO3 (1.1 equiv), DCM, rt
TMP (1.1 equiv), DCM, rt
1.7:1.0
2.5:1.0
3.0:1.0
4.4:1.0
3.7:1.0
7.9:1.0
11.2:1.0
11.7:1.0
3.8:1.0
4.0:1.0
8.5:1.0
5.1:1.0
3.6:1.0
3.7:1.0
3.2:1.0
5.8:1.0
1.6:1.0
7.5:1.0
4.4:1.0
8.5:1.0
1.8:1.0
>98
>98
79
b
c
DABCO (1.1 equiv), DCM, rt
DIPEA (1.1 equiv), DCM, rt
DIPEA (1.1 equiv), THF, rt
DIPEA (1.1 equiv), CCl4, rt
DIPEA (1.1 equiv), toluene, rt
DIPEA (1.1 equiv), toluene, rt
70c
b
>98
>98
79
b
c
65b
b
a
none, toluene, rt
>98
93
b
1
1
1
1
1
1
1
1
1
1
2
2
DIPEA (1.0 equiv), toluene, rt
DIPEA (1.3 equiv), toluene, rt
DIPEA (1.5 equiv), toluene, rt
DIPEA (1.7 equiv), toluene, rt
DIPEA (2.0 equiv), toluene, rt
DIPEA (5.0 equiv), toluene, rt
DIPEA (1.1 equiv), toluene, rt
88b
77b
70b
75b
74b
60c
87c
72c
88c
60c
98c
a
4c
none, toluene, rt
4d
4d
4e
DIPEA (1.1 equiv), toluene, rt
a
none, toluene, rt
DIPEA (1.1 equiv), toluene, rt
a
ent-4f
Bn
none, toluene, rt
a
R-Amino ester was preliminarily treated with NaHCO3. b Determined by 19F and H NMR. c Overall isolated yields.
1
hydrolysis reaction of a peptide bond (high electron density
on the trifluoromethyl group, tetrahedral backbone carbon).
The key aza-Michael reactions between 2 (1.5 equiv) and
an array of R-amino esters, generated in situ from the
7
Moreover, the presence of the bulky CF
3
group is probably
hydrochlorides 3 (1.0 equiv) with a base, were operatively
very simple and took place almost instantaneously at room
temperature, affording the diastereomeric R′-Tfm-â′-nitro
the driving force for the high stability of turn-like conforma-
tions of appropriately configured retropeptides A both in low
polarity organic solvent solutions and in the solid state. In
this paper, we report a significant advancement of our project,
consisting of the stereocontrolled synthesis of brand new
peptidomimetics, much closer to natural peptides, having a
8
R-amino esters 4 (major) and 5 (minor).
The diastereomers 4 and 5 were obtained in chemically
and stereoisomerically pure form by flash chromatography.
The diastereoselectivity of the process was studied in detail
conducting model reactions with L-Val benzyl and tert-butyl
ester hydrochlorides 3a,b. We found that the diastereose-
lectivity depends mainly on four reaction parameters: (1)
the base, (2) the solvent, (3) the stoichiometry of the base,
fluoroalkyl backbone modification: ψ[CH(CF
peptides 1 (Figure 1, R ) H).
3
)NH]Gly-
trans-3,3,3-Trifluoro-1-nitropropene 2 (Scheme 1) was
5
prepared by a Henry reaction of hydrate fluoral with an
(4) and the R side chain of 3. We first investigated the effect
of the base (1.1 equiv in dichloromethane, DCM) on the
diastereoselectivity (Table 1, entries 1-4). Modest stereo-
control was achieved with NaHCO , and slightly better with
3
Scheme 1. Synthesis of the Nitro-alkene
TMP (sym-collidine) and DABCO (1,4-diazabicyclo[2.2.2]-
octane) (entries 1-3, respectively). The best result was
observed with DIPEA (diisopropylethylamine) (63% de,
entry 4).
excess of nitromethane, followed by dehydration on P
2
O
5
(5) For a review, see: Luzzio, F. A. Tetrahedron 2001, 57, 915-945.
(6) Klenz, O.; Evers, R.; Miethchen, R.; Michalik, M. J. Fluorine Chem.
of the intermediate nitroaldol 1 and distillation.6
1
997, 81, 205-210 and references therein.
(7) For a review of asymmetric conjugate additions to nitroalkenes, see:
(
4) (a) Volonterio, A.; Bravo, P.; Zanda, M. Org. Lett. 2000, 2, 1827-
Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak, P. J. Am.
Chem. Soc. 2002, 124, 11689-11698 and references therein.
(8) Typical Procedure. To a stirred solution of 2 (0.84 mmol, 119 mg)
and 3a (0.88 mmol, 216 mg) in toluene (3 mL) was added DIPEA (0.93
mmol, 160 µL) at room temperature. After 0.5 h at room temperature, the
solvent was removed in vacuo, and the crude was dissolved in EtOAc and
washed once with 1 N HCl. The organic layer was dried over anhydrous
Na2SO4. The crude was purified by FC (hexane/diisopropyl ether 9:1)
affording 232 mg (79%) of the two diastereoisomers 4a and 5a in an 11.0:1
ratio.
1
3
830. (b) Volonterio, A.; Bravo, P.; Zanda, M. Tetrahedron Lett. 2001, 42,
141-3144. (c) Volonterio, A. Bellosta, S.; Bravo, P.; Canavesi, M.;
Corradi, E.; Meille, S. V.; Monetti, M.; Moussier, N.; Zanda, M. Eur. J.
Org. Chem. 2002, 428-438. (d) Volonterio, A.; Bellosta, S.; Bravin, F.;
Bellucci, M. C.; Bruch e´ , L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille,
S. V.; Meli, M.; Ram ´ı rez de Arellano, C.; Zanda, M. Chem. Eur. J. 2003,
in press. “Fluorine-effect” refers to the unique modification of chemical,
physical, biophysiological, and pharmacological properties of fluorinated
molecules brought about by fluorine atom(s).
3888
Org. Lett., Vol. 5, No. 21, 2003

The effect of the solvent was investigated next (entries
4
-8) using DIPEA (1.1 equiv) as a base. As recently ob-
Scheme 2. Aza-Michael Reaction
served for a tandem process involving an aza-Michael reac-
tion with fluorinated acceptors, we found that low-polarity
9
or apolar solvents provided remarkably higher diastereocon-
trol. Thus, DCM (entry 4) and THF (entry 5) afforded modest
des, while less polar toluene increased the de to 84% (entries
7
and 8). Intermediate results were observed using apolar
CCl (entry 6).
4
Surprisingly, the stoichiometry of DIPEA was also found
to have a profound effect on the stereocontrol. In the absence
10
of free DIPEA (entries 9 and 10), the de dropped dramati-
cally. Accordingly, a progressive decrease of stereoselectivity
was observed by increasing the amount of DIPEA from 1.1
to 1.7 (entries 11-13), whereas little variation occurred
beyond this quantity (entries 14 and 15). Further experiments
The main drawback of the use of DIPEA as the base is
that somewhat modest yields were achieved in most cases
(
60-72%). Optimal yields (87-98%) were obtained using
free R-amino esters (entries 11, 13, 15, 17), generated upon
preliminary treatment of 3 with aqueous NaHCO , but in
3
(not included in Table 1) showed that other bases such as
this case, the diastereoselectivities were remarkably lower.
The stereochemistry of the minor diastereomer 5a was
assessed by X-ray diffraction, whereas the configurations of
the other adducts 4 and 5 were confidentially assigned on
the basis of their spectroscopic and analytical features in
TMP and NaHCO do not feature the same “stoichiometry-
3
effect”, affording comparable des upon changing the number
of equivalents used.
No interconversion took place when pure diastereomers
4
and 5 were submitted to the exact reaction conditions for
12
comparison with those of 4a and 5a.
up to 16 h. Furthermore, no effect of the reaction time on
the stereocontrol was detected. These aza-Michael reactions
must therefore occur under kinetic control.
Elaboration of the major adducts 4 into the target
ψ[CH(CF )NH]Gly-peptides 7 (Scheme 3) was addressed
3
The effect of the R side chain of 3 is evident taking into
account the reaction of different R-amino esters under the
optimized conditions. In fact, less bulky R groups gave rise
to lower degrees of stereocontrol in comparison with 4a,b,
as observed for L-Ala-OtBu 3c (71% de, entry 16) and L-Phe-
OtBu 3e (79% de, entry 20).
Scheme 3. Elaboration of the Aza-Michael Adducts 4 into
ψ[CH(CF )NH]Gly-Peptides 7
3
An important effect of the stereogenic sec-butyl side-chain
is more than likely in the case of L-Ile-OMe 3d (77% de,
entry 18), so this result should be weighted in a different
manner.
Ancillary experiments showed that the ester group X of 3
has a negligible effect (compare entries 7 and 8). In contrast,
the temperature is very important. Room temperature is
essential in order to achieve high yields, whereas at both
-
40 and -70 °C, very complex mixtures of products were
obtained. This rather surprising finding can be interpreted
by supposing that at low temperatures there are several
competitive side-processes, whereas the formation of 4 and
5
is favored at higher temperatures.
All the experimental evidence above suggests that this
next. The nitro group of 4b-d was hydrogenated to an amino
group using Pearlman’s catalyst (Scheme 3); the diamino
compounds 6b-d were trapped as hydrochlorides and sub-
mitted without purification to coupling with Cbz-L-Phe-OH,
aza-Michael reaction involves a tight, polar, termolecular
transition state (TS), involving 2, 3, and DIPEA, which
appears to play a fundamental catalytic role.11 Polar sol-
vents, as well as the presence of more than one molecule of
DIPEA in the TS, may disrupt it, thus lowering the
stereocontrol.
affording the ψ[CH(CF )NH]Gly tripeptides 7b-d in good
3
overall yields. Analogously, the nitro-adduct ent-4f de-
rived from D-Phe-OMe was transformed into Cbz-L-Phe-ψ-
3
[CH(CF )NH]Gly-D-Phe-OMe 7f.
(9) Sani, M.; Bruch e´ , L.; Chiva, G.; Fustero, S.; Piera, J.; Volonterio,
A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42, 2060-2063. However, it
should be stressed that the two processes are conceptually and mechanisti-
cally unrelated, since the stereocontrol of the reaction described in the
reference above arose from an enolate protonation following the aza-Michael
reaction, that per se was not stereogenic.
(11) Catalytic effect of amine bases in Michael-type reactions is well-
known. See for example: (a) McDaid, P.; Chen, Y.; Deng, L. Angew. Chem.
Int. Ed. 2002, 41, 338-340 and references therein. (b) van Axel Castelli,
V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt, D. N.; Schiaffino, L. Eur. J.
Org. Chem. 2003, 627-633.
(12) Full X-ray data and criteria for the stereochemistry assignments will
be published in a full paper.
(10) In the experiment of entry 9, DIPEA was not added at all, whereas
in entry 10 (1.0 equiv added), it is completely neutralized as hydrochloric
acid salt.
Org. Lett., Vol. 5, No. 21, 2003
3889

An in depth study of the aza-Michael reaction mechanism
and an investigation of the conformational, structural, and
00181), MIUR (Cofin 2002, Project “Peptidi Sintetici Bio-
attivi”), Politecnico di Milano, and C.N.R. for financial
support.
biological properties of ψ[CH(CF
currently underway. A synthesis of more complex ψ[CH-
CF )NH]-peptides incorporating Tfm-analogues of chiral
3
)NH]Gly-peptides are
Supporting Information Available: Detailed descrip-
tions of experimental procedures and spectral data of com-
pounds 4, 5, and 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
3
amino acids, rather than Gly, is being developed.
Acknowledgment. We thank the European Commission
(IHP Network Grant “FLUOR MMPI” HPRN-CT-2002-
OL0354730
3890
Org. Lett., Vol. 5, No. 21, 2003