Highly stereoselective tandem aza-Michael addition-enolate protonation to form partially modified retropeptide mimetics incorporating a trifluoroalanine surrogate

Article abstract of DOI:10.1002/anie.200250711

Fine-tuning of key reaction parameters, such as the solvent and the base used, led to a dramatic improvement in d.r. (from ≈1:1 to 38:1) in a tandem aza-Michael addition-enolate protonation sequence. Thus, the reaction of α-amino ester nucleophiles 1 with N-(α-trifiuoromethyl)acryloyl-α-amino ester acceptors 2 produced an array of partially modified retropeptide mimetics 3 with good to excellent stereocontrol (R, R¹, R², X, X¹ = alkyl).

Full text of DOI:10.1002/anie.200250711

Communications
Fluorinated Peptidomimetics
3,3,3-trifluoroalanine (TF-Ala) unit. Unfortunately, the incor-
poration of TF-Ala into a peptide sequence to give a modified
peptide A is a challenging endeavor,[5] as such peptides have
low chemical and configurational stability at pH > 6.[6] To the
Highly Stereoselective Tandem Aza-Michael
Addition–Enolate Protonation to Form Partially
Modified Retropeptide Mimetics Incorporating a
Trifluoroalanine Surrogate**
O
CF3
O
O
CF3
O
H
H
H
H
N
N
N
N
Monica Sani, Luca BruchØ, Gema Chiva,
Santos Fustero,* Julio Piera, Alessandro Volonterio,*
and Matteo Zanda*
R
N
NHR3 RHN
NHR3
*
*
H
R1
O
R2
R1
O
R2
A
1
Poor bioavailability and rapid in vivo degradation are the two
main drawbacks to the use of peptides as drugs.[1] Peptide-
backbone modification has emerged as a powerful tool for
overcoming these disadvantages, while retaining specific and
potent bioactivity.[2] A number of modifications have been
proposed, many of which have proved successful, such as the
replacement, addition, or deletion of one or more amino acids
in the parent sequence, the replacement of peptide bonds with
surrogates, and the incorporation of synthetic scaffolds (often
cyclic) into the backbone. We recently described novel
peptidomimetic structures that incorporate a trifluoromethyl
group,[3] within the frame of a research project aimed at the
development of fluorine-containing protease inhibitors. The
current project stems from the belief that the beneficial
pharmacological effect of introducing fluorine substituents
into a druglike molecule could be extended to peptides and
peptidomimetics. Little information on the synthesis or the
structural, conformational, and biological properties of fluo-
rinated peptidomimetics is available in the literature.[4]
Recently, we became interested in the development of
peptide mimetics that incorporate a stereochemically defined
best of our knowledge, no mimetics of TF-Ala-containing
peptides have been described to date. For this reason, we
planned the synthesis of partially modified retro (PMR)
y[NHCH2] peptide mimetics[7] 1, which incorporate a chemi-
cally stable and stereodefined CH2CH(CF3)CO surrogate for
TF-Ala.
Retrosynthetic analysis suggested that the asymmetric
conjugate N-addition of a-amino esters to N-(a-trifluorome-
thyl)acryloyl-a-amino esters could represent a viable entry to
the target structures 1. However, surprisingly few studies have
been dedicated to the asymmetric conjugate addition of
nitrogen nucleophiles (such as amines, hydroxylamines, or
amino acid derivatives) to a-substituted acryloyl acceptors,
formally a tandem nonstereoselective aza-Michael reaction–
stereoselective enolate protonation.[8] None of the previous
studies addressed the issue of double stereoinduction. In our
case, further challenges were expected because of the
presence of the stereoelectronically demanding trifluoro-
methyl group and the strongly acidic nature of the
CH(CF3)CO proton, which could lead to epimerization of
the stereogenic center under the basic reaction conditions.
Herein we describe the smooth and general synthesis of
PMR-y[NHCH2]-tripeptides 4 (Scheme 1) by tandem asym-
metric aza-Michael addition–enolate protonation of a-amino
esters 2 with N-(a-trifluoromethyl)acryloyl-a-amino esters 3.
This sequence takes place with good to excellent 1,4-
asymmetric induction (up to 95% de) depending on the
substrate. Very high stereocontrol was observed upon the
fine-tuning of key reaction parameters, such as the solvent
and the base used. Side chains (R and R1) and chirality
(matched/mismatched pairs) of both reaction partners 2 and 3
were also found to have a strong influence on the diaste-
reoselectivity.
[*] Dr. M. Zanda, M. Sani
C.N.R. – Istituto di Chimica del Riconoscimento Molecolare (ICRM)
Sezione “A. Quilico”
via Mancinelli 7, 20131 Milano (Italy)
Fax: (+39)02-2399-3080
E-mail: matteo.zanda@polimi.it
Dr. A. Volonterio, Prof. Dr. L. BruchØ
Dipartimento di Chimica, Materiali ed
Ingegneria Chimica “Giulio Natta”
Politecnico di Milano
via Mancinelli 7, 20131 Milano (Italy)
Fax: (+39)02-2399-3080
Michael acceptors 3 (Scheme 2) were obtained by treat-
ment of the appropriate a-amino ester H-AA-OX1 with (a-
trifluoromethyl)acryloyl chloride 6,[9] which was prepared in
turn from the acid 5. Yields were generally high and the
substrates 3 could be readily purified by flash chromatog-
raphy (FC).
The reactions of a-amino esters (generated in situ by the
treatment of commercially available hydrochlorides 2 with a
tertiary amine) with Michael acceptors 3 were operationally
very straightforward, quite fast, and efficient. Thus, 2, 3, and
the amine base were simply mixed in the appropriate solvent,
and at the end of the reaction (usually after 2 h at RT) the
solvent was evaporated. The PMR-tripeptides 4 were isolated
in yields of 75–98% (Scheme 3 and Table 1).
E-mail: alessandro.volonterio@polimi.it
Prof. Dr. S. Fustero, G. Chiva, J. Piera
Departamento de Química Orgµnica
Facultad de Farmacia, Universidad de Valencia
46100-Burjassot, Valencia (Spain)
Fax: (+34)96-386-4939
E-mail: santos.fustero@uv.es
[**] We thank the European Commission (IHP Network grant “FLUOR
MMPI” HPRN-CT-2002-00181), MIUR (Cofin 2002, Project “Peptidi
Sintetici Bioattivi”), CNR (Italy), and MCYT (PPQ2000–0824)
(Spain) for financial support. We are indebted to Prof. Takeo Taguchi
and Prof. Takashi Yamazaki for useful experimental information on
the preparation of (a-trifluoromethyl)acryloyl chloride.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2060 ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200250711
Angew. Chem. Int. Ed. 2003, 42, 2060 – 2063

Angewandte
Chemie
CF3 R2
N
renders the experimental procedure less practical.
.
HCl
XO2C
NH2
CO2X1
Surprisingly, the de dropped when the chiral bases
quinidine and cinchonine were used (54% and
9% de for 4b, respectively Table 1, entries 19 and
20).
+
R
O
R1
2
3
CF3 R2
N
CF3 R2
N
Reaction temperature was not a major factor in
the range À408C to RT (Table 1, entries 1, 3 and 4).
Concentration had negligible effect on the stereo-
control, but we qualitatively observed (TLC mon-
itoring) a clear-cut increase in the reaction rate with
increasing concentrations of 2 and 3. This effect was
particularly pronounced with the Pro-derived
acceptor 3b.[11] Ancillary control experiments dem-
onstrated that, as expected, the reaction is kineti-
cally controlled, and that under the optimized
conditions (DABCO, CCl4, RT) the CF3-substituted
stereogenic center of the products 4 is configura-
tionally stable.
H2
H
N
protonation
CO2X1
XO2C
N
CO2X1
XO2C
+
d.r. ≤ 38:1
R1
4
R
O
R1
R
O
–
Scheme 1. Tandem reaction to produce PMR-y[NHCH2]-tripeptides 4.
CF3 R2
CF3
CF3
a
CO2X1
b
N
OH
Cl
3
6
5
O
R1
O
O
Scheme 2. Preparation of the chiral Michael acceptors 3. a) Phthaloyl
chloride, 1408C; b) HCl·H-AA-OX1, TMP (2 equiv), CH2Cl2, 0–258C,
75–95%. AA=Gly, Val, Pro, Ala, Phe, Leu, etc.
The full scope of the methodology in the
synthesis of PMR-peptides 4 and the effect of the
structure and stereochemistry of the reactants 2 and
3 on diastereoselectivity were investigated next. To
this end, a variety of amino ester hydrochlorides
2a–j were treated with acceptors 3a–h under the
optimized conditions (DABCO, CCl4, RT) to pro-
vide a library of molecules 4d–u, in generally good
to excellent yields (Scheme 4 and Table 2).
CF3 R2
CF3 R2
N
2 h, RT
solvent
H
.
XO2C
NH2 HCl
XO2C
N
N
CO2X1
CO2X1
+
*
base
(2 equiv)
O
R1
O
R1
4a,b
2a,b
3a,b
a: R1 = iPr; R2 = H; X = Bn; X1 = Bn
b: R1 = R2 = -(CH2)3-; X = tBu; X1 = Bn
(1 equiv)
(1 equiv)
Scheme 3. Reaction optimization: influence of base and solvent on stereo-
selectivity.
The R side chain of 2 has a strong influence, as
was clearly demonstrated in the addition of 2b–g to
We first investigated the effect of the tertiary amine base
on the diastereoselectivity of the reaction by conducting
model reactions in CH2Cl2 between l-Val ester hydrochlo-
rides 2a (X = Bn) and 2b (X = tBu), and acceptors 3a
(derived from l-Val) and 3b (derived from l-Pro), respec-
tively (Scheme 3, Table 1, entries 1–10). These experiments
showed that the amine base has a profound influence. Modest
stereocontrol was observed with TMP, DMAP, TEA, and
DIPEA (Table 1, entries 1–6). Of these, the best result was
obtained with DIPEA (65% de for 4a, Table 1, entry 6).
Considerably higher diastereocontrol was obtained with
DABCO, which promoted the formation of 4a and 4b in
77% and 83% de, respectively (Table 1, entries 7 and 8).
Lower de (70%) was observed in the absence of an amine
(Table 1, entry 9). The effect of solvent, which is the other
main factor in this reaction, was investigated next in the
presence of DABCO as the base (Table 1, entries 10–17). We
found that the use of low-polarity or apolar solvents resulted
in much higher diastereocontrol. Thus, acetonitrile (Table 1,
entry 10) promoted modest de (63% for 4b), lower than that
observed for CH2Cl2, whereas use of the less polar solvent
THF increased the de to 88% (Table 1, entry 11). Even better
results were obtained with toluene, in which 4a and 4b were
formed in 89% and 90% de, respectively (entries 12 and
14).[10] Use of the apolar solvent CCl4 gave the best
diastereoselectivity with 4a and 4b formed in 94.9% and
94.6% de, respectively (Table 1, entries 16 and 17). Very good
de was also observed in the presence of Me3N as the base
(94.3% de for 4a, Table 1, entry 18), but its high volatility
Table 1: Influence of base and solvent.
Entry
Product
Base[a]
Solvent
Yield [%]
d.r.[b]
3.7:1.0
3.8:1.0
4.0:1.0
4.2:1.0
3.0:1.0
4.7:1.0
1[c]
2
4a
4a
4a
4a
4b
4a
4a
4b
4a
4b
4b
4a
4a
4b
4a
4a
4b
4a
4b
4b
TMP
DMAP
TEA
TEA
TEA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
toluene
toluene
toluene
toluene
CCl4
>98
90
86
84
77
95
>98
84
94
91
95
83
75
95
85
90
90
94
79
84
3
4[d]
5
6[c]
7
DIPEA
DABCO
DABCO
–
DABCO
DABCO
DABCO
DABCO (cat.)
DABCO
–
DABCO
DABCO
TMA
quinidine
cinchonine
7.6:1.0
10.5:1.0
5.7:1.0
8
9[c,e]
10
11
12
13[f]
14
15[g]
16
17
18[h]
19[g]
20[g]
4.4:1.0
15.0:1.0
17.4:1.0
13.3:1.0
18.0:1.0
3.3:1.0
38.0:1.0
36.0:1.0
34.0:1.0
3.3:1.0
1.2:1.0
CCl4
CCl4
toluene
toluene
[a] TMP=2,4,6-trimethylpyridine (sym-collidine), DMAP=4-dimethyl-
aminopyridine, TEA=triethylamine, DIPEA=diisopropylethylamine,
DABCO=1,4-diazabicyclo[2,2,2]octane, TMA=trimethylamine.
[b] Determined by 19F NMR spectroscopy and/or HPLC analysis.
[c] Reaction carried out at 08C. [d] Reaction carried out at À408C.
[e] Hydrochloride 2a was treated prior to reaction with aqueous
NaHCO3. [f] DABCO (0.1 equiv) was used after treatment of 2a with
aqueous NaHCO3. [g] Reaction time: 48 h. [h] Reaction carried out at
À108C.
Angew. Chem. Int. Ed. 2003, 42, 2060 – 2063
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2061

Communications
The configurations of the PMR-peptides
4j and 4n were determined by X-ray
diffraction,[12] and the configurations of the
other main diastereomers 4 were tentatively
assigned by analogy with 4j and 4n, based
on their spectroscopic and physical data.
The striking effects of the amine catalyst
and the solvent on the diastereoselectivity of
the reaction had not been described in
previous studies on the asymmetric addition
of nitrogen nucleophiles to a-substituted
acryloyl acceptors,[8] in which the best ster-
eocontrol was often achieved in protic
solvents, in the absence of an amine base.
Although detailed kinetic and computa-
tional studies will be necessary before we
can draw a reliable mechanistic picture of
this process, the body of experimental
evidence discussed above suggests that the
amino ester 2, Michael acceptor 3, and
DABCO might form a tight termolecular
ion-pair transition state, which is energeti-
cally favored and not disrupted in nonpolar
solvents.[13]
Scheme 4. Synthesis of an array of PMR-y[NHCH2]-tripeptides (4).
Table 2: Validation of the methodology and influence of R, R1, R2, and configuration on diastereose-
lectivity.
Entry
2
3
4
R[a]
X
R1[a]
R2
X1
Yield [%]
d.r.[b]
7.0:1.0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
c
a
a
a
a
a
c
b
b
b
e
d
e
f
g
h
i
H
iBu
Bn
Me
sBu
iPr
Et
Bn
iPr
iPr
iPr
iPr
iPr
iPr
-(CH2)3-
-(CH2)3-
-(CH2)3-
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
tBu
Bn
Bn
Bn
Bn
tBu
tBu
tBu
Me
Me
Bn
Bn
Bn
98
80
85
82
80
90
84
85
83
70
71
76
70
73
87
85
82
89
d
e
f
g
b
e
f
g
h
a
i
d-i
d-j
j
10.6:1.0
13.0:1.0
14.0:1.0
23.0:1.0
33.0:1.0
12.5:1.0
24.0:1.0
29.0:1.0
6.0:1.0
29.2:1.0
17.0:1.0
3.2:1.0[c]
2.8:1.0
1.0:1.0[c]
2.0:1.0
Me
Me
Me
tBu
Me
Me
Me
Bn
j
Bn
k
L
m
n
o
p
q
r
Me
sBu
Bn
Bn
H
H
H
H
H
H
H
H
H
f
f
f
iPr
Bn
Me
Me
Me
d-Ph
d-Ph
H
Me
d-Me
d-Ph
Ph
Bn
sBu
iPr
tBu
tBu
Me
Me
Me
Me
Bn
d-g
d-g
h
h
h
In conclusion, we have described a
highly stereoselective synthesis of PMR-
y[NHCH2]-peptides that incorporate a ster-
eochemically defined and stable TF-Ala
mimetic by means of a novel tandem
asymmetric aza-Michael addition–enolate
protonation reaction. The process is opera-
tionally very simple, makes use of readily
e
g
a
s
t
u
H
H
3.0:1.0
6.0:1.0
[a] l-Configured amino esters were used unless otherwise indicated. [b] Determined by 19F NMR
spectroscopy and/or HPLC analysis. [c] The stereochemistry at the carbon center a to the CF3 group was
not assigned.
the l-Val acceptors 3a and 3c (Table 2, entries 1–6). The de of
the products 4d–i increased in the sense R = H < iBu < Bn <
Me < sBu < iPr, such that the best stereocontrol was achieved
with the bulkiest R groups. This trend was confirmed with the
other acceptors 3b (l-Pro-derived, Table 2, entries 7–9), 3 f
(l-Ala-derived, entries 11 and 12), and 3h (Gly-derived,
entries 16–18). The R1 side chain of the acceptors 3 also had a
strong influence, as shown by the fact that l-Phe amino esters
such as 2e and 2h (R = Bn) reacted with 3h (Gly acceptor,
Table 2, entry 16), 3e (l-Phe acceptor, entry 10), 3b (L-Pro
acceptor, entry 7), and 3a (l-Val acceptor, entry 3) with
progressively higher diastereocontrol (d.r. of products
increased from 2.0:1.0 to 13.0:1.0). The effect of R1 on the
de followed the same trend observed for R. The configuration
of the reaction partners 2 and 3 also had a profound effect, as
demonstrated by the use of matched/mismatched pairs of the
l- and d-Ala methyl esters 2i and the l-Ala acceptor 3 f
(Table 2, entries 12 and 13), and the d- and l-phenylglycine
methyl esters 2j and the d-phenylglycine acceptor 3g
(Table 2, entries 14 and 15). In both cases the “like”
combination (d/d or l/l) resulted in higher diastereoselectiv-
ity, with the striking case of like-2i/3 f, which gave an excellent
17.0:1.0 ratio in favor of the 4o diastereomer (Table 2,
entry 12), whereas a modest 3.2:1.0 diastereomeric ratio was
found in the case of unlike-2i/3 f (Table 2, entry 13). The X
and X1 ester groups had minor (if any) influence on stereo-
selectivity.
available and cheap reagents, occurs under very mild
conditions, and produces compounds suitable for combinato-
rial applications, all of which are of interest for potential
industrial development. Additional interest in this reaction
stems from its peculiar mechanism and the underlying
stereochemical implications, such as the high double stereo-
induction and the strong stereodirecting solvent and base
effects, which deserve further in-depth mechanistic investi-
gations.
Received: December 6, 2002 [Z50711]
Keywords: diastereoselectivity · Michael addition ·
.
peptidomimetics · protonation · solvent effects
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[10] In toluene the absence of an amine produced a dramatic drop in
stereoselectivity (54% de for 4a, Table 1, entry 15). The de also
decreased when DABCO was used in a catalytic amount (86%
for 4a, Table 1, entry 13).
[11] Faster reactions were also observed when DABCO was used
instead of TEA, DIPEA, or TMP.
[12] The crystal structures of 4j and 4n will be published in a full
paper.
[13] The asymmetric addition of chiral alcohols to ketenes (“Merck
reaction”), a conceptually related reaction, shows a very similar
dependence on the polarity of the solvent and the structure of
the catalyst (the amine base). See, for example: a) R. D. Larsen,
E. G. Corley, P. Davis, P. J. Reider, E. J. J. Grabowski, J. Am.
Chem. Soc. 1989, 111, 7650 – 7651; see also: b) B. L. Hodous, J. C.
Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637 – 2638;
c) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, W. J. Drury III,
T. Lectka, J. Am. Chem. Soc. 2000, 122, 7831 – 7832; d) M.
Angew. Chem. Int. Ed. 2003, 42, 2060 – 2063
www.angewandte.org
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