Unexpected formation of new chiral 3-amino-5-alkyl-2,5-dihydro-1H-pyrrolin- 2-ones from N-Boc-α-amino esters

Article abstract of DOI:10.1016/j.tetlet.2005.03.067

We describe a one-pot process involving the DiBAl-H reduction of the ester moiety of N-protected α-amino esters, followed by Horner-Wadsworth-Emmons olefination in the presence of the trimethyl ester phosphonoglycinate carbanion allowing the formation of new chiral 3-amino-5-alkyl-2,5-dihydro-1H pyrrolin-2-one 5. The Z-enoate 4b, which is formed during this reaction, could be converted into the corresponding lactam 5b under UV irradiation with the presence of BuLi.

Full text of DOI:10.1016/j.tetlet.2005.03.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3517–3520
Unexpected formation of new chiral 3-amino-5-alkyl-2,5-
dihydro-1H-pyrrolin-2-ones from N-Boc-a-amino esters
*
Nicolas Inguimbert, Helene Dhotel, Pascale Coric and Bernard P. Roques
´ `
ˆ
´ ´
´
´
Laboratoire de Pharmacologie Chimique et Genetique, Universite Rene Descartes Paris V, UFR des Sciences
Pharmaceutiques et Biologiques, INSERM U640, CNRS UMR 8151, 4 avenue de l’observatoire, 75270 Paris Cedex 06, France
Received 10 February 2005; revised 10 March 2005; accepted 14 March 2005
Available online 1 April 2005
Abstract—We describe a one-pot process involving the DiBAl-H reduction of the ester moiety of N-protected a-amino esters,
followed by Horner–Wadsworth–Emmons olefination in the presence of the trimethyl ester phosphonoglycinate carbanion
allowing the formation of new chiral 3-amino-5-alkyl-2,5-dihydro-1H pyrrolin-2-one 5. The Z-enoate 4b, which is formed during
this reaction, could be converted into the corresponding lactam 5b under UV irradiation with the presence of BuLi.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, we have reported the synthesis of non-peptidic
aminopeptidase A (APA) inhibitors,1 which could con-
stitute a new class of antihypertensive drugs acting on
the central Renin–Angiotensin system.2 In order to en-
hance their affinity for the targeted zinc metallopepti-
dase, APA, docking experiments of putative inhibitors
were undertaken in leukotriene A4 hydrolase.3,4 Indeed,
this enzyme is also a monozinc aminopeptidase, which
presents significant primary sequence homology with
APA and was therefore used for the building of an
APA model.5 This docking study results in the identifi-
cation of b-mercaptoacid 1 as a potential APA inhibitor
acting as a bidentate with the catalytic zinc (Fig. 1). As
part of our investigation into the synthesis of target mol-
ecule 1, we imagined that the potential intermediate
c-amino-a,b-didehydroamino acid derivative 2 could
be obtained from the corresponding N-benzylyoxycar-
bonyl-a-amino ester 3a through DiBAl-H reduction of
N-protected a-amino ester and trapping of the interme-
diate aluminate with the N-protected phosphonoglyci-
nate trimethyl ester carbanion (Fig. 2).
of the stereocentre and production of the a-amino alco-
hol. When the reaction was performed using 3a, this
one-pot process afforded a mixture consisting of the
enoate 4a and of the unexpected 3-amino-5-alkyl-2,5-
dihydro-1H-pyrrolin-2-one 5a, which was fully charac-
1
terized by means of H, 13C NMR and MS. To the best
of our knowledge, such highly functionalized pyrrolin-
2-ones 5 were not previously described. Furthermore,
these kind of five-membered ring lactams are found as
substructures in numerous natural products bearing
interesting pharmacological activities, among other
examples are the potent cytotoxic and immunopressive
lipopeptides microcolin A and B,8 which contain a
Pro-pyrrolin-2-one unit, although they do not contain
an amino group in the 3-position of the ring. Moreover,
such lactam derivatives bearing also an enamine func-
tionality are useful building blocks in organic and asym-
metric synthesis.9 In this letter we report our initial
discovery and the preliminary exploration of the scope
of this one-pot process,10 which was applied to various
N-Boc-a-amino esters 3b–f and to a fully protected
dipeptide 3g yielding new highly functionalized pyrrolin-
2-one 5 as well as the obtention of compounds 4 (Fig. 2).
We provide also a method for the conversion of the
Z-enoates 4 into the lactam 5.
This method is analogous to those developed by Takacs
et al.6 and David et al.7 for the obtention of a,b-unsat-
urated esters, which allowed to avoid both racemization
The reduction in THF at ꢀ78 °C of N-Boc-a-amino
esters 3 (1 equiv) with 2 equiv of DiBAl-H to the
aluminoxyacetal was conducted in the presence of
the phosphonoglycinate trimethyl ester carbanion (2
equiv) previously generated by addition of n-BuLi on
Keywords: Pyrrolin-2-one; Horner–Wadsworth–Emmons olefination;
a-b-Didehydro amino acids; Enamine.
Corresponding author. Tel.: +33 153739568; fax: +33 143266918;
e-mail: nicolas.inguimbert@univ-paris5.fr
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.067

3518
N. Inguimbert et al. / Tetrahedron Letters 46 (2005) 3517–3520
Figure 1. Putative APA inhibitor and its retrosynthetic scheme.
Figure 2. One-pot process for the synthesis of 4a–g and 5a–f. The various substituents R, R1 and R2 are defined in Table 1.
commercially available phosphonoglycine trimethyl-
ester. The intermediate aluminate then underwent a
Horner–Wadsworth–Emmons (HWE) reaction. After
1 h at ꢀ78 °C, the reaction mixture was allowed to warm
to room temperature in order to complete the reaction
thus affording a mixture of the Z-enoate 4 and the lac-
tam 5 (Fig. 2 and Table 1). In all experiments, HPLC
analysis performed on the reaction mixture have showed
that the initially fully protected a-amino ester was to-
tally consumed and that only the two expected products
were formed in nearly equivalent proportions. In order
to dispose of analytical pure material, the two products
were purified and separated by semi-preparative HPLC
yielding compounds 4 and 5 in 40% overall yield.
Surprisingly, when the dipeptide 3g was submitted to
this one-pot process, only the orthogonally protected
lactam 5g was isolated.
which led to compounds 4b–c and 5b–c, respectively,
showing, as expected, opposite optical rotation.
This reaction was further investigated starting from
commercially available N-Boc-phenylalaninal 6, in
order to discard DiBAl-H in the cyclization (Table 2,
Fig. 3). The N-Boc-phenylalaninal 6 was treated in the
presence of 1 equivof trimethylphosphonoglycinate tri-
methyl ester and solely the base amount was variable.
If this reaction was performed in presence of DBU (1
or 2 equiv), only the Z-enoate 4b was formed in almost
quantitative yield independently of the number of equiv-
alents of base (Table 2). The Z configuration was con-
firmed by NOE measurements. NOEÕs were observed
between HB and HC but also between HA and the hydro-
gens of the methyl ester moiety (Fig. 3). Furthermore
the ethylenic proton chemical shift is analogous to those
observed for previously described Z-didehydro-a-amino
acid d = 6.5 ppm while for the E configuration the ethyl-
enic proton is deshielded d = 6.7 ppm.11 Contrary to the
former trials, when the reaction was performed using
n-butyl lithium (1 or 2 equiv) the two products 4b and
Furthermore, it is noteworthy that the phosphonate
anion reacted with the aluminate without epimerization
of the stereocentre as shown by the reaction with the two
enantiomers of N-Boc-phenylalanine methyl ester,
Table 1. Yields, optical rotations and HPLC retention time for compounds 4a–f and 5a–g
20
a
b
Compound 4
R
R1
R2
Configuration
½aꢁD
—
d HA
Yield (%)
tR
a
b
c
d
e
f
–CH2CH2SO3CH2C(CH3)3
–CH2Ph
–CH2Ph
Z
Boc
Z
S
6.12
6.16
6.16
6.47
5.96
6.24
17
25
22
11
23
24
10.1
9.3
Boc
Boc
Boc
Boc
Boc
S
+106 1.2
ꢀ103 0.9
Z
R
—
S
9.3
5.1
–H
–CH2–CH2COOt-Bu
–CH2O–t-Bu
Z
—
+100.9 1.5
+94.5 1.2
Z
11.3
10.8
Z
S
Compound 5
a
b
c
d
e
f
–CH2CH2SO3CH2C(CH3)3
–CH2Ph
–CH2Ph
Z
Boc
Z
S
+6.5 1
+21.7 1.7
6.77
6.80
6.80
6.89
6.81
7.01
6.95
10
16
18
10
14
10
14
11.9
12.2
12.2
5.8
Boc
Boc
Boc
Boc
Boc
Boc-Ala
S
Z
R
ꢀ20.6 1.5
–H
Z
—
S
—
–CH2–CH2COOt-Bu
–CH2O–t-Bu
–CH2Ph
Z
+29.7 1.0
+19.5 0.2
+61.6 0.6
12.8
11.9
12.2
Z
S
g
Z
S–S
a Chemical shift (ppm) recorded in CDCl3.
b
˚
HPLC retention time (tR, min) Kromasil C18 5l 100 A with a mobile phase consisting of 30% H2O, 70% CH3CN.

N. Inguimbert et al. / Tetrahedron Letters 46 (2005) 3517–3520
Table 2. Effect of the base on the formation of compound 4b and 5b
3519
Assay
Base
EquivReaction times and temperature
tR and %,a yield of 4b
tR and %,a yield of 5b
1
DBU
1
2
1
2
1 h 25 °C
+2 h 25 °C
9.3 (100%)
9.3 (100%), 93
Not detected
Not detected
2
3
4
DBU
BuLi
BuLi
1 h 25 °C
+2 h 25 °C
9.3 (100%)
9.3 (100%), 97
Not detected
Not detected
1 h ꢀ78 °C
+2 h 25 °C
9.3 (70%)
9.3 (68%), 38
12.3 (30%)
12.3 (32%), 17
1 h ꢀ78 °C
+2 h 25 °C
9.3 (66%)
9.3 (75%), 40
12.3 (34%)
12.3 (25%), 16
a
˚
tR: HPLC retention time (min) Kromasil C18 5l 100 A with a mobile phase consisting of 30% H2O, 70% CH3CN; %: area of the eluted peaks.
Figure 3. Synthesis of 4b and 5b starting from N-Boc-phenylalaninal 6.
5b were isolated and the overall yield 55% was slightly
improved (Table 2). This result are consistent with pre-
vious reports where DBU under salt free conditions had
afforded Z-selective reactions12 while alkyl lithium
reagents afforded the geometrical mixture of (Z) and
(E)-enoates in 1.5 Z/E ratio.11–13 Furthermore, it is
known that HWE reactions lead to the formation of
the thermodynamically more favoured alkene,14–16
which in our case corresponds to compound 4a and that
the products of this reaction do not undergo E/Z iso-
merization17 under the reaction conditions.
a way to convert the Z-enoate 4b into the more original
lactam 5b, compound 4b was submitted to a photoiso-
merization under UV irradiation in THF at ꢀ78 °C in
the presence of n-BuLi (Fig. 4). After 6 h of reaction
and usual workup, analysis of the crude reaction mix-
ture by LC–MS allowed the detection of two products.
The first eluted peak with an area of 75% (50% yield
after semi preparative HPLC) corresponded to the ini-
tial (Z)-enoate 4b (MS: 477 M+Na+) and the second
eluted peak to the cyclized lactam 5b (area: 25%, 20%
yield after semi preparative HPLC, MS: 445 M+Na+).
This could be interpreted as the result of the photoiso-
merization of the Z-enoate 4b to the E-enoate, which
spontaneously cyclized to the lactam 5b (Fig. 4). Fur-
thermore when the Z-enoate 4b was allowed to react
with n-BuLi in the absence of UV irradiation, product
4b was recovered unchanged after 6 h. Therefore, this
method could constitute an alternative to obtain the
pyrrolone 5 starting from the Z-enoate 4.
Therefore, taking into account this last fact, but also
that compounds 4b/5b are obtained in a ratio compara-
ble to those observed when alkyl lithium are used in
classical HWE reaction and finally the E configuration
of the enamine bond in compound 5b, we postulated
that the (E)-enoate 7 (Fig. 4) was the reaction intermedi-
ate, which cyclized in the presence of a base to yield
lactam 5b. Since in the reaction with 1 equiv, there is
no BuLi left after the deprotonation of the phosphogly-
cinate, therefore methylate is probably responsible for
the postulated deprotonation–cyclization sequence
(Table 2). In order to confirm this hypothesis and to find
In the course of this work, we have shown that new chi-
ral 3-amino-5-alkyl-2,5-dihydro-1H-pyrrolin-2-ones 5
are easily obtained in a one-pot process starting from
commercially available products. Despite the relatively
Figure 4. Photoisomerization of the Z-enoate 4b and conversion in 5b.

3520
N. Inguimbert et al. / Tetrahedron Letters 46 (2005) 3517–3520
room temperature for 1 h. The solvents were removed
under reduced pressure. Diethylether (10 mL) and 5 mL of
1 M hydrochloric acid were added to the residue and the
mixture was stirred for 1 h. The organic layer was
separated, washed with brine, dried (Na2SO4), filtered
and concentrated in vacuo. After column chromatography
on silica gel (c-hexane/ethyl acetate 8:2) the products are
isolated as an oil. Analytical pure material were obtained
low yields resulting from tricky HPLC purifications
due to the overlapping peaks of compounds 4 and 5, this
reaction has a relatively broad application, since, we
have successively applied this process not only to Z-
or Boc N-protected a-amino esters bearing various
lateral functionalized or non functionalized side chains,
but also to a dipeptide.
˚
by semipreparative HPLC Kromasil C18 5l 100 A,
CH3CN 80%.
Acknowledgements
Compound 4b: Rf = 0.06 (c-hexane/ethyl acetate = 8:2);
1H NMR (CDCl3, 400 MHz):
d
1.37 (s, 9H,
NCOOC(CH3)3), 2.85 (dd, 1H, J = 13.9 Hz, J = 7.8 Hz,
CH2Ph), 2.98 (dd, 1H, J = 12 Hz, J = 5.7 Hz, CH2Ph),
3.73 (s, 3H, OCH3), 4.63 (td, 1H, NCH), 4.68 (d, 1H,
J = 7.5 Hz, BocNH), 5.15 (s, 2H, OCH2Phe), 6.17 (d, 1H,
J = 8.7 Hz, CH@C), 7.17–7.36 (m, 10H, H arom), 7.59 (s,
The authors thank Dr. Armand Blommaert for assis-
tance with the manuscript. The authors also thank
Dr. Nicolas Auzeil and Dr. Martine Libot for the LC–
MS and HRMS analysis.
1H, NHZ); 13C NMR (CDCL3, 100 MHz):
d 28.4
(CH2COOC(CH3)3), 38.8 (CH2Ph), 48.9 (NCH), 52.5
(COOCH3), 67.4 (OCH2Phe), 80.5 ((CH3)3COCON),
121.6 (CH@C), 127.2 (C arom), 128.4 (C arom), 128.7
(C arom), 128.8 (C arom), 128.9 (C arom), 129.5 (C arom),
129.7 (C@CH), 135.7 (C arom), 149.2 (t-BuOCON), 153.2
(COOCH2Phe), 165.2 (COC@CH); HRMS (ESI):
References and notes
ˆ
1. Inguimbert, N.; Coric, P.; Dhotel, H.; Bonnard, E.;
Llorens-Cortes, C.; De Mota, N.; Fournie-Zaluski,
´
M.-C.; Roques, B. P. J. Pept. Res. 2005, 65, 175–188.
´
20
477.1980 calcd for C25H30N2O6Na+: 477.2002; ½aꢁD
2. Fournie-Zaluski, M. C.; Fassot, C.; Valentin, B.; Djord-
+106 1.2 (c 0.2 in CHCl3).
Compound 5b: Rf = 0.13 (c-hexane/ethyl acetate = 8:2);
jijevic, D.; Reaux-Le Goazigo, A.; Corvol, P.; Roques, B.
P.; Llorens-Cortes, C. Proc. Natl. Acad. Sci. U.S.A. 2004,
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1H NMR (CDCl3, 400 MHz):
d
1.63 (s, 9H,
NCOOC(CH3)3), 2.76 (t, 1H, J = 12 Hz, CH2Ph), 3.52(d,
1H, J = 12 Hz, CH2Ph), 4.71 (d, 1H, J = 5.7 Hz, NCH),
5.17 (s, 2H, OCH2Phe), 6.80 (s, 1H, CH@C), 7.0–7.36 (m,
11H, H arom, NHZ); 13C NMR (CDCL3, 100 MHz): d
28.4 (CH2COOC(CH3)3), 39.1 (CH2Ph), 60.7 (NCH), 67.7
(OCH2Phe), 84.0 ((CH3)3COCON), 121.6 (CH@C), 127.2
(C arom), 128.4 (C arom), 128.7 (C arom), 128.8 (C arom),
128.9 (C arom), 129.5 (C arom), 129.7 (C@CH), 135.7 (C
arom), 149.2 (t-BuOCON), 153.2 (COOCH2Phe), 165.2
(COC@CH); HRMS (ESI): 445.1722 calcd for
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10. General procedure for the obtention of 4 and 5: A solution
of n-butyl lithium 1.6 M in hexane (0.62 mL, 1 mmol,
2 equiv) is added at ꢀ78 °C to a solution of N-benzyloxy-
carbonyl-phosphonoglycine trimethyl ester (0.331 g,
1 mmol) in 3 mL anhydrous THF. After 30 min stirring,
compound 3 (0.5 mmol) in 1 mL anhydrous THF was
added, followed immediately by a dropwise addition of
0.66 mL, 1 mmol of DiBAl-H solution (1.5 M in toluene).
The resulting mixture was stirred for 4 h at ꢀ78 °C and at
20
C24H26N2O5Na+: 445.1739; ½aꢁD +21.7 1.7 (c 0.2 in
CHCl3).
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