Synthesis of substituted pyrrolin-4-ones from amino acids in mild conditions via a gold-catalyzed approach

Article abstract of DOI:10.1021/jo900693a

(Chemical Equation Presented) The gold-catalyzed cyclization of various α-amino-ynone derivatives gave the corresponding pyrrolin-4-ones in high yields. Moreover, the use of gold(III) oxide as catalyst allows a moderate to total stereocontrol during the cyclization. These pyrrolin-4-ones are highly useful intermediates for the synthesis of functionalized pyrrolidines and other natural products.

Full text of DOI:10.1021/jo900693a

pubs.acs.org/joc
plethora of nitrogen-containing derivatives.2 Furthermore,
Synthesis of Substituted Pyrrolin-4-ones from Amino
Acids in Mild Conditions via a Gold-Catalyzed
Approach
they are also used as useful chiral auxiliaries and ligands for
asymmetric syntheses.3
Many methodologies have been reported for their synth-
eses over the years.4 More recently, much work has been
focused on metal-mediated approaches from unsaturated
amines5 or diazo compounds.6 Nevertheless, the develop-
ment of flexible strategies that would allow for a stereose-
lective construction of multisubstituted pyrrolidine deri-
vatives employing versatile building blocks is still highly
desirable. Therefore, although R-amino-ynones are easily
accessible from R-amino acids, their use as intermediates for
the synthesis of enantiopure pyrrolidine derivatives has
remained largely unexplored. In a seemingly unique contri-
bution, Overhand and Hecht7 reported a mercury-promoted
approach. Nevertheless their strategy required a stoichio-
metric amount of mercuric acetate to achieve the ring
closure.
ꢀ
Nicolas Gouault,* Myriam Le Roch, Carole Cornee,
ꢁ
Michele David, and Philippe Uriac
ꢀ
ꢀ
EA Substances Licheniques et Photoprotection, Universite de
Rennes1, 2 avenue du Pr. Leon Bernard, 35043 Rennes Cedex,
ꢀ
France
nicolas.gouault@univ-rennes1.fr
Received April 2, 2009
In this context, we decided to explore the use of the
chiral pool of amino acids combined with the potential of
gold for the synthesis of pyrrolin-4-ones that could
be used for further transformations (Scheme 1). The
above-mentioned approach reported by Overhand and
Hecht did not allow the isolation of pyrrolin-4-one deri-
vatives (I). Actually the use of mercuric salt afforded an
intermediate organomercuric chloride that must be sub-
jected to reductive demercuration with sodium borohy-
dride leading to an hydroxypyrrolidine (II). Due to its
ability to coordinate and activate carbon-carbon multi-
ple bonds toward the intramolecular addition of a variety
of nucleophiles, gold-catalysis emerged as the preferred
choice.8 Thus, the addition of various nucleophiles to
alkynes offered a fascinating opportunity to build up
several complex cyclic molecules under extremely mild
conditions.
Initially, a series of R-amino-ynone derivatives 1a-l was
generated from commercially available amino acids via
Weinreb amide formation and subsequent addition of var-
ious lithium acetylides (Table 1). The enantiomeric purity of
the intermediate 1a was confirmed by chiral HPLC to be
>99% ee, suggesting that minimal racemization had oc-
curred during the process. Thus amino-ynones 1a-l could be
produced in two steps with moderate to good overall yield
from corresponding L-amino acids.
The gold-catalyzed cyclization of various R-amino-ynone
derivatives gave the corresponding pyrrolin-4-ones in
high yields. Moreover, the use of gold(III) oxide as
catalyst allows a moderate to total stereocontrol during
the cyclization. These pyrrolin-4-ones are highly useful
intermediates for the synthesis of functionalized pyrroli-
dines and other natural products.
Functionalized pyrrolines and pyrrolidines are found in a
broad array of biologically active natural products1 and are
used as excellent building blocks for the synthesis of a
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1995, 36, 1621. (d) Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1987, 30,
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We then performed a catalyst screening to optimize the
cyclization conditions. In this way, substrate 1a was sub-
jected to various catalysts and other activating agents in
different conditions (Table 2).
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5614 J. Org. Chem. 2009, 74, 5614–5617
Published on Web 06/10/2009
DOI: 10.1021/jo900693a
r
2009 American Chemical Society

Gouault et al.
JOCNote
SCHEME 1. Synthetic Approach
TABLE 2. Catalyst Screening for the Cyclization of 1a
entry
catalyst (mol %)
conditions
yield (%)
1
2
3
4
5
6
7
8
9
10
AuCl (10)
PdCl2 (10)
CuOAc (10)
AgOTf (10)
GaCl3 (10)
PTSAd(10)
NaH (100)
AuCl (5)
THF, rt, 1 h
THF, rt, 4 h
THF, rt, 24 h
THF, rt, 4 h
THF, rt, 24 h
DCM, rt, 24 h
THF, rt, 24 h
THF, rt, 1.5 h
THF, rt, 4 h
THF, rt, 24 h
96
dega
(31)b
(8)b
nrc
nrc
nrc
97
TABLE 1. Synthesis of the R-Amino-ynones 1a-l
AuCl (1)
94
nrc
a Degradation of starting material. b Conversion determined by 1H
NMR on the crude material. c No reaction. d p-Toluenesulfonic acid.
R1 (Aa)
PG
R2
1
yield (%)
TABLE 3. Screening of Substrates
iPr (V)
iPr (V)
iPr (V)
iPr (V)
H (G)
H (G)
H (G)
Me (A)
Bn (F)
sec-Bu (I)
sec-Bu (I)
indol-3-ylmethyl (W)
Boc
Boc
Boc
Boc
Boc
Cbz
Ac
Boc
Cbz
Boc
Boc
Cbz
Ph
Hc
nPr
pMeO-Ph
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
58
72
60
52
66
58
63
89
71
56
68
74
nPr
nPr
Ph
entry
1
R1
R2
PG
2
fyield (%)
1j
1k
1l
1
2
3
4
5
6
7
8
9
1a iPr
1b iPr
1c iPr
1d iPr
Ph
H
nPr
Boc 2a
Boc 2b
Boc 2c
96
92
87
94
95
85
94
83
95
90
89
85
Ph
a O-(1H-Benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium
tetra-
fluoroborate. b Diisopropylethylamine. c Ethynyl magnesium bromide
was used in this case.
4-MeOPh Boc 2d
1e
1f
1g
H
H
H
Ph
Ph
Ph
Ph
nPr
nPr
Ph
Boc 2e
Cbz 2f
Ac
2g
1h Me
Boc 2h
Cbz 2i
Boc 2j
Boc 2k
Cbz 2l
We initially confirmed the highly catalytic activity of gold
salt for this intramolecular cyclization (Table 2, entry 1).
Actually, the use of 10 mol % of AuCl in THF at room
temperature for 1 h cleanly afforded the corresponding
pyrrolidin-4-one 2a in an excellent yield (96%). The effi-
ciency of this gold(I) salt was then compared to that of other
catalytic systems. The ring closure did not proceed (or was
not efficient) in the presence of 10 mol % of a variety of
transition metal salts such as CuOAc,9 AgOTf,10 PdCl2,11
and GaCl312 (entries 2-5). As a comparison, we also tested a
Brønsted acid (PTSA,13 entry 6), but no trace of compound
2a has been detected even after 24 h. In a last set of
experiments we decided to evaluate the potential of cycliza-
tion via 1,4-addition. The use of NaH14 that should increase
the nucleophilic character of nitrogen (entry 7) did not
1i
1j
Bn
sec-Bu
10
11
12
1k sec-Bu
1l
indol-3-ylmethyl Ph
promote the present reaction at all. Decreasing the catalyst
loading from 10 to 5 or 1 mol % only affected the reaction
time without any change in yield (entries 8 and 9). In the
absence of catalyst, the reaction did not occur (entry 10).
To extend the generality of this reaction, the versatility of
AuCl was then evaluated for other functionalized amino-
ynone derivatives. As shown in Table 3, several structural
variations were tolerated under these mild conditions, in-
cluding substituent on the triple bond (entries 1-4), protect-
ing group (entries 5-7), and choice of starting amino acid
(entries 1, 5, 8-10). These intermediates 1a-l were efficiently
converted to the corresponding pyrrolin-4-ones (2a-l) in
good to excellent yields.
(9) (a) Knight, D. W.; Sharland, C. M. Synlett 2004, 119. (b) Gabriele, B.;
Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72,
6873.
(10) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149.
(11) (a) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes, F.
P. J. T. Org. Lett. 2003, 5, 1717. (b) Utimoto, K. Pure Appl. Chem. 1983, 55,
1845. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(12) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414.
(13) Knight, D. W.; Sharland, C. M. Synlett 2003, 2258.
(14) Ishikawa, T.; Aikawa, T.; Watanabe, S.; Saito, S. Org. Lett. 2006, 8,
3881.
To further examine the scope of this gold-catalyzed cycli-
zation, we then turned our attention to the synthesis of
enantiopure pyrrolin-4-ones, since our strategy was devel-
oped from amino acids (Table 4). Using stereodefined sub-
strate 1a (ee >99%), keeping the chirality of the stereogenic
center after cyclization was evaluated by chiral HPLC.
J. Org. Chem. Vol. 74, No. 15, 2009 5615

Gouault et al.
JOCNote
TABLE 4. Stereocontrol of the Cyclization of 1a
entry
catalyst
base (2 equiv)
temp (°C)
time (h)
yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
AuCl
AuCl
AuCl
AuCl
PPh3AuCl AgSbF6
Au2O3
Au2O3
Au(OH)3
Au(OH)3
Au(OAc)3
Au(OAc)3
rt
rt
rt
rt
rt
rt
60
rt
60
rt
60
1
1
1
1
1
48
1.5
5
24
5
96
90
85
82
90
91
95
nrc
80
nrc
42
0
60
70
10
10
82
99
K2CO3
DBPb
amylene
99
25
10
11
24
a Determined by chiral HPLC. b 2,6-Di-tert-butylpyridine. c No reaction.
SCHEME 2. Keto-Enol Equilibrium of 2a
SCHEME 3. Synthetic Approach to Hydroxypyrrolidine 4a
TABLE 5. Stereocontrolled Cyclization of 1
entry
1
R1
iPr
iPr
Me
Bn
sec-Bu
sec-Bu
R2
PG
2
yield (%)
ee (%)a
1
2
3
4
5
6
1a
1c
1h
1i
1j
1k
Ph
nPr
Ph
nPr
nPr
Ph
Boc
Boc
Boc
CBz
Boc
Boc
2a
2c
2h
2i
2j
2k
95
95
85
90
92
90
99
99
60
50b
99
96
carried out in the presence of a catalytic amount of gold(III)
oxide or hydroxide (entries 7 and 9). For a complete conver-
sion of 1a at room temperature, the reaction time is longer
(48 h) compared to the cyclization promoted with AuCl. On
the other hand, the pyrrolin-4-one 2a was isolated with a
slight epimerization (entry 6) ee (82%). Performing the
cyclization at 60 °C considerably decreased the reaction
time (1 h instead of 48 h) without epimerization (ee g99%)
(entry 7). No epimerization occurred also by substituting
gold oxide with gold(III) hydroxide. Only a decrease in the
yield was observed (entry 9). Gold(III) acetate displayed
poor reactivity (entries 10 and 11).
To expand the scope of this cyclization in a stereocon-
trolled manner, we investigated the reaction with other
enantiopure substrates 1 (Table 5). The results indicate that
no epimerization occurred with hindered substrates (Table 5,
entries 1, 2, 5, and 6). The nature of the R2 moiety (alkyl or
aromatic) seemed to have no influence on the epimerization.
However, less hindered substrates such as 1h or 1i were par-
tially epimerized in the same conditions. This problem of
epimerization of peptide aldehydes or related compounds
has already been reported.16
a Determined by chiral HPLC. b Enantiomeric excess determined by
1H NMR experiment, using an europium complex.
The first attempt with the conditions previously described
revealed disappointing results since epimerization occurred
during the reaction (Table 4, entry 1). This could be ex-
plained by the keto-enol equilibrium15 favored by acidic
conditions (traces of HCl in the reaction medium) leading to
a hydroxypyrrole (Scheme 2). This first result prompted us to
investigate novel catalytic conditions. When the reaction was
conducted in the presence of 2 equiv of base such as K2CO3
(entry 2) or 2,6-di-tert-butylpyridine (entry 3), the chirality
was partially retained. The use of amylene as proton scaven-
ger led to a loss of chirality (entry 4).
Therefore, we envisioned the use of other gold species that
could avoid the generation of HCl in situ. We were pleased to
observe the absence of epimerization when the reaction was
(16) Ganneau, C.; Moulin, A.; Demange, L.; Martinez, J.; Fehrentz,
J.-A. J. Pept. Sci. 2006, 12, 497.
(15) Capon, B.; Kwok, F.-C. J. Am. Chem. Soc. 1989, 111, 5346.
5616 J. Org. Chem. Vol. 74, No. 15, 2009

Gouault et al.
JOCNote
Finally, as shown in Scheme 3, this approach can be exten-
ted to the stereoselective formation of 3-hydroxypyrrolidine.
Thus, hydrogenation of 2a over Pd/C afforded stereospe-
cifically 3a in 88% yield. This compound was obtained as a
single diastereoisomer (the other diastereoisomer was not
detected by NMR) and NOESY experiment confirmed that
3a has the cis stereochemistry (reduction from the less hindered
face, i.e., opposite the isopropyl group). Furthermore 1H NMR
experiment with a europium complex17 allowed the high
enantiomeric purity of 3a (ee >98%) to be confirmed.
Experimental Section
Representative Experimental Procedure for the Synthesis of
(S)-2a. To the amino-ynone (S)-1a (prepared from (L)-Boc-
valine) (50 mg, 0.166 mmol) in THF (1.5 mL) at rt under Ar
atmosphere was added gold(III) oxide (7.3 mg, 10 mol %). After
the resulting mixture was stirred at 60 °C for 1.5 h, Et2O (5 mL)
was added and the resulting mixture was filtered through Celite.
After removal of solvents under reduced pressure, the crude
product was purified by silica gel column chromatography by
using a mixture of dichloromethane and ethyl acetate (98/2) as
an eluant to give (S)-2a (47.5 mg) in 95% yield as a pale yellow
solid. Mp 70-72 °C. The ee was 99% by HPLC (Chiralpak AD-
H column, eluant: heptane/2-propanol 99/1; 1 mL/min); RT=
10.6 min; [R]2D5 -4.0 (c 1, CH2Cl2); 1H NMR (270 MHz, CDCl3)
δ 7.42-7.47 (m, 5H), 5.61 (s, 1H), 4.18 (d, J=3.6 Hz, 1H), 2.54-
2.67 (m, 1H), 1.25 (s, 9H), 1.18 (d, J=7.2 Hz, 3H), 1.03 (d, J =
6.9 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 201.0, 173.0, 150.4,
133.3, 130.2, 128.1, 127.1, 113.7, 82.7, 71.6, 32.2, 27.7, 17.2, 17.1;
IR (ATR) 2964, 1712, 1694, 1567, 1367, 1319, 1159, 972, 767,
695 cm-1; HRMS (EI, m/z) calcd for C18H23NO3 301.1678,
found [M]+• 301.1681.
Lastly, reduction of 3a with NaBH4/EtOH gave 4a stereo-
specifically in an excellent yield. The other diastereoisomer
1
was not detected by H NMR on the crude product and
NOESY experiment confirmed that 4a has the cis arrange-
ment of substituants (hydride adds from the less hindered
face). This final product was confirmed by chiral HPLC with
DDL detector (light scattering detector) to be >99% ee,
suggesting that no racemization occurred during the reduc-
tions steps.18
In conclusion, we have developed a gold-catalyzed cycli-
zation of R-amino-ynones. This provides an efficient
method for the synthesis of substituted pyrrolin-4-one
derivatives. Moreover, the use of the chiral pool of amino
acids in this process led to pyrrolin-4-ones with moderate
to excellent stereocontrol during the cyclization. This ap-
proach provides a straightforward tool for further synthetic
application.
Acknowledgment. We thank Dr. Marc Capet, Isabelle
ꢀ
Delimoge, and Stephanie Le Moing from Bioprojet Biotech
(St Gregoire, France) for chiral HPLC analyses. We also
ꢀ
ꢀ
gratefully acknowledge the CRMPO (Universite de Re-
nnes1, Rennes, France) for mass spectroscopy experiments.
This work was supported by Rennes Metropole.
Supporting Information Available: Representative experi-
mental procedures, as well as chiral HPLC traces and NMR
spectra for the novel cyclized products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Eu(hfc)3 was used for the 1H NMR experiment.
(18) The two enantiomers were synthesized individually starting from L-
and D-valine and analyzed with use of a Chiralpak AD-H column (compared
to the racemic mixture).
J. Org. Chem. Vol. 74, No. 15, 2009 5617