Methanesulfonic acid mediated cyclization and meyer-schuster rearrangement of γ-amino-ynones: Access to enantiopure pyrrolidine exocyclic vinylogous amides

Article abstract of DOI:10.1002/ejoc.201402336

α- and β-Amino-ynones have been largely used to prepare heterocyclic rings in the presence of various electrophiles such as protic acids or gold(I). Herein we disclose the unprecedented formation of pyrrolidine exocyclic vinylogous amides, in place of the expected azepinones or piperidinones, starting from γ-amino-ynones derived from amino acids. The process involves a tandem 1,2-addition of the protected nitrogen to the carbonyl group followed by a Meyer-Schuster rearrangement, which efficiently afforded enantiopure pyrrolidine exocyclic vinylogous amides. The sequence is poorly catalyzed by gold salts, but proved to be very efficient in the presence of methanesulfonic acid. Copyright

Full text of DOI:10.1002/ejoc.201402336

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201402336
Methanesulfonic Acid Mediated Cyclization and Meyer–Schuster
Rearrangement of γ-Amino-ynones: Access to Enantiopure Pyrrolidine
Exocyclic Vinylogous Amides
Huy-Dinh Vu,[a,b] Jacques Renault,*[a] Thierry Roisnel,[c] Nicolas Gouault,[a] and
Philippe Uriac[a]
Keywords: Rearrangement / Nitrogen heterocycles / Alkynes / Amines / Cyclization / Regioselectivity
α- and β-Amino-ynones have been largely used to prepare
heterocyclic rings in the presence of various electrophiles
such as protic acids or gold(I). Herein we disclose the unprec-
edented formation of pyrrolidine exocyclic vinylogous
amides, in place of the expected azepinones or piperidin-
ones, starting from γ-amino-ynones derived from amino ac-
ids. The process involves a tandem 1,2-addition of the pro-
tected nitrogen to the carbonyl group followed by a Meyer–
Schuster rearrangement, which efficiently afforded enantio-
pure pyrrolidine exocyclic vinylogous amides. The sequence
is poorly catalyzed by gold salts, but proved to be very ef-
ficient in the presence of methanesulfonic acid.
the success of these methodologies largely depends upon
the control of the cyclization mode: exo- versus endo-dig.
Introduction
The use of ynones bearing a proximate nucleophile is a Owing to electronic effects, endo-dig cyclization predomi-
straightforward approach to the construction of small and nates over exo-dig cyclization and results in good regiose-
medium-sized heterocyclic rings by intramolecular Michael lectivity. Although various types of heterocycles have been
additions,[1] and these substrates have been efficiently used obtained from these starting materials, the above approach
for the synthesis of various natural products.[2] In general, is not uniformly effective for the formation of seven-mem-
Scheme 1. Intramolecular cyclizations of β- and γ-amino-ynones (n = 1 or 2).
[a] Produits Naturels, Synthèse et Chimie Médicinale, UMR 6226,
bered and larger rings[3] because these cyclization reactions
Sciences Chimiques de Rennes, Université de Rennes 1,
2, Avenue du Pr Léon Bernard, 35043 Rennes Cedex, France
E-mail: jacques.renault@univ-rennes1.fr
are less favored, in accord with Baldwin’s rules.[4]
http://www.scienceschimiques.univ-rennes1.fr/equipes/pnscm
[b] Department of Chemistry, Vietnam Forestry University,
Hanoi, Vietnam
In a recent report, we described the gold-catalyzed cycli-
zation of β-amino-ynones to N-protected dihydropyridones
I and their various reductions to diverse pipecolic acid de-
rivatives (n = 1, Scheme 1).[5] We subsequently became in-
terested in similar electrophilic gold- or acid-catalyzed cycli-
zations of γ-amino-ynones (n = 2) bearing two electrophilic
[c] Institut des Sciences Chimiques de Rennes, Centre de
diffraction X, UMR 6226 CNRS – Université de Rennes 1,
35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402336.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
H.-D. Vu, J. Renault, T. Roisnel, N. Gouault, P. Uriac
FULL PAPER
sites. We first considered the activation of the triple bond
by the “alkynophilic” gold to form azepinone derivatives and Boc protection of the amine in the presence of
II. The required trajectory for nucleophilic attack does not DMAP[8] led to the protected compound
(83%;
Initially, the esterification of the carboxylic acid of 1[7]
2
seem to be in favor of such a 7-endo-dig cyclization accord- Scheme 2). The next step involved the addition of lithium
ing to Baldwin’s rules. If 6-exo-dig is favored, however, alk- propylacetylide, phenylacetylide, or ethynylmagnesium
yne polarity disfavored the formation of piperidone deriva- bromide, which furnished γ-amino-ynones 3a–c in good
tives III. Faster alternative pathways, if available, may com- yields.[9] We then attempted to optimize the conditions of
pete with these two routes. Thus, we also envisaged the for- the cyclization reaction and then analyzed the results of
mation of five-membered-ring compounds IV by intramo- three different reactions.
lecular 1,2-addition and then, depending on the conditions,
Our experiments were conducted on small batches of
transformation of such hemi-aminal propargylic intermedi- propyl ynone 3a (1 mmol) dissolved in various solvents
ates into pyrrolidines V by a Meyer–Schuster rearrange- (1 mL). We first experimented with gold catalysis, which
ment.
had been found in most cases to be efficient for the cycliza-
tion of β-amino-ynones,[5] by using (triphenylphosphine)-
gold chloride (PPh3AuCl) in the presence of an equimolar
amount of silver hexafluoroantimonate (AgSbF6) or silver
Results and Discussion
The γ-amino-ynones were obtained from l-pyroglutamic triflate (AgOTf) as co-catalyst. We also tested gold(III)
acid 1, which has been extensively used in organic synthesis chloride (AuCl3), (triphenylphosphine)gold(I) bis(trifluoro-
as a cheap source of chirality. This amino acid derivative methanesulfonyl) imidate (PPh3AuNTf2), and chloro-
with two differentially activated carbonyls has been ex- [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]gold(I)
ploited in various asymmetric syntheses.[6] Its commercially (“AuCl-Imidazole”) in the presence of AgSbF6. The
available (R) enantiomer was subjected to the same reaction amount of catalyst, and co-catalyst when relevant, was
steps to assess the stereochemistry of the described com- chosen to be 0.2 equiv. The yields were estimated by 1H
pounds.
NMR spectroscopy in the presence of an internal standard,
Scheme 2. Synthesis of ynones 3a–c.
Table 1. Preliminary investigation of the gold-catalyzed cyclization from 3a.
Entry
Conditions
3a/4a [%]
1
2
3
4
5
6
7
8
9
PPh3AuCl/AgOTf (0.2 equiv.), CH2Cl2, 12 h, r.t.
PPh3AuCl/AgSbF6 (0.2 equiv.), CH2Cl2, 12 h, r.t.
AuCl3 (0.2 equiv.), CH2Cl2, 12 h, r.t.
45:5
90:10
100:0
100:0
100:0
80:20
60:25
PPh3AuNTf2 (0.2 equiv.), C2H4Cl2, 12 h, r.t.
PPh3AuNTf2 (0.2 equiv.), C2H4Cl2, 6 h, 80 °C
PPh3AuNTf2 (0.2 equiv.), toluene, 6 h, 110 °C
AuCl–Imidazole/AgSbF6 (0.2 equiv.), CH2Cl2, 12 h, r.t.
AuCl–Imidazole/AgSbF6 (0.2 equiv.), CH2Cl2, CH3OH (10:1), 12 h, r.t.
AuCl–Imidazole/AgSbF6 (0.2 equiv.), CH3OH, 12 h, r.t.
0:60
40:0 (5a: 60)
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
Access to Enantiopure Pyrrolidine Exocyclic Vinylogous Amides
which allowed for a global quantitative estimation of yields.
In many experiments, CH2Cl2 was found equivalent to
C2H4Cl2 and was preferred due to its easier removal. The
main results are reported in Table 1.
The preliminary experiments showed poor results. On the
one hand, we never obtained azepinone IIa nor piperidi-
none derivative IIIa. On the other hand, the poorly
oxophilic properties of gold(I) and gold(III) only resulted
in low (Table 1, entries 1, 2, and 6) or even non-existent
conversion of the starting material into 4a (entries 3–5). The
use of Au-Imidazole slightly improved the yield to 25% (en-
try 7), which was increased to 60% in the presence of a
small portion of methanol (entry 8). However, in pure dry
methanol (entry 9), only the product of addition, 5a, was Figure 1. ORTEP drawing of the X-ray crystal structure of 4a.
obtained in 60% yield; the (Z) geometry of 5a was attested
by NOESY experiments. A few attempts at AuCl-Imidazole
catalysis starting from 3b,c, aimed at preparing 4b,c, ana- Boc-protected compounds 4a–c in varying yields. Then the
logues of 4a, only resulted in 4c in an acceptable yield of reactions were carried out at two different concentrations
60% under the conditions described in entry 7; 4b was not of methanesulfonic acid (entries 2 and 3); good results were
found.
obtained only with 3c (90% in both cases). The favorable
The formation of the five-membered ring 4a, albeit in role of methanol in the gold-catalyzed Meyer–Schuster re-
low yield, could only result from carbonyl attack by the arrangement[13] was again observed: Indeed, 3a and 3b were
poorly nucleophilic carbamate nitrogen lone pair to form a almost completely converted into pyrrolidine derivatives 4a
pyrrolidine (Scheme 1), which then underwent Meyer– and 4b in the presence of (or in) methanol (entries 4 and 5).
Schuster rearrangement.[11] The X-ray structure[10] of 4a is In contrast, 3c was converted almost entirely into the stable
given in Figure 1.
acetal 6c (see Scheme 3), resulting in a very low yield of 4c.
Hence, we directed our efforts to obtaining a better yield Finally, the presence of water had a deleterious effect on
of 4a–c. We first attempted acidic removal of the Boc pro- the reactivity, whether in the absence (entry 6) or presence
tecting group followed by treatment with K2CO3,[12] which of a co-solvent (methanol, entry 7). Camphorsulfonic acid
we have previously used for similar cyclizations of β-amino- was found to be as efficient as anhydrous methanesulfonic
ynones.[5] As observed for the gold-catalyzed reactions, acid in this reaction (entry 8).
these reactions starting from 3a–c never yielded azepinones,
If the results reported in Tables 1 and 2 are different in
but mainly gave a mixture of small amounts of 4a–c to- terms of yields, they are similar in terms of products. Ac-
gether with the corresponding unprotected compounds. We cording to Baldwin’s rules,[4] endo-dig cyclization
also successfully tested a non-nucleophilic acid, meth- (Scheme 1) is disfavored and the azepinone derivatives II
anesulfonic acid, under various conditions. The results, ob- were never observed, whereas the exo-dig cyclization, even
1
tained by H NMR analysis in the presence of an internal if favored by Baldwin’s rules, did not occur because of the
standard, are reported in Table 2.
electronic effect of the carbonyl group. The unique cycliza-
First, as expected, the absence of sulfonic acid (entry 1) tion of 3a–c to the pyrrolidine derivatives 4a–c can be ex-
left the starting material unchanged. In other cases, as par- plained by the following considerations: 1) The electrophilic
tially observed with hydrochloric acid, we mainly obtained character of the carbonyl carbon atom (better for R = H
Table 2. Acid-mediated cyclization of 3a–c to give 4a–c.
Entry
Conditions
3a/4a
3b/4b
3c/4c
1
2
3
4
5
6
7
8
CH2Cl2/CH3OH 9:1, 12 h, r.t.
CH3SO3H (0.2 equiv.), CH2Cl2, 4 h, r.t.
CH3SO3H (0.8 equiv.), CH2Cl2, 4 h, r.t.
CH3SO3H (0.8 equiv.), CH2Cl2/CH3OH 9:1, 4 h, r.t.
CH3SO3H (0.8 equiv.), CH3OH, 4 h, r.t.
CH3SO3H (0.8 equiv.), CH2Cl2, H2O (50 μL), 4 h, r.t.
CH3SO3H (0.8 equiv.), CH3OH/H2O 20:1 (v/v), 4 h, r.t.
Camphorsulfonic acid (0.8 equiv. ), CH2Cl2/CH3OH 9:1, 4 h, r.t.
100:0
80:20
55:10
0:90
0:90
95:0
n.d.[a]
70:0
15:0
0:85
0:90
100:0
n.d.[a]
n.d.[a]
n.d.[a]
.
0:90[b]
0:90[b]
0:50
0:5
90:5
0:70
0:95
n.d.[a]
n.d.[a]
[a] n.d: not done. [b] Obtained in 30 min for 3c.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
H.-D. Vu, J. Renault, T. Roisnel, N. Gouault, P. Uriac
FULL PAPER
Scheme 3. Possible pathways to pyrrolidine derivatives from 3a–c.
Scheme 4. Proposed mechanism for the formation of 4a from 5a.
than Pr or Ph), 2) the extremely favorable formation of a
five-membered ring, and 3) the possible Meyer–Schuster re-
arrangement of the hemi-aminal IV.
Depending on the substrates and experimental condi-
tions, two pathways are possible, as shown in Scheme 3.
First, the expected classical mechanism involving intermedi-
ate IV occurred in CH2Cl2 as the only solvent [Equa-
tion (1)]. Under these conditions, the efficiency of the cycli-
zation increased with the electrophilicity of the carbonyl
compounds 3a–c (R = PhϽ ProϽ H). The resulting inter-
mediate IV then underwent a Meyer–Schuster rearrange-
ment to give 4a–c. Secondly, in the presence of methanol
[Equation (2)], we suggest that under acidic conditions
methanol adds to the alkyne to yield intermediate VI. To
support this pathway, as a control experiment, we per-
formed the reaction with the (Z)-enol ether 5a, prepared
by gold catalysis (Table 1). Compound 5a was activated by
methanesulfonic acid (0.8 equiv.), which induced its com-
plete and immediate conversion into 4a (Scheme 4). It
seems reasonable to assume that the attractive effect of the
protonated methoxy group promotes the attack by nitrogen
to give VIIa, which undergoes the migration of water to
give VIIIa. The subsequent loss of a proton and methanol
would then lead to 4a.
Scheme 5. Synthesis of compounds 7a–c.
The unprotected compounds 7a–c were easily obtained
from 4a–c in the presence of trifluoroacetic acid followed
by treatment in an alkaline medium (Scheme 5). In contrast
to 4a–c, which have an (E) configuration, 7a–c possess a
(Z) geometry, as confirmed by NOESY experiments. The
Figure 2. ORTEP drawing of the X-ray crystal structure of 7b con-
formers.
The synthesis of further pyrrolidines starting from pyr-
X-ray crystal structures[10] of both conformations of 7b con- rolidin-2-one (8) and l-pyroglutaminol (12; Scheme 6)
firmed the (Z) configuration (Figure 2).
proved the reliability of the method. In the first example,
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
Access to Enantiopure Pyrrolidine Exocyclic Vinylogous Amides
Scheme 6. Synthesis of pyrrolidines from pyrrolidin-2-one (8) and l-pyroglutaminol (12).
pyrrolidin-2-one (8) was N-protected[14] and then treated
with various alkyne salts to give 10a–c. Subsequent cycliza-
tion and rearrangement furnished 11a–c in good yields. In
a similar manner, l-pyroglutaminol (12) was protected to
yield 13,[15] ring-opened with the pent-1-yne lithium salt 14,
cyclized to 15, and finally deprotected to give 16,[16] which
was obtained in an overall yield of 60%.
of signals are reported as follows: s (singlet), d (doublet), t (triplet),
q (quadruplet), quint. (quintet), sext (sextet), m (multiplet), br. s
(broad singlet), dt (doublet of triplets), and td (triplet of doublets).
IR spectra were recorded with a Perkin–Elmer Spectrum 2 spec-
trometer by using a Universal ATR Sampling Accessory. HRMS
analyses were performed with a Waters Q-TOF 2, a Micromass
ZABSpec TOF, a Bruker MicrO-TOF QII, or a LTQ Orbitrap XL
spectrometer for ESI MS. X-ray crystallographic data were col-
lected with an APEXII crystal diffractometer. Optical rotations
were recorded with a Perkin–Elmer Model 341 polarimeter. TLC
was performed on precoated silica gel plates (0.2 mm thickness).
Chiral HPLC was performed by using a Shimadzu (Prominence
Evolutive) instrument equipped with a Chiralpak IA column
(5 μm, 4.6ϫ250 mm).
Conclusions
The method presented herein provides a new rapid access
to various enantiopure pyrrolidine vinylogous amides in
good yields. Such compounds, which can be prepared by
Eschenmoser coupling[17] or Knoevenagel-type reactions,[18]
have been used as intermediates in the synthesis of many
natural compounds,[19] such as anisomycin,[20a] apomito-
mycin,[20b] mesembrenone,[20c] desoxoprosophylline,[20d] cas-
sine,[19c] pinidinone,[20e] deoxyfebrifugine,[20f] and sedacryp-
tine.[20g] Optimised conditions have allowed the efficient
production of 4a–c. In the case of an alkyl or aromatic
group (3a and 3b), the use of methanol proved to be very
efficient (90% yields), whereas it was necessary to use only
dichloromethane with 3c (R = H) to achieve a faster and
as efficient transformation. The stereochemistry was ana-
lyzed and revealed no racemization of the nitrogen-pro-
tected 4a–c or unprotected 7a–c. The scope of this method
was successfully extended to similar starting compounds 8
and 12.
1-tert-Butyl 2-Methyl (S)-5-Oxopyrrolidine-1,2-dicarboxylate (2):
Concentrated hydrochloric acid (50 μL) was added to a solution of
pyrroglutamic acid (1; 5 g, 38.7 mmol) in dry methanol (30 mL).
The solution was allowed to react at room temperature for 24 h
and then concentrated under vacuum to yield methyl (S)-5-oxopyr-
rolidine-2-carboxylate (5.15 g) as a pale oil. This compound was
used without purification (93%). Rf = 0.40 (dichloromethane/meth-
1
anol, 90:10). [α]2D5 = +12.0 (c = 1, CH3OH). H NMR (300 MHz,
CDCl3): δ = 7.09 (s, 1 H), 4.29 (dd, J = 5.1, J = 8.4 Hz, 1 H), 3.78
(s, 3 H), 2.43 (m, 3 H), 2.23 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 178.5, 172.6, 55.5, 52.6, 29.3, 24.8 ppm. IR (neat):
ν = 3241, 1736, 1683, 1436, 1206 cm–1. HRMS (ESI): calcd. for
˜
C6H9NO3Na [M + Na]+ 166.04801; found 166.0479.
Di-tert-butyl dicarbonate (12.0 g, 52.2 mmol), triethylamine
(3.62 g, 35.85 mmol), and 4-(dimethylamino)pyridine (DMAP;
0.426 g, 3.49 mmol) were added to a solution of methyl (S)-5-oxo-
pyrrolidine-2-carboxylate (5 g, 34.9 mmol) in dichloromethane
(25 mL). The mixture was allowed to react at room temperature
for 24 h and then extracted with diethyl ether (3ϫ 100 mL). The
organic layer was washed with an aqueous solution of NaHSO4
(50 mL), then a 1 m aqueous solution of Na2CO3 (50 mL), then
with brine (2ϫ 50 mL), dried with MgSO4, and concentrated under
vacuum. The residue was purified over silica gel (diethyl ether/pe-
troleum ether, 80:20) to yield 2 as a white solid (7.6 g, 89%), m.p.
70–72 °C. Rf = 0.60 (diethyl ether). [α]2D5 = –48.7 (c = 1, CH3OH).
1H NMR (300 MHz, CDCl3): δ = 4.62 (dd, J = 3.9, J = 9.3 Hz, 1
H), 2.64 (m, 1 H), 2.49 (ddd, J = 3.7, J = 9.3, J = 17.4 Hz, 1 H),
Experimental Section
General Methods: All reagents were of high quality and purchased
from commercial suppliers. They were used without further purifi-
cation or purified/dried according to literature procedures.[21] 1H
and 13C NMR were recorded at 300 and 75 MHz, respectively,
using TMS as an internal standard. Chemical shifts (δ) are given
in ppm, coupling constants (J) are given in Hz, and the multiplicity
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
H.-D. Vu, J. Renault, T. Roisnel, N. Gouault, P. Uriac
2.32 (m, 1 H), 2.04 (m, 1 H), 1.49 (s, 9 H) ppm. 13C NMR perature for 4 h. Diethyl ether (10 mL) and Na2CO3 (0.409 g) were
FULL PAPER
(75 MHz, CDCl3): δ = 173.3, 171.9, 149.3, 83.6, 58.8, 52.6, 31.2,
27.9, 21.5 ppm. IR (neat): ν = 2993, 1792, 1742, 1439, 1256,
then added to this solution and the mixture was stirred for 30 min,
filtered, and the organic layer concentrated under vacuum. The res-
˜
1193 cm–1. HRMS (ESI): calcd. for C11H17NO5Na [M + Na]+ idue was purified by silica gel chromatography (pentane/diethyl
266.10044; found 266.1004.
ether, 50:50) to yield a white solid (0.90 g, 90%), m.p. 64–66 °C. Rf
= 0.60 (pentane/diethyl ether, 50:50). [α]2D5 = +27.6 (c = 1, CH3OH).
1H NMR (300 MHz, CDCl3): δ = 7.02 (s, 1 H), 4.59 (dd, J = 3.5,
J = 9.4 Hz, 1 H), 3.75 (s, 3 H), 3.41 (dddd, J = 1.5, J = 3.8, J =
9.0, J = 18.5 Hz, 1 H), 3.05 (m, 1 H), 2.44 (t, J = 7.4 Hz, 2 H),
2.21 (m, 1 H), 2.01 (m, 1 H), 1.63 (sext, J = 7.4 Hz, 2 H), 1.49 (s,
9 H), 0.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 201.2, 172.2, 155.9, 151.1, 104.5, 83.0, 61.8, 52.4, 46.7,
Methyl (S)-2-(tert-Butoxycarbonylamino)-5-oxodec-6-ynoate (3a): A
2.5 m solution of nBuLi in hexane (10.7 mL, 26.7 mmol) was added
dropwise to a solution of pent-1-yne (2.24 g, 32.9 mmol) in anhy-
drous THF (50 mL) cooled to –50 °C. The mixture was stirred for
30 min, added dropwise to a solution of oxopyrrolidine 2 (5.0 g,
20.55 mmol) in anhydrous THF (50 mL) at –50 °C, and stirred for
3 h. A 1 m aqueous solution of NaHSO4 (30 mL) was then added
and the mixture extracted with diethyl ether (3ϫ 100 mL). The
organic layer was washed with an aqueous saturated solution of
Na2SO4 (2ϫ 300 mL), dried with MgSO4, and concentrated under
vacuum. The crude residue was purified by silica gel chromatog-
raphy (dichloromethane/diethyl ether, 9.5:0.5) to yield a clear yel-
low oil (6.1 g, 95%). Rf = 0.80 (diethyl ether/petroleum ether,
60:40). [α]2D5 = –12.1 (c = 1, CH3OH). 1H NMR (300 MHz, CDCl3):
δ = 5.11 (d, J = 7.7 Hz, 1 H), 4.31 (m, 1 H), 3.75 (s, 3 H), 2.66 (m,
2 H), 2.35 (t, J = 7.0 Hz, 2 H), 2.21 (m, 1 H), 1.99 (m, 1 H), 1.61
(sext, J = 7.2 Hz, 2 H), 1.44 (s, 9 H), 1.02 (t, J = 7.4 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 186.4, 172.7, 155.4, 95.0, 80.7,
30.7, 28.0, 25.6, 18.2, 13.9 ppm. IR (neat): ν = 2961, 1728, 1575,
˜
1314, 1273, 1042 cm–1. HRMS (ESI): calcd. for C16H25NO5Na [M
+ Na]+ 334,16249; found 334,1625.
1-tert-Butyl 2-Methyl (S,E)-5-(2-Oxo-2-phenylethylidene)pyrrol-
idine-1,2-dicarboxylate (4b): A 0.25 m solution of CH3SO3H in
CH2Cl2 (9.26 mL) was added to a solution of ynone 3b (1.0 g,
2.90 mmol) in methanol (10 mL) and the mixture was stirred at
room temperature for 4 h. Diethyl ether (10 mL) and Na2CO3
(0.368 g) were added to this solution and the mixture was stirred
for 30 min, filtered, and the organic layer concentrated under vac-
uum. The residue was purified by silica gel chromatography (pent-
ane/diethyl ether, 50:50) to yield a white solid (0.90 g, 90%), m.p.
110–112 °C. Rf = 0.50 (pentane/diethyl ether, 50:50). [α]2D5 = –5.3 (c
= 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.97 (m, 2 H), 7.82
(s, 1 H), 7.40 (m, 3 H), 4.66 (dd, J = 3.5, J = 9.4 Hz, 1 H), 3.77 (s,
3 H), 3.56 (dddd, J = 1.5, J = 3.8, J = 9.0, J = 18.5 Hz, 1 H), 3.22
(m, 1 H), 2.28 (m, 1 H), 2.07 (m, 1 H), 1.51 (s, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 191.0, 172.2, 158.4, 151.1, 140.1,
131.7, 128.3, 127.9, 101.4, 83.2, 62.1, 52.4, 31.2, 28.0, 25.5 ppm. IR
80.1, 52.8, 52.4, 41.4, 28.3, 26.7, 21.2, 20.9, 13.5 ppm. IR (neat): ν
˜
= 3366, 2967, 2210, 1712, 1673, 1365, 1160 cm–1. HRMS (ESI):
calcd. for C16H25NO5Na [M + Na]+ 334.16304; found 334.1626.
Methyl
(S)-2-(tert-Butoxycarbonylamino)-5-oxo-7-phenylhept-6-
ynoate (3b): Compound 3b was obtained from phenylacetylene
(3.36 g, 32.9 mmol) following the procedure described above for the
synthesis of 3a. The residue was purified by silica gel chromatog-
raphy (dichloromethane/diethyl ether, 9.5:0.5) to yield a brown oil
(7.1 g, 95%). Rf = 0.55 (dichloromethane/diethyl ether, 95:5). [α]2D5
= +14.0 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.57
(m, 2 H), 7.43 (m, 3 H), 5.21 (d, J = 8.1 Hz, 1 H), 4.37 (m, 1 H),
3.76 (s, 3 H), 2.80 (m, 2 H), 2.28 (m, 1 H), 2.06 (m, 1 H), 1.45 (s,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 186.2, 172.6, 155.4,
133.1, 130.8, 128.6, 119.8, 91.3, 87.5, 80.1, 52.8, 52.5, 41.4, 28.3,
(neat): ν = 2976, 1732, 1644, 1561, 1320, 1243, 1147, 1039 cm–1.
˜
HRMS
(ESI):
calcd.
for
C19H23NO5Na
[M
+
Na]+ 368.14739; found 368.1472.
1-tert-Butyl 2-Methyl (S,E)-5-(2-Oxoethylidene)pyrrolidine-1,2-di-
carboxylate (4c): A 0.25 m solution of CH3SO3H in CH2Cl2
(2.97 mL) was added to a solution of ynone 3c (1.0 g, 3.71 mmol)
in dry CH2Cl2 (10 mL) and the mixture was stirred at room tem-
perature for 30 min. Diethyl ether (10 mL) and Na2CO3 (0.118 g)
were added to this solution and the mixture was stirred for 30 min,
filtered, and the organic layer concentrated under vacuum. The res-
idue was purified by silica gel chromatography (diethyl ether) to
yield a white solid (0.85 g, 85%), m.p. 96–98 °C. Rf = 0.55 (diethyl
ether). [α]2D5 = +20.0 (c = 1, CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ = 9.73 (d, J = 7.3 Hz, 1 H), 6.74 (d, J = 7.3 Hz, 1 H), 4.66 (dd,
J = 3.1, J = 9.2 Hz, 1 H), 3.76 (s, 3 H), 3.29 (dddd, J = 1.4, J =
3.5, J = 8.8, J = 16.9 Hz, 1 H), 3.06 (m, 1 H), 2.29 (m, 1 H), 2.09
(m, 1 H), 1.49 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
191.3, 171.8, 160.2, 150.7, 108.3, 83.9, 62.3, 52.6, 29.0, 28.0,
26.7 ppm. IR (neat): ν = 3363, 2977, 2201, 1711, 1668, 1490,
˜
1158 cm–1. HRMS (ESI): calcd. for C19H23NO5Na [M + Na]+
368.14739; found 368.1473.
Methyl (S)-2-(tert-Butoxycarbonylamino)-5-oxohept-6-ynoate (3c):
A 0.5 m solution of ethynylmagnesium bromide in THF (82.2 mL,
41.10 mmol) was added to oxopyrrolidine 2 (5.0 g, 20.55 mmol) at
0 °C, and the mixture was allowed to react for 2 h. A 1 m aqueous
solution of NaHSO4 (30 mL) was then added and the mixture was
extracted with diethyl ether (3ϫ 100 mL). The organic layer was
washed with an aqueous saturated solution of Na2SO4 (3ϫ
100 mL), dried with MgSO4, and concentrated under vacuum. The
crude residue was purified by silica gel chromatography (dichloro-
methane/diethyl ether, 9.5:0.5) to yield a clear yellow solid (4.43 g,
80%), m.p. 47–50 °C. Rf = 0.45 (dichloromethane/diethyl ether,
25.4 ppm. IR (neat): ν = 2977, 1731, 1369, 1133 cm–1. HRMS
˜
(ESI): calcd. for C13H19NO5Na [M + Na]+ 292.11609; found
292.1160.
1
95:5). [α]2D5 = +16.9 (c = 1, CHCl3). H NMR (300 MHz, CDCl3):
δ = 5.22 (d, J = 7.5 Hz, 1 H), 4.32 (m, 1 H), 3.76 (s, 3 H), 3.34 (s,
1 H), 2.72 (m, 2 H), 2.23 (m, 1 H), 1.97 (m, 1 H), 1.44 (s, 9 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 185.6, 172.5, 155.4, 81.1, 80.1,
Methyl (S,Z)-2-(tert-Butoxycarbonylamino)-7-methoxy-5-oxodec-6-
enoate (5a): Chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylid-
ene]gold(I) (103 mg, 0.192 mmol) and silver hexafluoroantimonate
(AgSbF6, 66 mg, 0.192 mmol) were added to a solution of com-
pound 3a (300 mg, 0.96 mmol) in dry methanol (2 mL). The mix-
ture was stirred for 12 h at room temperature, then filtered through
Celite, concentrated under vacuum, and purified by chromatog-
raphy over silica gel (diethyl ether/pentane, 6:4) to yield a colorless
79.3, 52.6, 52.5, 41.4, 28.3, 26.4 ppm. IR (neat): ν = 3361, 3252,
˜
2978, 2092, 1740, 1682, 1512, 1366, 1160 cm–1. HRMS (ESI): calcd.
for C13H19NO5Na [M + Na]+ 292.11609; found 292.1161.
1-tert-Butyl 2-Methyl (S,E)-5-(2-Oxopentylidene)pyrrolidine-1,2-di-
carboxylate (4a): A 0.25 m solution of CH3SO3H in CH2Cl2
(10.3 mL) was added to a solution of ynone 3a (1.00 g, 3.21 mmol)
in dry methanol (10 mL) and the mixture was stirred at room tem-
oil (182 mg, 55%). Rf = 0.70 (diethyl ether/pentane, 6:4). [α]2D5
=
1
+10.3 (c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ = 5.39 (s, 1
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
Access to Enantiopure Pyrrolidine Exocyclic Vinylogous Amides
H), 5.22 (d, J = 8.0 Hz, 1 H), 4.28 (m, 1 H), 3.74 (s, 3 H), 3.64 (s,
3 H), 2.68 (m, 2 H), 2.53 (m, 2 H), 2.14 (m, 1 H), 1.96 (m, 1 H),
1.54 (m, 2 H), 1.43 (s, 9 H), 0.93 (t, J = 7.4 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 197.3, 176.9, 173.1, 155.5, 98.3, 79.8,
5.15 (d, J = 1.4 Hz, 1 H), 4.49 (dd, J = 5.2, J = 8.6 Hz, 1 H), 3.77
(s, 3 H), 2.73 (m, 2 H), 2.34 (m, 1 H), 2.28 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 186.8, 171.6, 167.6, 91.8, 61.2, 52.7,
31.5, 25.4 ppm. IR (neat): ν = 3278, 2955, 1737, 1592, 1539, 1374,
˜
55.4, 53.3, 52.3, 40.2, 34.5, 28.3, 26.9, 20.8, 13.9 ppm. IR (neat): ν
1173 cm–1. HRMS (ESI): calcd. for C8H11NO3Na [M + Na]+
192.06366; found 192.0637.
˜
= 3356, 2965, 1743, 1712, 1579, 1436, 1161 cm–1. HRMS (ESI):
calcd. for C17H29NO6Na [M + Na]+ 336.18926; found 336.1891.
tert-Butyl 2-Oxopyrrolidine-1-carboxylate (9): A solution of di-tert-
Methyl
(S)-2-(tert-Butoxycarbonylamino)-7,7-dimethoxy-5-oxo-
butyl dicarbonate (14.10 g, 26.25 mmol) in acetonitrile (20 mL) was
heptanoate (6c): A 0.25 m solution of CH3SO3H in CH2Cl2 (3 mL) added dropwise to a 0 °C solution of pyrrolidin-2-one (8; 5 g,
was added to a solution of ynone 3c (0.500 g, 1.86 mmol) in dry
CH3OH (5 mL). The solution was stirred for 4 h at room tempera-
ture and then Na2CO3 (106 mg, 1 mmol) and diethyl ether (5 mL)
were added. The mixture was stirred for 30 min, diethyl ether
(10 mL) was added, and the precipitate was filtered. The solution
was concentrated and the residue purified by chromatography over
silica gel using diethyl ether as eluent to yield a colorless oil (46%).
Rf = 0.66 (diethyl ether). 1H NMR (300 MHz, CDCl3): δ = 5.20
58.75 mmol) in acetonitrile (50 mL). DMAP (718 mg, 5.88 mmol)
was added portionwise and the mixture was stirred at room tem-
perature for 3 h. It was then concentrated under vacuum and the
residue dissolved in ethyl acetate (200 mL) and washed with a 1 m
aqueous solution of HCl (10 mL). The organic layer was evapo-
rated under vacuum and the crude residue purified over silica gel
(EtOAc/petroleum ether, 9:1) to yield the desired compound as a
1
pale oil (10.34 g, 95%). H NMR (300 MHz, CDCl3): δ = 3.75 (t,
(d, J = 8.0 Hz, 1 H), 4.78 (t, J = 5.6 Hz, 1 H), 4.27 (m, 1 H), 3.74 J = 7.2 Hz, 2 H), 2.52 (t, J = 8.1 Hz, 2 H), 2.01 (m, 2 H), 1.53 (s,
(s, 3 H), 3.35 (m, 6 H), 2.72 (d, J = 5.6 Hz, 2 H), 2.57 (m, 2 H), 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.4, 150.2, 82.8,
2.13 (m, 1 H), 1.88 (m, 1 H), 1.44 (s, 9 H) ppm. 13C NMR 46.5, 33.0, 28.0, 17.4 ppm. IR (neat): ν = 2979, 1780, 1749, 1709,
˜
(75 MHz, CDCl3): δ = 206.2, 172.9, 155.5, 101.5, 79.9, 53.9, 53.8,
1366, 1297, 1145, 1015 cm–1.
52.8, 52.4, 46.5, 39.6, 28.3, 26.1 ppm. IR (neat): ν = 3357, 2976,
˜
tert-Butyl 4-Oxonon-5-ynylcarbamate (10a): A 2.5 m solution of n-
butyllithium (35.10 mmol) in hexanes (14.0 mL) was added to a
solution of pent-1-yne (2.76 g, 40.49 mmol) in anhydrous THF
(100 mL) at –50 °C under nitrogen. This mixture was stirred at
–50 °C for 30 min and added to a solution of tert-butyl 2-oxopyrro-
lidine-1-carboxylate (9; 5 g, 26.99 mmol) in THF (20 mL) cooled
to –50 °C amd then stirred at room temperature for 3 h. The solu-
tion was diluted with diethyl ether (100 mL), washed with a 1 m
aqueous solution of NaHSO4 (36 mL) and then aqueous saturated
solution of Na2SO4 (3ϫ 50 mL), dried with MgSO4, and concen-
trated under vacuum. The crude mixture was purified by
chromatography over silica gel (CH2Cl2/diethyl ether, 95:5) to yield
1743, 1708, 1513, 1365, 1161, 1049 cm–1. HRMS (ESI): calcd. for
C15H27NO7Na [M + Na]+ 356.16852; found 356.1686.
Methyl (S,Z)-5-(2-Oxopentylidene)pyrrolidine-2-carboxylate (7a):
TFA (1.5 mL) was added to a solution of 4a (500 mg, 1.61 mmol)
in CH2Cl2 (1.5 mL). The solution was allowed to react at room
temperature for 2 h and then diethyl ether (10 mL) was added. So-
dium carbonate (1.5 g) was added and the mixture was stirred for
30 min and then filtered. The organic layer was concentrated under
vacuum and the residue purified by chromatography over silica gel
using diethyl ether as eluent to yield a colorless oil (326 mg, 96%),
m.p. 99–101 °C. Rf = 0.62 (diethyl ether). [α]2D5 = –191.3 (c = 1,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 9.92 (s, 1 H), 5.16 (s, 1 a yellow oil (6.50 g, 95%). Rf = 0.54 (CH2Cl2/diethyl ether, 95:5).
H), 4.44 (dd, J = 5.2, J = 8.5 Hz, 1 H), 3.75 (s, 3 H), 2.67 (m, 2
H), 2.31 (m, 1 H), 2.27 (t, J = 7.4 Hz, 2 H), 2.14 (m, 1 H), 1.62
1H NMR (300 MHz, CDCl3): δ = 4.74 (br. s, 1 H), 3.15 (m, 2 H),
2.60 (t, J = 7.3 Hz, 2 H), 2.35 (t, J = 7.1 Hz, 2 H), 1.84 (quint., J
(sext, J = 7.4 Hz, 2 H), 0.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR = 7.1 Hz, 2 H), 1.61 (sext, J = 7.2 Hz, 2 H), 1.44 (s, 9 H), 1.02 (t,
(75 MHz, CDCl3): δ = 199.1, 172.1, 165.9, 90.6, 61.0, 52.6, 44.0,
31.4, 25.6, 19.4, 14.1 ppm. IR (neat): ν = 3298, 2958, 1740, 1623,
J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.5,
156.0, 94.6, 80.9, 79.2, 42.8, 39.8, 28.4, 24.4, 21.2, 20.9, 13.5 ppm.
˜
1544, 1201, 1059 cm–1. HRMS (ESI): calcd. for C11H17NO3Na [M IR (neat): ν = 3356, 2968, 2935, 2211, 1671, 1514, 1365, 1248,
˜
+ Na]+ 234.11061; found 234.1104.
1162 cm–1. HRMS (ESI): calcd. for C14H23NO3Na [M + Na]+
276.15756; found 276.1577.
Methyl (S,Z)-5-(2-Oxo-2-phenylethylidene)pyrrolidine-2-carboxyl-
ate (7b): Compound 7b was obtained from 4b (500 mg, 1.45 mmol)
by following the procedure described above for the synthesis of 7a
and purified by chromatography over silica gel (CH2Cl2/diethyl
ether, 85:15) to yield a pale-yellow solid (337 mg, 95%), m.p. 99–
101 °C. Rf = 0.65 (CH2Cl2/diethyl ether, 75:25). [α]2D5 = –188.0 (c =
tert-Butyl 4-Oxo-6-phenylhex-5-ynylcarbamate (10b): Compound
10b was obtained from phenylacetylene (4.13 g, 40.49 mmol) fol-
lowing the procedure described above for the synthesis of 10a to
yield, after chromatography (CH2Cl2/diethyl ether, 95:5), a yellow
solid (7.29 g, 94%), m.p. 64 °C. Rf = 0.51 (CH2Cl2/diethyl ether,
1
1
1, CHCl3). H NMR (300 MHz, CDCl3): δ = 10.36 (s, 1 H), 7.89
95:5). H NMR (300 MHz, CDCl3): δ = 7.58 (m, 2 H), 7.47 (m, 1
(m, 2 H), 7.42 (m, 3 H), 5.87 (s, 1 H), 4.53 (dd, J = 5.3, J = 8.5 Hz,
H), 7.39 (m, 2 H), 4.65 (br. s, 1 H), 3.20 (m, 2 H), 2.74 (t, J =
1 H), 3.77 (s, 3 H), 2.80 (m, 2 H), 2.19 (m, 1 H), 2.36 (m, 1 H) ppm.
7.2 Hz, 2 H), 1.92 (quint., J = 7.0 Hz, 2 H), 1.44 (s, 9 H) ppm. 13C
13C NMR (75 MHz, CDCl3): δ = 188.8, 171.8, 167.7, 139.9, 130.8, NMR (75 MHz, CDCl3): δ = 187.3, 156.0, 133.1, 130.8, 128.6,
128.8, 127.1, 87.5, 61.1, 52.6, 31.8, 25.5 ppm. IR (neat): ν = 3289,
119.8, 91.1, 87.7, 79.3, 42.7, 39.8, 28.4, 24.4 ppm. IR (neat): ν =
˜
˜
2956, 1740, 1608, 1578, 1505, 1322, 1210, 1178, 1058, 706 cm–1.
HRMS (ESI): calcd. for C14H15NO3Na [M + Na]+ 268.09496;
found 268.0948.
3368, 2978, 2868, 2203, 1663, 1516, 1247, 759 cm–1. HRMS (ESI):
calcd. for C17H21NO3Na [M + Na]+ 310.14191; found 310.1418.
tert-Butyl 4-Oxohex-5-ynylcarbamate (10c): tert-Butyl 2-oxopyrrol-
idine-1-carboxylate (9; 5 g, 26.99 mmol) was added at 0 °C under
Methyl (S,Z)-5-(2-Oxoethylidene)pyrrolidine-2-carboxylate (7c):
Compound 7c was obtained from 4c (500 mg, 1.86 mmol) by fol-
lowing the procedure described above for the synthesis of 7a and
purified by chromatography over silica gel (CH2Cl2/diethyl ether,
50:50) to yield a pale-yellow oil (236 mg, 75%). Rf = 0.25 (CH2Cl2/
diethyl ether, 50:50). [α]2D5 = –167.9 (c = 1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 10.01 (s, 1 H), 9.07 (d, J = 2.0 Hz, 1 H),
nitrogen to
a 0.5 m solution of ethynylmagnesium bromide
(53.98 mmol) in THF (108 mL) and stirred for 3 h at room tem-
perature. The solution was diluted with diethyl ether (100 mL),
washed with a 1 m aqueous solution of NaHSO4 (81 mL) and then
an aqueous saturated solution of Na2SO4 (2ϫ 50 mL), dried with
MgSO4, and concentrated under vacuum. The crude mixture was
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
H.-D. Vu, J. Renault, T. Roisnel, N. Gouault, P. Uriac
FULL PAPER
purified by chromatography over silica gel (pentane/diethyl ether,
were added to the crude residue dissolved in CH2Cl2 (100 mL). The
60:40) to yield a yellow solid (3.99 g, 70%), m.p. 68–70 °C. Rf = mixture was stirred at room temperature for 5 h, washed with a
0.53 (pentane/diethyl ether, 60:40). 1H NMR (300 MHz, CDCl3): δ
= 4.73 (br. s, 1 H), 3.29 (s, 1 H), 3.16 (m, 2 H), 2.66 (t, J = 7.2 Hz,
2 H), 1.86 (quint., J = 7.0 Hz, 2 H), 1.44 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 186.7, 156.0, 81.3, 79.3, 79.0, 42.7, 39.6,
saturated aqueous solution of Na2SO4, and concentrated under
vacuum. The crude residue was purified by chromatography over
silica gel (diethyl ether/pentane, 50:50) to yield a yellow solid
(8.56 g, 82%), m.p. 112–113 °C. Rf = 0.43 (diethyl ether/pentane,
50:50). [α]2D5 = –37.6 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.61 (m, 4 H), 7.40 (m, 6 H), 4.21 (m, 1 H), 3.90 (dd, J = 10.4,
J = 4.1 Hz, 1 H), 3.71 (dd, J = 10.4, J = 2.4 Hz, 1 H), 2.80 (dt, J
= 17.5, J = 10.4 Hz, 1 H), 2.42 (m, 1 H), 2.15 (m, 2 H), 1.43 (s, 9
H), 1.05 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.0,
149.7, 135.5, 133.0, 132.6, 129.9, 127.8, 82.6, 65.0, 58.8, 32.3, 28.0,
28.4, 24.1 ppm. IR (neat): ν = 3379, 3186, 2974, 2950, 2086, 1703,
˜
1678, 1366, 1273, 1160, 1003, 778 cm–1. HRMS (ESI): calcd. for
C11H17NO3Na [M + Na]+ 234.11061; found 234.1105.
tert-Butyl (E)-2-(2-Oxopentylidene)pyrrolidine-1-carboxylate (11a):
A 0.25 m solution of CH3SO3H in CH2Cl2 (12.6 mL) was added to
a solution of ynone 10a (1 g, 3.95 mmol) in anhydrous methanol
(10 mL). The mixture was stirred at room temperature for 3 h, neu-
tralized with Na2CO3 (0.5 g), and diethyl ether (10 mL) was added.
The mixture was filtered and the organic layer concentrated under
vacuum. The residue was purified by chromatography over silica
gel (pentane/diethyl ether, 5:5) to yield a white solid (0.91 g, 91%),
m.p. 68–70 °C. Rf = 0.55 (pentane/diethyl ether, 5:5). 1H NMR
(300 MHz, CDCl3): δ = 6.96 (t, J = 1.7 Hz, 1 H), 3.66 (t, J =
7.2 Hz, 2 H), 3.19 (td, J = 7.8, J = 1.7 Hz, 2 H), 2.41 (t, J = 7.4 Hz,
2 H), 1.87 (quint., J = 7.5 Hz, 2 H), 1.63 (sext, J = 7.4 Hz, 2 H),
1.54 (s, 9 H), 0.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 201.2, 157.1, 151.9, 103.9, 82.1, 49.5, 46.7, 32.5, 28.2,
26.8, 21.1, 19.1 ppm. IR (neat): ν = 2930, 1746, 1706, 1307, 1105,
˜
704, 503 cm–1. HRMS (ESI): calcd. for C26H35NO4NaSi [M + Na]
+
476.22331; found 476.2235.
tert-Butyl
(S)-1-(tert-Butyldiphenylsilyloxy)-5-oxodec-6-yn-2-yl-
carbamate (14): A 2.5 m solution of n-butyllithium (5.73 mL,
14.33 mmol) in hexanes was added dropwise to a solution of pent-
1-yne (1.12 g, 16.53 mmol) in anhydrous THF (25 mL) at –50 °C.
The mixture was stirred for 30 min and slowly added at –50 °C to
a solution of tert-butyl (S)-2-[(tert-butyldiphenylsilyloxy)methyl]-5-
oxopyrrolidine-1-carboxylate (13; 5.00 g, 11.02 mmol) in anhydrous
THF (50 mL). The mixture was allowed to react at –50 °C for 3 h
and a 1 m aqueous solution of NaHSO4 (12 mL) was then added.
The organic layer was extracted with diethyl ether (300 mL),
washed with an aqueous saturated solution of Na2SO4 (2ϫ
30 mL), and dried with MgSO4. After filtration, the organic layer
was concentrated under vacuum and the crude residue was purified
by chromatography over silica gel (diethyl ether/pentane, 50:50) to
yield a pale oil (5.29 g, 92%). Rf = 0.64 (diethyl ether/pentane,
50:50). [α]2D5 = –12.8 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.64 (m, 4 H), 7.41 (m, 6 H), 4.67 (d, J = 8.6 Hz, 1 H), 3.64
(m, 3 H), 2.59 (td, J = 7.6, J = 1.9 Hz, 2 H), 2.33 (t, J = 7.1 Hz, 2
H), 1.90 (m, 2 H), 1.60 (sext, J = 7.2 Hz, 2 H), 1.44 (s, 9 H), 1.07 (s,
9 H), 1.01 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 187.5, 155.6, 136.5, 135.5, 133.2, 133.1, 129.8, 127.8, 94.4, 80.9,
79.3, 65.8, 51.4, 42.3, 28.4, 26.9, 26.2, 21.2, 20.9, 19.3, 13.5 ppm.
21.0, 18.4, 14.0 ppm. IR (neat): ν = 2958, 1708, 1578, 1375, 1314,
˜
1237, 1142 cm–1. HRMS (ESI): calcd. for C14H23NO3Na [M +
Na]+ 276.15756; found 276.1577.
tert-Butyl (E)-2-(2-Oxo-2-phenylethylidene)pyrrolidine-1-carboxyl-
ate (11b): Ynone 10b (1 g, 3.48 mmol) was treated with a 0.25 m
solution of CH3SO3H in CH2Cl2 (11.1 mL) under the conditions
described above for the synthesis of 11a. The residue was purified
by chromatography over silica gel (pentane/diethyl ether, 5:5) to
yield a white solid (0.90 g, 90%), m.p. 138–139 °C. Rf = 0.48 (pent-
1
ane/diethyl ether, 6:4). H NMR (300 MHz, CDCl3): δ = 7.97 (m,
2 H), 7.75 (t, J = 1.7 Hz, 1 H), 7.45 (m, 3 H), 3.73 (t, J = 7.3 Hz,
2 H), 3.66 (td, J = 7.7, J = 1.7 Hz, 2 H), 1.94 (quint., J = 7.5 Hz,
2 H), 1.56 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 191.0,
159.6, 152.0, 140.4, 131.6, 128.3, 127.8, 100.8, 83.2, 49.8, 33.0, 28.2,
IR (neat): ν = 3356, 2963, 2932, 2212, 1712, 1673, 1498, 1365, 1166,
˜
21.0 ppm. IR (neat): ν = 2983, 1716, 1641, 1561, 1369, 1307, 1141,
˜
1111, 701, 503 cm–1. HRMS (ESI): calcd. for C31H43NO4NaSi [M
+ Na]+ 544.28591; found 544.2858.
836, 705 cm–1. HRMS (ESI): calcd. for C17H21NO3Na [M + Na]+
310.14191; found 141.1418.
tert-Butyl
(S,E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-5-(2-oxo-
tert-Butyl (E)-2-(2-Oxoethylidene)pyrrolidine-1-carboxylate (11c):
Ynone 10c (1 g, 4.73 mmol) was treated with a 0.25 m solution of
CH3SO3H in CH2Cl2 (7.57 mL) under the conditions described
above for the synthesis of 4c. The residue was purified by
chromatography over silica gel (diethyl ether) to yield a white solid
pentylidene)pyrrolidine-1-carboxylate (15): A 0.25 m CH3SO3H in
CH2Cl2 (6.1 mL) was added to a solution of ynone 14 (1 g,
1.92 mmol) in CH3OH (10 mL). The solution was stirred for 4 h at
room temperature and then Na2CO3 (250 mg) and diethyl ether
(10 mL) were added. The mixture was stirred for 30 min, concen-
trated under vacuum, and the residue was purified by chromatog-
raphy over silica gel (pentane/diethyl ether, 60:40) to yield colorless
1
(0.83 g, 83%), m.p. 70–72 °C. Rf = 0.45 (diethyl ether). H NMR
(300 MHz, CDCl3): δ = 9.74 (d, J = 7.6 Hz, 1 H), 6.65 (td, J = 7.6,
J = 1.7 Hz, 1 H), 3.75 (t, J = 7.1 Hz, 2 H), 3.16 (td, J = 7.7, J =
oil (0.93 g, 93%). Rf = 0.83 (pentane/diethyl ether, 60:40). [α]2D5
=
1.7 Hz, 2 H), 1.98 (quint., J = 7.4 Hz, 1 H), 1.54 (s, 9 H) ppm. 13
C
1
+21.3 (c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.61 (m,
4 H), 7.40 (m, 6 H), 4.26 (m, 1 H), 3.69 (m, 2 H), 3.48 (m, 1 H),
3.10 (m, 1 H), 2.41 (t, J = 7.4 Hz, 2 H), 2.13 (m, 1 H), 1.99 (m, 1
H), 1.62 (sext, J = 7.4 Hz, 2 H), 1.39 (s, 9 H), 1.00 (s, 9 H), 0.91
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.2,
158.0, 151.4, 135.5, 133.2, 132.9, 129.8, 127.8, 127.7, 104.0, 82.1,
64.6, 61.8, 46.7, 31.8, 28.1, 26.6, 24.0, 19.1, 18.4, 13.9 ppm. IR
NMR (75 MHz, CDCl3): δ = 191.4, 161.1, 151.5, 108.0, 83.0, 50.0,
30.5, 28.1, 20.9 ppm. IR (neat): ν = 2978, 1720, 1650, 1603, 1369,
˜
1308, 1122, 847 cm–1. HRMS (ESI): calcd. for C11H17NO3Na [M
+ Na]+ 234.11061; found 234.1107.
tert-Butyl (S)-2-[(tert-Butyldiphenylsilyloxy)methyl]-5-oxopyrrolid-
ine-1-carboxylate (13): l-Pyroglutaminol (12; 5 g, 43.4 mmol), tert-
butyldiphenylsilyl chloride (14.32 g, 52.11 mmol), and imidazole
(7.39 g, 108.57 mmol) were dissolved in DMF (50 mL) and the
mixture stirred at 0 °C for 12 h. AcOEt (300 mL) and toluene
(200 mL) were then added. The organic layer was washed with
water and dried with MgSO4. The solution was concentrated under
vacuum and di-tert-butyl dicarbonate (14.22 g, 65.14 mmol), trieth-
ylamine (4.39 g, 43.43 mmol), and DMAP (2.65 g, 21.71 mmol)
(neat): ν = 2959, 2859, 1721, 1578, 1383, 1367, 1290, 1111, 700,
˜
503 cm–1. HRMS (ESI): calcd. for C31H43NO4NaSi [M + Na]+
544.28591; found 544.2859.
(S,Z)-1-[5-(Hydroxymethyl)pyrrolidin-2-ylidene]pentan-2-one (16):
Compound 15 (1 g, 1.92 mmol) was dissolved in a 10% KOH meth-
anolic solution (10 mL) and stirred for 5 h at 50 °C. The mixture
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
Access to Enantiopure Pyrrolidine Exocyclic Vinylogous Amides
Lett. 2008, 10, 3985–3988; c) A. R. Ranade, G. I. Georg, J.
was concentrated under vacuum and the residue purified by
chromatography over silica gel (diethyl ether/MeOH, 9:1) to yield
a colorless oil (0.31 g, 88%). Rf = 0.61 (diethyl ether/MeOH, 9:1).
[α]2D5 = –14.6 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
9.89 (s, 1 H), 5.06 (s, 1 H), 4.17 (s, 1 H), 4.01 (m, 1 H), 3.73 (dd,
J = 11.5, J = 3.7 Hz, 1 H), 3.53 (dd, J = 11.5, J = 3.7 Hz, 1 H),
2.62 (m, 2 H), 2.20 (t, J = 7.6 Hz, 2 H), 2.05 (m, 1 H), 1.78 (m, 1
H), 1.59 (sext, J = 7.5 Hz, 2 H), 0.91 (t, J = 7.4 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 198.4, 167.7, 89.4, 65.1, 62.1, 43.9,
Org. Chem. 2014, 79, 984–992; d) J.-I. Matsuo, S. Sasaki, T.
Hoshikawa, H. Ishibashi, Tetrahedron 2008, 64, 11224–11229;
e) K. Sakamoto, E. Honda, N. Ono, H. Uno, Tetrahedron Lett.
2000, 41, 1819–1823.
[4] a) J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734–
736; b) K. Gilmore, V. Alabugin, Chem. Rev. 2011, 111, 6513–
6556.
[5] H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault, Eur. J.
Org. Chem. 2013, 6677–6686.
[6] S. K. Panday, J. Prasad, D. K. Dikshit, Tetrahedron: Asym-
metry 2009, 20, 1581–1632.
[7] T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata, H. Schedel,
J. Am. Chem. Soc. 2007, 129, 12890–12895.
[8] a) V. S. Kubyshkin, P. K. Mykhailiuk, S. Afonin, A. S. Ulrich,
I. V. Komarov, Org. Lett. 2012, 14, 5254–5257; b) J. Yu, V. Truc,
P. Riebel, E. Hierl, B. Mudryk, Tetrahedron Lett. 2005, 46,
4011–4013.
32.2, 23.4, 19.8, 14.1 ppm. IR (neat): ν = 3293, 2958, 2930, 2871,
˜
1609, 1521, 1300, 1057 cm–1. HRMS (ESI): calcd. for
C10H17NO2Na [M + Na]+ 206.1157; found 206.1160.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds; chiral HPLC of
compounds 3a–c, 4a–c, 5a–b, and 7a–c.
[9] a) P. K. Mandal, K. K. Kaluarachchi, D. Ogrin, S. G. Bott,
J. S. McMurray, J. Org. Chem. 2005, 70, 10128–10131; b) V. J.
Colandrea, I. E. Legiec, P. Huo, L. Yan, J. J. Hale, S. G. Mills,
J. Bergstrom, D. Card, G. Chebret, R. Hajdu, C. A. Keohane,
J. A. Milligan, M. J. Rosenbach, G.-J. Shei, S. M. Mandala,
Bioorg. Med. Chem. Lett. 2006, 16, 2905–2908.
[10] CCDC-932590 (for 4a) and -992751 (for 7b) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
[11] a) L. Kürti, B. Czako (Ed.), Strategic Applications of Named
Reactions in Organic Synthesis Elsevier, London, 2005, p. 284–
285; b) for a recent review, see: D. A. Engel, G. B. Dudley, Org.
Biomol. Chem. 2009, 7, 4149–4158.
[12] M. J. Niphakis, B. J. Turunen, G. I. Georg, J. Org. Chem. 2010,
75, 6793–6805.
[13] M. N. Pennell, M. G. Unthank, P. Turner, T. D. Sheppard, J.
Org. Chem. 2011, 76, 1479–1482.
[14] L. Banfi, A. Basso, V. Cerulli, G. Guanti, R. Riva, J. Org.
Chem. 2008, 73, 1608–1611.
[15] N. Ikota, Chem. Pharm. Bull. 1992, 40, 1925–1927.
[16] A. A. Malik, R. J. Cormier, C. M. Sharts, Org. Prep. Proced.
Int. 1986, 18, 345–352.
[17] a) M. Roth, P. Dubs, E. Götschi, A. Eschenmoser, Helv. Chim.
Acta 1971, 54, 710–734; b) B. A. D. Neto, A. A. M. Lapis,
A. B. Bernd, D. Russowsky, Tetrahedron 2009, 65, 2484–2496.
[18] a) M. M. Gugelshuk, D. J. Hart, Y. M. Tsaï, J. Org. Chem.
1981, 46, 3671–3675; b) J.-P. Célérier, E. Deloisy, G. Lhommet,
P. Maitte, J. Org. Chem. 1979, 44, 3089–3089.
[19] a) A. Oppedisano, C. Prandi, P. Venturello, A. Deagostino, G.
Goti, D. Scarpi, E. G. Occhiato, J. Org. Chem. 2013, 78, 11007–
11016; b) R. J. Carra, M. T. Epperson, D. Y. Gin, Tetrahedron
2008, 64, 3629–3641; c) C. Herdeis, P. Küpper, S. Plé, Org. Bio-
mol. Chem. 2006, 4, 524–529; d) M. T. Epperson, D. Y. Gin,
Angew. Chem. Int. Ed. 2002, 41, 1778–1780; Angew. Chem.
2002, 114, 1856; e) T. Honda, M. Kimura, Org. Lett. 2000, 2,
3925–3927.
[20] a) L. Felner, K. Shenker, Helv. Chim. Acta 1970, 53, 754–763;
b) T. Kametani, Y. Kigawa, H. Nemoto, M. Ihara, K. Fukum-
oto, J. Chem. Soc. Perkin Trans. 1 1980, 1607–1613; c) A. S.
Howard, R. B. Katz, J. P. Michael, Tetrahedron Lett. 1983, 24,
829–830; d) C. Herdeis, J. Tesler, Eur. J. Org. Chem. 1999, 1407–
1414; e) S. Fréville, P. Delbecq, V. M. Thuy, H. Petit, J.-P.
Célérier, G. Lhommet, Tetrahedron Lett. 2001, 42, 4609–4611;
f) J. P. Michael, C. B. de Koning, D. P. Pienaar, Synlett 2006,
383–386; g) A. G. H. Wee, G.-H. Fan, Org. Lett. 2008, 10,
3869–3872.
Acknowledgments
The authors are deeply grateful to M. Le Roch for technical assist-
ance with the chiral HPLC, Claudia Lalli for manuscript prepara-
tion, P. Jéhan (CRMPO, Université de Rennes 1) for the mass spec-
tra, L. Toupet (IPR, Rennes) and the Ministry of Education and
Training of Vietnam for its financial support.
[1] a) Y. Liu, M. Liu, S. Guo, H. Tu, Y. Zhou, H. Gao, Org. Lett.
2006, 8, 3345–3448; b) K. Stevens, A. J. Tyrrell, S. Skerrat, J.
Robertson, Org. Lett. 2011, 13, 5964–5967; c) N. Gouault, M.
Le Roch, C. Cornée, M. David, P. Uriac, J. Org. Chem. 2009,
74, 5614–5617; d) R. Spina, E. Colacino, B. Gabriele, G. Sa-
lerno, J. Martinez, F. Lamaty, Org. Biomol. Chem. 2012, 10,
9085–9089; e) M. Ostovar, C. M. Marson, Tetrahedron 2013,
69, 6639–6647; f) M. Yoshida, Y. Fujino, T. Doi, Org. Lett.
2011, 13, 4526–4529; g) H. Harkat, A. Blanc, J.-M. Weibel, P.
Pale, J. Org. Chem. 2008, 73, 1620–1623; h) N. Gouault, M.
Le Roch, A. Cheignon, P. Uriac, M. David, Org. Lett. 2011,
13, 4371–4373; i) H. Fuwa, K. Mizunuma, S. Matsukida, M.
Sasaki, Tetrahedron 2011, 67, 4995–5010; j) B. J. Turunen, G. I.
Georg, J. Am. Chem. Soc. 2006, 128, 8702–8703; k) J. Renault,
Z. Qian, P. Uriac, N. Gouault, Tetrahedron Lett. 2011, 52,
2476–2479; l) F. Silva, M. Reiter, R. Mills-Webb, M. Sawicki,
D. Klär, N. Bensel, A. Wagner, V. Gouverneur, J. Org. Chem.
2006, 71, 8390–8394; m) T. Kataoka, H. Kinoshita, S. Kinosh-
ita, T. Iwamura, Tetrahedron Lett. 2002, 43, 7039–7041; n) S.
Dreessen, S. Schabbert, E. Schaumann, Eur. J. Org. Chem.
2001, 245–251; o) K. H. Nguyen, S. Tomasi, M. Le Roch, L.
Toupet, J. Renault, P. Uriac, N. Gouault, J. Org. Chem. 2013,
78, 7809–7815; p) D.-W. Chuang, M. El-Shazly, B. D. Balaji,
Y.-M. Chung, F.-R. Chang, Y.-C. Wu, Eur. J. Org. Chem. 2012,
4533–4540; q) S.-L. Shi, M. Kanai, M. Shibasaki, Angew.
Chem. Int. Ed. 2012, 51, 3932–3935; Angew. Chem. 2012, 124,
3998; r) C. Zhou, A. V. Dubrovsky, R. C. Larock, J. Org. Chem.
2006, 71, 1626–1632; s) M. Schuler, F. Silva, C. Bobbio, A.
Tessier, V. Gouverneur, Angew. Chem. Int. Ed. 2008, 47, 7927–
7930; Angew. Chem. 2008, 120, 8045.
[2] a) M. J. Niphakis, G. I. Georg, J. Org. Chem. 2010, 75, 6019–
6022; b) N. Gouault, M. Le Roch, G. de Campos Pinto, M.
David, Org. Biomol. Chem. 2012, 10, 5541–5546; c) D. Liu,
H. P. Acharya, M. Yu, J. Wang, V. S. C. Yeh, S. Kang, C. Chi-
ruta, S. M. Jachak, D. L. J. Clive, J. Org. Chem. 2009, 74, 7417–
7428; d) T. T. H. Trinh, K. H. Nguyen, P. de Aguiar Amaral,
N. Gouault, Beilstein J. Org. Chem. 2013, 9, 2042–2047; e) M. J.
Niphakis, G. I. Georg, Org. Lett. 2011, 13, 196–199.
[21] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory
Chemicals, 6th ed., Elsevier, Oxford, UK, 2009.
[3] a) M. J. Niphakis, B. J. Turunen, G. I. Georg, Org. Lett. 2011,
13, 196–199; b) T. N. Grant, C. L. Benson, F. G. West, Org.
Received: March 31, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42336
/KAP1
Date: 11-06-14 18:31:32
Pages: 10
H.-D. Vu, J. Renault, T. Roisnel, N. Gouault, P. Uriac
FULL PAPER
Exocyclic Vinylogous Amides
H.-D. Vu, J. Renault,* T. Roisnel,
N. Gouault, P. Uriac ....................... 1–11
Methanesulfonic Acid Mediated Cycli-
zation and Meyer–Schuster Rearrangement
of γ-Amino-ynones: Access to Enantiopure
Pyrrolidine Exocyclic Vinylogous Amides
Starting from γ-amino-ynones, the 1,2-ad-
dition of the protected nitrogen to the
rolidine exocyclic vinylogous amides. This
tandem reaction proved to be very efficient
in the presence of methanesulfonic acid,
leading to various enantiopure products.
Keywords: Rearrangement / Nitrogen het-
erocycles / Alkynes / Amines / Cyclization /
Regioselectivity
carbonyl group followed by
a Meyer–
Schuster rearrangement leads to pyr-
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0