SmI2-mediated coupling of nitrones and tert -butanesulfinyl imines with allenoates: Synthesis of β-methylenyl-γ -lactams and tetramic acids

Article abstract of DOI:10.1021/ol300550x

Nitrones and tert-butanesulfinyl imines undergo conjugate addition to alkyl allenoates under SmI₂-mediated reductive coupling conditions to produce novel β-methylenyl-substituted γ -amino esters. The latter were readily transformed into the cor

Full text of DOI:10.1021/ol300550x

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2034–2037
SmI2-Mediated Coupling of Nitrones and
tert-Butanesulfinyl Imines with
Allenoates: Synthesis of β-Methylenyl-γ-
lactams and Tetramic Acids
Chu-Pei Xu,†,‡ Pei-Qiang Huang,*,‡ and Sandrine Py*,†
ꢀ
Departement de Chimie Moleculaire (SERCO) UMR 5250, ICMG FR-2607, CNRS-
Universite Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France, and Department of
ꢀ
ꢀ
Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005,
P. R. China
sandrine.py@ujf-grenoble.fr; pqhuang@xmu.edu.cn
Received March 4, 2012
ABSTRACT
Nitrones and tert-butanesulfinyl imines undergo conjugate addition to alkyl allenoates under SmI2-mediated reductive coupling conditions to
produce novel β-methylenyl-substituted γ-amino esters. The latter were readily transformed into the corresponding β-methylenyl-γ-lactams by
simple zinc reduction (N-hydroxy amines) or by acid hydrolysis (sulfinamides). The diastereoselective preparation of various β-methylenyl-γ-
lactams offers a route to tetramic acids, the key structural features of an important class of bioactive natural products.
The development of reactions involving samarium diio-
dide is unceasingly a topic of interest in synthetic chem-
istry, in large part because this mild reducing agent allows
the selective creation of CÀC bonds from various organic
functional groups.1 In recent years, the SmI2-mediated
cross-coupling reactions of nitrones2 sulfinyl imines3 and
other iminium equivalents4 with acrylic esters and amides
have been developed for the synthesis of γ-amino acid
derivatives, including γ-lactams. With these precedents,
the SmI2-mediated reductive cross-coupling of nitrones 1
or sulfinylimines 2 with allenoates 3,5 possibly yielding
β-methylenyl-γ-amino acid derivatives 4, was anticipated
(Scheme 1).
Synthetic methods to prepare compounds 4 are scarce.
They usually involve the addition of amidomalonate6 or
glycinate7 anions to allenoates and, thus, are limited to the
ꢀ
(2) (a) Masson, G.; Cividino, P.; Py, S.; Vallee, Y. Angew. Chem., Int.
Ed. 2003, 42, 2265–2268. (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5,
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229. (c) Masson, G.; Zeghida, W.; Cividino, P.; Py, S.; Vallee, Y. Synlett
2003, 1527–1529. (d) Johannesen, S. A.; Albu, S.; Hazell, R. G.;
Skrydstrup, T. Chem. Commun. 2004, 1962–1963. (e) Desvergnes, S.;
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Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459–1462. (f) Cividino, P.; Py,
S.; Delair, P.; Greene, A. E. J. Org. Chem. 2007, 72, 485–493. (g)
Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H-w.;
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Py, S. Bioorg. Med. Chem. 2007, 15, 6443–6449. (h) Rehak, J.; Fisera, L.;
†
ꢀ
CNRS-Universite Joseph Fourier.
ꢁ ꢁ
ꢁ
ꢀ
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Kozısek, J.; Perasınova, L.; Steiner, B.; Koos, M. ARKIVOC 2008, viii,
ꢁ ꢁ
‡ Xiamen University.
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18–27. (i) Rehak, J.; Fisera, L.; Podolan, G.; Kozısek, J.; Perasınova, L.
ꢀ
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(1) For recent reviews on the use of SmI2, see: (a) Procter, D. J.,
Flowers, R. A., II., Skrydstrup, T., Eds. Organic Synthesis Using
Samarium Diiodide: A Practical Guide; Royal Society of Chemistry
Publishing: 2010. (b) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew.
Chem., Int. Ed. 2009, 48, 7140–7165. (c) Gopalaiah, K.; Kagan, H. B.
New J. Chem. 2008, 32, 607–637.
Synlett 2008, 1260–1264. (j) Rehak, J.; Fisera, L.; Pronayova, N.
ARKIVOC 2009, vi, 146–157. (k) Vogel, J. C.; Butler, R.; Procter,
D. J. Tetrahedron 2008, 64, 11876–11883. (l) Burchak, O. N.; Masson,
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G.; Py, S. Synlett 2010, 1623–1626. (m) Rehak, J.; Fisera, L.; Kozısek, J.;
Bellovicova, L. Tetrahedron 2011, 67, 5762–5769. (n) Gilles, P.; Py, S.
Org. Lett. 2012, 14, 1042–1045.
ꢁ
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r
10.1021/ol300550x
Published on Web 04/10/2012
2012 American Chemical Society

giving access to 4-methylenyl-5-substituted-pyrrolidin-2-
ones (5).
Nitrone 1a13 and allenoate 3a14 (1.4 equiv) were first
treated at À78 °C with 3 equiv of SmI2 in the presence of
water, conditions previously described for the reductive
coupling of nitrones with acrylic esters (Scheme 2).2a,e The
expected N-hydroxyamine 4aa was formed, although in a
disappointing 30% yield; nitrone 1a was recovered (44%),
along with benzyl but-3-enoate (6a),15 resulting from the
reduction of allenoate 3a by SmI2.16 A screening of condi-
tions was next carried out in the presence of various
additives,17 in an attempt to favor the desired cross-
coupling of allenoate 3a with nitrone 1a rather than its
competitive conjugate reduction.18 In light of the work of
Ellman,3 we next introduced 12 equiv of this salt19 in the
reaction mixture: the yield of 4aa was increased to 49%,
but compound 6a was still a major side product. The use of
a noncoordinating source of protons instead of water was
also found to be beneficial to increase the yield in 4aa up to
60%.20 It was finally found that better yields of the desired
product 4aa could be obtained by iterative introduction of
excess allenoate and SmI2 to limit the formation of 6a.
Scheme 1. General Approach
preparation of glutamic acid derivatives (R1 = CO2R). A
method to prepare a large variety of compounds 4 would
therefore be useful, especially since they might serve as
precursors of β-methylenyl-γ-lactams 5, themselves being
potential intermediates for the synthesis of tetramic acids.8
Published approaches for the construction of β-methyle-
nyl-γ-lactams include radical cyclization of propargyl
bromoamides in the presence of Bu3SnH and AIBN,9
MgI2-promoted ring expansion of secondary methylene-
cyclopropyl amides,10 and indium-catalyzed Conia-ene
reactions.11 Alternative synthetic routes to 5, however,
remain highly desirable.
Nitrones are known to react with activated allenes under
thermal conditions to produce cycloadducts which can re-
arrange to give pyrrolidin-3-ones.12 We assumed that
SmI2-promoted reductive coupling of nitrones and alleno-
ates would manifest a complementary pattern of reactivity,
Scheme 2. SmI2-Mediated Cross-Coupling of 1a and 3a
a See Supporting Information for the conditions screened.
(3) Peltier, H. M.; McMahon, J. P.; Patterson, A. W.; Ellman, J. A.
J. Am. Chem. Soc. 2006, 128, 16018–16019.
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Y.-P.; Ma, J.; Huang, P.-Q. Org. Biomol. Chem. 2012, 10, 1275–1284.
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2009, 38, 3102–3116.
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G.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897–
4905.
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of tetramic acids, see: (a) Holloway, C. A.; Matthews, C. J.; Jeong,
Y.-C.; Moloney, M. G.; Roberts, C. F.; Yaqoob, M. Chem. Biol. Drug
Des. 2011, 78, 229–235. (b) Schobert, R.; Schlenk, A. Bioorg. Med.
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Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757–8760. (c)
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6231. (d) Pattenden, G.; Rescourio, G. Org. Biomol. Chem. 2008, 6,
3428–3438.
Optimal conditions consisted in treating a mixture of
nitrone 1a, 1.4 equiv of allenoate 3a, 3.5 equiv of tert-
butanol, and 12 equiv of LiBr at À40 °C with 3 equiv of SmI2,
again after 30 min with additional 0.6 equiv of allenoate and
1 equiv of SmI2, and once more, after 30 min with another
0.5 equiv of allenoate and 0.5 equiv of SmI2. After 3 h,
consumption of nitrone 1a was almost complete and
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3393–3403. See also ref 1.
(18) For the screening of conditions, see Supporting Information.
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Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett. 1997, 38, 8157–8158.
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Org. Lett., Vol. 14, No. 8, 2012
2035

the desired N-hydroxyamine 4aa could be isolated in
80% yield.
Scheme 3. Coupling of Nitrone with Substituted Allenoates
Using these conditions, the scope of the reaction was
next evaluated. With benzyl buta-2,3-dienoate (3a) as the
allenic partner, in most of the cases the expected N-hydro-
xyamines 4 were obtained in good yields (Table 1, entries
1À6). However, compounds 4ga and 4ha (Table 1, entries 7
and 8) were formed in only 44% and 26% yield, respec-
tively, a decrease probably due to steric hindrance. The
nature of the ester group also seemed to play a role in the
efficiencyof the processastert-butyl ester 3cdid not couple
with nitrones as efficiently as its benzyl (3a) or ethyl (3b)
analogues (Table 1, entries 1, 3 and 9À11).
Table 1. Cross-Coupling of Nitrones 1aÀh with Allenoates
3aÀc
Table 2. Preparation of β-Methylenyl-γ-lactams 5 from
N-Hydroxyamino Esters 4
% yield
product
entry
substrate
R1
R2
(% yield)
(% recovered
entry
R1
R2
R3
product
nitrone 1)
1
2
3
4
4aa
4ba
4ca
4ga
i-Pr
Me
Et
H
H
H
H
5a (99)
5b (75)
5c (91)
5g (88)
1
i-Pr
Me
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Et
4aa
4ba
4ca
4da
4ea
4fa
80 (16)
68 (31)
74 (23)
71 (29)
62 (31)
56 (43)
44 (52)
26 (30)
64 (33)
32 (52)
36 (ND)
2
3
Et
t-Bu
4
i-Bu
c-Hex
c-Pr
t-Bu
5
6
Interestingly, exo-β,γ-unsaturated lactams 5 were found
to be very stable under both neutral and acidic conditions:
after several months, no trace of double bond migration
could be observed by NMR analysis of these compounds.
An enantioselective version of the SmI2-mediated synthe-
sis of β-methylenyl-γ-lactams 5 was next examined with
chiral, nonracemic N-tert-butanesulfinyl imines (t-BS-
imines)21 as the substrates for the cross-coupling with alleno-
ates. t-BS-Imines have previously been shown to under-
go homocoupling22 and heterocoupling with aldehydes,23
nitrones,24 and methyl methacrylate3 in the presence of
SmI2. First, the conditions found optimal with nitrone 1a
(Conditions A) were used for the coupling of the RS-sulfinyl
imine 2a and allenoate 3a (Table 3, entry 1). The expected
product 11a was obtained in good yield (64%), as a 7:1
mixture of diastereomers, although the reaction was incom-
plete and 35% of starting sulfinyl imine 2a was recovered.
On increasing the initial concentration of the sulfinyl imine
from 18 to 26 mM (Conditions B, Table 3, entry 2), the
starting material RS-2a was completely consumed and the
yield of 11a increased to 85%, but the diastereomeric ratio
decreased slightly to 5:1. Application of Conditions B to the
7
4ga
4ha
4ab
4ac
4cc
8
(ÀCH2À)5
9
i-Pr
i-Pr
Et
H
H
H
10
11
t-Bu
t-Bu
The effect of an R- or γ-substituent in the allenoate
partner was also investigated. When ethyl 2-methylbuta-
2,3-dienoate (7) was treated with nitrone 1a under the
cross-coupling conditions, the coupling product 8 was iso-
lated in 40% yield, as a 2:1 mixture of diastereomers, along
with 46% of recovered nitrone 1a (Scheme 3). The γ,γ-
disubstituted allenoate, benzyl 4-methylpenta-2,3-dienoate
(9), underwent cross-coupling with nitrone 1a, but the
expected product 10 was obtained in only poor yield
(22%) and 70% of the starting nitrone 1a was recovered,
along with benzyl 4-methylpent-3-enoate. Steric hindrance
in the allenoate may favor its conjugate reduction over
cross-coupling with the nitrone.
With γ-N-hydroxyamino esters 4 in hand, an easy-to-
perform and high-yielding preparation of β-methylenyl-γ-
lactams was developed next. Treatment of 4aa with zinc in
acetic acid, under ultrasound activation at 80 °C, afforded
the desired lactam 5a in nearly quantitative yield (Table 2,
entry 1). Following the same procedure, other lactams
(5b, 5c and 5g) were also obtained in good yield (Table 2,
entries 2À4).
(21) For recent reviews on applications of chiral N-tert-butanesulfi-
nyl imines in asymmetric synthesis, see: (a) Robak, M. T.; Herbage,
M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740. (b) Ferreira, F.;
Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162–
1186. (c) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem.
Res. 2008, 41, 831–840.
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2036
Org. Lett., Vol. 14, No. 8, 2012

coupling of allenoate 3a with t-BS-imines 2bÀe also yielded
the expected sulfinamides 11 in high yields and with similar
diastereomeric ratios (Table 3, entries 4À7).
EtOH)}. Thus, the configuration of the major diastereo-
mer of 11a was determined to be RS,S.
Scheme 4. Application to the Synthesis of Tetramic Acid 13a
Table 3. Scope of the Cross-Coupling between Chiral Sulfinyl
Imines 2 and Allenoate 3a
In conclusion, we have developed a new and efficient
approach to β-methylenyl γ-amino esters and γ-lactams
through the SmI2-mediated coupling of allenoates with
nitrones and chiral sulfinyl imines. Fine tuning of conditions
and use of adequate additives were necessary to ensure selec-
tive reduction of the imine derivatives (by electron transfer
from SmI2) rather than the competitive allenoate reduction.
The β-methylenyl γ-amino acid derivatives prepared by this
methodology can be easily converted to tetramic acids, which
are important building blocks for the total synthesis of many
natural products, such as sintokamide A,26 malyngamide
X,27 and gallinamide A.28
% yield
(% recovered
entry
conditionsa
product (R)
imine 2)
drb,c
1
2
3
4
5
6
7
A
B
A
B
B
B
B
11a (i-Pr)
11a (i-Pr)
11b (i-Bu)
11b (i-Bu)
11c (c-Hex)
11d (n-Pr)
11e (Bn)
64 (35)
85
7:1
5:1
55 (24)
87
10:1
5:1
85
4.5:1
5.5:1
8:1
78
61
a Conditions A: initial concentration of t-BS-imine = 0.18 mM.
Conditions B: initial concentration of t-BS-imine = 0.26 mM. b The dr’s
were determined by NMR analysis of the crude reaction mixtures. c The
minor diastereomers are not shown.
Acknowledgment. C.P.X. is grateful to the China Scho-
larship Council (Grant No. 2010631073) for a doctoral
fellowship that allowed him to spend one year working
The configuration of the newly generated chiral center in
compound 11a (major diastereomer) was assigned from
the sign of the optical rotation of the enantioenriched
tetramic acid 13a (Scheme 4). First, the chiral auxiliary in
11a (5:1 mixture of diastereomers) was removed by treat-
ment with 12 M HCl in methanol, to give the correspond-
ing lactam 12a in 77% yield. Ozonolysis of 12a yielded the
known enantioenriched tetramic acid 13a in 60% yield,
which was recrystallized to give enantiopure tetramic acid
ꢀ
ꢀ
in the Departement de Chimie Moleculaire, UMR 5250
ꢀ
CNRS À Universite Joseph Fourier. We also thank the
National Basic Research Program (973 Program) of
China (Grant No. 2010CB833200) and the NSF of China
(20832005; 21072160) for partial financial support.
Supporting Information Available. Characterization
1
data, full experimental procedures, and copies of H and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
13a {[R]20 À42.3 (c 0.32, EtOH); lit.25 À46.4 (c 1.00,
D
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2037