SmI2-induced umpolung of the C=N bond: First reductive conjugate addition of nitrones to α,β-unsaturated esters

Article abstract of DOI:10.1002/anie.200250480

Enantioselective approach to γ-amino acid derivatives: Umpolung of the C=N bond of nitrones by reduction with SmI₂, generates a species that adds smoothly to α,β-unsaturated esters. The corresponding γ-N-hydroxyamino esters are obtained with excellent stereoselection (see scheme).

Full text of DOI:10.1002/anie.200250480

Angewandte
Chemie
Umpolung of C-N Bonds
addition by running the reaction at higher temperature led to
the corresponding oxazinanone as the main product (Table 1,
entry 3). However, the desired products were obtained with
dramatically increased reaction rates by addition of a proton
source such as water (Table 1, entries 5, 6, 8, and 9). The effect
of water[9,11] was particularly significant in the reductive
additions of a hydroxy-containing nitrone (Table 1, entry 5)
and a ketonitrone (Table 1, entry 6) to ethyl acrylate. In both
examples, reaction times were shorter (7-fold and 12-fold,
respectively) and yields were much better in the presence of
this safe and convenient additive.
The possibility of 1,2-diastereomeric induction was next
addressed by using carbohydrate-derived nitrones as sub-
strates. A recently described d-mannose-derived (E)-aldoni-
trone[12] reacted with ethyl acrylate (Table 1, entry 7) to afford
a 75:25 mixture of diastereomers, thus offering a new,
reasonably stereoselective route to diversely substituted
sugar mimics (azasugars).[13] Similarly, the (R)-2,3-O-isopro-
pylidene-d-glyceraldehyde-derived nitrone[14] added to ethyl
acrylate with good diastereoselectivity (Table 1, entry 8) and
yielded an important intermediate[15,16] for the synthesis of
Vigabatrin,[17] a potent and selective GABA-transaminase
inhibitor used for treatment and prevention of epilepsy. The
relative stereochemistry displayed in the product in entry 8 of
¼
SmI2-Induced Umpolung of the C N Bond:
First Reductive Conjugate Addition of Nitrones
to a,b-Unsaturated Esters**
GØraldine Masson, Pascale Cividino, Sandrine Py,* and
Yannick VallØe*
Polarity inversion of organic functional groups is of great
interest because it allows added flexibility in the design of
complex synthetic schemes. While the umpolung of carbonyl
groups is well documented,[1] a similar inversion of the C N
¼
bond has been demonstrated in significantly fewer exam-
ples.[2,3] We have recently reported a general and high-
yielding pinacol-type heterocoupling of nitrones with alde-
hydes and ketones in presence of SmI2 that produces the
corresponding b-N-hydroxyamino alcohols.[4] In that work,
nitrones proved to be far superior to imines,[5] oximes,[6] and
hydrazones[7] for the intermolecular cross-coupling reaction
with carbonyl partners. Concerning the mechanism of this
coupling, evidence was found that SmI2 first reduces the
nitrone, as opposed to the carbonyl component, to generate
an a-aza-nucleophilic species (radical or anion), which
¼
then adds to the C O bond of the aldehyde or ketone.
H2, Raney Ni
HO Bn
a)
Herein we demonstrate that nitrone umpolung chemistry
can be extended to other electrophiles, namely a,b-
unsaturated esters, to generate important g-amino ester
derivatives.
BocHN
N
(Boc)2O
OMe
O
OMe
O
O
O
82%
O
O
Owing to its finely tunable reactivity, samarium(ii)
diiodide has found wide application in organic synthesis[8]
since the seminal work by Kagan and co-workers in the
early 1980s.[9] In particular, this mild reducing agent has
become a popular reagent for the reductive addition of
carbonyl compounds to a variety of electrophilic species,
as exemplified by the conjugate addition to a,b-unsatu-
rated acid derivatives.[10] Owing to the apparent persis-
tency of the nitrone-derived species generated upon
treatment with SmI2, it appeared that they might undergo
addition to electron-deficient alkenes and alkynes.
Indeed, when a solution of an aliphatic nitrone and
ethyl acrylate in THF at ꢀ788C was treated with two
equivalents of SmI2, the g-N-hydroxyamino ester resulting
from conjugate addition was isolated in about 75% yield
(Table 1, entries 1, 2, and 4). An attempt to accelerate the
[α]D25-16 (c = 1.6, CHCl3)
H2, Raney Ni
(Boc)2O
HO Bn
N
b)
c)
BocHN
OMe
OMe
62%
O
O
O
1) 6 equiv SmI2
8 equiv H2O
THF, –78 °C to RT
HO
Bn
O
N
TsN
OMe
2) H2, Pd(OH)2
3) NaH, TsCl
23%
Scheme 1. Determination of the stereochemistry of the products in entries 8 (a),
9 (b), and 11 (c) of Table 1. See text for details. Boc=tert-butyloxycarbonyl.
[*] Dr. S. Py, Prof. Y. VallØe, G. Masson, P. Cividino
LEDSS, UMR 5616
Table 1 was determined by reduction of the hydroxylamine
and carbamoylation to give a known[15a] Boc-protected g-
amino ester (Scheme 1a).
UniversitØ Joseph Fourier-CNRS; BP53
38041 Grenoble Cedex 9 (France)
Fax: (+33)04-7663-5983
E-mail: sandrine.py@ujf-grenoble.fr
syrca.ledss@ujf-grenoble.fr
Following these encouraging results, the addition of
nitrones to substituted acrylates was studied. Both methyl
methacrylate (Table 1, entries 9, 10), and (E)-methyl croto-
nate (entry 11) proved to be good acceptors. Furthermore,
their reactions displayed excellent diastereoselectivities, and
afforded the 2-and 3s-ubstituted- g-N-hydroxyamino acid
derivatives respectively, in > 95% purity. The relative stereo-
chemistry (Table 1, entry 9) was assigned by hydrogenation/
[**] We thank Drs. Andrew E. Greene and C. Morin for helpful
discussions and encouragement, and Dr. M. Christian Philouze for
the X-ray structure analysis. This work was supported by the Centre
National de la Recherche Scientifique (CNRS) and the UniversitØ
Joseph Fourier. G.M. thanks the French Ministry of Education,
Research, and Technology (MENRT) for a doctoral fellowship.
Angew. Chem. Int. Ed. 2003, 42, 2265 – 2268
DOI: 10.1002/anie.200250480
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Table 1: Preparation of g-N-hydroxyamino esters by reductive conjugate addition of nitrones to a,b-
unsaturated esters.
carbonylation reactions of the prod-
uct (Scheme 1b) and comparison to
a known carbamate.[18] In the case
of the product in entry 10 (Table 1),
although the proposed assignment
should be considered tentative, it is
most likely as depicted by analogy
with that in entry 9 (Table 1). To
determine the stereochemistry of
the product in entry 11, the product
was cyclized into a pyrrolidinone
(Scheme 1c) in which the observed
coupling constant (J4,5 = 7.7 Hz) is
indicative[19] of a trans relationship.
The method, however, seems to
reach a limit with b,b-disubstituted
esters, as no addition product was
detected with 3,3-dimethyl acrylate
(Table 1, entry 12); the starting
nitrone merely undergoes reduc-
tion. The outcome of this reaction
strongly suggests a mechanism for
these additions that involves initial
reduction of the nitrone followed by
conjugate addition, rather than ini-
tial reduction of the a,b-unsatu-
rated ester and addition of the
resulting radical anion to the
nitrone.
HO Bn
N
R3
O
R5
O
Bn
R2
SmI2, THF
N
OR6
+
R4
OR6
R1
R1
Method A or B
R5
R
3 R4
O
1.4 equiv
Entry Nitrone
1
Electrophile
Product
Method[a] t [h] Yield [%][b] (d.r.)[c]
A
10
76
2
3
A
10
7
75
58
74
A[d]
4
5
A
9
A
B
7
1
60
73
6
A
B
96
8
45
55
While intramolecular SmI2-
induced conjugate additions to
a,b-acetylenic esters have been
reported to be sluggish[20] and have
allowed only the elaboration of
five-membered rings,[21] no exam-
ples of the intermolecular version of
these additions have been disclosed.
It is noteworthy that the conjugate
addition of nitrone-derived a-aza-
nucleophilic species to propiolates
in presence of water proceeded
smoothly (Table 1, entries 13, 14)
7
8
B
5
63 (75:25)
A
B
7
1
72 (90:10)
81 (85:15)
9
A
B
7
2
29 (>95:5)
74 (>95:5)
10
11
B
3
76 (>95:5)
B
B
2.5
3
66 (>95:5)
[a] Method A: A solution of the nitrone
and a,b-unsaturated ester in THF at
ꢀ788C was treated with two equivalents
of SmI2, and the reaction mixture was
then kept at ꢀ788C for the indicated
reaction time. Method B: A solution of
the nitrone, a,b-unsaturated ester and
degassed water (8 equiv) in THF at
ꢀ788C was treated with three equiva-
lents of SmI2, and the reaction mixture
was then kept at ꢀ788C for the indicated
reaction time. [b] Yields of isolated
product after column chromatography.
[c] According to 1H NMR analysis of the
crude products. [d] The reaction mixture
was allowed to reach ꢀ508C over 7 h.
12
13
54
A
B
8
0.5
<10
71
14
B
7
58
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to produce the corresponding g-N-hydroxyamino-a,b-ethyl-
enic esters as single isomers (100% E). The effect of water in
these additions was even more dramatic than in those above:
the presence of eight equivalents of water resulted in both a
remarkable acceleration of the reaction and an improvement
of the yield (< 10% to 71%). The products represent
versatile intermediates for the synthesis of a variety of
naturally occurring g-amino-a,b-ethylenic and g-amino-a,b-
dihydroxy acid derivatives.[22]
Scheme 2. Determination of the stereochemistry of the product in
entry 4 of Table 2.
To achieve enantioselectivity in the synthesis of g-amino
acid derivatives, nitrones bearing a chiral auxiliary at the
nitrogen center were prepared and treated with ethyl acrylate
(Table 2).[23] These additions proceeded in good yield[24] to
afford diastereomeric g-N-hydroxyamino esters, which could
be separated by column chromatography (Table 2, entries 1–
4). In the case of entry 4 (and by analogy entry 5), the major
diastereomer was assigned the depicted stereochemistry from
its conversion to a known derivative (Scheme 2).[25]
(Table 2, entry 6); a single-crystal X-ray crystallographic
analysis of the major diastereomer provided its relative
configuration.[27]
In conclusion, reduction of nitrones by SmI2 yields a-
azacarbon nucleophiles that undergo efficient and highly
selective intermolecular conjugate addition to acrylic and
propiolic esters. Outstanding diastereoselectivities are
observed and the use of chiral auxiliaries at the nitrogen
center provides an expedient, enantioselective approach to g-
amino acid derivatives. The 4-substituted, 2,4-disubstituted,
and 3,4-disubstituted g-N-hydrox-
When the 1-(triisopropylphenyl)ethyl auxiliary[26] was
used, an excellent diastereoselectivity (> 95:5) was observed
yamino and g-amino acid deriva-
tives[16] produced by this novel,
Table 2: Reductive conjugate addition of chiral nitrones to ethyl acrylate.
direct method should find consid-
erable application, both as syn-
thetic intermediates and as precur-
sors of conformationally defined,
protease-resistant
g-peptides.[28]
Entry
1
Nitrone
Electrophile
Product
t [h]
Yield [%]
78
d.r.[a]
Current work is aimed at extending
this method to other unsaturated
systems.
2
75:25[b]
Experimental Section
Preparation of 0.1m SmI2 in THF:[29]
A
2
3
4
5
0.5
4.5
3
36
56
96
84
70:30
60:40
85:15
85:15
suspension of samarium powder (4 g,
26.6 mmol) and I2 (5 g, 19.7 mmol) in
dry THF (200 mL) was vigorously stir-
red at room temperature for at least 2 h,
during which time the color changed
from yellow-brown to green and finally
to blue. Titration of this SmI2 solution
was performed with a 0.1m solution of I2
in THF (the end point is reached when
the solution turns yellow and SmI3
precipitates).
General procedure for intermolec-
ular conjugate addition of nitrones to
acrylic and propiolic esters: A stirred
and carefully deoxygenated solution of
the nitrone (N-alkylidenebenzylamine-
N-oxide) (0.5 mmol) in dry THF
(10 mL) was cooled to ꢀ788C under
3.25
argon.
The
unsaturated
ester
6[c]
11.5
73
>95:5
(0.7 mmol), water (4 mmol, degassed
by boiling under a stream of argon for
30 min) when method B was employed,
and a solution of SmI2 (ca. 0.1m, 10 mL,
1 mmol) in THF were then added. The
temperature was kept at ꢀ788C until
the reaction was judged to be complete
by TLC, whereupon a saturated aque-
[a] According to 1H NMR analysis of the crude product. [b] In this case the diastereomeric ratio (d.r.)
could not be determined from 1H NMR analysis of the crude material because of signal overlap and was
therefore based on the yields of the isolated diastereomers. [c] In this case the chiral nitrone was used as
a racemic mixture.
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Communications
ous solution of Na2S2O3 (30 mL) was added. The yellow mixture was
[15] a) M. Alcon, M. Poch, A. Moyano, M. A. Pericàs, A. Riera,
Tetrahedron: Asymmetry 1997, 8, 2967; b) C. Dagoneau, A.
Tomassini, J.-N. Denis, Y. VallØe, Synthesis 2001, 150.
[16] N-hydroxylamines can be easily reduced to amines by using
excess SmI2 in the presence of a proton source: A. S. Kende, J. S.
Mendoza, Tetrahedron Lett. 1991, 32, 1699; see also ref. [4].
[17] S. M. Nanavati, R. B. Silverman, J. Am. Chem. Soc. 1991, 113,
9341.
extracted with AcOEt (3 ” 50 mL) and the combined organic layers
were washed with a saturated aqueous solution of NaCl, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
resulting residue by chromatography on silica gel afforded the
expected g-N-hydroxyamino ester as a single product (or a mixture of
diastereomers). All new compounds gave spectroscopic and analyt-
ical data in agreement with the assigned structures.
[18] M. Brenner, D. Seebach, Helv. Chim. Acta 2001, 84, 2155.
[19] H. Nagashima, H. Wakamatsu, N. Ozaki, T. Ishii, M. Watanabe,
T. Tajima, K. Itoh, J. Org. Chem. 1992, 57, 1682.
Received: November 5, 2002
Revised: January 1, 2003 [Z50480]
[20] Z. Zhou, D. Larouche, S. M. Bennett, Tetrahedron 1995, 51,
11623.
Keywords: amino acids · chiral auxiliaries · nitrones · samarium ·
umpolung
.
[21] G. A. Molander, C. R. Harris, J. Org. Chem. 1997, 62, 7418.
[22] For examples of biologically active natural products see: a) A. B.
Smith III, G. K. Friestad, J. Barbosa, E. Bertounesque, J. J. W.
Duan, K. G. Hull, M. Iwashima, Y. Qiu, P. G. Spoors, B. A.
Salvatore, J. Am. Chem. Soc. 1999, 121, 10478; b) A. K. Ghosh,
A. Bischoff, J. Cappiello, Org. Lett. 2001, 3, 2677; c) A.
Zampella, M. V. D'Auria, L. G. Paloma, A. Casapullo, L.
Minale, C. Debitus, Y. Henin, J. Am. Chem. Soc. 1996, 118, 6202.
[23] Following the submission of this manuscript, a paper appeared
describing chiral ester induced diastereoselection, D. Riber, T.
Skydstrup, Org. Lett. 2003, 5, 229.
[1] a) D. Seebach, Angew. Chem. 1979, 91, 259; Angew. Chem. Int.
Ed. Engl.. 1979, 18, 239; b) D. J. Ager in Umpoled Synthons: A
Survey of Sources and Uses in Synthesis (Ed.: T. A. Hase), Wiley,
New York, 1987.
[2] For examples of a-amino anion equivalents from sterically
hindered hydrazones, see: a) R. M. Adlington, J. E. Baldwin,
J. C. Bottaro, M. W. D. Perry, J. Chem. Soc. Chem. Commun.
1983, 1040; b) R. Fernandez, J. M. Lassaletta, Synlett 2000, 1228,
and references therein.
[24] When nitrones with C-aryl substituents were used as substrates,
products resulting from reductive dimerization of the nitrone
were also isolated.
¼
[3] For generation of a-amino radicals from other C N bonds, see:
a) S. F. Martin, C. P. Yang, W. L. Laswell, H. Rueeger, Tetrahe-
dron Lett. 1988, 29, 6685; b) P. Renaud, L. Giraud, Synthesis
1996, 913, and references therein; c) J. M. Aurrecoechea, A.
Fermandez, J. M. Gorgojo, C. Saornil, Tetrahedron 1999, 55,
7345; d) C. E. McDonald, A. M. Galka, A. I. Green, J. M.
Keane, J. E. Kowalchick, C. M. Micklitsch, D. D. Wisnoski,
Tetrahedron Lett. 2001, 42, 163.
[25] U. Schmidt, B. Rield, G. Haas, H. Griesser, A. Vetter, S.
Weinbrenner, Synthesis 1993, 216.
[26] P. Delair, A. M. Kanazawa, M. B. M. de Azevedo, A. E. Greene,
Tetrahedron: Asymmetry 1996, 7, 2707.
[27] CCDC-201303 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.can.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Center, 12 Union Road, Cambridge
CB21EZ, UK; Fax: (+ 44)1223-336033; or deposit@ccdc.cam.
ac.uk).
[28] a) J. Frackenpohl, P. I. Arvidsson, J. V. Schreiber, D. Seebach,
ChemBioChem 2001, 2, 445; b) D. Seebach, M. Brenner, M.
Rueping, B. Jaun, Chem. Eur. J. 2002, 8, 573, and references
therein.
[4] G. Masson, S. Py, Y. VallØe, Angew. Chem. 2002, 114, 1850;
Angew. Chem. Int. Ed. 2002, 41, 1772.
[5] a) E. J. Roskamp, S. F. Pedersen, J. Am. Chem. Soc. 1987, 109,
6551; b) T. Imamoto, S. Nishimura, Chem. Lett. 1990, 1141; c) T.
Shono, N. Kise, N. Kunimi, R. Nomura, Chem. Lett. 1991, 2191;
d) D. Guijarro, M. Yus, Tetrahedron 1993, 49, 7761; e) A. Clerici,
L. Clerici, O. Porta, Tetrahedron Lett. 1995, 36, 5955; f) J.-N.
Denis, A. Fkyerat, Y. Gimbert, C. Coutterez, P. Mantellier, S.
Jost, A. E. Greene, J. Chem. Soc. Perkin Trans. 1 1995, 1811; g) F.
Machrouhi, J.-L. Namy, Tetrahedron Lett. 1999, 40, 1315; h) N.
Taniguchi, M. Uemura, J. Am. Chem. Soc. 2000, 122, 8301.
[6] a) T. Shono, N. Kise, T. Fujimoto, Tetrahedron Lett. 1991, 32, 525;
b) T. Hanamoto, J. Inanaga, Tetrahedron Lett. 1991, 32, 3555.
[7] T. Shono, N. Kise, T. Fujimoto, A. Yamanami, R. Nomura, J.
Org. Chem. 1994, 59, 1730.
[29] a) T. O. M. Imamoto, Chem. Lett. 1987, 501; b) D. P. Curran, W.
Zhang, P. Dowd, Tetrahedron 1997, 53, 9023.
[8] a) G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307; b) T.
Skrydstrup, Angew. Chem. 1997, 109, 355; Angew. Chem. Int. Ed.
Engl. 1997, 36, 345; c) G. A. Molander, C. R. Harris, Tetrahedron
1998, 54, 3321; d) A. Krief, A.-M. Laval, Chem. Rev. 1999, 99,
745.
[9] a) P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980,
102, 2693; b) H. B. Kagan, J. L. Namy, P. Girard, Tetrahedron
Suppl. 1981, 37, 175.
[10] a) A. Gansauer, H. Bluhm, Chem. Rev. 2000, 100, 2771; b) P. G.
Steel, J. Chem. Soc. Perkin Trans. 1 2001, 2727, and references
therein.
[11] E. Hasegawa, D. P. Curran, J. Org. Chem. 1993, 58, 5008.
[12] O. Tamura, A. Toyao, H. Ishibashi, Synlett 2002, 1344.
[13] For a review on natural occurrence, biological activity, and
prospects for therapeutic applications of sugar-mimic glycosi-
dase inhibitors, see: N. Asano, R. J. Nash, R. J. Molyneux,
G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11, 1645.
[14] P. DeShong, C. M. Dicken, J. M. Leginus, R. R. Whittle, J. Am.
Chem. Soc. 1984, 106, 5598.
2268
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