SmI2-mediated cross-coupling of nitrones with β-silyl acrylates: Synthesis of (+)-Australine

Article abstract of DOI:10.1021/ol203396s

The SmI₂-mediated cross-coupling of nitrones with β-silyl-α,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through Ta

Full text of DOI:10.1021/ol203396s

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1042–1045
SmI2-Mediated Cross-Coupling of
Nitrones with β-Silyl Acrylates: Synthesis
of (þ)-Australine
Pierre Gilles and Sandrine Py*
ꢀ
Departement de Chimie Moleculaire (SERCO) UMR-5250, ICMG FR-2607, CNRS,
Universite Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France
ꢀ
ꢀ
sandrine.py@ujf-grenoble.fr
Received December 20, 2011
ABSTRACT
The SmI2-mediated cross-coupling of nitrones with β-silyl-R,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly
diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through TamaoꢀFleming oxidation. By applying the
method to a cyclic, carbohydrate-derived nitrone, a new synthesis of (þ)-australine has been realized in only 11 steps and in 21% overall yield from
L-xylose.
Since its introduction in 1977, samarium diiodide has
become a useful reagent for the reduction of a wide range
of organic functions and for stereoselective formation of
carbonꢀcarbon bonds.1 A few years ago, the SmI2-
mediated cross-coupling of nitrones with R,β-unsaturated
esters was reported2 and has since proved useful for
elaboration of the bicyclic skeleton of pyrrolizidine imino-
sugars, such as (þ)-hyacinthacine A2.3 Recently, we have
become interested in designing syntheses of other naturally
occurring pyrrolizidines, especially those bearing hydroxyl
groups in position 6 and/or 7 (Figure 1).
The introduction of a hydroxyl group in position 7 of
pyrrolizidines was first attempted through reductive cross-
coupling of nitrone 1 with R,β-unsaturated esters bearing
an oxygen atom in the β position. However, treatment of
Figure 1. Natural polyhydroxylated pyrrolizidines.
nitrone 1 and ethyl (E)-3-trimethylsilyloxypropenoate4 (2)
with SmI2 in the presence of water3a did not provide the
expected cross-coupled product, but N-hydroxy-pyrroli-
dine 3, resulting from the reduction of the starting nitrone
(Scheme 1).
Although alkoxy-substituted captodative olefins have
been used as Michael acceptors for the synthesis of
β-hydroxy-γ-lactones through SmI2-mediated cross-
coupling with ketones5 and aldehydes,6 the yields are often
(1) (a) Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5.
(b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693. (c) Procter, D. J., Flowers, R. A., II, Skrydstrup, T., Eds.; Organic
Synthesis Using Samarium Diiodide: A Practical Guide; Royal Society of
Chemistry Publishing: 2010.
ꢀ
(2) (a) Masson, G.; Cividino, P.; Py, S.; Vallee, Y. Angew. Chem., Int.
Ed. 2003, 42, 2265. (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229.
(c) Cividino, P.; Py, S.; Delair, P.; Greene, A. E. J. Org. Chem. 2007, 72,
485.
ꢀ
(3) (a) Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459.
(b) Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H.-w.;
ꢀ
ꢁ
Py, S. Bioorg. Med. Chem. 2007, 15, 6443. (c) Rehak, J.; Fisera, L.;
ꢁ ꢁ
ꢁ
ꢀ
Kozısek, J.; Bellovicova, L. Tetrahedron 2011, 67, 5762.
(4) Foehlisch, B.; Giering, W. Synthesis 1980, 231.
r
10.1021/ol203396s
Published on Web 01/31/2012
2012 American Chemical Society

yields.13 Under these conditions, the desired N-hydroxyl-
amines 6a,b were obtained, but proved to be relatively
unstable in air. Fortunately, a direct, single-pot reduction
of the reaction product using Zn/AcOH14 afforded the
lactams 7a,b in 51% yield and in a 90/10 cis/trans15 ratio
(Table 1, entry 1), accompanied by the β-silylpropanoate
8,16 arising from reduction of 5 (35%).
Scheme 1. Attempted Cross-Coupling of Nitrone 1 and Acrylate 2
Table 1. SmI2-Mediated Cross-Coupling of Nitrone 4 and Ac-
rylate 5
moderate in the case of intermolecular reactions. Probably
due to electronic effects, β-alkoxy-estersare poor acceptors
for nitrone conjugate addition reactions. In contrast, the
SmI2-mediated cross-coupling of nitrones with alkyl
β-substituted R,β-unsaturated esters, such as methyl cro-
tonate, afforded the expected coupling product in good
yields and with excellent stereoselectivities.2a,c Carbon and
silicon, being in the same column of the periodic table,
present similar electronic properties.7 We thus thought
that the SmI2-mediated cross-coupling of nitrones with
β-silyl-substituted R,β-unsaturated esters could be more
successful than with the alkoxy esters. The silyl group
would then serve as a masked hydroxyl group, to be later
revealed by TamaoꢀFleming oxidation.8 β-Silyl acrylates
or acrylamides have already been used in conjugate addi-
tion reactions9 but, to the best of our knowledge, never
in a SmI2-mediated cross-coupling reaction.10 Here, we
report the SmI2-mediated cross-coupling of nitrones with
a β-silyl acrylate and its application to the synthesis of
(þ)-australine.
SmI2
additives
(equiv)
temp
time
(h)
7a,b
cis/
entry (equiv)
(°C)
(yield %) transa
1
2
3
3
4
4
H2O
(8)
ꢀ78
28
51
53
84
90/10
90/10
>98/2
H2O
(8)
ꢀ78 to
ꢀ30
0.1
H2O/LiBr ꢀ78 to
0.1
(8/12)
ꢀ30
a Ratio determined by 1H analysis of the crude reaction mixture.
In a preliminary assay, nitrone 411 and ethyl (E)-
3-(dimethylphenylsilyl)propenoate (5)12 in the presence
of water (8 equiv) at ꢀ78 °C were treated with SmI2.
Through coordination to SmI2, water forms a more reac-
tive species, often allowing faster reactions and better
Next, the same reagents were mixed at ꢀ78 °C and the
cooling bathwas removed at the end of SmI2 addition. At a
temperature of ꢀ30 °C (reached after 5 min), the starting
nitrone was completely consumed. However, after zinc
reduction of the intermediate N-hydroxylamines 6a,b,
lactams 7a,b (90/10 cis/trans ratio) were isolated in a
similar 53% yield (Table 1, entry 2). The introduction into
the reaction mixture of LiBr17 proved to be more reward-
ing. Indeed, with a combination of SmI2 and H2O/LiBr
additives, only the cis lactam 7a was formed and in an
improved yield of 84% (Table 1, entry 3). Flowers has
demonstrated that the addition of 12 equiv of LiBr to
solutions of SmI2 in THF provides a system with an
oxidation potential of ꢀ1.98 V as compared with ꢀ1.33
V for SmI2 alone vs the Ag/AgNO3 reference electrode.18
The increase in the reducing ability of the system may well
account for the improvement in the reaction efficiency.
Furthermore, introduction of the lithium cation seems to
favor the formation of the cis lactam.
(5) Kerrigan, N. J.; Upadhyay, T.; Procter, D. J. Tetrahedron Lett.
2004, 45, 9087.
ꢀ
(6) Donadel, O. J.; Martın, T.; Martın, V. S.; Padron, J. M. Bioorg.
Med. Chem. Lett. 2007, 17, 18.
(7) As a consequence, silicon has been considered as an isostere of
carbon in drug discovery: (a) Showell, G. A.; Mills, J. S. Drug Discovery
Today 2003, 8, 551. (b) Bains, W.; Tacke, R. Curr. Opin. Drug Discovery
Dev. 2003, 6, 526. (c) Gately, S.; West, R. Drug Dev. Res. 2007, 68, 156.
(8) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organome-
tallics 1983, 2, 1694. (b) Fleming, I.; Henning, R.; Plaut, H. J. Chem.
Soc., Chem. Commun. 1984, 29.
(9) (a) Klumpp, G. W.; Mierop, A. J. C.; Vrielink, J. J.; Brugman, A.;
Schakel, M. J. Am. Chem. Soc. 1985, 107, 6740. (b) Fleming, I.;
Lawrence, N. J. J. Chem. Soc., Perkin Trans. 1 1998, 2679. (c) Clayden,
J.; Watson, D. W.; Helliwell, M.; Chambers, M. Chem. Commun. 2003,
2582. (d) Stork, G.; Tang, P. C.; Casey, M.; Goodman, B.; Toyota, M.
J. Am. Chem. Soc. 2005, 127, 16255. (e) Shintani, R.; Okamoto, K.;
Hayashi, T. Org. Lett. 2005, 7, 4757. (f) Lipshutz, B. H.; Tanaka, N.;
Taft, B. R.; Lee, C.-T. Org. Lett. 2006, 8, 1963. (g) Balskus, E. P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810.
(14) See Supporting Information.
(15) Relative configuration was determined by NOESY experiments.
See Supporting Information.
(16) (a) Sommer, L. H.; Marans, N. S. J. Am. Chem. Soc. 1950, 72,
1935. (b) Nakashima, T.; Fujiyama, R.; Fujio, M.; Tsuno, Y. Bull.
Chem. Soc. Jpn. 1999, 72, 741.
(10) For the SmI2-mediated hydrodimerization of silyl acrylates, see:
(a) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Chem. Commun. 1992, 1775.
(b) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 2711.
(11) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.; Merino, P.;
Tejero, T. Synth. Commun. 1994, 24, 2537.
(12) (a) Takeshita, K.; Seki, Y.; Kawamoto, K.; Murai, S.; Sonoda,
N. J. Org. Chem. 1987, 52, 4864. (b) Sieburth, S. M.; Lang, J. J. Org.
Chem. 1999, 64, 1780.
(17) Peltier, H. M.; McMahon, J. P.; Patterson, A. W.; Ellman, J. A.
J. Am. Chem. Soc. 2006, 128, 16018.
(13) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem.
Commun. 2012, 8, 330.
(18) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II.
Tetrahedron Lett. 1997, 38, 8157.
Org. Lett., Vol. 14, No. 4, 2012
1043

The cross-coupling of nitrone 4 was also considered with
ethyl (Z)-3-(dimethylphenylsilyl)propenoate (9).19 Sur-
prisingly, at ꢀ78 °C and in the presence of water, no trace
of N-hydroxyamino esters 6a,b was detected (Scheme 2).
The starting nitrone was mostly recovered (74%), while
acrylate 9 was reduced to propanoate 8 (28%) and dimer-
ized adipic acid derivatives 10a,b (31%). These results
suggest that acrylate 9 is reduced by SmI2 faster than
nitrone 4 (and than its E-isomer, 5). This reduction com-
peting with the formation of a (ketyl-type) radical anion
from 420 would thus hamper conjugate addition onto the
unsaturated ester.21
Table 2. Direct Preparation of Lactam 11
Scheme 2. Attempted Reaction of Nitrone 4 with Z-Acrylate 9
additives
(equiv)
temp
time
(h)
11
entry
1
(°C)
(%)
dra
H2O/LiBr
ꢀ78 to
ꢀ30
0.1
0.1
0.1
0.1
49
32
50
64
>98/2
(8/12)
2
3
4
PhOH/LiBr
(8/12)
ꢀ78 to
ꢀ30
>98/2
>98/2
>98/2
2,4,6-triCl-PhOH/LiBr
(8/12)
ꢀ78 to
ꢀ30
HFIP/LiBr
(8/12)
ꢀ78 to
Having in hand suitable reaction conditions for the
coupling of nitrone 4 with 5, we next turned to studying
the reaction of this β-silyl acrylate with nitrone 1,3a which
exhibits an appropriate substitution pattern for the synthe-
sis of the different alkaloids represented in Figure 1. When
nitrone 1 was treated with acrylate 5 under the same
conditions (Table 1, entry 3), lactam 11 was isolated in
49% yield as a single diastereomer (Table 2, entry 1). The
intermediate N-hydroxypyrrolidine 12 could also be iso-
lated in 49% yield and as a single diastereomer when the
zinc reduction step was omitted.
With the aim of improving the efficiency of the reductive
coupling step, various alternative proton sources were
investigated, with a particular focus on the effect of their
acidity. Indeed, the rate of SmI2-mediated reduction of
acetophenone has been shown to be proportional to the
acidity of the proton source used as an additive.22 The
groups of Procter23 and Nicolaou24 have also demon-
strated the role of the acidity of additives on the efficiency
of CꢀC bond formation induced by SmI2. In the presence
of phenol (pKa 9.9) or 2,4,6-trichlorophenol (pKa 6.2), the
yields of the expected lactam 11 were lower (or similar) than
with water (Table 2, entries 2 and 3). On the other hand, use
of the noncoordinating hexafluoroisopropanol (HFIP,
pKa 9.3) as the additive afforded improved efficiency in
ꢀ30
a Only one diastereomer was detected by 1H NMR analysis of the
crude reaction mixture.
the coupling, with 11 being isolated in 64% yield (Table 2,
entry 4). It is not clear how to rationalize the effect of
HFIP, its pKa being intermediate between those of the two
phenols tested. Although the role of proton sources in such
reactions has been extensively investigated, it is still not
fully understood and acidity is certainly not the only
parameter to consider.25
The configuration of the new stereocenters in 11 was
determined to be S at both C-7 and C-7a from NOESY
correlations.14 The approach of the β-silyl acrylate by the
Re face of nitrone 1 is directed by the substituents of the
nitrone (at C-1 and C-3 in the product).3a Remarkably, the
configuration of the silylated stereocenter is also comple-
tely controlled in this SmI2-mediated cross-coupling reac-
tion. Such control may be explained by a favored chelated
transition state A, similar to those proposed in Heath-
cock’s model for conjugate addition of E-enolates on
β-substituted acrylic esters (Scheme 3).26
Pyrrolizidinone 11 is thus a possible precursor of (þ)-
australine, a polyhydroxylated pyrrolizidine isolated from
(19) Cardona, F.; Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri,
P.; Sim, L.; Gloster, T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti,
A. Chem.;Eur. J. 2009, 15, 1627.
(25) (a) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5,
4811. (b) Amiel-Levy, M.; Hoz, S. J. Am. Chem. Soc. 2009, 131, 8280.
(c) Sadasivam, D. V.; Teprovich, J. A.; Procter, D. J.; Flowers, I. I. R. A.
Org. Lett. 2010, 12, 4140.
(26) Oare, D. A.; Heathcock, C. H. Stereochemistry of the Base-
Promoted Michael Addition Reaction. In Topics in Stereochemistry;
Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1989; Vol. 19,
pp 227ꢀ408. For a recent discussion and computational investigation
on intermolecular Michael reactions, see: Kwan, E. E.; Evans, D. A.
Org. Lett. 2010, 12, 5124. The authors thank one of the referees for
bringing this paper to their attention.
ꢀ
(20) Masson, G.; Py, S.; Vallee, Y. Angew. Chem., Int. Ed. 2002, 41,
1772.
(21) For previous work showing easier reductive dimerization of Z-β-
silyl acrylates in comparison to their E-isomers see, ref 10.
(22) Chopade, P. R.; Prasad, E.; Flowers, R. A. J. Am. Chem. Soc.
2004, 126, 44.
(23) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem. 2003,
68, 3190.
(24) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P.
J. Am. Chem. Soc. 2009, 131, 16905.
1044
Org. Lett., Vol. 14, No. 4, 2012

natural substance ([R]20 = 17.1 (c 2.9, MeOH); lit.:
D
[R]20D = 18.6 (c 2.5, MeOH)).29b
Scheme 3. Possible Transition State for the SmI2-Promoted
Reductive Coupling of Nitrone 1 and Acrylate 5
Scheme 4. Synthesis of (þ)-Australine
the seeds of Castanospermum australe.27 This natural
product has attracted the interest of chemists because it
not only alters amyloglucosidase activity28 but also pos-
sesses a structure exhibiting five contiguous stereogenic
centers, which represents a synthetic challenge.29
When the TamaoꢀFleming oxidation of pyrrolizidi-
none 11 was first carried out under acidic (HBF4•OEt2
in DCM, then H2O2, KF in DMF) or electrophilic (Br2
and AcO2H) conditions, decomposition of the starting
material was observed. The protocol reported by Woerpel
for silyl group oxidation under basic conditions was proved
more successful:30 pyrrolizidinone 11 was treated with po-
tassium hydride, TBAF, and cumene hydroperoxide.
Pyrrolizidinone 13, obtained in moderate yield (57%),
was reduced by a BH3•DMS complex to give pyrrolizi-
dine 14 (Scheme 4).31 The use of cumene hydroperoxide,
instead of tert-butyl hydroperoxide, reportly avoids
desilylation.32 Finally, it was found that reduction of
pyrrolizidinone 11 to pyrrolizidine 15 prior to Tamaoꢀ
Fleming oxidation gave a better overall yield (65% vs 50%
for the first sequence). Deprotection of the hydroxyl
groups was then accomplished by hydrogenolysis to afford
quantitatively (þ)-australine. The spectroscopic data and
optical rotation of our synthetic sample of (þ)-australine
were in accordance with those previously reported for the
Inconclusion, wehaveshown that the β-silylacrylate 5 is
an excellent partner for the SmI2-mediated intermolecular
cross-coupling of nitrones, one that is capable of yielding
β-silyl γ-amino acid derivatives or β-silyl γ-lactams with
nearly complete diastereoselection. Through the use of this
new cross-coupling, (þ)-australine could be obtained in 11
steps and with an overall yield of 21% from L-xylose. This
methodology should be useful for the synthesis of other
polyhydroxylated pyrrolizidines.
ꢂ
Acknowledgment. P.G. is grateful to the Ministere de
l Enseignement Superieur et de la Recherche for a doctoral
0
ꢀ
fellowship.
(27) Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.;
Elbein, A. D. J. Nat. Prod. 1988, 51, 1198.
(28) Tropea, J. E.; Molyneux, R. J.; Kaushal, G. P.; Pan, Y. T.;
Supporting Information Available. Characterization
data, full experimental procedures, and copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Mitchell, M.; Elbein, A. D. Biochemistry 1989, 28, 2027.
(29) Selected syntheses of (þ)-australine: (a) White, J. D.; Hrnciar,
P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359. (b)
Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999,
121, 3046. (c) Romero, A.; Wong, C.-H. J. Org. Chem. 2000, 65,
8264. (d) Lauritsen, A.; Madsen, R. Org. Biomol. Chem. 2006, 4,
2898. (e) Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Org. Lett.
2007, 9, 77. (f) Trost, B. M.; Aponick, A.; Stanzl, B. N. Chem.;Eur.
J. 2007, 13, 9547. (g) Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G.
J. Org. Chem. 2010, 75, 815.
(30) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(31) Pearson, W. H.; Hines, J. V. J. Org. Chem. 2000, 65, 5785.
(32) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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