Enantioselective henry addition of methyl 4-nitrobutyrate to aldehydes. Chiral building blocks for 2-pyrrolidinones and other derivatives

Article abstract of DOI:10.1021/ol1010888

A catalytic highly enantioselective Henry addition of methyl 4-nitrobutyrate to aldehydes using a Cu(II)-amino pyridine complex as catalyst is described. The products resulting from this reaction constitute a new, highly versatile family of chiral buildin

Full text of DOI:10.1021/ol1010888

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3058-3061
Enantioselective Henry Addition of
Methyl 4-Nitrobutyrate to Aldehydes.
Chiral Building Blocks for
2-Pyrrolidinones and Other Derivatives
Gonzalo Blay,* V´ıctor Herna´ndez-Olmos, and Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia,
C/Dr. Moliner, 50, E-46100 Burjassot (Vale`ncia), Spain
gonzalo.blay@uV.es; jose.r.pedro@uV.es
Received May 12, 2010
ABSTRACT
A catalytic highly enantioselective Henry addition of methyl 4-nitrobutyrate to aldehydes using a Cu(II)-amino pyridine complex as catalyst
is described. The products resulting from this reaction constitute a new, highly versatile family of chiral building blocks as a result of the
presence of three different functional groups on the molecule. These products have been transformed into nonracemic chiral γ-lactams,
5-hydroxy-5-substituted levulinic acid derivatives, and δ-lactones.
Organic molecules containing chiral pyrrolidine and 2-pyrro-
lidinone (γ-lactam) heterocycles are common among natural
products and pharmaceuticals with structures ranging from the
simple to the architecturally complex.1 These heterocyclic
compounds are also important building blocks for the synthesis
of complex natural products2 and other heterocycles,3 and the
Figure 1. Natural and bioactive hydroxyalkyl pirrolidines and
biological activity of these compounds is strongly modulated
by the ring substitution pattern and its absolute stereochemistry.
In particular, the 5-(1′-hydroxyalkyl)pyrrolidinone and the 2-(1′-
hydroxyalkyl)pyrrolidine (prolinol) moieties can be found in
several natural products such as the unusual amino acid (-)-
detoxinine,4 indolizinic alkaloids such as swainsonine,5 or the
antitumoral agent aza-muricatacin (Figure 1).6
pyrrolidinones.
tioselective reactions.8 Therefore, the development of pro-
cedures to obtain them, especially in enantiomerically pure
form, constitutes an appealing goal. These compounds have
been mainly synthesized by functional modification of the
parent five-membered heterocycles. Examples include modi-
fications of proline and pyroglutamic acid,3,7 hydroxyalky-
lation of 2-silyloxypyrroles and pyrrolidinones with al-
dehydes,2c,d,i,9 and the hydroxylation of 5-alkylidene-2-
pyrrolidinones.10 Furthermore, some examples in which the
heterocyclic ring is formed via cyclization reactions have
Compounds bearing this moiety have also been used as
organocatalysts7 and chiral ligands in metal-catalyzed enan-
(1) (a) Robson, R. H.; Prescott, L. F. Br. J. Clin. Pharmacol. 1979, 7,
81–87. (b) Ward, J. W.; Gilbert, D. L.; Franko, B. V.; Woodard, G.; Mann,
G. T. Toxicol. Appl. Pharmacol. 1968, 13, 242–250. (c) Courley, J. M.;
Heacock, R. A.; McInnes, A. G.; Nikolin, B.; Smith, D. G. J. Chem. Soc.,
Chem. Commun. 1969, 709–710.
10.1021/ol1010888  2010 American Chemical Society
Published on Web 06/10/2010

been described.4c,11 Despite this, only a few of these
procedures provide the expected hydroxyalkyl-γ-lactams and
prolinols in a highly enantioselective way.
with functionalized nitroalkanes is rather scarce. In this Letter
we describe the enantioselective Henry reaction between
aldehydes and methyl 4-nitrobutyrate and the transformation
of the resulting products into chiral nonracemic γ-lactams,
levulinic acid derivatives, and δ-lactones (Scheme 1).
The construction of multifunctional chiral building blocks
that can provide access to different structural motifs has raised
much interest among synthetic chemists. The Henry (nitro-aldol)
reaction is a straightforward way to prepare ꢀ-hydroxy nitroal-
kanes that are versatile building blocks as a result of the
chemical versatility of both the hydroxyl and the nitro groups.
In recent years there has been much progress in the development
of enantioselective versions of the Henry reaction, especially
using nitromethane and other unfunctionalized nitroalkanes.12
However, the number of enantioselective procedures described
Scheme 1. Synthetic Applications of the Henry Products
between Aldehydes and Methyl 4-Nitrobutyrate
(2) (a) Berini, C.; Pelloux-Le´on, N.; Minassian, F.; Denis, J.-N. Org.
Biomol. Chem. 2009, 7, 4512–4516. (b) Despinoy, X. L. M.; McNab, H.
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Wojciechowski, J.; Wolf, W. M.; Krajewska, U.; Rozalski, M. Tetrahedron
2008, 64, 6307–6314. (e) Kanizsai, I.; Szakonyi, Z.; Sillanpa¨a¨, R.; D’hooghe,
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2863. (f) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952–8955.
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Berlin, S.; Ericsson, C.; Engman, L. J. Org. Chem. 2003, 68, 8386–8396.
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Recently our group has developed camphor-derived C1-
symmetric amino pyridine ligands 4 that in the presence of
Cu(II) salts catalyze the addition of nitroalkanes to aldehydes
with very high enantioselectivity (up to 98% ee) under very
advantageous experimental conditions.13 When these conditions
were applied to the reaction of benzaldehyde (1a) and methyl
4-nitrobutyrate (2), compound 3a was obtained as an anti:syn
67:33 diastereomeric mixture with 92% and 91% ee, respec-
tively (Scheme 2, Table 1, entry 1). Further optimization was
(3) (a) Calvez, O.; Chiaroni, A.; Langlois, N. Tetrahedron Lett. 1998,
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Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D. J.
Nat. Prod. 1988, 29, 2487–2490.
Scheme 2. Henry Reaction between Aldehydes and Methyl
4-Nitrobutyrate Catalyzed by 4-Cu(II) Complexes
(6) (a) Cave, A.; Chaboche, C.; Figadere, B.; Harmange, J. C.; Laurens,
A.; Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-Lafitte, J.; Quero, A. M.
Eur. J. Med. Chem. 1997, 32, 617–623. (b) Baussanne, I.; Schwardt, O.;
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Tetrahedron: Asymmetry 2001, 12, 1503–1509.
(7) (a) For proline and prolinol-related catalysis, see: EnantioselectiVe
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (b)
Asymmetric Organocatalysis; Berkessel, A.,; Gro¨ger, H., Eds.; Wiley-VCH:
Weinheim, 2004. (c) Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(d) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e)
Marigo, M.; Jørgensen, K. A. Chem. Commun 2006, 2001.
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1987, 109, 7111. (b) Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y.
Tetrahedron: Asymmetry 1995, 6, 2109. (c) Shi, M.; Satoh, Y.; Masaki, Y.
J. Chem. Soc., Perkin Trans. 1 1998, 2547. (d) Wallbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1993, 4, 637. (e) Wilken, J.; Gro¨ger, H.; Kossenjans,
M.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 2761. (f) Wassmann, S.;
Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1999, 10, 4437.
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G. Tetrahedron Lett. 2009, 50, 3428–3431. (b) Yoshimitsu, T.; Atsumi, C.;
Iimori, E.; Nagaoka, H.; Tanaka, T. Tetrahedron Lett. 2008, 49, 4473–4475.
(c) Pichon, M.; Hocquemiller, R.; Figadere, B. Tetrahedron Lett. 1999, 40,
8567–8570. (d) Pichon, M.; Jullian, J.; Figadere, B.; Cave, A. Tetrahedron
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Reginato, G. Tetrahedron 1998, 54, 10403–10418. (f) Rassu, G.; Pinna, L.;
Spanu, P.; Zanardi, F.; Battistini, L.; Casiraghi, G. J. Org. Chem. 1997,
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carried out by changing solvent, copper salt, and base (Table
1). The best result was reached with Cu(OTf)2 and Et3N in
MeOH (entry 8), which produced compound 3a as an anti:syn
85:15 diastereomeric mixture with 96% and 90% ee, respec-
tively. We also checked the reaction with tert-butyl 4-nitrobu-
tyrate and obtained the corresponding product in excellent yield
but lower stereoselectively than with methyl ester 2 (entry 9).
The scope of the reaction under the optimized conditions was
studied with a number of aldehydes (Table 2). The reaction
temperature was adjusted according to the reactivity of the
(10) (a) Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. J. Org. Chem.
2007, 72, 8904–8909. (b) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.;
Nagasaka, T. Tetrahedron 2000, 56, 8855–8865.
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5442–5444. (c) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315–3326. (d) Palomo, C.; Oiarbide,
M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574.
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Weerassekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188–1189.
Org. Lett., Vol. 12, No. 13, 2010
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Table 1. Henry Reaction between Benzaldehyde (1a, R ) Ph) and Methyl 4-Nitrobutyrate (2) Catalyzed by 4-Cu(II)a
entry
Cu(II) salt
base
solvent
temp (°C)
time (h)
anti:synb
ee (% anti/syn)c
1
2
3
4
5
6
7
8
9d
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Bu3N
EtOH
MeOH
THF
toluene
CH2Cl2
MeOH
MeOH
MeOH
MeOH
-45
-45
-25
-35
-35
-45
-45
-45
-45
48
17
24
24
40
16
19
17
22
67:33
83:17
56:44
56:44
41:59
85:15
85:15
85:15
76:24
92/91
95/80
94/95
92/95
79/93
95/87
96/86
96/90
88/84
Et3N
Et3N
a 4 (11 mol %), Cu(II) salt (10 mol %), 2 (10 equiv), base (1 equiv). b Determined by 1H NMR. Full conversion. c Determined by chiral HPLC. d Reaction
carried out with tert-butyl 4-nitrobutyrate.
a
Table 2. Henry Reaction between Aldehydes 1 and Methyl 4-Nitrobutyrate (2) Catalyzed by 4-Cu(OTf)2
entry
2
R
temp (°C)
time (h)
3
yield (%)b
anti:sync
ee (%)d anti/syn
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Ph
-45
-45
-45
-45
-45
-45
-45
-45
-45
-45
-5
17
17
21
43
25
20
20
21
19
18
22
70
a
b
c
d
e
f
g
h
i
99
99
99
95
99
99
98
99
99
99
67
86
85:15
77:23
85:15
76:24
84:16
81:19
81:19
80:20
85:15
74:26
26:74
43:57
96/90
96/93
93/74
90/82
95/76
88/56
95/86
95/85
95/76
91/62
54/87
49/59
2-MeOC6H4
2-ClC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
3-MeOC6H4
3-ClC6H4
Ph-CHdCH
cyclohexyl
PhCH2CH2
9
10
11
12
j
k
l
j
k
l
-5
c
a 4 (11 mol %), Cu(OTf)2 (10 mol %), 2 (10 equiv), Et3N (1 equiv), MeOH. b Yield of isolated product. Determined by H NMR. d Determined by
1
chiral HPLC. Absolute stereochemistry assigned according to reference.13
aldehyde. With aromatic aldehydes, the reaction provided the
expected products 3 in high to quantitative yields, fair to good
diastereoselectivities and excellent enantioselectivities, with ee
values above 90% for the major diastereoisomer in most cases,
regardless of the electronic nature and location of the substituent
on the aromatic ring (entries 1-5 and 7-9). Only the presence
of a strongly electron-withdrawing nitro group (entry 6) brought
about a small decrease in the enantioselectivity especially in
the minor diastereoisomer. Most remarkably, the reaction could
also be performed with unbranched and even branched aliphatic
aldehydes (entries 11 and 12). In these cases, the reaction had
to be carried out at higher temperature (-5 °C), and the resulting
products were obtained in high yields but lower stereoselectivity
than with aromatic aldehydes. The reaction with the unsaturated
aldehyde 1j exclusively afforded the 1,2-addition product with
good stereoselectivity (entry 10).
with yields around 70% (Table 3). We observed small changes
in the diastereomeric ratios of products 5 with respect to the
Scheme 3
.
Synthesis of γ-Lactams by Hydrogenation of
Compounds 3
diastereomeric ratios of the starting materials 3. Normally a little
increase in the percentage of the anti isomer was observed in
most cases, except for compound 5f. A possible explanation for
this change could be a slight epimerization or the retro-Henry
reaction of one of the diastereomers during storage.14
The Henry reaction-lactamization sequence has been
applied to a short synthesis of syn- and anti-aza-muri-
catacin (5m), which are compounds with an important
antitumoral activity (Scheme 4).6 The synthesis was
carried out from tridecanal (1m). Because of the low
solubility of 1m in MeOH, the 4-copper(II)-catalyzed
Henry reaction was carried out in EtOH at -10 °C, giving
compound 3m in 90% yield as a 36:64 anti:syn mixture
With nitroalkanols 3 in hand, we studied their transformation
into γ-lactams. Reduction of the nitro group was carried out
by hydrogenation on 10% Pd/C to give directly the desired
γ-lactams 5 (Scheme 3).
We carried out the lactamization reaction with a representa-
tive number of compounds 3, obtaining the expected lactams 5
(13) (a) Blay, G.; Domingo, L. R.; Herna´ndez-Olmos, V.; Pedro, J. R.
Chem.sEur. J. 2008, 14, 4725–4730. (b) Blay, G.; Herna´ndez-Olmos, V.;
Pedro, J. R. Chem. Commun. 2008, 4840–4842.
3060
Org. Lett., Vol. 12, No. 13, 2010

Table 3. Representative Examples of Lactamization of Compounds 3 According to Scheme 3
entry
3
R
time (h)
5
yield (%)a
anti:synb
ee (%)c anti/syn
1
2
A
B
D
F
G
H
K
Ph
23
25
25
25
41
26
41
a
b
d
f
g
i
70
75
66
66
73
74
65
89:11
80:20
80:20
63:37
85:15
84:16
26:74
96/80
96/94
90/84
85/55
94/75
94/85
56/85
2-MeOC6H4
4-MeOC6H4
4-NO2C6H4
4-MeC6H4
3-MeOC6H4
cyclohexyl
3
4d
5
6
7
k
b
a Yield of isolated product. Determined by H NMR. c Determined by chiral HPLC. d Reduction of the aromatic nitro group also took place.
1
with 87% ee for both diastereomers. Hydrogenation of
with Bu3SnH/AIBN to give 7a in 61% yield, which after
the mixture gave syn-5m and anti-5m, which were
deprotection of the hydroxyl group under acidic conditions gave
Scheme 6. Enantioselective Synthesis of δ-Lactones
Scheme 4. Enantioselective Synthesis of Aza-muricatacin
lactone 10a.16 Unfortunately, the compound was obtained with
only 49% ee, indicating a partial racemization of the C-OH
atom, probably due to formation of stabilized benzyl radicals.
As a matter of fact, using a similar sequence, starting from
compound 6m, derived from an aliphatic aldehyde, lactone 10m
was obtained, this time without any loss of enantiomeric purity
separated by HPLC. It should be mentioned that this is
the shortest synthesis of aza-muricatacin reported so far.
To explore the synthetic versatility of compounds 3 as chiral
building blocks, we have also carried out the synthesis of
5-hydroxy-5-phenyllevulinic acid methyl ester (8a), a compound
with known analgesic activity (Scheme 5).15 In this case the
with respect to the starting material.
In summary, we have prepared a new highly versatile
family of chiral building blocks via a catalytic enantiose-
lective Henry reaction of aldehydes with methyl 4-nitrobu-
tyrate. The synthetic applicability of these new building
blocks has been shown with the synthesis of chiral γ-lactams,
5-hydroxy-5-phenyllevulinic acid methyl ester, and δ-lac-
tones with high ee (up to 96% ee).
Scheme 5. Enantioselective Synthesis of
5-Hydroxy-5-phenyllevulinic Acid Methyl Ester
Acknowledgment. Financial support from the Ministerio
de Ciencia e Innovacio´n and FEDER (CTQ2006-14199 and
CTQ2009-13083) and from Generalitat Valenciana (ACOMP/
2009/338) is acknowledged. V.H.-O. thanks the Universitat de
Vale`ncia for a predoctoral grant (V segles program).
Supporting Information Available: Representative ex-
1
perimental procedures, characterization data, H and 13C
NMR spectra and chiral analysis for compounds 3, 5, 8, and
10. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL1010888
hydroxyl group needed to be protected as a THP ether in order
to avoid a retro-Henry reaction. Ozonolysis of the nitronate gave
ketone 7a in 87% yield. Finally deprotection of the hydroxyl
group afforded compound 8a with 93% ee.
δ-Lactones are also available from compounds 3 (Scheme
6). Denitration of compound 6a was achieved upon treatment
(14) We did not observe noticeable changes of dr during hydrogenation
of freshly prepared compounds 3.
(15) Wetzel, E. R.; Osterberg, A. C.; Borders, D. B. J. Med. Chem.
1974, 117, 249–250.
(16) (a) Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahedron: Asymmetry
2003, 14, 1575–1580. (b) Estep, K. G.; Fliri, A. F. J.; O’Donnell, C. J.
U.S. Patent 2008120093, 2008.
Org. Lett., Vol. 12, No. 13, 2010
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