Diastereoselective addition of nitro compounds to α,β- unsaturated γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2005.10.163

Herein, we report our results on the diastereoselective addition of nitro compounds to α,β-unsaturated γ-butyrolactones, which afforded the corresponding Michael adducts 9-17 in moderate to good yields and good to excellent diastereoisomeric ratio. A one-pot conversion of α,β- unsaturated γ-butyrolactones 7 and 8 to the corresponding trisubstituted keto-γ-butyrolactones 24 and 25 via a tandem Michael-Nef protocol is also described.

Full text of DOI:10.1016/j.tetlet.2005.10.163

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 185–188
Diastereoselective addition of nitro compounds to
a,b-unsaturated c-butyrolactones
Giovanni B. Rosso and Ronaldo A. Pilli*
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP, PO Box 6154, 13083-970, Campinas, Sa˜o Paulo, Brazil
Received 16 July 2005; revised 28 October 2005; accepted 31 October 2005
Abstract—Herein, we report our results on the diastereoselective addition of nitro compounds to a,b-unsaturated c-butyrolactones,
which afforded the corresponding Michael adducts 9–17 in moderate to good yields and good to excellent diastereoisomeric ratio. A
one-pot conversion of a,b-unsaturated c-butyrolactones 7 and 8 to the corresponding trisubstituted keto-c-butyrolactones 24 and 25
via a tandem Michael–Nef protocol is also described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The Michael addition reaction is one of the most impor-
tant methods for carbon–carbon bond formation in
organic synthesis,1 and generally enolates derived from
active methylene or methine compounds are used as
nucleophiles under basic conditions. In this way, nitro
compounds are synthetically useful due to the acidity
of C–H bonds a to the nitro group and its easy transfor-
mation into a broad range of functionalities2,3 as
revealed by their application in the total synthesis of
natural products4 and biologically active compounds.5
rated c-butyrolactones 5–8. For that purpose, we ini-
tially examined the allylation and cyanoethylation of
2-triisopropylsilyloxyfurans 3 and 4, prepared in 92%
and 99% yield, respectively, from 1 and 2 as described
elsewhere.11 Reaction of the lithiated form of silyloxy-
furan 3 with allyl bromide, followed by hydrolysis with
aqueous HCl (10% v/v), afforded 5 in 76% yield (two
steps). For the allylation of 3-methyl-5-allyl-2(5H)-fura-
none (6), we turned to the use of silver(I) trifluoracetate
as Lewis acid which afforded 6 in 58% yield (Scheme
1).12 Silyloxyfurans 3 and 4 proved to be competent
Michael donors when reacting with acrylonitrile afford-
ing the cyanoethylation products 7 and 8 in 89% and
91% yield, respectively, when BF3ÆOEt2 was employed
as Lewis acid (Scheme 1).13
A variety of reaction conditions including the use of
amines, aqueous media, heterogeneous catalysis, micro-
wave, ultrasound, and solvent-free media have been de-
scribed for the reaction of nitro compounds with
Michael acceptors.1 The limited number of examples
available in the literature6 and the poor yields observed
in the preparation of 4-nitromethyl-c-butyrolactones7
prompted us to investigate the conjugate addition of
nitro derivatives to unsubstituted and substituted
a,b-unsaturated c-butyrolactones as an entry to the total
synthesis of some Stemona alkaloids8,9 and GABA
analogues.10
The Michael addition of nitro compounds to a,b-unsatu-
rated c-butyrolactones could be efficiently carried out
with 10 mol % of DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene) as catalyst in moderate to excellent yields as shown
by the formation of nitrolactones 9 and 10 in 69% and
88% yield (Table 1, and Scheme 2) from 1.14 Due to
the highly acidic nature of the nitroalkyl substituent,
nitrolactone 10 was isolated as an equimolar mixture
of diastereoisomers at the CHNO2 stereogenic center.
Commercially available 2(5H)-furanone (1) and 3-
methyl-2(5H)-furanone (2) were employed as starting
materials for the preparation of substituted a,b-unsatu-
When this experimental condition was employed in the
reaction of lactone 2 (R1 = Me, R2 = H, entry 3) with
nitromethane, Michael adduct 11 was obtained in poor
yield (34%) and moderate (4:1 ratio) diastereomeric
ratio as determined by 1H NMR and gas chromatography
analyses. The trans stereochemistry of the major isomer
Keywords: Michael reaction; Nitro compound; c-Butyrolactone and
silyloxyfuran.
*
Corresponding author. Tel.: +55 19 37883083; fax: +55 19
37883023; e-mail: pilli@iqm.unicamp.br
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.163

186
G. B. Rosso, R. A. Pilli / Tetrahedron Letters 47 (2006) 185–188
H
H
O
O
O
O
O
O
CN
OTIPS
O
i
ii, iii or iv
or
R
R
R
R
3, R = H
4, R = Me
1, R = H
2, R = Me
7, R = H
8, R = Me
5, R = H
6, R = Me
Scheme 1. Preparation of substituted c-butyrolactones (+/ꢀ)-5–8. Reagents and conditions: for compound (+/ꢀ)-5: (i) 1, TIPSOTf, Et3N, CH2Cl2,
0 ꢁC to rt, 2 h, 92%; (ii) 3, TMEDA, THF, t-BuLi, 2 h, 0 ꢁC; then allyl bromide, 2 h, 0 ꢁC to rt, HCl aq 10% (v/v), 76% (two steps); for compound
(+/ꢀ)-6: (i) 2, TIPSOTf, Et3N, CH2Cl2, rt, 1.5 h, 99%; (iii) F3CCO2Ag, CH2Cl2, ꢀ78 ꢁC; then 4, CH2Cl2, allyl bromide, 1 h, ꢀ78 ꢁC to rt, 58%;
for compounds (+/ꢀ)-7, and (+/ꢀ)-8: (iv) 3 or 4, acrylonitrile, CH2Cl2, ꢀ78 ꢁC; then BF3ÆOEt2, 2 h, ꢀ78 ꢁC, (7, 89%); (8, 91%).
Table 1. Michael adducts derivatives (+/ꢀ)-9–17 (Scheme 2)a,b
Entry
Lactone
Conditions
R1
R2
R3
Nitrolactone
Yield (%)
3,4-trans:cis ratio
4,5-trans:cis ratio
1
2
3
4
5
6
7
8
9
1
1
2
2
2
2
5
6
7
8
16 h, rt
12 h, rt
24 h, rt
24 h, 60 ꢁC
24 h, rt
12 h, 60 ꢁC
1 h, rt
2 h, rt
4 h, rt
1 h, rt
H
H
H
H
H
H
H
H
Allyl
Allyl
H
9
69
88
34
75
78
91
61
68
88
93
—
—
—
—
—
—
—
—
98:2
100:0
100:0
100:0
CO2Me
H
H
CH3
10
11
11
12
13
14
15
16
17
CH3
CH3
CH3
CH3
H
CH3
H
CH3
81:19
89:11
100:0
100:0
—
100:0
—
100:0
CO2Me
H
H
H
H
CH2CH2CN
CH2CH2CN
10
a The yields in Table 1 are based on isolated products (silica gel chromatography).
b The diastereoisomeric ratio was determined from the crude reaction by GC and proven by 1H NMR data.
H
H
R3CH2NO2,
DBU (0.1 equiv.)
When 5-allyl substituted lactone 5 was employed (entry
7), the corresponding adduct 14 was obtained as a 49:1
ratio of diastereoisomers at C4–C5. The same trend was
observed when 5(2-ethylcyano) substituted lactone 7
was employed (entry 9). Complete 3,4-trans-4,5-trans
diastereoselectivity and better yields were observed
when 3,5-disubstituted lactones 6 and 8 (entries 8 and
10) were employed.
R2
O
R2
O
O
O
2
5
4
3
R3
6
Table 1
R1
1,2,5-8
R1
H
NO2
( )-9-17
Scheme 2. Synthesis of nitrolactones (+/ꢀ)-9–17 (see Table 1).
In order to unambiguously establish the trans-stereo-
chemistry at C4 and C5 in the adducts obtained, we
reacted (+)-5-hydroxymethyl-c-butyrolactone 18, pre-
pared in four steps from D-(+)-mannitol as described
in the literature by Mann and co-workers,17 with nitro-
methane under the conditions described above to afford
nitrolactone (+)-1918 as a single diastereoisomer in 78%
yield which was converted to (+)-20 in 84% yield after
acetylation with Ac2O/HClO4 (Scheme 3).
1
was established by inspection of the H NMR spectrum
of the mixture, which displayed the major methyl dou-
blet less shielded (d 1.33 ppm) than the minor isomer
one (d 1.22 ppm) in good agreement with the literature
data reported for cis- and trans-11 (d 1.19 and
1.28 ppm, respectively).15 Additionally, NOE experi-
ments showed a 0.57% increment of the methyl doublet
in the major isomer upon irradiation of H4 while no
increment at H4 was observed when H3 was irradiated.
Finally, the diastereoisomeric ratio and the yield were
significantly improved (8:1 ratio and 75% yield, respec-
tively) when the reaction was carried at 60 ꢁC (entry
4). This observation corroborates the assignment of
the trans configuration to the major stereoisomer and
it is in line with the results by Costa and coworkers
who described a quantitative epimerization of all cis
3,4,5-trisubstituted c-butyrolactone to the correspond-
ing 3,4-trans isomer upon treatment with DBU at rt.16
The thermodynamically favored trans-nitrolactones 12
and 13 were formed as a 1:1 mixture of epimers at C6
in the addition of nitroethane and methyl nitroacetate,
respectively, to lactone 2 (entries 5 and 6). The trans ste-
reochemistry at C3–C4 was assumed based on the
assignment previously described for c-butyrolactone 11.
1
Unfortunately, the H5 signal in the H NMR spectrum
of (+)-20 appeared overlapped making it difficult to
compare it with the corresponding cis isomer described
in the literature.19 Although the H5 diagnostic signal
H
H
i
O
O
O
O
OH
OR
78%
H
NO2
(+)-18
(+)-19, R = H
(+)-20, R = Ac
ii
84%
Scheme 3. Synthesis of chiral nitrolactones. Reagents and conditions:
(i) CH3NO2, DBU 0.1 equiv, 4 h, rt; (ii) HClO4, Ac2O, 1 h, rt.

G. B. Rosso, R. A. Pilli / Tetrahedron Letters 47 (2006) 185–188
187
appears in a distinct spectral region in compound (+)-
19, the NMR data for the corresponding 4,5-cis nitro-
lactone (+)-21 was not available in the literature. In
order to unambiguously establish the relative
stereochemistry of Michael adducts (+)-19 and (+)-20,
we have prepared 4,5-cis-nitrolactone (+)-21 according
to the procedure described by Costa and co-workers.19
described by Ballini and co-workers.4 In the event, treat-
ment of nitro compounds 7 and 8 with methyl 4-nitro-
butanoate and excess DBU (2.0 equiv) in refluxing
acetonitrile afforded ketolactones 24 and 25 in 30%
and 35% overall yields, respectively.
In summary, the utility of the addition of silyloxyfurans
to acrylonitrile and of nitro compounds to c-butyrolac-
tones has been demonstrated. The synthetic route de-
scribed can be considered as an alternative method to
synthesis cyclic GABA analogues and studies toward
the stereoselective total synthesis of Stemona alkaloids
employing this synthetic methodology are currently
underway in our laboratory and will be reported in
due course.
1
Not only the H NMR spectra of compounds (+)-19
and (+)-21 are clearly distinguishable but differential
NOE experiments have firmly established their trans-
and cis-4,5 relative stereochemistry, respectively
(Fig. 1). Based on these results, the trans relationship
for H4 and H5 was assumed for compounds 14–17.
The approach described above was successfully imple-
mented for the preparation of ketolactones 24 and 25,
which are key intermediates in our approach to Stemona
alkaloids.8,9
Acknowledgement
We thank FAPESP and CNPq for financial support and
fellowship.
DBU-catalyzed addition of methyl 4-nitrobutanoate to
c-butyrolactones 7 and 8 in refluxing acetonitrile affor-
ded the corresponding nitrolactones 22 and 23 in mod-
erate yield (60% and 62% yield, respectively) as a 1:1
mixture of epimers at the nitromethine carbon. Nef oxi-
dation3 of each mixture of nitrolactones with KMnO4
adsorbed on silica gel (0.2 mmol of KMnO4/g of silica
gel) in refluxing benzene provided ketolactones 24 and
25, in 45% and 42% yield, respectively (Scheme 4).
Supplementary data
Characterization data, 1H and 13C NMR spectra for
compounds 5–25 are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2005.10.163.
The preparation of ketolactones 24 and 25 could be
achieved in a one-pot procedure by combining the
DBU-catalyzed Michael addition of nitroesters to c-
butyrolactones and the use of DBU for the Nef reaction
References and notes
1. Perlmutter, P. In Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, UK, 1992; pp 1–373.
2. Ono, N. In The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001; pp 70–125.
4.79 ppm, J5,4= 8.2 Hz
H
4.42 ppm, J5,4= 5.2 Hz
H
O
O
O
O
3. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
4. (a) Ballini, R.; Gil, M. V.; Fiorini, D.; Palmieri, A.
Synthesis 2003, 665; (b) Ballini, R.; Bosica, G. Synthesis
1994, 723; (c) Lee, W. Y.; Jang, S. Y.; Chae, W. K.; Park,
O. S. Synth. Commun. 1993, 23, 3037; (d) Ballini, R. J.
Chem. Soc., Perkin Trans. 1 1991, 1419; (e) Ballini, R.;
Petrini, M.; Rosini, G. J. Org. Chem. 1990, 55, 5159; (f)
Ballini, R.; Petrini, M. Synth. Commun. 1989, 19, 575.
5. (a) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257; (b)
Baldoli, C.; Maiorana, S.; Licandro, E.; Perdicchia, D.;
Vandoni, B. Tetrahedron: Asymmetry 2000, 11, 2007.
6. Ciampini, M., Perlmutter, P., Watson, K., Arkivoc 2003,
Part 3, 146.
OH
5
OH
5
4
4
H
H
NO2
NO2
nOe 1.2%
nOe 0.13%
(+)-19
(+)-21
Figure 1. Differential NOE and coupling constants measurements on
lactones (+)-19 and (+)-21.
H
H
O
O
CN
NO2
O
O
CN
CO2Me
i
CO2Me
+
R
R
H
7. Mo, C. L.; Williams, N. R. J. Chem. Res. (S) 1990,
386.
NO2
( )-7, R = H
( )-22, R = H
8. For a review on Stemona alkaloids see: (a) Pilli, R. A.; de
Oliveira, M. C. F. Nat. Prod. Rep. 2000, 17, 117; (b) Pilli,
R. A.; de Oliveira, M. C. F.; Rosso, G. B.. In The
Alkaloids; Cordell, G., Ed.; Elsevier: New York, 2005;
Vol. 62, Chapter 2, pp 77–174.
( )-8, R = CH3
( )-23, R = CH3
iii
H
O
ii
O
CN
CO2Me
9. Pilli, R. A.; Correˆa, I. R., Jr.; Maldaner, A. O.; Rosso, G. B.
Pure Appl. Chem. 2005, 77, 1153.
R
H
O
10. Chebib, M.; Johnston, G. A. R. J. Med. Chem. 2000, 43,
1427.
( )-24, R = H
( )-25, R = CH3
11. (a) Brimble, M. A.; Brimble, M. T.; Gibson, J. J. J. Chem.
Soc., Perkin Trans. 1 1989, 179; (b) Martin, S. F.; Barr, K.
J. J. Am. Chem. Soc. 1996, 118, 3299; (c) Martin, S. F.;
Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc.
1999, 121, 6990.
Scheme 4. Synthesis of (+/ꢀ)-24 and (+/ꢀ)-25. Reagents and condi-
tions: (i) DBU (0.1 equiv), CH3CN, reflux; (22, 60%; 23, 62%); (ii)
KMnO4/SiO2, C6H6, reflux; (24, 45%; 25, 42%) (iii) DBU (2 equiv),
CH3CN, reflux; (24, 30%; 25, 35%).

188
G. B. Rosso, R. A. Pilli / Tetrahedron Letters 47 (2006) 185–188
12. (a) Jefford, C. W.; Sledeski, A. W.; Boukouvalas, J.
Tetrahedron Lett. 1987, 28, 949; (b) Jefford, C. W.;
Sledeski, A. W.; Boukouvalas, J. J. Chem. Soc., Chem.
Commun. 1988, 364; (c) Jefford, C. W.; Sledeski, A. W.;
Boukouvalas, J. Helv. Chim. Acta 1989, 72, 1362; (d)
Jefford, C. W.; Sledeski, A. W.; Rossier, J.-C.; Boukouv-
alas, J. Tetrahedron Lett. 1990, 31, 5741; (e) Jefford, C. W.;
Sledeski, A. W.; Lelandais, P.; Boukouvalas, J. Tetra-
hedron Lett. 1992, 33, 1855.
0.5 mmol) at rt. The resulting orange solution was stirred
for an additional 16 h at rt. The crude was evaporated
under reduced pressure to remove the excess of CH3NO2
and the residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate 1:1) without any
extractions, yielding 0.50 g of 9 (69 %) as an oil. IR
(neat): 3022, 2920, 1774, 1732, 1560, 1421, 1382, 1176,
1
1025, 757 cmꢀ1. H NMR (300 MHz, CDCl3) d: 4.58 (dd,
2
2
3
3J = 7.4, J = 9.8, 1H), 4.54 (dd, J = 2.0, J = 7.4, 2H),
3
2
13. A typical procedure follows: To a stirred solution of
2-(triisopropylsilyloxy)furan 3 (0.17 g, 0.66 mmol) and
previously distilled acrylonitrile (0.060 g, 1.05 mmol) in
anhydrous CH2Cl2 (3 mL) at ꢀ78 ꢁC and under an argon
atmosphere was slowly added BF3ÆOEt2 (0.12 g,
0.84 mmol) dropwise. The reaction was monitored by
TLC and after completion, aqueous satd. NaHCO3
(15 mL) was added. The solution was washed with CH2Cl2
(3 · 20 mL), the organic phase extracted, dried (MgSO4),
filtered and evaporated under vacuo to afford a crude oil.
The resulting crude product was purified by chromato-
graphy silica column (hexanes/ethyl acetate 1:1) yielding 7
as a colorless oil (0.08 g, 89% yield). IR (neat): 3097, 2940,
4.16 (dd, J = 6.4, J = 9.8, 1H), 3.38 (m, 1H), 2.82 (dd,
3J = 8.9, 2J = 17.7, 1H), 2.38 (dd, 3J = 7.4, 2J = 17.7, 1H).
13C NMR (75 MHz, CDCl3) d: 174.4, 76.1, 69.9, 33.5,
31.5. HRMS (IE, 70 eV) m/z: calcd for C5H7NO4 [M]+:
145.0375, found 145.0392 [M]+.
15. Jaworski, T.; Kolodziejek, W.; Prejzner, J.; Wlostowski,
M. Polish J. Chem. 1981, 55, 1321.
16. Pinto, A. C.; Freitas, C. B. L.; Dias, A. G.; Pereira, V. L.
P.; Tinant, B.; Declercq, J.-P.; Costa, P. R. R. Tetra-
hedron: Asymmetry 2002, 13, 1025.
17. Mann, J.; Partlett, N. K.; Thomas, A. J. Chem. Res. (S)
1987, 369.
18. Analytical data for (4R,5S)-4-nitromethyl-5-hidroxy-
25
1
2248, 1747, 1602, 1427, 1335, 1165, 1109 cmꢀ1. H NMR
methyl-2-(5H)-furanone, (+)-19: ½aꢁD +0.2 (c 0.7, MeOH).
(500 MHz, CDCl3) d: 7.53 (dd, 3J = 1.5, 3J = 5.8, 1H),
6.22 (dd, 4J = 2.1, 3J = 5.8, 1H), 5.18 (dddd, 2J = 1.8,
3J = 3.7, 3J = 6.1, 3J = 8.6, 1H), 2.60 (ddd, 3J = 7.1,
3J = 8.3, 2J = 17.2, 1H), 2.55 (ddd, 3J = 5.9, 3J = 7.2, 2J =
17.2, 1H), 2.28 (dddd, 3J = 3.7, 3J = 7.2, 3J = 8.4,
2J = 14.4, 1H), 1.92 (dddd, 3J = 5.8, 3J = 7.3, 3J = 8.7,
2J = 14.4, 1H). 13C NMR (125 MHz, CDCl3) d: 171.9,
154.6, 122.6, 118.4, 80.6, 29.1, 13.4. HRMS (IE, 70 eV)
m/z: calcd for C8H10O2 [M]+: 137.0477, found 137.0353
[M]+.
IR (neat): 3422, 2937, 1772, 1635, 1557, 1428, 1383, 1197,
1080, 1032, 940 cmꢀ1. 1H NMR (500 MHz, CDCl3) d: 4.59
(dd, 3J = 7.6, 2J = 13.7, 1H), 4.51 (dd, 3J = 7.0, 2J = 13.4,
1H), 4.42 (dt, 3J = 3.1, 3J = 5.2, 1H), 3.99 (ddd, 3J =
3
3
3
3.2, J = 4.7, J = 12.3, 1H), 3.79 (ddd, 3J = 3.1, J = 6.0,
2J = 12.3, 1H), 3.31–3.39 (m, 1H), 3.01 (dd, 3J = 9.9,
3J = 18.0, 1H), 2.42 (dd, 3J = 6.3, 2J = 18.2, 1H), 2.27
(t, J = 5.3, 1H). 13C NMR (125 MHz, CDCl3) d: 174.3,
3
81.6, 76.4, 63.1, 34.8, 32.5.
´
19. (a) Costa, P. R. R.; Patrocınio, V. L.; Monteiro, M. D.;
14. Representative experimental procedure for 9: To a stirred
solution of 2(5H)-furanone (1) (0.42 g, 5.0 mmol) and
CH3NO2 (18.9 g, 310 mmol) was added DBU (7.5 mg,
Anholeto, A. L.; Dias, A. G.; Costa, J. S. J. Org. Chem.
´
1997, 62, 4002; (b) Patrocınio, V. L.; Costa, P. R. R.;
Correia, C. R. D. Synthesis 1994, 474.