Selective conjugate addition of nitromethane to enoates derived from D-mannitol and L-tartaric acid

Article abstract of DOI:10.1016/S0957-4166(02)00230-6

The conjugate addition of nitromethane to enoates prepared from D-(+)-mannitol, substituted at the α-position by a methyl or a benzyl group, was investigated. While excellent syn-selectivity (d.e. >90%) was obtained from α-benzyl enoates (used as a mixture of epimers, E/Z=1.8:1), for α-methyl enoates the selectivity depended on the stereochemistry of the double bond in the acceptor (d.e. >90% for the (Z)-enoate and 50% for the (E)-enoate). In all cases, a mixture of epimers was formed at the newly generated stereocenter at the α-position. The epimeric syn-adducts were transformed into the corresponding pure α,β,γ-trisubstituted γ-butyrolactones by cyclization in acid medium followed by epimerization of the stereocenter at the α-position in DBU/CH₂Cl₂. When enoates derived from L-tartaric acid were used as acceptors, syn-selective conjugate additions were also observed (d.e. >90% for the (Z)-isomer and 50% for the (E)-isomer). The configuration at the newly generated stereogenic centers were assigned based on X-ray analyses, ¹H-¹H coupling constants and NOE experiments in NMR spectroscopy.

Full text of DOI:10.1016/S0957-4166(02)00230-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1025–1031
Selective conjugate addition of nitromethane to enoates derived
from -mannitol and -tartaric acid
D
L
Ame´rico C. Pinto,a Cleide B. L. Freitas,a Ayres G. Dias,c Vera L. P. Pereira,b,* Bernard Tinant,d
Jean-Paul Declercqd and Paulo R. R. Costaa,*
aLaborato´rio de Qu´ımica Bioorgaˆnica (LQB), Nu´cleo de Pesquisas de Produtos Naturais, Centro de Cieˆncias da Sau´de, Bloco H,
Ilha da Cidade Universita´ria, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro, Brazil
bLaborato´rio de S´ıntese Estereosseletiva de Substaˆncias Bioativas (LASESB), Nu´cleo de Pesquisas de Produtos Naturais,
Centro de Cieˆncias da Sau´de, Bloco H, Ilha da Cidade Universita´ria, Universidade Federal do Rio de Janeiro, 21941-590,
Rio de Janeiro, Brazil
cInstituto de Qu´ımica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
dLaboratorie de Chimie Physique et de Cristallographie, Universite´ Catholique de Louvain, 1, Place Pasteur,
1348 Louvain-la-Neuve, Belgium
Received 13 July 2001; accepted 9 April 2002
Abstract—The conjugate addition of nitromethane to enoates prepared from
D
-(+)-mannitol, substituted at the a-position by a
methyl or a benzyl group, was investigated. While excellent syn-selectivity (d.e. >90%) was obtained from a-benzyl enoates (used
as a mixture of epimers, E/Z=1.8:1), for a-methyl enoates the selectivity depended on the stereochemistry of the double bond in
the acceptor (d.e. >90% for the (Z)-enoate and 50% for the (E)-enoate). In all cases, a mixture of epimers was formed at the newly
generated stereocenter at the a-position. The epimeric syn-adducts were transformed into the corresponding pure a,b,g-trisubsti-
tuted g-butyrolactones by cyclization in acid medium followed by epimerization of the stereocenter at the a-position in
DBU/CH2Cl2. When enoates derived from L-tartaric acid were used as acceptors, syn-selective conjugate additions were also
observed (d.e. >90% for the (Z)-isomer and 50% for the (E)-isomer). The configuration at the newly generated stereogenic centers
1
were assigned based on X-ray analyses, H–1H coupling constants and NOE experiments in NMR spectroscopy. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
described by our group.2a syn-Adducts were obtained
stereoselectively in these conjugate additions and the
best stereoselectivities (d.e. >90% at C(3)) were achieved
from (Z)-enoates. Herein, we disclose the results
obtained when enoates (S)-2a and 2b, substituted at the
a-position by a methyl and a benzyl group, respectively,
were used as acceptors.3 The conjugate addition of
Enoates such as (S)-1, prepared in three steps from
D
-(+)-mannitol, have been extensively used as acceptors
in stereoselective conjugate additions1 (Fig. 1). The
reaction of these enoates with nitromethane and deriva-
tives in the presence of TBAF or DBU was recently
Figure 1.
* Corresponding authors. E-mail: lqb@nppn.ufrj.br
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00230-6

1026
A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
nitromethane and derivatives to enoates (R)-3a,b and
(R)-4a,b, that are prepared from
-(+)-tartaric acid4
and represent a potential source of adducts with an
enantiomeric relationship at the C(3) stereogenic center,
was also investigated.
a-stereocenter, was formed (Table 1, entry 1). Analysis
of the 13C NMR spectra of each isolated product
showed the presence of only one stereoisomer as the
result of a highly selective syn-conjugate addition at
C(3) (d.e. at C(3) >90%). This mixture of epimers was
also formed from enoate (E)-2a, but in this case 13C
NMR spectra showed that these compounds were
obtained in lower d.e. at C(3) (50% for both products,
entries 2 and 3). In contrast with these results, the
addition to enoate 2b, used as a mixture of geometric
isomers (E/Z=1.8/1.0), led to a mixture of syn-adducts
9b and 10b, which are epimers at the a-stereocenter, in
excellent d.e. at C(3) for each product (>90%). Thus,
for this enoate the stereoselectivity is not affected by
the geometry of the double bond.
L
2. Results and discussion
Aldehydes 5 and 6, easily prepared from
D
-(+)-
mannitol5 and -(+)-tartaric acid,4 respectively, were
L
used as precursors of enoates 2 and 3 (Scheme 1).
Compound (E)-2a was stereoselectively obtained by
reaction of 5 with phosphorane 7a. On the other hand,
a mixture of (Z)- and (E)-2a (Z/E=1.3:1.0), easily
separated by chromatography, was prepared by react-
ing 5 with phosphonate 7b.6 However, reaction of 6
with phosphonate 7c6 led to an inseparable mixture of
(Z)- and (E)-2b (E:Z=1.8:1.0). The reaction of 6 with
phosphonate 7d led exclusively to (E)-3a and this
adduct was transformed in the O-silyl derivative (E)-4a
by reaction with TBDMSCl. On the other hand, the
reaction of 6 with phosphorane 7e at 0°C led to a
mixture of (Z)- and (E)-3b (Z:E=3:1). This mixture
was allowed to react with TBDMSCl leading to a
corresponding mixture of (Z)- and (E)-4b (Z:E=3:1).
Table 1.
Entry Enoate Conditionsb
Yield
(%)
syn/anti
(d.e.)c
1
2
3
4
5
6
7
(Z)-2a
(E)-2a
(E)-2a
2ba
2b
2b
TBAF/1 equiv./4 h
TBAF/1 equiv./20 h
TBAF/1 equiv./7 h
76
54
56
\90
50
50
80
80
TBAF/0.5 equiv./20 h 75
TBAF/1 equiv./12 h
TBAF/1 equiv./20 h
DBU/1 equiv./4 days
65
93
41
80
\90
2b
Scheme 2 shows the results obtained in the conjugate
addition of nitromethane 8 to enoates 2a and 2b.7
When (Z)-2a was used as acceptor, a mixture of two
easily separable syn-adducts 9a and 10a, epimeric at the
a Used as a mixture of E/Z-isomers (1.8:1.0).
b All reactions were completed at rt and the base/solvent systems used
were TBAF/THF or DBU/CH3CN.
c Measured by quantitative 13C NMR.
Scheme 1. Reagents and conditions: (i) MeOH, 2 h, 7a, 0°C (68%), E-2a; (ii) NaH, THF, 1 h, 7b, −78°C to rt (61%), 1.0:1.3
E:Z-2a, and 7c (68%), 1.8:1.0 E:Z-2b; (iii) NaH, THF, 1 h, 7d, −78°C to rt (81%), E-3a; (iv) MeOH, 1 h, 7e, 0°C (70%), 3:1
Z:E-3b; (v) TBDMSCl, imidazol, CH2Cl2, 10 h, rt (82%).
Scheme 2.

A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
1027
In order to establish unambiguously the stereochem-
istry at the newly generated stereogenic center of 13,
this adduct was transformed into the lactone 14
Unfortunately, the enoates alkylated at the a-position
are less reactive than (S)-1 and adducts were not
obtained when nitroethane and 2-nitropropane were
used as nucleophiles under the conditions employed.
The adducts 9a and 10a were separated by column
chromatography and the absolute configuration at the
newly generated stereogenic centers were determined
through their transformation into the corresponding
lactones 11a and 12a, respectively (Scheme 3). X-Ray
crystallographic analysis of lactone 11a (Fig. 2)8 con-
firmed the cis–cis relationship of the substituents and,
as a consequence, the 2S,3S-stereochemistry of adduct
9a. The lactone 11a was promptly transformed into its
thermodynamic epimer 12a by treatment with DBU. In
this manner, the stereochemistry of 9b was assigned as
2R,3S. The mixture of adducts 9b and 10b were lac-
tonized and subsequently separated into the lactones
11b and 12b. A trans–cis relationship in 12b was deter-
mined by X-ray crystallographic analysis (Fig. 2)9 and
this compound was also obtained from the epimeric
lactone 11b, by reaction with DBU.
Scheme 4 shows the addition of nitromethane deriva-
tives to (R)-enoates 3 and 4. When (E)-3a was allowed
to react with nitromethane 8 in the presence of TBAF/
THF or DBU/CH3CN only starting material was
recovered (Table 2, entries 1 and 2). However, the
corresponding O-silyl enoates 4 reacted with 8 in both
reaction conditions, leading to the corresponding syn-
adduct 13. While very good stereoselectivity was
observed in the reactions of (Z)-4b (d.e.=90%, entries 3
and 4), moderate stereoselectivity was observed in the
additions to (E)-4a (d.e.=52%, entries 4–7). Similarly
to that observed for enoates 2a and 2b, enoates 4a and
4b did not react with nitroethane and 2-nitropropane.
Scheme 3.
Scheme 4.
Figure 2.

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A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
Table 2.
3.2. General procedure for the preparation of enoates
Entry
Enoate
Conditionsa
Yield
(%)
D.e.
(%)b
3.2.1. Procedure A—using phosphonate. To a stirred
suspension of NaH (0.50 g, 21.0 mmol) in anhydrous
THF (50 mL) at rt, was added dropwise 7b (0.50 g, 1
mmol). After 0.5 h the mixture was cooled at −78°C
1
2
3
4
5
6
7
(E)-3a
(Z)- or (E)-3b
(Z)-4bd
(Z)-4b
TBAF/8 h/34°Cc
DBU/8 h/34°C
TBAF/8 h/34°C
DBU/8 h/34°C
TBAF/8 h/34°C
TBAF/12 h/35°C
DBU/8 h/34°C
–
–
–
–
and
D
-(+)-glyceraldehyde 5 (3.28 g, 25.1 mol) was
65
64
70
65
64
90
90
52
52
52
added dropwise and the mixture was stirred, allowing
to warm to rt. After 1 h, saturated aqueous NH4Cl
solution (30 mL) was added. The organic layer was
removed in vacuum and the residual oil was dissolved
with AcOEt (120 mL) and washed with saturated solu-
tion of K2CO3 (45 mL), brine (2×45 mL). The organic
phase was dried with MgSO4, filtered and the solvent
was removed in vacuum. The residue was purified by
flash column chromatography on silica gel
(AcOEt:Hex., 15:85) furnished 2a, as a colorless oil
(2.76 g, 61%) (E:Z, 1:1.3). Analytical samples were
obtained by flash column chromatography on silica gel
(AcOEt:Hex., 5:95).
(E)-4b
(E)-4a
(E)-4a
a The reactions used TBAF/THF or DBU/CH3CN as a base/solvent
system.
b Measured by quantitative 13C NMR.
c Room temperature observed was 34°C.
d Enoate (Z)-4b was used with an enriched mixture (86:14, Z:E) after
flash column chromatography.
(Scheme 5). The trans-relationship between the sub-
stituents at C(3) and C(4) was suggested by the cou-
pling constant between the C(3) and C(4) protons
3.2.2. Procedure B—using phosphorane. The phospho-
rane 7e (0.97 g, 2.78 mmol) was added to a solution of
(S)-2-O-benzyloxyglyceraldehyde 6 (0.50 g, 2.78 mmol)
in methanol (2 mL) cooled to 0°C. The mixture was
stirred at 0°C for 1 h and the solvent was removed in
vacuum. The residue was extracted with hot hexane, the
solvent was removed in vacuum to give a white oil,
which was purified by flash chromatography on silica
gel eluted with hexane to give 3b as a yellow oil (0.41 g,
60%; ratio Z:E, 76:24). The isomers were separated by
preparative plate chromatography.
1
(J=7.1 Hz) in the H NMR spectra, and this relation-
ship could be confirmed by the absence of any NOE
effect at C(3) after irradiation at C(4).10
3. Experimental
3.1. Materials
All conjugate additions were performed under N2
atmosphere. THF was distilled from sodium benzophe-
none under N2 and DMF from CaH2. Acetonitrile was
3.2.2.1. Ethyl (4S)-2-methyl-4,5-O-isopropylidene-cis-
2-pentenoate, (Z)-2a. Colorless oil; [h]2D5=+66.3 (c 1.02,
CHCl3), lit. [h]D25=+64.6 (c 1.02, CHCl3);11 1H NMR
(200 MHz, CDCl3) l (ppm): 1.31 (t, 3H, J=7.1 Hz),
1.38 (s, 3H), 1.45 (s, 3H), 1.93 (d, 3H, J=1.4 Hz), 3.59
(dd, 1H, J=8.2 Hz, J=6.9 Hz), 4.20 (q, 2H, J=7.1
Hz), 4.31 (dd, 1H, J=9.2 Hz, J=6.7 Hz), 5.27 (ddd,
1H, J=6.9 Hz, J=6.9 Hz, J=6.7 Hz), 6.07 (dq, 1H,
J=6.9 Hz, J=1.4 Hz); 13C NMR (50 MHz, CDCl3) l
(ppm): 13.9 (CH3), 19.6 (CH3), 25.2 (CH3), 26.3 (CH3),
60.3 (CH2), 69.3 (CH2), 73.7 (CH), 109.0 (C), 129.0
(CH2), 142.0 (CH), 166.6 (C); MS (70 eV) m/z (%): 213
(2.4), 199 (11.2), 111 (100), 98 (75.8), 83 (61.5), 72
(77.0), 55 (31).
,
dried over molecular sieves 4 A. TBAF·3H2O solid,
nitroethane, MeOH, benzene, 2-nitropropane, HCl
(37%), TBDMSCl and imidazole were commercially
available (Aldrich, Fluka or Merck) and were used as
purchased. The enoates, 2a,b and 3a,b, were prepared
according to literature procedures.2 1H and 13C NMR
spectra were recorded on a Varian Gemini-200 (200
MHz) instrument in CDCl3 unless specified otherwise.
The coupling constant (J) is in hertz (Hz). HPLC
analyses were performed on a Shimadzu LC-A10 chro-
matograph using a Shimadzu column C18 (25×1.6 cm,
ID×5 mm). High-resolution mass spectra were recorded
on Micromass MM12F and VG AutoSpec spectrome-
ters. IR spectra were recorded on a Perkin–Elmer
model 783 spectrophotometer and optical rotations
were measured on a Perkin–Elmer model 243-B polar-
imeter. All melting points are uncorrected and were
determined on a Thomas Hoover apparatus.
3.2.2.2. Ethyl (4S)-2-methyl-4,5-O-isopropylidene-
trans-2-pentenoate, (E)-2a. Colorless oil; [h]2D5=+17.6 (c
1.25, CHCl3). lit. [h]2D5=+16.4 (c 1.01, CHCl3);11 1H
NMR (200 MHz, CDCl3) l (ppm): 1.30 (t, 3H, J=7.1
Scheme 5.

A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
1029
Hz), 1.41 (s, 3H), 1.46 (s, 3H), 1.90 (d, 3H, J=1.5 Hz),
3.63 (dd, 1H, J=8.2 Hz, J=7.6 Hz), 4.16 (dd, 2H,
J=8.2 Hz, J=6.2 Hz), 4.21 (q, 2H, J=7.0 Hz), 4.87
(ddd, 1H, J=6.2 Hz, J=6.6 Hz, J=7.6 Hz), 6.65 (dq,
1H, J=6.6 Hz, J=1.5 Hz); 13C NMR (50 MHz,
CDCl3) l (ppm): 12.7 (CH3), 13.9 (CH3), 25.6 (CH3),
26.3 (CH3), 60.6 (CH2), 68.5 (CH2), 72.5 (CH), 109.5
(C), 130.8 (C), 137.9 (CH), 167.0 (C); MS (70 eV) m/z
(%): 213 (2.4), 199 (11.2), 111 (66.4), 98 (45.3), 83
(42.5), 72 (100.0), 55 (37.3).
4.19 mmol) in CH2Cl2 (3 mL) and imidazole (0.28 g,
4.19 mmol) in CH2Cl2 (2 mL) and the mixture was
stirred at rt for 12 h. The reaction mixture was dis-
solved in AcOEt, the resulting solution was washed
with 5% aqueous HCl (30 mL), saturated NaHCO3 (30
mL) and the organic phase was dried over anhydrous
Na2SO4. The solvent was removed in vacuum and the
residue was purified by column chromatography on
silica gel (Hex./AcOEt 98:2) yielding methyl (4R)-ben-
zyloxy-5-tert-butyldimethylsilanoxy-trans-2-pentenoate
(E)-4a as an oil (1.02 g, 80%); [h]2D5=−3.9 (c 2.2,
CH2Cl2); 1H NMR (200 MHz, CDCl3) l (ppm): 0.00 (s,
6H), 0.90 (s, 9H), 3.64 (dd, 1H, J=10.4 Hz, J=5.6 Hz),
3.75 (dd, 1H, J=10.4 Hz, J=6.3 Hz), 3.76 (s, 3H), 4.10
(m, 1H), 4.55 (d, 1H, J=12.0 Hz), 4.67 (d, 1H, J=12.0
Hz), 6.12 (dd, 1H, J=16.0 Hz, J=1.0 Hz), 6.92 (dd,
1H, J=16.0 Hz, J=6.0 Hz), 7.35 (m, 5H); 13C NMR
(50 MHz, CDCl3) l (ppm): −5.5 (CH3), −5.6 (CH3),
18.1 (C), 25.7 (3CH3), 51.5 (CH3), 65.4 (CH2), 71.5
(CH2), 78.8 (CH2), 122.3 (CH), 127.5–128.2 (CH), 137.9
(C), 145.9 (CH), 166.4 (C); MS (70 eV) m/z (%): 73
(21), 91 (100), 293 (6).
3.2.2.3. Methyl (4S)-2-benzyl-4,5-O-isopropylidene-
trans-2-pentenoate, (E)-2b. (Maj.); 1H NMR (200 MHz,
CDCl3) l (ppm): 1.40 (s, 3H), 1.45 (s, 3H), 3.55–3.64
(m, 1H), 3.72 (s, 3H), 3.83 (d, 1H, J=15.1 Hz), 4.00
(dd, 1H, J=8.2 Hz, J=6.3 Hz), 4.92 (ddd, 1H, J=8.5
Hz, J=7.5 Hz, J=6.3 Hz), 6.85 (d, 1H, J=8.5 Hz),
7.10–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3) l
(ppm): 25.4 (CH3), 26.2 (CH3), 32.3 (CH2), 51.6 (CH3),
68.3 (CH2), 72.2 (CH), 109.6 (C), 125.9 (CH), 127.7
(2CH), 128.1 (2CH), 133.4 (C), 138.6 (CH), 139.6 (CH),
166.8 (C); MS (70 eV) m/z (%): 276 (1.2), 218 (71.4), 91
(93.2), 72 (100).
3.2.2.4. Methyl (4S)-2-benzyl-4,5-O-isopropylidene-
3.3.1.1. Ethyl (4R)-benzyloxy-5-tert-butyldimethylsil-
anoxy-cis-2-pentenoate, (Z)-4b. Oil; [h]2D5=−3.6 (c 1.1,
CHCl3); H NMR (200 MHz, CDCl3) l (ppm): 0.08 (s,
1
cis-2-pentenoate, (Z)-2b. (Min.); H NMR (200 MHz,
1
CDCl3) l (ppm): 1.38 (s, 3H), 1.42 (s, 3H), 3.55–3.64
(m, 1H), 3.69 (s, 3H), 4.32 (dd, 1H, J=8.2 Hz, J=6.3
Hz), 5.26 (d, 1H, J=6.9 Hz, J=6.8 Hz, J=6.8 Hz),
6H), 0.80 (s, 9H), 1.25 (t, 3H, J=7.0 Hz), 3.70 (dd, 1H,
J=10.4 Hz, J=5.6 Hz), 4.45 (q, 2H, J=7.0 Hz), 4.50
(d, 1H, J=12.0 Hz), 4.52 (d, 1H, J=12.0 Hz), 5.10 (m,
1H), 5.90 (dd, 1H, J=11.8 Hz, J=1.0 Hz), 6.25 (dd,
1H, J=11.8 Hz, J=8.4 Hz), 7.30 (m, 5H); 13C NMR
(50 MHz, CDCl3) l (ppm): −5.4 (CH3), 14.1 (CH3),
18.2 (C), 25.8 (3CH3), 60.1 (CH2), 65.4 (CH2), 71.4
(CH2), 76.1 (CH), 122.3 (CH), 138.4 (C), 147.6 (CH),
165.0 (C); MS (70 eV) m/z (%): 73 (26), 91 (100), 149
(11).
6.08 (dt, 1H, J=6.9, J=1.2 Hz), 7.10–7.40 (m, 5H); 13
C
NMR (50 MHz, CDCl3) l (ppm): 25.1 (CH3), 26.2
(CH3), 39.2 (CH2), 51.3 (CH3), 69.3 (CH2), 73.8 (CH),
109.1 (C), 126.1 (CH), 128.1 (2CH), 128.3 (2CH), 132.4
(C), 138.1 (C), 143.3 (CH), 166.4.
3.2.2.5. Methyl (4R)-benzyloxy-5-hydroxy-trans-2-
pentenoate, (E)-3a. Colorless oil; [h]2D5=−45.5 (c 2.2,
1
CH2Cl2); H NMR (200 MHz, CDCl3) l (ppm): 1.30 (t,
3H, J=7.1Hz), 3.59 (dd, 1H, J=11.7 Hz, J=6.8 Hz),
3.69 (dd, 1H, J=11.7, J=3.9 Hz), 4.15 (m, 1H), 4.22
(q, 2H, J=7.1 Hz), 4.43 (d, 1H, J=11.6 Hz), 4.67 (d,
1H, J=11.6 Hz), 6.12 (dd, 1H, J=15.8, J=1.3 Hz),
6.85 (dd, 1H, J=15.8 Hz, J=6.1 Hz), 7.25–7.45 (m,
5H); 13C NMR (50 MHz, CDCl3) l (ppm): 51.5 (CH3),
64.3 (CH2), 71.3 (CH2), 78.8 (CH), 123.2 (CH), 127.7–
128.3 (CH), 137.3 (C), 144.5 (CH), 166.1 (C).
3.4. General procedures for the addition of
nitromethane
3.4.1. Procedure A—TBAF as base. A solution of
TBAF·3H2O (0.14 g, 0.55 mmol) in THF (2 mL) was
added to a mixture of enoate 2b (0.30 g, 1.10 mmol),
nitromethane (0.067 g, 1.10 mmol) in THF (3 mL). The
mixture was stirred at rt for 10 h then washed with H2O
(10 mL), extracted with CH2Cl2 (3×15 mL), the organic
phase was dried over Na2SO4 and the solvent was
removed in vacuum. The residue was purified by flash
column chromatography on silica gel (Hex.:AcOEt
90:10) yielding a mixture of 9b and 10b as an oil (0.27
g, 72%; syn:anti, 9:1 at C(3)/C(4) and 54:46 at C(2)).
3.2.2.6. Ethyl (4R)-benzyloxy-5-hydroxy-cis-2-pent-
enoate, (Z)-3b. Colorless oil; [h]2D5=−74.4 (c 0.40,
1
CH2Cl2); H NMR (200 MHz, CDCl3) l (ppm): 1.20 (t,
3H, J=7.0 Hz), 2.10 (s, 1H), 3.62 (dd, 1H, J=5.2 Hz),
3.72 (dd, 1H, J=4.4 Hz), 4.16 (q, 2H, J=7.0 Hz), 4.46
(d, 1H, J=11.5 Hz), 4.58 (d, 1H, J=11.5 Hz), 5.1 (m,
1H), 5.96 (dd, 1H, J=11.8 Hz, J=1.28 Hz), 6.22 (dd,
1H, J=11.8 Hz, J=8.15 Hz), 7.3 (m, 5H); 13C NMR
(50 MHz, CDCl3) l (ppm): 14.0 (CH3), 60.4 (CH2), 64.5
(CH2), 71.3 (CH2), 76.3 (CH), 122.9 (CH), 127.4–128.5
(C), 137.7 (C), 147.3 (CH), 165.7 (C).
3.4.2. Procedure B—DBU as base. A solution of (Z)-4b
(0.20 g, 0.55 mmol) and nitromethane (0.03 g, 0.55
mmol) in 2 mL CH3CN was added DBU (0.08 mL,
0.55 mmol). The mixture was stirred at rt for 8 h, then
washed with H2O (2 mL) and 5% aqueous HCl solution
was added dropwise until the mixture had a pH of 7 (12
to other adducts). The resulting solution was extracted
with AcOEt (3×10 mL). The organic phases were dried
3.3. Representative procedure for O-silylation
To a solution of enoate (E)-3a (0.86 g, 3.64 mmol) in
CH2Cl2 (6 mL) at 0°C was added TBDMSCl (0.63 g,

1030
A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
over Na2SO4 and the solvent was removed in vacuum.
The residue was purified by column chromatography
on silica gel (Hex.:AcOEt 95:5) yielding adduct 13 (0.15
g, 64%).
3.5.1.
(3S,4S,5S)-5-Hydroxymethyl-3-methyl-4-nitro-
methyldihydrofuran-2-one, 11a. Mp=71–72°C; [h]2D5=
1
+43.6 (c 1.09, MeOH); H NMR (200 MHz, CD3CN) l
(ppm): 1.18 (d, J=7.6 Hz, 3H), 2.98 (dq, J=9.6, J=
7.6, 1H), 3.25 (t, J=5.3, 1H), 3.48–3.64 (m, 1H), 3.61
(ddd, J=12.6, J=5.3, J=3.7, 1H), 3.78 (ddd, J=12.6,
J=5.2, J=3.8), 4.56–4.66 (m, 1H), 4.62 (dd, J=15.3,
J=7.2, 1H), 4.73 (dd, J=15.3, J=7.2, 1H); 13C NMR
(50 MHz, CD3CN) l (ppm): 11.1 (CH3), 37.9 (CH),
38.7 (CH), 60.9 (CH2), 72.5 (CH2), 80.3 (CH), 179.3
(C); MS m/z (%): 158 (M+−31, 5), 111 (63), 83 (38), 55
(100). Crystallographic data: C7H11NO5, Mr=189.17,
3.4.2.1. Ethyl (2S,3S,4S)-2-methyl-3-nitromethyl-4,5-
O-isopropylidenepentanoate, 9a. Colorless oil; [h]2D5=
1
+13.3 (c 1.35, CHCl3); H NMR (200 MHz, CDCl3) l
(ppm): 1.27 (t, 3H, J=7.1 Hz), 1.27 (d, 3H, J=7.2 Hz),
1.31 (s, 3H), 1.37 (s, 3H), 2.63 (dq, 1H, J=7.2, J=4.8
Hz), 2.73–2.84 (m, 1H), 3.70 (ddd, 2H, J=11.6 Hz,
J=6.0 Hz, J=3.9 Hz), 4.15 (q, 2H, J=7.1 Hz), 4.54
(dd, 1H, J=14.1 Hz, J=6.0 Hz), 4.63 (dd, 1H, J=14.1
Hz, J=5.4 Hz); 13C NMR (50 MHz, CDCl3) l (ppm):
13.9 (CH3), 14.1 (CH3), 24.9 (CH3), 25.9 (CH3), 39.5
(CH), 43.0 (CH), 60.9 (CH2), 67.8 (CH2), 74.0 (CH2),
74.9 (CH), 109.4 (C), 173.6 (C).
monoclinic, P21, a=6.524(1), b=12.741(2), c=
3
,
,
10.437(2) A, i=97.86(2)°, V=859.4(3) A , Z=4,
D
calcd=1.46 g cm−3, v=1.08 mm−1, F(000)=400, T=
291 K; parallelepiped crystal with dimensions 0.28×
0.24×0.10 mm. Lattice parameters refined using 30
reflections in the range 1552q560°. Huber four circle
diffractometer with a Rigaku rotating anode generator,
graphite monochromatized CuKa radiation (u=
3.4.2.2. Ethyl (2R,3S,4S)-2-methyl-3-nitromethyl-4,5-
O-isopropylidenepentanoate, 10a. Colorless oil; [h]2D5=
,
1.54178 A). 2896 independent reflections with sin q/u5
0.60 A ; 05h57, −155k515, −125l512; 2684 with
−1
,
1
−7.0 (c 1.48, CHCl3); H NMR (200 MHz, CDCl3) l
I]2.0|(I). A standard reflection (−2 0 −3) was checked
every 50 reflections, no significant decay was observed.
The structure was solved by directs methods using
SHELXS-86.8 All H atoms from difference Fourier
(ppm): 1.20 (d, 3H, J=7.2 Hz), 1.28 (t, 3H, J=7.1 Hz),
1.31 (d, 3H, J=0.5 Hz), 1.38 (d, 3H, J=0.5 Hz), 2.63
(dq, 1H, J=7.2, J=5.0 Hz), 2.77–2.88 (m, 1H), 3.66–
3.77 (m, 1H), 4.08–4.21 (m, 2H), 4.16 (q, 2H, J=7.1
Hz), 4.58 (d, 2H, J=5.8 Hz); 13C NMR (50 MHz,
CDCl3) l (ppm): 13.6 (CH3), 13.9 (CH3), 25.8 (CH3),
25.9 (CH3), 39.8 (CH), 42.7 (CH), 61.0 (CH2), 68.0
(CH2), 73.8 (CH2), 75.0 (CH), 109.4 (C), 173.7 (C).
synthesis.
Anisotropic
least-squares
refinement
(SHELXL-93)9 using F2; H isotropic with common
2
,
refined temperature factor (U=0.049 A ). 302 parame-
ters. w=1/(|2(Fo )+0.0705P2+0.06P), R=0.038, R (all
2
data)=0.041, wR=0.098, S=1.042. Final maximum
shift to error=0.001. Maximum and heights in final
−3
,
Fourier synthesis=0.12 and −0.19 e A . Full lists of
3.4.2.3. Ethyl (3R,4R)-3-nitromethyl-4-benzyloxy-5-
1
atomic coordinates, bond lengths and angles, thermal
parameters have been deposited with the Cambridge
Crystallographic Data Center (CCDC 186717).
tert-butyldimethylsilanoxypentanoate, 13. Yellow oil; H
NMR (200 MHz, CDCl3) l (ppm): 0.06 (s, 6H), 0.89 (s,
9H), 1.25 (t, 3H, J=7.2 Hz), 2.45 (dd, 1H, J=16.5 Hz,
J=6.8 Hz), 2.62 (dd, 1H, J=16.5 Hz, J=6.8 Hz), 3.03
(m, 1H), 3.60 (dd, 2H, J=10.1 Hz, J=4.5 Hz), 3.75 (sl,
1H), 4.10 (q, 2H, J=7.2 Hz), 4.40–4.80 (m, 4H), 7.3 (m,
5H); 13C NMR (50 MHz, CDCl3) l (ppm): −5.7 (CH3),
18.0 (C), 25.7 (CH3), 33.1 (CH2), 36.2 (CH), 51.7
(CH3), 62.5 (CH2), 72.4 (CH2), 75.4 (CH2), 78.4 (CH),
127.6–128.3, 137.7 (CHAr), 171.4 (CAr); MS (70 eV) m/z
(%): 73 (08), 91 (100).
3.5.2.
(3R,4S,5S)-5-Hydroxymethyl-3-methyl-4-nitro-
methyldihydrofuran-2-one, 12a. Oil; [h]2D5=+113.7 (c
1
1.16, MeOH); H NMR (200 MHz, CD3CN) l (ppm):
1.16 (d, 3H, J=7.0), 2.65 (dq, 1H, J=11.7, J=7.0 Hz),
3.10 (ddd, 1H, J=11.7 Hz, J=9.1 Hz, J=8.1 Hz,
J=5.5 Hz), 3.29 (t, 1H, J=4.8 Hz), 3.59 (ddd, 3H,
J=12.8 Hz, J=4.8 Hz, J=2.2 Hz), 3.84 (ddd, 1H,
J=12.8 Hz, J=4.8 Hz, J=3.1), 4.66 (ddd, 1H, J=8.1
Hz, J=3.1 Hz, J=2.2 Hz), 4.72 (dd, 1H, J=14.9 Hz,
J=5.5 Hz), 4.63 (dd, 1H, J=14.9 Hz, J=9.1 Hz); 13C
NMR (50 MHz, CD3CN) l (ppm): 14.7 (CH3), 38.2
(CH), 43.6 (CH), 61.5 (CH2), 72.4, 75.0 (CH2), 79.2
(CH), 179.0 (CH); MS (70 eV) m/z (%): 158 (6), 111
(70), 83 (46), 55 (100).
3.5. General procedure for lactonization
A solution of 20% aqueous HCl (200 mL) was added to
a solution of adduct 13 (0.5 g, 1.19 mmol) in MeOH (5
mL). The mixture was stirred at rt for 3 h, then diluted
in CH2Cl2, washed with saturated NaHCO3 and the
organic phase was dried over Na2SO4. The solvent was
removed in vacuum. The residue was purified by
column chromatography on silica gel (Hex./AcOEt
60:40) yielding (4R,5R)-5-benzyloxy-4-nitromethyltetra-
hydropyran-2-one 14 as a solid (0.25 g, 85%); [h]2D5=
3.5.3.
(3S,4S,4S)-3-Benzyl-5-hydroxymethyl-4-nitro-
methyldihydrofuran-2-one, 11b. Mp=133–134°C; [h]2D5=
1
+76.5 (c 1.05, MeOH); H NMR (200 MHz, CD3CN) l
(ppm): 2.20–2.60 (l, 1H), 2.81 (dd, J=15.0 Hz, J=8.4
Hz, 1H), 3.12 (dd, J=15.0 Hz, J=6.6 Hz, 1H), 3.30–
3.41 (m, 1H), 3.41–3.61 (m, 1H), 4.56 (dd, J=15.5 Hz,
J=9.1 Hz, J=5.3 Hz, 1H), 4.56–4.64 (m, 1H), 4.73 (dd,
J=15.5 Hz, J=8.0 Hz, 1H), 7.10–7.40 (m, 5H); 13C
NMR (50 MHz, CD3CN) l (ppm): 32.24 (CH2), 39.11
(CH), 44.15 (CH), 60.72 (CH2), 72.05 (CH2), 80.32
(CH), 127.47 (CH), 129.47 (2CH), 129.54 (2CH), 139.59
(C), 177.43 (C); MS m/z (%): 265 (1), 91 (100).
1
+52.8 (c 1.02, CH2Cl2); H NMR (200 MHz, CDCl3) l
(ppm): 2.45 (m, 1H), 2.85 (m, 3H), 3.74 (ddd, 1H,
J=7.1 Hz, J=6.2 Hz, J=4.3 Hz), 4.26 (dd, 1H, J=
12.0 Hz, J=6.2 Hz), 4.40 (dd, 1H, J=12.0 Hz, J=4.3
Hz); 13C NMR (50 MHz, CDCl3) l (ppm): 31.0 (CH2),
36.4 (CH), 68.0 (CH2), 71.5 (CH), 72.0 (CH2), 76.1
(CH2), 127.9–128.6 (CH), 136.5 (C), 168.4 (C).

A. C. Pinto et al. / Tetrahedron: Asymmetry 13 (2002) 1025–1031
1031
3.5.4.
(3R,4S,5S)-3-Benzyl-5-hydroxymethyl-4-nitro-
Santos for the 1H and 13C NMR spectra, and CNPq and
CAPES for financial support and fellowships for some
of the authors.
methyldihydrofuran-2-one, 12b. Mp=103–104°C; [h]2D5=
1
+45.08 (c 1.22, MeOH); H NMR (200 MHz, CD3CN)
l (ppm): 1.80–2.70 (l, 1H), 2.80 (dd, J=13.4 Hz, J=8.6
Hz, 1H), 2.96 (ddd, J=11.0 Hz, J=8.6 Hz, J=4.0 Hz,
1H), 3.08–3.28 (m, 1H), 3.28 (dd, J=13.4 Hz, J=4.0 Hz,
1H), 3.74 (dd, J=13.2 Hz, J=1.4 Hz, 1H), 3.88 (dd,
J=15.0 Hz, J=3.9 Hz, 1H), 4.05 (dd, 1H, J=13.2 Hz,
J=2.4 Hz), 4.65 (dd, 1H, J=15.0 Hz, J=10.7 Hz),
4.62–4.70(m, 1H), 7.15–7.45 (m, 5H);13C NMR (50 MHz,
CD3CN) l (ppm): 35.99 (CH2), 40.34 (CH), 43.76 (CH),
61.06 (CH2), 73.50 (CH2), 78.82 (CH), 127.32 (CH),
128.78 (2CH), 129.04 (2CH), 136.70 (C), 177.25 (C).
Crystallographic data: C13H15NO5, Mr=265.26, mono-
References
1. (a) Pinto, A. C.; Abdala, R. V.; Costa, P. R. R. Tetra-
hedron: Asymmetry 2000, 11, 4239; (b) Ferreira, A. R. G.;
Dias, A. G.; Pinto, A. C.; Costa, P. R. R.; Miguez, E.;
Silva, A. J. R. Tetrahedron Lett. 1998, 39, 5305; (c) Lima,
P. G.; Sequeira, L. C.; Costa, P. R. R.; Tetrahedron Lett.
2001, 42, 3525.
2. (a) Costa, J. S.; Dias, A. G.; Anholeto, A. L.; Monteiro,
M. D.; Patrocinio, V. L.; Costa, P. R. R. J. Org. Chem.
1997, 62, 4002; For recents examples of Michael addition
of nitromethane, see: (b) Krief, A.; Provins, L.; Froidbise,
A. Synlett 1999, 12, 1936; (c) Gallos, J. K.; Koumbis, A.
E.; Xiraphaki, V. P.; Dellios, C. C.; Coutouli-Argyropou-
lou Tetrahedron 1999, 55, 15167; (d) Ballini, R.; Barboni,
L.; Bosica, G.; Filippone, P.; Sabina, P. Tetrahedron
2000, 56, 4095; (e) Choudary, B. M.; Kantam, M. L.;
Kavita, B.; Reddy, Ch. V.; Figueras, F. Tetrahedron
2000, 56, 9357; (f) Choudary, B. M.; Kantam, M. L.;
Kavita, B.; Reddy, Ch. V.; Figueras, F. Appl. Catal. A:
Gen. 2000, 194, 227; (g) Kabashima, H.; Tsuji, H.;
Shibuya, T.; Hattori, H. J. Mol. Catal. A: Chem. 2000,
155, 23.
3. To the best of our knowledge, this is the first report on
the use of these enoates as acceptors in conjugate addi-
tions.
4. Ja¨ger, V.; Wehner, V. Angew. Chem. Int. Ed. Engl. 1989,
28, 469.
5. Mann, J.; Partlett, N. K.; Thomas, A. J. Chem. Res. (S)
1987, 369.
6. These phosponates were prepared as described by Clark,
R. D.; Kozar, L. G.; Heathcock, C. H. Synthesis 1975,
635.
,
clinic, P21, a=6.241(2), b=11.538(4), c=9.128(2) A,
3
,
i=100.56(3)°, V=646.2 (3) A , Z=2, Dcalcd=1.36 g
cm−3, v=0.89 mm−1, F(000)=280, T=291 K; paral-
lelepiped crystal with dimensions 0.28×0.24×0.10 mm.
Lattice parameters refined using 30 reflections in the range
1552q560°. Huber four circle diffractometer with a
Rigaku rotating anode generator, graphite monochrom-
,
atized CuKa radiation (u=1.54178 A). 2045 independent
−1
,
reflections with sin q/u50.60 A ; 05h57, −135k513,
−105l510 1978 with I]2.0|(I). A standard reflection
(−1 −3 −1) was checked every 50 reflections, no significant
decay was observed. The structure was solved by directs
methods using SHELXS-86.8 All H atoms from difference
Fourier synthesis. Anisotropic least-squares refinement
(SHELXL-93)9 using F2; H isotropic with common
2
,
refined temperature factor (U=0.075 A ). 219 parame-
ters. w=1/(|2(Fo )+0.0767P2+0.05P), R=0.038, R (all
2
data)=0.039, wR=0.110, S=1.09. Final maximum shift
to error=0.001. Maximum and heights in final Fourier
−3
,
synthesis=0.15 and −0.13 e A . Full lists of atomic
coordinates, bond lengths and angles, thermal parameters
have been deposited with the Cambridge Crystallographic
Data Center (CCDC 186716).
3.6. General procedure to epimerization
7. These compounds are commercially available and were
used as purchased.
8. Sheldrick G. M. SHELXS-86. Program for the Solution of
Crystal Structures. University of Go¨ttingen, Germany,
1985.
9. Sheldrick G. M. SHELXL-93. Program for the Refine-
ment of Crystal Structures. University of Go¨ttingen, Ger-
many, 1993.
DBU (11 mL, 0.08 mmol) was added to a solution of
g-butyrolactone 11a (0.08 mL, 0.55 mmol), in CH2Cl2 (1
mL). The mixture was stirred at rt for 48 h and the solvent
was removed in vacuo. The residue was purified by
column chromatography on silica gel (Hex./AcOEt 50:50)
yielding 12b (100%).
10. After irradiation of C(4)H, at 3.74 ppm, NOEs were
observed for C(5)H (2.3%) and the benzylic hydrogens
(2.3 and 1%).
Acknowledgements
11. Casas, R.; Parella, T.; Branchadell, V.; Oliva, A.; Ortun˜o,
R. M. Tetrahedron 1992, 48, 2659.
The authors would like to thank FINEP-PADCT,
FAPERJ and FUJB for financial support, Francisco A.