Syn-Selective Michael Addition of Nitromethane Derivatives to Enoates Derived from (R)-(+)-Glyceraldehyde Acetonide

Article abstract of DOI:10.1021/jo960788x

We report the syn-selective Michael addition of a series of substituted primary and secondary nitromethane derivatives 4a-g to chiral enoates (Z)-2a and (E)-2a in the presence of TBAF·3H₂O or DBU. Regardless of the base employed, adducts syn-5a-g were obtained in good de (80-100%) from the reactions of 4a-g with (Z)-2a. However, in the addition to (E)-2a, the syn-diastereo-selectivities depended on the structure of the nucleophile (80-90% de for nitromethane (4a), 80% de for phenylnitromethane (4g), 50 and 34% de for the primary nitromethane derivatives 4b and 4d, and 0 and 6% de for the secondary nitromethane derivatives 4c and 4f). A mixture of epimers (2:1/1:1) was obtained at the chiral center bearing the nitro group in 5b and 5d-g. The syn/anti ratio C-3,C-4 is kinetically controlled, while the epimeric ratio at the CNO₂ chiral center (C-1′) seems to be thermodynamicaliy controlled. Adducts 5a,b,c,g were transformed into the respective cis-β,γ-disubstituted γ-butyrolactones 6a, 7, 9a, and 9c. A mechanistic rationale to explain the observed diastereoselectivities is proposed.

Full text of DOI:10.1021/jo960788x

4002
J . Org. Chem. 1997, 62, 4002-4006
Syn -Selective Mich a el Ad d ition of Nitr om eth a n e Der iva tives to
En oa tes Der ived fr om (R)-(+)-Glycer a ld eh yd e Aceton id e
J eronimo S. Costa,† Ayres G. Dias,†,‡ Aline L. Anholeto,† Moˆnica D. Monteiro,†
Vera L. Patrocinio,*,§ and Paulo R. R. Costa*,†
Laborato´rio de Sı´ntese Orgaˆnica I, Laborato´rio de S´ıntese Orgaˆnica III, Nu´cleo de Pesquisas de Produtos
Naturais, Universidade Federal do Rio de J aneiro, CCS, Bloco-H, Ilha da cidade Universita´ria,
21941-590, Rio de J aneiro, RJ , Brazil, and Instituto de Qu´ımica,
Universidade Estadual do Rio de J aneiro
Received April 29, 1996X
We report the syn-selective Michael addition of a series of substituted primary and secondary
nitromethane derivatives 4a -g to chiral enoates (Z)-2a and (E)-2a in the presence of TBAF‚3H2O
or DBU. Regardless of the base employed, adducts syn-5a -g were obtained in good de (80-100%)
from the reactions of 4a -g with (Z)-2a . However, in the addition to (E)-2a , the syn-diastereo-
selectivities depended on the structure of the nucleophile (80-90% de for nitromethane (4a ), 80%
de for phenylnitromethane (4g), 50 and 34% de for the primary nitromethane derivatives 4b and
4d , and 0 and 6% de for the secondary nitromethane derivatives 4c and 4f). A mixture of epimers
(2:1/1:1) was obtained at the chiral center bearing the nitro group in 5b and 5d -g. The syn/anti
ratio C-3,C-4 is kinetically controlled, while the epimeric ratio at the CNO2 chiral center (C-1′)
seems to be thermodynamically controlled. Adducts 5a ,b,c,g were transformed into the respective
cis-â,γ-disubstituted γ-butyrolactones 6a , 7, 9a , and 9c. A mechanistic rationale to explain the
observed diastereoselectivities is proposed.
In tr od u ction
Different strategies using the Michael addition of
nucleophiles to R,â-unsaturated carbonyl compounds
have been developed to obtain enantiomerically enriched
adducts.1 In particular, the use of enantiomerically pure
Michael acceptors with a chiral center in the γ-position
bearing an oxygen has been extensively studied and is a
powerful tool in synthesis.1a-c,2 Compounds such as 2 are
among the most studied chiral Michael acceptors of this
type, since they can be easily prepared from (R)-(+)-
glyceraldehyde acetonide (1), a chiral building block
obtained from inexpensive D-(+)-mannitol3 (Figure 1).
The stereochemical outcome of these reactions depends
on the structure of the nucleophile, and both syn-1b,4,5 and
anti-addition1b,6 have been reported. In some cases, the
selectivity has been shown to be dependent on the
geometry of the double bond in the Michael acceptor.7
F igu r e 1. Diastereoselective Michael addition to enoates 2
derived from (R)-(+)-glyceraldehyde acetonide 1.
Recently, we described4 a highly syn-selective Michael
addition of nitromethane (4a ) to both enoates (Z)-2a and
(E)-2a in the presence of TBAF‚3H2O or DBU. Herein,
we disclose the results obtained in the addition of a series
of nitromethane derivatives 4b-g to these enoates
(Scheme 1).
† Laborato´rio de S´ıntese Orgaˆnica I, Universidade Federal do Rio
de J aneiro.
Resu lts
‡ Universidade Estadual do Rio de J aneiro.
§ Laborato´rio de S´ıntese Orgaˆnica III, Universidade Federal do Rio
de J aneiro.
In Scheme 1, our optimized results for the Michael
addition of 4a -g to (Z)-2a (Z/E ) 9/1) and (E)-2a (Z/ E
) 1/32) are presented. In the resulting adducts 5a -g a
new chiral center is diastereoselectively formed (C-3). In
adducts 5b and 5d -g, an additional chiral center, that
bearing the nitro group (C-1′), is also created. The
reactions were run with DBU in CH3CN9a or TBAF‚3H2O
in THF;9b,c the observed syn-5a -g/anti-5a -g ratios (C-
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) (a) Yamamoto, Y.; Pyne, S. G.; Schinzer, D.; Feringa, B. L.;
J ansen J . F. G. A. In Stereoselective Synthesis; Helmchen, G., Hoff-
mann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
1995; Vol. E 21b. Little, R. D.; Masjedizadeh, M. R. Org. React. 1995,
47, 315. Cook, C. E.; Allen, D. A.; Miller, D. B.; Whisnant, C. C. J .
Am. Chem. Soc. 1995, 117, 7269. d’Angelo, J .; Cave´, C.; Desmaele, D.;
Dumas, F. Trends Org. Chem. 1993, 4, 555. (b) Leonard, J . Contemp.
Org. Synth. 1994, 387. (c) Rossiter, B. E.; Swingle, N. M. Chem. Rev.
1992, 92, 771.
(2) Yoshida, S.; Yamanaka, J .; Miyake, T.; Moritani, Y.; Ohmizu,
H.; Iwasaki, T. Tetrahedron Lett. 1995, 36, 7271. Revesz, L.; Briswalter,
C.; Heng, R.; Leutwiler, A.; Mueller, R.; Wuethrich, H. Tetrahedron
Lett. 1994, 35, 9693. Smajda, W.; Zahouily, M.; Malacria, M. Tetra-
hedron Lett. 1992, 38, 5511.
(3) Leonard, J .; Mohialdin, S.; Swain, P. A. Synth. Commun. 1989,
19, 3529. Mann, J .; Partlett, N.; Thomaz, A. J . Chem. Res., Synop.
1987, 369. Marshall, J . A.; Trometer, J . D.; Cleary, D. G. Tetrahedron
1989, 45, 391.
(7) Matsubara, S.; Yoshioka, M.; Utimoto, K. Chem. Lett. 1994, 827.
Morikawa, T.; Washio, Y; Harada, S.; Hanai, R.; Kayashita, T.; Nemoto,
H.; Shiro, M.; Taguchi, T. J . Chem. Soc., Perkin Trans. 1 1995, 1, 271.
(8) For recent studies in racemic series on the Michael of nitronates
see, inter alia: Francke, W.; Schro¨der, F.; Walter, F.; Sinnwell, V.;
Baumann, H.; Kaib, M. Liebigs Ann. 1995, 965. Thomas, A.; Rajappa,
S. Tetrahedron 1995, 51, 10571. Ballini, R.; Marziali, P.; Mozzicafreddo,
A J . Org. Chem. 1996, 61, 3209. Marti, R. E.; Helnzer, J .; Seebach, D.
Liebigs Ann. Chem. 1995, 7, 1193.
(4) Patrocinio, V. L.; Costa, P. R. R.; Correia, C. R. D. Synthesis 1994,
474.
(5) Nomura, M.; Kanemasa, S. Tetrahedron Lett. 1994, 35, 143.
(6) Nilsson, K.; Ullenius, C. Tetrahedron 1994, 50, 13173.
(9) (a) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213. Ono, N.;
Kamimura A.; Kaji, A. Synthesis 1984, 226. (b) Clark, J . H. Chem.
Rev. 1980, 80, 429. (c) The use of old solutions of TBAF‚3H2O in THF
can lead to a decrease in the chemical yield.
S0022-3263(96)00788-8 CCC: $14.00 © 1997 American Chemical Society

Michael Addition of Nitromethane Derivatives
J . Org. Chem., Vol. 62, No. 12, 1997 4003
Sch em e 1. Syn -Mich a el Ad d ition of Nitr om eth a n e
Sch em e 2. Con fir m a tion of Syn -Ster eoch em istr y
in Ad d u cts 5a ,b,c,g
Der iva tives 4a -g to En oa tes (Z)-2a a n d (E)-2a
γ-butyrolactone derivative 6a . As previously reported,4
the cis-relationship between H-3 and H-4 in lactone 6a ,
and thus the syn-stereochemistry in adduct 5a , was
determined by the coupling constant (J H-3,H-4 ) 7.5 Hz)
and confirmed by irradiation at H-4 (δ 4.95), which led
to an enhancement of 3% in intensity of H-3 (δ 3.59).
With 5c and 5g, however, the C-NO2 bond was first
cleaved with Bu3SnH,12 leading to compounds 8a and 8b,
respectively. Reaction of 8a with 20% HCl in MeOH
selectively furnished the cis-γ-butyrolactone 9a (J H-3,H-4
) 7.3 Hz), while treatment 8b under the same conditions,
followed by acetylation of the resulting intermediate 9b,
furnished the corresponding cis-lactone 9c (J H-3,H-4 ) 7.2
Hz).
The syn-stereochemistry for adducts 5d -f was as-
signed through comparison of their 13C NMR spectra with
those of syn-5a -c,g. Specifically the syn-diastereomer
in all cases showed greater shielding of the C-1′ asym-
metric carbon (CNO2) and less shielding of the carbon
C-3.
a
Other bases such as TMAF/DMSO and KF/Al2O/THF were
used, and similar de and yields were observed. bAfter purification
by flash chromatography. cMeasured by quantitative 13C NMR
and/or HPLC. dMethyl ester was used.
3) and the epimeric ratios at the CNO2 (C-1′) center in
the products were shown to be independent of the base
employed.
The additions of nitromethane (4a ) and phenylnitro-
methane (4g) led, respectively, to 5a and 5g in a good
syn/anti ratio (de at C-3 ) 80-90% and 80%), regardless
of the stereochemistry of the double bond in 2a (entries
1, 2, and 15-18, Scheme 1). A mixture of epimers at C-1′
was observed for adduct 5g (2/1 ratio). On the other
hand, when 4b-f were used, the syn/anti ratio (de at C-3)
depended on the stereochemistry of 2a . High de (90-
100%) were observed in the reactions of these nitro
derivatives with (Z)-2a (entries 3, 4, 7, 8, 10, 12, and 13,
Scheme 1), in contrast with the results obtained when
(E)-2a was used as acceptor. In these latter cases, the
addition of primary nitromethane derivatives 4b and 4d
led to the corresponding adducts 5b and 5d in moderate
de (50% and 34%, respectively, entries 5, 6, and 11,
Scheme 1), while adducts 5c and 5f were obtained in very
low de from the addition of secondary nitromethane
derivatives 4c and 4f (0% and 6%, entries 9 and 14,
Scheme 1). The adducts 4b and 4d -f were obtained as
mixtures of epimers at C-1′.
The syn stereochemistry of 5b was unambiguously
determined by chemical correlations with the known
lactone 7 (cyclization, silylation, and denitration, Scheme
2). Compounds 5a , 5c, and 5g were transformed into
lactones 6a , 9a , and 9c, respectively, in order to establish
the syn-stereochemistry (Scheme 2). Hydrolysis of the
ketal group in 5a with 20% HCl in MeOH, was followed
in situ by selective lactonization10 of the resulting diol.
Acetylation of the crude product obtained led to the nitro
Discu ssion
In order to obtain information on the nature of the
stereochemical control in these Michael additions, the
nitromethane derivatives 4a , 4b, and 4g were allowed
to react with enoates (Z)-2a and (E)-2a in the presence
of TABAF‚3H2O in THF or DBU in CH3CN, and the
product distribution was analyzed after 10%, 50%, and
80% of enoate conversion. It was observed that the syn/
anti ratio at C-3 in the resulting adducts 5a , 5b, and 5g,
as well as the epimeric ratio at the CNO2 (C-1′) chiral
center in adducts 5b and 5g, was constant, regardless
the reaction time and the base employed. Due to the
acidity of the hydrogen atoms on the carbon bearing the
nitro group, it seems reasonable to assume that formation
of these chiral centers is thermodynamically controlled,
particularly in light of the report that for aldol addition
reactions involving nitronates the stereogenic center
bearing the nitro group is easily epimerizable.13 In
(11) (a) Ziegler, F. E.; Tung, J . S. J . Org. Chem. 1991, 56, 6530 and
references cited therein. (b) Brown, H. C.; Kulkarni, S. V.; Racherla,
U. S. J . Org. Chem. 1994, 59, 365 and references cited therein.
(12) Ono, N.; Miyake, H.; Kati, A. J . Org. Chem. 1984, 49, 4997.
(13) Whener, V.; J a¨gger, V. Angew Chem., Int. Ed. Engl. 1990, 29,
1169. Hanessian, S.; Kloss, J . Tetrahedron Lett. 1985, 26, 1261.
(10) Leonard, J .; Mohialdin, S.; Reed, D.; Ryan, G.; J ones, M. F. J .
Chem. Soc., Chem. Commun. 1993, 23.

4004 J . Org. Chem., Vol. 62, No. 12, 1997
Costa et al.
F igu r e 2. Most stable conformers for enoates (Z)-2a and (E)-
2a (molecular mechanics, AM1).
F igu r e 3. Synclinal approach of nitronates to the Re face of
(Z)-2a (conformer CZ), leading to syn-5.
contrast, the constant syn/anti ratios seemed to indicate
that the chirality at the newly generated center C-3 is
kinetically controlled, although the possibility of a rapid
equilibration through a retro-Michael-Michael reaction
could not, a priori, be completely excluded. Unambiguous
evidence favoring kinetic control, though, was obtained
when pure syn-5c and pure anti-5c, purified by flash
chromatography, were allowed to react with TBAF‚3H2O
and CH3CHCH3NO2 in THF or DBU and CH3CHCH3NO2
in CH3CN. In all cases, syn-5c and anti-5c were recov-
ered diastereomerically pure, showing that product equili-
bration does not occur under the reaction conditions.
Thus, since the syn/anti ratio is kinetically controlled,
the product distribution shown in Scheme 1 must be due
to the difference in energy of the transition states leading
to the syn- and anti-adducts.
The diastereoselectivities in the addition of methyl-
copper6,14 and fluoride15a to enoates having a chiral center
in the γ-position bearing an oxygen were previously
explained by transition-state energies derived from theo-
retical calculations (ab initio and MM2, respectively). In
particular, for the reactions involving enoates (Z)- and
(E)-2a , different explanations depending on the nucleo-
phile used have been advanced to account for the syn or
anti diastereoselectivities of the addition.1b,4 A modified
Felkin-Anh model has been suggested to rationalize the
syn-addition observed in the absence of chelation between
the nucleophile and 2a .1b,4 More recently, transition
states for the addition of tin-centered radicals7b and
Diels-Alder cycloadditions15b to 2a were calculated using
a semiempirical method (AM1). In our calculations
(AM1), conformer CZ (Figure 2) was determined to be
the most stable for enoate (Z)-2a (>99% of contribution),
while for enoate (E)-2a conformers CE1 and CE2 were
found to be almost isoenergetic.16
be discarded and an anti-periplanar approach of these
anions to the less hindered Re-face of conformer CZ might
be expected.18 However, in this approach, a destabilizing
electronic interaction between the oxygen atom at the
stereogenic center and the polar nitronate group in the
incoming nucleophile would occur. For this reason, we
propose a synclinal approach (Figure 3), in which this
interaction would be minimized. According to this hy-
pothesis, two transition states can be proposed for the
reactions of the prochiral nitronates derived from 4b and
4d -g with (Z)-2a , namely TSZa and TSZb (Figure 3).
Considering the addition of primary nitronates derived
from 4b,d -e,g, TSZa would be favored over TSZb, since
the more bulky group (R4) of the incoming nucleophile
assumes the less hindered outside position. This transi-
tion state would lead to adducts syn-5b, syn-5d -e, and
syn-5g with the S stereochemistry at the CNO2 stereo-
genic center as indicated, but due to fast equilibration,
this stereochemical information is lost. The transition
state for the addition of secondary nitromethane deriva-
tives 4c and 4f is more crowed since in these cases an
alkyl group is always in the more sterically hindered
inside position. However, these steric interactions are
minimized due to the synclinal approach. For the addi-
tion of 4f, the epimeric ratio at the CNO2 center is
kinetically controlled (no H atom is available for epimer-
ization). The low π-facial discrimination with the corre-
sponding nitronate (epimeric ratio at CNO2 center in
adduct 5f ) 1.4:1.0, entry 13, Scheme 1) shows that the
methyl and the methylene groups are almost sterically
equivalent in this reaction.
Our mechanistic interpretation for the reactions in-
volving enoate (E)-2a is shown in Figure 4. Conformers
CE1 and CE2 are isoenergetics;15a,17 while the first would
give syn-adducts by attack of the nitronate on the Re-
face, the second, with a sterically less hindered Si-face,
would give anti-adducts. A synclinal approach of the
nitronates to conformers CE1 and CE2 seems likely; two
possible transition states originate from each conformer
In attempting to rationalize our results, we have
assumed the involvement of conformer CZ in the transi-
tion state leading from enoate (Z)-2a to adducts syn-5a -
g. Since our nitronate anions were generated in the
absence of metallic cations, cyclic transition states can
(14) Dorigo, A. E.; Morokuma, K. J . Am. Chem. Soc. 1989, 111, 6524.
(15) (a) Bernardi, A.; Capelli, A. M.; Gennari, C.; Scolastico, C.
Tetrahedron: Asymmetry 1990, 1, 21. (b) Casas, R.; Parella, T.;
Branchadell, V.; Oliva, A.; Ortun˜o, R. M. Tetrahedron 1992, 48, 2659.
(16) It has been demonstrated by VT-1H NMR that for E-enoates
bearing an alkoxy group at the stereogenic center the main conformer
has H-3 (at the olefinic â-carbon) and H-4 (at the stereogenic center)
in an antiperiplanar relationship: Gung, B. W.; Melnick, J . P.; Wolf,
M. A.; King, A. J . Org. Chem. 1995, 60, 1947 and references cited
therein. The s-cis/ s-trans conformational preferences of the ester group
in enoates has been studied by supersonic jet spectroscopy, NOE, and
X-ray analyses: Shida, N.; Kabuto, C.; Niwa, T.; Ebata, T.; Yamamoto,
Y. J . Org. Chem. 1994, 59, 4068.
(17) Our calculations (AM1) show CZ-2a as the most important
conformation of enoate (Z)-2a (99%) while for enoate (E)-2a conformers
CE1-2a and CE2-2a are isoenergetic. These data are in complete
agreement with previous studies.15b The calculation of transition states
for the addition of nitronates to these conformers is under investigation.
Amorim, M. B.; Filho, U. F.; Lima, P. G.; Costa, P. R. R. Unpublished
results.
(18) The anti-periplanar approximation has been proposed to explain
the stereoselectivity in other Michael addition and aldol addition where
a metal is not available for coordination. Heathcock, C. H. In Asym-
metric Synthesis; Morrison, J . D., Ed.; Academic Press: New York,
1984; Vol. 3, Part B. See also ref 1c.

Michael Addition of Nitromethane Derivatives
J . Org. Chem., Vol. 62, No. 12, 1997 4005
Finally, the high de obtained in the addition of 4a
shows that for this unhindered nucleophile TSE1 is
highly favored over TSE2.
Con clu sion s
The work described in this paper shows that it is
possible to add substituted nitromethane derivatives
(primary and secondary nitroalkanes, nitro ketals, and
nitro esters) to chiral enoates 2a in good chemical yields
and with high syn selectivity. The easy removal of the
nitro group in adducts 5 by reduction of the C-N bond
and the possibility of functional group interconversions
involving the nitro group,19 leading to alkyl and func-
tionalized alkyl groups, respectively, makes this meth-
odology complementary to other conjugate addition meth-
ods.
Finally, this work provides a synthesis of cis-3,4-
disubstituted γ-butyrolactones, which are difficult to
prepare by other methodologies,11a but present in several
classes of natural products.11b The total synthesis of
some naturally occurring lactones of this type using the
present methodology is under investigation in our labo-
ratories.
Exp er im en ta l Section
Ma ter ia ls. All conjugate additions were performed under
N2 atmosphere. THF was distilled from sodium benzophenone
under N2 and DMF from CaH2. Acetonitrile was dried over 4
Å molecular sieves, TBAF‚3H2O (solid), nitroethane, 2-nitro-
propane, TBDMS-Cl, TBDPS-Cl, AIBN, Bu3SnH, and imid-
azole are commercially available and were used directly. The
enoates (Z)-2a and (E)-2a as well as the nitro compounds 4d
and 4g were prepared according to literature procedures.20,21
The nitro compound 4e was prepared from 3-nitropropanal21
by reduction with NaBH4, under standard conditions, followed
by acetylation of the alcohol obtained. The nitro compound
4f was prepared in quantitative yield by conjugate addition
of nitroethane to methyl acrylate in the presence of KF
supported on Al2O3/THF. 1H-NMR and 13C-NMR spectra were
recorded on Gemini-200 (200 MHz) Varian Instruments in
CDCl3 unless specified otherwise. The coupling constants (J )
are in hertz (Hz). The analyses by HPLC were performed on
a Shimadzu LC-A10 chromatograph using a Shimadzu column
C18 (25 cm × 1.6 i.d. × 5 mm). High-resolution mass spectra
were recorded on a Micromass MM12 F and a VG AutoSpec
spectrometer. IR spectra were recorded on a Perkin-Elmer
Model 783 spectrophotometer, and optical rotations were
measured on a Perkin-Elmer Model 243-B polarimeter. All
melting points are uncorrected and were determined on a
Thomas Hoover apparatus.
P r ep a r a tion of 5b-g, Typ ica l P r oced u r e: Nitr oa d d u ct
5b, Usin g TBAF ‚3H2O a s Ba se. To a stirred solution of (Z)-
2a (3.0g, 15 mmol) and EtNO2 (1.13g, 1.5 mmol) in THF (15
mL) was added TBAF‚3H2O (0.39 g, 1.5 mmol) at rt. The
resulting yellow solution was stirred for an additional 4 h and
poured into H2O (50 mL), followed by extraction with CH2Cl2
(3 × 50 mL). The combined organic extracts were dried with
anhydrous sodium sulfate and evaporated under reduced
pressure. The residue was purified by column chromatography
on silica gel (Hex/AcOEt 9/1), yielding 3.1 g (75% of pale yellow
oil of 5b as a mixture of syn/anti diasteromers (95/5) and
epimeric at the nitro stereocenter, in the syn-isomer 1.4:1.0).
5b, Usin g DBU a s Ba se. A solution of EtNO2 (0.21 g, 2.75
mmol) and (Z)-2a (0.5 g, 2.5 mmol) in acetonitrile (10 mL) was
mixed with DBU (1,8-diazabicyclo[5.4.0.]undec-7-ene) (0.38 g,
2.5 mmol). The resulting orange solution was kept at room
F igu r e 4. Synclinal approach of nitronates to (E)-2a . Re face
of conformer CE1 and Si face of conformer CE2.
when prochiral nitronates were used as nucleophiles,
named TSE1a and TSE1b (from CE1) and TSE2a and
TSE2b (from CE2).
The very low diastereoselectivity observed in the
additions of secondary nitromethane derivatives 4c and
4f (0 and 6%, entries 9 and 14, Scheme 1) clearly
indicates that in these cases the transition states TSE1a
,
TSE1b, TSE2a , and TSE2b are almost equivalent in en-
ergy. In these transition states there is a strong de-
stabilizing interaction between an alkyl group in the
outside position and the carbethoxy group of the enoate.
This strong interaction, maximized in the synclinal
approach, would seem to be responsible for bringing the
transition states to the same energy level. To explain
the higher diastereoselectivities obtained in the addition
of the primary nitronates derived from nitroethane (4b)
(50% de, entries 5 and 6, Scheme 1) and phenylnitro-
methane (4g) (80% de, entries 16 and 18, Scheme 1), we
assume to avoid the highly destabilizing steric interac-
tions between R4 (ethyl or phenyl) and the carbethoxy
group, presents in TSE1a and TSE2a , the addition of 4b
and 4g to CE1 and CE2 occurs through TSE1b and TSE2b
,
respectively. The degree of steric hindrance of the inside
position in conformers CE1 and CE2 also needs to be
considered to explain the difference in de for 4b and 4g.
In CE1, H-4 is at 60° with respect to the enoate plane,
while in CE2 this angle is 90°. Thus, H-4 is closer to the
position of nucleophilic attack in CE2 and, as a conse-
quence, the inside position is more sterically hindered
in this conformer. Once a phenyl group is larger than
an ethyl group, TSE2b is of higher energy for 4g than
for 4b, explaining the the better syn-diastereoselection
observed for 4g.
(19) Rosini, G.; Ballini, R. Synthesis 1988, 833. Seebach, D.; Colvin,
E.; Lehr, F.; Weller, T. Chimia 1979, 33, 1.
(20) Kornblum, N. Org. React. 1962, 12, 101.
(21) O¨ hr, R.; Schwab,W; Ehrler, R.; J a¨ger, V. Synthesis 1986, 535.

4006 J . Org. Chem., Vol. 62, No. 12, 1997
Costa et al.
temperature for 4 h and then poured into 20 mL of water. The
mixture was acidified with HCl (10%) until pH 2 and extracted
with AcOEt (3 × 30 mL). The combined organic phases were
washed with 30 mL of H2O, dried with anhydrous sodium
sulfate, and evaporated under reduced pressure. A viscous
residue was obtained and purified as above. Compound 5b
(0.48g, 70%, pale yellow oil) as a mixture of syn/anti diaster-
eomers (95/5) and epimeric at nitro stereocenter (in the syn-
isomer 1.5/1.0) was obtained: 1H NMR δ 1.29 (t, J ) 7.5, 3H),
1.30 (t, J ) 7.5, 3H), 1.36 (s, 6H), 1.42 (s, 3H), 1.45 (s, 3H),
1.57 (d, J ) 7.5, 3H), 1.64 (d, J ) 7.5, 3H), 2.17-2.41 (m, 2H),
2.41-2.60 (m, 2H), 2.65-2.84 (m, 1H), 2.88-3.04 (m, 1H),
at 80 °C for 90 min. The reaction mixture was subjected to
column chromatography (silica gel, hexane/AcOEt 96/4) to give
0.09 g (yield 64%) of 8a as a colorless oil (syn/anti ) 97:3):
[R]25 ) +11 (1.0; CHCl3); 1H NMR δ 0.90 (d, J ) 6.0, 3H),
D
0.93 (d, J ) 6.0, 3H), 1.26 (t, J ) 7.0, 3H), 1.34 (s, 3H), 1.39 (s,
3H), 1.81-2.00 (m, 1H), 2.15-2.27 (m, 3 H), 3.57 (dd, J ) 8.0,
8.0, 1H), 3.95 (dd, J ) 8.0, 6.0, 1H), 4.13 (q, J ) 7.0, 2H), 4.05-
4.20 (m, 1H); 13C NMR δ 14.0, 18.5, 20.2, 25.2, 26.3, 28.3, 31.6,
43.0, 60.3, 66.8, 76.5, 108.1, 173.3; MS (70 eV) m/ z 229 (M+
Me, 100), 141 (87), 101 (74), 72 (45).
-
Ack n ow led gm en t. We are grateful to Conselho
Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico
(CNPq) and Coordenac¸a˜o de Apoio ao Pessoal de Ensino
Superior (CAPES) for financial support and for fellow-
ships for all authors. Fundac¸a˜o Universita´ria J ose´
Bonifa´cio (FUJ B, Rio de J aneiro) and Universidade
Federal do Rio de J aneiro (UFRJ ) are thanked for for
financial support. The help of Prof. Antonio J . R. Silva,
Francisco Santos, Eduardo Miguez, Cristina Holanda
(NPPN-UFRJ ), and Leonardo C. M. Coutada (Far-
Manguinhos) with the NMR and mass spectra is ap-
preciated. We also thank MSc Ubiracir F. L. Filho
(NPPN-UFRJ ) and Prof. Warner B. Koover (IQ-UFRJ )
for helpful discussions.
3.57-3.82 (m, 2H), 3.97-4.27 (m, 8H), 4.85-5.01 (m, 2H); 13
C
NMR δ 13.9, 14.3, 16.0, 25.0, 25.1, 26.1, 26.2, 31.3, 31.5, 41.8,
42.5, 60.9, 67.3, 75.4, 75.5, 82.1, 82.3, 109.3, 170.9, 171.2; MS
(70 eV) m/ z 260 (M+ - Me, 35), 169 (47), 141 (64), 127 (45),
101 (100), 95 (89); HRMS (70 eV) m/ z for C11H18NO6 (M+
Me), calcd 260.113 413, found 260.113 019.
-
La cton iza tion of 5b, 8a , a n d 8b to 6b, 9a , a n d 9b,
Resp ectively. Typ ica l P r oced u r e: (3S,4S)-3-Isop r op yl-
4-(h yd r oxym eth yl)bu ta n -4-olid e (9a ). To a stirred solution
of 8a (97:3, 0.2 g, 0.82 mmol) in MeOH (4 mL) was added HCl
(10%, 1.1 mL) at rt. After 1 h, the solvent was evaporated
and the residue filtered through a short pad of silica gel topped
with a layer of solid NaHCO3 and anhydrous sodium sulfate
(hexane/EtOAc 1:1), providing 9a (0.11 g, 90%, cis/trans 97/3)
1
as a white solid: [R]25 ) +23 (1.0, MeOH); mp ) 118 °C; H
D
NMR δ 0.96 (d, J ) 4.2, 3H), 0.99 (d, J ) 4.1, 3H), 1.70-1.98
(m, 1H), 2.20-2.65 (m, 3H), 3.75-4.05 (m, 1H, OH, exchange
with D2O; 2H), 4.59 (ddd, J ) 7.3, 4.3, 3.0); 13C NMR δ 21.0,
21.6, 27.6, 33.3, 45.8, 61.0, 82.4, 177.9; MS (70 eV) m/ z 127
(M+ - 31, 100), 81 (35), 55 (44).
Den itr a tion of 5c, 5g, a n d 6c to 8a , 8b, a n d 7, Resp ec-
tively. Typ ica l P r oced u r e: Eth yl (3S,4S)-Isop r op yl-4,5-
O-isop r op ylid en ep en ta n oa te (8a ). A mixture of 5c (syn/
anti, 97:3, 0.18 g, 0.62 mmol), Bu3SnH (0.23 g, 0.80 mmol),
and AIBN (0.33 g, 0.20 mmol) in benzene (1.5 mL) was heated
Su p p or tin g In for m a tion Ava ila ble: Copies of both the
1H and 13C NMR spectra of 5b-g, 6a -c, 8a ,b, and 9a -c and
the 1H NMR spectra of syn-5c (methyl ester) and anti-5c
(methyl ester (30 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O960788X