Diastereoselective Electrochemical Carboxylation of Chiral α-Bromocarboxylic Acid Derivatives: An Easy Access to Unsymmetrical Alkylmalonic Ester Derivatives

Article abstract of DOI:10.1021/jo0343836

The diastereoselective electrochemical carboxylation of chiral N-(2-bromoacyl)oxazolidin-2-ones has been studied. This reaction was carried out by cathodic reduction of the C - Br bond, in the presence of carbon dioxide, followed by treatment with diazomethane. The yields and the diastereomeric ratio of the two epimeric alkylmalonic acid derivatives are strongly affected by various factors: solvent-supporting electrolyte system, temperature, electrode material, electrolysis conditions, oxazolidinone moiety. The higher yields (88%) were obtained starting from N-(2-bromopropionyl)-4R-phenyloxazolidin-2-one la, but with poor diastereoselectivity (61:39). The two epimers were easily separated by flash chromatography. The best results were achieved using a different chiral auxiliary: Oppolzer's camphor sultam. Starting from 1j a good yield in carboxylated product was obtained (80%) with excellent diastereoselectivity (98:2). These chiral alkylmalonic acid derivatives are valuable building blocks in the synthesis of molecules with biological activity and of chiral propane-1,3-diols derivatives.

Full text of DOI:10.1021/jo0343836

Dia ster eoselective Electr och em ica l Ca r boxyla tion of Ch ir a l
r-Br om oca r boxylic Acid Der iva tives: An Ea sy Access to
Un sym m etr ica l Alk ylm a lon ic Ester Der iva tives1,†
Marta Feroci,*,‡ Monica Orsini,§ Laura Palombi,§ Giovanni Sotgiu,| Marcello Colapietro, and
Achille Inesi*,§
Dip. Ingegneria Chimica, Materiali, Materie Prime e Metallurgia, Universita` “La Sapienza”,
via Castro Laurenziano, 7, I-00161 Roma, Italy, Dip. Chimica, Ingegneria Chimica e Materiali,
Universita` degli Studi, I-67040, Monteluco di Roio, L’Aquila, Italy, Dipartimento di Ingegneria
Elettronica, Universita` di Roma Tre, Via Vasca Navale 84, I-00146 Roma, Italy, and Dip. Chimica,
Universita` “La Sapienza”, P.le Aldo Moro, 5, I-00185 Roma, Italy
marta.feroci@uniroma1.it; inesi@ing.univaq.it
Received March 25, 2003
The diastereoselective electrochemical carboxylation of chiral N-(2-bromoacyl)oxazolidin-2-ones has
been studied. This reaction was carried out by cathodic reduction of the C-Br bond, in the presence
of carbon dioxide, followed by treatment with diazomethane. The yields and the diastereomeric
ratio of the two epimeric alkylmalonic acid derivatives are strongly affected by various factors:
solvent-supporting electrolyte system, temperature, electrode material, electrolysis conditions,
oxazolidinone moiety. The higher yields (88%) were obtained starting from N-(2-bromopropionyl)-
4R-phenyloxazolidin-2-one 1a , but with poor diastereoselectivity (61:39). The two epimers were
easily separated by flash chromatography. The best results were achieved using a different chiral
auxiliary: Oppolzer’s camphor sultam. Starting from 1j a good yield in carboxylated product was
obtained (80%) with excellent diastereoselectivity (98:2). These chiral alkylmalonic acid derivatives
are valuable building blocks in the synthesis of molecules with biological activity and of chiral
propane-1,3-diols derivatives.
SCHEME 1
In tr od u ction
Electrochemistry is now a useful tool for organic
chemists, as some organic transformations take place
only by electrochemical means,2 and also because “elec-
trochemistry affords a very facile and precise way to
generate highly energetic intermediates via control of the
electrode potential”,3 so it offers good alternatives to
traditional “chemical” methods.
The cathodic behavior of halogenated organic com-
pounds has been extensively studied4 and normally leads
to the cleavage of the carbon-halogen bond with forma-
tion of a carbanion that can successively react in various
ways. One of the classical experiments to demonstrate
the formation of such an anion is to trap it by reaction
with carbon dioxide, giving a carboxylated product. This
procedure works well in many cases (aliphatic and
aromatic halides, for example), but to our knowledge, no
electrochemical carboxylation of R-haloesters or amides
has been reported.
Recently, we studied the possibility of inducing, by
electrochemical means, the diastereoselective carboxyl-
ation of halogenated organic compounds. Our preliminary
results have been reported in a recent communication:1
the cathodic reduction of N-(2-bromopropionyl)-4R-phen-
yloxazolidin-2-one 1a in the presence of carbon dioxide
gave rise to the formation of the corresponding unsym-
metrical methylmalonic ester derivatives 2a and 2a ′
(after treatment with diazomethane) in enriched diaster-
eomeric form (Scheme 1). The two epimers could be easily
separated by flash chromatography, obtaining both pure
* To whom correspondence should be addressed. Tel: +39-06-
49766780. Fax: +39-06-49766749.
† Dedicated to Paolo Silvestroni (1917-2003), Professor of Chem-
istry.
‡ University of Roma “La Sapienza”.
§ University of L’Aquila.
(4) (a) Peters, D. G. In Organic Electrochemistry; Lund, H., Ham-
merich, O., Eds.; Marcel Dekker, Inc.: New York, 2001; pp 341-377.
(b) Klein, L. J .; Peters, G. D. In Rodd’s Chemistry of Carbon
Compounds; Sainsbury, M., Ed.; Elsevier: 2002; Vol. V, Organic
Electrochemistry, pp 1-51. (c) Silvestri, G.; Gambino, S.; Filardo, G.;
Gulotta, A. Angew. Chem., Int. Ed. Engl. 1984, 23, 978-979. (d) Sock,
O.; Troupel, M.; Pe´richon, J . Tetrahedron Lett. 1985, 26, 1509-1512.
(e) Heintz, M.; Sock, O.; Saboureau, C.; Pe´richon, J . Tetrahedron 1988,
44, 1631-1636. (f) Durandetti, M.; Pe´richon, J .; Ne´de´lec, J .-Y. J . Org.
Chem. 1997, 62, 7914-7915.
| University of Roma Tre.
Author for X-ray analysis. University of Rome “La Sapienza”, Dip.
Chimica.
(1) Feroci, M.; Inesi, A.; Orsini, M.; Palombi, L. Org. Lett. 2002, 4
(16), 2617-2620.
(2) Fry, A. J . In Synthetic Organic Electrochemistry, 2nd ed.; J ohn
Wiley & Sons: New York, 1989; pp 1-3.
(3) Amatore, C. In Organic Electrochemistry; Lund, H., Hammerich,
O., Eds.; Marcel Dekker, Inc.: New York, 2001; p 53.
10.1021/jo0343836 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/30/2003
J . Org. Chem. 2004, 69, 487-494
487

Feroci et al.
SCHEME 2
chiral products. These substrates are valuable synthons
in asymmetric synthesis, as chiral half esters of alkyl-
malonic acid were used as precursors of chiral R-alkyl-
R-amino acids, useful molecules with biological activity5
and in the synthesis of indole alkaloids.6 Moreover, they
are used as precursors of chiral propane-1,3-diol deriva-
tives.7
The usual approach to optically active propane-1,3-diol
derivatives is the enzymatic differentiation of the prochiral
2-position of a 2-substituted-1,3-diol,8 while chemical
approaches are rare.9
derivatives. The carboxylation can be achieved, as sug-
gested by our preliminary results,1 via cathodic reduction
of R-bromo carboxylic acid derivatives carried out in the
presence of carbon dioxide.
Resu lts a n d Discu ssion
N-(2-Bromopropionyl)-4R-phenyloxazolidin-2-one 1a was
taken as a model compound, and its electrochemical
behavior was studied using various chemical and physical
parameters.
The cathodic bielectronic cleavage of the carbon-
bromine bond of 1a in MeCN-Et4NClO4 (TEAP)12 leads
to the formation of an enolate anion with loss of bromide
ion; the behavior of this enolate depends on its partner
of reaction (Scheme 3). If it is in the presence of a proton
donor, it is protonated, giving rise to the formation of
N-propionyloxazolidinone 3a (Scheme 3, eq 2; Table 1,
entry 2); if it is in the presence of carbon dioxide, it is
carboxylated forming the couple of epimers 2a and 2′a
(after reaction with diazomethane) (Scheme 3, eq 3; Table
1, entries 5-7); if there is enough time between the
enolate formation and its subsequent protonation, a
decomposition of the enolate (probably via a ketene
pathway)13 is efficient, giving rise to the formation of
oxazolidinone 4a (Scheme 3, eq 1; Table 1, entries 1 and
4-7).
Our aim was to minimize both the protonation and the
decomposition reactions, favoring the formation of the
carboxylated product. Keeping this objective in mind,
various chemical and electrochemical parameters were
varied (Table 1): the use of MeCN/TEAP as solvent
system seems to favor the protonation and decomposition
reactions (entries 1-7). To lower the temperature does
not enhance the yields in carboxylated products, probably
also because of a decrease in the solubility of the
supporting electrolyte (but there is a considerable en-
hancement in the diastereomeric ratio, see entries 5-7).
Moreover, the electrolysis conditions seem to influence
the outcome of the reaction and the distribution of the
products (galvanostatic conditions would be preferable
with respect to potentiostatic conditions in view of a
possible industrial application).14 The role of Et3N in this
reaction is not so clear: when the reaction in MeCN-
TEAP was carried out in the absence of amine, no
One of the chemical methods uses the condensation of
a monoalkylmalonic acid and a molar equivalent of chiral
alcohol (CA*) to obtain the corresponding mixture of
chiral half esters. These esters are transformed, after
functionalization, into the corresponding epimeric mix-
ture of hydroxy esters and then separated by HPLC
means. After protection of the alcoholic function, the
reduction of the ester to alcohol can be carried out, thus
obtaining an optically active protected propane-1,3-diol
(Scheme 2).7 In particular, if the substituent in 2- position
is a methyl group, the propandiol was used as a precursor
of a potent antibiotic related to thienamicin.10
The diastereoselective synthesis of alkylmalonic ester
derivatives is therefore a goal of considerable interest (the
subsequent selective reduction of the amidic function in
the presence of the methyl ester group of 2 and 2′, to yield
the corresponding chiral alcohol, is well described in the
literature).11
Herein, we wish to report a new general methodology
for this synthesis based on the diastereoselective car-
boxylation in the R-position of chiral carboxylic acid
(5) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui,
K.; Fukumoto, K. J . Org. Chem. 1989, 54, 5413-5415.
(6) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Niitsuma,
H.; Fukumoto, K. J . Chem. Soc., Perkin Trans. 1 1991, 525-535.
(7) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Fukumoto,
K.; Kametani, T. J . Chem. Soc., Perkin Trans. 1 1989, 897-903.
(8) (a) Cohen, N.; Eichel, W. F.; Lopresti, R. J .; Neukom, C.; Saucy,
G. J . Org. Chem. 1976, 41, 3505-3511. (b) J ones, J . B. Tetrahedron
1986, 42, 3351-3403. (c) Luyten, M.; Mu¨ller, S.; Herzog, B.; Keese, R.
Helv. Chim. Acta 1987, 70, 1250-1254. (d) Kitazume, T.; Sato, T.;
Ishikawa, N. Chem. Lett. 1984, 1811-1814. (e) Kitazume, T.; Murata,
K.; Ikeya, T. J . Fluorine Chem. 1986, 31, 143-150. (f) Tombo, G. M.
R.; Scha¨r, N.-P.; Busquets, X. F.; Ghisalba, O. Tetrahedron Lett. 1986,
27, 5707-5710. (g) Bjo¨rkling, F.; Boutelje, J .; Gatenbeck, S.; Hult, K.;
Norin, T. Tetrahedron Lett. 1985, 26, 4957-4958. (h) Wang, Y.-F., Sih,
C. J . Tetrahedron Lett. 1984, 25, 4999-5002.
(9) (a) Harada, T.; Hayashiya, T.; Wada, I.; Iwa-ake, N.; Oku, A. J .
Am. Chem. Soc. 1987, 109, 527-532. (b) Tomioka, K.; Ando, K.;
Takemasa, Y.; Koga, K. J . Am. Chem. Soc. 1984, 106, 2718-2719. (c)
Tomioka, K.; Ando, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986,
27, 715-716. (d) Quinkert, G.; Schmalz, H.-G.; Walzer, E.; Gross, S.;
Du¨rner, G.; Bats, J . W. Angew. Chem., Int. Ed. Engl. 1986, 98, 732-
733. (e) Gennari, C.; Bernardi, A.; Scolastico, C.; Potenza, D. Tetra-
hedron Lett. 1985, 26, 4129-4132.
(12) CAUTION! Although in more than 100 experiments no par-
ticular safety problem has been encountered, the use of perchlorates
in organic solvent must be considered as potentially dangerous
(explosive). Take adequate precautions.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737-1739.
(14) Galvanostatic is an experimental technique whereby the current
is kept constant throughout the electrolysis; potentiostatic is the
technique whereby the electrode potential is kept constant against a
reference electrode. See: Shono, T. In Electroorganic Synthesis;
Academic Press: London, 1991; p 11.
(10) Ihara, M.; Takahashi, M.; Fukumoto, K.; Kametani, T. J . Chem.
Soc., Perkin Trans. 1 1989, 2215-2221.
(11) Tietze, F.; Schu¨nke, C. Angew. Chem., Int. Ed. Engl. 1995, 34
(16), 1731-1733.
488 J . Org. Chem., Vol. 69, No. 2, 2004

Access to Unsymmetrical Alkylmalonic Ester Derivatives
SCHEME 3
TABLE 1. Electr olysesa of Solu tion s of 1a u n d er Differ en t Exp er im en ta l Con d ition s
products (yields,%)b
entry
anode/cathode
electrolysis conditions
solvent/electrolyte
T (°°C)
3a
4a
2a + 2′a (dr)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Mg/Pbd
Mg/Pbe
Mg/Pb
Mg/Pb
Mg/Pbf
Mg/Pbf
Mg/Pbf
Mg/Pb
Mg/Pbf
Mg/Pb
Mg/Pt
potentiostatic
potentiostatic
potentiostatic
galvanostatic
potentiostatic
potentiostatic
potentiostatic
galvanostatic
galvanostatic
galvanostatic
galvanostatic
galvanostatic
galvanostatic
galvanostatic
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
MeCN/Et4NClO4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
THF/Bu4NBF4
rt
rt
rt
rt
55
86
77
50
33
65
72
37
32
22
14
11
30
20
22
rt
36 (57:43)
15 (65:35)
5 (83:17)
62 (63:37)
40 (69:31)
55 (59:41)
70 (60:40)
36 (68:32)
78 (59:41)
27 (52:48)
-10
-20
-20
-20
-40
-20
-20
-20
-20
5
Mg/Ptf
Al/Pt
53
7
22
10
Al/Ptf
a
2 F/mol of 1a , undivided cells, CO2 atmosphere, galvanostatic conditions: I ) 4 mA/cm2; potentiostatic conditions: E ) -1.7 V vs
SCE. Yields of isolated products, calculated with respect to the starting oxazolidinone 1a . c The diastereoisomeric ratio was determined
b
by 1H NMR. Electrolysis carried out under nitrogen atmosphere (no CO2 added). e Electrolysis carried out under nitrogen atmosphere
d
(no CO2 added) in the presence of a proton donor (acetic acid). f Et3N was added to the solution prior to electrolysis.
carboxylated product could be evidenced (Table 1, entries
3 and 4), while in the presence of Et3N, (2a + 2′a ) were
isolated in 36% yield (Table 1, entry 5). Moreover, Evans15
reported that Et3N forms a kind of aggregated complex
with the enolate that derives from the reduction of the
C-Br bond, and so it should enhance the diastereose-
lectivity of the carboxylation reaction.
The use of DMF-TEAP as solvent-supporting electro-
lyte system led to unsatisfactory yields in carboxylated
products and high yields in hydrogenated product 3a .
To avoid the use of a solvent that acts as a proton
donor, THF was selected as solvent of electrolysis, and
tetrabutylammonium tetrafluoroborate was used as sup-
porting electrolyte (it is one of the few salts that are
soluble in this solvent). The yields of carboxylated
products increase both in the presence and in the absence
of Et3N, but the higher yields are obtained in the absence
of amine (Table 1, entries 8 and 9), while the diastereo-
meric ratio is similar. Therefore, in THF Et3N seems to
have little influence on the outcome of this carboxylation.
Operating at lower temperature does not increase the
yields in carboxylated products nor the diastereomeric
ratio (Table 1, entry 10). Only a change in the electrode
materials leads to good yields in (2a + 2′a ) reaching the
value of 78% using an aluminum sacrificial anode16 and
a platinum cathode (Table 1, entry 13). Also in this case,
the diastereomeric ratio was not different from those
obtained in the previous experiments.
To verify if the experimental conditions of entry 13
could be improved, the effects of temperature and of the
amount of electricity supplied to the electrodes were
studied (Table 2).
The yield of (2a + 2′a ) is strongly affected by the
temperature at which the electrolysis is carried out
(Table 2, entries 1-5); in particular, the choice of this
parameter seems crucial for the selectivity of the elec-
trode process. In fact, at a temperature higher of -20
°C, a considerable amount of starting bromide can be
isolated from the electrolyzed mixture, while the result
obtained at -40 °C is probably due both to a decrease in
the supporting electrolyte solubility and to a lower
conductivity of the solution (that lower the electric
current yield). It may be noted a peculiar result as a
consequence of a strong variation of the temperature (30
°C vs -40 °C; Table 2, entries 1 and 5): with respect to
(16) The anodic process involves the oxidation of the electrode
material. See: Lund, H. In Organic Electrochemistry; Lund, H.,
Hammerich, O., Eds.; Marcel Dekker, Inc.: New York, 2001; p 245.
(15) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urp´ı, F. J . Am.
Chem. Soc. 1991, 113, 1047-1049.
J . Org. Chem, Vol. 69, No. 2, 2004 489

Feroci et al.
SCHEME 4 a
TABLE 2. Effect of Tem p er a tu r e a n d Am ou n t of
Electr icity in th e Electr olyses of Solu tion s of 1a a
products (yields,%)b
entry
F/mol of 1a
T (°C)
rec. 1a
3a
2a + 2′a (dr)c
1
2
2.0
2.0
2.0
2.0
2.0
0.5
0.8
1.0
2.0
3.0
30
15
0
-20
-40
-20
-20
-20
-20
-20
55
47
27
14
35
79
72
67
14
4
34 (61:39)
52 (64:36)
63 (56:44)
78 (59:41)
34 (61:39)
17 (56:44)
26 (58:42)
32 (59:41)
78 (59:41)
88 (61:39)
3
9
7
10
4d
5
a
Key: a -e, see Table 3.
6
7
8
TABLE 3. Effect of Differ en t Su bstitu en ts (Sch em e 4)
on th e Electr och em ica l Ca r boxyla tion of 1a -ea
9d
10
7
7
products (yields,%)b
entry
R
X (1)
rec. 1
3
2 + 2′ (dr)c
δ(Me)d
a
Solutions of 1a in THF/Bu4NBF4, undivided cells, Al anode
and Pt cathode, CO2 atmosphere, galvanostatic conditions: I ) 4
1e
2
3
4
5
Me
Et
Bu
i-Pr
Ph
Br (1a )
Br (1b)
Br (1c)
Br (1d )
Cl (1e)
4
7
9
5
88 (61:39)
90 (52:48)
76 (60:40)
79 (58:42)
3.71-3.67
3.64-3.70
3.64-3.70
3.64-3.71
mA/cm2. Yields of isolated products, calculated with respect to
b
18
20
the starting oxazolidinone 1a . c The diastereoisomeric ratio was
traces
100
determined by 1H NMR. This electrolysis (the same as entry 13,
d
Table 1) was repeated here for clarity.
a
Solutions of 1a -e in THF/Bu4NBF4, undivided cells, Al anode
and Pt cathode, CO2 atmosphere, T ) -20 °C, galvanostatic
conditions: I ) 4 mA/cm2, 3 F/mol of 1a -e. Yields of isolated
b
products, calculated with respect to the starting oxazolidinone 1a -
e. c The diastereoisomeric ratio was determined by 1H NMR.
d
Chemical shifts of the hydrogen atoms of the methoxycarbonyl
group (1H NMR, ppm with respect to tetramethylsilane) of the
major and minor diastereoisomes, respectively. e This experiment
(the same of entry 10, Table 2) was repeated here for clarity.
F IGURE 1. Two possible conformations of enolate ion.
potentially chelate both oxygen atoms, but is probably
present in too low concentration relative to the non-
chelating electrolyte cation R4N+. It is also possible that
in a solvent such as THF (with low dielectric constant)
the metal cation is not free, but ion-paired with the
bromide ion released during the electrolysis.
The diastereomeric ratio was not encouraging, but as
both carboxylated diastereomers are very easy to isolate
in pure form (simple flash chromatography of the elec-
trolysis solution permits the resolution of this diastereo-
meric mixture), this methodology permits an easy access
to this methylmalonic ester derivatives in pure chiral
form.
As many alkylmalonic acid derivatives are precursors
of biologically active molecules, this reaction was carried
out (using the same experimental conditions as entry 10
in Table 2) with substrates in which the group in the
position R to the bromine atom was other than methyl
(Scheme 4).
the electrolysis carried out at 30 °C, in the electrolysis
at -40 °C the amount of consumed starting 1a increases
(65% vs 45%), but the percentage of reduced 1a converted
to carboxylated product decreases (76% vs 52%). Conse-
quently the yield of (2a + 2′a ), with respect to starting
1a , is occasionally the same (34%).
The effect of the amount of electricity supplied to the
electrodes (Table 2, entries 6-10) is consistent with a
bielectronic process in which the current yield is not
100%; increasing the number of faradays per mole of 1a ,
the yield in carboxylated products increases, but not
linearly, so the better compromise between current
efficiency and chemical yield seems to be the choice of 3
F/mol of 1a (88%; Table 2, entry 10). To have a total
consumption of starting bromide, about 6 F/mol are
necessary,17 but in this case the current efficiency is too
low and the electrolysis time quite long, rendering this
synthesis not attractive from an economic point of view.
The absolute configuration of the major diastereoiso-
mer obtained in these electrolyses was established by
X-ray analysis,1 and this compound was identified as 2a ,
3-(2′S-methoxycarbonylpropionyl)-4R-phenyl-2-oxazolidi-
none.
The results of these electrolyses are reported in Table
3.
It can be seen that this electrochemical synthesis works
well when an alkyl group is geminal to the bromine atom,
albeit with similarly modest diastereomeric ratios (76-
90% yields in carboxylated products; Table 3, entries
1-4). However, if a phenyl group is present, no carboxyl-
ated product can be detected and only the protonated
molecule can be isolated (Table 3, entry 5). This fact can
be explained with the higher stability of the enolate ion
(produced by the bielectronic cleavage of the C-Cl bond)
due to the presence of the phenyl group. However, the
hypothesis of an one-electron reduction of 1e and the
formation of 3 via the radical cannot be excluded.
This is probably due to the preferential “non-Evans”
conformation18 (that is the nonchelated one) of the enolate
ion during the carboxylation (Figure 1). The metal ion
derived from consumption of the sacrificial anode could
(17) The yields of (2 + 2′) increase on increasing the amount of
electricity supplied to the electrodes, but not in a straightforward
manner. Therefore, the current efficiency decreases on decreasing of
the concentration of 1a . In fact, the electrolyses are carried out under
galvanostatic conditions (in all the experiments I ) 4 mA/cm2), and
consequently, the cathodic reduction of the last quantity of 1a (4%) is
associated with a particularly elevated amount of electricity supplied
to the electrode (i.e., a strong decrease of the current efficiency).
(18) Yan, T.-H:; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-J . J .
Am. Chem. Soc. 1984, 106, 1154-1156.
Having obtained high yields in carboxylated products,
we tried to improve the diastereomeric ratio, varying the
substituents in the 4-position of oxazolidin-2-one (in fact,
it is known that substituents in this position of the chiral
490 J . Org. Chem., Vol. 69, No. 2, 2004

Access to Unsymmetrical Alkylmalonic Ester Derivatives
TABLE 4. Electr och em ica l Ca r boxyla tion of 1a ,f-h a
SCHEME 5 a
a
Experimental conditions: see Table 4. Recovered starting
material: 37%.
SCHEME 6 a
a
Solutions of 1a ,f-h in THF/Bu4NBF4, undivided cells, Al
anode and Pt cathode, CO2 atmosphere, T ) -20 °C, galvanostatic
conditions: I ) 4 mA/cm2, 3 F/mol of 1a ,f-h . Yields of isolated
b
a
products, calculated with respect to the starting oxazolidinone
1a ,f-h . c The diastereoisomeric ratio was determined by 1H NMR.
No correlation between NMR signals reported in the last column
and structures 2 and 2′ can be inferred, except for compounds 2a
and 2′a (confirmed by X-ray analysis). Thus, the dr reports only
the ratio between the major and the minor diastereoisomers.
Experimental conditions: see Table 4. Recovered starting
material: 19%.
d
Chemical shifts of the hydrogen atoms of the methoxycarbonyl
group (1H NMR, ppm with respect to tetramethylsilane) of the
major and minor diastereoisomers, respectively. e This experiment
(the same of entry 10, Table 2) was repeated here for clarity. f The
diastereoisomeric ratio was determined by 13C NMR.
TABLE 5. Effect of Tem p er a tu r e on th e Dia ster eom er ic
Ra tio of 2h + 2′h
T (°C)
20
71:29
0
-20
74:26
-40
72:28
dra
70:30
a
The diastereoisomeric ratio was determined by 1H NMR.
F IGURE 2. ORTEP drawing of compound 2j (major diastereo-
isomer).
auxiliary can greatly affect the outcome of the asym-
metric reaction). These results are reported in Table 4.
A higher diastereomeric ratio (ca. 3:1) was obtained
using (4R,5S)-indano[1,2-d]oxazolidin-2-one as chiral ox-
azolidinone (Table 4, entry 4), and this ratio was not af-
fected by the reaction temperature, as reported in Table
5.
SCHEME 7 a
Our last attempt to improve the diastereomeric ratio
of the two methylmalonic acid derivatives was to change
the kind of chiral auxiliary, at first taking into account
2,3-O-isopropylidene-D-ribonic γ-lactone. This electrolysis
gave very poor results both in the yields in carboxylated
products and in their diastereomeric ratio (Scheme 5).
On the other hand, when Oppolzer’s camphor sultam
was used as chiral auxiliary the best result was ob-
tained: a good yield (80%) and a very satisfactory
diastereomeric ratio of 98:2 (Scheme 6).
a
Key: j-m , see Table 6.
This high diastereoselectivity, due to the presence of
Oppolzer’s camphor sultam as chiral auxiliary, was
confirmed using different acyl groups (Scheme 7 and
Table 6):
Con clu sion s
The absolute configuration of the major diastereoiso-
mer has been established by X-ray analysis, and this com-
pound has been identified as the R-isomer (Figure 2).
Unsymmetrical alkylmalonic ester derivatives (valu-
able precursors of chiral propane-1,3-diol derivatives, of
J . Org. Chem, Vol. 69, No. 2, 2004 491

Feroci et al.
TABLE 6. Effect of Differ en t Su bstitu en ts (Sch em e 7)
3-(2-Br om op r op ion yl)-4R-p h en yl-2-oxa zolid in on e 1a
(Both Isom er s).20
on th e Electr och em ica l Ca r boxyla tion of 1j-m a
3-(2-Meth oxyca r bon ylp r op ion yl)-4R-p h en yl-2-oxa zoli-
products (yields,%)b
d in on e 2a +2′a (Both Isom er s).1
entry
R
1
rec. 1
2 + 2′ (dr)c
δ(Me)d
4R-P h en yl-3-p r op ion yl-2-oxa zolid in on e 3a .21
4R-P h en yl-2-oxa zolid in on e 4a : commercial.
1e
2
3
Me
Et
Bu
i-Pr
1j
1k
1l
19
21
25
23
80 (2:98)
77 (2:98)
71 (3:97)
70 (4:96)
3.71-3.66
3.71-3.67
3.71-3.66
3.71-3.67
3-(2-Br om ob u t a n oyl)-4R-p h en yl-2-oxa zolid in on e 1b
(Both Isom er s).1
4
1m
3-(2-Meth oxyca r bon ylbu ta n oyl)-4R-p h en yl-2-oxa zoli-
d in on e 2b + 2′b (Both Isom er s).1
a
Solutions of 1j-m in THF/Bu4NBF4, undivided cells, Al anode
and Pt cathode, CO2 atmosphere, T ) -20 °C, galvanostatic
3-Bu ta n oyl-4R-p h en yl-2-oxa zolid in on e 3b.22
b
conditions: I ) 4 mA/cm2, 3 F/mol of 1j-m . Yields of isolated
3-(2-Br om oh exa n oyl)-4R-p h en yl-2-oxa zolid in on e 1c
(less p ola r isom er ): 1H NMR δ (CDCl3) 7.38-7.24 (m, 5H),
5.62 (t, 1H, J ) 7.2 Hz), 5.42 (dd, 1H, J ) 8.8, 3.4 Hz), 4.73 (t,
1H, J ) 8.8 Hz), 4.29 (dd, 1H, J ) 8.8, 3.4 Hz), 1.99-1.92 (m,
2H), 1.62-1.29 (m, 4H), 0.80 (t, 3H, J ) 6.7 Hz); 13C NMR δ
(CDCl3): 168.6, 152.8, 138.7, 129.2, 128.9, 125.9, 70.0, 58.1,
44.1, 33.9, 29.1, 21.9, 13.7; GC-MS m/z (M+ absent), 285 (10),
283 (11), 260 (M+ - Br, 16), 162 (17), 104 (100); [R]20D ) -96.8
(c ) 0.78, AcOEt). Anal. Calcd for C15H18BrNO3: C, 52.96; H,
5.33; N, 4.12. Found: C, 53.11; H, 5.35; N, 4.17.
products, calculated with respect to the starting oxazolidinone 1j-
m . c The diastereoisomeric ratio was determined by 1H NMR.
d
Chemical shifts of the hydrogen atoms of the methoxycarbonyl
group (1H NMR, ppm with respect to tetramethylsilane) of the two
diastereoisomes reported in the dr. e This experiment (the same
of Scheme 6) was repeated here for clarity.
chiral R-alkyl-R-amino acids and of indole alkaloids) have
been obtained, under mild conditions, in good to high
yields by electrochemical reduction (under CO2 atmo-
sphere) of R-bromocarboxylic acid derivatives. The two
epimers can be easily separated by flash chromatography.
3-(2-Br om oh exa n oyl)-4R-p h en yl-2-oxa zolid in on e 1c
(m or e p ola r isom er ): 1H NMR δ (CDCl3) 7.38-7.31 (m, 5H),
5.62 (t, 1H, J ) 7.3 Hz), 5.43 (dd, 1H, J ) 8.9, 4.8 Hz), 4.70 (t,
1H, J ) 8.9 Hz), 4.24 (dd, 1H, J ) 8.9, 4.8 Hz), 2.04-1.94 (m,
2H), 1.43-1.26 (m, 4H), 0.87 (t, 3H, J ) 7.0 Hz); 13C NMR δ
(CDCl3) 168.5, 152.7, 137.7, 129.2, 128.9, 125.8, 69.9, 57.8, 43.9,
33.2, 29.4, 22.1, 13.8; GC-MS m/z (M+ absent), 285 (10), 283
The absolute configuration, obtained by X-ray analysis,
of the major diastereoisomer of 3-(2-methoxycarbonyl-
propionyl)-4R-phenyl-2-oxazolidinone has been related to
the “non-chelated conformation” of the enolate that
undergoes carboxylation.
(11), 260 (M+ - Br, 16), 162 (17), 104 (100); [R]20 ) -67.1 (c
D
) 0.80, AcOEt). Anal. Calcd for C15H18BrNO3: C, 52.96; H,
5.33; N, 4.12. Found: C, 53.06; H, 5.37; N, 4.14.
3-(2-Meth oxyca r bon ylh exa n oyl)-4R-p h en yl-2-oxa zoli-
d in on e 2c or 2′c (less p ola r isom er ): 1H NMR δ (CDCl3)
7.37-7.24 (m, 5H), 5.47 (dd, 1H, J ) 8.8, 3.9 Hz), 4.70 (t, 1H,
J ) 8.8 Hz), 4.56 (t, 1H, J ) 7.0 Hz), 4.26 (dd, 1H, J ) 8.8, 3.9
Hz), 3.70 (s, 3H), 1.86-1.82 (m, 2H), 1.23-1.16 (m, 4H), 0.78
(t, 3H, J ) 6.6 Hz); 13C NMR δ (CDCl3) 170.0, 168.7, 153.6,
138.8, 129.2, 128.8, 125.9, 70.0, 57.8, 52.4, 50.6, 29.4, 28.3, 22.3,
13.7; GC-MS m/z 288 (M+ - OCH3, 5), 263 (43), 104 (88), 69
The influence of the electrolysis conditions and of the
various chiral auxiliaries on the yields and on the
diastereoisomeric ratio has been studied. The use of
Oppolzer’s camphor sultam as chiral auxiliary allowed
the achievement of good yields in carboxylated product
(80%) and above all a very high diastereoisomeric ratio
(98:2). The major diastereoisomer was identified as the
(2R)-isomer.
(89), 55 (100); [R]20 ) -72.0 (c ) 1.01, AcOEt). Anal. Calcd
D
for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 64.07;
H, 6.67; N, 4.41.
Exp er im en ta l Section
3-(2-Meth oxyca r bon ylh exa n oyl)-4R-p h en yl-2-oxa zoli-
d in on e 2c or 2′c (m or e p ola r isom er ): 1H NMR δ (CDCl3)
7.38-7.24 (m, 5H), 5.44 (dd, 1H, J ) 8.8, 3.8 Hz), 4.70 (t, 1H,
J ) 8.8 Hz, 4.47 (dd, 1H, J ) 8.4 Hz, J ) 5.5 Hz), 4.25 (dd,
1H, J ) 8.8 Hz, J ) 3.8 Hz), 3.64 (s, 3H), 1.94-1.86 (m, 2H),
1.32-1.24 (m, 4H), 0.85 (t, 3H, J ) 6.6 Hz); 13C NMR δ (CDCl3)
169.9, 168.2, 153.6, 138.4, 129.2, 129.0, 128.7, 125.8, 70.2, 57.9,
52.2, 50.9, 29.7, 27.9, 22.5, 13.7; GC-MS m/z 288 (M+ - OCH3,
Gen er a l P r oced u r e. A solution of 3-(2-bromopropionyl)-
4R-phenyl-2-oxazolidinone 1a (1.0 mmol) in 30 mL of THF-
0.2 M Bu4NBF4 was electrolyzed (undivided cells, Pt or Pb
cathode, Al or Mg anode, at -20°C) under galvanostatic
conditions (I ) 4 mA cm-2) in the presence of carbon dioxide
(p ) 1 atm). After the consumption of 2 F/mol of 1a , the current
flow was stopped, the solvent was evaporated under reduced
pressure, and the residue was poured into water. This aqueous
phase was extracted with diethyl ether (3 × 30 mL), and this
organic solution was worked up as usual, giving the starting
material 1a , (R)-(-)-4-phenyl-3-propionyl-2-oxazolidinone 3a
and (R)-(-)-4-phenyl-2-oxazolidinone 4a , if any. The aqueous
solution was then acidified (pH 3) with dilute HCl and
extracted again with ether. This second ethereal phase was
cooled at 0 °C and treated with ethereal CH2N2.19 (CAUTION!
Diazomethane is toxic and prone to cause development of
specific sensitivity; in addition, it is potentially explosive). The
usual workup gave the mixture of 2a and 2b, whose ratio was
calculated by 1H NMR. The two pure isomers were obtained
after flash column chromatography (n-hexanes-ethyl acetate
8:2 as eluent).
5), 263 (43), 104 (88), 69 (89), 55 (100); [R]20 ) -88.0 (c )
D
0.78, AcOEt). Anal. Calcd for C17H21NO5: C, 63.94; H, 6.63;
N, 4.39. Found: C, 64.11; H, 6.71; N, 4.38.
3-Hexa n oyl-4R-p h en yl-2-oxa zolid in on e 3c: GC-MS m/z
261 (M+, 1), 218 (12), 205 (61), 162 (15), 118 (60), 104 (61), 91
(31), 43 (100).
3-(2-Br om o-3-m eth ylbu ta n oyl)-4R-p h en yl-2-oxa zolid i-
n on e 1d (Both Isom er s).1
3-(2-Meth oxyca r bon yl-3-m eth ylbu ta n oyl)-4R-p h en yl-
2-oxa zolid in on e 2d + 2′d (Both Isom er s).1
3-(3-Meth ylbu ta n oyl)-4R-p h en yl-2-oxa zolid in on e 3d .23
3-(2-Ch lor o-2-p h en yla cetyl)-4R-p h en yl-2-oxa zolid in o-
n e 1e (Both Isom er s).1
3-(2-P h en yla cetyl)-4R-p h en yl-2-oxa zolid in on e 3e.1
Sta r tin g Ma ter ia ls a n d Electr olyses P r od u cts (the
spectral data of known compounds have been compared with
those reported in the literature):
(20) Ito, Y.; Sasaki, A.; Tamoto, K.; Sunagawa, M.; Terashima, S.
Tetrahedron 1991, 47, 2801-2820.
(21) Ager, D. J .; Allen, D. R.; Schaad, D. R. Synthesis 1283-1285.
(22) Feroci, M.; Inesi, A.; Palombi, L.; Rossi, L. Sotgiu, G. J . Org.
Chem. 2001, 66 (18), 6185-6188.
(19) de Boer, T. J .; Backer, H. J . Organic Syntheses; Wiley: New
York, 1936; Collect. Vol. IV, pp 250-253.
(23) Kuznetsov, N. Yu; Khrustalev, V. N.; Terentiev, A B.; Belokon,
Yu. N. Russ. Chem. Bull. 2001, 50 (3), 548-550.
492 J . Org. Chem., Vol. 69, No. 2, 2004

Access to Unsymmetrical Alkylmalonic Ester Derivatives
3-(2-Br om op r op ion yl)-4S-ben zyl-2-oxa zolid in on e 1f.20
3-(2-Meth oxyca r bon ylp r op ion yl)-4S-ben zyl-2-oxa zoli-
d in on e 2f + 2′f (Mixtu r e of Tw o Isom er s). More abundant
4.47 (dd, AB, 1H, J AB ) 12.5 HZ, J ) 2.6 Hz, ∆ν ) 44.9 Hz),
4.32 (q, 1H, J ) 6.8 Hz), 4.24 (dd, AB, 1H, J AB ) 12.5 Hz, J )
2.6 Hz, ∆ν ) 44.9 Hz), 1.74 (d, 3H, J ) 6.8 Hz), 1.41 (s, 3H),
1.33 (s, 3H); 13C NMR δ (CDCl3) 173.2, 169.0, 113.7, 79.3, 77.5,
75.1, 64.6, 39.0, 26.6, 25.4, 21.4; GC-MS m/z (M•+ absent) 309
(M+ + 2 - CH3, 21), 307 (M+ - CH3, 23), 109 (13), 107 (14),
1
isomer: H NMR δ (CDCl3) 7.33-7.14 (m, 5H), 4.75-4.62 (m,
1H), 4.50 (q, 1H, J ) 7.2 Hz), 4.27-4.02 (m, 2H), 3.71 (s, 3H),
3.38-3.21 (m, 1H), 2.81-2.70 (m, 1H), 1.45 (d, 3H, J ) 7.2
Hz); 13C NMR δ (CDCl3) 170.8, 169.3, 153.2, 135.2, 129.3,
128.8, 127.2, 66.2, 55.3, 52.4, 45.4, 37.2, 13.1; GC-MS m/z 291
(M•+, 4), 260 (M+ - OCH3, 5), 115 (100), 91 (34), 59 (44). Less
abundant isomer: 1H NMR δ (CDCl3) 7.33-7.14 (m, 5H), 4.75-
4.62 (m, 1H), 4.54 (q, 1H, J ) 7.2 Hz), 4.27-4.02 (m, 2H), 3.68
(s, 3H), 3.38-3.21 (m, 1H), 2.81-2.70 (m, 1H), 1.46 (d, 3H, J
) 7.2 Hz); 13C NMR δ (CDCl3) 170.7, 169.6, 153.3, 134.9, 129.4,
128.8, 127.3, 66.4, 55.1, 52.4, 45.4, 37.7, 13.2; GC-MS m/z 291
(M•+, 4), 260 (M+ - OCH3, 5), 115 (100), 91 (34), 59 (44).
4S-Ben zyl-3-p r op ion yl-2-oxa zolid in on e 3f: commercial.
3-(2-Br om op r op ion yl)-4S-isop r op yl-2-oxa zolid in on e 1g
(Both Isom er s).20
3-(2-Met h oxyca r b on ylp r op ion yl)-4S-isop r op yl-2-ox-
a zolid in on e 2 g+2′g (Mixtu r e of Tw o Isom er s). More
abundant isomer: 1H NMR δ (CDCl3) 4.59-4.39 (m, 2H), 4.34-
4.10 (m, 2H), 3.69 (s, 3H), 2.52-2.30 (m, 1H), 1.42 (d, 3H, J )
7.2 Hz), 0.93 (s, 3H), 0.89 (s, 3H); 13C NMR δ (CDCl3) 170.9,
169.2, 154.0, 63.6, 58.6, 52.4, 45.5, 28.2, 17.8, 14.5, 13.1; GC-
MS m/z (M•+ absent) 212 (M+ - OCH3, 7), 200 (M+ - iPr, 4),
115 (100), 87 (21), 59 (32). Less abundant isomer:1H NMR δ
(CDCl3) 4.59-4.39 (m, 2H), 4.34-4.10 (m, 2H), 3.69 (s, 3H),
2.52-2.30 (m, 1H), 1.42 (d, 3H, J ) 7.2 Hz), 0.93 (s, 3H), 0.89
(s, 3H); 13C NMR δ (CDCl3) 170.9, 169.2, 154.0, 63.6, 58.6, 52.4,
45.5, 28.4, 17.8, 14.7, 13.4; GC-MS m/z (M•+ absent) 212 (M+
- OCH3, 6), 200 (M+ - iPr, 4), 115 (100), 87 (16), 59 (28).
4S-Isop r op yl-3-p r op ion yl-2-oxa zolid in on e 3g: commer-
cial.
43 (100); [R]20 ) -20.9 (c ) 0.52, AcOEt). Anal. Calcd for
D
C
11H15BrO6: C, 40.89; H, 4.68. Found: C, 40.93; H, 4.70.
2,3-O-Isop r op ylid en e-γ-D-r ibon ola cton e 2-br om op r o-
p ion a te 1i (less p ola r isom er ): 1H NMR δ (CDCl3) 4.91 (d,
AB, 1H, J AB ) 5.6 Hz, ∆ν ) 43.6.1 Hz), 4.69 (app d, AB, 1H,
J AB ) 5.6 Hz, ∆ν ) 43.6 Hz), 4.77 (dd, 1H, J ) 2.2, 2.2 Hz),
4.37 (d, 2H, J ) 2.2 Hz), 4.33 (q, 1H, J ) 6.8 Hz), 1.78 (d, 3H,
J ) 6.8 Hz), 1.44 (s, 3H), 1.36 (s, 3H); 13C NMR δ (CDCl3) 173.3,
169.2, 113.8, 79.4, 77.6, 75.2, 64.8, 38.8, 26.6, 25.5, 21.2; GC-
MS m/z: (M•+ absent) 309 (M+ + 2 - CH3, 54), 307 (M+
-
CH3, 63), 109 (13), 107 (14), 43 (100); [R]•+ ) -25.0 (c ) 0.83,
AcOEt). Anal. Calcd for
Found: C, 4.90; H, 4.69.
C11H15BrO6: C, 40.89; H, 4.68.
2,3-O-Isop r op ylid en e-γ-D-r ibon ola cton e 2-Meth oxyca r -
bon ylp r op ion a te 2i + 2′i (Mixtu r e of Tw o Isom er s). More
abundant isomer: 1H NMR δ (CDCl3) 4.80-4.21 (m, 5H), 3.72
(s, 3H), 3.43 (q, 1H, J ) 7.2 Hz), 1.45 (s, 3H), 1.38 (d, 3H, J )
0.2 Hz), 1.36 (s, 3H); 13C NMR δ (CDCl3) 173.4, 169.7, 168.8,
113.8, 79.5, 75.1, 64.3, 52.9, 45.9, 29.6, 26.7, 25.6, 13.6; GC-
MS m/z (M•+ absent) 287 (M+ - CH3, 23), 307 (M+ - CH3, 63),
1
213 (6), 115 (76), 59 (75), 43 (100). Less abundant isomer: H
NMR δ (CDCl3) 4.80-4.21 (m, 5H), 3.71 (s, 3H), 3.43 (q, 1H, J
) 7.2 Hz), 1.45 (s, 3H), 1.40 (d, 3H, J ) 0.2 Hz), 1.36 (s, 3H);
13C NMR δ (CDCl3) 173.3, 170.0, 169.0, 113.8, 79.4, 75.1, 64.3,
52.8, 45.7, 29.6, 26.7, 25.5, 13.4; GC-MS m/z (M•+ absent) 287
(M+ - CH3, 23), 307 (M+ - CH3, 63), 213 (6), 115 (76), 59 (75),
43 (100).
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-br om op r op ion a m id e 1j (Both Iso-
m er s).25
3-(2-Br om opr opion yl)-(4R,5S)-in dan o[1,2-d]oxazolidin -
2-on e 1h (isola ted on ly on e isom er ): 1H NMR δ (CDCl3)
7.62-7.59 (m, 1H), 7.38-7.22 (m, 3H), 5.92 (d, 1H, J ) 6.8
Hz), 5.68 (q, 1H, J ) 6.7 Hz), 5.33 (dt, 1H, J ) 6.8 Hz, J ) 3.5
Hz), 3.38 (d, 2H, J ) 3.3 Hz), 1.84 (d, 3H, J ) 6.7 Hz); 13C
NMR δ (CDCl3) 170.1, 152.1, 139.5, 138.6, 130.1, 128.3, 127.2,
125.3, 78.5, 63.7, 38.5, 37.8, 20.8; GC-MS m/z 311 (M•+ + 2,
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylp r op ion a m id e 2j′
(m or e a bu n d a n t, less p ola r isom er ): 1H NMR δ (CDCl3)
4.05 (q, 1H, J ) 7.1 Hz), 3.85 (dd, 1H, J ) 7.5, 5.1 Hz), 3.66
(s, 3H), 3.47 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 12.09 Hz), 3.41 (d,
AB, 1H, J ) 13.8 Hz, ∆ν ) 12.09 Hz), 2.12-1.79 (m, 5H), 1.40
(d, 3H, J ) 7.1 Hz), 1.38-1.25 (m, 2H), 1.35 (s, 3H), 0.93 (s,
3H); 13C NMR δ (CDCl3) 170.2, 168.0, 65.1, 52.9, 52.4, 48.5,
47.8, 45.9, 44.5, 37.8, 32.7, 26.4, 20.2, 19.9, 13.2; GC-MS m/z
(M•+ absent) 298 (M+ - OCH3, 10), 214 (14), 115 (100), 87 (40),
20
16%) 309 (M+, 17%), 230 (62%), 115 (100%). [R]D ) -206.5
(c ) 0.77, AcOEt). Anal. Calcd. for C13H12BrNO3: C, 50.34; H,
3.90; N, 4.52. Found: C, 50.51; H, 3.94; N, 4.61.
3-(2-Meth oxyca r bon ylp r op ion yl)-(4R,5S)-in d a n o[1,2-d ]-
oxa zolid in -2-on e 2h or 2′h (m or e p ola r isom er ): 1H NMR
δ (CDCl3) 7.62-7.59 (m, 1H), 7.37-7.27 (m, 3H), 5.97 (d, 1H,
J ) 6.8 Hz), 5.29 (dt, 1H, J ) 6.8, 3.4 Hz), 4.52 (q, 1H, J ) 7.2
Hz), 3.57 (s, 3H), 3.37 (d, 2H, J ) 3.4 Hz), 1.48 (d, 3H, J ) 7.2
Hz); 13C NMR δ (CDCl3) 170.6, 170.0, 152.8, 139.2, 138.6,
129.9, 128.1, 127.2, 125.1, 78.6, 63.1, 52.3, 45.3, 37.8, 13.2;
GC-MS m/z (M•+ absent) 258 (M+ - OCH3, 7), 245 (M+ - CO2,
59 (95); [R]20 ) -77.9 (c ) 0.68, AcOEt). Anal. Calcd for
D
C
15H23NO5S: C, 54.69; H, 7.04; N, 4.25. Found: C, 54.73; H,
7.10; N, 4.20.
This isomer was identified as the (2R) compound, and this
assignment is supported by an X-ray crystallographic structure
determination.
17), 174 (5), 130 (100), 115 (65); [R]20 ) -85.1 (c ) 0.47,
D
AcOEt). Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84.
Found: C, 62.41; H, 5.27; N, 4.90.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylp r op ion a m id e 2j
(less a bu n d a n t, m or e p ola r isom er in m ixtu r e w ith less
p ola r isom er ): 1H NMR δ (CDCl3) 4.07 (q, 1H, J ) 7.1 Hz),
3.92 (t, 1H, J ) 6.4 Hz), 3.71 (s, 3H), 3.50 (d, AB, 1H, J ) 13.9
Hz, ∆ν ) 8.57 Hz), 3.46 (d, AB, 1H, J ) 13.9 Hz, ∆ν ) 8.57
Hz), 2.12-1.79 (m, 5H), 1.44 (d, 3H, J ) 7.1 Hz), 1.38-1.25
(m, 2H), 1.21 (s, 3H), 0.94 (s, 3H); 13C NMR δ (CDCl3): 169.8,
169.3, 65.3, 52.9, 52.5, 48.5, 47.8, 46.2, 44.6, 38.2, 32.8, 26.4,
20.8, 19.8, 14.8; GC-MS m/z (M•+ absent) 298 (M+ - OCH3,
18), 214 (19), 115 (80), 87 (40), 59 (100).
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-br om obu tyr a m id e 1k (less p ola r
isom er ): 1H NMR δ (CDCl3) 4.74 (t, 1H, J ) 7.2 Hz), 3.91
(dd, 1H, J ) 6.9, 5.6 Hz), 3.50 (d, AB, 1H, J ) 13.8 Hz, ∆ν )
15.12 Hz), 3.43 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 15.12 Hz), 2.23-
1.88 (m, 6H), 1.45-1.23 (m, 3H), 1.17 (s, 3H), 1.00 (t, 3H, J )
3-(2-Meth oxyca r bon ylp r op ion yl)-(4R,5S)-in d a n o[1,2-d ]-
oxa zolid in -2-on e 2h or 2′h (less p ola r isom er ): 1H NMR δ
(CDCl3) 7.60-7.57 (m, 1H), 7.37-7.24 (m, 3H), 5.97 (d, 1H, J
) 6.9 Hz), 5.33 (dt, 1H, J ) 6.9, 3.1 Hz), 4.54 (q, 1H, J ) 7.2
Hz), 3.72 (s, 3H), 3.38 (d, 2H, J ) 3.1 Hz), 1.45 (d, 3H, J ) 7.2
Hz); 13C NMR δ (CDCl3): 170.9, 170.1, 153.0, 139.4, 138.9,
130.0, 128.23, 127.1, 125.2, 78.3, 63.2, 52.5, 45.3, 38.0, 13.3;
GC-MS m/z (M•+ absent) 258 (M+ - OCH3, 7), 245 (M+ - CO2,
17), 174 (5), 130 (100), 115 (65); [R]20 ) -200.0 (c ) 0.87,
D
AcOEt). Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84.
Found: C, 62.39; H, 5.31; N, 4.87.
3-P r opion yl-(4R,5S)-in dan o[1,2-d]oxazolidin -2-on e 3h .24
2,3-O-Isop r op ylid en e-γ-D-r ibon ola cton e 2-br om op r o-
p ion a te 1i (m or e p ola r isom er ): 1H NMR δ (CDCl3) 4.89
(d, AB, 1H, J AB ) 5.6 Hz, ∆ν ) 38.1 Hz), 4.69 (app. d, AB, 1H,
J AB ) 5.6 Hz, ∆ν ) 38.1 Hz), 4.75 (dd, 1H, J ) 2.5, 2.5 Hz),
(25) Csuk, R.; Schro¨der, C.; Krieger, C. Tetrahedron 1997, 53 (38),
12947-12960.
(24) Ho, G.-J .; Mathre, D. J . J . Org. Chem. 1995, 60, 2271-2273.
J . Org. Chem, Vol. 69, No. 2, 2004 493

Feroci et al.
7.2 Hz), 0.96 (s, 3H); 13C NMR δ (CDCl3) 168.3, 64.9, 53.1, 48.7,
47.9, 46.5, 44.5, 37.6, 32.7, 27.3, 26.5, 20.6, 19.9, 11.9; GC-
MS m/z (M•+ absent) 337 (3), 335 (3), 284 (M+ - Br, 10), 220
(47), 135 (82), 134 (100); [R]20D ) -64.4 (c ) 0.26, AcOEt). Anal.
Calcd for C14H22BrNO3S: C, 46.16; H, 6.09; N, 3.84. Found:
C, 46.63; H, 6.21; N, 3.92.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-br om obu tyr a m id e 1k (m or e p ola r
isom er , in m ixtu r e w ith less p ola r isom er ): 1H NMR δ
(CDCl3) 4.83 (t, 1H, J ) 7.0 Hz), 3.91 (t, 1H, J ) 6.4 Hz), 3.52
(d, AB, 1H, J ) 13.8 Hz, ∆ν ) 6.80 Hz), 3.45 (d, AB, 1H, J )
13.8 Hz, ∆ν ) 6.80 Hz), 2.23-1.88 (m, 6H), 1.45-1.23 (m, 3H),
1.11 (s, 3H), 1.00 (t, 3H, J ) 7.2 Hz), 0.96 (s, 3H); 13C NMR δ
(CDCl3) 167.8, 65.5, 52.8, 48.6, 47.7, 47.6, 44.4, 38.2, 32.6, 29.7,
26.3, 20.6, 19.8, 11.6; GC-MS m/z (M•+ absent) 337 (3), 335
(3), 284 (M+ - Br, 10), 220 (47), 135 (82), 134 (100).
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylbu tyr a m id e 2k or
2′k (m or e a bu n d a n t, less p ola r isom er ): 1H NMR δ
(CDCl3) 3.97-3.86 (m, 2H), 3.66 (s, 3H), 3.51 (d, AB, 1H, J )
13.8 Hz, ∆ν ) 11.29 Hz), 3.39 (d, AB, 1H, J ) 13.8 Hz, ∆ν )
11.29 Hz), 2.20-1.80 (m, 6H), 1.44-1.19 (m, 3H), 1.13 (s, 3H),
0.97 (t, 3H, J ) 7.3 Hz), 0.94 (s, 3H); 13C NMR δ (CDCl3) 169.5,
167.2, 65.1, 53.0, 52.3, 48.4, 47.7, 44.5, 37.8, 32.7, 26.4, 22.0,
20.1, 19.9, 11.9; GC-MS m/z (M•+ absent) 312 (M+ - OCH3,
1), 214 (2), 129 (49), 59 (100); [R]20D ) -77.4 (c ) 0.67, AcOEt).
Anal. Calcd for C16H25NO5S: C, 55.96; H, 7.34; N, 4.08.
Found: C, 56.03; H, 7.51; N, 4.16.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylbu tyr a m id e 2k or
2′k (Less Abu n d a n t, Mor e P ola r Isom er ). In all our
experiments, it has never been possible to obtain a chromato-
graphic fraction of this isomer sufficiently pure to describe its
NMR spectra. Only the signal of the methyl group of the
carboxylate moiety can be given with precision: 3.71 ppm;
GC-MS m/z (M•+ absent) 312 (M+ - OCH3, 1), 214 (2), 129
(50), 59 (100).
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-br om oh exa n a m id e 1l (less p ola r
isom er ): 1H NMR δ (CDCl3) 4.80 (t, 1H, J ) 7.2 Hz), 3.91
(dd, 1H, J ) 6.9, 5.6 Hz), 3.52 (d, AB, 1H, J ) 13.8 Hz, ∆ν )
15.34 Hz), 3.39 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 15.34 Hz), 2.16-
1.88 (m, 6H), 1.45-1.22 (m, 7H), 1.17 (s, 3H), 0.96 (s, 3H), 0.90
(t, 3H, J ) 6.8 Hz); 13C NMR δ (CDCl3) 168.3, 64.9, 53.1, 48.7,
47.9, 44.8, 44.5, 37.6, 33.5, 32.7, 29.3, 26.5, 22.1, 20.6, 19.9,
13.7; GC-MS m/z (M•+ absent) 337 (4), 335 (3), 312 (M+ - Br,
12), 248 (16), 135 (100); [R]20D ) -44.3 (c ) 0.41, AcOEt). Anal.
Calcd for C16H26BrNO3S: C, 48.98; H, 6.68; N, 3.57. Found:
C, 49.16; H, 6.41; N, 3.82.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za -tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-b r om oh exa n a m id e 1l (m or e p ola r
isom er ): 1H NMR δ (CDCl3) 4.86 (t, 1H, J ) 7.1 Hz), 3.90 (t,
1H, J ) 6.3 Hz), 3.48 (d, AB, 1H, J ) 14.9 Hz, ∆ν ) app. 0.00
Hz), 3.48 (d, AB, 1H, J ) 14.9 Hz, ∆ν ) app. 0.00 Hz), 2.13-
1.85 (m, 6H), 1.45-1.22 (m, 7H), 1.10 (s, 3H), 0.94 (s, 3H), 0.85
(t, 3H, J ) 6.7 Hz); 13C NMR δ (CDCl3) 167.1, 65.6, 52.8, 48.6,
47.8, 45.9, 44.6, 38.2, 36.0, 32.8, 29.2, 26.3, 21.8, 20.7, 19.8,
13.7; GC-MS m/z (M•+ absent) 337 (4), 335 (3), 312 (M+ - Br,
12), 248 (16), 135 (100); [R]20D ) -74.4 (c ) 0.34, AcOEt). Anal.
Calcd for C16H26BrNO3S: C, 48.98; H, 6.68; N, 3.57. Found:
C, 49.03; H, 6.71; N, 3.68.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za -tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylh exa n a m id e 2l or
2′l (m or e a bu n d a n t, less p ola r isom er ): 1H NMR δ
(CDCl3): 3.98 (dd, 1H, J ) 8.6, 5.4 Hz), 3.88 (dd, 1H, J ) 7.6,
5.0 Hz), 3.66 (s, 3H), 3.47 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 11.31
Hz), 3.42 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 11.31 Hz), 2.19-1.79
(m, 7H), 1.43-1.19 (m, 6H), 1.12 (s, 3H), 0.94 (s, 3H), 0.86 (t,
3H, J ) 6.9 Hz); 13C NMR δ (CDCl3) 169.7, 167.2, 65.1, 53.0,
52.3, 51.6, 48.4, 47.7, 44.5, 37.8, 32.7, 29.4, 28.3, 26.4, 22.4,
20.1, 19.8, 13.7; GC-MS m/z (M•+ absent) 340 (M+ - OCH3,
2), 214 (5), 157 (66), 69 (100); [R]20D ) -70.3 (c ) 0.77, AcOEt).
Anal. Calcd for C18H29NO5S: C, 58.20; H, 7.87; N, 3.77.
Found: C, 58.43; H, 7.91; N, 3.79.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon ylh exa n a m id e 2l or
2′l (Less Abu n d a n t, Mor e P ola r Isom er ). In all our experi-
ments, it has never been possible to obtain a chromatographic
fraction of this isomer sufficiently pure to describe its NMR
spectra. Only the signal of the methyl group of the carboxylate
moiety can be given with precision: 3.71 ppm; GC-MS m/z
(M•+ absent) 340 (M+ - OCH3, 1), 214 (5), 157 (67), 69 (100).
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-br om o-3-m eth ylbu tyr a m id e 1m (less
p ola r isom er ): 1H NMR δ (CDCl3) 4.54 (d, 1H, J ) 9.4 Hz),
3.91 (dd, 1H, J ) 7.2, 5.4 Hz), 3.51 (d, AB, 1H, J ) 13.7 Hz,
∆ν ) 15.35 Hz), 3.40 (d, AB, 1H, J ) 13.7 Hz, ∆ν ) 15.35 Hz),
2.41-2.26 (m, 1H), 2.07-1.87 (m, 4H), 1.44-1.22 (m, 3H), 1.16
(s, 3H), 1.13 (d, 3H, J ) 6.6 Hz), 0.99 (d, 3H, J ) 6.6 Hz), 0.94
(s, 3H); 13C NMR δ (CDCl3) 168.0, 64.9, 53.1, 52.8, 48.6, 47.8,
44.5, 37.5, 32.7, 31.4, 26.4, 20.6, 20.5, 19.8; GC-MS m/z (M•+
absent) 337 (12), 335 (13), 298 (M+ - Br, 10), 234 (28), 165
(7), 163 (8), 135 (100); [R]20 ) -65.6 (c ) 0.32, AcOEt). Anal.
D
Calcd for C15H24BrNO3S: C, 47.62; H, 6.39; N, 3.70. Found:
C, 47.77; H, 6.49; N, 3.76.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]dec-4-yl]-2-br om o-3-m eth ylbu tyr am ide 1m (m or e
p ola r isom er ): 1H NMR δ (CDCl3) 4.66 (d, 1H, J ) 7.7 Hz),
3.92 (t, 1H, J ) 6.3 Hz), 3.51 (d, AB, 1H, J ) 13.9 Hz, ∆ν )
6.63 Hz), 3.46 (d, AB, 1H, J ) 13.9 Hz, ∆ν ) 6.63 Hz), 2.28
(app sept, 1H, J ) 6.7 Hz), 2.10-1.86 (m, 4H), 1.58-1.27 (m,
3H), 1.11 (s, 3H), 1.09 (d, 3H, J ) 6.7 Hz), 1.02 (d, 3H, J ) 6.7
Hz), 0.96 (s, 3H); 13C NMR δ (CDCl3) 167.9, 65.7, 54.1, 52.9,
48.5, 47.7, 44.6, 38.3, 33.6, 32.9, 26.3, 20.7, 19.9, 19.8, 19.6;
GC-MS m/z (M•+ absent) 337 (12), 335 (13), 298 (M+ - Br,
10), 234 (28), 165 (7), 163 (8), 135 (100); [R]20 ) -71.9 (c )
D
0.31, AcOEt). Anal. Calcd for C15H24BrNO3S: C, 47.62; H, 6.39;
N, 3.70. Found: C, 47.73; H, 6.51; N, 3.74.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon yl-3-m eth ylbu tyr a -
m id e 2m or 2′m (m or e a bu n d a n t, less p ola r isom er ): 1H
NMR δ (CDCl3) 3.88 (dd, 1H, J ) 7.3, 5.3 Hz), 3.81 (d, 1H, J
) 7.6 Hz), 3.67 (s, 3H), 3.49 (d, AB, 1H, J ) 13.8 Hz, ∆ν )
10.57 Hz), 3.39 (d, AB, 1H, J ) 13.8 Hz, ∆ν ) 10.57 Hz), 2.51-
2.41 (m, 1H), 2.16-1.79 (m, 4H), 1.43-1.19 (m, 3H), 1.09 (s,
3H), 1.01 (t, 6H, J ) 6.2 Hz), 0.93 (s, 3H); 13C NMR δ (CDCl3)
168.8, 166.7, 65.2, 58.4, 53.1, 52.1, 48.4, 47.8, 44.6, 37.9, 32.8,
28.8, 26.5, 20.9, 20.2, 20.0, 19.9; GC-MS m/z (M•+ absent) 326
(M+ - OCH3, 7), 143 (100), 115 (17), 59 (65), 43 (25); [R]20
)
D
-66.2 (c ) 0.27, AcOEt). Anal. Calcd for C17H27NO5S: C, 57.12;
H, 7.61; N, 3.92. Found: C, 57.83; H, 7.84; N, 4.02.
N-[(5R)-10,10-Dim eth yl-3,3-d ioxo-3-th ia -4-a za tr icyclo-
[5.2.1.01,5]d ec-4-yl]-2-m eth oxyca r bon yl-3-m eth ylbu tyr a -
m id e 2m or 2′m (Less Abu n d a n t, Mor e P ola r Isom er in
Mixtu r e w ith Less P ola r Isom er ). In all our experiments,
it has never been possible to obtain a chromatographic fraction
of this isomer sufficiently pure to describe its NMR spectra.
Only the signal of the methyl group of the carboxylate moiety
can be given with precision: 3.71 ppm; GC-MS m/z (M•+
absent) 326 (M+ - OCH3, 5), 143 (100), 115 (16), 59 (65), 43
(24).
Ack n ow led gm en t. We thank Mr. M. Di Pilato for
his contribution to the experimental part of this work.
This work was supported by research grants from
MURST (Cofin 2002) and CNR, Roma, Italy.
Su p p or tin g In for m a tion Ava ila ble: General remarks
and proton-decoupled 13C NMR spectra of 1c, 2c, 2f,g, 1h , 2h ,
1i, 2i, 2′j, 1k , 2k , 1l, 2l, 1m , and 2m . Details of X-ray analysis
of compound 2′j. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0343836
494 J . Org. Chem., Vol. 69, No. 2, 2004