Asymmetric Michael addition of chiral lithiated sulfonates to nitroalkenes: Diastereo- and enantioselective synthesis of α,β-disubstituted γ-nitro and β-alkoxycarbonyl methyl sulfonates

Article abstract of DOI:10.1055/s-2002-34368

The diastereoselective Michael addition of lithiated enantiopure sulfonates to nitroalkenes is described. High asymmetric inductions were obtained by using 1,2:5,6-di-O-isopropylidene-α-D-allofuranose as a cheap and easily available chiral auxiliary. Race

Full text of DOI:10.1055/s-2002-34368

PAPER
1945
Asymmetric Michael Addition of Chiral Lithiated Sulfonates to Nitroalkenes:
Diastereo- and Enantioselective Synthesis of , -Disubstituted -Nitro and
-Alkoxycarbonyl Methyl Sulfonates
A
symmetric Micha
i
el
A
dd
e
itionof Ch
t
iral
L
it
e
hiatedSulf
o
r
nates to
N
itr
o
E
s
nders,*a Otto Mathias Berner,b Nicola Vignola,a Wacharee Harnyinga
a
Institut für Organische Chemie, Rheinisch–Westfälische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
b
Kemira Fine Chemicals Oy, P.O. Box 44, 02271 Espoo, Finland
Fax +358(10)862 2000; E-mail: mathias.berner@kemira.com
Received 15 July 2002
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday.
propriate changes to the cleavage conditions.
Abstract: The diastereoselective Michael addition of lithiated
enantiopure sulfonates to nitroalkenes is described. High asymmet-
ric inductions were obtained by using 1,2:5,6-di-O-isopropylidene-
-D-allofuranose as a cheap and easily available chiral auxiliary.
Racemization-free cleavage of the auxiliary led to , -disubstituted
-nitro methyl sulfonates. A change of the cleavage conditions re-
sulted in , -disubstituted -alkoxycarbonyl sulfonates via the
Meyer reaction (de 98%, ee 98%).
According to our first report on the diastereoselective -
alkylation of chiral lithiated sulfonates using 1,2:5,6-di-
O-isopropylidene- -D-allofuranose as a removable alco-
hol auxiliary,12 we have extended our methodology using
aliphatic nitroalkenes as further electrophiles. The aim of
our project was the asymmetric synthesis of functional-
ized sulfonic acid derivatives with the simultaneous gen-
eration of an additional stereogenic centre as well as
introducing the versatile nitro group into the molecule cre-
ating bifunctional building blocks. The chiral substrates
1a and 1b13 (Figure 1) for the Michael additions were ob-
tained by the reaction of the chiral auxiliary with benzylic
sulfonyl chlorides, which are commercially available or
prepared according to known procedures14 starting from
the corresponding sodium sulfonates.15
Key words: Michael additions, nitroalkenes, sulfonates, chiral aux-
iliaries, carbohydrates, Meyer reaction
Primary nitro compounds are known as very potent inter-
mediates and consequently have been extensively used in
organic synthesis.1 In recent years, a great variety of
asymmetric Michael additions have been developed,2 in-
cluding nitroalkenes as excellent acceptors,3 which are
easily obtained via the Henry reaction4 and subsequent de-
hydration. In addition to being very reactive, the nitro
group can be converted into a broad range of functional-
ities.5 The conversion to aldehydes by Nef reaction6 or the
reduction to the amine7 can be viewed as the most useful
transformations of primary nitro compounds. Also of im-
portance is the Meyer reaction8 where primary nitro com-
pounds are treated with hot concentrated mineral acids to
give a carboxylic acid and hydroxylamine. Recently, an
efficient procedure for the oxidation of primary nitro com-
pounds to carboxylic acids was reported using sodium ni-
trite and acetic acid in DMSO.9
O
H3C
O
H3C
O
O
CH3
CH3
O
O
R1
O
S
O
1a (R1 = H)
1b (R1 = t-Bu)
Figure 1
The enantiopure sulfonates 1a and 1b were metallated
with exactly one equivalent of n-butyllithium in tetrahy-
drofuran and allowed to react with aliphatic nitroalkenes
at 90 °C to –95 °C without any side reactions. The
Michael adducts 2a–e were obtained in very good to ex-
cellent yields (84–99%) and high diastereoselectivities
(ds 80–88%, Scheme 1, Table 1).
Although several reports of enantioselective Michael
additions to nitroalkenes do exist,10 no asymmetric 1,4-
additions of metalated sulfonates bearing a chiral aux-
iliary have been described so far. Recently, we have de-
veloped an asymmetric synthesis of homotaurine
precursors via diastereoselective Michael addition of
lithiated chiral sulfonates to nitroalkenes.11 We now
wish to report in detail on the 1,4-additions to nitroal-
kenes and describe the extension of this methodology
to obtain a carboxylic acid moiety by making the ap-
Deprotonation at –78 °C resulted in lower yields mainly
caused by the attack of n-butyllithium on the sulfonate
moiety.
In all cases only three of the possible four diastereomers
could be detected. In the case of 2a, for example, a ratio
of 88:8:4 was obtained. In most cases purification via pre-
parative HPLC or recrystallization provided the 1,4-ad-
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,1945,1952,ftx,en;C04302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1946
D. Enders et al.
PAPER
1) n-BuLi, THF, −(90–95)°C
SO3R*
NO2
–(90–95)°C
2)
R2
NO2
SO3R*
R2
84–99%
R1
R1
1a (R1 = H)
1b (R1 = t-Bu)
(R,R)-2a-e
ds = 80-88% (84 - ≥ 99%)a
O
O
H3C
H3C
O
O
CH3
CH3
R* =
O
a After HPLC or recrystallization
Scheme 1 Asymmetric Michael addition of sulfonates 1 to nitroal-
kenes to afford the 1,4-adducts (R,R)-2
Figure 2 X-ray crystal structure of 2c
Table 1 Asymmetric Michael Addition of Sulfonates 1 to Nitroalk-
enes to Afford the 1,4-Adducts (R,R)-2
more accessible form, the sulfonic acids were directly
converted with diazomethane to the corresponding , -
disubstituted -nitro methyl sulfonates (Scheme 2). In
contrast to the non-functionalized alkylation products,
special reaction conditions had to be investigated to obtain
high yields. The reaction time had to be minimized in or-
der to suppress a possible Meyer reaction, which may be
caused by the liberated sulfonic acid converting the pri-
mary nitro group into a carboxylic acid (vide infra). The
yields could be significantly increased if additional water
was added to the reaction in order to slow the Meyer reac-
tion. In analogy, it has been reported that additional water
slows the related Nef-reaction.16 This reduction of the side
reactions allowed an increase of reaction time, which re-
sulted in higher yields. In general, the reaction mixture
was refluxed until the solution became yellow (approxi-
mately 24 h) which was taken as an indication of side
products. Thus, the -nitro methyl sulfonates, which are
precursors of pharmacologically interesting homotaurine
derivatives,17 were obtained in moderate to good yields
and as virtually pure stereoisomers (Table 2).
Product R1 R2
Yield dra
(%)
ds (%)
[ ]D
r.t.
(c, CHCl3)
(R,R)-2a
(R,R)-2b
(R,R)-2c
(R,R)-2d
H
H
H
H
Et
88
90
84
4:8:88b 88 ( 99)a,b +86.2
(0.98)
n-Pr
i-Pr
5:9:86b 86 ( 99)a,b +81.2
(0.82)
4:10:86c 86 ( 99)c,d +101.0
(1.15)
Ph(CH2)2 99
5:15:80 80 (84)a,c
(84:16)c
+75.0
(1.10)
(R,R)-2e t-Bu Et
91
87:10:3c 87 ( 98)a,c +80.7
(0.94)
a In brackets after HPLC.
b Determined by HPLC using a chiral stationary phase (Daicel AD, n-
heptane–i-propanol, 95:5).
c Determined by 13C NMR.
d In brackets after recrystallization.
ducts with high diastereomeric purity. In the case of
compound 2d, preparative HPLC purification resulted in
a mixture of the two major diastereomers in a ratio of
84:16.
The absolute configuration of the newly formed stereo-
genic centers was determined to be R,R by X-ray crystal
structure analysis in the case of product 2c and shows that
the protons at the - and -position of the major dia-
stereomer are anti to each other (Figure 2).11
By assuming a uniform reaction mechanism, all examples
described should possess the same configuration. Further
evidence is obtained for this assumption by the fact that
the related electrophilic substitution under -alkylation
shows the same relative topicity.12
Originally, the removal of the chiral auxiliary to form the
corresponding sulfonic acids was achieved by refluxing
the Michael adducts in 98% EtOH containing a catalytic
amount of Pd(OAc)2. To isolate the final products in a
Scheme 2 Removal of the chiral auxiliary to form the methyl sulfo-
nates (R,R)-4
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Michael Addition of Chiral Lithiated Sulfonates to Nitroalkenes
1947
Table 2 Removal of the Chiral Auxiliary to Form the -Nitro
Methyl Sulfonates (R,R)-4
SO3R*
Pd(OAc)2 (20 mol%),
R2OH (98%),
NO2
r.t.
Product
R1
R2
Yield de
(%)
ee
[ ]D
R1
reflux, 7 d
(%)a
(%)b
(c, CHCl3)
SO3H
(R,R)-2a-c
ds ≥ 99%
CO2R2
(R,R)-4a
(R,R)-4b
(R,R)-4c
(R,R)-4d
H
H
H
H
Et
71
98
98
98
98
98
98
+33.1 (0.72)
+25.3 (1.15)
+49.6 (0.73)
+24.4 (0.62)
+27.6 (0.81)
R1
n-Pr
i-Pr
70
CH2N2,
Et2O
SO3CH3
49
5
84–95%
CO2R2
Ph(CH2)2 76
63
68 (93)c 98
98 96
R1
(R,R)-4e t-Bu Et
(R,R)-6a-d
a Measured by 1H NMR and 13C NMR.
de ≥ 98%, ee ≥ 98%
b Based on the de values of the Michael adducts 2a–e.
c In brackets after recrystallization.
Scheme 3 Removal of the chiral auxiliary to form the diesters
(R,R)-6
Confirmation that the cleavage of the auxiliary occured
without epimerization at the -position of the sulfonyl
group was obtained after the cleavage of compound 2d,
which consists of only the two major diastereomers in a
ratio of 84:16 (Table 1). After treatment with Pd(OAc)2
and diazomethane the ratio of the resulting diastereomers
of the methyl sulfonate remained the same. This result
also proves that the two major diastereomers of the
Michael addition are in an anti and syn relation to each
other. The diastereomeric ratio could be easily increased
to 97:3 via recrystallization from a diethyl ether–pentane
mixture.
Table 3 Removal of the Chiral Auxiliary and Meyer Reaction to
Form the -Alkoxycarbonyl Methyl Sulfonates (R,R)-6
Product
R1
R2
Yield de
(%)
ee
[ ]D
r.t.
(%)a
(%)b (c, CHCl3)
98 +17.5 (1.08)
98c + 6.0 (1.00)
(R,R)-6a
(R,R)-6b
(R,R)-6c
(R,R)-6d
Et
Et
Et
Et
94
98
98
98
98
n-Pr
i-Pr
i-Pr
84
87
98
98
+14.7 (1.01)
+12.6 (1.04)
i-Pr 95
a Measured by 1H NMR and 13C NMR.
b Based on the de values of the Michael adducts 2a–c.
We were interested in converting the nitro group into a
carboxylic acid derivative via the Meyer reaction in order
to demonstrate the versatility of the nitro group to obtain
another useful bifunctional building block. Our prelimi-
nary results of the cleavage of the auxiliary showed that an
increase of reaction time increased also the amount of the
Meyer product. Thus, compounds 2a–c were refluxed in
an ethanolic solution containing Pd(OAc)2 for 7 days, and
after normal work-up procedure with diazomethane the
diesters 6a–c were obtained in high yield. The initially
formed Meyer product may be converted in the ethanolic
solution to the corresponding ethyl ester whereas the dia-
zomethane treatment provides the methyl sulfonate. By
changing the solvent to isopropanol the corresponding
isopropyl ester 6d was obtained in excellent yield
(Scheme 3, Table 3).
c Determined by HPLC using a chiral stationary phase (Daicel OD, n-
heptane–i-PrOH, 98:2).
tered which may be difficult to reach via a different
synthetic route. Those compounds bearing the same di-
ester fragment like 6 are found, for example, in the synthe-
sis of side-chain-modified sulfonic analogues of aspartic
acids18 or as products after the ozonolysis and oxidative
workup of curacin A.19
In conlusion, we have developed a very efficient asym-
metric synthesis of , -disubstituted γ-nitro methyl sul-
fonates leading to excellent de- and ee-values. By making
appropriate changes to the cleavage conditions the corre-
sponding -sulfonato carboxylic acid esters 6a–d were
obtained with high diastereomeric and enantiomeric ex-
cesses demonstrating the versatility of this methodology.
Furthermore, additional transformations of the nitro group
can be envisioned thus providing an array of useful bi-
functional building blocks.
To confirm that the cleavage of the auxiliary occurs with-
out racemization at the -position of either the sulfonyl or
the newly formed ester group, compound 2b was prepared
at 0 °C to obtain a mixture of all diastereomers. Removal
of the auxiliary, under the Meyer conditions, yielded 6b as
a mixture of stereoisomers. By comparison of the analyti-
cal HPLC data of the induced sample (R,R)-6b with the
isomeric mixture of 6b none of the other possible stereo-
isomers could be detected. This also proves that the reac-
tion occurs without racemization and hence we can
assume that the relative configuration of the stereogenic
centres is analogous to the nitro counterparts 4a–e. Thus,
by making a seemingly small change in the cleavage con-
ditions a new bifunctional class of compounds can be en-
All moisture-sensitive reactions were carried out by using standard
Schlenk techniques unless stated otherwise. Solvents were dried
and purified by conventional methods prior to use. THF was freshly
distilled from sodium–lead alloy under argon. Reagents of commer-
cial quality were used from freshly opened containers or purified by
common methods. BuLi (1.6 M in hexane) was purchased from
Merck, Darmstadt. Preparative column chromatography used
Merck silica gel 60, particle size 0.040–0.063 mm (230–240 mesh,
flash). Analytical TLC used silica gel 60 F254 plates from Merck,
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

1948
D. Enders et al.
PAPER
Darmstadt. Optical rotation values were measured on a Perkin–
Elmer P241 polarimeter. Microanalyses were obtained with a Vario
EL element analyzer. Mass spectra were acquired on a Finnigan
SSQ7000 (CI 100 eV; EI 70 eV) spectrometer. High resolution
mass spectra were recorded on a Finnigan MAT95 spectrometer. IR
spectra were taken on a Perkin–Elmer FT/IR 1760. 1H and 13C NMR
spectra were recorded on Gemini 300 or Varian Inova 400 and all
measurements were performed with tetramethylsilane as internal
standard. Melting points were determined on a Tottoli melting point
apparatus and are uncorrected.
1H NMR (400 MHz, CDCl3): = 0.89 (t, 3 H, J = 7.4 Hz, CH2CH3),
1.15–1.27 (m, 1 H, CHHCH3), 1.31 [s, 3 H, (O)2C(CH3)2], 1.36 [s,
3 H, (O)2C(CH3)2], 1.46 [s, 3 H, (O)2C(CH3)2], 1.56 [s, 3 H,
(O)2C(CH3)2], 1.65–176 (m, 1 H, CHHCH3), 3.14–3.24 (m, 1 H,
CHCH2NO2), 3.85 (dd, 1 H, J = 6.0, 8.5 Hz, CHHOC), 4.04 (dd, 1
H, J = 6.8, 8.5 Hz, CHHOC), 4.09 [dd, 1 H, J = 4.3, 8.7 Hz,
CH(OC)CH(OC)CH2O], 4.14 [t,
1
H, J = 4.1 Hz,
CH(OC)CH(OC)2], 4.27 [dt, 1 H, J = 4.1, 6.6 Hz, CH(OC)CH2O],
4.66 (d, 1 H, J = 8.5 Hz, CHSO3), 4.69 (dd, 1 H, J = 4.7, 8.5 Hz,
CHOSO2), 4.72 (dd, 1 H, J = 6.0, 13.7 Hz, CHHNO2), 4.78 (dd, 1
H, J = 6.6, 13.7 Hz, CHHNO2), 5.67 [d, 1 H, J = 3.6 Hz, CH(OC)2],
7.39–7.45 (m, 3 H, ArH), 7.46–7.50 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): = 9.7 (CH2CH3), 21.1 (CH2CH3),
25.1, 26.1, 26.5, 26.6 [(O)2C(CH3)2], 39.8 (CHCH2NO2), 65.2
(CH2OC), 68.6 (CHSO3), 74.5 [CH(OC)CH2O], 74.8 (CH2NO2),
76.7 [CH(OC)CH(OC)CH2O], 77.3 [CH(OC)CH(OC)2], 77.7
(CHOSO2), 103.4 [CH(OC)2], 110.0 [(O)2C(CH3)2], 113.6
[(O)2C(CH3)2], 128.9, 129.4, 129.9 (ArCH), 130.3 (ArC).
Michael Adducts (R,R)-2a–e; General Procedure 1 (GP 1)
The enantiopure sulfonate 1 (1.0 equiv) was dissolved in anhyd
THF (20 mL per mmol sulfonate). The solution was cooled to be-
tween –95 and –90°C. After 30 min BuLi (1.0 equiv) was added
dropwise. The solution was stirred for an additional 1 h, after which
the nitroalkene (1.5 equiv) was added dropwise over a period of
30 min. The mixture was allowed to stir at –95 °C to –90 °C for 1–
3 h. The reaction was quenched by adding pH 7 buffer (2 mL per
mmol sulfonate). The mixture was partitioned between CH2Cl2 and
H2O. The aq layer was extracted with CH2Cl2 until TLC control of
the extract indicated no presence of product. The combined organic
layers were dried (MgSO4), filtered and concentrated under reduced
pressure. The crude product was purified by flash column chroma-
tography (SiO2; Et2O–n-pentane) to give the product mixture.
MS (CI, 100 eV, isobutane): m/z (%) = 518 (11) [M+ + 3], 517 (26)
[M+ + 2], 516 (100) [M+ + 1], 500 (8), 458 (7), 192 (9).
Anal. Calcd for C23H33NO10S (515.57): C, 53.58; H, 6.45; N, 2.72.
Found: C, 53.39; H, 6.43; N, 2.55.
(R,R)-2-Nitromethyl-1-phenylpentane-1-sulfonic Acid Ester
[(R,R)-2b]
Removal of the Chiral Auxiliary to Give the , -Disubstituted
-Nitro Methyl Sulfonates (R,R)-4a–e; General Procedure 2
(GP2)
According to GP1 the sulfonate 1a (474.3 mg, 1.14 mmol) was
deprotonated with BuLi (0.72 mL, 1.6 M) and allowed to react with
(E)-nitropent-1-ene (201.0 mg, 1.75 mmol in 1.5 mL THF) for 2 h.
Work-up and flash chromatography (Et2O–n-pentane, 1:3–1:1)
gave (R,R)-2b.
The Michael adduct 2 was dissolved in a solution of EtOH–H2O
(20:2 mL per 0.7 mmol). To the solution was added Pd(OAc)2 (20
mol%) and the mixture was refluxed until the solution became yel-
low (in general approximately 24 h, TLC control). The palladium
residues were removed by filtration and the filter cake was washed
twice with EtOH. The filtrate was treated with an ethereal solution
of diazomethane until the yellow color persisted. The solvent was
evaporated under reduced pressure and the crude product was puri-
fied by flash column chromatography (SiO2; Et2O–n-pentane).
Yield: 547.8 mg (90%); colorless foam; dr 5:9:86, ds 86% (HPLC).
The major diastereomer was separated by preparative HPLC; ds
99% (HPLC); [ ]Dr.t. +81.2 (c 0.82, CHCl3).
IR (KBr): 2989 (vs), 2938 (s), 2877 (s), 1555 (vs), 1498 (m), 1457
(s), 1436 (m), 1375 (vs), 1218 (vs), 1169 (vs), 1120 (s), 1019 (vs),
931 (m), 874 (vs), 847 (vs), 821 (s), 743 (m), 702 (vs), 600 (s), 515
(s) cm–1.
Removal of the Chiral Auxiliary to Give the , -Disubstituted
-Alkoxycarbonyl Methyl Sulfonates (R,R)-6a–d; General Pro-
cedure 3 (GP3)
1H NMR (400 MHz, CDCl3): = 0.83 (t, 3 H, J = 7.2 Hz, CH2CH3),
1.10–1.35 (m, 3 H, CHHCH2CH3), 1.30 [s, 3 H, (O)2C(CH3)2], 1.36
[s, 3 H, (O)2C(CH3)2], 1.46 [s, 3 H, (O)2C(CH3)2], 1.55 [s, 3 H,
(O)2C(CH3)2], 1.60–1.71 (m, 1 H, CHHCH2CH3), 3.17–3.27 (m, 1
H, CHCH2NO2), 3.84 (dd, 1 H, J = 6.4, 8.6 Hz, CHHOC), 4.03 (dd,
1 H, J = 6.9, 8.5 Hz, CHHOC), 4.08 [dd, 1 H, J = 4.1, 8.8 Hz,
The Michael adduct 2 (1 mmol) was dissolved in EtOH (30 mL). To
the solution was added Pd(OAc)2 (20 mol%) and the mixture was
refluxed for 7 days. The palladium residues were removed by filtra-
tion and the filter cake was washed twice with EtOH. The filtrate
was treated with an ethereal solution of diazomethane until the yel-
low color persisted. The solvent was evaporated under reduced
pressure and the crude product was purified by flash column chro-
matography (SiO2; Et2O–n-pentane).
CH(OC)CH(OC)CH2O], 4.10 [t,
1
H, J = 4.2 Hz,
CH(OC)CH(OC)2], 4.27 [dt, 1 H, J = 4.1, 6.6 Hz, CH(OC)CH2O],
4.60 (dd, 1 H, J = 6.6, 13.7 Hz, CHHNO2), 4.68 (dd, 1 H, J = 4.7,
8.8 Hz, CHOSO2), 4.69 (d, 1 H, J = 7.7 Hz, CHSO3), 4.74 (dd, 1 H,
J = 5.8, 13.7 Hz, CHHNO2), 5.66 [d, 1 H, J = 3.8 Hz, CH(OC)2],
7.39–7.46 (m, 3 H, ArH), 7.46–7.51 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): = 13.8 (CH2CH3), 18.9 (CH2CH3),
25.1, 26.2, 26.5, 26.6 [(O)2C(CH3)2], 30.1 (CH2CH2CH3), 38.6
(R,R)-2-Nitromethyl-1-phenylbutane-1-sulfonic Acid Ester
[(R,R)-2a]
According to GP1 the sulfonate 1a (433.1 mg, 1.04 mmol) was
deprotonated with BuLi (0.66 mL, 1.6 M) and allowed to react with
(E)-1-nitrobut-1-ene [180.0 mg, 1.78 mmol in THF (2.0 mL)] for
3 h. Work-up and flash chromatography (Et2O–n-pentane, 1:3–1:1)
gave (R,R)-2a.
(CHCH2NO2),
65.3
(CH2OC),
68.8
(CHSO3),
74.5
[CH(OC)CH2O], 75.3 (CH2NO2), 76.8 [CH(OC)CH(OC)CH2O],
77.4 [CH(OC)CH(OC)2], 77.8 (CHOSO2), 103.5 [CH(OC)2], 110.1
[(O)2C(CH3)2], 113.7 [(O)2C(CH3)2], 129.1, 129.6, 130.2 (ArCH),
130.4 (ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 531 (24) [M+ + 2] 530 (100)
[M+ + 1], 472 (8), 261 (16), 259 (6), 207 (8), 206 (43), 203 (35), 185
(5), 177 (9), 159 (7).
Yield: 474.8 mg (88%); colorless foam; dr 4:8:88, ds 88% (HPLC).
The major diastereomer was separated by preparative HPLC;
ds 99% (HPLC); [ ]Dr.t. +86.2 (c 0.98, CHCl3).
IR (KBr): 2980 (vs), 2937 (s), 2883 (s), 1555 (vs), 1496 (w), 1456
(s), 1437 (m), 1374 (vs), 1319 (m), 1256 (s), 1217 (vs), 1168 (vs),
1118 (vs), 1070 (vs), 1019 (vs), 932 (m), 874 (vs), 847 (s), 773 (w),
739 (w), 702 (s), 625 (m), 598 (m), 518 (m) cm–1.
Anal. Calcd for C24H35NO10S (529.60): C, 54.43; H, 6.66; N, 2.64.
Found: C, 54.31; H, 7.00; N, 2.56.
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Michael Addition of Chiral Lithiated Sulfonates to Nitroalkenes
1949
(R,R)-3-Methyl-2-nitromethyl-1-phenylbutane-1-sulfonic Acid
Ester [(R,R)-2c]
Hz, CHHNO2), 5.67 [d, 1 H, J = 3.5 Hz, CH(OC)2], 6.96–7.02 (m,
2 H, arom. CH), 7.14–7.30 (m, 3 H, ArH), 7.38–7.48 (m, 5 H, ArH).
According to GP1 the sulfonate 1a (478.0 mg, 1.15 mmol) was
deprotonated with BuLi (0.73 mL, 1.6 M) and allowed to react with
(E)-3-methyl-1-nitrobut-1-ene [224.0 mg, 1.95 mmol in THF
(2.0 mL)] for 1 h. Work-up and flash chromatography (Et2O–n-pen-
tane, 1:4–1:1) gave (R,R)-2c.
13C NMR (75 MHz, CDCl3, major diastereomer): = 25.4, 26.4,
26.8, 26.9 [(O)2C(CH3)2], 30.3 (ArCH2CH2), 32.3 (ArCH2CH2),
38.5 (CHCH2NO2), 65.6 (CH2OC), 69.0 (CHSO3) 74.8
[CH(OC)CH2O], 75.5 (CH2NO2), 77.1 [CH(OC)CH(OC)CH2O],
77.7 [CH(OC)CH(OC)2], 78.0 (CHOSO2), 103.8 [CH(OC)2], 110.5
[(O)2C(CH3)2], 114.0 [(O)2C(CH3)2], 126.7, 128.5, 128.9, 129.5,
130.0, 130.5 (ArCH), 130.6, 140.2 (ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 594 (2) [M+ + 3], 593 (4)
[M+ + 2] 592 (20) [M+ + 1], 261 (18), 259 (9), 243 (9), 237 (7), 203
(100),185 (6).
Yield: 511.4 mg (84%); colorless solid; mp 128 °C; dr 4:10:86,
ds 86% (1H NMR, 13C NMR). The major diastereomer was separat-
ed by recrystallization from Et2O–n-pentane 1:1; ds 99% (13C
NMR); [ ]Dr.t. +101.0 (c 1.15, CHCl3).
IR (KBr): 2981 (s), 2938 (m), 2915 (m), 1562 (vs), 1497 (w), 1457
(m), 1430 (w), 1385 (vs), 1369 (vs), 1340 (m), 1260 (s), 1221 (vs),
1177 (vs), 1166 (vs), 1125 (s), 1102 (m), 1047 (vs), 1034 (vs), 1017
(vs), 938 (w), 884 (vs), 856 (s), 835 (s), 790 (w), 709 (s), 650 (w),
588 (vs), 598 (m), 521 (m), 508 (m) cm–1.
1H NMR (400 MHz, CDCl3): = 0.66 [d, 3 H, J = 6.8 Hz,
CH(CH3)2], 0.95 [d, 3 H, J = 7.1 Hz, CH(CH3)2], 1.34 [s, 3 H,
(O)2C(CH3)2], 1.36 [s, 3 H, (O)2C(CH3)2], 1.44 [s, 3 H,
(O)2C(CH3)2], 1.59 [s, 3 H, (O)2C(CH3)2], 1.80 [dsept, 1 H, J = 3.0,
6.9 Hz, CH(CH3)2], 3.35–3.42 (m, 1 H, CHCH2NO2), 3.84 (dd, 1 H,
J = 6.3, 8.5 Hz, CHHOC), 4.04 (dd, 1 H, J = 6.9, 8.8 Hz, CHHOC),
4.13 [dd, 1 H, J = 3.8, 8.8 Hz, CH(OC)CH(OC)CH2O], 4.26–4.32
[m, 2 H, CH(OC)CH(OC)2, CH(OC)CH2O], 4.51 (d, 1 H, J = 10.2
Hz, CHSO3), 4.59 (dd, 1 H, J = 5.5, 14.9 Hz, CHHNO2), 4.70 (dd,
1 H, J = 4.6, 8.8 Hz, CHOSO2), 5.11 (dd, 1 H, J = 4.9, 14.8 Hz,
CHHNO2), 5.72 [d, 1 H, J = 3.9 Hz, CH(OC)2], 7.41–7.45 (m, 3 H,
ArH), 7.48–7.51 (m, 2 H, ArH).
Anal. Calcd for C29H37NO10S (591.67): C, 58.87; H, 6.30; N, 2.37.
Found: C, 58.86; H, 6.14; N, 2.14.
(R,R)-1-(4-tert-Butylphenyl)-2-nitromethylbutane-1-sulfonic
Acid Ester [(R,R)-2e]
According to GP1 the sulfonate 1b (489.7 mg, 1.04 mmol) was
deprotonated with BuLi (0.66 mL, 1.6 M) and allowed to react with
(E)-1-nitrobut-1-ene [160.0 mg, 1.58 mmol in THF (1.5 mL)] for 1
h. Work-up and flash chromatography (Et2O–n-pentane, 1:3–1:1)
gave (R,R)-2e.
Yield: 543.7 mg (91%); colorless foam; dr 3:10:87, ds 87% (1H
NMR, 13C NMR). The major diastereomer was separated by prepar-
ative HPLC; ds 98% (1H NMR, 13C NMR); [ ]Dr.t. +80.7 (c 0.94,
CHCl3).
IR (KBr): 2967 (s), 1655 (w), 1617 (w), 1556 (vs), 1511 (w), 1465
(m), 1437 (w), 1375 (vs), 1218 (s), 1169 (vs), 1117 (s), 1020 (vs),
933 (w), 875 (s), 843 (s), 792 (m), 646 (w), 610 (s), 544 (w), 509
(w) cm–1.
1H NMR (400 MHz, CDCl3): = 0.90 (t, 3 H, J = 7.4 Hz, CH2CH3),
1.15–1.27 (m, 1 H, CHHCH3), 1.31 [s, 3 H, (O)2C(CH3)2], 1.32 [s,
9 H, (CH3)3C], 1.36 [s, 3 H, (O)2C(CH3)2], 1.46 [s, 3 H,
(O)2C(CH3)2], 1.56 [s, 3 H, (O)2C(CH3)2], 1.70–1.81 (m, 1 H,
CHHCH3), 3.13–3.22 (m, 1 H, CHCH2NO2), 3.86 (dd, 1 H, J = 6.3,
8.7 Hz, CHHOC), 3.99 [t, 1 H, J = 4.4 Hz, CH(OC)CH(OC)2], 4.04
(dd, 1 H, J = 6.8, 8.6 Hz, CHHOC), 4.08 [dd, 1 H, J = 4.4, 8.8 Hz,
13C NMR (100 MHz, CDCl3):
= 16.0 [CH(CH3)2], 20.5
[CH(CH3)2], 25.2, 26.1, 26.5, 26.6 [(O)2C(CH3)2], 28.0
[CH(CH3)2], 43.1 (CHCH2NO2), 65.1 (CH2OC ), 69.7 (CHSO3),
73.1
(CH2NO2),
74.3
77.3
[CH(OC)CH2O],
[CH(OC)CH(OC)2],
76.6
77.6
[CH(OC)CH(OC)CH2O],
(CHOSO2), 103.5 [CH(OC)2], 110.0, 113.5 [(O)2C(CH3)2], 129.0,
129.4, 129.7 (ArCH), 131.3 (ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 532 (10) [M+ + 3], 531 (27)
[M+ + 2] 530 (100) [M+ + 1], 472 (6), 261 (14), 206 (10), 203 (25).
Anal. Calcd for C24H35NO10S (529.60): C, 54.43; H, 6.66; N, 2.64.
Found: C, 54.44; H, 6.74; N, 2.57.
CH(OC)CH(OC)CH2O], 4.27 [dt, 1 H, J = 4.1, 6.3 Hz,
CH(OC)CH2O], 4.63 (d, 1 H, J = 8.2 Hz, CHSO3), 4.65 (dd, 1 H,
J = 4.7, 8.8 Hz, CHOSO2), 4.67 (dd, 1 H, J = 6.3, 13.5 Hz,
CHHNO2), 4.75 (dd, 1 H, J = 6.4, 13.8 Hz, CHHNO2), 5.64 [d, 1 H,
J = 3.5 Hz, CH(OC)2], 7.37–7.44 (m, 4 H, ArH).
(R,R)-2-Nitromethyl-1,4-diphenylbutane-1-sulfonic Acid Ester
[(R,R)-2d]
According to GP1 the sulfonate 1a (415.6 mg, 1.00 mmol) was
deprotonated with BuLi (0.63 mL, 1.6 M) and allowed to react with
(E)-(4-nitrobut-3-enyl)benzene [230 mg, 1.30 mmol in THF
(1.5 mL)] for 1.5 h. Work-up and flash chromatography (Et2O–n-
pentane, 1:3–1:1) gave (R,R)-2d.
Yield: 587.0 mg (99%); colorless foam; dr 5:15:80, ds 80% (1H
NMR, 13C NMR); dr 16:84, ds 84% (after preparative HPLC, 13C
NMR, 1H NMR); [ ]Dr.t. +75.0 (c 1.10, CHCl3).
13C NMR (75 MHz, CHCl3): = 9.9 (CH2CH3), 21.0 (CH2CH3),
25.2, 26.2, 26.5, 26.6 [(O)2C(CH3)2], 31.2 [(CH)3C], 34.7 [(CH)3C],
40.0 (CHCH2NO2), 65.3 (CH2OC), 68.4 (CHSO3), 74.6
[CH(OC)CH2O], 75.0 (CH2NO2), 76.7 [CH(OC)CH(OC)CH2O],
77.3 [CH(OC)CH(OC)2], 78.0 (CHOSO2), 103.5 [CH(OC)2], 110.2
[(O)2C(CH3)2], 113.7 [(O)2C(CH3)2], 126.0 (ArCH), 127.1 (ArC),
129.9 (ArCH), 152.9 (ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 574 (11) [M+ + 3], 573 (28)
[M+ + 2] 572 (82) [M+ + 1], 514 (5), 471 (5), 261 (26), 259 (13), 250
(11), 249 (28), 248 (89), 245 (10), 243 (14), 232 (6), 204 (12), 203
(100), 202 (8), 201 (14), 185 (13), 163 (15), 101 (5).
IR (KBr): 3064 (w), 3029 (m), 2988 (s), 2934 (s), 1604 (m), 1555
(vs), 1497 (m), 1457 (s), 1375 (vs), 1218 (vs), 1168 (vs), 1120 (vs),
1018 (vs), 931 (m), 874 (vs), 849 (s), 750 (m), 701 (vs), 629 (m),
583 (m), 518 (m) cm–1.
1H NMR (300 MHz, CDCl3, major diastereomer): = 1.30 [s, 3 H,
(O)2C(CH3)2], 1.36 [s, 3 H, (O)2C(CH3)2], 1.46 [s, 3 H,
(O)2C(CH3)2], 1.54 [s, 3 H, (O)2C(CH3)2], 1.45–1.55 (m, 1 H,
ArCH2CHH), 1.93–2.06 (m, 1 H, ArCH2CHH), 2.53–2.64 (m, 2 H,
ArCH2), 3.16–3.28 (m, 1 H, CHCH2NO2), 3.83 (dd, 1 H, J = 6.1, 8.5
Anal. Calcd for C27H41NO10S (571.68): C, 56.73; H, 7.23; N, 2.45.
Found: C, 56.99; H, 7.30; N, 2.22.
(R,R)-2-Nitromethyl-1-phenylbutane-1-sulfonic Acid Methyl
Ester [(R,R)-4a]
According to GP2 the Michael adduct (R,R)-2a (388.9 mg, 0.75
mmol) was refluxed in a solution of EtOH–H2O containing
Pd(OAc)2 (31.8 mg, 0.14 mmol) for 24 h. Work-up and flash chro-
matography (Et2O–n-pentane, 1:9–1:4) gave (R,R)-4a.
Hz,
CHHOC),
3.97–4.10
[m,
2
H,
CHHOC,
CH(OC)CH(OC)CH2O], 4.14 [t,
1
H, J = 4.1 Hz,
CH(OC)CH(OC)2], 4.22–4.32 [m, 1 H, CH(OC)CH2O], 4.65–4.77
(m, 3 H, CHSO3, CHOSO2, CHHNO2), 4.84 (dd, 1 H, J = 5.8, 13.7
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

1950
D. Enders et al.
PAPER
Yield: 154.4 mg (71%); colorless solid; mp 59–60°C; de 98% (1H
NMR, 13C NMR), ee 98% (based on the ds value of the Michael
adduct); [ ]Dr.t. +33.1 (c 0.72, CHCl3).
991 (vs), 903 (m), 813 (vs), 767 (m), 731 (m), 701 (vs), 654 (m),
609 (s), 526 (w), 505 (47), 462 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 0.65 [d, 3 H, J = 7.2 Hz,
CH(CH3)2], 0.96 [d, 3 H, J = 7.1 Hz, CH(CH3)2], 1.82 [dsept, 1 H,
J = 3.0, 6.9 Hz, CH(CH3)2], 3.29–3.38 (m, 1 H, CHCH2NO2), 3.54
(s, 3 H, SO3CH3), 4.40 (d, 1 H, J = 10.4 Hz, CHSO3), 4.64 (dd, 1 H,
J = 5.2, 15.1 Hz, CHHNO2), 4.99 (dd, 1 H, J = 5.0, 14.8 Hz,
CHHNO2), 7.40–7.51 (m, 5 H, ArH).
IR (KBr): 2980 (w), 2962 (w), 2888 (w), 1555 (vs), 1456 (w), 1440
(w), 1385 (s), 1356 (vs), 1335 (s), 1297 (w), 1228 (m), 1165 (vs),
1134 (w), 984 (vs), 851 (w), 833 (s), 782 (s), 735 (m), 700 (s), 623
(m), 586 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 0.89 (t, 3 H, J = 7.4 Hz, CH2CH3),
1.16–1.32 (m, 1 H, CHHCH3), 1.58–1.73 (m, 1 H, CHHCH3), 2.99–
3.12 (m, 1 H, CHCH2NO2), 3.62 (s, 3 H, SO3CH3), 4.56 (d, 1 H,
J = 9.0 Hz, CHSO3), 4.71 (dd, 1 H, J = 5.8, 14.0 Hz, CHHNO2),
4.84 (dd, 1 H, J = 5.5, 14.0 Hz, CHHNO2), 7.40–7.50 (m, 5 H,
ArH).
13C NMR (75 MHz, CDCl3):
= 16.1 [CH(CH3)2], 20.8
[CH(CH3)2], 28.2 [CH(CH3)2], 42.8 (CHCH2NO2), 57.6 (SO3CH3),
68.4 (CHSO3), 73.6 (CH2NO2), 129.5, 129.8, 130.0 (ArCH), 131.9
(ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 304 (6) [M+ + 3], 303 (15)
[M+ + 2], 302 (99) [M+ + 1], 286 (10), 270 (8), 207 (18), 206 (100),
190 (10), 187 (12), 177 (18), 162 (5), 161 (44), 159 (15), 147 (5),
146 (6), 107 (25), 99 (6).
13C NMR (75 MHz, CDCl3): = 10.2 (CH2CH3), 21.3 (CH2CH3),
39.7 (CHCH2NO2), 57.4 (CH3), 67.1 (CHSO3), 74.7 (CH2NO2),
129.2, 129.6, 129.8 (ArCH), 130.9 (ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 290 (5) [M+ + 3], 289 (12)
Anal. Calcd for C13H19NO5S (301.35): C, 51.81; H, 6.35; N, 4.65.
Found: C, 51.66; H, 6.47; N, 4.58.
[M+ + 2], 288 (84) [M+ + 1], 193 (12), 192 (100), 147 (7), 145 (10).
Anal. Calcd for C12H17NO5S (287.33): C, 50.16; H, 5.96; N, 4.87.
Found: C, 49.96; H, 5.86; N, 4.66.
(R,R)-2-Nitromethyl-1,4-diphenylbutane-1-sulfonic Acid
Methyl Ester [(R,R)-4d]
According to GP2 the Michael adduct (R,R)-2d (378.9 mg, 0.64
mmol) was refluxed in a solution of EtOH–H2O containing
Pd(OAc)2 (27.4 mg, 0.12 mmol) for 23 h. Work-up and flash chro-
matography (Et2O–n-pentane, 1:9–1:4) gave (R,R)-4d.
Yield: 177.4 mg (76%); colorless solid; de 68% (1H NMR, 13C
NMR), de 93% (after recrystallization from Et2O–n-pentane 1:1 at
–24 °C, 1H NMR, 13C NMR), ee 98% (based on the ds value of the
Michael adduct); [ ]Dr.t. +24.4 (c 0.62, CHCl3).
(R,R)-2-Nitromethyl-1-phenylpentane-1-sulfonic Acid Methyl
Ester [(R,R)-4b]
According to GP2 the Michael adduct (R,R)-2b (409.8 mg, 0.77
mmol) was refluxed in a solution of EtOH–H2O containing
Pd(OAc)2 (32.3 mg, 0.14 mmol) for 22 h. Work-up and flash chro-
matography (Et2O–n-pentane, 1:9–1:4) gave (R,R)-4b.
Yield: 162.8 mg (70%); colourless solid; mp 49 °C; de 98% (1H
NMR, 13C NMR), ee 98% (based on the ds value of the Michael
adduct); [ ]Dr.t. +25.3 (c 1.15, CHCl3).
IR (KBr): 2950 (m), 1602 (m), 1571 (vs), 1543 (vs), 1497 (m), 1456
(s), 1430 (m), 1384 (s), 1363 (vs), 1328 (m), 1278 (w), 1237 (63),
1169 (vs), 1042 (w), 1030 (w), 989 (vs), 926 (w), 910 (w), 854 (m),
818 (s), 777 (s), 749 (s), 734 (s), 697 (vs), 644 (w), 597 (m), 580
(vs), 541 (w), 510 (m), 465 (m) cm–1.
IR (KBr): 2966 (vs), 2934 (m), 2876 (m), 1558 (vs),1498 (w),1468
(m), 1455 (m), 1437 (m), 1386 (s), 1356 (vs), 1332 (m), 1162 (vs),
986 (vs), 845 (w), 818 (s), 776 (m), 730 (m), 700 (s), 608 (m), 588
(w), 574 (m), 460 (m) cm–1.
1H NMR (400 MHz, CDCl3, major diastereomer): = 1.50–1.61
(m, 1 H, ArCH2CHH), 1.86–1.97 (m, 1 H, ArCH2CHH), 2.49–2.68
(m, 2 H, ArCH2CH2), 3.02–3.11 (m, 1 H, CHCH2NO2), 3.60 (s, 3 H,
SO3CH3), 4.61 (d, 1 H, J = 8.7 Hz, CHSO3), 4.70 (dd, 1 H, J = 5.7,
14.0 Hz, CHHNO2), 4.89 (dd, 1 H, J = 5.2, 14.0 Hz, CHHNO2),
6.95–7.00 (m, 2 H, ArH), 7.15–7.26 (m, 3 H, ArH), 7.36–7.44 (m,
5 H, ArH).
13C NMR (100 MHz, CHCl3, major diastereomer): = 29.9
(ArCH2CH2), 32.2 (ArCH2CH2), 37.7 (CHCH2NO2), 57.3
(SO3CH3), 67.0 (CHSO3), 74.8 (CH2NO2), 126.3, 128.1, 128.4,
129.0, 129.5, 129.6 (ArCH), 130.5,139.6 (ArC).
1H NMR (300 MHz, CDCl3): = 0.82 (t, 3 H, J = 7.2 Hz, CH2CH3),
1.14–1.40 (m,
3 H, CHHCH2CH3), 1.50–1.65 (m, 1 H,
CHHCH2CH3), 3.03–3.16 (m, 1 H, CHCH2NO2), 3.63 (s, 3 H,
SO3CH3), 4.58 (d, 1 H, J = 8.6 Hz, CHSO3), 4.64 (dd, 1 H, J = 6.1,
14.3 Hz, CHHNO2), 4.82 (dd, 1 H, J = 5.2, 14.0 Hz, CHHNO2),
7.40–7.50 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): = 13.7 (CH2CH3), 19.2 (CH2CH3),
30.2 (CH2CH2CH3), 38.3 (CHCH2NO2), 57.4 (SO3CH3), 67.1
(CHSO3), 75.1 (CH2NO2), 129.2, 129.6, 129.8 (ArCH), 130.8
(ArC).
MS (CI, 100 eV, isobutane): m/z (%) = 304 (5) [M+ + 3], 303 (13)
[M+ + 2], 302 (91) [M+ + 1], 207 (13), 206 (100), 161 (18), 159 (11),
133 (20).
MS (CI, 100 eV, isobutane): m/z (%) = 366 (7) [M+ + 3], 365 (19)
[M+ + 2], 364 (100) [M+ + 1], 268 (21), 223 (2), 222 (7), 221 (28),
191 (5), 190 (42), 143 (12), 107 (6).
Anal. Calcd for C13H19NO5S (301.35): C, 51.81; H, 6.35; N, 4.65.
Found: C, 51.79; H, 6.27; N, 4.57.
Anal. Calcd for C18H21NO5S (363.42): C, 59.49; H, 5.82; N, 3.85.
Found: C, 59.52; H, 6.10; N, 3.67.
(R,R)-3-Methyl-2-nitromethyl-1-phenylbutane-1-sulfonic Acid
Methyl Ester [(R,R)-4c]
According to GP2 the Michael adduct (R,R)-2c (246.8 mg, 0.47
mmol) was refluxed in a solution of EtOH–H2O containing
Pd(OAc)2 (19.8 mg, 0.09 mmol) for 23 h. Work-up and flash chro-
matography (Et2O–n-pentane, 1:9–1:4) gave (R,R)-4c.
Yield: 68.5 mg (49%); colourless solid; mp 107 °C; de 98% (1H
NMR, 13C NMR), ee 98% (based on the ds value of the Michael
adduct); [ ]Dr.t. +49.6 (c 0.73, CHCl3).
(R,R)-1-(4-tert-Butylphenyl)-2-nitromethylbutane-1-sulfonic
Acid Methyl Ester [(R,R)-4e]
According to GP2 the Michael adduct (R,R)-2e (416.1 mg, 0.73
mmol) was refluxed in a solution of EtOH–H2O containing
Pd(OAc)2 (31.0 mg, 0.14 mmol) for 21 h. Work-up and flash chro-
matography (Et2O–n-pentane, 1:9–1:4) gave (R,R)-4e.
Yield: 157.5 mg (63%); colorless solid; mp 87–88°C; de 98% (1H
NMR, 13C NMR), ee 96% (based on the ds value of the Michael
adduct); [ ]Dr.t. +27.6 (c 0.81, CHCl3).
IR (KBr): 2968 (vs), 2876 (m), 1563 (vs), 1498 (w), 1459 (s), 1428
(m), 1384 (vs), 1329 (vs), 1268 (w), 1237 (m), 1160 (vs), 1059 (w),
IR (KBr): 2966 (s), 2939 (m), 2908 (w), 2875 (w), 1610 (w), 1554
(vs), 1512 (w), 1466 (m), 1432 (m), 1417 (w), 1385 (m), 1352 (vs),
1331 (m), 1272 (m), 1256 (w), 1200 (m), 1169 (vs), 1126 (w), 1114
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Michael Addition of Chiral Lithiated Sulfonates to Nitroalkenes
1951
(w), 1013 (w), 978 (vs), 938 (w), 860 (s), 772 (s), 758 (vs), 735 (m),
648 (w), 602 (vs), 547 (w) cm–1.
13C NMR (75 MHz, CDCl3): = 13.8 (CH2CH2CH3), 14.4
(OCH2CH3), 20.1 (CH2CH2CH3), 33.3 (CH2CH2CH3), 45.8
[SO2CH(Ph)CH], 57.4 (CH3OSO2), 61.5 (OCH2CH3), 68.5
[SO2CH(Ph)CH], 129.5, 129.8, 130.0 (ArCH), 131.9 (ArC), 173.9
(C=O).
MS (EI, 70 eV): m/z (%) = 314 (6) [M+], 219 (92), 173 (20), 145
(100), 135 (99), 117 (36), 91 (68).
1H NMR (300 MHz, CDCl3): = 0.90 (t, 3 H, J = 7.4 Hz, CH2CH3),
1.18–1.33 (m, 1 H, CHHCH3), 1.33 [s, 9 H, (CH3)3C], 1.62–1.78
(m, 1 H, CHHCH3), 2.99–3.12 (m, 1 H, CHCH2NO2), 3.62 (s, 3 H,
SO3CH3), 4.53 (d, 1 H, J = 8.5 Hz, CHSO3), 4.68 (dd, 1 H, J = 6.0,
14.0 Hz, CHHNO2), 4.80 (dd, 1 H, J = 5.8, 14.0 Hz, CHHNO2),
7.35 (d, 2 H, J = 8.8 Hz, ArH), 7.43 (d, 2 H, J = 8.5 Hz, ArH).
13C NMR (75 MHz, CDCl3): = 10.5 (CH2CH3), 21.4 (CH2CH3),
31.5 [(CH3)3C], 35.0 [(CH3)3C], 40.1 (CHCH2NO2), 57.6
(SO3CH3), 66.9 (CHSO3), 75.0 (CH2NO2), 126.4 (ArCH), 127.7
(ArC), 129.7 (ArCH), 153.0 (ArC).
Anal. Calcd for C15H22SO5 (314.40): C, 57.30; H, 7.05. Found: C,
57.16; H, 7.39.
(R,R)-2-(1-Methoxysulfonyl-1-phenylmethyl)-3-methylbutyric
Acid Ethyl Ester [(R,R)-6c]
According to GP3 the Michael adduct (R,R)-2c (529.6 mg, 1.0
mmol) was refluxed in EtOH (98%; 30 mL) containing Pd(OAc)2
(44.3 mg, 0.2 mmol) for 7 d. Work-up and flash chromatography
(Et2O–n-pentane, 1:3) gave (R,R)-6c.
Yield: 273.5 mg (87%); colorless solid; mp 73 °C; de 98% (1H
NMR, 13C NMR), ee 98% (based on the ds value of the Michael
adduct); [ ]Dr.t. +14.7 (c 1.01, CHCl3).
MS (CI, 100 eV, isobutane): m/z (%) = 346 (1) [M+ + 3], 345 (3)
[M+ + 2], 344 (15) [M+ + 1], 249 (19), 248 (100), 203 (10), 163 (7).
Anal. Calcd for C16H25NO5S (343.43): C, 55.96; H, 7.34; N, 4.08.
Found: C, 55.84; H, 7.28; N, 3.88.
(R,R)-2-(1-Methoxysulfonyl-1-phenylmethyl)butyric Acid
Ethyl Ester [(R,R)-6a]
According to GP3 the Michael adduct (R,R)-2a (515.6 mg, 1.0
mmol) was refluxed in EtOH (98%; 30 mL) containing Pd(OAc)2
(44.3 mg, 0.2 mmol) for 7 d. Work-up and flash chromatography
(Et2O–n-pentane, 1:3) gave (R,R)-6a.
Yield: 282.3 mg (94%); colorless oil; de 98% (1H NMR, 13C
NMR), ee 98% (based on the ds value of the Michael adduct);
[ ]Dr.t. +17.5 (c 1.08, CHCl3).
IR (CHCl3): 2971 (s), 2939 (m), 1719 (vs, C=Oester), 1461 (m), 1383
(s), 1356 (vs), 1335 (s), 1301 (w), 1273 (s), 1251 (w), 1225 (m),
1161 (vs), 1133 (m), 1092 (w), 1051 (w), 1023 (m), 979 (vs), 810
(vs), 785 (vs), 728 (s), 706 (s), 612 (w), 587 (vs), 513 (w), 461 (w)
cm–1.
1H NMR (300 MHz, CDCl3): = 0.75 [d, 3 H, J = 6.59 Hz,
CH(CH3)CH3], 0.94 [d, 3 H, J = 7.15 Hz, CH(CH3)CH3], 1.35 (t, 3
H, J = 7.14 Hz, OCH2CH3), 1.72 [m, 1 H, CH(CH3)CH3], 3.36 [dd,
1 H, J = 3.84 Hz, 11.53 Hz, SO2CH(Ph)CH], 3.67 (s, 3 H,
CH3OSO2), 4.26 (q, 2 H, J = 7.14 Hz, OCH2CH3), 4.76 [d, 1 H,
J = 11.81 Hz, SO2CH(Ph)CH], 7.43 (m, 5 H, ArH).
IR (KBr): 3064 (w), 2977 (s), 2939 (m), 2884 (w), 1723 (vs,
C=Oester), 1460 (m), 1381 (s), 1354 (vs), 1300 (w), 1266 (m), 1162
(vs), 1092 (m), 981 (vs), 840 (m), 818 (s), 787 (s), 728 (m), 705 (s),
611 (m), 581 (s), 512 (w), 462 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 0.81 (t, 3 H, J = 7.42 Hz,
CH2CH3), 1.10–1.25 (m, 2 H, CH2CH3), 1.34 (t, 3 H, J = 7.5 Hz,
OCH2CH3), 3.24 [m, 1 H, SO2CH(Ph)CH], 3.66 (s, 3 H, CH3OSO2),
4.27 (q, 2 H, J = 7.14 Hz, OCH2CH3), 4.62 [d, 1 H, J = 11.26 Hz,
SO2CH(Ph)CH], 7.41 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): = 11.0 (CH2CH3), 14.2 (OCH2CH3),
24.3 (CH2CH3), 47.0 [SO2CH(Ph)CH], 57.1 (CH3OSO2), 61.2
(OCH2CH3), 68.0 [SO2CH(Ph)CH], 128.8, 129.2, 129.9 (ArCH),
130.5 (ArC), 173.2 (C=O).
13C NMR (75 MHz, CDCl3): = 14.3 (OCH2CH3), 15.7, 21.3
[CH(CH3)2], 27.9 [CH(CH3)2], 49.6 [SO2CH(Ph)CH], 57.1
(CH3OSO2), 60.9 (OCH2CH3), 67.1 [SO2CH(Ph)CH], 1.0
(CH2CH3),
14.2
(OCH2CH3),
24.3
(CH2CH3),
47.0
[SO2CH(Ph)CH], 57.1 (CH3OSO2), 61.2 (OCH2CH3), 68.0
[SO2CH(Ph)CH], 128.7, 129.1, 130.1 (ArCH), 130.3 (ArC), 171.2
(C=O).
MS (EI, 70 eV): m/z (%) = 314 (2) [M+], 219 (68), 177 (23), 173
(62), 145 (100), 135 (34), 131 (68), 91 (81).
Anal. Calcd for C15H22SO5 (314.40): C, 57.30.; H, 7.05. Found: C,
57.26; H, 6.98.
MS (EI, 70 eV): m/z (%) = 300 (5) [M+], 205 (74), 191 (10), 159
(13), 135 (100), 131 (49), 91 (11), 59 (24).
Anal. Calcd for C14H20SO5 (300.37): C, 55.98; H, 6.71. Found: C,
55.82; H, 6.98.
(R,R)-2-(1-Methoxysulfonyl-1-phenylmethyl)-3-methylbutyric
Acid Isopropyl Ester [(R,R)-6d]
According to GP3 the Michael adduct (R,R)-2c (529.6 mg, 1.0
mmol) was refluxed in i-PrOH (98%; 30 mL) containing Pd(OAc)2
(44.3 mg, 0.2 mmol) for 7 d. Work-up and flash chromatography
(Et2O–n-pentane, 1:3) gave (R,R)-6d.
Yield: 312.0 mg (95%); colorless solid; mp 90 °C; de 98% (1H
NMR, 13C NMR), ee 98% (based on the ds value of the Michael
adduct); [ ]Dr.t. +12.6 (c 1.04, CHCl3).
(R,R)-2-(1-Methoxysulfonyl-1-phenylmethyl)pentanoic Acid
Ethyl Ester [(R,R)-6b]
According to GP3 the Michael adduct (R,R)-2b (529.6 mg, 1.0
mmol) was refluxed in EtOH (98%; 30 mL) containing Pd(OAc)2
(44.3 mg, 0.2 mmol) for 7 d. Work-up and flash chromatography
(Et2O–n-pentane, 1:3) gave (R,R)-6b.
Yield: 264.1 mg (84%); colorless oil; de 98% (1H NMR, 13C
IR (KBr): 2972 (s), 2938 (m), 2881 (w), 1715 (vs, C=Oester), 1466
(m), 1389 (s), 1374 (m), 1356 (vs), 1273 (s), 1250 (m), 1195 (s),
1164 (vs), 1106 (vs), 980 (vs), 926 (m), 809 (vs), 785 (s), 728 (m),
707 (s), 586 (vs), 513 (w), 461 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 0.74 [d, 3 H, J = 6.92 Hz,
CH(CH3)CH3], 0.92 [d, 3 H, J = 7.17 Hz, CH(CH3)CH3], 1.31 [d, 3
H, J = 6.18 Hz, OCH(CH3)CH3], 1.32 [d, 3 H, J = 6.17 Hz,
OCH(CH3)CH3], 1.70 [m, 1 H, CH(CH3)CH3], 3.31 [dd, 1 H,
J = 3.96, 11.62 Hz, SO2CH(Ph)CH], 3.65 (s, 3 H, CH3OSO2), 4.74
NMR), ee 98% (HPLC); [ ]Dr.t. +5.96 (c 1.0, CHCl3).
IR (KBr): 3031 (w), 2962 (s), 2874 (w), 2400 (w), 1733(vs,
C=Oester), 1456 (m), 1361 (vs), 1301 (w), 1247 (s), 1185 (vs), 1029
(w), 988 (vs), 847 (w), 816 (s), 764 (s), 703 (s), 669 (w), 614 (m),
584 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 0.73 (t, 3 H, J = 7.4 Hz,
CH2CH2CH3), 1.10–1.25 (m, 4 H, CH2CH2CH3), 1.29 (t, 3 H,
J = 7.14 Hz, OCH2CH3), 3.27 [dt, 1 H, J = 3.57, 10.98 Hz,
SO2CH(Ph)CH], 3.61 (s, 3 H, CH3OSO2), 4.22 (q, 2 H, J = 7.14 Hz,
OCH2CH3), 4.56 [d, 1 H, J = 10.99 Hz, SO2CH(Ph)CH], 7.20–7.50
(m, 5 H, ArH).
[d,
1 H, J = 11.84 Hz, SO2CH(Ph)CH], 5.13 [m, 1 H,
OCH(CH3)CH3], 7.41 (m, 5 H, ArH).
Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York

1952
D. Enders et al.
PAPER
13C NMR (75 MHz, CDCl3): = 15.7 [CH(CH3)CH3], 21.3
[CH(CH3)CH3], 21.7 [OCH(CH3)CH3], 22.0 [OCH(CH3)CH3],
27.9 [CH(CH3)CH3], 49.5 [SO2CH(Ph)CH], 57.0 (CH3OSO2), 67.0
[SO2CH(Ph)CH], 68.5 [OCH(CH3)CH3], 128.60, 129.0, 130.3
(ArCH), 130.1 (ArC), 170.6 (C=O).
MS (EI, 70 eV): m/z (%) = 328 (4) [M+], 269 (8), 233 (75), 191
(100), 173 (81), 149 (40), 145 (64), 131 (68), 105 (19), 91 (83), 69
(18), 57 (8).
(6) For a review on the Nef reaction, see: Pinnick, H. W. Org.
React. 1990, 38, 655.
(7) (a) Grundmann, C.; Ruske, W. Chem. Ber. 1953, 86, 939.
(b) Corey, E. J.; Andersen, N. H.; Carlson, R. M.; Paust, J.;
Vedejs, E.; Vlattas, I.; Winter, R. E. K. J. Am. Chem. Soc.
1968, 90, 3245.
(8) Edward, J. T.; Tremaine, P. H. Can. J. Chem. 1971, 49,
3483.
(9) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997,
62, 234.
(10) For some recent examples, see: (a) Schäfer, H.; Seebach, D.
Tetrahedron 1995, 51, 2305. (b) Enders, D.; Otten, T.
Synlett 1999, 747; and literature cited therein. (c) Enders,
D.; Teschner, P.; Raabe, G. Synlett 2000, 637. (d) Enders,
D.; Tedeschi, L.; Bats, J. W. Angew. Chem. Int. Ed. 2000, 39,
4605; Angew. Chem. 2000, 112, 4774.
(11) Enders, D.; Berner, O. M.; Vignola, N.; Bats, J. W. Chem.
Commun. 2001, 2498.
(12) Enders, D.; Vignola, N.; Berner, O. M. Angew. Chem. Int.
Ed. 2002, 41, 109; Angew. Chem. 2002, 114, 116.
(13) The experimental data will be reported in a separate full
paper on the -alkylations.
Anal. Calcd for C16H24SO5 (328.42): C, 58.51; H, 7.37. Found: C,
58.27; H, 7.35.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG and Bayer AG for the
donation of chemicals. The X-ray structure determination by Dr. J.
W. Bats, University of Frankfurt, and the NOE-measurements by
Dr. J. Runsink, RWTH-Aachen, are gratefully acknowledged.
(14) For a representative synthesis of the sulfonyl chloride, see:
Brundish, D.; Bull, A.; Donovan, V.; Fullerton, J. D.;
Garman, S. M.; Hayler, J. F.; Janus, D.; Kane, P. D.;
McDonell, M.; Smith, G. P.; Wakeford, R.; Walker, C. V.;
Howarth, G.; Hoyle, W.; Allen, M. C.; Ambler, J.; Butler,
K.; Talbot, M. D. J. Med. Chem. 1999, 42, 4584.
(15) For representative syntheses of the sodium sulfonates, see:
(a) Otto, S.; Engberts, J. B. F. N.; Kwak, J. C. T. J. Am.
Chem. Soc. 1998, 120, 9517. (b) Abdellaoui, H.; Depreux,
P.; Lesieur, D.; Pfeiffer, B.; Bontempelli, P. Synth. Commun.
1995, 25, 1303.
(16) Sun, S. F.; Folliard, J. T. Tetrahedron 1971, 27, 323.
(17) Kalir, A.; Kalir, H. H. In The Chemistry of Sulfonic Acids,
Esters and their Derivatives, Biological Activity of Sulfonic
Acid Derivatives; Patai, S.; Rappoport, Z., Eds.; Wiley: New
York, 1991, 767.
References
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Synthesis 2002, No. 14, 1945–1952 ISSN 0039-7881 © Thieme Stuttgart · New York