Asymmetric synthesis of α- and α,β-substituted β-alkoxycarbonyl sulfonates

Article abstract of DOI:10.1055/s-2005-872164

An efficient asymmetric synthesis of substituted β-alkoxycarbonyl sulfonates is described. Enantiopure α-substituted β-alkoxycarbonyl sulfonates can be obtained via α-alkylation of metalated sulfonates bearing 1,2:5,6-di-O-isopropylidene-α-D-allofuranose

Full text of DOI:10.1055/s-2005-872164

2962
PAPER
Asymmetric Synthesis of a- and a,b-Substituted b-Alkoxycarbonyl Sulfonates
A
symmetric Synth
i
esis of
e
a
-
and
a
,
b
-
t
Substit
e
uted
b
-Alko
r
xycarbonyl Su
E
lfonates nders,*a Jean-Claude Adelbrecht,a Wacharee Harnyingb
a
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@rwth-aachen.de
Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
b
Received 17 May 2005
screened in order to identify optimum conditions in terms
of yield and diastereoselectivity (Scheme 1). Typical re-
actions involved the addition of 1.5 equivalents of bro-
moester to the lithiated substrate at –95 °C. The results are
Abstract: An efficient asymmetric synthesis of substituted b-
alkoxycarbonyl sulfonates is described. Enantiopure a-substituted
b-alkoxycarbonyl sulfonates can be obtained via a-alkylation of
metalated sulfonates bearing 1,2:5,6-di-O-isopropylidene-a-D-allo-
furanose as the chiral auxiliary with alkyl bromoacetates. a,b-Di- collected in Table 1.
substituted b-alkoxycarbonyl sulfonates were prepared starting
from the corresponding enantiopure g-nitro sulfonates by using
TFA for the cleavage of the chiral auxiliary and causing a simulta-
neous Meyer reaction.
1. n-BuLi, THF, −95 °C, 1 h
O
2.
Br
CO2R
OR
OR*
THF, −95 to −78 °C, 16 h
OR*
S
S
O O
Key words: asymmetric synthesis, sulfonates, esters, alkylation,
sugar auxiliary
O O
74–80%
1a
(R)-2
de = 75–84% (≥ 98%)
O
R* = H3C
H3C
O
O
Sulfonic acids and their derivatives represent important
synthetic targets because they often exhibit interesting
biological activities. b-Carboxy sulfonates and their ami-
no substituted analogues represent a special class among
which cysteic acid (CA, 2-amino-3-sulfopropionic acid)
is probably the most prominent one. In organisms it is
present in high concentrations in the plasma, urine and tis-
sues.1 However, the number of methods for the synthesis
of this class of compounds in enantiomerically pure form
is scarce.2 In our ongoing research concerning the chem-
istry of sulfonates we have now developed a methodology
for the asymmetric synthesis of substituted b-alkoxycar-
bonyl sulfonates.
O
CH3
O
CH3
Scheme 1 Asymmetric a-alkylations of the sulfonate 1a with diffe-
rent bromoesters.
Table 1 a-Alkylations of the Chiral Sulfonate 1a with Different
Bromoesters To Give the Sulfonates (R)-2a–c
(R)-2
R
Yield (%)
de (%)a,b
84 (≥ 98)
80 (≥ 98)
75 (≥ 98)
a
b
c
Me
i-Pr
t-Bu
80
76
74
The strategy used for the asymmetric synthesis of the title
compounds is based on previous work undertaken in our
group employing 1,2:5,6-di-O-isopropylidene-a-D-allo-
furanose as the chiral auxiliary,3 which resulted in a high-
ly efficient route towards a variety of different sulfonic
acid derivatives.3–8 Therein we also reported an efficient
asymmetric synthesis of a,b-disubstituted b-alkoxycarbo-
nyl sulfonates from a,b-disubstituted g-nitro sulfonates
obtained by asymmetric Michael addition of chiral lithi-
ated sulfonates to nitroalkenes.4
a Determined by 1H NMR spectroscopy.
b In brackets after recrystallization from EtOH.
As it was anticipated, the reactions proceeded smoothly,
with both good yields and diastereomeric excesses of the
desired products (R)-2. Recrystallization of the products
from EtOH was amenable in all cases to furnish the dia-
stereomerically pure sulfonates (de ≥ 98%). It should be
mentioned that the assignment of the configuration of the
newly formed stereocenter to be R is based on results ob-
tained from related reactions using unfunctionalized alkyl
halides as electrophiles.3
We now wish to describe a direct and efficient entry to a-
substituted b-alkoxycarbonyl sulfonates starting from
enantiopure lithiated sulfonates obtained by metalation
with n-butyllithium in THF and using bromoesters as
electrophiles. At the beginning of our studies it was not
clear which bromoester should be used and if different
bromoesters would lead to significantly different results.
With substrate 1a in hand, a range of bromoesters was
From this screening, marginally higher yields were con-
sistently obtained from reactions employing the methyl
bromoacetate, indicating it as the electrophile of choice.
Obviously and rather unexpected the asymmetric induc-
tion increases with a decreasing steric demand of the ester
function. With optimum conditions determined, using the
methyl bromoacetate as electrophile, the next step of our
investigation centered on the extension to other chiral sul-
SYNTHESIS 2005, No. 17, pp 2962–2968
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872164; Art ID: Z09705SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of a- and a,b-Substituted b-Alkoxycarbonyl Sulfonates
2963
O
O
1. Pd(OAc)2 (cat.),
MeOH/H2O, reflux, 4 d
2. CH2N2/Et2O
fonate substrates 1a–d (Scheme 2). The results of these
reactions are collected in Table 2.
OCH3
OR*
OCH3
OCH3
Whereas benzylic sulfonates 1a–c show results consistent
with our earlier trials, in which related electrophilic sub-
stitutions proceeded in high yields and with good diaste-
reoselectivity, the allylic sulfonate 1d gave product 2f
with a de value of only 40% and in a moderate yield. The
major diastereomers (R)-2a,d,e could be easily obtained
as pure stereoisomers with diastereomeric excesses supe-
rior to 98% by recrystallization from EtOH.
S
O O
S
O O
94%
(R)-2a
de ≥ 98%
(R)-3a
ee ≥ 98%
Scheme 3 Removal of the chiral auxiliary to give the methyl sulfo-
nate (R)-3.
Racemization-free cleavage of the chiral auxiliary was
carried out following procedures that have already been
described.3,4 By refluxing the sulfonate (R)-2a in a
MeOH–H2O mixture containing a catalytic amount of
Pd(OAc)2 for four days followed by treatment with diazo-
methane, the desired methyl sulfonate (R)-3a was ob-
tained in 94% yield (Scheme 3). Due to the fact that (R)-
2a bears a methyl ester moiety it was found to be more ef-
fective to use MeOH as the solvent avoiding side products
arising from transesterification.
the chiral auxiliary, i.e. using trifluoro acetic acid (TFA)
instead of Pd(OAc)2,5 we investigated its applicability to
the nitro sulfonates 4.
As is shown in Scheme 4, the cleavage of the auxiliary
with simultaneous conversion of the primary nitro group
to the corresponding ethyl esters (R,R)-5 in a Meyer
reaction9 were accomplished in good yields upon treat-
ment with TFA in refluxing EtOH for two days. On the
other hand, the chiral auxiliary could be removed selec-
tively by the combination of the addition of water and
shorter reaction time. Thus, the g-nitro isopropyl sul-
fonates (R,R)-6 were obtained in moderate to good yields
by refluxing the g-nitro sulfonates (R,R)-4 in an EtOH–
H2O solution containing 2% TFA for 15 hours and subse-
quent protection of the resulting sulfonic acids with triiso-
propylorthoformate in refluxing CH2Cl2.
As we have previously described, the cleavage of the
chiral auxiliary of the g-nitro sulfonates 4 with Pd(OAc)2
led to either b-alkoxycarbonyl methyl sulfonates or g-ni-
tro methyl sulfonates in excellent diastereo- and enantio-
meric excesses using different conditions.4 Since we
could develop a less expensive method for the removal of
R1
CO2Et
1. 2% TFA/EtOH,
reflux, 2 d
2. CH2N2/Et2O
1. n-BuLi, THF, −95 °C, 1 h
O
S
2.
Br
CO2CH3
SO3CH3
OR*
OCH3
OR*
THF, −95 to −78 °C, 16 h
R1
S
R1
O O
R1
de, ee ≥ 98%
(R,R)-5a; R1 = n-Pr (62%)
(R,R)-5b; R1 = i-Pr (78%)
49–80%
NO2
O O
SO3R*
(R)-2a, d–f
1a–d
1. 2% TFA/EtOH-H2O,
reflux, 15 h
2. CH(Oi-Pr)3, CH2Cl2,
reflux, 3 h
R1
de = 40–84% (≥ 98%)
de, ee ≥ 98%
NO2
(R,R)-4a; R1 = n-Pr
(R,R)-4b; R1 = i-Pr
(R,R)-4c; R1 = Et
Scheme 2 Asymmetric a-alkylations of the sulfonates 1 with
methyl bromoacetate.
SO3i-Pr
de, ee ≥ 98%
(R,R)-6a; R1 = n-Pr (75%)
(R,R)-6b; R1 = i-Pr (43%)
(R,R)-6c; R1 = Et (84%)
Table 2 a-Alkylations of the Sulfonates 1a–d with Methyl Bro-
moacetate To Give the Sulfonates (R)-2a,d–f
R1
Yield (%) de (%)a,b
Scheme 4 TFA cleavage of the chiral auxiliary of the g-nitro sulfo-
nates 4 to form either the b-ethoxycarbonyl methyl sulfonates 5 or the
g-nitro ispropyl sulfonates 6.
1
a
(R)-2
a
80
84 (≥ 98)
Under reaction conditions comparable to those using
Pd(OAc)2, TFA gave lower yields of the b-ethoxycarbon-
yl sulfonates (R,R)-5a,b. Whereas the g-nitro sulfonates
(R,R)-6a,c were obtained in higher yields, (R,R)-6b was
isolated in slightly lower yield. However, using TFA in-
stead of Pd(OAc)2 seems to be a viable alternative for
such transformations since the reactions proceed faster
and give satisfactory yields.
b
d
75
80 (≥ 98)
t-Bu
c
e
f
78
49
80 (≥ 98)
MeO
d
40
a Determined by 1H NMR spectroscopy.
b In brackets after recrystallization from EtOH.
The further synthetic transformation of b-alkoxycarbonyl
sulfonates to the phamacologically interesting g-hydroxy
sulfonates,10 previously synthesized in our group by ring-
Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York

2964
D. Enders et al.
PAPER
were performed with TMS as internal standard. Melting points were
determined with a Tottoli melting point apparatus and are uncor-
rected.
opening of enantio- and diastereomerically pure g-sul-
tones,7 was next investigated.
We found that the reduction of compound (R,R)-5b with
BH3·THF,11 BH3·SMe2,12 LiEt3BH,13 or LiAlH4 did not
only proceed with the reduction of the ester group but also
with a reductive cleavage of the methyl group to furnish
the g-hydroxy sulfonic acid. However, a chemoselective
reduction of the ester group leaving the methyl sulfonate
intact could be achieved by treatment with DIBAL-H at
low temperature (Scheme 5). The desired a,b-substituted
g-hydroxy methyl sulfonate (R,R)-7 was obtained in an
excellent yield of 95% as well as diastereo- and enantio-
meric excess (de, ee ≥98%).
Preparation of the Chiral Sulfonates 1; General Procedure 1
(GP 1)
To a solution of the corresponding sodium sulfonate (6 mmol) in
DMF (30 mL) was added thionylchloride (2.1 mL) at 0 °C. Upon
completion of the reaction after 4 h at r.t., ice-cold water and EtOAc
were added to the reaction mixture. The organic phase was washed
with water (5 ×) and dried over MgSO4. After concentration under
reduced pressure, the resulting sulfonyl chloride was diluted in
EtOAc (40 mL) before pyridine (18 mmol) was added. 1,2:5,6-Di-
isopropylidene-a-D-allofuranose (2 mmol) was added to the reac-
tion mixture and then stirred for 24 h. The organic phase was
washed with 1 M HCl (2 ×), followed by brine and dried over
MgSO4. Concentration under reduced pressure and chromatography
(SiO2, Et2O–n-pentane) yielded the enatiopure sulfonate 1. The data
of the chiral sulfonates 1a,b have been previously reported, see
ref.3b
The ee value of (R,R)-7 was determined by HPLC analysis
using a chiral stationary phase by comparison with its
racemate and showed that this reaction proceeds without
any detectable degree of racemization.
Alkylation of Chiral Sulfonates with Bromoesters; General
Procedure 2 (GP 2)
CH3
CH3
DIBAL (2.6 equiv)
CH2Cl2, −78 °C, 30 min
then −20 °C, 3 h
CO2Et
H3C
H3C
OH
A solution of the enantiopure sulfonate 1 (1 equiv) in THF (20 mL/
mmol) was cooled down to –95 °C prior to the addition of n-BuLi
(1.1 equiv of a 1.6 M solution in hexane). Upon completion of the
addition the reaction mixture was stirred for 45 min at –95 °C before
a solution of the bromoester (1.5 equiv) in THF (2 mL/mmol of
electrophile) was added dropwise. The mixture was stirred for a fur-
ther 1 h at –95 °C and left at –78 °C for 16 h. The reaction mixture
was quenched with a pH 7 buffer solution (2 mL/mmol). After sep-
aration of the organic layer, the aqueous phase was extracted with
EtOAc. The combined organic phases were washed with brine and
SO3CH3
SO3CH3
95%
(R,R)-5b
de, ee ≥ 98%
(R,R)-7
de, ee ≥ 98%
Scheme 5 Reduction of (R,R)-5b to give the g-hydroxy methyl sul-
fonate (R,R)-7.
In summary, we have developed an efficient asymmetric dried over MgSO4. Concentration under reduced pressure and puri-
fication by flash chromatography (SiO2, EtOAc–n-pentane) afford-
access to benzylic a-substituted b-alkoxycarbonyl sul-
ed the sulfonate (R)-2.
fonates in good yields as well as diastereo- and enantio-
meric excesses via a-alkylation of lithiated chiral
Removal of the Chiral Auxiliary To Give the a,b-Disubstituted
sulfonates with methyl bromoacetate. In addition, we
b-Ethoxycarbonyl Methyl Sulfonates (R,R)-5; General Proce-
have demonstrated an alternative removal of the chiral
sugar auxiliary using TFA instead of Pd(OAc)2 in the case
dure 3 (GP 3)
A mixture of the g-nitro sulfonate (R,R)-4 (1 mmol) in a solution of
of a,b-disubstituted g-nitro sulfonates leading to either b- 2% TFA–EtOH (20 mL) was refluxed for 2 d. The resulting color-
less solution was treated with an ethereal solution of diazomethane
until the yellow color persisted. The solvent was evaporated under
alkoxycarbonyl sulfonates or g-nitro sulfonates in good
yields. We have also shown that the enantioenriched title
reduced pressure and the crude product was purified by flash col-
compounds are valuable substrates for the transformation
umn chromatography (SiO2, Et2O–n-pentane) to give the b-ethoxy-
to g-hydroxy sulfonates. Additional transformations can
be envisioned thus providing an array of useful bifunc-
tional building blocks.
carbonyl sulfonate (R,R)-5. The data of these compounds have been
previously reported, see ref.4b
Removal of the Chiral Auxiliary To Give the a,b-Disubstituted
g-Nitro Isopropyl Sulfonates (R,R)-6; General Procedure 4
(GP 4)
All moisture-sensitive reactions were carried out 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 Ar. Reagents of commercial
quality were used from freshly opened containers or purified by
common methods. n-BuLi (1.6 M in hexane) was purchased from
Merck, Darmstadt. Preparative column chromatography was car-
ried out on Merck silica gel 60, (particle size 0.040–0.063 mm, 230–
240 mesh, flash). Analytical TLC was performed on silica gel 60
F254 plates (Merck, Darmstadt). Optical rotation values were mea-
sured with a Perkin-Elmer P241 polarimeter. Microanalyses were
obtained with a Vario EL element analyzer. Mass spectra were ac-
quired with a Finnigan SSQ7000 (CI, 100 eV, EI 70 eV) spectrom-
eter. HRMS data were recorded with a Finnigan MAT95
spectrometer. IR spectra were taken with a Perkin-Elmer FT/IR
A mixture of the g-nitro sulfonate (R,R)-4 (1 mmol) in a solution of
2% TFA–EtOH (18 mL) and H2O (2 mL) was refluxed for 15 h. Af-
ter removal of the solvent in vacuo, the crude sulfonic acid was dis-
solved in CH2Cl2 (10 mL) and triisopropylorthoformate (0.8 mL, 5
mmol) was added. The mixture was refluxed for 3 h. The solvent
was evaporated under reduced pressure and the crude product was
purified by flash column chromatography (SiO2, Et2O–n-pentane)
to give the g-nitro isopropyl sulfonates (R,R)-6.
Enantiopure Sulfonate 1c
According to GP 1, the crude product was purified by column chro-
matography (SiO2; Et2O–n-pentane, 1:2) to give 1c as a colorless
solid (1.51 g, 84%); mp 104 °C; [a]D24 +53.8 (c = 1.0, CHCl3).
1
1760 instrument. H and 13C NMR spectra were recorded with
IR (KBr): 3423, 2994, 2894, 1601, 1494, 1374, 1258, 1224, 1165,
1073, 1021, 884, 856, 831, 808, 696, 516 cm–1.
Gemini 300 or Varian Inova 400 instruments and all measurements
Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a- and a,b-Substituted b-Alkoxycarbonyl Sulfonates
2965
1H NMR (400 MHz, CDCl3): d = 1.41, 1.41, 1.51, 1.65 [4 × s, 12 H,
O2C(CH3)2], 3.86 [s, 3 H, OCH3], 3.90 [dd, J = 6.2, 8.7 Hz, 1 H,
OCHHCH], 4.06 [dd, J = 6.9, 8.7 Hz, 1 H, OCHHCH], 4.20 [dd,
J = 4.2, 8.4 Hz, 1 H, CH(OC)CH(OC)CH2O], 4.32 [dt, J = 4.2, 6.4
Hz, 1 H, CH(OC)CH2O], 4.46 [d, J = 14.0 Hz, 1 H, ArCH2SO3],
4.55 [d, J = 14.0 Hz, 1 H, ArCH2SO3], 4.68 [dd, J = 4.0, 4.7 Hz, 1
H, CH(OC)CH(OC)2], 4.80 [dd, J = 4.7, 8.4 Hz, 1 H, CHOSO2],
5.82 [d, J = 3.7 Hz, 1 H, CH(OC)2], 6.96–7.38 (m, 4 H, ArH).
13C NMR (100 MHz, CDCl3): d = 25.2, 26.3, 26.7, 26.8
[O2C(CH3)2], 55.3 [OCH3], 57.7 [ArCH2SO3], 65.3 [OCH2CH],
74.8 [CH(OC)CH2O], 76.7, 77.5, 77.9 [CHO], 103.9 [CH(OC)2],
110.2, 113.8 [O2C(CH3)2], 114.7, 116.6, 123.1, 129.9 [ArCH],
128.8 [ArC], 159.9 [ArCOCH3].
3.8 Hz, 1 H, CH(OC)2], 7.30–7.33 (m, 3 H, ArH), 7.42–7.46 (m, 2
H, ArH).
13C NMR (100 MHz, CDCl3): d = 25.4, 26.3, 26.7, 26.8
[O2C(CH3)2], 35.4 [CH2CO2CH3], 52.4 [OCH3], 64.1 [ArCHSO3],
65.7
[OCH2CH],
74.9
77.6
[CH(OC)CH2O],
[CH(OC)CH(OC)2],
77.1
77.9
[CH(OC)CH(OC)CH2O],
[CHOSO2], 103.9 [CH(OC)2], 110.2, 113.8 [(O)2C(CH3)2], 128.9,
129.5, 129.7 (ArCH), 131.0 (ArC), 169.5 (C=O).
MS (EI, 70 eV): m/z (%) = 471 (53) [M+ – CH3], 397 (6), 163 (39),
121 (100), 113 (46), 101 (55), 59 (11).
Anal. Calcd for C22H30O10S (486.54): C, 54.31; H, 6.22. Found: C,
53.96; H, 5.90.
MS (CI, 100 eV, methane): m/z (%) = 445 (35) [M+ + 1], 429 (55)
[M+ – CH3], 387 (33), 329 (11), 303 (10), 285 (15), 247 (5), 202
(16), 185 (37), 121 (88), 101 (100).
b-Isopropoxycarbonyl Sulfonate (R)-2b
According to GP2, the sulfonate 1b (0.205 g, 0.5 mmol) was depro-
tonated with n-BuLi (0.35 mL, 1.1 equiv) and reacted with isopro-
pyl bromoacetate (100 mL, 1.5 equiv). Work up and flash
chromatography (EtOAc–n-pentane, 1:3) yielded the sulfonate 2b
as a mixture of diastereomers (0.190 g, 76%); de = 80% (NMR).
The major diastereomer (R)-2b was obtained as a colorless solid af-
ter recrystallization from EtOH; de ≥ 98% (NMR); mp 148 °C;
[a]D24 +80.1 (c = 1.0, CHCl3).
Anal. Calcd for C20H28O9S (444.15): C, 54.04; H, 6.35. Found: C,
54.08; H, 6.22.
Enantiopure Sulfonate 1d
According to GP 1, the crude product was purified by column chro-
matography (SiO2; Et2O–n-pentane, 1:2) to give 1d as a colorless
solid (774 mg, 59%); mp 92 °C; [a]D24 +51.1 (c = 1.0, CHCl3).
IR (KBr): 3439, 2984, 2936, 1729, 1456, 1370, 1335, 1262, 1232,
1162, 1111, 1045, 1014, 875, 844, 826, 808, 695 cm–1.
IR (KBr): 2988, 2936, 2881, 1455, 1378, 1260, 1216, 1171, 1018,
891, 860, 837, 580 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12 [d, J = 5.2 Hz, 3 H,
CH(CH3)2], 1.16 [d, J = 5.2 Hz, 3 H, CH(CH3)2], 1.40, 1.43, 1.51,
1.63 [4 × s, 12 H, O2C(CH3)2], 3.26 [dd, J = 11.1, 16.1 Hz, 1 H,
1H NMR (400 MHz, CDCl3): d = 1.30, 1.30, 1.41, 1.51 [4 × s, 12 H,
O2C(CH3)2], 1.91 [s, 3 H, CH2=CCH3], 3.82 [d, J = 14.0 Hz, 1 H,
CH2SO3], 3.86 [dd, J = 6.3, 8.8 Hz, 1 H, OCH2CH], 3.91 [d, J = 14.2
Hz, 1 H, CH2SO3], 4.01 [dd, J = 6.9, 8.5 Hz, 1 H, OCH2CH], 4.08
[dd, J = 4.1, 8.2 Hz, 1 H, CH(OC)CH(OC)CH2O], 4.32 [dt, J = 4.1,
6.6 Hz, 1 H, CH(OC)CH2O], 4.73 [dd, J = 3.6, 7.1 Hz, 1 H,
CHOSO2], 4.76 [br dd, J = 3.6, 4.7 Hz, 1 H, CH(OC)CH(OC)2],
5.13 [br s, 1 H, CH2=CH(CH3)], 5.16 [m, 1 H, CH2=CH(CH3)], 5.75
[d, J = 3.6 Hz, 1 H, CH(OC)2].
13C NMR (100 MHz, CDCl3): d = 22.3 [CH2=C(CH3)], 25.1, 26.2,
26.4, 26.8 [O2C(CH3)2], 59.6 [CH2SO3], 65.4 [OCH2CH], 74.7
[CH(OC)CH2O], 76.7, 77.1, 78.0 [CHO], 103.9 [CH(OC)2], 110.1,
113.7 [O2C(CH3)2], 121.1 [CH2=C(CH3)], 132.7 [CH2=C(CH3)].
CH2CO2CH(CH3)2], 3.53 [dd,
J = 4.2, 16.1 Hz, 1 H,
CH2CO2CH(CH3)2], 3.92 [dd, J = 6.4, 8.7 Hz, 1 H, OCH2CH], 4.10
[dd, J = 6.7, 8.7 Hz, 1 H, OCH2CH], 4.18 [dd, J = 4.5, 8.4 Hz, 1 H,
CH(OC)CH(OC)CH2O], 4.19 [dt,
J = 4.5, 6.4 Hz, 1 H,
CH(OC)CH2O], 4.51 [br t, J = 3.9 Hz, 1 H, CH(OC)CH(OC)2], 4.72
[dd, J = 4.7, 8.5 Hz, 1 H, CHOSO2], 4.91–4.98 [m, 2 H, ArCHSO3,
CH(CH3)2], 5.79 [d, J = 3.8 Hz, 1 H, CH(OC)2], 7.42–7.45 (m, 3 H,
ArH), 7.55–7.58 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.6, 21.7 [CH(CH3)2] 25.4, 26.4,
26.7, 26.8 [(O)2C(CH3)2], 35.7 (CH2CO2CH3), 64.3 (ArCHSO3),
65.7 [OCH2CH], 68.9 [CH(CH3)2], 74.9 [CH(OC)CH2O], 77.3
[CH(OC)CH(OC)CH2O],
(CHOSO2), 103.9 [CH(OC)2], 110.2, 113.7 [O2C(CH3)2], 128.7,
129.4, 129.8 (ArCH), 131.0 (ArC), 168.4 (C=O).
MS (EI, 70 eV): m/z (%) = 499 (91) [M+ – CH3], 397 (19), 245 (8),
191 (32), 149 (56), 133 (25), 113 (82), 101 (100), 91 (30), 59 (15).
77.7
[CH(OC)CH(OC)2],
77.9
MS (EI, 70 eV): m/z (%) = 363 (100) [M+ – CH3], 305 (1), 245 (2),
167 (9), 127 (16), 113 (62), 101 (72), 55 (57).
HRMS: m/z [M+ – CH3] calcd for C16H26O8S: 363.1114; found:
363.1113.
b-Methoxycarbonyl Sulfonate (R)-2a
Anal. Calcd for C24H34O10S (514.59): C, 56.02; H, 6.66. Found: C,
55.68; H, 6.71.
According to GP2, the sulfonate 1a (0.615 g, 1.5 mmol) was depro-
tonated with n-BuLi (1.15 mL, 1.1 equiv) and reacted with methyl
bromoacetate (240 mL, 1.5 equiv). Work up and flash chromatogra-
phy (EtOAc–n-pentane, 1:3) yielded the sulfonate 2a as a mixture
of diastereomers (0.580 g, 80%); de = 84% (NMR). The major
diastereomer (R)-2a was obtained as a colorless solid after recrys-
tallization from EtOH; de ≥ 98% (NMR); mp 151 °C; [a]D24 +91.5
(c = 1.0, CHCl3).
b-tert-Butoxycarbonyl Sulfonate (R)-2c
According to GP2, the sulfonate 1a (0.294 g, 0.5 mmol) was depro-
tonated with n-BuLi (0.35 mL, 1.1 equiv) and reacted with tert-bu-
tyl bromoacetate (160 mL, 1.5 equiv). Work up and flash
chromatography (EtOAc–n-pentane, 1:3) yielded the sulfonate 2c
as a mixture of diastereomers (0.284 g, 74%); de = 75% (NMR).
The major diastereomer (R)-2c was obtained as a colorless solid af-
ter recrystallization from EtOH; de ≥ 98% (NMR); mp 156 °C;
[a]D23 +75.16 (c = 2.4, CHCl3).
IR (KBr): 3439, 2949, 1729, 1456, 1371, 1344, 1241, 1214, 1169,
1114, 1049, 1016, 975, 877, 837, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27, 1.29, 1.38, 1.49 [4 × s, 12 H,
O2C(CH3)2], 3.16 [dd, J = 10.7, 16.5 Hz, 1 H, CH2CO2CH3], 3.47
[dd, J = 4.1, 16.5 Hz, 1 H, CH2CO2CH3], 3.53 [s, 3 H, OCH3], 3.79
[dd, J = 6.3, 8.5 Hz, 1 H, OCH2CH], 3.95 [dd, J = 6.6, 8.5 Hz, 1 H,
OCH2CH], 4.06 [dd, J = 4.7, 8.5 Hz, 1 H, CH(OC)CH(OC)CH2O],
4.19 [dt, J = 4.7, 6.3 Hz, 1 H, CH(OC)CH2O], 4.39 [br dd, J = 3.9,
4.7 Hz, 1 H, CH(OC)CH(OC)2], 4.62 [dd, J = 4.7, 8.5 Hz, 1 H,
CHOSO2], 4.85 [dd, J = 3.9, 10.4 Hz, 1 H, ArCHSO3], 5.67 [d, J =
IR (KBr): 3429, 2940, 2936, 1711, 1460, 1367, 1338, 1262, 1223,
1176, 1145, 1076, 1016, 888, 840, 697, 571, 505 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.19 [s, 9 H, C(CH3)3], 1.28, 1.31,
1.39, 1.51 [4 × s, 12 H, O2C(CH3)2], 3.09 [dd, J = 11.3, 15.9 Hz, 1
H, CH2CO2C(CH3)3], 3.37 [dd,
J = 4.4, 15.9 Hz, 1 H,
CH2CO2C(CH3)3], 3.80 [dd, J = 6.9, 8.8 Hz, 1 H, OCH2CH], 3.97
[dd, J = 6.3, 8.5 Hz, 1 H, OCH2CH], 4.05 [dd, J = 4.4, 8.2 Hz, 1 H,
CH(OC)CH(OC)CH2O], 4.18 [dt,
J = 4.7, 6.6 Hz, 1 H,
Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York

2966
D. Enders et al.
PAPER
CH(OC)CH2O], 4.38 [dd, J = 3.9, 4.6 Hz, 1 H, CH(OC)CH(OC)2],
4.59 [dd, J = 4.7, 8.5 Hz, 1 H, CHOSO2], 4.77 [dd, J = 4.1, 11.2 Hz,
1 H, ArCHSO3], 5.67 [d, J = 3.8 Hz, 1 H, CH(OC)2], 7.30–7.32 (m,
3 H, ArH), 7.42–7.45 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 25.3, 26.3, 26.7, 26.7
[O2C(CH3)2], 27.8 [CO2C(CH3)3], 36.4 [CH2CO2C(CH3)3], 64.4
(ArCHSO3), 65.7 [OCH2CH], 74.9 [CH(OC)CH2O], 77.1
[dd, J = 4.1, 16.7 Hz, 1 H, CH2CO2CH3], 3.65 [s, 3 H, CO2CH3],
3.87 [s, 3 H, ArOCH3], 4.08 [dd, J = 6.6, 8.5 Hz, 1 H, OCH2CH],
4.16 (dd, J = 4.7, 8.5 Hz, 1 H, OCH2CH), 4.30 [dd, J = 4.4, 8.5 Hz,
1 H, CH(OC)CH(OC)CH2O], 4.19 [dt, J = 4.4, 6.3 Hz, 1 H,
CH(OC)CH2O], 4.52 [br t, J = 4.1 Hz, 1 H, CH(OC)CH(OC)2], 4.72
(dd, J = 4.9, 8.5 Hz, 1 H, CHOSO2), 4.93 (dd, J = 4.1, 10.7 Hz, 1 H,
ArCHSO3), 5.78 [d, J = 3.9 Hz, 1 H, CH(OC)2], 6.85 (dd, J = 2.4,
8.2 Hz, 1 H, ArH), 6.97 (br t, J = 2.4 Hz, 1 H, ArH), 7.13 (d, J = 8.0
Hz, 1 H, ArH), 7.30 (br s, 1 H, ArH).
[CH(OC)CH(OC)CH2O],
77.7
[CH(OC)CH(OC)2],
77.9
(CHOSO2), 81.7 [C(CH3)3], 103.9 [CH(OC)2], 110.2, 113.7
[O2C(CH3)2], 128.7, 129.4, 129.9 (ArCH), 131.1 (ArC), 168.0
(C=O).
MS (EI, 70 eV): m/z (%) = 513 (100) [M+ – CH3], 397 (23), 149
(82), 129 (17), 113 (62), 101 (83).
HRMS: m/z [M+ – CH3] calcd for C25H36O10S: 513.1795; found:
13C NMR (100 MHz, CDCl3): d = 25.4, 26.4, 26.7, 26.8
[O2C(CH3)2], 35.4 (CH2CO2CH3), 52.4 (CO2CH3), 55.4 (ArOCH3),
64.1 (ArCHSO3), 65.7 (OCH2CH), 74.9 [CH(OC)CH2O], 76.8
[CH(OC)CH(OC)CH2O],
77.7
[CH(OC)CH(OC)2],
78.0
(CHOSO2), 103.9 [CH(OC)2], 110.2, 113.8 [O2C(CH3)2], 114.9,
115.6, 121.9, 132.4 (ArCH), 129.8 (ArC), 159.9 (ArCOCH3), 169.5
(C=O).
513.1795.
MS (CI, 100 eV, methane): m/z (%) = 517 (2) [M+ + 1], 516 (14)
[M+], 501 (34) [M+ – CH3], 459 (22), 429 (7), 375 (36), 274 (11),
203 (42), 193 (100), 151 (35), 101 (69).
b-Methoxycarbonyl Sulfonate (R)-2d
According to GP2, the sulfonate 1b (0.294 g, 0.5 mmol) was depro-
tonated with n-BuLi (0.35 mL, 1.1 equiv) and reacted with methyl
bromoacetate (80 mL, 1.5 equiv). Work up and flash chromatogra-
phy (EtOAc–n-pentane, 1:3) yielded the sulfonate 2d as a mixture
of diastereomers (0.235 g, 75%); de ≥ 80% (NMR). The major
diastereomer (R)-2d was obtained as a colorless solid after recrys-
tallization from EtOH; de ≥ 98% (NMR); mp 120 °C; [a]D24 +79.7
(c = 1.1, CHCl3).
Anal. Calcd for C23H32O11S (516.56): C, 53.48; H, 6.24. Found: C,
53.53; H, 6.39.
b-Methoxycarbonyl Sulfonate (R)-2f
According to GP2, the sulfonate 1d (0.189 g, 0.5 mmol) was depro-
tonated with n-BuLi (0.35 mL, 1.1 equiv) and reacted with methyl
bromoacetate (80 mL, 1.5 equiv). Work up and flash chromatogra-
phy (EtOAc–n-pentane, 1:3) yielded the sulfonate 2f as a mixture of
diastereomers (0.110 g, 49%); de = 40% (NMR).
IR (KBr): 3457, 2976, 2950, 2899, 1737, 1372, 1235, 1162, 1117,
1048, 1017, 994, 878, 837, 606 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.34 [s, 9 H, C(CH3)3], 1.38, 1.40,
1.48, 1.60 [4 × s, 12 H, O2C(CH3)2], 3.25 [dd, J = 10.4, 16.8 Hz, 1
H, CH2CO2CH3], 3.91 [dd, J = 4.1, 16.8 Hz, 1 H, CH2CO2CH3],
3.65 [s, 3 H, OCH3], 3.91 [dd, J = 6.5, 8.5 Hz, 1 H, OCH2CH], 4.08
[dd, J = 6.6, 8.5 Hz, 1 H, OCH2CH], 4.17 [dd, J = 4.4, 8.5 Hz, 1 H,
IR (KBr): 2990, 2901, 1727, 1651, 1442, 1370, 1252, 1163, 1114,
1017, 929, 879, 842, 607 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37 [s, 6 H, O2C(CH3)2], 1.45,
1.56 [2 × s, 6 H, O2C(CH3)2], 1.98 [s, 3 H, CH2=CCH3], 2.99 [dd,
J = 10.6, 16.6 Hz, CHHCO2CH3 (minor)], 3.00 [dd, J = 11.1, 16.3
CH(OC)CH(OC)CH2O], 4.31 [dt,
J = 4.4, 6.6 Hz, 1 H,
CH(OC)CH2O], 4.46 [br t, J = 4.2 Hz, 1 H, CH(OC)CH(OC)2], 4.72
[dd, J = 4.9, 8.5 Hz, 1 H, CHOSO2], 4.93 [dd, J = 4.1, 10.4 Hz, 1 H,
ArCHSO3], 5.78 [d, J = 3.9 Hz, 1 H, CH(OC)2], 7.40–7.47 (m, 4 H,
ArH).
13C NMR (100 MHz, CDCl3): d = 25.4, 26.4, 26.8, 26.8
[O2C(CH3)2], 31.4 [C(CH3)3], 34.8 [C(CH3)3], 35.4 [CH2CO2CH3],
52.4 (OCH3), 63.8 (ArCHSO3), 65.6 (OCH2CH), 74.9
Hz, CHHCO2CH3 (major)], 3.25 [dd, J = 4.2, 16.6 Hz,
CHHCO2CH3 (minor)], 3.29 [dd, J = 3.7, 16.3 Hz, CHHCO2CH3
(major)], 3.70 (s, 3 H, CO2CH3), 3.91 (m, 1 H, OCHHCHO], 4.10
[m, 2 H, OCHHCHO, CH(OC)CH(OC)CH2O], 4.31 [m, 2 H,
CH(OC)CH2O, CH(OC)CH(OC)2], 4.80 [m, 2 H, CHOSO2,
CHSO3], 5.22 [m, 1 H, CH2=CH(CH3) (minor)], 5.28 [br s, 1 H,
CH2=CH(CH3) (major)], 5.49 [d, J = 3.7 Hz, 1 H, CH(OC)2 (mi-
nor)], 5.82 [d, J = 3.5 Hz, 1 H, CH(OC)2 (major)].
[CH(OC)CH2O],
76.8
[CH(OC)CH(OC)CH2O],
77.6
[CH(OC)CH(OC)2], 77.8 (CHOSO2), 103.9 [CH(OC)2], 110.2,
113.8 [(O)2C(CH3)2], 125.8 (ArCH), 127.8 (ArC), 129.3 (ArCH),
152.6 (ArC), 169.7 (C=O).
MS (CI, 100 eV, methane): m/z (%) = 543 (0.1) [M+ + 1], 542 (0.3)
[M+], 527 (10) [MH+ – CH3], 421 (12), 219 (100), 203 (12), 177
(14), 101 (10).
13C NMR (75 MHz, CDCl3, major isomer): d = 22.0 [CH2=C(CH3)],
25.1, 26.2, 26.6, 26.7 [O2C(CH3)2], 34.0 (CH2CO2CH3), 52.2
(CO2CH3), 64.4 (CHSO3), 65.7 [OCH2CH], 74.9 [CH(OC)CH2O],
76.7, 77.2, 77.6 [CHO], 104.0 [CH(OC)2], 110.2, 113.7
[O2C(CH3)2], 119.8 [CH2=C(CH3)], 136.1 [CH2=C(CH3)], 169.9
(C=O).
MS (EI, 70 eV): m/z (%) = 435 (82) [M+ – CH3], 361 (8), 167 (7),
127 (100), 113 (34), 101 (52), 85 (41), 59 (11).
Anal. Calcd for C26H38O10S (542.22): C, 57.55; H, 7.07. Found: C,
57.59; H, 7.35.
Anal. Calcd for C19H30O10S (450.51): C, 50.66; H, 6.71. Found: C,
50.66; H, 6.85.
b-Methoxycarbonyl Sulfonate (R)-2e
According to GP2, the sulfonate 1c (0.222 g, 0.5 mmol) was depro-
tonated with n-BuLi (0.35 mL, 1.1 equiv) and reacted with methyl
bromoacetate (80 mL, 1.5 equiv). Work up and flash chromatogra-
phy (EtOAc–n-pentane, 1:3) yielded the sulfonate 2e as a mixture
of diastereomers (0.201 g, 78%); de = 80% (NMR). The major
diastereomer (R)-2e was obtained as a colorless solid after recrys-
tallization from EtOH; de ≥ 98% (NMR); mp 108 °C; [a]D24 +81.8
(c = 1.2, CHCl3).
Methyl (R)-3-Methoxysulfonyl-3-phenylpropionate [(R)-3a]
The sulfonate (R)-2a (0.560 g, 1.15 mmol) was dissolved in a solu-
tion of MeOH–H2O (18:2 mL). To the solution was added
Pd(OAc)2 (15 mol%) and the mixture was refluxed for 4 d. The pal-
ladium residues were removed by filtration and the filter cake was
washed with MeOH. The filtrate was treated with an ethereal solu-
tion of diazomethane until the yellow color persisted. The solvent
was evaporated under reduced pressure and the crude product was
purified by flash column chromatography (SiO2; Et2O–n-pentane,
1:3) to give the methyl sulfonate (R)-3a as a colorless solid (0.279
g, 94%); ee ≥ 98% [based on the de value of (R)-2a]; mp 95 °C;
[a]D25 +13.85 (c = 1.2, CHCl3).
IR (KBr): 3439, 2985, 2950, 1729, 1598, 1493, 1441, 1374, 1323,
1261, 1238, 1214, 1166, 1114, 1049, 1014, 877, 832, 694, 546 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.38, 1.41, 1.49, 1.60 [4 × s, 12 H,
O2C(CH3)2], 3.25 [dd, J = 10.7, 16.7 Hz, 1 H, CH2CO2CH3], 3.55
Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York

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Asymmetric Synthesis of a- and a,b-Substituted b-Alkoxycarbonyl Sulfonates
2967
IR (KBr): 2966, 1728, 1602, 1496, 1454, 1354, 1243, 1156, 1087,
986, 824, 795, 773, 743, 700, 569 cm–1.
Hz, 1 H, ArCHSO3), 4.54–4.68 [m, 2 H, SO3CH(CH3)2, CHHNO2],
5.03 (dd, J = 5.0, 14.8 Hz, 1 H, CHHNO2), 7.39–7.49 (m, 5 H, ArH).
1H NMR (300 MHz, CDCl3): d = 3.15 (dd, J = 8.9, 16.8 Hz, 1 H,
CHHCO2CH3), 3.41 (dd, J = 5.4, 16.8 Hz, 1 H, CHHCO2CH3), 3.63
(s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 4.83 (dd, J = 5.4, 8.9 Hz, 1 H,
CH2CHSO3CH3), 7.36–7.48 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 16.0, 20.6 [CH(CH3)2], 22.2, 23.4
[SO3CH(CH3)2], 28.1 [CH(CH3)2], 42.9 (CHCH2NO2), 68.8
(CHSO3), 73.4 (CH2NO2), 79.1 (SO3CH), 129.0, 129.3, 129.7
(ArCH), 132.3 (ArC).
13C NMR (75 MHz, CDCl3): d = 35.3 (CH2), 52.3 (OCH3), 57.3
(OCH3), 62.4 (CHSO3), 129.0, 129.4, 129.5 (ArCH), 131.6 (ArC),
169.8 (C=O).
MS (CI, 100 eV, methane): m/z (%) = 330 (24) [M+ + 1], 316 (2),
288 (48), 206 (100), 159 (14), 117 (2), 91 (2).
Anal. Calcd for C15H23NO5S (329.41): C, 54.69; H, 7.04; N, 4.25.
Found: C, 54.63; H, 7.15; N, 4.34.
MS (EI, 70 eV): m/z (%) = 258 (8) [M+], 163 (31), 121 (100), 104
(9), 91 (6), 77 (5), 59 (6).
Isopropyl (1R,2R)-2-Nitromethyl-1-phenylbutane Sulfonate
[(R,R)-6c]
Anal. Calcd for C11H14O5S (258.30): C, 51.15; H, 5.46. Found: C,
50.62; H, 5.52.
According to GP 4, the sulfonate (R,R)-4c (510 mg, 1.0 mmol) was
refluxed in a solution of 2% TFA–EtOH (18 mL) and H2O (2 mL)
for 15 h. After removal of the solvent in vacuo, a solution of the
crude sulfonic acid and triisopropylorthoformate (0.8 mL, 5 mmol)
in CH2Cl2 (10 mL) was refluxed for 3 h. The crude product was pu-
rified by column chromatography (SiO2; Et2O–n-pentane, 1:9) to
give (R,R)-6c as a colorless viscous liquid (262 mg, 84%); de ≥ 98%
(1H NMR); ee ≥ 98% [based on the de value of the sulfonate (R,R)-
4c]; [a]D22 +29.5 (c = 1.0, CHCl3).
Isopropyl (1R,2R)-2-Nitromethyl-1-phenylpentane Sulfonate
[(R,R)-6a]
According to GP 4, the sulfonate (R,R)-4a (500 mg, 1.0 mmol) was
refluxed in a solution of 2% TFA–EtOH (18 mL) and H2O (2 mL)
for 15 h. After removal of the solvent in vacuo, a solution of the
crude sulfonic acid and triisopropylorthoformate (0.8 mL, 5 mmol)
in CH2Cl2 (10 mL) was refluxed for 3 h. The crude product was pu-
rified by column chromatography (SiO2; Et2O–n-pentane, 15:85) to
give (R,R)-6a as a colorless solid (234 mg, 75%); mp 44 °C; de ≥
98% (1H NMR); ee ≥ 98% [based on the de value of the sulfonate
(R,R)-4a]; [a]D23 +13.3 (c = 1.0, CHCl3).
IR (film): 2980, 2940, 2882, 1555, 1497, 1459, 1354, 1170, 1093,
912, 755, 704, 605 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.03 [d, J = 6.2 Hz, 3 H, OCH(CH3)CH3], 1.23 (m, 1 H,
CHCHHCH3), 1.29 [d, J = 6.2 Hz, 3 H, OCH(CH3)CH3], 1.67 (dqd,
J = 3.7, 7.4, 14.6 Hz, 1 H, CHCHHCH3), 3.08 (m, 1 H,
CHCH2NO2), 4.47 (d, J = 8.7 Hz, 1 H, ArCHSO3), 4.66 [sept, J =
6.2 Hz, 1 H, CH(CH3)2], 4.72 (dd, J = 5.9, 14.1 Hz, 1 H, CHHNO2),
4.80 (dd, J = 6.2, 14.1 Hz, 1 H, CHHNO2), 7.38–7.48 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 10.1 (CH2CH3), 21.4 (CH2CH3),
22.2, 23.4 [CH(CH3)2], 39.8 (CHCH2NO2), 68.1 (CHSO3), 75.0
(CH2NO2), 79.3 (SO3CH), 129.1, 129.4, 129.9 (ArCH), 131.4
(ArC).
IR (KBr): 3036, 2970, 2937, 2876, 1552, 1455, 1386, 1355, 1325,
1224, 1161, 1089, 909, 736, 701, 632, 555 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 7.3 Hz, 3 H, CH2CH3),
1.04 (d, J = 6.3 Hz, 3 H, OCH(CH3)CH3), 1.20 (m, 1 H,
CHCHHCH2CH3), 1.20–1.39 (m, 2 H, CH2CH3), 1.30 (d, J = 6.0
Hz, 3 H, OCH(CH3)CH3), 1.60 (m, 1 H, CHCHHCH2CH3), 3.10 (m,
1 H, CHCH2NO2), 4.49 (d, J = 8.0 Hz, 1 H, ArCHSO3), 4.62 (dd,
J = 6.3, 14.0 Hz, 1 H, CHHNO2), 4.67 [sept, J = 6.3 Hz, 1 H,
CH(CH3)2], 4.78 (dd, J = 5.5, 14.0 Hz, 1 H, CHHNO2), 7.39–7.46
(m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.7 (CH2CH3), 19.2 (CH2CH3),
22.2, 23.4 [CH(CH3)2], 30.3 (CH2CH2CH3), 38.4 (CHCH2NO2),
68.1 (CHSO3), 76.9 (CH2NO2), 79.0 (SO3CH), 128.8, 129.2, 129.7
(ArCH), 131.0 (ArC).
MS (CI, 100 eV, methane): m/z (%) = 316 (1) [M+ + 1], 302 (3), 274
(18), 220 (2), 192 (100), 145 (18), 91 (1).
Anal. Calcd for C14H21NO5S (315.39): C, 53.32; H, 6.71; N, 4.44.
Found: C, 53.06; H, 6.74; N, 4.71.
MS (CI, 100 eV, methane): m/z (%) = 330 (1) [M+ + 1], 316 (2), 288
(11), 206 (100), 159 (22), 117 (2), 91 (1).
Methyl (1R,2R)-2-Hydroxymethyl-3-methyl-1-phenylbutane
Sulfonate [(R,R)-7]
Anal. Calcd for C15H23NO5S (329.41): C, 54.69; H, 7.04; N, 4.25.
Found: C, 54.90; H, 7.13; N, 4.24.
To a solution of the ester (R,R)-5b (77 mg, 0.25 mmol) in anhyd
CH2Cl2 (2.5 mL) was added a solution of DIBAL in CH2Cl2 (1 M,
0.65 mL) dropwise at –78 °C under Ar. The reaction mixture was
stirred at –78 °C for 30 min, then stirring was continued at –20 °C
for 3 h. The mixture was quenched with a large excess of MeOH and
a few drops of methanolic HCl (2 N). After removal of MeOH in
vacuo, the solid was triturated with CH2Cl2 for 30 min. The mixture
was filtered and washed with CH2Cl2. The solvent was evaporated
under reduced pressure and the crude product was purified by flash
column chromatography (SiO2; Et2O–n-pentane, 3:7) to give the
product (R,R)-7 as a colorless viscous liquid (63 mg, 95%); de ≥
98% (NMR and HPLC); ee ≥ 98% (HPLC, Chiralpak AD; n-hep-
tane–i-PrOH, 95:5); [a]D22 +39.0 (c = 1.6, CHCl3).
Isopropyl (1R,2R)-2-Nitromethyl-3-methyl-1-phenylbutane
Sulfonate [(R,R)-6b]
According to GP 4, the sulfonate (R,R)-4b (530 mg, 1.0 mmol) was
refluxed in a solution of 2% TFA–EtOH (18 mL) and H2O (2 mL)
for 15 h. After removal of the solvent in vacuo, a solution of the
crude sulfonic acid and triisopropylorthoformate (0.8 mL, 5 mmol)
in CH2Cl2 (10 mL) was refluxed for 3 h. The crude product was pu-
rified by column chromatography (SiO2; Et2O–n-pentane, 1:4) to
give (R,R)-6b as a colorless solid (141 mg, 43%); mp 101 °C; de ≥
98% (1H NMR); ee ≥ 98% [based on the de value of the sulfonate
(R,R)-4b]; [a]D24 +33.7 (c = 1.1, CHCl3).
IR (CHCl3): 3397, 2961, 1537, 1497, 1456, 1349, 1163, 1041, 990,
823, 758, 704, 594 cm–1.
IR (KBr): 3066, 2965, 1565, 1499, 1460, 1427, 1386, 1349, 1333,
1167, 1091, 916, 707, 601 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 0.96 [d, J = 7.0 Hz, 3 H, CH(CH3)2], 1.52 (m, 1 H,
CHCH(CH3)2], 2.33 (m, 1 H, CHCH2OH), 2.62 (br s, 1 H, OH),
3.45 (s, 3 H, SO3CH3), 3.98 (dd, J = 3.0, 13.1 Hz, 1 H, CHHOH),
4.15 (dd, J = 3.5, 13.1 Hz, 1 H, CHHOH), 4.63 (d, J = 11.1 Hz, 1 H,
ArCHSO3), 7.39–7.49 (m, 5 H, ArH).
1H NMR (300 MHz, CDCl3): d = 0.65 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.95 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 1.02 [d, J = 6.4 Hz,
3 H, SO3CH(CH3)2], 1.28 [d, J = 6.2 Hz, 3 H, SO3CH(CH3)2], 1.81
(m, 1 H, CHCH(CH3)2], 3.33 (m, 1 H, CHCH2NO2), 4.29 (d, J = 9.9
Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York

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D. Enders et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 16.8, 21.8 [CH(CH3)2], 27.8
[CH(CH3)2], 46.9 (CHCH2OH), 57.5 (SO3CH3), 60.0 (CHCH2OH),
68.1 (CHSO3), 129.0, 129.1, 129.7 (ArCH), 132.7 (ArC).
(4) (a) Enders, D.; Berner, O. M.; Vignola, N. Chem. Commun.
2001, 2498. (b) Enders, D.; Berner, O. M.; Vignola, N.;
Harnying, W. Synthesis 2002, 1945.
(5) (a) Enders, D.; Harnying, W.; Vignola, N. Synlett 2002,
1727. (b) Enders, D.; Harnying, W.; Vignola, N. Eur. J. Org.
Chem. 2003, 3939.
(6) Enders, D.; Harnying, W. Arkivoc 2004, ii, 181; www.arkat-
usa.org.
MS (CI, 100 eV, methane): m/z (%) = 273 (1) [M+ + 1], 177 (17),
159 (100), 147 (8), 137 (9), 119 (5), 105 (5), 91 (3), 75 (14).
Anal. Calcd for C13H20O4S (272.36): C, 57.33; H, 7.40. Found: C,
57.07; H, 7.19.
(7) Enders, D.; Harnying, W.; Raabe, G. Synthesis 2004, 590.
(8) Enders, D.; Harnying, W. Synthesis 2004, 2910.
(9) (a) Meyer, V.; Wurster, C. Ber. 1873, 6, 1168. (b) Edward,
J. T.; Tremaine, P. H. Can. J. Chem. 1971, 49, 3483.
(c) Edward, J. T.; Tremaine, P. H. Can. J. Chem. 1971, 49,
3489. (d) Edward, J. T.; Tremaine, P. H. Can. J. Chem.
1971, 49, 3493.
Acknowledgment
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.
(10) (a) Traynor, S. G.; Kane, B. J.; Betkouski, M. F.; Hirschy, L.
M. J. Org. Chem. 1979, 44, 1557. (b) Higashiura, K.;
Morino, H.; Matsuura, H.; Toyomaki, Y.; Ienaga, K. J.
Chem. Soc., Perkin Trans. 1 1989, 1476. (c)Higashiura,K.;
Ienaga, K. J. Org. Chem. 1992, 57, 764. (d) Kitamura, M.;
Yoshimura, M.; Kanda, N.; Noyori, R. Tetrahedron 1999,
55, 8785. (e) Xu, J. Tetrahedron: Asymmetry 2002, 13,
1129.
(11) Brown, H. C.; Heim, P.; Yoon, N. M. J. Am. Chem. Soc.
1970, 92, 1637.
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References
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Synthesis 2005, No. 17, 2962–2968 © Thieme Stuttgart · New York