Stereoselective sulfonate aldol reactions: Asymmetric synthesis of α,β-substituted β-hydroxy sulfonates

Article abstract of DOI:10.1055/s-2007-986642

An efficient asymmetric synthesis of β-hydroxy sulfonates is described via stereocontrolled aldol reactions of sulfonates using 1,2:5,6-di-O- isopropylidene-α-D-allofuranose as the chiral auxiliary. The aldol reactions with aromatic aldehydes yielded pred

Full text of DOI:10.1055/s-2007-986642

LETTER
2529
Stereoselective Sulfonate Aldol Reactions: Asymmetric Synthesis
of a,b-Substituted b-Hydroxy Sulfonates
Asymmetric Synthesis
o
a
f
a
,
b
-Subst
c
ituted
b
-H
y
h
droxy Sulfo
a
a
Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
Fax +66(43)202373; E-mail: hwacha@kku.ac.th
b
c
Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Received 18 July 2007
moderate diastereomeric excesses (9–17%).5 In an
attempt to synthesize a,b-epoxysulfonic acids via the
Darzens reaction, Ghosez et al. described the reaction of
the lithiated tetrabutylammonium chloromethane-
Abstract: An efficient asymmetric synthesis of b-hydroxy
sulfonates is described via stereocontrolled aldol reactions of
sulfonates using 1,2:5,6-di-O-isopropylidene-a-D-allofuranose as
the chiral auxiliary. The aldol reactions with aromatic aldehydes
yielded predominantly syn adducts in very good yields and excel- sulfonate with a D-alaninal derivative to afford the corre-
lent diastereo- and enantiomeric excesses (de, ee ≥98%).
sponding a-chloro-b-hydroxy sulfonate in 72% yield as a
mixture of four diastereomers.6
Key words: asymmetric synthesis, sulfonates, aldol reaction, sugar
auxiliary, hydroxy sulfonates
In our previous work, we described a highly efficient
asymmetric route towards a variety of different sulfonic
acid derivatives employing 1,2:5,6-di-O-isopropylidene-
a-D-allofuranose as the chiral auxiliary.7–13 Therein we
also reported an efficient asymmetric synthesis of substi-
tuted g-hydroxy sulfonates by hydrolysis of enantiopure
g-sulfones11 and by reduction of enantiopure b-alkoxy-
carbonyl sulfonates.13 In this context, we now wish to
describe a direct and efficient methodology for the asym-
metric synthesis of a,b-substituted b-hydroxy sulfonates
by performing stereocontrolled aldol reactions with
enantiomerically pure sulfonates.
Derivatives of sulfonic acids are important constituents of
living organisms and are involved in various physiologi-
cal processes.1 However, in many cases the physiological
role of these sulfonic acid derivatives remains unclear. To
get further insight into their mode of action a stereo-
selective access to these derivatives is desirable and com-
pulsory for physiological tests. In our ongoing research
concerning the chemistry of sulfonates we have now
developed an efficient diastereo- and enantioselective
approach to one class of these derivatives, namely the title
b-hydroxy sulfonates. Hitherto, only a few synthetic
routes for the asymmetric synthesis of these interesting
compounds have been described. Optically active b-hy-
droxy sulfonates could be synthesized by nucleophilic
opening of enantiomerically pure epoxides with either
sodium sulfite2 or sodium bisulfite3 and by Ru–BINAP-
catalyzed hydrogenation of b-keto sulfonates.4
Our studies started with the model reaction between the
enantiopure sulfonate 1 and benzaldehyde as outlined in
Scheme 1. In the first test reaction, the enantiopure
sulfonate 1 was deprotonated with one equivalent of LDA
at –78 °C and treated with benzaldehyde at –78 °C for one
hour. After aqueous workup, the desired aldol adduct
could not be observed. Instead only the starting material 1
and a small amount of the cleaved chiral auxiliary could
be identified by 1H NMR analysis. A change of the reac-
tion temperature to either –40 °C or –100 °C did not yield
the desired product either.
It is widely accepted that the aldol reaction is one of the
most powerful tools for the stereoselective construction of
new carbon–carbon bonds. In this respect, the asymmetric
aldol reaction of sulfonate derivatives appears to be the
most direct route to these title compounds. To the best of
our knowledge, however, no method has been reported so
far for an asymmetric aldol reaction utilizing chiral sul-
fonates. Furthermore, even reports about aldol reactions
of a-metalated achiral sulfonates are very scarce.
We then examined the reaction in the presence of various
Lewis acidic additives. For this purpose the aldehyde was
complexed with the additive before its addition to the
OH
O
O
1. LDA, THF
2. PhCHO, LA
O
O
S
S
Ph
Ph
R*O
Zwanenburg and Nkunya reported on the asymmetric
Darzens reaction of L-menthyl chloromethanesulfonate
with aldehydes and symmetrical ketones under phase-
transfer conditions (PTC) leading to (trans-)epoxy
sulfonates in moderate to good yields, but with only
R*O
Ph
2a
1
+ minor syn isomer (2′a)
+ anti isomers (3a/3′a)
O
O
O
Me
Me
R* =
O
Me
Me
O
SYNLETT 2007, No. 16, pp 2529–2532
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986642; Art ID: G21507ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Asymmetric aldol reaction of the sulfonate 1 with
benzaldehyde (LA = Lewis acid)

2530
W. Harnying et al.
LETTER
Table 1 Optimization of the Reaction Conditions of the Aldol
Reaction of the Sulfonate 1 with Benzaldehyde
lithiated sulfonate. When the lithiated sulfonate 1 was
reacted with benzaldehyde precomplexed with t-
BuMe2SiCl at –78 °C for two hours, the four diastereo-
meric aldol products 2a:2¢a:3a:3¢a were obtained in 63%
yield in a ratio of 58:6:30:6 (see Table 1, entry 2). The
product ratio was determined by 1H NMR analysis of the
crude product by comparing the integrals of the four me-
thine protons (CHOH) resonating as doublets at d = 5.80,
5.82, 5.35 and 5.39 ppm, and comparing the order of these
values with the order above, i.e. 2a:2¢a:3a:3¢a, respective-
ly, as shown in Figure 1. The assignment of the relative
configuration of the aldol adducts was based on the com-
parison of the vicinal coupling constants (J1,2 = 2.3 Hz for
both syn isomers 2a and 2¢a; J1,2 = 9.6 and 9.5 Hz for the
anti isomers 3a and 3¢a, respectively).
Entry Lewis acida
equiv
Temp.b Yieldc
Ratiod
(°C)
–78
–78
–78
–100
–78
–78
–100
–78
–78
–78
–78
–78
–78
–78
(%)
syn/anti
1
2
none
0
0
–
t-BuMe2SiCl 1.5
63
88
45
trace
60
52
51
0
(58:6)/(30:6)
(79:0)/(18:3)
(82:0)/(15:3)
–
3
ZnCl2
1.2
1.2
2.5
3
4
ZnCl2
e
5
ZnCl2
6
ZnCl2
(76:0)/(20:4)
(84:0)/(14:2)
(62:7)/(25:6)
–
7
ZnCl2
3
8
BF3·OEt2
BF3·OEt2
MgCl2
Cy2BCl
ZnBr2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
e
9
10
11
12
13
14
22
18
39
52
10
(65:0)/ (18:17)
(78:0)/ (11:11)
(81:0)/ (17:2)
(65:0)/ (30:5)
(39:6)/ (47:8)
ZnI2
ZnEt2
a Unless stated otherwise, the lithiated sulfonate 1 was treated with
PhCHO (2 equiv) precomplexed with the indicated Lewis acid.
b Temperature at which the reaction was performed for both the
enolate formation and the addition of PhCHO.
Figure 1 1H NMR spectrum (400 MHz) of the crude product of the
aldol reaction between 1 and PhCHO (the region of the methine pro-
tons of the four diastereomers 2a, 2¢a, 3a and 3¢a is shown)
c Yield after chromatography.
d Determined by 1H NMR analysis of the crude reaction mixture.
e The reaction was performed by adding the Lewis acid to the lithium
enolate followed by stirring for 1 h and addition of PhCHO.
To further improve both yield and diastereoselectivity, we
investigated the effects of a number of other Lewis acids,
including BF3·OEt2, Cy2BCl, MgCl2, ZnX2 (X = Cl, Br, I)
and ZnEt2, as summarized in Table 1.
the Lewis acid to the lithiated sulfonate prior to the addi-
tion of the aldehyde, occurs, it appears to be a dead end.
From these investigations, the best results in terms of both
yield and diastereoselectivity arose from the experimental
conditions shown in entry 3. We then proceeded to apply
these conditions to a wide range of other aldehydes
(Scheme 2). Therefore, the enantiopure sulfonate 1 was
deprotonated with LDA (1 equiv) in THF at –78 °C,
followed by the addition of the corresponding aldehyde
(2 equiv) precomplexed with ZnCl2 (1.2 equiv) at –78 °C,
to furnish predominantly the syn-configured b-hydroxy
sulfonates 2a–l.14 The results are illustrated in Table 2.
As can be seen in Table 1, the use of ZnCl2 as the Lewis
acid at –78 °C gave the best results in the aldol reaction of
the sulfonate 1 regarding both yield and diastereoselectiv-
ity (entry 3). The aldol adduct was obtained in 88% yield
as a 79:21 mixture of syn and anti isomers. The minor syn
diastereomer 2¢a could not be detected in this case.
Furthermore, we also observed that a lower reaction
temperature had no significant influence on the syn/anti
selectivity as shown in entry 4: carrying out the reaction
at –100 °C gave a comparable diastereoselectivity but a
lower yield. Using an excess of ZnCl2 gave 2a with a
similar selectivity but with a lower overall yield (entries 6
and 7).
Obviously, the nature of the aldehyde had a profound
influence on both the yield and the diastereoselectivity of
the reaction. The reaction with aromatic aldehydes
It should also be noted that only a trace of product was
observed when the lithiated sulfonate 1 was subjected to a
transmetalation with one of the Lewis acids (ZnCl2 or
BF3·OEt2) prior to the addition of benzaldehyde (entries 5
and 9). These results strongly indicate that the Lewis acid
acts as an indispensable activating agent for the carbonyl
group. If a transmetalation, promoted by the addition of
1. LDA, THF, –78 °C, 1 h
2. RCHO, ZnCl2, THF,
–78 °C, 1 h
OH
O
O
O
O
S
S
Ph
R
R*O
R*O
Ph
2a–l
1
Scheme 2 Asymmetric aldol reaction of sulfonate 1 with different
aldehydes
Synlett 2007, No. 16, 2529–2532 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of a,b-Substituted b-Hydroxy Sulfonates
2531
afforded the corresponding aldol products in very good to Pd(OAc)2 for one day followed by treatment with diazo-
excellent yields (84–96%) and with high diastereoselec- methane yielded the b-hydroxy sulfonic acid (1S,2R)-4 in
tivities (63–89%). In all of these cases, only three (i.e. one a nonoptimized yield of 42% as a single diastereoisomer
syn and two anti diastereomers) out of four possible dia- showing that the cleavage reaction proceeded without
stereomers could be detected. Moreover, the major epimerization and/or racemization (Scheme 3).15,16 Ac-
sulfonate could be easily obtained diastereomerically pure cordingly, the ee value of the b-hydroxy sulfonic acid
by flash column chromatography and recrystallization (de (1S,2R)-4 is expected to be greater than 98% based on the
≥98%) in all cases. In contrast, the reaction with aliphatic de value of the corresponding aldol adduct. It should be
aldehydes resulted in low diastereoselectivities but still noted that the attempted methylation of the sulfonic acid
moderate to very good yields (entries 9–12).
group did not furnish the corresponding methyl sulfonate,
probably due to intramolecular H-bonding between the
sulfonic acid moiety and the b-hydroxyl group.
Table 2 Asymmetric Aldol Reaction of the Sulfonate 1 with
Representative Aldehydes
1. Pd(OAc)2 (cat.)
EtOH–H2O, reflux, 24 h
2. CH2N2, Et2O
Entry Product
R
Yielda (%) drb
79:0:18:3 (≥99)
OH
OH OH
O S
O
O
S
1
2
2a
2b
2c
2d
2e
2f
Ph
88
84
89
91
93
92
96
92
92
60
48
42
Ph
Ph
R*O
O
42%
Ph
Ph
4-(i-Pr)C6H4
2-MeOC6H4
3-MeOC6H4
2-NO2C6H4
4-NO2C6H4
2-ClC6H4
4-ClC6H4
Me
79:0:18:3 (≥99)
83:0:9:8 (≥99)
75:0:20:5 (≥99)
71:0:15:14 (≥99)
63:0:19:18 (≥99)
89:0:6:5 (≥99)
75:0:22:3 (≥99)
48:36:16c
(1S,2R)-4
de, ee ≥ 98%
(1S,2R)-2a
de ≥ 98%
3
4
Scheme 3 Removal of the chiral auxiliary to form the b-hydroxy
sulfonic acid (1S,2R)-4
5
6
In summary, we have developed an efficient asymmetric
access to a,b-substituted b-hydroxy sulfonates by per-
forming stereocontrolled aldol reactions of enantiopure
sulfonates using 1,2:5,6-di-O-isopropylidene-a-D-allo-
furanose as the chirality auxiliary. A thoughtful study and
optimization of the reaction conditions led to the conclu-
sion that the best conditions regarding both yield and
diastereoselectivity involve the reaction of the lithiated
sulfonates with aldehydes precomplexed with zinc chlo-
ride. In addition, the reaction with aromatic aldehydes led
to the corresponding aldol adducts in very good yields and
with excellent diastereoselectivities. Studies towards a
more efficient cleavage of the chiral auxiliary are current-
ly underway in our laboratories.
7
2g
2h
2i
8
9
10
11
12
2j
i-Pr
48:44:8c
2k
2l
n-Pr
56:31:13c
n-Bu
55:31:14c
a Yield of a diastereomeric mixture.
b Determined by 1H NMR analysis of the crude reaction mixture. The
value in parentheses shows the dr value after flash column chroma-
tography and recrystallization.
c Diastereomeric ratio of all observed isomers.
Acknowledgment
In all examples employing aromatic aldehydes, the reac-
tion predominantly gave the syn adduct 2a–h. The relative
configuration of 2b–h/2¢b–h was assigned by comparison
of their 1H NMR spectra to that of 2a/2¢a described above.
The absolute configurations of the two newly formed
stereogenic centers in the b-hydroxy sulfonates 2a–h were
assigned to be 1S,2R based on the results obtained from
related reactions in previous reports using functionalized
electrophiles.8,13 Further evidence for this assumption was
obtained from the fact that related electrophilic a-alkyla-
tions show the same relative topicity.7,9 By assuming a
uniform reaction mechanism, all examples described
herein should possess the same absolute configuration.
This work was supported by the Thailand Research Fund (TRF), the
Commission on Higher Education (CHE-RG) and the Center for
Innovation in Chemistry: Postgraduate Education and Research
Program in Chemistry (PERCH-CIC).
References and Notes
(1) Kalir, A.; Kalir, H. H. In The Chemistry of Sulfonic Acids,
Esters and their Derivatives; Patai, S.; Rappoport, Z., Eds.;
Wiley: Chichester / New York, 1991, 767.
(2) Traynor, S. G.; Kane, B. J.; Betkouski, M. F.; Hirschy, L. M.
J. Org. Chem. 1979, 44, 1557.
(3) Prager, R. H.; Schafer, K.; Hamon, D. P. G.; Massy-
Westropp, R. A. Tetrahedron 1995, 51, 11465.
(4) Kitamura, M.; Yoshimura, M.; Kanda, N.; Noyori, R.
Tetrahedron 1999, 55, 8785.
(5) Nkunya, M. H. H.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1983, 102, 461.
In a first attempt, the removal of the chiral auxiliary to
yield the corresponding sulfonic acids was successfully
accomplished using a procedure that had been described
previously:7 refluxing the aldol adduct (1S,2R)-2a in an
EtOH–H2O mixture containing a catalytic amount of
(6) Carretero, J. C.; Davies, J.; Marchand-Brynaert, J.; Ghosez,
L. Bull. Soc. Chim. Fr. 1990, 127, 835.
Synlett 2007, No. 16, 2529–2532 © Thieme Stuttgart · New York

2532
W. Harnying et al.
LETTER
(7) (a) Enders, D.; Vignola, N.; Berner, O. M. Angew. Chem.
Int. Ed. 2002, 41, 109; Angew. Chem. 2002, 114, 116.
(b) Enders, D.; Vignola, N.; Berner, O. M.; Harnying, W.
Tetrahedron 2005, 61, 3231.
(8) (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.
(9) (a) Enders, D.; Harnying, W.; Vignola, N. Synlett 2002,
1727. (b) Enders, D.; Harnying, W.; Vignola, N. Eur. J. Org.
Chem. 2003, 20, 3939.
(10) Enders, D.; Harnying, W. ARKIVOC 2004, (ii), 181.
(11) Enders, D.; Harnying, W.; Raabe, G. Synthesis 2004, 590.
(12) Enders, D.; Harnying, W. Synthesis 2004, 2910.
(13) Enders, D.; Adelbrecht, J.-C.; Harnying, W. Synthesis 2005,
2962.
(14) General Procedure for Aldol Reactions of the Sulfonate
1: To a cooled (–78 °C) solution of freshly generated lithium
diisopropylamide [prepared by treatment of diisopropyl-
amine (1.1 mmol) in anhyd THF (3 mL) with n-BuLi (1
mmol) at –78 °C for 30 min] was added dropwise a solution
of the sulfonate 1 (1 mmol) in THF (2 mL) under N2. After
stirring for 1 h, a mixture of aldehyde (2 mmol) and 1 M
ZnCl2 in THF (1.2 mmol) was added dropwise. The reaction
mixture was stirred at –78 °C for 1 h and then quenched with
sat. NH4Cl. The mixture was poured into an ice-cooled 1 N
HCl solution (10 mL) and extracted with EtOAc. The
combined organic layers were washed with H2O, brine and
dried over Na2SO4. The solvent was removed under reduced
pressure to give the crude product. The diastereomeric ratio
was determined at this stage by 1H NMR (400 MHz). The
crude product was purified by flash column chromatography
(SiO2, EtOAc–hexane) to give the aldol product 2.
(1S,2R)-2a: colorless solid; de ≥ 98%; mp 103–104 °C;
[a]D29 +93.1 (c = 0.105, EtOH). IR (KBr): 3446 (s), 2986,
1630, 1375, 1344 (s), 1217, 1150 (s), 1059 (s), 1017 (s), 886,
705 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.29, 1.30, 1.37,
1.57 (4 ꢀ s, 12 H, 4 ꢀ Me), 3.65 (br s, 1 H, OH), 3.75 (dd,
J = 6.6, 8.7 Hz, 1 H, CHH), 3.95 (dd, J = 6.7, 8.7 Hz, 1 H,
CHH), 4.09 [dd, J = 4.1, 8.6 Hz, 1 H, CH2CHCHO), 4.25 (dt,
J = 4.1, 6.6 Hz, 1 H, CH2CHCHO), 4.46 [t, J = 4.4 Hz, 1 H,
OCHCH(OC)2], 4.47 (d, J = 2.2 Hz, 1 H, CHSO3), 4.81 (dd,
J = 4.7, 8.6 Hz, 1 H, CHOSO2), 5.71 [d, J = 3.7 Hz, 1 H,
CH(OC)2], 5.80 (br d, J = 1.8 Hz, 1 H, CHOH), 7.01–7.30
(m, 10 H, ArH). 13C NMR (100 MHz, CDCl3): d = 25.2,
26.1, 26.6, 26.7 (4 ꢀ Me), 65.4 (CH2), 72.1 (CHOH), 74.0
(CHSO3), 74.6, 76.4, 76.9, 77.6 (4 ꢀ CHO), 103.8 (OCHO),
110.3, 113.8 [2 ꢀ C(CH3)2], 126.0 (ArCH), 127.76 (ArC),
127.83, 128.1, 128.2, 129.1, 131.3 (ArCH), 139.2 (ArC). MS
(EI, 70 eV): m/z (%) = 520 (0.2)[M+], 505 (22), 399 (16), 341
(23), 292 (17), 197 (31), 167 (31), 127 (51), 91 (100), 77
(33), 55 (17). Anal. Calcd for C26H32O9S (520.59): C, 59.99;
H, 6.20. Found: C, 60.13; H, 6.19.
(15) (1S,2R)-4: colorless solid; de, ee ≥ 98%; mp 169–170 °C;
[a]D29 +122.0 (c = 0.115, EtOH). IR (KBr): 3467 (s), 1220,
1163 (s), 1049 (s), 795, 713, 651, 572 cm–1. 1H NMR (400
MHz, CDCl3–CD3OD): d = 3.87 (br s, 1 H, OH), 4.02 (d,
J = 1.8 Hz, 1 H, CHSO3), 5.71 (d, J = 1.8 Hz, 1 H, CHOH),
6.93–6.97 (m, 2 H, ArH), 7.02–7.11 (m, 6 H, ArH), 7.17–
7.21 (m, 2 H, ArH). 13C NMR (100 MHz, CDCl3–CD3OD):
d = 71.7, 73.1 (2 ꢀ CH), 126.0, 127.0, 127.19, 127.22, 127.6,
130.7 (ArCH), 132.5, 140.7 (2 ꢀ ArC). MS (EI, 70 eV):
m/z (%) = 179 (100)[PhCH=C(Ph)+], 165 (55), 152 (20).
(16) epi-4 obtained from the cleavage of the anti isomer 3a under
the same conditions exhibits a different 1H NMR spectrum.
1H NMR (400 MHz, CDCl3–CD3OD): d = 3.67 (br s, 1 H,
OH), 4.16 (d, J = 10.1 Hz, 1 H, CHSO3), 5.29 (d, J = 10.1
Hz, 1 H, CHOH), 7.00–7.30 (m, 10 H, ArH).
Synlett 2007, No. 16, 2529–2532 © Thieme Stuttgart · New York