Stereoselective hydrolysis of sec-mono-alkyl sulfate esters with retention of configuration

Article abstract of DOI:10.1016/j.tet.2004.11.075

An optimised method for the stereoselective hydrolysis of sec-alkylsulfate monoesters with absolute retention of configuration was developed. Under optimised conditions, clean hydrolysis of (R)-2-octyl sulfate was achieved in aqueous t-butyl methyl ether

Full text of DOI:10.1016/j.tet.2004.11.075

Tetrahedron 61 (2005) 1517–1521
Stereoselective hydrolysis of sec-mono-alkyl sulfate esters with
retention of configuration
*
Sabine R. Wallner, Bettina Nestl and Kurt Faber
Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 31 August 2004; revised 23 November 2004; accepted 25 November 2004
Available online 16 December 2004
Abstract—An optimised method for the stereoselective hydrolysis of sec-alkylsulfate monoesters with absolute retention of configuration
was developed. Under optimised conditions, clean hydrolysis of (R)-2-octyl sulfate was achieved in aqueous t-butyl methyl ether (3:97) using
0
.6 equiv of p-toluenesulfonic acid as catalyst and 0.33 equiv of dioxane as mediator to give (R)-2-octanol as the sole product in the absence
of side reactions, such as racemisation or elimination.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Driven by the increased demand to enhance the economic
balance of chemical processes, the development of methods,
which allow the transformation of a racemate into a single
stereoisomeric product in 100% theoretical yield without
the occurrence of an ‘unwanted’ stereoisomer has become a
1
prime target in asymmetric synthesis. Among the various
strategies proposed to date, dynamic resolution, stereo-
2
3
4
inversions and enantio-convergent processes have proven
their applicability.
As depicted in Scheme 1, the latter method constitutes of
two reactions, which are generally independent of each
other. (i) One enantiomer of the racemic starting material is
transformed in a stereo- and enantio-selective fashion with
retention (or inversion) of configuration to yield the
corresponding homochiral product enantiomer by following
Scheme 1. Deracemisation of sec-alcohols via combined bio- and chemical
hydrolysis of the corresponding sulfate esters through inversion and
retention of configuration, respectively.
the chiral catalyst has to be enantioselective (with respect to
the selection of a single enantiomer from the racemate) and
stereoselective (with respect to retention/inversion of
configuration). The requirements for such ‘double’ selec-
tivities are hard to meet for chemical catalysts and, as a
consequence, biocatalysts are more often used. Once the
faster reacting enantiomer has been converted, the require-
ments for the catalyst to effect the second step becomes
easier, that is, only stereoselectivity with respect to
inversion/retention is required which could be accomplished
by a chemical catalyst.
5
a kinetic resolution. (ii) The non-reacting mirror-image
enantiomer, however, has to be converted via inversion (or
retention) of configuration, thus forming the same enantio-
meric product. In an ideal case, combination of both
reactions in a simultaneous fashion would create additional
6
benefits of a parallel kinetic resolution. Since the require-
ments regarding the simultaneous stereo- and enantioselec-
tivity of the respective catalyst(s) are very difficult to fulfil
in practice, both reactions are usually combined in a
sequential/stepwise fashion, albeit without separation of
intermediates in a one-pot procedure. Thus, in the first step,
In order to complete our studies aiming at the development
of a deracemisation process for sec-alcohols based on the
stereo- and enantioselective biohydrolysis of a (rac)-sec-
alkylsulfate ester using microbial alkyl sulfatases acting
Keywords: Monoalkyl sulfate ester; Hydrolysis; Retention of configuration;
Alkyl sulfatase.
*
Corresponding author. Tel.: C43 316 380 5332; fax: C43 316 380 9840;
e-mail: kurt.faber@uni-graz.at
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.075

1518
S. R. Wallner et al. / Tetrahedron 61 (2005) 1517–1521
7
1
estimated as pK K8.4 or pK K3.4 ), only strong
4
15
with inversion of configuration, we required a reliable
synthetic protocol for the stereoselective hydrolysis of the
remaining non-reacted sulfate ester enantiomer with strict
retention of configuration.
a
a
acids are effective as catalysts. The formation of sulfur
trioxide as short-lived intermediate was initially
1
6
17
proposed, but later excluded. Studies on chiral
sec-monoalkyl esters, however, revealed that the
expected retention of configuration is significantly
weakened by significant amounts of side reactions, in
particular racemisation going hand in hand with
elimination, which severely diminishes the overall
8
In contrast to dialkyl sulfate esters, such as dimethyl
sulfate, which are highly reactive species and thus
intrinsically unstable in aqueous solution, monoalkyl esters
are much more stable and thus are more resistant towards
hydrolysis. Depending on the reaction conditions, hydroly-
sis of a monoalkyl sulfate ester may either proceed via C–O
1
3
efficiency of this process.
(iii) A remarkable rate-enhancement in the (pH-indepen-
dent) hydrolysis of monoalkyl sulfate esters was also
shown to be effected by organic solvents possessing
Lewis-base electron-donor capabilities through oxy-
9
versus S–O-bond cleavage. Alkaline hydrolysis acts
K
through nucleophilic attack of [OH ] at carbon by making
use of the (formal) leaving group properties of sulfate anion,
thus affecting inversion of configuration through breakage
of the C–O-bond. On the other hand, acid-catalysed
hydrolysis causes protonation of the substrate (assumed to
take place at the internal C–O–S oxygen atom rather than at
1
8,23,24
gen-lone pairs, such as ethers, DMSO and DMF.
In particular, impressive rate accelerations with respect
7
to the uncatalysed reaction of up to 10 were reported
1
9
using moist dioxane. This method for the cleavage of
sulfate esters is unique with respect to its mechanism
and it relies on the unusual stability of the dioxane-
sulfur trioxide complex as a Lewis acid–base adduct,
K
10–12
terminal the S–O species
), which causes breakage of
K
the S–O bond. Thus, HSO4 is formally expelled, which
retains the configuration at carbon. Evaluation of the
existing procedures for the chemical hydrolysis of mono-
alkyl sulfate esters reveals that several methods have been
investigated (Scheme 2).
2
0
first described by Suter et al. A related, but largely
unexplained catalytic phenomenon was observed for
cyclodextrins.
1
8
(
i) Base-catalysed hydrolysis was shown to proceed with
The majority of the studies reported to date on the chemical
hydrolysis of monoalkyl sulfate esters emphasised physical-
organic and mechanistic/theoretical aspects rather than the
development of a reliable synthetic protocol for preparative-
scale transformations. Few studies deal with the de-sulfation
of sulfated materials from biological origin, such as
1
0
inversion of configuration. However, the reaction
rates were found to be exceedingly low and alkaline
hydrolysis is not feasible for preparative purposes,
although the expected inversion of configuration takes
1
3
place. This unreactivity may be explained by the
properties of sulfate anion (SO ), which—being the
2
4
K
21
22–24
sulfolipids and steroid sulfates.
K
anion of the weak acid HSO4 (pK Z1.9–2.7,
a
depending on the conditions)—is a very bad leaving
group. In line with these observations, our own
attempts to hydrolyze (R)-2-octyl sulfate under alka-
line conditions with inversion of configuration using
a variety of nucleophiles/bases, such as NaOAc,
NaOH, Ba(OH) , or LiOMe in aqueous-organic
2
solvent systems composed of acetone, dioxane and/or
t-BuOMe were unsuccessful.
The most useful study in view of its preparative utility
revealed that a combination of methods (ii) and (iii)
discussed above by using a strong acid (p-TsOH) in moist
dioxane gave best results for the chemo-selective hydrolysis
of a triterpenoid microbial metabolite. However, solu-
bility problems causing decreased reaction rates persisted
for more lipophilic derivatives and rearrangement reactions
involving bis-allylic alcohol moieties within the complex
natural product structure were observed as side reactions,
when MeOH was used as co-solvent.
2
5
(
ii) On the contrary, acidic conditions generate the
protonated sulfate monoester species, which is able
K
to (formally) expel HSO4 as excellent leaving
group—being the anion of a strong acid H SO
2
In order to provide a reliable synthetic protocol for the
stereoselective hydrolysis of sec-monoalkyl sulfate esters
applicable to our deracemisation process, we undertook a
more detailed investigation.
4
1
1
(
pK ZK9 to K3, depending on the conditions).
a
Due to the very acidic pK of monoalkyl sulfate esters
the pKa of methyl monosulfate was calculated/
a
(
Scheme 2. Chemical hydrolysis of monoalkyl sulfate ester.

S. R. Wallner et al. / Tetrahedron 61 (2005) 1517–1521
1519
Scheme 3. Stereoselective hydrolysis of (R)-2-octyl sulfate.
2
. Results and discussion
Since pyridine and its derivatives were reported to be able to
effect sulfuryl-group transfer reactions between nucleo-
2
Since Rhodococcus ruber sulfatase RS2 displayed best
6
17
philes, we anticipated that various heterocyclic donor
7
enantioselectivities on (rac)-2-octyl sulfate (rac-1), the
solvents/mediators might exert catalytic effects in sulfate
ester hydrolysis (entries 13–18). This assumption proved to
be correct. While pyridine hydrochloride or -toluenesulfo-
nate was ineffective, various N-nucleophiles, such as
piperidine and piperazine (used as the corresponding
hydrochlorides) were found to be moderately effective.
Best results, which are comparable to those obtained from
the dioxane-p-TsOH-system, were obtained by using
morpholine p-toluenesulfonate (83 and 89% yield, respec-
tively). Since the neutralisation of these N-bases required
additional equivalents of acid, the benefit of using morpho-
line over dioxane as ‘mediator’ was not striking. Further
attempts to reduce the amount of dioxane required were
undertaken and it was found that 0.33 mol equiv represent
the optimum (entries 19–21).
latter compound was chosen as test-substrate. Various
reaction conditions for stereoselective hydrolysis were
chosen, the expected (R)-2-octanol was analyzed by GLC
on a chiral stationary phase (Scheme 3, Table 1).
In order to obtain a quick estimate on the efficiency of the
2
5
method published by Singh, hydrolysis of (R)-1 was
performed in aqueous dioxane with a water-content ranging
from 25 to 2.5% using 1.5 mol equiv of p-TsOH (entries
1
8
1
–3). In line with previous observations, best yields were
obtained at a low water-content (entry 3). Since the use of
large amounts of dioxane as a solvent invokes considerable
safety-hazards due to its facile formation of peroxides, we
next tried to replace it by a safer solvent analog by using
dioxane only as a ‘mediator’ at a fixed concentration of
0
.33 mol equiv rather than as a solvent. The influence of the
Finally, the nature and amount of the acid catalyst was
optimised (entries 22–27). Whereas, no reaction was
observed by using phosphate buffer within a range of pH
2–7 (data not shown), the use of amidosulfuric acid (a cheap
industrial organic acid) failed, which is probably due to its
polarity of various solvents from a wide range, such as
MeOH, MeCN and CH Cl was remarkably small; however,
2
2
we were pleased to see that best results were obtained in the
peroxide-stable’ t-butyl methyl ether (entries 4–7). Tuning
‘
2
7
of the water-content of this solvent system turned out to be
optimal at 3% (entries 7–10). In this system, 40 8C was the
optimal reaction temperature (cf. entries 8, 11 and 12).
insufficient acidity (pK -value ca. 1.0). On the other hand,
a
methanesulfonic acid (pKa K1.2 to K2) was equally
effective as p-toluenesulfonic acid (pK K1.0).
a
Table 1. Results from stereoselective hydrolysis of (R)-2-octyl sulfate
Entry
Organic solvent/H O [%]
2
Temperature [8C]
Time [h]
Catalyst/mediator [mol equiv]
Yield (R)-2 [%]
1
2
3
Dioxane/H
Dioxane/H
Dioxane/H
2
2
2
O [75:25]
O [95:5]
O [97.5:2.5]
60
60
60
24
3
4
p-TsOH [1.5]
p-TsOH [1.5]
p-TsOH [1.5]
40
50
85
4
5
6
7
8
9
CH
MeOH/H
MeCN/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
2
Cl
2
/H
2
O [99:1]
O [99:1]
O [99:1]
45
60
45
45
40
40
40
2
2
2
2
2
2
2
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
38
42
42
46
62
42
31
2
2
2
2
2
2
O [99:1]
O [97:3]
O [95:5]
O [90:10]
10
1
1
1
2
t-BuOMe/H
t-BuOMe/H
2
2
O [97:3]
O [97:3]
30
50
2
2
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
20
53
13
14
15
16
17
18
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
2
2
2
2
2
2
O [97:3]
O [97:3]
O [97:3]
O [97:3]
O [97:3]
O [97:3]
40
40
40
40
40
40
48
24
1.5
18
0.5
0.5
Py$HCl [2.0]
Py$p-TsOH [0.55]/DMAP cat.
Piperidine$HCl [0.5]
Piperazine$2 HCl [1.4]
Morpholine [1.0], p-TsOH [2.5]
p-TsOH [1.0], dioxane [1.0]
0
0
40
70
89
83
1
2
2
9
0
1
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
2
2
2
O [97:3]
O [97:3]
O [97:3]
40
40
40
2
2
2
p-TsOH [0.6], dioxane [0.11]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.6], dioxane [0.80]
39
49
43
22
23
24
25
26
27
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
t-BuOMe/H
2
2
2
2
2
2
O [97:3]
O [97:3]
O [97:3]
O [97:3]
O [97:3]
O [97:3]
40
40
40
40
40
40
2
2
2
2
2
2
NH
Me-SO
2
-SO
3
H [0.6], dioxane [0.33]
H [0.6], dioxane [0.33]
6
3
76
47
77
74
62
p-TsOH [0.5], dioxane [0.33]
p-TsOH [0.6], dioxane [0.33]
p-TsOH [0.7], dioxane [0.33]
p-TsOH [0.8], dioxane [0.33]

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S. R. Wallner et al. / Tetrahedron 61 (2005) 1517–1521
It is interesting to note that under all conditions mentioned
above, neither racemisation nor b-elimination (which would
proceed through a carbo-cationic intermediate) were
detected as side reactions.
After cooling to room temperature, the reaction was
quenched with saturated NaHCO (5 mL) and extracted
3
with ethyl acetate (3!). The combined organic layers were
washed with brine (3!), dried over anhyd Na SO and
2
4
the solvent was evaporated under reduced pressure. Rf
(2-octanol)Z0.53 (petroleum ether/EtOAcZ1:3).
In summary, a preparative-scale method for the stereo-
selective hydrolysis of sec-alkylsulfate monoesters was
achieved under strict retention of configuration. Under
optimised conditions, acid-catalysed hydrolysis of (R)-2-
octyl sulfate in presence of 0.33 equiv of dioxane as
mediator was achieved in t-butyl methyl ether at low
water content (3%) on a gram-scale in 90% yield. The
reaction proved to be essentially ‘clean’, as no side
reactions, such as racemisation or b-elimination could be
detected.
3
.2. Preparative-scale procedure
(
1
R)-2-Octylsulfate (1 g, 4.3 mmol, 97% ee) was dissolved in
2 ml H O and 388 ml t-BuOMe to give a final concen-
2
tration 0.01 mM. Dioxane (120 mL) and p-TsOH mono-
hydrate (470 mg, 2.6 mmol) were added and the reaction
mixture was stirred at 40 8C for 5 h. After cooling to room
temperature, the reaction was quenched with saturated
NaHCO (100 mL) and extracted with ethyl acetate (3!
3
1
brine (3!100 mL), dried over anhyd Na SO and the
00 mL). The combined organic layers were washed with
3. Experimental
2
4
solvent was evaporated under reduced pressure. (R)-2 was
obtained as colourless oil (0.5 g, 90% yield, R97% ee).
RfZ0.53 (petroleum ether/EtOAcZ1:3). [a]D K108 (cZ
1.0, EtOH).
TLC plates were run on silica gel Merck 60 (F254) and
compounds were visualised by spraying with Mo-reagent
2
0
[
in H SO (10%)].
(NH ) Mo O $4H O (100 g/L), Ce(SO ) $4H O (4 g/L)
2
4
6
7
24
2
4 2
2
4
GC analyses were carried out on a Varian 3800 gas
chromatograph equipped with FID using a HP 1301
capillary column (30 m!0.25 mn!0.25 mm film, column
Acknowledgements
This study was performed in cooperation with Degussa AG
(Frankfurt) within the Competence Center Applied Bio-
catalysis and financial support by the TIG, the City of Graz,
the Province of Styria and Degussa AG is gratefully
acknowledged.
A) and N as carrier gas (14.5 psi). Enantiomeric purities
2
were analysed using a CP-Chiralsil-DEX CB column
(25 m!0.32 mm!0.25 mm film, column B) and H2 as
carrier gas (14.5 psi).
(
(
rac)-2-Octanol was purchased from Aldrich, (R)- and
S)-2-octanol (ee 97 and 99%, respectively) was obtained
from Lancaster. (Rac)- and (R)-2-octyl sulfate were
prepared by sulfatation of the corresponding alcohol using
References and notes
7
b
NEt $SO according to a known procedure.
3
3
1
. Faber, K. Chem. Eur. J. 2001, 7, 5004–5010.
Determination of conversion: The degree of conversion was
monitored by GC using 2-dodecanol as an internal standard.
The conversion was calculated from a calibration curve.
2. Huerta, F. F.; Minidis, A. B. E.; B a¨ ckvall, J.-E. Chem. Soc.
Rev. 2001, 30, 321–331. El Gihani, M. T.; Williams, J. M. J.
Curr. Opin. Chem. Biol. 1999, 3, 11–15. Noyori, R.;
Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68,
36–56. Ward, R. S. Tetrahedron: Asymmetry 1995, 6,
1475–1490.
Determination of absolute configuration: (R)- and (S)-2-
Octanol were analysed as the corresponding acetate esters
(
Ac O/DMAP/rt/18 h) on GC (column B), their absolute
2
3. Azerad, R.; Buisson, D. Curr. Opin. Biotechnol. 2000, 11,
565–571. Carnell, A. J. Adv. Biochem. Eng. Biotechnol. 1999,
63, 57–72.
configuration was elucidated by co-injection using authentic
reference samples (Table 2).
4
. Kroutil, W.; Mischitz, M.; Faber, K. J. Chem. Soc., Perkin
Trans. 1 1997, 3629–3636. Orru, R. V. A.; Kroutil, W.; Faber,
K. Tetrahedron Lett. 1997, 38, 1753–1754. Faber, K.; Kroutil,
W. Tetrahedron: Asymmetry 2002, 13, 377–382. Pedragosa--
Moreau, S.; Archelas, A.; Furstoss, R. J. Org. Chem. 1993, 58,
5533–5536.
3
.1. General procedure for optimisation study
Sulfate ester (R)-1 (50 mg, 0.2 mmol) was dissolved in H O/
2
t-BuOMe (3:97, 20 mL) to give a final concentration of
0
.01 mM. Dioxane (0.33 equiv, 0.07 mmol), p-TsOH mono-
hydrate (0.6 equiv, 0.12 mmol) and 1 ml of a stock solution
of 2-dodecanol (1.05 mg/mL) as internal standard were
added and the reaction mixture was stirred at 40 8C for 2 h.
5. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18,
249–330.
6. Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885–918.
Table 2. GC-data
Compound
Column
Conditions
R
t [min]
(
(
(
rac)-2-Octanol
R)-2-Octanol
S)-2-Octanol
A
B
B
115 8C/4 min—308/min—250 8C/0 min
60 8C/7 min—48/min—80 8C/0 min—160 8C/5 min
60 8C/7 min—48/min—80 8C/0 min—160 8C/5 min
2.1
13.2
11.1

S. R. Wallner et al. / Tetrahedron 61 (2005) 1517–1521
1521
7
. (a) Pogorevc, M.; Kroutil, W.; Wallner, S. R.; Faber, K.
Angew. Chem., Int. Ed. 2002, 41, 4052–4054. (b) Porogevc,
M.; Faber, K. Tetrahedron: Asymmetry 2002, 13, 1435–1441.
17. Hopkins, A.; Day, R. A.; Williams, A. J. Am. Chem. Soc. 1983,
105, 6062–6070. Bourne, N.; Hopkins, A.; Williams, A. J. Am.
Chem. Soc. 1985, 107, 4327–4331.
(
c) Pogorevc, M.; Strauss, U. T.; Riermeier, T.; Faber, K.
18. Davis, J. M.; Cameron, D. R.; Kubanek, J. M.; Mizuyabu, L.;
Thatcher, G. R. J. Tetrahedron Lett. 1991, 32, 2205–2206.
Tetrahedron: Asymmetry 2002, 13, 1443–1447. (d) Wallner,
S. R.; Pogorevc, M.; Trauthwein, H.; Faber, K. Eng. Life Sci.
1
2
9. Batts, B. D. J. Chem. Soc. (B) 1966, 547–551.
2
004, 4, 512–516.
. Lopez, X.; Dejaegere, A.; Karplus, M. J. Am. Chem. Soc. 1999,
21, 5548–5558.
. Marker, A.; Roy, A. B. Biochim. Biophys. Acta 1983, 742,
46–451.
0. Suter, C. M.; Evans, P. B.; Kiefer, J. F. J. Am. Chem. Soc.
8
9
1
938, 60, 538–540.
1. Mayers, G. L.; Pousada, M.; Haines, T. H. Biochemistry 1969,
, 2981–2986.
1
2
2
2
2
8
4
2. Lieberman, S.; Hariton, L. B.; Fukushima, D. K. J. Am. Chem.
Soc. 1948, 70, 1427–1432.
1
1
0. Batts, B. D. J. Chem. Soc. (B) 1966, 551–555.
1. Bethell, D.; Fessey, R. E.; Namwindwa, E.; Roberts, D. W.
J. Chem. Soc., Perkin Trans. 2 2001, 1489–1495.
3. McKenna, J.; Norymberski, J. K. J. Chem. Soc. (A) 1957,
3
889–3893.
4. Burstein, S.; Lieberman, S. J. Am. Chem. Soc. 1958, 80,
235–5239.
1
2. Burlingham, B. T.; Pratt, L. M.; Davidson, E. R.; Shriner, V. J.
Jr; Fong, J.; Widlanski, T. S. J. Am. Chem. Soc. 2003, 125,
5
1
3036–13037.
2
5. Singh, S. B. Tetrahedron Lett. 2000, 41, 6973–6976.
1
3. Burwell, R. L. J. Am. Chem. Soc. 1952, 74, 1462–1466.
4. Klages, H. F.; Jung, A.; Hegenberg, P. Chem. Ber. 1966, 99,
2
6. Pogorevc, M.; Faber, K. Appl. Environ. Microbiol. 2003, 69,
1
2
810–2815.
7. Kurz, J. L.; Ferrar, J. M. J. Am. Chem. Soc. 1969, 91,
057–6062.
1
704–1711.
2
1
5. Guthrie, J. P. Can. J. Chem. 1978, 56, 2342–2354.
6. Guthrie, J. P. J. Am. Chem. Soc. 1980, 102, 5177–5180.
6
1