A sulfitylation-oxidation protocol for the preparation of sulfates

Article abstract of DOI:10.1021/jo060404v

A novel, high-yielding method for sulfation of alcohols has been developed, proceeding via sulfite- and sulfate diester intermediates. Sulfite diesters serve as versatile sulfate monoester precursors, allowing for transformations that are difficult or impossible with the latter compounds.

Full text of DOI:10.1021/jo060404v

structure, a pure amount of a selected sulfated substrate is often
required. Isolation from natural sources, however, can be a
tedious task due to low or transient availability of sulfates or
microheterogeneity problems. Consequently, the preparation of
organic sulfates or sulfamidates by chemical synthesis is a
worthwhile alternative. To this end, an alcohol (or amine) is
converted to a sulfate monoester (or sulfamidate) by reaction
with a sulfur trioxide-nitrogen base complex or chlorosulfonic
acid, typically by subjection to excess of reagents (2-10 equiv,
see Figure 1).10,11 More disturbingly, since the anionic nature
of a sulfate encumbers straightforward purification on silica gel,
introduction of the sulfate is inevitably postponed to the last
stage of a synthesis. A logical consequence of such a strategy
is that an alcohol targeted for eventual sulfation requires
temporary protection during earlier steps of the synthesis.
A Sulfitylation-Oxidation Protocol for the
Preparation of Sulfates
M. Huibers, AÄ lvaro Manuzi, Floris P. J. T. Rutjes, and
Floris L. van Delft*
Institute for Molecules and Materials, Organic Chemistry,
Radboud UniVersity Nijmegen, ToernooiVeld 1, 6525 ED
Nijmegen, The Netherlands
f.Vandelft@science.ru.nl
ReceiVed February 26, 2006
We reasoned that the latter disadvantages could be circum-
vented by development of a strategy proceeding through
intermediate diesters sulfite I and sulfate II (see Figure 1). Such
diesters are neutral, can be introduced at a convenient stage of
a synthesis, and if chosen carefully can be compatible with
subsequent transformations before final deprotection to the
desired sulfate monoester. We here wish to report that such a
strategy is successful in the preparation of organic sulfates.
A novel, high-yielding method for sulfation of alcohols has
been developed, proceeding via sulfite- and sulfate diester
intermediates. Sulfite diesters serve as versatile sulfate
monoester precursors, allowing for transformations that are
difficult or impossible with the latter compounds.
A few papers report sulfate diesters as protected precursors
of the final monosulfate. Early studies12 employed phenyl sulfate
intermediates, which could be unmasked in a two-step protocol
involving hydrogenation (phenyl f cyclohexyl) and base
hydrolysis. Trifluoroethyl (TFE) esters were shown13,14 to be
compatible with a variety of conditions, including TFA, TBAF,
hydrogenation, Zemple´n conditions, and heat, whereas removal
of the TFE group could be effected in good yield, usually by
tert-butoxide in refluxing tert-butyl alcohol. Two years ago, a
report15 on the application of trichloroethyl (TCE) intermediates
en route to aryl sulfates demonstrated that TCE esters can be
carried several steps through a synthesis without decomposition,
before final conversion to the sulfate monoester by hydro-
genolysis. Widlanski et al. most recently further elaborated such
an approach by application of neopentyl and iso-butyl sulfate
diester precursors in the synthesis of aryl sulfates and two
selected aliphatic sulfates.16 Nevertheless, each of these proce-
dures is associated with some specific disadvantages, like harsh
deprotection conditions, low yields, requirement of large
excesses of (hazardous) reagents, or limited application, e.g
aromatic alcohols and sterically hindered secondary alcohols.
One of the body’s regulatory mechanisms involves the
functional modification of heteroatoms with a sulfate group.
For example, extracellular traffic and cell-cell communication
involves the covalent modification of glycoproteins with a
sulfate moiety.1,2 Carbohydrate sulfates, found extensively at
the cell surface or in the extracellular space in the form of
proteoglycans3 or mucins,4 play an essential role in cellular
communication. Sulfate functionality is found in sulfotyrosine-
bearing peptide hormones5 and sulfated steroids,6 and the
number of glycoproteins and glycolipids shown to bear sulfates
is also rapidly growing. Consequently, sulfotransferases7 and
sulfatases,8 the enzymes responsible for regulation of addition
and removal of sulfates, respectively, have become the focus
of intense interest, both from a fundamental point of view as
well as for therapeutic intervention.9
Inspiration for our approach came from the synthetic strategy
for the conversion of diols to cyclic sulfates via cyclic sulfite
To accurately establish the biological role of a (de)sulfating
enzyme or structure-activity relationship of a particular sulfated
(1) Moore, K. L. J. Biol. Chem. 2003, 278, 24243.
(2) Hsu, W.; Rosenquist, G. L.; Ansari, A. A.; Gershwin, M. E.
Autoimmun. ReV. 2005, 4, 429-435.
(10) Gunnarson, G. T.; Riaz, M.; Adams, J.; Desai, U. R. Bioorg. Med.
Chem. 2005, 13, 1783-1789 and references cited herein.
(11) Most recently, the use of isobutene as proton scavenger was also
reported: Papy-Garcia, D.; Barbier-Chassefie`re, V.; Rouet, V.; Kerros, M.
E.; Klochendler, C.; Tournaire, M. C.; Barritault, D.; Caruelle, J. P.; Petit,
E. Macromolecules 2005, 38, 4647-4654.
(3) Linhard, R. J.; Toida, T. Acc. Chem. Res. 2004, 37, 431-438.
(4) van Nieuw Amerongen, A.; Bolscher, J. G. M.; Bloemena, E.;
Veerman, E. C. I. J. Biol. Chem. 1998, 379, 1-18.
(5) Strott, C. A. Endocr. ReV. 2002, 23, 703-732.
(6) Reed, M. J.; Purohit, A.; Woo, L. W. L.; Newman, S. P.; Potter, B.
V. L. Endocr. ReV. 2005, 26, 171-202.
(12) Penney, C. L.; Perlin, A. S. Carbohydr. Res. 1981, 93, 241-246.
(13) Proud, A. D.; Prodger, J. C.; Flitsch, S. L. Tetrahedron Lett. 1997,
38, 7243-7246.
(7) Rath, V. L.; Verdugo, D.; Hemmerich, S. Drug DiscoVery Today
2004, 23, 1003-1011.
(14) Karst, N. A.; Islam, T. F.; Avci, F. Y.; Linhardt, R. J. Tetrahedron
Lett. 2004, 45, 6433-6437.
(8) Hanson, S. R.; Best, M. D.; Wong, C.-H. Angew. Chem., Int. Ed.
2004, 43, 5736-5763.
(15) Liu, Y.; Lien, I. F. F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D. Org.
Lett. 2004, 6, 209-212.
(9) Hemmerich, S.; Verdugo, D.; Rath, V. L. Drug DiscoVery Today
2004, 9, 967-975.
(16) Simpson, L. S.; Widlanski, T. S. J. Am. Chem. Soc. 2006, 128,
1605-1610.
10.1021/jo060404v CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/16/2006
J. Org. Chem. 2006, 71, 7473-7476
7473

TABLE 2. Preparation of Alkyl Chlorosulfites
ratioa
products
R
(5:6)
stability
5a + 6a
5b + 6b
5c + 6c
5d + 6d
Et
i-Pr
t-Bu
neopentyl
4:1
++
-
5:2
b
-
NA
+
>100:1
FIGURE 1. Concept of three-step sulfation.
a Based on NMR analysis after distillation. b Isobutene formation.
TABLE 1. Two-Step Synthesis (See Scheme 1) of Sulfate Diesters
3a-f via Sulfite Intermediates, Followed by Unmasking to Sulfate 4
sufficiently stable for silica gel column chromatography. Finally,
conversion of sulfate diester into sulfate monoester (3 f 4) was
found to proceed smoothly upon subjection of compound 3b
or 3c to a single equivalent of NaI in acetone at ambient
temperature, leading to a quantitative production of 4. After
evaporation of solvent and in situ formed iodoalkane (ethyl or
isopropyl iodide, respectively), the pure sulfate monoester
remains as the sole product. It is important to note that the last
transformationsthe result of nucleophilic attack of iodide at
the alkyl carbon leading to SN2 displacement of sulfates
proceeds with regiospecificity for both 3b and 3c. In contrast,
the neopentyl substituent of 3e proved unsuitable for generation
of solketal sulfate 4, because deprotection led to a mixture
consisting of mostly neopentyl sulfate (20:1 ratio with 4).18 This
reversal in regioselectivity is probably caused by the greatly
increased steric hindrance of the alkyl moiety.
yield
(%)
yield
(%)
R
sulfite
sulfate
Me
Et
i-Pr
t-Bu
neopentyl
Bn
2a
2b
2c
2d
2e
2f
24a
35
3a
3b
3c
3d
3e
3f
-
95
88
-
63
-
25
40b
21
36a
a Decomposition, before or during oxidation. b Ten equiv of t-BuOH used.
SCHEME 1. Preparation of Solketal Sulfate via Sulfite and
Sulfate Esters
In order for the sulfation route to be synthetically useful, we
focused our attention on an alternative approach for the
generation of sulfite diesters involving condensation with an
alkyl chlorosulfite reagent of type 5 (Table 2). Alkoxychloro-
sulfites are readily produced upon the condensation of thionyl
chloride (neat) with an alcohol.19,20 The concomitant formation
of minor amounts of symmetrical dialkyl sulfites (6) was not
disturbing, since the symmetrical diesters 6 are inert in the
subsequent sulfitylation (Table 3, step i).
At this point, we decided to focus on ethyl protected sulfate
esters for two reasons: first, the isopropyl chlorosulfite 5b was
rather unstable (complete decomposition in matter of days) and,
second, because unmasking of isopropyl sulfate esters was
expected to have a higher likeliness to lead to problems during
deprotection.21 Indeed, we were delighted to find that subjection
of solketal 1 to 1.2 molar equivalents of ethyl chlorosulfite 5a
in the presence of pyridine (0 °C, EtOAc) led to a near
quantitative production of ethyl sulfite ester (95%, entry 1 in
Table 3).22
diesters.17 Such a procedure proceeds under mild conditions and
requires minimal excess of reagents. Furthermore, the sulfite
intermediates appeared of particular interest, due to the reduced
electrophilicity, and hence better stability, of sulfites with respect
to sulfates. Nevertheless, it was apparent from the outset that
the choice of the most suitable sulfite/sulfate protective group
R is fundamental in balancing the stability of the intermediates
with ease of deprotection in the final step.
With 1,2-O-isopropylidene-rac-glycerol (1) as a model
compound, we set out to investigate the synthetic feasibility of
a three-step sulfation technology. Conversion of the alcohol to
a sulfite ester was initially investigated in a two-step one-pot
procedure, involving sequential treatment with thionyl chloride
and condensation with an alcohol (1 f 2, Table 1).As becomes
clear from Table 1, the desired sulfite esters were successfully
obtained, albeit with mediocre yields due to concomitant
formation of symmetrical sulfite diester from the in situ formed
alkyl chlorosulfite. Moreover, both methyl (2a) and benzyl (2f)
sulfite diester were found unsufficiently stable for practical
application, while preparation of the tert-butyl ester 2d required
large excess of tert-butyl alcohol. In contrast, we were delighted
to find that the ethyl, i-propyl, and neopentyl esters were stable
and that the subsequent oxidation (2 f 3) proceeded rapidly,
cleanly, and in excellent yield under the action of two
equivalents of NaIO4 and catalytic RuCl3. During this process,
the initially formed diastereomeric mixture of sulfite diesters
converges into a single product. The sulfate diesters were found
Having achieved high yields for each step of the sequence,
the iterative sulfation protocol was applied to a number of
(18) Poor regioselectivity was also encountered by Widlanski in depro-
tection of neopentyl glucose 3-sulfate with sodium azide. It was also reported
that, in contrast to our findings, a neopentyl sulfate derivative is completely
inert to deprotection with sodium iodide.
(19) Sharman, S. H.; Caserio, F. F.; Nystrom, R. F.; Leak, J. C.; Young,
W. G. J. Am. Chem. Soc. 1958, 80, 5965.
(20) Carre´, P.; Libermann, D. Bull. Soc. Chim. Fr. 1933, 53, 1050-
1075.
(21) Xie, M.; Widlanski, T. S. Tetrahedron Lett. 1996, 37, 4443-4446.
(22) A one-step conversion of alcohols into ethyl sulfate esters using
(commercially available) EtOSO2Cl was found unsatisfactory due to the
extremely unstable nature of the reagent. Second, ethyl sulfate esters are
less suitable for a synthetic strategy involving early introduction of a sulfate
precursor due to the lower stability with respect to sulfite esters.
(17) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-
7539.
7474 J. Org. Chem., Vol. 71, No. 19, 2006

TABLE 3. Application of the Three-Step Sulfation Protocol to the Sulfation Alcohols
a Adapted procedure, see text.
different aliphatic primary and secondary alcohols, diols, sugars,
and aromatic alcohols (Table 3). As becomes clear from Table
3, all three steps usually proceed in excellent yield, under mild
conditions, and with near stoichiometric amounts of reagents.
Purification of intermediates and products was generally un-
necessary or rather disadvantageous (see below). The potential
of the methodology is nicely reflected in the successful
tetrasulfation of methyl â-D-glycoside 9.23
It was found that sulfation of phenol requires an adapted
procedure, involving sulfitylation-oxidation without intermedi-
ate purification, because phenyl ethyl sulfite is rather unstable
and easily decomposes back to phenol. Much to our surprise,
phenyl ethyl sulfate diester was more stable than the sulfite
intermediate. In this particular case, deprotection also required
special attention, as the standard sodium iodide conditions
yielded phenol instead of phenyl sulfate.16 Fortunately, the
desired product was obtained uneventfully upon treatment with
sodium methoxide in methanol, leading to quantitative produc-
tion of the desired product.
In summary, with the exception of phenyl ethyl sulfite, sulfite
and sulfate esters of aliphatic alcohols were found to be apolar,
stable compounds, which readily dissolved in common organic
solvents and allowed for silica gel column chromatography. The
ultimate question to be addressed on the described three-step
sulfation strategy is the suitability of application sulfite/sulfate
diesters in reaction sequences that would otherwise be incon-
venient due to the polarity of free sulfates. Thus, sulfite 11a
was subjected24 to a variety of typical conditions for O-protective
group interconversion (Figure 2).
First, removal of the 5,6-O-isopropylidene group (AcOH/H2O
) 1/1) proceeded in excellent yield (11a f 15). Subsequent
acetylation (Ac2O, pyridine) to 16a or silylation to 16b
(TBDMSCl, imidazole, DMF) of the primary alcohol was also
(24) Only the ethyl sulfite diester was investigated, as ethyl sulfate
diesters are considerably less stable.
(23) Wessel, H. P.; Bartsch, S. Carbohydr. Res. 1995, 274, 1-9.
J. Org. Chem, Vol. 71, No. 19, 2006 7475

Preparation of Ethyl Chlorosulfite (5a). Thionyl chloride
(25.46 g, 2.14 mol) and ethanol (82.95 g, 1.80 mol) were reacted
as described in the general chlorosulfite synthesis procedure.
Distillation was performed at 43 °C (63 mbar), yielding 5a as a
1
colorless liquid (∼75%). H NMR (CDCl3, 400 MHz, ppm): δ
4.63 (dq, 1H, J ) 7.1, 10.1 Hz), 4.49 (dq, 1H, J ) 7.1 Hz, 10.1
Hz), 1.49 (t, 3H, J ) 7.1 Hz). 13C NMR (CDCl3, 300 MHz, ppm)
δ: 63.9, 14.7.
General Procedure for Sulfite Diester Formation by Con-
densation with Ethyl Chlorosulfite (Step i in Table 3). The
starting material and pyridine (1.3 equiv) are dissolved in EtOAc.
The solution is cooled to 0 °C, and ethyl chlorosulfite 5a (1.2 equiv)
is added dropwise. After about 1 h (depending on TLC analysis),
the reaction mixture is quenched with water and extracted with
water and brine. The organic layer is dried (NaSO4), filtered, and
concentrated. Further purification is usually unnecessary but can
optionally be done by means of flash chromatography with EtOAc/
heptane mixtures.
FIGURE 2. Compatibility of ethyl sulfite diester functionality with
typical carbohydrate protective group manipulations.
well tolerated, as was the subsequent desilylation of 16b to 11a
(pyridine‚HF, pyridine, 63%).25 Some other transformations
were less satisfactory, for example full deacetonation (TFA/
H2O ) 1/1) or benzylation (NaH, BnBr, TBAI, THF or BnOC-
(NH)CCl3, TMSOTf, THF) led predominantly to decomposition.
These findings demonstrate the potential of ethyl sulfite esters
as sulfate precursors in organic sequences, but further optimiza-
tion is still required.
In conclusion, a new sulfation methodology has been
developed with several advantages over conventional sulfation
procedures.26 Yields are high, purification is easy or redundant,
and reactions proceed with near stoichiometric amounts of
reagents. Moreover, the sulfite diesters show promise as
protected sulfate precursors, although compatibility with com-
mon reaction conditions requires further fine-tuning. We are
currently addressing this issue with alternative sulfate precursors.
General Sulfite Oxidation Procedure (Step ii in Table 3). The
sulfite diester is dissolved in a 2/2/3 MeCN/CH2Cl2/water mixture,
to which NaIO4 (2 equiv) and RuCl3 (cat.) are added. The mixture
is stirred vigorously for 1 h. TLC analysis (usually EtOAc:heptane
1:1) shows a spot-to-spot conversion into a slightly lower running
(sometimes co-running) product. The reaction mixture is diluted
with CH2Cl2 (about 2 reaction volumes) and is then extracted with
water and brine. After drying (Na2SO4) the organic layer is filtered
and concentrated. The crude product is then subjected to flash
chromatography (often a short column suffices). The product
fractions are pooled and concentrated, yielding the product.
General Sulfate Deprotection Procedure (Step iii in Table
3). Sodium iodide is added to a solution of the sulfate diester in
acetone. The reaction is left at room temperature for 3 to 18 h.
When TLC analysis (usually EtOAc:heptane 1:1) shows the starting
material is gone, the reaction mixture is concentrated. After EtOAc
addition, the organic layer is extracted twice with water. The
aqueous layer is concentrated, yielding the crude product. Traces
of sodium iodide can be removed by flash column chromatography
with acetonitrile/water mixtures.
Experimental Section
General Procedure for Sulfite Diester Formation by Con-
secutive Thionyl Chloride and Alcohol Addition. Thionyl chloride
(1.05 equiv) and pyridine (1.1 equiv) are dissolved in EtOAc. The
solution is cooled to 0 °C, and the starting material is added
dropwise. After 30 min a solution of an alcohol (1.1 equiv) and
pyridine (1.1 equiv) is added dropwise. After another 30 min the
reaction mixture is quenched with water and extracted with water
and brine. The organic layer is dried (Na2SO4), filtered, and
concentrated. The crude product is purified by flash chromatography
with EtOAc/heptane mixtures.
Acknowledgment. This work is part of the NWO-ACTS
IBOS program. Financial support by Organon, Diosynth, and
Syncom is gratefully acknowledged.
(25) Glycosylation of 15 was also carried out with the trichloroacetimidate
derived from 2,3,4,6-tetra-O-benzyl-R/â-D-glucopyranose under the influ-
ence of BF3‚OEt2. The reaction was found to proceed smoothly and in
excellent yield (90%) to give a mixture of four diastereomeric products, as
confirmed by NMR and mass spectrometric analysis.
(26) Condensation of reagent 5a with primary amines failed to lead to
sulfamidite, presumably due to sulfinylamine formation via elimination of
EtOH from the intermediate.
Supporting Information Available: General experimental
methods, procedures for the synthesis of selected compounds with
full characterization data, and copies of NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO060404V
7476 J. Org. Chem., Vol. 71, No. 19, 2006