Sulfonylcarbamate as a versatile and unique hydroxy-protecting group: A protecting group stable under severe conditions and labile under mild conditions

Article abstract of DOI:10.1039/c3cc43968b

The sulfonylcarbamate group is a unique hydroxyl protecting group. In contrast to typical acyl protecting groups, the sulfonylcarbamate group is stable under harsh basic conditions, while showing labile behavior under mild basic conditions. Its compatibility with other hydroxyl protecting groups and application to carbohydrate chemistry is demonstrated.

Full text of DOI:10.1039/c3cc43968b

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Sulfonylcarbamate as a versatile and unique hydroxy-
protecting group: a protecting group stable under
severe conditions and labile under mild conditions†
Cite this: Chem. Commun., 2013,
49, 8332
Received 27th May 2013,
Accepted 24th July 2013
Shino Manabe,*ab Masanori Yamaguchiab and Yukishige Ito*a
DOI: 10.1039/c3cc43968b
www.rsc.org/chemcomm
The sulfonylcarbamate group is a unique hydroxyl protecting group. In
contrast to typical acyl protecting groups, the sulfonylcarbamate group
is stable under harsh basic conditions, while showing labile behavior
under mild basic conditions. Its compatibility with other hydroxyl
protecting groups and application to carbohydrate chemistry is
demonstrated.
The development of new protecting groups is highly desirable in
the field of synthetic organic chemistry. The introduction and
removal of protecting groups are among the most common
transformations during the multistep synthesis of polyfunctional
molecules.1,2 However, protection–deprotection processes increase
the number of reaction steps and can lower overall yields,
especially in the synthesis of complex molecules. Consequently,
there is a continuing demand for more varied, economical,
Scheme 1 Protection of alcohol by the sulfonylcarbamate group and its stability
under various basic conditions. Reagents and conditions: (a) p-toluenesulfonyl
isocyanate, THF, quant.; (b) TMSCHN2, MeOH, PhH, 90%; (c) ICH2CN, K2CO3,
CH3CN, 82%; (d) EtOH, PPh3, DEAD, THF, 92%; (e) pyridine–MeOH (7 : 3), 92%;
(f) 1 M NaOH, THF quant. Ts = p-toluenesulfonate.
The sulfonylcarbamate group was introduced under neutral
and/or chemically differentiable protecting groups. Further- conditions in high yield using commercially available p-toluene-
more, in carbohydrate chemistry, protecting groups play an sulfonyl isocyanate (Scheme 1). Sulfonylcarbamate 1b was com-
important role in controlling stereochemistry at the anomeric pletely stable under strongly alkaline conditions (1 M to 5 M
position, as well as in tuning the reactivity of glycosyl donors aqueous NaOH, 1.5 equivalents of 2,8,9-trimethyl-2,5,8,9-tetraaza-1-
and acceptors in glycosylation reactions.3,4 Moreover, protecting phosphabicyclo[3.3.3]undecane5 in MeOH, or 1,8-diazabicyclo-
groups can change the properties of substrates, including their [5.4.0]undec-7-ene (DBU) in MeOH) and was recovered quantitatively.
solubility, polarity, crystallinity, and volatility. In general, protecting On the other hand, the sulfonylcarbamate group was removed
groups are stable under mild conditions and are removed under under extremely mild basic conditions such as in pyridine–MeOH
severe ones. For instance, typical acyl protecting groups such as (Scheme 1(e)). It was also possible to remove the sulfonylcarbamate
acetyl, and benzoyl groups are stable under pyridine–H2O (weakly group using a two-step alkylation–deprotection sequence.
basic conditions), but are cleavable under aqueous NaOH The sulfonylcarbamate group is acidic enough to react with
(more basic conditions). Here, we report the sulfonylcarbamate trimethylsilyldiazomethane (TMSCHN2). After the methylation
moiety as a novel hydroxyl protecting group possessing unique of 1b with TMSCHN2 in MeOH–benzene, deprotection could be
characteristics. In contrast to conventional protecting groups, achieved under mildly basic conditions, as well as under
this group could be deprotected under mildly basic conditions, strongly basic ones. Similarly, after alkylation of the sulfonyl-
while being completely stable under strongly basic and other carbamate group with iodoacetonitrile in the presence of K2CO3
conventional reaction conditions.
and under typical Mitsunobu conditions, it was possible to
remove the sulfonylcarbamate group quantitatively under basic
conditions (Scheme 1(b)–(d), and (f ), respectively).
Since the protection reaction could be carried out under
neutral conditions and was operationally very simple, the scope of
substrates examined was wide. The protection reaction was com-
pleted within approximately 30 min in most cases. Primary alcohols
1a–5a and 10a and secondary alcohols 6a–8a and 11a–13a were
a RIKEN, Synthetic Cellular Chemistry Laboratory, Hirosawa, Wako,
Saitama 351-0198, Japan. E-mail: smanabe@riken.jp; Fax: +81 48 462 4680;
Tel: +81 48 467 9432
b PRESTO, JST, Honcho, Kawaguchi, Saitama 332-0012, Japan
† Electronic supplementary information (ESI) available: Experimental details and
1H-NMR and 13C-NMR spectra. See DOI: 10.1039/c3cc43968b
c
8332 Chem. Commun., 2013, 49, 8332--8334
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Table 1 Scope of protection and deprotection of sulfonylcarbamate-protected
hydroxyl groups
Protection
yield (%)
Deprotection
yield (%)
Entry
Substrate
Method
Scheme 2 A glucose scaffold with the orthogonal protecting group. Reagents
and conditions: (a) p-toluenesulfonyl isocyanate, THF, quant.; (b) NaOMe, MeOH,
89%; (c) aq. HF, CH3CN, 92%; (d) DDQ, CH2Cl2, H2O, 40 1C, 68%; (e) pyridine–H2O
(7 : 3), 50 1C, 93%; (f) NBS, acetone, H2O, 83%.
1
2
3
4
5
6
7
8
2a/2b
3a/3b
4a/4b
5a/5b
6a/6b
7a/7b
8a/8b
9a/9b
10a/10b
11a/11b
12a/12b
13a/13b
98
88
77
Aa
Bb
Bc
C
C
A/C
C
C
C
C
C
quant.
quant.
quant.
quant.
quant.
94
85
95
95
90
80
quant.d
80e
95/quant.
aq. NaOH; (c) pyridine–MeOH (7 : 3), 50 1C. The two-step
sequences gave products in good yields (entries 1–3 and 6).
The operationally simple one-step procedure gave satisfactory
yields (entries 4–11), especially in the case of substrates with base-
sensitive functional groups such as esters and Phth (entries 4, 5
and 10). Because of the mild deprotection conditions (pyridine–
MeOH 7 : 3), racemization of the deprotected compounds was
negligible in the cases of 5b and 6b (by chiral HPLC analyses).
Unfortunately, the Fmoc group was removed faster than the
sulfonyl carbamate group (entry 12).
90
90
90
85
89
0
9
10
11
12
94
C
a
b
Method A: ICH2CN, K2CO3, CH3CN, then 1 M NaOH. Method B:
TMSCHN2, MeOH, PhH, then 1 M aq. NaOH. Method C: pyridine–
c
d
MeOH (7 : 3), 50 1C. > 99% ee by CHIRALPAK AD, hexane : i-PrOH
e
9 : 1 1.0 mL minÀ1, 254 nm. > 99% ee by CHIRALCEL OD-H, hexane :
i-PrOH 9 : 1 1.0 mL minÀ1, 254 nm.
After having established ideal protection and deprotection
conditions for the sulfonylcarbamate-protected hydroxyl groups,
we next investigated its compatibility with other established
hydroxyl protecting groups (Scheme 2). We chose 15 as a model
compound because the differentially protected sugar unit would
be a useful carbohydrate scaffold for further divergent synthetic
manipulations.6–10 Compound 15 was prepared from the known
compound 14 in quantitative yield.11 The benzoate of 15 was
deprotected with NaOMe in MeOH, yielding 16 in quantitative
yield without any removal or migration of the sulfonylcarbamate
group to the C-2 position. The cleavage of the silyl group by
aqueous HF afforded 17 in 92% yield. The benzyl group at
the C-4 position was cleaved by the oxidation of 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ) at 40 1C.12 Additionally, the
thioglycoside was converted to the corresponding hemiacetal
19 using N-bromosuccinimide (NBS) in aqueous acetone, in 83%
yield. Finally, the sulfonylcarbamate group was cleaved by
pyridine–MeOH without migration of the benzoate, resulting
in 14 in 93% yield. Thus, a completely orthogonal set of
protecting groups for glucose was established.
In the glycosylation reaction, the sulfonylcarbamate group
was shown to be effective in controlling stereochemistry at the
anomeric position, although it is not clear whether the sulfonyl-
carbamate group functions as a neighboring participating
Pg = protecting group.
protected in high yields (Table 1). Even the reaction involving group to the oxocarbenium intermediate.3,4 The thioglycoside
tertiary alcohol 9a was complete within 1 h, resulting in a donor 19 was quantitatively prepared from compound 18. After
satisfactory yield. In numerous cases, the protection yields were glycosylation between donor 19 and acceptor 20 by the action of
quantitative, and many functional groups such as alkenes (2a), N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid
acetals (3a (racemic) and 11a), epoxides (4a), esters (5a and 6a), (TfOH), only the b-disaccharide 21 was obtained in 94% yield.
carbamates (5a and 7a), and phthalimide (11a) were stable The sulfonylcarbamate group was then removed in 90% yield
under the reaction conditions. Three different methodologies using pyridine–MeOH (Scheme 3).13
were applied for the deprotection step: (a) ICH2CN, K2CO3,
Furthermore, the sulfonylcarbamate group was stable under
CH3CN, then 1 M NaOH; (b) TMSCHN2, MeOH, PhH, then 1 M several typical reaction conditions (Scheme 4). For instance, the
c
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Scheme 5 Mechanism underlying the unique characteristics of the sulfonyl-
carbamate group.
Scheme 3 Utility of the sulfonylcarbamate group in glycosylation reaction.
Reagents and conditions: (a) p-toluenesulfonyl isocyanate, THF, 97%; (b) NIS,
TfOH, CH2Cl2, À40 1C, 94%; (c) pyridine–H2O (7 : 3), 40 1C, 90%.
‘‘Safety-catch’’ protecting groups and linkers developed by
Kenner and Ellman are typically used for carboxylic acids and
require a two-step protocol for deprotection.15 The hydroxyl
protecting group described above does not necessarily require a
two-step deprotection process. It has the potential to be used as
a versatile protecting group in the field of synthetic organic
chemistry as it can reduce the number of steps involved during
the total synthesis of a variety of important compounds; the
sulfonylcarbamate would be of considerable use in the final
stages of a total synthesis with many functional groups.
We thank Ms A. Takahashi for technical assistance; Dr Kaori
Otsuki, Dr Masaya Usui, and Dr Aya Abe of the Research
Resource Center at the Brain Science Center, RIKEN, for help
with the HRMS measurements. We also thank Dr Hirohisa Doi
of PRESTO, JST, for his contributions during the exploratory
stage of this work. S.M. was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (Grant No. 24590041),
the Yamada Science Foundation, the Takeda Foundation, and
by a Shiseido Female Research Grant.
Scheme 4 Stability of the sulfonylcarbamate group under various conditions.
Reagents and conditions: (a) (i) TFA–H2O (1 : 1), then TBDPSCl, DMAP, pyridine,
91%; (b) Dess–Martin periodinane, CH2Cl2, 63% or Jones reagent, acetone, 71%;
(c) NaBH4, MeOH, THF, quant.; (d) allylmagnesium bromide, THF, 92%; (e) OsO4,
NMO, acetone, H2O, 90%.
toluenesulfonylcarbamate group of compound 3b was stable
under acidic conditions (TFA–H2O 1 : 1) for acetal removal. The
secondary alcohol of 25 was oxidized using either Dess–Martin
periodinane or Jones reagent to give 26. Nucleophilic attack of
the carbonyl group of compound 26 by organometallic reagents
such as Grignard reagents and hydride gave corresponding
compounds 27 and 25. The sulfonylcarbamate group was also
stable under OsO4 oxidation conditions.
The underlying principle responsible for the unique
characteristics of the protecting group can be explained as
follows. Because of the strong electron-withdrawing nature of
the sulfonyl group, nucleophilic attack on the carbonyl carbon
occurs readily, and deprotection can be achieved under weakly
basic conditions. However, once the rather acidic proton on
the nitrogen14 is removed by a base, nucleophilic attack is
prevented. As a result, the sulfonylcarbamate group is stable
under strongly basic conditions. This assumption is supported
by the alkylation–cleavage sequence. After alkylation at the
nitrogen atom, an acidic proton is no longer present, allowing
for nucleophilic attack on the carbonyl group to occur under
both weakly and strongly basic conditions (Scheme 5).
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In conclusion, we have developed and established the utility
of the sulfonylcarbamate group as a novel protecting group for
10 I. Velter, B. La Ferla and F. Nicotra, J. Carbohydr. Chem., 2006, 25, 97.
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3379–3380.
`
addition, the sulfonylcarbamate group has the unique property 14 A. Vigroux, M. Bergon, C. Bergonzi and P. Tisnes, J. Am. Chem. Soc.,
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of being stable under severe conditions and labile under mild
conditions. This unique and synthetically useful characteristic
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This journal is The Royal Society of Chemistry 2013
8334 Chem. Commun., 2013, 49, 8332--8334