[[(tert-Butyl)dimethylsilyl]oxy]-methylGroup for sulfur protection

Article abstract of DOI:10.1021/ol2002573

Aromatic and aliphatic thiols can be protected by reaction with t-BuMe ₂SiOCH₂Cl in DMF in the presence of a base (2,6-lutidine or proton sponge); the resulting t-BuMe₂SiOCH₂SR or t-BuMe₂SiOCH₂SAr are deprotected by sequential treatment with Bu₄NF and I₂ to give symmetrical disulfides. Another mode of deprotection involves reaction with a sulfenyl chloride; this process gives an unsymmetrical disulfide and was examined with Me(CH₂) ₁₁SCH₂OSiMe₂Bu-t and three sulfenyl chlorides.

Full text of DOI:10.1021/ol2002573

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1734–1737
[[(tert-Butyl)dimethylsilyl]oxy]-
methyl Group for Sulfur
Protection
Lihong Wang and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.clive@ualberta.ca
Received January 26, 2011
ABSTRACT
Aromatic and aliphatic thiols can be protected by reaction with t-BuMe2SiOCH2Cl in DMF in the presence of a base (2,6-lutidine or proton sponge);
the resulting t-BuMe2SiOCH2SR or t-BuMe2SiOCH2SAr are deprotected by sequential treatment with Bu4NF and I2 to give symmetrical disulfides.
Another mode of deprotection involves reaction with a sulfenyl chloride; this process gives an unsymmetrical disulfide and was examined with
Me(CH2)11SCH2OSiMe2Bu-t and three sulfenyl chlorides.
In connection with work on the synthesis of the anti-
tumor agent MPC1001 (1, Figure 1), we needed to intro-
ducesulfur ina temporarilyprotectedformby reaction of a
carbanion with a sulfenylating reagent. For initial studies,
reagent 3 was used1 (Scheme 1) because it gave a satisfac-
tory yield and stereoselectivity, but it subsequently proved
to be unsuitable as the sulfur protecting group could not be
removed from a more advanced intermediate under suffi-
ciently mild conditions (Bu4NF2 or ArSCl3). The excessive
robustness of the CH2CH2SiMe3 group forced us to devise
a sulfenylating reagent in which the sulfur is protected
in such a way that the protecting group can be removed
under mild conditions, and we were led to consider reagent
5 as a suitable candidate for evaluation. Our experience
had shown that arylsulfonothioic acid esters (such as 6)
Figure 1. Antitumor agent MPC1001.
silicon. We would also require that the released alcohol (or
alkoxide 8) would collapseasshown(Scheme2). A number
of hydroxymethyl sulfides (RSCH2OH, R = alkyl or aryl)
are known and are isolable, but there are indications4 that,
under appropriate conditions, they do fragment to release
(Figure 2) are able to deliver a protected sulfur to carba-
nions derived from 2, and we expected that the choice of a
silyl ether, as in 5, would allow fine control, if necessary, of
the conditions required for deprotecting the oxygen; such
control would be exercised by changingthe alkyl groupson
(1) Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513–519.
(2) Cf. (a) Koreeda, M.; Yang, W. J. Am. Chem. Soc. 1994, 116,
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mer, D. G. J. Org. Chem. 1996, 61, 9356–9361. (c) For higher aldehydes
than formaldehyde, see: Harpp, D. N.; Kobayashi, M. Tetrahedron Lett.
1986, 27, 3975–3978. (d) Gong, Y.; Ma, M.; Luo, Y.; Bong, D. J. Am.
Chem. Soc. 2008, 130, 6196–6205. (e) Horner, L.; Jurgens, E. Annalen
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ꢀ
ꢀ
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€
(3) Cf. Gerland, B.; Desire, J.; Lepoivre, M.; Decout, J.-L. Org. Lett.
2007, 9, 3021–3023.
r
10.1021/ol2002573
Published on Web 03/10/2011
2011 American Chemical Society

(one is commercially available7) have been used before for
O-protection of alcohols8,9 and protection of N-1 of
pyrimidines.6 Reaction of 13 with TolSO2SNa in MeCN
gave 5 (53%), which was used for the sulfenylation shown
in Scheme 4. Reagent 13 can be kept in a freezer (-20 °C)
for 1-2 days; likewise, reagent 5 should be stored in a
freezer and can be kept in this manner for several months;
both reagents are most conveniently generated just before
use, and we have made them on a 1-3 g scale.
Scheme 1. Original Sulfenylation
Scheme 4. Sulfenylation with 5
a thiol and an aldehyde (cf. 8f9), although the fragmenta-
tion occurs less readily with derivatives of formaldehyde
(cf. 8) than with derivatives of higher aldehydes. In the
event, the fragmentation step was not problematic.
As we would later need to deprotect the sulfur in a more
advanced intermediate than 15, and have now actually
done so (88% yield), we next examined the deprotection
step of our plans. For this purpose, the thiols listed in
Scheme 5 were converted into the corresponding com-
Figure 2. Aryl sulfonothioic acid esters.
Scheme 2. Protecting Group Design
Scheme 5. Preparation of RSCH2OSiMe2Bu-ta
The obvious way to prepare reagents of type 5, a structure
that appears to represent a new compound class,5 is by reac-
tion of TolSO2SNa with t-BuMe2SiOCH2Cl (13), a com-
pound that is easily prepared by the reported method,6 which
is summarized in Scheme 3; several chloromethoxysilanes
Scheme 3. Formation of t-BuMe2SiOCH2Cl
a Pg = CH2OSiMe2Bu-t.
pounds in which the sulfur is protected with a [[(tert-
butyl)dimethylsilyl]oxy]methyl group. In each case, the
thiol was treated with 13 in the presence of a base. DMF
(5) Numerous O-C, as opposed to O-Si, analogues are known.
(6) Benneche, T.; Gundersen, L.-L.; Undheim, K. Acta Chem. Scand.
1988, 42B, 384–389.
(7) i-Pr3SiOCH2Cl is commercially available.
(8) (a) Gundersen, L.-L.; Benneche, T.; Undheim, K. Acta Chem.
Scand. 1989, 43, 706–709. (b) Hunziger, J.; Hall, J.; Martin, P. European
Patent 1565479B1, 2006.
(9) Pitsch, S.; Weiss, P. A.; Jenny, L.; Stutz, A.; Wu, X. Helv. Chim.
Acta 2001, 84, 3773–3795.
Org. Lett., Vol. 13, No. 7, 2011
1735

Scheme 6. Deprotection of RSCH2OSiMe2Bu-ta
Table 1. Stability Tests of 20a
20a
decomp
(%)
temp
reagent
solvent
(°C)
time
a
1
2
3
4
5
6
7
8
9
H2, Pd/C
MeOH-CH2Cl2
rt 5.5 h
rt 4 h
rt 1 h
0
0
H2, Rh/Al2O3 EtOAc
Zn dust
NaBH4
LiAlH4
DIBAL
LDA
AcOH-Et2O (1:2)b
THF-H2O (8:1)
THF
3
0
1 h
0
rt 1 h
7
CH2Cl2
THF
-78 1 h
-78 45 min
3
10
7
EtMgBr
BuLic
THF
0
1 h
THF
-78 15 min
rt 20 min
4
10 piperidined
11 CF3CO2He
12 TsOH.H2O
13 PPTSf
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
0
0
30 min
100
94
47
2
rt 4.5 h
rt 4.7 h
rt 4.5 h
14 PPTS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
15 BF3.Et2O
16 CBr3/Ph3Pg
17 PCCh
0
0
1 h
100
7
30 min
rt 40 min
rt 2 h
100
100
10
100
5
18 Dess-Martin CH2Cl2
19 IBXi
DMSO
CH2Cl2
CH2Cl2
rt 2 h
j
20 Swern
21 Et3SiOTfk
-78 25 min
a A small amount of CH2Cl2 was used to solubilize 20a. When the
experiment was repeated using 2:3 MeOH-CH2Cl2 at rt for 40 min in
the presence of [2-(2-bromophenyl)ethoxy]triethylsilane the Et3Si group
was completely removed (ref 13) and 20a was unchanged. b These are
conditions for removal of a Troc group (ref 14). c Experiment done in the
presence of (PhS)2CH2, and the mixture was quenched with D2O; all the
dithioketal had been converted into (PhS)2CHD, and 20a was un-
changed. d Piperidine/CH2Cl2 = 1:4 by volume. When done in the
presence of Fmoc-Pro-OMe, the Fmoc group was removed (cf. ref 15),
but 20a was unchanged. e CF3CO2H/CH2Cl2 = 1:2 by volume; these are
standard conditions for Boc removal (ref 16). f Under these conditions,
O-SiMe2Bu-t groups are desilylated (ref 17). g Done in the presence of
2-(2-bromophenyl)ethanol; all of the alcohol was converted into the
corresponding bromide, and 93% of 20a remained. h Oxidation of a
secondary alcohol in the presence of a methylthiomethyl ether is known
(cf. ref 18). i A hydroxyl can be oxidized in the presence of a sulfide (ref
19). j Standard Swern procedure. k The experiment was done in the
presence of 2-(2-bromophenyl)ethanol and 2,6-lutidine; after 25 min,
50% of the alcohol had been silylated and 95% of 20a remained.
a Pg = CH2OSiMe2Bu-t.
is a satisfactory solvent and proton sponge or 2,6-lutidine
aresuitablebases, buttheoptimum conditions are sensitive
to the structure of the starting thiol. For entries 1 and 2,
proton sponge gave a satisfactory result, but for entry 3 the
yield with 2,6-lutidine was a little better than with proton
sponge (61% versus 55%). In these three cases, we also
tried NaH in THF; for entries 1 and 2, the yields were
comparable to those obtained with proton sponge, but the
aliphatic thiol of entry 3 did not react cleanly under these
(NaH) conditions. In the case of the amino acid (entry 4),
use of 2,6-lutidine gave a better yield (86%) than proton
major side product was the disulfide arising from adven-
titious oxidation of the starting thiol.
With a number of S-protected compounds in hand, we
then examined several methods for deprotection and quickly
found, as might be expected, that the most convenient
procedure involves sequential deprotection and oxidation
to the corresponding disulfide. Treatment of 16a with
Bu4NF (THF, -78 to -10 °C) released the parent thiol 16,
as did similar treatment of 12 (ca. 76% conversion by
1H NMR). If I2 is added after removal of the silicon group
then the expected symmetrical disulfides are formed in the
indicated yields, which are generally well above 80%. It
should be noted that we did not establish if desilylation is
followed by spontaneous extrusion of formaldehyde or
whether loss of formaldehyde occurs after reaction of
iodine with the sulfur; while of mechanistic interest, the
actual sequence is immaterial to the outcome. For removal of
the silicon unit we used Bu4NF/THF, Bu4NF/AcOH/THF,
€
sponge (76%), but Hunig’s base led to a poor yield (ca.
25%). The case of dodecanethiol (entry 5) was examined in
detail: several combinations of solvent (CH2Cl2, PhMe,
MeCN, DMF, THF, EtOAc, and Et2O) and base (Hunig’s
€
base, 2,6-lutidine, DMAP, t-BuOK, DBU) were tried; the
DMF/2,6-lutidine combination emerged from these ex-
periments as likely to be generally satisfactory. Monopro-
tection of the hydroxy thiol 21 (entry 6) was best done with
t-BuOK in DMF, using a slight excess of the hydroxy thiol
(1.3 equiv); the yield was much lower with BuLi/THF or
with 2,6-lutidine/DMF or proton sponge/DMF. Entry 7 of
Scheme 5 does not involve sulfur protection, the hydroxyl
group being acylated by a standard method to give 21b, the
desired substrate for deprotection studies. In each case, the
1736
Org. Lett., Vol. 13, No. 7, 2011

or HF pyridine/THF, our experience being that Bu4NF
alone sometimes gave poorer yields than the buffered
conditions.
O-triethylsilyl ether can be selectively deprotected in the
presence of 20a, using H2/Pd/C in MeOH-CH2Cl2 (entry 1).
The protecting group appears to survive typical condi-
tions for removal of a Troc group (entry 3), and an Fmoc
group can be removed in its presence by using piperidine
(entry 10). Hydride reducing agents either have no effect
(NaBH4, entry 4) or little effect (LiAlH4, DIBAL, entries 5
and 6, respectively). (PhS)2CH2 can be deprotonated with
BuLi with very little decomposition (4%) of 20a (entry 9).
LDA has some effect on 20a (entry 7).20 Acidic reagents
(entries 11-15) are not compatible with the protecting
group, except for PPTS in CH2Cl2 (entry 14) and exposure
to silica gel during chromatography. A primary alcohol
can be converted into the corresponding bromide in the
presence of 20a (entry 16), but oxidizing agents (entries
17-20) damage the protecting group. A primary alcohol
can be silylated with Et3SiOTf in its presence (entry 21).
3
In dealing with sulfur compounds, it is sometimes con-
venient to protect a thiol as an unsymmetrical disulfide
from which the original thiol (or derived thiolate) can be
regenerated by reduction.10 Accordingly, we exposed 20a,
as a test case, to the action of 2-nitrophenylsulfenyl chloride
and observed a very efficient conversion to unsymmetrical
disulfide 20c. This type of process would appear to be
general, as the sulfenyl chlorides Ph3CSSCl11 and BnSCl12
behaved analogously giving 20d (93%) and 20e (66%),
respectively.
The experimentalresults summarizedin Schemes 5 and 6
show that the [[(tert-butyl)dimethylsilyl]oxy]methyl group
can serve as a protecting group for thiols in a wide range of
substrates; both the protection and deprotection occur
under mild conditions and several methods are available
for both steps. The reactions investigated so far involve
tert-butyldimethylsilyl compounds; we assume that the
procedures would also be successful when the conditions
needed for desilylation are altered by changing the substi-
tuents on silicon; however, we have not tested this possibility.
We have also evaluated the stability of the protecting
group by exposing 20a to a variety of conditions, which are
summarized in Table 1. The compound is stable to H2/Pd/
C in MeOH-CH2Cl2 and to H2/Rh/Al2O3/EtOAc. An
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support. L.W. holds an Alberta Heritage Foundation for
Medical Research Graduate Studentship.
Supporting Information Available. Experimental de-
1
tails for synthesis and H and 13C NMR spectra for the
compounds. This material is available free of charge via
Internet at http://pubs.acs.org.
(10) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley-Interscience: Hoboken, 2007; p 687. (b)
Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2004, p 380.
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acylation of an enolate containing the new protecting group.
Org. Lett., Vol. 13, No. 7, 2011
1737