Wang p-alkoxyphenylsulfoxide as a new linker and Pummerer cleavage strategy in solid-phase preparation of 1,2-diols

Article abstract of DOI:10.1016/S0040-4039(01)01557-X

para-Hydroxyphenyl-β-ketosulfide was attached to a Wang resin and oxidised to the corresponding sulfoxide with a N-protonated oxaziridinium trifluoroacetate. Reduction of the β-ketosulfoxides to the corresponding β-hydroxysulfoxides with Dibal-H was shown to be as stereoselective as in solution. Finally it was shown that the Pummerer reaction could be carried out on solid-phase and was a very efficient way to obtain diols that validates the sulfoxide group as a versatile linker for solid-phase chemistry.

Full text of DOI:10.1016/S0040-4039(01)01557-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7563–7566
Wang p-alkoxyphenylsulfoxide as a new linker and Pummerer
cleavage strategy in solid-phase preparation of 1,2-diols
Catherine Rolland, Gilles Hanquet,a,* Jean-Bernard Ducepb and Guy Solladie´a,*
aLaboratoire de Ste´re´ochimie associe´ au CNRS, ECPM, Universite´ Louis Pasteur, 25 rue Becquerel, 67087 Strasbourg, France
bSanofi-Synthelabo 16, rue d’Ankara, 67000 Strasbourg, France
Received 6 July 2001; revised 20 July 2001; accepted 23 August 2001
Abstract—para-Hydroxyphenyl-b-ketosulfide was attached to a Wang resin and oxidised to the corresponding sulfoxide with a
N-protonated oxaziridinium trifluoroacetate. Reduction of the b-ketosulfoxides to the corresponding b-hydroxysulfoxides with
Dibal-H was shown to be as stereoselective as in solution. Finally it was shown that the Pummerer reaction could be carried out
on solid-phase and was a very efficient way to obtain diols that validates the sulfoxide group as a versatile linker for solid-phase
chemistry. © 2001 Elsevier Science Ltd. All rights reserved.
There has been enormous interest in combinatorial
and parallel synthesis in the last decade using solid-
phase methodology.1 A crucial key fragment in plan-
ning a solid-phase synthetic strategy is the linker
group which connects the target molecule to the resin
matrix.2 It must be stable to the diverse reaction con-
ditions on solid-phase and allow facile attachment,
functionalisation and release of the target. We have
focused our attention on sulfoxide functionality
because, surprisingly, it has not been used as a linker
so far. It presents several advantages, including a vari-
ety of possible cleavages and its use in an enantiomeri-
cally pure form allowing asymmetric parallel synthesis.
Sulfoxide linker should allow the preparation of differ-
ent products depending on the cleavage conditions
(desulfurization, Pummerer reaction or syn-elimina-
tion).3
We decided to adapt the well-known b-ketosulfoxide
chemistry4 to the solid support in order to develop an
efficient synthetic route to hydroxy-derivatives involv-
ing a new linker with sulfoxide moiety and Pummerer
type cleavage of the target.
In this letter, we present the preliminary results of this
strategy exemplified by racemic compounds.
In order to easily monitor the different reactions, we
selected a Wang resin5 and a sulfoxide linker which
contains an alkoxy-phenyl group attached to the poly-
Scheme 1.
* Corresponding authors. Fax: (33) 3 90 24 27 42; e-mail: ghanquet@chimie.u-strasbg.fr; solladie@chimie.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01557-X

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C. Rolland et al. / Tetrahedron Letters 42 (2001) 7563–7566
With polymer-bound b-ketosulfoxides 1 in hand, we
studied the reduction of the carbonyl functionality to
the corresponding alcohols using two methodologies.
The first one using an excess of NaBH4 in THF, which
is not stereoselective in solution,12 gives after acetic acid
treatment and cleavage with CH2Cl2/TFA the four
diastereomers 7 in an equimolar ratio. The second one,
using 5 equiv. of Dibal-H in THF at −78°C, which is
highly diastereoselective in solution,13 gives as expected,
after acetic acid treatment and cleavage, quantitatively
only two diastereomers with a de up to 95% (Scheme
4). Attempts to obtain the two other diastereomers by
addition of a chelating Lewis acid (ZnX2)13 failed and
gave a mixture of the four diastereomers. The very low
solubility of ZnX2 in THF and the fact that the sub-
strate was on a polymeric matrix probably explains this
last result.
mer which allows a facile cleavage under acidic
conditions6 (Scheme 1).
We planned to prepare the supported b-ketosulfoxides
1 by oxidation of the corresponding b-ketosulfide Wang
derivatives 2 obtained from the corresponding para-
hydroxyphenyl-b-ketosulfides 3 and a modified Wang
resin.
The para-hydroxyphenyl-b-ketosulfide derivatives
3
were easily prepared from commercially available 4-
mercaptophenol 4 and the corresponding a-bromo-
ketones 5. They were quantitatively attached to the
polymer using trichloroacetimidate-activated Wang
resin (Scheme 2).7 The reaction was monitored by
IR-analysis of a bead.14
Next, we studied the selective oxidation of the sulfides 2
to the corresponding sulfoxides 1 and found that classi-
cal oxygen transfer reagents (mCPBA,8 ozone9) were
inefficient or non-selective. Finally, we carried out this
oxidation using the very chemoselective acid-catalysed
oxaziridine oxygen transfer methodology.10
The reduction was monitored by ATR (attenuated
transmitted reflectance) IR spectroscopy of a bead14
extracted from the reaction mixture; this showed with-
out any ambiguity the decrease of the intensity of the
CO-stretch at 1690 cm−1 and the concomitant appear-
ance of the OH-stretch at 3600 cm−1. The diastereo-
1
selectivity was assigned from the H NMR spectra of
Using 5 equiv. of oxaziridine 6, easily prepared in 2
steps from 1,2,3,4-tetrahydroisoquinoline, and 5.5
equiv. of trifluoroacetic acid in dichloromethane, all
sulphide derivatives 2 were quantitatively transformed
into the corresponding sulfoxides 1 (Scheme 3). The
efficiency of this reaction was determined by monitor-
ing the ratio imine/oxaziridine+nitrone in the reaction
mixture (see Ref. 11).
the alcohols 7 and their correlation with the data of
the corresponding well-known b-hydroxy-p-tolyl-
sulfoxides13 based on the non-equivalence between the
methylene protons a to the sulfoxide.
Finally, after protection of the alcohol by a tert-
butyldimethylsilyl group under standard conditions,15
we examined conditions for releasing the target from
Scheme 2.
Scheme 3.

C. Rolland et al. / Tetrahedron Letters 42 (2001) 7563–7566
7565
Scheme 4.
Scheme 5.
the linker and found that Pummerer rearrangement
using the mild conditions described by Bravo16 gave the
corresponding monoprotected diols 10 almost quantita-
tively (Scheme 5). The treatment of the resulting
product with TFA/CH2Cl2 provided the 4-mercap-
tophenol 4 as a single product.
2. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000,
100, 2091–2157.
3. Pata¨ı, S. The Chemistry of Sulfinic Acid, Ester and Their
Derivatives; John Wiley: Chichester, 1990.
4. (a) Solladie´, G. Comprehensive Organic Synthesis; Perga-
mon, 1991; Vol. 6, p. 148; (b) Solladie´, G. Pure Appl.
Chem. 1988, 60, 1699; (c) Solladie´, G. Enantiomer 1999,
4, 183.
5. Wang, S. S. J. Am. Chem. Soc. 1973, 95, 1328–1340.
6. Kiselyov, A. S.; Armstrong, R. W. Tetrahedron Lett.
1997, 38, 6163–6165.
In conclusion we have demonstrated that an
alkoxyphenyl-sulfinyl type linker is suitable for solid-
phase chemistry and that this system is efficient for the
diastereoselective preparation of hydroxy derivatives
involving reactions easily followed by ATR-IR spec-
troscopy of a bead.
7. (a) Hanessian, S., Xie, F. Tetrahedron Lett. 1998, 39,
733–736 and 737–740; (b) Hanessian, S.; Huynh, H. K.
Tetrahedron Lett. 1999, 40, 671–674.
8. Patek, M.; Drake, B.; Lebl, M. Tetrahedron Lett. 1995,
36, 2227–2230.
9. Sylvain, S.; Wagner, A.; Mioskowsky, C. Tetrahedron
Lett. 1997, 38, 1043–1044.
Acknowledgements
10. Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett.
We are indebted to Sanofi-Synthelabo for financial
support and for CIFRE grant to Catherine Rolland.
1988, 23, 2817–2818.
11. The oxygen-atom transfer reaction from a protonated
oxaziridine to a sulphide gives the corresponding sulfox-
ide and the protonated imine. Excess of oxaziridine is
isomerised in presence of trifluoroacetic acid to the corre-
sponding protonated nitrone.10
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In the reaction conditions the oxygen-atom transfer is
also completely achieved when the ratio imine/
oxaziridine+nitrone reaches 20%.

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