Enantioselective organocatalytic oxidation of functionalized sterically hindered disulfides

Article abstract of DOI:10.1021/ol070056z

Figure presented The first study on enantioselective oxidation of functionalized sterically hindered disulfides is reported. This study shows that the Shi organocatalytic system using carbohydrate-derived ketone with oxone is superior to the Ellman-Bolm v

Full text of DOI:10.1021/ol070056z

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1255-1258
Enantioselective Organocatalytic
Oxidation of Functionalized Sterically
Hindered Disulfides
Noureddine Khiar,*,† Siham Mallouk,§ Victoria Valdivia,† Khalid Bougrin,§
Mohammed Soufiaoui,§ and Inmaculada Ferna´ndez*,‡
Instituto de InVestigaciones Qu´ımicas, C.S.I.C-UniVersidad de SeVilla,
c/. Ame´rico Vespucio, 49, Isla de la Cartuja, 41092 SeVilla, Spain, Departamento de
Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, UniVersidad de SeVilla,
41012 SeVilla, Spain, and Laboratoire de Chimie des Plantes et de Synthe`se
Organique et Bio-organique, UniVersite´ Mohammed V-Agdal, Faculte´ des Sciences,
B.P. 1014 R.P. Rabat, Morrocco
khiar@iiq.csic.es; inmaff@us.es
Received January 9, 2007
ABSTRACT
The first study on enantioselective oxidation of functionalized sterically hindered disulfides is reported. This study shows that the Shi
organocatalytic system using carbohydrate-derived ketone with oxone is superior to the Ellman Bolm vanadium catalyst in terms of chemical
−
yield and enantioselectivity. Whereas the latter system afforded mostly racemic thiosulfinates in low to moderate yields, the former one
afforded thiosulfinates with up to 96% ee.
The preparation of chiral sulfinyl derivatives has been a
standing area of interest over the past 3 decades.1 This interest
was mainly directed toward the preparation of chiral sul-
foxides as a consequence initially of their high efficiency as
chiral controllers in asymmetric carbon-carbon and carbon-
heteroatom bond formation2 and also because of the phar-
macological significance of some synthetically and naturally
occurring sulfoxides.1 Nevertheless, the advances made in
the preparation of chiral sulfinyl derivatives at the beginning
of the 1990s have widened their applicability to all branches
of asymmetric synthesis.3 Among the recent applications of
chiral sulfoxides is their utilization as chiral ligands or ligand
precursors in metal-catalyzed asymmetric reactions,1 in
coordination chemistry1,4 and as Lewis base in organoca-
talysis.5 Additionally, one of the most significant break-
(3) Senanayake, C.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93.
(4) (a) Evans, D. R.; Huang, M. S.; Seganish, W. M.; Fettinger, J. C.;
Williams, T. L. Inorg. Chem. Commun. 2003, 6, 462. (b) Khiar, N.; Arau´jo,
C. S.; Alcudia, F.; Ferna´ndez, I. J. Org. Chem. 2002, 67, 345. (c) Pettinari,
C.; Pellei, M.; Cavicchio, G.; Crucianelli, M.; Panzeri, W.; Colapietro, M.;
Caseta, A. Organometallics 1999, 18, 555.
† C.S.I.C-Universidad de Sevilla.
‡ Facultad de Farmacia, Universidad de Sevilla.
§ Universite´ Mohammed V-Agdal.
(1) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
(2) Carren˜o, C. Chem. ReV. 1995, 95, 1717.
10.1021/ol070056z CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/07/2007

throughs in the chemistry of sulfinyl derivatives is the
development of efficient approximations for the synthesis
of sulfinamides6,7 and the corresponding sulfinylimines.
Accordingly, the exceptional behavior of the chiral sulfinyl
group in sulfinylimines as activator, chiral controller, and
finally as useful protective group makes the sulfinamides
an extremely versatile chiral ammonia equivalent.8,9 On the
other hand, recent studies have demonstrated that hindered
alkyl substituents on the sulfur confer better stereochemical
control in different processes compared to their aryl
counterparts.10-13 These results promoted an active search
of new and more hindered sulfinylating agents, of which
there are a number in the literature.14 Surprisingly, the
synthesis of functionalized sterically demanding sulfinating
agents did not attract much interest. Significantly, the high
interest in the synthesis of complex molecules on solid
support and the recent use of chiral sulfoxides as Lewis bases
in organocatalysis make the synthesis of conveniently
functionalized sterically hindered sulfinylating agents an
attractive research goal. With these premises in mind, we
started a research program for development of an efficient
route for the synthesis of enantiomerically pure functionalized
sterically demanding thiosulfinates.15 In the present work we
report our preliminary results on the catalytic enantioselective
oxidation of sterically hindered disulfide diols and the corre-
sponding diesters and diethers I using two different catalytic
systems. The first system employs an oxovanadium complex
derived from indanol Schiff base 1, which represents the
actual state of the art in the oxidation of sterically hindered
alkyl disulfides,16 and the carbohydrate Schiff base 217
(Scheme 1). The second system is based on the Shi organo-
surprisingly has never been used in the synthesis of chiral
sulfinyl derivatives.21 Aliphatic aldehydes 6 and 7, with an
enolizable proton, react with sulfur monochloride (S2Cl2) to
give 2,2,5,5-tetraalkyl (ethyl or cyclohexyl)-3,4-dithiahexane-
1,6-dial 8 and 9 in excellent yields. A chemoselective
reduction of the dialdehydes with sodium borohydride
afforded the corresponding diols. Acylation or etherification
of these diols affords the fully protected disulfides 12-15
as white crystalline compounds in general.
It is worth mentioning that following the modular strategy
described in Scheme 2 various sterically hindered disulfides
Scheme 2
with different protective groups can be obtained. The
possibility of changing the protective group enhances the
probability of tuning the structure of the disulfide for a high
(6) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, V.; Portonovo,
P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org.
Chem. 1997, 62, 2555.
(7) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913.
(8) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (b) Ellman, J. A. Pure. Appl. Chem. 2003, 75, 39.
(9) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27,
13. (b) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60,
8003.
Scheme 1
(10) In Michael addition: Casey, M.; Manage, A. C.; Nezhat, L.
Tetrahedron Lett. 1988, 29, 5821.
(11) In the synthesis of chiral amines: (a) Liu, G.; Cogan, D. A.; Owens,
T. D.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,
1278. (b) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 1539.
(12) Garc´ıa-Ruano, J. L.; Ferna´ndez, I.; del Prado, M.; Alcudia, A.
Tetrahedron: Asymmetry 1996, 7, 3407.
(13) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7441.
(14) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880.
(15) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 10127.
(16) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(17) Cucciolito, M. E.; Del Littto, R.; Roviello, G.; Ruffo, F. J. Mol.
Catal. A: Chem. 2005, 236, 176.
(18) (a) Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5794. (b) Crane, Z.; Goeddel, D.; Gan, Y.; Shi, Y.
Tetrahedron 2005, 61, 6409.
(19) (a) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792.
(b) Nieto, P.; Molas, P.; Benet-Buccholz, Vidal-Ferran, A. J. Org. Chem.
2005, 70, 10143.
(20) In the course of this work, Colonna’s group has reported on the
oxidation of tert-butyl disulfide with this system: Colonna, S.; Piroti, V.;
Drabowizcz, J.; Brebion, F.; Fensterbank, L.; Malacria, M. Eur. J. Org.
Chem. 2005, 1727.
catalytic process and utilizes chiral diooxiranes derived from
D-fructose (3 and 4)18-20 and D-glucose (5) (Scheme 1).
The synthesis of the starting disulfides was achieved using
an approximation developed more than 3 decades ago, which
(5) (a) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem.
Soc. 2003, 125, 6610. (b) Massa, A.; Malkov, A. V.; Kocovky, P. Scettri,
A. Tetrahedron Lett. 2003, 44, 7179. (c) Rowlands, G.; Barnes, W. K. Chem.
Commun. 2003, 2712. (d) Ferna´ndez, I.; Valdivia, V.; Gori, B.; Alcudia,
F.; AÄ lvarez, E.; Khiar, N. Org. Lett. 2005, 7, 1307.
(21) (a) Hayashi, K. Macromolecules 1970, 3, 5. (b) Roy, B.; du
Moulinet, d’hardemare, A.; Fontecave, M. J. Org. Chem. 1994, 59, 7019.
(c) Stec, W. J.; Karwowski, B.; Boczkowska, M.; Guga, P.; Koziolkiewicz,
M.; Sochacki, M.; Wieczorek, M. W.; Blaszyk, J. J. Am. Chem Soc. 1998,
120, 7156.
1256
Org. Lett., Vol. 9, No. 7, 2007

and 29%). The protection of the hydroxyl groups has a
dramatic effect on the reaction, as the final thiosulfinate esters
19-21 (Table 1, entries 3-5) and the thiosulfinate ether 22
(Table 1, entry 6) were always obtained in very low yields
and in most cases in racemic form (Table 1, entries 3-6).
As part of a research program directed toward the utiliza-
tion of carbohydrates as cheap ligands in asymmetric
catalysis,22 we were also interested on the behavior of the
glucosamine-derived Schiff base 2 in the same process. As
can be seen (Table 1, entries 7 and 8), ligand 2 behaves as
1 with regard to the oxidation of functionalized sterically
hindered thiosulfinates. Interestingly, an appealing 58% ee
(Table 1, entry 10) was obtained in the oxidation of 16 albeit
in low yield.
In keeping with our interest in using carbohydrates as
ligands, our second approximation was the organocatalytic
oxidation of the sought disulfides using chiral dioxiranes
derived from carbohydrates. Three ketones, 3-5, were used
in this study, employing the optimal Shi conditions described
for the oxidation of alkenes, and the results are given in Table
2. Screening the three ketones in the oxidation of disulfide
Figure 1. Structures of disulfides used in the synthesis of chiral
thiosulfinates.
enantioselectivity. The disulfides used in the present study,
10-15, are shown in Figure 1 and were chosen mainly to
determine the influence of the electronic nature of the pro-
tective group on the enantioselective process. In order to
determine the role of the hydroxylic function on the enan-
tioselectivity, the oxidation of tert-butyl disulfide 16 was also
carried out with both approximations.
Our first approach for the synthesis of our enantiomerically
pure thiosulfinates was by the Ellman-Bolm process as it
constitutes the actual state of the art for the oxidation of
disulfide 16. Additionally, taking into account the presence
of a hydroxylic function in the substrate, which may permit
a well-defined transition state, we were confident on the
enantioselectivity of the process.
Table 2. Enantioselective Oxidation of Disulfides 10-16 with
Oxone and Carbohydrate-Derived Ketones 3-5
Surprisingly, employing the best conditions in terms of
catalyst loading, temperature, and solvent described in the
literature for ligand 1, the final thiosulfinate esters 17-22
have been obtained in very low ee’s in general and in low
to modest yields at best (Table 1, entries 1-6). With the
yield ee
entryb disulfide
R
R′ ligand thiosulfinate (%)c (%)d
1
2
3
4
5
6
7
8
9
10
10
10
11
12
13
14
15
16
Et
Et
Et
C5H10
Et
C5H10 Ac
Et
Et
H
H
H
H
Ac
3
4
5
3
3
3
3
3
3
17
17
17
18
19
20
21
22
23
80
76
70
82
89
57
89
20
97
72
60
0
70
89
96
93
90
84
Table 1. Enantioselective Oxidation of Disulfides 10-15 and
16 with Schiff Base-Vanadium Complexes3
Bz
PMB
a DMM: dimethoxymethane. b Reactions were conducted in CH3CN/
DMM (1:2) using 30 mol % of the ketone and 1.4 molar equiv of oxone.
c Isolated yield. d Enantiomeric excesses were determined by chiral HPLC
analysis.
yield ee
entrya disulfide
R
R′ ligand thiosulfinate (%)b (%)c
1
2
10
11
12
13
14
15
10
12
16
16
Et
C5H10
Et
H
1
1
1
1
1
1
2
2
1
2
17
18
19
20
21
22
17
19
23
23
61
71
8
29
0
0
H
Ac
3
4
5
6
diol 6 shows that ketone 5 is not suitable for this transforma-
tion (Table 2, entry 3), while ketone 3 behaves better than
ketone 4 and gives the best results both in terms of reactivity
and enantioselectivity (Table 2, entry 1). The oxidation of
the other disulfides has thus been conducted with ketone 3,
which affords in all cases the final thiosulfinates in very good
yields and in good to excellent enatioselectivities. Interest-
ingly, the acylation of the starting disulfides has a beneficial
effect both on their reactivities and on the enantioselectivities
C5H10 Ac
20
15
15
47
7
17
0
0
Et
Et
Et
Et
Bz
PMB
H
7
8
9
10
0
Ac
28
85
58
90
20
a Reactions were conducted in CHCl3 using 0.5 mol % of the ligand
and 1.1 mol equiv of H2O2. b Isolated yield. c Enantiomeric excesses were
determined by chiral HPLC analysis.
(22) (a) Khiar, N.; Arau´jo, C. S.; AÄ lvarez, E.; Ferna´ndez, I. Tetrahedron
Lett. 2003, 44, 3401. (b) Khiar, N.; Sua´rez, B.; Valdivia, V.; Ferna´ndez, I.
Synlett 2005, 2963. (c) Khiar, N.; Arau´jo, C. S.; Sua´rez, B.; Ferna´ndez, I.
Eur. J. Org. Chem. 2006, 1685.
free hydroxyl groups, the reaction takes place with modest
yield (up to 71%, Table 1, entry 2) and very low ee (0%
Org. Lett., Vol. 9, No. 7, 2007
1257

of the processes, in contrast to the results obtained with the
Schiff base/VO(acac)2 system.
mides and sulfoxides in order to develop recyclable sulfur-
based ligands for asymmetric catalysis.
The acetylated thiosulfinates (19, 20) and the benzoylated
thiosulfinate 21 were obtained in very good yields and
excellent enantioselectivities (up to 96%, Table 2, entries 6
and 7). The oxidation of the electronically rich disulfide 15
gave the corresponding thiosulfinate 22, in a good 90% ee
but in low yield (Table 2, entry 19). These results show that
the structure of the starting disulfide is crucial for a good
result with the oxone/chiral ketone system. Electron-poor
protective groups afford better results than electron-rich
protective groups both in terms of chemical yields and
enantioselectivities. In conclusion, we have shown for the
first time that it is possible to have excellent enantioselec-
tivities and reactivities in the oxidation of functionalyzed
sterically demanding disulfides. These disulfides are actually
being used in the synthesis of polymer-supported sulfina-
Acknowledgment. The authors thank the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica for financial
support (grant nos. CTQ2006-15515-CO2-01 and CTQ2004-
01057) and la Fundacio´n Ramo´n Areces for Financial
support.
Supporting Information Available: Representative
experimental procedures for the synthesis of compounds
10-15 and the corresponding thiosulfinates 17-22, and
1H and 13C NMR and HPLC data for the determination of
enantiomeric excesses of thiosulfinates. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070056Z
1258
Org. Lett., Vol. 9, No. 7, 2007