Enantioselective synthesis of thiosulfinates and of acyclic alkylidenemethylene sulfide sulfoxides

Article abstract of DOI:10.1002/ejoc.200400892

Enantioselectivities up to 75 % have been found in the catalytic mono-oxidation of di-tert-butyl disulfide and related compounds as well as of ketene-S,S-acetals with an in situ generated chiral dioxirane. The effect of solvents on the enantiomeric excess

Full text of DOI:10.1002/ejoc.200400892

SHORT COMMUNICATION
Enantioselective Synthesis of Thiosulfinates and of Acyclic
Alkylidenemethylene Sulfide Sulfoxides
Stefano Colonna,*[a] Vincenza Pironti,[a] Jozef Drabowicz,[b] Franck Brebion,[c] and
Louis Fensterbank,[c] and Max Malacria*[c]
Keywords: Chiral dioxirane / Thiosulfinate / Asymmetric synthesis / Bovine serum albumin / Enantioselectivity
Enantioselectivities up to 75% have been found in the cata- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lytic mono-oxidation of di-tert-butyl disulfide and related
compounds as well as of ketene-S,S-acetals with an in situ
generated chiral dioxirane. The effect of solvents on the en-
antiomeric excess has also been examined.
Germany, 2005)
sis.[8] Enantiomerically pure 1 was initially synthesized in
two steps from the inexpensive petroleum byproduct di-tert-
butyl disulfide (2) in 68% overall yield.[9] Asymmetric oxi-
dation of 2 provided thiosulfinate (3) with high enantio-
selectivity and conversion using only 0.25 mol-% catalyst
and with 30% hydrogen peroxide as an inexpensive, easy to
handle oxidant. Although the reaction sequence is short
and efficient and has enabled extensive use of the reagent,
the oxidation of 2 to 3 needs several improvements to en-
able industrial-scale production of 1. The enzymatic process
constitutes a challenging approach; indeed, enantiomer-
ically pure tert-butanethiosulfinate (3) can be obtained by
oxidation of the corresponding disulfide 2 catalyzed by cy-
clohexanone monooxygenase (CHMO).[10]
Introduction
tert-Butanesulfinamide (1) has proven to be a versatile
chiral ammonia equivalent for the asymmetric synthesis of
amines. Condensation of 1 (Figure 1) with a wide range of
aldehydes and ketones provides N-sulfinyl imines in very
high yields. The tert-butanesulfinyl group both activates
these imines to attack by nucleophiles and behaves as a chi-
ral-directing group to provide N-tert-butanesulfinylamine
derivatives in high yields and with high diastereoselectivity.
Removal of the tert-butanesulfinyl group under mild condi-
tions cleanly provides the functionalized amines. In view of
these features, 1 has enjoyed rapidly growing use both in
academic laboratories and industry.[1]
Results and Discussion
Figure 1. tert-Butanesulfinamide.
The enantioselective oxidation of sulfides to sulfoxides is
a well-studied reaction, in which a large variety of chemical
oxidations have been used.[11]
In the light of the high stereoselectivity of the bovine
serum albumin (BSA) catalysed oxidation of a wide range
of sulfides,[12] we decided to investigate the possibility of
using this chiral auxiliary for the preparation of chiral tert-
Applications include the asymmetric synthesis of α-
branched amines,[2] tertiary carbinamines,[3] highly substi-
tuted β-amino acids,[4] α-amino acids,[5] 1,2-amino
alcohols,[6] and 1,3-amino alcohols.[7] In addition, tert-bu-
tanesulfinamide has been employed in a large number of
drug discoveries and is used as the key chirality-bearing
component of new classes of ligands for asymmetric cataly-
butyl tert-butanethiosulfinate by the oxidation of
2
(Table 1) with different achiral oxidizing agents.
In all the experiments the only isolated product was the
thiosulfinate 3 with no trace of the overoxidation product.
However, its enantiomeric excess was low and for this
reason, we decided to investigate another oxidizing system.
At first we considered the oxidation of tert-butyl disul-
fide using a chiral dioxirane in a two-phase system. This
procedure could be included into catalysis by small organic
molecules, termed organocatalysis, which recently has been
getting increasing interest in organic synthesis. When com-
[a] Istituto di Chimica Organica “A. Marchesini”, Facoltà di Farm-
acia, Università degli Studi di Milano,
Via Venezian, 21 Milano 20131, Italy
Fax: +39-02-50314476
E-mail: Stefano.Colonna@unimi.it
[b] Department of Heteroorganic Chemistry, Polish Academy of
Sciences,
90-363 Łòdz´, Sienkiewicza 112, Poland
[c] Université Pierre et Marie Curie, Laboratoire de Chimie Or-
ganique, UMR CNRS 7611, case 229,
4, place Jussieu, 75252 Paris Cedex 05, France
Eur. J. Org. Chem. 2005, 1727–1730
DOI: 10.1002/ejoc.200400892
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Colonna, M. Malacria et al.
SHORT COMMUNICATION
Table 1. Oxidation of tert-butyl disulfide in the presence of BSA.
1
[a] The conversion was calculated by H NMR spectroscopy. [b] Enantiomeric excess was determined by HPLC analysis using a chiral
column.
Table 2. Oxidation of tert-butyl disulfide using the fructose derived dioxirane and KHSO5.
1
[a] The conversion was calculated by H NMR spectroscopy. [b] Enantiomeric excess was determined by HPLC analysis using a chiral
column.
pared to transition-metal-catalysed procedures, such reac- Table 3. Effect of solvents in the catalytic asymmetric oxidation of
tert-butyl disulfide using the fructose derived dioxirane and
KHSO5.
tions have advantages in terms of easy product purification
and of their relative insensitivity to air and water, thus al-
lowing for easier experimental execution.
Entry
Solvent
t [h] Conversion [%] ee [%][a]
The reaction conditions chosen were the same as used by
Shi and coworkers for the epoxidation of a wide range of
styrene derivatives, namely with the disulfide 2 (Table 2),
ketone 4 and Oxone in a 1.0:0.30:1.38 molar ratio, respec-
tively.[13] The fructose-derived ketone 4 (Figure 2) was used
as chiral precursor and Oxone as achiral oxidant, which
generate the chiral dioxirane in a catalytic cycle.
1
2
3
4
CH3CN/DMM (1:2)
CH3CN
1
1
1
1
Ͼ98
Ͼ98
41
75
67
60.5
41
CMM
CH2Cl2
5
[a] Enantiomeric excess was determined by HPLC analysis.
The low ee value for compound 8 is a consequence of
the low optical stability of the product. Indeed, it has been
reported that, apart from tert-butyl tert-butanethiosulfinate
and diaryl thiosulfinate, the other thiosulfinates are op-
tically unstable and racemize at room temperature.[10]
In contrast with the CHMO-promoted oxidation, which
was completely regioselective,[10] in the case of compound 6
the fructose oxirane derivative led to a mixture of the two
thiosulfinates 10, 11 in a 2:1 ratio, with modest ee.
Figure 2. Fructose-derived ketone.
Screening of the solvent for the reaction was then under-
In the case of compound 7 the sulfoxide formed 12 was
taken, and the proper choice of solvents was found to be a racemic mixture, as a consequence of the direct oxidation
significant for obtaining good yields and enantioselectivit- of the substrate by Oxone; in fact, in the blank experiment
ies.
carried out in the absence of ketone 4 the chemical yield
On the basis of these results, the mixed CH3CN/DMM did not change.
(dimethoxymethane) [1:2] was chosen as the reaction sol-
vent for further studies (Table 3).
Another class of intriguing substrates to be explored in
the context of chiral dioxirane-mediated oxidation is the
The disulfide 2 was completely oxidized to the corre- family of acyclic alkylidenemethylene disulfides (S,S-ketene
sponding thiosulfinate 3 with high enantiomeric excess (en- acetals), since the corresponding enantiopure disulfoxide
try 1). The product was easily isolated from the reaction congeners have been shown to be highly versatile partners
mixture by a simple extraction with petroleum ether, with- for asymmetric synthesis.[14] Thus, we have examined the
out need of further purification.
behavior of substrate 13 (see Table 5 and Scheme 1). In the
This favourable result led us to test the oxidation of di- presence of 2.1 equiv. of KHSO5, a very clean reaction was
sulfides 5, 6 and of 1,3-dithiane 7 in the presence of the observed with full consumption of starting material 13.
chiral dioxirane. The results obtained are listed in Monosulfoxide 14 was obtained as the major product,
Table 4.
whose E stereochemistry was deduced from nOe studies.
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Eur. J. Org. Chem. 2005, 1727–1730

Thiosulfinates and Acyclic Alkylidenemethylene Sulfide Sulfoxides
SHORT COMMUNICATION
Table 4. Oxidation of disulfide 5–7.
1
[a] The conversion was calculated by H NMR spectroscopy. [b] Enantiomeric excess was determined by HPLC analysis.
Minor disulfoxides 15 and 16 were also isolated. On two solvent (entries 4–6) conversion was low and ee even
runs (entries 1 and 2), similar yields of products 15 and dropped in the case of dichloromethane (entry 6). This con-
16 with consistent ees were recorded. In contrast with the firmed Shi’s and our findings[13b] that a mixture of acetoni-
behavior of 1,3-dithiane (7), partially soluble in the reaction trile and dimethoxymethane is the best solvent for this reac-
medium, a blank experiment with no ketone 4 left starting tion.
material 13 untouched; this is possibly a consequence of the
total insolubility and demonstrates the catalytic role of the
ketone. Attempts to force the oxidation to produce 15 and/
or 16 (entry 3) did not give a satisfactory result since the
Conclusions
monosulfoxide 14 remained the major product. The poor
The chiral dioxirane oxidation appears to be a very
solubility of 14 under the reaction conditions could be re- promising tool for the asymmetric mono-oxidation of di-
sponsible for this failure. Moreover, when we changed the tert-butyl disulfide (2), as well as of the S,S-ketene acetal 13.
Table 5. Oxidation of 13.
Entry
Solvent
KHSO5 [equiv.]
14
15
16
Yield [%]; ee [%][a]
Yield [%]; ee [%]
Yield [%]; ee [%]
1
2
3
4
5
6
CH3CN/DMM (1:2)
CH3CN/DMM (1:2)
CH3CN/DMM (1:2)
CH3CN
2.1
2.1
6
2.1
2.1
2.1
70; 43.9 (RS)[b]
70; 46.1 (RS)
30; 43.9 (RS)
30 (42); 38.2 (RS)
14 (85); 43.0 (RS)
4 (88); 30.4 (RS)
9; 36.5 (SS,RS)
8; 37.0 (SS,RS)
12; 16.1 (SS,RS)
18; 32.5 (RS,RS)
16; 31.5 (RS,RS)
14; 34.0 (RS,RS)
nd
nd
nd
nd
nd
nd
DMM
CH2Cl2
[a] All ees determined by chiral HPLC: CHIRALPAK AD-H or AD column. [b] Absolute configurations were deduced by comparison
with enantiopure materials obtained by other synthetic methods. [c] Yield in parentheses corresponds to recovered starting material.
Scheme 1.
Eur. J. Org. Chem. 2005, 1727–1730
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S. Colonna, M. Malacria et al.
SHORT COMMUNICATION
45 min (by means of addition funnels). After completion of the
addition, the reaction mixture was stirred for 15 min at 0 °C, di-
luted with water and extracted with dichloromethane. The com-
bined extracts were washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by silica gel
chromatography (pentane/ethyl acetate, from 100:0 to 50:50).
Totally unprecedented in this context, this organo-catalyzed
oxidation has given highly encouraging ees for 3 and for
14, respectively, 75% and 46%. Further refinements of this
process will include optimization of the structure of the
ketone catalyst and reaction conditions, including scale up,
as well extension to other sulfur-based substrates. Utiliza-
tion of 14 as a Michael acceptor is also an intriguing pos-
sibility.
Determination of the Absolute Configuration of 14, 15 and 16: Abso-
lute configurations of (Rs) 14, (Ss, Rs) 15 and (Rs, Rs) 16 were
determined by comparison with authentic samples made by other
synthetic methods. (Ss) 14 was prepared in a two-step sequence:
Enantiopure (Rs)-methyl sulfoxide was alkylated with p-tolyl disul-
fide in the presence of lithium diisopropyl amide (LDA). The re-
sulting dithiane monoxide was then alkylated with benzaldehyde in
the presence of triton B, giving (Ss) 14 with 94% ee. (Ss) 14 was
then oxidized with m-chloro perbenzoic acid (MCPBA) and pro-
vided a mixture of the (Rs, Ss) antipode of 15 and of the (Ss, Ss)
antipode of 16 which is known.[14a] Careful spectroscopic studies
including MS ensured this assignment. All these data will be pre-
sented in a forthcoming article.
Experimental Section
General Remarks: Oxone and disulfides 2, 5 and 7 were purchased
from Aldrich. The fructose-derived ketone 4[13b] and disulfide 6[10]
were synthesized according to known methodologies. S,S-ketene
acetal 13 was prepared through the following sequence: alkylation
of the lithium anion of bis(p-tolylthio)methane with benzaldehyde,
acetylation and elimination by diazabicycloundecene (DBU). All
glassware used for the oxidations was carefully washed to eliminate
any trace metals in order to avoid the decomposition of Oxone.
The 300 MHz 1H NMR spectra were measured on a Bruker AC
300 apparatus with CDCl3 as solvent. HPLC analyses were per-
formed on a Jasco HPLC instrument (model 980-PU pump, model
975-UV detector) using known conditions.[10] All reactions were
monitored by analytical TLC on Merck silica gel 60 F254 plates
and visualized by UV irradiation or by iodine.
Acknowledgments
We thank Murst (Programmi di Ricerca Scientifica di Interesse Na-
zionale) for financial support and the Université Franco-Italienne
exchange programme and Dr. Emmanuel Lacôte for his collabora-
tion.
General Procedure for Oxidation of 2 in the Presence of BSA: The
disulfide 2 (1 mmol) and BSA (3.3 g, 5×10–2 mmol) were stirred
magnetically in 12.5 mL of buffer solution for 2 h at 20 °C, then
the relevant oxidant (1 mmol) was added, and stirring continued
for an appropriate time. Extraction with four portions (60 mL
each) of diethyl ether, and evaporation of the organic layer after
drying with Na2SO4 gave the product 3, which was analyzed by
HPLC.
[1] D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317–1320 and
references citated therein.
[2] G. Liu; D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1997,
119, 9913–9914.
[3] D. A. Cogan; G. Liu; J. A. Ellman, Tetrahedron 1999, 55, 8883–
8904.
[4] T. P. Tang, J. A. Ellman, J. Org. Chem. 2002, 67, 7819–7832.
[5] D. D. Staas, K. L. Savage, C. F. Homnick, N. N. Tsou, R. G.
Ball, J. Org. Chem. 2002, 67, 8276–8279.
General Procedure for Oxidation of Disulfide 2, 5–7: The disulfide
(1 mmol) was dissolved in the appropriate solvent (see Tables 2, 3
and 4) (15 mL). The buffer [10 mL, 0.05 m solution of
Na2B4O7·10H2O in 4×10 –4 m aqueous Na2(EDTA)], tetrabu-
tylammonium hydrogen sulfate (15 mg, 0.04 mmol) and ketone 4
(77 mg, 0.30 mmol) were added and the mixture was cooled to the
appropriate temperature (Table 2). A solution of Oxone (0.85 g,
1.38 mmol) in aqueous Na2(EDTA) (4×10–4 m, 6.5 mL) and a solu-
tion of K2CO3 (0.8 g, 5.8 mmol) in water (6.5 mL) were added
dropwise separately over a period of 1 h. After complete addition
of Oxone, the reaction mixture was stirred for another 1 h and then
extracted with petroleum ether (3×10 mL). The combined organic
layers were dried with Na2SO4, filtered, and evaporated to yield the
corresponding thiosulfinates, which were analyzed by HPLC.
[6] G. K. Prakash, M. Mandal, G. A. Olah, Angew. Chem. Int. Ed.
2001, 40, 589–590.
[7] T. P. Tang; S. K. Volkman, J. A. Ellman, J. Org. Chem. 2001,
66, 8772–8778.
[8] Z. Han, D. Krishnamurthy, D. Pflum, P. Grover, S. A. Wald,
C. H. Senanayake, Org. Lett. 2002, 4, 4025–4028.
[9] D. A. Cogan, G. L. Liu, K. Kim, B. J. Backes, J. A. Ellmann,
J. Am. Chem. Soc. 1998, 120, 8011–8019.
[10] S. Colonna, N. Gaggero, G. Carrea, P. Pasta, V. Alphand, R.
Furstoss, Chirality 2001, 13, 40–43.
[11] M. Madesclaire, Tetrahedron 1986, 42, 5459–5495.
[12] a) S. Colonna, S. Banfi, F. Fontana, M. Sommaruga, J. Org.
Chem. 1985, 50, 769–771; b) S. Colonna, N. Gaggero, Tetrahe-
dron Lett. 1989, 30, 6233–6236; c) S. V. Dzyuba, A. M. Klib-
anov, Tetrahedron: Asymmetry 2004, 15, 2771–2777.
[13] a) Y. Shi, Acc. Chem. Res. 2004, 37, 488–496; b) Z. X. Wang,
Y. Tu, Frohn, M. J. R. Zhang, Y. Shi, J. Am. Chem. Soc. 1997,
119, 11224–11235.
Oxidation of 13: Ketene-S,S-acetal 13 (104 mg, 0.3 mmol) was dis-
solved in acetonitrile/ DMM (6 mL, 1:2, v/v). Subsequently buffer
[3 mL, 0.05 m solution of Na2B4O7·10H2O in 4×10–4 m aqueous
Na2(EDTA)], tetrabutylammonium hydrogen sulfate (4 mg,
0.012 mmol) and ketone 4 (23 mg, 0.09 mmol) were added. A solu-
tion of Oxone (196 mg, 0.63 mmol) in aqueous Na2(EDTA)
(4×10–4 m, 3 mL) and a solution of K2CO3 (470 mg) in distilled
water (3 mL) were added dropwise separately over a period of
[14] For a review on the chemistry of disulfoxides, see: a) B. De-
louvrié, L. Fensterbank, F. Nájera, M. Malacria, Eur. J. Org.
Chem. 2002, 3507–3525; b) F. Brebion, B. Delouvrié, F. Nájera,
L. Fensterbank, M. Malacria, J. Vaissermann, Angew. Chem.
Int. Ed. 2003, 42, 5342–5345.
Received: December 17, 2004
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Eur. J. Org. Chem. 2005, 1727–1730