A new functionalized, chiral disulfide derived from L-cysteine: (R,R)- bis[(3-benzyloxazolan-4-yl)-methane] disulfide as a catalyst in the diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/S0957-4166(99)00145-7

A new, easily accessible, chiral disulfide 3 was prepared from L- cysteine in a short synthetic sequence (Scheme 1) and applied successfully as a highly efficient catalyst for the enantioselective addition of diethyl zinc to aromatic and aliphatic aldehydes to afford the product alcohols in up to more than 99% ee. In contrast to the more common amino alcohols used in similar reactions, catalyst 3 does not have a protic hydrogen in the form of a free hydroxy group.

Full text of DOI:10.1016/S0957-4166(99)00145-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1733–1738
A new functionalized, chiral disulfide derived from L-cysteine:
(R,R)-bis[(3-benzyloxazolan-4-yl)-methane] disulfide as a
catalyst in the diethylzinc addition to aldehydes
Antonio L. Braga,a,∗ Helmoz R. Appelt,a Paulo H. Schneider,a Claudio C. Silveira a and
Ludger A. Wessjohann b,†
aDepartamento de Química, Universidade Federal de Santa Maria, BR-97105-900, Santa Maria, RS, Brazil
bInstitut für Organische Chemie, Ludwig-Maximilians-Universität München, Karlstr. 23, D-80333 München, Germany
Received 29 March 1999; accepted 5 April 1999
Abstract
A new, easily accessible, chiral disulfide 3 was prepared from L-cysteine in a short synthetic sequence (Scheme 1)
and applied successfully as a highly efficient catalyst for the enantioselective addition of diethyl zinc to aromatic
and aliphatic aldehydes to afford the product alcohols in up to more than 99% ee. In contrast to the more common
amino alcohols used in similar reactions, catalyst 3 does not have a protic hydrogen in the form of a free hydroxy
group. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The stereoselective synthesis of optically active secondary alcohols is a well studied topic in organic
chemistry.1 In some cases, high enantiomeric excesses have been obtained. Commonly, asymmetric
induction is achieved by the application of non-racemic chiral ligands, which complex with one or
more participants in metal-ion centered reactions.2 The asymmetric nucleophilic addition of dialkyl zinc
reagents to carbonyl groups has been extensively studied, especially since this process has been found
to be catalytic in the chiral ligands.3 Mainly chiral β-amino alcohols have proven to be highly effective
catalysts. Superior catalysts incorporating amino and sulfur or selenium groups have also been reported
recently.4–6
These impressive findings together with the availability of a wide variety of diorganozinc reagents
carrying labile functionality7 ensure the continued importance for the development of improved catalysts
∗
†
Corresponding author. E-mail: albraga@quimica.ufsm.br
New address: Vrije Universiteit Amsterdam, FEW/OAC, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00145-7

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derived from non-toxic and inexpensive starting materials. With this aim, together with our interest in
obtaining sulfur and selenium containing catalysts, we report the synthesis of the new chiral disulfide 3
derived from L-cysteine ((R)-cysteine), that proved to be a highly effective catalyst for the enantioselec-
tive addition of diethylzinc to aldehydes, including aliphatic ones.
2. Results and discussion
The chiral disulfide 3 is readily prepared from (R)-cysteine in a three step synthesis (Scheme 1). In
the first step, (R)-cysteine was cyclized with benzaldehyde leading to 1.8 The resultant thiazolidine was
reduced with NaBH4/I2 to give the disulfide amino alcohol 2. Oxazolidine 3 was obtained by treatment
of the disulfide 2 with paraformaldehyde. Disulfides 2 and 3 were reduced with NaBH4 and alkylated
with MeI to give methyl-thioethers 4 and 5. It is important to mention that the yields of most steps were
around 90% and none were below 75% without much optimization.
Scheme 1.
Products 2, 3, 4, and 5 were tested as catalysts for the diethyl zinc addition to benzaldehyde (Scheme 2).
Most likely, the active catalyst is the corresponding ethylzinc thiolate, obtained from disulfide cleavage
by diethyl zinc as described by Kellogg et al.4 However, this likely process was not rigorously proven
for our catalysts, but offers the future prospect of cutting the amount of catalyst required in half, if the
reduced thiol-form is applied. When catalysts 2, 4, or 5 were used, the results showed low excesses of
one of the enantiomers (0–41%, Table 1, entries 2, 6 and 7). However, excellent results were obtained
when 2 mol% of the oxazolidine 3 (Table 1, entry 3 and 5) was used. Thus (1S)-phenylpropanol was
obtained in 81% yield and >99% ee at 0°C (or in 98% yield and 80% ee at room temperature).
Scheme 2.
Et2Zn was added to some substituted benzaldehydes in the presence of the best catalyst (3, see
Scheme 1 and Table 2). In this small selection, satisfactory yields and enantiomeric ratios were obtained,
the latter being much better at 0°C. The electronic nature of the substituents seems to exhibit a small

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Table 1
Asymmetric addition of diethylzinc to benzaldehyde using chiral ligands 2–5 (2 mol%)
effect, as increased electron density in the aromatic ring appears to result in slight decreases in yield and
enantiomeric excess (entries 3–6, Table 2). However, ees are often better than those reported with other
(disulfide) catalysts,5 distinctly so for aliphatic aldehydes like phenylacetaldehyde and hexanal at low
temperatures (entries 8 and 10, respectively). The extraordinary increase in ee at 0°C with hexanal (and
phenacetaldehyde) in comparison to decanal remains unexplained. However, the experiment has been
repeated successfully, and as a control, racemate was synthesized in order to check for an accidental
misinterpretation of the GC data.
3. Conclusion
In summary, several inexpensive chiral disulfides and sulfides were prepared in a short and easy
synthetic route from commercial L-cysteine as the starting material. Oxazolidine disulfide 3 proved to be
the best catalyst for the Et2Zn addition to aldehydes. This disulfide catalyzes the highly enantioselective
ethylation of various aldehydes, including aliphatic ones, with up to >99% ee.
Further studies dealing with the preparation of new chiral dichalcogenides and their application in
catalytic as well as stoichiometric reactions are in progress.
4. Experimental
All aldehydes used are commercially available and were distilled before use. Optical rotations were
measured on a Perkin–Elmer 341 polarimeter. The 1H and 13C NMR spectra were registered on a Bruker
AC 200 spectrometer using TMS as an internal standard. Elemental analyses (C, H, N) were performed
on a Vario EL and Perkin–Elmer CHN 2400 analyzer. Gas chromatography (GC) was performed using
a Varian 3800 gas chromatograph with (2,6-Me-3-Pe)-β-cyclodextrin column as chiral stationary phase
for ee determination of the secondary alcohols obtained.

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Table 2
Addition of diethylzinc to various aldehydes in the presence of 2 mol% of catalyst (R,R)-3
4.1. 1-(4R)-2-Phenylthiazolidine-4-carboxylic acid 1
Compound 1 was prepared according to previous reports.8 To a solution of 8.75 g (50 mmol) of (R)-
cysteine hydrochloride hydrate in 75 mL of water was added 7.60 g (56 mmol) of sodium acetate. After
a solution was obtained, 75 mL of 95% ethanol was added followed immediately by 5.1 mL (5.36 g, 50
mmol) of benzaldehyde, added in one portion. The product thiazolidine 1 soon began to crystallize. The
reaction was kept at 25°C for 3 h and an additional 3 h at 0°C. The product was filtered, washed with
ethanol, and dried to afford 11.0 g (90%) of the thiazolidine 1: mp 158–159°C; IR (KBr) 2700–2400
+
−
(NH3 ), 1600–1550 (CO2 ), 1360 cm−1; 1H NMR (DMSO) δ=7.51–7.30 (m, 5H), 5.8 (s, 1H), 4.2 (dd,
1H), 3.5–3.0 (m, 2H).
4.2. N,N0-Dibenzyl-(R)-cystinol 2
In a 100 mL two necked round-bottomed flask equipped with a reflux condensor and an addition
funnel, 85 mL dry THF, 3.24 g (85.5 mmol) of NaBH4 and 8.40 g (34.2 mmol) of 2 were introduced
under argon. Under stirring, 8.68 g (34.2 mmol) iodine dissolved in 30 mL THF was added slowly. After
complete addition, the reaction mixture was heated at reflux for 20 h and then cooled to room temperature.
Methanol was added to the mixture until a clear solution was obtained. The solvent was removed under

A. L. Braga et al. / Tetrahedron: Asymmetry 10 (1999) 1733–1738
1737
vacuum and the residue dissolved in 70 mL of a 20% aqueous K2CO3 solution, stirring for 4 h at room
temperature. After the mixture was extracted with CH2Cl2 (3×30 mL) and the combined organic layers
dried with MgSO4 and filtered, the solvent was removed under vacuum to yield 6.13 g (75%) of 2: mp
105.7–106.1°C; [α]D20 −29.0 (c 1.0, CH3OH); 1H NMR (DMSO) δ=7.30–7.17 (m, 10H), 3.78–3.70 (m,
4H), 3.43–3.39 (m, 4H), 2.90–2.74 (m, 6H); 13C NMR (DMSO, 50 MHz) δ=40.90 (2×CH2S); 50.31
(2×CH2N); 57.90 (2×CHN); 61.82 (2×CH2OH); 126.53 (2×aromat.-C); 127.90, 128.07 (10×aromat.-
C). Anal. calcd for C20H28N2O2S2; C, 61.19; H, 7.19; N, 7.14. Found: C, 60.84; H, 6.84; N, 7.13.
4.3. (R,R)-Bis[(3-benzyloxazolan-4-yl)methane]disulfide 3
In a 50 mL round-bottomed flask with Dean Stark apparatus was added 30 mL benzene, 392 mg (1
mmol) of 3, 90 mg (3 mmol) of paraformaldehyde and p-toluenesulfonic acid (catalytic quantities). The
mixture was heated at reflux for 5 h and cooled to room temperature. The benzene was removed under
vacuum and the residue dissolved in 30 mL CH2Cl2, washed with 0.5 N NaOH solution, dried with
20
MgSO4, filtered, and the solvent removed under vacuum to afford 353 mg (87%) of 3; [α]D +14.8 (c
1.96, CHCl3); 1H NMR (CDCl3) δ=7.34–7.19 (m, 10H), 4.29 (s, 4H), 4.08–4.00 (m, 2H), 3.76–3.73 (m,
4H), 3.51–3.45 (m, 2H), 3.28–3.28 (m, 2H), 2.81–2.71 (m, 2H), 2.53–2.43 (m, 2H); 13C NMR (CDCl3, 50
MHz): δ=41.08 (2×CH2S); 58.92 (2×CH2N); 62.06 (2×CHN); 69.06 (2×CH2O); 85.98 (2×CH2NO);
127.19 (2×aromat.-C); 127.97, 128.24, 128.40, 128.60 (10×aromat.-C).
4.4. (R)-2-Benzylamino-3-methylthiopropanol 4
To a solution of 2 (1.0 g, 2.55 mmol) and sodium hydroxide (204 mg, 5.1 mmol) in dry ethanol (10
mL) under an argon atmosphere sodium borohydride (208 mg, 5.5 mmol) was added in portions, and the
mixture was stirred for 30 min at room temperature. Methyl iodide (1.42 g, 10.2 mmol) was added and the
resulting mixture was stirred again for 30 min at room temperature. Ethanol was removed under vacuum
and the residue was dissolved in 20 mL CH2Cl2, washed with water, dried with MgSO4, filtered, and the
solvent removed under reduced pressure to afford 461 mg (91%) of 4; [α]D25 −39.7 (c 1.12, CH3OH); 1H
NMR (CDCl3) δ=7.36–7.24 (m, 5H), 3.47–3.39 (m, 2H), 2.82–2.62 (m, 3H), 3.80–3.71 (m, 2H), 1.99 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ=15.59 (CH3S); 36.28 (CH2S); 50.99 (CH2N); 56.04 (CHN); 61.82
(CH2OH); 126.53 (1×aromat.-C); 127.90, 128.07 (5×aromat.-C)
4.5. (4R)-N-Benzyl-4-(methylthiomethyl) oxazolane 5
To a solution of 3 (2.30 g, 5.48 mmol) and sodium hydroxide (440 mg, 10.4 mmol) in dry ethanol (20
mL) under an argon atmosphere sodium borohydride (416 mg, 11 mmol) was added in portions at room
temperature. The mixture was stirred for 30 min and methyl iodide (3.09 g, 21.9 mmol) was added. After
30 min ethanol was removed under vacuum and the residue was dissolved in 30 mL CH2Cl2, washed with
water, dried with MgSO4, filtered, and the solvent removed under reduced pressure to afford 1.08 g (93%)
of 5; [α]D25 −25.9 (c 1.02, CHCl3); 1H NMR (CDCl3) δ=7.36–7.24 (m, 5H), 4.38 (s, 2H), 3.76–3.58 (m,
5H), 2.78–2.70 (m, 2H), 1.99 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ=15.89 (CH3S); 33.38 (CH2S); 50.63
(CH2N); 59.23 (CHN); 69.60 (CH2O); 86.24 (CH2NO); 126.24 (aromat.-C); 121.93, 122.27 (5×aromat.-
C).

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4.6. General procedure for asymmetric addition of diethylzinc to aldehydes
In a 25 mL flask with 7 mL toluene, 3 mmol aldehyde and 60 µmol (2 mol%) catalyst, 5 mL (5
mmol) of a 1 M solution of diethyl zinc in hexane was slowly injected with constant stirring. Stirring was
continued for the time and at the temperature indicated in Tables 1 and 2. Finally the temperature was
adjusted to 0°C (ice bath) and 5 mL of 1 N HCl was slowly added (10 min) with continuous stirring. The
organic layer was separated and washed with 2×8 mL of 1 N HCl. After drying over sodium sulfate, and
filtration, toluene was removed under reduced pressure. The crude alcohol was purified by bulb-to-bulb
distillation under reduced pressure (oil pump, ca. 0.1 mbar).
Acknowledgements
The authors wish to thank CAPES and DAAD (German Academic Exchange Service) for travel grants
as part of PROBAL, and CNPq, FAPERGS and Degussa AG for financial support and gifts of chemicals,
respectively.
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