Synthesis of new chiral imidazolidine disulfides derived from L-cystine and their application in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)00300-3

Several chiral imidazolidine disulfides 4a-d derived from L-cystine have been synthesized. These ligands have been applied as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes. The best results were obtained by employing 5 mol% of imidazolidine disulfide 4a, and chiral secondary alcohols were obtained in up to 91% e.e.

Full text of DOI:10.1016/S0040-4039(02)00300-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2335–2337
Synthesis of new chiral imidazolidine disulfides derived from
-cystine and their application in the enantioselective addition of
diethylzinc to aldehydes
L
Antonio L. Braga,* Fabr´ıcio Vargas, Claudio C. Silveira and Leandro H. de Andrade
Departamento de Qu´ımica, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Received 22 January 2002; accepted 6 February 2002
Abstract—Several chiral imidazolidine disulfides 4a–d derived from
L-cystine have been synthesized. These ligands have been
applied as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes. The best results were obtained by employing 5
mol% of imidazolidine disulfide 4a, and chiral secondary alcohols were obtained in up to 91% e.e. © 2002 Elsevier Science Ltd.
All rights reserved.
One of the most challenging subjects in organic synthe-
sis during this decade is the development of new and
efficient chiral ligands for catalytic asymmetric synthe-
sis.1 Numerous reports have shown that reagents like
b-amino thiols and b-amino disulfides are efficient for
asymmetric induction.1b Among them, we can find
with the availability of a wide variety of diorganozinc
reagents10 have attracted much attention by research
groups in this field. As part of our continuing interest
in sulfur-containing catalysts,6 we report herein the
studies of the synthesis of new chiral imidazolidine
disulfides 4 derived from
L-cystine and their use as
chiral ligands in the addition of ZnEt2 to aldehydes.
some derived from ephedrine,2 norephedrine,3
L
-pro-
line,4 (S)-phenylglycine,5 (R)-cysteine,6 (S)-valine,7
(1R,2S)-(−)-1,2-diphenyl-2-amino-1-ethanol8 and oth-
ers.9 They have been used as highly effective catalysts
for the diethylzinc addition to aldehydes. The interest
in the development of cost-effective catalysts that
exhibit high reactivity and enantioselectivity together
The chiral imidazolidine disulfides 4a–d were prepared
from commercially available
tially we protected the amino group of
L
-cystine as follows: ini-
-cystine with
ClCO2Et in 1 M aq. NaOH (98% yield). The protected
-cystine was treated with the appropriated amines
L
L
Scheme 1. Synthesis of chiral imidazolidine disulfides 4a–d. Reagents: (i) 1 M aq. NaOH, ethyl chloroformate; (ii) N-methylmor-
pholine, CHCl3; (iii) ethyl chloroformate; (iv) RNH2 (a: R=(R)-methylbenzyl; b: R=(S)-methylbenzyl; c: R=phenethyl; d:
R=n-butyl); (v) LiAlH4, reflux in THF; (vi) (CH2O)n, reflux in benzene.
Keywords: chiral ligands; disulfides; imidazolidine; enantioselective addition; L-cystine.
* Corresponding author. E-mail: albraga@quimica.ufsm.br
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00300-3

2336
A. L. Braga et al. / Tetrahedron Letters 43 (2002) 2335–2337
using the mixed anhydride coupling method11 to give
the amides 2 in 75–85% yields. The amines disulfides 3
were obtained by treatment of 2 with LiAlH4 in THF
followed by stirring with aqueous basic and aerial
oxidation (45–54%). These compounds were treated
with paraformaldehyde to give the desired imidazo-
lidine disulfides 4a–d in 45–55% yields (Scheme 1).
In order to examine the effectiveness of these ligands
(4a–d), we first evaluated their behavior in the enan-
tioselective addition of diethylzinc to benzaldehyde
(Table 1). The active catalyst is most likely to be the
corresponding ethylzinc thiolate, obtained from
disulfide cleavage by diethylzinc as described by Kel-
logg.2a 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
thiol-form is applied.
Table 1. Enantioselective addition of ZnEt2 to benzalde-
hyde promoted by chiral ligands 4a–ba
We investigated the effects of a variety of reaction
conditions including solvent, temperature, ligand and
the amount of ligand (Table 1, entries 1–10). We found
that the use of 5 mol% imidazolidine disulfide 4a, as the
ligand in toluene at 0°C gave the best result (99% yield,
91% e.e., entry 4). When catalysts 4b–d were used
(66–86% e.e., Table 1, entries 7–9), the results showed
lower enantiomeric excess than 4a. These results sug-
gest that the substituent at the nitrogen atom plays an
important role in the enantioselection of the addition
reaction.
Entry
Ligand (mol%)
Yieldb (%)
E.e. (%)c (config.)d
1
2
3
4
5
6
7
8
9
4a (30.0)
4a (15.0)
4a (10.0)
4a (5.0)
4a (5.0)e
4a (5.0)f
4b (5.0)
4c (5.0)
4d (5.0)
99
99
99
99
99
82
99
99
92
91 (S)
91 (S)
91 (S)
91 (S)
84 (S)
77 (S)
86 (S)
68 (S)
66 (S)
Next, we decided to apply the addition of diethylzinc to
various aldehydes under standard conditions and the
results are summarized in Table 2. As can be seen from
the results, p-methoxybenzaldehyde and o-methoxybenz-
aldehyde gave low e.e.s of 70 and 76%, respectively
(entries 5 and 6). This fact can be explained by the
presence of an electron-donating group on the benzene
ring, due to an electronic effect.13 When we tested other
aldehydes such as o-bromobenzaldehyde, o-chlorobenz-
aldehyde and p-chlorobenzaldehyde (entries 2–4) a
good enantioselectivity comparable to that of benzalde-
hyde was observed (entry 1). For aliphatic aldehydes
the enantioselectivity of the reaction was moderate (66
and 76% e.e., entries 8 and 9). In this reaction, all the
product alcohols were obtained with (S)-configuration.
a The reactions were carried out in toluene at 0°C for 48 h; benzalde-
hyde/ZnEt2=1.0/2.0 (mmol).
b Based on isolated product.
c Determined by GC analysis using a chiral column (2,6-Me-3-Pe)-b-
cyclodextrin (20% in Polysiloxan OV-1701).
d Configurations were assigned by comparison with the sign of optical
rotation of known compound.12
e The reaction was carried out in toluene at rt for 24 h.
f Tetrahydrofuran as reaction solvent.
Table 2. The enantioselective addition of ZnEt2 to alde-
hydes promoted by ligand 4aa
In summary, we have successfully synthesized a new
class of chiral disulfides (imidazolidine disulfides)14 and
evaluated their catalytic efficiency in the enantioselec-
tive addition of diethylzinc to aldehydes. Further stud-
ies of these ligands in other catalytic asymmetric
reactions are in progress.
Entry
R%
Yieldb (%)
E.e. (%)c (config.)d
1
2
3
4
5
6
7
8
9
Ph
99
92
93
94
60
62
94
52
59
91 (S)
89 (S)
89 (S)
90 (S)
70 (S)
76 (S)
84 (S)
66 (S)e
76 (S)e
p-ClPh
o-ClPh
o-BrPh
p-MeOPh
o-MeOPh
p-MePh
n-Nonyl
n-Pentyl
Acknowledgements
The authors thank the following agencies for support:
FAPERGS, CAPES, DAAD (German Academic
Exchange Service) for travel grants part of PROBRAL.
L.H.A. thanks CAPES for a Ph.D. fellowship.
a The reactions were carried out in toluene at 0°C for 48 h; aldehyde/
ZnEt2=1.0/2.0 (mmol).
b Based on isolated product.
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+145 (c 0.80, CHCl3); H NMR (CDCl3, 400 MHz): 3.64
(d, J=5.56 Hz, 2H), 3.11 (d, J=5.52 Hz, 2H), 2.94 (dd,
J=9.20, 7.36 Hz, 2H), 2.90 (dd, J=12.64, 4.36 Hz, 2H),
2.67 (dd, J=12.78, 7.84 Hz, 2H), 2.54 (dd, J=9.34, 6.20
Hz, 2H), 2.49 (m, 4H), 2.36 (s, 6H), 1.39 (quint, J=7.60
Hz, 4H), 1.27 (sext, J=7.68 Hz, 4H), 0.84 (t, J=7.28 Hz,
6H). 13C NMR (CDCl3, 100 MHz): 78.89, 64.39, 58.33,
54.65, 43.26, 40.70, 30.81, 20.52, 13.91.; IR (film; cm−1
)
2927, 2860, 2792, 1456, 1368, 1243, 1127, 1038, 904;
LRMS (rel. int.) m/z 373 (1), 220 (3), 187 (57), 163 (8),
158 (16), 141 (100), 116 (9), 102 (9), 70 (36), 56 (27).