Synthesis of new chiral aliphatic amino diselenides and their application as catalysts for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1021/ol034773e

(Matrix presented) A set of chiral aliphatic amino diselenides have been synthesized from readily available starting materials in a straightforward synthetic route via the ring-opening reaction of the parent aziridines. These ligands have been tested as catalysts for the enantioselective addition of diethylzinc to aldehydes. The influence of the alkyl group substituents on the stereoselectivity has been studied, and in the best case, an enantiomeric excess up to 99% could be obtained by using only 0.5 mol % of the chiral diselenide 3a.

Full text of DOI:10.1021/ol034773e

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2635-2638
Synthesis of New Chiral Aliphatic Amino
Diselenides and Their Application as
Catalysts for the Enantioselective
Addition of Diethylzinc to Aldehydes
Antonio L. Braga,* Marcio W. Paixa˜o, Diogo S. Lu1dtke, Claudio C. Silveira, and
Oscar E. D. Rodrigues
Departamento de Qu´ımica, UniVersidade Federal de Santa Maria,
Santa Maria, RS, 97105-900, Brazil
albraga@quimica.ufsm.br
Received May 7, 2003
ABSTRACT
A set of chiral aliphatic amino diselenides have been synthesized from readily available starting materials in a straightforward synthetic route
via the ring-opening reaction of the parent aziridines. These ligands have been tested as catalysts for the enantioselective addition of diethylzinc
to aldehydes. The influence of the alkyl group substituents on the stereoselectivity has been studied, and in the best case, an enantiomeric
excess up to 99% could be obtained by using only 0.5 mol % of the chiral diselenide 3a.
Nucleophilic addition of organometallic reagents to carbonyl
compounds is a very important operation in organic synthesis,
and the asymmetric version of this reaction is particularly
useful. Several highly enantioselective additions to prochiral
aldehydes leading to optically active alcohols have been
reported,1 and among the various organometallic compounds,
diorganozincs serve as excellent alkyl nucleophiles.
After the discovery by Oguni and Omi that various
additives catalyze the addition of dialkylzinc reagents to
aldehydes,2 there has been a rapid growth of research aimed
at this reaction.3 Much of these efforts have been directed
toward the design of new chiral ligands, specially â-amino
alcohols.
classes of organoselenium compounds, the chiral diselenides
have received special attention due to their higher stability
and easier handling when compared with the parent selenols.
They can be used in the stereoselective ring opening of
epoxides,5 anti-stereoselectivity, and Markovnikoff regio-
selectivity in the electrophilic selenenylation of alkenes.6
Most importantly chiral diselenides have been employed as
useful ligands and catalysts in various asymmetric transfor-
mations such as diethylzinc addition to aldehydes,7 asym-
(4) (a) Wessjohann, L.; Sinks, U. J. Prakt. Chem. 1998, 340, 189-203.
(b) Wirth, T. Tetrahedron 1999, 55, 1-28. (c) Wirth, T. Angew. Chem.,
Int. Ed. 2000, 39, 3740-3749. (d) Topics in Current Chemistry: Or-
ganoselenium Chemistry, Modern DeVelopments in Organic Synthesis;
Wirth, T., Ed.; Springer: Berlin, Germany, 2000.
(5) (a) Fukuzawa, S.; Takahashi, K.; Kato, H.; Yamazaki, H. J. Org.
Chem. 1997, 62, 7711-7716. (b) Tomoda, S.; Iwaoka, M. J. Chem. Soc.,
Chem. Commun. 1988, 1283-1284. (c) Nishibayashi, Y.; Singh, J. D.;
Fukuzawa, S.-I.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 1995, 2871-
2876.
(6) (a) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2000, 11, 4645-4650.
(b) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.; Bagnoli,
L.; Temperini, A. Tetrahedron: Asymmetry 2001, 12, 3053-3059. (c) Back,
T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67, 499-509.
On the other hand, chiral selenium-based methods have
developed rapidly over the past few years and are now a
very important tool in organic synthesis.4 Among the many
(1) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H.; Eds; Springer: Berlin, Germany, 1999.
(2) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823-2824.
(3) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49-69. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856. (b) Pu,
L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
10.1021/ol034773e CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/24/2003

metrichydrosilylation,8 and 1,4 addition of Grignard reagents
to enones.9 To the best of our knowledge, an interesting
feature of the ligands used in such transformations is that
all of them have a selenium atom attached to an aromatic
ring.
To extend our studies in the organochalcogen mediated
stereoselective transformations,9,10 we sought to obtain a new
class of Se, N-ligands in a straightforward synthetic route,
using inexpensive and easily available starting materials, and
to test them as chiral ligands in the enantioselective addition
of diethylzinc to aldehydes. The present paper reports the
development of a new class of chiral amino diselenides 3
and 4 with the selenium atom attached to an alkyl group.
To examine the possibility of steric and electronic re-
finement in the structure of ligands 3 at the amine moiety,
the replacement of the Boc group by another bulky alkyl
group was realized. Deprotection of the chiral diselenide 3a
with TFA proceeded smoothly at room temperature to give
the free amino diselenide. Subsequent treatment of this
compound with di-iodopentane in the presence of po-
tassium carbonate in boiling acetonitrile furnished the
respective piperidine diselenide 4 in 35% yield for the 2
steps.
Scheme 2. Synthesis of Piperidine Diselenide 4
Scheme 1. Synthesis of Amino Diselenides 3a
With this sterically and electronically varied set of
enantiopure aminodiselenides in hand, we have examined
their efficiency as chiral catalysts in the enantioselective
addition of diethylzinc to benzaldehyde.
a Reagents and conditions: (i) Boc2O, CH3CN, rt, 3 h; (ii) KOH,
TsCl, THF, reflux, 4 h; (iii) Li2Se2, THF, rt, 12 h.
Aiming to evaluate the catalytic potential of the amino
diselenides synthesized, ligand 3a was chosen as a model
compound to determine the optimum conditions for the
reaction. Our studies had started varying the loading of the
catalyst and the results are depicted in Table 1.
The chiral amino diselenides 3 were easily prepared from
the corresponding, commercially available R-amino alcohols
1, which were further quantitatively converted into the Boc-
protected derivatives by reaction with di-tert-butyl dicar-
bonate in acetonitrile. The chiral aziridines 2 were obtained
in good yields by treatment of N-Boc amino alcohols with
p-toluenesulfonyl chloride and potassium hydroxide in boil-
ing THF. Finally, the selenium atom was efficiently intro-
duced by regioselective nucleophilic ring opening by attack
of Li2Se211 at the less hindered carbon12 of the aziridines 2,
furnishing the aliphatic chiral amino diselenides 3a-d13
without any loss of enantiomeric purity, as determined by
chiral HPLC.
Table 1. Enantioselective Addition of Diethylzinc to
Benzaldehyde Varying the Loading of the Catalyst 3a
loading of 3a
entry
(mol %)
% yielda
% eeb
1
2
3
4
5
10
5
2.5
1
93
93
92
92
91
96 (R)
95 (R)
95 (R)
95 (R)
95 (R)
0.5
a Determined by GC analysis. b Determined by chiral GC analysis with
use of a Hydrodex â-3P column; the absolute configuration was determined
by comparing the sign of the optical rotation.
(7) (a) Wirth, T. Tetrahedron Lett. 1995, 36, 7849-7852. (b) Wirth, T.;
Kulieke, K. J.; Fragale, G. HelV. Chim. Acta 1996, 79, 1957-1966. (c)
Santi, C.; Wirth, T. Tetrahedron: Asymmetry 1999, 10, 1019-1023.
(8) (a) Nishibayashi, Y.; Singh, J. D.; Segawa, K.; Fukuzawa, S.-I.;
Uemura, S. J. Chem. Soc., Chem. Commun. 1994, 1375-1376. (b)
Nishibayashi, Y.; Segawa, K.; Singh, J. D.; Fukuzawa, S.-I.; Ohe, K.;
Uemura, S. Organometallics 1996, 15, 370-379.
(9) Braga, A. L.; Silva, S. J. N.; Lu¨dtke, D. S.; Drekener, R. L.; Silveira,
C. C.; Rocha, J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002, 43, 7329-
7331.
(10) (a) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira, C. C.;
Wessjohann, L. A. Tetrahedron: Asymmetry 1999, 10, 1733-1738. (b)
Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Rodrigues, O. E. D.; Silveira,
C. C.; Wessjohann, L. A. Tetrahedron 2001, 57, 3291-3295. (c) Braga,
A. L.; Vargas, F.; Silveira, C. C.; de Andrade, L. H. Tetrahedron Lett.
2002, 43, 2335-2337. (d) Braga, A. L.; Rodrigues, O. E. D.; Paixa˜o, M.
W.; Appelt, H. R.; Silveira, C. C.; Bottega, D. P. Synthesis 2002, 2338-
2340. (e) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413-10416.
It could be observed that the level of enantioselection in
the reaction is not affected by changing the amount of 3a.
Even when 0.5 mol % was used, the enantiomeric excess of
1-phenyl-1-propanol was 95%. The yield has slighty de-
creased with lowering the loading of the catalyst. The
conversion to the desired alcohol is still high with the lowest
amount used of the chiral amino diselenide, showing that a
highly effective catalytic cycle is formed.
With these results, the efficiency of the other ligands
prepared as chiral catalysts in the addition of diethylzinc to
benzaldehyde was also examined. The results obtained in
this reaction in the presence of ligands 3 and 4 are shown in
Table 2. The reactions were performed under standard
(11) Gladysz, J. A.; Hornby, J. L.; Garbe, J. E. J. Org. Chem. 1978, 43,
1204-1208.
(12) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619.
(b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347-1365.
2636
Org. Lett., Vol. 5, No. 15, 2003

the reactions were performed in toluene at room temperature
and, as for the addition to benzaldehyde, the corresponding
(R) configuration alcohol was always obtained as the major
isomer, all with similar enantiomeric excesses (Table 3). For
Table 2. Screening of Ligands 3a-d and 4 in the Catalytic
Enantioselective Addition of Diethylzinc to Benzaldehyde
Table 3. Enantioselective Addition of Diethylzinc to Aromatic
and Aliphatic Aldehydes Employing Chiral Diselenide 3a
entry
catalyst
% yielda
% eeb
entry
aldehyde
% yielda
% ee
1
2
3
4
5
6c
3a
3b
3c
3d
4
91
71
80
72
82
51
95 (R)
91 (R)
92 (R)
91 (R)
90 (R)
91 (R)
1b
2b
3c
4c
5c
o-methoxybenzaldehyde
p-methoxybenzaldehyde
2-pyridinecarboxaldehyde
decanal
93
93
85
56
63
95 (R)
>99 (R)
91 (R)
45 (R)
>99 (R)
3a
hexanal
a Determined by GC analysis. b Determined by chiral GC analysis with
use of a Hydrodex â-3P column; the absolute configuration was determined
by comparing the sign of optical rotation. c Reaction performed at 0 ° C.
a Conversion was determined by GC analysis. b Determined by chiral
GC analysis with use of a Hydrodex â-3P column; the absolute configuration
was determined by comparing the sign of optical rotation. c Determined by
chiral HPLC analysis with use of a Daicel Chiralcel OD column.
conditions: 0.5 mol % of ligand 3 or 4, benzaldehyde
(1 mmol), diethylzinc (2.5 mmol) in toluene, at room
temperature. The reaction was also performed at 0 °C but a
dramatic decrease in the yield was observed (Table 2, entry
6).
the aromatic aldehydes, high levels of enantioselection were
observed. Additions to the less reactive aliphatic aldehydes
gave distinct results (Table 3, entries 4 and 5). Reaction with
hexanal results in an excellent ee of >99%. A four-carbon
extension decreases the ee dramatically to 45%.
The stereochemistry of the products is in accordance with
the mechanistic rationalization described in the work of
Noyori.3a,14
To elucidate the mechanistic aspects and to identify the
catalytically active species, we treated the diselenide 3a with
an excess of diethylzinc in toluene, at room temperature
(Scheme 3).
All the reactions led to the predominant formation of the
alcohol (R)-1-phenyl-1-propanol with different levels of
enantiocontrol. We can verify the effect of the R substituents
derived from amino alcohols in Table 2 (entries 1-4). The
catalyst 3a (R ) Bn) showed better enantioselection than
the other alkyl groups (3b-d). Interestingly, when the
reaction was carried out at lower temperature (Table 2, entry
6), a significant decrease in the yield was observed. Probably,
the complexes are formed slower at this temperature,
decreasing the efficiency of the complexation. The effect of
the amine group substituents was also studied, using the
modificated catalyst 4. This ligand showed good perfor-
mance, but the results obtained with 3a are still higher in
terms of conversion and enantiomeric excess, as well as the
simplicity of the catalyst.
Scheme 3
To extend the scope of the optimal ligand 3a as a chiral
catalyst in the addition of diethylzinc to aldehydes, several
aromatic and aliphatic aldehydes were screened. In all cases,
We assumed that the diselenide linkage is cleaved by
nucleophilic attack of diethylzinc, resulting in the selenolate
5 and the selenoether 6, according to the results reported by
Kellogg15 and Wirth.7b We believe that the active catalyst
of the reaction is the selenolate 5, since in an additional
experiment, the selenoether 6 did not catalyze the alkylation
reaction of benzaldehyde.
In summary, a new series of chiral, aliphatic, amino-
containing diselenides was synthesized in a straightforward
synthetic route, starting from an inexpensive and easily
available chiral pool. The crucial step was the regioselective
ring opening of the chiral aziridines by a selenium nucleo-
phile, leading to the aliphatic diselenides in good yields.
(13) General Procedure for the Ring-Opening Reaction of Aziridines
2a with Li2Se2. Synthesis of Aminodiselenide 3a. Lithium diselenide was
generated by reaction of gray elemental selenium (0.0947 g, 1.2 mmol)
with lithium triethylborohydride (1.2 mL, 1.2 mmol) in dry THF (5 mL).
The suspension was allowed to stir for at least 20 min,11 and a THF (10
mL) solution of aziridine 2a (0.233 g, 1.0 mmol) was added dropwise within
20 min. The resulting solution was stirred for 12 h at room temperature,
quenched with a saturated NH4Cl solution (20 mL), and extracted with
CH2Cl2, the combined organic fractions were collected, dried over
magnesium sulfate, and filtered, and the solvent was removed in vacuo
yielding a yellow solid that was purified by flash chromatography (hexane/
ethyl acetate 90:10). Drying in vacuo afforded 0.235 g (0.375 mmol, 75%)
of the amino diselenide 3a: The enantiomeric purity was determined by
HPLC analysis (column, Chiralcel-OD; eluent, hexane/2-propanol 98:02;
flow rate, 1 mL/min; R isomer, tR ) 16.3 min, S isomer, tR ) 17.2 min) and
found to be >99.9%: mp 96 - 98 °C; [R]20D -8 (c 1.0, CH2Cl2); 1H NMR
(CDCl3, 400 MHz) δ 7.24-7.11 (m, 5H), 4.89-4.87 (m, 1H), 4.09-4.05
(m, 1H), 3.11-2.99 (m, 2H), 2.83-2.80 (m, 2H), 1.33 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ 155.06, 137.46, 129.22, 128.95, 126.35, 79.14, 51.99,
39.75, 34.77, 28.25. 77Se NMR (CDCl3) δ 314.421. HRMS-ESI m/z calcd
for C28H40N2O4Se2 + Na+ 651.1209980, found 651.1210725.
(14) (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028-4036. (b) Yamakawa, M.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 6327-6335.
(15) Fitzpatrick, K.; Kellogg, R. M. Tetrahedron: Asymmetry 1995, 6,
1861-1864.
Org. Lett., Vol. 5, No. 15, 2003
2637

Besides, these compounds have been evaluated in the
enantioselective addition of diethylzinc to aldehydes. The
chiral secondary alcohols could be obtained in high yields
and enantiomeric excesses by using a very small amount of
catalyst. Further studies are in progress in our laboratories
concerning new metal-catalyzed asymmetric reactions and
will be reported in due course.
financial support. O.E.D.R. thanks CNPq for a Ph.D.
fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The authors gratefully acknowl-
edge CAPES, PROBAL, CNPq, and FAPERGS for
OL034773E
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Org. Lett., Vol. 5, No. 15, 2003