The readily available tert-pentyl group as a most effective simple directing group for asymmetric synthesis: A case study on Salen-Mn(III)-catalyzed epoxidation

Article abstract of DOI:10.1016/S0957-4166(02)00582-7

The tert-pentyl group has been found to produce a pronounced stereodirecting effect, which is manifested in a study on Salen-Mn(III) complexes bearing such groups.

Full text of DOI:10.1016/S0957-4166(02)00582-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2089–2093
The readily available tert-pentyl group as a most effective simple
directing group for asymmetric synthesis: a case study on
Salen–Mn(III)-catalyzed epoxidation
a
a
b
a,
Anne Gaquere, Sidney Liang, Fu-Lian Hsu and Xiu R. Bu *
a
Department of Chemistry, Clark Atlanta University, Atlanta, GA 30314 USA
b
US Army Edgewood Chemical and Biological Center, Aberdeen Proving Ground, MD 21010, USA
Received 27 June 2002; accepted 12 September 2002
Abstract—The tert-pentyl group has been found to produce a pronounced stereodirecting effect, which is manifested in a study
on Salen–Mn(III) complexes bearing such groups. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
steric effect generated in such ways can efficiently cover
more areas by attaching two t-Pen groups at the 3- and
3%- positions of Salen-based catalysts (Fig. 1b).
Steric effects often play the most important role in
asymmetric catalysis. While a variety of groups can
serve to act as steric/directing groups as a result of their
bulk, simple groups are the most favorable due to
practical considerations and cost-effectiveness. The
ideal simple directing group should be easily synthe-
sized, and should possess characters of effectiveness,
solubility, and stability. By and large, not many simple
groups can provide desirable steric effectiveness. The
tert-butyl group is a unique directing group that has
8
,9
Asymmetric epoxidation by Salen–Mn complexes is a
suitable reaction for testing this idea because over the
past decade it has been one of most intensively studied
reactions, in which many simple and more elaborate
10–13
directing groups have been investigated.
Available
data can therefore be used directly as a reference.
Herein, we wish to report the results from asymmetric
epoxidation using Salen–Mn catalysts incorporating t-
pentyl groups.
1
–6
been widely used in many catalysts.
disclosed that the tert-pentyl (t-Pen) group gave a
Recently, we
superb directing effect in Salen–Ti catalysts for asym-
metric cyanation. The t-Pen group is simple, and
readily available from commercially inexpensive phe-
nols. However, its general potential as a directing group
has never been thoroughly examined. We reasoned that
the flexibility of the ethyl unit of the t-Pen group can
offer significant rotational freedoms (Fig. 1a). The
7
The new catalysts were prepared from the correspond-
ing Salen ligands, which were developed from the reac-
tion of the readily available 3,5-di-tert-pentylsalicyl-
7
aldehyde with (1R,2R)-(+)-1,2-diaminocyclohexane or
(
1R,2R)-(+)-1,2-diphenylethylenediamine. According to
14,15
Jacobsen’s procedure,
styrene with NaOCl in the presence of 1 (10 mol%) in
treatment of cis-b-methyl-
methylene chloride at 4°C afforded (+)-(1R,2S)-cis-1-
1
6
phenylpropylene oxide with ee of 94% (Scheme 1).
This high enantioselectivity is comparable to that (92%
ee) induced when the t-Bu analogue was used as a
15
catalyst. The present result is achieved without the use
of any additives.
Figure 1.
When 2 (10 mol%) was employed together with 0.4
equiv. of 4-phenylpyridine N-oxide (4-PPNO), the reac-
tion gave product with 91% ee. Again, this high ee is
*
Corresponding author. E-mail: xbu@cau.edu
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00582-7

2
090
A. Gaquere et al. / Tetrahedron: Asymmetry 13 (2002) 2089–2093
Scheme 1.
Figure 2. Enantiomeric excess (ee) and yields of product with
varying amounts of 1. The results were obtained from reac-
tions that were run for 14 h at 4°C.
very similar to those observed using the t-Bu analogues.
It is notable that two structurally similar t-Bu ana-
logues gave 83% and 88% ee, respectively.
9
15
After these preliminary investigations, a more thorough
examination was completed to determine the efficiency
of the catalysts at different loadings. We first used
catalyst 1 to determine the optimal amount of catalysts
and found the best loading was 10 mol%. The reactions
were run for 2 h using different mol% of catalyst 1
(
Table 1). The enantioselectivity is independent of the
amount of catalyst used (Fig. 2, 14 h), and is always
high, even in the presence of only 1 mol% of catalyst.
Increased catalyst loading mainly serves to accelerate
the reaction rate, a trend paralleling that of the t-Bu
analogue. The yield of the cis-epoxide rises greatly
from <2 to 52% when the loading of 1 is increased from
1
1
7
Figure 3. Enantioselectivity (ee) versus reaction time using
catalyst 1 (5% mol).
to 10 mol%. Examination of the relationship between
ee and reaction time revealed that the ee is fairly
consistent during the course of the reaction (Fig. 3, 5
min to 24 h).
improves the yield from 16 to 89% within 4 h. More-
over, it increases the cis/trans ratio from 5.30 to 14.8.
Increasing the level of the additive from 0.4 to 1.0
equiv. led to further acceleration of the rate with yield
enhancement from 72 to 89% in 2 h (Table 4, runs 1–3).
It should be added that the reaction was complete
within 2 h in the presence of 1.0 equiv. 4-PPNO as
opposed to incomplete with the use of only 0.4 equiv.
4-PPNO. Based on these observations, the effectiveness
of the catalyst was further evaluated with 5 and 3 mol%
catalyst (Table 4, runs 4–9). The results clearly show its
inherent effectiveness: 91% ee and 87% yield from 5
mol% catalyst with 1 equiv. 4-PPNO, and 91% ee and
84% yield from just 3 mol% catalyst with 2 equiv.
4-PPNO.
17
The effect of additives was then investigated. The use
of two donor molecules led to conclude that this effect
depends on the backbone of the catalysts. The addition
of donor molecules such as pyridine N-oxide (PNO)
and 4-phenylpyridine N-oxide (4-PPNO) does not have
any dramatic effect on enantioselectivity when 1 is used
(
Table 2). In marked contrast, the improvement by
catalyst 2 is significant.
Using 2, the ee is dramatically improved from 86%
without additive to 91% when 0.4 equiv. of 4-PPNO is
used (Table 3, runs 1 and 4). This additive also
Table 1. Epoxidation of cis-b-methylstyrene using different mol% catalyst 1
Run
mol%
t (h)
ee (%)a
Yieldcis (%)b
Yieldtotal (%)c
1
2
3
4
1
5
7
2
2
2
2
94
94
94
94
B2
12
16
2
15
20
63
10
52
a
Determined by GC using chiral G-TA (Gamma-cyclodextrin, Trifluoroacetyl) column.
Determined by GC (G-TA column) against an internal standard.
The sum of yields of cis- and trans-isomers.
b
c

A. Gaquere et al. / Tetrahedron: Asymmetry 13 (2002) 2089–2093
2091
Table 2. Epoxidation of cis-b-methylstyrene using 10 mol% catalyst 1 with or without additives
Run
Additive
t (h)
ee (%)a
Yieldcis (%)a
Yieldtotal (%)a
1
2
3
4
None
PNO
4-PPNO
None
2
2
2
4
94
93
92
94
52
55
53
66
63
64
63
77
a
Determinations and definitions are the same as those in Table 1 footnotes.
Table 3. Epoxidation using 10 mol% of catalyst 2 with or without additives
Run
t (h)
Additive (equiv.)
ee (%)a
Yieldcisa (%)
Yieldtotala (%)
cis/trans
1
2
3
4
5
4
4
14
4
None
86
91
90
91
91
16
39
72
89
87
19
42
76
95
92
5.30
13.0
18.0
14.8
17.4
PNO (0.4)
PNO (0.4)
PPNO (0.4)
PPNO (0.4)
14
a
Determinations and definitions are the same as those in Table 1 footnotes.
Table 4. Effect of amount of additive 4-PPNO on ee
Run
% mol 2
t (h)
4-PPNO (equiv.)
ee (%)a
Yieldcisa (%)
Yieldtotala (%)
cis/trans
1
2
3
4
5
6
7
8
9
10
10
10
5
5
5
3
3
3
2
2
2
4
2
2
4
4
4
0.2
0.4
1.0
1.0
1.0
2.0
1.0
2.0
3.0
91
91
91
91
91
90
90
91
90
42
72
89
87
57
75
73
84
85
45
76
95
91
60
80
77
88
90
14.0
18.0
14.8
21.8
19.0
15.0
18.3
21.0
17.0
a
Determinations and definitions are the same as those in Table 1 footnotes.
With these results, we have extended the applications of
these catalysts to other substrates. In order to make
comparison possible, we used Jacobsen’s catalyst (t-Bu
analogue of 1) for the epoxidation of 1,2-dihydronaph-
thalene to obtain 70% ee without any additive and 75%
ee using PNO as additive, respectively, as reference. For
the same reaction, the catalyst 1 gave 78% ee without
additives and 85% ee with PNO (Table 5, runs 3 and 4),
respectively. We then used Jacobsen’s catalyst for the
epoxidation of trans-b-methyl styrene without additives
to obtain the corresponding epoxide with 22% ee. The
catalysts 1 gave 33% ee under the same conditions
(Table 5, run 1). The results from similar reactions
using 2 are listed in Table 6.
In summary, through this epoxidation study, the signifi-
cant directing role played by the t-Pen group has been
revealed. The present results, coupled with the previous
Table 5. Epoxidation of olefins using catalyst 1 with or without additives

2
092
A. Gaquere et al. / Tetrahedron: Asymmetry 13 (2002) 2089–2093
Table 6. Epoxidation of olefins using catalyst 2 with or without additives
1
ones from cyanation reactions with Salen–Ti complexes
unambiguously establish the t-Pen group as one of the
most effective simple directing groups. The inherent
advantages include facile preparation and cost-effective-
ness, since the ligands are readily prepared from commer-
cially available and inexpensive phenols. The t-Pen group
may very well be effective as a bulky group with directing
effects in other asymmetric reactions.
696.3; H NMR (CDCl ) l ppm: 0.59 (m, 12H), 1.18 (s,
3
12H), 1.35 (s, 12H), 1.52 (m, 4H), 1.90 (m, 4H), 4.71 (s,
2H), 6.89 (s, 2H), 7.17 (m, 12H), 8.36 (s, 2H), 13.53 (s,
1
3
2H); C NMR (CDCl ) l ppm: 9.61, 10.02, 27.89, 28.87,
3
33.09, 37.24, 37.40, 38.90, 80.80, 118.09, 127.50, 127.93,
128.49, 128.65, 129.47, 135.03, 138.46, 140.32, 158.29,
167.76. Anal. calcd for C H N O : C, 82.24; H, 9.20;
48
62
2
2
N, 4.00. Found: C, 82.02; H, 9.04; N, 3.97%.
2
.2.2. (R,R)-(−)-N,N%-Bis(3,5-di-t-pentylsalicylidene)-1,2-
2. Experimental
cyclohexanediamine. The preparation of this compound
7
is reported elsewhere.
2.1. General
2
.3. General procedure for preparation of catalysts
Melting points were obtained in open capillary tubes with
a Mel-Temp II Laboratory Devices, Inc. melting point
apparatus and are uncorrected. Infrared (IR) spectra
were recorded on an Omnic Impact 400 FT-IR spectrom-
The chiral Salen ligand (0.143 mmol) was mixed with
Mn(OAc) ·4H O (38.5 mg, 0.157 mmol) in dry ethanol
2
2
(3 mL) at rt overnight. The resultant solution was diluted
with water (5.0 mL), and sodium chloride (1.0 g, excess)
was added. The resulting mixture was stirred at rt for 24
h. After the solvent was removed under vacuum, the
brown residue was dissolved in dichloromethane (5.0
mL). The organic phase was washed with water (3.0 mL)
and dried with sodium sulfate. The solvent was then
removed under vacuum to give a brown solid, which was
purified by column chromatography on silica gel, using
hexane/CH Cl (9/1) as an eluent to afford the pure
1
eter as thin films for oil and KBr pellets for solids. H
13
NMR (400 MHz) and C NMR (100.6 MHz) spectra
were recorded on a Bruker instrument with TMS as an
internal standard for reference. Elemental analysis was
performed at Atlantic Microlab at Norcross, Georgia.
The mass spectrometry data were recorded with a
Hewlett–Packard 5972 mass spectrometer. Enantiomeric
excesses (ee) were determined on capillary GC using
chiral column (Chiraldex, 20 m×0.25 mm ID×0.125 mm
film). The oven temperature is about 100°C, and isother-
mal at 65 kPa. Optical rotation was obtained with a
Rudolph Research Autopol III Digital Polarimeter in a
thermostat cell at 20°C.
2
2
catalyst.
2.3.1. Chloro-(R,R)-(−)-[[N,N%-bis(3,5-di-t-pentylsalicyli-
dene) - 1,2 - cyclohexanediamine] - N,N%,O,O%]manganese-
(
III), complex 1. Dark brown solid, yield: >70%, mp
−1
2
2
.2. Synthesis of Schiff base ligands
299–301°C; IR/cm 3446.6, 3138.0, 2962.5, 2873.8,
608.5, 1535.3, 1431.1, 1384.8, 1340.5, 1305.7, 1236.3,
1
.2.1. (R,R)-(−)-N,N%-Bis(3,5-di-t-pentylsalicylidene)-1,2-
1166.9, 831.3, 783.1, 732.9, 563.2. Anal. calcd for
C H ClMnN O : C, 69.50; H, 8.75; N, 4.05. Found: C,
diphenylethylenediamine.2-Hydroxy-3,5-di-t-pentylbenz-
aldehyde (1.09 g, 4.16 mmol) and 1,2-diphenylethylene-
diamine (441 mg, 2.08 mmol) were stirred in dry ethanol
40
60
2
2
69.50; H, 8.80; N, 4.01%.
(
20 mL), at rt overnight. The ethanol was partially
2.3.2.
Chloro-(R,R)-(−)-[[N,N%-bis(3,5-di-t-pentylsali-
reduced under vacuum and the white solid was filtered
and washed with cold ethanol. The crude product was
recrystallized with hexane to afford Schiff base as a
yellow solid (1.03 g, 71%). Mp. 142–144°C; [h] =−53 (c
0
cylidene) - 1,2 - diphenylethylenediamine] - N,N%,O,O%]-
manganese(III), complex 2. Dark brown solid, yield,
−
1
>75%, mp 310°C; IR/cm 2926.7, 2855.4, 2367.9, 2341.1,
1557.0, 1467.5, 1384.2, 1261.6, 1088.4, 1030.0, 812.9,
516.8. Anal. calcd for C H ClMnN O : C, 73.03; H,
2
2
D
−
1
.10 CHCl ); IR/cm 3463.9, 3062.8, 3031.9, 2962.5,
3
48 62
2
2
2875.7, 1625.9, 1598.9, 1460.0, 1382.9, 1274.9, 771.5,
7.92; N, 3.55. Found: C, 72.75; H, 7.85; N, 3.58%.

A. Gaquere et al. / Tetrahedron: Asymmetry 13 (2002) 2089–2093
2093
2.4. General procedure for epoxidation reactions
References
Racemic mixture references were prepared as follows: a
solution of cis-b-methylstyrene and m-CPBA (meta-
chloroperbenzoic acid) in excess in dichloromethane was
stirred at rt for 2 h. The reaction was quenched by an
aqueous solution of sodium carbonate. The phases were
then separated and the aqueous layer was extracted with
dichloromethane. The combined organic phases were
dried over Na SO . The volume of solvent was properly
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−
2
(
100 mg, 0.850 mmol), 2 (66 mg, 8.5×10 mmol, 10%),
and 4-PPNO (58 mg, 0.34 mmol, 40%) in
dichloromethane (1.0 mL) was cooled to 4°C. Buffered
bleach in excess (pH 11.5, 2.5 mL), pre-cooled at 4°C,
was added to the solution. The reaction mixture was
vigorously stirred at 4°C for 4 h. Then the reaction
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extracted with dichloromethane (2×2.0 mL) and the
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2
4
crude product was purified by column chromatography,
using hexane/ethyl acetate (8/2) as an eluent.
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Acknowledgements
16. Reactions were run at 4°C. The ee was determined by GC
using chiral G-TA column.
Financial support by NIH/NIGMS (S06GM08247 and
R25GM60414) as well as NASA (NCC3-552) is grate-
fully acknowledged.
17. Wu, M. H.; Jacobsen, E. N. In Comprehensive Asymmet-
ric Catalysis, Springer; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; 1999; p. 649.