Synthesis of prolinal dithioacetals as catalysts for the highly stereoselective Michael addition of ketones and aldehydes to β-nitrostyrenes

Article abstract of DOI:10.1016/j.tetlet.2007.06.085

Catalytic highly enantioselective (up to >99% ee) and diastereoselective (up to 99% de) direct Michael addition of ketones and aldehydes to β-nitrostyrenes have been achieved with readily accessible and highly tunable prolinal dithioacetal catalysts.

Full text of DOI:10.1016/j.tetlet.2007.06.085

Tetrahedron Letters 48 (2007) 5803–5806
Synthesis of prolinal dithioacetals as catalysts
for the highly stereoselective Michael addition of ketones
and aldehydes to b-nitrostyrenes
Tanmay Mandal and Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
Received 18 May 2007; accepted 15 June 2007
Available online 22 June 2007
Abstract—Catalytic highly enantioselective (up to >99% ee) and diastereoselective (up to 99% de) direct Michael addition of ketones
and aldehydes to b-nitrostyrenes have been achieved with readily accessible and highly tunable prolinal dithioacetal catalysts.
Ó 2007 Elsevier Ltd. All rights reserved.
Michael addition is one of the most important C–C
bond formation reactions in organic synthesis1 and,
therefore, developing enantioselective Michael addition
reactions has been the focus of organic chemists for dec-
ades.2 Due to its environmentally friendly nature and its
relevance to biocatalysis, organocatalysis is currently in
vogue.3 In this regard, many proline derivatives4,5 have
been proposed as the catalysts for the direct addition
of ketones and/or aldehydes to b-nitrostyrenes via the
enamine intermediate6 in recent years, and excellent
enantio- and/or diastereoselectivities have been obtained
with some of these reported catalysts. In order to
achieve the desired stereoselectivities, most of these pro-
line-derived catalysts have a hydrogen-bonding moiety,
such as hydroxy, amide, ammonium salt, and thiourea,
in the side-chain to direct the substrate approach.4
Ph
Ph
SR
SR
N
N
H
H
2
H
OTMS
1
a
: R = Ph
b: R =
c: R = 2, 6-Me2C6H3
d: R = -Bu
p-MeC6H4
t
Figure 1. Catalysts utilized for the Michael addition.
therefore, it is not certain whether this catalyst is limited
for aldehyde substrates only.5a,b
The design and synthesis of highly stereoselective, read-
ily accessible and tunable catalysts are always desirable
for asymmetric catalysis. In the current Letter, we wish
to disclose the synthesis of some prolinal dithio-
acetals (2a–d, Fig. 1) as the highly diastereoselective
and enantioselective catalysts for the asymmetric
Michael addition of both ketones and aldehydes to b-
nitrostyrenes.
As a tool of achieving stereocontrol, steric factors have
been widely used in the asymmetric synthesis and catal-
ysis. Surprisingly, the design and synthesis of highly effi-
cient catalysts for this direct Michael reaction on the
basis of pure steric interactions are much less studied.5
The diphenylprolinol silyl ether catalyst 1 (Fig. 1)5a,b
reported by Hayashi et al.5a represents the most success-
ful example in this category. Nevertheless, the synthesis
of this catalyst involves Grignard reagent.7 Further-
more, no ketone substrates have been studied and,
As shown in Figure 1, in our catalyst design, we replaced
the normal C–C bonds in the side chain (such as those in
1) with the C–S (thioacetal) bonds. Due to the ease of
the thioacetal formation (vs the C–C bond formation)
and the variety of available thiol structures, this design
makes it much easier for the synthesis and fine-tuning
of the catalyst structures. For example, these catalysts
(2a–d) may be synthesized in high yields in just one step
from commercially available N-Boc-prolinal and thiols.8
Additionally, these catalysts are very stable under nor-
mal experimental conditions.
Keywords: Asymmetric; Dithioacetals; b-Nitrostyrene; N-Boc-prolinal;
Proline; Enantioselective; Diastereoselective.
*
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458
7428; e-mail: cong.zhao@utsa.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.085

5804
T. Mandal, C.-G. Zhao / Tetrahedron Letters 48 (2007) 5803–5806
Table 1. Catalyst screening and reaction condition optimizationa
To understand the scope of this new catalytic system, we
studied the reaction of various ketones and aldehydes
and b-nitrostyrenes under the optimized conditions
(0.3 mmol of carbonyl compounds, 0.1 mmol of b-nitro-
styrene, 10 mol % of catalyst 2b, and 10 mol % benzoic
acid in 0.5 mL CH2Cl2 at rt). The results are collected
in Table 2.
O
O
Ph
2 / PhCO2H
NO2
NO2
+
Ph
3a
4a
5a
Entry Cat. Solvent Time Yieldb dr (syn/anti)c eed (%)
(h)
(%)
As is evident from Table 2, the reaction of cyclohexa-
none with various substituted b-nitrostyrenes gives the
desired Michael products in excellent yields, diastereo-
selectivity (syn:anti P 97:3) and enantioselectivities
(P95% ee, entries 1–8). The electronic nature and sub-
stitution pattern of the substituents on the phenyl ring
have almost no influence on the stereoselectivities.
Besides cyclohexanone, 4-oxacyclohexanone (entry 9)
and 4-thiacyclohexanone (entry 10) produce similar
results.
1
2
3
4
5
6
7
8
9e
2a
2b
2c
2d
2b
2b
2b
2b
2b
CH2Cl2 29
CH2Cl2 28
CH2Cl2 30
CH2Cl2 40
81
88
85
75
80
75
81
78
76
97:3
99:1
97:3
95:5
98:2
94:6
96:4
97:3
96:4
97
>99
95
80
95
96
97
97
96
CHCl3
DMF
30
33
Hexane 30
Toluene 29
CH2Cl2 40
a Unless otherwise specified, all reactions were carried out with cyclo-
hexanone (3a, 0.30 mmol), trans-b-nitrostyrene (4a, 0.10 mmol), the
catalyst (2, 0.01 mmol, 10 mol %), and benzoic acid (0.01 mmol) in
the specified solvent (0.5 mL) at rt.
b Yield of isolated product after chromatography.
Determined by H NMR analysis of the crude product.
Cyclopentanone is an especially difficult substrate for
this direct Michael reaction in terms of stereoselectivi-
ties: the best diastereoselectivity4r achieved so far was
77:23 and the highest ee value4q obtained for the major
syn product was 83%. With our catalyst 2b, the reaction
generates the syn product in high diastereoselectivity
(dr 90:10) and excellent enantioselectivity (98% ee, entry
11).
c
1
d ee value of the major enantiomer was determined by HPLC analysis
on a Chiralpak AD-H column. Absolute configuration was deter-
mined by comparison of the measured optical rotation with the
reported data (Ref. 4t).
e Without benzoic acid.
By using cyclohexanone and trans-b-nitrostyrene as the
model compounds, we first screened the catalysts (2a–d)
for their ability in asymmetric inductions. The results
are summarized in Table 1.
Besides ketones, our catalysts may also be applied to
enolizable aldehyde substrates (entries 12–14). In the
case of aldehydes, it was found that adding benzoic acid
actually slows down the reaction (data not shown) and,
therefore, these reactions were carried out without benz-
oic acid. Additionally, the reaction temperature was
lowered to 0 °C to obtain optimum enantioselectivities
of the products. Under these conditions, the reaction
of butanal gives the desired syn product in perfect dia-
stereoselectivity (dr 99:1) and enantioselectivity (99%
ee, entry 12). The reactions of more hindered iso-valeral-
dehyde and 2-methylpropanal require more loading of
2b (20 mol %). Also the enantioselectivities obtained
for these products are lower. For example, with iso-val-
eraldehyde the Michael product was obtained in 92% de
and 85% ee for the major syn diastereomer (entry 13). 2-
Methylpropanal led to an even lower ee value of 76% of
the Michael product (entry 14). Nonetheless, this result
is not surprising: catalyst 1 leads to an ee value of 68%
for the product of 2-methylpropanal.5a It should be
pointed out the aldehyde substrates lead to the opposite
enantiomer of the syn diastereomer as compared with
cyclic ketones.
As shown in Table 1, in the presence of 10 mol % of benz-
oic acid and 10 mol % of the thiophenol acetal catalyst
2a, the desired Michael product 5a was obtained in
81% yield after reacting in CH2Cl2 at rt for 29 h (entry
1). Both excellent diastereoselectivity (97:3 dr) and
enantioselectivity (97% ee) of the product were obtained.
Catalyst 2b, with a methyl group at the para position of
the phenyl ring, generated even better results under these
conditions: essentially a single enantiomer (>99% ee) of
the syn diastereomer (99:1 dr; entry 2) was obtained. In
contrast, the more hindered 2,6-dimethylthiophenol
derivative 3b gave slightly inferior results (97:3 dr, 95%
ee; entry 3). Similarly, the tert-butyl mercaptan acetal
2d also led to inferior results (entry 4). Thus, catalyst
2b was identified as the best catalyst for the Michael
addition, whereas catalysts 2a and 2c are also very good
catalysts. By using 2b as the catalyst, some common
organic solvents were then screened, and CH2Cl2 was
found to be the best solvent for this reaction (entry 2).
CHCl3 (entry 5), DMF (entry 6), hexane (entry 7), and
toluene (entry 8) are all inferior solvents in terms of both
enantioselectivity and diastereoselectivity, although the
differences are not essential. It was also found that, even
though benzoic acid does accelerate the reaction, it is
not necessary for achieving the high enantioselectivity
and diastereoselectivity in this reaction (entries 2 and
9). These results exclude the involvement of hydrogen-
bond directing effects in the reaction and, therefore,
the stereocontrol is achieved mainly through steric
factors.
The stereoselectivity of this reaction may be explained
by using the acyclic synclinal transition state proposed
originally by Seebach and Golinski (Fig. 2).9 The forma-
tion of opposite enantiomers of the syn adduct as the
major products in the cases of cyclic ketones and alde-
hydes is due to the differences in the favored conforma-
tions of the enamine intermediates. As shown in Figure
2, for cyclohexanone (left structure), the enamine double
bond is nearer to the thioacetal group, and attacking of
the enamine onto re face of nitrostyrene leads to the
observed major enantiomer. In contrast, for aldehyde

T. Mandal, C.-G. Zhao / Tetrahedron Letters 48 (2007) 5803–5806
Table 2. Asymmetric Michael addition of ketones and aldehydes to b-nitrostyrenesa
5805
O
O
Ar
*
2b/PhCO2H
NO2
NO2
R2
Ar
+
*
R2
R1
R1
CH2Cl2
3
4
5
Entry
1
Product
Time (h)
28
Yieldb (%)
drc (syn/anti)
eed (%)
O
Ph
NO2
88
99:1
>99
99
NO2
O
2
3
4
5
33
36
20
20
90
79
86
90
99:1
>99:1
99:1
99:1
NO2
NO2
NO2
O
O
O
97
99
99
OMe
Cl
Br
NO2
O
6
38
77
>99:1
97e
MeO
NO2
O
7
8
25
30
81
85
99:1
97:3
97
95
Br
NO2
O
O2N
Ph
O
NO2
9
27
29
79
76
99:1
98:2
96
95
O
O
Ph
Ph
NO2
NO2
10
S
O
11
26
46
80
70
90:10
99:1
98
99
Ph
12f
OHC
OHC
NO2
Et
Ph
13f,g
14f,g
59
72
70
60
96:4
—
85
76
NO2
Ph
OHC
NO2
a Unless otherwise specified, all reactions were carried out with 3 (0.30 mmol), nitrostyrene 4 (0.10 mmol), catalyst 2b (0.01 mmol, 10 mol %), and
benzoic acid (0.01 mmol) in CH2Cl2 (0.5 mL) at rt.
b Yield of isolated product after chromatography.
c Determined by 1H NMR analysis of the crude product.
d ee value of the major diastereomer; unless otherwise indicated, ee value was determined by HPLC analysis on a Chiralpak AD-H column. Absolute
configuration was determined by comparison of the measured optical rotation with the reported data (Refs. 4t and 5c).
e On a chiralpak AS column.
f The reaction was carried out at 0 °C without adding benzoic acid.
g With 0.02 mmol (20 mol %) catalyst.

5806
T. Mandal, C.-G. Zhao / Tetrahedron Letters 48 (2007) 5803–5806
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Figure 2. Proposed transition state models.
R1
aldehyde
substrate (right structure), the trans-enamine5a double
bond is away from the thioacetal group and the attack
of this enamine onto the si face of the nitrostyrene leads
to the formation of the observed opposite enantiomer of
the syn diastereomer. Similar phenomena have been
observed for other proline-derivatives, too.5d
In summary, we have synthesized some readily accessi-
ble and highly tunable prolinal dithioacetal catalysts
for the direct Michael addition of both ketones and
aldehydes to b-nitrostyrenes. Uniformly high diastereo-
selectivities and enantioselectivities have been obtained
for both ketone and aldehyde substrates.
Acknowledgements
The authors thank the Welch Foundation (Grant No.
AX-1593) and the NIH-MBRS program (S06
GM08194) for the generous financial support of this
research.
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