Chiral sulfamide-catalyzed asymmetric Michael addition of protected 3-hydroxypropanal to β-nitrostyrenes

Article abstract of DOI:10.1016/j.tetlet.2012.01.072

Organocatalytic asymmetric Michael addition of 3-(OTBS)-propanal to β-nitrostyrenes catalyzed by chiral sulfamides was investigated. Good d.r. (up to 80:20) and excellent enantioselectivities (up to >99% ee) were achieved. Both the N-[(1R,2R)-2-aminocyclo

Full text of DOI:10.1016/j.tetlet.2012.01.072

Tetrahedron Letters 53 (2012) 1878–1881
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Tetrahedron Letters
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Chiral sulfamide-catalyzed asymmetric Michael addition of protected
3-hydroxypropanal to b-nitrostyrenes
Simone Tortoioli a, , Sergio Bacchi b, Cecilia Tortoreto c, John B. Strachan d, Alcide Perboni b
⇑
a Process Research Chemistry, Actelion Pharmaceuticals Ltd., Switzerland
b API Development & Manufacturing, Aptuit Srl, Via Fleming 4, Verona, Italy
c Département de chimie organique, Université de Genève, Switzerland
d Chemical Development, GlaxoSmithKline, Stevenage, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic asymmetric Michael addition of 3-(OTBS)-propanal to b-nitrostyrenes catalyzed by chiral
sulfamides was investigated. Good d.r. (up to 80:20) and excellent enantioselectivities (up to >99% ee)
were achieved. Both the N-[(1R,2R)-2-aminocyclohexyl]-N’-(phenylmethyl)sulfamide 7b and the novel
chiral N-[(1R,2R)-2-aminocyclohexyl]-N’-[3,5-bis(trifluoromethyl)phenyl]sulfamide 7a were identified
as efficient primary amine organocatalysts.
Received 1 December 2011
Revised 17 January 2012
Accepted 18 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric organocatalysis
Chiral sulfamides
Michael addition
Trans-b-nitrostyrenes
C–C bond
Carbon–Carbon bond formation through Michael reaction is one
of the most powerful and versatile tools available in organic syn-
thesis. By means of asymmetric catalysis, the formation of stereo-
genic centers can be controlled and predicted, affording,
selectively, products with a stereo-defined architecture.1 The en-
amine organo-catalysis in the addition to aldehydes and ketones
meets the criteria of an elegant and efficient asymmetric process
Ar
O
cat.
OHC
NO2
Target
NO2
H
Ar
+
OTBS
OTBS
1
2
3
under simple and environmentally friendly conditions.2
L-proline,
Scheme 1. Michael addition of aldehyde 1 into b-nitrostyrenes 2.
and some of its analogues, were the first catalysts of this type
found to be effective in such a transformation3a leading to the rapid
growth of the asymmetric organocatalysis. Recent publications
highlighted the beneficial effect of a chiral H-bond donor for elec-
trophile activation as a way of mimicking the mode of action of
many enzymes in a biological matrix.3b Therefore, new types of
bifunctional organocatalysts were designed: ureas, thioureas,
guanidinium, and amidinium were found to be effective H-bond
donors and chiral primary amine-thiourea organocatalysts were
used to develop several enantioselective conjugate additions of
carbonyl compounds to enones and nitroolefins.2,4
One of the applications we became interested in was the organ-
ocatalyzed asymmetric Michael addition of the aldehyde 1 to
trans-b-nitrostyrenes 2 as the key step to access highly functional-
ized adducts of type 3, with a wide opportunity of functional
groups manipulation. Adducts 3 were further progressed to the
targets of biological relevance, of which we cannot disclose the
nature at the present time (Scheme 1).
Primary amine organocatalysis with un-substituted aldehydes
such as 1 is a relatively unexplored field due to the risk of side
reactions.2 In particular, the use of aldehyde 1 as nucleophile, to
the best of our knowledge, has never been reported.5 To address
the issue of the stereoselectivity, we took into consideration
several types of primary and secondary amine organocatalysts
which proved to be successful in similar reactions (Fig. 1). Some
commercially available
as well as Jacobsen’s
-t-leucine thiourea derived catalyst 5.4d Sim-
ple thiourea catalyst 6a was recently used by Barbas and co-work-
L
-proline derivatives 4a–c6 were selected,
L
ers in
a very elegant anti-selective asymmetric addition of
(TBS)acetaldehyde to nitroolefins2 and the structural related thio-
urea catalyst 6b was also selected.4c Sulfamides are structurally
similar to thioureas with an increased H-bond donor ability due
to the effect of the strong electron-withdrawing sulfonyl group
which results in higher acidity of N–H bonds compared to the
⇑
Corresponding author. Present address: Département de chimie organique,
Université de Genève, Switzerland. Fax: +41 61 565 6402.
E-mail address: simone.tortoioli@actelion.com (S. Tortoioli).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.072

S. Tortoioli et al. / Tetrahedron Letters 53 (2012) 1878–1881
1879
Table 1
HO
Ph
Ph
Preliminary catalysts/conditions screening
Ph
Ph
N
Br
OMe
N
H
N
H
N
H
O
OTMS
4a
4b
Ph
4c
O
tBu
S
NO2
cat.(20 mol%)
20h
H
N
OHC
NO2
Ph
Ph
NH2
H
N
N
H
+
H
Br
O
OTBS
OTBS
5
1
2a
3a
CF3
f
f
d.r.e
eeM
eem
Cg (%)
Yh (%)
S
S
Entry
Cat.
1
2
3
4
5
6
7
8
9
4aa
4ba
4ca
5b
62:38
65:35
80:20
—
80:20
75:25
65:35
75:25
76:24
69
71
90
—
93
98
>99
98
>99
57
45
29
—
75
82
78
92
96
>99
>99
94
12
95
>99
89
>99
91
42
52
60
—
63
41
47
66
69
F3C
N
H
N
H
Ph
N
H
N
H
NH2
NH2
6a
6b
CF3
6ab
6bb
7ac
7bc
7bd
O
O
O
O
S
S
F3C
N
H
N
H
Ph
N
H
N
H
NH2
NH2
7a
7b
a
b
c
Conditions: MeCN/H2O, 5 °C.
Conditions: CH2Cl2, 25 °C and a catalytic amount of water (Ref. 4d).
Conditions: CH2Cl2/Imidazole (0.2 equiv), 25 °C.
Figure 1. Selected organocatalysts.
d
e
Conditions: CH2Cl2/Imidazole (0.2 equiv), 0 °C, 48 h.
thioureas.7 Surprisingly, the use of simple chiral bifunctional sulfa-
mides as organocatalysts has been very limited, despite their po-
tential as double H-bond donors. Only recently, sulfamide 7b was
used by Yan and co-workers in the enantioselective conjugate
addition of isobutyraldehyde to trans-b-nitrostyrenes.7b
In order to explore the promising potential of sulfamides organ-
ocatalysts, we decided to use 7b as a model and to prepare and test
the new sulfamide 7a due to the similarity with the thiourea 6a8.
In this Letter, we report preliminary results on the asymmetric
addition of 3-(tert-butyldimethylsilyloxy)propanal (1) to b-nitro-
styrenes 2. These studies identified the new sulfamide 7a and sulf-
amide 7b as efficient primary amine organocatalysts. The
preparation of 7a is also described.
Diastereomeric ratios were measured with chiral HPLC (See Supplementary
data) and 1H NMR analyses; the sense of diastereomeric induction was the same in
all cases.
f
ee were measured with chiral HPLC analysis; the sense of enantiomeric
induction was the same (See Supplementary data).
Reaction conversions were measured by LC/MS.
Yields of isolated products after column chromatography (adducts 3a was
found to partially decompose over silica; no retro-Michael products observed); the
results are the average of at least two runs.
g
h
OH
(a)
OH
We began the screening of the catalysts using trans-(4-bromo)-
b-nitrostyrene 2a as Michael acceptor. The results are reported in
Table 1.
CF3
SO2Cl2, Py
CH2Cl2, 5 °C
CF3
The different conditions applied for each catalyst were designed
combining both the solvent screening experiments and the exam-
ples already reported in the literature.2,4d,6,7 The proline class gave
F3C
NH2
O
O
8
X
O
O
SO2
S
F3C
N
O
Et3N, DMF/CH2Cl2
r.t. 20h
H
high to full conversion after 20 h and in particular, L-diphenyl pro-
OH
linol trimethylsilylether 4c was the more promising catalyst, giving
a good 80:20 d.r. with 90% ee for the major diastereomer in a
respectable yield (entry 3).
The thioureas derivatives gave disappointing results with the
Jacobsen’s catalyst 5 achieving a modest 12% conversion (entry
4). The simple thioureas 6a and 6b instead gave high to full conver-
sion raising the d.r. up to an interesting level (80:20 and 75:25,
respectively) alongside with high ee for the major diastereomers
(93% and 98%, respectively).9
We were thus pointed toward the study of the effect of bifunc-
tional sulfamides as catalysts. Compound 7b was easily prepared
according to the literature,7b while the preparation of sulfamide
7a in a standard stepwise route via cathecol sulfate failed due to
the reduced nucleophilic ability of 3,5-bis(trifluoromethyl)aniline
(8) (Scheme 2a). A new synthetic approach for 7a was devised
and it is shown in Scheme 2b. Treatment of aniline 8 with chloro-
sulfonic acid gave the corresponding sulfamate salt, converted
with PCl5 into the sulfamyl chloride 9 that reacted with (À)-
(1R,2R)-1,2-diaminocyclohexane to give (+)-N-[(1R,2R)-2-amin-
ocyclohexyl]-N’-[3,5-bis(trifluoromethyl)phenyl]sulfuric diamide
(7a) with in an overall yield of 17% molar over 3 steps (see
Supplementary data).
CF3
CF3
(b)
1. ClSO3H
CH2Cl2, 0 °C
SO2Cl
F3C
N
F3C
NH2
H
2. PCl5
PhCH3, rfx o.n.
8
9
H2N
H2N
(1R,2R)-(-)
CH2Cl2, 0 °C
CF3
O
O
S
N
H
N
H
F3C
NH2
7a
Scheme 2. Synthesis of sulfamide 7a.

1880
S. Tortoioli et al. / Tetrahedron Letters 53 (2012) 1878–1881
Table 2
Asymmetric Michael addition of 3-(OTBS)-propanal to b-nitrostyrenes catalyzed by 7ba
R
O
NO2
7b (20 mol%)
OHC
NO2
H
R
+
CH2Cl2 25 °C, 20h
imidazole (20 mol%)
OTBS
OTBS
1
2a-f
d.r.b
3a-f
Entry
R
eeM
eem
Yd (%)
c
c
1
2
3
4
5
6
4-Br (2a)
H (2b)
4-Me (2c)
4-OMe (2d)
2,4-diCl (2e)
4-CF3 (2f)
75:25
76:24
68:32
70:30
60:40
74:26
98
92
99
98
98
99
92
78
98
99
97
99
66
62
46
65
42
48
a
Representative procedure (see Supplemenatry data): nitrostyrene 2a–f (0.88 mmol), 3-[(tert-butyldimethylsilyl)oxy]propanal 1 (1.76 mmol,
2.0 equiv), imidazole (0.2 equiv), and the catalyst 7b (0.2 equiv) were dissolved in dichloromethane (2 ml). The resulting mixture was stirred at
room temperature for 20 h before quenching with 2 ml of HCl 0.5 M.
b
Diastereomeric ratios were measured with chiral HPLC (See Supplementary data) and 1H NMR analyses on the isolated material.
ee were measured with chiral HPLC analysis (See Supplementary data) on the isolated material.
Yields of isolated products after column chromatography; the results are the average of at least two runs.
c
d
The two catalysts 7a and 7b were tested in the model reaction
using imidazole as the additive as reported in the literature.7b The
reaction with sulfamide 7a provided an 89% conversion after 20 h
with a significant >99% ee for the major diastereomer, while the
d.r. was moderate (entry 7). Catalyst 7b showed to be more active,
giving full conversion, an increased d.r. (75:25), and more impor-
tantly, the reaction was highly enantioselective, especially for the
major diastereomer (entry 8). Lowering the temperature did not
significantly improve the selectivity (entry 9).
Y
X
(a)
R
N
H
O
N
H
O
NH
H
OTBS
N
Ar
CF3
(b)
Having identified sulfamide 7b as the best catalyst for the
asymmetric conjugate addition of 3-(OTBS)-propanal 1 to trans-
(4-bromo)-b-nitrostyrene (2a), we decided to extend the reaction
to a series of trans-b-nitrostyrenes 2b–f (Table 2). Sulfamide 7b
proved to be an efficient catalyst for all the substrates examined,
providing a level of diastereoselectivity up to 76:24 (entry 2), the
lowest being b-nitrostyrene 2e with a modest 60:40 (entry 5), with
yields ranging from 42 to 66% molar. By using sulfamide 7b, we ob-
served an unprecedented high level of enantioselectivity, espe-
cially for the major enantiomer (92–99% ee) for the entire series.
Moreover, the selectivity observed seemed to be independent of
the presence of electron-withdrawing or electron-donating groups
on the phenyl ring of styrenes.
S
S
(13.1)
(12.1)
N
H
F3C
N
N
H
Ph
Ph
N
H
H
NH2
NH2
6a
6b
CF3
O
O
O
O
(9.8)
N
H
(11.2)
S
S
F3C
N
N
H
N
H
H
NH2
NH2
7a
7b
Figure 2. (a) Plausible transition state; (b) pKa’s of sulfamides versus thioureas.
From the mechanistic point of view, when using bifunctional
organocatalysts 6a–b, 7a–b a double activation effect could be con-
ceived as depicted on Figure 2a.7 As already described in a detailed
study,7a there is no general correlation between the acidity of N–H
bond with the catalytic activity and enantioselectivity of the cata-
lyst. When looking at the pKa values (Fig. 2b), sulfamides 7a–b are
relatively more acidic than the corresponding thioureas 6a–b.10 No
relevant differences in reactivity could be found between catalysts
6b and 7b however, sulfamide 7a showed to be slightly less active
than the corresponding thiourea 6a. Similarly, the increase in
enantioselectivity observed using sulfamide 7b cannot be only jus-
tified with the acidity of the N–H bonds of the sulfamide, but it
might advocate a substrate specific effect.
In summary, the examined chiral bifunctional sulfamides were
found to be effective organocatalysts for the enantioselective
Michael addition of unbranched aldehyde 1 to various trans-
b-nitrostyrenes 2. The chiral (1R,2R)-trans-1,2-diaminocylohexyl
moiety seemed to play a fundamental role for the asymmetric
induction of most of the studied catalysts. This privileged
structure,11 in combination with the sulfamide moiety, pointed
us toward the identification of organocatalysts with an improved
efficacy. The recent results on chiral bifunctional sulfamides indi-
cate a new class of promising organocatalysts for which scope
and application are mostly to be unveiled.
Acknowledgments
We are grateful to Massimo Sampaolo and Riet Dams for
developing chiral methods and performing chiral HPLC analyses,
Ornella Curcuruto for HRMS measurements, Lucilla Turco and
Stefano Provera for NMR support and Giorgio Ottaviani for pKa
calculations. The Univeristà di Perugia is also thanked for a stage
fellowship accorded to C.T.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.072.

S. Tortoioli et al. / Tetrahedron Letters 53 (2012) 1878–1881
5. Primary amine organocatalysts were mostly used for
1881
a,a
-disubstituted
References and notes
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