Practical access to highly enantioenriched quaternary carbon Michael adducts using simple organocatalysts

Article abstract of DOI:10.1039/c0ob00822b

A three component catalyst system entailing an amino acid (O ^tBu-l-threonine), a hydrogen bond donor (sulfamide), and an amine base (DMAP) allows α-branched aldehyde addition to nitroalkenes in good to high yield and excellent ee. Importantly,

Full text of DOI:10.1039/c0ob00822b

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Chemistry
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ISSN 1477-0520
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Thomas C. Nugent et al.
Practical access to highly
enantioenriched quaternary carbon
Michael adducts using simple
organocatalysts
1477-0520(2011)9:1;1-H

Organic &
Biomolecular
Chemistry
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COMMUNICATION
Practical access to highly enantioenriched quaternary carbon Michael
adducts using simple organocatalysts†
Thomas C. Nugent,* Mohammad Shoaib and Amna Shoaib
Received 4th October 2010, Accepted 6th October 2010
DOI: 10.1039/c0ob00822b
A three component catalyst system entailing an amino acid
(OtBu-L-threonine), a hydrogen bond donor (sulfamide),
and an amine base (DMAP) allows a-branched aldehyde
addition to nitroalkenes in good to high yield and excellent ee.
Importantly, the lowest reported catalyst loading (5.0 mol%)
and aldehyde stoichiometry (1.2–2.0 equiv) is demonstrated
and in most instances the best current product profile is
observed.
Two bodies of unrelated literature piqued our interest in the
Michael reaction. The first is recent, constituting amino acid
catalyzed Michael reactions in the presence of a base,10a,d,f,14,15 while
the other has been studied for decades and details the now well
understood self-assembly of carboxylate anions with hydrogen
bond donors, e.g. amino acids with ureas or thioureas.16 Our open
question was whether the self-assembly of a hydrogen bond donor
to the carboxylate of an amino acid would facilitate cooperative
bifunctional organocatalysis, and thereby constructively impact
stereoselectivity, reaction rate, and/or substrate breadth. In this
light, we demonstrate here what we believe is the first synergistic
use of an amino acid, a hydrogen bond donor, and a base for an
organocatalytic reaction. Importantly, each catalyst component is
commercially available.
Natural product and pharmaceutical drug synthesis present multi-
ple levels of challenge and complication that must be concurrently
overcome. Beyond the chosen synthetic strategy, a simplistic view
holds that construction of the carbon backbone and functional
group manipulation are the basic tasks. In this context methods
allowing carbon–carbon bond forming reactions under mild
conditions are of interest and especially so when they address
the long standing problem of stereogenic quaternary carbon bond
formation.1,2 The Michael reaction affords this possibility when
employing a,a¢-substituted aldehydes, and the resulting products
would be considered high value multifunctional building blocks
for natural product elaboration.
Organocatalysts requiring synthesis are common and reports
on their facilitation of unbranched aldehyde, e.g. 2–3 equiv of n-
pentanal, addition to b-nitrostyrene in the presence of 1–5 mol% of
a proline derivative allow product formation in excellent yield, dr,
and ee.3 However, these low catalyst loadings are not sustainable
when branched (a,a- or a,a¢-substituted) aldehydes are examined.4
Investigations detailing the use of multiple a,a-substituted and
a,a¢-substituted aldehydes are uncommon and have waned since
the thorough reports of Barbas,5 Jacobsen,6 and Connon.7 These
reports and others highlight the continuing challenge associated
with quaternary carbon bond formation, and expound the use of
10 mol%,8,9 20 mol%,10,11 or 30 mol%12 organocatalyst loading to
add isobutyraldehyde (minimum of 2.0 equiv)13 to 2-substituted-
nitroethenes. Hence, advances have been made, but room for
improvement remains regarding catalyst loading, aldehyde stoi-
chiometry, substrate scope, and reaction time.
Fig. 1 Hydrogen bond donors and amino acids of interest.
Amino acids are well-known to favor their zwitterionic form.
In this context addition of a base, to free the primary amine for
catalysis, made sense. Our proof of concept succeeded when we
combined isoleucine, Et3N, and urea (1, Fig. 1) in the presence
of isobutyraldehyde and b- nitrostyrene (Table 1, entry 1).17
The reaction was further optimized (Table 1) by examining a
large number of amino acid, hydrogen bond donor, and base
combinations (see ESI for a complete list†).18,19 Entries 3, 6, 8,
9, and 12 (Table 1) are of particular interest and five salient
points follow. (1) The lowest aldehyde-to-b-nitrostyrene (1.2 : 1.0)
ratio is used (entries 4, 6, 9).13 (2) The lowest catalyst loading
Department of Chemistry, School of Engineering and Science, Jacobs Univer-
sity Bremen, Campus Ring 1, 28759 Bremen, Germany. E-mail: t.nugent@
jacobs-university.de; Fax: +49 421 200 3229; Tel: +49 421 200 3232
† Electronic supplementary information (ESI) available: Experimental
procedures, full spectroscopic data for compounds, and copies of 1H NMR
spectra and HPLC data. See DOI: 10.1039/c0ob00822b
52 | Org. Biomol. Chem., 2011, 9, 52–56
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The Royal Society of Chemistry 2011
©

Table 1 Optimization of isobutyraldehyde addition to b-nitrostyrene (see Fig. 1 for catalyst components)a
Entry
7 (equiv)
L-AA 5 or 6/mol (%)
H-bond donor/mol (%)
DMAP (mol%)
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
2
2
2
1.2
2
1.2
2
2
1.2
1.2
1.2
2
isoLeu/10
isoLeu/5
Urea 1/10
10d
5
8
8
5
5
3
5
24
24
5
5
2
3
24
4
7
7
53
65
82
65
99
99
86
99
97
~5e
~0e
99
92
90
97
93
91
94
93
97
98
98
—
—
95
88
Sulfamide 3/5
Thiourea 4/2
Thiourea 4/2
Thiourea 4/5
Thiourea 4/5
Sulfamide 3/3
Sulfamide 3/5
Sulfamide 3/5
—
OtBu-Thr/2
OtBu-Thr/2
OtBu-Thr/5
OtBu-Thr/5
OtBu-Thr/3
OtBu-Thr/5
OtBu-Thr/5
OtBu-Thr/5
OtBu-Thr/5
OtBu-Thr (Li salt)/5
OtBu-Thr (Li salt)/5
9
5
5
10
11
12
13
Sulfamide 3/5
Sulfamide 3/5
—
—
—
—
7
5
24
f
f
2
a 25 ◦C, toluene (1.0 M), except entries 3–6: cyclohexane (1.0 M) is optimal. b Isolated yield data. c HPLC data (Chiralcel OD-H column). d Et3N was used
instead of DMAP. e HPLC area % data. f Preformed lithium salt of OtBu-L-threonine (5 mol%) used, no DMAP added.
Table 2 Isobutyraldehyde addition to 2-substituted-nitroethenesa
(OtBu-L-threonine, 2 mol%) to date was demonstrated (entries 3
& 4). (3) High yield and enantioselectivity are coupled with short
reaction times (3–7 h).4,8–12,15 (4) The active organocatalyst is
extraordinary because it requires no synthesis, requiring only the
addition of commercially available compounds (Fig. 1). Finally,
(5) to our knowledge this is the first demonstration of the utility
of the most simple sulfamide (Fig. 1, 3) as a hydrogen bond donor
in the field of organocatalysis.
Entry
Product, R =
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9e
C6H5 (8)
7
97
98
93
98
96
98
96
99
98
96
98
96
Although thiourea 420 allowed a 2.0 mol% catalyst loading it
consistently provided lower enantioinduction than 3 (5 mol%),
see Table 1 (entries 3 & 4 vs. 8 & 9). Consequently, we used
the sulfamide (3) hydrogen bond donor for the remainder of
our study. It is important to note that removal of one of the
three catalyst components results in reaction failure (Table 1,
entries 9–11). Interestingly, the lithium salt of OtBu-L-threonine
enabled the reaction to occur without the presence of a hydrogen
bond donor (Table 1, entry 13), but required greater quantities
of the aldehyde (2.0 equiv vs. 1.2 equiv), provided notably lower
ee (88 vs. 98), and drastically longer reaction time (24 vs. 7 h).
These limitations made the lithium salt, alone, impracticable for
the more challenging substrates shortly discussed. Furthermore,
when using the optimized reaction conditions (Table 1, entry 9)
replacing sulfamide (3) by urea (1) or thiourea (2) resulted in much
slower reactions and moderate product ee (80%) for both. Finally,
n-heptane can be used instead of toluene without detriment.
A current theme within organocatalysis is to meet the stoi-
chiometry requirements governing practical organic synthesis. In
this vein, we reacted a range of electron deficient and rich aryl
substituted b-nitrostyrenes with only 1.2 equiv of isobutyraldehyde
(Table 2, entries 1–8).13 In all instances, except one (Table 2, entry
7), excellent isolated yields 85–98% and ees ≥96% were found
within 24 h. Of particular note, 2-isobutyl-nitroethene and 2-
styryl-nitroethene were examined to highlight the electronic, steric,
and functional group diversity the method can afford. Again
using 1.2 equiv of isobutyraldehyde, both substrates provided
excellent product profiles (Table 2, entries 9 and 10), in fact
the best currently known.7,10d The method is of further value
p-ClC6H4 (9)
p-FC6H4 (10)
o-BrC6H4 (11)
p-MeC6H4 (12)
p-MeOC6H4 (13)
o-MeOC6H4 (14)
2-furyl (15)
24
24
24
24
24
36
8
88
85d
90d
72d
98
36
70d
10e
6
98
97
a 25 ◦C, toluene (1.0 M). b Isolated yield data after water work-up followed
by high vacuum drying, see ESI data for proof of purity (1H NMR and
HPLC).† c HPLC data. d Required chromatography.
because several products (Table 2, entries 1–4, 8, and 10) could
be isolated in high chemical purity (>96%, 1H NMR and HPLC)
after a simple water work-up and high vacuum drying. This was
possible because these reactions, in general, are by-product free,
the b-nitrostyrene was fully consumed, the small excess of volatile
isobutyraldhyde was readily removed under high vacuum drying,
and the amino acid, DMAP, sulfamide catalyst system is water
soluble on work-up.
Cyclopentane-
and
cyclohexanecarboxaldehydes
are
more sterically congested and infrequently examined. For
cyclopentanecarboxaldehyde,5,7,10b,d,e,21 we achieved the top
result to date concerning starting material ratio (2 : 1), catalyst
loading (5 mol%), and product profile (Table 3, entry 1).
We then turned our attention to cyclohexanecarboxaldehyde
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Table 3 Various aldehyde additions to 2-substituted-nitroethenesa
entries 4–8). The diastereomeric ratios are likely a reflection of the
(E)- to (Z)-enamine ratios of the in situ formed enamine. This is
supported by the fact that our drs broadly match those reported
in the literature for the same (20–22) or similar products (23 and
24) when using unrelated organocatalysts.5–7
Entry
1
Product
t/h
7
Yield (%)b
89
drc
ee (%)c
—
97
Catalyst self-assembly as a strategy for organocatalytic Michael
reactions with b-nitrostyrene is known,15,24 but only Demir has
examined quaternary carbon bond formation.25–27 Evidence for
catalyst self-assembly in our system is based on precedent and
preliminary evidence. For example, it is well established that hydro-
gen bond donors strongly bind to amino acid carboxylate anions
having ammonium counter ions.16 It is therefore a reasonable
and strong possibility that sulfamide (3) binds to the carboxylate
anion of OtBu-L-threonine having a protonated DMAP counter
ion (Fig. 2).28 Furthermore, decreasing the amount of DMAP
or sulfamide, relative to the optimal 1 : 1 : 1 ratio with OtBu-L-
threonine, results in a non-linear decrease in the reaction rate.
Moderate increases in the amount of DMAP or sulfamide,
relative to the optimal 1 : 1 : 1 ratio with OtBu-L-threonine, have
little effect on the reaction; but addition of larger quantities of
DMAP (15 mol% vs. 5 mol%) results in reaction rate acceleration
(Table 3, see reaction conditions). This base effect has been
previously described by Yan.10c Finally, the lack of solubility of
OtBu-L-threonine and sulfamide, until all three catalyst com-
ponents are present, is another indicator that self-assembly is
occurring. With this background, a preliminary mechanism is
proposed.
2
30
48
64
88
—
—
90
91
3d
4
5
6
12
12
12
84
71
70
70 : 30
78 : 22
77 : 23
97
91
98
7
36
80
77 : 23
99
The presence of a thiourea moiety in a bifunctional Michael
organocatalyst is associated with the orbital activation of a
nitroalkene and the simultaneous forced proximity (pre-transition
organization) of the nitroalkene with the enamine.6,29 Here it is
reasonable to assume, after self-assembly has occurred, that a sim-
ilar scenario unfolds; albeit with sulfamide (3) strongly associating
with the carboxylate anion and simultaneously hydrogen bonding
with the nitroalkene (Fig. 2, synclinal I).30–32
8
16
83
76 : 24
97
Why sulfamide (3), and not simple urea (1) or thiourea (2),
Fig. 1, is more effective can be rationalized by invoking the
distorted tetrahedral geometry at the sulfur atom of 3. This allows
one of the oxygens of sulfamide to always be in a position to take
part in an electrostatic interaction with the protonated nitrogen
atom of DMAP. If occurring, the carboxylate, protonated DMAP,
sulfamide aggregate would represent a closed, or cyclic, assembly
of the three interacting partners as depicted in Fig. 2. This
configuration would be expected to be more rigid and populated
than the corresponding ‘open acyclic systems’ based on urea (1)
or thiourea (2), leading to increased levels of stereoinduction and
increased reaction rate.
a Reaction conditions: aldehyde/nitroalkene (2 : 1), OtBu-L-threonine (6)
(5 mol%), sulfamide (3) (5 mol%), DMAP (15 mol%) in toluene (1.0 M) at
25 ◦C. b Isolated yield data after chromatography. c HPLC analysis. d OtBu-
L-threonine (6) (10 mol%), sulfamide (3) (10 mol%), DMAP (10 mol%) in
toluene (1.0 M) at 25 ◦C.
When a lithium counter ion is present and no hydrogen bond
donor is present (Table 1, entry 13), the basic model would still
be valid, but now the nitro group would be directly associated
with the lithium cation. To overcome the shortened interaction
distance (no hydrogen bond donor intermediary), a synperiplanar
transition state (not shown) would be required. In this situation,
increased substituent eclipsing effects would raise the transition
state energy, slowing down the reaction and possibly allowing the
non-productive steric pathway (Fig. 2, synclinal IV) to compete.
These after the fact explanations account for the much slower
reaction time and lower ee in the absence of a hydrogen bond
donor (Table 1, compare entries 9 and 13).
which is inexpensive compared to cyclopentanecarboxaldehyde,
but essentially not reported on.22,23 The best previous ee was
64%,23 and using our standard 5 mol% catalyst loading with
a cyclohexanecarboxaldehyde/b-nitrostyrene ratio of 2 : 1, we
isolated compound (S)-19 in 64% yield with the greatly increased
ee of 90% within 30 h. When the catalyst loading was increased
to 10 mol% the yield increased to 88% (Table 3, entries 2 and 3).
Aldehydes with nonequivalent a-substituents (a,a¢-substituted
aldehydes) provide Michael products containing stereogenic qua-
ternary carbons and these products were obtained in good yield
and excellent ee, but with moderate diastereomeric ratios (Table 3,
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Fig. 2 Postulated transition states for a,a¢-substituted aldehyde addition to b-nitrostyrene (Table 3, entry 6 modelled).
A synclinal Newman transition state model rationalizes the
stereochemical outcome of enamine additions to nitroalkenes, as
elaborated on in the work of Risaliti33 and Seebach;34 and, more
recently, for the amino acid catalyzed version, by Yoshida.10a,f
With these points in mind, we sought to explain the observed
absolute and relative stereochemistry of our products (8–24).
For this purpose, we used an a,a¢-substituted aldehyde for our
transition state model: 2,6-dimethylhept-5-enal (Table 3, entry
the nitroalkene and directs it into bonding distance proximity
of the b-carbon of the enamine via hydrogen bonding. The
carboxylate-sulfamide assembly may also increase the rate of
enamine formation by enforcing a conformational preference in
the amino acid backbone. These combined facets may account for
the low catalyst loading and need for only a small excess of the
aldehyde as reported here.
In closing, we have developed a new catalyst assembly based
approach for the catalytic enantioselective formation of an im-
portant class of Michael products bearing quaternary carbons.
Through the hitherto unknown synergistic combination of an
amino acid, a base, and a hydrogen bond donor, it is now
possible to promote these reactions with lower loadings of both
the catalyst and the aldehyde than previously feasible, and within
relatively short reaction times. The cooperation of the three
catalyst components, and their inherently tunable nature, may
open up new avenues for the pursuit of organocatalytic reactions
in general.19 Preliminary modelling suggests that other Michael
acceptors (e.g. maleimide, DEAD, unsaturated sulfones, etc.), the
Mannich reaction, and mechanistically related reactions, will be
amenable to this approach.
1
6). The major product is (S,S)-22, based on chiral HPLC, H
NMR spectroscopic data, and comparison of these data with the
published values.5,6 In the proposed transition states (Fig. 2), the
L-threonine backbone of the enamine minimizes steric interactions
via gauche staggering, which projects the carboxylate moiety to the
a-face of the enamine. A reasonable assumption is that the (E)-
enamine prevails, in this scenario the synclinal I facial approach
accounts for the enantio- and diastereocontrol observed in the
major product (S,S)-22 (Fig. 2) and consequently for all other
products shown here. The minor product, (R,S)-22, is explainable
based on the (Z)-enamine (synclinal II, Fig. 2). A steric based
model (synclinal III, no H-bonding assistance) can also explain the
stereochemical outcome for the major product (S,S)-22 (Fig. 2).
However, it requires the minor (Z)-enamine, and thereby fails to
explain how the major product would be formed.
Acknowledgements
In summary, quaternary carbon–carbon bond formation in
these Michael reactions entails cooperative bifunctional catalysis
(synclinal I and II, Fig. 2). The amino acid’s primary amine
transforms the aldehyde into an enamine, while the second func-
tional group, here the carboxylate-sulfamide assembly, activates
We are grateful to Jacobs University Bremen for funding, MS
gratefully acknowledges support from the HEC of Pakistan,
and AS gratefully acknowledges a scholarship from TCN (grant
number 01).
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17 The preformed lithium salt of isoleucine/urea (5 : 5 or 10 : 10 mol%)
resulted overwhelmingly in by-product formation.
Notes and references
18 Squaramide is an interesting new hydrogen bond donor, the parent
primary diamine would be interesting to examine, see: J. P. Malerich,
K. Hagihara and V. H. Rawal, J. Am. Chem. Soc., 2008, 130, 14416–
14417.
19 Interesting to examine will be: amino acids related to isoleucine and
L-threonine, alternative O-protected threonines, and b-amino acids. It
can be further imagined that replacing the carboxylic acid moiety of
amino acids with a sulfate or phosphate ester, or a phosphonate or
sulfonate moiety will be valuable to pursue.
1 The Way of SynthesisT. Hudlicky´ and J. W. Reed, ed.; Wiley
VCH:Weinheim, 2010, specifically see p. 9.
2 For recent reviews on stereogenic quaternary carbon formation, see:
(a) O. Riant and J. Hannedouche, Org. Biomol. Chem., 2007, 5, 873–
888; (b) B. M. Trost and C. Jiang, Synthesis, 2006, 369–396; (c) J.
Christoffers and A. Baro, Adv. Synth. Catal., 2005, 347, 1473–1482.
3 (a) D. Lu, Y. Gong and W. Wang, Adv. Synth. Catal., 2010, 352, 644–
650; (b) Z. Zheng, B. L. Perkins and B. Ni, J. Am. Chem. Soc., 2010,
132, 50–51; (c) M. Lombardo, M. Chiarucci, A. Quintavalla and C.
Trombinia, Adv. Synth. Catal., 2009, 351, 2801–2806; (d) M. Wiesner,
J. D. Revell and H. Wennemers, Angew. Chem., Int. Ed., 2008, 47, 1871–
1874; (e) S. Zhu, S. Yu and D. Ma, Angew. Chem., Int. Ed., 2008, 47,
545–548.
4 One 5 mol% catalyst loading example was demonstrated, see ref. 3c:
isobutyraldehyde/b-nitrostyrene (2 : 1), 5 mol% catalyst loading, 22 h,
99% yield, 76% ee.
5 N. Mase, R. Thayumanavan, F. Tanaka and C. F. Barbas III, Org. Lett.,
2004, 6, 2527–2530.
20 M. Kotke and P. R. Schreiner, (Thio)urea Organocatalysts. In Hydrogen
Bonding in Organic Synthesis, P. M. Pihko, Ed.; Wiley-VCH: Weinhein,
2009, p. 141–352.
21 J. Wang, H. Li, B. Lou, L. Zu, H. Guo and W. Wang, Chem.–Eur. J.,
2006, 12, 4321–4332.
22 See ref. 5: cyclohexylcarboxaldehyde/b-nitrostyrene (2 : 1), 30 mol%
loading, 96 h, 90% yield, 59% ee.
23 See ref. 21: cyclohexylcarboxaldehyde/b-nitrostyrene (10 : 1), 20 mol%
loading, 96 h, 42% yield, 64% ee.
24 (a) D.-Q. Xu, H.-D. Yue, S.-P. Luo, A.-B. Xia, S. Zhang and Z.-Y. Xu,
Org. Biomol. Chem., 2008, 6, 2054–2057; (b) Z.-B. Li, S.-P. Luo, Y. Guo,
A.-B. Xia and D.-Q. Xu, Org. Biomol. Chem., 2010, 8, 2505–2508.
25 To see all of Demir’s relevant research, see: (a) A. S. Demir and S.
Eymur, Tetrahedron: Asymmetry, 2010, 21, 405–409; (b) A. S. Demir
6 M. P. Lalonde, Y. Chen and E. N. Jacobsen, Angew. Chem., Int. Ed.,
2006, 45, 6366–6370.
7 S. H. McCooey and S. J. Connon, Org. Lett., 2007, 9, 599–
602.
8 10 mol% catalyst loading. For lead references of those methods
requiring £5 equiv of an a,a-substituted aldehyde and providing ≥84%
ee, see ref. 3e, 7, and: (a) J. Xiao, F.-X. Xu, Y.-P. Lu and T.-P. Loh, Org.
Lett., 2010, 12, 1220–1223; (b) P. Li, L. Wang, M. Wang and Y. Zhang,
Eur. J. Org. Chem., 2008, 1157–1160; (c) N. Mase, K. Watanabe, H.
Yoda, K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc.,
2006, 128, 4966–4967.
9 Regarding 10 mol% catalyst loadings and the lowest reported
isobutyraldehyde/b-nitrostyrene ratio (2 : 1), ref. 3e and 8a provide the
best results, respectively: 96 h, 86% yield, 95% ee and 60 h, 97% yield,
92% ee. All other cited work in reference 8 provided < 89% ee.
10 20 mol% catalyst loading. For lead references of those methods
requiring £ 4 equiv of an a,a-substituted aldehyde and providing ≥85%
ee, see ref. 6 and: (a) M. Yoshida, A. Sato and S. Hara, Org. Biomol.
Chem., 2010, 8, 3031–3036; (b) C. Chang, S.-H. Li, R. J. Reddy and
K. Chen, Adv. Synth. Catal., 2009, 351, 1273–1278; (c) X.-j. Zhang,
S.-p. Liu, J.-h. Lao, G.-j. Du, M. Yan and A. S. C. Chan, Tetrahedron:
Asymmetry, 2009, 20, 1451–1458; (d) X.-j. Zhang, S.-p. Liu, X.-m. Li,
M. Yan and A. S. C. Chan, Chem. Commun., 2009, 833–835; (e) Q.
Zhang, B. Ni and A. D. Headley, Tetrahedron, 2008, 64, 5091–5097;
(f) A. Sato, M. Yoshida and S. Hara, Chem. Commun., 2008, 6242–
6244.
¨
and S. Eymur, Tetrahedron: Asymmetry, 2010, 21, 112–115; (c) O. Reis,
S. Eymur, B. Reis and A. S. Demir, Chem. Commun., 2009, 1088–1090.
26 Demir’s quaternary carbon bond formation conditions and results:
isobutyraldehyde/b-nitrostyrene (3 : 1), 20 mol% proline/20 mol%
Schreiner’s thiourea, 36 h, 66% yield, 72% ee, as found in ref. 25b.
27 Related self-assembly based approaches characterize other reactions,
for an aldol reaction and an a-hydroxylation of aldehydes, see
respectively:(a) X. Company, G. Valero, L. Crovetto, A. Moyano and R.
Rios, Chem.–Eur. J., 2009, 15, 6564–6568; (b) S. L. Poe, A. R. Bogdan,
B. P. Mason, J. L. Steinbacher, S. M. Opalka and D. T. McQuade,
J. Org. Chem., 2009, 74, 1574–1580.
28 (a) Sulfonamides and sulfamides are already established as strong
hydrogen bond donors, see: A. A. Rodriguez, H. Yoo, J. W. Ziller and
K. J. Shea, Tetrahedron Lett., 2009, 50, 6830–6833; (b) O. Mammoliti, S.
Allasia, S. Dixon and J. D. Kilburn, Tetrahedron, 2009, 65, 2184–2195.
29 See for example: (a) C. G. Kokotosa and G. Kokotos, Adv. Synth.
Catal., 2009, 351, 1355–1362; (b) D. A. Yalalov, S. B. Tsogoeva and S.
Schmatz, Adv. Synth. Catal., 2006, 348, 826–832.
30 Depictions of nitro groups hydrogen bonding to thioureas are normally
drawn with both N–H groups of the thiourea and both oxygen atoms
of the nitro group coplanar and hydrogen bonded, for example see:
ref. 20 and ref. 31 Some debate remains in the literature, with a 2006
computational study suggesting a ‘one oxygen model’ (see ref. 29b)
and other groups having variously used this model (see ref. 6). Our
depicted and favored transition state model, synclinical I (Fig. 2), can
only accommodate a one oxygen activation model.
11 Ref. 6,10a,c,d,f report ≥98% ee for the reaction of isobutyraldehyde (2.0
to 3.7 equiv, 20 mol% cat. loading) with b-nitrostyrene.
12 For a 30 mol% example, see ref. 5.
13 To our knowledge the use of < 2.0 equiv of an a,a-branched aldehyde
has only been elaborated on by Yoshida, see Table 4 (only entry 2) of
ref. 10a.
31 S. J. Connon, Chem.–Eur. J., 2006, 12, 5418–5427.
32 Orbital activation of the nitroalkene alone, e.g. a nitroalkene, sulfamide
pair independent of the carboxylate moiety is unlikely. This is borne
out by performing the reaction in the absence of a base; the nitroalkene,
sulfamide pair would still exist, yet no product formation was noted
(Table 1, entry 11).
33 (a) A. Risaliti, M. Forchiassin and E. Valentin, Tetrahedron, 1968, 24,
1889–1898; (b) F. P. Colonna, E. Valentin, G. Pittaco and A. Risaliti,
Tetrahedron, 1973, 29, 3011–3017; (c) E. Valentin, G. Pittaco, F. P.
Colonna and A. Risaliti, Tetrahedron, 1974, 30, 2741–2746; (d) S.
Fabrissin, S. Fatutta and A. Risaliti, J. Chem. Soc., Perkin Trans. 1,
1981, 109–112.
14 (a) L.-q. Gua and G. Zhaoa, Adv. Synth. Catal., 2007, 349, 1629–1632;
(b) B. M. Choudary, Ch. V. Rajasekhar, G. G. Krishna and K. R. Reddy,
Synth. Commun., 2007, 37, 91–98.
15 A single a,a-substituted aldehyde was studied, isobutyraldehyde/b-
nitrostyrene (3 : 1), 5 mol% catalyst loading, 84 h, 71% yield, 85% ee,
see Supp Info (page S-6†) of: T. Mandal and C.-G. Zhao, Angew. Chem.,
Int. Ed., 2008, 47, 7714–7717.
16 For example, see: (a) M. Herna´ndez-Rodr´ıguez and E. Juaristi,
Tetrahedron, 2007, 63, 7673–7678; (b) G. M. Kyne, M. E. Light, M. B.
Hursthouse, J. de Mendoza and J. D. Kilburn, J. Chem. Soc., Perkin
Trans. 1, 2001, 1258–1263; (c) B. C. Hamann, N. R. Branda and J.
Rebek, Jr., Tetrahedron Lett., 1993, 34, 6837–6840.
34 D. Seebach and J. Golin´ski, Helv. Chim. Acta, 1981, 64, 1413–1423.
56 | Org. Biomol. Chem., 2011, 9, 52–56
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