Noncovalent bifunctional organocatalysts: Powerful tools for contiguous quaternary-tertiary stereogenic carbon formation, scope, and origin of enantioselectivity

Article abstract of DOI:10.1002/chem.201103005

Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α-branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α-iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96-99 % ee is observed. Using racemic α-branched aldehydes, two contiguous (quaternary-tertiary) stereogenic centers can be formed in high diastereo- and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2 equiv of the aldehyde, a 5.0 mol % loading of each catalyst component, for example, O-tBu-L-threonine (O-tBu-L-Thr), sulfamide, DMAP or O-tBu-L-Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde (7) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product (8) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system's exceptionality: an alternative hydrogen bond motif for the donor-acceptor pair than currently suggested for non-assembled catalysts. Noncovalent by nature: Commercially available building blocks allow in situ formation of bifunctional organocatalysts for the enantioselective formation of quaternary carbons (see scheme). This new catalyst approach is general in nature and the catalyst platform is readily adaptable. Copyright

Full text of DOI:10.1002/chem.201103005

DOI: 10.1002/chem.201103005
Noncovalent Bifunctional Organocatalysts: Powerful Tools for Contiguous
Quaternary-Tertiary Stereogenic Carbon Formation, Scope, and Origin of
Enantioselectivity
Thomas C. Nugent,* Abdul Sadiq, Ahtaram Bibi, Thomas Heine, Lei Liu Zeonjuk,
Nina Vankova, and Bassem S. Bassil[a]
Abstract: Relying on the assembly of
commercially available catalyst build-
ing blocks, highly stereocontrolled qua-
ternary carbon (all carbon substituted)
formation has been achieved with un-
matched substrate diversity. For exam-
ple, the in situ assembly of a tricompo-
nent catalyst system allows a-branched
aldehyde addition to nitroalkene or
maleimide electrophiles (Michael prod-
ucts), while addition to an a-iminoester
affords Mannich reaction products.
Very good yields are observed and for
fifteen of the eighteen examples 96–
99% ee is observed. Using racemic a-
branched aldehydes, two contiguous
(quaternary–tertiary) stereogenic cen-
ters can be formed in high diastereo-
and enantiomeric excess (eight exam-
ples) via an efficient in situ dynamic ki-
netic resolution, solving a known short-
coming for maleimide electrophiles in
particular. The method is of practical
value, requiring only 1.2 equiv of the
aldehyde, a 5.0 mol% loading of each
catalyst component, for example, O-
tBu-l-threonine (O-tBu-l-Thr), sulfa-
mide, DMAP or O-tBu-l-Thr, KOH,
and room temperature reactions. As a
highlight, the first demonstration of
ethylisovaleraldehyde (7) addition is
disclosed, providing the most congested
quaternary stereogenic carbon contain-
ing succinimide product (8) known to
date. Finally, mechanistic insight, via
DFT calculations, support a noncova-
lent assembly of the catalyst compo-
nents into a bifunctional catalyst, cor-
rectly predict two levels of product ste-
reoselectivity, and suggest the origin of
the tricomponent catalyst systemꢀs ex-
ceptionality: an alternative hydrogen
bond motif for the donor-acceptor pair
than currently suggested for non-as-
sembled catalysts.
Keywords: computational chemis-
try · maleimide · Mannich reaction ·
organocatalysis · quaternary carbon
Introduction
lysts has ensued, producing more complex organocatalysts
that strongly outperform amino acids regarding starting ma-
terial stoichiometry, catalyst loading, reaction time, yield,
and stereocontrol.[3] Yet single amino acids remain appeal-
ing,[4–6] especially so because they are commercially avail-
able, diverse, and require no synthesis.
The high selectivities of enzymes are generally attributed to
their folded and coiled protein architectures which impose
pin point noncovalent attractive and repulsive forces, while
also exploiting temporary (activating) covalent bonds, to
control the size, trajectory, facial approach, and conforma-
tion of reacting chemical partners. In recent years, chemists
have been mimicking these control mechanisms, albeit with
simple organic molecules lacking the atom inefficient scaf-
folds of natureꢀs catalysts. Using organocatalysts they have
shown: expanded substrate scope, greater reaction diversity,
and at times chemical selectivities on par with enzymes.[1]
The field of organocatalysis was reinvigorated, in large
part, by the examination of simple single amino acids over
ten years ago.[2] Since then, a decade of tailor designed cata-
Here we show that single amino acids have regained their
status as the best performing catalysts, with rare exception,
for the outlined Michael and Mannich reactions. To accom-
plish this we have augmented the natural attributes of
amino acids by selectively binding their carboxylate moiety,
in situ, to a hydrogen-bond donor (Scheme 1). The resulting
bifunctional catalyst has a catalytically active primary amine
and hydrogen bond donor site for the respective activation
of a carbonyl and an electrophile. This approach represents
a rare example of a highly efficient catalyst relying on the
self-assembly of purely organic components to permit the
higher ordered task of a conventional (covalently formed)
bifunctional organocatalyst. Finally, the simplicity and
known availability of the catalyst building blocks used here
raises the question of whether these or similar systems were
among precursor catalysts to enzymes, enabling increased
molecular diversity on a prebiotic earth.[7]
[a] Prof. Dr. T. C. Nugent, A. Sadiq, A. Bibi, Prof. Dr. T. Heine,
L. L. Zeonjuk, Dr. N. Vankova, Dr. B. S. Bassil
School of Engineering & Science
Jacobs University Bremen
Campus Ring 1, 28759 Bremen (Germany)
Fax : (+49)421-200-3229
E-mail: t.nugent@jacobs-university.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103005.
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FULL PAPER
and Et3N. Holding the amino acid (O-tBu-l-threonine) and
hydrogen-bond donor (sulfamide) constant, DMAP was also
found to be superior to common alkali hydroxides (Table 1,
entries 1–3 and Supporting Information). Furthermore, for
these tricomponent catalyst systems, the superior qualities
of the sulfamide hydrogen-bond donor have been reaf-
firmed. For example, the known hydrogen-bond donors
urea, thiourea, and Schreinerꢀs thiourea (Ar=-3,5-(CF3)2-
phenyl), can approach the usefulness of sulfamide, but pro-
vide lower yield and/or ee (compare entry 1 to 4–6); while
previously uninvestigated hydrogen bond donors (entries 7–
13) have proven to be less effective but show potential for
future exploitation, for example, salicylic amide enables an
extremely fast reaction (entry 13). For an extensive list of all
examined hydrogen-bond donors, see the Supporting Infor-
mation. Examination of the corresponding bicomponent cat-
alyst systems, that is, without the presence of a hydrogen-
bond donor, resulted in reduced yields and ee values
(Table 1, entries 14–17). Finally, when the catalyst system is
reduced to O-tBu-l-Thr alone (entry 18), only starting mate-
rial is observed after the extended reaction time of 18 h. In
brief, the catalyst system of O-tBu-l-Thr, sulfamide, DMAP
remains the best currently known for the addition of a
broad range of a-branched aldehydes to aryl or alkyl substi-
tuted-b-nitroalkenes based on all measurable parameters,
Scheme 1. Assembly based bifunctional catalyst concept.
Results and Discussion
Quaternary carbon bond formation remains formidable.[8] It
is consequently unsurprising that a limited number of a-
branched carbonyl additions, versus unbranched carbonyl
additions, have been reported. The challenge, as seen from a
broader context, is the lack of organocatalytic examples
with practical reaction conditions regarding natural product
or pharmaceutical drug applica-
tions. To address this, an across-
the-board multi-parameter im-
provement in starting material
stoichiometries, catalyst loading
(turn-over number and frequen-
cy implicit), and reaction time,
with excellent reaction product
profiles, is required. Here we
have come one step closer to
this idealized goal.
Table 1. Nitroalkene additions: expanded catalyst system investigations.
Entry
Catalyst system: O-tBu-l-Thr (5 mol%) + additive(s)
base (5 mol%)
t [h]
Yield [%][a]
ee [%][b]
HBD[c] (5 mol%)
1
2
3
DMAP
LiOH
KOH
7
5
4
98
>99
>99
98
96
94
In a recent communication
we reported the addition of a-
branched aldehydes to aryl or
4
5
6
DMAP
DMAP
DMAP
7
7
3
23
88[11]
88[11]
94
60
alkyl
substituted-b-nitroal-
kenes.[9,10] Here we show the
ease of fine tuning the catalyst
system for new reaction types,
and use DFT calculations to
elicit the first understanding for
the synergy arising when com-
bining an amino acid, a hydro-
gen-bond donor, and a base for
catalysis.
100
7
8
DMAP
KOH
7
7
4
98
80
80
9
10
DMAP
KOH
7
7
48
93
81
79
11
12
13
DMAP
KOH
7
6
2
24
100
98
90
87
65
KOH[d]
Table 1 details an expanded
catalyst study of the model Mi-
chael reaction, isobutyralde-
hyde addition to trans-b-nitro-
styrene. We previously identi-
fied DMAP as superior to imi-
dazole, DABCO, DBU, N-
14
15
16
17
18
DMAP
LiOH
LiOH[d]
KOH
–
–
–
–
–
–
7
7
7
7
8
86
92
91
91
–
60
76
67
<1
18
[a] HPLC area% yields. [b] Determined by chiral HPLC analysis (OD-H chiral column). [c] hydrogen bond
iPr2NEt, donor (HBD). [d] 10 mol% used.
methylmorpholine,
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T. C. Nugent et al.
for example, catalyst loading, starting material stoichiome-
try, and product profile.[9]
donor essentially shutdown the reaction, for example, the bi-
component catalyst systems of O-tBu-l-Thr, DMAP or O-
tBu-l-Thr, KOH provided <5 area% and <15 area%
(HPLC), respectively, of product 3a after 6 h (the optimal
reaction time). In conclusion, for Mannich product forma-
tion, the only synthetically viable catalyst system is: O-tBu-
l-Thr, sulfamide, DMAP.
Despite the vast number of organocatalyzed Mannich re-
actions reported to date,[12] scant attention has been given to
those producing a quaternary carbon in the b-amino alde-
hyde product.[13] Table 2 provides a summary of our Man-
nich reaction products 3a–d between a-iminoethyl glyoxa-
late (2) and two symmetrical (achiral) and two unsymmetri-
cal (racemic) a-branched aldehydes. Using the tricomponent
catalyst system (O-tBu-l-Thr, sulfamide, DMAP) a syntheti-
cally useful aldehyde stoichiometry (1.2 equiv) could be re-
alized with the lowest reported catalyst loading (5.0 mol%)
and short reaction times (6 or 12 h). Entries 1, 2, and 4
(Table 2) delineate the best current product profiles, albeit
3d is a new compound and reported here for the first time.
Barbas and co-workers, who pioneered this and many other
organocatalyzed reactions, reported a more favorable prod-
uct profile for 3c[14] compared to our data (Table 2, entry 3).
Unlike the other reactions detailed in this manuscript, all
Mannich reactions required the addition of 5 ꢂ molecular
sieves.[15]
It is instructive to note that replacing sulfamide with thio-
urea, that is, using O-tBu-l-Thr, thiourea, DMAP, resulted
in gross by-product formation, ~40 area% (HPLC), and
lower product ee (92%) for 3a. Similar low yields resulted
when holding O-tBu-l-Thr and sulfamide constant, but ex-
changing DMAP with LiOH or KOH, respectively, provid-
ing 80% and 85% ee for Mannich product 3a. Finally, ex-
amination of catalyst systems lacking a hydrogen-bond
The addition of in situ generated enamines to maleimide
electrophiles allows access to chiral pyrrolidinediones (succi-
nimides). These products, and the reduction products there-
of, chiral pyrrolidines and pyrrolidinones (d-lactams),[16] are
core structural units found within natural products and some
clinical drug candidates.[17,18] When the nucleophilic carbonyl
(enamine) is an a-branched aldehyde, increased molecular
complexity is featured in the succinimide product, that is, an
all carbon substituted quaternary carbon is present. Cordova
and co-workers were the first to demonstrate this possibility
when he added isobutyraldehyde to N-phenylmaleimide, but
the yield and ee were low.[19] In 2010 three more reports ap-
peared, each employing a monothiourea of trans-1,2-diami-
nocyclohexane as the organocatalyst.[20] In general, these re-
ports expanded the substrate scope while providing very
good to excellent yields and ee values, but the aldehyde stoi-
chiometries (2–10 equiv) and catalyst loadings (5–20 mol%)
can be improved. Additionally, when forming contiguous
quaternary–tertiary stereogenic centers, a glaring lack of
diastereocontrol was noted for the current methods and
higher catalyst loadings were required.[21] Here we show that
this problem has been largely solved and do so with the
greater substrate diversity.
Building on our catalyst
knowledge from the examina-
tion of nitroalkenes (Table 1)
Table 2. Quaternary carbon containing Mannich products of a-iminoethyl glyoxalate.[a]
and
Mannich
precursors
(Table 2), we were surprised to
find not one, but several reac-
tion conditions allowing excel-
lent product profiles, for 6a,
when adding isobutyraldehyde
to N-phenylmaleimide (Table 3,
entries 1–4).[22] For example, the
tricomponent catalyst system of
O-tBu-l-Thr (5 mol%), thiour-
ea (5 mol%), DMAP (5 mol%)
proved to be very useful
(Table 3, entry 3), while the
same catalyst system was
deemed to be of lower value
when examining nitroalkenes,
and of no practical value when
examining the a-iminoethyl
glyoxalate electrophile (Man-
nich reaction). In the end, suc-
cinimide product formation was
found to be optimal when using
one of the following two cata-
lyst systems: i) O-tBu-l-Thr
Entry
1
Product
Aldehyde (equiv)
1.2
T [8C]
t [h]
Yield [%][b]
92
d.r.[c]
ee [%][d]
23
6
–
97
2
3
1.2
1.5
23
0
6
72
84
–
96
12
3:1
79/84[e]
4
1.2
0
12
90
4:1
99/99[e]
[a] Aldehyde (0.6 mmol), imine (0.5 mmol), CH2Cl2 (1.0m), O-tBu-l-Thr (5 mol%), DMAP (5 mol%), sulfa-
mide (5 mol%), 5 ꢂM.S. (50 mg). [b] Isolated yield. [c] Determined by chiral HPLC analysis (AS-H column)
of the crude product. [d] Determined by chiral HPLC analysis (AS-H column) after silica gel purification.
[e] ee of major diastereomer/ee of minor diastereomer.
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Noncovalent Bifunctional Organocatalysts
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Table 3. Quaternary carbon containing succinimide products.[a]
Entry
Method
Product
t [h]
Yield [%][b]
d.r.[c]
–
ee [%][d]
1
2
3
4
A
B
C
D
4
6
5
14
96
91
81
93
>99
96
94
98
5
B
5
6
94
–
–
97
6
A
96
>99
7
8
B
B
16
11
93
86
–
–
97
99
9
B
B
20
20
77
80
–
–
97
96
10
11
12
13
A
B
C
10
24
24
86
82
81
>99:1
>99:1
>99:1
94
92
92
14
15
A
B
4
20
89
84
96:4
93:7
>99
98
16
17
A
B
4
16
87
89
97:3
97:3
98
94
18
19
A
B
4
5
94
98
92:8
90:10
>99/>99[e]
>99/>99[e]
20
B
16
88
74:26
98/86[e]
[a] Reaction conditions: maleimide (1.0 mmol, 1.0 equiv), aldehyde (1.2 equiv), CH2Cl2 (2.0m), 238C. [b] Isolated yield data after column chromatogra-
phy. [c] Determined by chiral HPLC analysis on the crude reaction product.[25] [d] Determined by chiral HPLC analysis after silica gel purification. [e] ee
of major diastereomer/ee of minor diastereomer.
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T. C. Nugent et al.
(5 mol%), KOH (5 mol%) or ii) O-tBu-l-Thr (5 mol%),
sulfamide (5 mol%), DMAP (5 mol%), Table 3 (entries 1
and 2).[23] It is also noteworthy that l-isoleucine can replace
O-tBu-l-Thr and provided an excellent product profile,
albeit with a longer reaction time (Table 3, compare entry 4
with 1 and 2). Further note that the use of O-tBu-l-Thr
(5 mol%) alone resulted in recovered starting materials
after 18 h.
Many substrates are outlined in Table 3 and represent a
broad set of a-branched aldehyde additions to N-phenyl-
and N-benzylmaleimides. Compounds 6e, 6g, 6i, and 6j are
reported here for the first time. Taken in total, the product
profiles can be characterized as excelling, in particular, be-
cause of very good yields, short reaction times, and high ste-
reoselectivity, while only requiring 5 mol% of the catalyst
system and 1.2 equiv of the aldehyde. In particular en-
tries 11–20 are of far reaching consequence because they
demonstrate the first examples of excellent diastereocontrol,
a known shortcoming of this reaction which is now dis-
cussed.[21]
For the formation of two contiguous (quaternary–tertiary)
stereogenic centers, the addition of racemic a-substituted al-
dehydes is required, and high product d.r., and ee, is made
possible via an efficient in situ dynamic kinetic resolution.
For example hydratropaldehyde addition provided succini-
mide 6h (Table 3, entry 11) as one diastereomer in 86%
yield with 94% ee within 10 h (5 mol% catalyst loading), no
other catalyst system can achieve similar results.[24] Using a
less hindered a-branched aldehyde, substituent is an a-
benzyl derivative, an 89% yield of 6i was achieved with a
96:4 d.r. and >99% ee in 4 h (Table 3, entry 14). Examina-
tion of the same aldehyde with N-benzylmaleimide, instead
of N-phenylmaleimide, resulted in 6j with a 97:3 d.r.
(entry 16). Further reduction of the steric bulk of the larger
a-subsubstituent on the aldehyde starting material, for ex-
ample, as in product 6k (entry 18), led to very good d.r.
(92:8), with high yield (94%) and ee (>99%) within 4 h, ex-
ceeding the reported d.r. of 2:1.[20b] Finally, examination of
2-methylpentanal revealed a mediocre d.r. (74:26), nonethe-
less this ratio would be considered high when it is noted
that a methyl group has been differentiated from an n-
propyl moiety, and this represents an improvement over the
best reported d.r. of 1:1.[20b]
Scheme 2. Congested quaternary carbon formation: first demonstration
of 2-ethyl-3-methylbutanal (7) addition.
amples represent the most diverse set of a-branched alde-
hyde additions known.
In our opening communication on nitroalkenes,[9] we
speculated that a synclinal approach of the electrophile and
enamine best accounted for the observed diastereo- and
enantiocontrol. Here we have used DFT studies to obtain
greater insight into the complexes leading to product forma-
tion, and the unique role hydrogen bonding is playing in the
tricomponent catalyst system (O-tBu-l-Thr, sulfamide,
DMAP) versus potassium activation in the bicomponent cat-
alyst system (O-tBu-l-Thr, KOH). Those findings, discussed
shortly, support a synperiplaner approach of maleimide via
two critical, bridging, hydrogen bonds: oxygenmaleimide···H-
Nsulfamide and N-Hsulfamide···oxygencarboxylate (Scheme 3, bottom).
For the bicomponent system, O-tBu-l-Thr, KOH, a synclinal
approach was found to be optimal (Scheme 3, top). Regard-
ing the iminoester electrophile (Mannich reaction) it can be
speculated that a synclinal approach is favored (Scheme 4).
Importantly, these models (Schemes 3 and 4) support our
conclusions regarding the diastereo- and enantiocontrol for
both the maleimide and iminoester electrophiles, and the
stereochemistry has been corroborated by comparison with
earlier reported chiral HPLC data (see Supporting Informa-
tion). In the case of structure 6k (Table 3, entries 18 and
19), unambiguous relative and absolute stereochemistry was
established via X-ray crystallographic analysis (Figure 1).
Based on this larger body of stereochemical findings, we
have similarly assigned the stereochemistry for the six newly
identified compounds, 3d, 6e, 6g, 6i, 6j, and 8. Within the
context of this mechanistic discussion, it is noteworthy that
Barbas et al.[6b,e] and Yoshida et al.,[5] among others, have
meaningfully contributed to the conceptual development of
amino acid catalyzed reaction models, albeit for systems
without the intermediacy of a hydrogen-bond donor as
noted here (Schemes 3 and 4).
The above results demonstrate that quaternary carbons,
all carbon substituted, can be formed with relative ease, and
compounds 6c (entry 6) and 6h (entry 11) reveal that con-
gested quaternary carbons can be formed in high yield. Nev-
ertheless, to better appreciate the steric limitations of the
current method, we investigated the addition of ethylisova-
leraldehyde (7), a highly congested aldehyde (Scheme 2).
Under our standard reaction conditions no product was ob-
served, but solvent and temperature screening (see Support-
ing Information) showed 1,2-dimethoxyethane to be optimal
at 508C over 14 h, forming product 8 which was isolated in
diastereopure form in 74% yield (92% ee). Product 8 is sig-
nificant because it represents the most sterically crowded
succinimide formed to date. In summary, these combined ex-
To better appreciate the reaction pathways leading to the
above noted products, we simulated the reaction of hydra-
tropaldehyde with N-phenylmaleimide (Scheme 3). The suc-
cinimide product thereof, 6h, was chosen for two major rea-
sons: i) the product can be formed using three different cat-
alyst systems (Table 3, entries 11–13), consequently insight
into the nuances of each complex can be evaluated; and ii)
the model would have to predict two levels of stereoselectiv-
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Noncovalent Bifunctional Organocatalysts
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Scheme 3. DFT supported intermediates: correctly predict stereochemical outcome for hydratropaldehyde addition to maleimide.
complexes are local minima, relatively stable, and are the
key to understanding the chemical reactions that take place.
Consequently, they represent species in which the reacting
centers are in close proximity for appreciable amounts of
time and will govern the preferred stereochemical pathways.
The second step of the reaction is a straightforward bond
formation process, a chemical reaction transforming the
complex into the product.
Our computational study concentrates on step one, to un-
derstand the structure and stability of the complexes of re-
actants and catalyst, while step two, responsible for the reac-
tion rates, is the subject of a future study. The simulation of
multi-component assemblies is not trivial, and this work rep-
resents the first attempt to model these intricate systems. As
the quantitative description of hydrogen bonds is crucial for
this study, we employed density functional theory with em-
pirical corrections for London dispersion (BP86-D)[26] to-
gether with the all electron TZP basis as implemented in
the ADF code.[27] Free enthalpies have been calculated
using the harmonic approximation and solvent effects have
been accounted for using COSMO.[28]
Scheme 4. Postulated reaction intermediate: correctly predicts 2,6-dime-
thylhept-5-enal addition to an a-iminoester.
Assembly of the tricomponent catalyst system, O-tBu-l-
Thr, sulfamide, DMAP, is assumed to be facial. Experimen-
tally this is convincing because the catalyst components
readily dissolve but only when all three are present in equa-
molar quantities in the presence of the starting materials.
The tricomponent assembly itself, is calculated to be robust
by DFT (Supporting Information, Computational Sections 1
and 2). Accordingly, our study began by modeling trans en-
amine attack on maleimide with a Reenamine, Remaleimide facial
Figure 1. ORTEP diagram of (S,S)-6k, Table 3, (50% probability ellip-
soids): O-tBu-l-Thr, sulfamide, DMAP catalyst system.
ity, that is, the diastereo- and enantiocontrol imposed during
the carbon–carbon bond forming step.
approach (Scheme 3); and conversely with
a Sienamine,
The reaction can be thought of as working in two steps:
first, van der Waals complexes (complexes), where reactants
and catalyst are held together by temporary covalent bonds
(aldehyde activation to an enamine) and hydrogen bridges
(maleimide-to-hydrogen-bond donor and hydrogen bond
donor-to-carboxylate), are formed in the liquid phase. These
Remaleimide facial attack for the cis enamine. This is a reasona-
ble starting point because, if supported by DFT calculations,
it would: i) explain the diastereo- and enantioselectivity for
the major and minor products; ii) differentiate synclincal
from synperiplanar approaches; iii) account for the fate of
both the cis and trans enamines; and iv) support, or refute,
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T. C. Nugent et al.
the propensity of the maleimide electrophile to preorganize
(hydrogen bond) at the assembled catalystꢀs hydrogen bond
donor site (sulfamide).
Four low energy trans enamine complexes (A, B, C, D)
were identified, with relative energy differences (DG) of 0,
0.56, 1.03, and 1.50 kcalmolÀ1. All four complexes (Figure 2)
The three remaining, higher energy, complexes (B, C, D)
share a common conformational feature, the enamine and
threonineꢀs a- and b-carbons are in the same plane, but now
the carboxylate moiety is approximately perpendicular to
the Re face of the enamine. In response, the assembled sul-
famide component rotates by an equal degree, again align-
ing maleimide in a plane parallel to the Re face of the en-
amine, albeit at an increased carbon-carbon pre-bond form-
ing distance (3.42–3.51 ꢂ) for complexes B, C, D as com-
pared to complex A (3.20 ꢂ). In two of the complexes, B
and C, the OtBu group is essentially contiguous with the
plane containing the enamine, that is, no moiety blocks the
Si face of the enamine; while in complexes A and D the
OtBu group blocks the Si face. As found for complex A,
complexes B–D have a Reenamine, Remaleimide facial approach,
thus all four complexes (A–D) lead to the same major prod-
uct (S,R)-6h (Scheme 3). Finally, four cis enamine com-
plexes (analogous to complexes A–D, Figure 2) were addi-
tionally identified for the O-tBu-l-Thr, sulfamide, DMAP
catalyst system. Of those, the lowest energy cis complex was
4.34 kcalmolÀ1 greater in energy than trans enamine A
(Figure 2), making analysis of the cis enamines inconsequen-
tial, see Supporting Information (Computational Section 3,
Table S7).
It is noteworthy that these energy optimized complexes
always choose to participate in hydrogen bonding, and when
doing so, the catalystꢀs sulfamide component becomes the
preeminent handle regarding stereocontrol. In complexes
A–D the carboxylate–sulfamide unit is always directed to
the Re face of the enamine, and there it directs the Re face
of maleimide within bonding distance proximity of the en-
amine (Reenamine, Remaleimide approach). A Si face approach of
maleimide, that is, Reenamine, Simaleimide, is unattainable under
the organization of hydrogen bonding due to the over-
whelming steric impediment imposed by the N-phenyl
moiety of N-phenylmaleimide. These findings provide a con-
ceptual basis for understanding the very high stereoselectiv-
ity (>99:1 d.r., 96:4 e.r.) noted for this reaction.
Figure 2. Hydratropaldehyde addition to maleimide, complexes for 6h
(Table 3, entry 12): O-tBu-l-Thr, sulfamide, DMAP catalyst system.
reveal a Reenamine, Remaleimide facial attack and are enabled by
two critical, bridging, hydrogen bonds.[29] For visualization
purposes, the protonated DMAP counter ion is excluded
from the drawn complexes in Figure 2, but all conclusions
were reached after thorough examination of the three di-
mensional representations containing DMAP. Computation-
al snapshots including DMAP can be found in the Support-
ing Information (Computational Section 3, Figure S3). Fur-
thermore, all unmarked hydrogen bonds (Figures 2 and 4)
were found to be >2.90 ꢂ.
An open question is the viability of a purely steric based
reaction pathway, that is, the random approach of malei-
mide, without the aid of hydrogen bonding, onto the enam-
ine. Entropically this reaction pathway is less competitive
with product formation via preorganization with hydrogen
bonding. Regardless, it is important to model this possibility.
For this analysis, complexes A–D (Figure 2) are of little
value, even though, for example, complexes B and C have
an accessible Si enamine face, because they represent inter-
mediates that already contain a highly integrated maleimide
molecule. A more realistic approach is to consider the same
complexes, albeit modeled without the presence of malei-
mide, and then consider the facial approach of maleimide
on the enamine without the aid of hydrogen bonding. In the
event, four energy optimized trans enamine complexes (hy-
dratropaldehyde, O-tBu-l-Thr, sulfamide, DMAP) were ob-
served. Of those, the lowest energy complex (E), Figure 3,
has a relative energy difference (DG) with the next lowest
complex of 11.3 kcalmolÀ1, see Supporting Information
The lowest energy complex (A) displays a linear arrange-
ment of threonineꢀs carboxylate, a-carbon, and nitrogen,
with the enamine (aldehyde) atoms (Figure 2, A). This con-
formation, which is stabilized by a 2.15 ꢂ intramolecular hy-
drogen bond (not marked), N-Henamine···OC(O)Rcarboxylate, jet-
tisons the b-carbon of threonine to the Si face of the enam-
ine where the OtBu group blocks this face.
Because the assembled sulfamide engages in hydrogen
bonding with only one of the carboxylate oxygens,[30] it has
the rotational freedom to place its remaining NH2 hydrogen
bonding unit in a plane parallel to the unoccupied Re face
of the enamine (Figure 2, A). Here, maleimide participates
in hydrogen bond donor–acceptor pairing with the sulfamide
NH2 group via
a convincingly robust hydrogen bond
(1.85 ꢂ). This pairing has the consequence of placing the
electrophilic carbon of maleimide within bonding distance
proximity (3.20 ꢂ) of the nucleophilic enamine carbon
(Figure 2, complex A).
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Noncovalent Bifunctional Organocatalysts
FULL PAPER
tions support hydrogen bond preorganization of maleimide
at the assembled catalyst, and consequently the origin of the
high stereoselectivity of (S,R)-6h can be better appreciated.
With a plausible reaction pathway clarified, it is important
to note the mode of hydrogen bonding, catalyst to electro-
phile, departs from those depicted for non-assembled bi-
functional catalysts. For example, the O-tBu-l-Thr, sulfa-
mide, DMAP catalyst system used here employs one resil-
ient hydrogen bond (Figure 2, complex A, 1.85 ꢂ) to preor-
ganize the maleimide electrophile to the hydrogen bond
donor catalyst site; while non-assembled catalysts, to the
best of our knowledge, are depicted as anchoring electro-
philes via two critical hydrogen bonds.[34] These divergences
are conceivable because sulfamide (Figure 4) is a new hy-
drogen-bond donor platform, and its structure departs from
the traditionally used hydrogen bond donors, for example,
ureas and thioureas. For example, in thiourea all atoms are
essentially coplanar, see Supporting Information (Computa-
tional Sections 2 and 4, respectively, Figures S2 and S4), re-
sulting in a hydrogen bond donor with both NH2 units in the
same plane (Figure 4). By contrast, sulfamideꢀs NH2 groups
are in parallel planes to one another. These geometric reali-
ties permit fundamentally different transition states to exist
for sulfamide versus thiourea.
Figure 3. Steric based model, low energy complex E: hydratropaldehyde,
O-tBu-l-Thr, sulfamide, DMAP.
(Computation Section 7, Table S32). This extremely large
energy difference focuses the analysis to complex E alone
(Figure 3);[31] its Re enamine face is completely blocked by
the protonated DMAP counter ion, while the Si face (enam-
ine) is exposed. This leaves the Si enamine face open to
attack by maleimide, but the two possible approaches,
Sienamine, Remaleimide and Sienamine, Simaleimide, do not lead to the
major product, (S,R)-6h, which is formed in good yield
(82%) and with high stereoselectivity (>99:1 d.r., 92% ee).
Finally, it is possible that a steric based reaction pathway
could occur via a complex without sulfamide, that is, malei-
mide attack on a complex of only hydratropaldehyde, O-
tBu-l-Thr, DMAP (no bound sulfamide). This is less proba-
ble for two reasons: i) sulfamide is expected to have a high
binding constant for the carboxylate,[32] suggesting that sulfa-
mide will more often be bound, for example, as in complex
E (Figure 3), than not, and ii) experimentally, there is little
support for this hypothesis. Regarding the last point, per-
forming the reaction, which normally takes 24 h (Table 3,
entry 12), without sulfamide provided 6h in 29 area% yield
(HPLC), 4:1 d.r., and 92% ee, over 24 h.[33]
In Figure 2, the O-tBu-l-Thr, sulfamide, DMAPcatalyzed
reaction is depicted in its four lowest energy complexes. Of
note, the diagonal hydrogens of sulfamide always form the
two critical (1.78–2.08 ꢂ) hydrogen bonds required to
bridge maleimide to the catalystꢀs carboxylate moiety.[29,35]
When O-tBu-l-Thr, thiourea, DMAP, is modeled[36] a differ-
ent pattern is observed, here the two critical, bridging, hy-
drogens of thiourea come from the same NH2 unit (Figure 4,
compare thiourea F and sulfamide A complexes).[37]
A
closer comparison of these two complexes additionally re-
veals a threonine conformational difference between the
two minima. When sulfamide is present, a linear arrange-
ment of the enamine and carboxylate is preferred, as dis-
cussed earlier. The hydrogen bridging required for this con-
formation of O-tBu-l-Thr is not capable of being replicated
by thiourea, based on its preferred hydrogen bonding motif
in complex F (Figure 4).[36] Finally, it should be noted that a
third hydrogen bond is observed for all of the sulfamide and
thiourea complexes (Figures 2 and 4), but at 2.31–2.46 ꢂ are
expected to play a supportive, but not “anchoring”, role.
It was demonstrated experimentally that O-tBu-l-Thr, sul-
famide, DMAP, was optimal for nitroalkene additions
(Table 1), while this catalyst system was the only useful one
for the Mannich reactions (Table 2). By contrast, additions
to maleimide electrophiles were faster when using the bi-
component catalyst system of O-tBu-l-Thr, KOH (Table 3,
compare entries 11–13). A persuasive argument, for why
this might be, is noted when comparing the low energy cal-
culated complexes of Figure 4. For example, under potassi-
um cation activation, complex G, the synclinal complex is
noteworthy for minimizing the steric repulsion between the
maleimide N-phenyl and the hydratropaldehyde phenyl moi-
eties (Scheme 3, top complex). A likely consequence is the
The above findings can be summarized as follows. A
Reenamine, Remaleimide reaction pathway, via a hydrogen bond
donor–acceptor pair (maleimide···sulfamide, Figure 2), over-
comes the entropic disadvantage of maleimideꢀs random ap-
proach (steric model) onto the enamine, selectively forming
(S,R)-6h (Scheme 3). The high propensity for the Reenamine
,
Remaleimide facial approach is in complete agreement, after the
fact, with the stereochemical data. For example, experimen-
tally hydratropaldehyde adds to maleimide providing only
one diastereomer (>99:1 d.r.). This fact rules out the possi-
bility of a Reenamine, Simaleimide or a Sienamine, Remaleimide facial ap-
proach, but the enantiomeric ratio, at 96:4, does suggest that
the minor enantiomer, (R,S)-6h, may be forming via com-
plex E (Figure 3) using the non-competitive steric based ap-
proach (Sienamine, Simaleimide). In summary, the DFT calcula-
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T. C. Nugent et al.
These combined results dem-
onstrate the conformational
relay effects imposed on the
amino acid, sthe assembled cat-
alyst, in the presence of a thio-
urea based catalyst component
(approximately two dimension-
al) versus a sulfamide catalyst
component (three dimensional)
versus
a
potassium cation
(spherical), and the consequen-
ces on the trajectory of the ap-
proaching electrophile. When
only considering the maleimide
additions, all three catalyst sys-
tems enable similar product ste-
reochemistry, albeit via clearly
different complexes (Figure 4).
These differences alone make it
easier to appreciate why differ-
ent reactions, with dissimilar
electrophiles, might favor one
of these catalyst systems over
the other two. An extreme ex-
ample is the Mannich reaction
(Table 2), where only the mild
tricomponent catalyst system of
O-tBu-l-Thr, sulfamide, DMAP
can be used to catalyze practi-
cal product formation. In total,
these experimental and compu-
tational studies have provided a
foundation for how these newly
Figure 4. Hydratropaldehyde addition to N-phenylmaleimide: local minima for purely organic vs metal activat-
ed catalyst systems.
noted, and significantly shorter, carbon–carbon pre-bond
forming distance of 2.77 ꢂ under potassium activation (com-
plex G)[38] versus sulfamide activation (3.20 ꢂ, complex A,
Figure 4 and Scheme 3, bottom complex). The more com-
pact potassium complex may be contributing to the in-
creased rate of reaction (10 h versus 24 h, Table 3 entries 11
and 12). This line of reasoning is perhaps strengthened by
the fact that formation of succinimide product 6k (Table 3)
requires the same reaction time for both the bicomponent
(entry 18, 4 h) and tricomponent (entry 19, 5 h) catalyst sys-
tems. In this instance, the above noted steric interaction
(phenyl-on-phenyl for 6h, Scheme 3, bottom complex) is re-
duced to phenyl-on-linear alkyl in 6k. The sulfamide reac-
tion complex, for formation of 6k (not shown), may conse-
identified catalyst systems might be activating and preorgan-
izing the starting materials. The concept insights gained here
can now be leveraged to exploit alternative catalyst compo-
nents and different reaction types.
Conclusion
The introduction of self-assembled organocatalysts has
lagged behind the use of covalently formed organocatalysts,
and efficient examples thereof are rare. Here we have pro-
vided a new general direction for their further use and ex-
ploitation, while simultaneously addressing a challenge in
organic synthesis: stereogenic quaternary carbon formation.
Tricomponent and bicomponent catalyst systems based on
amino acids have been described, with the former requiring
the addition of a hydrogen bond donor and DMAP, while
the latter only requires the addition of KOH. This flexible
catalyst platform, currently only based on commercially
available materials, has permitted straight forward reaction
fine tuning, unprecedented substrate diversity, and excellent
stereoselectivity. For example, O-tBu-l-Thr, sulfamide,
DMAP is optimal for nitroalkene Michael reactions, while it
is necessary for Mannich product formation. For maleimide
À
quently have a shortened carbon carbon pre-bond forming
distance that is similar to that found in the corresponding
K+ complex for 6k. It should be noted that unlike the or-
ganic based tricomponent catalyst system calculations, the
bicomponent system (potassium cation present) required in-
clusion of the solvent parameters, in particular, to differenti-
ate the relative energy differences between the cis and trans
enamine complexes, see Supporting Information (Computa-
tional Section 5, Figure S5 and Table S20, and General De-
tails of the Computational Section).
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Noncovalent Bifunctional Organocatalysts
FULL PAPER
Michael reactions, O-tBu-l-Thr, KOH is optimal because of
shortened reaction times. For the DFT calculated maleimide
example, we have elaborated on how metal (potassium)
cation activation can be replaced by a purely organic com-
pound, for example, sulfamide, via two critical bridging hy-
drogen bonds. For example, in the lowest energy sulfamide
complex (Figure 4, complex A), the oxygenmaleimide····H-
Nsulfamide hydrogen bond holds maleimide within bonding dis-
tance proximity of the enamine by a convincingly strong,
lone, hydrogen bond (1.85 ꢂ). This departs from the hydro-
gen bond preorganization generally espoused for non-assem-
bled catalysts with thioureas, and is perhaps the basis for the
exceptional performance of the catalysts noted here. In clos-
ing, these results represent the first evidence for the likely
reaction pathway enabled by these self-assembled catalysts.
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Experimental Section
[6] For threonine examples, see a) C. Wu, X. Fu, S. Li, Eur. J. Org.
Chem. 2011, 1291–1299; b) The text and supporting information
(specifically pages S2–3) of: H. Uehara, C. F. Barbas III, Angew.
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2007, 129, 288–289.
Extensive details can be found in the Supporting Information, which is
divided into three sections: Experimental Section (19 pages of experi-
mental descriptions, 42 pages of HPLC and NMR data), Computational
Section (64 pages), and an X-ray Section (4 pages).
CCDC-840712 (6k) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
General procedure for enantioselective Mannich reactions: To a screw
cap vial was added 50 mg of powdered molecular sieves (5 ꢂ), O-tBu-l-
Thr (4.4 mg, 0.025 mmol, 5.0 mol%), sulfamide (2.40 mg, 0.025 mmol,
5.0 mol%), and DMAP (3.05 mg, 0.025 mmol, 5.0 mol%). To this mix-
ture was added dichloromethane (1.0m, 0.50 mL), N-p-methoxyphenyl
protected a-imino ethyl glyoxylate (1.00 equiv, 0.5 mmol, 103 mg), and
the aldehyde (1.2 equiv, 0.6 mmol). This mixture was stirred at room tem-
perature. Once complete, the reactions were quenched by adding water
(15 mL) and the resulting mixture was extracted with dichloromethane
(3ꢃ15 mL). The combined organic extracts were dried over sodium sul-
fate, filtered, and evaporated under reduced pressure. The crude reaction
mixture, without delay, was purified by column chromatography (EtOAc/
pet ether) and the chromatographic and spectroscopic data collected im-
mediately for these semi-labile Mannich products.
[7] a) J. L. Bada, A. Lazcano, Science 2003, 300, 745–746; b) S. L.
Miller, Science 1953, 117, 528–529.
[8] a) A. R. Brown, W.-H. Kuo, E. N. Jacobsen, J. Am. Chem. Soc. 2010,
132, 9286–9288; b) O. Riant, J. Hannedouche, Org. Biomol. Chem.
2007, 5, 873–888; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J.
Org. Chem. 2007, 5969–5994; d) B. M. Trost, C. Jiang, Synthesis
2006, 369–396; e) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005,
347, 1473–1482.
[9] T. C. Nugent, M. Shoaib, A. Shoaib, Org. Biomol. Chem. 2011, 9,
52–56.
[10] Alkyl substituted nitroalkenes are particularly challenging sub-
strates. For the sake of clarity, in ref. [9] (Table 2, entries 9 and 10),
the results reported for 2-isobutyl-nitroethene and 2-styryl-nitroe-
thene required a 5 mol% catalyst loading (O-tBu-l-Thr, sulfamide,
and DMAP) and 1.2 equiv of the aldehyde, i.e., the normal reaction
conditions were used for the just noted substrates.
[11] In our initial report, ref. [9], we incorrectly stated that urea and thi-
ourea provided an 80% ee, further experimentation has repeatedly
shown an 88% ee.
[12] For reviews focusing on Mannich reactions, see: a) J. M. M. Verkade,
L. J. C. van Hemert, P. J. L. M. Quaedflieg, F. P. J. T. Rutjes, Chem.
Soc. Rev. 2008, 37, 29–41; b) A. Ting, S. E. Schaus, Eur. J. Org.
Chem. 2007, 5797–5815.
[13] a) H. Zhang, Y. Chuan, Z. Li, Y. Peng, Adv. Synth. Catal. 2009, 351,
2288–2294; b) M. Pouliquen, J. Blanchet, M.-C. Lasne, J. Rouden,
Org. Lett. 2008, 10, 1029–1032; c) H. Zhang, S. Mitsumori, N.
Utsumi, M. Imai, N. Garcia-Delgado, M. Mifsud, K. Albertshofer,
P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas III, J. Am.
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Barbas III, Org. Lett. 2004, 6, 2507–2510.
General procedure for the enantioselective addition of aldehydes to mal-
eimides: To a screw cap vial was added O-tBu-l-Thr (8.75 mg, 0.05 mmol,
5.0 mol%), sulfamide (4.80 mg, 0.05 mmol, 5.0 mol%), and DMAP
(6.10 mg, 0.05 mmol, 5.0 mol%). To this mixture was added CH2Cl2
(2.0m, 0.50 mL) and the aldehyde (1.20 equiv, 1.20 mmol). This mixture
was stirred for 2 min at room temperature. N-phenylmaleimide or N-ben-
zylmaleimide (1.00 equiv, 1.00 mmol), was then added and the reaction
mixture became homogenous, regardless of the substrate examined. At
complete conversion, the reaction mixture was diluted with H2O (15 mL)
and extracted with dichloromethane (3ꢃ15 mL). The combined organic
extracts were dried (Na2SO4), filtered, and the solvent removed (rotary
evaporator). The crude product was purified by column chromatography
and the yield obtained.
Acknowledgements
[14] See ref. [13d], compound 3c was produced in 66% yield, 5.7:1 d.r.,
86% ee, in 6 h, using a 30 mol% proline catalyst loading.
[15] See footnote [a] of Table 2 and the Supporting Information for de-
tails.
[16] For the regioselective reduction of succinimides to lactams, see for
example; a) K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang,
We are grateful for financial support from Jacobs University Bremen.
T.C.N., A.S., and A.B. thank the HEC of Pakistan, and T.H., L.L.Z., and
N.V. thank the European Commission (REA-FP7-MC-IAPPQUASINA-
NO, GA 251149). This work has been performed within the graduate
program of Nanomolecular Science.
Chem. Eur. J. 2012, 18, 4088 – 4098
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T. C. Nugent et al.
Angew. Chem. 2010, 122, 3101–3104; Angew. Chem. Int. Ed. 2010,
49, 3037–3040; b) Y. Vo- Hoang, C. Gasse, M. Vidal, C. Garbay, H.
Galon, Tetrahedron Lett. 2004, 45, 3603–3605.
[30] When reactants are not included, hydrogen-bond donors based on
ureas are well known to form two hydrogen bonds, one to each of
the carboxylate oxygens. Sulfamide appears to prefer one hydrogen
bond, see Supporting Information, Computational Section, compare
snapshots in Figure S1 and S2 of Sections 1 and 2. When chemically
reactive starting materials are added, e.g., an aldehyde and malei-
mide, the resulting low energy reaction complexes, for both thiourea
and sulfamide, show only one critical (1.78–1.86 ꢂ) hydrogen bond
to the carboxylate.
[31] As an aside, complex E may be the overwhelmingly preferred low
energy complex, in part, because of a secondary stabilizing effect
marked by a dipole-dipole attractive force (3.30 ꢂ distance between
the b-carbon of the enamine and the indicated electron deficient
carbon on the pyridium ring, Figure 3).
[32] T. R. Kelly, M. H. Kim, J. Am. Chem. Soc. 1994, 116, 7072–7080.
[33] See the Supporting Information, Computational Section: Discussion
A: Steric model considerations (there we explain why the same
major product is formed in the absence or presence of sulfamide)
and Section 6.
[34] We are unaware of any computational studies modeling the malei-
mide reactions shown here. For a computational study with a nitro-
alkene depicting two, critical (<2.2 ꢂ) hydrogen bonds, only to the
electrophile (non-assembled catalyst), see: D. A. Yalalov, S. B. Tso-
goeva, S. Schmatz, Adv. Synth. Catal. 2006, 348, 826–832.
[35] In Figure 2, seven of the eight critical hydrogen bonds range from
1.78–2.08 ꢂ, the remaining hydrogen bond, at 2.39 ꢂ, is an outlier, it
is noted in complex B.
[36] Noted in the Supporting Information, but not discussed in the main
text, two more low energy thiourea complexes were identified. The
3.88 kcalmolÀ1 higher energy complex used the same hydrogen
bonding pattern as the lowest energy complex F (Figure 4). The re-
maining complex, which was 3.16 kcalmolÀ1 higher in energy, was
judged to be unlikely to result in product formation (DMAP partial-
ly between the reacting starting materials). For snapshots of these
complexes see the Supporting Information, Computational Section
4, Figure S4 and Table S16.
[37] Schreinerꢀs thiourea was (experimentally)investigated but proved to
be of lower value, for details, see Supporting Information, Computa-
tional Section, Discussion B: Computational extrapolations for
future research.
[38] The potassium complex in Figure 4 is a low energy island unto itself,
the next lowest trans enamine potassium complex is 5.33 kcalmolÀ1
higher in energy, while the corresponding lowest energy cis enamine
potassium complex is 2.87 kcalmolÀ1 higher in energy. The Figure 4
potassium complex, alone, is consequently the only complex that
needs to be considered here. See the Supporting Information, Com-
putation Section 5, Figure S5 and Table S20.
[17] For a succinimide drug candidate, see: M. L. Curtin, R. B. Garland,
H. R. Heyman, R. R. Frey, M. R. Michaelides, J. Li, L. J. Pease,
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[20] Interestingly, all three of these publications employ a mono thiourea
of cyclohexane trans diamine, see: a) F. Xue, L. Liu, S. Zhang, W.
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[21] Except for a lone report on the formation of contiguous quaterna-
ry–tertiary stereogenic centers, see Table 3 within ref. [20b], all cur-
rent reports avoid substrates that produce these products.
[22] For initial solvent screening studies, see the Supporting Information.
[23] It is important to note that the use of O-tBu-l-Thr (5 mol%),
Schreinerꢀs thiourea (5 mol%), DMAP (5 mol%), provided a less
valuable reaction profile for 6a (9 h, 92% ee, HPLC result).
[24] The best prior result for compound 6h was: 90% yield, 8:1 d.r.,
91% ee, after 36 h at 358C, when using 20 mol% of a thiourea cata-
lyst and 2.0 equiv of the starting aldehyde, see Table 3 of ref. [20b].
[25] The d.r. measurements before and after silica gel chromatography
were consistent, for more details see the Supporting Information.
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[29] Three hydrogen bonds are always noted for each complex A–D,
Figure 2, but the third one appears to play an auxiliary role (second
hydrogen bond to the carboxylate oxygen is weaker, ranging from
2.32–2.46 ꢂ), perhaps fine tuning the rigidity of the complex initially
provided via the two critical, anchoring, hydrogen bonds (1.78–
2.08 ꢂ).
Received: September 25, 2011
Published online: February 22, 2012
4098
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Chem. Eur. J. 2012, 18, 4088 – 4098