Asymmetric synthesis of rauhut-currier type products by a regioselective mukaiyama reaction under bifunctional catalysis

Article abstract of DOI:10.1021/jacs.6b07851

The reactivity and the regioselective functional-ization of silyl-diene enol ethers under a Afunctional organocatalyst provokes a dramatic change in the regioselectiv-ity, from the 1, 5- to the 1, 3-functionalization. This variation makes possible the 1, 3-addition of silyl-dienol ethers to nitroalkenes, giving access to the synthesis of tri- and tetrasubstituted double bonds in Rauhut-Currier type products. The process takes place under smooth conditions, nonanionic conditions, and with a high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments.

Full text of DOI:10.1021/jacs.6b07851

Subscriber access provided by University of Newcastle, Australia
Article
Asymmetric Synthesis of Rauhut-Currier type Products by a
Regiose-lective Mukaiyama Reaction under Bifunctional Catalysis
Maria Frias Rodríguez, Ruben Mas-Balleste, Saira Arias, Cuauhtémoc Alvarado, and José Alemán
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Asymmetric Synthesis of Rauhut-Currier type Products by a Regiose-
lective Mukaiyama Reaction under Bifunctional Catalysis
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
María Frias,a Rubén Mas-Ballesté,b Saira Arias,c Cuauhtemoc Alvarado,c José Alemána*
a
Department of Organic Chemistry (module 01), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid
(Spain) b Department of Inorganic Chemistry (module 07), Universidad Autónoma de Madrid, 28049 Madrid (Spain
). c División Académica de Ciencias Básicas. Universidad Juárez Autónoma de Tabasco (México).
Supporting Information Placeholder
Anionic compounds such as fluoride anions and alkoxides
are the most common reagents for the activation of silyl
ABSTRACT: The reactivity and the regioselective func-
tionalization of silyl-diene enol ethers under a bifunction-
reagents which are usually incompatible with epimeriza-
al organocatalyst provokes a dramatic change in the regi-
ble chiral centers and other functionalities. Mukaiyama6
oselectivity, from the 1,5 to the 1,3-functionalization. This
and Deng´s7 groups have described the use of chiral salts
variation makes possible the 1,3 addition of silyl-dienol
-
(PhO- and CF3CO2 anions) as catalysts in which the anion
ethers to nitroalkenes, giving access to the synthesis of
attacks the silyl reagent and provoke the desired trans-
tri- and tetra-substituted double bonds in Rauhut-Currier
formation. In recent years, the use of catalysts based on a
type products. The process takes place under smooth
neutral (uncharged) coordinate organocatalyst (NCO)
conditions, non-anionic conditions, and with a high enan-
which can coordinate with a silyl-reagent to form an ac-
tiomeric excess. A rational mechanistic pathway is pre-
tive complex, was developed by Kobayashi and others.8
sented based on DFT and mechanistic experiments.
Different NCOs such as sulfoxides, phosphine oxides or
amines have been used for the activation of silyl reagents,
1. INTRODUCTION
but never in a bifunctional manner. This reaction is gen-
erally limited to the use of allylsilanes and only an α-
attack on C=N and C=O bonds has been achieved. How-
ever, the application of this NCO to a bifunctional or-
ganocatalyst has not yet been applied. This strategy will
allow the activation of different electrophiles by the bi-
functional catalyst to give the functionalized products
together with regeneration of Bifunctional Neutral Coor-
dinate Organocatalyst (right, Figure 1). In principle, the
use of these bifunctional catalysts would be problematic
since the neutral coordinate center (previously used as a
Brønsted base) of these species would attack the silyl
reagent (forming the covalent bond N+-SiMe3) and stop
the catalytic cycle (right, Figure 1). However, the devel-
opment of these processes could provide access to the
unknown reactivity of these silyl-reagents
In the organocatalytic field, the limited number of activa-
tion-methods for the preparation of different and novel
asymmetric molecules has long impeded their expansion
in organic synthesis.1 This outlook is changing rapidly,
and the development of modern organocatalysts has con-
tributed to the emergence of new activation modes. The
low price, low toxicity, and the unique reactivity of these
catalysts make these processes particularly attractive.
Despite vast efforts in this area, the development of new
,
bifunctional organocatalysts, such as thiourea2 3 or squar-
amide4 derivatives, is still very limited.5 The development
of new reactions under bifunctional organocatalysts that
could increase the number of different activations, and
therefore the synthesis of valuable enantio-enriched mol-
ecules, would be highly desirable. However, most of bi-
functional catalysts are based on the combination of a
Brønsted acid and a Brønsted base (left, Figure 1).
In order to test these initial hypotheses, the addition
of the (Z)-(buta-1,3-dien-1-yloxy)trimethylsilane 1a (R1=
R2= H) to the nitroalkene 2a was chosen as a model reac-
tion (Scheme 1). Different excellent and brilliant asym-
metric metal catalyzed examples from Denmark´s,9
Katsuki´s,10 Campagne’s,11 Evans’12 and Carreira´s13
groups among others,14 as well as the organocatalytic
examples from Schneider,15 Kalesse,16 List,17 and Deng7,
have shown that the most reactive position of the formal
dienolate (1a) is the remote C5-position (left, Scheme 1).18
The orbital coefficients and electrophilic susceptibility are
mainly responsible for this reactivity,18a provoking the
observed 1,5 nucleophilic attack. It would be highly desir-
able if a catalyst could change to the 1,3-selectivity. In
addition, the double bond of the intermediate obtained
Figure 1. Comparison of the two activation modes of
bifunctional catalysts.
ACS Paragon Plus Environment

Journal of the American Chemical Society
would be isomerized and result in Rauhut-Currier type
Page 2 of 9
mide 4f showed higher rigidity and increased H-bond
distance and canted H-bond angle than thioureas,4b offer-
ing a higher enantioselectivity in this reaction.
1
2
3
4
5
6
7
8
products, which are excellent building blocks for the
synthesis of complex molecules (right, Scheme 1).19 The
lack of reactivity of the mono-β-substituted and β,β-
disubstituted double bonds makes difficult the synthesis
of these enantioenriched tri and tetrasubstituted double
bonds with different electron withdrawing groups in the
Rauhut-Currier reaction (bottom-right). In this work, for
the first time, the addition of silyl dienol ethers to ni-
troalkenes, catalyzed by bifunctional catalysts to obtain
any kind of Rauhut-Currier products with high ee’s is
achieved. In addition, a rational mechanistic pathway
based on DFT and mechanistic experiments are present-
ed.
Table 1. Optimization of the Rauhut-Currier Reaction
under Squaramide and Thiourea Catalysis.a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Solvent, additive
Ee
(%)
50
67
56
64
56
81
Conversionb
ent Catalyst (mol%)
(%)
21
10
30
20
55
48
n.r.
22
63
69
88
100
100 (86)d
53
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a (20 mol%)
4b (20 mol%)
4c (20 mol%)
4d (20 mol%)
4e (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (20 mol%)
4f (10 mol%)
4f (5 mol%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Dry-xylene
THF
Scheme 1. Comparison of the known asymmetric
reactivity of 1,5-Mukaiyama silylenolates with the
present work.
2. RESULTS AND DISCUSSION
-
2.1 Screening and Scope. Our screening started with the
trimethylsilane derivative 1a and nitrostyrene 2a in the
presence of 20 mol % of the cinchona thiourea catalyst 4a
(entry 1, Table 1). Surprisingly and by contrast with the
previous catalytic results reported in the literature,9-17 only
the 1,3 nucleophilic attack product (3a) was observed with
a low conversion (20 %) and moderate enantiomeric ex-
cess (50 %). Other thiourea cinchona catalysts 4b-c gave
similar conversions with a slightly better ee’s in the case
of the catalyst 4b (entries 2-4). Driven by our experience
in bifunctional catalysis,20 we decided to explore Takemo-
to´s (4e) and Rawal´s catalysts (4f) (entry 5 and 6). We
found a similar result with 4e to those obtained previous-
ly with 4a-d (ee= 56 %, entry 5). However, a better enan-
tiomeric excess (ee= 81 %) was found with the squaramide
4f (entry 6). In the next step we explored different sol-
vents under 4f catalysis. Interestingly, the use of dry xy-
lene did not result in any conversion at all, whereas other
bench-solvents, such as THF and DCE, promoted the
reaction from low to moderate conversion (entries 7-9).
However, the addition of 5 equiv. of water increased the
conversion (entries, 10-12, see S.I. for the full study), re-
maining equal to or similar in enantioselectivity. In the
case of DCE a conversion of >99 % and >99 % ee was
found (entry 12). Then lower catalytic loadings were stud-
ied, these also produced a similar result with 10 mol %
catalyst 4f (entry 13) but a 5 mol % provoked a substantial
decrease in the final conversion (entry 14). The squara-
96
99
96
96
>99
>99
97
DCE
Xylene+H2O
Tol+H2Oc
DCE+H2Oc
DCE+H2Oc
DCE+H2Oc
a
Conditions: 1a (0.3 mmol), 2a (0.1 mmol), catalyst (mol
%) in the solvent indicated (0.3 mL) at rt and stopped at
48 h. Conversion measured by H-NMR. c 5.0 equiv. of
b
1
d
H2O was used as an additive. Isolated yield between
brackets.
Under these optimized conditions, the scope of the
reaction using different substituted nitroalkenes 2 and
silyl reagents 1 was carried out (Table 2 and Scheme 2).
Different electron donating (p-MeO, p-Me, 3b, 3c) or
electron withdrawing groups (p-F, p-CN, 3d, 3e) as well as
ortho-substituent groups (o-Cl, 3f) at the aryl group of the
nitroalkene were tolerated under these conditions. Other
synthetically useful halogens such as p-Br or, 3,4-dichloro
(3g, 3h) were also studied, and also showed excellent
enantioselectivies and diastereoselectivities (only one
double bond stereoisomer was found in all these cases).
Very interestingly, an alkene containing a boronic acid
(2l), with acid protons that would interact with the cata-
lytic system, was also compatible, giving the final Rauhut-
Currier product 3l with 99 % ee and 71 % yield. Heterocy-
2
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
positions led to the β,β-disubstituted and β-
cles, double bonds and alkyl chains (3i, 3j, 3k) also
1
2
3
4
5
6
7
8
worked with excellent yields and good ee’s in all cases,
but with a lower diastereoselectivity for compounds 3i
and 3k. The more challenging reactions with trisubstitut-
ed nitroalkenes 2m and 2n were also studied. The optical-
ly enriched quaternary center product 3m was obtained
with a good yield and excellent enantioselectivity (96 %
ee), whereas the reaction with 2n gave the final product
3n with an excellent ee and good diastereocontrol at the
bromo position (dr= 91:9). The absolute configuration of
the asymmetric center and the configuration of the dou-
ble bond of 3n were unequivocally assigned as (E, 1S, 2S)
(bottom, Table 2) by X-ray crystallographic analysis.21 We
assigned the same absolute configuration to all the dou-
ble enals 3 as E, 2S.
monosubstituted adducts 3o and 3p in good yields and
enantioselectivies which are not possible to obtain by the
reported Rauhut-Currier reactions (equation a and b).22 In
addition, the reaction tolerated different groups in α
position to the TMSO group at the silylenolate 1d-f.
Therefore, the phenyl group led to the ketone 3q with an
excellent enantioselectivity (equation c) whereas the silyl
reagent 1e reacted with 2o to give the intermediate 5, that
spontaneously cyclized under the basic conditions to give
the final lactone 3r with a good ee and yield (equation d).
Finally, the synthesis of amides, which cannot be activat-
ed under the standard Rauhut-Currier reaction, gave the
adduct 3s in an excellent yield and enantioselectivity
(equation e).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of the Rauhut-Currier Reaction under
bifunctional neutral squaramide organocatalysis.a,b
Scheme 2. Different Substitution and functional
groups at the double bond of the silyl dienolate.
The Rauhut-Currier products obtained can be selec-
tively reduced to obtain precursors of important amino
acids, which are analogs of important pharmaceutical
products.23 The products 3a-3b were reduced with Zn in
an acidic media to produce the aminoalcohols 7a and 7b
with good enantioselectivity (left, Scheme 3). In addition,
the pyrrolidine 6 was obtained with excelent ee when H2
under a palladium catalyst was used (right, Scheme 3).
a
Conditions: 1 (0.3 mmol), 2 (0.1 mmol), 4f (10 mol %)
b
and H2O (5 equiv.) in DCE (0.3 mL) at rt for 24-48 h.
Conversion measured by 1H-NMR.
The substitution at the silyl dienol ether was studied
with 1b-f (Scheme 2). The substitution at the 4 and 5-
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
functional catalyst 4f, because the N+-TMS adduct is un-
1
2
3
4
5
6
7
8
reactive to hydrolysis. Therefore, the 4f-O species are a
dead-end in the catalytic cycle. Secondly, the anion bind-
ing of the squaramide moiety25 with the oxygen anion
(N-H···-O(C4H5)···H-N) indicates that the catalytic cycle
can be initiated by a species in which the silyl dienol ether
1A is coordinated to the squaramide fragment, instead of
the proposal in which the nitro group is stabilized by a
hydrogen bond interaction (as in the Takemotos’
el26).
Scheme 3. Derivatization of Rauhut-Currier adducts.
2.2 Mechanism Proposal. A fascinating feature of the
results reported herein is the functionalization of the C-3
carbon instead of the C-5 of the silyl-dienol-ether 1, even
though the latter is significantly the most nucleophilic
(Scheme 1). By contrast, in all the reported systems, the
functionalization of the C-5 instead of the C-3 has been
observed.9-17 Indeed, a natural population charge analysis
of the silyl dienol ether 1a, by means of DFT calculations,
indicates a higher negative charge in C-5 than in C-3 (see
S.I. for further details). Therefore, the bifunctional cata-
lyst should in some way direct the reactivity of substrates
(1 and 2) towards this unprecedented reactivity. In order
to understand how bifunctional organocatalyst works,
numerous experimental evidence has been collected,
which oriented further DFT calculations on the catalytic
mechanism.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OTMS
X-
H
N
N
H
H
TMS
H
H
N
N
CDCl2
N
N
F3C
O
O
F3C
O
O
TMSCl,
CDCl2
4f-O (X- -O-CH=CH-CH=CH)
4f-Cl (X- Cl-)
4f
H2O (5.0 equiv)
Scheme 4. NMR studies in the silylation of the squar-
amide catalyst 4f.
In a subsequent series of experiments, it was deter-
mined that five equivalents of water were required to
obtain good yields (see supporting information). This
observation suggests that the activation of reagent 1a
proceeds via hydrolysis. In fact, the K.I.E value of 2.2,
measured by comparing the initial rates of reaction in the
presence of either H2O or D2O, indicates that the hydrol-
ysis of silyl dienol ether is involved in the rate determin-
ing step (see S.I.).
Water Role. Firstly, we mixed a stoichiometric
amount of the catalyst 4f and TMSCl, obtaining a new
silylated species (4f-Cl, Scheme 4) that contained the
N+-TMS adduct and a chloride anion stabilized by hydro-
gen bonding (N-H···Cl-···H-N), which was confirmed by
comparison of 1H-NMR and 13C-NMR of the initial 4f cata-
lyst with the 4f-Cl. In addition, this structure was also
established by 2D-HMBC{1H, 29Si}, where a 29Si chemical
shift at 7.33 ppm, according to a Si-N bond,24 was found
(see S.I. for details). In parallel, a mixture of 4f and silyl
dienol ether 1A lead to a similar species (4f-O), which also
contained an ammonium adduct (N+-TMS) and, instead
of a chloride anion, contained the dienolate fragment,
establishing hydrogen bonding between the two NH pro-
tons of squaramide and dienolate anion (see S.I.). Howev-
er, the addition of 5 equiv. of water did not affect 4f-Cl or
4f-O, after some hours, even when solutions were heated.
Hydrogen bond coordination. Combining all the
experimental evidence presented above, we carried out a
series of DFT calculations27 in order to define a plausible
pathway that could explain all the results obtained. Re-
garding the squaramide bifunctional catalyst we consid-
ered a simplified structure, in which the CF3 group in the
benzene ring was substituted by a hydrogen atom and the
six-membered ring cycle NC5H10 was modelled as
N(CH3)2. Such simplifications decreased the computa-
tional costs by decreasing the number of basis functions
and avoiding dealing with conformational equilibrium in
the NC5H10 ring. In order to validate this approximation,
the catalytic activity of a simplified bifunctional catalyst
(Ph, and NMe2 derivative) has been experimentally test-
ed, leading to 3a as a product with a slightly lower enan-
tioselectivity (ee= 93%) and conversion (90%) than when
4f was used.
In addition, we carried out the NMR-titration of cata-
lyst 4f (Host) and silyldienolether 2a (Guest) in the pres-
ence and absence of water (see S.I.). Without water, a new
silylated species is formed (4f-O), confirmed by 2D-
HMBC{1H, 29Si}, where a new 29Si chemical shift at 7.33
ppm appeared. This is in accordance with a Si-N bond
which is identical to the one obtained by direct silylation
with TMS-Cl (4f-Cl). However, when water was present in
the reaction media, silylation of the catalyst 4f was not
observed by 2D-HMBC{1H, 29Si}. Therefore, water is pre-
venting the dead-end of the catalytic cycle and favoring
the observed reactivity.
Firstly, in order to determine the most feasible initial
species, the equilibrium shown in Scheme 5 was calculat-
ed. In accordance with the experimental observations,
coordination to squaramide is more favorable for the silyl
dienol ether 1a than for the nitrostyrene 2a by 3.8
kcal/mol (I versus II). Therefore, the process studied is
initiated by the hydrolysis step as a consequence of add-
ing a water molecule to species II (Scheme 5).
Two important hints can be extrapolated from these
results: Firstly, the activation of the reagent 1a should not
proceed by direct interaction with the amine of the bi-
4
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
energy of IV´ is higher than IV. Therefore, the process
1
2
3
4
5
6
7
8
from III to IV´ is probably a barrierless process. Further
evolution of such a putative intermediate IV´ consists on
an elongation of the Si-OR bond (TSV in Figure 2) that
produces the silanol byproduct and the nucleophile
[C4H4O-]. The later one is stabilized by the hydrogen
bonding with the squaramide in a structure very close to
the experimentally detected 4f-O species. At this point,
the hydrolysis step is finished and the C-C bond for-
mation starts. Evolution from V to VI implies the substi-
tution of silanol by nitrostyrene 2a which has an energetic
cost of at least 4.7 kcal/mol, due to multiple hydrogen
bonding interactions in V, in contrast with the simple N-
H-ONO(R) interaction found in VI. Moreover, this inter-
mediate VI is in accordance with the well-known Papai’s
model.28 Such pre-organization of the two fragments
orientate the geometry of the system to specifically gen-
erate the new C-C bond (C3 with the Cβ of 2a), even
though C5 is the most nucleophilic site (see top, Figure 3).
In addition to the regioselectivity, the enantioselective
discrimination in the two different pathways is taking
place in this step (VI vs VI´).
9
Scheme 5. DFT studies in the equilibrium between 1a
and 2a with the squaramide catalyst.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Energetic Profile of the Reaction. In this initial
structure (see III, Figure 2), a hydrogen bond is found
between the water molecule and the amine group (N···H =
1.81 Å). In addition, the oxygen atom of the water mole-
cule is correctly orientated to easily attack the Si center.
Further evolution of this system implies at first a proton
transfer from the water molecule to the amine nitrogen,
followed by a nucleophilic attack of the resulting hydrox-
ide to the silicon atom. In fact, from the starting species
III to the IV there is an energetic cost of 15.5 kcal/mol. In
addition, in the potential energy surface, a minimum has
been located in which an hipervalent penta-coordinated
RO-Si(OH)(CH3)3 silicon environment is found (structure
IV´), and formed through the transition state IV (Figure
2). However, when thermal corrections are included, free
Therefore, the C-C bond formation requires the ap-
proach of both C3 and Cβ atoms up to 2.24 and 2.29 Å,
which are the distances found in the TSVI and TSVI’ re-
spectively, (Figure 2). Once adduct VI and VI´ are formed,
Figure 2. DFT M062x/6-31+G(p,d) reaction energy profile in the addition of 1a to 2a.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
Alternatively, the coordination of the nitroalkene to
1
2
3
4
5
6
7
8
the squaramide moiety, following the Takemoto´s mod-
el,5f was also considered (see DFT-calculations in support-
ing information). From intermediate V, the intramolecu-
lar protonation of the enolate with the ammonium frag-
ment occurs without kinetic barrier to give the enol with
simultaneous coordination of the nitroalkene to the
squaramide (pro-R or pro-S face, see VIII and VIII´, see
S.I.). Although this pathway is also plausible, the kinetic
barriers found for the C-C formation in both approaches
(TS-VIII and TS-VIII´) are significantly higher (12.5 and
12.3 kcal/mol) than the approaches shown in Figure 2
TSVI and TSVI´, 6.1. and 8.9 Kcal/mol).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To understand the energetic differences in TSVI and
TSVIII, an analysis of hydrogen bond distance in the
lowest energy transition states for both models has been
carried out (Figure 4). A very similar interaction scheme
is observed in both cases. In fact, the proton of the enol is
completely transferred to the aminic nitrogen in TSVIII
(1.058 Å, which is comparable to a similar distance in
TSVI, 1.042 Å). Consequently, an enolate stabilized by
hydrogen bonding is found at both transition states (1.759
and 1.903 Å vs 1.748 Å). Therefore, a negative charge is
located on the oxygen atom in TSVIII as in TSVI. The
charge distribution (NPA) was in fact analyzed in both
TSVI and TSVIII (see S.I.). Based on the collected data,
the similarity between these systems from a charge distri-
bution perspective can be verified. For instance, the
charge of the oxygen atom in the enolate is -0.76002 for
TSVI and -0.74707 for TSVIII. Moreover, the charge dis-
tribution in the newly formed C-C bonds are very similar.
Therefore, the activation mode from an electronic point
of view is comparable in both models.
Figure 3. DFT M062x/6-31+G(p,d) of TSVI (top) and
TSVI’ (bottom).
further evolution to form the key C-C bond proceeds
through a lower kinetic barrier (5.9 and 9.1 Kcal/mol,
respectively). As observed in the profile, one enantiomer
(VI) follows a path with an energy barrier around 3.0
kcal/mol lower than the other one (VI´), accounting for
the kinetic control responsible for the final enantioselec-
tivity observed. Such energetic differences are related to
the geometric constrictions imposed by the relative posi-
tions of nitrostyrene and the dienolate nucleophile both
fixed by the hydrogen bonding. As a consequence, the
hydrogen bonding interaction between dienolate and
squaramide are different in TSVI and TSVI’ (for TSVI:
dO···H=1.76, 1.90; TSVI´: dO···H=1.92, 1.92, see Figure 3). The
lower energy of the fixed conformation of TSVI as a result
of the bifunctional design of the catalyst is, at the end, not
only the responsible for the regio-, but also for the enan-
tio-selectivity (compare TSVI and TSVI´). Evolution of
this transition state results in species VII in which the C-
C bond is already formed. Species VII and VII´ are very
close to the final product 3a and only differs from it in a
proton transfer from the amine N atom of the squaramide
to the Cα of the nitronate, followed by a double bond
isomerization (bottom and top-right). The double bond
isomerization led to the more stable product E, which is
~2 kcal/mol more stable than Z isomer (calculated by
DFT, see S.I.). Furthermore, the protonation of the nitro-
nate VII would also be assisted by the generated silanol
from III to VI.
As the electronic effects are not responsible for the
system preference of one model over another, an alterna-
tive factor should be claimed. When the structure of both
transition states are studied, a more tensioned structure is
found for TSVIII. Such structural distortion can be de-
scribed as the deviation of the ideal orientation angle of
C-C attack. It is commonly known that the ideal Bürgi–
Dunitz angle (BD angle) value is 109°, which is exactly the
value found in TSVI (see Figure 4). However, in the case
of TSVIII such value is 104.3°. This distortion implies a
subtle energetic cost in the activation barrier in the C-C
bond formation. Overall, this phenomenon is a product of
the relative orientation of both substrates (nucleophile
and electrophile) by hydrogen bond interactions imposed
by the bifunctional design of the catalyst.
6
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
change in the regioselectivity, from the 1,5 to the 1,3-
1
2
3
4
5
6
7
8
functionalization, and this variation make possible the 1,3
addition of silyl-dienol ethers to nitroalkenes for the syn-
thesis of tri- and tetra-substituted double bonds in Rau-
hut-Currier type products. This methodology is compati-
ble with the use of a large variety of nitroalkenes, and
different silyl dienol ethers, to give aldehydes, esters,
amides and ketones Rauhut Currier products which are
not possible to obtain by other methods. The process
takes place under smooth and non-anionic conditions
with high enantiomeric excess. A rational mechanistic
pathway based on DFT and mechanistic studies indicates
that the hydrolysis of the silyl dienol ether is the rate
determining step and it is followed by the C-C formation
in a regio- and enantio-selective manner due to the ap-
propriate orientation of the reagents in the transition
state by the bifunctional catalyst.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental procedures, DFT calculations (PDF),
1H and 13C-NMR spectra; GC and HPLC traces (pdf).
AUTHOUR INFORMATION
Corresponding Author
Jose.aleman@uam.es
Figure 4. Detailed angles and hydrogen bond dis-
tances of TSVI (top) and TSVIII (bottom).
The high enantio- and regio-selectivity and the high
reactivity in the activation of the silyl-reagent 1 is a con-
sequence of the bifunctional structure of catalysts 4.
Therefore, when the same reaction was catalyzed by tri-
Present Addresses
M.F. and J.A. Department of Organic Chemistry (module 01),
Universidad Autónoma de Madrid, Cantoblanco, 28049 Ma-
drid (Spain)
ethylamine and the monofunctional squaramide
8
(Scheme 6). a very low conversion (15%)29 and exclusively
the 1,5 addition (9) was observed in the crude mixture.
This is in agreement with all the previous catalytic reports
described in the literature9-18 which are monofunctional
systems and afford only 1,5 addition products. Therefore,
our new approach allows a highly enantioselective and 1,3
regioselective functionalization of silyldienolate deriva-
tives, giving access to Rauhut-Currier products that pre-
viously were inaccessible through other methodologies.19
R.M.B. Department of Inorganic Chemistry (module 07),
Universidad Autónoma de Madrid, 28049 Madrid (Spain ).
C.A. and S. A. División Académica de Ciencias Básicas. Uni-
versidad Juárez Autónoma de Tabasco (México).
ACKNOWLEDGMENT
M. F. would like to express thanks to the UAM for a pre-
doctoral fellowship-UAM. Financial support from the Spanish
Government (CTQ-2012-12168, CTQ2015-64561-R), Euro-
pean Research Council (ERC-CG, contract number: 647550),
CONACYT (Programas de redes temáticas: red de investi-
gación en organocatálisis asimétrica 252435) is also gratefully
acknowledged. We acknowledge the generous allocation of
computing time at the Centro de Computación Científica of
the Universidad Autónoma de Madrid (CCC-UAM).
REFERENCES
Scheme 6. System under two different catalysts.
3. CONCLUSIONS
(1) For some selected reviews in organocatalysis, see: (a)
Berkessel, A.; Göger, H. Asymmetric Organocatalysis, WILEY-
VCH, Weinheim, Germany, 2005. (b) Dalko, P. I. Enantioselec-
In conclusion, we have found that bifunctional cata-
lysts are able to change the reactivity and the regioselec-
tive of silyl-dienol ethers. This provokes a dramatic
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
1
2
3
4
5
6
7
8
9
tive Organocatalysis, WILEY-VCH, Weinheim, 2007. (c) MacMil-
(15) Gupta, V.; Sudhir V., S.; Mandal, T.; Schneider, C.; Angew.
Chem. Int. Ed. 2012, 51,12609
(16) (a) Christmann, M.; Kalesse, M. Tetrahedron Lett. 2001, 42,
1269; (b) Gieseler, M. T.; Kalesse, M. Org. Lett. 2011, 13, 2430.
(17) Ratjen, L.; García-García, P.; Lay, F.; Edmund-Beck, M. List,
B. Angew. Chem. Int. Ed. 2011, 50, 754.
(18) For review of catalytic vinylogous aldol reactions, see: (a)
Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem. Int.
Ed. 2005, 44, 4682. (b) Pansere, S. V.; Paul, E. K. Chem. Eur. J.
2011, 17, 8770. (c) Bisai, V. Synthesis 2012, 44, 1453. For Mannich
reactions, see: (d) Schneider, C.; Sickert, M. Chiral amine synthe-
sis: Methods, developments and applications, Edited by T. C.
Hugent, Wiley-VCH Verlag-2010.
(19) For reviews of the Rauhut-Currier Reaction, see: (a) Arroyan,
C. E.; Dermenci, A.; Miller, S. Tetrahedron, 2009, 65, 4069. (b)
Bharadwaj, K. RSC Adv., 2015, 5, 75923. (c) Methot, J. L.; Roush,
W. R. Adv. Synth. Catal. 2004, 346, 1035. (d) Xie, P.; Huang, Y.
Eur. J. Org. Chem. 2013, 6213.
(20) (a) Jarava-Barrera, C.; Esteban, F.; Navarro-Ranninger, C.;
Parra, A.; Alemán, J. Chem. Commun. 2013, 49, 2001. (b) Parra,
A.; Alfaro, R.; Marzo, L.; Moreno-Carrasco, A.; García Ruano, J.
L.; Alemán, J. Chem. Commun 2012, 48, 9759. (c) Marcos, V.;
Alemán, J.; García Ruano, J. L.; Marini, F.; Marcello Tiecco, Org.
Lett. 2011, 13, 3052.
(21) CCDC 1471840 (3n) contains the crystallographic data. These
data can be obtained free of charge at www.ccdc.cam.ac.uk.
(22) The Rauhut-Currier reaction works well with β,β-
unsubstituted double bonds (see reference 19). Only two asym-
metric inter- and intra-molecular examples with β,β-
unsubstituted α,β-unsaturated double bonds has been recently
reported: see: (a) Dong, X.; Liang, L.; Li, E.; Huang, Y. Angew.
Chem. Int. Ed. 2015, 54, 1621. (b) For an intramolecular asymmet-
ric version, see: Zhao, X.; Gong, J.; Yuan, K.; Sha, F.; Wu, X.
Tetrahedron Lett. 2015, 56, 2526.
(23) For references related to the importance of these type of
aminoalcohols and pyrrolidines see (a) M. Tamura, R. Tamura,
Y. Takeda, Y. Nakagawa, K. Tomishige, Chem. Commun., 2014,
50, 6656; (b) B. Han, Y. Xiao, Z. He, Y. Chen, Org. Lett. 2009, 11,
4660 and references cited inthere.
(24) See, www.pascal-man.com/periodic-table/29Si.pdf.
(25) The coordination of oxygen anions to thiourea or squara-
mide has been proposed in other works. For reviews in the field,
see: (a) Beckendorf, S.; Asmus, S.; García Mancheño, O. Chem.
Cat. Chem. 2012, 4, 926. (b) Brak, K.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2013, 52, 534. (c) Phipps, R. J.; Hamilton, G. L.,
Toste, F. D. Nature Chem. 2012, 4, 603.
lan, D. W. C. Nature 2008, 455, 304. (d) Moyano A.; Rios, R.
Chem. Rev. 2011, 111, 4703. (e) Bernardi, L.; Fochi, M.; Franchini
M. C.; Ricci, A. Org. Biomol. Chem. 2012, 10, 2911. (f) Cabrera, S.;
Alemán, J. Chem. Soc. Rev. 2013, 42, 774.
(2) For a deep and pioneering study in H-bonding additives acting
as a Lewis acid, see: (a) Schreiner, P. R.; Wittkopp, A. Org. Lett.
2002, 4, 217. (b) Sigman, M.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 4901; (c) Corey, E. J.; Grogan, M. Org. Lett. 1999, 1, 157.
For a reviews, see: (d) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev.
2009, 38, 1187; and references cited therein;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) For pioneer work on bifunctional thiourea organocatalyst,
see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672. (b) Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. For review in thiourea
bifunctional catalysts, see: ; (c) Zhang, Z.; Schreiner, P. R. Chem.
Soc. Rev. 2009, 38, 1187; (d) Takemoto, Y. Chem. Pharm. Bull.
2010, 58, 593.
(4) For pioneering study, see: (a) J. P. Malerich, K. Hagihara, V.
H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416; for a review, see: (b)
Alemán, J.; Parra, A.; Jiang; H.; Jørgensen, K. A. Chem. Eur. J.
2011, 17, 6890.
(5) For reviews in hydrogen bond catalysis, see: (a) Pihko, P. M.
Hydrogen Bonding in Organic Synthesis, Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, Germany, 2009. (b) Schreiner, P.
R. Chem. Soc. Rev., 2003, 32, 289. (c) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713. (d) McGilvra, J. D.; Gondi, V. D.;
Rawal, V. H. in Enantioselective Organocatalysis (Eds.: P. I.
Dalko), Wiley-VCH: Weinheim, 2007; pp 189-254. (e) Yu, X.;
Wang, W. Chem. Asian. J. 2008, 3, 516. For calculations, see: (f)
T. Okino, Y. Hoashi, T. Furukawa, X. N. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119.
(6) (a) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2006,
35, 1398. (b) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett.
2007, 36, 666.
(7) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2010,
132, 9558.
(8) For a pioneering work, see: (a) Kobayashi, S.; Nishio, K.,
Tetrahedron Lett. 1993, 34, 3453; (b) Kobayashi, S.; Nishio, K. J.
Org. Chem. 1994, 59, 6620. For a review, see: (c) Kobayashi, S.;
Sugiura, M.; Ogawa, C. Adv. Synth. Catal. 2004, 346, 1023 and
references cited therein.
(9) (a) Denmark, S. E.; Xie, M. J. Org. Chem. 2007, 72, 7050. (b)
Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800.
(10) Shimada, Y.; Matsuoka, Y.; Irie, R.; Katsuki, T. Synlett 2004,
57.
(11) (a) Bluet, G.; Campagne, J. M. Tetrahedron Lett. 1999, 40,
5507. (b) Bluet, G.; Campagne, J. M. J. Org. Chem. 2001, 66, 4293.
(c) Bluet, G.; Bazan-Tejada, B.; Campagne, J. M. Org. Lett. 2001,
3, 3807.
(12) Evans, D. A.; Hu, E.; Burch, j. D.; Jaeschke, G. J. Am. Chem.
Soc. 2002, 124, 5654.
(13) Pagenkopf, B. L.; Kruger, J.; Stojanovic, Carreira, E. M. An-
gew. Chem. Int. Ed. 1998, 37, 3124. (b) Krüger, J.; Carreira, E. M. J.
Am. Chem.Soc. 1998, 120, 837.
(14) (a) Wang, G.; Wang, B.; Qi, S.; Zhao, J.; Zhou, Y., Qu, J. Org.
Lett. 2012, 14, 2734; (b) Wang, G.; Zhao, J.; Zhou, Y.; Wang, B.;
Qu, J. J. Org. Chem. 2010, 75, 5326; (c) Scettri, A.; Villano, R.;
Manzo, P.; Acocella, M. R. Cent. Eur. J. Chem. 2012, 10, 47; (d) Li,
H.; Wu, J. Org. Lett. 2015, 17, 5424.
(26) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Tameoto, Y. J.
Am. Chem. Soc. 2006, 128, 13151.
(27) Quantum chemistry calculations were carried out using the
density functional theory (DFT). In particular, geometry optimi-
zations were performed using the M06-2X functional in combi-
nation with the 6-31G+(d,p) basis set including dichloroethane (ε
= 10.4) solvent effects with the solvation model density (SMD).
For more details see S.I.
(28) Hamza, A.; Schubert, G.; Sóos, T.; Pápai, I. J. Am. Chem. Soc.
2006, 128, 13151.
(29) In addition, the reaction with Et3N and squaramide 8 were
carried out in two different experiments. A similar conversion
(15%) was only found when 8 was used.
8
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
1
2
3
SYNOPSIS TOC
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
ACS Paragon Plus Environment