Controlling the molecular topology of vinylogous iminium ions by logical substrate design: Highly regio- and stereoselective aminocatalytic 1,6-addition to linear 2,4-dienals

Article abstract of DOI:10.1002/anie.201305870

All about topology control: The title reaction yields valuable tetrahydrofuran spirooxindoles (see scheme; TMS=trimethylsilyl), and exemplifies a rare asymmetric 1,6-addition to linear 2,4-dienals proceeding with high δ-site- and stereoselectivity. A steering group at the β-dienal position ensured molecular preorganization of the catalytically active vinylogous iminium ion intermediate for highly predictable reaction outcomes. Copyright

Full text of DOI:10.1002/anie.201305870

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Angewandte
Communications
DOI: 10.1002/anie.201305870
Synthetic Methods
Controlling the Molecular Topology of Vinylogous Iminium Ions by
Logical Substrate Design: Highly Regio- and Stereoselective
Aminocatalytic 1,6-Addition to Linear 2,4-Dienals**
Mattia Silvi, Indranil Chatterjee, Yiankai Liu, and Paolo Melchiorre*
This work was prompted by our interest in devising a versatile
catalytic strategy for stereoselectively accessing tetrahydro-
furan spirooxindole derivatives.[1] In spite of their promising
biological activities (Figure 1a),[2] the direct and stereocon-
trolled synthesis of these molecular scaffolds is a difficult goal,
and there are few catalytic asymmetric methodologies
substituted 3-hydroxyoxindole derivatives.[4b] We wondered if
the synthetic potential of the dioxindole reactivity could be
further harnessed to directly access tetrahydrofuranyl spi-
rooxindoles. Specifically, we sought to apply the recently
identified vinylogous iminium ion strategy[5] (Figure 1b) to
promote the regio- and stereoselective 1,6-addition of 1 to
polyunsaturated linear enals (2) upon activation by a chiral
aminocatalyst. The design plan, based on the cascade
reaction[6] detailed in Figure 1c, would conclude with an
intramolecular oxa-Michael cyclization event to forge the
spiro-stereocenter within the product 3. The main difficulty is
that the chiral catalyst must forge a remote stereocenter[7]
with high fidelity while inducing exclusive d-site selectivity in
the 1,6-addition manifold.[8] To date, the only effective
catalytic strategy has capitalized upon the ability of a chiral
amine to stereochemically bias intermediary cyclic vinylogous
iminium ion intermediates (species I in Figure 1b), which are
generated upon condensation with cyclic a,b,g,d-unsaturated
dienones.[5] However, controlling the molecular topology of
an acyclic intermediate, so as to ensure highly predictable
reaction outcomes, poses a more challenging problem.[9]
Herein, we describe how this synthetic issue has been
successfully addressed. Spectroscopic conformational analy-
ses were crucial to understanding how the structural features
of the 2,4-dienal substrate 2 could be modulated to encode for
a given molecular topology of the transient vinylogous
iminium ion intermediate, which is formed upon condensa-
tion with the chiral aminocatalyst.[10] This understanding was
critical to the rational design of an optimal linear dienal which
allowed the development of a highly regio- and stereoselec-
tive 1,6-addition/oxa-Michael cascade with dioxindole (1),
thus directly leading to tetrahydrofuran spirooxindole deriv-
atives (3).
Figure 1. a) A biologically active tetrahydrofuranyl spirooxindole; Ar:
anisyl. b) The vinylogous iminium ion strategy; X=H or alkyl. c) The
proposed design plan for vinylogous organocascade catalysis: 1,6-
addition/oxa-Michael sequence driven by vinylogous iminium ion/
iminium ion activation.
available.[3] We recently discovered that dioxindole (3-
hydroxy-2-oxindole; 1) is characterized by a strong nucleo-
philic behavior.[4] This reactivity offers efficient pathways for
the preparation of versatile optically enriched complex
molecules such as spirooxindole g-butyrolactones[4a,c] and 3-
In our initial experiments, we examined the reactivity of
N-methyl dioxindole (1a) toward the proposed vinylogous
cascade reaction with (E,E)-hexa-2,4-dienal (2a; Figure 2a).
The commercially available diphenyl prolinol silylether
catalyst A was selected because of its established ability to
activate a,b-unsaturated aldehydes toward asymmetric trans-
formations.[11] The reaction did indeed proceed with high
reactivity, but followed an exclusive b-site-selective path-
way.[4a] Only the classical Michael addition product 4 was
detected. This result is consonant with the established
catalytic profile of amine A, which is not generally able to
induce a 1,6-addition manifold when activating unbiased
dienals of type 2a.[12]
[*] Prof. Dr. P. Melchiorre
ICREA—Instituciꢀ Catalana de Recerca i Estudis AvanÅats
Passeig Lluꢁs Companys 23, 08010 Barcelona (Spain)
M. Silvi, Dr. I. Chatterjee, Dr. Y. Liu, Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia
Avenida Paꢂsos Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.es/portal/862/default.aspx
[**] Research support from the Institute of Chemical Research of
Catalonia (ICIQ) Foundation, MICINN (grant CTQ2010-15513), and
the European Research Council (ERC Starting Grant n. 278541-
ORGA-NAUT to P.M.) is gratefully acknowledged. We thank Grace
Fox for proofreading the manuscript, and Dr. Antonio Moran and
Alexandre Rossignon for initial experimental assistance.
We next considered the possibility of structurally modify-
ing the substrate scaffold in 2 to direct the dioxindole attack
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305870.
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facial discrimination of the covalent intermedi-
ate, factors which are essential in enforcing high
levels of enantioselectivity in iminium ion-
based chemistry (Figure 2 f).
We hypothesized that the presence of
a bulky substituent at the b-position of 2 could
be useful for freezing out a specific geometry of
the molecular iminium ion assembly by enhanc-
ing repulsive interactions with the catalyst
framework. The dienal 2c, bearing a tert-butyl
moiety, was purposely synthesized (Figure 2d).
We were pleased to confirm that the defined
E,E double bond geometry was stable under
the reaction conditions, since no isomerization
was observed in the presence of A. NMR
spectroscopic analyses were then used to gain
information on the geometry of the covalent
vinylogous iminium ion intermediate II, which
is actively involved in the stereodefining step
(Figure 2e). When mixing A with 2c in CDCl3
and in the presence of 4 ꢀ molecular sieves, the
corresponding intermediate II was formed. A
single isomer was detected, and the conforma-
tional behavior was investigated by conven-
tional NMR techniques, particularly vicinal
coupling constant analysis, nuclear Overhauser
enhancement (nOe) spectroscopy, and deute-
rium-labeling experiments (see Figures S5–S9
in the Supporting Information). Overall, the
NMR studies indicated that the dominant
ground-state conformer in solution has an
E,E,E topology, with the same configuration
Figure 2. Progress towards an effective vinylogous cascade initiated by a d-selective 1,6-
addition under vinylogous iminium ion activation of linear 2,4-dienals (2). °Yield of the
single, major diastereomer of 3 isolated after purification on silica gel. TMS=trimethyl-
silyl.
toward a 1,6-addition pathway. We reasoned that the inherent
steric bias of a b-substituent on the dienal 2 could provide
a suitable control element for securing d-site selectivity by
suppressing the competing 1,4-addition manifold. The results
shown in Figure 2b validate the feasibility of this idea.
Introducing a phenyl moiety at the b-position of 2b com-
pletely switched the site selectivity toward the desired 1,6-
addition driven by vinylogous iminium ion activation. The
tetrahydrofuran spirooxindole 5 was quantitatively formed
with a good control over the relative stereochemistry of the
three stereogenic centers (8:1 d.r.). However, the enantiose-
lectivity of the process was far below a synthetically useful
level (46% ee). During these investigations, we noticed that
2b was not configurationally stable, since a scrambling of the
double-bond geometry of the a,b-olefin was observed in the
presence of the catalyst A (from an E- to a Z-configured
double bond, Figure 2c).[13] We ascribed the low enantiose-
lectivity observed in the cascade reaction of 2b to the
configurational lability of the substrate. NMR spectroscopic
studies of the covalent vinylogous iminium ion intermediate,
formed in CDCl3 by condensation of A and 2b in the presence
of molecular sieves, confirmed that the geometrical promis-
cuity of 2b is translated into the catalytically active species:
two geometries for the iminium ion were detected (details can
be found in Figures S10–12 of the Supporting Information).
The lack of structural preorganization makes it difficult for
the chiral catalyst A to ensure configurational control and p-
for the three double bonds. Interestingly, the steric prom-
inence of the tert-butyl group makes it a topologically
dominant element, since it is able to enforce an uncommon
[14]
À
s-cis conformation around the single C(b) C(g) bond.
Collectively, these features contribute to a highly preorgan-
ized, configurationally stable, transient intermediate (II),
which may be crucial to reaction development. Indeed, the
chiral fragment in A seems positioned close enough to the
reactive d-carbon atom to determine an effective shielding of
the Re face of the extended iminium ion, thus leaving the
opposite Si face available for the approach of the dioxindole
1a (see the model in Figure 2 f).
We then evaluated the impact of the tert-butyl group of 2c
on the stereochemical outcome of the vinylogous cascade
reaction. As seen in Figure 2g, the spirocompound 3a was
obtained with perfect d-site selectivity and an enantioselec-
tivity as high as 88% ee. The use of the chloro-containing
dioxindole 1b resulted in similar reaction efficiency. The
corresponding tetrahydrofuran spirooxindole 3b was
obtained with synthetically useful results (Figure 2h). The
absolute and relative configuration for the major diastereo-
mer of compound 3b was unambiguously determined by
anomalous dispersion X-ray crystallographic analysis: an S
absolute configuration at the newly formed d-stereocenter
was inferred.[15] The sense of asymmetric induction is in
agreement with the stereochemical model extrapolated from
the conformational analysis discussed above (Figure 2 f).
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Having identified a viable strategy to control the regio-
and stereoselectivity of the vinylogous cascade, we sought to
increase the efficiency of the catalytic system. Starting from
the conditions detailed in Figure 2g, we evaluated variations
of the standard reaction parameters. The complete progress
towards the optimized reaction conditions for the reaction of
1a with 2c is detailed in Tables S1–3 within the Supporting
Information. Dichloromethane emerged as the most appro-
priate solvent for this transformation. The use of 50% of the
benzoic acid cocatalyst with 358C as the reaction temperature
positively influenced the reactivity, thus allowing a decrease
in the catalyst A loading to 10 mol%. These reaction
conditions were selected to evaluate the scope of the vinyl-
ogous cascade.
conditions. As for the d-position of the dienal substrate 2,
different substitution patterns at the aromatic moiety were
well-tolerated regardless of their electronic properties and
position on the phenyl ring (products 3i–m). A heteroaryl
framework can be included in the final product as shown for
the thienyl-substituted adduct 3n (entry 14).
As a limitation of the system, an aliphatic R1 substituent in
2 resulted in a complete loss of reactivity.[16] Replacing the
tert-butyl moiety at the b-position of 2 with a less sterically
prominent substituent profoundly influenced the selectivity
of the process (see Table S4 in the Supporting Information).
While an isopropyl group could still infer d-site selectivity,
albeit with a decreased stereocontrol (78% ee, 2.3:1.5:1 d.r.),
a methyl group was not able to effectively partition the 1,6-
and the 1,4-addition manifolds (products of type 3 and 4 in
Figure 2 obtained in a 1:1 ratio).[16] These results highlight
how strongly the steric profile of the b-substituent in 2 is
connected with an effective control over the molecular
topology of the vinylogous iminium ion intermediate. Con-
sistent with this hypothesis, a trimethylsilyl group, character-
ized by a similar Charton steric parameter[17] of a tert-butyl
moiety, directed the process exclusively toward a 1,6-addition
manifold while preserving the high enantioselectivity
(Scheme 1). This approach can be useful for directly accessing
As highlighted in Table 1, there appears to be significant
tolerance for structural and electronic variations of both
substrates to access a variety of complex spirotetrahydrofur-
ans (3) with good diastereomeric ratio, a high optical purity,
Table 1: Generality of the 1,6–1,4 sequential addition.[a]
Entry R1
R2 R3
R4
3
Yield [%][b] d.r.[c] ee [%][d]
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bn
H
Me Me
Me Cl
Me MeO
Me Me
Me
H
H
H
H
H
H
H
H
H
Me
Br
H
H
H
H
H
H
a
c
d
e
b
f
g
h
i
j
k
l
m
n
72
75[e]
66
56
66
79
64
73
74
84
84
71
82
76
6.1:1
6.5:1
4.3:1
5.3:1
6.3:1
8.9:1
6.6:1
11:1
6.7:1
9.4:1
15:1
5.4:1
8.7:1
5.6:1
91
92
90
90
90
90
92
91
90
93
93
94
93
92
4[f]
5[g]
6
7[h]
8
H
H
H
H
H
H
H
9
10
4-MeOC6H4 Me
4-BrC6H4
Me
Me
H
Me
Me
11[g] 3-ClC6H4
12
13
14
3-ClC6H4
2-MeC6H4
3-thienyl
[a] Reactions performed on a 0.1 mmol scale. Results represent the
average of two runs per substrate. All the 2,4-dienals 2 used have a E/E
configuration of the olefins. [b] Yield of the single, major diastereomer of
Scheme 1. The trimethylsilyl group as a traceless stereocontrol ele-
ment. The stereochemistry of 7a was unambiguously determined by
anomalous dispersion X-ray crystallographic analysis.[15] DMSO=dime-
thylsulfoxide.
1
3 isolated after purification on silica gel. [c] Determined by H NMR
analysis of the crude reaction mixture. [d] Determined by HPLC analysis
on a chiral stationary phase. [e] Product 3c was isolated as a 13.5:1
mixture of diastereomers. [f] Reaction time: 48 h. [g] The absolute and
relative configuration for the major diastereomer of compounds 3b and
3k was unambiguously determined by anomalous dispersion X-ray
crystallographic analysis, see Ref. [15]. [h] Reaction time: 72 h.
biologically relevant silicon-containing spirocompounds (see
structure in Figure 1a).[2a,b] Remarkably, we could easily
access the enantioenriched compound 8a upon protiodesily-
lation of the isolated major diastereomer 7a under basic
conditions.[18] This highlights that the trimethylsilyl moiety
can be used as a traceless directing group[19] to achieve d-site
selectivity, thus providing a formal 1,6-addition of geometri-
cally unbiased, linear dienals.
In conclusion, we have developed a novel aminocatalytic
vinylogous cascade reaction yielding valuable tetrahydro-
furan spirooxindole derivatives. The chemistry is based on
a rare example of asymmetric 1,6-addition to linear 2,4-
dienals proceeding with high d-site and stereoselectivity.
and exquisite site selectivity. It is of synthetic relevance that
a simple chromatographic purification on silica gel afforded
the isolation of the pure major diastereomer. A wide range of
dioxindole derivatives are compatible with the catalytic
system. The presence of a different substituent at the nitrogen
atom or the use of unprotected dioxindole (R2 = Bn or H,
respectively; entries 2 and 3) preserved the stereoselectivity
of the process, while substrates with different substituents at
C5 and C7 (entries 4–8) performed well under the reaction
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b) H. Jiang, Ł. Albrecht, K. A. Jørgensen, Chem. Sci. 2013, 4,
2287; c) I. D. Jurberg, I. Chatterjee, R. Tannert, P. Melchiorre,
Chem. Commun. 2013, 49, 4869.
Central to this study was the rational design of the substrate,
as inspired by conformational studies. A steering group at the
b-dienal position ensured molecular preorganization of the
catalytically active vinylogous iminium ion intermediate,
which was essential to achieve highly predictable reaction
outcomes. Expanding upon these findings, we are pursuing
the possibility of using traceless silyl-based directing groups to
design other vinylogous cascade reactions of linear 2,4-
dienals.
[8] The few enantioselective organocatalytic 1,6-additions of
carbon-centered nucleophiles developed so far are based on
the selective activation of the nucleophiles, see: a) L. Bernardi, J.
Lꢁpez-Cantarero, B. Niess, K. A. Jørgensen, J. Am. Chem. Soc.
2007, 129, 5772; b) J. J. Murphy, A. Quintard, P. McArdle, A.
Alexakis, J. C. Stephens, Angew. Chem. 2011, 123, 5201; Angew.
Chem. Int. Ed. 2011, 50, 5095; c) D. Uraguchi, K. Yoshioka, Y.
Ueki, T. Ooi, J. Am. Chem. Soc. 2012, 134, 19370. An iminium
ion catalyzed, intramolecular 1,6-oxa-addition has been used in
the total synthesis of (+)-dactylodide: d) K. Lee, K. Hyoungsu,
H. Jiyong, Angew. Chem. 2012, 124, 5833; Angew. Chem. Int. Ed.
2012, 51, 5735.
Received: July 6, 2013
Revised: August 2, 2013
Published online: September 3, 2013
[9] During the preparation of this manuscript, a remarkable 1,6-
addition to linear polyunsaturated aldehydes under iminium ion
activation was reported, see: L. DellꢂAmico, Ł. Albrecht, T.
Naicker, P. H. Poulsen, K. A. Jørgensen, J. Am. Chem. Soc. 2013,
135, 8063.
[10] For selected examples of the importance of conformational
analyses in rationalizing the behaviors of covalent reactive
intermediates involved in aminocatalytic processes, see: a) D.
Keywords: cascade catalysis · chemoselectivity ·
conformational analysis · heterocycles · spiro compounds
.
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