Catalytic asymmetric intermolecular stetter reactions of enolizable aldehydes with nitrostyrenes: Computational study provides insight into the success of the catalyst

Article abstract of DOI:10.1002/anie.201107597

Fluorine helps: A fluorinated triazolium salt precatalyst has been developed that efficiently promotes the asymmetric intermolecular Stetter reaction of enolizable aldehydes and nitrostyrenes (see scheme). Trans fluorination of the catalyst architecture results in unparalleled reactivity and enantioselectivity in the desired transformation. A DFT study provides evidence of an electrostatic interaction as the source of the increased enantio-induction. Copyright

Full text of DOI:10.1002/anie.201107597

Angewandte
Chemie
DOI: 10.1002/anie.201107597
Asymmetric Catalysis
Catalytic Asymmetric Intermolecular Stetter Reactions of Enolizable
Aldehydes with Nitrostyrenes: Computational Study Provides Insight
into the Success of the Catalyst**
Daniel A. DiRocco, Elizabeth L. Noey, K. N. Houk,* and Tomislav Rovis*
Over the past decade, N-heterocyclic carbenes (NHCs) have
À
been used as catalysts in a variety of C C bond forming
reactions.[1] Our group has been interested in the develop-
ment of chiral NHCs as catalysts for the asymmetric intra-
molecular Stetter reaction[2,3] and more recently, the inter-
molecular variant.[4,5] We recently reported that hetaryl
aldehydes and enals react efficiently with nitroalkenes in
the Stetter reaction, leading to b-nitro ketones with high
enantioselectivity.[4d] Crucial to the success of this method was
the development of a fluorinated triazolium salt pre-catalyst
that provides significantly enhanced enantioselectivity over
des-fluoro analogues.[6] Although the new catalyst system
greatly expands the scope of this method, these conditions are
not amenable to the use of unactivated aliphatic aldehydes.
Because of their lower electrophilicity relative to aryl
aldehydes, aliphatic aldehydes have rarely been successfully
Scheme 1. Catalyst optimization studies. Reactions conducted with
1.5 equiv 1a and 1.0 equiv 2a. Yields shown are of product isolated
used in the asymmetric intermolecular Stetter reaction.[7,8]
Our initial attempts at rectifying this problem began by
after chromatography. Enantiomeric excesses determined by HPLC
À
evaluating more reactive Michael acceptors, such as b-nitro-
styrenes. The unstable nature of the reaction components
mandated milder reaction conditions; a brief screen revealed
tertiary alcohol solvents and weak inorganic bases as being
optimal.[9] Under these conditions, pre-catalyst 5, which
previously demonstrated high reactivity and enantioselectiv-
ity for hetaryl aldehydes and enals, affords only modest yield
(53%) with low enantioselectivity (48%; Scheme 1). Inter-
estingly, this reaction affords the opposite major enantiomer
to that observed in our previous work using the same pre-
analysis on a chiral stationary phase. BF4 counterions omitted for
clarity.
catalyst with aliphatic nitroalkenes.[4d] Surprisingly, trans-
fluorinated pre-catalyst 6 provides substantial increases in
both yield (78%) and enantioselectivity (74%). To further
increase selectivity we evaluated the more sterically demand-
ing pre-catalyst 7, derived from t-leucine. This pre-catalyst
displays low reactivity compared to the valine-derived pre-
catalysts (4–6), but with greatly increased enantioselectivity
(80%). Further evaluation of this scaffold shows the same
trends in reactivity and selectivity as the valine-derived series;
trans-fluorinated pre-catalyst 9 provides drastically better
selectivity (93% ee) than both cis-fluoro (74%) and des-
fluoro (80%) catalysts.
[*] D. A. DiRocco, Prof. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, CO 80526 (USA)
E-mail: rovis@lamar.colostate.edu
E. L. Noey, Prof. K. N. Houk
Under optimized conditions, the scope of this trans-
formation was evaluated with respect to both the aldehyde
and nitrostyrene derivative (Table 1). Using b-nitrostyrene 2a
as the Michael acceptor, a variety of aliphatic aldehydes were
examined. Straight-chain aliphatic substitution provides
products in high yield (80–87%) and excellent enantioselec-
tivity (92–93%), with the exception of acetaldehyde, which
gives good yield (71%), but is only modestly selective (62%
ee). b-Branched aldehydes are tolerated and provide excel-
lent enantioselectivity (95%), albeit in lower yield, while a-
branched aldehydes do not participate. Avariety of functional
groups are well-tolerated, including thio ethers, silyl ethers,
alkyl halides, and terminal olefins. Substitution on the aryl
ring of the nitroalkene leads to fairly invariant results. Ortho-,
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
[**] We thank NIGMS for generous support of this research (GM 36700
to K.N.H. and GM 72586 to T.R.). T.R. thanks Amgen and Roche for
unrestricted support. E.L.N. is grateful to the National Institutes of
Health Chemistry-Biology Interface Training Program Grant
(T32M008496). K.N.H. is grateful to the National Science Founda-
tion (CHE-0548209) for financial support, to the UCLA Academic
Technology Services (ATS) Hoffman2 and IDRE clusters for
computational resources, and for the TeraGrid resources provided
by NCSA (CHE-0400414).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107597.
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Table 1: Reaction Scope.[a]
We were intrigued by the large differences in both
reactivity and enantioselectivity between diastereomeric
catalysts 8 and 9. To further probe this variance, a series of
competition experiments was performed between the cata-
lysts, which allowed us to assess their relative rates of product
formation.[10] By means of this assessment, we determined
that trans-fluorinated pre-catalyst 9 is drastically (ca. 13 fold)
more active than cis-fluorinated pre-catalyst 8. Even more
remarkable is the difference in reactivity between pre-catalyst
9 and achiral catalyst 12. Pre-catalyst 9 is the most sterically
encumbered scaffold that we have examined to date, yet it is
still more reactive than achiral pre-catalyst 12, which lacks
a bulky directing group (Scheme 3).
Entry
R
Ar
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
nPr
Et
Me
iBu
Ph
Ph
Ph
Ph
Ph
Ph
80
87
71
32
68
67
93
92
62
95
87
92
7
8
Ph
Ph
76
83
83
<5
70
75
83
63
50
70
81
62
93
93
9
Ph
Ph
93
N/A
91
93
94
91
91
92
92
10
11
12
13
14
15
16
17
18
Cy
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
2-Cl-C6H4
2-F-C6H4
2-MeO-C6H4
3-MeO-C6H4
3-Br-C6H4
4-Cl-C6H4
4-Me-C6H4
4-[B(pin)]-C6H4
Scheme 3. Influence of catalyst structure on relative rate. See Support-
ing Information for details. BF4À counterions omitted for clarity.
91
[a] Reactions conducted with 1.5 equiv 1 and 1.0 equiv 2 for 24–48 h.
[b] Yield of isolated product after chromatography. [c] Enantiomeric
excess determined by HPLC analysis on a chiral stationary phase.
In our initial report on the asymmetric intermolecular
Stetter reaction using fluorinated triazolium salt pre-catalyst
5, we proposed that backbone fluorination of the triazolium
salt results in a conformational change owing to the gauche
effect.[4c] Our recent DFT study has provided evidence that an
meta-, and para-substitutions were examined, providing both
fair to good yields (50–83%) and excellent enantioselectiv-
ities (91–94%) in all cases. A 2.5 mmol scale experiment was
also performed using 10 mol% of 9, which provided the
product in 84% yield and 93% ee.
Derivatization of product 3a was performed to demon-
strate the synthetic utility of b-nitro ketone products
(Scheme 2). Reduction with NaBH4 leads to the desired
À
attractive electrostatic interaction between the C F dipole in
the catalyst and the developing nitronate in the transition
state is the source of increased selectivity.[11] Because of the
divergence in both the stereochemical outcome of this
reaction as well as the relative stereochemistry of the
fluorinated catalyst architecture required for good selectivity,
a different effect may be operative in this case.
To further understand the effect of fluorination of the
catalyst architecture in this system we undertook a DFT study.
Reactions with catalysts 7–9 were quantum-mechanically
investigated to resolve the origin of selectivity. The focus of
our investigation is to determine why the R enantiomer of the
product is favored, and why trans-fluorinated catalyst 9 is
more selective than both cis-fluorinated catalyst 8 and des-
fluoro catalyst 7.
Calculations were performed with Gaussian09.[12] All
geometries were optimized using B3LYP/6-31G(d) with the
CPCM solvation model[13] for methanol (UAKS radii, meth-
anol, e = 32.6). Single-point calculations were performed on
the B3LYP geometries with M06-2X/6-31 + G(d,p), again
using the CPCM model for methanol. Aldehyde 1a was
modeled with propionaldehyde. DFT calculations predict
good transition state geometries[14] and have been used to
study the Stetter and related reactions.[11,15] M06-2X provides
more accurate selectivities and thermodynamic values and
incorporates dispersion effects.[16] Including the implicit
solvation model was important for predicting accurate
selectivities.
Scheme 2. Derivatization of b-nitro ketone products. [a] Absolute and
relative configuration determined by X-ray analysis; see the Supporting
Information.
nitro alcohol in quantitative yield and 8:1 d.r. The major
diastereomer is easily isolated by chromatography, providing
82% of 10 in 93% ee. Reduction of the nitro group is
accomplished using NiCl2/NaBH4, which, following a simple
workup, is transformed to the corresponding benzamide in
81% yield and 98% ee.
Catalysts 7–9 react with propionaldehyde to form acyl
anion equivalents 13–15, respectively (Scheme 4). The
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Scheme 4. Relative free energies (M06-2X/6-31+G(d,p),CPCM-
(MeOH)//B3LYP/6-31G(d),CPCM(MeOH) of acyl anion equivalents
13–15. Endo conformations were located by freezing the triazolium
ring.
favored conformations of intermediates 13–15 are important
for determining the stereocenter that is formed in the
product. No minima for the endo conformers could be
located, as all optimizations beginning from endo conforma-
tions converge to the exo conformations. Optimizations with
the triazolium ring frozen in the endo conformation predict
that these conformations are disfavored by 5.2–7.5 kcalmolÀ1
and are therefore too high in energy to be involved in the
reaction. As shown in our previous computational study,[11]
the A1,3-like strain involving the alkyl substituent (here tBu) is
extremely large in the endo conformers of the enol inter-
mediates, and these conformers are not involved in subse-
quent reactions steps.
Figure 1. Transition structures TS1-TS6 and energies (M06-2X/6-
31+G(d,p),CPCM(MeOH)//B3LYP/6-31G(d),CPCM(MeOH). The
dipole moments are based on Mulliken charges and are given in
Debye.
Acyl anion equivalents 13–15 exo attack either the Si or
Re face of the nitrostyrene 2 leading to transition structures
TS1, TS3, TS5 or TS2, TS4, TS6, respectively (Figure 1). This
step determines the stereocenter formed, but is not the rate-
determining step.[17] Conformations resulting from rotation
about the forming carbon–carbon bond were considered. The
optimized geometries for the most favorable transition
structures are shown in Figure 1. Unlike previous studies on
similar Stetter reactions,[11] TS1–TS6 do not all follow
Seebachꢀs topological rule,[18] which describes a preference
for a synclinal orientation of the double bonds of donors and
acceptors in Michael-addition transition states.
In agreement with experiment, addition to the Re face of
the nitrostyrene is favored (TS2, TS4, TS6) and catalyst 9 is
computed to be the most selective. A gauche (À) orientation
of the double bonds in the Si face attack (TS1 and TS3) places
the nitro group under the catalyst ring. This is electrostatically
favorable for TS1 and TS3. However, for TS5, the negative
electrostatic interactions between the fluorine, which points
down in catalyst 9, and the nitro group disfavors this
conformation. For TS5 the gauche (+) conformation is
favored because it is well solvated owing to its large dipole
moment. The anti conformation for the Re-face attack is
favored[19] because of the stabilizing interaction between the
hydrogen of the hydroxy group and the carbon a to the nitro
group,[20] favorable electrostatic interactions between the
alkyl group of the aldehyde and the nitro group, and because
it is well solvated. These combined effects are enough to favor
the Re-face attack over the Si-face attack. Also, TS6 is
especially favorable because the negative p cloud of the
phenyl ring is near the electropositive catalyst ring and the
positive part of the phenyl ring is near the electronegative
fluorine. Therefore, TS6 has the lowest barrier, making
catalyst 9 the most selective.
The calculated and experimental enantiomeric excesses
are given in Table 2. The calculated values are determined by
a Boltzmann distribution of all optimized transition struc-
tures.[21] These values correlate well with the experiment but
are slightly underestimated.
Table 2: Calculated and experimental enantiomeric excesses.
Calculated[a]
Experimental
Catalyst
% ee
% ee
7
8
9
62
51
80
80
74
93
[a] Using M06-2X/6-31+G(d,p), CPCM(MeOH)//B3LYP/6-31G(d),
CPCM(MeOH).
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H. Lv, Y. R. Chi, Angew. Chem. 2011, 123, 11986 – 11989; Angew.
Chem. Int. Ed. 2011, 50, 11782 – 11785.
In conclusion, we have identified a novel catalyst, one
capable of inducing high levels of enantio-induction in the
intermolecular Stetter reaction of aliphatic aldehydes and
nitrostyrenes. Trans fluorination of the catalyst architecture
promotes unparalleled reactivity and enantioselectivity in this
transformation, as compared to previously known scaffolds.
Computations show that catalyst 9 is the most stereoselective
because the Re-face attack (TS6) is stabilized by favorable
electrostatic interactions between the phenyl group and the
fluorine on the catalyst backbone. Further computational
studies on relative reaction rates and on the selectivities of
triazolium catalysts 7–9 are underway.
[6] For reviews on the effect of fluorine on molecular conformation,
see: a) L. Hunter, Beilstein J. Org. Chem. 2010, 6, No. 38; b) L. E.
Zimmer, C. Sparr, R. Gilmour, Angew. Chem. 2011, 123, 12062 –
12074; Angew. Chem. Int. Ed. 2011, 50, 11860 – 11871.
[7] Enders has reported the asymmetric Stetter of butanal and
chalcone with two different chiral thiazolium catalysts (4%
yield, 39% ee and 29% yield, 30% ee); see: a) D. Enders, B.
Bockstiegel, H. Dyker, U. Jegelka, H. Kipphardt, D. Kownatka,
H. Kuhlmann, D. Mannes, J. Tiebes, K. Papadopoulos in “Wege
zu neuen Verfahren und Produkten der Biotechnologie”,
DECHEMA-Monographie 1993, 129, 209; b) D. Enders in
Stereoselective Synthesis (Eds.: E. Ottow, K. Schçllkopf, B.-G.
Schulz), Springer, Berlin, 1994, p. 63; c) D. Enders, K. Breuer,
Comprehensive Asymmetric Catalysis, Springer, Berlin, 1999,
pp. 1093 – 1104; d) D. Enders, T. Balensiefer, Acc. Chem. Res.
2004, 37, 534 – 541.
Experimental Section
Triazolium salt
9 (22 mg, 0.05 mmol, 0.2 equiv), b-nitrostyrene
[8] a) Glorius et al. reported a single example of an asymmetric
intermolecular Stetter reaction of an aliphatic aldehyde adding
to a b-unsubstituted Michael acceptor; see ref. [5c]; b) An
enzyme catalyzed asymmetric Stetter reaction has recently been
published, providing Stetter products of acetaldehyde: C.
Dresen, M. Richter, M. Pohl, S. Lꢃdeke, M. Mꢃller, Angew.
Chem. 2010, 122, 6750 – 6753; Angew. Chem. Int. Ed. 2010, 49,
6600 – 6603.
[9] The use of stronger bases and/or more polar solvents leads to
base-induced decomposition products.
[10] See the Supporting Information for complete experimental
details.
[11] J. M. Um, D. A. DiRocco, E. L. Noey, T. Rovis, K. N. Houk, J.
Am. Chem. Soc. 2011, 133, 11249 – 11254.
[12] M. J. Frisch, et al. Gaussian 09, revision A.1, Gaussian, Inc.,
Wallingford, CT, 2009 (See the Supporting Information for full
reference).
[13] a) V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995 – 2001;
b) M. Cossi, N. Rega, G. Scalmani, V. Barone, J. Comput. Chem.
2003, 24, 669 – 681.
(38 mg, 0.25 mmol, 1.0 equiv), sodium acetate (8 mg, 0.10 mmol,
0.4 equiv), and tert-amyl alcohol (2 mL, 0.125m) were added to a dry
4 mL vial with a magnetic stir bar. The vial was cooled to 08C in
a cooling bath with stirring and purged with argon. Butyraldehyde
(34 mL, 0.375 mmol, 1.5 equiv) was added dropwise and the reaction
was stirred at 08C until TLC indicated consumption of the nitro-
styrene (24–48 h), at which point the reaction was concentrated
in vacuo. The residue was purified by flash chromatography (20:1,
hexanes/ether), which provided the desired b-nitro ketone as a color-
less oil.
Received: October 27, 2011
Revised: December 20, 2011
Published online: January 26, 2012
Keywords: density functional calculations · fluorination ·
.
N-heterocyclic carbenes · organocatalysis · Stetter reaction
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[19] The anti conformation is favored for TS4 and TS6. The
gauche (+) conformation is only slightly favored (0.5 kcal)
over the anti conformation for TS2.
[20] The addition of the acyl anion equivalent to the olefin is
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[21] A table of all transition structure energies is given in the
Supporting Information.
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