Scalable and Highly Diastereo- and Enantioselective Catalytic Diels-Alder Reaction of α,β-Unsaturated Methyl Esters

Article abstract of DOI:10.1021/jacs.8b07092

Despite tremendous advances in enantioselective catalysis of the Diels-Alder reaction, the use of simple α,β-unsaturated esters, one of the most abundant and useful class of dienophiles, is still severely limited in scope due to their low reactivity. We report here a catalytic asymmetric Diels-Alder methodology for a large variety of α,β-unsaturated methyl esters and different dienes based on extremely reactive silylium imidodiphosphorimidate (IDPi) Lewis acids. Mechanistic insights from accurate domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) calculations rationalize the catalyst control and stereochemical outcome.

Full text of DOI:10.1021/jacs.8b07092

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Scalable and Highly Diastereo- and Enantioselective Catalytic Diels−
Alder Reaction of α,β-Unsaturated Methyl Esters
Tim Gatzenmeier, Mathias Turberg, Diana Yepes, Youwei Xie, Frank Neese, Giovanni Bistoni,
and Benjamin List*
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈ ̈
S
* Supporting Information
ABSTRACT: Despite tremendous advances in enantio-
selective catalysis of the Diels−Alder reaction, the use of
simple α,β-unsaturated esters, one of the most abundant
and useful class of dienophiles, is still severely limited in
scope due to their low reactivity. We report here a
catalytic asymmetric Diels−Alder methodology for a large
variety of α,β-unsaturated methyl esters and different
dienes based on extremely reactive silylium imidodiphos-
phorimidate (IDPi) Lewis acids. Mechanistic insights
from accurate domain-based local pair natural orbital
coupled-cluster (DLPNO-CCSD(T)) calculations ration-
alize the catalyst control and stereochemical outcome.
In our efforts to overcome existing challenges in asymmetric
Lewis acid catalysis, we have recently proposed a new strategy
to catalyze the Diels−Alder reaction of α,β-unsaturated esters
with an achiral, cationic silylium ion and an enantiopure
counteranion (eq 1).11 This asymmetric counteranion-directed
silylium Lewis acid catalysis (silylium-ACDC)12 differs
conceptually from conventional enantioselective Lewis acid
catalysis, which typically utilizes metal(loid) complexes with
chiral ligands or substituents.13 Rendering such complexes
cationic and combining them with weakly coordinating, achiral
counteranions is often a powerful measure to increase their
activity. In contrast, the inversion of the chiral entities within
the ion pair, as provided with silylium-ACDC, allows for the
unique feature in silylium catalysis of possessing a repair
pathway upon hydrolytic deactivation.11,14 The source of
chirality is hydrolytically stable, converts back to the Brønsted
acidic state, and can be reactivated in the presence of a suitable
silylating reagent. Providing a slight excess of the silylating
reagent compared to the chiral Brønsted acid then allows for
very low catalyst loadings of the chiral Brønsted acid
he discovery of the Diels−Alder reaction by Kurt Alder
Tand Otto Diels is regarded as one of the transforming
events in organic chemistry.1 The power and efficiency to
rapidly build up complexity by forming up to four stereo-
centers at once was quickly realized and led to many important
and elegant applications in the chemical synthesis of complex
natural products,2 agrochemicals, pharmaceuticals and fra-
grances.3 In the historical development of stereoselective
synthesis, the Diels−Alder reaction has served as one of the
most prominent platforms and α,β-unsaturated carboxylic acid
derivatives have been a widely applied class of dienophiles. In
fact, a very early approach to asymmetric synthesis was the
Lewis acid-mediated Diels−Alder reaction of enantiopure
acrylates with cyclopentadiene.4 Within the area of asymmetric
Lewis acid catalysis, chiral complexes based on aluminum,
titanium, copper, boron and others have emerged,5 which
enabled high enantioselectivities with α,β-unsaturated N-acyl
oxazolidinones, aldehydes, ketones, and trifluoroethyl esters as
dienophiles. Also some simple, unactivated α,β-unsaturated
esters, such as methyl or ethyl acrylate and crotonate, in
combination with cyclopentadiene can engage in highly
enantioselective Diels−Alder reactions catalyzed either by
chiral alkyldichloroboranes introduced by Hawkins6 or Corey’s
cationic oxazaborolidines (CBS),5c,7 which undoubtedly
represent the most versatile family of chiral Lewis acids to
date. In addition, various organocatalytic approaches have been
described for α,β-unsaturated aldehydes and ketones via
asymmetric iminium ion or Brønsted acid catalysis.8,9 Despite
these examples, the application of simple α,β-unsaturated
esters as a highly abundant and fundamental class of
dienophiles is still severely limited in scope due to their
particularly low reactivity.10
Figure 1. Reaction development and catalyst systems.
Received: July 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b07092
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Journal of the American Chemical Society
Communication
Figure 2. Substrate/diene scope and catalyst recycling. Reactions of α,β-unsaturated methyl esters with dienes: awith catalyst 4a; bwith catalyst 4b;
d
cwith catalyst 4c; with catalyst 4d (3 mol %).
precatalyst. In addition, the logic of designing more stabilized
and weaker coordinating enantiopure anions also applies here
and leads to higher activity of the corresponding cationic
silylium species.
see the Supporting Information). Gratifyingly, we could
identify two distinct families of IDPi catalysts, which after
optimization gave very high enantio- and diastereoselectivities.
Catalysts 4a and 4b possess 3,5-(trifluoromethyl)phenyl
substituents, while IDPi 4c features cyclobutyl-derivatized 3-
fluorenyl substituents on the BINOL backbone. In general,
inner core modification toward longer perfluoroalkyl groups
(e.g., R = C2F5)15e−h increased catalytic activity, while the
impact on enantioselectivity varied. The type of silylating
reagent (5) suitable to activate the IDPi Brønsted acid
precatalysts to the silylium-Lewis acids depends on catalyst
acidity and activation temperature. We investigated silyl ketene
acetals (SKA), methallylsilanes, and allylsilanes as activators
and found that their silylating power decreased in this order.
Though the type of reagent had no effect on enantioselectivity,
the impact of the silyl group on both reaction rate and
stereoselectivity was quite significant. Independent reaction
optimization with both privileged catalysts revealed triethyl
allylsilane 5a as the optimal activator of catalyst 4a (condition
A), while catalyst 4c performed best with triisopropylsilyl
(TIPS) SKA 5b (condition B). Both catalyst systems gave
After demonstrating this concept for the catalytic asym-
metric Diels−Alder reactions of 9-fluorenylmethyl cinnamate
esters with a chiral C−H acid as the Lewis acid precursor,11 we
were recently able to utilize simple α,β-unsaturated methyl
esters in enantioselective Mukaiyama−Michael reactions with
silyl ketene acetals (SKA) and highly acidic and confined
imidodiphosphorimidate (IDPi) catalysts.15 We now report
the development of a catalytic asymmetric Diels−Alder
methodology for a large variety of α,β-unsaturated methyl
esters and different dienes, including normally unreactive
substrate combinations.
We chose the Diels−Alder reaction between only weakly
reactive methyl trans-cinnamate (1a) and cyclopentadiene
(2a) as our model reaction (Figure 1) and conducted an
extensive catalyst evaluation. We found that our IDPi acids
provided both sufficient activity and promising enantioselec-
tivities compared to other chiral acids tested (for more details,
B
DOI: 10.1021/jacs.8b07092
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Figure 3. Scale-up experiments and reduced catalyst loadings.
Figure 4. Computational Studies. (A) Catalyst activation. (B) Diels−Alder reaction profiles. (C) Interaction within the chiral ion pair (CIP);
Geometry optimizations with PBE-D3(BJ)/def2-SVP; single-point energies with DLPNO-CCSD(T)/def2-TZVP+C-PCM(toluene).
equally high yields and enantioselectivities (e.r. ≥ 97:3) in our
model reaction using only 1 mol % of IDPi and a
substoichiometric amount of silylating reagent at −40 °C.
With this flexibility and optional fine-tuning in hand, we
proceeded to explore the scope of α,β-unsaturated esters as
dienophiles with cyclopentadiene (2a) (Figure 2). As
condition A provided higher reactivity and increased
diastereoselectivity, we tested a variety of methyl- and
bromo-substituted cinnamates with catalyst 4a and found
that these arene-substitutions were well tolerated, and the
desired products (3b−g) were obtained in high yields and
excellent enantio- and diastereoselectivities. Similar results
were achieved for para-fluoro- or trifluoromethyl-substituted
products 3h and 3i under the same conditions. For stronger
electron-deficient substrates such as cinnamate 1j and 3-
heteroaryl-substituted acrylates 1n and 1o, we used catalyst 4b
to efficiently catalyze the reaction. When electron-rich
substrates were tested to afford products 3k and 3i, increased
catalyst loading (3 mol % of 4a) and temperature (−20 °C)
provided sufficient reactivity to obtain high yields and
stereocontrol. As 3-alkyl acrylates were empirically found to
be more reactive than 3-aryl acrylates,5c both available catalyst
systems were explored at decreased temperatures (−80 °C)
and gave product 3p in comparably excellent yields and
enantioselectivities. With catalyst 4a, various alkyl-substituted
products (3q−s, 3u−v) were isolated with consistently very
high levels of stereocontrol, while the enantioselectivities
slightly decreased with shorter chain lengths. With γ-branched
methyl 4-methylpent-2-enoate (1t) and methyl crotonate
(1w); however, switching to catalyst 4c in combination with
the triethylsilyl (TES) group under neat conditions was
necessary to obtain excellent results for products 3t and 3w.
In light of the extremely high activity of our silylium-Lewis
acids, we proceeded to explore other representative dienes,
such as 2,3-dimethylbutadiene 2b (krel = 4.9), trans-pentadiene
2c (krel = 3.3), isoprene 2d (krel = 2.3) and cyclohexadiene 2e
(krel = 1.9), which are orders of magnitude less reactive than
cyclopentadiene 2a (krel = 1350), in reference to butadiene (krel
= 1).16 We found that IDPi’s of the 3-fluorenyl substitution
family were generally superior over 3,5-(trifluoromethyl)-
phenyl derivatives 4a and 4b in enantiodiscrimination, whereas
significantly higher activities could be achieved by attaching a
longer, linear perfluoroalkyl chain (R = C6F13) to the inner
core sulfonyl groups. This led to the identification of
cyclopentyl-derivative 4d as the optimal catalyst in combina-
tion with TIPS methallylsilane 5d as the activator. Diels−Alder
reactions of representative dienophiles 1a and 1p covering a
range of reactivity and both 2,3-dimethylbutadiene and
isoprene proceeded with a very high degree of stereocontrol
in good yields under neat conditions. A higher catalyst loading
of 3 mol % was used in these cases. However, catalyst
recyclability over five cycles gave consistently high yields and
enantioselectivities, while only small losses of the catalyst were
observed, presumably due to chromatographic reisolation.
C
DOI: 10.1021/jacs.8b07092
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Journal of the American Chemical Society
Communication
Diels−Alder transition states. The competing transition states
for each of the endoenantiomers (TSs‑trans; marked in black and
blue) are predicted to give an e.r. of 93:7 (ΔΔG‡ = 1.2 kcal/
mol), which is in good agreement with the experimental data
(e.r. 97:3, ΔΔG‡ = 1.6 kcal/mol). The most stable TS features
two stabilizing nonclassical C−H···O hydrogen bonds
(between an oxygen atom of the SO2CF3 group of the catalyst
and the C−H groups of the cyclopentadiene) that are missing
in the other TS structures. Subsequently, desilylation and
release of the product is thermodynamically favored rendering
the silylated IDPi as the resting state within the catalytic cycle.
We further investigated the CIP in greater detail to understand
the origin of enantioselectivity (Figure 4C). The electrostatic
potential maps revealed that the most favorable interaction
mode (ΔG = −23.8 kcal/mol) for this structure orients the
phenyl ring of 1a far from the counteranion, consistent with
the high enantioselectivities observed for various substitutions
at the 3-position. In addition, the methyl group of the substrate
is pointing inside the chiral pocket of the IDPi moiety, overall
resulting in a striking geometrical match of the ion pair. In this
context, we also tested ethyl and benzyl trans-cinnamate as
substrates, but not only detected sluggishly reactivity with 4a
but also significantly diminished enantioselectivities (e.r. 75:25
with ethyl cinnamate; e.r. 57.5:42.5 with benzyl cinnamate),
which can be rationalized by an improper fit with such bulkier
groups. Upon rationalizing catalyst-substrate interactions and
enantioinduction, we derived a stereochemical mnemonic
based on steric shielding of the enantiotopic faces by the IDPi
anion (Figure 5).
Figure 5. Stereochemical mnemonic.
Highly challenging reactant combinations involving trans-
pentadiene and cyclohexadiene gave significantly lower
conversions and only low enantioselectivity for product 3y.
With methyl cinnamate, both dienes gave no isolatable
amounts of the products even after prolonged reaction time.
In contrast, the expected order of diene reactivity was observed
in nonenantioselective Diels−Alder reactions with TMS-NTf2
as the catalyst, confirming the strong influence of the confined
IDPi environment in these cases. We also found that increasing
the reaction temperature to above 0 °C proved to be
deleterious for the reaction rate and a significant amount of
catalyst methylation was observed, presumably due to a
collapse of the chiral ion pair consisting of the silylated methyl
ester substrate and its counteranion.
To highlight the synthetic potential of our methodology for
scale-up applications, we lowered the catalyst loading further to
only 0.1 mol % and conducted several gram-scale reactions
under neat conditions to furnish products 3a,k,e,w in nearly
quantitative yields and very high enantioselectivities (Figure
3). Importantly, only small amounts of easily filterable
cyclopentadiene polymerization products were formed. As
our silylium-Lewis acid approach conveniently includes self-
drying conditions,11,15g we could also run these reactions
without an inert gas atmosphere and observed essentially
identical results. On the other hand, strictly anhydrous
conditions allowed us to reduce the amount of silylating
reagent to 5 mol %.
In summary, we report the development of a catalytic
asymmetric Diels−Alder methodology for a large variety of
poorly reactive α,β-unsaturated methyl esters and different
dienes to give the cycloaddition products in excellent yields,
enantio- and diastereoselectivities. Many of the products have
previously been inaccessible with known chiral Lewis acids,
while the corresponding Diels−Alder reactions can now be
accomplished with very low catalyst loadings of only 0.1−3
mol %. Future work will focus on overcoming remaining
challenges in catalytic asymmetric Diels−Alder reactions and
on synthetic applications toward important target structures.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b07092.
■
S
Additional detailed information on reaction develop-
ment, synthetic protocols, analytical data for all
compounds, and the computational strategy (PDF)
In order to obtain deeper insight into the reaction
mechanism and the catalyst’s mode of action, we investigated
the reaction profile for methyl cinnamate, cyclopentadiene and
(S,S)-4a at the DLPNO-CCSD(T)/def2-TZVP + C-PCM-
(toluene) // PBE-D3 (BJ)/def2-SVP level of theory.17
Silylation of the IDPi acid with allylsilane 5a to give the active
catalyst occurs instantaneously at r.t. as observed by NMR and
propene formation was detected (Figure 4A).
Subsequently, the silyl group is transferred onto the carbonyl
group of the substrate to form a chiral ion pair (CIP, Figure
4B) in an endothermal process (ΔG = 7.4 kcal/mol) with the
s-trans conformation as the most stable intermediate.
Interaction of cyclopentadiene with the CIP gives a reactant
complex (RCs‑trans) as a subsequent intermediate toward the
AUTHOR INFORMATION
Corresponding Author
*list@kofo.mpg.de
ORCID
Frank Neese: 0000-0003-4691-0547
Giovanni Bistoni: 0000-0003-4849-1323
Benjamin List: 0000-0002-9804-599X
■
Notes
The authors declare the following competing financial
interest(s): Patent WO2017037141 (A1) has been filed by
the MPI fur Kohlenforschung covering the IDPi catalyst class
̈
and their applications in asymmetric synthesis.
D
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ACKNOWLEDGMENTS
■
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L.), the Fonds
der Chemischen Industrie (Kekule Fellowship to M.T.), and
the European Research Council (Advanced Grant “C−H Acids
for Organic Synthesis, CHAOS”) are gratefully acknowledged.
This work is part of the Cluster of Excellence RESOLV (EXC
1069) funded by the DFG. We thank the technicians of our
́
̈
group, especially Arno Dohring for large-scale preparation of
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Phosphoramide as a Strong Chiral Brønsted Acid and Its Application
to Asymmetric Diels−Alder Reaction. J. Am. Chem. Soc. 2006, 128,
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cyclopentadiene. Also special thanks to the GC, NMR, and
HPLC departments of our institute for their excellent service.
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DOI: 10.1021/jacs.8b07092
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX