Enantioselective Palladium-Catalyzed [3+2] Cycloaddition of Trimethylenemethane and Fluorinated Ketones

Article abstract of DOI:10.1002/anie.201807308

A nitrile-substituted trimethylenemethane (TMM) donor undergoes palladium-catalyzed [3+2] cycloadditions with fluorinated ketones to generate tetrasubstituted trifluoromethylated centers in high enantioselectivity under mild conditions. The generation of the palladium–TMM complex was achieved by a self-deprotonation strategy, which shows remarkable improvements in regiocontrol, efficiency, and atom economy of asymmetric [3+2] cycloadditions. Moreover, the versatility of the nitrile group provides direct access to a variety of synthetically useful intermediates, including amides, aldehydes, and esters. The developed reaction conditions allow for the synthesis of a wide variety of aromatic, heteroaromatic, and aliphatic fluorinated dihydrofurans in excellent regio- and enantioselectivities.

Full text of DOI:10.1002/anie.201807308

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Accepted Article
Title: Enantioselective Palladium-Catalyzed [3+2] Cycloaddition of
Trimethylenemethane and Fluorinated Ketones
Authors: Barry M. Trost and Guillaume Mata
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Enantioselective Palladium-Catalyzed [3+2] Cycloaddition of
Trimethylenemethane and Fluorinated Ketones
Barry M. Trost* and Guillaume Mata
Abstract: A nitrile-substituted trimethylenemethane (TMM) donor
undergoes palladium-catalyzed [3+2] cycloadditions with fluorinated
ketones to generate tetrasubsituted trifluoromethylated centers in
high enantioselectivity under mild conditions. The generation of the
palladium-TMM complex was achieved via a self-deprotonation
strategy which shows remarkable improvements in regiocontrol,
efficiency and atom economy of asymmetric [3+2] cycloadditions.
Moreover, the versatility of the nitrile group provides a direct access
to a variety of synthetically useful intermediates, including amide,
aldehyde and ester. The developed reaction conditions allow the
synthesis of a wide variety of aromatic, heteroaromatic and aliphatic
fluorinated dihydrofurans in excellent regio- and enantioselectivities.
corresponding chiral trifluoromethyl-substituted tertiary alcohol
(Scheme 1A).[ These desired tertiary alcohol intermediates are
usually prepared by asymmetric addition of nucleophiles to
trifluoromethyl ketones[5] or nucleophilic trifluoromethylation of
4]
prochiral ketones.[6] Although highly enantioselective, these
methods are very limited to a specialized class of substrate.[
6a]
A
more general approach was recently developed by the
Buchwald group and involved the nucleophilic ring-opening of
enantioenriched 2-trifluoromethyloxiranes functionalized using
Negishi coupling.[
7]
Despite the development of elegant
strategies to access chiral trifluoromethyl-substituted tertiary
alcohols, methods that directly assemble 2,2-disubstituted
dihydrofurans in a single step from available fluorinated ketones
would be of high interest (Scheme 1B).[
8]
Fluorinated substituents are considered to be an integral
component in pharmaceuticals due to their ability to affect the
pharmacological activity of drugs (i.e. adsorption, distribution,
metabolism and excretion).[1] As a result, the introduction of
fluorine atoms, such as the strongly electron-withdrawing
trifluoromethyl (CF
lead optimization in drug discovery.[2] Among these fluorinated
building blocks, 2,2-disubstituted isoxazolidines and
dihydrofurans bearing tetrasubstituted trifluoromethylated
3
) group, represents a general strategy during
a
center are found in many bioactive molecules, such as the
®
antiparasitic drugs fluralaner (1a, Bravecto , Merck, (Figure 1),
lotilaner (1b, CredelioTM, Novartis) and sarolaner (1c, Simparica®,
Pfizer).[3]
Scheme 1. Asymmetric Construction of 2,2-Disubstituted Dihydrofurans with
Trifluoromethyl Ketones. Nu = nucleophile; X = EWG = electron withdrawing
group; LG = leaving group.
Figure 1. Examples of Commercial and Patented Pharmaceuticals Containing
a Tetrasubsituted Trifluoromethylated Carbon Center.
Our group has a long-standing interest in [3+2] cycloaddition
of trimethylenemethane (TMM) donors with electron-deficient
acceptors.[9] Recently, we have demonstrated that the σ-electron
One common strategy to enantioselectively generate 2,2-
disubstituted dihydrofurans relies on multistep sequences where
the five-membered ring is forged following the formation of the
withdrawing properties of the CF
3
group could be used to
promote the [3+2] cycloaddition affording cyclopentanes bearing
a quaternary center, albeit without absolute control of chirality
(
Scheme 1C).[10] Given the fact that aldehydes[8e] and ketones[8f]
[*]
Prof. Dr. B. M. Trost, Dr. G. Mata
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: bmtrost@stanford.edu
were shown to be suitable acceptors in TMM chemistry, we
envisioned the use of trifluoromethyl ketones to generate the
corresponding 2,2-disubstituted dihydrofurans (Scheme 1D).
One important challenge associated with trifluoromethyl ketones
Supporting information for this article is given via a link at the end of
the document.
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deals with the differentiation of enantiotopic faces considering
acceptors, the addition of species III to ketone 3 occurs at a
competitive rate with the π−σ−π isomerization, potentially
leading to the formation of 5 and 6.
the significantly larger van der Waals volume and shape of the
1a,11]
CF
3
group as compared to the CH
3
group.[
In addition, the
enhanced electrophilicity of fluorinated ketones renders
uncatalyzed pathways more competitive, preventing the
formation of product in high enantioselectivity. Nevertheless, the
recent discovery of bulky phosphoramidite as effective ligands
with remarkable activity in asymmetric palladium-catalyzed [3+2]
cycloadditions prompted us to explore this challenging task.[12]
At the same time, we hoped to introduce molecular
complexity using a nitrile-substituted donor which can serve as a
versatile synthetic intermediate.[13] Although we have previously
observed that simple ketones were not reactive with nitrile-
substituted donor 2a,[14] we anticipated that the enhanced
electrophilicity of fluorinated ketones would resolve this issue.
When reacting with highly electron-withdrawing acceptors such
as imines,[15] however, we have previously observed that donor
Using simple olefins as acceptors in racemic [3+2]
cycloadditions, Tsuji demonstrated the ability to generate the
desired cyclopentane from ethyl 2-(cyanomethyl)allyl carbonate
at elevated temperatures.[ Based on this study, we anticipated
that compound 2c would be a compatible TMM donor, forming
species I and the desired product 4 directly through catalytic
cycle A. In addition, we designed donor 2c with a Boc functional
group to facilitate the enantioselective cycloaddition at lower
temperatures.
16]
To test this hypothesis, we compared the reactivity of donors
2a and 2c with 2,2,2-trifluoroacetophenone 3a in the presence of
2 3
Pd (dba)
and phosphoramidite ligand L1 (Figure 2).[ Under
17]
such conditions, donor 2a afforded trifluoromethylated
cycloadducts 4a and 6 in a 4:1 ratio respectively (entry 1 in
Table 1), while under the same conditions, donor 2c essentially
formed 4a as a single regioisomer (>20:1, entry 2 in Table 1).
Interestingly, the enantioselectivity of 4a was similar (50% ee)
independent of the donor used which highlight that cycloadduct
2a gave rise to the formation of an undesired mixture of
regioisomers giving cycloadducts of type 5 or 4 as well as
adduct 6 having the nitrile group at the exocyclic double bond
(
Scheme 2).
4a is formed via the same chiral species II. In addition to
improving regioselectivity, the overall asymmetric [3+2]
cycloaddition using the deprotonation approach with 2c, is a
more atom-economic process and produces tert-butanol as the
only waste.[18]
Encouraged with the regioselectivity of this process, we then
explored different ligands to optimize the enantioselectivity of the
trifluoromethylated cycloadduct 4a (Table 1). It is worth noting
that all the different ligands tested gave exclusive regiocontrol of
the reaction (>20:1) when using donor 2c even when the
reaction was performed at 50 °C.
Scheme 2. Proposed Catalytic Cycles for the deprotonation and desilylative
approaches of the [3+2] Cycloaddition with Trifluoromethylated Ketones.
Such mixtures of regioisomers can be anticipated when
reacting donor 2a with highly activated fluorinated ketones 3. As
shown in Scheme 2, when palladium (0) reacts with donor 2a,
π−allyl species III is formed while displacing trimethylsilyl
acetate. This step is followed by the formation of the more stable
species I through π−σ−π isomerization. Due to the highly
nucleophilic character of the palladium-phosphoramidite-donor
system and the highly activated nature of trifluoromethyl ketone
Table 1. Optimization of [3+2] Cycloaddition with Trifluoromethyl Ketones. [a]
Reactions were performed in a 0.1 mmol scale. 19F NMR analysis of the crude
mixture was used to monitor conversions and to determine ratio of
regioisomers. Yields represent isolated product. Enantiomeric excess values
(ee) were determined by HPLC using a chiral stationary phase. [b] Donor 2a
was used. [c] Ketone 3a was freshly distilled prior to use.
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With these optimized reaction conditions in hand, we decided
to explore the scope of the transformation (Scheme 3). Within
the variety of fluorinated ketones evaluated, we found that in all
cases the reaction afforded the cycloadducts with excellent
regioselectivity (>20:1) for the endo isomer. Substitution at the
ortho-, meta-, or para-position of aryl-bearing ketones with
fluorine (3b), bromine (3c) and chlorine (3e) is well tolerated,
affording adducts 4b, 4c, and 4d in up to 86% yield and 95% ee.
Of particular note, compound 4d constitutes
a common
structural motif found in many commercialized and patented
bioactive molecules such as 1a and 1d and could be used to
access structural analogs (Figure 1). Electron-rich trifluoromethyl
ketones (3f and 3g) and electron-poor ketones (3i–3l) were very
well tolerated as well as a variety of functional groups giving
cycloadducts containing thioether (4h), sulfone (4j) and ester
(
3
4k) moieties. In particular, we conducted a scale-up with ketone
k using only 1.5 mol% of CpPd(η -C ) to obtain 4k in 84%
3
3 5
H
yield in excellent regio- (>20:1) and enantioselectivity (91% ee),
demonstrating the robustness and scalability of this
transformation. Trifluoromethyl ketones containing heterocycles
such as pyridine (3l), thiophene (3m) and furan (3n) gave the
desired products 4l-4n with excellent stereocontrol (94% yield
and 97% ee for 4n). Importantly, the scope of the cycloaddition
was not restricted to aromatic ketones since adducts 4p and 4r
were obtained in good enantioselectivity (97% ee and 82% ee,
respectively), albeit with lower isolated yields due to
regioselectivity and reactivity issues associated with their
corresponding ketones 3p and 3q.
Figure 2. Ligands used in this study.
Generally, the enantioselectivity of the reaction was
enhanced with increased rigidity of the ligand. The key structural
feature was a pyrrolidine ring substituted with a larger aromatic
surface leading to 50% ee with L1, 78% ee with L4 and 86% ee
with L5 (Table 1 and Figure 2). As shown in previous reports on
cycloadditions with aldehydes[8e] and ketones,[8f] L6, bearing an
unsymmetrical binol core and defined stereochemistry at
phosphorus outperformed its less bulky siblings L5 and afforded
4a in 90% yield and 94% ee (entry 11).
Scheme 3. Scope of the Palladium-Catalyzed [3+2] Cycloaddition with Fluorinated Ketones. [a] Reactions were performed at 23 °C. [b] Reactions were performed
with 8 mol% CpPd(η -C ), 10 mol% ligand L6, and 1.4 equiv. of 2c at 50 °C. [c] Cycloadduct 4p was obtained as a mixture (1:1.7) with the corresponding
cyclopentane derived from reaction at the olefin. [d] Reaction was performed on 1.2 mmol scale.
3
3 5
H
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COMMUNICATION
Under similar conditions, we were pleased that a variety of α,α-
difluoroketones, where a fluorine atom was substituted with a
chlorine (3r), a trifluoromethyl (3s), or alkyl groups (3u-v), were
compatible substrates in the [3+2] cycloadditions producing 4r-
4
v in excellent enantioselectivities (up to 99% ee with 3r). Even
ketone 3t, containing an acidic proton,[19] was well tolerated with
the self-deprotonation donor.
The absolute configuration of the cycloadducts was
unambiguously determined after generating compound 7,
[20]
suitable for crystallographic characterization (Scheme 4). The
absolute stereochemistry obtained with 2c is consistent with the
results obtained with donor 2a in both imine[15] and nitroalkene[21]
cycloadditions.
Scheme 5. Functionalization and Derivatization of the Products. Reaction
Scheme 4. Reaction conditions: a)
dioxane, 16 h, 90 °C, 84%. Structure of cycloadduct 7 in the solid state.
Thermal ellipsoids are drawn at the 50% probability level.
5
mol% Pd(dppf)Cl
2
·CH
2
Cl
2
,
AcOK,
conditions: a) CrO
mol% Parkin’s catalyst, PtH-[(PMe
82% (9), 87% (13). c) Raney-Nickel, B(OH)
3 °C, 24h, 74%. d) NaBH , MeOH/CH Cl
NaH PO , 2-methyl-2-butene, tBuOH/H O, 23 °C, 24h, ii) K
°C, 1h, 65%. f) 1,10-phenantholine, Cs CO CuI, DMSO, 110 °C,
3
, 3,5-dimethylpyrazole, CH
O) H](PMe
, PPTS, H
, 1h, 23 °C, 94%. e) i) NaClO
CO , MeI, acetone,
2
Cl
OH), EtOH/H
(balloon), iPrOH/H
2
, –20 °C, 1h, 78%. b) 10
O, 45 °C, 48h,
O,
2
2
2
2
3
2
2
2
4
2
2
2
,
2
4
2
2
3
50
2
3
,
To demonstrate the synthetic utility of the cycloadducts and
the benefits of incorporating the nitrile group, various
modifications of the parent cycloadduct 4a were performed
microwave, 30 min, 70%. 4z was obtained in 60% yield and 42% ee.
(
Scheme 5). First, allylic oxidation of 2,5-dihydrofuran 4a using
In summary, a catalytic asymmetric [3+2] cycloaddition of
fluorinated ketones has been developed, giving 3-cyano-2,2-
disubstituted dihydrofurans in excellent yields and regio- and
enantioselectivities (up to 96% yield and 99% ee). The
successful enantiocontrol of the reaction hinges on the chiral
phosphoramidite ligand L6 which was found very effective even
in the particularly challenging case of trifluoromethyl ketones. In
addition to having a remarkable atom-economic process from
the deprotonation strategy, the nitrile group provides direct
the combination of CrO and 3,5-dimethylpyrazole afforded the
3
fully substituted butenolide 8 in 78% yield.[22] This strategy
represents a short route to a higly functionalized butenolide,
which constitutes the structural core of numerous natural
products.[ Next, the sterically hindered ,-unsaturated nitrile
substituent was converted into different oxidation states.
Hydration of 4a into the corresponding amide was achieved
using the hydride-platinum(II) catalyst developed by Parkins and
co-workers[ to give 9 in 82% yield. Reduction of 4a using
Raney-Nickel[25] afforded ,-unsaturated aldehyde 10 in 74%
yield, which was then used to generate primary alcohol 11 with
23]
24]
access to
a variety of synthetically useful intermediates,
including amides, esters, aldehydes and alcohols, which could
serve as handles for further modifications. The reported
synthetic protocol for the assembly of trifluoromethyl-substituted
dihydrofurans represents a powerful tool for the construction of
highly functionalized potential pharmaceuticals.
NaBH
addition, hydration of 4w into the corresponding amide afforded
3 which was subjected to a copper-mediated intramolecular
4
and methyl ester 12 using a Pinnick oxidation.[26] In
1
Goldberg coupling giving the tricyclic structure 14 in 70%
yield.[27]
Acknowledgements
We thank the National Science Foundation (CHE-1360634) for
their generous support of our program. We thank Dr. Jana
Maclaren (Stanford University) for X-ray crystallographic
analysis. We gratefully acknowledge the Swiss National Science
Foundation (P300P2-171434) for financial support (fellowship to
G.M.).
Keywords: asymmetric catalysis • cycloaddition • dihydrofuran •
fluorine • palladium
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COMMUNICATION
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COMMUNICATION
COMMUNICATION
Barry M. Trost* and Guillaume Mata
Page No. – Page No.
Enantioselective Palladium-Catalyzed
[
3+2] Cycloaddition of
Trimethylenemethane and
Fluorinated Ketones
Self-Deprotonation: A palladium-catalyzed enantioselective [3+2] cycloaddition of
a nitrile-substituted trimethylenemethane (TMM) donor has been developed. The
generation of the TMM was achieved using the C-H bond acidity adjacent to the
nitrile group. The donor reacted with various fluorinated ketones to generate 2,2-
disubstituted dihydrofurans in high yield and enantioselectivity.
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