Unanticipated Silyl Transfer in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis Using Silyl Nitronates

Article abstract of DOI:10.1021/acs.orglett.9b04404

The use of silyl nitronates is reported for the isothiourea-catalyzed synthesis of ?3-nitro-substituted silyl esters containing up to two contiguous stereocenters in good yields with excellent enantioselectivities (up to 93% yield and 99:1 er). The serendipitously discovered formation of silyl ester products in this reaction demonstrates a novel platform for catalyst turnover in α,β-unsaturated acyl ammonium catalysis.

Full text of DOI:10.1021/acs.orglett.9b04404

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Unanticipated Silyl Transfer in Enantioselective α,β-Unsaturated
Acyl Ammonium Catalysis Using Silyl Nitronates
Anastassia Matviitsuk,† Mark D. Greenhalgh,† James E. Taylor,†,§ Xuan B. Nguyen,‡
David B. Cordes,† Alexandra M. Z. Slawin,† David W. Lupton,*,‡ and Andrew D. Smith*,†
†EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, U.K.
‡School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
S
* Supporting Information
ABSTRACT: The use of silyl nitronates is reported for the
isothiourea-catalyzed synthesis of γ-nitro-substituted silyl
esters containing up to two contiguous stereocenters in
good yields with excellent enantioselectivities (up to 93% yield
and 99:1 er). The serendipitously discovered formation of silyl
ester products in this reaction demonstrates a novel platform
for catalyst turnover in α,β-unsaturated acyl ammonium
catalysis.
ithin the field of Lewis base organocatalysis, the
ammonium precursors, where catalyst turnover was promoted
Wgeneration and exploitation of α,β-unsaturated acyl by the aryloxide counterion released in situ during the reaction
(Scheme 1b).4 While demonstrating a successful proof of
ammonium intermediates has been showcased recently in a
range of enantioselective catalytic processes.1−3 These
concept, this work was limited by the relatively long reaction
time (16 h) and the requirement of using a nitroalkane as both
the pronucleophile and the solvent.5 In this letter, a new
protocol for α,β-unsaturated acyl ammonium catalysis is
demonstrated. When silyl nitronates are used as reactants,6
γ-nitro-substituted silyl ester products containing up to two
contiguous stereocenters are obtained in good yields with
excellent enantioselectivities (12 examples, up to 95% yield
and 99:1 er) (Scheme 1c). The silyl nitronate is therefore not
only required for the initial conjugate addition but also serves
an essential role in enabling catalyst turnover. Significantly, the
catalytic reactions take ≤1 h and require only 1.5−2 equiv of
the silyl nitronate, allowing the application of structurally
diverse nitroalkane substrates in this methodology.
synthetically versatile intermediates provide new avenues to
access stereodefined products through electrophilic reactivity
at C(1) and C(3) as well as latent nucleophilicity at C(2)
(Scheme 1). Traditionally, such processes require a reaction
partner that contains two nucleophilic sites to perform first
C(3) conjugate addition and second intramolecular turnover
of the Lewis base catalyst through addition at C(1) (Scheme
1a).1−3 To overcome this limitation, we recently reported the
use of α,β-unsaturated aryl esters as α,β-unsaturated acyl
Scheme 1. Catalyst Turnover Strategies in α,β-Unsaturated
Acyl Ammonium Catalysis
Initial studies investigated the application of silyl nitronates
in an isothiourea-catalyzed Michael addition to α,β-unsatu-
rated aryl ester 1 (Scheme 2a). Using silyl nitronate 2 (1
equiv), HyperBTM 3 as the catalyst (20 mol %), and i-Pr2NEt
as the base (1 equiv) in MeCN gave Michael addition product
4 in 45% yield with 95:5 er after 5 h at room temperature.
Interestingly, a second Michael addition product was also
observed (∼5%), which was identified as silyl ester 5. Intrigued
by the origin of this unanticipated product, further
optimization studies focused on maximizing the yield of silyl
ester 5.7 Variation of the α,β-unsaturated acyl ammonium
precursor demonstrated that the use of α,β-unsaturated
anhydride 6 provided silyl ester 5 in 41% yield with an
excellent 99:1 er (Scheme 2b). Significantly, the reaction was
complete within just 30 min. In addition to silyl ester 5, an
Received: December 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
d
Scheme 2. Reaction Optimization
Scheme 3. Reaction Scope: Variation of the α,β-Unsaturated
Anhydride
a
a
Isolated yields are given; er values were determined by CSP-HPLC
analysis. TIPS = triisopropylsilyl. For clarity, most of the hydrogen
atoms have been omitted from the representation of the X-ray crystal
structure of 9.
a
The er was determined following conversion to the corresponding
morpholinyl amide.4 The yield was determined by 1H NMR
b
spectroscopy of the crude product mixture using an internal standard.
c
d
ND = not determined. Isolated yields are given; er values were
use of a cyclic silyl nitronate provided cyclohexyl-substituted
derivative 11 in 60% yield with excellent enantioselectivity
(98:2 er), again in just 30 min. Notably, in our previous
methodology4 the use of nitrocyclohexane as the solvent
provided no Michael addition product, emphasizing the vastly
improved reactivity obtained by using silyl nitronates. The
application of unsymmetrically substituted silyl nitronates,
leading to products containing two contiguous stereocenters,
was investigated next. The use of a dialkyl-substituted nitronate
allowed a single diastereoisomer of 12 to be isolated in 26%
yield with >99:1 er. The relative and absolute configurations of
12 were confirmed by single-crystal X-ray analysis following
conversion to the benzylamide derivative 13. Signals
corresponding to the other diastereoisomer could not be
identified in the 1H NMR spectra of the crude reaction
mixture; however, a nitroso fumarate ester product (analogous
to 10) was also isolated in ∼50% yield,7 contributing to the
low yield of 12. The nitroso ester product was presumably also
formed following O-acylation of the silyl nitronate and may be
a consequence of the increased steric demands of this nitronate
retarding the rate of the desired Michael addition. Next, a
selection of (hetero)aryl-alkyl-substituted nitronates was
investigated. Michael addition products 14, 16, and 17 were
obtained in moderate to good yields with high enantiose-
lectivities (94:6 to 96:4 er). The diastereoselectivity in each
case was ∼70:30; however, the diastereoisomers were readily
separable by column chromatography. The relative and
absolute configurations of the major diastereoisomer within
this series were confirmed by single-crystal X-ray analysis
following conversion of silyl ester 14 to the morpholinyl amide
derivative 15. The protocol was further extended to monoaryl-
substituted nitronates,12,13 with additional optimization
showing that 2 equiv of silyl nitronate and the absence of
base were optimal for these substrates.7 Variation of the aryl
group within this series provided Michael addition products
18−21 in good yields with ∼75:25 dr and consistently
excellent er (up to >99:1). The relative and absolute
determined by CSP-HPLC analysis. TIPS = triisopropylsilyl.
approximately equal quantity of carboxylic acid 7 was
identified in the crude reaction product mixture,8 indicating
that ∼80% of the silyl nitronate had been transformed in the
desired Michael addition process. Increasing the amount of
silyl nitronate 2 to 1.5 equiv and using anhydrous MeCN9
minimized the amount of carboxylic acid 7, allowing isolation
of silyl ester 5 in 92% yield with 99:1 er (Scheme 2c). This
methodology therefore represents a significant advance over
our previous work using α,β-unsaturated aryl ester 1 and 2-
nitropropane as the solvent, in which only a 46% yield of
Michael addition product 4 was obtained after 16 h.4
With the use of 1.5 equiv of silyl nitronate, 1 equiv of i-
Pr2NEt, and 20 mol % 3 in anhydrous MeCN at room
temperature for 30 min as the standard conditions, the scope
and limitations of the method were investigated (Schemes 3
and 4). Variation of the β-substituent of the anhydride showed
that methyl ester and morpholinyl amide substituents were
tolerated, giving products 8 and 9 in excellent yields with high
enantioselectivities (Scheme 3). The absolute configuration of
9 was confirmed by single-crystal X-ray analysis. The use of
cinnamic anhydride did not provide the expected Michael
addition product but instead gave the isolable nitroso
cinnamate ester derivative 10 in 55% yield.10 On the basis of
literature precedent, this side product 10 is proposed to form
through O-acylation of the silyl nitronate followed by a formal
[2,3]-sigmatropic rearrangement (Scheme 3, gray box).11 This
result indicates that conjugate addition was disfavored in this
case and is consistent with previous examples of α,β-
unsaturated acyl ammonium catalysis where the presence of
an electron-withdrawing β-substituent is often beneficial for
activity.
The potential to apply this method to access more
structurally complex products was next probed through the
use of a diverse set of silyl nitronate reactants (Scheme 4). The
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g
a
Scheme 4. Reaction Scope: Variation of the Silyl Nitronate
Scheme 5. Epimerization Studies
a
1
dr values were determined by H NMR spectroscopy of the crude
product mixtures; er values were determined by CSP-HPLC analysis.
TIPS = triisopropylsilyl.
Scheme 6. Mechanistic Outline and Control Studies
a
b
The product was isolated as a single diastereoisomer. ND = not
c
d
determined. The reaction was performed at 0 °C. Each
diastereoisomer was isolated separately; the yield given is the sum
for the two diastereoisomers. 2 equiv of silyl nitronate and no i-
e
f
Pr2NEt were used. Isolated yield for a mixture of diastereoisomers.
g
1
Isolated yields are given; dr values were determined by H NMR
spectroscopy of the crude product mixtures; er values were
determined by CSP-HPLC analysis. TIPS = triisopropylsilyl. For
clarity, most of the hydrogen atoms have been omitted from the
representations of the X-ray crystal structures of 13, 15, and 22.
configurations of the major diastereoisomer within this series
were confirmed by single-crystal X-ray analysis following
conversion of silyl ester 21 to the morpholinyl amide derivative
22.
a
1
Followed by in situ H NMR spectroscopy through comparison to
Epimerization studies were performed to provide insight
into the origin of the diastereoselectivity for each series of silyl
nitronate (Scheme 5). Applying a single diastereoisomer of 14
under the standard reaction conditions resulted in no change
in diastereo- or enantiopurity (Scheme 5a), indicating that the
∼70:30 dr obtained in the catalytic reaction arises from kinetic
control. In contrast, when a single diastereoisomer of 21 was
treated with HyperBTM (20 mol %) in MeCN, the dr
readjusted to 78:22 within 30 min (Scheme 5b). This result
can be rationalized by epimerization at the C(1′) stereocenter
(α to the NO2 group), indicating that the diastereoselectivity
observed in the catalytic reaction most likely reflects the
relative thermodynamic stability of the two diastereoisomers.
On the basis of previous work,1−4 the following reaction
mechanism is tentatively outlined (Scheme 6a). N-Acylation of
authentic samples of expected reaction products.
HyperBTM 3 by α,β-unsaturated anhydride 23 gives the key
α,β-unsaturated acyl isothiouronium intermediate 24, to which
the silyl nitronate 25 undergoes stereoselective Michael
addition. The α,β-unsaturated acyl isothiouronium 24 is
believed to adopt an s-cis conformation, with a syn-coplanar
non-covalent 1,5-O···S interaction providing a conformational
lock.2c,3a,14,15 The stereochemical outcome of the reaction can
be rationalized by the stereodirecting phenyl substituent of the
isothiourea catalyst controlling Michael addition of the silyl
nitronate to the Si face of α,β-unsaturated acyl isothiouronium
24 to give ammonium enolate 26.16 To release the silyl ester
product 27 and regenerate 3, three events are required: (i)
C
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protonation at C(2), (ii) incorporation of an oxygen atom, and
(iii) silyl transfer. A variety of reasonable mechanisms can be
postulated in which these steps can take place in any order.
One of the simplest possibilities is desilylation of alkyl
nitronium ion 26 by adventitious water to generate silanol
29, which is then responsible for catalyst turnover; however,
control experiments suggest that direct O-acylation of silanol
29 is unlikely (Scheme 6b). Although alternative mechanisms
for catalyst turnover can be speculated,7 differentiation among
these possibilities is the subject of ongoing investigations and is
beyond the scope of this communication.
ACKNOWLEDGMENTS
■
We thank the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007−2013),
ERC Grant Agreement 279850 (A.D.S.), the EPSRC (EP/
J018139/1, A.M.), and the Royal Society of Chemistry
(Researcher Mobility Grant). A.D.S. thanks the Royal Society
for a Wolfson Research Merit Award. D.W.L. thanks the
Australian Research Council for a Discovery Award
(DP170103567). We also thank the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
In conclusion, a new approach for isothiourea catalyst
turnover in α,β-unsaturated acyl ammonium catalysis has been
demonstrated. The use of a silyl nitronate in this Michael
addition was essential to promote catalyst turnover, giving γ-
nitro-substituted silyl esters with up to two contiguous
stereocenters in good yields with excellent enantioselectivities
(12 examples, up to 93% yield and >99:1 er). The catalytic
reactions are complete within 1 h and require only 1.5−2 equiv
of the silyl nitronate. This methodological advance therefore
allows significantly more valuable, bespoke, and structurally
diverse nitroalkane substrates to be applied in α,β-unsaturated
acyl ammonium conjugate additions for the first time. Further
investigation and exploitation of the synthetic potential and
mechanistic aspects of this catalyst turnover approach are
currently underway in our laboratory.17
REFERENCES
■
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ASSOCIATED CONTENT
■
S
* Supporting Information
́
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04404.
(5) We recently expanded the scope of aryloxide-facilitated catalyst
turnover to include the use of N-heterocyclic pronucleophiles. See:
Shu, C.; Liu, H.; Slawin, A. M. Z.; Carpenter-Warren, C.; Smith, A. D.
Chem. Sci. 2020, 11, 241−247.
Experimental details, compound characterization, NMR
spectra, and HPLC traces (PDF)
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Accession Codes
CCDC 1962792−1962795 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
(7) See the Supporting Information for further details.
■
(8) The er of carboxylic acid side product 7 was not assessed.
(9) Anhydrous MeCN was obtained following distillation over
CaH2. The use of anhydrous MeCN purchased from Acros Organics
provided comparable results.
Corresponding Authors
*E-mail: ads10@st-andrews.ac.uk.
*E-mail: David.Lupton@monash.edu.
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ORCID
Anastassia Matviitsuk: 0000-0002-1543-0746
James E. Taylor: 0000-0002-0254-5536
David B. Cordes: 0000-0002-5366-9168
David W. Lupton: 0000-0002-0958-4298
Andrew D. Smith: 0000-0002-2104-7313
Present Address
§J.E.T.: Department of Chemistry, University of Bath,
Claverton Down, Bath BA2 7AY, U.K.
Notes
The authors declare no competing financial interest.
D
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(12) Monoalkyl-substituted nitronates are also applicable as
substrates. For example, reaction of α,β-unsaturated anhydride 6
with the silyl nitronate derived from 1-nitropropane provided the
corresponding γ-nitro silyl ester in 68% yield with 55:45 dr and
excellent enantioselectivity (97:3 ermajor; 96:4 erminor). See pp S26−
S27 in the Supporting Information for full details.
(13) Silyl nitronates derived from nitromethane have been stated to
be potentially explosive, and therefore, their use was not investigated
in this work (see ref 6f).
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2012, 14, 3288−3291. (b) Abbasov, M. E.; Hudson, B. M.; Tantillo,
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D.; Cheong, P. H.-Y.; Smith, A. D. Chem. Sci. 2016, 7, 6919−6927.
(d) West, T. H.; Walden, D. M.; Taylor, J. E.; Brueckner, A. C.;
Johnston, R. C.; Cheong, P. H.-Y.; Lloyd-Jones, G. C.; Smith, A. D. J.
Am. Chem. Soc. 2017, 139, 4366−4375. (e) Greenhalgh, M. D.; Smith,
S. M.; Walden, D. M.; Taylor, J. E.; Brice, Z.; Robinson, E. R. T.;
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(16) Desilylation of the silyl nitronate may take place prior to or
during the Michael addition, but alkyl nitronium ion 26 was shown to
avoid implied knowledge of the stage at which desilylation takes place.
See the Supporting Information for more discussion.
(17) Research data underpinning this publication can be found at
DOI: 10.17630/987798e4-e872-4007-bc92-931c73232a6b.
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