Asymmetric Aza-Diels-Alder Reactions of in Situ Generated β,β-Disubstituted α,β-Unsaturated N-H Ketimines Catalyzed by Chiral Phosphoric Acids

Article abstract of DOI:10.1021/acs.orglett.0c01994

A novel asymmetric synthesis of dihydropyridinones with vicinal quaternary stereocenters has been realized by asymmetric aza-Diels-Alder reactions of 3-amido allylic alcohols with oxazolones enabled by chiral phosphoric acid catalysis. A series of aryl/alkyl- and alkyl/alkyl-disubstituted 3-amido allylic tertiary alcohols and 4-substituted oxazolones could be well tolerated in these reactions, producing dihydropyridinones with excellent diastereoselectivities and high enantioselectivities. Mechanistic study and control experiments were performed to shed light on the reaction mechanism, in which a configurationally defined β,β-disubstituted α,β-unsaturated N-H ketimine was proposed as the key intermediate.

Full text of DOI:10.1021/acs.orglett.0c01994

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Letter
Asymmetric Aza-Diels−Alder Reactions of in Situ Generated β,β-
Disubstituted α,β-Unsaturated N−H Ketimines Catalyzed by Chiral
Phosphoric Acids
Shunlong He, Huanchao Gu, Yu-Peng He,* and Xiaoyu Yang*
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ABSTRACT: A novel asymmetric synthesis of dihydropyridinones
with vicinal quaternary stereocenters has been realized by
asymmetric aza-Diels−Alder reactions of 3-amido allylic alcohols
with oxazolones enabled by chiral phosphoric acid catalysis. A
series of aryl/alkyl- and alkyl/alkyl-disubstituted 3-amido allylic
tertiary alcohols and 4-substituted oxazolones could be well
tolerated in these reactions, producing dihydropyridinones with
excellent diastereoselectivities and high enantioselectivities. Mech-
anistic study and control experiments were performed to shed light on the reaction mechanism, in which a configurationally defined
β,β-disubstituted α,β-unsaturated N−H ketimine was proposed as the key intermediate.
ihydropyridinones are a type of privileged six-membered
Dazacycles, which are widely present in a series of
biologically active small molecules and natural products.1
Among various synthetic methods for preparation of these
heterocycles, the inverse-electron-demand aza-Diels−Alder
(ADA) reaction2 is one of the most efficient methods, which
was pioneered by Boger and co-workers.3 The asymmetric
catalytic versions4 of these reactions have also drawn
considerable research interest due to the significance of chiral
dihydropyridinone scaffolds, and numerous of elegant
enantioselective methods have been developed in the past
two decades. In general, an enolate-type (or enolate analog)
intermediate is generated under diverse catalytic systems,
which undergoes the enantioselective aza-Diels−Alder reac-
tions with α,β-unsaturated imines to generate the chiral
dihydropyridinone products.5 Since the landmark work of
using chiral N-heterocyclic carbene (NHC) catalysts in the
asymmetric ADA reactions between enals and α,β-unsaturated
imines by Bode and co-workers,6 asymmetric NHC catalysis
Figure 1. Asymmetric aza-Diels−Alder reactions of α,β-unsaturated
imines.
has become a versatile approach for the synthesis of
enantioenriched dihydropyridinones, using ketenes,7 α-chlor-
enols/enamines and α,β-unsaturated imines, which could be
oaldehyde,8 and alkylacetic ester9 as enolate precursors by Ye
enabled by chiral Lewis acid catalysis,13 chiral amine
and Chi group, respectively. The Smith group disclosed
catalysis,14 and chiral Brønsted acid catalysis (Figure 1a,
enantioselective synthesis of dihydropyridinones through
bottom).15
asymmetric ADA reactions between α,β-unsaturated imines
and arylacetic acids10 and N-acyl imidazoles11 via chiral
Received: June 15, 2020
isothiourea catalysis. The Gong group reported the asymmetric
three-component ADA reaction between enals, anilines, and
oxazolones under chiral Brønsted acid catalysis12 (Figure 1a,
top). On the other hand, asymmetric ADA reactions have also
been well employed in the asymmetric synthesis of
tetrahydropyridine derivatives via cycloadditions between
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© XXXX American Chemical Society
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A

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Despite the fact that a series of different asymmetric catalytic
methods have been developed for asymmetric synthesis of
dihydropyridinones and tetrahydropyridines via enantioselec-
tive ADA reactions, the other coupling partner for cyclo-
addition in these reactions was limited to α,β-unsaturated
imines possessing a mono-β-substitution, thus leading to the
generation of azacyles with only a tertiary stereocenter at the
C-4 position.5f,g To the best of our knowledge, no example of
β,β-disubstituted α,β-unsaturated imine precursors has been
utilized in asymmetric ADA reactions, probably due to their
relatively low reactivities and challenges in stereoselectivities
control. With our continuous interest in developing novel
asymmetric reactions of amido allylic alcohols,16 herein we
report a novel asymmetric synthesis of dihydropyridinones
with vicinal quaternary stereocenters via enantioselective aza-
Diels−Alder reactions between 3-amido allylic alcohols and
oxazolones17 enabled by chiral phosphoric acid (CPA)
catalysis,18 in which an in situ generated β,β-disubstituted
α,β-unsaturated N−H ketimine19 was proposed as the key
intermediate (Figure 1b).
one, in which an improved er was afforded (entry 4).
Subsequently, a range of BINOL-derived CPA catalysts were
screened; however, unfortunately, none of them could provide
improved results (entries 5−9). Interestingly, using C8-TRIP
(cat A7) as catalyst led to an improved yield with retained er
(entry 10), while switching the chiral scaffold to H8-BINOL
type did not provide better results (entry 11). Due to the
vulnerability of 1a under these conditions, increasing the
amount of 1a to 1.5 equiv provided significantly improved
yield (entry 12). Finally, decreasing the reaction temperature
to 18 °C generated the dihydropyridinones 3a in 61% yield
with >20:1 dr and 95:5 er (entry 13; see Table S1 in the
Supporting Information (SI) for more optimization con-
ditions).20 It is worth mentioning that the oxazolone ring-
opening addition product 3a′ was isolated as the major
byproduct in 27% yield with 55.5:44.5 er under these optimal
conditions.
With the optimal conditions in hand, we sought to explore
the scope of this reaction (Scheme 1). A series of aryl groups at
the 1-position of 3-amido allylic alcohols 1 were first examined,
and we found that various para- and meta-substituted phenyl
groups could be well tolerated under the optimal conditions
We commenced our study by choosing racemic 3-amido
allylic alcohol 1a and oxazolone 2a as model substrates under
CPA catalysis (Table 1). The initial attempt between these two
Scheme 1. Scope for Enantioselective Synthesis of
Dihydropyridinones with Vicinal Chiral Quaternary
Stereocenters
a
Table 1. Optimization of Reaction Conditions
a
a
b
c
d
entry
cat.
solvents
yield
dr
er
91:9
1
2
3
4
5
6
7
8
A1
A1
A1
A1
A2
A3
A4
A5
A6
A7
A8
A7
A7
toluene
DCM
CHCl3
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
30
11
23
37
16
24
13
24
28
44
34
56
61
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
85:15
89.5:10.5
93.5:6.5
78:22
62.5:37.5
93.5:6.5
91.5:8.5
91:9
9
10
11
12
93:7
92.5:7.5
93.5:6.5
95:5
e
e f
,
13
a
Reactions were performed with 1a (0.1 mmol), 2a (0.1 mmol), CPA
catalyst (0.01 mmol), solvents (1 mL), AW-300 MS (10 mg) at 25
b
c
d
°C. Isolated yield. Dr value was determined by NMR analysis. Er
value was determined by HPLC analysis on a chiral stationary phase.
e
f
1a (0.15 mmol) was used. At 18 °C.
substrates (1:1 mol ratio) under the catalysis of TRIP catalyst
(cat A1, 10 mol %) in toluene in the presence of acid-wash
molecular sieves (AW-300 MS) at 25 °C successfully produced
the dihydropyridinone 3a in 30% yield with >20:1 diaster-
eoselectivity and 91:9 enantiomeric ratio (er) (entry 1).
Interestingly, the N-1 benzoyl group of the product was
removed under these conditions. Next, a series of solvents were
first examined (entries 2−4), indicating CCl4 was the optimal
a
Reactions were performed with 1 (0.15 mmol), 2 (0.1 mmol), (R)-
A7 cat (0.01 mmol), CCl4 (1 mL), AW-300 MS (10 mg) at 18 °C for
40 h. Yields were isolated yield. Dr values were determined by NMR
analysis. Er values were determined by HPLC analysis on a chiral
stationary phase.
B
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(3b−3g), generating the dihydropyridinone products with
excellent diastereoselectivities and high enantioselectivities.
The absolute configurations of the dihydropyridinone products
were confirmed by analogy to product 3c, whose structure was
unambiguously assigned by X-ray crystallography (CCDC
1993830).20 Next, we investigated the scope of the
substitutions at the 3-position of allylic alcohols. Encourag-
ingly, a variety of substituted phenyl groups were amenable
with the standard conditions (3h−3l), as well as a thienyl
substituent (3m). Finally, the scope of the 4-subsitutions of
oxazolone 2 was also explored, and a range of alkyl groups
were well compatible with the optimal conditions (3n−3o), as
well as the benzyl (3p) and allyl groups (3q). In addition, the
functional group-containing substituents were also well
tolerated, producing the products with high stereoselectivities
(3r and 3s).
were performed (Scheme 3). Treatment of oxazolone 2a with
the β,β-disubstituted α,β-unsaturated N-tosyl ketimine 4a9 did
Scheme 3. Control Experiments and Mechanistic Studies
To further extend the scope of these reactions, nPr/Me-
disubstituted 3-amido allylic alcohol 1t was examined under
the optimal conditions, however, which provided the
dihydropyridinone product with poor enantioselectivity.20
Encouragingly, after brief optimizations of the CPA catalysts
(see Table S2 in SI), the 2,4,6-trimethylphenyl substituted
SPINOL-derived phosphoric acid (R)-A9 was determined to
be the optimal catalyst for this reaction, which generated the
product in 70% yield with 98:2 dr and 98:2 er (Scheme 2, 3t).
Scheme 2. Scope for Enantioselective Synthesis of
Dihydropyridinones from Dialkyl-Substituted 3-Amido
Allylic Alcohols
not afford any desired dihydropyridinone product under the
standard conditions (Scheme 3a). In an attempt to prepare the
β,β-disubstituted α,β-unsaturated N-benzoyl imine 5a via
condensation9 between the corresponding enone and
BzNH2, only the dienamide product 6a was obtained.
Theoretically, this dienamide could still undergo isomerization
to give the α,β-unsaturated imine 5a under CPA catalysis
conditions; however, no dihydropyridinone product was
detected in the reaction between dienamide 6a and oxazolone
2a under the standard conditions, as well as no oxazolone ring-
opening addition product (Scheme 3b). Treatment of the
oxazolone ring-opening addition product 3a′ with the standard
conditions could not provide any dihydropyridinone product,
which indicated 3a′ was probably not an intermediate in these
cycloaddition reactions (Scheme 3c). The absence of the N-1
Bz group in the products is a key feature of these reactions,
which is also very important to understand the reaction
mechanism. Selective benzoylation of the dihydropyridinone
product 3a gave the N-1 benzoylated product 7a, whose
structure was confirmed by 2D NMR analysis. Treatment of 7a
with CPA catalyst A7 and H2O did not give any
debenzoylation product, even at higher reaction temperature,
which suggested that 7a was also not an intermediate of these
reactions21 (Scheme 3d). All these results clearly suggested
that the α,β-unsaturated N-Bz ketimine 5a is probably not the
intermediate in these reactions. Accordingly, we envisioned
that the relatively rare α,β-unsaturated N−H ketimine may be
the key intermediate of these cycloaddition reactions. To prove
this hypothesis, irradiation of the mixture of α- and γ-allyl
azides22 (8a and 8a′) by ruthenium catalysis (9a) under
fluorescent light in THF led to the formation of α,β-
unsaturated N−H ketimine (10a) in 41% conversion, which
existed as an E/Z mixture.23 After removal of the solvent, the
obtained crude mixture was directly subjected into the
standard reaction conditions with oxazolone 2a, which finally
provided the desired dihydropyridinone 3a in 39% yield with
a
a
Reactions were performed with 1 (0.15 mmol), 2a (0.1 mmol), (R)-
A9 cat (0.01 mmol), CCl4 (1 mL), AW-300 MS (10 mg) at 18 °C for
40 h. Yields were isolated yields. Dr and er values were determined by
HPLC analysis on a chiral stationary phase.
Subsequently, a series of alkyl groups were examined at the 1-
position of the allylic alcohols, which provided the
dihydropyridinones with high diastereo- and enantioselectiv-
ities (3u and 3v), including the aryl- and olefine-containing
substituents (3w and 3x). It is worth mentioning that even the
Et/Me-disubstituted 3-amido allylic alcohol could afford the
product with excellent stereoselectivity under the standard
conditions without exception (3y).
To shed light on the reaction mechanism and demonstrate
the uniqueness of these reactions, some control experiments
C
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76.5:23.5 er, with the diastereomer 3a′′ in 34% yield and
oxazolone ring-opening product 3a′ in 21% yield (Scheme
3e).20
Scheme 6. Derivatizations of the Chiral Products
Based on these results and previous reports, a plausible
reaction mechanism was proposed (Scheme 4). First, the
Scheme 4. Plausible Reaction Mechanism
NOE analysis.20 Further reduction of 11a with LiAlH4 afforded
the piperidine 12a in 92% yield, without erosion of the optical
purity (Scheme 6a). Direct subjection of dihydropyridinone 3a
26
into the reduction with the mixture of DIBAL-H and LiAlH4
produced the tetrahydropyridine 13a in 74% yield with
retained ee (Scheme 6b).
In conclusion, we have disclosed a novel asymmetric
synthesis of dihydropyridinones bearing vicinal chiral quater-
nary stereocenters via enantioselective aza-Diels−Alder re-
action between 3-amido allylic alcohols and oxazolones
enabled by chiral phosphoric acid catalysis. A wide array of
substituents at the 1- and 3-position of 3-amido allylic tertiary
alcohols and 4-position of oxazolones could be well tolerated,
generating dihydropyridinones with excellent diastereoselectiv-
ities and high enantioselectivities, especially highlighting the
compatibility of the 1,1-dialkyl substituted 3-amido allylic
alcohols. Control experiments were performed to elucidate the
mechanism of these reactions, in which a configurationally
defined β,β-disubstituted α,β-unsaturated N−H ketimine was
proposed as the key intermediates for these asymmetric [4 + 2]
cycloaddition reactions. Further application of this protocol for
in situ generation of reactive α,β-unsaturated N−H ketimine
intermediates in CPA catalyzed asymmetric reactions was
under investigation in our lab, especially for the asymmetric
construction of chiral quaternary stereocenters.
oxazolone 2 was activated by CPA catalyst to generate its
active enol form INT A;12,17k,o at the same time, the CPA also
mediated the addition of the hydroxyl group to amide group in
1 to generate the orthoester INTB,24 which then underwent
the rearrangement to give the configurationally defined α,β-
unsaturated N−H ketimine INT C. Subsequently, dual
hydrogen bonding activation of the enol form of oxazolone
(INT A) and α,β-unsaturated N−H ketimine INT C led to the
facile [4 + 2] cycloaddition,25 generating the bicyclic
intermediate INT D, which then went through the isomer-
ization process to give the dihydropyridinone product 3. On
the other hand, the α,β-unsaturated N−H ketimine INT C
could also undergo the imine−enamine tautomerism to
generate the primary dienamide INT E, which would attack
the oxazolone to give the ring-opening addition byproduct 3′.
To account for the observed stereoselectivities, a possible
stereochemical model was depicted (Scheme 5). Through the
ASSOCIATED CONTENT
■
sı
* Supporting Information
Scheme 5. Possible Stereochemical Model
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01994.
Full experiment procedures, spectroscopic character-
izations, NMR and HPLC spectra (PDF)
Accession Codes
CCDC 1993830 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
bifunctional activation of the α,β-unsaturated N−H ketimine
intermediate and the enol form of oxazolone via dual
hydrogen-bonding activation with the CPA catalyst, the Re
face of the enol form of oxazolone attacks the Re face of α,β-
unsaturated N−H ketimine in an endo-type fashion to generate
the (3R,4R)-dihydropyridinone products.
To demonstrate the applicability of these reactions, the
derivatizations of the chiral products were studied (Scheme 6).
Catalytic hydrogenation of dihydropyridinone 3a using Raney
Ni as the catalyst generated the pyridinone 11a in 85% yield
with 90:10 dr, whose relative configuration was assigned by
AUTHOR INFORMATION
Corresponding Authors
■
Yu-Peng He − College of Chemistry, Chemical Engineering and
Environmental Engineering, Liaoning Shihua University, Fushun
113001, China; Email: yupeng.he@lnpu.edu.cn
Xiaoyu Yang − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China;
orcid.org/0000-0002-0756-0671; Email: yangxy1@
shanghaitech.edu.cn
D
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Authors
pubs.acs.org/OrgLett
Letter
aza-[4 + 2] cycloaddition reactions of allenamides. Tetrahedron 2004,
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Shunlong He − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China; College of
Chemistry, Chemical Engineering and Environmental
Engineering, Liaoning Shihua University, Fushun 113001,
China
Huanchao Gu − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NSFC (Grant No. 21702138) and
ShanghaiTech University start-up funding for financial support.
The authors thank the support from Analytical Instrumenta-
tion Center (contract no. SPST-AIC10112914), SPST,
ShanghaiTech University, and Dr. Na Yu for the X-ray
crystallographic analysis.
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(20) For details, see Supporting Information.
(21) Interestingly, using the β-monosubstituted α,β-unsaturated N-
Bz imine or 3-amido allylic secondary alcohol as coupling partners
with oxazolones under the standard conditions provided the N-1-
benzoylated dihydropyridinone products with poor to moderate
diastereo- and enantioselectivities (see Scheme S1 in SI), which
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