Zn-ProPhenol Catalyzed Enantioselective Mannich Reaction of 2 H-Azirines with Alkynyl Ketones

Article abstract of DOI:10.1021/acs.orglett.0c03737

The enantioselective Mannich reaction of 2H-azirines with alkynyl ketones is achieved under Zn-ProPhenol catalysis, delivering various aziridines with vicinal tetrasubstituted stereocenters in high yields with excellent enantioselectivities. The bimetalli

Full text of DOI:10.1021/acs.orglett.0c03737

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Letter
Zn-ProPhenol Catalyzed Enantioselective Mannich Reaction of
2H‑Azirines with Alkynyl Ketones
Barry M. Trost* and Chuanle Zhu
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ABSTRACT: The enantioselective Mannich reaction of 2H-azirines
with alkynyl ketones is achieved under Zn-ProPhenol catalysis,
delivering various aziridines with vicinal tetrasubstituted stereocenters
in high yields with excellent enantioselectivities. The bimetallic Zn-
ProPhenol complexes activate both the nucleophile and the electro-
phile in the same chiral pocket. A unique intramolecular hydrogen
bond is observed in the obtained Mannich adducts, which lowers the
basicity of the product’s aziridine nitrogen thus favoring enantioselective control and allowing catalyst turnover.
wing to their intrinsic ring strain and medicinal
priorities, incorporation of the chiral aziridines into
potential medicines has impressive impacts that can substan-
tially improve the bioactive properties of the parent molecules,
especially for those bearing quaternary carbon centers (Figure
1).1 Moreover, the aziridine motif is found in many natural
Scheme 1. Background and Reaction Design
O
Figure 1. Chiral aziridines bearing quaternary centers in bioactive
compounds.
products and pharmaceuticals and also serves as versatile
synthetic intermediates for the construction of complex
nitrogen containing molecules.2 Thus, the synthesis and
application of chiral aziridines becomes more significant in
drug library design and drug discovery.3 As depicted in Scheme
1a, three general methods have been reported to access chiral
aziridines bearing quaternary carbon centers: (i) enantiose-
lective reaction of carbene with imines; (ii) asymmetric
nitrogen transfer to a Michael acceptor; (iii) stereoselective
intramolecular SN2 reactions of α-halo-β-amines.4 These well-
established ring-construction strategies usually release stoi-
Received: November 9, 2020
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© XXXX American Chemical Society
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chiometric amounts of byproducts. On the other hand, the
catalytic enantioselective addition of nucleophilies to readily
available cyclic 2H-azirines could also become a straightfor-
ward strategy for the construction of chiral aziridines.5−8
However, the lower reactivity of the poorly electrophilic 2H-
azirines has led to much fewer developments in this area and
limited these nucleophiles to heteroatom nucleophiles6 or
highly activated carbon nucleophiles such as organolithium
reagents,7 Breslow intermediates,8 and decarboxylative carbox-
ylic acids.9
Scheme 2. Reaction Development
Enolates are among the most important and powerful carbon
nucleophiles for enantioselective carbon−carbon bond for-
mation,10 especially for those directly derived from unmodified
carbonyl donors.10d,11 Therefore, the direct enantioselective
Mannich reaction of enolates with 2H-azirines would become
an atom-economic strategy for the synthesis of chiral
aziridines. To the best of our knowledge, the only enolate
example was reported by Feng et al., which employed very
easily enolizable 1,3-dicarbonyl compounds as the nucleophiles
(Scheme 1b).12 Expectedly, addition of the enolizable 1,3-
dicarbonyl compound to the 2H-azirine would generate an
aziridine nitrogen anion intermediate. However, the strong
basicity of the product’s aziridine nitrogen anion could directly
deprotonate the enolizable 1,3-dicarbonyl compound without
the presence of the catalyst, which is fatal to the stereo-
selectivity of the products. Although Feng and co-workers used
the additional free acidic amide N−H bond of the nucleophile
to reduce the influence of the strong basicity of the aziridine
nitrogen anion, however, the Mannich adduct was still
obtained in 35% enantiometric excess (ee) and 45:55
diastereoisomer ratio (dr). On the other hand, less acidic
nucleophiles, such as prochiral nonstabilized ketone enolates,
may be preferable, making the enantiodeterminating step the
attack of the enolate on the imine. However, this useful but
challenging enantioselective Mannich reaction of poorly
electrophilic 2H-azirines with nonstabilized enolates has not
been reported and remains a challenge. Presumably such a
process, if possible, requires a powerful catalytic system that
activates both the electrophile and the nucleophile.
The treatment of ProPhenol with Et2Zn could generate
dinuclear main group metal salts that have proven to be
effective metal catalysts for the addition of nonstabilized
enolates with activated imines.13,14 Activation of the imine with
a strong electron-withdrawing group on the nitrogen proved
critical also to allow turnover. Indeed, if the product lacked
such electron-withdrawing groups on the nitrogen, the
resulting product would be a basic amine which would have
killed the use of the ProPhenol zinc complexes as catalysts. On
the other hand, these chiral bimetallic complexes have a
Brønsted basic and a Lewis acidic moiety and are capable of
simultaneous activation of both the nucleophile and the
electrophile in the same chiral pocket. Given our recent success
of Zn-ProPhenol catalyzed enantioselective Mannich reactions
of acyclic imines activated with electron-withdrawing groups
with nonstabilized enolates,14 we herein report the Zn-
ProPhenol catalyzed enantioselective Mannich reaction of
cyclic 2H-azirines with alkynyl ketones, delivering various
chiral aziridines with vicinal tetrasubstituted stereocenters in
high yields with excellent enantioselectivities (Scheme 1c).
As presented in Scheme 2a, the reactions of methyl ketones
and α-monosubstituted ketones with 2H-azirines usually gave
pyrrole derivatives as the products, because the newly formed
aziridine nitrogen anions, by addition of ketone enolates to
2H-azirines, would attack the carbonyl moiety of these ketone
nucleophiles which was followed by a dehydrative ring-opening
process to give the pyrrole rings.5 Thus, α-disubstituted
ketones become the choice regarding nucleophiles, which
could prohibit the dehydrative ring-opening process. However,
the higher pKa of the C−H bond in α-disubstituted ketones
and the larger steric hindrance become hurdles that need to be
conquered in their asymmetric Mannich reaction with 2H-
azirines. We settled on cyclobutyl substituted alkynyl ketone as
the nucleophile and investigated its Mannich reaction with 2H-
azirines for several advantages (Scheme 2b). First, due to their
high ring strain and structural rigidity, cyclobutanes are also
highly valuable building blocks in numerous bioactive small
molecules and chemical sciences and have also found
prominence as synthetic intermediates.15 Direct modification
of cyclobutyl substituted ketones is a straightforward and
promising strategy to construct cyclobutyl contained complex
molecules.16 Second, the higher s character of the attached
alkyne could activate the carbonyl moiety which should
increase the acidity of its α-C(sp3)−H bond and facilitate its
enolization process. Importantly, the high unsaturation of
alkynes compared to alkenes and alkanes allows a broad scope
of reactivities, providing a useful platform for structural
diversification.17 Most importantly, the obtained Mannich
adduct features a β-amino cyclobutyl ketone skeleton, which
has been found in many bioactive compounds, such as the
CCR1 antagonist and the inhibitors of hepatitis C NS3/4A
protease.18
After settling on the cyclobutyl substituted alkynyl ketone 1a
as the nucleophile, we performed its reaction with 2H-azirine
2a in the presence of our standard Zn-ProPhenol catalyst L1.
Remarkably, Mannich adduct 3a was obtained in 83% isolated
yield (Table 1, entry 1). However, the intramolecular hydrogen
bond between the N−H bond of the aziridine moiety and the
carbonyl moiety might result in a chiral center at the nitrogen
atom; thus, compound 3a had a very complex 1H NMR
spectrum19 and was found to be difficult for HPLC analysis.
Therefore, a sequential quantitative N−H bond acetylation of
3a was conducted to give product 4a in 82% overall isolated
yield with 95% ee. We believe that this unique intramolecular
hydrogen bond has a positive influence toward the excellent
enantioselectivity of the product. Next, various types of
ProPhenol ligands (L2−L6) with different electronic proper-
B
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a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 3. Scope of Alkynyl Ketone Nucleophiles
b
c
entry
ligand
solvent
yield (%)
ee
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L1
L1
L1
THF
THF
THF
THF
THF
THF
Et2O
toluene
dioxane
83 (84)
73 (74)
79 (80)
70 (72)
36 (39)
82 (83)
53 (55)
72 (73)
37 (40)
95
82
91
96
20
95
81
56
33
a
All reactions were carried out with 1a (0.1 mmol), 2a (1.5 equiv),
ZnEt2 (20 mol %), and ligand (10 mol %) at rt in solvent (0.33 M)
b
for 12 h under Ar. Isolated yield of 4a. The number in the
c
parentheses was isolated yield of 3a. Ee of 4a was determined by
chiral HPLC.
ties and structural diversities and solvents were investigated,
but no superior results were obtained (entries 2−9).
With the optimized conditions (Table 1, entry 1) in hand,
we set out to evaluate the scope of alkynyl ketones that would
participate in this reaction (Scheme 3). Electron-neutral
naphthalene and phenanthrene substituted alkynyl ketones
were well suitable substrates for this Zn-ProPhenol catalytic
system (4b and 4c). Alkynyl ketones with diverse valuable
electron-withdrawing groups, such as the trifluoromethyl,
carbonyl, cyano, and fluoro substituent on the para-, meta-,
and ortho-position of the phenyl ring, all gave the desired
products 4d−i in high yield with high to excellent ee values.
Especially, our Zn-ProPhenol catalytic system could efficiently
distinguish two different carbonyl moieties in the same
substrate, and adduct 4e was isolated in 64% yield with 96%
ee. An alkynyl ketone which has an electron-donating methyl
group on the phenyl ring could also deliver adduct 4j in
reasonable yield with 90% ee. A heteroaromatic thienyl
substituted alkynyl ketone afforded 4k in 81% yield with
98% ee. The triethylsily group in 4l can potentially be removed
to deliver the terminal alkyne, and the benzyldimethylsily
group in 4m might be suitable for cross-coupling functionaliza-
tion. Notably, an aliphatic cyclopropyl substituted alkynyl
ketone also delivered product 4n in acceptable yield with 94%
ee. Furthermore, substrates bearing 3,3-difluorocyclobutyl and
3-methylenecyclobutyl moieties afforded products 4o and 4p
in high yields with good ee values. It is worth noting that this
cyclobutyl substituent in alkynyl ketones could be extended to
the cyclopentyl, cyclopent-3-en-1-yl, and cycloheptyl group.
The corresponding products 4q−s were isolated in good to
high yields with high enantioselectivities. Additionally, alkynyl
ketones bearing both terminal and internal alkene moieties
could be well tolerated in this catalytic system (4p and 4r).
Next, various 2H-azirine electrophiles were examined with
cyclobutyl substituted alkynyl ketone 1a as the reaction
partner. The results are summarized in Scheme 4. 2H-Azirines
a
Unless otherwise noted, all reactions were carried out with 1 (0.1
mmol), 2a (1.5 equiv), ZnEt2 (20 mol %), and ligand L1 (10 mol %)
b
at rt in THF (0.33 M) for 12 h under Ar. Isolated yields of 4; the
numbers in the parentheses were the isolated yield of 3; ee was
determined by chiral HPLC. L4 was used instead of L1. AcCl was
used instead of Ac2O.
c
d
a b
,
Scheme 4. Scope of 2H-Azirine Electrophiles
a
All reactions were carried out with 1a (0.1 mmol), 2 (1.5 equiv),
ZnEt2 (20 mol %), and ligand L1 (10 mol %) at rt in THF (0.33 M)
b
for 12 h under Ar. Isolated yields of 4; the numbers in the
parentheses were the isolated yield of 3; ee was determined by chiral
HPLC.
C
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with electron-withdrawing chloro, fluoro, cyano, trifluorometh-
yl, and ester groups at different positions of the phenyl ring
could all afford the desired products 4t−z in high yields and
high to excellent enantioselectivities. Electron-neutral 2-
naphthyl and [1,1′-biphenyl]-4-yl substituted 2H-azirines are
also good substrates as good results were obtained (4aa and
4ab).
Scheme 6. Proposed Mechanism
To further explore this unique protocol, a 2 mmol scale
Mannich reaction of 2H-azirine 2a and alkynyl ketone 1a was
carried out to afford 3a in 78% yield with 95% ee (Scheme 5,
Scheme 5. Further Derivatizations of the Mannich Products
success of this unactivated imine derives from the strain and
hybridization of the azirine. Importantly, the low basicity of the
product’s aziridine nitrogen decreases its coordination to zinc
thus allowing catalyst turnover.
In summary, our Zn-ProPhenol system efficiently achieves
the direct Mannich reaction of a variety of alkynyl ketones to
various 2H-azirines, delivering chiral aziridines with vicinal
tetrasubstituted stereocenters in high yields (up to 91% yield)
and excellent enantioselectivities (up to 98% ee). The key to
the success of this reaction is that the dual roles (Brønsted base
and Lewis acid) of the bimetallic Zn-ProPhenol complexes are
capable of simultaneous activation of both the nucleophile and
the electrophile in the same chiral pocket, which overcomes
the hurdles associated with using nonstabilized enolates and
poorly electrophilic cyclic 2H-azirines as the reactants. A
unique intramolecular hydrogen bond is observed in the
obtained Mannich adducts. These obtained Mannich adducts
are densely functionalized and can be further elaborated into
various potentially attractive molecules.
above). Furthermore, the synthetic applications of these
aziridines were explored with 3a as a model substrate (Scheme
5, below). Ring opening of 3a with hydrogen chloride gave the
tertiary amine hydrogen chloride salt 5 in 99% yield. Given the
broad applications of tosylated aziridines,20 compound 6 was
synthesized in 67% yield. Importantly, boc-protected aziridine
7 proved to be crystalline, and its structure, including its
absolute configuration (R), was then determined by means of
X-ray crystallographic analysis. Condensation of 7 with
hydrazine monohydrate afforded pyrazole 8 smoothly, whereas
treating 7 with benzamidine furnished pyrimidine 9 in 90%
yield. Conjugate addition of 7 with methoxide delivered 10 in
78% yield. Finally, the hydration and selective dehydrative
condensation of 7 with H2O and O-methoxyamine hydro-
chloride gave ketone product 11 in 87% yield as a single
regioisomer.
Based on the configuration of the obtained Mannich adduct,
we propose the mechanism as outlined in Scheme 6 initiated
by the generation of the dinuclear Zn-ProPhenl complex.
Coordination and deprotonation of the alkynyl ketone by the
Brønsted basic site of the catalyst gives zinc enolate A. Then
the 2H-azirine coordinates to the Lewis acidic site of A to
deliver the complex B, which directs the re face attack of
alkynyl ketone to the 2H-azirine and affords complex C.
Subsequently, the protonation and decomplexation of C with a
second equivalent of alkynyl ketone provides the Mannich
aziridine adduct and regenerates the zinc enolate A. The
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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AUTHOR INFORMATION
Corresponding Author
■
Barry M. Trost − Department of Chemistry, Stanford
University, Stanford, California 94305-5080, United States;
D
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(e) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600−1632.
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4348. (g) Zou, Y.-Q.; Hormann, F. M.; Bach, T. Chem. Soc. Rev. 2018,
stanford.edu
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47, 278−290. (h) Trost, B. M.; Tracy, J. S. Acc. Chem. Res. 2020, 53,
Author
1568−1579.
Chuanle Zhu − Department of Chemistry, Stanford University,
Stanford, California 94305-5080, United States
(11) (a) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600−
1632. (b) Meyer, C. C.; Ortiz, E.; Krische, M. J. Chem. Rev. 2020, 120,
3721−3748.
Complete contact information is available at:
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(12) Hu, H.; Xu, J.; Liu, W.; Dong, S.; Lin, L.; Feng, X. Org. Lett.
2018, 20, 5601−5605.
(13) (a) Trost, B. M.; Bartlett, M. J. Acc. Chem. Res. 2015, 48, 688−
701. (b) Trost, B. M.; Hung, C. I. J.; Mata, G. Angew. Chem., Int. Ed.
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Notes
The authors declare no competing financial interest.
(14) (a) Trost, B. M.; Saget, T.; Lerchen, A.; Hung, C. I. J. Angew.
Chem., Int. Ed. 2016, 55, 781−784. (b) Trost, B. M.; Saget, T.; Hung,
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ACKNOWLEDGMENTS
■
We thank the Tamaki Foundation for financial support of our
programs. C.Z. thanks the Visiting Scholarship of China
Scholarship Council (201906155063).
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