Direct enantioselective Mannich reactions of α-azido cyclic ketones: Asymmetric construction of chiral azides possessing an α-quaternary stereocenter

Article abstract of DOI:10.1039/c9cc08000g

Direct enantioselective Mannich reactions of α-azido cyclic ketones with aldimines are realized through chiral phosphoric acid catalysis, which generate chiral azides possessing an α-quanternary stereocenter with complete regioselectivities and high diast

Full text of DOI:10.1039/c9cc08000g

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Direct enantioselective Mannich reactions of
a-azido cyclic ketones: asymmetric construction
of chiral azides possessing an a-quaternary
stereocenter†
Cite this: Chem. Commun., 2020,
6, 98
5
Received 12th October 2019,
Accepted 25th November 2019
ab
a
a
Xueqian Ye, Yongkai Pan and Xiaoyu Yang
*
DOI: 10.1039/c9cc08000g
rsc.li/chemcomm
10
Direct enantioselective Mannich reactions of a-azido cyclic ketones anticancer natural product (Fig. 1a). On the other hand, Shibasaki
with aldimines are realized through chiral phosphoric acid catalysis, and co-workers developed a series of asymmetric reactions of
which generate chiral azides possessing an a-quanternary stereo- a-azido amides catalysed by a chiral copper catalyst, including
1
1
12
center with complete regioselectivities and high diastereoselectivities aldol reactions with aldehydes and trifluoromethyl ketones
and enantioselectivities.
a-Chiral azides represent a special type of masked amines,
1
which not only exist in some bioactive compounds, but also
act as important building blocks in the synthesis of a variety of
value-added chiral products, due to the fact that they can
undergo a range of stereospecific transformations, such as
1
,2
reduction, cycloaddition, aza ylide formation and so on.
Owing to their significance, numerous elegant catalytic asym-
metric methods have been developed for the construction of
a-chiral azides, which could be categorized into three types
of strategies: nucleophilic azidation reactions, electrophilic
3
azidation reactions and functionalizations of organic azides.
4
Although the enantioselective nucleophilic and electrophilic
azidation reactions have provided straightforward methods
5
to produce a-chiral azides, the alternative strategy based on
asymmetric functionalizations of organic azides also turns out
to be fruitful, which has the advantage of more expanded
reaction types and avoiding the use of some unreadily available
azidation reagents. Among these, the asymmetric nucleophilic
6
additions of a-azido carbonyl compounds to various electro-
7
philes represent the most general ones. For example, Barbas
and co-workers developed the asymmetric Mannich reactions
of a-azido ketones catalysed by a chiral secondary amine
8
catalyst. Amo and co-workers achieved asymmetric aldol reactions
9
of a-azido ketones enabled by proline catalysis. The McNulty group
reported the asymmetric Michael reaction of a-azido ketones,
which was further adopted in the asymmetric synthesis of an
a
School of Physical Science and Technology, ShanghaiTech University,
Shanghai 201210, China. E-mail: yangxy1@shanghaitech.edu.cn
Fig. 1 (a) Asymmetric reactions of a-azido ketones via chiral amine catalysis;
(b) asymmetric reactions of a-azido amides via chiral Lewis acid catalysis;
(c) asymmetric functionalizations of a-substituted cyclic ketones via chiral
phosphoric acid (CPA) catalysis; (d) direct asymmetric Mannich reactions of
racemic a-azido cyclic ketones with aldimines via CPA catalysis.
b
University of Chinese Academy of Sciences, Beijing 100049, China
†
Electronic supplementary information (ESI) available. CCDC 1968655 and
965952. For ESI and crystallographic data in CIF or other electronic format
1
see DOI: 10.1039/c9cc08000g
9
8 | Chem. Commun., 2020, 56, 98--101
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1
3
a
and Mannich reactions (Fig. 1b). However, among the afore- Table 1 Optimization of the reaction conditions
mentioned examples, only chiral azides possessing an a-tertiary
stereocenter were generated. To the best of our knowledge,
asymmetric synthesis of chiral azides with an a-quaternary
stereocenter through asymmetric functionalizations of organic
azides has not been realized to date.
1
4
Recently, the chiral phosphoric acid (CPA) catalysed asym-
metric functionalizations of a-substituted cyclic ketones have
become a powerful protocol for the asymmetric construction of
a-chiral quaternary stereocenters for cyclic ketones, which were
1
5
16
developed by the List and Toste group, respectively (Fig. 1c).
A range of different electrophiles were utilised in these reac-
tions, affording products with chiral all-carbon and hetero-
atom containing quaternary stereocenters regiospecifically with
high enantioselectivities, which was attributed to the formation
of the thermodynamically favoured more-substituted enol
intermediate enabled by CPA catalysis. Herein, we report the
asymmetric synthesis of chiral azides possessing an a-quaternary
stereocenter through enantioselective direct Mannich reactions
of racemic a-azido cyclic ketones with aldimines under chiral
phosphoric acid catalysis (Fig. 1d).
We initiated our study by choosing racemic a-azido cyclo-
hexanone (1a) and N-Boc aldimine 2a as model substrates and
BINOL/H8-BINOL-derived chiral phosphoric acids as catalysts. 15
Upon exploring a range of conditions, we determined the
reaction between 1a (1.0 equiv.) and 2a (2.0 equiv.) under the (10 mol%), 4 Å molecular sieves (150 mg) in DCM (0.1 mL) at 40 1C for
b
c
d
Entry Variation from the standard conditions Yield (%) dr
ee (%)
1
2
3
4
5
6
7
8
9
1
None
93
86
49
92
71
65
50
29
86
70
NR
88
64
42
60
90 : 10 95
63 : 37 55
85 : 15 92
72 : 28 72
90 : 10 96
82 : 18 86
46 : 54 60
43 : 57 81
88 : 12 96
85 : 15 95
A1 instead A8
A2 instead A8
A3 instead A8
A4 instead A8
A5 instead A8
A6 instead A8
A7 instead A8
In toluene
In CHCl
In THF
Without 4 Å MS
Without solvents
25 1C instead of 40 1C
In toluene (0.25 M) for 2 h
17
0
3
11
—
—
1
1
1
2
3
4
84 : 16 92
88 : 12 93
89 : 11 95
89 : 11 95
e
a
Reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol), catalyst
b
c
1
1
6 h. Yields were isolated yields. dr was determined by H NMR.
ee was determined by chiral HPLC analysis. With 1.0 equiv. 2a.
catalysis of CPA catalyst cat. A8 (10 mol%) in DCM (0.1 mL) at
0 1C for 16 h as the optimal reaction conditions, under which
the desired Mannich product 3a was obtained in 93% yield,
d
e
4
with 90 : 10 diastereomeric ratio (dr) and 95% ee (Table 1, entry 1). groups) at the para- and meta-positions of benzaldimine sub-
Switching the catalysts from cat. A8 to other chiral phosphoric strates were well tolerated under the standard conditions,
acid catalysts led to either an erosion of enantioselectivities producing products in high yields, with good diastereoselec-
1
8
(
entries 2, 4, and 6–8) or a decrease of yields (entries 3 and 5). tivities and excellent enantioselectivities (Table 2, 3b–3j). An
Performing this reaction in toluene and CHCl both led to ortho-substituted benzaldimine was also examined under the
3
decreased yields and diastereoselectivities (entries 9 and 10), while optimal conditions, which provided the chiral azide product
conducting the reaction in THF couldn’t provide the desired with a slightly diminished enantioselectivity (3k). 2-Naphthyl
Mannich product (entry 11). The role of molecular sieves was also (2l) and heteroaryl substituted aldimines (2m, 2n) had good
studied, which provided diminished stereoselectivities without compatibility with the optimal conditions as well. With regard
the presence of 4 Å MS. It is worth mentioning that the reaction to the cyclic ketone scope, switching the cyclohexanone moiety
under the standard conditions generated a solvent-free mixture to other six-membered cyclic ketones (2o, 2p) and five-membered
after the reaction, due to the low boiling point of DCM. Thus, the cyclopentanone (2q) was all well amenable to the standard con-
reaction under exactly solvent-free conditions was also performed; ditions, producing the desired Mannich products with good
however, it afforded the product in diminished yield, demonstrating stereoselectivities. A benzo-fused a-azido cyclohexanone substrate
the importance of predissolving the substrates and catalysts in DCM was also compatible with the optimal conditions, providing the
(entry 13). Conducting the reaction at room temperature (25 1C) product with excellent stereoselectivities, albeit with moderate
resulted in diminished reactivity, affording the product with yield (3r). Switching the N-protecting group on aldimine to Cbz
poor yield (42%, entry 14). Interestingly, conducting the reaction was also explored, which generated the product in moderate yield
with 1.0 equiv. aldimine 2a in toluene (0.25 M) for 2 h resulted in with high stereoselectivities (3s). However, expanding the cyclic
the isolation of the product 3a in 60% yield with the same ketone moiety to cycloheptanone or using an acyclic a-azido
stereoselectivity, while the a-azido cyclohexenone (1a) was recovered ketone as the substrate resulted in no desired products under
with 70% ee, which indicated the presence of kinetic resolution of the standard conditions (1t and 1u).
the racemic starting material under these conditions (entry 15, for
more information see ESI†).
To demonstrate the synthetic applicability of these reac-
tions, the derivatizations of the chiral products were studied.
16a
With the optimal conditions in hand, we set out to explore Reduction of the azido group in 3c by catalytic hydrogenation
the substrate scope of this reaction. A series of substitutions using Pd/C as the catalyst afforded the free amine product 4c in
(including both electron-donating and electro-withdrawing 63% yield with the completely retained enantioselectivity
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Table 2 Substrate scope of asymmetric Mannich reactions of a-azido
a
cyclic ketones
Scheme 1 Derivatizations of the chiral products.
Scheme 2 Asymmetric functionalization of a-azido cyclic ketones with
azodicarboxylates.
apart from aldimines were also attempted in the reactions with
a-azido cyclic ketones under the catalysis of CPA catalyst. Encoura-
gingly, we found that the reaction between a-azido cyclohexanone
1a with azodicarboxylate 8 in the presence of CPA catalyst A4
afforded the chiral amination product 9a in 96% yield with 81%
ee (Scheme 2), which represents a rare example of the asymmetric
synthesis of the acyclic N,N-aminal-type product. However, using
6 h. Yields were isolated. dr was determined by H NMR. ee was a-azido cyclopentanone 1q as the substrate generated the product
a
Reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol), cat. (S)-A8
21
(10 mol%), 4 Å molecular sieves (150 mg) in DCM (0.1 mL) at 40 1C for
1
1
b
determined by chiral HPLC analysis. The ee values of the minor
diastereomers are provided in the parentheses.
9b in 80% yield with 52% ee under these conditions.
In summary, we have described the direct asymmetric
Mannich reactions of a-azido cyclic ketones with aldimines
(
Scheme 1a), whose absolute configuration was unambiguously enabled by chiral phosphoric acid catalysis, which provide access
1
9
assigned by X-ray crystallography.
Cycloaddition of 3a to chiral azides with an a-quaternary stereocenter regiospecifically
4
with phenylacetylene in the presence of CuSO and sodium with good diastereoselectivities and high enantioselectivities. The
20
ascorbate proceeded smoothly to provide the triazole containing asymmetric catalytic system is further extended to asymmetric
product 5a in 69% yield, without the erosion of the chiral amination with azodicarboxylates, which broadens the applica-
information (Scheme 1b). Stereoselective reduction of the ketone tions of this method in the enantioselective synthesis of chiral
moiety in 3a with L-selectride in THF at À78 1C gave alcohol 6a in organic azides with an a-quaternary stereocenter.
96% yield with 2 : 1 diastereoselectivity, which could be easily
We gratefully acknowledge NSFC (Grant No. 21702138),
separated by flash column chromatography. The stereochemistry ‘‘Thousand Talents Plan’’ Youth program and ShanghaiTech
of the newly generated alcohol of the major diastereomer University start-up funding for the financial support. We thank
(
6a1) was determined as trans to the azido group via X-ray Analytical Instrumentation Centre of ShanghaiTech for facilities
1
9
crystallography. Further deprotection of the Boc group of the and services of characterization of compounds.
major diastereomer 6a1 by treatment with HCl/EA solution
facilely generated the g-amino alcohol product 7a1 in good
yield (Scheme 1c).
Conflicts of interest
To further demonstrate the versatility of this method in the
asymmetric synthesis of chiral organic azides, other electrophiles There are no conflicts to declare.
1
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