Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl Rearrangement of 1,3-Diketones toward Bicyclic Lactams

Article abstract of DOI:10.1002/anie.202107909

Although copper-nitrene has been extensively studied as a versatile active species in various transformations, asymmetric reactions involving copper-nitrene have been limited to the aziridination of olefins. Herein, we report the novel copper-nitrene-catalyzed desymmetric oxaziridination reaction of cyclic diketones with alkyl azides and the subsequent rearrangement of the resulting highly active intermediate, which produces a synthetically challenging chiral bicyclic lactam containing a quaternary carbon center. This procedure not only enriches the copper-nitrene-catalyzed asymmetric reactions, but also provides an alternative strategy to address the inherent challenges of catalytic asymmetric Schmidt reactions. This unique reaction could inspire the investigation of novel copper-nitrene-catalyzed asymmetric transformations and their reaction mechanisms.

Full text of DOI:10.1002/anie.202107909

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Accepted Article
Title: Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl
Rearrangement of 1,3-Diketones toward Bicyclic Lactams
Authors: Yongqiang Tu, Xue Han, Li-Xin Shan, Jin-Xin Zhu, Chang-
Sheng Zhang, Xiao-Ming Zhang, Fu-Min Zhang, Hong Wang,
Ming Yang, Wen-Shuo Zhang, and yong qiang Tu
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Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl
Rearrangement of 1,3-Diketones toward Bicyclic Lactams
Xue Han, Li-Xin Shan, Jin-Xin Zhu, Chang-Sheng Zhang, Xiao-Ming Zhang, Fu-Min Zhang,* Hong
Wang, Yong-Qiang Tu,* Ming Yang, Wen-Shuo Zhang
[ ]
*
X. Han, L.-X. Shan, C.-S. Zhang, Dr. X.-M. Zhang, Prof. Dr. F.-M. Zhang, Prof. Dr. Y.-Q. Tu, Prof. Dr. M. Yang, W.-S. Zhang
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (China)
E-mail: zhangfm@lzu.edu.cn
tuyq@lzu.edu.cn
J.-X. Zhu, Prof. Dr. H. Wang
College of Pharmaceutical Science and Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals
Zhejiang University of Technology
Hangzhou 310014 (China)
Prof. Dr. Y.-Q. Tu
School of Chemistry and Chemical Engineering and Shanghai Key Laboratory of Chiral Medicine Chemistry
Shanghai Jiao Tong University
Shanghai 200240 (China)
E-mail: tuyq@sjtu.edu.cn
Abstract: Although copper-nitrene has been extensively studied as
a versatile active species in various transformations, asymmetric
reactions involving copper-nitrene have been limited to the
aziridination of olefins. Herein, we report the novel copper-nitrene-
catalyzed desymmetric oxaziridination reaction of cyclic diketones
with alkyl azides and the subsequent rearrangement of the resulting
highly active intermediate, which produces
a
synthetically
challenging chiral bicyclic lactam containing a quaternary carbon
center. This procedure not only enriches the copper-nitrene-
catalyzed asymmetric reactions, but also provides an alternative
strategy to address the inherent challenges of catalytic asymmetric
Schmidt reactions. This unique reaction could inspire the
investigation of novel copper-nitrene-catalyzed asymmetric
transformations and their reaction mechanisms.
The investigation of asymmetric transformations involving
reactive intermediate species[1] has received considerable
interest from the chemical community. In recent years, chiral
metal-nitrene complexes[2], an important class of reaction
intermediates, have received continued research attention. The
transformations involving metal-nitrene intermediates are
reliable and practical approaches to produce chiral compounds
containing nitrogen atoms, which are widely found in clinical
drugs,[3] bioactive natural products,[2c,2d,4] and functional
materials.[5] Among transition metals, copper is preferred by
synthetic chemists[6] because of its low cost, multivalence in
catalytic cycles, and abundance in nature. However, the
development of chemical transformations based on chiral
copper-nitrene has mainly focused on the aziridination of C=C
bonds to generate synthetically important aziridines[7] (Scheme
1a). To further explore other novel transformations involving
chiral copper-nitrene species, we speculated that a polarized
C=O bond could react with in-situ generated copper-nitrene and
the resulting highly active intermediate oxaziridine[8] could
subsequently rearrange to produce a synthetically challenging
chiral lactam[4,9] (Scheme 1b). Such an asymmetric
transformation could efficiently address the intrinsic challenges
of the classic intramolecular Schmidt reaction,[10] including the
use of azides with low nucleophilicity as a substrate, the general
requirement for stoichiometric amounts of a strong Lewis or
Brønsted acid to activate the carbonyl group of the other
reactant, the relatively strong Lewis basic nature of the
Scheme 1. The outline of Cu-catalyzed asymmetric reactions involving
nitrenoid intermediates.
resulting lactam, and the lack of the corresponding catalytic
asymmetric fashion. Notably, the resulting chiral bicyclic lactams
could be used as the key precursors for the total synthesis of
various bioactive alkaloids, such as cephalotaxine,[4b]
squarrosine A,[4c] and fluvirosaone B.[4d] Herein, we report a
novel copper-nitrene-catalyzed asymmetric intramolecular
tandem oxaziridination/rearrangement reaction to produce a
chiral fused bicyclic lactam.
Initially, we performed our designed catalytic asymmetric
reaction with a combination of Cu(CH3CN)4PF6 (10 mol%) and a
bisoxazoline (BOX)-type ligand (L1) without any additive and
used 2-benzyl-2- azidopropyl-1,3-cyclohexadione (1a) as the
1
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Table 1. Optimization of ligand and reaction conditions[a]
Table 2. Scope of 1,3-cyclohexanedione substrate[a]
Entry
1
2[d]
CuX/AgSbF6
Cu(CH3CN)4PF6
CuCl
Additive
-
L
Solvent
DCM
DCM
DCM
PhCF3
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Y[%][b]
9
ee[%][c]
93
-
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
-
NR
46
19
8
3
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
CuCl/AgSbF6
-
93
92
88
94
94
94
94
94
94
82
94
94
4
-
5
-
6[e]
7[f]
8[g]
9
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
55
78
84
52
65
67
67
30
41
10
11
12
13
14[h]
[a] Unless otherwise specified, reactions were conducted at room temperature
with 1a (0.2 mmol, 1.0 equiv), CuCl (0.02 mmol, 0.1 equiv), AgSbF6 (0.024
mmol, 0.12 equiv), L1 (0.024 mmol, 0.12 equiv), NaBArF (0.5 equiv) in 4 mL
DCM. Isolated yields. ee value was determined by chiral HPLC. [b] The
reaction was carried out at 45 °C, and no product was observed at room
temperature.
[a] Unless otherwise stated, the reactions were conducted with 1a (0.2 mmol,
1 equiv), CuX/AgSbF6 (0.1 equiv/0.12 equiv), L (0.12 equiv), NaBArF in
solvent (4 mL). [b] Isolated yield. [c] Determined by chiral HPLC. [d] No
reaction. [e] NaBArF (0.12 equiv). [f] NaBArF (0.3 equiv). [g] NaBArF (0.5
equiv). [h] CuCl/AgSbF6 (0.05 equiv/0.06 equiv), L1 (0.06 equiv), NaBArF (0.3
equiv).
Using the optimal conditions, the generality of this novel tandem
reaction was investigated. Various substituents on the aryl ring
were studied, and the results showed that the substrates bearing
electron-donating or electron-withdrawing groups generated the
expected lactams 2b-2i with high enantioselectivities in
moderate to high yields. The o-substituted phenyl and 1-
naphthyl substrates produced the desired products with
diminished yields and slightly higher enantioselectivities, which
may be a result of the steric hindrance caused by the
substituents (2c, 2e, 2g, 2i). Heteroaromatic substrates also
produced the corresponding lactams 2j and 2k in high yields
with slightly reduced enantioselectivities (75% and 80% ee,
respectively.). In addition to the different benzyl groups listed
above, simple alkyl substituents such as ethyl, n-propyl, and 2-
phenylethyl, were also examined. It was found that these
substrates yielded the desired lactams in moderate to high
yields. Esters and methyl ketones, which are functional handles
for further derivation, were compatible with the current reaction
conditions, and the corresponding lactams 2o and 2p were
obtained with 85% and 83% ee in 75% and 34% yields,
respectively. For the methyl ketone substrate 1o, the competing
reactions on the carbonyl group at the side chain may be
accountable for the poor yield. The benzyl azide 1q was also
suitable under the optimal reaction conditions, and the desired
tricyclic product 2q was obtained with a 66% yield and 72% ee.
The absolute configurations of products 2a, 2c, 2e, and 2f were
further verified by X-ray crystallography, and the stereochemistry
of the other lactams was assigned by their analogs. The ketone
groups of the products could be utilized as versatile sites for
structural functionalization. For example, the reduction of 2m
with NaBH4 produced the cyclic alcohol 2m' in a 71% yield as a
major diastereoisomer.[13] The absolute configuration of 2m' was
confirmed by X-ray diffraction.
substrate. The expected lactam (2a) was obtained with a 9%
yield and 93% enantiomeric excess (ee) (Table 1, entry 1),
which indicated a higher enantioselectivity compared to our
previously developed asymmetric Schmidt reaction[10e] and
Marsden’s results.[10d] When Cu(CH3CN)4PF6 was replaced with
CuCl, no reaction was observed, and the unreacted azide 1a
was recovered (entry 2). Then, CuSbF6 prepared in situ from
CuCl and AgSbF6 was examined in CH2Cl2, PhCF3, and CHCl3,
which resulted in moderate to excellent ee values but low yields
despite a prolonged reaction time (entries 3-5). From these
experimental results, we speculated that a suitable chiral
copper(I)-complex could induce high enantioselectivity while the
above-tested Cu(I)-species did not convert substrate 1a
completely.
Considering
that
sodium
tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate (NaBArF)[11] could generate an
active LCuX complex,[12] NaBArF (12 mol%) was used as an
additive to improve the reaction outcome. This resulted in an
improved yield (55%) and higher ee (94%) (entry 6). Increasing
the quantity of NaBArF to 50 mol% produced significantly
improved results (entries 7 and 8). However, other structurally
related BOX ligands (L2-L4 with smaller H-, Me-, or iPr-
substituted phenyl groups, L5 with a strong electron-withdrawing
CF3 substituent, and L6 bearing merely a Me substituent) were
investigated under the same reaction conditions used for entry 8,
but the results did not improve (entries 9-13). Finally, a lower
loading (6 mol%) of CuSbF6/L1 with 30 mol% NaBArF was
tested, which produced unsatisfactory results. Therefore, the
reaction parameters listed in entry 8 (Table 1) were selected as
the optimal reaction conditions for further investigation.
2
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Table 3. Scope of 1,3-cyclopentanedione substrate[a]
[a] Unless otherwise specified, reactions were conducted at room temperature
with 1a (0.2 mmol, 1 equiv), CuCl (0.02 mmol, 0.1 equiv), AgSbF6 (0.024
mmol, 0.12 equiv), L1 (0.024 mmol, 0.12 equiv), NaBArF (0.5 equiv) in 4 mL
DCM. Isolated yields. ee determined by chiral HPLC. [b] The reaction was
carried out at 45 °C, and low isolated yield was obtained at room temperature.
[c] The reaction was carried out at 45 °C, and no product was observed at
room temperature.
Scheme 2. The designed control experiments.
Moreover, the liberation of gases was observed under these
mild reaction conditions, preliminarily excluding the involving of a
classical Schmidt rearrangement in the current transformations.
Although a series of trapped experiments were performed, the
capture of the active copper-nitrene intermediate failed (for
details, see SI). Considering the high reactivity of the copper-
nitrene species, the oxaziridine was the key intermediate,
followed by a rapid 1,2-alkyl shift process with Cu(I) as the
catalyst, which produced the corresponding lactam. As we could
not isolate the oxaziridine under these copper-catalyzed reaction
conditions, the oxaziridine 3nb was prepared via a two-step
synthesis, and its structure was confirmed by an X-ray analysis
of its derivative 3nc.[15] Then, the intermediate 3nb was
subjected to the optimized reaction conditions, and the racemic
product 4e was obtained in a 76% yield (Scheme 2b).
Considering the importance of lactams,[14] we then turned our
attention to the scope of other ketones. Specifically, [6,5]-fused
bicyclic lactams are important subunits found in various
bioactive alkaloids (Figure 1); thus,
a
series of 1,3-
cyclopentanedione derivatives were subjected to the optimized
reaction conditions. The R group represented different aryl rings,
such as phenyl (4a), 4-methyl phenyl (4b), 2-methyl phenyl (4c),
4-methoxyl phenyl (4d), 4-trifluoromethyl phenyl (4e), 2-nitro
phenyl (4f) and 4-methoxyl carbonyl phenyl (4g), all of which all
produced the desired [6,5]-fused bicyclic lactams with a high ee
of 99%. Except for the o-substituted products 4c (63% yield) and
4f (44% yield), the yields produced were >70%. Notably, both 2-
furyl and 2-thienyl substrates produced significantly improved
results (99% ee) than their 1,3-cyclohexanedione analogs.
Different alkyl groups were also tested under the optimized
reaction conditions. In addition to the linear methyl, ethyl and n-
propyl groups and the sterically hindered i-propyl groups, the
cyclopropyl and cyclopentyl groups produced the desired
lactams with high enantioselectivities. A simple alkenyl group
was also suitable under the optimized conditions; it produced
lactams containing C=C bonds with 98% ee (4p) and 99% ee
(4q), respectively. The substrate 3r, bearing an alkynyl group,
yielded the lactam 4r with a 99% ee but low yield of 36%.
Additionally, the activity of the key catalyst possibly reduced
because of the coordination of the alkyne to the copper center.
The acyclic 1,3-dicarbonyl substrates did not produce the
desired lactams.
A few designed control experiments were conducted to gain
further information regarding the reaction mechanism. When the
substrate 1e was reacted under dark reaction conditions, the
desired product 2e was isolated in a 80% yield with a 92% ee.
This implied that the photoinduced transformation was not the
dominant mechanism in the current reaction (Scheme 2a).
Scheme 3. The proposed reaction mechanism.
3
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Additionally, when the probe compound 3db was subjected to
the optimal reaction conditions, the recovery of the starting
material was observed (Scheme 2c), therefore, demonstrating
that the carbonyl group of substrates is necessary in the current
transformation. These results supported our speculation that the
copper(I)-catalyzed oxaziridination is a vital step in the current
reaction.
Based on the above results and previous literature, a possible
reaction mechanism was proposed, as shown in Scheme 3. First,
CuCl complexed with a BOX-type ligand and then reacted with
AgSbF6 to yield an intermediate, which was stabilized by the
sterically bulky anion BArF to generate the intermediate Int-A.
Subsequently, the substrate 1a reacted with the intermediate
Int-A to release N2 and produce the key active species Cu-
nitrene[1a,16] Int-C through the complex Int-B. The electronic
interactions between the carbonyl group and the copper center
perhaps had a crucial role in this process. Subsequently, Int-D
was generated by asymmetric oxaziridination, resulting in the
origin of the enantiocontrol in this procedure. Then, the three-
Keywords: chiral copper-nitrene • oxaziridination •
rearrangement reaction • Schmidt reaction • bicyclic lactams
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a N-O bond cleavage
accompanied by an alkyl C-N 1,2-shift[17] to generate Int-E,
which produced the final product lactam 2a and simultaneously
released the catalyst Int-A for the next catalytic cycle (Scheme
3).
In conclusion, we have developed a novel copper(I)-catalyzed
asymmetric
intramolecular
tandem
oxaziridination/rearrangement reaction. This reaction facilitated
the production of various chiral bicyclic lactams with moderate to
high enantioselectivities under the mild reaction conditions. This
novel reaction could be used to solve practical synthetic
problems associated with the classic asymmetric Schmidt
reaction. Furthermore, it could be useful as a synthetic method
for the discovery of new therapeutics and agrochemicals
composed of lactams. Notably, this study provides novel
information on the asymmetric transformations involving Cu-
nitrene species and their corresponding mechanisms. Further
exploration of these unique Cu-nitrene-catalyzed asymmetric
transformations and their detailed mechanistic investigation is
currently underway.
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Acknowledgements
We thank the NSFC (No. 21502080, 21772019, 21772076,
21871117, 91956203, and 21971095), the ‘111’ Program of
MOE, the Major Project (2018ZX09711001-005-002) of MOST,
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Crystallographic Data
Crystallographic data generated during this study has been
deposited in the Cambridge Crystallographic Data Centre
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2058852 (2c), 2058853 (2e), 2058850 (2f), 2058851 (2i),
2058855 (2k), 2058856 (4a), 2058860 (4c), 2058857 (4g),
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10.1002/anie.202107909
Angewandte Chemie International Edition
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Cu-nitrene-catalyzed asymmetric transformation is merely limited in the aziridination of C=C double bonds in the past decades.
Herein, we not only developed a novel Cu-nitrene catalyzed oxiazididition of C=O double bonds, but also achieved a tandem
asymmetric oxiazidation/rearrangement reaction of cyclic diketones, affording a series of bicyclic lactams bearing a quaternary
carbon center.
6
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