Rhodium(III)-Catalyzed Enantio- and Diastereoselective C?H Cyclopropylation of N-Phenoxylsulfonamides: Combined Experimental and Computational Studies

Article abstract of DOI:10.1002/anie.201913794

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio- and diastereoselective construction of cyclopropanes through C?H activation of arenes and coupling with readily available cyclopropenes is highly appealing but

Full text of DOI:10.1002/anie.201913794

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Accepted Article
Title: Rhodium(III)-Catalyzed Enantio- and Diastereoselective C–
H Cyclopropylation of N-Phenoxylsulfonamides: Combined
Experimental and Computational Studies
Authors: Xingwei Li, Guangfan Zheng, Zhi Zhou, Guoxun Zhu, Shuailei
Zhai, Huiyin Xu, Xujing Duan, and Wei Yi
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Angewandte Chemie International Edition
10.1002/anie.201913794
RESEARCH ARTICLE
Rhodium(III)-Catalyzed
Enantio-
and
Diastereoselective
C–H
Cyclopropylation of N-Phenoxylsulfonamides: Combined Experimental
and Computational Studies
Guangfan Zheng,†[b] Zhi Zhou,†[a] Guoxun Zhu,†[a] Shuailei Zhai,[b] Huiying Xu,[a] Xujing Duan,[b] Wei Yi*[a] and
Xingwei Li*[b]
Abstract: Cyclopropane ring is a prominent structural motif in a number of
bioactive molecules, natural products, and pharmaceutical drugs. From a
perspective of atom-/step-economy, enantio- and diastereoselective
classical metal-catalyzed decomposition of diazoalkanes,[6] Simmons-
Smith type cyclopropanations,[7] Michael addition-initiated ring
closure,[ and enzymatic synthesis.[9]
8]
construction of cyclopropanes via C–H activation of arenes and coupling
with readily available cyclopropenes is highly appealing but remains very
challenging. In this article, by virtue of a dual directing-group-assisted C–H
activation strategy, Rh(III)-catalyzed mild and redox-neutral C–H
activation and cyclopropylation of N-phenoxylsulfonamides have been
realized in a highly enantioselective, diastereoselective, and regioselective
fashion with cyclopropenyl secondary alcohols as a cyclopropylating
reagent. Synthetic and biological applications have been demonstrated,
which manifested potentials of the developed protocol. Integrated
experimental and computational mechanistic studies revealed that the
reaction proceeds via a Rh(V) nitrenoid intermediate, and Noyori-type
outer sphere concerted proton-hydride transfer from the secondary alcohol
to the Rh=N bond conduces to the observed trans selectivity.
Introduction
Figure 1. The representative examples for FDA-approved drugs bearing a
Cyclopropanes are key structural motifs found in a broad range of
cyclopropane motif.
bioactive compounds and natural products.[1] They are also of great
importance as synthetic intermediates and building blocks.[2,3] In
particular, there is an increasing trend in applying cyclopropyl rings in
cyclopropylating reagents owing to the ring strain (approximately 54
drug discovery owing to their prominent pharmacological properties
Cyclopropenes[11] represent versatile and reactive electrophilic
kcal/mol). Metal-catalyzed cis-selective carbofunctionalization of
such as (1) reducing off-target effects, (2) increasing metabolic
cyclopropenes has been realized via insertion of main group
stability, and (3) improving brain permeability.[4,5] Thus, an overall
improvement of the pharmacological property can be well expected
with introduction of proper cyclopropyl ring. Especially, the 1,1-
[12]
organometallics, terminated by an electrophile (Scheme 1a). On the
other hand, enantioselective hydrofunctionalization[13] (such as
hydroamination, hydroboration, hydrostannylation and hydroacylation)
of cyclopropenes have also been extensively studied under various
dimethylcyclopropane motif as
a privileged structural unit has
frequently appeared in FDA-approved drugs, such as boceprevir and
cilastatin (Figure 1).[4c] Therefore, the development of efficient
synthetic methods for rapid construction of highly valuable
cyclopropane core represents an important research objective.
Consequently, notable synthetic progress has been made,[6-10] including
metal-catalyzed
conditions.
Arenes
represent
abundant
carbonucleophiles (Scheme 1b). From the perspective of atom/step-
economy, metal-catalyzed C–H activation of arenes offers a highly
desirable strategy for direct construction of cyclopropanes using
[14]
readily available cyclopropenes. Despite the conceptual simplicity,
successful examples are rather rare (Scheme 1c). The main obstacle
resides in the high activity but low compatibility of cyclopropenes
[a]
Z. Zhou, G. Zhu, H. Xu, Prof. Dr. W. Yi
associated with the ring strain, which generally conduces to ring-
Key Laboratory of Molecular Target and Clinical Pharmacology & the
State Key Laboratory of Respiratory Disease, School of Pharmaceutical
Sciences & the Fifth Affiliated Hospital
[15]
opening reactions in C–H activation chemistry
instead of
cyclopropylation reactions. Thus, although various couplings of
arenes and cyclopropenes have been realized by Wang, Glorius, and
Guangzhou Medical University
Guangzhou, Guangdong 511436, P. R. China
E-mail: yiwei@gzhmu.edu.cn
G. Zheng, S. Zhai, X. Duan, Prof. Dr. X. Li
Key Laboratory of Applied Surface and Colloid Chemistry of MOE,
School of Chemistry and Chemical Engineering, Shaanxi Normal
University (SNNU), Xi’an 710062, P. R. China
E-mail: lixw@snnu.edu.cn
Rovis under Rh(III) catalysis, the majority of such functionalization
[16,17]
falls into ring-scission couplings.
In 2017, by using a designed
[
b]
+]
Rh(III) catalyst, Rovis reported the first redox-neutral cis-
diastereoselective (2.3:1 to >20:1 dr) synthesis of
cyclopropa[c]dihydroisoquinolones (Scheme 1c), where the
[14b]
cyclopropene acted as a special olefin in this [4+2] annulation.
[
These authors contributed equally to this work.
Given the rarity of C–H cyclopropylation systems and the improvable
diastereoselectivity of orphaned example, it is highly desirable to
develop efficient synthesis of cyclopropanes in both excellent
Supporting information for this article is given via a link at the end of the
document.
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Angewandte Chemie International Edition
10.1002/anie.201913794
RESEARCH ARTICLE
diastereoselectivity and enantioselecvitiy, especially with the
embedment of synthetically useful functionalities. We now report the
first Rh(III)-catalyzed redox-neutral C–H cyclopropylation of arenes
with cyclopropenyl alcohols for straightforward synthesis of
functionalized trans-cyclopropanes in a specific diastereoselective and
enantiostereoselective fashion (Scheme 1d). Further experimental and
computational studies revealed that the O–NHTs and OH dual-
directing-group (DDG)-assisted Noyori-type outersphere concerted
proton-hydride transfer to a Rh(V) nitrenoid conduces to this exclusive
regioselective, trans-diastereoselective, and excellent (S,S)-
enantioselective cyclopropanation. We also demonstrated synthetic and
biological applications in the rapid derivation of natural products and
as promising antitumor agents.
(Scheme 2). Thus, N-phenoxytosylamides bearing various commonly
encountered functional groups such as alkyl (4 and 6), phenyl (7),
halogens (8-10), trifluoromethyl (11), cyano (12), and ester (13) were
fully compatible, delivering the cyclopropanes in moderate to good
yields, and the C–H bond cleavage occurred regioselectively at the less
hindered site when meta-substituted substrates were used (16-20).
Subsequently, a diverse array of cyclopropenyl alcohols was examined.
It was found that aryl, naphthyl (42), furyl (44), thienyl (46), and
indolyl (47) groups were well tolerated in the coupling with 1a.
Importantly, alkyl-substituted cyclopropenyl alcohols were also viable
substrates (48 and 49). Finally, high-yielding synthesis of 47 on a 2.0
mmol scale further demonstrated the scalability. In all cases only the
trans cyclopropane products were consistently detected.
Scheme 1. Metal-catalyzed cyclopropylation of nucleophiles.
Scheme 2. Scope of racemic cyclopropylation. Reaction conditions: 1 (0.2
mmol), 2 (0.4 mmol), [Cp*RhCl ] (2.5 mol%) and CsOAc (1 equiv) in
2 2
Results and Discussion
DCM (0.1 M) at room temperature for 20 h under air; isolated yields were
reported. [a] Performed on a 2.0 mmol scale.
We reasoned that high diastereoselectivty of C–H cyclopropylation
system calls for a rapid, irreversibly transformation in post-insertion
reactions, ideally under mild conditions. This may be fulfilled in a
putative cyclopropyl Rh(V) species[18] that is highly reactive toward
reductive elimination and other elementary reactions. We thus chose
reactive N-phenoxyacetamide and (3,3-dimethylcycloprop-1-en-1-
yl)(phenyl)methanol (2a) as model substrates for racemic studies under
typical Cp*Rh(III)-catalyzed reaction conditions (see the Supporting
Information). The desired cyclopropylation-internal redox product 3
was obtained under rhodium-catalyzed simple conditions and was
produced in exclusively trans selectivity as determined X-ray
crystallography (CCDC 1907914).[19] Solvent screening indicated that
While asymmetric insertion of olefins into C–H bond has been
[20-23]
increasingly employed using chiral Rh(III) catalysts,
including
the olefins have been limited to
and intramolecular olefins.[21a] We next
[21]
under internal redox-conditions,
terminal,[
21b-e,23]
strained,
[21d-e,22]
screened the reaction parameters in the asymmetric C–H
cyclopropylation[13a-c] of 1a with (rac)-2a using a set of four chiral (R)-
RhCpX catalysts (Table 1). Application of Rh1 and Cu(OAc)
2
as an in
situ generated Rh(III) catalyst afforded (S,S)-3 in 93% ee albeit with
less satisfactory yield (DCM, entry 1), and no improved yield was
obtained in other common solvents (entries 2-5). Switching to the
Rh(III) catalyst Rh3 significantly increased the yield without much
o
2
CH Cl
2
was the optimal medium, and CsOAc was established as the
loss of the enantioselectivity (0 C, entry 7), and the Rh(III) chloride
optimal additive. Variation of the directing groups revealed that N-
phenoxytosylamide (1a) outperformed others. By adjusting the
substrate ratio, the optimized conditions were eventually identified
catalyst drastically outperformed the iodide congener (entry 6). Both
high yield and excellent enantioselectivity (95% ee) were secured
when the Rh4 catalyst was used (entry 8). Variations of additive,
temperature, and arene source (PhONHAc) all failed to offer improved
efficiency and enantioselectivity. The absolution configuration of the
product has been determined to be (S,S) by X-ray crystallographic
(
Scheme 2).
The scope of this racemic system was found to be quite broad
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RESEARCH ARTICLE
analysis of the O-sulfonylated derivative (vide infra). In all cases, only
the trans product was detected.
para position all coupled smoothly with 2a in consistently excellent
enantioselectivities (> 95% ee) and moderate to good yields (3-13).
Introduction of ortho Me and Cl groups was also tolerated (14 and 15),
suggesting compatibility with steric effect of the arene. A few meta
substituted arene substrates coupled regioselectively with 2a at the less
hindered ortho site in excellent enantioselectivity (> 97% ee). The
scope of the cyclopropenyl alcohol was next examined in the coupling
with arene 1a. Introduction of various electron-donating (OMe, OPh,
Table 1. Asymmetric optimization studies.[a]
3 3
OBn), -withdrawing (CF , OCF ), and halogen groups into the para
position of the alcohol phenyl ring was fully tolerated, with the
enantioselectivity ranging from 89% to 96% ee (21-32). Comparably
excellent enantioselectivity and good efficiency were also realized for
those alcohols bearing ortho and meta substituents (33-40), indicative
of tolerance of steric and electronic perturbation. The aryl group was
also smoothly extended to 1- and 2-naphthyls and to 2- and 3-furyls
Catalyst
4 mol %)
T
o
Yield[b]
(%)
ee[c]
(%)
Entry
Solvent
DCM
(
( C)
[
d]
1
2
3
4
5
(R)-Rh1
(R)-Rh1
(R)-Rh1
(R)-Rh1
(R)-Rh1
(R)-Rh2
(R)-Rh3
(R)-Rh4
(R)-Rh4
(R)-Rh4
(R)-Rh4
-15
-15
-15
-15
0
0
0
0
0
40
31
35
38
51
<5
78
76
73
<5
79
93
94
89
89
91
nd
89
95
94
nd
89
[
d]
d]
d]
d]
CHCl
3
(
88-91% ee). In contrast to the smooth racemic coupling of alkyl-
[
DCE
PhCl
[
substituted alcohols, essentially no reactivity was observed in the
asymmetric system (48), which indicates limitation of the alcohol
substrate.
Synthetic applications of this coupling system were next
demonstrated. Scale-up synthesis of (S,S)-3 has been achieved at a 1.0
mmol scale under a reduced catalyst loading (Scheme 4a). Subsequent
[
DCM
DCM
DCM
DCM
DCM
DCM
DCM
6
7
8
[
e]
9
1
0[f]
0
25
1
1
[
a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Rh cat. (4 mol%) in a solvent
protection of the OH group with BsCl afforded product (S,S)-50
(2 mL) under air, for 72 h. [b] Isolated yield after column chromatography. [c]
[19]
(
CCDC 1971788) with essentially no erosion of the enantiopurity,
Determined by HPLC with a chiral stationary phase. [d] Rh cat. (8 mol%) together
with Cu(OAc) (16 mol%). [e] CsOPiv was used instead of CsOAc. [f] PhONHAc was
used instead of 1a.
which allowed determination of the absolute configuration of 3. In
subsequent racemic coupling, the reaction of 1a with the corresponding
alkyl-functionalized cyclopropenyl alcohols (2ad and 2ae, derived
from bioactive natural products cyclamen aldehyde and citronellal,
respectively) proceeded smoothly, to afford their desired derivatives
2
(
51-52) in good yield (Schemes 4b, c). The ketone unit allows for
further transformations (scheme 4d). Wittig reaction of 3 afforded
product 53 in 73% yield. 3 could undergo nucleophilic addition with
lithium phenylacetylide in high diastereoselectivity. When treated with
t
KO Bu or concentrated H
2
SO
4
, 3 underwent ring opening to give
dihydrobenzofuran derivate 55 in good yield (scheme 4e).
Scheme 3. Scope of asymmetric C-H cyclopropylation. Reaction
conditions: 1 (0.1 mmol), 2 (0.2 mmol), (R)-Rh4 (4.0 mol%), CsOAc (2.0
o
equiv) in DCM (2.0 mL) under air at 0 C for 72 h, isolated yield.
The scope of this enantioselective synthesis was next explored under
the optimal reaction conditions (Scheme 3) and was found to be quite
broad. Thus, arenes bearing various alkyl, halogen, and EWGs at the
Scheme 4. Synthetic applications
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RESEARCH ARTICLE
Besides synthetic applications, the biological application of five
The mechanism of the asymmetric coupling system was also briefly
trans-cyclopropane products was also investigated. As given in Table 2, explored. A stoichiometric reaction of 1a and (R)-Rh4 allowed
our initial in vitro screening demonstrated that all these products
displayed potent antitumor activities in a panel of human tumor cell
lines, including HepG2, MCF-7, A549 and SH-SY5Y, as determined
by a dose-dependent CCK8 assay. In particular, products 20 and 27
exhibited more potent inhibitory activities than the marketed anticancer
drug 5-Fluorouracil. These results suggested the potential and interest
of such products in broad-spectrum anticancer drug discovery.
Correlation with the chemical structures of these products suggests that
the introduction of aryl functional group to 3 can be beneficial in
enhancing the antitumor potentiality.
isolation of
a
rhodacycle 57 as the enantiometrically and
diastereomerically pure product (Scheme 5b), which was characterized
by NMR spectroscopy and mass spectrometry. Designation of 57 as a
catalyst for the coupling of 1a and 2a afforded the (S,S)-3 in 68% yield
and 95% ee, indicating that the reaction follows a C–H activation
pathway and the chiral environment in 57 offers sufficient control of
the enantioselectivity.[21b,24]
To better explore the mechanistic details, we then conducted a set of
density functional theory (DFT) studies, particularly to uncover the
role of the DDGs and the origin of the regioselectivity, the specific
trans-diastereoselectivity as well as the (S,S)-enantioselectivity. Unless
otherwise specified, all structures were optimized at the B3LYP level
and single point energy calculations at the M06L level were performed
in experimental solvent (DCM). The N−H cleavage and C−H
Table 2. Biological Applications.
IC50 (μM)
Compounds
HepG2
MCF-7
>200
26.3±1.17
5.2±2.93
25.44±2.45
>200
A549
SH-SY5Y
>200
35.18±1.42
17.35±3.19
34.38±1.4
>200
3
41.48±8.17
31.42±1.87
21.25±1.38
25.35±1.52
69.47±1.31
51.61±0.93
65.46±11.26
38.73±2.65
33.0±1.08
35.04±1.84
>200
‡
‡
activations occurred via TS-1 (ΔG = 13.7 kcal/mol) and TS-2 (ΔG =
2.3 kcal/mol via concerted metalation-deprotonation), respectively, to
afford rhodacycle INT-3 (see the Supporting Information).
1
8
0
7
0
2
2
2
3
a
Subsequent coordination and regioselective migratory insertion of
olefin 2a proceeded via TS-3 with an energy barrier of 23.5 kcal/mol
to give a seven-membered rhodacycle intermediate INT-5. In contrast,
insertion with the other regioselectivity took place with a free energy
barrier of 26.8 kcal/mol (INT-3 to TS-3iso). Therefore, formation of the
intramolecular hydrogen bonding between the Ts and the OH groups
plays a crucial role in controlling the insertion regioselectivity.
5-FU
31.74±1.07
39.03±3.34
2.97±0.56
From INT-5, several possible pathways have been examined to
dwell on the mechanistic details of this racemic reaction (Figure 2). In
path a, the coordination of the hydroxyl group to Rh center generated a
more stable intermediate INT-6 with a free energy of -7.8 kcal/mol,
followed by the oxidative addition of the N-O bond with a free energy
barrier of 7.9 kcal/mol (from INT-6 to TS-4a) to produce a Rh(V)
nitrenoid INT-7a. [25,26] In path b, an alternative oxidative addition
process along with the cleavage of O–N bond was involved to yield the
Rh(V) species INT-8b, followed by intramolecular dual hydrogen
transfer, in which the hydrogen on hydroxyl group was shifted to the
phenol oxygen while the methine C–H of the alcohol was transferred to
the NTs, to provide the INT-9b. Obviously, this pathway via TS-8b
‡
carried a relatively high free energy (ΔG = 16.4 kcal/mol), rendering it
less likely compared with the path a. Besides, another reaction pathway
without hydrogen-bonding assistance was also excluded sicne a
relatively high free energy of 7.9 kcal/mol was involved in its
transition state (see TS-4b). These results futher emphasized the
significance of the formation of a hydrogen bonding between DDGs
for this transformation. In addition, ring-opening of the cyclopropane
moiety by the selective β–C elimination via either the Rh(III) species
TS-4c or the Rh(V) species TS-5c could be ruled out because
Scheme 5. Mechanistic studies and proposals
A series of experiments have been conducted to probe the
mechanism of this coupling system (Scheme 5). The racemic coupling
between arene 1a and a mono-deuterated alcohol (rac)-2a-d revealed
1
complete transposition of the D atom to the α position of carbonyl
group (Scheme 5a, above). Consistently, the coupling of 1a and 2a in
3
the presence of CD OD resulted in no deuterium incorporation into the
product, indicating that the hydrogen originates from the methine C–H.
A crossover experiment using 1a and two distinguishable cyclopropyl
alcohols further reinforced this conclusion, where the corresponding
two products were generated without crossover (Scheme 5a, below).
‡
relatively high energy barriers (ΔΔG = 28.7 kcal/mol from INT-5 to
‡
TS-4c and ΔΔG = 23.6 kcal/mol from INT-7a to TS-5c) were noted.
Instead, nitrenoid INT-7a underwent irrversible, concerted proton and
hydride transfer via Noyori's outer sphere mechanism with a low
energy barrier of 6.5 kcal/mol (via TS-5a) to give intermediate INT-8a.
It should be noted that, in an alternative stepwise pathway of OH
nucleophilic addition to the Rh=N bond (via TS-5b) and subsequent β–
H elimination (via TS-6b) was unfavorable due to the ring strain. Thus,
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RESEARCH ARTICLE
‡
our calculations highlighted that the outer-sphere concerted proton-
hydride transfer effectively lowers the reaction barrier and avoids the
thermodynamic sink INT-7b. Following formation of INT-8a, facile
C–H reductive elimination via the three-membered transition state TS-
6a instead of enolized 1,3-Rh(III) migration (ΔΔG = 5.4 kcal/mol vs
‡
ΔΔG = 16.6 kcal/mol) takes place to deliver the Rh(III) phenoixde
INT-9a, which upon protonolysis furnished the final trans-product
together with regeneration of the Rh(III) catalyst.
Figure 2. Computed Gibbs free energy changes of the reaction pathways for alkyne insertion, oxidative addition, Noyori-type outer sphere concerted
proton-hydride transfer, reductive elimination and protonlysis in DCM.
rationalized the enantioselectivity of the asymmetric coupling of 1a
and 2a catalyzed by chiral (R)-Rh4 catalyst by DFT studies. Migratory
insertion of the Rh-C(aryl) into the C=C bond constitutes the
steterodeterming step. Two transition states TS-3SS and TS-3RR with
respect to different stereoselectivity of olefin insertion were
investigated and the differences of activation energies are given in
Figure 3. Our calculations using different levels of theoretical studies
confirmed that the free energy of TS-3RR was consistently higher than
that of TS-3SS, with the energy difference between TS-3SS and TS-3RR
o
ranging from 0.6 to 1.8 kcal/mol (0 C), which correponds to a good to
excellent calculated ee values (up to 99% ee). The results are indeed in
Figure 3. Optimized geometries, energy differences and ee values of the
transition states TS3SS and TS3RR for the alkene insertion step in the (R)-
Rh4 catalyzed cyclopropanation reaction.
line with our results in asymmetric C–H cyclopropylation. Thus, on the
basis of both DFT calculations and experimental mechanistic studies, a
tandem C−H activation, alkyne migratory insertion, oxidative addition,
outer sphere concerted proton-hydride transfer, reductive elimination,
and protonolysis process is proposed (See the Supporting Information).
After the exploration of the racemic coupling system, we further
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RESEARCH ARTICLE
Conclusion
[4]
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We have developed the first Rh(III)-catalyzed and DDG-assisted
enantio- and diastereoselective C–H cyclopropylation of N-
phenoxytosylamides with cyclopropenyl alcohols as a result of ring-
retentive internal redox coupling, which complements the few existing
methods to synthesize trans-cyclopropanes. Both racemic and
enantioselective reactions have also been realized with broad
functional group compatibility under mild and operationally simple
conditions. Subsequent derivatization of natural products and
biological application of the selected products as the screening of the
promising antitumor drugs further highlighted the utility of the
developed protocol. Through detailed experimental and
computational investigations, the role of the DDGs, the origin of the
regioselectivity, the specific trans-diastereoselectivity, and the (S,S)-
enantioselectivity have been elucidated. Significantly, Noyori-type
outer sphere concerted proton-hydride transfer mechanism was
identified as a key factor for controlling such trans-specific selectivity.
Future studies on asymmetric C–H activation using other strained rings
are ongoing in our laboratories and will be reported in due course.
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Acknowledgements
We acknowledge financial support from NSFC (21525208, 21877020,
and 21603279), Guangdong Natural Science Funds for Distinguished
Young Scholar (2017A030306031), China Postdoctoral Science
Foundation (2019TQ0192), and Fundamental Research Funds for the
Central Universities (GK201903028).
[9]
Keywords: Rhodium
• trans-cyclopropane • asymmetric C–H
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RESEARCH ARTICLE
RESEARCH ARTICLE
†
†
†
Guangfan Zheng, Zhi Zhou, Guoxun Zhu, Shuailei Zhai, Huiying Xu,
Chiral Rh(III)-catalyzed C–H activation and cyclopropylation of
O-sulfonyl phenols have been realized in a highly enantioselective, Xujing Duan, Wei Yi* and Xingwei Li*
diastereoselective, and regioselective manner with cyclopropenyl
secondary alcohols as the cyclopropylating reagent. Integrated Page No. – Page No.
experimental and computational mechanistic studies suggest that
the reaction proceeds via a Rh(V) nitrenoid intermediate that Rhodium(III)-Catalyzed Enantio- and Diastereoselective C–H
participates in Noroyi-type outer sphere concerted proton-hydride Cyclopropylation of N-Phenoxylsulfonamides: Combined
transfer to deliver such selectivity.
Experimental and Computational Studies
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