Highly enantioselective nickel-catalyzed hydrocyanation of disubstituted methylenecyclopropanes enabled by taddol-based diphosphite ligands

Article abstract of DOI:10.1021/acs.orglett.9b04374

A vast range of novel TADDOL-based diphosphite ligands were first synthesized and applied in the nickel-catalyzed asymmetric hydrocyanation of disubstituted methylenecyclopropanes. By employing these new catalysts, the conversion of diverse methylenecyclo

Full text of DOI:10.1021/acs.orglett.9b04374

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Enantioselective Nickel-Catalyzed Hydrocyanation of
Disubstituted Methylenecyclopropanes Enabled by TADDOL-based
Diphosphite Ligands
Rongrong Yu and Xianjie Fang*
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao
Tong University, 800 Dongchuan Road, Shanghai 200240, People’s Republic of China
S
* Supporting Information
ABSTRACT: A vast range of novel TADDOL-based diphosphite ligands were first synthesized and applied in the nickel-
catalyzed asymmetric hydrocyanation of disubstituted methylenecyclopropanes. By employing these new catalysts, the
conversion of diverse methylenecyclopropanes into their corresponding allylic nitriles was first enabled, in good yield with
excellent enantioselectivities.
Thus the development of new chiral ligands and new prochiral
he transition-metal-catalyzed asymmetric hydrocyanation
Tof alkenes is probably the most atom-economical strategy substrates for the highly enantioselective hydrocyanations
remains highly desirable.
Methylenecyclopropanes (MCPs) are highly strained but
easily accessible adequately reactive synthetic intermediates that
are well-established and useful building blocks in organic
synthesis.6,7 Owing to the unique chemical reactivity and
electronic properties, the chemistry of MCPs was thoroughly
explored during the last few decades, in particular, in the
presence of transition-metal catalysts.8 Notably, Arai and
coworkers described in 2017 a nickel-catalyzed hydrocyanation
of MCPs (Scheme 1a) and suggested that the reactions may
proceed through a cyclopropane cleavage/conjugated diene
hydrocyanation sequence.9 However, this reaction is restricted
to monosubstituted MCPs as substrates, and to the best of our
knowledge, the asymmetric variation of this reaction has not yet
been reported.
Scheme 1. Hydrocyanation of MCPs
Since the pioneering report from Seebach in 1987,10
TADDOL-based derivatives have now been established as an
important source of chirality in organic synthesis.11 To the best
of our knowledge, although complexes of transition metals with
TADDOL-based phosphorus ligands have shown excellent
performance in various enantioselective reactions (Scheme
2a),12−14,4g,h the TADDOL-based diphosphite ligands have no
literature precedent.15 Herein we report the synthesis of novel
TADDOL-based diphosphite ligands, which allow for the
for enantiomerically enriched nitrile preparation.1 During the
past several decades, the emergence of a wide range of chiral
ligands has allowed for the construction of various chiral nitriles
through asymmetric hydrocyanation.2 Nonetheless, these
asymmetric catalysts are usually restricted to prochiral
substrates, namely, norbornene,3 vinylarenes,4 and 1,3-dienes.5
Received: December 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. TADDOL-based Phosphorus Ligands
Table 1. Optimization of Reaction Conditions
b
c
entry
L*
3a yield (%)
3a ee (%)
1
2
3
L1
L2
L3
0
trace
0
4
(R)-SEGPhos
0
5
(R)-MonoPhos
0
6
7
8
9
(R)-BINAP
(S,S)-Ph-BPE
(R,R)-DIOP
L4a
0
0
56
34
3
94
96
d
10
11
12
13
14
15
16
17
L4b
L4b′
L4c
L4d
L4e
L4f
L4g
L4h
L4b
L4b
L4b
87 (85)
0
76
78
58
52
18
28
0
0
46
24
94
94
95
94
nickel-catalyzed asymmetric hydrocyanation of disubstituted
MCPs with excellent enantioselectivities (Scheme 1b).
We successfully prepared a series of novel TADDOL-derived
diphosphite ligands following the general method described in
Scheme 2b. (See the SI for details.) These ligands are accessible
from the commercially available tartaric acid dimethyl ester in
only three steps. Their modular nature allows a facile structural
fine-tuning to obtain both high conversion and high
enantioselectivity. In this Letter, we focus on TADDOL-based
diphosphite ligands with sterically and electronically different
aryl substituents.
81
e
18
f
19
20
g
67
87
h
21
L4b
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Ni(cod)2 (5 mol
b
%), ligand (5 mol %), toluene (0.3 mL), 80 °C, 12 h. Determined by
GC analysis using n-dodecane as the internal standard. Determined
c
With these new ligands in hand, we began our studies by
testing the asymmetric hydrocyanation of MCP 1a with acetone
cyanohydrin (2) as the HCN source under nickel catalysis with a
variety of chiral ligands and examined the yield and the ee value
of the corresponding product 3a (Table 1). When the ligands
L1−L3 were used, which proved to be effective in the
asymmetric hydrocyanation of alkenes,4a,b,g,h,5 no conversion
or just trace amounts of the desired product were observed
(Table 1, entries 1−3). Commercially available chiral ligands
showed no reactivity in the formation of the desired product 3a
(Table 1, entries 4−7). DIOP exhibited moderate reactivity and
nearly no enantioselectivity in the formation of 3a (Table 1,
entry 8). These studies failed to reveal a system that could
provide good yield and good enantioselectivity. Hence, our
TADDOL-based diphosphite ligands with different steric
properties were tested (Table 1, entries 9−16). To our delight,
these ligands were effective in this asymmetric transformation.
The substituents on the aryl group have a significant influence
on both the yield and ee value of the reaction. It was remarkable
that the para-tert-butyl -substituted L4b gave the product 3a in
85% isolated yield with 96% ee (Table 1, entry 10). In a contrast,
for the ligand L4b′, with mismatched chiralities, no conversion
was observed (Table 1, entry 11). The optimization of other
d
e
f
g
by chiral HPLC. Isolated yield. Ni(acac)2. NiCl2. 1,4-Dioxane.
h
DMSO.
reaction parameters was then performed with optimal ligand
L4b. Ni(II) precatalysts such as Ni(acac)2 and NiCl2 led to the
recovery of the starting materials under the reaction conditions
(Table 1, entries 18 and 19). Polar solvents such as 1,4-dioxane
and DMSO led to much lower yields and enantioselectivities
than toluene (Table 1, entries 20 and 21).
Next, we examined the general scope of our asymmetrical
synthetic protocol. As shown in Scheme 3, various 1-methyl-1-
aryl disubstituted MCPs with electron-neutral, electron-
deficient, and electron-rich substituents underwent efficient
hydrocyanation to afford the corresponding allyl nitriles in good
yield with excellent enantioselectivities (3a−n). The absolute
configuration of product 3c was confirmed as R by X-ray
diffraction analysis, and stereochemical assignments of the other
products were tentatively made on this basis. Substrates having
different functional groups (i.e., −CO2Me, −OH, −NHAc, and
CC) were well tolerated (3i, 3j, 3k, 3n). Substrates with
heterocyclic substituents (such as quinolyl, thiophenyl, and furyl
groups) were established to be efficient coupling partners to
B
DOI: 10.1021/acs.orglett.9b04374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope
a
All reactions were performed on a 0.2 mmol scale under the standard reaction conditions (see Table 1, entry 10). Yields of isolated products after
flash column chromatography. The ee and dr values were determined by chiral HPLC.
produce corresponding products in acceptable yield with
excellent enantioselectivities (3o−q). Moreover, 1-methyl-1-
vinyl-disubstituted MCPs were well tolerated and afforded the
hydrocyanated products in good yield with high ee values (3s).
The efficient use of the method in the late-stage asymmetric
hydrocyanation of a perillal (3s), estradiol (3r), and citronellal
(3aa) showcases its feasibility for relatively more complicated
molecular scaffolds. Besides the methyl substituent at the R2
position, a variety of alkyl-substituted MCPs were all suitable for
the reaction, and the corresponding allylic nitrile products (3u−
aa) were obtained in 51−88% yield with 93−97% ee. Notably,
cyclic MCPs were tolerated to provide products (3ab−ad) in
good yield with excellent ee values. To our delight, with our
current catalytic system being regiospecific, the substrates with
substituents on the cyclopropane ring underwent the cleavage of
the Ca−Cb bond of cyclopropane, giving the desired products
(3ae and 3af) in acceptable to good yield with high levels of
enantioselectivity.
94% ee, Scheme 4a). Considering that the product 3a contains a
cyano and an alkene, two unsaturated functional groups, the
selective reductions can be readily performed. With NiCl2/
NaBH4 in MeOH, 3a can be fully reduced and converted into
the aliphatic chiral amine 3a-1 in good yield. Additionally, even
in the presence of cyano group, the alkene could be selectively
reduced to give aliphatic chiral nitrile 3a-2 in excellent yield.
Alternatively, the nitrile can be selectively reduced in the
presence of the alkene group to give chiral homoallylic amine 3a-
3 in acceptable yield. Importantly, the enentiomeric purity was
intact in these manipulations (Scheme 4b).
In summary, we have developed a new class of TADDOL-
based diphosphite ligands, which enable, for the first time, the
nickel-catalyzed asymmetric hydrocyanation of disubstituted
MCPs. Our protocol provides versatile optically active allylic
nitriles with excellent enantioselectivities. We also demonstrated
that the hydrocyanated products can be used as diverse
precursors in the preparation of chiral aliphatic amine and
nitrile as well as chiral homoallylic amine.
Finally, to verify the synthetic utility of the current
enantioselective hydrocyanation reaction, several transforma-
tions were conducted, as shown in Scheme 4. A gram-scale
reaction of 1a was achieved, producing the desired chiral nitrile
3a in excellent yield and with excellent ee values (92% yield and
C
DOI: 10.1021/acs.orglett.9b04374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04374.
■
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Accession Codes
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CCDC 1949402 contains the supplementary crystallographic
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request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fangxj@sjtu.edu.cn.
ORCID
Xianjie Fang: 0000-0002-3471-8171
Notes
Kuhnle, F. N. M.; Bernd Schweizer, W.; Weber, B. Helv. Chim. Acta
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1995, 78, 1636−1650.
(14) For the TADDOL-based phosphine−phosphite ligands in
The authors declare no competing financial interest.
asymmetric catalysis, beyond hydrocyanation, see: (a) Werle, S.; Fey,
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T.; Neudorfl, J.-M.; Schmalz, H.-G. Org. Lett. 2007, 9, 3555−3558.
ACKNOWLEDGMENTS
■
(b) Robert, T.; Velder, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2008,
This work was financially supported by the Recruitment
Program of Global Experts and the start-up funding from
Shanghai Jiao Tong University. We thank Prof. Bill Morandi
̈
47, 7718−7721. (c) Lolsberg, W.; Ye, S.; Schmalz, H.-G. Adv. Synth.
Catal. 2010, 352, 2023−2031. (d) Robert, T.; Abiri, Z.; Wassenaar, J.;
̈
Sandee, A. J.; Romanski, S.; Neudorfl, J.-M.; Schmalz, H.-G.; Reek, J. N.
H. Organometallics 2010, 29, 478−483. (e) Robert, T.; Abiri, Z.;
Sandee, A. J.; Schmalz, H.-G.; Reek, J. N. H. Tetrahedron: Asymmetry
2010, 21, 2671−2674. (f) Naeemi, Q.; Robert, T.; Kranz, D. P.; Velder,
J.; Schmalz, H.-G. Tetrahedron: Asymmetry 2011, 22, 887−892.
(ETH, Zurich) and Dr. Bastien Cacherat (SIOC, Shanghai) for
̈
the critical proofreading of this manuscript.
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DOI: 10.1021/acs.orglett.9b04374
Org. Lett. XXXX, XXX, XXX−XXX