Communication
doi.org/10.1002/chem.202102024
Chemistry—A European Journal
Table 1. Optimization of reaction conditions.[a]
from enynamides and VECs (Scheme 1b). Researches suggested
that VECs could undergo decarboxylation to afford a nucleo-
philic 1,3-dipolar π-allylpalladium intermediate[9] (Scheme 1a),
which later developed into a typical method for synthesis of
chiral multi-substituted tetrahydrofuran derivatives.[10] Inspired
by our previous works in developing the catalytic [3+2]-
cycloaddition between 1,3-dipoles and chiral Lewis acid
activated dipolarophiles,[11] it would be logical to expect that
the zwitterionic π-allylpalladium intermediate would react with
unsaturated electrophiles under catalysis of chiral-at-metal
rhodium(III) complexes[12] via a stereocontrolled addition and
ring-closing reaction to afford the desired multi-substituted
tetrahydrofuran (Scheme 1c).
Much progress has been made in one-pot multimetallic
catalysis,[13] which not only behaves economic and environ-
mental benefits but also enables some complex transformations
that would be difficult to access by conventional methods.
However, fewer examples of asymmetric syntheses via syner-
gistic multi-metallic catalysis have been realized,[14] not to
mention the construction of multiple stereogenic centers in
one-pot in such catalytic system. Transition metal catalysis is
highly dependent on ligands to confer specific reactivity,
especially chiral ligands for asymmetric catalysis. However, in a
multi-metal catalyzed system, competitive coordination and
activation between each metal, ligand and substrate is always a
crucial problem influencing reaction success. But the character-
istic of the chiral-at-metal complex was somewhat different, the
central metal binds with ligands through stable covalent bonds,
and the complex would mediate the catalytic cycle without
major ligands exchanged or released.[15] Thus, we envisioned
that the chiral-at-metal complex would be more suitable for
asymmetric multimetallic catalysis to work with other metal
cooperatively.[11c,16] Herein, a highly efficient palladium-rhodium-
catalyzed asymmetric decarboxylative [3+2]-cycloaddition of
α,β-unsaturated 2-acyl imidazoles 1 with VECs 2 was reported
(Scheme 1d). A novel approach for synthesizing chiral 1,2,3,3-
tetrasubstituted tetrahydrofurans has been developed from
racemic raw compounds in high level of stereoselectivities and
yields.
The research was commenced by testing the model
substrates α,β-unsaturated 2-acyl imidazole 1a and racemic
phenyl-VEC 2a. In the presence of 2 mol% Δ-Rh1[15] and
1 mol% Pd(PPh3)4, after 24-hours reaction under argon atmos-
phere in DCM at room temperature, the desired product 3a
was obtained in 81% yield with 90% ee and >20:1 d.r.
(Table 1, entry 1). The encouraging result supports our hypoth-
esis that the chiral-at-metal complex fits for such bimetallic
catalytic system. Chiral rhodium complexes Δ-Rh2, Δ-Rh3[17]
and Λ-Rh4[16] were synthesized and examined, but yields and
stereoselectivities were less than that derived from Δ-Rh1
(entries 2–4). Without the rhodium complex, the reaction did
not proceed at all (entry 5). Several Pd(0) and Pd(II) without
chiral ligands were tested while the best option was
Pd2(dba)3·CHCl3 (entries 6–9). A control experiment shows Pd(II)
gave no reaction (entry 8). Besides, a series of anhydrous aprotic
solvents were examined (entries 10–12). THF could give the
best reactivity performance to reach 96% ee as there is a little
Entry Rh
Pd (mol %)
Solvent
Yield
(%)[b]
ee (%)[c]
d.r.[d]
1
2
3
4
Δ-
Rh1
Δ-
Rh2
Δ-
Rh3
Λ-
Rh4
none
Δ-
Pd(PPh3)4 (1)
Pd(PPh3)4 (1)
Pd(PPh3)4 (1)
Pd(PPh3)4 (1)
DCM
DCM
DCM
DCM
81
79
75
68
90, >20:1
83, >20:1
86, >20:1
61, >20:1
5
6
Pd(PPh3)4 (1)
Pd2(dba)3·CHCl3
(1)
DCM
DCM
n.a.
82
–
94, >20:1
Rh1
Δ-
7
Pd2(dba)3 (1)
DCM
DCM
DCM
THF
75
94, >20:1
Rh1
Δ-
8
Pd(OAc)2 (1)
none
n.a.
n.a.
83
–
Rh1
Δ-
9
–
Rh1
Δ-
Rh1
Δ-
Rh1
Δ-
Rh1
Δ-
10
11
12
13
Pd2(dba)3·CHCl3
(1)
Pd2(dba)3·CHCl3
(1)
Pd2(dba)3·CHCl3
(1)
Pd2(dba)3·CHCl3
(2)
96, >20:1
95, >20:1
–
toluene
80
1,4-diox-
ane
THF
n.a.
88
98, >20:1
Rh1
[a] Unless otherwise noted, reactions were carried out by using 1a
(0.2 mmol), 2a (0.22 mmol), Rh-complex (0.004 mmol, 2 mol%) and Pd-
catalyst (0.002 mmol, 1 mol%) in anhydrous solvent (1 mL) at room
temperature under argon atmosphere for 24 h. [b] Isolated yields of
diastereomeric mixtures. [c] Enantiomeric excess of the major isomer,
determined by chiral HPLC analysis. [d] Diastereomeric ratio, determined
via 1H NMR analysis of diastereomeric mixtures. n.a.=not available.
increase in the yield and enantioselective (entry 10). Notably, an
increment of the yield was detected by increasing the
equivalent of Pd2(dba)3·CHCl3 to 2 mol%, delivering the target
molecular in 88% yield together with 98% ee (entry 13). In all
cases, a>20:1 d.r. value was obtained.
With the optimal reaction conditions, the generality of this
protocol was first evaluated with different α,β-unsaturated 2-
acyl imidazoles 1, a wild range of substrates with different
electronic and steric properties were tolerated under the
standard conditions (Table 2). Significantly, excellent diastereo-
selectivities were obtained with more than 20:1 d.r. from
reactions between various substrates 1 and phenyl-VEC 2a.
Absolute configuration of the product 3a was determined by
single-crystal X-ray diffraction.[18] In some cases the steric
Chem. Eur. J. 2021, 27, 1–6
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