Journal of the American Chemical Society
Article
the product (4a) was observed, suggesting that the phenyl
group of the BOX ligand affects the stereochemistry (Figure
2B). When the reaction was performed with 7-chloro-2-
methylhept-1-en-3-yne (1x), which lacks an aryl substituent, a
product (5) was isolated with almost no enantiomeric excess.
These results suggest the possibility of a π−π interaction
between the allenyl radical and the aryl ring of the BOX ligand.
Consequently, we performed density functional theory (DFT)
calculations at the B3LYP-D3(SMD)/Def2-TZVP//B3LYP-
D3/Def2-SVP level of theory to examine the structures of
chiral catalysts (see more details in the Supporting
Information). Isocyanocopper(II) complexes with ligands L1
and L4 were selected as representatives containing alkyl and
aryl substituents, respectively.
The optimized structures of isocyanocopper(II) intermedi-
ates m1-[L1Cu(II)] and m1-[L4Cu(II)] with ligands L1 and
L4 are shown in Figure 2C. The planarities of the oxazoline
moiety in m1-[L1Cu(II)] and m1-[L4Cu(II)] are significantly
different. The dihedral angle between the two oxazoline rings
D(N1−C2−C2′−N1′) are 18.7 and 3.2° in m1-[L1Cu(II)]
and m1-[L4Cu(II)], respectively. These geometrical parame-
ters are similar to those in the relevant crystal structure of a
We hypothesized that this planarity of the oxazoline−metal
complex is critical in the stereocontrolling step and that a
variation of the substituents on the oxazolines might further
improve the enantioselectivity. Therefore, we carried out
further DFT calculations on some isocyanocopper(II)
complexes and found that m1-[L5Cu(II)], which bears two
aryl substituents, has the smallest dihedral angle (2.5°). A
reaction with ligand L5 was conducted. The enantioselectivity
was indeed drastically improved to er = 94:6. Ligands L6 and
L7 were also tested, and similar enantioselectivities and lower
yields were observed (Figure 2D). L5 was therefore chosen for
further investigation. These results of the planarity correlated
to the enantioselectivity fit to the strategy of a quantitative
structure selective relationship (QSSR), which is a useful tool
in the development of asymmetric catalytic reactions.72
The substrate scope of conjugate 1,3-enynes in the reaction
was examined under the optimized conditions (Figure 3A).
Electron-rich alkyl-substituted aryl groups with primary and
tertiary alkyl groups afforded the corresponding products in
good yields with a high er, and substrates bearing halogenated
aromatic substituents were compatible with the reaction
conditions. The long alkyl chain in the 1,3-enyne substrates
can be replaced by short alkyl chains or haloalkyl chains, a free
alcohol group, a cyclopropyl group, or an ester group. Due to
the utilization of (4S,4′S,5R,5′R)-L7, which has the opposite
absolute configuration in comparison to L5 and L6, the
opposite enantiomer for products 4h,j,k,m can be obtained.
The absolute configuration of the products (R forms of 4l,p)
was confirmed by X-ray single-crystal diffraction. The
successful preparation of highly enantioenriched tetrasubsti-
tuted allenes with the established catalytic system prompted us
to study the use of other peroxides. For phenyl-substituted
peroxides, both electron-donating and electron-withdrawing
phenyl groups were tolerated under the standard reaction
conditions, affording the corresponding chiral allenes in high
yields and enantioselectivities. This enantioselective radical
1,4-difunctionalization of 1,3-enynes can also be successfully
achieved with carbon-centered radicals. As shown in Figure 3B,
perfluoroalkyl iodides, ethyl difluoroiodoacetate, and cyclo-
hexanecarboxylic peroxyanhydride engaged in the asymmetric
radical 1,4-carbocyanation of 1,3-enynes, affording the
corresponding allenes in good yields and with high er.
Although some racemic allenyl cyanides have been
synthesized previously, the generation of enantioenriched
allenyl cyanides and their stereoselective transformations has
not been reported. Accordingly, we explored their stereo-
selective transformations and synthetic utility (Figure 3C,D).
The construction of chiral quaternary carbon centers is a major
challenge in synthetic chemistry, and the development of
methods for the formation of such chiral centers is an
important goal. In the presence of FeCl3, the benzoyloxy group
of 4a can be easily converted into a free alcohol group and the
allenyl alcohol (8) can be produced quantitatively without loss
of enantiomeric excess (Figure 3C).
The transfer of axial chirality to central chirality was also
studied. For example, the chiral allenyl cyanide 4u smoothly
reacted with N-iodosuccinimide (NIS) or N-bromosuccini-
mide (NBS) to produce the enantioenriched 3,6-dihydro-2H-
pyrans 9 and 10 with a chiral quaternary carbon center via a
cyclization process (Figure 3D). Moreover, E/Z selective
transformations corresponding to the E-selective vinyl cyanides
(E)-11 and (E)-12 were accessed upon treatment of the
racemic allene 4a under basic or acidic reaction conditions
(Figure 3E). Treatment of the allenyl cyanide 13 with NIS led
to a practical synthesis of the highly substituted conjugated
cyanide 14, which is a versatile building block.
Control experiments were conducted to further probe the
mechanism of this radical reaction (Figure 4). The addition of
the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) or butylated hydroxytoluene (BHT) inhibited the
formation of the desired product, suggesting that the reaction
could involve a radical pathway (Figure 4A). The observation
of the BHT·OBz adduct supports the formation of a
benzoyloxyl radical, and the detection of trimethylsilyl
benzoate indicates an interaction of the benzoyloxyl group
hand, the CH3OH adduct 15, whose appearance would suggest
the formation of the allenyl cation, was not observed (Figure
4B). The presence of the radical adduct and the absence of
cation adducts indicate that the allenyl radical pathway is more
likely to be adopted rather than the allenyl cation pathway.
Although only a low yield was obtained, the formation of the
cyclized product 17 strongly suggests that an allenyl radical is
indeed generated in situ (Figure 4C). A linear correlation
between the ee of ligand L5 and the ee of 4a was observed
(Figure 4D), indicating that the active catalytic species is a
monomeric copper complex bearing a single chiral ligand.
DFT calculations on the asymmetric radical 1,4-oxy-
cyanation of 1,3-enynes were performed to elucidate the key
factors of stereocontrol in this reaction. The mechanism is
similar to that in our previous case.28 In addition, an inner-
sphere pathway via Cu(III) intermediates has also been
considered, but no transition states for reductive elimination
could be located, which is similar to the very recent study by
Lin, Liu, et al.73 Therefore, we focused on the enantiode-
termining step.
With a comprehensive conformational search of radical
trapping transition states (TSs), TS-L5-R1 and TS-L5-S1 were
found to be the lowest enthalpic conformers leading to the
products of R and S enantiomers, respectively (Figure 4E; see
the conformational search). TS-L5-R1 is preferred with an
enthalpy difference of 1.7 kcal/mol, consistent with exper-
D
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX