Background and Originality Content
The remarkable modification ability of α -chiral allylic alcohols
has attracted extensive attentions of researchers, and has demonstrated
fascinating functionalities in the field of natural product synthesis as
well as polymer and material science.[1] As one of
the most direct and efficient strategies, asymmetric 1,2-reduction of
readily available α,β-unsaturated ketones was adopt by many researchers
to synthesize α-chiral allylic alcohols with various chiral catalyst
systems, such as Ru,[2]Ir,[3] Cu,[4]etc.[5] However, there were relatively few reports
involving fertile metallic nickel. In 2017, Zhu’s group reported the
first nickel-catalyzed chemoselective 1,2-reduction of α,β-unsaturated
ketones with oxazoline-pyrimidine ligand with central chirality,
affording the allylic alcohols with excellent reactivity and
enantioselectivity.[6] Until now, there were no
other type ligands applied in this catalytic system. Therefore, it is
extremely attractive to exploit a novel type of chiral ligands to
achieve nickel-catalyzed enantioseletive 1,2-reduction of
α,β-unsaturated ketones with high enantioselectivity.
In recent years, planar-chiral ligands have been widely applied as a
class of unique and significant ligands in asymmetric catalysis.
Planar-chiral ligands mainly include ferrocenes, metal carbonyl-
complexes, paracyclophane units, etc.[7] Among
them, the skeleton of [2.2]paracyclophane has the advantages of
stable properties, rigid structure and large steric
hindrance.[8] Considering the characteristics of
this skeleton, our group has been committed to design and synthesis of
various kinds of [2.2]paracyclophane-derived ligands with planar
chirality, such as chiral oxzole-pyridine ligands and tridentate PNO
ligands.[9] Inspired by the excellent performance
of the [2.2]paracyclophane skeleton, a series of [2.2]
paracyclophane-derived oxazole-pyrimidine ligands containing planar
chirality (abbreviated as PYMCOX) were designed, synthesized, and
successfully applied in nickel-catalyzed asymmetric 1,2-reduction of
α,β-unsaturated ketones with up to 99% yield and 99% ee. Furthermore,
the reduction could be conducted at gram-scale without loss of activity,
and the oxazole-pyrimidine ligand could be also recovered by flash
column chromatography.
Scheme 1 Metal-catalyzed
asymmetric 1,2-reduction of α,β-unsaturated ketones
Results and Discussion
At the beginning, the paracyclophane-derived chiral N,N -ligands
PYMCOX (R p)-L1-10 were synthesized from
the known [2,2]paracyclophane-derived chiral aminophenol
(R p)-1 through two approaches according
to the known similar procedures (see Supporting Information). Method A:
2-cyanopyrimidines 2 under- went the nucleophilic addition with
methanol to give the intermediates methyl ester of imino-pyrimidine acid
derivatives.[10] Then, the intermediates underwent
the condensation reaction with paracyclophane-derived aminophenol
(R p)-1 to afford the chiral PYMCOX
ligands (R p)-L1-9 . Method B:
2-cyanopyrimidine 2 underwent the hydrolysis to give the
carboxylic acid 3 .[11] Then, two step
condensation/cyclization reactions between chiral aminophenol
(R p)-1 and carboxylic acid 3were conducted to provide the chiral PYMCOX ligand
(R p)-L10 .[12]
Scheme 2 The synthesis of chiral PYMCOX ligands
With the chiral PYMCOX ligands in hand, we began our investigation with
(E )-4-phenylbut-3-en-2-one (4a ) as model substrate.
Ni(COD)2 (2.0 mol %) and PYMCOX L1 (2.4 mol
%) were employed in the presence of 1.2 equivalent of pinacolborane
(HBpin), 1.5 equivalent of 1,4-diazobicyclo[2.2.2]octane (DABCO) and
toluene at -25 °C for 1 hour. To our delight, the chemoselective
reduction underwent smoothly to afford the desired allylic alcohol5a (entry 1, 92% yield, 97% ee), and the product of
1,4-reduction was not detected. The other parameters were summarized as
follows: (a) Ni precursors such as nickel triflate and nickel acetate
were completely inefficient (entries 2, 3). (b) The base is of utmost
importance, in which DABCO was optimum. Others like DBU and DIPEA, the
target product was obtained with lower yield or enantioselectivity
(entries 4, 5). (c) While the reductant HBpin was a competent hydrogen
source, both catcholborane (CB) and
Ph2SiH2 were ineffective (entries 6, 7).
(d) The activity and enantio- selectivity were also affected by the
changes in solvents. It was found that the solvents like dichloromethane
(DCM), ethyl acetate (EA) and diethyl ether were superior to polar
aprotic and protic alternatives (entries 8-11). Encouraged by these
results, compared with different chiral ligands
((R p)-L1 to
(R p)-L10 ), the oxazole-pyrimidine ligandL2 bearing 4-methylpyrimidine motif povided the highest 99% of
yield and 98% of enantioselectivity.
Table 1 Optimization of reaction
parameters.a