Organic Letters
Letter
substituents at the other phenyl ring were also investigated.
Usually, due to the challenge in differentiating the enantiotopic
faces, it was difficult to achieve highly enantioselective
reduction of a substrate having a nearly symmetric structure.
To our delight, substrate 1h containing 2-chloro and 2′-methyl
on the two phenyl rings was afforded in excellent yield with a
good enantioselectivity. Substrates containing substituents at
the 3′- or 4′-position were suitable for this catalytic system,
giving 2i−2m in excellent yield and enantioselectivity. Phenol
(1n), ester (1o), and amide (1p) could also be tolerated to
deliver 2n−2p in 44−86% yields and 96−98% ee. Substrates
with disubstituents were good partners to give 2q−2t in 93−
99% yields with 89−98% ee. N-Methyl-protected indole could
also be tolerated to obtain 2u in 81% yield with 95% ee.
Additionally, reaction of aryl heteroaryl ketones like 1v and 1w
afforded corresponding heteroarylmethanols 2v and 2w in 69
and 53% yield and 85 and 93% ee, respectively, with increased
catalyst loading. The absolute configurations of 2a−2d and 2h
were verified by comparison of their optical rotation with
previously reported data.3f,15,16a The configuration of 2z was
verified by X-ray diffraction, and other products were then
assigned by analogy.
blocks broadly present in many natural products and
biologically active compounds.1a,b,16 The ortho-methyl-ester-
substituted diaryl ketone 1z could smoothly undergo
sequential asymmetric hydroboration/lactonization reactions
to afford (S)-3-phenylisobenzofuran-1(3H)-one (2z) in 66%
yield with 92% ee (Scheme 3b). The structure and absolute
configuration of (S)-2z were determined via X-ray diffraction
analysis.17 Benzhydrol 2aa can be obtained with 95% yield and
98% ee via hydroboration of 1aa under standard conditions.
Further debromination of 2aa delivered 3aa in 91% yield and
98% ee, which was used to synthesize the (S)-neobenodine in
60% overall yield and 97% ee.
Based on the previous work of Chirik,18 we considered that
it was cobalt chloride LCoCl that generated rather than cobalt
hydride LCoH when 1 equiv of NaBHEt3 was used as the
activator. So the key catalytic species is LCoCl rather than
LCoH, which is so common for catalysis based on cobalt.
Meanwhile, given the possibility that LCoCl might undergo
other transformations, such as oxidative addition, it could also
be the precursor of real catalytic species. It should be noted
that the actual chemical valence of cobalt is not confirmed. The
IIP ligand is proposed as a redox-active ligand.19 As mentioned
in Table 1, excess NaBHEt3 led to lower ee and higher yield.
We owed that to the generation of IIP·Co(I)H when more
than 1 equiv of NaBHEt3 was used as IIP·Co(I)H might lead
to another type of catalytic mechanism. This mechanism based
on IIP·Co(I)H might be similar to that described by Gade’s
group in 2018, which was based on Mn20 and resulted in lower
ee in this case. Meanwhile, given that the isomerization of
terminal alkene was observed under standard conditions when
terminal alkene was contained in the substrate, the mechanism
based on IIP·Co(I)H could not be simply ruled out.
To showcase the utility of this transformation, a gram-scale
reaction was carried out to give the corresponding chiral
alcohol 2c in 93% yield with 96% ee under the standard
conditions (Scheme 3a). Chiral 3-substituted phthalide
frameworks (1(3H)-isobenzofuranones) are versatile building
Scheme 3. Gram-Scale Reaction and Further Derivatizations
In summary, a cobalt-catalyzed highly enantioselective
hydroboration of diaryl ketones with pinacolborane was
developed using chiral imidazole iminopyridine as a ligand to
deliver chiral benzhydrols in good to excellent yield and ee.
Various functional groups such as halides, ethers, phenol,
esters, and amides are well-tolerated under the mild conditions.
The developed methodology could also be utilized to construct
the biologically active 3-substituted phthalide in an asymmetric
hydroboration/lactonization sequence. Additionally, the asym-
metric reduction could be easily carried out in a gram scale
without any decrease in yield and ee. Further studies on the
mechanism and asymmetric catalysis via ligand design are
underway in our laboratory.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures and characterization data for
Accession Codes
CCDC 1962316 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Org. Lett. XXXX, XXX, XXX−XXX