Organic Letters
Letter
are generally required for good results (Scheme 1a). A more
intractable problem is that the reaction requires that substrate
room temperature (25−30 °C). Under these conditions, the
reaction was catalyzed by (R)-1a, which has P-phenyl groups,
and gave a 96% yield of desired product 3a, but the ee was only
33%. In contrast, (R)-1b, which has 3,5-dimethyl substitution
on each of the P-phenyl rings, gave a 65% ee. The
enantioselectivity could be increased to 72% ee by using
catalyst (R)-1c, which has bulky 3,5-di-tert-butyl substitution
on the P-phenyl rings (Scheme 2a). These results clearly
Scheme 1. Asymmetric Hydrogenation Synthesis of Chiral
Carboxylic Acids/Esters with β-Tertiary Benzylic
Stereocenters
Scheme 2. Evaluation of Spiro Iridium Catalysts (R)-1 for
a,b
Asymmetric Hydrogenation of 2a
be a pure Z or E isomer; because such isomers are difficult to
separate, this reaction has limited utility despite its high atom
economy.
We have found that the chiral iridium complexes of spiro
pyridine-aminophosphine ligands, Ir-SpiroPAP, are extremely
efficient catalysts for the asymmetric hydrogenation of ketones
with turnover numbers (TONs) exceeding 106.12 The high
efficiency of this type of metal-NH bifunctional catalyst is
attributed to the hydrogenation proceeding via an outer-sphere
six-membered-ring transition state.13 In this reaction model,
the substrate receives a hydride from the metal center and a
proton from the amino group of the ligand but does not
coordinate with the metal center of the catalyst, so the activity
of the catalyst is maintained.14 However, the reported metal-
NH bifunctional catalysts, including Noyori’s Ru-BINAP-
diamine catalyst,15 are effective only for the hydrogenation of
highly polar double bonds such as the CO and CN bonds
of ketones and imines.13 With this fact in mind, we speculated
that introduction of an ester group at the α-position of α,β-
unsaturated carboxylic esters would increase the polarity of the
CC double bond, making the resulting alkylidene malonates
suitable substrates for chiral metal-NH bifunctional catalysts
(Scheme 1b). More importantly, the use of such substrates
would eliminate the need to prepare α,β-unsaturated
carboxylic esters in pure Z or E form. In this paper, we report
a protocol for highly enantioselective hydrogenation of
alkylidene malonates catalyzed by Ir-SpiroPAP catalysts.12 By
carefully tailoring the catalyst, we achieved high yields and
good to excellent enantioselectivities (up to 99% ee) in the
synthesis of β-aryl alkyl malonates (Scheme 1b), which could
be decarboxylated to afford chiral carboxylic acids and esters
bearing a β-tertiary benzylic stereocenter.
a
Reaction conditions: 1.0 mmol scale, (R)-1/tBuOK/2a =
1:400:1000, EtOH (2.0 mL), room temperature (25−30 °C), 30
b
atm H2, 12−24 h. 80−99% NMR yield (80−100% conversion).
showed that catalyst bulk was beneficial for enantioselectivity.
Next, we evaluated catalysts bearing various groups on the
pyridine ring (Scheme 2b). Comparison of catalysts with a
methyl group at each of the four open positions on the
pyridine ring showed that the catalyst with a methyl group at
the 3-position, (R)-1d, gave the highest enantioselectivity
(82% ee). Then we increased the steric bulk of the substituent
at the 3-position (Scheme 2c) and found that (R)-1m, which
has a 3-di(3,5-di-tert-butylphenyl)methyl-2-pyridine moiety,
was the most enantioselective, giving a 99% yield of 3a with an
ee of 94%. Using this highly efficient catalyst, we optimized the
reaction conditions for the asymmetric hydrogenation of 2a.
Evaluation of various solvents showed that other alcohols
were suitable, although EtOH gave the highest yield and
enantioselectivity (Table 1, entries 1−4). In addition to
tBuOK, other bases (tBuONa and K2CO3) could also be used,
but the yield and enantioselectivity were slightly lower
(compare entries 1, 5, and 6). Lowering the tBuOK/2a ratio
to 1:5 decreased the yield but had a negligible effect on the
enantioselectivity (entry 8). A decrease in enantioselectivity
was observed when the reaction temperature was increased to
50 °C (entry 9). When the H2 pressure was increased to 50
atm, the reaction time could be shortened to 10 h (entry 10),
and we were delighted to find that the catalyst loading could be
To evaluate various Ir-SpiroPAP catalysts 1, we carried out
the hydrogenation of diethyl 2-(1-phenylethylidene)malonate
(2a) with 0.1 mol % catalyst in EtOH under 30 atm of H2 at
1676
Org. Lett. 2021, 23, 1675−1680