Organic Letters
Letter
and changing the ketone substituent to ethyl and phenyl
provided good ee values of 92% and 96%, respectively (3c and
3d). Compound 3d was previously hydrogenated by iridium
catalysts and rhodium catalysts (81% ee and 63% ee,
respectively) with significantly lower enantiocontrol.6b,8a
Linear n-propyl olefin 3e showed good selectivity (95% ee),
whereas the sterically more demanding i-butyl olefin
substituent on substrate 3f resulted in 94% ee.
Table 3. Asymmetric Hydrogenation of Aromatic-
Substituted Enones*
To demonstrate the synthetic utility, this developed catalytic
system for dialkyl-substituted enones was applied in the partial
synthesis of anti-HIV agent 7 (Table 2). Hydrogenation of α,β-
dialkyl substituted enone 5 yielded key intermediate α-chiral
ketone 6 in 98% ee (97% isolated yield), which has previously
been synthesized via a stereoselective alkylation, using an
auxiliary strategy.9
Then, aromatic enones were evaluated and our library of
ligands were shown to be well-tolerated in the hydrogenation
of model substrate 8a, in terms of selectivity, showing excellent
ee values of up to 99% (see Table S3 in the Supporting
Information). Catalyst B was chosen for further studies on the
class of α-prochiral aromatic enones (Table 3).11 The
introduction of various electron-donating or electron-with-
drawing substituents on the aromatic ring gave equal results
and substrates 8b−8g gave uniformly excellent ee values of
99%. Moreover, the scalability of the methodology was
demonstrated by the hydrogenation of 8b on a 1.3 mmol
scale (99% yield). Changing the substituent to 2-naphthalene
8h led to a slight decrease in enantioselectivity (97% ee).
Thereafter, substrates with a variety of substituents on the
ketone side chain were hydrogenated and n-butyl, i-propyl, and
phenyl ketones all yielded the desired product in perfect ee of
99% (8i−8k). An increase in the bulk of the α-substituent to
ethyl (8l) gave a similar result. The ring size of cyclic enones
with an exocyclic olefin was shown to affect the enantiose-
lectivity. Whereas cyclopentanone derivative 8m was hydro-
genation in moderate ee of 76%, six-membered and seven-
membered cyclic enones were hydrogenated in excellent ee of
99% (8n−8o). Furthermore, heterocyclic substrates 8p−8t
were also well-tolerated (99% ee, 93%−99% yield).
Finally, β-prochiral aromatic enone 10a was evaluated in the
hydrogenation to the corresponding saturated ketone.
Fortunately, catalyst D, which has successfully been applied
in the hydrogenation of β-prochiral unsaturated esters,10 gave
higher chiral induction of 94% ee in the hydrogenation of
substrate 10a (see Table S4 in the Supporting Information).
Changing the carbonyl side chain to a methyl and ethyl group
increased the enantioselectivity to 98% and 99% ee,
respectively (10b and 10c). The presence of an electron-
donating methyl group at the para position (10d) of the aryl
substituent on the olefin was hydrogenated in similar ee
(94%), compared to the unsubstituted equivalent 10a.
Increasing the length of the β-alkyl group to ethyl did not
affect either the conversion or the enantioselectivity and
compound (E)-10e was hydrogenated in 99% ee. The isomeric
purity of the olefin turned out to be important for the
enantioselection of the catalyst. Whereas the hydrogenation of
(E)-10e produces (S)-11e, an opposite enantiomeric outcome
was formed when (Z)-10e was hydrogenated (57% ee),
demonstrating that the reaction is enantiodivergent.
*
Reaction conditions: 0.2 mmol of substrate, 0.5 mol % catalyst, 2 mL
of solvent, 20 bar of H2, 16 h, rt, unless stated otherwise. Absolute
stereochemistry assigned by comparing optical rotation with literature
values. If no reference is given then assignment is tentative. Yields
given are in their isolated forms. Enantiomeric excess was determined
a
by SFC or GC analysis, using chiral stationary phases. 1.3 mmol
scale. 0.75 mol % of catalyst. 1.0 mol % of catalyst. 5 bar of H2. 2
bar of H2.
b
c
d
e
been hydrogenated with moderate enantioinduction, efficient
hydrogenation of these challenging substrates was achieved by
using the conditions described in this study giving 88%−99%
ee. The method was successfully applied in the synthesis of an
anti-HIV agent. Furthermore, various (hetero)aromatic-sub-
stituted enones were well-tolerated, resulting in 94%−99% ee
of the corresponding chiral ketones.
ASSOCIATED CONTENT
■
In conclusion, an efficient protocol for the synthesis of α-
and β-chiral ketones via asymmetric hydrogenation of
conjugated unsaturated enones by Ir−N,P catalysis is
described. Although dialkyl-substituted enones have previously
sı
* Supporting Information
The Supporting Information is available free of charge at
C
Org. Lett. XXXX, XXX, XXX−XXX