Highly Enantioselective Iridium-Catalyzed Hydrogenation
FULL PAPER
According to this selectivity model, (E)-ethyl a-methylcin-
namate 18a should be hydrogenated to the corresponding R
product (Figure 3c); however, the experimental result was
the opposite, as the S product was formed (Table 3, entry 1).
Calculations on the former system allowed this effect to be
attributed to the polarity of the double bond; when 18a
binds to iridium in the sterically most favored configuration
(i.e., shown in Figure 3c), hydrogenation must occur by a hy-
dride transfer to the electron-rich terminus of the olefin.[31]
The electronic penalty is greater than the steric one for
binding the opposite face of the olefin to Ir, so 18a is hydro-
genated to the enantiomer opposite to that predicted by the
model. This effect may also direct the hydrogenation of all
a,b-disubstituted unsaturated carboxylates present in
Shishido et al. have used (R)-3-(2,5-dimethoxy-4-methyl-
phenyl) butanoic acid (36) in an enantioselective total syn-
thesis of the strongly allelopathic (À)-Heliannuol A.[34] They
started from the lipase-mediated transesterification of a pro-
chiral diol to create a chiral monoacetate (78% ee), which
was elaborated in five steps to give 36. Recently, the same
group has also employed 36 as the key intermediate in the
total synthesis of (+)-Heliannuol D, which has phytotoxic
allelopathic activity.[35] They shortened the synthetic route to
36 to two steps by using a diastereoselective conjugate addi-
tion; however, a chiral auxiliary had to be introduced to
promote the diastereoselective reaction and then removed
afterwards to give the free acid. We reached the key inter-
mediate carboxylic acid 36 from 34 via 35 with 92% ee and
in 96% yield of the isolated product (Scheme 3). Reduction
of ester 35 with LiAlH4 provided the corresponding alcohol
37 (93% isolated product yield from 34), which is another
key intermediate in the syntheses of Helibisabonol A,[36]
(which also exhibits allelopathic activity), and (À)-Curcuhy-
droquinone,[6a] which has been isolated from the Caribbean
gorgonian Pseudopterogorgia rigida and has shown antibac-
terial activity against Staphylococcus aureus and the marine
pathogen Vibro anguillarum.
+A[BArF]À.
Tables 3 and 4 through [(D)*IrACTHNUGTRENNUG(cod)] HCTUNGTRENNUGN
To demonstrate the utility of this highly efficient catalytic
asymmetric hydrogenation, we prepared key intermediates
for the total synthesis of several natural products and bioac-
tive compounds. The first orally active, nonsteroidal andro-
gen receptor modulator, LG 121071, has been generated
from (R)-ethyl 3-phenylpentanoate (28) by using a Cu-cata-
lyzed asymmetric conjugate reduction (86% ee).[32] We have
established that the hydrogenation of a,b-unsaturated ester
4 gives direct access to 28 with >99% ee and in 98% yield
of the isolated product (Scheme 1).
The asymmetric hydrogenation of (Z)-ethyl 3-(p-tolyl)-
but-2-enoate 39 gave (S)-ethyl 3-(p-tolyl)butanoate 40 as
a single enantiomer in 98% yield (Scheme 3). This can be
transformed to (S)-3-(p-tolyl)butanal 41,[37] which has been
used in the total syntheses of (+)-Dehydrocurcumene,
(+)-Curcumene, and (+)-Tumerone.[38] Ester 40 could also
be converted to 4-(p-tolyl)pentanal 42,[39] a precursor in the
syntheses of (+)-Nuciferol, (+)-Nuciferal, and (+)-Erogor-
giaene.[40]
Scheme 1. Catalytic enantioselective synthesis of LG 121071 starting ma-
+A[BArF]À, CH2Cl2, 50 bar H2, RT.
terial 28. a) [(A)*IrACHTUNGTRENNUNG(cod)] HCTUNGTRENNUGN
Carboxylic acid 32 was used as the key intermediate in
Brown and Coreyꢁs enantioselective synthesis of 9-isocyano-
pupukeannane.[33] Through the iridium-catalyzed asymmetric
hydrogenation of substrate 30 and subsequent conversion of
the ester to an acid, we synthesized 32 in 98% ee and with
95% yield of the isolated product (Scheme 2).
Conclusion
In summary, we have used an iridium-catalyzed asymmetric
hydrogenation to convert a,b-unsaturated esters to their cor-
responding saturated chiral products. Notably, good to ex-
cellent enantioselectivities were obtained in the hydrogena-
tions of (E)-b,b-dialkyl and (Z)-b,b-disubstituted a,b-unsatu-
rated esters and (E)-a,b-disubstituted unsaturated esters,
which are very challenging substrates in N,P-ligated-iridium-
catalyzed asymmetric hydrogenation. Furthermore, the satu-
rated chiral esters have been used in synthetic transforma-
tions as well as in the formal syntheses of natural products.
Experimental Section
General procedure: A vial was charged with the substrate (0.25m) and
the Ir complex (0.0025–0.005m). Dry CH2Cl2 was added (2 mL) and the
vial was placed in a high-pressure hydrogenation apparatus. The reactor
was purged three times with Ar, then filled with H2 to a pressure of 20 or
50 bar. The reaction was stirred at room temperature for 15 h before the
H2 pressure was released and the solvent was removed in vacuum. The
crude product was filtered through a short plug of silica. Conversions
Scheme 2. Enantioselective synthesis of 9-isocyanopupukeanane inter-
mediate 31. a) (EtO)2POCH2CO2Et, NaH, THF, 08C to reflux;
b) [(B)*Ir
MeOH, RT.
ACHTUNGTRENNUNG(cod)] CHTUNGTRENNUNG
+A[BArF]À, CH2Cl2, 50 bar H2, RT; c) NaOH (aq. 1m),
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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