2
I. Pérez, J.G. Ávila-Zárraga / Tetrahedron Letters xxx (2018) xxx–xxx
Table 1
Organocatalytic synthesis of the aldehyde 6.
Entry
Catalyst
Solvent
Time
Conv. to 6
1
2
Pyrrolidine
THF
THF
18 h
18 h
25%
5%
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
3
4
5
6
7
8
CH
CH
2
Cl
2
18 h
18 h
18 h
18 h
18 h
18 h
7%
3%
–
3
CN
Scheme 2. Synthetic pathway to the puleganic amides 3.
2
THF/H O
H
2
O
–
EtOH
99%
70%
MeOH
Scheme 3. Route to the synthesis of the ketoaldehyde 5.
[
(
10,11]. This methodology was used with some modification
Scheme 3). First, the regioselective hydrogenation of the disubsti-
tuted double bond on (R)-(+)-limonene was achieved using 1% of
PtO as the catalyst under a H atmosphere (15 psi). After stirring
2
2
overnight, the cyclohexene 8 was obtained with a yield of 99%.
Without purification, 8 was oxidized to the corresponding mixture
of diols 9 using freshly prepared performic acid (95% yield). The
mixture of diols 9 was finally oxidized using sodium periodate in
a mixture of water/tetrahydrofuran (THF) to obtain the ketoalde-
hyde 5 in a total yield of 85% in three steps. The final product
was purified by distillation.
With 5 in hand, we next attempted cyclization through an
organocatalytic aldolic condensation. This strategy has been imple-
mented successfully in the past [11,12] but using harsher condi-
tions. First, the reaction of 5 with 10 mol% pyrrolidine as a
catalyst in THF as a solvent produced the aldehyde 6, but only with
Scheme 4. Synthesis of the aldehyde 7.
were possible [13]. The reaction proceeded in a diastereoselective
manner, however, because the isopropyl group to the double
bond directed the approach of the activated hydrogen to the
anti-face, ensuring that the methyl and carbonyl groups were syn
to the isopropyl. The diastereoselectivity was confirmed in the H
NMR of the crude reaction product, which revealed two doublets
at d 9.78 (major) and d 9.57 (minor), corresponding to the hydro-
gen atoms of the aldehydes, in a ratio of 3:1 [11].
Considering that both reactions, the cyclization of 5 and the
hydrogenation of 6, were performed in ethanol, we attempted a
one-pot protocol to obtain 7 from 5 (Scheme 4b). First, a flask
was charged with ketoaldehyde 5, proline, and EtOH. After stirring
18 h, the flask was opened. Pd/C was added, a balloon containing
a
1
a conversion of 25% (Entry1). The use of L-proline as a catalyst pro-
duced an average 5% yield of the desired product in different sol-
vents (entries 2–6). The principal product was the aldol 10
(
Table 1), which provided an excellent conversion yield (90% aver-
age) with a diastereoselectivity of 3:1. The reaction of 5 in ethanol
EtOH) surprisingly produced 6 in a 99% yield (Entry 7). The reac-
tion in methanol (MeOH) was slightly worse than in EtOH (Entry
). The aldehyde 6 was easily purified by distillation under reduced
pressure.
The next step was the chemoselective reduction of the double
bond in 6, which was easily achieved using 5 mol% Pd/C
Scheme 4a). The reaction was carried out in ethanol as the solvent,
using a pressure of 22 psi of H . After a 2 h reaction time, the alde-
H was connected, and the flask was purged. After 2 h, the mixture
2
(
was filtered through Celite, the solvent was evaporated, and an ali-
1
quot was examined using H NMR, revealing the almost total con-
8
version to 7. We next attempted the addition of Pd/C with L-proline
in the first step of the reaction. Again, after 18 h, an aliquot of the
1
mixture was decanted and evaporated. The H NMR revealed that
the aldolic condensation was not modified by the presence of Pd/
C. In view of this result, a balloon of H2 was connected, the flask
was purged, and the reaction was stirred over 2 h. A standard
workup was then applied. After distillation, the aldehyde 7 was
obtained from 5 in a one-pot two-step procedure with a total yield
(
2
hyde 7 was obtained in a yield of 90%. According to the accepted
mechanism for catalytic hydrogenation, two diastereoisomers