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OH
7
(
S
)-(-)-lpsenol
(Pheromone)
MeO
O
O
NH
C
7
H
15
OH
HN
18
N
MeO
HO
O
O
O
3
OMe
HO
9
8
FR252921
(Immunosuppressant)
Ansamycin antibiotic
Figure 7.1
Biologically active compounds prepared using the Duthaler-Hafner acetate aldol
reaction.
formed, if no cyclopentadienyl ligands are involved [12], in contrast to the
anti
-
aldols obtained with the Li enolate.
Duthaler and coworkers have demonstrated that, in the case of propionyl-
enolates with chiral Ti-complexes, both
(Z)
and
(E)
enolates are available and add
to aldehydes in a highly diastereo- and enantioselective manner [5, 13].
Transmetalation of lithium enolate
10,
derived from 2,6-dimethylphenylpropi-
onate, with the titanium complex
3
at
78 °C yields, after 24 h, the corresponding
(E)
-configurated enolate
11
(Scheme 7.3). This
(E)
-enolate added to the
Re
side of aldehydes, affording various
syn
-aldols
13,
with high dia- and enantioselec-
tivity (84-94% ds, 91-96% ee, Scheme 7.3). In a similar way, racemic
anti
-aldols
(
−
)-
14
can be obtained from the achiral Li enolate
10
(72-96% ds, Scheme 7.3).
However, in contrast to this unstable Li enolate
10,
the Ti enolate
11
isomerizes
at
±
30°C, probably via a titanium-bound ketene intermediate [14], to the thermo-
dynamically more stable
(Z)
-enolate
12
(Scheme 7.3), which afforded
anti
-aldols
14
of high optical purity (94-98% ee) and, in most cases, with acceptable-to-
good diastereoselectivity (62-78% ds). In this case, important exceptions were
methacrolein and benzaldehyde, that is, branched unsaturated and aromatic
aldehydes, which yielded larger amounts of
syn
-epimers of lower optical
purity.
In this way, both epimers that result from the attack of
11
and
12
to the
Re
side
of aldehydes can be obtained from the same precursor, according to the reaction
conditions, using the cheap and easily accessible diacetone-d-glucose as the only
chiral inductor.
The stereochemical outcome of the aldol additions of both enolates has been
explained by assuming in both cases a boat conformation for the transition states,
ET-11
for the
(E)
-enolate and
ET-12
for the
(Z)
-enolate (Figure 7.2) [14].
−
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