Aldol-Type Reactions - Carbohydrates: Tools for Stereoselective Synthesis - page 140

The best results were obtained in Et 2 O or toluene as solvent; the HCl evolved is
neutralized with a slight excess of Et 3 N. Complex 3 can be isolated under anhy-
drous conditions and stored in solution.
Other stable analogs can be prepared in a similar way, by using different acetal
protection of the d-glucose derived ligands [3]. However, it must be taken into
account that small changes of the sugar skeleton lead to extremely labile com-
pounds, such as those derived from

-L-idofuranose, d-xylose, or d-allose [4].
The titanium complex 3 has been applied by Duthaler and Hafner to solve one
of the most important challenges with the aldol reaction, namely, the addition of
acetyl groups with the stereocontrolled formation of one new stereogenic center.
For this purpose, transmetalation of the Li enolate of tert -butyl acetate 4 by treat-
ment with complex 3, at

α

30 °C in toluene, yields the titanium enolate 5, which
adds with high enantioselectivity (90-96% ee) and good chemical yields to different
aldehydes (Scheme 7.2) [5]. The favored attack at the Re face of the aldehyde is
independent of temperature.

−

OH

1) R 1 - CHO

Ti
O

OLi
O t Bu

CO 2 t Bu

DAGO

Ti ODAG

R 1

DAGO

ODAG

2) H 2 O

Cl

6a , R 1 : n -Hept (87%), 95% ee

4

3

O t Bu

6b , R 1 : Ph (69%), 95% ee 5

Scheme 7.2 Addition of an acetyl group in the aldol reaction with titanium enolate 5.

The enantioselectivities obtained with the chiral acetate enolate 5 are higher
than those obtained by others methods at room temperature and are matched
only by those obtained with 2,4-dialkylborolane developed by Masamune [6] and
Reetz [7].
The Duthaler-Hafner acetate aldol reaction has been applied as one of the key
steps in the total asymmetric synthesis of different biologically active compounds,
such as the aggregation pheromone of various species of bark beetles, (-)- (S) -
ipsenol 7 (Figure 7.1) [8]. This has also been the strategy applied more recently by
Kirschning et al . in the synthesis of the ansatrienol derivative 8, a known precursor
of ansamycin antibiotics, for introduction of the stereocenter at C3 (Figure 7.1)
[9]. Cossy et al . have prepared the novel immunosuppressant FR252921, 9, using
the chiral titanium complex 3 to control the configuration of the stereogenic center
at C18 [10].
In the case of substituted enolates, the situation is more complex as two new
stereogenic centers are simultaneously generated. The double bond geometry of
the enolate ( E or Z ) is directly related to the relative configuration ( syn or anti ) of
the aldol products when the reaction takes place via a cyclic transition state [11].
Interestingly, with achiral titanium enolates, the syn diastereomers are mainly