1,2-Addition of Nucleophiles to Carbonyl Compounds - Carbohydrates: Tools for Stereoselective Synthesis - page 290

OH

O

ZnEt 2 / 9 , 10

RH R

TiCl 4

O O

Ph Ph

O O

O O

OBn

HO HO

TsHN

TsHN

OMe

9 10

O

O O

O O

O

H H

H H H

H

4

MeO

Cl

9/10 yield(%)
ee (%)

99 /98 85

90

73
39

80
88

95
89

94
86

97 /10

Scheme 13.5 Addition of diethylzinc to aldehydes catalyzed by aminoalcohols 9 and 10.

While the previous studies were carried out with Lewis bases as catalyst, the
diethylzinc addition with 9 and 10 was carried out using a Lewis acid catalyst.
Thus, when benzaldehyde (1 mmol) was reacted with diethylzinc (3 mmol) at room
temperature in the presence titanium tetrachloride (1.4 mmol) and 9 (7 mol.%),
(R) -1-phenyl-propan-1-ol was obtained in 99% yield and 97% ee (Scheme 13.5).
The reaction was still highly enantioselective when the amount of ligand was
reduced to 1.8 mol.%, but the conversion dropped. The influence of the configura-
tion at the anomeric center was studied by carrying out the reaction in the presence
of ligand 10 (0.1 mmol). The yield was quantitative, but the enantioselectivity was
very low (10%); the results are not fully comparable since the anomeric substituent
is different. Other aromatic aldehydes and hexanal also reacted with diethylzinc
under similar conditions in the presence of TiCl 4 / 9 to provide ee values of up
to 90%.
Davis carried out a systematic study preparing four diastereomeric ligand fami-
lies ( 14-17, Scheme 13.6) that result from varying the configurations at positions
1, 2, and 3, and introducing different substituents on the nitrogen [12]. The
ligands were easily prepared from glucosamine. Notably, the reaction of 14a with
H 2 O 2 /Na 2 WO 4 [13], followed by reduction with LiAlH 4 , afforded 17a in a simple
and fast procedure for inverting the amine configuration. The following conclu-
sions were derived from this study (Table 13.1): (i) The stereoselectivity varied
according to the ligand configuration in the order α -d- gluco ( 14 ) > β -d- gluco ( 15 ) >

α -d- manno ( 17 ). (ii) The presence of a tertiary amine at C2 caused

a reversal from (S) to (R) in enantioselectivity [e.g., tertiary amine ligand 14e
the (S) enantiomer in 56% ee and secondary amine ligand 14d preferentially
gave the (R) enantiomer in 30% ee], suggesting different modes of asymmetric
induction. (iii) Bulkier NR 1 R 2 groups also influenced the enantioselectivity, in the

-d- allo ( 16 ) > α