Cyclopropanation - Carbohydrates: Tools for Stereoselective Synthesis - page 115

including the best selling drug omeprazol, a proton pump inhibitor, comprise a
chiral non-racemic sulfinyl group [23, 25]. Therefore, the last two decades have
witnessed an exponential use of these chiral auxiliaries in asymmetric synthesis,
establishing the chiral sulfinyl group as one of the most efficient and versatile
chiral controllers in C-C and C-X bond formation. One of the most efficient and
general methods developed so far for the synthesis of enantiopure sulfoxide is the
so-called “DAG-methodology” introduced by the group of Fernández, Khiar, and
Alcudia (Scheme 5.9) [26].

O
Me 2 C

O

O

R 2 MgX

R 1 S

O

O

R 2

Pyridine

R 1
O

O
CMe 2

S

Toluene

O

35

O THF / -78 ° C

D-Gluco

(75-87%)

S

34- R S (de: 70-96%)

R 1 Cl

O

33

Me 2 C

O

O

HO

O
CMe 2

O
Me 2 C

O

O

O

DAG-OH

O

R 2 MgX DIPEA

O

R 1

R 1 S

O
CMe 2

S

Toluene

O

R 2

Toluene / -78 ° C
(80-90%)

O

ent- 35

R = alky, aryl

34- S S (de: 87-96%)

R' = alky, aryl

Scheme 5.9 Enantiodivergent synthesis of enantiopure sulfoxide using the DAG
methodology.

The reaction of diacetone-d-glucose with various racemic alkyl and aryl sulfinyl
chlorides in THF at

78 °C, using pyridine as base, gave the corresponding sulfi-
nate esters 33 in high yield and selectivity in favor of the ( R S )-enantiomer. When
Hunig's base ( i -Pr 2 NEt) (DIPEA) was used as catalyst the diastereoselectivity of
the reaction was improved and a single isomer was obtained in most cases. Sur-
prisingly, this isomer has the opposite configuration ( S S ) at the sulfinyl stereocenter
to the one obtained using pyridine as base (Table 5.8, entries 1 and 2). Another
important feature of the DAG methodology is that the formation of sulfinate ester
intermediates takes place with dynamic kinetic resolution of the racemic sulfinyl
chlorides.
The reaction of a Grignard reagent with the intermediate sulfinate esters 33
leads smoothly to the corresponding sulfoxides 34 or ent- 34 in high yield and
selectivity (Table 5.9). Hindered and unhindered dialkyl, alkyl aryl, and diaryl
sulfoxides have been obtained in both enantiomeric forms [27]. These results,
which show the high capacity of the DAG methodology for the synthesis of opti-
cally pure sulfoxides, confirm the stereo-directing effect of the achiral tertiary
amine used in the first step. This stereo-directing effect allows the utilization of a
single inducer of chirality, DAG, for the synthesis either ( R S )- or ( S S )-sulfinate ester
in an diastereodivergent manner by simply changing the base from pyridine to
-DIPEA-.

−