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conducted on a production scale with little or no modification from the originally
reported standard conditions (
n-
Bu
2
BOTf, NEt
3
, CH
2
Cl
2
or toluene,
78 °C to room
temperature) to produce, in almost all cases, the
syn-
aldol adduct with extremely
high diastereoselectivity [29]
.
The large-scale synthesis of discodermolide employs
a hybrid route that combines the best reactions of total syntheses developed by the
groups of Smith [30] and Paterson [31]. The
(R)
-3-propionyl-4-benzyloxazolidinone
59
was used in two aldol reactions to install 8 out of the 13 stereocenters embed-
ded in discodermolide at C2-C3, C11-C12, C16-C17, and C18-C19 (Scheme 3.20).
−
O
7
5
O
22
18
20
16
1
10
14
OH
OH
OCONH
2
12
OH
OH
discodermolide
Ph
Ph
O
N
Common precursor for
stereocenters at:
C2-C3, C16-C17, C18-C19
O
59
O
O
N
PMBO
PMBO
CHO
O
n-
Bu
2
-BOTf, NEt
3
, rt
80%
O
OH
100% de
Ph
Ph
CHO
O
O
N
N
OO
17
16
O
59
O
O
Stereocenters at:
C16-C17
OH
O
OO
n-
Bu
2
-BOTf, NEt
3
,
-78 °C to -10 °C
85%
OMe
100% de
OMe
Scheme 3.20
Large-scale synthesis discodermolide based on the Evans aldol reaction.
Obviously, the carbohydrate-based aldol reactions developed so far cannot
compete yet with the gold standard developed in the literature. One of the main
reasons for this state of affair is paradoxically the rich stereochemical information
encoded by the polyfunctional sugar ring. In substrate-controlled chiral transfor-
mations, a decisive requirement for efficient transfer of chirality from the chiral
auxiliary to the product is the formation of a well-organized transition state, gener-
ally granted by appropriate coordination between the reagent and the chiral
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