Chemistry Reference
In-Depth Information
14
Cyclopropanation
Mike M.K. Boysen
Asymmetric cyclopropanation [1] is not only an important method for setting up
chiral three-membered rings, which occur as motifs in many natural products [2]
but, due to the inherent reactivity of the cyclopropyl ring, the products may also
be transformed into other useful chiral building blocks. Chiral bis(oxazolines)
(box) and pyridyl bis(oxazolines) (pybox) [3] are among the most useful ligands for
transition-metal-catalyzed asymmetric cyclopropanation of alkenes with diazo
compounds via carbene complexes. The first highly stereoselective examples of
intermolecular cyclopropanations with copper(I) box complexes were reported
independently by Evans [4] and Masamune [5] and have inspired the design of
many new ligands.
A successful family of carbohydrate-derived box ligands was reported by the
Boysen group. In the first approach, d-glucosamine (
1
) was transformed into box
ligand
5
[6] in four steps (Scheme 14.1). As the 3-position of the pyranose subunits
in
5
is closest to the coordinating nitrogen atoms, this position was envisaged to
have a major impact on stereoselectivity. Therefore ligands
9a-f
with 3-
O
-acyl,
-alkyl, or -silyl groups of varying steric demand and type were prepared from
4,6-
O
-benzylidene protected thioglucoside
6
as key intermediate [7]. The
cyclization to the desired 3-
O
-R
1
gluco
Box ligands (
12a-f
) was effected using NIS
(Scheme 14.1).
Ligands
5
and
9a-f
were subsequently tested in the asymmetric cyclopropana-
tion of styrene (
10
) with ethyl diazoacetate (
11
), yielding the diastereomeric prod-
ucts
12
trans
and
12
cis
(Table 14.1). The per-O-acetylated ligand
5
gave the
products
12
in moderate overall yield, a
trans/cis
ratio of 70 : 30 and 82% ee for
both diastereomers (entry 1). The series of selectively 3-
O
-functionalized ligands
9a-f
led to some important findings: As expected, the size of the 3-O-substituent
had a fundamental impact on stereoselectivity and 3-
O
-acetylated ligand
9a
gave
a greatly improved result with 90% yield and 93% ee for the major trans-
diastereomer of
12
(entry 2). However, an increase of the steric demand of the
3-
O
-acyl residues (
9b,c,
R
1
Bz, Piv) led do a drop in enantioselectivity (64% ee
and 62% ee respectively), while yield and diastereoselectivity were less affected
(entries 3, 4); therefore, improved stereoselectivity was expected for ligand
9d
with
=
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