Chemistry Reference
In-Depth Information
one another. A full discussion of the mechanism and historical background can be found
in the second edition of this topic [2].
This chapter describes the advances in the fi eld of asymmetric carbometallation reac-
tions since 2000. Reactions catalyzed by zirconium, copper, palladium, and rhodium will
be highlighted. In addition, several other asymmetric carbocyclization reactions will be
discussed, as carbocylizations provide effi cient methods for the rapid synthesis of “drug-
like” frameworks through only a few synthetic transformations.
8C.2. Z r - CATALYZED ASYMMETRIC CARBOALUMINATION ( ZACA )
REACTIONS
8C.2.1. ZACA Reaction of Unactivated Alkenes
The ZACA of alkenes was fi rst reported by Negishi and Kondakov in 1995 [3]. The
ZACA reaction is believed to proceed via a noncyclic mechanism and involves a Zr-
centered carbometallation [2,3]. The ZACA reaction is an enantioselective carbon-
carbon bond-forming reaction with one-point binding. In contrast to other widely used
asymmetric carbon-carbon bond-forming reactions for the synthesis of enantioenriched
methyl- or alkyl-substituted acyclic compounds, the ZACA process is catalytic and
does not require the presence of heterofunctional groups to achieve a useful level of
asymmetric induction [4] .
The Zr-catalyzed enantioselective methylalumination of monosubstituted alkenes
1
was reported to yield the corresponding 2 - methyl - 1 - alkanols
2
after oxidation with
molecular oxygen (Scheme 8C.1) [3]. A variety of chiral catalysts were explored
for optimization of this process, and dichlorobis(1-neomenthylindenyl)zirconium,
Cl
2
Zr(NMI)
2
was found to be the catalyst of choice. Both carbon- and heteroatom-
substituted alkenes were shown to undergo the transformation in high yields and good
enantioselectivity up to 75% ee.
1) Me
3
Al
(NMI)
2
ZrCl
2
(8 mol %)
2) O
2
R
R
OH
1
2
Scheme 8C.1.
Although the enantioselectivity was moderate (65-75% ee), the results demonstrated
that controlled, single-stage carboalumination of 1-alkenes using a zirconocene catalyst
could be achieved selectively without generating unwanted side products [2]. The
ethyl/
n
-propylalumination of monosubstituted alkenes was also reported [5]. In these
cases, high to excellent enantioselectivity (86-96% ee) was achieved although the iso-
lated yields of products were slightly lower than those for methylalumination.
An extension of Zr-catalyzed asymmetric transformations, the tandem hydroalumi-
nation/Zr-catalyzed alkylalumination of unactivated alkenes
3
was developed, as shown
in Scheme 8C.2, which gave 3-methylalkanols
4
with high enantiopurity (Table 8C.1)
[6]. The reactions of terminal alkenes bearing proximal oxygenated substituents were,
however, sluggish, presumably due to catalyst stabilization/deactivation by the oxygen-
