CONCEPTS
cyclic quaternary all-carbon stereocenters include the Heck
reaction, alkylation, arylation, and Michael addition,[1,2]
whereas for the creation of all-carbon quaternary centers in
non-cyclic system (more complicated due to the number of
degrees of freedom associated with these structures), the
most promising results are either the asymmetric allylic al-
kylations,[3] asymmetric conjugate addition,[4] sigmatropic[5]
and Jung epoxide rearrangements,[6] asymmetric alkylation,[7]
and asymmetric nucleophilic allylation[8] (Scheme 1). The
last route to products with quaternary all-carbon stereocen-
ters—nucleophilic allylation of electrophilic species—results
from a combination of a cationic synthon with an ambident
nucleophile provided that the latter is 1) configurationally
stable (no metallotropic equilibrium) and 2) attacked at the
g-carbon atom (Scheme 1).[8]
Abstract: The current state-of-the-art synthesis for the
formation of enantiomerically enriched all-carbon qua-
ternary stereocenters in acyclic system relies on the for-
À
mation of a single carbon carbon bond per chemical
step by asymmetric catalysis. These extraordinary so-
phisticated methods were logically classified among the
most powerful and innovative ones. In this concept arti-
cle, we are proposing a new retrosynthetic paradigm to
solve differently such challenging problems. These new
synthetic pathways lead to the diastereo- and enantio-
À
merically pure formation of three new carbon carbon
bonds in acyclic system, in a one-pot reaction, including
the formation of all-carbon quaternary stereocenters by
using classical reagents and experimental conditions and
from common starting materials.
Keywords: allylation
·
carbometalation
· synthetic
methods · zinc carbenoids
Introduction
Our field of research, synthetic organic chemistry, has now
reached a situation where major changes are needed. We
would like to illustrate this provocative statement by focus-
ing on one of the major achievements of the last few de-
cades, namely asymmetric synthesis. The development of
new and highly enantioselective processes for the creation
Scheme 1. General methods for the creation of all-carbon quaternary ste-
reocenters in acyclic system.
À
À
of carbon carbon or carbon heteroatom bonds was, and
still is, one of the main problems of chemical synthesis. In
contrast to tertiary stereocenters, where a wide variety of
chiral auxiliaries, reagents and catalysts nowadays form the
basis for modern asymmetric synthesis and are a guarantee
for high selectivity, the construction of a quaternary stereo-
center, that is carbon centers with four different non-hydro-
gen substituents, represents the most challenging and dy-
namic area in organic synthesis and still remains the touch-
stone of every enantioselective procedure.[1] The state-of-
the-art would be the asymmetric construction of quaternary
all-carbon stereocenters (all-carbon substituted excluding
therefore tertiary alcohols, ethers, amines, etc.).[2] To under-
stand why this field needs major changes, we should briefly
review the different synthetic approaches for the construc-
tion of quaternary all-carbon stereocenters. The methods
that have been successfully employed for the formation of
These methods are currently the state-of-the-art in our
field (all by asymmetric catalysis). However, one can easily
À
see that only a single carbon carbon bond is formed in the
reaction sequence between two components. Despite this
obvious lack of efficiency, the synthetic challenge imposed
by the inherent difficulties in the creation of all-carbon qua-
ternary centers in acyclic system led logically the synthetic
community to classify them among the most powerful and
innovative ones. This clearly shows that synthetic organic
chemistry reached nowadays an extraordinary levels of
À
sophistication for the creation of one carbon carbon bond
but the development of more efficient synthetic methodolo-
À
gies (i.e., more than one enantioselective carbon carbon
bond created per reaction), is still in its complete infancy.
Indeed, a seemingly trivial but rather serious limitation in
practice in our field is set by the mere number of chemical
steps accumulating in linear sequences. This challenging
goal of efficiency (step economy) can be achieved only
through the use of reactions that allow a great increase in
complexity or through operations that incorporate many
steps that collectively achieve the same high complexity in-
crease. Therefore, the invention of new reactions, reaction
sequences, reagents or strategies that allow this complexity
increase in a one-pot reaction are critical to the realization
of step economical syntheses. Surprisingly, multicompo-
[a] Prof. I. Marek
Contribution from the Mallat Family Laboratory of
Organic Chemistry
Schulich Faculty of Chemistry and
the Lise Meitner-Minerva Center for
Computational Quantum Chemistry
Technion-Israel Institute of Technology, Haifa 32 000 (Israel)
Fax : (+972)4-829-3709
Chem. Eur. J. 2008, 14, 7460 – 7468
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7461