Communication
A New Iron(III)−Salen Catalyst for Enantioselective Conia-ene
Carbocyclization
Subrata Shaw and James. D. White*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
S
* Supporting Information
(3) forms the C2-symmetric scaffold of the salen ligand.7 Our
ABSTRACT: A chiral iron(III)−salen complex based on
a cis-2,5-diaminobicyclo[2.2.2]octane scaffold catalyzes
asymmetric Conia-ene-type cyclization of α-functionalized
ketones containing an unactivated terminal alkyne and
produces an exo-methylenecycloalkane possessing a stereo-
defined quaternary center.
previous studies with metal−salen complexes based on 3 found
that they can be highly effective asymmetric catalysts for a variety
of reactions,8 and we reasoned that the catalytic principle ex-
pressed in Scheme 1 could be transferred to a system in which 3
sets the stage for stereogenesis.
Exploratory studies were conducted with β-keto ester 4 and
were guided initially by a report that 4 in the presence of catalytic
nickel acetylacetonate and ytterbium triflate gave cyclopentane 5.9
However, treatment of 4 with Ni(II)−salen complex 6,7 Cr(III)
complex 7, or Al(III) complex 8 (Figure 1) in the presence of
ntramolecular addition of enols and enolates to unactivated
alkenes and alkynes is a powerful method for obtaining carbo-
I
cycles bearing multiple substituents.1 The Conia-ene synthesis
exemplifies this concept even though its early thermal version
required high temperatures that were incompatible with sensitive
functionality.2 Advances in transition-metal catalysis made the
Conia-ene synthesis a more practical method of carbocycliza-
tion,3 but it took three decades from the reaction’s inception to
develop an enantioselective version of the process. Recent
studies by Toste,4 Dixon,5 and Shibasaki6 have addressed this
problem and have led to a working hypothesis for effecting asym-
metric cyclization of α-pentynyl-β-dicarbonyl structures 1 in
which a dual catalyst system consisting of a hard Lewis acid to
promote enolization and a soft Lewis acid, usually a transition
metal, to activate the alkyne is the key feature (Scheme 1). The
Figure 1. Diamine 3 and metal−salen complexes 6−10 based on a cis-
2,5-diaminobicyclo[2.2.2]octane scaffold.
several rare-earth triflates as cocatalysts gave 5 in only modest
yield with very low enantiomeric excess (ee) (Table 1, entries 1
and 2). On the other hand, Mn(III)− and Fe(III)−salen com-
plexes 9 and 10 resulted in a marked increase in the yield of 5
even in the absence of a cocatalyst (entries 3 and 4).10 The
predominant enantiomer of 5 formed with these catalysts was
found to have the R absolute configuration by comparison of its
optical rotation with the literature value.4 Although the enantio-
selectivity was still low with 9 and 10, a study carried out with 10
in the presence of silver salts as additives (entries 5−8) revealed
that further improvement in the yield of cyclization product 5
could be achieved, with silver trifluoroacetate and silver triflate
showing the most promise.
Scheme 1. General Mechanism of Carbocyclization of Alkynyl
β-Keto Esters Catalyzed by a Combination of Hard and Soft
Lewis Acids
In an effort to identify the active catalyst in these reactions, 10
was treated with an equimolar quantity of silver trifluoroacetate
in dichloromethane, and after removal of insoluble silver chlo-
ride, iron−salen complex 11 was isolated as a brown amorphous
solid (Scheme 2). This substance was used in subsequent experi-
ments with 4. Examination of solvent effects on the reaction of 4
in the presence of 11 showed a strong dependence of the product
yield and reaction time on the solvent polarity, with dichloro-
ethane (DCE) giving the best results (Table 2, entries 6 and 7).
Unfortunately, the ee of 5 remained low.
Toste−Dixon−Shibasaki methodology represents a valuable tech-
nique for generating a carbocycle bearing malleable functional
groups and a stereogenicquaternary carbon, but it hasbeenapplied
only to the synthesis of chiral cyclopentanes 2 and frameworks
containing this ring.
In a project designed to enlarge the scope of enantioselective
metallo−ene carbocyclization, we have examined several chiral metal−
salen systems as catalysts in which cis-2,5-diaminobicyclo[2.2.2]octane
Received: July 31, 2014
Published: September 12, 2014
© 2014 American Chemical Society
13578
dx.doi.org/10.1021/ja507853f | J. Am. Chem. Soc. 2014, 136, 13578−13581