Angewandte
Chemie
DOI: 10.1002/anie.201403844
Asymmetric Catalysis
Iridium-Catalyzed Enantioselective Allylic Substitution of
Unstabilized Enolates Derived from a,b-Unsaturated Ketones**
Ming Chen and John F. Hartwig*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
Abstract: We report Ir-catalyzed, enantioselective allylic sub-
stitution reactions of unstabilized silyl enolates derived from
a,b-unsaturated ketones. Asymmetric allylic substitution of
a variety of allylic carbonates with silyl enolates gave allylated
products in 62–94% yield with 90–98% ee and > 20:1
branched-to-linear selectivity. The synthetic utility of this
method was illustrated by the short synthesis of an anticancer
agent, TEI-9826.
Michael additions with another a,b-unsaturated ketone.
Consistent with this assertion, Ir-catalyzed asymmetric allylic
substitution has not been reported with enolates derived from
a,b-unsaturated ketones. Nevertheless, such a transformation
would be valuable because products generated from the
allylic substitution of such a reagent contain three functional
groups: an electron-deficient alkene, an electron-rich alkene
and a carbonyl group. A set of orthogonal reactivities of these
functional groups should allow the ketone products to
undergo a variety of transformations to generate valuable
intermediates.
We describe Ir-catalyzed, enantioselective allylic substi-
tution reactions with unstabilized silicon enolates derived
from a,b-unsaturated ketones that occur in good yields and
high enantioselectivities with excellent branched-to-linear
selectivities (Figure 1). The use of KF and 18-crown-6 as
T
he asymmetric alkylation of unstabilized ketone enolates is
[1]
a long-standing synthetic challenge in organic chemistry.
[
2]
One classic approach involves the SAMP and RAMP chiral
auxiliaries; a second, catalytic approach involves Pd-cata-
[3]
lyzed decarboxylative allylation. Both of these approaches
create products containing a stereocenter a to the carbonyl
group. Methods for alkylation of enolates that form products
containing a stereogenic center at the b position are
challenging, in part, because of the difficulty in conducting
nucleophilic substitution at a secondary position. One
approach to address this synthetic problem involves Ir-
[
4]
catalyzed asymmetric allylic substitution. In contrast to
[5]
the regioselectivity of Pd-catalyzed reactions, the regiose-
lectivity of the Ir-catalyzed reactions favor bond formation at
the more substituted position of an allyl electrophile. There-
fore, a stereocenter is created at the position b to the carbonyl
[
6,7]
Figure 1. Ir-catalyzed enantioselective allylic substitution of silyl eno-
lates with a,b-unsaturated ketones.
group in the product.
However, the scope of Ir-catalyzed allylic substitution
reactions with unactivated, monocarbonyl enolates is limited.
Most of the allylic substitution reactions with carbon nucleo-
[
8]
philes have been conducted with stabilized enolates. The
majority of reactions with unstabilized ketone enolates have
additives is one key to the development of this reaction.
Under these conditions, products from competing pathways
derived from the electrophilicity of the starting or product
ketone were not observed. The utility of this process was
illustrated by the syntheses of syn- and anti-4-methyl-pentan-
2-ols and the total synthesis of TEI-9826.
[
9]
been conducted with derivatives of acetophenone.
a,b-Unsaturated ketones are valuable building blocks in
organic synthesis because they contain two functional
[1]
groups. Most transformations of this class of molecule
exploit its electrophilicity. Reactions in which a,b-unsatu-
rated ketones would act as the nucleophile are less common
because the enolate can undergo aldol condensation or
We initiated our studies to identify an appropriate
activator for the reactions of methyl cinnamyl carbonate 1a
with silyl enolate 2a in the presence of [Ir(cod)Cl] (cod =
2
cyclooctadiene) and the phosphoramidite ligand. Fluoride
additives, such as KF, ZnF or the combination of CsF and
2
[
*] M. Chen, Prof. J. F. Hartwig
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
ZnF have been shown to promote the a-arylation reactions
2
of silyl ketene acetals and a-silyl nitriles, as well as the
[
10]
allylation of acetophenones.
Therefore, we evaluated
E-mail: jhartwig@berkeley.edu
several fluoride salts as the additive for the allylic substitution
reactions of 1a with 2a. Treatment of carbonate 1a (1 equiv)
[
**] Financial support provided by the National Institutes of Health
(
GM-58108) is gratefully acknowledged. We thank Johnson-Matthey
for gifts of [Ir(cod)Cl]2.
and silyl enolate 2a (2 equiv) with 2 mol% [Ir(cod)Cl] and
2
4
mol% (R ,R ,R )-L in the presence of KF (1 equiv) at 508C
a c c
for 12 h, did not provide any of product 3a (entry 1, Table 1),
Angew. Chem. Int. Ed. 2014, 53, 8691 –8695
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8691