Angewandte
Chemie
Enantioselective Synthesis
Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and
Aryl Trifluoroborates: a Synthetic Strategy for Discoipyrrole D**
Jiun-Le Shih, Thien S. Nguyen, and Jeremy A. May*
Abstract: Bis-heteroaryl or bis-aryl stereocenters were formed
by an organocatalytic enantioselective conjugate addition
using the respective trifluoroborate salts as nucleophiles.
Control studies suggested that fluoride dissociation is necessary
in the anhydrous conditions. This strategy is applicable to the
synthesis of discoipyrrole D, an inhibitor of BR5 fibroblast
migration.
Scheme 1. Thiophenyl/indolyl stereocenter.
B
is-heteroaryl and heteroaryl/aryl stereocenters are found
in many bioactive compounds, including pharmaceutical
agents and natural products.[1] Recent stereospecific[2] and
order to define reaction conditions that were strong enough to
use aryl boronates as nucleophiles, yet mild enough to be
compatible with heterocycles in either reacting partner, we
used the model reaction in Scheme 1.
enantioselective[3] C C bond-forming methods have been
À
reported for such stereocenters that usually rely on transition
metal catalysis, limiting functional group tolerance. For
example, compatibility with nitrogen-containing or electron-
rich heterocycles is rare, although such compounds are
important in pharmaceutical development.[4] Additionally,
stereospecific approaches require prior synthesis of enan-
tioenriched substrates. Currently, most enantioselective
approaches are Friedel–Crafts 1,4-additions that limit the
nucleophileꢀs point of substitution. Our recent efforts in the
synthesis of a-chiral heterocycles led us to believe that a 3,3’-
(C7F7)2-BINOL-catalyzed enantioselective addition would
enable the use of heteroaryl and aryl nucleophiles to provide
an orthogonal approach that was fully compatible with
heterocycles.[5]
The conjugate addition of vinyl boronates was first
reported by Suzuki et al.[6] Later, Chong et al. reported an
enantioselective version with 3,3’-I2-BINOL as a catalyst.[7]
Subsequently, they reported the use of neat aryl boronate
esters with enones at 1208C. Harsh conditions were necessary
due to the decreased activity of the aryl boronates.[8] These
conditions were not shown to be compatible with heterocycles
in the electrophile or the nucleophile. Furthermore, the use of
boronic acids[9] or trifluoroborate salts would be preferred to
boronate esters from a practical standpoint for ease of use and
long-term stability.
2-Thiophene boronic acid was the most reactive nucleo-
phile in a preliminary screen, but the yield of product was 35–
85% depending on boronic acid purity. Careful observation
showed that no boronic acid was present after 6 h. Instead,
substantial amounts of thiophene were seen from proto-
deboronation. As the stereoselectivity was high, we postu-
lated that improving the boronate stability would lead to
a reliable reaction. In Suzuki couplings, boronate longevity
increases with the trifluoroborate salt,[10,11] which hydrolyzes
in situ to maintain a low concentration of boronic acid.[12]
However, three potential problems for the reaction in
Scheme 1 are: 1) the reaction must be anhydrous, preventing
hydrolysis of 5 to the boronic acid 7 (Scheme 2), 2) the
Scheme 2. Putative reaction mechanism.
Our studies led to 3,3’-(C7F7)2-BINOL (1, Scheme 1) as
a sufficiently reactive catalyst for the addition of conveniently
handled boronic acids to b-heterocycle-appended enones.[5] In
trifluoroborate salt would be poorly soluble in the nonpolar
solvents, and 3) if fluoride dissociation from the trifluorobo-
rate 5 to form difluoro boronate 6 (X,Y= F) were to occur,
the latter may be Lewis acidic enough to proceed through
a racemic reaction on its own via 11 (X,Y= F).
With knowledge of these potential problems, we repeated
the experiment in Scheme 1 with 2-thiophene potassium
trifluoroborate (3, R = BF3K), and butanone 4 was quickly
formed in nearly quantitative yield and with exquisite
stereoselectivity. While the use of heteroaryl trifluoroborates
as nucleophiles without hydrolysis has been reported,[13] those
[*] J.-L. Shih, T. S. Nguyen, Prof. J. A. May
Department of Chemistry, University of Houston
112 Fleming Building, Houston, TX 77204-5003 (USA)
E-mail: jmay@uh.edu
[**] We thank the Welch Foundation for funding (grant E-1744), CBIP
(UH), the Studying Abroad Scholarship of Taiwan (fellowships for
J.S.), and Prof. John Macmillan for NMR data.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 9931 –9935
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9931