Angewandte
Chemie
Gold Catalysis
Gold(I)-Catalyzed Enantioselective Desymmetrization of 1,3-Diols
through Intramolecular Hydroalkoxylation of Allenes
Weiwei Zi and F. Dean Toste*
Abstract: A gold(I)-catalyzed enantioselective desymmetriza-
tion of 1,3-diols was achieved by intramolecular hydroalkox-
ylation of allenes. The catalyst system 3-F-dppe(AuCl)2 /(R)-
C8-TRIPAg proved to be specifically efficient to promote the
desymmetrizing cyclization of 2-aryl-1,3-diols, which have
proven challenging substrates in previous reports. Multisub-
stituted tetrahydrofurans were prepared in good yield with
good enantioselectivity and diastereoselectivity by this method.
lective hydroalkoxylation of allenes enabled by a chiral
counter anion strategy.[7] Herein we disclose our recent efforts
towards a gold-catalyzed desymmetrizing hydroalkoxylation
of allenes that implements this same tactic, and provides
access to multisubstituted tetrahydrofurans containing two
stereogenic centers with good enantioselectivity and excellent
diastereoselectivity.
Previous studies have demonstrated that the chiral
induction induced by a chiral counteranion can be sharply
modulated by achiral ligands.[8] Thus, our exploration com-
menced with the examination of varying achiral phosphine
ligands and their synergistic properties in combination with
Ag-(S)-TRIP in the desymmetrization of 1,3-diols. The fact
that 2-aryl-1,3-diol (R = Ar, Figure 1) derived substrates were
A
symmetric desymmetrization of prochiral 1,3-diols pro-
vides an indirect but powerful way to form stereogenic
centers, especially for the synthesis of chiral all-carbon
quaternary centers.[1] During the past decade, substantial
effort has been made towards the development of methods
for the enantioselective intermolecular desymmetrization of
such substrates;[2,3] however, intramolecular asymmetric
desymmetrization reactions of 1,3-diols to generate two or
more stereogenic centers have only recently been realized by
organocatalysis.[4] Sun et al. described a chiral phosphoric
acid-catalyzed intramolecular transacetalization of 1,3-diols
to form tetrahydrofuran skeletons with high efficiency and
stereoselectivity.[4a] Yeung et al. reported enantioselective
desymmetrizing bromoetherification reactions of olefinic
1,3-diols catalyzed by a quinidine derived amino-thiocarba-
mate[4b] or a C2 symmetric sulfide.[4c]
In contrast, transition-metal catalyzed reactions for the
intramolecular asymmetric desymmetrization of 1,3-diols
have been far less explored.[5] Palladium-catalyzed asymmet-
À
ric C O bond formation, including allylic alkylation reac-
tion[5a] and Ullmann-type coupling reaction,[5b] were designed
for this purpose; however, only modest enantioselectivities
were obtained. A copper-catalyzed consecutive desymmetri-
zation and kinetic resolution sequence was designed to obtain
highly enantioenriched products.[5c]
Figure 1. Strategies for enantioselective intramolecular desymmetriza-
tion of 1,3-diols.
absent in Sun and Yeungꢀs reports,[4] prompted us to employ
2-phenyl substituted 1,3-diol 1a as the model substrate
(Table 1). Various mono- and bis-phosphines ligands for
gold were first investigated. Excellent diastereoselectivity and
reactivity was obtained with monophosphine ligands (Ph3P,
tBu3P); however, the enantioselectivity was very low
(entries 1 and 2). Switching to the a bisphosphine ligand,
diphenylphosphinomethane (dppm), produced an improve-
ment in the enantioselectivity of the reaction, but with a slight
loss of diastereoselectivity (d.r. = 15:1, 50% ee). Other
bisphosphine ligands were subsequently examined (entries 4
and 5).[9] Among them, diphenylphosphinoethane (dppe)
proved optimal not only in enantioselectivity but also in
diastereoselectivity (> 25:1 d.r., 57% ee).
Gold-catalyzed asymmetric hydrofuctionalization of
allenes has drawn extensive interest during the last
decade.[6] These reactions serve as atom-economical and
highly stereoselective methods to assemble commonly
encountered heterocycle motifs found in natural products
and bioactive molecules. Despite these achievements, no
succesful method has been established to construct hetero-
cycles incorperating more than one stereocenter via these
transformations. In 2007, our group reported an enantiose-
[*] Dr. W. Zi, Prof. Dr. F. D. Toste
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
Further optimization of the ligand focused on the adjust-
ment of its electronic properties. Neither strongly electron-
donating groups (4-MeO) nor strongly electron-withdrawing
groups (4-CF3) were beneficial to the reaction (entries 4, 6
E-mail: fdtoste@berkeley.edu
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 14447 –14451
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14447