Angewandte
Chemie
DOI: 10.1002/anie.201207356
Asymmetric Synthesis
Rhodium-Catalyzed Enantioselective Nucleophilic Fluorination: Ring
Opening of Oxabicyclic Alkenes**
Jiangtao Zhu, Gavin C. Tsui, and Mark Lautens*
The application of organofluorine compounds in pharma-
ceuticals, agrochemicals, high performance materials, and
medical imaging [e.g., positron emission tomography (PET)]
agents has seen an explosive increase in the past decade.[1]
Great strides have been made for developing new methods to
introduce fluorine into organic molecules, particularly in the
À
emerging area of transition-metal-catalyzed C F bond for-
mation.[2] While aryl fluoride bond formation has been
extensively studied,[3] asymmetric aliphatic C F bond forma-
À
tion remains challenging and less developed.[4] In this regard,
the majority of the reported methods relied on using electro-
philic “F+” equivalents to achieve highly enantioselective
a fluorination of carbonyl-containing compounds by employ-
ing elegantly designed chiral metal complexes, Lewis acids,
and organocatalysts.[5] However, the disadvantages of using
electrophilic fluorine sources are their high costs, limited
reactivity choices, and lower specific activity in PET applica-
tions. In contrast, the use of more abundant and inexpensive
Scheme 1. Transition-metal-catalyzed enantioselective nucleophilic
fluorinations. HFIP=1,1,1,3,3,3-hexafluoroisopropyl alcohol.
nucleophilic “FÀ” equivalents such as metal fluorides or HF-
containing reagents becomes highly desirable and provides
complementary reactivity which can lead to useful fluorinated
scaffolds which are more amenable to 18F radiolabeling.[2a]
While racemic palladium- and iridium-catalyzed nucleophilic
allylic fluorinations have been successfully developed,[6] to the
best of our knowledge, only a few examples of transition-
metal-catalyzed enantioselective nucleophilic fluorination
methods exist. Doyle and co-workers have recently devel-
oped powerful protocols of this type of fluorination.[7] For
example, asymmetric palladium-catalyzed fluorination of
cyclic and acyclic allylic halides using AgF gave chiral allylic
fluorides (Scheme 1a). A salen/cobalt catalyst with an amine
cocatalyst led to enantioselective ring opening of epoxides
using benzoyl fluoride as a latent source of fluoride and
provided chiral fluorohydrins (Scheme 1b).[8] We herein
report the first rhodium-catalyzed asymmetric ring opening
(ARO) of oxabicyclic alkenes (1) using triethylamine trihy-
drofluoride (Et3N·3HF) as the source of nucleophilic fluorine
(Scheme 1c). The chiral ring-opened products 2 contain both
allylic fluoride and fluorohydrin moieties.[9,4d]
Our group has demonstrated that rhodium-catalyzed
ARO of strained bicyclic alkenes is a highly efficient and
enantioselective process for generating a functionalized dihy-
dronaphthalene core.[10] Chiral rhodium(I) complexes cata-
lyze the ring-opening reaction of oxa- and azabicyclic alkenes
with a variety of nucleophiles such as amines and alcohols in
high yield and enantioselectivity.[11] The products are gener-
ated by an SN2’ nucleophilic displacement of the bridgehead
leaving group with inversion to give the 1,2-trans product as
a single regio- and diastereomer.[10a]
[*] Dr. J. Zhu,[+] G. C. Tsui,[+] Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
The use of a halide as the nucleophile in ARO has not
been demonstrated, and the stereochemical outcome (trans/
cis) of the halogenated ring-opened product is unknown. We
envisioned that by employing a suitable fluoride nucleophile
and a chiral rhodium(I) catalyst, the ARO of 1 could lead to
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
[+] These authors contributed equally to this work.
À
the direct construction of an aliphatic C F bond for the rapid
[**] We gratefully thank the NSERC, Merck Frosst, and Merck for an
Industrial Research Chair. We also thank the University of Toronto
for support of our program, Dr. Alan Lough (Chemistry Department,
University of Toronto) for single-crystal X-ray structure analysis, and
Solvias AG for the generous gift of chiral ligands. J.Z. thanks SIOC
for a postdoctoral fellowship. G.C.T. thanks NSERC for a postgrad-
uate scholarship.
synthesis of the chiral fluorinated scaffolds 2.
One major challenge lies in identifying the best fluoride
source because of the dual reactivity profile of fluoride
(nucleophile versus base). It is known that the nucleophilicity
of fluoride is significantly reduced in its solvated form,
whereas desolvated fluoride can act as a strong base which
causes a competitive elimination pathway.[2a,9a] To this end, we
began by reacting oxabenzonorbornadiene (1a) with a variety
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