DOI: 10.1002/anie.201103151
Asymmetric Catalysis
Organocatalyzed Enantioselective Fluorocyclizations**
Oscar Lozano, George Blessley, Teresa Martinez del Campo, Amber L. Thompson,
Guy T. Giuffredi, Michela Bettati, Matthew Walker, Richard Borman, and
Vꢀronique Gouverneur*
Asymmetric halogen-promoted cyclizations have been the
object of extensive investigations, the ultimate aim being the
emulation of natureꢀs remarkable ability to construct archi-
tecturally complex enantiopure halogenated compounds from
prochiral precursors. Progress has been slow, but significant
advances have recently been made in iodo-, bromo-, and
chlorocyclizations.[1] A catalytic enantioselective fluorocycli-
zation induced by an electrophilic fluorinating reagent has not
been reported to date. This fact represents a significant gap
Figure 1. Enantioselective fluorocyclization of prochiral indoles.
PG=protecting group.
since such a transformation can streamline synthetic access to
enantiopure fluorinated heterocycles, a class of compounds
that plays an important role in medicinal chemistry.[2] We
became interested in this problem because of the information
available on organocatalytic enantioselective fluorination[3]
and our recent work in cascade fluorination–heterocycliza-
tions.[4] Herein, we disclose the first successful catalytic
process that delivers enantioenriched fluorinated heterocyclic
products upon fluorocyclization of prochiral precursors.
For this study, we selected the prochiral indoles 1 and 2
with a pendant heteronucleophile tethered at C3 or at the
nitrogen atom, respectively, based on the typical position of
this heteroaromatic motif in nitrogen-containing natural
products (Figure 1).[5] The established reactivity profile of
indoles towards achiral electrophilic fluorinating reagents
offered a starting point to identify suitable reaction conditions
to allow for organocatalyzed enantioselective fluorocycliza-
tions.[6] Two recent discoveries support the use of cinchona
alkaloids to induce enantiocontrol. Shibata and co-workers
reported that N–F reagents in the presence of catalytic
amounts of cinchona alkaloids induce asymmetric fluorina-
tion of activated substrates.[7] In addition, we demonstrated
that asymmetric fluoroetherification of a silyl-activated
homoallylic alcohol can be performed with stoichiometric
amounts of chiral N–F reagents prepared in situ from Select-
fluor and (DHQ)2PHAL. Although the enantioselectivity of
this fluorocyclization was modest, the lead result was
encouraging.[4a]
From the onset, we appreciated the conceptual difficulties
in developing such a catalytic asymmetric fluorocyclization.
The uncatalyzed reaction must be significantly slower than
the catalyzed process, a requirement difficult to meet as any
in situ generated transient chiral N–F cinchona species will be
of similar reactivity or less reactive with respect to the parent
achiral fluorinating agent. In addition, the paucity of infor-
mation on the factors that control the catalytic asymmetric
delivery of halogens onto alkenes in the presence of cinchona
alkaloids is limiting.[1,7] Our studies commenced with the
fluorocyclization of the prototypical indole 1a, a substrate
that requires the creation of a stereogenic fluorinated
quaternary benzylic carbon center upon fluorocyclization
(Table 1).
Both Selectfluor and NFSI induced fluorocyclization at
room temperature to afford tetrahydrofuroindole (ꢀ )-3a as a
single cis diastereomer (d.r. > 20:1) with average yields of
70% (Table 1, entries 1–3). The process was similarly effec-
tive at ꢁ788C with NFSI in acetone (Table 1, entry 4).
Premixing various cinchona alkaloids with Selectfluor at
room temperature followed by the addition of 1a at ambient
temperature or at ꢁ788C led to the formation of 3a with the
ee value reaching 74% (Table 1, entries 5–10). The best
enantiocontrol was observed when the fluorocyclization was
performed with 1.2 equivalents of (DHQ)2PHAL in acetone
at ꢁ788C (Table 1, entry 9), all other alkaloids that were
screened were found to be less efficient.[8] To our great
delight, when using a catalytic amount of (DHQ)2PHAL
(20 mol%), 3a was formed with 66% ee (Table 1, entry 12).
This reaction was best performed at ꢁ788C in acetone with
NFSI and an excess of K2CO3. Decreasing the catalyst load,
changing the base, or using Selectfluor instead of NFSI
proved detrimental (Table 1, entries 11–16). The beneficial
effect of the use of an inorganic carbonate base for the
[*] Dr. O. Lozano, G. Blessley, Dr. T. Martinez del Campo,
Dr. A. L. Thompson, G. T. Giuffredi, Prof. V. Gouverneur
Chemistry Research Laboratory
University of Oxford
12 Mansfield Road OX1 3TA Oxford (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
Dr. M. Bettati, Dr. M. Walker, Dr. R. Borman
GlaxoSmithKline R&D, Stevenage Herts SG1 2NY (UK)
[**] We thank the European Union (PIEF-GA-2009-235510 to T.M., PIEF-
GA-2008-220034 to O.L.), GSK (G.B.) and the Berrow Foundation
for a scholarship to G.T.G. We also thank Dr. S. Fletcher for very
helpful discussions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 8105 –8109
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8105