Organocatalyzed enantioselective fluorocyclizations

Article abstract of DOI:10.1002/anie.201103151

Enantioenriched fluorinated heterocycles can be prepared through fluorocyclizations of prochiral indoles (see scheme; Ts=tosyl, Bn=benzyl, Boc=tert-butoxycarbonyl). More than twenty examples for this cascade fluorination-cyclization, which is catalyzed by cinchona alkaloids and employs N-fluorobenzenesulfonimide as the electrophilic fluorine source have been explored, and an unprecedented catalytic asymmetric difluorocyclization has also been identified.

Full text of DOI:10.1002/anie.201103151

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
under http://dx.doi.org/10.1002/anie.201103151.
Angew. Chem. Int. Ed. 2011, 50, 8105 –8109
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8105

Communications
Table 2: Fluorocyclization of indoles 1a–1t.
Table 1: Validation and optimization of the fluorocyclization of 1a.[8]
Entry F+
Alkaloid[b] Base
Solvent T[e]
Yield ee
Entry Cond.[a]
1
R1
R2
XH
3
Yield ee
source[a] (mol%)
[%][f] [%][g]
[%][b] [%][c]
[c]
1
2
3
4
5
6
7
8
A
A
B
B
A
A
A
A
A
A
B
B
B
B
B
A
–
NaHCO3 MeCN
RT 73
RT 60
RT 76
–
–
–
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
1a
1a
1b
1b
1c
1c
1d
1e OMe
1e OMe
1 f
1 f
1g OEt
1g OEt
1h O(allyl) Me OH
1h O(allyl) Me OH
1i
1i
1k Mes
1k Mes
1l
1l
1m OMe
1m OMe
1n Ph
1n Ph
1o Mes
1o Mes
1p
1p
1q Mes
1q Mes
H
H
H
H
H
H
H
Me OH
Me OH
Et
Et
allyl OH
allyl OH
H
Me OH
Me OH
Me OH
Me OH
Me OH
Me OH
3a 56
3a 72
3b 51
3b 68
3c 62
3c 76
3d 33
3e 90
3e 65
3 f
3 f
3g 60
3g 78
3h 53
3h 65
74
66
56
52
60
60
40
86
74
84
74
84
72
86
78
72
62
90
84
76
64
78
70
82
70
92
84
[c]
–
NaHCO3 acetone
[c]
–
NaHCO3 MeCN
OH
OH
[c]
–
NaHCO3 acetone ꢁ788C 73
–
[c]
C (100)
D (100)
E (100)
F (100)
F (100)
F (100)
F (10)
F (20)
F (20)
F (20)
F (20)
F (20)
NaHCO3 MeCN
RT 50
RT 53
20
5
[c]
NaHCO3 MeCN
[c]
NaHCO3 acetone ꢁ788C 49
0
OH
[c]
NaHCO3 MeCN
RT 72
55
74
64
50
66
66
58
34
32
[c]
9
NaHCO3 acetone ꢁ788C 56
9
[c]
10
11
12
13
14
15
16
NaHCO3 THF
ꢁ788C 64
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
OBn
OBn
69
78
[d]
K2CO3
K2CO3
Cs2CO3
K2CO3
–
K2CO3
acetone ꢁ788C 50
acetone ꢁ788C 72
acetone ꢁ788C 58
[d]
[d]
[d]
acetone
RT 50
acetone ꢁ788C 36
[d]
acetone ꢁ788C 47
Ph
Ph
Me OH
Me OH
Me OH
Me OH
Me NHTs
Me NHTs
Me NHTs
Me NHTs
Me NHTs
Me NHTs
Me NHTs
Me NHTs
3i
3i
55
61
[a] A=1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate) (Selectfluor), B=N-fluorobenzenesulfonimide
(NFSI). [b] C=2,5-diphenyl-4,6-bis(dihydroquininyl)pyrimidine
((DHQ)2PYR), D=hydroquinidine-9-phenanthryl ether, E=1,4-
bis(dihydroquinidinyl)anthraquinone ((DHQD)2AQN), F=1,4-bis(dihy-
droquininyl)phthalazine ((DHQ)2PHAL). [c] 1 equiv. [d] 6 equiv.
[e] Reaction time up to 5 h at RT and up to 15 h at ꢁ788C. [f] Yield of
isolated product. [g] ee value determined by HPLC on a chiral stationary
phase.
3k 57
3k 55
3l
3l
3m 55
3m 51
3n 50
3n 70
3o 60
3o 80
H
H
54
59
catalytic asymmetric fluorination with cinchona alkaloids is
not unprecedented.[7]
H
H
Me NHCOMe 3p 45[d] 66
Me NHCOMe 3p 95 80
Me NHCOMe 3q 38[d] 92
Me NHCOMe 3q 65
Me NHCO2Me 3r
Me NHCO2Me 3r
Me NHCO2Bn 3s 40
Me NHCO2Bn 3s 47
Me NHBoc
Me NHBoc
The scope and limitation of this organocatalyzed process
was investigated with respect to both the substitution pattern
of the indolic structural core and the attached nucleophile. To
evaluate the efficiency of the catalytic protocol, the yields and
enantiomeric excesses of the products of reactions carried out
with either an equimolar (conditions A) or a catalytic amount
of the cinchona alkaloid (conditions B) were compared
(Table 2).[8]
92
78
74
78
77
86
78
1r
1r
1s
1s
1t
1t
H
H
H
H
H
H
56
76
3t
3t
67
70
[a] Conditions A: Selectfluor (1.2 equiv), (DHQ)2PHAL (1.2 equiv),
The reaction tolerates various substituents on the indolic
nitrogen atom, including hydrogen, but the highest enantio-
meric excess was observed for the fluorocyclized product 3a
derived from N-methyl substituted precursors (Table 2,
entries 1–7). The presence of a substituent at position 5
(R1 ¼ H) led to a markedly improved control over the
enantioselectivity (Table 2, entries 8–19). When an equimolar
amount of alkaloid was used (conditions A), enantiomeric
excesses ranging from 72% to 90% were observed; under
catalytic conditions only a slight decrease of enantiomeric
excesses (up to 84% ee) was observed with no compromise on
yields (conditions B). Indolic precursors with pendant unpro-
tected primary amines did not afford any fluorinated ring-
closed products; this behavior is likely due to a competing N-
fluorination reaction. Various N-protected amines were found
to be efficient nucleophiles (Table 2, entries 20–37). N-
Tosylated indoles underwent fluorocyclization to afford the
desired tetrahydropyrroloindoles 3l–3o in good yields and
NaHCO3 (1.2 equiv), acetone, ꢁ788C; conditions B: NFSI (1.2 equiv),
(DHQ)2PHAL (0.2 equiv), K2CO3 (6 equiv), acetone, ꢁ788C. [b] Yields of
isolated products. [c] ee value determined by HPLC on a chiral stationary
phase. [d] Conversion determined by 1H NMR spectroscopy of the crude
product.
with enantiomeric excesses reaching 84% under conditions B
(Table 2, entry 27). Indoles 1p–1q with a pendant N-acetam-
ido nucleophile engaged very effectively in organocatalytic
asymmetric fluorocyclization (Table 2, entries 28–31). This N-
protected nucleophile led to a very efficient control over
enantiofacial selectivity (ee = 92%; Table 2, entries 30 and
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Angew. Chem. Int. Ed. 2011, 50, 8105 –8109

31). The methyl-, benzyl-, and tert-butylcarbamates of N-
methyl tryptamine (1r–1t) were also found to be suitable
substrates for organocatalysis, and delivered the products in
up to 78% ee (Table 2, entries 32–37).
cinchona alkaloid is responsible for the enantiocontrol.[7]
19F NMR studies confirmed that NFSI (19F NMR: d =
ꢁ38 ppm) is able to fully transfer fluorine to (DHQ)2PHAL
(F(DHQ)2PHAL+ 19F NMR: d = + 45 ppm) at room temper-
ature within 30 min.[11] Under conditions A (stoichiometric
amount of alkaloid), fluorination is therefore likely induced
by an N-fluoroammonium salt of the cinchona alkaloid as
both NFSI and the alkaloid are premixed prior to the addition
of the substrate. Fluorine transfer from NFSI to
(DHQ)2PHAL was however found to be ineffective at low
temperature (ꢁ788C), with only a trace amount of F-
(DHQ)2PHAL+ (less than 2%) being detected by 19F NMR
spectroscopy in the presence or absence of K2CO3. Exper-
imentally, we observed that when all components of the
organocatalytic reaction are mixed at ꢁ788C, the reaction
proceeds as expected with the fluorocyclized product 3a
obtained in 50% ee. When the alkaloid (20 mol%) is mixed
with NFSI at room temperature prior to reducing the
temperature to ꢁ788C and addition of the prochiral indole
1a (conditions B), 3a is isolated with a slightly improved ee
value of 66%. Taken together, these experimental observa-
tions suggest that a reaction pathway that does not involve
F(DHQ)2PHAL+ may operate, and thus account for the
observed enantioselectivity. Associative complexation of the
alkaloid with the substrate, for example through hydrogen
bonding with the pendant nucleophile, cannot be ruled out.[12]
This hypothesis would be consistent with the level of
selectivity found to be dependent on the nature of the
nucleophile. Indeed, while 3a and 3l (X = O, NTs) were
generated with 66% and 64% ee, respectively, the selectivity
was markedly increased for 3p (X = NCOMe, 80% ee), 3r
(X = NCO2Me, 74% ee), 3s (X = NCO2Bn, 77% ee) and 3t
(X = NBoc, 78% ee).
The cyclization products 3a–3t were formed as single cis
1
diastereomers, as judged by H NMR analysis of the crude
products of the reactions.[8] X-ray diffraction studies of the
sulfonamide-containing product (3aR,8aS)-3o confirmed its
structure (Figure 2).[8,9]
Figure 2. Crystal structure of one molecule of (3aR,8aS)-3o from
diffraction data with displacement ellipsoids shown at the 50%
probability level.
The fluorocyclization of 6-substituted indoles as well as an
indole bearing a phenolic nucleophile were equally successful
(Figure 3). The yields and enantiomeric excesses are given for
the organocatalytic reactions only. Tetrahydrofuroindoles 3u
and 3v were formed in moderate yields and with ee values in
the range of 60%. The fluorinated tetracyclic dihydro-
benzofuro[2,3-b]indole 3w was obtained in 80% ee.
Prochiral indole 2, which bears an O nucleophile at the
nitrogen atom, was also subjected to fluorocyclization
(Scheme 1). Extensive screening of various alkaloids
showed that asymmetric fluorocyclization of 2 using equimo-
lar amounts of Selectfluor and (DHQ)2PHAL delivered the
difluorinated tricyclic tetrahydrooxazolo[3,2-a]indole 4 in
Figure 3. Organocatalytic asymmetric synthesis of 3u–3w.
From a mechanistic point of view, catalytic enantioselec-
tive fluorocyclizations benefit from the fluorination being the
stereochemistry-determining step. This fact contrasts advan-
tageously with the complications intrinsic to iodo- and
bromocyclizations, which arise from the propensity of iodo-
nium and bromonium to undergo degenerate halogen
exchange.[10] Products 3a–3w are therefore likely to result
from an irreversible fluoroquaternization at C3 followed by
the intramolecular capture of the transient iminium inter-
mediate by the pendant nucleophile. A series of observations
led us to speculate on the origin of enantiocontrol. Our data
indicate that similar enantiomeric excesses are observed
whether the cinchona alkaloid is used in equimolar or
catalytic amounts, although the catalyzed reactions were
overall slightly less enantioselective. The same enantiomer is
formed preferentially under both conditions (A and B), thus
suggesting that the same N-fluoroammonium salt of the
Scheme 1. Asymmetric difluorocyclization of 2, and crystal structure of
4. Displacement ellipsoids shown at the 50% probability level.
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Communications
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50% yield and with 68% ee. The identity of 4 was
unambiguously confirmed by single crystal X-ray diffraction
studies.[8] The stereochemical stability of 4 was assessed by
measuring the enantiomeric excess at various times. No
variation or decrease was observed, thus testifying to the
remarkable stereochemical integrity of these compounds
under the reaction conditions. This result is likely due to the
presence of the proximal gem-difluoro motif, which prevents
postreaction racemization. A plausible reaction pathway
accounting for these difluorocyclizations involves the forma-
tion of 3-fluoroindole, which subsequently undergoes enan-
tioselective fluorocyclization. Our attempt to prepare 4 under
organocatalytic conditions B was equally successful (60% ee).
This reaction represents a unique example of organocatalytic
asymmetric dihalocyclization.
In conclusion, we have developed an organocatalytic
route to enantioenriched fluorinated heterocycles. These are
the first examples of organocatalyzed asymmetric fluorocyc-
lizations. The process installs the fluorine substituent on a
quaternary benzylic stereogenic carbon center and leads to
new fluorinated analogues of natural products featuring the
hexahydropyrrolo[2,3-b]indole or the tetrahydro-2H-furo-
[2,3-b]indole skeleton. We have also demonstrated that
asymmetric dihalocyclization is a feasible process by taking
advantage of the newly formed gem-difluoro motif to prevent
postreaction racemization. A catalytic asymmetric variant is
also presented. Detailed kinetic studies are under way to
elucidate the mechanism and origin of enantioinduction in
these processes.
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Experimental Section
General procedure: (DHQ)2PHAL (20 mol%) and NFSI (1.2 equiv)
in acetone (1.5 mL) were stirred under argon at RT for 30 min. K2CO3
(6.0 equiv) was then added to the solution, and the reaction mixture
was stirred for 30 min at ꢁ788C. A precooled solution (ꢁ788C) of the
indole (1 equiv) in acetone (0.5 mL per 20 mg of indole) was added
dropwise to the catalyst solution and the reaction was stirred at the
same temperature overnight. The reaction mixture was evaporated
and the residue was purified on neutral alumina (hexane/EtOAc =
6:4) to give the fluorocyclized product.
[5] For numerous examples, see: K. C. Nicolaou, S. A. Snyder
Classics in Total Synthesis II, 1st ed., Wiley-VCH, Weinheim,
2003; K. C. Nicolaou, E. J. Sorensen Classics in Total Synthesis,
1st ed., Wiley-VCH, New York, 1996.
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[8] For full details, see the Supporting Information. Compounds 3
are unstable under acidic conditions or when kept neat over an
extended period of time, as they slowly convert into defluori-
nated oxindoles. These compounds are stable in solution
(benzene, acetonitrile, acetone).
[9] Low-temperature single-crystal diffraction data were collected
by using an Oxford Diffraction (Agilent) SuperNova with CuKa
radiation (3o) or a Nonius KCCD diffractometer with MoKa
radiation (4 & 5). Data were reduced by using CrysAlisPro or
DENZO/SCALEPACK,[13] solved by using SIR92[14] and refined
within the CRYSTALS suite.[15] Data were also collected for 3l,
but indicated the structure was modulated at 150 K and room
temperature, and thus it could not be solved. Compound 3o was
found to be a non-merohedral twin, thus the Rogers, Flack, and
Hooft parameters conventionally used as measures of correct-
Received: May 8, 2011
Published online: July 12, 2011
Keywords: alkaloids · asymmetric catalysis · fluorocyclizations ·
.
indoles · organocatalysis
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ness of the absolute structure,[16] were inappropriate in this
context and the crystal was treated as a four-component twin as
described in the Supporting Information (CIF). The four twin
scale factors refined to c. 0.6 0.4 0 0 (for the identity; rotation
about [ꢁ1 1 0]; reflection about (ꢁ1 1 0) and inversion,
respectively). Recrystallization was performed with enantioen-
riched 3o (e.r. 93:7), it was therefore concluded that the crystal
was twinned purely by rotation (i.e., each component is a single
enantiomer) and the absolute configuration was tentatively
assigned on the basis that a crystal of the major enantiomer was
selected. Full refinement details are given in the Supporting
Information. CCDC 827531 (3o), 827532 (4), 827533 (oxindole
of 3m) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.; The absolute configuration for 3o corrob-
orates with the sense of enantiocontrol observed upon catalytic
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www.angewandte.org 8109