A doubly axially chiral phosphoric acid catalyst for the asymmetric tandem oxyfluorination of enamides

Article abstract of DOI:10.1002/anie.201205383

Double agent: Enantioselective tandem oxyfluorination of enamides using a doubly axially chiral phosphoric acid catalyst is reported. The chiral phosphoric acid catalyst controls both a fluorination step, using a chiral anion phase-transfer strategy, and addition to the resulting imine under the guise of Br?nsted acid catalysis. Copyright

Full text of DOI:10.1002/anie.201205383

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DOI: 10.1002/anie.201205383
Enantioselective Fluorination
A Doubly Axially Chiral Phosphoric Acid Catalyst for the Asymmetric
Tandem Oxyfluorination of Enamides**
Takashi Honjo, Robert J. Phipps, Vivek Rauniyar, and F. Dean Toste*
The selective construction of carbon–fluorine bonds is of
great interest to medicinal chemists because the replacement
of a carbon–hydrogen bond with a carbon–fluorine bond
continues to be an effective approach to the development of
biologically active molecules with improved physical and
metabolic profiles and biological activities.[1] To this end,
a number of impressive examples of catalytic enantioselective
fluorination have been reported over the last decade.[2,3] Our
laboratory has recently introduced a novel strategy for
asymmetric fluorination based on phase-transfer catalysis
using chiral anionic catalysts based on BINOL-derived
phosphates [Eq. (1)].[4,5] Motivated by the importance of the
prevalent in natural products and the effect of fluorine
introduction on this motif remains, to the best of our
knowledge, thus far unexplored.[8] With regard to existing
asymmetric N,O-aminal synthesis, Antilla and co-workers
have reported the phosphoric acid-catalyzed addition of
alcohols[9] and hydroperoxides[10] to N-acylimines, although
examples delivering high enantioselectivity were restricted to
aromatic imines and in no cases could simple water be used as
nucleophile in order to obtain a hemiaminal.
We were aware that our aim of utilizing a single catalyst to
carry out two consecutive enantioselective transformations
presented complications. Not only must the catalyst be
capable of promoting both reactions, but the inherent
diastereocontrol from the initially installed stereocenter
could be matched or mismatched with the catalyst control
for formation of the second stereocenter.
However, this same effect might enable the effect of
double stereodifferentiation to be exploited, potentially
leading to extremely high stereocontrol in certain cases.
Furthermore, observations during our previous studies sug-
gested that, despite drying at 808C under vacuum, the
Selectfluor employed in our fluorination contains intrinsic
moisture that we hypothesized may be sufficient to enable
in situ formation of the hemiaminal.
b-fluoroamine motif in medicinal chemistry we employed this
strategy to develop a highly asymmetric fluorination of cyclic
enamides, allowing us to isolate stable but highly versatile
enantioenriched a-fluoro-N-acylimines.[4b] Given the proven
ability of BINOL phosphoric acid catalysts to control addition
to imines,[6] we posited that aldehyde-derived enamides
should be of particular interest as our protocol, upon enamide
fluorination, would generate in the first instance a protonated
N-acyliminium ion [Eq. (2)]. This intermediate should exhibit
hydrogen-bonding interactions with the chiral phosphate
anion, allowing catalyst-controlled addition of an external
oxygen nucleophile, constituting an oxyfluorination of enam-
ides.[7] The resulting stereodefined a-fluoro-N,O-aminal
would be of particular interest as chiral N,O-aminals are
We began our investigations employing (E)-configured N-
benzoyl enamide (E)-1 (Table 1). Using TRIP or C8-TRIP as
catalysts, the desired a-fluoro-N,O-aminal 3 was isolated with
excellent selectivity for the syn-diastereomer (entries 1 and
2).[11] However, the lack of any significant enantioselectivity
was disappointing, given our previous results with cyclic
enamides.[12] By using our previously reported cyclohexyl-
substituted catalyst TCYP (2c),[13] promising enantioselectiv-
ity was observed in the minor diastereomer, while the major
remained low but improved (entry 3). Encouragingly, 2-
naphthyl-substituted catalyst 2d gave high diastereoselectiv-
ity as well as moderate enantioselectivity (53% ee), although
this could not be improved upon by use of the 1-naphthyl (2e)
or 9-anthracyl (2 f) variants (entries 5 and 6). Intriguingly, the
spirocyclic catalyst STRIP[14] (2g) delivered the hitherto
disfavored anti-3 as the major diastereomer with high
enantiomeric excess (87% ee), although diastereoselectivity
(2.5:1) and yield were prohibitive (entry 7). The VAPOL-
derived catalyst 2h gave low enantioselectivity (entry 8, 32%
ee). Having examined three distinct chiral phosphoric acid
scaffolds, including a representative range derived from the
privileged BINOL architecture, we next synthesized bis-
BINOL catalyst 2i.[15] While 2i produced disappointing
results in our oxyfluorination reaction (entry 9), we hypothe-
sized that replacing the alkoxy substitution at the 4,4’ position
with phenyl (as in 2j) might generate a more rigid and
[*] Dr. T. Honjo, Dr. R. J. Phipps, Dr. V. Rauniyar, Prof. F. D. Toste
Department of Chemistry, University of California Berkeley
Berkeley, CA 94720 (USA)
E-mail: fdtoste@berkeley.edu
[**] We thank the University of California, Berkeley, and Amgen for
financial support. T.H. gratefully acknowledges support from
Mitsubishi Tanabe Pharma Corporation. R.J.P. thanks the European
Commission for a Marie Curie International Outgoing Fellowship
and V.R. thanks NSERC for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205383.
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Table 1: Catalyst screening for fluorohydration of enamides (E)-1 and (Z)-1.
Catalyst
Entry
Substrate
Yield
[%][a]
syn:anti[b]
% ee
Entry
Substrate
Yield
[%][a]
syn:anti[b]
% ee
(syn/anti)[c]
(syn/anti)[c]
(R)-TRIP
(S)-C8-TRIP
(R)-2c
(R)-2d
(R)-2e
(R)-2 f
(R)-STRIP
(S)-2h
(R,R)-2i
(R,R)-PhDAP
1
2
3
4
5
6
7
8
9
10
70
37
34
32
49
27
38
32
86
78
>20:1
>20:1
10:1
>20:1
10:1
5:1
1:2.5
10:1
8:1
2/–
À5/–
11[d]
12
13
14
15
64
62
12
30
39
<5
20
9
>20:1
>20:1
5:1
8:1
10:1
–
1:1
4:1
>20:1
>20:1
À85/–
90/–
21/82
À25/31
À53/–
À20/9
À16/20
À17/À87
32/À10
17/12
9/65
À28/5
–
45/À49
À40/À54
À89/–
À98/–
16
17[d]
18
19
20
35
86
6:1
60/83
[a] Isolated yield of mixture of syn and anti diastereomers. [b] Determined by 19F NMR analysis of crude reaction mixture. [c] Determined by chiral
HPLC. [d] Reaction time was 65 h.
constrained pocket for the substrate, leading to higher
selectivity. Satisfyingly, this proved to be the case; while
diastereoselectivity was modest (6:1), phenyl-substituted
doubly axially chiral phosphate PhDAP (2j) produced
a clear improvement and the combined enantioselectivities
were the highest obtained thus far in our investigation
(entry 10, 60% and 83% ee). We next turned our attention
to the (Z)-configured isomer of 1.[16] The outcome with (Z)-
1 utilizing TRIP and C8-TRIP was in stark contrast to the E
isomer; these catalysts delivered high enantioselectivities
while maintaining high diastereoselectivity (entries 11 and 12,
85 and 90% ee), although reactivity was lower with TRIP
requiring 65 h reaction time to achieve good conversion.
Conversely, catalysts 2c–2 f gave poor results, giving
moderate d.r. and low enantioselectivity (entries 13–15) or
no reaction at all (entry 16). STRIP and VAPOL-derived 2h
were mediocre; both gave poor d.r. albeit with moderate
enantioselectivity (entries 17 and 18). The Du catalyst 2i gave
excellent d.r. and high enantioselectivity (entry 19, 89% ee),
although the yield was moderate due to low conversion.
Finally, the best results were obtained with PhDAP as
a catalyst, which delivered syn-3 in high isolated yield
(86%), as essentially a single diastereomer and with excep-
tional enantioselectivity (entry 20, 98% ee).[17]
entries 1–3) and aliphatic (entries 4–10) substituted enamides
were compatible with our tandem hydroxyfluorination pro-
cess. A broad range of functional groups were tolerated under
our conditions (entries 8–10), although strongly electron-
donating groups on the aromatic ring reduced enantioselec-
tivity (entry 3), Formation of undesired dimer 16, which
eroded the yield of 15, could be reduced by use of
monohydrous sodium carbonate as base, albeit with a small
reduction in enantioselectivity (entries 4 and 5). Finally, in
accord with the hypothesis that catalyst control is operative in
the hydration of our fluorination-generated imine, substrate
12 delivered a product (22) chiral only at the N,O-aminal with
high enantioselectivity (entry 11).
We next demonstrated that running the reaction in the
presence of alcohols results in their addition being preferred
over hydration, with high enantioselectivities being obtained
(Scheme 1a). Furthermore, the N,O-aminal products are
amenable to both oxidation (Scheme 1b), to give chiral a-
fluoroimides, and reduction (Scheme 1c), to give chiral b-
fluoroamines, with negligible loss of enantioselectivity at the
fluorine stereocenter.
In order to test the limits of our reaction, we turned our
attention to a substrate possessing a chiral quaternary fluorine
stereocenter, specifically the benzoyl enamide derived from
2-phenylpropionaldehyde. This substrate is notably challeng-
ing; organocatalytic aldehyde a-fluorination processes have
With optimal conditions in hand, we explored the scope of
the hydroxyfluorination reaction. Both aromatic (Table 2,
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Table 2: Substrate scope of fluorohydration of enamides.
Entry Substrate
Product
Yield[b] (ee)[c]
(both in %)
1
2
3
R2 =H ((Z)-1)
R2 =H (syn-3)
R2 =F (13)
86 (98)
63 (97)
59 (70)
R2 =F (4)
R2 =OMe (5)
R2 =OMe (14)
Scheme 1. Fluoroalkoxylation and elaboration of products. Yields refer
to yields of isolated syn and anti diastereomers. See the Supporting
Information for reaction conditions.
15: 52 (92)
16: 29,
4
d.r. =3:1[a]
5[d]
6
15+16
15: 80%
(85)
16: trace
6
52 (91)
67 (90)
7
Scheme 2. Double stereodifferentiation in the formation of a quaternary
fluorine stereocenter. Relative and absolute configuration of syn-29
determined by X-ray crystallography (see the Supporting Information
for details). All other products assigned by tentative analogy.
8
60 (92)
73 (89)
61 (87)
9
a result of double stereodifferentiation:[19] while our initial
fluorination likely occurs with good stereocontrol, this is
refined by the catalyst to excellent levels at the hydration step,
albeit at the expense of final product yield, providing > 99%
ee in the matched case. By employing (Z)-28, we found that
(R,R)-PhDAP delivered syn-29 as the major diastereomer
(4:1 d.r.), and although the effects of double stereodiffer-
entation were not as pronounced in this case, synthetically
useful levels of enantioselectivity in syn-29 were obtained
(Scheme 2b, 83% ee).
Following the initial reaction optimization, we were struck
by the observation that, of the relatively diverse set of
catalysts screened, the only able to provide both excellent
enantioselectivities and diastereoselectivites with (Z)-1 were
the two TRIP-based catalysts (TRIP and C8-TRIP) and the
two doubly axially chiral catalysts (2i and PhDAP). No other
was able to achieve > 50% ee and in many cases diaster-
eoselectivies were modest. This similarity is especially intri-
guing considering the fundamentally different architectures
of these two classes of catalyst. We were able to obtain an X-
ray crystal structure of PhDAP and overlaid this with that of
TRIP (Figure 1). It can be seen that the two catalysts map
10
11
80 (90)
[a] Determined by 19F NMR analysis of crude reaction mixture. [b] Yields
of isolated product. [c] Determined by chiral HPLC. Relative and absolute
configuration of 17 determined by X-ray crystallography. All other
products assigned by analogy. [d] Na2CO3·H2O was used instead of
Na2CO3.
generally failed to give > 50% ee on the parent aldehy-
de.[3k,l,18] Fluorination of (E)-28 under our conditions, rather
than giving a single diastereomer as with secondary enamides,
instead gave a pair of readily separable diastereomers, syn-29
and anti-29, in an approximately 1:1 ratio (Scheme 2a). While
syn-29 had low ee (17%), anti-29 was formed with exquisite
selectivity (> 99% ee). We propose that the outcome is
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Keywords: Brønsted acid catalysis · enantioselectivity ·
.
fluorination · phase-transfer catalysis · phosphoric acids
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Figure 1. Overlay of X-ray crystal structures of TRIP (cyan) and PhDAP
(blue).
remarkably closely onto one another, providing a compelling
explanation for the observed similarities. Given the large
number of enantioselective transformations reported over the
last decade for which TRIP has been successfully employed, it
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asymmetric catalysis. Recent elegant progress has been
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In summary, we have developed an enantioselective
tandem oxyflourination of enamides, taking advantage of
the ability of a chiral phosphoric acid catalyst to control both
fluorination, through our chiral anion phase-transfer strategy,
as well as addition to the resulting imine, most likely through
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Received: July 8, 2012
Published online: && &&, &&&&
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Communications
Enantioselective Fluorination
T. Honjo, R. J. Phipps, V. Rauniyar,
F. D. Toste*
&&&& — &&&&
A Doubly Axially Chiral Phosphoric Acid
Catalyst for the Asymmetric Tandem
Oxyfluorination of Enamides
Double agent: Enantioselective tandem
oxyfluorination of enamides using
a doubly axially chiral phosphoric acid
catalyst is reported. The chiral phosphoric
acid catalyst controls both a fluorination
step, using a chiral anion phase-transfer
strategy, and addition to the resulting
imine under the guise of Brønsted acid
catalysis.
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