Organocatalytic enantioselective olefin aminofluorination

Article abstract of DOI:10.1021/ol101167z

(Equation Presented). Chiral β-fluoroamines are increasingly prevalent in medicinal compounds, but there are few efficient methods to access them from achiral starting materials. To address this, a multicomponent organocascade reaction was developed in which chiral α-fluoro-β-amino aldehydes were generated in a single flask from achiral α,β-unsaturated aldehydes (2), using catalyst 12a. Conversions up to 85%, drs up to 98:2 and ees up to 99% of the corresponding alcohol (9) were achieved in this reaction.

Full text of DOI:10.1021/ol101167z

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3356-3359
Organocatalytic Enantioselective Olefin
Aminofluorination
Chandrakumar Appayee and Stacey E. Brenner-Moyer*
Department of Chemistry, Brooklyn College and the City UniVersity of New York,
2900 Bedford AVenue, Brooklyn, New York 11210
sbrenner@brooklyn.cuny.edu
Received May 20, 2010
ABSTRACT
Chiral ꢀ-fluoroamines are increasingly prevalent in medicinal compounds, but there are few efficient methods to access them from achiral
starting materials. To address this, a multicomponent organocascade reaction was developed in which chiral r-fluoro-ꢀ-amino aldehydes
were generated in a single flask from achiral r,ꢀ-unsaturated aldehydes (2), using catalyst 12a. Conversions up to 85%, dr’s up to 98:2 and
ee’s up to 99% of the corresponding alcohol (9) were achieved in this reaction.
The incorporation of fluorine into medicinal compounds is
increasingly prevalent with “20-25% of drugs in the
pharmaceutical pipeline contain[ing] at least one fluorine
atom.”1 MK-0731 (1, Figure 1) is one example, developed
by Merck for the treatment of Taxane-refractory cancer.2
More specifically, ꢀ-fluoroamines, as in 1, are increasingly
common substructures in medicinal compounds, because
fluorine can improve the bioavailability of amine drugs by
decreasing the basicity of neighboring amine groups.1
Additionally, R-fluoro-ꢀ-amino acids are useful building
blocks of therapeutic ꢀ-peptides.3 Despite the increasing use
of ꢀ-fluoroamino moieties in medicinal compounds, efficient
synthetic methods for their preparation are sparse. Recently,
Figure 1. MK-0731.
Pd-catalyzed olefin aminofluorination reactions were re-
ported, in which achiral ꢀ-fluoroamines were generated in
a single step.4 ꢀ-Fluoroamines containing a single stereo-
center can be produced using a one-pot organocatalytic
R-fluorination/reductive amination protocol.5 Accessing chiral
ꢀ-fluoroamines with Vicinal stereocenters (as in 1) usually
requires the use of chiral starting materials. We are aware
of only two efficient (i.e., one-pot) methods for preparing
these compounds from achiral starting materials. One is an
asymmetric olefin aminofluorination reaction, in which chiral
ꢀ-fluoroamines are generated from achiral R,ꢀ-unsaturated
esters.6 The asymmetric induction in this method is not
catalytic; stoichiometric quantitites of a chiral amine nu-
cleophile are used. In addition, an organocatalytic Mannich
reaction using R-fluoro-ꢀ-dicarbonyl compounds as nucleo-
philes produced chiral ꢀ-fluoroamines in high yield and
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
ReV. 2008, 37, 320–330.
(2) Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.;
Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.; Walsh, E. S.; Hamilton, K.;
Schaber, M. D.; Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams,
M. T.; South, V. J.; Huber, H. E.; Torrent, M.; Prueksaritanont, T.; Li, C.;
Slaughter, D. E.; Mahan, E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.;
Kohl, N. E.; Hartman, G. D. J. Med. Chem. 2008, 51, 4239–4252.
(3) Seebach, D.; Dubost, E.; Mathad, R. I.; Jaun, B.; Limbach, M.;
Lo¨weneck, M.; Flo¨gel, O.; Gardiner, J.; Capone, S.; Beck, A. K.; Widmer,
H.; Langenegger, D.; Monna, D.; Hoyer, D. HelV. Chim. Acta 2008, 91,
1736–1786.
10.1021/ol101167z  2010 American Chemical Society
Published on Web 06/24/2010

selectivity (dr g92:8).7 However, the dr decreased to 4:1
during subsequent decarboxylation to produce R-fluoro-ꢀ-
amino acid derivatives.7b We supposed that an organocascade
reaction (Scheme 1) would be a highly selective and green
have enamine-catalyzed fluorinations of saturated aldehydes.9
It was anticipated that these two complementary function-
alizations could be combined as an organocatalytic asym-
metric olefin aminofluorination reaction. As such, an achiral
R,ꢀ-unsaturated aldehyde (2) and an iminium catalyst would
combine to form chiral iminium 3. Iminium 3 would undergo
an asymmetric conjugate addition of an amine nucleophile,
liberating saturated aldehyde 4. In the presence of an enamine
catalyst, chiral enamine 5 would be generated. Reaction of
enamine 5 with an electrophilic source of fluorine would
produce chiral ꢀ-fluoroamine 6.
Scheme 1. Proposed One-Pot Organocascade Reaction
The development of a one-pot organocatalytic asymmetric
olefin aminofluorination reaction began using amine nucleophile
8 and N-fluorosulfonimide (NFSI, 7) as an electrophilic source
of fluorine (Table 1). It was anticipated that it would be
necessary to use an iminium organocatalyst in conjunction with
an enamine catalyst,10 as no single organocatalyst had been
reported for both fluorination reactions and aza-Michael addi-
tions of amines of type 8. Investigations began with iminium
catalyst 10, the most selective MacMillan catalyst for the
conjugate addition of amine nucleophiles of type 8 to R,ꢀ-
unsaturated aldehydes.8a Using optimal solvent and temperature
conditions reported for this reaction, the CBZ-protected amine
(8) produced 4a in higher yield and ee than the corresponding
BOC protected amine (entries 1 and 2). Compound 4a was
subsequently fluorinated using catalyst 11 (or ent-11), the most
selective MacMillan catalyst for fluorinations.9b Under a variety
of solvent and temperature conditions, 9a was produced as, at
most, a 1:3 (syn:anti) ratio of diastereomers (entry 3). We
simultaneously discovered that 10 nonselectiVely catalyzed the
chemical method for accessing ꢀ-fluoroamines, including
R-fluoro-ꢀ-amino acid derivatives, containing vicinal ste-
reocenters.
Iminium-catalyzed conjugate additions of amine nucleo-
philes to R,ꢀ-unsaturated aldehydes have been reported,8 as
Table 1. Reaction Developmenta b
,
step 1
step 2
entry 1st cat. solvent t (°C) yield 4a(%) ee 4a(%)c 2nd cat.
solvent
t (°C) convn 9a (%)d dr 9a (syn:anti)c ee 9a (%)c
1e
2
3
4
5
6
7
8
10
10
CHCl3 -20
CHCl3 -20
70
80
80 (S)
84 (S)
11
CHCl3/IPA (9:1) -10
29
1:3
nd
12a
12a
12a
12a
12a
CHCl3 -20
CHCl3 -20
CHCl3 -20
CHCl3 -20
63
94 (R)
ent-11 CHCl3/IPA (9:1) -10
11
11
nd
46
56
59f
1:1
1:3
3:1
nd
nd
nd
99
CHCl3/IPA (9:1) -10
CHCl3/IPA (9:1)
rt
MTBE
rt
MTBE
0
95:5
a Reaction conditions for step 1: 2a (0.125 mmol), 8 (0.15 mmol), 1st cat. (0.025 mmol), solvent (0.5 mL), temp. b Reaction conditions for steps 2 and
3: (2) NFSI (0.125 mmol), 2nd cat. (0.025 mmol), solvent (0.5 mL), cosolvent (0.055 mL), temp; (3) NaBH4 (0.25 mmol), MeOH (1 mL), 0 °C. c Determined
d
by chiral phase HPLC. Determined by H NMR. e BOC-protected amine used. f Isolated yield.
1
Org. Lett., Vol. 12, No. 15, 2010
3357

fluorination step (data not shown). This would preclude the
development of the organocatalytic olefin aminofluorination
reaction as a highly selective one-pot process, as the presence
of 10 during the fluorination step would erode the already
modest selectivity attained using 11.
Extensive optimization12 revealed that modifying the
reaction time and concentration was most effective for
increasing the yield of 9a, which was improved to 73%
(average yield per step ) 90%; Table 2, entry 1). Other R,ꢀ-
Investigations began anew using 12a, the only other orga-
nocatalyst reported for the conjugate addition of amine nucleo-
philes of type 8 to R,ꢀ-unsaturated aldehydes.8b Pleasingly, this
catalyst afforded 4a in the highest ee obtained thus far (entry
4). Although 12a can also participate in enamine catalysis, it
was expected that this catalyst would not interfere in the
subsequent fluorination step. Related catalyst 12b was the only
organocatalyst, aside from 11, reported for highly selective
fluorination reactions of saturated aldehydes.9a Jørgensen and
co-workers ran 12b-catalyzed fluorination reactions in methyl
tert-butyl ether (MTBE), as they noted that 12b was desilylated
and thereby deactivated by NFSI in more polar solvents such
as CH2Cl2.9a It was anticipated that catalyst 12a, being more
nucleophilic than 12b, would be more rapidly deactivated by
NFSI in polar solvents and would therefore not interfere with
11-catalyzed fluorinations in 9:1 CHCl3/iPrOH. When reactions
were set up as one-pot procedures to test this, 9a was once
again produced as, at most, a 1:3 (syn:anti) ratio of diastereo-
mers (entries 5 and 6).
Table 2. Substrate Studya
When the fluorination step was run at a higher temperature,
the selectivity of the cascade process was reversed, and 9a
was generated as a 3:1 (syn:anti) ratio of diastereomers (entry
7). Evidently, and much to our surprise, the syn selectivity
of catalyst 12a was overriding the anti selectivity of catalyst
11 at higher temperatures. We then speculated that the olefin
aminofluorination reaction could be catalyzed solely by 12a,
using MTBE as solvent to maximize the efficacy of 12a in
the fluorination step. Aldehyde 2a, amine 8 and catalyst 12a
were combined in MTBE at rt. After 24 h, the reaction was
cooled to 0 °C and NFSI was added. After workup and
subsequent reduction, chiral ꢀ-fluoroamine 9a was isolated
in 59% yield, in 99% ee, and as a 95:5 (syn:anti) ratio of
diastereomers (entry 8).
This is, in fact, the highest dr achieved in 12-catalyzed
organocascade reactions in which multiple carbon-heteroatom
bonds are formed; dr’s in a 12a-catalyzed aminosulfenylation
reaction ranged from 1:1 to 3:1 and those in a 12b-catalyzed
diamination reaction were 3:1 and 4:1.8c,11 Furthermore, this
is the first demonstration of the use of catalyst 12a in a
fluorination reaction.
(4) (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354–
16355. (b) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2010, 132, 2856–2857.
(5) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 943–946.
(6) Andrews, P. C.; Bhaskar, V.; Bromfield, K. M.; Dodd, A. M.;
Duggan, P. J.; Duggan, S. A. M.; McCarthy, T. D. Synlett 2004, 791–794.
(7) (a) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem., Int. Ed. 2009, 48, 7604–7607. (b) Pan, Y.; Zhao, Y.; Ma, T.; Yang,
Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem.sEur. J. 2010, 16, 779–782.
(8) (a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 9328–9329. (b) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao,
G.-L.; Xu, Y.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 2193–2198. (c)
Jiang, H.; Nielsen, J. B.; Nielsen, M.; Jørgensen, K. A. Chem.sEur. J.
2007, 13, 9068–9075. (d) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 1983–1987. (e) Lin, Q.; Meloni,
D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf,
B.; Yue, T.-Y.; Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999–2002.
a Reaction conditions: (1) (a) 2 (0.125 mmol), 8 (0.15 mmol), 12a (0.025
mmol), MTBE (0.625 M), rt, 24-48 h; (b) NFSI (0.125 mmol), MTBE
(0.25M), 0 °C, 40-72 h. (2) NaBH4 (0.25 mmol), MeOH (1 mL), 0 °C.
b Determined by 1H NMR. c Numbers in parentheses are isolated yields.
d Determined by chiral phase HPLC.
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Org. Lett., Vol. 12, No. 15, 2010

unsaturated aldehydes with linear alkyl substituents were
effective in this reaction (entries 2 and 3). Branched alkyl
substituents resulted in slightly reduced conversions but
maintained the high selectivity of this process (entries 4 and
5). Even R,ꢀ-unsaturated aldehydes with very bulky alkyl
substituents underwent this transformation, albeit in low
conversion and reduced ee (entry 6). Importantly, the
presence of other olefins, ether protecting groups, and remote
reactive functional groups, such as cyano groups, is tolerated
(entries 7-9). A cinnamaldehyde derivative was unreactive
under the reaction conditions.
Notably, crude aldehyde products can be converted into
chiral R-fluoro-ꢀ-amino acid derivatives with virtually no
loss of selectiVity (Scheme 2). Conversion of 4e to a known
compound and comparison of its optical rotation to the
literature value established the stereochemistry of 4e (and
of the corresponding stereocenter in 9 and 13) as R.12 The
relative stereochemistry of 13 (and by analogy 9) was
assigned as threo on the basis of the chemical shift of its R
proton relative to that of the minor diastereomer.12
Scheme 2. R-Fluoro-ꢀ-amino Acid Derivative
conversion, 99% ee and 98:2 dr. Significantly, this method-
ology enables the rapid access of chiral R-fluoro-ꢀ-amino
acids in outstanding dr and ee, from simple achiral starting
materials. Further investigations into this organocascade
reaction, including its synthetic applications, are presently
underway.
Acknowledgment. This work was supported by a grant
from the National Institutes of Health (1SC2GM082360).
The authors gratefully acknowledge Dr. Cliff Soll (City
University of New York at Hunter College) for assistance
with high-resolution mass spectrometry. The authors also
wish to thank Prof. Gary Molander (University of Pennsyl-
vania) and Dr. Cindy Kan (Memorial Sloan Kettering Cancer
Center) for thoughtful discussions.
In conclusion, an organocatalytic asymmetric olefin ami-
nofluorination reaction has been developed. This reaction
generates chiral R-fluoro-ꢀ-amino aldehydes in a single flask
from achiral R,ꢀ-unsaturated aldehydes in up to 85%
(9) (a) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703–3706. (b) Beeson,
T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826–8828.
(10) Known as cycle-specific cascade reactions. See: (a) Simmons, B.;
Walji, A. B.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349–
4353. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051–15053.
Supporting Information Available: General experimental
conditions and full characterization data for compounds 2i,
9a-9i, and 13. This material is available free of charge via
the Internet at http://pubs.acs.org.
(11) Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Co´rdova, A. Angew.
Chem., Int. Ed. 2008, 47, 8468–8472.
(12) See Supporting Information
OL101167Z
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