Enantioselective Suzuki cross-couplings of unactivated 1-fluoro-1-haloalkanes: Synthesis of chiral β-, γ-, δ-, and ε-fluoroalkanes

Article abstract of DOI:10.1021/jacs.5b00473

The incorporation of fluorine atom into a stereogenic center is a highly challenging transformation with current methodologies offering access mainly to chiral α- and β-fluoroalkanes. In this article, the development of a novel general approach to constru

Full text of DOI:10.1021/jacs.5b00473

Article
pubs.acs.org/JACS
Enantioselective Suzuki Cross-Couplings of Unactivated 1‑Fluoro-1-
haloalkanes: Synthesis of Chiral β‑, γ‑, δ‑, and ε‑Fluoroalkanes
Xiaojian Jiang and Mark Gandelman*
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
S
* Supporting Information
ABSTRACT: The incorporation of fluorine atom into a stereo-
genic center is a highly challenging transformation with current
methodologies offering access mainly to chiral α- and β-
fluoroalkanes. In this article, the development of a novel general
approach to construct β-, γ-, δ-, and ε- fluoroalkanes with good
enantioselectivity is described. Different directing groups, such as
benzyl, ketone, and sulfonyl, were shown to give good
enantioselectivity under Suzuki cross-coupling conditions in the
presence of a Ni catalyst and chiral diamine ligand. It includes the
first examples of enantioselective synthesis of chiral fluorine-
containing centers at as distant as δ or ε positions from the
functional groups.
Scheme 1. Synthesis of Secondary Fluoroalkanes via Suzuki
Cross-Coupling of 1-Fluoro-1-haloalkanes
INTRODUCTION
■
Organic compounds bearing fluorine substituents have found
wide and important applications in medicinal, pharmaceutical,
and agricultural chemistries.1,2 Therefore, selective fluorination
of organic molecules has rapidly become a field of great
synthetic interest. Despite the existence of a number of
synthetic strategies for the preparation of fluoroorganic
compounds,3 the enantioselective construction of stereogenic
centers bearing a fluorine substituent remains a challenging task
in organic chemistry. Most of the advances have been described
for the enantioselective fluorination of the position α to a
carbonyl or other functional group (i.e., phenyl, alkene,
enamine, hydroxyl).4−10 Reports describing enantioselective
generation of chiral F-containing centers at nonactivated more
distant positions are extremely rare.11 To the best of our
knowledge, no general efficient approach has been discovered
for the formation of enantioenriched CHF-bearing stereo-
centers at the selected β, γ, δ, or even ε positions.
Recently, we developed an efficient and straightforward
synthesis of geminal dihaloalkanes from carboxylic acids and
initiated an active program on studies of these polyfunctional
compounds in cross-coupling reactions.12,13 Thus, we discov-
ered that 1-halo-1-fluoroalkanes are suitable electrophiles for
selective and facile Suzuki cross-coupling reactions to produce
secondary fluoroalkanes in excellent yields13 (Scheme 1a). This
approach allows for selective installation of the fluorine
substituent in a distant, unactivated position of the alkane
chain. Importantly, we demonstrated the feasibility of extending
this method to its asymmetric version once a suitable chiral
catalyst is identified. We demonstrated that the racemic mixture
of 1-bromo-1-fluoroalkanes bearing a sulfonamide moiety
(Scheme 1b) can be converted to enantiomerically enriched
alkyl fluorides upon stereoconvergent Suzuki cross-coupling.
Employment of a Ni salt and chiral ligand 3a provided high
enantioselectivity, albeit with modest yields.
Herein, we disclose our extended, comprehensive studies on
enantioselective synthesis of nonactivated secondary fluoroal-
kanes by alkyl−alkyl Suzuki cross-couplings of geminal 1-halo-
1-fluoroalkanes. We demonstrate that racemic 1-halo-1-
fluoroalkanes bearing phenyl, keto, or sulfonamide substituents
(as the directing groups) at various distant positions can
efficiently participate in stereoconvergent enantioselective
Suzuki reactions with alkylboranes. It establishes, for the first
time, a universal efficient method for enantioselective
construction of linear secondary fluoroalkanes bearing an F-
containing stereocenter at β, γ, δ, and even ε positions from the
functional group. The same chiral ligand (3a), which has been
identified by us as an effective ligand for this type of reaction,
Received: October 15, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
provides chiral recognition to the wide scope of substrates.14
Interestingly, employing haloalkanes wherein a keto directing
group is responsible for ensuring an enantioselective cross-
coupling has not previously been demonstrated. In addition,
asymmetric cross-coupling reactions of alkyl halides bearing the
directing groups at as distant as δ or even ε positions from the
reaction center, as well as incorporation of a chiral CHF center
at such distant positions, are largely unprecedented.15
bromo(fluoro)alkane substrates; all of them provided low
enantioselectivity in the tested reaction (entries 12−17). After
examination of different amine ligands, we were gratified to
discover that employing (R,R)-2,2′-bispyrrolidine (ligand 3a) in
the presence of NiCl2·glyme leads to formation of fluoroalkane
4a in 76% isolated yield and 99% ee (entry 1). Any
modifications of these reaction conditions led to deteriorated
results. Thus, essentially no coupling product was obtained
when the Ni salt, ligand, or i-BuOH is absent (entries 2−4).
NiCl2·glyme performs somewhat better compared to NiBr2·
diglyme under the optimized conditions (compare entries 1
and 5). Replacement of isobutanol with n-hexanol leads to
lower enantioselectivity (entry 6). Carrying out the reaction at
elevated temperature reduces both yield and ee (entry 7).
Lower loadings of Ni salt and ligand provide inferior results
(entry 8). Isopropyl ether proved superior in comparison to
other examined solvents (entries 9−11).
RESULTS AND DISCUSSION
■
Recently, Fu et al. reported the first asymmetric Suzuki cross-
coupling of unactivated secondary alkyl halides with organo-
boranes.15,16 In this seminal work, it was demonstrated that a
functional group (e.g., phenyl, aniline, amide, carbamate,
sulfonamide), usually located in the β or γ position from the
reaction center of electrophiles, is necessary for ensuring good
enantioselectivity, most likely due to a weak secondary
interaction with the catalyst.
Having these optimized conditions in hand, we explored
numerous 1-bromo-1-fluoro-2-arylethanes in this reaction
(Table 2). When the aryl group is a nonsubstituted phenyl or
On the basis of these findings, we first investigated an
enantioselective cross-coupling reaction of 1-bromo-1-fluoro-2-
arylethanes with alkylboranes in order to generate fluoroalkanes
bearing chiral F-containing centers β to the aryl unit. A
representative example, cross-coupling of bromo(fluoro)alkane
1a with alkyl-9-BBN 2a, and its optimization studies are shown
in Table 1. Most strikingly, we found that chiral ligands 3c and
3d, previously utilized in efficient enantioselective alkyl−alkyl
Suzuki reaction of secondary alkyl halides,16 as well as their
structural analogs 3e−g proved inappropriate for geminal
Table 2. Scope of 1-Bromo-1-fluoroalkane Substrates
Bearing Benzylic Directing Group
b
entry
R
product
yield, ee (%)
1
Ph
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
79, 99
72, 90
67, 98
73, 50
66, 85
71, 62
68, 75
69, 67
80, 57
66, 61
67, 44
2
2-naphthyl
3-OMe-C6H4
4-OMe-C6H4
4-CF3-C6H4
2-F-C6H4
Table 1. Optimization of Conditions for Enantioselective
Cross-Coupling of 1-Bromo-1-fluoro-2-arylethane
3
4
5
6
7
3-F-C6H4
1g
1h
1i
4g
4h
4i
8
4-F-C6H4
2-Me-C6H4
3-Me-C6H4
Bn
9
10
11
1j
4j
1k
4k
a
Reactions were conducted with 1 (0.3 mmol), 2b (0.6 mmol), Ni salt
(0.03 mmol), 3a (0.036 mmol), KOt-Bu (0.42 mmol), and i-BuOH
b
(0.6 mmol) in i-Pr2O (6 mL). Yields are isolated yields after
chromatography.
naphthyl ring highly enantioenriched products are obtained
(entries 1 and 2). Interestingly, substitution of the phenyl ring
in substrates 1 at the meta position with electronically different
groups provides homobenzylic fluorides in good to excellent
enantioselectivity (entries 3 and 7). However, the asymmetric
induction for the corresponding para-substituted substrates is
more variable (entries 4, 5, and 8).
An additional methylene group between the phenyl unit and
the reaction center substantially decreases the ee value to 44%
(substrate 1k, entry 11), supporting the hypothetical
importance of a secondary interaction between the catalyst
and the CH2Ar substituent for high enantiodiscrimination.16a
We also examined the scope of this asymmetric cross-
coupling of 1-bromo-1-fluoro-2-arylethane with respect to the
nucleophile. As illustrated in Table 3, the broad range of 9-
BBN-based alkyl nucleophiles bearing structural motifs such as
aryls (with both electron-donating and -withdrawing sub-
stituents), heterocycles, ethers, and amines are compatible with
a
Reactions were carried out with substrate 1a (0.1 mmol), 9-BBN
partner 2a (0.2 mmol), Ni salt (0.12 mmol), ligand 3a (0.16 mmol),
KOt-Bu (0.14 mmol), and i-BuOH (0.2 mmol) in i-Pr2O (2 mL).
b
Yields are isolated yields after chromatography.
B
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 3. Scope of Alkyl 9-BBN Coupling Partners
propyl ketone 8 with alkyl-9-BBN results in enantioenriched δ-
fluoroketones 10 possessing stereogenic CHF center (Table 4).
Table 4. Enantioselective Suzuki Cross-Coupling of 1-
Bromo-1-fluoroalkanes Bearing Ketone as a Directing Group
a
Reactions were conducted with 1 (0.3 mmol), 2 (0.6 mmol), Ni salt
(0.03 mmol), 3a (0.036 mmol), KOt-Bu (0.42 mmol), and i-BuOH
b
(0.6 mmol) in i-Pr2O (6 mL). Yields are isolated yields after
chromatography.
this asymmetric cross-coupling and furnish the desired chiral
fluoroalkanes in generally good yields and enantioselectivities
(on average, 70% ee).
a
Reactions were carried out with substrate 8 or 9 (0.2 mmol), 9-BBN
In order to conceptually expand the substrate scope of the
germinal bromo(fluoro)alkane electrophiles, we sought addi-
tional functional elements that might serve as potential
directing groups for enantioselective recognition. We selected
a keto group as this motif is ubiquitous in valuable organic
compounds or, alternatively, can be converted to a wide variety
of other functionalities. Notably, while the carbonyl-containing
functional groups amide and carbamate have been used as
directing groups in the Suzuki reaction of secondary alkyl
halides to generate all-carbon tertiary chiral centers,16c
employing ketone functionality is yet unreported in stereo-
convergent alkyl−alkyl couplings.
Interestingly, when 1-bromo-1-fluoro-3-phenylpropyl ketone
5 was subjected to the standard coupling reaction, no desired γ-
fluoroketone 7 was observed. Instead, an intramolecular 6-
membered cyclization took place to furnish a C−H-function-
alized fluorinated product 6 in high yield, albeit as a racemic
mixture (eq 1). This interesting reaction is being investigated,
and the results will be reported elsewhere.
partner 2 (0.4 mmol), Ni salt (0.24 mmol), ligand 3a (0.32 mmol),
KOt-Bu (0.28 mmol), and i-BuOH (0.4 mmol) in i-Pr2O (4 mmol).
Yields are isolated yields after chromatography.
b
We used the same catalyst system (NiCl2/ligand 3a) and
reaction conditions that were developed for homobenzylic
electrophiles 1. The process is sensitive to the stereoelectronic
parameters of the nucleophilic alkyl moiety: while some alkyl 9-
BBN lead to high ee values (79−99% ee, examples 10a, 10d,
10e, and 10f), others give moderately enantioenriched products
(10b, 10c, 10g, and 10h).
Remarkably, the keto group can be located even five carbons
away from the reaction center, and chiral recognition still
occurs. Thus, we were pleased to find that ε-bromo(fluoro)-
ketones 9 can undergo asymmetric Suzuki coupling under our
standard conditions to give a chiral ε-fluoroketone with
moderate to excellent enantioselectivity (Table 4, 11a−d).
Examples of alkyl electrophiles bearing a directing group at a
distance of four or five carbons away from the reaction center
and which are nevertheless able to deliver an appreciable
enantiodiscrimination in cross-coupling reactions are largely
Gratifyingly, introducing one more methylene unit between
the carbonyl group and the reaction center gave the desired
results, namely, cross-coupling of 1-bromo-1-fluoro-4-phenyl-
C
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
unreported. Most importantly, enantioselective installation of
the fluorine substituent at such distant positions from any
functional group to result in chiral δ- and ε-fluoroalkanes, to the
best of our knowledge, is unprecedented.
The optimized conditions proved general for the synthesis of
a wide variety of chiral γ-fluoroalkanes bearing a sulfonamide
moiety in high enantioselectivity, albeit with moderate yield
(Table 6). The reaction tolerates varied substitutions of both
Our further investigations focused on introduction of a
sulfonamide directing group to the geminal bromo(fluoro)-
alkane substrates for stereoconvergent Suzuki coupling. Since
sulfonamides are a potent structural motif for development of
antibacterial,17 antitumor,18 and anti-HIV19 agents, the
resulting selectively fluorinated chiral sulfonamides could be
of significant interest to biomedicinal research. When 1-bromo-
1-fluoro-3-sulfonamide 12a was subjected to the coupling
reaction with alkylborane 2a under similar conditions that were
developed for aforementioned geminal dihaloelectrophiles (1,
8, and 9) the desired γ-fluoroalkane 13a was obtained in 27%
yield and 79% ee. Optimization studies slightly improved the
outcome of this process (Table 5). The most striking
Table 6. Scope of Cross-Coupling Reaction of 1-Bromo-1-
fluoroalkanes Bearing Sulfonamide Directing Group
Table 5. Enantioselective Suzuki Cross-Coupling of 1-
Bromo-1-fluoroalkanes Bearing Sulfonamide Directing
Group
yield
a
b
entry
variation from the “optimized conditions-1”
(%)
ee (%)
83
1
none
35
2
no NiBr2·diglyme
no ligand 3a
trace
trace
trace
27
3
4
no i-BuOH
5
NiCl2·glyme instead of NiBr2·diglyme
n-hexanol instead of i-BuOH
45 °C instead of room temperature
10 mol % NiBr2·diglyme, 12 mol % ligand 3a
PhMe instead of i-Pr2O
dioxane instead of i-Pr2O
hexane/Et2O instead of i-Pr2O
3b instead of 3a
79
78
6
24
7
trace
22
8
80
9
30
73
10
11
12
13
14
15
16
17
19
58
30
80
16
36
3c instead of 3a
67
−45
−31
−41
−46
−21
3d instead of 3a
68
a
Reactions were carried out with substrate 12 (0.2 mmol), 9-BBN
3e instead of 3a
64
partner 2 (0.4 mmol), Ni salt (0.24 mmol), ligand 3a (0.32 mmol),
KOt-Bu (0.28 mmol), and i-BuOH (0.4 mmol) in i-Pr2O (4 mL).
3f instead of 3a
61
b
3g instead of 3a
69
Yields are isolated yields after chromatography.
a
Reactions were carried out with substrate 12a (0.1 mmol), 9-BBN
partner 2 (0.2 m mol), Ni salt (0.12 mmol), ligand 3a (0.16 mmol),
KOt-Bu (0.14 mmol), and i-BuOH (0.2 mmol) in i- Pr2O (2 mL).
Yields are isolated yields after chromatography.
the N-aryl and the N-sulfonyl moieties of the amine group in
the racemic electrophile 12 as well as a variety of alkyl-9-BBN
nucleophiles to provide product 13 with generally high ee
values (up to 91% ee).
b
conclusions from these optimization studies are (a) NiBr2·
diglyme outperforms NiCl2·diglyme for this type of electro-
phile, providing 13a in 35% yield and 83% ee (entry 1), and (b)
ligand 3a proved superior also for sulfonamide-decorated
geminal bromo(fluoro)alkanes; although other tested secon-
dary diamine ligands 3b−g can substantially improve yield, they
provide the product with low enantioselectivity (entries 12−
17). As anticipated, in the absence of Ni salt, ligand 3a, or i-
BuOH the coupling product is not formed (entries 2−4). In
addition, performing the reaction at elevated temperature
resulted in only trace amounts of 13a (entry 7).
We found that the unreacted substrate 12 (recovered after
reaction) is racemic. It rules out a kinetic resolution
mechanism, although the yields are below 50%. The moderate
yield in the stereoconvergent C−C coupling of 12 with 2 could
conceivably be the result of a relatively strong interaction
between the catalyst and the sulfonamide moiety, which inhibits
the catalytic cycle. Further ligand modifications are apparently
required in order to improve the yield of this particular
reaction.
It should be mentioned that racemic 1-iodo-1-fluoro-alkanes
and 1-chloro-1-fluoroalkanes bearing phenyl, ketone, or
D
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
sulfonamide directing groups can also be employed in the
developed asymmetric Suzuki reaction to produce the
corresponding chiral secondary fluoroalkanes with good ee;
however, the analogous 1-bromo-1-fluoroalkanes gave better
results in terms of yield and enantioselectivity under the same
conditions (eqs 2−4). We presume that the inferior results
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*chmark@tx.technion.ac.il
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the German-Israeli Project Cooperation
(DIP) and KAMIN program of the Industry, Trade and Lab-
our Ministry is acknowledged. We thank Dr. Natalia Fridman
(Technion) and Dr. Linda J. W. Shimon (Weizmann Institute
of Science) for X-ray crystallography analysis.
REFERENCES
■
(1) (a) In Modern Fluoroorganic Chemistry; Kirsch, P., Ed.; Wiley-
VCH: Weinheim, 2004. (b) In Organofluorine Compounds; Hiyama,
T., Ed.; Springer: Berlin, 2000. (c) O’Hagan, D. Chem. Soc. Rev. 2008,
37, 308.
(2) For some examples, see: (a) Muller, K.; Faeh, C.; Diederich, F.
̈
Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) In Fluorine in
Pharmaceutical and Medicinal Chemistry; Gouverneur, V., Muller, K.,
̈
Eds.; Imperial College Press: London, 2012.
(3) (a) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug
Discovery Dev. 2008, 11, 803. (b) Hollingworth, C.; Gouverneur, V.
Chem. Commun. 2012, 48, 2929. (c) In Efficient preparation of fluorine
compounds; Roesky, H. W., Ed.; John Wiley & Sons: Hoboken, NJ,
2013. (d) For recent progress in aromatic fluorination, see: Watson,
D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel,
T.; Buchwald, S. L. Science 2009, 325, 1661. (e) Furuya, T.; Klein, J. E.
M. N.; Ritter, T. Synthesis 2010, 1804. (f) Guo, C.; Wang, R.-W.; Guo,
Y.; Qing, F.-L. J. Fluorine Chem. 2012, 133, 86. (g) Guo, Y.; Tao, G.-H;
Blumenfeld, A.; Shreeve, J. M. Organometallics 2010, 29, 1818.
(h) Wang, W.; Jasinski, J.; Hammond, G. B.; Xu, B. Angew. Chem., Int.
Ed. 2010, 49, 7247. (i) Zhang, W.; Hu, J. Adv. Synth. Catal. 2010, 352,
2799.
(4) Reviews: (a) Gouverneur, V.; Lozano, O. In Science of Synthesis;
De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Georg Thieme:
Stuttgart, Germany, 2011; Vol. 3, p 851. (b) Cahard, D.; Xu, X.;
Couve-Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev. 2010, 39, 558.
(c) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013,
52, 8214. (d) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth.
observed for 1-iodo-1-fluoroalkanes, compared to their 1-
bromo-1-fluoro counterparts, may be due to the comparative
instability of the former. This may lead to release of trace
amounts of iodine in the starting material that partially poisons
the Ni catalyst.13 In the case of the 1-chloro-1-fluoroalkanes,
the difficulty of cleaving the stronger C−Cl bond may account
for the slightly poorer results.
CONCLUSIONS
■
We established a novel general method for efficient catalytic
preparation of β-, γ-, δ-, and ε-fluoroalkanes bearing a distant
chiral CHF center at the selected position.20 It includes the first
examples of enantioselective synthesis of chiral fluorine-
containing centers at as distant as δ or ε positions from the
directing functional groups. Our approach is general in a sense
that the generation of a F-bearing stereogenic center at all these
positions implies the same strategy, namely, a stereoconvergent
cross-coupling of the corresponding racemic 1-halo-1-fluoroal-
kanes with alkylboranes. Moreover, the same commercially
available chiral ligand, which was identified by us for the
asymmetric cross-couplings of geminal dihaloalkanes, is used in
all cases. We demonstrated that phenyl, keto (for the first
time), or sulfonamide substituents can be used as directing
groups for chiral recognition in the alkyl−alkyl cross-couplings
to generate unactivated fluoroalkanes with good enantioselec-
tivity. Although our approach opened a door for unprecedented
synthesis of chiral fluoroalkanes with distant chiral CHF
centers, the yield or enantioselectivity is moderate in some
cases. Therefore, further studies on ligand design for the
improvement of both efficiency and substrate scope of this
reaction is underway in our laboratories.
́
Catal. 2010, 352, 2708. (e) Valero, G.; Companyο, X.; Rios, R.
Chem.Eur. J. 2011, 17, 2018.
(5) Examples of α-fluorination of aldehydes: (a) Beeson, T. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. (b) Steiner, D.
D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706.
(c) Marigo, M.; Fidlenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.
(6) Examples of α-fluorination of ketones and amides: (a) Shibata,
N.; Kohno, J.; Takai, K.; Ishimaru, T.; Nakamura, S.; Toru, T.;
Kanemasa, S. Angew. Chem., Int. Ed. 2005, 44, 4204. (b) Nakamura,
M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem., Int. Ed. 2005, 44,
́
́
7248. (c) Belanger, E.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin,
J.-F. J. Am. Chem. Soc. 2007, 129, 1034. (d) Ishimaru, T.; Shibata, N.;
Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 4157. (e) Wu, L.; Falivene, L.; Drinkel, E.;
Grant, S.; Linden, A.; Cavalla, L.; Dorta, R. Angew. Chem., Int. Ed.
2012, 51, 2870. (f) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013,
135, 1268. (g) Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc.
E
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
2014, 136, 5225. (h) Shibatomi, K.; Futatsugi, K.; Kobayashi, F.;
Iwasa, S.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625. (i) Liang,
Y.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 5520. (j) Yang, X.; Phipps,
R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136, 5225. (k) Lee, S. Y.;
Neufeind, S.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 8899.
(7) Examples of α-fluorination of esters, including amides: (a) Reddy,
D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S.
Angew. Chem., Int. Ed. 2008, 47, 164. (b) Hamashima, Y.; Suzuki, T.;
Takano, H.; Shimura, Y.; Soseoka, M. J. Am. Chem. Soc. 2005, 127,
10164. (c) Tengeiji, A.; Shiina, I. Molecules 2012, 17, 7356.
(8) α-Fluorination of enamides: Phipps, R. J.; Hiramatsu, K.; Toste,
F. D. J. Am. Chem. Soc. 2012, 134, 8376.
(9) Fluorination of the α-position to alkene or aryl: (a) Talbot, E. P.
A.; Fernandes, T. A.; Mckenna, J. M.; Toste, F. D. J. Am. Chem. Soc.
2014, 136, 4101. (b) Shunatona, H. P.; Fruh, N.; Wang, Y.-M.;
̈
Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2013, 52, 7724.
(c) Wu, J.; Wang, Y.-M.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.; Toste,
F. D. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 13729. (d) Braun, M.-G.;
Doyle, A. G. J. Am. Chem. Soc. 2013, 135, 12990. (e) Katcher, M. H.;
Sha, A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133, 15902.
(10) Fluorination of the α-position to hydroxyl or amine: (a) Huang,
C.-Y.; Doyle, A. G. J. Am. Chem. Soc. 2012, 134, 9541. (b) Kalow, J. A.;
Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.
(11) (a) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P.
G. J. Am. Chem. Soc. 2007, 129, 4536. (b) Cochrane, N. A.; Nguyen,
H.; Gagne, M. R. J. Am. Chem. Soc. 2013, 135, 628.
(12) Kulbitski, K.; Nisnevich, G.; Gandelman, M. Adv. Synth. Catal.
2011, 353, 1438.
(13) Jiang, X.; Sakthivel, S.; Kulbitski, K.; Nisnevich, G.; Gandelman,
M. J. Am. Chem. Soc. 2014, 136, 9548.
(14) To the best of our knowledge, molecule 3a was not previously
used in asymmetric catalysis as is. For prior utilization of its scaffold in
the derivatives in enantioselective catalysis, see some examples:
(a) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem. 2006, 71,
1523. (b) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
(c) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney,
P.; Bernardinelli, G. Angew. Chem., Int. Ed. 2000, 39, 4093.
(15) To the best of our knowledge, one selected example of δ-
alkylation of secondary alkyl chlorides, namely, the reaction of 5-
chloro-N,N-diphenylhexanamide with (p-anisyl)(CH2)3-9-BBN, is
reported: Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2011, 133,
15362.
(16) Examples of asymmetric alkyl−alkyl Suzuki cross-couplings:
(a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694. (b) Lu, Z.;
Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154. (c) Wilsily, A.;
Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
5794. (d) Cong, H.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 3788.
(17) Example of antibacterial activity: Burns, M. R.; Jenkins, S. A.;
Vermeulen, N. M.; Balakrishna, R.; Nguyen, T. B.; Kimbrell, M. R.;
David, S. A. Bioorg. Med. Chem. Lett. 2006, 16, 6209.
(18) Example of antitumor activity: Tan, C.; Noronha, R.; Devi, N.
S.; Jabbar, A. A.; Kaluz, S.; Liu, Y.; Mooring, S. R.; Nicolaou, K. C.;
Wang, B.; Meir, E. G. V. Bioorg. Med. Chem. Lett. 2011, 21, 5528.
(19) Example of anti-HIV activity: Zhao, X.; Maddali, K.; Smith, S. J.;
́
Metifiot, M.; Johnson, B. C.; Marchand, C.; Hughes, S.; Pommier, Y.;
Burke, T. R., Jr. Bioorg. Med. Chem. Lett. 2012, 22, 7309.
(20) Absolute configuration of these new compounds was
determined by X-ray analysis of (S)-4-fluoro-5-phenyl-N-((R)-1-
phenylethyl)pentanamide (compound D in Supporting Information,
p 26), which was prepared from 4n. CCDC 1040972 contains
supplementary crystallographic data for compound D.
F
DOI: 10.1021/jacs.5b00473
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX