Iridium-Catalyzed Enantioselective Fluorination of Racemic, Secondary Allylic Trichloroacetimidates

Article abstract of DOI:10.1021/jacs.5b07492

The Ir-catalyzed enantioselective fluorination of racemic, branched allylic trichloroacetimidates with Et₃N·3HF is a mild and efficient route for selective incorporation of fluoride ion into allylic systems. We herein describe the asymmetric fluorination of racemic, secondary allylic electrophiles with Et₃N·3HF using a chiral-diene-ligated Ir complex. The methodology enables the formation of acyclic fluorine-containing compounds in good yields with excellent levels of asymmetric induction and overcomes the limitations previously associated with the enantioselective construction of secondary allylic fluorides bearing α-linear substituents.

Full text of DOI:10.1021/jacs.5b07492

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Communication
Iridium-Catalyzed Enantioselective Fluorination of
Racemic, Secondary Allylic Trichloroacetimidates
Qi Zhang, David P Stockdale, Jason C. Mixdorf, Joseph J. Topczewski, and Hien M. Nguyen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07492 • Publication Date (Web): 08 Sep 2015
Downloaded from http://pubs.acs.org on September 8, 2015
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Iridium-Catalyzed Enantioselective Fluorination of Racemic,
Secondary Allylic Trichloroacetimidates
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Qi Zhang, David P. Stockdale, Jason C. Mixdorf, Joseph J. Topczewski, and Hien M. Nguyen*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
aration of allylic fluorides from branched allylic trichloroaceꢀ
ABSTRACT: The iridiumꢀcatalyzed enantioselective fluoriꢀ
.
13
timidates with Et N 3HF. Given the paucity of enantioselecꢀ
3
nation of racemic, branched allylic trichloroacetimidates with
tive allylic fluorination reports via transitionꢀmetal catalyꢀ
.
Et N 3HF is a mild and efficient route for selective incorporaꢀ
14,15
3
sis,
we saw an opportunity to demonstrate the utility of our
tion of fluoride ion into allylic systems. We herein describe
catalytic system toward this end. Here, we describe the enantiꢀ
the asymmetric fluorination of racemic, secondary allylic elecꢀ
oselective fluorination of racemic, secondary allylic trichloroꢀ
.
trophiles with Et N 3HF using a chiral dieneꢀligated iridium
.
3
acetimidates with Et N 3HF using a chiral dieneꢀligated iridiꢀ
3
complex. The methodology allows for the formation of acyclic
fluorineꢀcontaining compounds in good yields with excellent
levels of asymmetric induction and overcomes the limitations
previously associated with the enantioselective construction of
secondary allylic fluorides bearing αꢀlinear substituents.
um complex (Figure 1b) to produce allylic fluorides in good
yields with excellent asymmetric induction. This process overꢀ
comes the challenges associated with the synthesis of secondꢀ
ary allylic fluorides possessing αꢀlinear substituents.
The varied roles that fluorineꢀcontaining compounds play in
pharmaceuticals, agricultural chemicals, and medical imaging
have made syntheses of this class of molecules a major focus
1
in recent years. As a result, methods that allow the selective
formation of the allylic carbonꢀfluorine bond are highly desirꢀ
2
able. Traditionally, allylic fluorides were prepared via nucleoꢀ
philic substitution of allylic alcohols with diethylaminosulfur
3
trifluoride (DAST). Gaining complete regioꢀ and stereoconꢀ
trol has been a challenging problem associated with DASTꢀ
mediated reactions, which typically rely on sterically and elecꢀ
tronically biased substrates to facilitate siteꢀselective fluorinaꢀ
4
tion. An evolving approach is the utilization of transition
5
metals to catalyze nucleophilic substitution in allylic systems;
however, incorporation of fluorine into allylic systems by CꢀF
bond formation via transition metal catalysis has proven diffiꢀ
Figure 1. Transitionꢀmetalꢀcatalyzed enantioselective syntheꢀ
sis of secondary allylic fluorides bearing αꢀlinear substituents.
6
cult. The ability of allylic fluoride to act as an efficient leavꢀ
7
ing group in transitionꢀmetal catalysis has also been reported.
Nevertheless, several examples of transitionꢀmetal catalyzed
By utilizing the unique features of the trichloroacetimidate
as the directing and leaving group at the allylic carbon, we
have developed a new program directed toward dynamic kinetꢀ
ic asymmetric transformations (DYKAT) of racemic, branched
allylic substrates with anilines. This DYKAT strategy allows
the enantioselective preparation of nitrogenꢀcontaining tertiary
and quaternary carbon centers. We hypothesized that a simiꢀ
lar strategy could facilitate the iridiumꢀcatalyzed enantioselecꢀ
tive fluorination. However, we anticipated some challenges
8
nucleophilic fluorination of allylic electrophiles and analoꢀ
9
ꢀ12
gous reactions have been reported.
In 2010, Katcher and Doyle reported the first palladiumꢀ
catalyzed enantioselective fluorination of cyclic allylic chloꢀ
8a
rides with AgF. In 2011, Doyle and coworkers extended this
work to the transformations of acyclic, allylic chlorides. Excelꢀ
lent asymmetric induction (90 – 97% ee) were attained with αꢀ
branching or oxygenꢀsubstituted allylic chlorides using the
16
8b
commercially available Trost naphthyl ligand L1 (Figure 1a).
associated with DYKAT of racemic allylic trichloroacetimiꢀ
.
In contrast, the authors found that substrates possessing αꢀ
linear substituents provided low to moderate enantioselectivity
dates with Et N 3HF. While the DYKAT process could lead to
3
productive fluorination, it might only provide the allylic fluoꢀ
8
b
(21– 71% ee) of acyclic, secondary allylic fluorides (Figure
ride products with moderate to low enantioselectivity. To
obtain high levels of asymmetric induction, equilibration of
the two possible πꢀallyl iridium complexes must be rapid and
1
a). Nevertheless, Doyle’s work provides the foundation for
the development of new allylic substrates and catalyst systems
to overcome the current limitations. Our group recently introꢀ
duced a new method for the highꢀyielding regioselective prepꢀ
17ꢀ19
faster than fluoride attack.
Employing a chiral dieneꢀ
ligated iridium complex would create a more sterically enꢀ
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cumbered environment, which decreases the rate of the fluoꢀ
ride attack and increases the time allowed for interconversion
mol% [IrCl(L6)] complex (entry 5) significantly improved the
2
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ee value of allylic fluoride 2 (66 → 79% ee). Use of fewer
.
1
8,19
between these two πꢀallyl iridium complexes.
Thus, judiꢀ
equivalents of Et N 3HF further increased ee value of 2 (entry
3
cious selection of the chiral diene ligand could circumvent the
issues associated with the enantioselective synthesis of acyꢀ
clic, secondary allylic fluorides bearing αꢀlinear substituents.
_________________________________________________
6). Varying the solvent (entries 7–10) did not have a proꢀ
nounced effect on the reaction outcome, although MTBE (enꢀ
try 10) was found to increase the enantioselectivity (84% →
88% ee) of the fluoride product 2. Iridium complex bearing 4ꢀ
fluorophenyl derivative ligand L2 (see Figure 2 for Xꢀray crysꢀ
a
Table 1. Optimization of Enantioselective Fluorination
24
tallographic structure of [IrCl(L2)]2) was superior to the L6ꢀ
iridium complex in terms of both enantioselectivity and conꢀ
version (entry 12), and allylic fluoride 2 was observed in 99%
NMR yield after 1 h with 93% ee and >20:1 branched:linear
selectivity. This result is consistent with our previous report
for the rhodiumꢀcatalyzed DYKAT of racemic tertiary allylic
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16a
substrates with anilines.
_
________________________________________________
Figure 2. ORTEP Diagram of [IrCl(L2)] Catalyst
2
_________________________________________________
Next, the optimized fluorination conditions were applied to
a number of trichloroacetimidate substrates (Table 2). Gratifyꢀ
ingly, the reaction tolerates a range of functional groups. For
instance, allylic imidates 1 and 3–6, bearing both electronꢀrich
a
The dieneꢀligated iridium complex was generated in situ from
the reaction of 2.5 mol% [IrCl(coe) ] and 5 mol% ligands (L3
2
2
b
– L6). 2.5 mol% [IrCl(L )] (L6 or L2) catalyst was used in
the reaction. Determined by F NMR analysis using PhCF3
as an internal standard. Determined by chiral HPLC.
n
2
c
19
and electronꢀwithdrawing βꢀoxygen substituents, reacted rapꢀ
.
d
idly with Et N 3HF to provide allylic fluorides 2 and 14–17
3
(entries 1–5) in good yields (61–82%) with excellent levels of
enantioselectivity (92–97% ee). The mild conditions are also
tolerant of the silyl ether group (entry 3) to provide fluoride 15
in 70% and with 97% ee. The result obtained with bulky silyl
substrate 4 (entry 3) is consistent with what has been observed
We previously established that the regioselective fluorinaꢀ
1
3
tion reactions work best with [IrCl(cod)] catalyst. Therefore,
2
chelating chiral diene ligands with iridium catalyst would likeꢀ
ly allow for the development of an enantioselective variant.
We examined several diene ligands in our initial studies (Taꢀ
8b
by Doyle and coworkers wherein higher asymmetric inducꢀ
tion was observed in substrates with greater steric hindrance.
The ability to introduce the azide and alkyne functional groups
at the βꢀposition provides significant flexibility with our apꢀ
proach. For example, the azide and alkyne substrates 7 and 8
(entries 6 and 7) proceeded with excellent enantioselectivity
(90 – 97% ee) and offered the functionality for subsequent use
2
0
21a
21b
ble 1). Although Hayashi ligands L3 and L4 (entries 1
22
and 2) and Carreira ligand L5 (entry 3) were able to promote
the fluorination, the yield and enantioselectivity were low.
However, excellent regioselectivity (>20:1 branched:linear)
was observed in the formation of the fluoride product 2 after
25
in bioorthogonal conjugation. The nitrogenꢀcontaining subꢀ
strate phathamide 9 (entry 8) also imparted good enantioinducꢀ
tion (82% ee) in the production of allylic fluoride 20. This
method is not limited to allylic imidate substrates possessing
αꢀheteroatoms. Trichloroacetimidates bearing αꢀlinear substitꢀ
uents 10–13 (entries 10–12) proved to be competent allylic
electrophiles, giving access to allylic fluoride products 21–24
with 90–95% ee. Overall, the new method addresses the curꢀ
rent limitations for the preparation of the αꢀlinear substituent
motif. For example, while the palladiumꢀbisphosphine comꢀ
1
2 h. We hypothesized that diene ligands with larger bite anꢀ
20
gles could induce higher asymmetric induction. As expected,
the enantioselectivity improved with utilization of 2.5 mol%
[IrCl(coe) ] in combination with Lin ligand L6 (66% ee,
2
3
2
2
entry 4) as L6 has a bite angle similar to that of cyclooctadiene
COD) ligand. We hypothesize that poor ligation of the ligand
(
to the iridium in situ may have resulted in moderate observed
ee values (entry 4). We developed a procedure for better ligaꢀ
tion and iridium complexes were isolated and recrystallized
2
6
before use in the fluorination. Accordingly, utilization of 2.5
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plexꢀcatalyzed fluorination reaction provided allylic fluorides
21 (21% ee) and 24 (58% ee) with moderate enantioselectiviꢀ
ty, 21 (entry 9) and 24 (entry 12) were obtained in 92% ee
and 94% ee, respectively, under our DYKAT conditions. To
illustrate the reproducibility of the reaction, 1.2 mmol scale of
Scheme 1. Fluorination of Chiral Allylic Imidate Substrates
1
2
3
4
5
6
7
8
9
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8b
1
(entry 1) was subjected to similar conditions: 2 was isolated
in 83% yield and with 92% ee, which are comparable to the
use of 0.15 mmol of allylic imidate 1 (82% and 93% ee).
a
Table 2. Survey of Allylic Trichloroacetimidates
CCl3
0
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2.5 mol % [IrCl(L2)]2
F
O
NH
.
Et3N 3HF (1.5 equiv)
R
R
MTBE, 25 oC, 0.5 - 3 h
(racemic)
___________________________________________
entry
imidates
products
time yield
h)
ee
(
c
d
(
%)
(%)
_
__________________________________________
CCl3
_
________________________________________________
F
O
NH
RO
RO
We next investigated the ability of the iridium catalyst to
1
2
3
1 (R = 4-F-Bz)
3 (R = Bz)
2 (R = 4-F-Bz)
14 (R = Bz)
1
1
82(83b) 93(92b)
control diastereoselectivity in fluorination reactions of chiral
allylic trichloroacetimidates (Scheme 1). Because chiral diene
ligand L6 and its enantiomer are commercially available, we
75
93
97
95
92
4 (R = TBDPS)
15 (R = TBDPS)
1.5 70
chose to investigate the ability of both [IrCl(R,R)ꢀL6] and
4
5
5 (R = 4-MeO-C6H4)
6 (R = 2-Br-C6H4)
16 (R = 4-MeO-C6H4) 1.5 77
2
[IrCl(S,S)ꢀL6] to enhance or overturn the substrate’s inherent
2
17 (R = 2-Br-C6H4)
1
3
70
61
selectivity preference. Accordingly, the reaction of Dꢀmannose
CCl3
substrate 25 (Scheme 1a) proceeded with excellent catalyst
control, providing the desired fluoride product 26 as a single
O
NH
F
6
7
8
27
O
O
diastereomer. In contrast, a substrateꢀiridium catalyst matchꢀ
N3
N3
4
95
4
7
8
O
18
ing and mismatching effect was observed with conformationꢀ
ally rigid estroneꢀderived imidate substrate 27 (Scheme 1b). In
O
CCl3
NH
the mismatched case with use of [IrCl(S,S)ꢀL6] complex, the
F
2
O
O
fluoride product 28 was produced with low diastereoselectiviꢀ
O
4
0.5 74
99
82
27
ty (dr = 1:3). In contrast, the matched case with utilization of
4
19
[
IrCl(R,R)ꢀL6] complex resulted in allylic fluoride 28 with
2
27
CCl3
NH
excellent diastereocontrol (dr = 24:1).
________________________________________________
O
O
O
F
_
1
73
N
N
Scheme 2. Synthesis of 15ꢀFluoro Prostaglandin Fragment
O
9
O
R
20
CCl3
NH
O
F
R
9
1
1
10: R = OBn
11: R = OTBDPS
12: R = Ph
21: R = OBn
22: R = OTBDPS
23: R = Ph
1
1
1
90
69
82
92
95
90
0
1
CCl3
F
O
NH
12
1
75
94
BnO
3
BnO
_________________________________________________
3
13
24
a
All reactions were carried out on a 0.15 – 0.3 mmol scale of
The allylic fluorides obtained under our DYKAT conditions
have potential utility for targetꢀdirected synthesis. To illustrate
this point, we studied the synthesis of allylic fluoride 32, an
important precursor of 15ꢀfluoroꢀprostaglandin 33 (Scheme 2).
Compound 33 is potentially useful in the treatment of glaucoꢀ
ma, a chronic disease that leads to optic nerve damage and
b
imidates and 2.5 mol% [IrCl(L2)] . Reaction was carried out
on a 1.2 mmol scale of imidate 1 and 1 mol% [IrCl(L2)]2
2
c
d
Isolated yield. Determined by chiral HPLC.
_
________________________________________________
28
To establish the absolute stereochemistry of the desired alꢀ
results in blindness. The fluorinated molecule 33 was previꢀ
lylic fluoride products, compound 2 (93% ee) was subjected to
crossꢀmetathesis with 4ꢀbromostyrene in the presence of Hovꢀ
eydaꢀGrubbs II catalyst because crystallization of 2 proved
difficult. The internal allylic fluoride was isolated as a crystalꢀ
line solid with almost no loss of enantiomeric purity (92% ee)
ously prepared via DASTꢀmediated dehydroxyfluorination of
29
its 15ꢀallylic alcohol starting material. However, this transꢀ
formation is neither regioselective nor enantioselective. Under
our DYKAT conditions, fluoride 30 (Scheme 2) was obtained
in 82% yield and 93% ee. Subsequent crossꢀmetathesis of 30
with Corey lactone derivative 31 afforded the desired fluoride
2
6
and shown to be Rꢀconfigured by Xꢀray analysis.
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product 32. Conversion of internal allylic fluoride 32 into 33
follows methods used in previous synthesis.
In summary, we have developed a new method for dynamic
(8) For representative examples of regioꢀ and enantioselective allylic
fluorination, see: (a) Katcher, M. H.; Doyle, A. G. J. Am. Chem. Soc.
010, 132, 17402. (b) Katcher, M. H.; Sha, A.; Doyle, A. G. J. Am.
Chem. Soc. 2011, 133, 15902. (c) Katcher, M. H.; Norrby, P.ꢀO.;
Doyle, A. G. Organometallics 2014, 33, 2121.
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kinetic asymmetric fluorination of racemic, secondary allylic
.
trichloroacetimidates with Et N 3HF. Our strategy, promoted
3
(
9) For other representative examples of regioselective allylic fluoriꢀ
by a chiral dieneꢀligated iridium catalyst, provides acylic alꢀ
lylic fluorides in high yields with enantioselectivity. Furtherꢀ
more, this method overcomes the limitations previously assoꢀ
ciated with the asymmetric synthesis of secondary allylic fluoꢀ
rides possessing αꢀlinear substituents. Investigations into the
full scope with racemic, branched allylic trichloroacetimidates
and further studies to understand the mechanism are ongoing
and will be reported in due course.
nation, see: (a) Hollingworth, C.; Hazari, A; Hopkinson, M.; Tredꢀ
well, M; Benedetto, E.; Huiban, M.; Gee, A. D.; Brown, J. M.; Gouꢀ
verneur, V. Angew. Chem. Int. Ed. 2011, 50, 2613. (b) Lauer, A. M.;
Wu, J. Org. Lett. 2012, 14, 5138. (c) Benedetto, E.; Tredwell, M.;
Hollingworth, C.; Khotavivattana, T.; Brown, J. M.; Gouverneur, V.
Chem. Sci. 2013, 4, 89.
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
10) For palladiumꢀcatalyzed carbofluorination of allenes to generate
allylic fluorides, see: Braun, M.ꢀG.; Katcher, M. H.; Doyle, A. G.
Chem. Sci. 2013, 4, 1216.
(
11) For rhodiumꢀcatalyzed regioselective ringꢀopening of vinyl epoxꢀ
ASSOCIATED CONTENT
.
ides with Et
3
N 3HF, see: Zhang, Q. and Nguyen, H. M. Chem. Sci.
Supporting Information.
2
014, 5, 291.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Xꢀray data (CIF)
Xꢀray data (CIF)
Experimental procedures and characterization data (NMR,
MS, IR, optical rotation) for all new compounds (PDF).
(12) For palladiumꢀcatalyzed allylic CꢀH fluorination, see: Braun, M.ꢀ
G.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135, 12990.
(13) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. J. Am. Chem.
Soc. 2011, 133, 19318.
(
14) For rhodiumꢀcatalyzed asymmetric ringꢀopening of oxabicyclic
alkenes to form allylic fluorides, see: Zhu, J.; Tsui, G. C.; Lautens, M.
Angew. Int. Ed. 2012, 51, 12353.
(15) For enantioselective synthesis of 1,1ꢀdisubstituted allylic fluoꢀ
rides using selectfluor as electrophilic fluoride source, see: (a) Wu, J.;
Wang, Y.ꢀM.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.; Toste, F. D.
Proc. Natl. Acad. Sci. 2013, 110, 13729. (b) Zi, W.; Wang, Y.ꢀM.;
Toste, F. D. J. Am. Chem. Soc. 2014, 136, 12864.
(16) Our group has demonstrated that a chiral dieneꢀligated rhodium
catalyst promotes DYKAT of racemic, branched allylic trichloroaceꢀ
timidates with anilines in high yield with excellent enantioselectivity,
see: (a) Arnold, J. S; Nguyen, H. M. J. Am. Chem. Soc. 2012, 134,
AUTHOR INFORMATION
Corresponding Author
hienꢀnguyen@uiowa.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank University of Iowa for financial support and Dr.
Swenson for Xꢀray crystallographic analysis. We also thank
Dr. Fei Yu for helping us prepare carbohydrate substrates.
Q.Z. thanks University of Iowa for the graduate fellowship.
8
380. (b) Arnold, J. S.; Cizio, G. T.; Heitz, D. R.; Nguyen, H. M.
Chem. Commun. 2012, 48, 11531. (c) Arnold, J. S.; Mwenda, E. T.;
Nguyen, H. M. Angew. Chem. Int. Ed. 2014, 53, 3688.
(
17) For recent review of iridiumꢀcatalyzed allylic substitution, see:
Hartwig, J. F.; Pouy, M. J. Top. Organomet.Chem. 2011, 34, 169
REFERENCES
(18) Proposed mechanism for iridiumꢀcatalyzed DYKAT of racemic,
.
(
(
1) (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
b) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem.
branched allylic imidates with Et
3
N 3HF, see below:
Int. Ed. 2008, 47, 8998. (c) Ametamey, S. M.; Honer, M.; Schubiger,
P. A. Chem. Rev. 2008, 108, 1501. (d) Cai, L.; Lu, S.; Pike, V. W.
Eur. J. Org. Chem. 2008, 2853 (e) Purser, S.; Moore, P. R.; Swallow,
S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (f) Gouverneur,
V. Science 2009, 325, 1630. (g) Qui, X.ꢀL.; Xu, X.ꢀH.; Qing, F.ꢀL.
Tetrahedron 2010, 66, 789. (h) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470.
(19) We previously subjected enantioenriched starting imidate (95%
ee) to our optimized fluorination conditions, and allylic fluoride was
generated in only 12% ee (see reference #13). The significant degree
of racemization of the fluoride product suggested that equilibration of
πꢀallyl iridium complexes occurs faster than fluoride attack.
(20) (a) Defieber, C.; Grützmacher, H.; Carreira, E. M. Angew.
Chem. Int. Ed. 2008, 47, 4482. (b) Xu, M.ꢀH.; Lin, G.ꢀQ. Synlett,
2011, 1345.
(21) (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.;
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584; (b)
Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009,
4815.
(
2) (a) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008,
108, 1943. (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem.
Rev. 2015, 115, 826; (c) Wu, J. Tetrahedron Lett. 2014, 55, 4289.
(
3) (a) Middleton, W. J.; J. Org. Chem. 1975, 40, 574. (b) Blackburn,
G. M.; Kent, D. E. J. Chem. Soc., Chem. Commun. 1981, 511. (c)
Piva, O. Synlett 1994, 729. (d) Boukerb, A.; Gree, D.; Laabassi, M.;
Gree, R. J. Fluorine Chem. 1998, 88, 23. (e) Singh, R. P.; Shreeve, J.
M. Synthesis 2002, 2561.
(4) Gree, D. M.; Kermarrec, C. J. M.; Martelli, J. T.; Gree, R. L.;
Lellouche, J.ꢀP.; Toupet, L. J. J. Org. Chem. 1996, 61, 1918.
(
2
(
5) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48,
929.
6) (a) Kemmitt, R. D. W.; Peacock, R. D.; Stocks, J. J. Chem. Soc. A
(22) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628.
1971, 846. (b) Pagenkopf, B. L.; Carreira, E. M. Chem. Eur. J. 1999,
5, 3437. (c) Grushin, V. V. Chem. Eur. J. 2002, 8, 1006. (d) Fagnou,
K.; Lautens, M. Angew. Int. Ed. 2002, 41, 26. (e) Hintermann, L.;
Lang, F.; Maire, P.; Togni, A. Eur. J. Inorg. Chem. 2006, 1397. (f)
Grushin, V. V. Acc. Chem. Res. 2010, 43, 160.
(23) (a) Wang, Z.ꢀQ.; Feng, C.ꢀG.; Xu, M.ꢀH.; Lin, G.ꢀQ. J. Am.
Chem. Soc. 2007, 129, 5336. (b) Helbig. S.; Sauer, S.; Cramer, N.;
Laschat, S.; Baro, A.; Frey, W. Adv. Synth. Catal. 2007, 349, 2331.
(c) Feng, C.ꢀG.; Wang, Z.ꢀQ.; Tian, P.; Xu, MꢀH.; Lin, G.ꢀQ. Chem.
Asian J. 2008, 3, 1511.
(
7) (a) Narumi, T.; Tomita, K.; Inokuchi, E.; Kobaysashi, K.; Oishi,
(24) The ligation of [IrCl(coe) ] with L2 to produce [IrCl(L2)] was
2
2
2
o
S.; Ohno, H.; Fujii, N. Org. Lett. 2007, 9, 3465. (b) Hazari, A.;
Gouverneur, V.; Brown, J. M. Angew. Chem. Int. Ed. 2009, 48, 1296.
accomplished by heating the mixture in hexane at 50 C for 48 h. See
the Supporting Information for detailed procedure.
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25) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
2
[IrCl(S,S)ꢀL6] . On the other hand, the Sꢀconfiguration can be asꢀ
1
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B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Thirumurugan, P.;
Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013, 113, 4905. (c) Sharpꢀ
less, K. B.; Manetsch, R. Exp. Opin. Drugs Discovery 2006, 1, 525.
signed for 26 and 28 with use of [IrCl(R,R)ꢀL6]2.
(28) Surgue, M. F. J. Med. Chem. 2007, 40, 2793.
(29) Klimko, P.; Hellberg, M.; McLaughlin, M.; Sharif, N.; Severns,
B.; Williams, G.; Haggard, K.; Liao, J. Bioorg. Med. Chem. 2004, 12,
3451.
(
(
26) See the Supporting Information.
27) On the basis of the Xꢀcrystal analysis for establishing the absoꢀ
lute stereochemistry for allylic fluoride 2, the major diastereomer of
26 and 28 can be analogously assigned to be Rꢀconfigured with use of
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