Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic Allylic Trichloroacetimidates Catalyzed by a Chiral Diene-Iridium Complex

Article abstract of DOI:10.1021/acscatal.7b03786

The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]octadiene-ligated iridium-catalyzed asymmetric fluorination with Et₃N·3HF is described. The methodology represents an effective route to prepare a wide variety of α-linear, α-branching, and β-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (R,R) or (S,S)-bicyclo[3.3.0]octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20.

Full text of DOI:10.1021/acscatal.7b03786

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Article
Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic
Allylic Trichloroacetimidates Catalyzed by a Chiral Diene-Iridium Complex
Jason C. Mixdorf, Alexandre Sorlin, Qi Zhang, and Hien M. Nguyen
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03786 • Publication Date (Web): 12 Dec 2017
Downloaded from http://pubs.acs.org on December 12, 2017
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ACS Catalysis
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Asymmetric Synthesis of Allylic Fluorides via
Fluorination of Racemic Allylic Trichloroacetimidates
Catalyzed by a Chiral DieneꢀIridium Complex
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Jason C. Mixdorf,†ID Alexandre M. Sorlin, †ID Qi Zhang, and Hien M. Nguyen*ID
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United Sates
Email: hienꢀnguyen@uiowa.edu
ABSTRACT
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The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral
bicyclo[3.3.0]octadieneꢀligated iridiumꢀcatalyzed asymmetric fluorination with Et3N·3HF is described.
The methodology represents an effective route to prepare a wide variety of αꢀlinear, αꢀbranching, and
βꢀheteroatom substituted allylic fluorides in good yields, excellent branchedꢀtoꢀlinear ratios, and high
levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of
optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields
with exclusively branched selectivity. Excellent levels of catalystꢀcontrolled diastereoselectivities using
either (R,R) or (S,S)ꢀbicyclo[3.3.0]octadiene ligand are observed. The synthetic utility of the fluorination
process is illustrated in the asymmetric synthesis of 15ꢀfluorinated prostaglandin and neuroprotective
agent P7C3ꢀA20.
Keywords: Enantioselective, Allylic Fluorination, Iridium, Transition-Metal, Trichloroacetimidate,
Catalysis
INTRODUCTION
Over the past decade, fluorineꢀcontaining molecules have become increasingly important in
several fields including medicinal chemistry, positron emission tomography (PET) imaging, agriculture,
and materials science.1 The introduction of carbonꢀfluorine bonds into organic molecules can lead to
improved bioavailability and, in turn, the efficacy of fluorinated drug candidates over their nonꢀ
fluorinated parent compounds by affecting a wide variety of properties including pKa, lipophilicity,
metabolic stability, and binding affinity.2 Roughly 30% of agrochemicals and 20% of pharmaceutical
targets currently on the market contain at least one fluorine atom.3 As a result, numerous methods have
been developed to address the unmet challenges previously associated with the syntheses of aryl
fluorides4,5 and enantioenriched aliphatic fluorides6,7,8 via nucleophilic fluorination.
Allylic fluorides are biologically important and can be found in many pharmaceuticals 1–3 and
PET radiotracers 4 (Figure 1).9,10,11 However, catalytic asymmetric methods for the direct nucleophilic
incorporation of fluoride into allylic systems remain significantly underdeveloped.12,13,14 A transitionꢀ
metalꢀcatalyzed asymmetric substitution of allylic electrophiles with nucleophilic fluoride sources could
be an ideal approach for the enantioselective synthesis of allylic fluorides.15,16 This strategy has proven
difficult in part due to strong metalꢀfluoride bonding17 and a high basicity of desolvated fluoride.18
Additionally, the ability of allylic fluorides to act as a leaving group has been reported in a palladiumꢀ
catalyzed allylic substitution reaction,19 allowing for a reversible reaction thus resulting in a loss of
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enantioselectivity. As a result, nucleophilic allylic fluorination has only been harnessed in the context of
enantioselective catalysis much more recently when compared to the aliphatic counterparts. 20,21,22,23
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Figure 1. Bioactive molecules and PET tracer possessing allylic fluoride unit
In 2010, Katcher and Doyle reported the first enantioselective synthesis of cyclic allylic
fluorides in excellent enantiomeric excess (85ꢀ96% ee) via a chiral bisphosphineꢀligated palladiumꢀ
catalyzed fluorination of cyclic allylic chlorides with silver fluoride as the nucleophilic fluorinating
reagent.24a In the following year, Doyle and coworkers extended their fluorination method to acyclic
allylic halides (Scheme 1a). The αꢀbranching and βꢀoxygenꢀsubstituted allylic halides are effective
substrates to provide allylic fluorides with excellent asymmetric induction (90–97% ee).24b However,
fluorination of αꢀlinear substituted halide substrates only provided the branched allylic fluoride products
with moderate to low enantioselectivity (21–71% ee) despite high regioselectivity.24b In 2012, Lautens
and coworkers reported the rhodiumꢀcatalyzed asymmetric ringꢀopening of oxabicyclic alkenes using
Et3N.3HF as the nucleophilic fluoride source (Scheme 1b).25 The ringꢀopening products possess both
allylic fluorides and fluorohydrin moieties and were obtained in excellent enantiomeric excess (94–99%
ee). A variety of substituents on the aryl ring were tolerated except for substrates bearing electronꢀ
donating groups. For unsymmetrical oxabicyclic alkene substrates, both regioisomers were obtained
with high levels of enantioselectivities. The work of Doyle and Lautens demonstrates the ability of
transition metal catalysts to enable enantioselective access to branched allylic fluorides. Nevertheless,
there is still a need to develop a more general catalytic asymmetric platform for access to various classes
of branched allylic fluorides which could be valuable building blocks for bioactive molecule syntheses.
In 2015, we described a new method for the catalytic enantioselective fluorination via dynamic
kinetic asymmetric transformations (DYKAT) of racemic allylic trichloroacetimidates (Scheme 1c). In
this process, trichloroacetimidate derivatives of secondary allylic alcohols were illustrated to react with
Et3N.3HF (1.5 equiv.) in the presence of 2.5 mol% chiral dieneꢀligated iridium complex to generate
secondary allylic fluorides, bearing αꢀlinear and βꢀoxygenꢀsubstituents, in high yields with excellent
enantiomeric purity (Scheme 1c).26 The fluorination reactions proceeded at room temperature with
excellent branchedꢀtoꢀlinear ratios (b:l >99:1). The process overcame several of the limitations
previously associated with the enantioselective syntheses of αꢀlinear substituted allylic fluorides along
with improved branchedꢀtoꢀlinear ratios.24b Herein, we delineate the scope of this novel catalytic system
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ACS Catalysis
for the asymmetric syntheses of different classes of branched allylic fluorides and the ability of the
chiral iridium catalyst to control the diastereoselectivities of the fluorinated products.
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Scheme 1. Asymmetric Allylic C-F Bond Formation
RESULTS AND DISCUSSION
Initial Studies. In 2011, we investigated regioselective fluorination reactions with allylic substrates 5
(Scheme 2a) bearing a branched trichloroacetimidate, which is used as both a leaving group and a
directing group at the allylic carbon.27 Cyclooctadiene iridium chloride dimer, [IrCl(COD)]2, was
identified as an effective catalyst at promoting the fluorination of 5 with Et3N.3HF as the preferred
fluoride source to form allylic fluorides 6 in moderate to high yields and excellent branchedꢀtoꢀlinear
ratios. These reactions performed optimally at room temperature and proceeded within 1 – 2 h in the
presence of 5 mol% [IrCl(COD)]2. In the absence of the iridium complex, no conversion was found to
occur towards the desired allylic fluoride product. In addition, only trace amounts of Overman
rearrangement,28 forming allylic trichloroacetamides, and eliminationꢀforming diene products were
observed.
Scheme 2. Discovery of Iridium-Catalyzed Regioselective Allylic Fluorination
To clarify the stereochemical outcome of our allylic fluorination process, a control experiment
with enantioenriched trichloroacetimidate 7 (94% ee) was conducted (Scheme 2b). The fluorination
reaction was not enantiospecific, as evidence by the racemization of the fluorinated product 8 (0% ee).
Based on this result, we explored the possibility of converting racemic allylic trichloroacetimidate
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substrates 9 and 12 to enantioenriched fluoride products through a DYKAT pathway (Figure 2).29 Such
a process is highly desirable as both enantiomers (9 and 12) of the starting material are transformed into
a single optically active fluorinated product, in contrast to a kinetic resolution which involves
conversion of only one enantiomer (9 or 12) of the starting material. For a DYKAT process to be
realized, a CurtinꢀHammett situation must be established such that equilibration of the πꢀallyliridium
intermediates 10 and 14 must be faster than the subsequent nucleophilic fluoride attack. We hypothesize
that the utilization of a chiral bulky ligand could establish a highly congested steric environment around
the iridium metal, and subsequently slow down the rate of fluoride addition to allow more time for a
rapid πꢀσꢀπ interconversion of the diastereomeric πꢀallyliridium complexes 10 and 14 via σꢀcomplex
13. An unfavorable interaction between one of the two πꢀallyliridium intermediates would determine
which enantiomer of the fluoride product (11 or 15) is formed preferentially.30
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Figure 2. Proposed DYKATꢀbased synthesis of allylic fluorides.
Reaction Development. With these considerations in mind, the 4ꢀfluorobenzoyl protected allylic
trichloroacetimidate 16 was chosen as a model substrate in our reaction development (Table 1). Based
on our previous regioselective fluorination results (Scheme 2a),27 we hypothesized that the use of chiral
diene ligands would enable access to enantioselective allylic fluorides. Our group has previously
developed a DYKAT type reaction for the synthesis of enantioenriched allylic amines using a chiral
dieneꢀligated rhodium complex;31 therefore, we reasoned that Hayashi’s bicyclo[2.2.2]octadiene ligand,
L2,32a would be a good starting point (entry 1). Although the reaction with in situ generated L2ꢀligated
iridium complex provided the desired allylic fluoride 17 in good conversion (51%) and excellent
branched selectivity (b:l > 99:1), the enantiomeric excess of 17 was low (13% ee). Further Hiyashi
ligand L332b and Carreira ligand L433 (entries 2 and 3) proved ineffective. We hypothesized that chiral
diene ligands with larger bite angles could induce higher asymmetric induction as they could bind more
tightly to the iridium center.34 Accordingly, fluorination of substrate 16 using Lin ligand L5 (entry 4)35
significantly improved the enantioselectivity of 17 (66% ee). Having established commercially available
Lin ligand, L5, as the most effective ligand at promoting the fluorination, we next investigated the
electronic effects by changing substituents on the phenyl ring (L6 and L1). While use of 4ꢀ
methoxyphenyl diene L6 did not result in improved enantiomeric excess (62% ee, entry 5), use of 4ꢀ
fluorophenyl diene L1 significantly induced higher asymmetric induction (81% ee, entry 6). Similar
diene ligand trends have been observed with our previous results for the rhodiumꢀcatalyzed DYKAT of
racemic tertiary allylic substrates with anilines.31a
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ACS Catalysis
Table 1. Reaction Optimization
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a The dieneꢀligated iridium complex was generated in situ from 2.5 mol%
[IrCl(COE)2]2 with 5 mol% ligands, L1 – L6. b 2.5 mol% [IrCl(Ln)]2 complex
(L6 or L1) was utilized in the reaction. c Determined by 19F NMR analysis using
PhCF3 as an internal standard. d Determined by chiral HPLC. e Isolated Yield.
Since L5 is commercially available, it was chosen as the model ligand to further optimize the
reaction conditions (Table 1, entries 7ꢀ13). To exclude the possibility that unbound cyclooctene (COE)
reversibly binds to the iridium catalyst resulting in degradation of the enantioselectivity, we developed a
procedure for superior ligation by heating a mixture of [IrCl(COE)2]2 with diene L5 in hexane at 50°C
for 48 h. The resulting iridium complex, [IrCl(L5)]2, was isolated and used in the fluorination without
further purification. As expected, use of 2.5 mol% [IrCl(L5)]2 complex (entry 7) resulted in much
higher asymmetric induction (66 → 79% ee). Higher enantioselectivity was also observed when fewer
equivalents of Et3N.3HF (entry 8) were used (79 → 84% ee). Varying the solvents (entries 9–12) did not
have a pronounced effect on the outcome of the reaction, although MTBE (entry 12) was found to
slightly increase the selectivity (84% → 88% ee) of 17. Additional efforts at reaction optimization
(higher temperature, ligands,36 additive,37 and concentration) provided similar levels of selectivity. With
these optimal conditions at hand, we ligated iridium with the most enantioselective 4ꢀfluorophenyl diene
L1 to produce [IrCl(S,S)ꢀL1]2 complex (see Figure 3 for its Xꢀray crystallographic structure), which was
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found to be superior to [IrCl(L5)]2 complex in terms of both yield and enantioselectivity (entry 14). The
fluorination proceeded to completion within 1 h to provide allylic fluoride 17 in 82% isolated yield with
excellent enantiomeric excess (93% ee).
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Figure 3. ORTEP diagram of [IrCl(S,S)ꢀL1]2
Attempts to crystallize allylic fluoride 17 were unsuccessful; therefore, to establish the absolute
stereochemistry of the allylic fluoride product, 17 was subsequently subjected to crossꢀmetathesis with
4ꢀbromostyrene 18 in the presence of HoveydaꢀGrubbs II catalyst (Scheme 3). Internal allylic fluoride
19 was isolated as a crystalline solid in 63% yield with no loss of enantiomeric purity (92% ee).
Subsequent crystallographic analysis showed allylic fluoride 19 to be Rꢀconfigured (Figure 4).
Scheme 3. Derivatization of Allylic Fluoride 17 for X-ray Analysis
Figure 4. ORTEP diagram of internal allylic fluoride 19.
Substrate Scope. With the optimized conditions in hand, we next sought to investigate the scope of the
fluorination reaction with respect to the βꢀoxygenꢀsubstituted trichloroacetimidate substrates (Table 2).
The fluorination reaction tolerates a range of functional groups and provides the fluorinated products
20–25 in good yields (61–75%) with excellent enantioselectivity (91–99% ee) and regioselectivity (b:l
>99:1). The mild conditions are also tolerant of the silyl ether group (TBDPS) to provide fluoride 21 in
70% yield and 97% ee. These results are consistent with what has been observed by the Doyle group
wherein higher asymmetric induction was observed with substrates bearing βꢀoxygen substituents.24b
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The ability to introduce the azide and alkyne functional groups (24 and 25) highlights the significant
flexibility of this method. Both the azide and alkyneꢀcontaining fluoride products offer the functionality
of subsequent incorporation into a variety of biologically relevant molecules.38 Having examined the
scope of βꢀoxygen substituted substrates, we sought to probe the effects of increasing the scale of the
fluorination while simultaneously decreasing the chiral iridium catalyst loading. Accordingly, allylic
trichloroacetimidate 16 was fluorinated on a 1.2 mmol scale using 1 mol% [IrCl(S,S)ꢀL1]2 to afford
allylic fluoride 17 in good yield (83%) with high levels of enantiocontrol (92% ee), similar to the result
obtained in a small scale (82% and 93% ee, Table 1). We also conducted the reaction with [IrCl(R,R)ꢀ
L1]2 and ent-17 was isolated in comparable yield and enantiomeric excess (Table 2).
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Table 2. Scope of β-Oxygen-Substituted Imidate Substratesa
a All reactions were carried out on a 0.04 – 0.3 mmol scale of allylic
trichloroacetimidates. b Isolated yield. c Determined by chiral HPLC.
d Reaction was conducted on a 1.2 mmol scale of imidate substrate 16.
e Reaction was conducted 2.5 mol% [IrCl(R,R)ꢀL1]2.
In addition to βꢀoxygenꢀsubstituted trichloroacetimidates, we found that substrates bearing αꢀ
linear and αꢀbranching substituents readily participated in catalytic fluorination process to deliver the
allylic fluoride products 26 – 33 (Table 3) in high yields (77 – 90%) and enantioselectivity (88 – 94%
ee). Importantly, our fluorination process is also suited for αꢀlinear substituted substrates, providing the
corresponding allylic fluorides 26–29 (Table 3) with excellent levels of asymmetric induction (90 – 95%
ee). Our method addresses the current limitation associated with the asymmetric synthesis of this motif.
For example, while our reaction affords 27 and 29 in 92% ee and 94% ee, respectively, a chiral
bisphosphineꢀpalladium complexꢀcatalyzed fluorination of acyclic allylic chlorides provided moderate
enantiomeric excess of 27 (21% ee) and 29 (58% ee).24b The sixꢀmembered ring substituted products
(30 and 31) induced higher enantiocontrol than their 4ꢀmembered ring counterparts (32 and 33).
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Furthermore, it has been determined that longer reaction times are necessary for substrates (30 – 33)
containing αꢀbranching unit. Interestingly, αꢀnaphthyl substituted allylic trichloroacetimidate provided
the branched product 34 preferentially albeit in reduced regioselectivity (b:l = 4:1) as a racemate (0%
ee). In previous reports by both the Gouverneur and Doyle groups, under palladium catalysis, cinnamyl
4ꢀnitrobenzoate20a and cinnamyl chloride24b produced linear allylic fluorides preferentially over the
branched allylic fluoride. Under our iridium conditions, we hypothesize that the αꢀnaphthyl substituted
substrate is more likely to proceed through a discreet benzylic and allylic cation, as previously reported
under our rhodium catalyzed benzylic fluorination conditions,39 to provide allylic fluoride 34.
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Table 3. Scope of α-Linear and α-Branching Substituted Imidatesa
a All reactions were carried out on a 0.04 – 0.3 mmol scale of allylic
imidate substrates, 2.5 mol% [IrCl(S,S)ꢀL1]2 complex, and 1.5 equiv.
of Et3N.3HF. b34 isolated with b:l = 4:1 c Isolated yield.
d Determined by chiral HPLC. e Isolated after hydrogenation.
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Table 4. Scope of Nitrogen-Containing Imidate Substratesa
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a All reactions were carried out on a 0.04 – 0.3 mmol scale of allylic
imidate substrates, 2.5 mol% [IrCl(S,S)ꢀL1]2 complex, and 1.5 equiv.
of Et3N.3HF. b Isolated yield. c Determined by chiral HPLC.
Next, we studied the scope of the reaction conditions with respect to βꢀnitrogen containing
substituents (Table 4). The allylic βꢀfluoroamine products generated from this reaction are valuable
building blocks for the synthesis of medicinally relevant molecules.40 A fluorine atom beta to an amine
provides a 1ꢀ2 log reduction in pKa while retaining bioactivity and improving the metabolic stability of
the targets.41 Only a few approaches to access enantioenriched βꢀfluoroamines have been reported.42
Transitionꢀmetalꢀcatalyzed asymmetric allylic substitutions to generate allylic βꢀfluoroamines remains
underdeveloped as amines can bind to metal centers effectively preventing catalyst turnover. To
overcome this challenge, we postulated that judicious choice of the protecting groups is critical to
attenuate the nitrogen basicity thus preventing catalyst deactivation. As a result, the pꢀtoluenesulfonyl
(Ts) protected amine substrate 35 was first investigated (Table 4, entry 1). Although allylic βꢀ
fluoroamine 40 was isolated in 88% yield, its enantiomeric excess was only moderate (49% ee). We
hypothesize that upon generating πꢀallyliridium complex from 35, due to an amino group proximal to
the electrophilic site of πꢀallyliridium complex, both the competing vinyl aziridine and the desired
product 40 (Table 4, entry 1) could be generated.43,44 Rapid interconversion of the vinyl aziridine
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intermediate and πꢀallylmetal complex, as proposed by Ibuka and coworkers in their studies of
palladiumꢀcatalyzed equilibrated reactions of vinyl aziridines,45 results in loss of enantioselectivity in
the product 40. To suppress competing vinyl azidirine formation, we aimed to explore the protecting
groups that either decrease nitrogen nucleophilicity and/or make nitrogen less accessible. Consequently,
substrate 36, bearing the more electronꢀwithdrawing paraꢀnitroꢀbenzenesufonyl group (Table 4, entry
2), was studied. As expected, the fluoride product 41 was obtained in higher enantioselectivity (82% ee)
than 40 bearing the tosyl group (49% ee, entry 1). Substrate 37 bearing the dinitroꢀbenzensulfony group
was the most effective, providing allylic fluoride 42 (entry 3) in 90% yield with excellent asymmetric
induction (91% ee). Similarly, use of the sterically and doubly protected amineꢀcontaining allylic
trichloroacetimidate 38 (entry 4) provided βꢀfluoroamine 43 in 79% yield with 90% ee. We also
investigated a γꢀnitrogen containing substrate 39 (entry 5). Allylic γꢀfluoroamine 44 was isolated in
excellent yield (93%) and showed excellent enantioselectivity (91% ee).
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Table 5. Scope of Nitrogen-Heterocycle Substituted Substratesa
a All reactions were carried out on a 0.04 – 0.3 mmol scale of allylic
imidate substrates, 2.5 mol% [IrCl(S,S)ꢀL1]2 complex, and 1.5 equiv.
of Et3N.3HF. b Isolated yield. c Determined by chiral HPLC.
Expanding the scope of enantioselective fluorination to other families of nitrogenꢀcontaining
allylic trichloroacetimidates is another important objective. We chose to pursue nitrogenꢀcontaining
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heterocycles (Table 5, entries 1–6) as their architectures have been used as promising lead compounds
in medicinal chemistry.11,46 We speculate that heterocycles such as indole, carbazole, and pyrrole could
potentially suppress vinyl aziridine formation as their nitrogen lone pair are comprised in the aromatic
πꢀsystem. As postulated, fluorination of indoleꢀcontaining allylic substrates 45–47 (entries 1–3)
proceeded smoothly to furnish the desired fluorinated products 51–53 in moderate yields (55–73%) and
high enantioselectivity (88–91% ee). A similar trend was observed with carbazoleꢀcontaining allylic
imidates 48 and 49 (entries 4 and 5), and their corresponding fluoride products 54 and 55 were formed
in 94% ee and 84% ee, respectively. We discovered that pyrroleꢀ2ꢀcarboxaldehyde 50 was the most
effective electrophile (entry 6), providing allylic βꢀfluoroamine 56 with excellent enantiomeric excess
(96% ee).
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Table 6. Scope of Allyic Imidate Substrates Bearing α-Stereocentera
a All reactions were carried out on a 0.04 – 0.3 mmol scale of chiral allylic imidate substrates 57– 61, 2.5 mol%
[Ir] complex, and 1.5 equiv. of Et3N.3HF. b Isolated yield. c Determined by 1H NMR.
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To this point, the substrates which have been studied bear only one stereocenter, set via iridiumꢀ
catalyzed asymmetric fluorination. The applicability of the new synthetic methodology in more complex
molecular settings is highly desirable, especially a method that can produce the desired product without
interference from the preꢀexisting stereocenter of the molecule. As a result, we studied the influence of
both [IrCl(R,R)ꢀL1]2 and [IrCl(S,S)ꢀL1]2 on the diastereoselective reactions with trichloroacetimidate
substrates 57 – 61 bearing an αꢀstereocenter (Table 6). A wide range of allylic fluorides 62 – 66 were
formed in moderate to good yields (52 – 99%) with excellent catalystꢀcontrolled diastereoselectivities.
The following trends were observed in the diastereoselective fluorination reactions: (1) use of achiral
[IrCl(COD)]2 catalyst provided the fluorinated products 62 – 66 as a 1:1 mixture of diastereomers; (2)
use of [IrCl(S,S)ꢀL1]2 provided the products with (R)ꢀconfigured at the allylic carbon (vide infra, Figure
5); and (3) use of [IrCl(R,R)ꢀL1]2 provided the products with (S)ꢀconfigured at the allylic carbon (Figure
5). For enantiomeric trichloroacetimidate substrates 57 and 58 (entries 1 and 2), the αꢀstereochemistry
of the starting materials did not influence the stereochemical outcome of the desired fluoride products
62 and 63. For Nꢀtosylꢀproline substrate 60 (entry 4),47 the ability of chiral dieneꢀligated iridium
complexes to effectively control diastereoselective fluorination outweighed the directing ability of the
tosyl (Ts) group, as proposed by Liu and coworkers in their studies of copperꢀcatalyzed regioselective
fluorination of allylic halides.48 Importantly, the Nꢀtosyl protected phenylalanine trichloroacetimidate 61
(entry 8) is a suitable substrate to deliver allylic βꢀfluoroamine 66 with high catalystꢀcontrolled
diastereoselectivity using either [IrCl(S,S)ꢀL1]2 (dr = 22:1) or [IrCl(R,R)ꢀL1]2 (dr = 49:1) catalysts.
Encouraged by the results obtained in Table 6 with substrates bearing αꢀstereocenter, we
extended the applicability of the asymmetric fluorination method with carbohydrateꢀ and estroneꢀ
derived allylic trichloroacetimidates 67 and 68 carrying multiple stereocenters (Table 7). For
carbohydrate substrate 67 (entry 1), use of [IrCl(COD)]2 catalyst provided the fluoride product 69a
(entry 1) as a 4:1 mixture, favoring the diastereomer with the (S)ꢀconfiguration at the allylic carbon.
This results shows the nature of the substrate to influence the selectivity of the fluorination. In stark
contrast, a substrateꢀiridium catalyst matching and mismatching effect was observed with chiral dieneꢀ
iridium complexes. In the mismatched case, with use of [IrCl(S,S)ꢀL1]2 catalyst, fluorinated glucoside
69b was obtained with moderate diastereoselectivity (dr = 4:1), opposite to the result obtained with use
of [IrCl(COD)]2 (dr = 4:1). In the matched case, use of [IrCl(R,R)ꢀL1]2 resulted in the major
diastereomer 69a with excellent levels of diastereocontrol (dr > 99:1). For estrone starting material 68
(entry 2), its major diastereomer was not established (dr = 5:1). Nevertheless, use of [IrCl(COD)]2
resulted in the fluorinated product 70a in 46% yield as a racemic mixture. On the other hand, excellent
catalystꢀcontrolled diastereoselectivities were observed with use of both [IrCl(S,S)ꢀL1]2 and [IrCl(R,R)ꢀ
L1]2 catalysts, and the fluorinated products 70b and 70c were obtained with dr = 13:1 – 24:1 (entry 2).
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Table 7. Fluorination of Carbohydrate- and Estrone-Derived Substratesa
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a All reactions were carried out on a 0.04 – 0.3 mmol scale of allylic
imidate substrates 67 and 68, 2.5 mol% [Ir] complex, and 1.5 equiv.
of Et3N.3HF. b Isolated yield. c Determined by chiral HPLC or 1H NMR.
To validate the fluoride products obtained as a function of the absolute configuration of the
diene ligand, Xꢀray crystallography was then performed to establish the absolute stereochemistry of the
major diastereomers of the allylic fluoride products (Tables 6 and 7). The major diastereomer of fluoride
64b, with use of [IrCl(S,S)ꢀL1]2 could be recrystallized, allowing the absolute stereochemistry at its
allylic carbon to be determined as the Rꢀconfiguration (Figure 5).41 The major diastereomer of prolineꢀ
containing allylic fluoride 65b with use of [IrCl(S,S)ꢀL1]2 could also be recrystallized; Xꢀray analysis
showed that the stereochemistry at the allylic carbon of 65b was determined to be Rꢀconfigured (Figure
5). On the other hand, use of [IrCl(R,R)ꢀL1]2 to generate estroneꢀcontaining product 70c whose
stereochemistry at the allylic carbon was determined to be Sꢀconfigured by Xꢀray analysis (Figure 5).
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Figure 5. ORTEP diagram of diastereoselective allylic fluorides 64b, 65b, and 70c.
In addition to monosubstituted allylic trichloroacetimidates described previously, we attempted
the fluorination of disubstituted substrate to test the limitation of our methodology. We found that allylic
imidate 71 (Scheme 4) with additional methyl substitutent at C(2) underwent fluorination to provide 72
in high yield (82%) with low enantioselectivity (20% ee). Unlike the monosubstituted allylic imidate
substrates, disubstittued allylic substrate 71 offers an additional hurdle in that both syn (73) and anti
(74) πꢀallyiridium complexes are likely to be generated in the reaction upon ionization of 71.49 In the
case of monsubstituted substrates, the anti πꢀallyiridium complex is much less stable than the syn
complex counterpart due to unfavorable A(1,3) interactions.50 However, in the case of disubstituted
substrate 71, the C(2)ꢀmethyl substituent on the allyl destabilizes the syn πꢀallyiridium complex through
unfavorable A(1,2) steric interactions. Since the chiral dieneꢀligated iridium catalyst was not effective at
controlling the relative population of complexes 73 and 74, the fluorinated product 72 (Scheme 4) was
obtained with poor enantiocontrol.
Scheme 4. Attempted Asymmetric Synthesis of Disubstituted Allylic Fluoride
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Synthetic Applications. The allylic fluorides obtained in our study have far reaching utility in targetꢀ
directed synthesis. To illustrate the point, we explored the asymmetric synthesis of allylic fluoride 76,
an important precursor of 15ꢀfluoroꢀprostaglandin (1, Scheme 5). Compound 1 can be potentially useful
for treating glaucoma, a chronic disease that leads to optic nerve damage and results in blindness, and
was derived from the internal allylic fluoride precursor 78.51 The fluoride intermediate 78 was
previously synthesized via nucleophilic substitution of its 15ꢀallylic alcohol starting material with
DAST.9a However, the DASTꢀmediated dehydrofluorination process is not regioꢀ or enantioselective.
We envisioned developing an asymmetric route to 78 by utilizing our fluorination reaction.
Accordingly, fluorination of trichloroacetimdiate substrate 75 with Et3N.3HF (1.5 equiv) in [IrCl(S,S)ꢀ
L1]2 (2.5 mol%) provided allylic fluoride 76 in high yield (82%) with excellent enantiomeric excess
(93% ee). Subsequent crossꢀmetathesis of 76 with Corey lactone derivative 77 afforded the fluorinated
product 78 as a single diastereomer (Scheme 5), suggesting that there is no loss of enantiomeric purity.
Transformation of the internal fluoride intermediate 78 into the corresponding 15ꢀfluoroꢀprostaglandin
(1) follows methods used in previous synthesis.9a
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Scheme 5. Asymmetric Synthesis of a 15-Fluoro-Prostaglandin Fragment
Finally, access to enantioenriched allylic fluorides by iridiumꢀcatalyzed asymmetric fluorination
provides an opportunity to further derivatize them into biologically relevant molecules. To illustrate this
point, the olefin moiety of the fluorinated compound 80 was elaborated to furnish P7C3ꢀA20 (83,
Scheme 6), a neuroprotective molecule which protects mature neurons from cell death.52 In addition,
compound 83 is orally available and nonꢀtoxic and can readily cross the bloodꢀbrain barrier. The
racemic synthesis of 83 has been previously reported51 via ring opening of 3,9ꢀdibromoꢀcarbazole
containing epoxide with aniline followed by conversions of the alcohol intermediate into the
corresponding fluorinated product with morpholinosulfur trifluoride (MORPHOꢀDAST) reagent.52
Under our asymmetric conditions, allylic βꢀfluroamine 80 was prepared in 90% yield with excellent
enantioselectivity (94% ee) and regiocontrol from trichloroacetimidate 79 (Scheme 6). Next, using an
improved procedure for the oxidative cleavage of the olefin in βꢀfluroamine 80,53 followed by
condensation of the aldehyde intermediate 81 with 3ꢀmethoxylaniline 82 and subsequent reductive
amination, provided the corresponding P7C3ꢀA20 (83) in 66% yield over 2 steps with slight loss of
enantiomeric excess (88% ee).
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Scheme 6. Asymmetric Synthesis of Bioactive P7C3-A20 Target
Conclusions
A useful catalytic enantioselective synthesis of branched allylic fluorides, from the reaction of
racemic allylic tricloroacetimidate substrates with a mild Et3N.3HF reagent, has been developed
utilizing chiral bicyclo[3.3.0]octadieneꢀligated iridium complexes. We propose this catalytic process is
likely to operate through dynamic kinetic asymmetric transformation (DYKAT) of racemic secondary
allylic substrates. The scope is suitable for a wide variety of allylic trichloroacetimidates bearing αꢀ
branching, αꢀlinear, βꢀoxygen, and βꢀnitrogen substituents, providing the fluorinated products in good
yields with excellent branchedꢀtoꢀlinear ratios and enantioselectivities. The current fluorination
methodology is also suitable to generate allylic fluorides possessing two contiguous stereocenters with
excellent catalystꢀcontrolled diastereoselectivities using either [IrCl(S,S)ꢀL1]2 and [IrCl(R,R)ꢀL1]2
catalysts. Importantly, the fluorination of carbohydrateꢀ and estroneꢀderived substrates, bearing multiple
stereocenters, proceeds with excellent diastereocontrol. The methodology is, however, limited to allylic
imidate substrates having 1,1ꢀdisubstituted double bonds. The utility of the fluorination process has
been demonstrated in the rapid and asymmetric synthesis of biologically relevant 15ꢀfluoroꢀ
prostaglandin and neuroprotective P7C3ꢀA20. We anticipate that these findings have important future
implications for designing other catalytic enantioselective processes utilizing racemic allylic
trichloroacetimidate substrates and transforming this methodology to radiofluorination.
The detailed mechanistic studies of the iridiumꢀcatalyzed asymmetric fluorination with racemic
trichloroacetimdiates are under investigation and will be reported in due course.30
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author: hienꢀnguyen@uiowa.edu
ORCID
Hien M. Nguyen: 0000ꢀ0002ꢀ7626ꢀ8439
Jason C. Mixdorf: 0000ꢀ0003ꢀ3045ꢀ5607
Alexandre M. Sorlin: 0000ꢀ0002ꢀ9589ꢀ6131
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Author Contributions: †equal contributions
Notes: The authors declare no competing financial interest.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: Full
experimental procedures and characterization data for all new compounds (PDF).
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ACKNOWLEDGMENTS
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Financial support from the University of Iowa is gratefully acknowledged. We also thank Dr. Dale
Swenson for assistance in Xꢀray crystallography analysis and the Nuclear Regulatory Commission
Program (NRCꢀHQꢀ84ꢀ14ꢀGꢀ0037) for the graduate fellowship to J.C.M.
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(43) A proposed mechanism for the formation of the competing vinyl aziridine pathway, resulting in loss of the
stereochemistry in the allylic fluoride products, is shown below. See supporting information Scheme S1.
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(44) To further validate our hypothesis that the competing vinyl aziridine intermediate is generated in the
reaction, a control experiment was conducted in the presence of Et3N.3HF. Only vinyl aziridine was isolated in
the reaction. See supporting information Scheme S2.
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