Stereoselective Synthesis of Chiral β-Fluoro α-Amino Acids via Pd(II)-Catalyzed Fluorination of Unactivated Methylene C(sp3)-H Bonds: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.5b03989

The synthesis of fluorinated complex molecules via direct C(sp³)-H fluorination is attractive yet remains challenging. Here we describe the Pd(II)-catalyzed fluorination of unactivated methylene C(sp³)-H bonds by an inner-sphere mech

Full text of DOI:10.1021/jacs.5b03989

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Article
Stereoselective Synthesis of Chiral #-Fluoro #-Amino
Acids via Pd(II)-Catalyzed Fluorination of Unactivated
Methylene C(sp3)–H Bonds: Scope and Mechanistic Studies
Qi Zhang, Xue-Song Yin, Kai Chen, Shuo-Qing Zhang, and Bing-Feng Shi
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 Jun 2015
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Stereoselective Synthesis of Chiral β-Fluoro α-Amino Acids via
Pd(II)-Catalyzed Fluorination of Unactivated Methylene C(sp3)–H
Bonds: Scope and Mechanistic Studies
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Qi Zhang, Xue‐Song Yin, Kai Chen, Shuo‐Qing Zhang, Bing‐Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
ABSTRACT: The synthesis of fluorinated complex molecules via direct C(sp3)–H fluorination is attractive yet remains
challenging. Here we describe the Pd(II)‐catalyzed fluorination of unactivated methylene C(sp3)–H bonds by an inner‐
sphere mechanism. This method allows the site‐ and diastereoselective fluorination of β‐methylene C(sp3)–H bonds of α‐
amino acid derivatives. A range of substrates containing both aliphatic and benzylic C(sp3)–H bonds were compatible
with this protocol, leading to an array of β‐fluorinated α‐amino acids. Stoichiometric fluorination of an isolated pal‐
ladacycle intermediate takes place rapidly under very mild reaction conditions (room temperature, 5–10 min). Data from
preliminary mechanistic studies are consistent with direct C–F reductive elimination from a high‐valent intermediate.
demonstrating poor functional group tolerance and site‐
1. INTRODUCTION
selectivity, and being operational inconvenient to execute.
The incorporation of fluorine into organic molecules
Recently, the seminal contributions of Groves8a and Lec‐
can dramatically affect their physicochemical and biologi‐
tka8b have inspired a number reports on site‐selective
cal properties and is now a common strategy for modulat‐
fluorination of C(sp3)–H bonds using a free radical strate‐
gy (Figure 1a).8 In general, these strategies were proposed
to proceed through the outer‐sphere mechanism,9 in
which stabilized alkyl radicals were generated by the em‐
ployment of metal catalysts, organic photocatalysts or
photosensitizers. Across these examples, several challeng‐
es have persisted, including narrow substrate scope, poor
selectivity, and low yields, which has hampered synthetic
applications in complex molecules. As a consequence,
these established methods are unsuitable for the stereose‐
lective synthesis of chiral βF‐AAs.10
ing the properties of chemical leads in drug discovery.1
Roughly 20% of pharmaceuticals and 40% of agrochemi‐
cals contain at least one fluorine atom.1f As an important
class of fluorinated compounds, β‐fluoro α‐amino acids
(βF‐AAs) are of particular importance due to their poten‐
tial applications as enzyme inhibitors, drugs and probes.2
In addition, 18F‐labeled amino acids are important radio‐
tracers in positron emission tomography (PET) that target
the increased rates of amino acid transport, which occurs
in numerous tumor cells.2c Given these promising applica‐
tions in medicine and biology, the synthesis of βF‐AAs
has been the subject of intense research efforts.3 However,
the majority of methods require multiple synthetic steps
and purifications, exhibit limited substrate scope and
poor functional group tolerance, or employ expensive
chiral auxiliaries or catalysts. In this context, an attractive
and straightforward strategy would be direct C(sp3)–H
fluorination of readily available, optically active α‐amino
acids.4
Although there are many methods for the incorpora‐
tion of fluorine atom through functional groups trans‐
formation,5 direct fluorination of aliphatic C(sp3)–H
bonds remains undeveloped.6 Historically, electrophilic
C–H fluorination of hydrocarbons with elemental fluorine
has been extensively studied by Rozen, Sandford and
Chambers.7 Although useful in certain contexts, these
methods suffer from limitations: requiring toxic F2 gas,
In 2006, Sanford and co‐workers reported a pioneering
study on Pd(II)‐catalyzed ortho‐C–H fluorination directed
by pyridyl groups using electrophilic fluorinating reagents
(F+ sources).11 Further experimental and mechanistic stud‐
ies revealed that C–F reductive elimination from high‐
valent Pd(IV) intermediates may be involved in the cata‐
lytic cycle.12 Subsequently, the Yu group reported the
Pd(II)‐catalyzed fluorination of aromatic C(sp2)–H bonds
of triflamide‐protected benzylamines and N‐perfluoroaryl
benzamides.13 Recently, Xu reported the nitrate‐promoted
fluorination of aromatic and olefinic C(sp2)–H bonds di‐
rected by oximes.14 Daugulis have demonstrated the cop‐
per‐catalyzed fluorination of C(sp2)–H bonds assisted by
8‐aminoquinoline and picolinic acid auxiliaries.15 Across
these examples, reactions are generally limited to C(sp2)–
H bonds.[11,13‐15] Sanford and co‐workers reported an exam‐
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ple of Pd‐catalyzed benzylic C(sp3)–H fluorination.[11]
yl)isopropylamine (PIP‐amine), which is easily attachable
However, the scope was limited to primary benzylic
C(sp3)–H bonds in 8‐aminoquinoline substrates (Figure
1b). A broadly applicable, mild approach to achieve site‐
and diastereoselective fluorination of unactivated C(sp3)–
H bond would thus be highly desirable.
Herein, we describe the synthesis of chiral βF‐AAs via
Pd(II)‐catalyzed methylene C(sp3)–H fluorination of α‐
amino acids derivatives. Notably, this represents the first
example of fluorination of β‐methylene C(sp3)–H bonds
through an inner‐sphere mechanism.16 Stoichiometric
fluorination of an isolated palladacycle intermediate takes
place rapidly under very mild reaction conditions (room
temperature, 5–10 min). Data from preliminary mechanis‐
tic studies are consistent with direct C–F reductive elimi‐
nation from a high‐valent intermediate (Figure 1c).12d
and removable and has been found to exhibit superior
reactivity in the activation of methylene C(sp3)–H
bonds.20,21 We thus hypothesized that the PIP directing
group would prove beneficial in the proposed methylene
C–H fluorination. Our rationale was as follows: (1) previ‐
ous DFT calculations and experimental studies revealed
that the presence of a gem‐dimethyl group in the PIP aux‐
iliary can facilitate otherwise difficult cyclopallada‐
tions;18a,22 (2) Gagne reported that steric congestion
around a high‐valent Pt(IV) center dramatically accelerat‐
ed C–F reductive elimination over competing β‐hydride
elimination.23 We reasoned that the sterically bulky PIP
directing group could facilitate an otherwise kinetically
disfavored C–F reductive elimination.
To test this hypothesis, we began our investigation us‐
ing N‐phthaloyl phenylalanine derivative 1a as a model
substrate.24 We were delighted to find that the desired
product 2a could be obtained in 8% yield in the presence
of 10 mol% Pd(OAc)2 when acetonitrile was used as the
solvent and Selectfluor was used as the “F+ reagent” (Ta‐
ble 1, entry 1).25 Subsequent investigations revealed that
the use of a mixture of DCM and i‐PrCN (v/v = 30:1) led to
an improvement in yield (64%, entry 6). The yield further
increased to 73% when the loading of Pd(OAc)2 was re‐
duced to 6 mol%, presumably due to suppression of cata‐
lyst‐mediated substrate and product decomposition (en‐
try 7, 65% isolated yield). After screening various com‐
mercially available electrophilic fluorinating reagents,
such as FP, FTMP and NFSI, Selectfluor was found to be
superior (entries 8–10). Consistent with precedents, N‐
phthaloyl was determined to be the optimal protecting
group for the fluorination reaction.24
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Table 1. Evaluation of Reaction Conditions for Ben‐
zylic C(sp3)–H Fluorination.
Figure 1. Strategies for Fluorination of unactivated
C(sp3)–H Bonds. a) Radical C(sp3)–H fluorination (outer‐
sphere mechanism). b) Benzylic 1° C(sp3)–H fluorination
(inner‐sphere mechanism). c) Unactivated methylene
C(sp3)–H fluorination (inner‐sphere mechanism).
2. RESULTS AND DISCUSSIONS
2.1. Fluorination of Benzylic Methylene
C(sp3)–H of α‐Amino Acids. Direct fluorination of
unactivated methylene C(sp3)–H bonds remains a tre‐
mendous challenge because of the inherently low reactivi‐
ty of methylene C(sp3)–H bonds and because C–F reduc‐
tive elimination is typically kinetically disfavored.6,17 In‐
spired by the seminal work of Daugulis on the Pd‐
catalyzed functionalization of methylene C(sp3)–H bonds
with N,N‐bidentate directing groups,18,19 we recently de‐
veloped a bidentate auxiliary derived from 2‐(pyridine‐2‐
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As illustrated in Table 2, this novel fluorination proto‐
to good yields (2g, 2h, 2j, 2l and 2r–2t). Importantly, all of
col allows for the direct incorporation of fluorine into a
broad range of substituted phenylalanine derivatives.
Both electron‐donating and ‐withdrawing substituents at
different positions on the aryl ring are well tolerated,
providing the corresponding fluorinated products in satis‐
factory yields. A variety of functional groups, such as ace‐
tyl (2k), methoxycarbonyl (2i), cyano (2m and 2n), nitro
(2o), and pinacolborane (2u) moieties, were compatible
with the optimized conditions. Moreover, halides, such as
fluoride, chloride, and bromide, remained intact during
the reaction, affording the desired products in moderate
the reactions described in this manuscript were set up on
the benchtop, without the need for an inert‐atmosphere
glovebox or rigorously moisture‐free conditions. The re‐
action was found to be highly diastereoselective, affording
a single diastereoisomer as the product. The relative and
absolute stereochemistry of the fluorinated products was
unambiguously determined by single‐crystal X‐ray dif‐
fraction of 2b, 2c, 2h and 2i .26 It was found that the N‐
phthaloyl group and the newly incorporated fluorine at‐
om are oriented anti to one another, consistent with pre‐
vious reports.18b,24
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Table 2. Pd(II)‐Catalyzed Fluorination of Benzylic Methylene C(sp3)–H Bondsa
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slightly (entry 6, 39% yield). Among the various acid an‐
2.2. Fluorination of Aliphatic Methylene C(sp3)–H
of α‐Amino Acids. The success of fluorination of ben‐
zylic C(sp3)–H bonds led us to test whether the fluorina‐
tion protocol could also be applied to aliphatic secondary
C(sp3)–H bonds. Gratifyingly, we found that the desired
product 4a was obtained in 33% yield under the estab‐
lished conditions (Table 3, entry 1). Considering the sig‐
nificant effects of acid or acid anhydride additives on C–H
functionalization reactions,27 we then surveyed the fluori‐
nation with a broad range of these additives (entries 2‐18).
Acid additives didn’t improve the efficiency (entries 2‐5).
When 0.2 equiv Ac2O was used, the yield was improved
hydride additives, 2‐methylbenzoic anhydride (2‐Me‐
BAH) was the optimal (entry 7‐15). Pd(OPiv)2 proved to
be a superior catalyst, giving the desired product in 54%
yield (entry 16). Other sterically more hindered acid an‐
hydrides, such as 2,4,6‐tri‐Me‐BAH and 2‐Ph‐BAH, re‐
sulted in reduced yields (entries 17 and 18, see Table S1‐S5
in supporting information for detailed optimization). The
exact role of this additive remains unclear at this stage.
Importantly, the desired product 4a was obtained without
any observable epimerization (99% ee, see SI for details).
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Table 3. Additive Screening in the Fluorination of Aliphatic Methylene C(sp3)–H Bonds
A large number of protected natural and unnatural
amino acid derivatives containing the PIP directing group
were compatible with the fluorination protocol, providing
the desired products in moderate yields (Table 4). Steri‐
cally hindered substrates containing adjacent secondary
alkyl groups were reactive, but the yields were slightly
diminished (4c). We were also pleased to observe that
several synthetically useful functional groups, such as
silyl‐protected alcohols (4h and 4j), a cyclic acetal (4i)
and an alkene (4k) were also tolerated under the standard
conditions.
Table 4. Pd(II)‐catalyzed Fluorination of Aliphatic Methylene C(sp3)–H bonds.a
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Scheme 1. Application of Direct C(sp3)‒H Fluorina‐
tion to Complex Molecules
2.3. Synthetic Applications. Because the palladium‐
catalyzed C–H fluorination protocol was found to tolerate
a diverse collection of functional groups, we further as‐
sessed the potential of this reaction for fluorination of
secondary C(sp3)–H bonds in more complex molecules.
We first conducted the palladium‐catalyzed fluorination
of a pair of glyco‐amino‐acids, which are fundamental
components of biologically important glycopeptides and
glycoproteins. Glycopeptides play a critical role in the
nucleocytosolic transportion and are widely used as anti‐
biotics and therapeutics to treat Alzheimer’s disease.28 As
most glycoproteins are heterogeneous, their isolation
from natural sources is frequently very difficult and time‐
consuming. The chemical synthesis of various homogene‐
ous glycopeptides and glycoproteins therefore is the most
reliable and preferred method for corresponding biologi‐
cal studies. As shown in Scheme 1a, two representative
glyco‐amino‐acid derivatives bearing Bn‐protected O‐
glucose (5 and 7) were subjected to C–H fluorination, af‐
fording the desired fluorinated glyco‐amino acids 6 and 8
(53% and 30% yield, respectively). Based on these results,
we anticipate that this C–H fluorination protocol should
be suitable for the synthesis of diverse fluorinated glyco‐
amino acids, which are valuable building blocks for the
synthesis of biologically important glycopeptides. The
late‐stage introduction of a fluorine atom into glycopep‐
tides or glycoproteins opens the opportunity for non‐
invasively imaging relevant metabolic changes in vivo by
PET.2c
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The ability to easily remove the PIP auxiliary from the
final products is crucial for synthetic applications of this
reaction. Thus, with the scope of the C(sp3)–H fluorina‐
tion firmly established, we next sought to demonstrate
that the PIP auxiliary could serve as a versatile masked
carboxylic acid. Previously, we reported that the PIP di‐
recting group could be easily removed through a mild
nitrosylation/hydrolysis sequence.18b In the present man‐
uscript, an additional, complementary protocol was de‐
veloped to remove the PIP auxiliary without affecting the
newly introduced fluorine atom. This two‐step, one‐pot
protocol involves in situ esterification of a highly electro‐
philic pyridinium triflate intermediate.29 Application of
this procedure allowed secondary amide 2a to be directly
converted to the corresponding anti‐β‐fluoro‐α‐amino
acid methyl ester, 15, in 52% yield with 98.6% ee (Scheme
2). This result also suggests the potential of attacking the
intervening PIP‐pyridinium triflate intermediate with
other nucleophilic reagents, and research on this topic is
ongoing.
Furthermore, the ability to incorporate “clickable” func‐
tional groups, such as an azide (10) and a terminal alkyne
(14), is especially useful, as these functional groups could
be used to attach biologically important fluorescent tags
for visualization and identification of cellular targets of
bioactive peptides and proteins (Scheme 1b).
The operationally convenient nature of this transfor‐
mation make it amenable to scale‐up. Thus, a gram‐scale
reaction was performed, and the fluorinated product 2a
was obtained in 69% yield (0.89 g) (Scheme 2).
Scheme 2. Large‐Scale Synthesis and Removal of the PIP Directing Group
without notable decomposition; however, attempts to
2.4. Mechanistic studies. To elucidate the mecha‐
nism of this reaction, several experiments were performed
(Figure 2). First, we allowed 1a to react with 1 equiv.
Pd(OAc)2 in DCM at room temperature and were able to
isolate the corresponding palladacycle intermediate (INT‐
A). The structure of INT‐A was characterized by NMR
spectroscopy. INT‐A is stable at ambient temperature
obtain X‐ray quality crystal were unsuccessful. The analo‐
gous complex 14 was synthesized from INT‐A via ligand
exchange with pyridine, and its structure was unambigu‐
ously confirmed by single‐crystal X‐ray diffraction (Figure
2a).26 The structure of complex 14 showed a trans‐
orientation of N‐Phth and the phenyl group.
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Second, we attempted a stoichiometric reaction of INT‐
ductive elimination from the palladium center.12d,23 The
A with 1.05 equivalents of Selectfluor in d3‐MeCN. We
observed that the reaction proceeded rapidly to give INT‐
C in 78% yield within 5–10 min. The 19F NMR spectrum of
stoichiometric fluorination of palladacycle INT‐A is of
particular interest, given its potential for use in 18F label‐
ing of α‐amino acids using [18F]Selectfluor.30 The present
reaction is rapid, highly diastereoselective, and opera‐
tionally convenient (room temperature, short reaction
time, and simple setup). Thus, the stoichometric version
of this reaction could potentially be used to prepare 18F‐
lableled amino acids that are difficult to access with con‐
ventional methods.31 However, the relatively long time to
remove the PIP group (> 24 h) might limit its application
to the preparation of 18F‐lableled amino acids. Further
studies to establish a quick removal of the protecting
group and PIP group are ongoing.
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INT‐C revealed a singlet at ‐170.59 ppm, and the H NMR
spectrum showed two characteristic hydrogen resonances
for the β‐H (6.52 ppm, dd, JH‐F = 46.8 Hz, JH‐H = 8.8 Hz)
and the α‐H (5.50 ppm, dd, JH‐F = 15.6 Hz, JH‐H = 8.4 Hz)
(Figure 2b and Figure S4 in the supporting information).
Treatment of INT‐C with an aqueous solution of NH4Cl
and Na2S provided the fluorinated product 2a in 86%
yield within 10 min. It is worth noting that in the conver‐
sion of INT‐A to 2a, the product was generated with re‐
tention of configuration, consistent with direct C–F re‐
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Figure 2. Synthesis and stoichiometric reaction of INT‐A.
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liminary mechanistic studies are consistent with direct C–
Finally, we found that INT‐A was a viable precatalyst
F reductive elimination. We anticipate that this C(sp3)–H
fluorination method may enable the synthesis of novel
peptide‐based drugs and probes for application in medi‐
cine and biology.
for C–H fluorination of 1a (eq 1). In the presence of added
catalytic AcOH, 2a was formed in 70% yield, comparable
with the result under the standard conditions.
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4. EXPERIMENTAL SECTION
4.1. General Procedure for Fluorination of Benzylic
C(sp3)–H Bonds (GP 2). To a 50 mL Schlenk tube, were
added 1 (0.3 mmol), Pd(OAc)2 (4.0 mg, 0.018 mmol), Se‐
lectfluor® (111.6 mg, 0.315 mmol), i‐PrCN (100 μL) and
DCM (3.0 mL). The tube was evacuated under high vacu‐
um, charged with N2, and sealed. The mixture was then
heated at 80 °C for 24 h. After cooling to room tempera‐
ture, the reaction mixture was diluted with DCM (10 mL)
and filtered through a short pad of MgSO4. After concen‐
tration in vacuo, the crude reaction mixture was purified
by silica gel flash chromatography.
On the basis of our experimental results and earlier
precedents, a catalytic cycle for this directed methylene
C(sp3)–H fluorination reaction is proposed in Figure 3.
We propose that i‐PrCN promotes C(sp3)–F bond for‐
mation in several ways. First, it facilitates the formation of
the Pd(II)‐palladacycle intermediate (INT‐A) by providing
a neutral ligand. Second, interaction with the PIP auxilia‐
ry to destabilize the cationic, pentacoordinate Pd(IV)–
fluoride complex INT‐B through steric crowding, thereby
promoting C–F reductive elimination.
4.2. General Procedure for Fluorination of Aliphat‐
ic Methylene C(sp3)–H Bonds (GP 3). To a 50 mL
Schlenk tube, were added 3 (0.15 mmol), Pd(OPiv)2 (4.6
mg, 0.015 mmol), Selectfluor® (63.8 mg, 0.18 mmol), 2‐
methylbenzoic anhydride (7.6 mg, 0.03 mmol), i‐PrCN (50
μL) and DCM (1.5 mL). The tube was evacuated under
high vacuum, charged with N2, and sealed. The mixture
was then heated at 80 °C for 24 h. After cooling to room
temperature, the reaction mixture was diluted with DCM
(10 mL) and filtered through a short pad of MgSO4. After
concentration in vacuo, the crude reaction mixture was
purified by silica gel flash chromatography.
1a
iPr
+N
2a
Pd(OAc)2
2 AcOH
O
Decomplexation
C-H Activation
2 AcOH
O
PhthN
Ph
INT-C
PhthN
Ph
N
N
L
F
Pd
N
Pd
N
ASSOCIATED CONTENT
Supporting Information
L
BF4
L
INT-A
L
= i-PrCN)
(
L
(
= i-PrCN)
Direct RE
(with retention of
Experimental procedures, spectra data for all new com‐
pounds and X‐ray for compound 2b, 2c, 2h, 2i and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Oxidation
Cl
N
N
configuration at -carbon)
2
BF4
F
O
Selectfluor
PhthN
N
Cl
N
Pd
Ph
N
N
BF4
AUTHOR INFORMATION
F
(
BF4
L
INT-B
L
= i-PrCN)
Corresponding Author
Figure 3. Proposed Mechanism.
bfshi@zju.edu.cn
Notes
The authors declare no competing financial interests.
3. CONCLUSION
In conclusion, we have reported the first example of
Pd(II)‐catalyzed fluorination of β‐methylene C(sp3)–H
bonds by an inner‐sphere mechanism.32 A range of sub‐
strates containing both aliphatic and benzylic C(sp3)–H
bonds were found to be compatible with this protocol,
leading to an array of β‐fluorinated α‐amino acids. Stoi‐
chiometric fluorination of an isolated palladacycle pro‐
ceeded at room temperature and was complete in 5–10
min, offering the potential for translation to a radiochem‐
istry setting for preparing 18F‐lableled amino acids. Pre‐
ACKNOWLEDGMENT
Financial support from the National Basic Research Program
of China (2015CB856600), the NSFC (21422206, 21272206) and
the Fundamental Research Funds for the Central Universities
is gratefully acknowledged. We thank Prof. Keary M. Engle
(The Scripps Research Institute) for helpful suggestions and
comments on this manuscript and Weihao Rao for initial
optimization.
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These data can be obtained free of charge from The Cam‐
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