Site-Selective Photochemical Fluorination of Ketals: Unanticipated Outcomes in Selectivity and Stability

Article abstract of DOI:10.1021/acs.joc.9b03047

We report a method for the regioselective photochemical sp³ C-H fluorination of acetonide ketals that presents interesting problems in chemical reactivity. The question of why certain products of the reaction are stable while others are not is addressed, as is the question of why only select α-ethereal hydrogen atoms are targeted in the reaction. We demonstrate that the method can be employed to synthesize unprecedented fluorinated sugars and steroids, and it can also be applied toward the fluorination of carbamates. Though some substrates contain up to eight discrete α-ethereal C-H bonds, we observed site-selectivity in each case, prompting us to investigate potential transition states for the reaction. Finally, a remarkable regiochemical switch upon minor structural modification of a diketal is also analyzed.

Full text of DOI:10.1021/acs.joc.9b03047

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Site-Selective Photochemical Fluorination of Ketals: Unanticipated
Outcomes in Selectivity and Stability
Joseph N. Capilato, Cody Ross Pitts, Rozhin Rowshanpour, Travis Dudding,* and Thomas Lectka*
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ABSTRACT: We report a method for the regioselective photochemical sp3
C−H fluorination of acetonide ketals that presents interesting problems in
chemical reactivity. The question of why certain products of the reaction are
stable while others are not is addressed, as is the question of why only select α-
ethereal hydrogen atoms are targeted in the reaction. We demonstrate that the
method can be employed to synthesize unprecedented fluorinated sugars and
steroids, and it can also be applied toward the fluorination of carbamates.
Though some substrates contain up to eight discrete α-ethereal C−H bonds,
we observed site-selectivity in each case, prompting us to investigate potential
transition states for the reaction. Finally, a remarkable regiochemical switch
upon minor structural modification of a diketal is also analyzed.
synthetic methods have been developed to access α-
fluoroethers that generally rely on nucleophilic or electrophilic
fluorination functional group interconversion (FGI) strategies.
For example, diethylaminosulfur trifluoride (DAST) and
Selectfluor have been employed as nucleophilic and electro-
philic sources of fluorine, respectively, in the synthesis of
glycosyl fluorides.11 These are the most commonly encoun-
tered type of fluorinated sugars in the literature due to the well-
established reactivity at the anomeric position. Other positions
have also been fluorinated utilizing the same nucleophilic and
electrophilic sources of fluorine; however, they typically
require specialized precursors and/or longer syntheses.12
Only a few C−H functionalization methods are known to
produce gem-oxyfluorides directly from their corresponding
ethers, esters, or other oxygen-containing substrates. For one,
Vincent and co-workers reported aliphatic α-fluorination of
simple cyclic ethers using N-fluorobis(trifluoromethane-
sulfonimide) (NFSI).13 The Hamashima group has also
described two examples of photochemical α-fluorination of
esters in moderate yield that is directed by a phthalimide group
tethered to the substrate.14 Beyond photochemical approaches,
the α-fluorination of ethers, esters, lactones, and carbonates
has been accomplished electrochemically, albeit on only simple
and symmetrical small molecules.15 Despite these initial
reports, a recent review on this topic echoes the fact that
1. INTRODUCTION
Although substantial progress has been made over the past
decade in taming radical fluorination methods,1 achieving
regioselective sp3 C−H fluorination on complex molecules
remains a fundamental problem in the field. In light of the
prominent role of fluorine in biology,2 medicine,3 and
materials,4 our group, among others, has begun to address
this problem.5 For instance, we have demonstrated that
carbonyl groups can direct aliphatic fluorination in polycyclic
enone- and ketone-containing substrates.6 Moreover, we and
others have shown that innate regioselective fluorination can
be achieved when the substrate contains an activated C−H
bond (e.g., at a benzylic or allylic site) or when bulky
substituents provide a steric bias.7 One type of activated site
that surprisingly is less targeted in the world of radical
fluorination is the α-ethereal C−H bond. Given our long-
standing interest in expanding the utility of aliphatic
fluorination, we have developed a site-selective photochemical
approach to the synthesis of relatively stable and isolable α-
fluoroketals and carbamates that presents interesting problems
in chemical reactivity. The first issue concerns stabilitywhy
of a pair of closely related products was only one isolable? The
question of why only select α-ethereal hydrogen atoms are
targeted is addressed through computations. Finally, an
interesting total regiochemical switch upon minor structural
modification of a diketal is also analyzed.
The gem-oxyfunctionalized products are of synthetic
interestparticularly in the case of more stable compounds
in this class, such as Teflon AF (a unique polymer material)8
and fluorinated carbohydrates9 (including 2′-OMe,4′-F-rU
an important tool for studying nucleic acids).10 Various
Received: November 11, 2019
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© XXXX American Chemical Society
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selective, radical C−H fluorination of carbohydrates is
significantly underexplored compared to traditional ap-
proaches.16 We believe the photochemical fluorination
described herein represents a piece of this expanding repertoire
and opens new avenues toward the synthesis of novel
fluorinated sugars and other carbohydrates.
interested in exploring milder visible-light-mediated ap-
proaches. Accordingly, we screened several known visible
light sensitizers in combination with compact fluorescent light
(CFL) bulbs. We were pleased to find that benzil, 5-
dibenzosuberenone, fluorenone, xanthone,18 and benzophe-
none were all competent promoters of the reaction, with
xanthone producing the highest yield of the desired fluoride
(Table 1, entries 5 and 7−10). Additionally, we explored NFSI
as an alternative fluorine source, but the desired product was
not observed, thereby hinting at the importance of Selectfluor
as the fluorinating reagent in this transformation. Lastly, we
found that short reaction times (around 2−3 h) work best, as
the fluorination occurs fairly rapidly, and slight product
decomposition was observed in some cases after longer periods
of time.
2. RESULTS AND DISCUSSION
2.1. Screening. The discovery of the reaction was tied to
two serendipitous results (Figure 1). In 2017, we reported a
2.2. Substrate Examples. In agreement with our previous
site-selective photochemical fluorination methods, the reaction
generally works best on complex polycyclic molecules (Table
2)a paradoxical finding that we can rationalize as a
consequence of the increased rigidity of the substrate and its
ease of oxidation.19 Sugar diacetonides are ideal substrates in
the reaction due to their rigid nature, in addition to their
abundance and ease of preparation.20 Moreover, sugar
acetonides possess a myriad of synthetic applications and are
biologically active in certain contexts.21 Diacetonide esters of
glucose, galactose, fructose, and mannose undergo regiose-
lective fluorination in good to excellent yields (54−91%) to
provide compounds 1, 2, 3, and 5, respectively. Another sugar
derivative that undergoes the site-selective fluorination in high
yield is an acetonide derivative of vitamin C to give compound
4.22 Additionally, fluoride 8 was synthesized selectively from an
adduct of glucose diacetonide and androstanediol. Such
glycosteroids play important roles in medicine and biology;23
however, their fluorinated counterparts are rare in the
literature. In addition to our survey of monosaccharide
substrates, aforementioned steroid 7 (a derivative of the
allergy drug Nasacort)24 formed with excellent regio- and
stereoselectivity to give a single isomer of an α-fluoroketal in
high yield under optimized conditions. Significantly, we noted
that the less-hindered (i.e., secondary) α-ethereal position is
often favored but found an anomalous instance in compound
3. Moreover, at a glance, it is not necessarily intuitive why
certain tertiary α-ethereal positions are favored over others.
We next turned our attention to another class of important
biomolecules, N-protected amino acids, to demonstrate
fluorination of carbamates in a site-selective manner (Figure
2a). For example, N-carbobenzoxy-L-isoleucine (Z-Ile-OH) is a
competent substrate in the reaction, producing compound 9
selectively. Significantly, no fluorination was observed on the
secondary or tertiary positions of the sec-butyl side chain found
in isoleucine, even with 2.0 equiv of Selectfluor. Analogous
oxazolidinones also work as substrates. They possess an array
of biological activity25 and are an important category of chiral
auxiliaries in synthetic organic chemistry.26 We synthesized
compound 10 in good yield from 3-benzoyl-2-oxazolidinone
(though enantioselective C−H fluorination of such a
compound remains an alluring goal). Only one similar gem-
oxyfluorinated oxazolidinone can be found in the literature;
however, the heterocycle was prepared in low yield from a
fluorinated precursor rather than direct C−H functionalization
of the oxazolidinone.27
Figure 1. Serendipitous discovery of α-ethereal C−H fluorination on
complex molecules.
peculiar instance of tandem site-selective sp3 C−H fluorina-
tion/hydroxylation of a complex spiroketal that suggested a key
intermediacy of an unstable α-fluoroether formed under our
photochemical conditions (see Figure S41 for a proposed
mechanistic pathway).17 More recently, we had an interest in
studying the steroid desonide to probe the aptitude of rigid
ketals in directing aliphatic fluorination using Selectfluor,
visible light, and a photoinitiatoranalogous to our carbonyl-
directed work. We found that the fluorination is highly
regioselective and the product very stable and isolable. Shortly
thereafter, we also discovered that regioselective fluorination of
glucose diacetonide acetate to produce compound 1 can also
be achieved under similar conditions, and we proceeded to
screen for optimized conditions with this substrate (Table 1).
It was quickly determined that the reaction requires a
photosensitizer (entries 1−3). Although the desired product
was observed under 300 nm irradiation in the presence of
catalytic 1,2,4,5-tetracyanobenzene (entry 4), we were also
Table 1. Screening for Reaction Conditions
The regioselectivity of the reaction to form compound 10 is
remarkable given the previously reported halogenations of
B
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a
Table 2. Product Examples
a
Yields were determined by integration of 19F NMR signals relative to an internal standard (isolated yields of chromatographically pure material in
parentheses). Major diastereomer indicated where known. Fluoride 6 was inseparable from starting material (see Experimental Section and
Supporting Information (SI)).
oxazolidinones (Figure 2b). For example, electrochemical
fluorination of N-acyl oxazolidinones gives exclusively the
“other” regioisomer (α to nitrogen).28 Moreover, photo-
chemical chlorination of these substrates using sulfuryl chloride
gives a 2:1 ratio of regioisomers, with the chloride α to
nitrogen being favored.29 Thus, our oxazolidinone fluorination
is uniquely selective as it not only results in a single
regioisomer, but the fluoride is geminal to oxygen rather
than to nitrogen. One further example of the carbamate α-
fluorination that we explored involves a much smaller molecule
known as urethane (ethyl carbamate). Although this method
seems to work best with larger, more complex substrates, this
compound undergoes fluorination in moderate yield to give a
molecule that, to our surprise, has not been previously
prepared (compound 11). Thus, the reaction can occur for
both aliphatic and benzylic carbamates, as well as both cyclic
and acyclic carbamates.
In addition to carbamates, we also found that both benzylic
and aliphatic carbonate esters can partake in the site-selective
fluorination; for example, both diethyl and dibenzyl carbonate
were competent substrates in the reaction. Unfortunately, we
observed that the yields were generally lower for these
reactions, which we attributed to decreased stability of the
gem-oxyfluorides relative to those of carbamates. Similarly, we
found that ethers, such as N-acetylmorpholine, are also able to
participate in the reaction, although the resulting fluorides also
seemed to be less stable and lower yielding than the ketals that
we tested.
2.3. Site-Selectivity in Sugar Diacetonides. We were
intrigued by the observed regioselectivity of the fluorination of
sugar diacetonides, as each substrate contains several distinct
α-ethereal C−H bonds, yet excellent site-selectivity was
observed in each case. Furthermore, the selectivity pattern
exhibited in Table 2 is not particularly consistent with putative
bond dissociation energies of α-ethereal C−H bonds. C−H
bonds that are geminal to both oxygen atoms of an acetal, for
instance, have bond dissociation energies (BDEs) that are ∼23
kJ/mol lower than that of α-ethereal C−H bonds of
acetonides.30 In Table 2, the fluorination of galactose
diactonide presents the most intriguing example, as one C−
H bond is targeted among a host of ethereal bonds, three of
which are fairly similar sterically and electronically (Figure 3,
top).
The radical dication derived from Selectfluor has been
proposed to play a key role in hydrogen atom abstractions
from alkanes and related classes of compounds (Figure 3,
bottom).31,32 In the case of ketal and carbamate substrates, a
hydrogen atom geminal to oxygen is selectively abstracted to
form a stabilized radical, which then is fluorinated by
Selectfluor, thereby forming an α-ethereal fluoride and
regenerating the Selectfluor radical dication to propagate a
chain reaction. To better understand the basis of this reactivity,
density functional theory (DFT) calculations were performed
at the IEFPCM(CH CN)UB3LYP/6-311++G(2d,2p)//
3
UB3LYP/6-31G(d)33 level using the Gaussian 09 software
C
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noncovalent interaction plot in Figure 4B (left-hand side).
Short C−H···O contacts of 2.34 and 2.39 Å and natural bond
order (NBO) charges (O = −0.644e, H = 0.307e, H = 0.296e)
additionally corroborated the presence of favorable inter-
actions, notably, with an underlying Coulombic charge
component. Coupled with these interactions was a stabilizing
stereoelectronic anomeric effect, viz. unshared oxygen lone pair
donation into an antibonding σ*-orbital of the exocyclic
C(1)−O bond as supported by NBO analysis (En(O)→C−O*
=
9.16 kcal mol−1). Last was a comparable distribution of spin
density across the hydrogen atom transfer bond breaking and
bond making subassembly with distances of 1.31 and 1.44 Å
(Figure 4b, right-hand side). Significantly, we established the
transition states in which hydrogen atom transfer occurs at the
other α-ethereal positions (especially the sites α to two ether
oxygen atoms and α to an acetate ester), that is, hydrogen
atom transfer from C(1), C(3), C(4), or C(5) via TSC1 or
TSC3−5 to be of higher energy (ΔG⧧ > 13 kcal mol−1) than
TSC2 (see SI for additional details and hydrogen atom transfer
transition state structures TSC1 and TSC3‑5). In each case, a
complex interplay of steric and electronic effects makes
generalizations difficult. This selectivity is additionally
remarkable as, based on the computed bond dissociation free
energies of C(1)−H−C(5)−H, a lack of hydrogen atom
transfer site-selectivity would be expected (Figure 4A).
2.4. Regioselectivity Switch. An important trend that was
noted in regard to regioselectivity was the general (although
not strict) preference for fluorination at secondary positions
over tertiary ones. For example, the glucose, mannose, ascorbic
acid, and glycosteroid derivatives described above reacted with
this selectivity pattern. Conversely, the fructose diacetonide
ester fluorinates at a tertiary position of the ketal, although an
enticing secondary position is available. We were astonished to
discover that the regioselectivity of this fluorination could be
switched by altering the substrate to include a ketone rather
than an acetoxy group (Figure 5a). This fructose diacetonide
ketone derivative, better known as Shi’s epoxidation diketal
catalyst,35 fluorinates in a site-selective fashion to give a
secondary fluoride (compound 6). Given some of our recent
work in the area, we attributed this selectivity switch to
carbonyl direction, as the ketone is properly poised to direct
fluorination to the β-position in a manner analogous to
terpenoidal ketone-directed fluorination.6 On the other hand,
exceptionally good overlap between the forming radical of the
hydrogen atom transfer C−H−N subarray and the endocyclic
σ*(C−O) (which can be overcome only by carbonyl
activation) could help explain this finding.36
Figure 2. Application to carbamates.
Another area that we briefly explored was site-selectivity in
the reaction of benzyl carbamates in the presence of other
benzylic sites. N-Carbobenzoxy-L-phenyalanine (Z-Phe-OH)
provides an ideal model substrate for this test. Fluorination of
Z-Phe-OH under our reaction conditions produces a 6:1
regioisomeric ratio of products in 58% yield, with fluorination
at the benzyl carbamate being greatly preferred over the
normal benzylic position (Figure 5b). Although this observed
selectivity is significant, we are currently investigating other
ways to improve the regioselectivity to further expand the
utility of this reaction.
2.5. Stability of Fluorinated Acetonides versus
Spiroketals. As previously mentioned, our isolation of ketal
7 was unexpected given our prior result of a fluorinated
spiroketal that was unstable and rearranged in situ. To gain
some insight on this discrepancy, we considered an isodesmic
Figure 3. Possible functionalization sites in galactose diacetonide;
hydrogen atom transfer through Selectfluor radical dication.
package.34 Emerging from these computations was hydrogen
atom transfer transition state TSC2 with a Gibbs free energy
activation barrier (ΔG⧧) of 7.4 kcal mol−1 with respect to the
separate reagents. Within this transition state, the reactive
Selectfluor radical dication species is positioned for hydrogen
atom transfer from carbon C(2), and there are minimal steric
contacts; for example, the shortest C−H···H distance between
the radical dication and the galactose diacetonide substrate was
2.38 Å, just inside the sum of the van der Waals radii of the two
hydrogen atoms (Figure 4A).
Present in this transition state structure as well were
stabilizing noncovalent interactions, clearly visible from the
D
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Figure 4. Computed transition state structure TSC2 for hydrogen atom transfer from galactose diacetonide.
relation between these two fluorides and their corresponding
defluorinated oxocarbenium ions (Figure 5c). At the B3LYP/
6-31+G** level of theory, we calculated the ΔE of the
isodesmic reaction to be −26.3 kcal/mol. This energy
difference is noteworthy and indicates a highly exothermic
process in which the α-ethereal fluoride of the spiroketal is
displaced to give a highly stabilized cation with an elongated
(C−O) bond. Significantly, this result is consistent with our
empirical findings that the fluorinated spiroketal was not
isolable, whereas the fluorinated acetonide was straightforward
to isolate.
In general, we found the α-ethereal fluorides of acetonide
ketals and carbamates to be surprisingly stable, persisting
through aqueous workup and silica gel chromatography.
Beyond the synthesis of the fluorides themselves, we imagined
that we could expand the scope of the reaction to derivatize the
products into other useful compounds through defluorination.
For example, we added 10 equiv of water into the reaction of
sugar 1 after the fluorination transpired and allowed the
mixture to stir overnight at room temperature. To our surprise,
most of the fluoride remained intact, as determined by 19F
NMR. Whereas some precedent exists for the nucleophilic
substitution of similar gem-oxyfluorides, the substrate scope is
generally limited to simple molecules.4,37
3. CONCLUSION
A site-selective photochemical fluorination was developed that
accesses α-ethereal fluorides from ketals and carbamates using
Selectfluor, catalytic xanthone, and visible light. The method
appears to be best suited for rigid substrates such as steroids
and sugar diacetonides and has also been demonstrated on
simpler molecules, as well. Moreover, the gem-oxyfluoride
products reported herein are notably stable and isolable. A
DFT-computed transition state illuminated details on the
origin of the site-selectivity of the reaction and presented a
possible explanation for a regioselectivity switch that was
observed in fructose derivatives. In all, developing this ability
to target the α-ethereal C−H bond represents a promising
approach to regioselective fluorination of complex molecules,
which is complementary to the existing tactics: (1) relying on
steric/electronic influences for serendipitous selectivity, (2)
E
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residue was purified via column chromatography on silica gel with
EtOAc/hexanes.
4.3. Characterization of Fluorinated Compounds.
4.3.1. (3aR,5S,6S,6aR)-5-((4S)-5-Fluoro-2,2-dimethyl-1,3-dioxolan-
4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Acetate
(Compound 1). Fluorination was run according to the general
procedure (1.5 equiv of Selectfluor, 2 h), and the major diastereomer
was isolated via gradient column chromatography on silica gel eluting
with 10−15% EtOAc/hexanes. Regiochemical assignment was made
on the basis of (1) chemical shift in the 19F NMR spectrum (δ −113.3
to −113.6 ppm) that indicates a secondary α-ethereal fluoride, (2)
1
2JHF coupling in the H NMR spectrum consistent with a secondary
fluoride (J = 68.2 Hz), (3) splitting pattern in the 19F NMR spectrum
2
3
with appropriate coupling constants (dd, JFH = 68.3 Hz, JFH = 16.6
Hz), and (4) identification of JCF,
3JCF, and JCF coupling to
2
4
distinguishable peaks in the 13C NMR spectrum; for example, the
3
quaternary carbon of the fluorinated acetonide (δ 113.9 ppm, JCF
=
2.9 Hz) and a methyl group of the fluorinated acetonide (δ 27.5 ppm,
4JCF = 3.3 Hz). Stereochemical assignment was made on the basis of 3J
1
coupling for the H−C−F proton in the H NMR spectrum (J = 0.9
Hz for the major diastereomer, J = 2.4 Hz for the minor
1
diastereomer): colorless oil (109 mg, 68%); H NMR (400 MHz,
CDCl3) δ 6.05−5.87 (2H, m, H−C−F and anomeric C−H), 5.29−
5.28 (1H, m), 4.51 (1H, d, J = 3.7 Hz), 4.45−4.39 (1H, m), 4.20−
4.17 (1H, m), 2.11 (3H, s), 1.50 (6H, s), 1.48−1.30 (6H, m);
13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 113.9 (d, J = 2.9 Hz),
112.4, 110.6 (d, J = 225.2 Hz), 105.2, 83.2, 80.7 (d, J = 32.3 Hz), 78.2
(d, J = 8.1 Hz), 75.7, 27.5 (d, J = 3.3 Hz), 27.1, 26.7, 26. 1, 20.7; 19F
2
NMR (282 MHz, CDCl3) δ −113.3 to −113.6 (1F, dd, JFH = 68.3
Hz, 3JFH = 16.6 Hz); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C14H22O7F+ 321.1350; found 321.1349.
Figure 5. Regioselectivity and stability studies.
4.3.2. ((3aR,5R,5aS,8aS,8bS)-8b-Fluoro-2,2,7,7-tetramethyltetra-
hydro-5H-bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-5-yl)methyl Acetate
(Compound 2). Fluorination was run according to the general
procedure (1.5 equiv of Selectfluor, 2 h), and the major diastereomer
was isolated via gradient column chromatography on silica gel eluting
with 10−15% EtOAc/hexanes. Regiochemical assignment was made
on the basis of (1) chemical shift in the 19F NMR spectrum (δ −97.1
to −97.2 ppm) that indicates a tertiary α-ethereal fluoride, (2) lack of
targeting benzylic/allylic C−H bonds, and (3) using enone or
ketone-based (or other external) directing groups.
4. EXPERIMENTAL SECTION
4.1. General Methods. Unless otherwise stated, all reactions were
carried out under strictly anhydrous conditions and N2 atmosphere.
1
All solvents were dried and distilled by standard methods. All H
1
2JHF coupling in the H NMR spectrum consistent with a tertiary
spectra were acquired on a 400 MHz NMR spectrometer in CD3CN
or CDCl3; 19F spectra were acquired on a 300 MHz NMR
spectrometer in CD3CN or CDCl3, and 13C NMR spectra were
acquired on a 400 MHz NMR spectrometer in CD3CN or CDCl3.
fluoride, (3) splitting pattern in the 19F NMR spectrum with
3
3
appropriate coupling constants (dd, JFH = 17.2 Hz, JFH = 2.9 Hz),
(4) agreement with the calculated 19F NMR shift (at B3LYP/6-311+
2
3
1
The H, 13C, and 19F NMR chemical shifts are given in parts per
+G**), and (5) identification of JCF and JCF coupling to
distinguishable peaks in the 13C NMR spectrum; for example, the
million (δ) with respect to an internal tetramethylsilane (TMS, δ =
0.00 ppm) standard and/or 3-chlorobenzotrifluoride (δ = −64.2 ppm
relative to CFCl3). 1H NMR data are reported in the following
format: chemical shift (integration, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constants
(Hz)). Spectral data were processed with Bruker software. Photo-
chemical reactions were run in a microwave vial irradiated with light
from two CFL light bulbs (14 W, 120 V, 800 lm, TCP brand, model
EDXO-14). The two bulbs were placed near opposite ends of a stir
plate about 4−5 in. away from the center of the plate where the
reaction vial was, and the entire photochemical setup was covered in a
sheet of aluminum foil.
4.2. General Fluorination Procedure. Selectfluor (266 mg, 0.75
mmol, 1.5 equiv) and xanthone (9.8 mg, 0.05 mmol, 0.1 equiv) were
added to an oven-dried microwave vial equipped with a stir bar; the
vial was then sealed with a cap with Teflon septum using a crimper
and evacuated/refilled with N2 multiple times. The substrate (0.5
mmol, 1.0 equiv) was then added in a solution of anhydrous CH3CN
(8 mL) (on the other hand, if the substrate is a solid, it is added along
with Selectfluor before sealing the vial). The reaction mixture was
irradiated with visible light from two CFL bulbs while being stirred at
room temperature. After 2−3 h, a 0.3 mL aliquot was taken for 19F
NMR yield determination (generally, ketals reacted for 2 h and
carbamates for 3 h). The reaction mixture was triturated with 40 mL
of 1:1 CH2Cl2/hexanes, filtered through Celite, and washed with
CH2Cl2. After the crude mixture was concentrated in vacuo, the
2
anomeric carbon (δ 97.2 ppm, JCF = 4.8 Hz). Stereochemical
assignment of the major diastereomer was made on the basis of the
chemical shift indicating the presence of the more deshielded cis-
isomer,38 JFH coupling constants (described above), and the
3
empirical preference for the cis-isomer that is observed during
1
synthesis of the starting material: colorless oil (133 mg, 83%); H
NMR (400 MHz, CDCl3) δ 5.53 (1H, d, J = 5.0 Hz, anomeric C−H),
4.50−4.45 (2H, m), 4.26−4.14 (3H, m), 2.09 (3H, s), 1.56 (6H, d, J
= 8.3 Hz), 1.47−1.36 (6H, m); 13C{1H} NMR (100 MHz, CDCl3) δ
170.8, 115.0 (d, J = 2.6 Hz), 113.9 (d, J = 237.3 Hz), 110.3, 97.2 (d, J
= 4.8 Hz), 79.5 (d, J = 31.2 Hz), 72.2 (d, J = 26.8 Hz), 67.7 (d, J = 7.3
Hz), 62.3 (d, J = 1.8 Hz), 27.7, 26.6 (d, J = 2.9 Hz), 25.9, 25.0, 20.8;
3
19F NMR (282 MHz, CDCl3) δ −97.1 to −97.2 (1F, dd, JFH = 17.2
3
Hz, JFH = 2.9 Hz); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C14H22O7F+ 321.1350; found 321.1344.
4 . 3 . 3 . ( 3 a ′ S , 4 S , 7 ′ S , 7 a ′ S ) - 3 a ′ - F l u o r o - 2 , 2 , 2 ′ , 2 ′ -
tetramethyltetrahydrospiro[[1,3]dioxolane-4,6′-[1,3]dioxolo[4,5-c]-
pyran]-7′-yl Acetate (Compound 3). Fluorination was run according
to the general procedure (1.5 equiv of Selectfluor, 2 h), and the major
diastereomer was isolated via gradient column chromatography on
silica gel eluting with 10−15% EtOAc/hexanes. Regiochemical
assignment was made on the basis of (1) chemical shift in the 19F
NMR spectrum (δ −97.0 − (−97.1) ppm) that indicates a tertiary α-
2
1
ethereal fluoride, (2) lack of JHF coupling in the H NMR spectrum
consistent with a tertiary fluoride, (3) splitting pattern in the 19F
F
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1
NMR spectrum consisting of a doublet of triplets (3JFH = 16.6 Hz,
fluoride, (3) disappearance of α-ethereal hydrogen atom in the H
1
2
3
3JFH = 3.7 Hz), and (4) identification of JCF and JCF coupling to
NMR spectrum (see H NMR spectrum of starting material in SI),
and (4) identification of 2JCF, 3JCF, and 4JCF coupling to distinguishable
peaks in the 13C NMR spectrum; for example, CO of the α-acetoxy
ketone (δ 198.7 ppm, 3JCF = 1.5 Hz) and the quaternary carbon of the
fluorinated acetonide (δ 112.6 ppm, 3JCF = 1.5 Hz): white solid (202
mg, 78%); 1H NMR (400 MHz, CDCl3) δ 6.92 (1H, d, J = 10.2 Hz),
6.29−6.26 (1H, m), 6.03 (1H, s), 5.55−5.52 (1H, m), 4.94−4.60
(2H, m), 2.57−2.49 (1H, m), 2.40−2.36 (1H, m), 2.26−2.10 (9H,
m), 1.97−1.90 (3H, m), 1.49−1.44 (6H, m), 1.33−1.20 (6H, m),
1.04 (3H, s); 13C{1H} NMR (100 MHz, CDCl3) δ 198.7 (d, J = 1.5
Hz), 185.8, 170.1, 169.7, 167.7, 153.9, 128.6, 124.1 (d, J = 259.0 Hz),
123.1, 112.6 (d, J = 1.5 Hz), 95.5 (d, J = 20.9 Hz), 70.7, 68.6, 53.7 (d,
J = 1.1 Hz), 47.0 (d, J = 7.3 Hz), 45.8 (d, J = 2.6 Hz), 42.8, 37.3 (d, J
= 29.3 Hz), 36.0, 33.7, 31.6, 30.2 (d, J = 1.5 Hz), 26.4 (d, J = 2.6 Hz),
26.2, 21.7, 20.7, 20.4, 16.3; 19F NMR (282 MHz, CDCl3) δ −105.9 to
−106.0 (1F, m); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C28H36O8F+ 519.2394; found 519.2393.
distinguishable peaks in the 13C NMR spectrum; for example, the
3
quaternary carbon of the fluorinated acetonide (δ 114.7 ppm, JCF
=
2.9 Hz) and the methylene α to the fluoride (δ 72.3 ppm, 2JCF = 26.8
Hz). Stereochemical assignment was made by analogy to compound
2: colorless oil (109 mg, 68%); 1H NMR (400 MHz, CDCl3) δ 4.51−
4.40 (3H, m), 4.13−4.08 (1H, m), 3.98 (1H, d, J = 11.8 Hz), 3.78−
3.73 (1H, m), 2.11 (3H, s), 1.58 (6H, d, J = 12.6 Hz), 1.47 (6H, d, J =
20.3 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 114.7 (d, J =
2.9 Hz), 113.6 (d, J = 237.3 Hz), 110.0, 103.2 (d, J = 5.5 Hz), 79.2 (d,
J = 30.8 Hz), 72.3 (d, J = 26.8 Hz), 64.3, 63.3 (d, J = 7.0 Hz), 27.6,
26.6 (d, J = 2.9 Hz), 26.3, 25.2, 20.8; 19F NMR (282 MHz, CDCl3) δ
3
3
−97.0 − (−97.1) (1F, dt, JFH = 16.6 Hz, JFH = 3.7 Hz); HRMS
(ESI-Orbitrap) m/z [M + H]+ calcd for C14H22O7F+ 321.1350; found
321.1345.
4.3.4. (2R)-2-((4R)-5-Fluoro-2,2-dimethyl-1,3-dioxolan-4-yl)-5-
oxo-2,5-dihydrofuran-3,4-diyl Diacetate (Compound 4). Fluorina-
tion was run according to the general procedure (2.0 equiv of
Selectfluor, 2 h), and the major diastereomer was isolated via gradient
column chromatography on silica gel eluting with 10−20% EtOAc/
hexanes. Regiochemical assignment was made by analogy to
compound 1. No stereochemical assignment was made: colorless oil
4.3.8. Compound 8. Fluorination was run according to the general
procedure (1.5 equiv of Selectfluor, 2 h), and the major diastereomer
was isolated via gradient column chromatography on silica gel eluting
with 10−15% EtOAc/hexanes. Regiochemical and stereochemical
assignment was made by analogy to compound 1: white solid (170
1
1
mg, 49%); H NMR (400 MHz, CDCl3) δ 6.05−5.88 (2H, m), 5.28
(132 mg, 83%); H NMR (400 MHz, CDCl3) δ 6.09−5.92 (1H, m,
(1H, d, J = 3.1 Hz), 4.72−4.64 (1H, m), 4.62−4.58 (1H, m), 4.52
(1H, d, J = 3.6 Hz), 4.46−4.40 (1H, m), 4.20−4.17 (1H, m), 2.70−
2.56 (4H, m), 2.19−2.10 (1H, m), 2.02 (3H, s), 1.83−1.79 (1H, m),
1.74−1.69 (2H, m), 1.65−1.60 (2H, m), 1.57 (3H, m), 1.50, (5H,
m), 1.48 (3H, s), 1.42−1.37 (2H, m), 1.30 (3H, s), 1.29−1.23 (6H,
m), 1.20−1.12 (2H, m), 1.07−0.99 (2H, m), 0.90−0.86 (2H, m),
0.82 (3H, s), 0.77 (3H, s), 0.69−0.62 (1H, m); 13C{1H} NMR (100
MHz, CDCl3) δ 172.0, 171.1, 170.7, 113.9 (d, J = 2.6 Hz), 112.4,
110.7 (d, J = 225.6 Hz), 105.2, 83.2 (d, J = 29.7 Hz), 80.6 (d, J = 31.9
Hz), 78.2 (d, J = 8.4 Hz), 76.0, 73.6, 54.1, 50.6, 44.6, 42.8, 36.8 (d, J =
16.1 Hz), 35.5, 35.2, 34.0, 31.5, 29.0 (d, J = 3.7 Hz), 28.4, 27.5 (d, J =
3.3 Hz), 27.4 (d, J = 5.1 Hz), 27.2, 26.7, 26.2, 23.5, 21.4, 20.7, 12.2,
12.1; 19F NMR (282 MHz, CDCl3) δ −113.2 to −113.5 (1F, dd, 2JFH
H−C−F), 5.34 (1H, d, J = 1.6 Hz), 4.62−4.58 (1H, m), 2.32 (3H, s),
2.27 (3H, s), 1.49 (6H, d, J = 29.7 Hz); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.1, 165.1, 164.7, 149.8 (d, J = 1.1 Hz), 122.5, 116.1 (d, J
= 3.0 Hz), 111.1−108.9 (m), 80.5−80.2 (m), 74.4−74.2 (m), 27.3,
26.5, 20.5−20.4 (m), 20.1−20.0 (m); 19F NMR (282 MHz, CDCl3) δ
2
3
−108.8 to −109.1 (1F, dd, JFH = 69.4 Hz, JFH = 17.8 Hz); HRMS
(ESI-Orbitrap) m/z [M + H]+ calcd for C13H16O8F+ 319.0829; found
319.0825.
4.3.5. (3aS,4R,6S,6aS)-6-((4S)-5-Fluoro-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl Acetate
(Compound 5). Fluorination was run according to the general
procedure (1.5 equiv of Selectfluor, 2 h), and the major diastereomer
was isolated via gradient column chromatography on silica gel eluting
with 10−15% EtOAc/hexanes. Regiochemical assignment was made
by analogy to compound 1. No stereochemical assignment was made:
colorless oil (86 mg, 54%); 1H NMR (400 MHz, CDCl3) δ 6.16 (1H,
s, anomeric C−H), 5.94 (1H d, J = 66.9 Hz, H−C−F), 4.89−4.86
(1H, m), 4.71 (1H, d, J = 5.9 Hz), 4.63−4.57 (1H, m), 3.93−3.90
(1H, m), 2.07 (3H, s), 1.57−1.35 (12H, m); 13C{1H} NMR (100
MHz, CDCl3) δ 169.2, 114.2 (d, J = 2.9 Hz), 113.6, 110.7 (d, J =
227.1 Hz), 100.8, 84.9, 80.9 (d, J = 3.3 Hz), 80.7 (d, J = 20.9 Hz),
79.1, 27.7 (d, J = 3.3 Hz), 27.6, 25.8, 24.6, 21.0; 19F NMR (282 MHz,
CDCl3) δ −113.6 to −113.8 (1F, dd, 2JFH = 67.1 Hz, 3JFH = 16.1 Hz);
HRMS (LIFDI-TOF) m/z [M − CH3]+ calcd for C13H18O7F+
305.1031; found 305.1043.
3
= 68.3 Hz, JFH = 16.6 Hz).
4.3.9. ((Fluoro(phenyl)methoxy)carbonyl)-L-isoleucine (Com-
pound 9). Fluorination was run according to the general procedure
(2.0 equiv of Selectfluor, 3 h), and the product was isolated via
gradient column chromatography on silica gel eluting with 10−20%
1
EtOAc/hexanes: colorless oil (95 mg, 67%); H NMR (400 MHz,
CDCl3) δ 7.53−7.51 (2H, m), 7.46−7.44 (3H, m), 7.17 (1H, d, J =
56.3 Hz), 5.51 (1H, d, J = 8.7 Hz), 4.49−4.45 (1H, m), 2.03−1.96
(1H, m), 1.53−1.46 (1H, m), 1.23−1.19 (1H, m), 1.00−0.93 (6H,
m); 13C{1H} NMR (100 MHz, CDCl3) δ 175.9, 153.6 (d, J = 1.5
Hz), 134.7 (d, J = 24.2 Hz), 130.2 (d, J = 1.8 Hz), 128.6, 126.1 (d, J =
5.9 Hz), 102.8 (d, J = 222.3 Hz), 58.2, 37.9, 24.8, 15.4, 11.6; 19F
NMR (282 MHz, CDCl3) (major diastereomer) δ −120.1 to −120.3
(1F, d, J = 56.8 Hz), (minor diastereomer) δ −119.2 to −119.4 (1F,
d, J = 56.2 Hz); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C14H19O4NF+ 284.1298; found 284.1299.
4.3.10. 3-Benzoyl-5-fluorooxazolidin-2-one (Compound 10).
Fluorination was run according to the general procedure (2.0 equiv
of Selectfluor, 3 h), and the product was isolated through gradient
column chromatography on silica gel eluting with 10−20% EtOAc/
hexanes. Regiochemical assignment was made by comparison to
reported characterization data for gem-O27 and gem-N28 fluorinated
oxazolidinones: white solid (59 mg, 56%); 1H NMR (400 MHz,
CDCl3) δ 7.71−7.69 (2H, m), 7.62−7.58 (1H, m), 7.48−7.44 (2H,
m), 6.76−6.59 (1H, m), 4.61−4.48 (2H, m); 13C{1H} NMR (100
MHz, CDCl3) δ 167.9 (d, J = 2.2 Hz), 151.5 (d, J = 2.2 Hz), 133.2,
131.5, 129.3, 128.1, 92.4 (d, J = 215.3 Hz), 68.4 (d, J = 28.6 Hz); 19F
NMR (282 MHz, CDCl3) δ −134.0 to −134.5 (1F, m); HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C10H9O3NF+ 210.0567; found
210.0563.
4 . 3 . 6 . ( 3 a ′ R , 4 R , 5 R , 7 a ′ R ) - 5 - F l u o r o - 2 , 2 , 2 ′ , 2 ′ -
tetramethyldihydrospiro[[1,3]dioxolane-4,6′-[1,3]dioxolo[4,5-c]-
pyran]-7′(4′H)-one (Compound 6). Fluorination was run according
to the general procedure (1.5 equiv of Selectfluor, 2 h), and the major
diastereomer was isolated via gradient column chromatography on
silica gel eluting with 10−15% EtOAc/hexanes. Note that we were
unsuccessful in isolating compound 6 in pure form, as we found it to
be inseparable from the starting material. Chromatography on silica
gel, Florisil, and alumina led only to a 1:1 mixture of starting material
and product, due to significant streaking which we believe is caused by
hydration of the unusually reactive ketone (see Figure S31 for the 19F
NMR spectrum of the major diastereomer and Figure S32 for the 1H
NMR spectrum of the 1:1 mixture): colorless oil (57 mg, 41%); 19F
2
NMR (282 MHz, CDCl3) δ −120.9 (1F, d, JFH = 64.3 Hz).
4.3.7. Compound 7. Fluorination was run according to the general
procedure (1.5 equiv of Selectfluor, 2 h), and the product was isolated
via gradient column chromatography on silica gel eluting with 10−
20% EtOAc/hexanes. Regiochemical assignment was made on the
basis of (1) chemical shift in the 19F NMR spectrum (δ −105.9 to
−106.0 ppm) that indicates a tertiary α-ethereal fluoride, (2) lack of
4.3.11. 1-Fluoroethyl Carbamate (Compound 11). Fluorination
was run according to the general procedure (2.0 equiv of Selectfluor, 3
h), and the product was isolated via gradient column chromatography
1
2JHF coupling in the H NMR spectrum consistent with a tertiary
G
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on silica gel eluting with 15−25% EtOAc/hexanes: colorless oil (23
further purification. The crude material from the previous step was
dissolved in MeOH (80 mL), and 5−10 mL of EtOAc was added
the mixture required mild heat for the compound to fully dissolve.
After being cooled back to rt, Pd/C (593 mg, 0.05 equiv, 10% Pd/C)
was carefully added, and then the mixture was hydrogenated at 1 atm
(via H2 balloon) for 8 h. The mixture was filtered over Celite, washed
with CH2Cl2, and concentrated to dryness. The crude white solid was
used in the next step without further purification. The crude material
from the previous step (11 mmol) was dissolved in MeOH (75 mL)
and cooled to 0 °C in an ice bath. Sodium borohydride (530 mg, 13.9
mmol, 1.25 equiv) was added in three portions. The mixture stirred at
0 °C for an additional 30 min and then slowly warmed to room
temperature and continued to stir for 4 h. The reaction was quenched
with 1 M HCl, and then MeOH was removed in vacuo. The mixture
was diluted with water and transferred to a separatory funnel. After
the aqueous layer was extraced with CH2Cl2 (50 mL × 3), the organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated to dryness. The crude solid was recrystallized from
boiling MeOH, yielding 1.452 g of colorless crystals. Succinic
anhydride (0.868 g, 8.68 mmol, 2.0 equiv), triethylamine (0.76 mL,
5.43 mmol, 1.25 equiv), and DMAP (53 mg, 0.43 mmol, 0.1 equiv)
were added to a solution of 1.452 g (4.34 mmol, 1.0 equiv) of the
alcohol from the previous step in CH2Cl2 (45 mL). After being stirred
overnight, an additional 0.5 g of succinic anhydride and 50 mg of
DMAP were added, and the mixture was allowed to stir overnight
again. The mixture was transferred to a separatory funnel (diluted
with CH2Cl2) and washed with 1 M HCl, followed by brine, dried
over Na2SO4, filtered, and concentrated to dryness. The crude mixture
was purified via column chromatography on silica gel with EtOAc/
hexanes to provide the succinate derivative as a white solid (1.49 g,
79%). Glucose diacetonide (0.98 g, 3.76 mmol, 1.1 equiv), EDC−
HCl (0.754 g, 3.93 mmol, 1.15 equiv), triethylamine (1.15 mL, 8.21
mmol, 2.4 equiv), and DMAP (0.460 g, 3.76 mmol, 1.1 equiv) were
added to the succinate derivative from the previous step (1.49 g, 3.42
mmol, 1.0 equiv) in CH2Cl2 (35 mL) at rt. The reaction was stirred at
rt overnight, and then an additional 0.5 g of EDC−HCl, 0.25 mL of
Et3N, and 0.25 g of DMAP were added. After being stirred for an
additional 14 h, the mixture was transferred to a separatory funnel
(dilute with CH2Cl2) and washed with water and then brine. The
organic layer was dried over Na2SO4, filtered, and concentrated to
dryness. The crude mixture was purified via column chromatography
on silica gel with EtOAc/hexanes to provide the glycosteroid
derivative as a white solid (1.435 g, 62%): 1H NMR (400 MHz,
CDCl3) δ 5.85 (1H, d, J = 3.7 Hz), 5.23 (1H, d, J = 2.5 Hz), 4.71−
4.63 (1H, m), 4.61−4.57 (1H, m), 4.49 (1H, d, J = 3.7 Hz), 4.24−
4.18 (2H, m), 4.09−4.06 (1H, m), 4.03−3.99 (1H, m), 2.68−2.56
(4H, m), 2.17−2.08 (1H, m), 2.01 (3H, s), 1.83−1.77 (1H, m),
1.74−1.65 (3H, m), 1.64−1.56 (2H, m), 1.54−1.25 (20H, m), 1.21−
0.93 (5H, m), 0.91−0.84 (1H, m), 0.82 (3H,s), 0.76 (3H,s), 0.68−
0.61 (1H, m); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 171.0,
170.7, 112.2, 109.3, 105.0, 83.3, 83.2, 79.7, 76.4, 73.6, 72.4, 67.2, 54.1,
50.6, 44.6, 42.7, 36.9, 36.7, 35.5, 35.2, 33.9, 31.4, 29.2, 29.1, 28.4,
27.5, 27.4, 26.8, 26.7, 26.2, 25.2, 23.5, 21.4, 20.6, 12.2, 12.1; HRMS
1
mg, 42%); H NMR (400 MHz, CDCl3) δ 6.50−6.32 (1H, m), 4.90
(2H, br s), 1.55−1.49 (3H, m); 13C{1H} NMR (100 MHz, CDCl3) δ
154.2 (m), 102.1 (d, J = 219.7 Hz), 19.7 (d, J = 24.7 Hz); 19F NMR
(282 MHz, CDCl3) δ −119.6 to −120.0 (1F, dq, 2JFH = 56.8 Hz, 3JFH
= 20.7 Hz); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C3H7O2NF+ 108.0461; found 108.0462.
4.4. Syntheses and Characterization of Starting Materials.
4.4.1. Previously Reported Starting Materials. Starting materials for
compounds 1, 2, 3, and 5: Diacetonide esters of glucose, galactose,
fructose, and mannose were prepared using previously reported
methods. NMR data match previously reported spectra for glucose
derivative 1,39 galactose 2,40 fructose 3,41 and mannose 5.42 Starting
material for ketone 6 is commercially available; however, we observed
higher yields with material that we synthesized, as described in Shi’s
original paper.43 Starting materials for compounds 944 and 1045 were
prepared using previously reported methods (NMR data matches
reported spectra). Starting material for compound 11 is commercially
available.
4.4.2. New Starting Materials. 4.4.2.1. (R)-2-((S)-2,2-Dimethyl-
1,3-dioxolan-4-yl)-5-oxo-2,5-dihydrofuran-3,4-diyl Diacetate
(Starting Material for Compound 4). Anhydrous CuSO4 (4.49 g,
28.10 mmol, 1.65 equiv) was added to a mixture of L-ascorbic acid
(3.0 g, 17.03 mmol) in dry acetone (70 mL). The reaction was stirred
for 24 h; then another 1.65 equiv of anhydrous CuSO4 was added and
the reaction stirred overnight. The mixture was filtered through Celite
(washed w/acetone) and concentrated to dryness, yielding pure
ascorbic acid acetonide. DMAP (85 mg, 0.693 mmol, 0.1 equiv) was
added to ascorbic acid acetonide (1.5 g, 6.93 mmol, 1.0 equiv) in
acetic anhydride (15 mL). The reaction was stirred at room
temperature for 24 h, and then Ac2O was removed via vacuum
distillation with mild heat. The crude mixture was purified via column
chromatography on silica gel with EtOAc/hexanes to provide (R)-2-
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-oxo-2,5-dihydrofuran-3,4-diyl
1
diacetate (1.41 g, 68%): white solid; H NMR (400 MHz, CDCl3) δ
5.14 (1H, d, J = 2.4 Hz), 4.41−4.37 (1H, m), 4.21−4.08 (2H, m),
2.30 (3H, s), 2.27 (3H, s), 1.39 (3H, s), 1.36 (3H, s); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.2, 165.5, 164.8, 150.8, 122.2, 110.9, 75.2,
72.9, 65.2, 25.7, 25.4, 20.5, 20.1; HRMS (ESI-Orbitrap) m/z [M +
+
H]+ calcd for C13H17O8 301.0923, observed 301.0920.
4.4.2.2. Desonide Diacetate (Starting Material for Compound 7).
Acetic anhydride (0.88 mL, 9.28 mmol, 4.0 equiv) was added to a
mixture of desonide (0.97 g, 2.32 mmol, 1.0 equiv), DMAP (28 mg,
0.232 mmol, 0.1 equiv), and triethylamine (0.78 mL, 5.57 mmol, 2.4
equiv) in CH2Cl2 (23 mL) at room temperature. The mixture was
stirred overnight and then was transferred to a separatory funnel
(dilute with CH2Cl2) and washed with 1 M HCl, saturated aqueous
sodium bicarbonate, and then brine. The organic layer was dried over
Na2SO4, filtered, and concentrated to dryness. The crude white solid
was recrystallized from boiling MeOH, yielding pure desonide
diacetate (0.95 g, 82%): colorless crystals; 1H NMR (400 MHz,
CDCl3) δ 6.93 (1H, d, J = 10.1 Hz), 6.28−6.25 (1H, m), 6.03 (1H, t,
J = 1.5 Hz), 5.56−5.54 (1H, m), 5.02−4.64 (3H, m), 2.56−2.47 (1H,
m), 2.39−2.34 (1H, m), 2.21−2.14 (4H, m), 2.13−2.06 (4H, m),
1.99−1.87 (2H, m), 1.74−1.69 (1H, m), 1.64−1.54 (2H, m), 1.42
(3H, s), 1.27−1.12 (8H, m), 0.82 (3H, s); 13C{1H} NMR (100 MHz,
CDCl3) δ 203.6, 185.9, 170.1, 169.8, 168.1, 154.1, 128.5, 123.0, 111.4,
97.3, 81.7, 71.1, 67.4, 53.8, 49.6, 45.5, 42.9, 36.5, 33.8, 33.7, 31.8,
30.8, 26.5, 25.5, 21.8, 20.8, 20.4, 16.5; HRMS (ESI-Orbitrap) m/z [M
+
(ESI-Orbitrap) m/z [M + H]+ calcd for C37H57O11 677.3901,
observed 677.3897.
ASSOCIATED CONTENT
■
+
+ H]+ calcd for C28H37O8 501.2488, observed 501.2485.
sı
* Supporting Information
4.4.2.3. Glycosteroid Derivative (Starting Material for Com-
pound 8). Acetic anhydride (2.11 mL, 22.3 mmol, 2.0 equiv) was
added to a mixture of dehydroepiandrosterone (3.22 g, 11.15 mmol,
1.0 equiv), DMAP (136 mg, 1.11 mmol, 0.1 equiv), and triethylamine
(1.95 mL, 13.94 mmol, 1.25 equiv) in CH2Cl2 (111 mL) at room
temperature. The mixture was stirred overnight and then was
transferred to a separatory funnel (dilute with CH2Cl2) and washed
with 1 M HCl, saturated aqueous sodium bicarbonate, and then brine.
The organic layer was dried over Na2SO4, filtered, and concentrated
to dryness. The crude white solid was used in the next step without
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03047.
NMR spectral data of fluorinated products, NMR
spectral data of starting materials, example of crude 19F
NMR spectrum for compound 1; determination of
diastereomeric ratio, preliminary mechanism for the
fluorination/hydroxylation of hecogenin derivative,
computational methods (PDF)
H
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́
N.; Merkens, H.; Benard, F.; Martin, R. E.; Schaffer, P.; Britton, R.
Site-Selective, Late-Stage C−H 18F-Fluorination on Unprotected
Peptides for Positron Emission Tomography Imaging. Angew. Chem.,
Int. Ed. 2018, 57, 12733−12736. (d) Wu, L.; Cao, X.; Chen, X.; Fang,
W.; Dolg, M. Visible-Light Photocatalysis of C(sp3)-H Fluorination
by the Uranyl Ion: Mechanistic Insights. Angew. Chem., Int. Ed. 2018,
57, 11812−11816.
AUTHOR INFORMATION
Corresponding Authors
■
Travis Dudding − Department of Chemistry, Brock University,
St. Catharines, ON L2S 3A1, Canada; orcid.org/0000-
0002-2239-0818; Email: dudding@brocku.ca
Thomas Lectka − Department of Chemistry, Johns Hopkins
University, Baltimore, Maryland 21218, United States;
orcid.org/0000-0003-3088-6714; Email: lectka@jhu.edu
(6) (a) Bume, D. D.; Pitts, C. R.; Ghorbani, F.; Harry, S. A.;
Capilato, J. N.; Siegler, M. A.; Lectka, T. Ketones as Directing Groups
in Photocatalytic sp3 C-H Fluorination. Chem. Sci. 2017, 8, 6918−
6923. (b) Bume, D. D.; Harry, S. A.; Pitts, C. R.; Lectka, T. Sensitized
Aliphatic Fluorination Directed by Terpenoidal Enones: A “Visible
Light” Approach. J. Org. Chem. 2018, 83, 1565−1575.
Authors
Joseph N. Capilato − Department of Chemistry, Johns Hopkins
University, Baltimore, Maryland 21218, United States;
orcid.org/0000-0001-5996-2456
Cody Ross Pitts − Department of Chemistry, Johns Hopkins
University, Baltimore, Maryland 21218, United States
Rozhin Rowshanpour − Department of Chemistry, Brock
University, St. Catharines, ON L2S 3A1, Canada
(7) (a) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M.
G.; Lectka, T. Iron(II)-Catalyzed Benzylic Fluorination. Org. Lett.
2013, 15, 1722−1724. (b) Liu, W.; Groves, J. T. Manganese-
Catalyzed Oxidative Benzylic C-H Fluorination by Fluoride Ions.
Angew. Chem., Int. Ed. 2013, 52, 6024−6027. (c) Bloom, S.; Knippel,
J. L.; Holl, M. G.; Barber, R.; Lectka, T. A Cooperative Allylic
Fluorination: Combination of Nucleophilic and Electrophilic Fluorine
Sources. Tetrahedron Lett. 2014, 55, 4576−4580. (d) Bume, D. D.;
Pitts, C. R.; Jokhai, R. T.; Lectka, T. Direct, Visible Light-Sensitized
Benzylic C-H Fluorination of Peptides using Dibenzosuberenone:
Selectivity for Phenylalanine-Like-Residues. Tetrahedron 2016, 72,
6031−6036. (e) Danahy, K. E.; Cooper, J. C.; Van Humbeck, J. F.
Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron
Transfer to Selectfluor. Angew. Chem., Int. Ed. 2018, 57, 5134−5138.
(8) Lowry, J. H.; Mendlowitz, J. S.; Subramanian, N. S. Optical
characteristics of Teflon AF® fluoroplastic materials. Opt. Eng. 1992,
31, 1982−1985.
(9) Sharma, M.; Bernacki, R. J.; Korytnyk, W. Fluorinated Analogs of
Cell-Surface Carbohydrates as Potential Chemotherapeutic Agents.
Fluorinated Carbohydrates, ACS Symposium Series; American
Chemical Society: Washington, DC, 1988; Vol. 374, pp 191−206.
(10) Malek-Adamian, E.; Patrascu, M. B.; Jana, S. K.; Martínez-
Montero, S.; Moitessier, N.; Damha, M. J. Adjusting the structure of
2′-modified nucleosides and oligonucleotides via C4′-α-F or C4′-α-
OMe substitution: synthesis and conformational analysis. J. Org.
Chem. 2018, 83 (17), 9839−9849.
(11) Hein, M.; Miethchen, R. Fluorinated Carbohydrates. Advances
in Organic Syntheses; Bentham Science Publishers, 2012; Vol. 2, pp
381−429.
(12) (a) Burton, A.; Wyatt, P.; Boons, G. J. Preparation of
fluorinated galactosyl nucleoside diphosphates to study the mecha-
nism of the enzyme galactopyranose mutase. J. Chem. Soc., Perkin
Trans. 1 1997, 1, 2375−2382. (b) Akiyama, Y.; Hiramatsu, C.;
Fukuhara, T.; Hara, S. Selective introduction of a fluorine atom into
carbohydrates and a nucleoside by ring-opening fluorination reaction
of epoxides. J. Fluorine Chem. 2006, 127, 920−923.
(13) Beniazza, R.; Abadie, B.; Remisse, L.; Jardel, D.; Lastecoueres,
D.; Vincent, J. Light-promoted metal-free cross dehydrogenative
couplings on ethers mediated by NFSI: reactivity and mechanistic
studies. Chem. Commun. 2017, 53, 12708−12711.
(14) Egami, H.; Masuda, S.; Kawato, Y.; Hamashima, Y. Photo-
fluorination of Aliphatic C−H Bonds Promoted by the Phthalimide
Group. Org. Lett. 2018, 20, 1367−1370.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03047
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.L. thanks the National Science Foundation (CHE 1800510)
for support. The authors also thank the Mass Spectrometry
Facility at the University of Delaware. T.D. acknowledges
financial support from the Natural Science and Engineering
Research Council (NSERC) Discovery grant (2019-04205).
Computations were carried out using facilities at SHARCNET
(Shared Hierarchical Academic Research Computing Network:
www.sharcnet.ca) and Compute/Calcul Canada.
REFERENCES
■
(1) For some of the pioneering work in contemporary radical
fluorination methodologies, see: (a) Rueda-Becerril, M.; Chatalova
Sazepin, C.; Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J.-
F.; Sammis, G. M. Fluorine Transfer to Alkyl Radicals. J. Am. Chem.
Soc. 2012, 134, 4026−4029. (b) Liu, W.; Huang, X.; Cheng, M.-J.;
Nielsen, R. J.; Goddard, W. A., III; Groves, J. T. Oxidative Aliphatic
C-H Fluorination with Fluoride Ion Catalyzed by a Manganese
Porphyrin. Science 2012, 337, 1322−1325. (c) Bloom, S.; Pitts, C. R.;
Miller, D.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. A
Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic
Fluorination. Angew. Chem., Int. Ed. 2012, 51, 10580−10583.
(2) Shah, P.; Westwell, A. D. The role of fluorine in medicinal
chemistry. J. Enzyme Inhib. Med. Chem. 2007, 22, 527−540.
(b) Hiyama, T.; Yamamoto, H. Biologically Active Organofluorine
Compounds. Organofluorine Compounds 2000, 1, 137−182.
́
̀
(3) O’Hagan, D. Fluorine in health care: Organofluorine containing
blockbuster drugs. J. Fluorine Chem. 2010, 131, 1071−1081.
́
́
(b) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to
the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114,
2432−2506.
(15) Hasegawa, M.; Ishii, H.; Cao, Y.; Fuchigami, T. Regioselective
Anodic Monofluorination of Ethers, Lactones, Carbonates, and Esters
Using Ionic Liquid Fluoride Salts. J. Electrochem. Soc. 2006, 153,
D162−D166.
̃
(16) Uhrig, M. L.; Lantano, B.; Postigo, A. Synthetic strategies for
fluorination of carbohydrates. Org. Biomol. Chem. 2019, 17, 5173−
(4) Ragni, R.; Punzi, A.; Babudri, F.; Farinola, G. M. Organic and
Organometallic Fluorinated Materials for Electronics and Optoelec-
tronics: A Survey on Recent Research. Eur. J. Org. Chem. 2018, 2018,
3500−3519.
(5) (a) Bume, D. D.; Harry, S. A.; Lectka, T.; Pitts, C. R. Catalyzed
and Promoted Aliphatic Fluorination. J. Org. Chem. 2018, 83, 8803−
8814. (b) Miao, J.; Yang, K.; Kurek, M.; Ge, H. Palladium-Catalyzed
Site-Selective Fluorination of Unactivated C(sp3)−H Bonds. Org. Lett.
2015, 17, 3738−3741. (c) Yuan, Z.; Nodwell, M. B.; Yang, H.; Malik,
5189.
(17) Pitts, C. R.; Siegler, M. A.; Lectka, T. An Intermolecular
Aliphatic C-F—H-C Interaction in the Presence of ’Stronger’
Hydrogen Bond Acceptors: Crystallographic, Computational, and
IR Studies. J. Org. Chem. 2017, 82, 3996−4000.
I
https://dx.doi.org/10.1021/acs.joc.9b03047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
(18) Xia, J.-B.; Zhu, C.; Chen, C. Visible Light-Promoted Metal-Free
C−H Activation: Diarylketone-Catalyzed Selective Benzylic Mono-
and Difluorination. J. Am. Chem. Soc. 2013, 135, 17494−17500.
(19) Pitts, C. R.; Bume, D. D.; Harry, S. A.; Siegler, M. A.; Lectka, T.
Multiple Enone-Directed Reactivity Modes Lead to the Selective
Photochemical Fluorination of Polycyclic Terpenoid Derivatives. J.
Am. Chem. Soc. 2017, 139, 2208−2211.
formula into a functional of the electron density. Phys. Rev. B:
Condens. Matter Mater. Phys. 1988, 37, 785.
(34) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi,
R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox,
J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.
(35) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. An
Efficient Catalytic Asymmetric Epoxidation Method. J. Am. Chem. Soc.
1997, 119, 11224−11235.
(36) Note that we were unsuccessful in isolating the fluorinated Shi
catalyst derivative, as we found it to be inseparable from the starting
material. Chromatography on silica gel, Florisil, and alumina led only
to a 1:1 mixture of starting material and product, due to significant
streaking which we believe is caused by hydration of the unusually
reactive ketone (see SI).
(37) Rye, C. S.; Baell, J. B.; Street, I. Synthesis, reactivity and
applications of 1-fluoroalkyl carboxylates: novel synthetic substrates
for esterases and lipases. Tetrahedron 2007, 63, 3306−3311.
(38) Dolbier, W. R. Guide to Fluorine NMR for Organic Chemists, 2nd
ed.; John Wiley & Sons, 2016; pp 66−68.
(39) Bantu, R.; Mereyala, H. B.; Nagarapu, L.; Kantevari, S. 3-O-
Acyl triggered tandem Lewis acid catalyzed intramolecular cyclization
of diacetone glucose derivatives to 5-O-acyl-3,6-anhydro-d-glucose.
Tetrahedron Lett. 2011, 52, 4854−4856.
(40) Ch, R.; Tyagi, M.; Patil, P. R.; Ravindranathan Kartha, K. P.
DABCO: an efficient promoter for the acetylation of carbohydrates
and other substances under solvent-free conditions. Tetrahedron Lett.
2011, 52, 5841−5846.
(41) Zhang, P.; Ling, C. C. A mild acetolysis procedure for the
regioselective removal of isopropylidene in di-O-isopropylidene-
protected pyranoside systems. Carbohydr. Res. 2017, 445, 7−13.
(42) Matassini, C.; Mirabella, S.; Ferhati, X.; Faggi, C.; Robina, I.;
Goti, A.; Moreno-Clavijo, E.; Moreno-Vargas, A. J.; Cardona, F.
Polyhydroxyamino-Piperidine-Type Iminosugars and Pipecolic Acid
Analogues from a D-Mannose-Derived Aldehyde. Eur. J. Org. Chem.
2014, 5419−5432.
(43) Tu, Y.; Wang, Z. X.; Shi, Y. An Efficient Asymmetric
Epoxidation Method for trans-Olefins Mediated by a Fructose-
Derived Ketone. J. Am. Chem. Soc. 1996, 118, 9806−9807.
(44) Theodoropoulos, D.; Craig, L. C. The Synthesis of Several
Isoleucyl Peptides and Certain of Their Properties. J. Org. Chem.
1955, 20, 1169−1172.
(20) Weymouth-Wilson, A. C.; Clarkson, R. A.; Jones, N. A.; Best,
́
D.; Wilson, F. X.; Pino-Gonzalez, M. S.; Fleet, G. W. J. Large scale
synthesis of the acetonides of l-glucuronolactone and of l-glucose:
easy access to l-sugar chirons. Tetrahedron Lett. 2009, 50, 6307−6310.
̈
(21) Movsisyan, L. D.; Schafer, E.; Nguyen, A.; Ehrmann, F. R.;
Schwab, A.; Rossolini, T.; Zimmerli, D.; Wagner, B.; Daff, H.; Heine,
A.; Klebe, G.; Diederich, F. Sugar Acetonides are a Superior Motif for
Addressing the Large, Solvent-Exposed Ribose-33 Pocket of tRNA-
Guanine Transglycosylase. Chem. - Eur. J. 2018, 24, 9957−9967.
(22) Padayatty, S. J.; Katz, A.; Wang, Y.; Eck, P.; Kwon, O.; Lee, J.
H.; Chen, S.; Corpe, C.; Dutta, A.; Dutta, S. K.; Levine, M. Vitamin C
as an Antioxidant: Evaluation of Its Role in Disease Prevention. J. Am.
Coll. Nutr. 2003, 22, 18−35.
̈
(23) Ekholm, F. S.; Schneider, G.; Wolfling, J.; Leino, R. Synthesis of
a Small Library of Estradiol-Based Glycosteroid Mimics Containing a
Modified D-Ring. Eur. J. Org. Chem. 2011, 2011 (6), 1064−1077.
(24) Tano, Y.; Chandler, D.; Machemer, R. Treatment of Intraocular
Proliferation with Intravitreal Injection of Triamcinolone Acetonide.
Am. J. Ophthalmol. 1980, 90, 810−816.
(25) Diekema, D. J.; Jones, R. N. Oxazolidinone antibiotics. Lancet
2001, 358, 1975−1982.
(26) Heravi, M. M.; Zadsirjan, V. Oxazolidinones as chiral auxiliaries
in asymmetric aldol reactions applied to total synthesis. Tetrahedron:
Asymmetry 2013, 24, 1149−1188.
(27) Verniest, G.; Colpaert, F.; Van Hende, E.; De Kimpe, N.
Synthesis and Reactivity of 1-Substituted 2-Fluoro- and 2,2-
Difluoroaziridines. J. Org. Chem. 2007, 72, 8569−8572.
(28) Cao, Y.; Suzuki, K.; Tajima, T.; Fuchigami, T. Electrolytic
partial fluorination of organic compounds. Part 78: Regioselective
anodic fluorination of 2-oxazolidinones. Tetrahedron 2005, 61, 6854−
6859.
(29) Gaenzler, F. C.; Smith, M. B. A Dichlorination−Reductive-
Dechlorination Route to N-Acetyl-2-Oxazolone. Synlett 2007, 2007,
1299−1301.
(30) Tumanov, V. E. Calculation of the C−H Bond Dissociation
Energies in Linear and Cyclic Acetals and Thioacetals from Kinetic
Data. Petroleum Chemistry 2005, 45, 350−363.
(31) (a) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.;
Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. Direct, Catalytic
Monofluorination of sp3 C-H Bonds: A Radical-Based Mechanism
with Ionic Selectivity. J. Am. Chem. Soc. 2014, 136, 9780−9791.
(b) Kee, C. W.; Chin, K. F.; Wong, M. W.; Tan, C. Selective
fluorination of alkyl C−H bonds via photocatalysis. Chem. Commun.
2014, 50, 8211−8214.
(32) (a) Capilato, J. N.; Bume, D. D.; Lee, W. H.; Hoffenberg, L. E.
S.; Jokhai, R. T.; Lectka, T. Fluorofunctionalization of CC Bonds
with Selectfluor: Synthesis of β-Fluoropiperazines through a
Substrate-Guided Reactivity Switch. J. Org. Chem. 2018, 83,
14234−14244. (b) Pitts, C. R.; Ling, B.; Snyder, J. A.; Bragg, A. E.;
Lectka, T. Aminofluorination of Cyclopropanes: A Multifold
Approach through a Common, Catalytically Generated Intermediate.
J. Am. Chem. Soc. 2016, 138, 6598−6609. (c) Bloom, S.; Bume, D. D.;
Pitts, C. R.; Lectka, T. Site-Selective Approach to β-Fluorination:
Photocatalyzed Ring Opening of Cyclopropanols. Chem. - Eur. J.
2015, 21, 8060−8063.
(45) Li, B.; Wang, H.; Zhu, Q.; Shi, Z. Rhodium/Copper-Catalyzed
Annulation of Benzimides with Internal Alkynes: Indenone Synthesis
through Sequential C-H and C-N Cleavage. Angew. Chem., Int. Ed.
2012, 51, 3948−3952.
(33) (a) Becke, A. D. Density-functional thermochemistry. III. The
role of exact exchange. J. Chem. Phys. 1993, 98, 5648−5652.
(b) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.;
Gordon, M. S.; DeFrees, D. J.; Pople, J. A. Self-consistent molecular
orbital methods. XXIII. A polarization-type basis set for second-row
elements. J. Chem. Phys. 1982, 77, 3654−3665. (c) Lee, C.; Yang, W.;
Parr, R. G. Development of the Colle-Salvetti correlation-energy
J
https://dx.doi.org/10.1021/acs.joc.9b03047
J. Org. Chem. XXXX, XXX, XXX−XXX