Direct, visible light-sensitized benzylic C[sbnd]H fluorination of peptides using dibenzosuberenone: selectivity for phenylalanine-like residues

Article abstract of DOI:10.1016/j.tet.2016.08.018

A visible light-sensitized benzylic sp³C[sbnd]H fluorination protocol using dibenzosuberenone (5?mol?%) and Selectfluoris optimized for the direct functionalization of phenylalanine-like residues in short chain peptides. Amino acids, dipeptides, and tripeptides undergo benzylic fluorination with remarkable regioselectivity in the presence of protected basic, acidic, and nonpolar side chains (including those with tertiary sites). Additionally, protecting group compatibility, a gram scale application, and competition experiments were explored.

Full text of DOI:10.1016/j.tet.2016.08.018

Tetrahedron 72 (2016) 6031e6036
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct, visible light-sensitized benzylic CeH fluorination of peptides
using dibenzosuberenone: selectivity for phenylalanine-like
residues
*
Desta Doro Bume, Cody Ross Pitts, Rayyan Trebonias Jokhai, Thomas Lectka
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
a r t i c l e i n f o
a b s t r a c t
A visible light-sensitized benzylic sp3 CeH fluorination protocol using dibenzosuberenone (5 mol %) and
SelectfluorÒ is optimized for the direct functionalization of phenylalanine-like residues in short chain
peptides. Amino acids, dipeptides, and tripeptides undergo benzylic fluorination with remarkable re-
gioselectivity in the presence of protected basic, acidic, and nonpolar side chains (including those with
tertiary sites). Additionally, protecting group compatibility, a gram scale application, and competition
experiments were explored.
Article history:
Received 1 June 2016
Received in revised form 31 July 2016
Accepted 4 August 2016
Available online 5 August 2016
Dedicated to Professor Gary H. Posner on
the occasion of his retirement.
Ó 2016 Published by Elsevier Ltd.
Keywords:
Fluorination
Photochemistry
Amino acids
Peptides
Regioselectivity
1. Introduction
phenylalanine in the substrate scope.7 Given our interest in the latter
approach, we asked: does the innate benzylic selectivity drop off
The typical procession of synthetic method development passes
through three arenas: 1) reaction discovery, 2) optimization and
mechanistic understanding, and 3) application. In the world of mod-
ern fluorine chemistry, our laboratory1 and others2 have discovered
some of the first mild ways to effect ‘radical fluorination’ of sp3 CeH
bonds e transformations of high interest in the fields of medicine and
agrochemistry (arena 1).3 Significant strides have been made in pro-
ducingand beginningtounderstandthesereactions;however, greater
selectivity and more tangible applications to the synthesis of bi-
ologically relevant molecules remainpromising goals (arenas 2 and 3).
Toward these efforts, we report a discrete photochemical method
optimized for the site-selective fluorination of peptides.4
when phenylalanine is incorporated into peptide chains (Fig. 1)?
Would we observe competitive fluorination on the tertiary sites of
valine8 and leucine,9 for example? To our satisfaction, we found that
our newly-developed photochemical approach using SelectfluorÒ,
catalytic dibenzosuberenone, and visible light (14-Watt CFL) is re-
markably selective for the benzylic sites of phenylalanine- and
tyrosine-like residues in short chain peptides that incorporate a vari-
ety of aliphatic and protected basic or acidic side chains.
Historically, chemists have gone to great lengths to access b-
fluorinated amino acids.5 Recently, a few examples regarding direct
CeH fluorination of individual amino acids have materialized in the
chemical literature. For instance, palladium catalysis has proven
valuable in ligand-directed syntheses of
a much lesser extent, photochemical benzylic fluorination tactics
b-fluoro-a
-amino acids.6 To
have also emerged that include a single derivative of
b-fluoro-
Fig. 1. Benzylic selectivity strategy toward ‘directed’ fluorination within peptide nat-
* Corresponding author. E-mail address: lectka@jhu.edu (T. Lectka).
ural products.
http://dx.doi.org/10.1016/j.tet.2016.08.018
0040-4020/Ó 2016 Published by Elsevier Ltd.

6032
D.D. Bume et al. / Tetrahedron 72 (2016) 6031e6036
2. Results and discussion
Subsequently, we turned our attention to the scope of N- and C-
termini protecting groups using phenylalanine derivatives (Table
2). Protecting group strategies are invaluable in peptide synthesis
and may also be necessary to maintain compatibility with photo-
chemical fluorination.14 For instance, basic nitrogen sites have been
particularly problematic in sp3 CeH fluorination methods;15 how-
ever, this may be circumvented through the installation of electron-
withdrawing groups. Along these lines, phthalimido16 (NPhth) and
trifluoroacetate17 (TFA) substituents at the N-terminus provided
the best results (80% and 67%), and acetate groups were also
competent (57%). On the other hand, Boc, Fmoc, and Cbz groups
were not compatible with fluorination (0e10% yield). At the C-
terminus, methyl and ethyl esters perform equally well,18 but tert-
butyl, trityl, and adamantyl esters decompose or undergo addi-
tional fluorination under the reaction conditions (accompanied
with a decrease in yield). Moreover, we found that the C-terminus
does not require a protecting group e photochemical benzylic
fluorination can be achieved in good yields in the presence of car-
boxylic acids without competitive decarboxylative fluorination.19
Our initial screen included an evaluation of existing photo-
chemical fluorination methods (developed in our laboratory7b,10
and by others11) on a simple dipeptide e NPhth-Ala-Phe-OEt (1).
Immediately, we found the methods that performed suitably in the
fluorination of a single amino acid experienced a decline in product
yield when applied to this dipeptide (Table 1). In some instances,
increased loadings of the photosensitizers improved yields, but
never above 50%. Accordingly, we expanded our survey to other
potential ultraviolet and visible light photosensitizers. To our sat-
isfaction, dibenzosuberenone12 (5 mol %) and visible light from
a 14-Watt CFL proved competent in the selective benzylic fluori-
nation of NPhth-Ala-Phe-OEt using SelectfluorÒ (2.0 equiv) to
provide 2 in 73% yield. We also noted that the diastereomeric ratio
of the fluorinated product was ca. 2.1:1, regardless of
photosensitizer.
Table 1
Photochemical fluorination optimized for dipeptides
Table 2
Protecting group compatibility
In addition to phenylalanine, we envisioned that other benzylic
residues could be targeted, such as tyrosine or other non-natural
amino acids. The hydroxy substituent on tyrosine activates the ar-
omatic ring toward background EAS with SelectfluorÒ, which sub-
stantially diminishes selectivity and the extent of benzylic
fluorination.20 Acetylation reduces ring fluorination, but still results
in poor desired product yields. However, transformation of the
hydroxy substituent to a trifluoroacetyl group makes tyrosine res-
idues viable candidates for direct benzylic fluorination (71%
yield).21 What is more, the phthalimide-protected p-fluoro-phe-
nylalanine, an isoelectronic and isosteric replacement for tyrosine,
underwent benzylic fluorination in 84% yield (Table 3).
At this juncture, we had established a visible light protocol on
a prototypical dipeptide, determined the compatibility of an array
of protecting groups, and investigated the viability of other
phenylalanine-like residues as targets for benzylic fluorination (3,
4, and 5). The next step was to examine the regioselectivity and
reaction efficiency in the presence of other amino acids. Thus, we
Control experiments revealed that 1) the reaction does not
proceed in the absence of either light or dibenzosuberenone, 2)
increasing the amount of SelectfluorÒ or dibenzosuberenone begins
to have a negative impact on yield (though SelectfluorÒ may be
decreased to 1.5 equiv in some cases with only a 5e10% decrease in
yield), and 3) some benzylic fluorination is observed by heating the
reaction mixture to reflux in the dark, albeit in poor yield (25%).13
Furthermore, most photochemical fluorination methods require
inert atmosphere, but this approach performs equally well in am-
bient air. Although anhydrous MeCN was used, rigorous exclusion
of air and moisture (e.g., by degasification and Schlenck techniques)
proved unnecessary e a testament to the robustness of the
protocol.

D.D. Bume et al. / Tetrahedron 72 (2016) 6031e6036
6033
Table 3
explored a number of dipeptides incorporating one phenylalanine-
like residue (Table 3).22 Consistent with our protecting group
screen, dipeptides with carboxylic acid side chains (i.e., aspartic
acid in TFA-Aspartame and glutamic acid methyl ester in NPhth-
Glu-(OMe)-Phe-OEt) were competent in regioselective fluorina-
tion (6 and 7). Likewise, dipeptides with basic amine side chains
were amenable to fluorination (8) after applying the same pro-
tecting group strategy discussed above (e.g., NPhth-Lys-(NPhth)-
Phe-OEt). In both instances (acidic and basic side chain de-
rivatives), benzylic fluorination was nearly site-specific; that is,
Substrate scope: phenylalanine-like residues targeted for fluorination in amino
acids and dipeptides
only trace secondary aliphatic or
all.
a-fluorination was observed, if at
When it comes to nonpolar amino acids, glycine, alanine, and b-
alanine derivatives intuitively are not susceptible to regioselectivity
issues (2, 9e11). Yet, valine, leucine, and isoleucine all contain
tertiary sites that could conceivably compete with benzylic fluori-
nation, assuming a radical-based mechanism.23 (In fact, photo-
chemical fluorination of the tertiary CeH site in valine has been
reported in the literature.8) Fortuitously, benzylic fluorination is
preferred over tertiary fluorination by more than an order of
magnitude (12 and 13), with only 4% and trace yield of the tertiary
fluoride on 12 and 13, respectively. This is particularly exciting as
NPhth-Val-OH undergoes tertiary fluorination in up to 73% yield
under identical reaction conditions when not associated with
phenylalanine.
We also extended our scope to a few phenylalanine-containing
tripeptides (Table 4). For instance, NPhth-Ala-Phe-Leu-OEt dis-
played similar propensity toward benzylic fluorination as the di-
peptides, providing the desired product 14 in 63% yield and high
regioselectivity. Also, in the presence of both valine and leucine in
NPhth-Phe-Val-Leu-OEt, the benzylic site of phenylalanine is still
highly favored for CeH fluorination (15).
Table 4
Regioselective fluorination showcased in tripeptides
In general, the diastereoselectivity of the fluorination reactions
on amino acids and dipeptides was low (ꢀ3:1 dr), but di-
astereomers were often separable by column chromatography.
Regarding the tripeptides, individual fluorinated diastereomers
were particularly difficult to isolate from starting material by
standard column chromatography. This can be remedied, to some

6034
D.D. Bume et al. / Tetrahedron 72 (2016) 6031e6036
extent, by resubmitting the crude reaction mixture (after workup)
to the same reaction conditions, thus driving the reaction near
complete conversion. However, difluorination of valine-containing
peptides (i.e., at the benzylic and tertiary sites) becomes prevalent
upon resubmission.
individual diastereomers (compounds 2, 4, 7, 8, and 9) or as mix-
tures of diastereomers via gradient column chromatography using
a CombiFlashÒ RfþLumenÔ either on silica gel eluting with 100:0
hexanes:EtOAc to 0:100 hexanes:EtOAc or on C18 eluting with
10:90 MeCN:H2O to 100:0 MeCN:H2O.
To explore the benzylic selectivity over tertiary sites further, we
conducted intra- and intermolecular competition experiments be-
tween phenylalanine and valine residues (Scheme 1).24 Under the
reaction conditions, the valine- and phenylalanine-containing di-
peptide, in an intramolecular competition, underwent fluorination
at the benzylic position (12) in a ratio >10:1 over the tertiary site
(17) by 19F NMR analysis of the crude reaction mixture. On the other
hand, a 1:1 mixture of phenylalanine and valine in an in-
termolecular competition experiment provided a somewhat un-
expected result e a 1:1 mixture of benzylic:tertiary fluorinated
products (3:18). Likely, there is a product-determining step that
ensues the rate-determining step in the dipeptide.25 This feature
would be the culprit for our ability to target benzylic residues in
small peptides, even in the presence of ‘equally reactive’ tertiary
sites.
4.1.1. Ethyl (2R)-2-((S)-2-(1,3-dioxoisoindolin-2-yl)propana-mido)-
3-fluoro-3-phenylpropanoate (2). Following the general procedure
and workup, the major diastereomer of 2 was isolated (70 mg,
49%) as a colorless oil (both diastereomers in 73% yield by 19F
NMR). 1H NMR (400 MHz, CDCl3):
d 7.85e7.82 (2H, m), 7.76e7.72
(2H, m), 7.28e7.21 (5H, m), 6.71 (1H, d, J¼8.9 Hz), 6.04 (1H, dd,
J¼45.3, 2.5 Hz), 5.08 (1H, ddd, J¼30.6, 9.0, 2.6 Hz), 4.84 (1H, q,
J¼7.4 Hz), 4.25 (2H, q, J¼7.1 Hz), 1.61 (3H, d, J¼7.4 Hz), 1.28 (3H, t,
J¼7.0 Hz); 13C NMR (400 MHz, CDCl3):
d 169.1, 168.5, 168.4, 167.6,
135.3, 135.1, 134.2, 131.7, 128.64, 128.63, 128.34, 128.33, 125.0,
124.9, 123.5, 92.7 (d, J¼179.1 Hz), 62.2, 56.6 (d, J¼22.5 Hz), 49.4,
14.9, 14.0; 19F NMR (300 MHz, CDCl3):
31.0 Hz).
d
ꢁ194.0 (1F, dd, J¼45.9,
4.1.2. (2R)-2-(1,3-Dioxoisoindolin-2-yl)-3-fluoro-3-phenylprop-
anoic acid (3). Following the general procedure and workup, 3 was
isolated (63 mg, 80%) as a yellow oil (mixture of diastereomers). 1H
NMR (400 MHz, CD3CN):
d 7.85e7.79 (2H, m), 7.74e7.69 (2H, m),
7.44e7.39 (1H, m), 7.37e7.30 (2H, m), 7.28e7.20 (2H, m),
6.36e6.20 (1H, m), 5.33e5.21 (1H, m); 13C NMR (400 MHz,
CD3CN):
d 168.7, 168.0, 167.5, 137.8, 137.6, 137.0, 136.7, 136.5, 135.8,
135.7, 132.2, 131.9, 130.4, 130.38, 129.97, 129.95, 129.4, 129.3, 127.9,
127.8, 127.5, 127.4, 124.4, 124.3, 91.8 (d, J¼175.1 Hz), 91.3 (d,
J¼178.8 Hz), 56.4 (d, J¼23.2 Hz), 55.1 (d, J¼35.8 Hz); 19F NMR
(300 MHz, CD3CN):
dd, J¼45.9, 19.5 Hz).
d
ꢁ170.4 (1F, dd, J¼46.5, 15.5 Hz), ꢁ180.6 (1F,
4.1.3. Methyl (2R)-3-fluoro-2-(2,2,2-trifluoroacetamido)-3-(4-(2,2,2-
trifluoroacetoxy)phenyl)propanoate (4). Following the general
procedure and workup, the major diastereomer of 4 was isolated
(59 mg, 41%) as a pale yellow solid (both diastereomers in 71%
yield by 19F NMR); mp 140e143 ꢂC. 1H NMR (400 MHz, CD3CN):
Scheme 1. Competition experiments.
3. Conclusion
d
8.12 (1H, d, J¼9.3 Hz), 7.54e7.50 (2H, m), 7.36e7.32 (2H, m), 6.24
In all, we have found that SelectfluorÒ (2.0 equiv), catalytic
dibenzosuberenone (5 mol %), and visible light (14-Watt CFL) pro-
vide suitable photochemical conditions for the direct, sp3 benzylic
CeH fluorination of phenylalanine-like residues in amino acids and
short chain peptides. Protecting group compatibility was explored
at both the C- and N-termini, and the propensity for benzylic
fluorination was studied in the presence of amino acids with pro-
tected basic, acidic, and nonpolar side chains (including those with
tertiary sites). Despite the near equal reactivity of benzylic and
tertiary sites, as shown in an intermolecular competition experi-
ment, the benzylic sites in dipeptides and tripeptides were ob-
served to favor CeH fluorination by over an order of magnitude.
(1H, dd, J¼44.6, 3.2 Hz), 5.11 (1H, ddd, J¼30.4, 9.3, 3.0 Hz), 3.79
(3H, s); 13C NMR (400 MHz, CD3CN): 170.1, 167.38, 167.35, 157.1,
156.8, 155.8, 155.4, 149.6, 136.0, 134.8, 134.6, 130.8, 127.5, 127.4,
120.9, 91.5 (d, J¼178.4 Hz), 56.8 (d, J¼22.1 Hz), 52.8;
d
19F NMR
(300 MHz, CD3CN):
d
ꢁ75.1 (3F, s), ꢁ75.6 (3F, s), ꢁ190.5 (1F, dd,
J¼44.7, 31.0 Hz).
4.1.4. (2R)-2-(1,3-Dioxoisoindolin-2-yl)-3-fluoro-3-(4-fluoro-phenyl)
propanoic acid (5). Following the general procedure and workup, 5
was isolated (70 mg, 84%) as a yellow oil (mixture of di-
astereomers). 1H NMR (400 MHz, CDCl3):
d 8.90 (1H, s), 7.83e7.77
(1H, m), 7.72e7.60 (3H, m), 7.42e7.24 (2H, m), 7.01e6.94 (1H, m),
6.91e6.82 (1H, m), 6.35e6.15 (1H, m), 5.29e5.18 (1H, m); 13C NMR
(400 MHz, CDCl3): 171.1, 170.0, 167.2, 166.7, 164.27, 164.25, 164.1,
161.8,161.78,161.7,134.37,134.35,131.3,130.9,128.9,128.86,128.83,
128.8, 128.7, 128.63, 128.55, 127.2, 123.7, 123.6, 115.5, 115.3, 90.1 (d,
J¼177.3 Hz), 89.3 (d, J¼179.1 Hz), 55.9, 55.7, 54.6, 54.2; 19F NMR
4. Experimental section
4.1. General procedure for photochemical fluorination of
peptides
(300 MHz, CDCl3):
J¼46.5, 14.3 Hz), ꢁ177.7 (1F, dd, J¼47.0, 14.9 Hz).
d
ꢁ110.7 (3F, m), ꢁ111.5 (3F, m), ꢁ168.1 (1F, dd,
The substrate (0.25 mmol), SelectfluorÒ (177 mg, 0.5 mmol),
dibenzosuberenone (3.0 mg, 0.01 mmol), and anhydrous MeCN
(3 mL) were added to an oven-dried microwave vial equipped with
a stir bar under ambient air; the vial was then sealed with a septum
to prevent solvent evaporation. The reaction mixture was stirred
and irradiated with visible light (14-Watt CFL) for 16 h. At this time,
0.3 mL aliquots were taken for 19F NMR analysis, while the re-
mainder of the reaction mixture was diluted with Et2O, filtered
through Celite, and concentrated. Products were purified as
4.1.5. (S)-4-(((2R)-1-Fluoro-3-methoxy-3-oxo-1-phenylpropan-2-yl)
amino)-4-oxo-3-(2,2,2-trifluoroacetamido)butanoic acid (6). Following
the general procedure and workup, 6 was isolated (80 mg, 78%) as
a colorless oil (mixture of diastereomers). 1H NMR (400 MHz,
CD3CN):
d 7.91e7.80 (1H, m), 7.42e7.32 (5H, m), 7.18e7.11 (1H, m),
6.13e5.79 (1H, m), 5.04e4.91 (1H, m), 4.75e4.65 (1H, m), 3.74e3.66
(3H, m), 2.83e2.77 (1H, m), 2.72e2.65 (1H, m); 13C NMR (400 MHz,

D.D. Bume et al. / Tetrahedron 72 (2016) 6031e6036
6035
CD3CN):
d
172.1, 172.0, 170.0, 169.9, 169.83, 169.76, 169.5, 169.4, 158.0,
(300 MHz, CDCl3):
J¼45.9, 20.7 Hz), ꢁ192.1 (1F, dd, J¼45.3, 30.4 Hz).
d
ꢁ75.31 (3F, s), ꢁ75.35 (3F, s), ꢁ190.9 (1F, dd,
157.9, 157.6, 157.5, 136.8, 136.6, 136.5, 136.3, 130.09, 130.08, 129.78,
129.77, 129.5, 129.4, 127.0, 126.9, 126.63, 126.56, 93.5 (d, J¼176.9 Hz),
93.3 (d, J¼178.4 Hz), 57.8 (d, J¼23.6 Hz), 53.5 (d, J¼35.8 Hz), 50.9,
4.1.10. Ethyl (2R)-2-(3-(1,3-dioxoisoindolin-2-yl)propanamido)-3-
fluoro-3-phenylpropanoate (11). Following the general procedure
and workup, 11 was isolated (49 mg, 47%) as a beige solid (mixture
of diastereomers); mp 134e138 ꢂC. 1H NMR (400 MHz, CDCl3):
50.8, 35.53, 35.45; 19F NMR (300 MHz, CD3CN):
d
ꢁ175.9 (3F, s),
ꢁ185.0 (1F, dd, J¼45.3, 16.1), ꢁ190.4 (1F, dd, J¼45.3, 29.8 Hz).
4.1.6. Methyl (S)-4-(1,3-dioxoisoindolin-2-yl)-5-(((2R)-1-ethoxy-3-
fluoro-1-oxo-3-phenylpropan-2-yl)amino)-5-oxopentanoate
(7). Following the general procedure and workup, the major di-
astereomer of 7 was isolated (82 mg, 48%) as a colorless oil (both
diastereomers in 71% yield by 19F NMR). 1H NMR (400 MHz,
d 7.80e7.76 (2H, m), 7.69e7.65 (2H, m), 7.33e7.18 (5H, m),
6.69e6.59 (1H, m), 6.04e5.7 (1H, m), 5.18e5.04 (1H, m), 4.23e4.16
(1H, m), 4.05e3.92 (2H, m), 3.86e3.75 (1H, m), 2.72e2.52 (2H, m),
1.25e1.00 (3H, m); 13C NMR (400 MHz, CDCl3):
d 171.4, 169.7, 169.6,
169.3, 168.74, 168.71, 168.3, 168.07, 168.02, 167.95, 167.9, 135.8,
135.6, 135.41, 135.37, 135.2, 133.9, 133.8, 131.9, 129.2, 128.58, 128.57,
128.53, 128.52, 128.3, 128.22, 128.21, 128.20, 125.13, 125.05, 125.04,
125.0, 123.18, 123.15, 92.9 (d, J¼182.1 Hz), 92.8 (d, J¼178.8 Hz), 62.0,
CDCl3):
d 7.84e7.82 (2H, m), 7.75e7.30 (2H, m), 7.28e7.16 (5H, m),
7.08e7.06 (1H, m), 6.04 (1H, dd, J¼45.3, 2.5 Hz), 5.07 (1H, ddd,
J¼31.1, 9.2, 2.6 Hz), 4.77 (1H, t, J¼7.8 Hz), 4.22 (2H, q, J¼7.1 Hz),
3.60 (3H, s), 2.45e2.40 (2H, m), 2.31e2.14 (2H, m), 1.24 (3H, m);
61.6, 57.0, 56.8, 56.3, 56.1, 34.5, 34.4, 34.1, 34.0, 33.8, 13.9, 13.6; 19
F
13C NMR (400 MHz, CDCl3):
d
172.6, 168.4, 168.3, 168.2, 167.7, 135.3,
NMR (300 MHz, CDCl3):
(1F, dd, J¼45.9, 22.4 Hz).
d
ꢁ191.2 (1F, dd, J¼45.3, 29.8 Hz), ꢁ192.5
135.1, 134.4, 134.3, 131.4, 129.2, 128.53, 128.52, 124.93, 124.85,
123.6, 92.7 (d, J¼179.5 Hz), 62.1, 56.6 (d, J¼22.1 Hz), 53.6, 51.7,
30.5, 24.0, 13.94; 19F NMR (300 MHz, CDCl3):
J¼45.3, 31.0 Hz).
d
ꢁ192.6 (1F, dd,
4.1.11. Ethyl ((2R)-2-(1,3-dioxoisoindolin-2-yl)-3-fluoro-3-
phenylpropanoyl)- -valinate (12). Following the general procedure
and workup, 12 was isolated (68 mg, 62%) as a colorless oil (mixture
of diastereomers). 1H NMR (400 MHz, CDCl3):
7.94e7.87 (1H, m),
L
4.1.7. Ethyl
(2R)-2-((S)-2,6-bis(1,3-dioxoisoindolin-2-yl)hexan-
d
amido)-3-fluoro-3-phenylpropanoate (8). Following the general
procedure and workup, the major diastereomer of 8 was isolated
(103 mg, 42%) as a colorless oil (both diastereomers in 61% yield by
7.80e7.74 (1H, m), 7.73e7.67 (1H, m), 7.64e7.60 (1H, m), 7.55e7.50
(1H, m), 7.41e7.36 (2H, m), 7.29e7.24 (2H, m), 7.21e7.15 (1H, m),
6.56e6.33 (1H, m), 5.36e5.30 (1H, m), 4.63e4.36 (1H, m),
4.31e4.18 (1H, m), 4.15e4.01 (1H, m), 2.30e2.02 (1H, m), 1.32e1.16
19F NMR). 1H NMR (400 MHz, CDCl3):
d 7.84e7.813 (2H, m),
7.811e7.78 (2H, m), 7.76e7.73 (2H, m), 7.70e7.67 (2H, m),
7.30e7.25 (5H, m), 7.19e7.16 (1H, m), 6.07 (1H, dd, J¼45.4, 2.5 Hz),
5.08 (1H, ddd, J¼31.5, 9.1, 2.5 Hz), 4.68 (1H, dd, J¼9.8, 6.4 Hz),
4.30e4.18 (2H, m), 3.58 (2H, t, J¼7.3 Hz), 2.42e1.97 (3H, m),
1.75e1.54 (3H, m), 1.23 (3H, t, J¼7.2 Hz); 13C NMR (400 MHz,
(3H, m), 0.98e0.77 (6H, m); 13C NMR (400 MHz, CDCl3):
d 171.2,
170.9, 167.8, 167.2, 165.84, 165.81, 165.0, 164.9, 135.7, 135.5, 135.4,
135.0, 134.8, 134.1, 131.5, 131.3, 129.83, 129.80, 129.77, 128.8, 128.62,
128.61, 127.32, 127.27, 127.1, 127.0, 123.8, 123.5, 91.9 (d, J¼169.9 Hz),
89.6 (d, J¼179.9 Hz), 61.4, 61.2, 59.3, 59.1, 57.7, 57.4, 56.4, 56.0, 31.3,
31.1, 18.9, 18.7, 17.6, 17.5, 14.1, 14.0; 19F NMR (300 MHz, CDCl3):
CDCl3):
d 171.1, 168.6, 168.41, 168.38, 168.2, 167.9, 135.4, 135.2,
134.3, 133.8, 132.0, 131.5, 129.2, 128.6, 128.37, 128.35, 128.34, 125.0,
124.9, 123.6, 123.1, 92.7 (d, J¼179.1 Hz), 62.1, 56.6 (d, J¼22.9 Hz),
54.8, 37.3, 28.1, 27.8, 23.4, 14.0; 19F NMR (300 MHz, CDCl3):
d
ꢁ164.0 to ꢁ164.2 (1F, m), ꢁ174.4 (1F, dd, J¼47.0, 11.5 Hz).
4.1.12. Ethyl ((2R)-2-(1,3-dioxoisoindolin-2-yl)-3-fluoro-3-
d
ꢁ193.1 (1F, dd, J¼45.3, 31.0 Hz).
phenylpropanoyl)- -leucinate (13). Following the general pro-
cedure and workup, 13 was isolated (74 mg, 65%) as a colorless oil
(mixture of diastereomers). 1H NMR (400 MHz, CDCl3):
7.94e7.88
(1H, m), 7.81e7.75 (1H, m), 7.72e7.69 (1H, m), 7.65e7.60 (1H, m),
7.54e7.50 (1H, m), 7.43e7.35 (2H, m), 7.29e7.24 (2H, m), 7.08e6.67
(1H, m), 6.55e6.32 (1H, m), 5.35e5.26 (1H, m), 4.73e4.41 (1H, m),
4.29e4.02 (2H, m), 1.75e1.59 (2H, m), 1.57e1.42 (1H, m), 1.32e1.15
(3H, m), 0.98e0.92 (3H, m), 0.86e0.79 (3H, m); 13C NMR (400 MHz,
L
4.1.8. Ethyl (2R)-2-(2-(1,3-dioxoisoindolin-2-yl)acetamido)-3-fluoro-
3-phenylpropanoate (9). Following the general procedure and
workup, the major diastereomer of 9 was isolated (75 mg, 52%) as
a white solid (both diastereomers in 69% yield by 19F NMR); mp
d
172e176 ꢂC. 1H NMR (400 MHz, CDCl3):
d 7.90e7.84 (2H, m),
7.76e7.70 (2H, m), 7.35e7.25 (5H, m), 6.54 (1H, d, J¼9.2 Hz), 6.00
(1H, dd, J¼45.2, 2.7 Hz), 5.08 (1H, ddd, J¼29.3, 9.1, 2.8 Hz),
4.38e4.23 (4H, m), 1.29 (3H, t, J¼7.1 Hz); 13C NMR (400 MHz,
CDCl3): d 172.3, 172.1, 167.8, 167.2, 165.61, 165.59, 164.8, 164.7, 135.6,
135.4, 135.0, 134.8, 134.5, 134.1, 131.5, 131.4, 129.85, 129.82, 129.80,
129.78, 128.80, 128.64, 128.63, 127.33, 127.27, 127.10, 127.05, 123.8,
123.5, 92.0 (d, J¼169.9 Hz), 89.5 (d, J¼179.9 Hz), 61.5, 61.3, 59.3,
59.1, 56.2, 55.9, 51.5, 51.1, 41.7, 41.4, 26.9, 24.9, 24.7, 22.7, 22.6, 22.0,
CDCl3):
d 168.44, 168.42, 167.4, 166.1, 135.2, 135.0, 134.2, 131.9,
128.84, 128.83, 128.46, 128.45, 125.2, 125.1, 123.6, 92.7 (d,
J¼179.5 Hz), 62.3, 56.6 (d, J¼22.9 Hz), 40.47, 14.0; 19F NMR
(300 MHz, CDCl3):
d
ꢁ191.3 (1F, dd, J¼45.3, 28.7 Hz).
21.8, 14.1, 14.0; 19F NMR (300 MHz, CDCl3):
J¼47.6, 13.8, 9.2 Hz), ꢁ176.2 (1F, dd, J¼47.0, 11.5 Hz).
d
ꢁ165.0 (1F, ddd,
4.1.9. Ethyl
(2R)-3-fluoro-3-phenyl-2-((S)-2-(2,2,2-trifluoroacet-
amido)propanamido)propanoate (10). Following the general pro-
cedure and workup,10 was isolated (64 mg, 67%) as a colorless solid
(mixture of diastereomers); mp 96e98 ꢂC. 1H NMR (400 MHz,
4.1.13. Ethyl
((2R)-2-((S)-2-(1,3-dioxoisoindolin-2-yl)propanami-
do)-3-fluoro-3-phenylpropanoyl)- -leucinate (14). Following the
L
general procedure and workup, 14 was isolated (83 mg, 63%) as
CDCl3):
d
7.40e7.27 (5H, m), 7.09 (1H, d, J¼7.1 Hz), 6.89e6.82 (1H,
a white solid (mixture of diastereomers); mp 138e141 ꢂC. 1H NMR
m), 6.13e5.79 (1H, m), 5.19e5.03 (1H, m), 4.66e4.50 (1H, m), 4.30
(1H, q, J¼7.1 Hz), 4.16e4.08 (1H, m), 1.45e1.39 (3H, m), 1.33e1.10
(400 MHz, CDCl3): d 7.86e7.78 (2H, m), 7.76e7.69 (2H, m),
7.39e7.22 (5H, m), 6.96e6.33 (2H, m), 6.24e5.86 (1H, m),
5.07e4.80 (2H, m), 4.58e4.42 (1H, m), 4.20e4.06 (2H, m),1.73e1.65
(2H, m), 1.64e1.45 (4H, m), 1.28e1.14 (3H, m), 0.98e0.82 (6H, m);
(3H, m); 13C NMR (400 MHz, CDCl3):
d 170.7, 168.5, 168.4, 167.9,
167.8, 157.2, 157.0, 156.81, 156.75, 156.7, 156.4, 156.3, 156.1, 155.9,
135.09, 135.06, 134.88, 134.85, 128.99, 128.98, 128.92, 128.91, 128.51,
128.50, 128.47, 128.46, 125.17, 125.15, 125.09, 125.07, 117.04, 116.96,
114.2, 114.1, 93.0 (d, J¼179.1 Hz), 92.6 (d, J¼182.8 Hz), 62.5, 62.2,
57.3, 57.0, 56.9, 56.7, 49.1, 48.9, 18.4, 18.2, 14.0, 13.8; 19F NMR
13C NMR (400 MHz, CDCl3):
d 171.9, 171.7, 168.9, 168.7, 167.5, 167.43,
167.41, 167.26, 167.25, 167.03, 166.98, 135.5, 135.33, 135.27, 135.1,
134.3, 134.2, 131.7, 131.6, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4,
125.7, 125.6, 125.2, 125.1, 123.48, 123.45, 92.2 (d, J¼180.2 Hz), 91.8
(d, J¼178.0 Hz), 61.19, 61.15, 57.6, 57.4, 57.3, 57.2, 51.30, 51.27, 49.0,

6036
D.D. Bume et al. / Tetrahedron 72 (2016) 6031e6036
48.9, 40.9, 40.8, 24.7, 24.6, 22.7, 22.6, 21.81, 21.77, 14.9, 14.8, 14.0; 19
F
2004, 60, 6711e6745; (f) Okuda, K.; Hirota, T.; Kingery, D. A.; Nagasawa, H. J.
Org. Chem. 2009, 74, 2609e2612.
NMR (300 MHz, CDCl3):
(1F, dd, J¼45.3, 24.7 Hz).
d
ꢁ189.0 (1F, dd, J¼45.3, 18.4 Hz), ꢁ192.4
6. (a) Zhu, R.-Y.; Tanaka, K.; Li, G.-C.; He, J.; Fu, H.-Y.; Li, S.-H.; Yu, J.-Q. J. Am. Chem.
Soc. 2015, 137, 7067e7070; (b) Zhang, Q.; Yin, X.-S.; Chen, K.; Zhang, S.-Q.; Shi,
B.-F. J. Am. Chem. Soc. 2015, 137, 8219e8226; (c) Miao, J.; Yang, K.; Kurek, M.; Ge,
H. Org. Lett. 2015, 17, 3738e3741; (d) Lu, X.; Xiao, B.; Shang, R.; Liu, L. Chin.
Chem. Lett. 2016, 27, 305e311.
Acknowledgements
7. (a) Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494e17500; (b)
Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16, 6338e6341.
8. (a) Xia, J.-B.; Zhu, C.; Chen, C. Chem. Commun. 2014, 11701e11704; (b) Halperin,
S. D.; Fan, H.; Chang, S.; Martin, R. E.; Britton, R. Angew. Chem., Int. Ed. 2014, 53,
4690e4693.
9. Halperin, S. D.; Kwon, D.; Holmes, M.; Regalado, E. L.; Campeau, L.-C.; Dirocco,
D. A.; Britton, R. Org. Lett. 2015, 17, 5200e5203.
T. L. would like to thank the National Science Foundation (NSF)
(CHE-1465131) for support. C. R. P. would like to thank Johns
Hopkins for a Glen E. Meyer ’39 Fellowship, and D. D. B. would also
like to thank Johns Hopkins for a Boggs Fellowship.
10. (a) Bloom, S.; Knippel, J. L.; Lectka, T. Chem. Sci. 2014, 5, 1175e1178; (b) Pitts, C.
R.; Bloom, M. S.; Bume, D. D.; Zhang, Q. A.; Lectka, T. Chem. Sci. 2015, 6,
5225e5229.
Supplementary data
11. Chatalova-Sazepin, C.; Hemelaere, R.; Paquin, J.-F.; Sammis, G. M. Synthesis
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.08.018.
2015, 47, 2554e2569 and references cited therein.
12. For a theoretical study on the excitation dynamics of dibenzo-suberenone, see
Nakai, H.; Baba, T. J. Mol. Struct. 2005, 735e736, 211e216.
13. Chambers, R. D.; Kenwright, A. M.; Parsons, M.; Sandford, G.; Moilliet, J. S. J.
References and notes
Chem. Soc., Perkin Trans. 1 2002, 2190e2197.
14. Sureshbabu, V. V.; Narendra, N. Protection Reactions In Amino Acids, Peptides
and Proteins in Organic Chemistry; Hughes, A. B., Ed.; Wiley-VCH Verlag GmbH &
KGaA: Weinheim, Germany, 2011.
15. In our experience, basic nitrogen sites are typically either oxidized or fluori-
nated (followed by a Stevens-like rearrangement) in the presence of N-F
reagents.
16. For standard phthalimide N-protection procedure, see Satzinger, G. Arzneim-
Forsch. Drug Res. 1994, 44, 261e266.
17. For a trifluoroacetate N-protection procedure, see Curphey, T. J. J. Org. Chem.
1. For some examples from our laboratory, see: (a) Bloom, S.; Pitts, C. R.; Miller, D.;
Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem., Int. Ed. 2012, 51,
10580e10583; (b) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.;
Lectka, T. Org. Lett. 2013, 15, 1722e1724; (c) Bloom, S.; Sharber, S. A.; Holl, M. G.;
Knippel, J. L.; Lectka, T. J. Org. Chem. 2013, 78, 11082e11086; (d) Pitts, C. R.; Ling,
B.; Woltornist, R.; Liu, R.; Lectka, T. J. Org. Chem. 2014, 79, 8895e8899; (e)
Bloom, S.; Bume, D. D.; Pitts, C. R.; Lectka, T. Chem.dEur. J. 2015, 21, 8060e8063.
2. For other recent advances in this research area, see: (a) Rueda-Becerril, M.;
Sazepin, C. C.; Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis,
G. M. J. Am. Chem. Soc. 2012, 134, 4026e4029; (b) Liu, W.; Huang, X.; Cheng, M.;
Nielson, R. J.; Goddard, W. A., III; Groves, J. T. Science 2012, 337, 1322e1325; (c)
Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134, 10401e10404; (d) Liu,
W.; Groves, J. T. Angew. Chem., Int. Ed. 2013, 52, 6024e6027; (e) Amaoka, Y.;
Nagamoto, M.; Inoue, M. Org. Lett. 2013, 15, 2160e2163; (f) Braun, M.-G.; Doyle,
A. J. Am. Chem. Soc. 2013, 135, 12990e12993; (g) Xia, J.-B.; Ma, Y.; Chen, C. Org.
Chem. Front. 2014, 1, 468e472; (h) Rueda-Becerril, M.; Mahe, O.; Drouin, M.;
Majewski, M. B.; West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J.-F. J. Am. Chem.
Soc. 2014, 136, 2637e2641; (i) Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem.
Soc. 2014, 136, 16439e16443; (j) Phae-nok, S.; Soorukram, D.; Kuhakarn, C.;
Reutrakul, V.; Pohmakotr, M. Eur. J. Org. Chem. 2015, 2015, 2879e2888.
3. (a) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637e643; (b) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320e330; (c) Patrick,
G. L. An Introduction to Medicinal Chemistry, 5th ed.; Oxford University Press:
Oxford, UK, 2013; (d) Ojima, I. J. Org. Chem. 2013, 78, 6358e6383; (e) Gillis, E. P.;
Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58,
8315e8359.
4. Applications of fluorinated peptides are numerous, diverse, and well precented.
For some recent reviews and other literature, see: (a) Okarvi, S. Eur. J. Nucl. Med.
2001, 28, 929e938; (b) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31,
335e341; (c) Salwiczek, M.; Nyakatura, E. K.; Gerling, U. I. M.; Ye, S.; Koksch, B.
Chem. Soc. Rev. 2012, 41, 2135e2171; (d) Kumar, D. N. T.; Mehdi, N.; Huang, F.;
Zhang, M.; Wei, Q. Int. J. Eng. Res. Appl. 2012, 2, 77e84.
1979, 44, 2805e2807.
18. For a sample esterification procedure for amino acids, see Armstrong, A.; Ed-
monds, I. D.; Swarbrick, M. E.; Treweeke, N. R. Tetrahedron 2005, 61,
8423e8442.
19. For examples of decarboxylative fluorination applied to a phenyl-alanine de-
rivative, see: (a) Wu, X.; Meng, C.; Yuan, X.; Jia, X.; Qian, X.; Ye, J. Chem. Com-
mun. 2015, 11864e11867; (b) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2015, 137, 5654e5657; (c) Huang, X.; Liu, W.; Hooker, J. M.;
Groves, J. T. Angew. Chem., Int. Ed. 2015, 54, 5241e5245.
20. Banks, R. E.; Besheesh, M. K.; Mohialdin-Khaffaf, S. N.; Sharif, I. J. Chem. Soc.,
Perkin Trans. 1 1996, 2069e2076.
21. Lugemwa, F. N.; Shaikh, K.; Hochstedt, E. Catalysts 2013, 3, 954e965.
22. Dipeptides were synthesized using a standard DCC coupling protocol. See Rich,
D. H.; Singh, J. The Carbodiimide Method In The Peptides: Analysis, Synthesis,
Biology; Gross, E., Meienhofer, J., Eds.; Academic: New York, NY, 1979;
pp 241e261.
23. Although photochemical CeH fluorination methods have not yet been studied
extensively, a few detailed mechanistic studies on “radical fluorination” using
SelectfluorÒ have appeared in recent literature. See: (a) Pitts, C. R.; Bloom, S.;
Woltornist, R.; Auvenshine, D. J.; Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. J. Am.
Chem. Soc. 2014, 136, 9780e9791; (b) Patel, N. R.; Flowers, R. A., II. J. Org. Chem.
2015, 80, 5834e5841; (c) Pitts, C. R.; Ling, B.; Snyder, J. A.; Bragg, A. E.; Lectka, T.
J. Am. Chem. Soc. 2016, 138, 6598e6609.
€
€
24. Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University
Science Books: Sausalito, CA, 2006.
5. For some examples, see: (a) Hart, B. P.; Coward, J. K. Tetrahedron Lett. 1993, 34,
4917e4920; (b) DeJesus, O. T.; Murali, D.; Kitchen, R.; Oakes, T. R.; Nickles, R. J. J.
Fluorine Chem. 1993, 65, 73e77; (c) Shi, G.-Q.; Cao, Z.-Y.; Zhang, X.-B. J. Org.
Chem. 1995, 60, 6608e6611; (d) Li, K.; Leriche, C.; Liu, H.-W. Bioorg. Med. Chem.
Lett. 1998, 8, 1097e1100; (e) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron
25. For a discussion on rate- and product-determining steps in competition ex-
periments (with respect to KIEs), see Simmons, E. M.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2012, 51, 3066e3072.