Preparation of fluoroalkenes via the Shapiro reaction: Direct access to fluorinated peptidomimetics

Article abstract of DOI:10.1021/ol401637n

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.

Full text of DOI:10.1021/ol401637n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Preparation of Fluoroalkenes via
the Shapiro Reaction: Direct Access
to Fluorinated Peptidomimetics
Ming-Hsiu Yang, Siddharth S. Matikonda, and Ryan A. Altman*
Department of Medicinal Chemistry, The University of Kansas, Lawrence,
Kansas 66045, United States
raaltman@ku.edu
Received June 10, 2013
ABSTRACT
Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group
commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in
good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from
widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would
be challenging to prepare by alternate strategies.
Fluoroolefins represent an underappreciated functional
group with applications in biological and material chem-
istry. The fluoroalkene group serves as an isopolar and
isosteric mimic of an amide with distinct biophysical
properties,1 including decreased H-bond donating and
accepting abilities.2 Thus, strategic incorporation of a
fluoroalkene into a biological probe can increase lipophili-
city and membrane permeability of the probe.3 This pepti-
domimetic is not subject to hydrolysis by proteases, and
incorporation of this group can improve the metabolic
stability of a peptide.3,4 Moreover, fluoroalkenes can
serve as probes for conducting conformational analyses
of amides by selective preparation of E- and Z-fluoroalk-
ene isomers.5 In addition to these biological applications,
fluoroalkenes also function as useful intermediates in
synthetic sequences. For example, they have been em-
ployed asdienophiles inDielsꢀAlder reactions,6 converted
to cyclopropane derivatives,7 and polymerized to access
materials.8
Several methods have been developed for preparing
fluoroalkenes, but have traditionally been limited by the
formation of complex mixtures of products that are challeng-
ing to separate.9 Strategies including elimination of allyldi-
fluoro compounds,10 additionꢀelimination sequences,11 and
HornerꢀWadsworthꢀEmmons,12 Peterson,13 and Juliaꢀ
Kocienski olefination reactions14 have been used to ac-
cess fluoroalkene products. Other approaches to gener-
ate fluorinated alkenes include fluorination reactions of
(6) Ernet, T.; Maulitz, A. H.; Wurthwein, E.-U.; Haufe, G. J. Chem.
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Qiu, W. Chem. Rev. 1996, 96, 1641–1716.
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r
10.1021/ol401637n
XXXX American Chemical Society

Scheme 1. Shapiro Reactions Have Not Been Employed to
Access Fluoroalkenes
Scheme 2. Only NFSI Provided Fluoroalkene Productsa
a Yields were determined by 19F NMR analysis using R,R,R-trifluoro-
toluene as an internal standard. b The reaction of the phenyl tosylhy-
drazone substrate was explored.
alkenylstannanes,15 -silanes,16 and -boronic acid derivatives17
and metal-catalyzed coupling reactions.18 However, these
methods typically provide low diastereoselectivities
of E- and Z-isomers (<1:3 dr).19 Further, many of these
methods are not suitable for introducing the fluoroalkene
at a late stage of a synthesis through modification of
a compound already in hand. Thus, alternate strategies
to access fluoralkenes are desirable.
It was envisaged that fluoroolefins could be accessed
through a Shapiro fluorination reaction (Scheme 1).20 The
Shapiro reactionhas been widelyappliedinthe synthesis of
natural products,21 and for the preparation of polysubsti-
tuted alkenes,22 many of which are not easily accessed
by other means. A prototypical Shapiro reaction involves
(1) condensation of an N-sulfonyl hydrazide with a ketone
to provide a sulfonyl hydrazone; (2) treatment of the
sulfonyl hydrazone with a base to provide a vinyllithium
intermediate; and (3) trapping of the vinyl anion with Hþ
to afford an alkene-based product.20 Alternatively, the in
situ formed alkenyllithium intermediate can also be
trapped with a variety of electrophiles to generate allylic
alcohols, acrylic acids, acrylic aldehydes, vinylsilanes, and
vinyl iodides and bromides.23 However, the Shapiro reaction
has not been employed to access fluoroalkenes. Herein, we
describe a Shapiro fluorination reaction to provide fluoro-
alkenes in high diastereoselectivity (Scheme 1).
The Shapiro fluorination reaction was scouted using a
variety of commercially available electrophilic fluorinating
reagents24 and biphenyl 2,4,6-triisopropyl-benzenesulfo-
nyl (Tris) hydrazone (1a) as a test substrate (Scheme 2).
Tris hydrazones were employed instead of phenylsulfonyl
or mesitylsulfonyl moieties because the former group (1)
does not undergo ortho-lithiation or R-lithiation, which
allows for the reaction to proceed using fewer equivalents
of base and electrophilic trapping agent;25 (2) decomposes
more easily than unhindered arylhydrazones, a phenomenon
that likely arises from the release of steric compression at the
transition state.26 Decomposition of the Tris hydrazone was
accomplished by lithiation with 2.5 equiv of n-butyllithium
(n-BuLi) in THF from ꢀ78 to 0 °C, followed by cooling
to ꢀ78 °C for the addition of the fluorinating reagent. No
fluorinated product was observed by 19F NMR when the in
situ formed vinyl anion was reacted with N-fluoropyridinium
salts or Selectfluor. Potentially, the poor reactivity of these
reagents arose from the low solubility of the ionic reagents
in THF at low temperature. In contrast, employment of
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1985, 107, 2811–2812. (b) Tsai, H. J. Tetrahedron Lett. 1996, 37, 629–
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(b) Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81–88.
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7877. (c) Ghosh, A. K.; Banerjee, S.; Sinha, S.; Kang, S. B.; Zajc, B.
J. Org. Chem. 2009, 74, 3689–3697.
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1461–1471. (b) Tius, M. A.; Kawakami, J. K. Tetrahedron 1995, 51,
3997–4010.
(16) Greedy, B.; Gourverneur, V. Chem. Commun. 2001, 233–234.
(17) (a) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash,
G. K. S.; Olah, G. A. Synlett 1997, 606–608. (b) Furuya, T.; Ritter, T.
Org. Lett. 2009, 11, 2860–2863.
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Gyorokos, A.; Tarasow, T. M.; Guiles, J. J. Org. Chem. 2008, 73, 9775–
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9858–9861.
(20) Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1–83.
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S. P. J. Am. Chem. Soc. 2012, 134, 13577–13579. (c) Granger, K.;
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1978, 43, 147–154. (b) Paquette, L. A.; Fristad, W. E.; Dime, D. S.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Shapiro Fluorination Reactiona
Scheme 3. Shapiro Fluorination Reaction of Acetophenone-
Derived Trishydrazones to Provide Fluorostyrenesa
entry
base
solvent 1
solvent 2
yieldb (%)
1
n-BuLi THF
n-BuLi THF
n-BuLi THF
THF
70
2
toluene
solid added
THF
67
3
54
4
n-BuLi THF/TMEDA (4:1)
n-BuLi TMEDA
68
5c
6
toluene
48
n-BuLi Hexane/TMEDA (9:1) toluene
53
7c
8
n-BuLi DME
s-BuLi THF
CH3Li THF
n-BuLi THF
n-BuLi THF
n-BuLi THF
n-BuLi THF
toluene
THF
THF
THF
THF
THF
THF
50
68
9
28
10d
11e
12f
13g
18
68
65
78 (75)h
a Standard reaction conditions: 3aꢀi (1.0 equiv, 0.20 M solution in
THF), n-BuLi (2.2 equiv), NFSI (1.5 equiv, 0.5 M solution in THF).
Yields were determined by 19F NMR analysis using R,R,R-trifluoroto-
luene as an internal standard (average of two runs) and the figure in the
parentheses indicates the isolated yield (average of two runs). b The Z/E
ratios were determined by integration of the 19F NMR spectrum of the
crude reaction mixture. c NFSI (1.1 equiv). d n-BuLi (2.5 equiv) and
NFSI (1.75 equiv). e s-BuLi (2.2 equiv).
a Standard reaction conditions: 1a (1.0 equiv, 0.20 M solution), base
(2.5 equiv), NFSI (1.5 equiv, 0.50 M THF solution or 0.20 M toluene
solution). b Yields were determined by 19F NMR using R,R,R-trifluoro-
toluene as an internal standard. c Reaction temperatures of ꢀ60 °C for
30 min followed by 0 °C for 20 min. d HMPA (1.0 equiv) was added
during lithiation. e NFSI (2.0 equiv). f 0.10 M solution was used in step i.
g n-BuLi (2.2 equiv). h Isolated yield of material deemed to be >95%
pure by 1H NMR.
products in good to excellent diastereoselectivitites (4gꢀi).
Presumably, the stereochemistry of these reactions was
dictated by the unfavorible steric repulsion of the syn
arrangement of the organic substituents. In contrast, the
E-fluoroalkene was accessed for a cyclic ketone (4f). How-
ever, no fluoroalkene products were obtained in reactions
of substrates bearing p- and m-CF3 and m-chloro electron-
withdrawing groups. As control experiments, subjection of
these three substrates to the Shapiro conditions and quench-
ing of the presumed vinyllithium intermediate with D2O did
not provide the anticipated deuterated or protonated alkenes
(GCꢀMS), indicating that these three substrates were not
compatible with the lithiation step.28
Aliphatic N-trishydrazones also provided the correspond-
ing fluoroalkene analogues (Scheme 4). Using t-BuLi,
the reaction of 2-phenylcyclohexanone trisylhydrazone
provided two regioisomers, 6aA and 6aB in a 15:1 ratio
(crude reaction mixutre), and 60% of the pure tetrasubsti-
tuted fluoroalkene 6aA, an amide mimic of a δ-lactam. The
substrate 5c afforded E-fluoroalkene in 5.7:1 diastereoselec-
tivity. In contrast to the selectivity observed for products
4gꢀi, the reaction to generate 6c seems to be controlled
by a syn-dianion chelation effect, which is frequently ob-
served in Shapiro reactions.20 Amines protected with benzyl
groups were compatible with the reaction conditions
and afforded 28ꢀ70% yields, depending on the substrates
(6dꢀe).29 Pyrrolidine-based derivative 6e could prove useful
N-fluorobenzenesulfonimide (NFSI), a neutral fluorinating
agent that maintains good solubility in ethers and hydro-
carbon solvents at lower temperature,27 provided the desired
fluoroalkene product in 70% yield based on 19F NMR.
Optimization of the Shapiro fluorination reaction in-
volved the evaluation of alternate bases, solvents, and
additives (Table 1). The use of THF as a solvent (entry 1)
proved superior to the use of TMEDA, DME, and hexane/
TMEDA (entries 5ꢀ7), although the use of a mixture of
THF/TMEDA provided a comparable yield (entry 4). The
addition of NFSI as a solid provided a lower yield of product
(entry 3) than addition of NFSI as a solution in THF (entry
1). The use of n-BuLi and s-BuLi afforded higher yields than
that of MeLi (entries 1, 8, and 9). The use of cation-chelating
agents, such as HMPA, did not improve the yield of 2a
(entry 10). Further optimization of the reaction concentra-
tion and stoichiometry of base did not improve the yield
(entries 11 and 12). Finally, the highest yield was obtained
by decreasing the quantity of base employed to 2.2 equiv
(entry 13).
Using the optimized reaction sequence, several aceto-
phenone-derived substrates afforded fluoroalkene products
(Scheme 3). Electron-rich aryl trisylhydrazones including
p-morpholine, ꢀSMe, and ꢀOMe were converted to fluoro-
alkenes 4aꢀd. The p-chloro-subsituted fluorostyrene was
provided in 52% yield (4e). Reactions of substrates bear-
ing substituents at the β-position provided Z-fluoroalkene
(27) (a) Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452–454. (b)
Lee, S. H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108, 2445–2447.
(28) Kerr, W. J.; Morrison, A. J.; Pazicky, M.; Weber, T. Org. Lett.
2012, 14, 2250–2253.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Shapiro Fluorination Reaction of Aliphatic
Trishydrazones to Provide Fluoroalkenesa
Scheme 5. One-Pot Sequence Converts Ketones
to Fluoroalkenesa
a Standard reaction conditions: (i) 7aꢀc (1.0 equiv, 0.50 M solution in
THF), TrisNHNH2 (1.0 equiv), TFA (0.1 equiv), rt, 1.5 h; (ii) THF
˚
(1.5 mL) for dilution, 4 A molecular sieves (800 mg/mmol), n-BuLi
(3.0 equiv), ꢀ78°C, 30 min ꢀ> 0 °C, 20min;(iii) NFSI (1.5equiv, 0.50M
solution in THF), ꢀ78 °C, 30 min f rt, 2 h. b Yields were determined by
19F NMR using R,R,R-trifluorotoluene as an internal standard.
a Standard reaction conditions: 5aꢀf (1.0 equiv, 0.20 M solution in
THF), n-BuLi (2.2 equiv), NFSI (1.5 equiv, 0.50 M solution in THF).
Yields were determined by 19F NMR analysis using R,R,R-trifluoroto-
luene as an internal standard (average of two runs), and the number in
the parentheses represents the isolated yield (average of two runs). b The
ratios of isomers were determined by integration of the 19F NMR
spectrum of the crude reaction mixture. c t-BuLi (2.2 equiv) afforded
improved regioselectivity. d s-BuLi (2.2 equiv) was used.
2a; 8bvs4e; 8cvs4c). Thissequenceenables easyaccesstoa
variety of fluoroalkenes from ketones without purifica-
tion of intermediates, and it is anticipated that this one-pot
procedure could be optimized to access nonstyrenyl
fluoroalkenes.
In conclusion, a procedure was developed for converting
a ketone into a fluoroalkene analogue through a Shapiro
fluorination reaction. The reaction employs inexpensive
and readily available reagents, and no expensive transi-
tion-metal catalysts/reagents and ligands are required.
Compared with many currently available methods, the
Shapiro fluorination reaction provides improved diaste-
reoselectivities (dr >5.5:1) and represents an orthogonal
strategy that should be useful for preparing fluoroalkene
analogues that might be difficult to access otherwise.
Moreover, the extensive number of ketone functional
groups that exist in natural products and pharmaceutically
important building blocks provides a wide variety of
potential substrates for this transformation.
for strategic replacement of proline-based residues to form
fluorinated peptide-based probes with distinct biophysical
properties. Finally, the method was used to rapidly access
new fluorinated analogues of natural products, including
camphor and a protected steroid (6b and 6f). However, the
silyl protecting group was not necessary, and the steroid
substrate bearing an unprotected hydroxyl group provided
33% yield by 19F NMR analysis (not shown in Scheme 4, 3.2
equiv n-BuLi employed). Thus, the present reaction provides
a new entrypoint for the preparation of fluorinated steroids,
which are clinically employed for the treatment of vaious
disease statess.30
In order to accomplish the direct conversion of
ketones to fluoroalkenes, a one-pot reaction sequence was
developed (Scheme 5). The use of an acid catalyst, in
combination with molecular sieves, facilitated the initial
condensation reaction and was compatible with the sub-
sequent lithiation and fluorination steps. Using this one-
pot procedure, yields of the fluoroalkene products were
comparable with those from the isolated hydrazones (8a vs
Acknowledgment. We thank the donors of the Herman
Frasch Foundation for Chemical Research (701-HF12)
for support of this project. Further financial support from
the University of Kansas Office of the Provost, Depart-
ment of Medicinal Chemistry, and New Faculty General
Research Fund (2302264) is gratefully acknowledged.
(29) For the 4-piperidone trisylhydrazone, N-Bn- and N-PMP-pro-
tected substrates provided similar yields of fluoroalkene products.
(30) Schimmer, B. P., Funder, J. W. ACTH, Adrenal Steroids, and
Pharmacology of the Adrenal Cortex. In Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 12th ed. [Online]; Brunton, L. L.,
Chabner, B. A., Knollmann, B. C., Eds.; McGraw-Hill: New York, 2011;
Chapter 42, http://www.accesspharmacy.com/content.aspx?aID=16674048
(accessed July 12, 2013).
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX