Optimized synthesis of a pentafluoro-gem-diol and conversion to a CF2Br-glucopyranose through trifluoroacetate-release and halogenation

Article abstract of DOI:10.1016/j.tetlet.2016.03.064

Pentafluoro-gem-diols are substrates that enable the synthesis of valuable difluoromethylene-containing organic molecules through the release of trifluoroacetate. Currently, only one synthetic strategy is available to assemble these important precursors.

Full text of DOI:10.1016/j.tetlet.2016.03.064

Accepted Manuscript
Optimized Synthesis of a Pentafluoro-gem-diol and Conversion to a CF2Br-
Glucopyranose through Trifluoroacetate-Release and Halogenation
Robert A. Hazlitt, Jinu P. John, Que-Lynn Tran, David A. Colby
PII:
S0040-4039(16)30286-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.064
TETL 47452
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
16 March 2016
18 March 2016
Please cite this article as: Hazlitt, R.A., John, J.P., Tran, Q-L., Colby, D.A., Optimized Synthesis of a Pentafluoro-
gem-diol and Conversion to a CF2Br-Glucopyranose through Trifluoroacetate-Release and Halogenation,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.064
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Graphical Abstract
Optimized Synthesis of a Pentafluoro-gem-
diol and Conversion to a CF2Br-
Leave this area blank for abstract info.
Glucopyranose through Trifluoroacetate-
Release and Halogenation
Robert A. Hazlitt, Jinu P. John, Que-Lynn Tran and David A. Colby
OH
BnO
O
O
HO OH
CF3
7 steps
LiBr, Et3N
O
BnO
BnO
O
glucose
CF2Br
Selectfluor®
BnO
F
F
OH
BnO BnO
trifluoroacetate-release
& halogenation

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Optimized Synthesis of a Pentafluoro-gem-diol and Conversion to a CF2Br-
Glucopyranose through Trifluoroacetate-Release and Halogenation
Robert A. Hazlitta,b, Jinu P. Johna, Que-Lynn Tranb and David A. Colbya,b,∗
a Department of Chemistry, Purdue University, West Lafayette, Indiana, 47907, USA
b Department of BioMolecular Sciences, University of Mississippi, Mississippi, 38677, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pentafluoro-gem-diols are substrates that enable the synthesis of valuable difluoromethylene-
containing organic molecules through the release of trifluoroacetate. Currently, only one
synthetic strategy is available to assemble these important precursors. Herein, two new synthetic
strategies to a complex pentafluoro-gem-diol are compared to the existing route, and an
improved synthetic route has completed. Moreover, the first synthesis of a CF2Br-glucopyranose
was finished by a tandem trifluoroacetate-release halogenation/cyclization protocol.
Available online
Keywords:
fluorine
2009 Elsevier Ltd. All rights reserved.
aldol reaction
halogenation
glycoside
pyranose
———
∗Corresponding author. Tel.: +1-662-915-1766; e-mail: dacolby@olemiss.edu

2
Tetrahedron
Fluorinated organic molecules have a prominent role in the
pharmaceutical and agrochemical industries.1,2 The incorporation
of fluorine can improve the pharmacokinetic properties of lead
molecules, as it is known to increase metabolic stability and
lipophilicity. Although there are many methods to introduce
fluorine3 and trifluoromethyl groups,4 there are substantially
fewer strategies to install a difluoromethylene group.5–7 The most
common synthetic protocols for installing a difluoromethylene
The synthesis commenced with the selective protection of the
known acyclic triol 3,22 that is derived in three steps from
glucose, to give the alcohol 4 (Scheme 2). Then, Swern oxidation
provided the aldehyde 5 in 92% yield. Methylation with
MeMgBr followed by TPAP/NMO-mediated oxidation afforded
the ketone 2. Trifluoroacetylation followed by difluorination with
Selectfluor® gave the pentafluoro gem-diol 1 in 43% yield over
two steps, and no α-epimerization of the ketone was observed
during any of the synthetic transformations. Although this path
provided the target 1 from the requisite aldehyde 5 in four
synthetic steps, we sought to develop a shorter and more efficient
route.
group are through the use of
a
difluoroenol8 or
a
difluoroenolate.9–11 Difluoroenolates are typically derived from
bromodifluoroacetate with a Reformatsky reaction.9 In 2011, we
demonstrated that difluoroenolates could be generated by the
mild release of trifluoroacetate from pentafluoro-gem-diols using
LiBr and Et3N.12 The difluoroenolates react well with
aldehydes,12 imines,13 and electrophilic halogenation reagents14
(Figure 1). Subsequent innovations mediated by the release of
trifluoroacetate include catalytic asymmetric aldol reactions,15
integration with light-induced photoredox catalysis,16 and
stereoselective additions to chiral N-sulfinyl imines.17 Indeed, the
major advantage of using trifluoroacetate release is that it is quite
mild yet compatible with many types of reagents. Even though
these reports have characterized the novel reactivity of the
difluoroenolates generated from trifluoroacetate release, none
have been applied to the construction of more complex,
O
OH
OH
2,2-dimethoxy-
propane, CSA
HO BnO
3 steps
HO
HO
HO
OH
CH3CN, rt, 81%
BnO BnO
OH
D-glucose
3
BnO
O
BnO
O
O
i) MeMgBr, Et2O,
–78 °C, 74%
(COCl)2,
O
O
DMSO, Et3N
H
OH
BnO BnO
BnO BnO
CH2Cl2,
ii) TPAP, NMO,
4 A MS, CH2Cl2,
rt, 92%
5
4
–65 oC, 92%
difluorinated organic molecules.18
i) LiHMDS, CF3CO2CH2CF3,
THF, –78 °C
O
2
1
O
OH
R2
R2
H
ii) Selectfluor®, CH3CN, rt
43% (two steps)
R1
F
F
trifluoroacetate
release
R3
R2
Scheme 2. Preparation of pentafluoro-gem-diol
trifluoroacetylation and difluorination of methyl ketone 2.
1
by
R3
O
O
HO OH
CF3
O
HN
R2
N
F
R1
R1
R1
R1
F
F
F
F
O
F
CF3CO2
Indium-mediated difluoroallylation of aldehydes is mild
reaction that installs a difluorinated group.23 This chemistry has
been aptly applied to synthesis of difluorinated sugar nucleosides
by Qing and coworkers.24 Accordingly, the aldehyde 5 was
smoothly difluoroallylated with indium in DMF at 100 oC to give
the difluoroalcohol 6 as an inseparable mixture of diasteromers
(Scheme 3). The high temperature was necessary to obtain a good
conversion. Oxidation of 6 with Dess-Martin periodinane
produced the ketone 7 in 88%. Ozonolysis of the terminal olefin
of 7 was attempted to generate the difluoroaldehyde 8; however,
X
X
F
X = Cl, Br, I
F
Figure 1. Generation and reactivity of difluoroenolates from the
release of trifluoroacetate.
Natural products serve as a valuable resource for drug
discovery.19 Moreover, a substantial portion of natural products
display a sugar on their respective structures.20 As part of our
ongoing efforts to modify the structures of natural products for
drug discovery,21 we aim to create tools to access derivatives of
complex glycosylated natural products. The synthesis of a
pentafluoro-gem-diol derived from glucose would not only be an
important first step toward achieving this goal, but also it would
demonstrate the compatibility of the pentafluoro-gem-diol in
complex organic structures. Accordingly, we herein report an
optimized synthetic route for the assembly of the requisite
pentafluoro-gem-diol derived from glucose, as well as a single
transformation, promoted by the release of trifluoroacetate, to
form the first CF2Br-glucopyranose.
a complex mixture was observed in the H, 19F and 13C NMR
1
spectra. Although difluoroaldehydes are known in the literature
to exist in equilibrium with the hydrate form, the free
difluoroaldehyde is usually observed.24 Unfortunately, some
difluoroaldehydes exclusively form multimers (i.e., polymerize
with other hydrates) and these complex mixtures are
characterized as other derivatives.24 In the case of 8, the reaction
mixture from 7 was reduced to the respective diol 9 using
LiBH4.25 Although this transformation validated the formation of
the difluoroaldehyde 8, this synthetic route was abandoned for a
new strategy.
Previously, our laboratory has reported that the substrates for
trifluoroacetate
release,
2,2,4,4,4-pentafluoro-3,3-
dihydroxyketones, can be assembled by trifluoroacetylation of
methyl ketones followed by difluorination.12 This method is the
only reported route to synthesize these types of compounds.12–18
Using this strategy, pentafluoro-gem-diol 1 was envisioned to
arise from the methyl ketone 2 which, in turn, would be accessed
from glucose (Scheme 1).
Dess-Martin
periodinane
BnO
OH
F
O
In,
CF2Br
O
5
DMF, 100 °C,
62%, (d.r. = 3:1)
CH2Cl2, rt,
88%
F
BnO BnO
6
BnO
O
O
BnO
O
O
O
O3, DMS
O
O
H
F
F
F F
CH2Cl2, –78 °C
BnO BnO
BnO BnO
O
OH
OH
HO
HO
BnO
O
O
BnO
O
O
HO OH
CF3
8
7
O
O
BnO
OH
O
O
F
F
OH
LiBH4, rt
BnO BnO
BnO BnO
OH
1
2
D-glucose
THF, 64% (d.r. = 3:2)
(two steps)
F
F
BnO BnO
Scheme 1. Synthetic strategy for glucose-derived pentafluoro-gem-
diol 1.
9

3
Scheme 3. Preparation of difluoroaldehyde 8 by an indium-mediated
difluoroallylation of aldehyde 5.
in 41% yield from a tandem cascade of the release of
trifluoroacetate, halogenation, acetonide cleavage, and
cyclization. Assignment of the relative stereochemical
configuration was accomplished by COSY, HMQC, HMBC,
NOESY, and 1H–19F 2D HOESY NMR data (see Scheme 4). The
utility of 1H–19F 2D HOESY experiments in assigning
stereochemical configuration of centers on cyclic structures has
been elegantly described by Crich and coworkers,29 and the data
for 13 was in excellent agreement with this precedent.
The third and final approach was inspired from the reported
addition of lithium-based pentafluoroenolates to aldehydes.26
Specifically, treatment of hexafluoroisopropanol (HFIP) with 2
equivalents of n-BuLi generates a perfluoroenolate that adds
smoothly to aldehydes. These unique pentafluorinated products
were studied by Guerrero, and it was reported that base-mediated
decomposition produces difluoroacetic acids by fluoroform
release.27 We aimed to exploit this class of compound, in a
different fashion, by oxidizing the secondary alcohol to a ketone
to produce the desired pentafluoro-gem-diol with an adjacent
ketone. Accordingly, the pentafluoroenolate was added to 2-
naphthaldehyde to generate the fluorinated substrate 10. Then,
compound 10 was treated with nine different oxidants to identify
conditions that would provide the gem-diol 1112 in good yield
(Table 1). DCC/DMSO, PDC, and TEMPO/NaOCl produced 11
in low yields (i.e., 33–45% based on 19F NMR). Dess-Martin
periodinane gave the product 11 in 63% yield, and TPAP/NMO
provided the highest yield of 11 at 90% after 24 h. These data
validate the potential of oxidation to the gem-diol and represent a
new route to access these types of fluorinated molecules.
OH
Dess-Martin
periodinane
BnO HO
O
HO OH
CF3
F3C
CF3
O
5
1
n-BuLi, THF,
–78 °C to rt, 52%
CH2Cl2, rt, 95%
F
F
BnO BnO
OH
12
NOESY
HOESY
O
LiBr, Et3N
BnO
BnO
OH
CF2Br
H
Selectfluor®, THF,
0 °C, 41%
H
BnO
OH
F
F
O
13
R
R
Br
H
R
H
OH
NOESY
13 (R = OBn)
Scheme 4. Optimized synthesis of pentafluoro-gem-diol 1 and
conversion to CF2Br-glucopyranose 13 with a depiction of the
NOESY and 1H–19F HOESY data.
Table 1. Oxidation of pentafluoroalcohol 10.
In conclusion, three synthetic routes to prepare complex
pentafluoro-gem-diols have been presented. The optimal route
requires an aldehyde and only two synthetic steps to assemble the
pentafluoro-gem-diol. This work offers an improved alternative
to the only reported method12 for the preparation of these
structures. These substrates are versatile intermediates for
assembling difluorinated organic structures through the use of
trifluoroacetate release. The CF2Br-glucopyranose was obtained
through a novel, tandem trifluoroacetate-release halogenation,
deprotection, and cyclization reaction. The reaction not only
demonstrates the importance of complex pentafluoro-gem-diols
but also extends the scope of trifluoroacetate release.
OH
n-BuLi (2 equiv.)
F3C
CF3
THF, –78 °C
OLi
F
HO
O
HO OH
CF3
F3C
F
H
F
F
THF, 60%
10
O
HO OH
CF3
conditions
F
F
11
Entry Conditions
Yielda
0%
1
2
3
4
5
6
7
8
DMSO, (COCl)2, Et3N, CH2Cl2, –78 °C to 0 °C
PDC, DMF, rt, 16 h
Acknowledgments
35%
33%
45%
0%
DCC, DMSO, AcOH, rt, 24 h
These studies were supported by the National Institute on
Aging (R21AG039718) and National Institute of General
Medical Sciences (P20GM104932) of the National Institutes of
Health (NIH), by the University of Mississippi, and by Purdue
University. Its contents are solely the responsibility of the authors
and do not necessarily represent the official view of the NIH. The
authors acknowledge Mark T. Hamann and Billie-Jean Forrest of
the University of Mississippi and the Mass Spectrometry and
Proteomics Facility of the University of Notre Dame for
acquisition of high-resolution mass spectrometry data. Also, the
authors acknowledge Joonseok Oh and Frank T. Wiggers from
the University of Mississippi for acquisition of NMR
spectroscopy data.
DCC, DMSO, TFA, rt, 24 h
Oxone, THF, H2O, rt, 24 h
TEMPO, NaOCl, NaBr, THF, H2O, 5 h
Dess-Martin periodinane, CH2Cl2, rt, 24 h,
TPAP, NMO, 4 Å MS, CH3CN, rt, 24 h
34%
63%
90%
a Yield determined by 19F NMR.
Commencing from aldehyde 5, addition of the
pentafluoroenolate generated from HFIP provided the alcohol 12
in an optimized yield of 52% (Scheme 4). Temperature control
was critical for obtaining good yields during this transformation,
as holding the reaction mixture at –40 °C for 15 min, during the
warming process, provided the highest conversion to the product
12. Based on the previous studies with compound 10, the
oxidation of 12 to the pentafluoro-gem-diol 1 was initially
conducted with TPAP/NMO (see Table 1), but Dess-Martin
periodinane gave a near quantitative conversion to 1 at 95%
isolated yield.28 This route was a substantial improvement over
the aforementioned four-step synthesis of 1 from 5, as the
substrate 1 was procured in only two synthetic steps. In order to
demonstrate that the complex pentafluoro-gem-diol 1 participates
in trifluoroacetate-release mediated additions, the substrate 1 was
treated with LiBr, Et3N, and Selectfluor® for 1 h to promote the
release of trifluoroacetate and halogenation.14 Remarkably, the
CF2Br-glucopyranose 13 was obtained as a single diastereomer
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4
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Full experiment details and spectroscopic data (PDF).

*Highlights
Highlights
 A complex glucose-derived pentafluoro-gem-diol is synthesized.
 A tandem trifluoroacetate-release halogenation/cyclization is executed.
 The first synthesis of a CF2Br-glucopyranose is completed.
S1