A Versatile Method to Prepare Difluorinated Primary Alcohols and Its Application to the Syntheses of Novel Acyclic Fluorinated Nucleosides

Article abstract of DOI:10.1016/j.tetlet.2013.10.037

The addition of fluorine to a molecule often leads to intriguing changes in the properties of the molecule. Many novel drug leads and drug candidates are the results of the incorporation of fluorine. This paper presents a versatile method to create molecules with the general structure R₁R₂CHCF₂CH₂OH from ketone R₁(CO)R₂. The key steps of this synthetic method involve the formation of a cyclic thiocarbonate and the regioselective radical opening of the thiocarbonate to yield the corresponding primary alcohol -CF₂CH₂OH. Using this synthetic method, novel fluorinated analogs of ganciclovir and penciclovir have been prepared.

Full text of DOI:10.1016/j.tetlet.2013.10.037

Tetrahedron Letters 54 (2013) 6909–6911
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A versatile method to prepare difluorinated primary alcohols and its
application to the syntheses of novel acyclic fluorinated nucleosides
⇑
Bruno Tse
TheraKem, 545 39th Avenue, Suite 7, San Francisco, CA 94121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of fluorine to a molecule often leads to intriguing changes in the properties of the molecule.
Many novel drug leads and drug candidates are the results of the incorporation of fluorine. This Letter
presents a versatile method to create molecules with the general structure R1R2CHCF2CH2OH from ketone
R1(CO)R2. The key steps of this synthetic method involve the formation of a cyclic thiocarbonate and the
regioselective radical opening of the thiocarbonate to yield the corresponding primary alcohol
–CF2CH2OH. Using this synthetic method, novel fluorinated analogs of ganciclovir and penciclovir have
been prepared.
Received 17 September 2013
Revised 7 October 2013
Accepted 8 October 2013
Available online 18 October 2013
This Letter is dedicated to my father Tse
Kuen
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Fluorination
Antiviral
Ganciclovir
Penciclovir
Introduction
A 4-step sequence from a ketone (R2 = alkyl) or an aldehyde (R2 = H)
to a molecule with -CF2CH2OH group
About 40% of agrochemicals and 20% of pharmaceuticals on the
market are fluorinated compounds. The percentage is even higher
for compounds under development, clearly illustrating the impor-
tance of fluorine in drug development.1
F
F
R1
O
R1
R2
BrCF2COOEt, Zn
THF, reflux
NaBH4, EtOH
rt
COOEt
R2
OH
1
0
0
2
The size of F (1.47 ÅA) is similar to that of H (1.20 ÅA) but the
incorporation of fluorine in a molecule can drastically change the
properties of the molecule. First, the high electronegativity of F
can lead to unique chemical properties. For example, the enhanced
activity of certain fluorinated steroids, for example, dexametha-
sone, has been partly attributed to the increased acidity of the alco-
hol with the substitution of an adjacent fluorine.2 Fluorine
substitution may also change the lipophilicity of the molecule, thus
its rate of transport across lipid membranes and its bioavailability.2
In addition, the incorporation of fluorine can be used to block com-
pound metabolism at a particular site. Due to these reasons, the
strategy of incorporating fluorine atoms is widely employed in
the design of pharmaceuticals.2 In particular, there has been much
effort dedicated to developing methods for the incorporation of a
gem-difluoromethylene (–CF2ꢀ) unit.3 A common method to in-
stall this unit is to react ketones with NEt2SF3 (DAST) or similar re-
agents. This method, however, cannot be readily applied to
sterically hindered ketones or compounds with sensitive
F
F
R1
R2
F
F
R1
R2
thiocarbonyldiimidazole, DMAP
ClCH2CH2Cl, reflux
O
O
OH OH
S
4
3
F
F
Bu3SnH, AIBN
toluene, reflux
R1
R2
OH
5
Scheme 1.
functional groups. There is therefore a need to develop effective
alternative methods to generate –CF2ꢀ molecules.
TheraKem has developed a four-step sequence (Scheme 1) to
convert ketones to fluorinated primary alcohols containing the
–CF2CH2OH moiety. The primary alcohol groups formed readily
enable further structural modifications. Therefore, this reaction
sequence can be easily adopted to synthesize new analogs of
existing drugs.
⇑
Tel.: +1 619 808 3773.
E-mail address: brunotse@therakem.com
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.037

6910
B. Tse / Tetrahedron Letters 54 (2013) 6909–6911
O
Results
NH
N
Syntheses of analogs of ganciclovir and penciclovir
NH2
N
N
HO
HO
Using the method described in Scheme 1, compound 7, as the
ketone precursor, was converted to the primary alcohol 10
(Scheme 2).12 Reformatsky’s reaction on ketone 7 using BrCF2COO-
Et and activated Zn in refluxing THF, followed by NaBH4 reduction
of the ethyl ester, afforded the corresponding diol intermediate 8.
Despite the fact that one of the alcohols in 8 was a tertiary alcohol,
reaction with thiocarbonyldiimidazole and 1 equiv of DMAP in
dichloroethane at 70 °C proceeded smoothly to yield the cyclic
fluorinated thiocarbonate 9 (56% yield over three-steps from 7).
Treatment of 9 with Bu3SnH and AIBN in refluxing toluene afforded
the primary alcohol 10 selectively. The opening of the thiocarbon-
ate was very regioselective and only the primary alcohol was ob-
served. After conversion of 10 to its triflate 11, displacement by
base13 compound 12 and subsequent deprotections of all the
para-methoxybenzyl groups with HCOOH, compound 13 was
formed (35% over three-steps from 10). Compound 13 represents
the difluoro-analog of ganciclovir and penciclovir.
X
ganciclovir (GCV): X = O
penciclovir (PCV): X = CH2
Target Analog: X = CF2
Figure 1.
Viral infections remain a serious health threat. Many antiviral
drugs show toxicity and side effects.4 Viruses also mutate and be-
come resistant to existing drugs.5 In addition, the most commonly
used antiviral drugs have poor bioavailability.6 Therefore, there is a
continual need for new therapeutics and room for improvement in
treatments.
Some classes of acyclic nucleoside analogs have been proven to
be effective antiviral drugs. Though they structurally resemble the
natural nucleosides, these acyclic nucleoside drugs function by
halting the formation of DNA double strands as they either lack
important alcohol groups for DNA chain extension or are conform-
ationally unfavorable for the formation of double strands.7
Some of the most studied acyclic nucleosides are shown in
Figure 1. Ganciclovir (GCV) and penciclovir (PCV) are the bench-
mark drugs used against the herpes viruses, for example, herpes
simplex (HSV).8,9 These compounds suffer from poor bioavailability,
and their ester pro-drugs have been commonly used.10,11
Ganciclovir (GCV) and penciclovir (PCV) share a similar back-
bone with variations at position X: –O– ether linkage in GCV and
–CH2ꢀ methylene linkage in PCV. Installing a –CF2ꢀ group at posi-
tion X could generate novel analogs of these drugs, allowing for the
studies of the effect of fluorine incorporation in the backbones of
GCV and PCV. The synthetic method shown in Scheme 1 has been
adopted to prepare this target difluorinated analog, illustrating the
versatility and the usefulness of the synthetic method shown in
Scheme 1.
Discussion
This Letter describes an example of how the synthetic method
shown in Scheme 1 was readily used to generate novel difluoro-
analogs of ganciclovir and penciclovir from the ketone precursor
7. With this synthetic method, many novel difluoro compounds
and drug analogs in other therapeutic areas can be similarly cre-
ated from carefully designed ketone precursors.
Preliminary biological testing has been conducted on compound
13. As expected, the incorporation of the difluoromethylene group
has caused profound changes in the properties of GCV and PCV. Full
details of the biological activity of 13 will be described elsewhere.
Conclusion
This Letter shows the versatility of Scheme 1 in the preparation
of novel –CF2ꢀ compounds. With the careful design of carbonyl
O
MPMO
(1) p-MeO-C6H4-CH2OH, NaH, DMF, 70 oC (66%)
O
(2) PCC, CH2Cl2, rt (68%)
Cl
6
MPMO
7
OH OH
MPMO
MPMO
thiocarbonyldiimidazole, DMAP
ClCH2CH2Cl, reflux (69%)
(1) BrCF2COOEt, Zn, THF, reflux
(2) NaBH4, EtOH, rt
(81% over 2 steps)
F
F
8
S
OH
MPMO
MPMO
Tf2O, pyridine
O
O
Bu3SnH, AIBN
MPMO
MPMO
CH2Cl2, 0 o
C
toluene, reflux (87%)
F
F
F
F
10
9
OMPM
O
N
N
NH
N
(1)
NH2
N
H
N
12
NH2
N
OTf
N
MPMO
MPMO
HO
HO
NaH, DMF, 70 oC
(2) HCOOH, 40 o
(35% overall from 10)
F
F
F
F
C
11
13
Scheme 2.

B. Tse / Tetrahedron Letters 54 (2013) 6909–6911
6911
3. For example, see: (a) Barton, D. H. R.; Hesse, R. H.; Markwell, R. E.; Pechet, M.
M.; Toh, H. T. J. Am. Chem. Soc. 1976, 98, 3034; (b) Shieh, T. C.; Yang, N. C.;
Chernick, C. L. J. Am. Chem. Soc. 1964, 86, 5021; (c) Middleton, W. J. J. Org. Chem.
1975, 40, 574; (d) Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452; (e) Miyake,
N.; Kitasume, T. J. Fluorine Chem. 2003, 122, 243; (f) Thayer, A. M. Chem. Eng.
News 2006, 84, 27.
4. For example, see: (a) Martin, J. L.; Brown, C. E.; Matthews-Davis, N.; Reardon, J.
E. Antimicrob. Agents Chemother. 1994, 38, 2743; (b) Thust, R.; Tomicic, M.;
Klocking, R.; Wutzler, P.; Kaina, B. Mutagenesis 2000, 15, 177.
5. For example, see: (a) Springer, K. L.; Chou, S.; Li, S.; Giller, R. H.; Quinones, R.;
Shira, J. E.; Weinberg, A. J. Clin. Microbiol. 2005, 43, 208; (b) Chou, S.; Lurain, N.
S.; Thompson, K. D.; Miner, R. C.; Drew, W. L. J. Infect. Dis. 2003, 188, 32.
6. For example, see: (a) Avery, R. K. Am. J. Transplant. 2007, 7, 2062; (b) Abete, J. F.;
Martin-Davila, P.; Moreno, S. Antimicrob. Agents Chemother. 2004, 48, 2782.
7. De Clercq, E. J. Clin. Virol. 2004, 30, 115.
precursors, compounds of the general formula R1R2CHCF2CH2OH
can be readily generated and can serve as useful building blocks
to many novel difluorinated drug analogs.
Acknowledgements
I would like to thank American Life Science Pharmaceuticals for
a great collaborative relationship. Special thanks are given to Pro-
fessor Erik De Clercq and NIAID for compound testing.
References and notes
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1636.
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12. Ketone
7 was first obtained by reacting epichlorohydrin 6 with 4-
methoxybenzyl alcohol and NaH in DMF, followed by PCC oxidation.
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