Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

186 Fluorine in Medicinal Chemistry and Chemical Biology

7.3.3.2.2 Synthesis of F dd G with Bromine Rearrangement during Fluorination W e

reported that the bromohydrin derivative 60b , which was easily prepared from guanosine

via 60a , gave the C - 3 ′ - α - ﬂ uorinated compound 61 in 59% yield accompanied by the for-

mation of a regioisomer (21%) under ﬂ uorination conditions (see Scheme 7.21 ) [84] . The

reaction can be explained by considering the rearrangement of the bromine atom from the

C - 3 ′ - β - to the C - 2 ′ - β - position via a bromonium ion intermediate on which the ﬂ uoride

anion attacks from the α - side of the C - 3 ′ - or C - 2 ′ - position. The C - 3 ′ - α - ﬂ uorinated product

61 was converted to FddG ( 2 ) by radical debromination and deprotection.

We further investigated the ﬂ uorination conditions to improve the yield of C - 3 ′ - α -

product 61 . We then found that the ﬂ uorination of compound 60b with SF

4

furnished the

C - 3 ′ - α - product 61 in 79% yield in an 3 ′ - F:2 ′ - F ratio of 7.8 : 1 [85] . This suggests that

the diethylamino group of DAST may have a negative inﬂ uence on the regioselectivity

of the reaction. To our surprise, we also found that the reaction of compound 60b with

NfF in the presence of NEt

3

did not afford ﬂ uorination product 61 , but produced a 2 ′ ,3 ′ -

didehydro - 2 ′ ,3 ′ - dideoxyguanosine derivative in 62% yield. This method has advantages

with respect to the number of reaction steps and high overall yield. However, one serious

drawback is that this method uses SF

4

- type reagents which require special equipment for

handling.

7.3.3.2.3 Synthesis of F dd G via Retentive Fluorination at the C - 3 ′ - α Position After

concluding that the ﬂ uorination with bromine rearrangement described above might

proceed via a bromonium ion intermediate, we considered that a similar reaction might

take place via a sulfonium ion intermediate. We chose readily available 8,2 ′ - anhydro - 8 -

mercaptoguanosine as the starting material, anticipating that ﬂ uorination might proceed

with the participation of a sulfur atom, which would facilitate the attack of ﬂ uoride ion to

the C - 3 ′ - α - rather than the C - 2 ′ - α - position for steric reasons [86] . 8,2 ′ - Anhydro - 8 -

mercaptoguanosine was ﬁ rst converted to the N

2

, O

5 ′

- diacetyl derivative 62 which was

subjected to ﬂ uorination with DAST (see Scheme 7.22 ). As anticipated, we obtained the

Scheme 7.21

Synthesis and Biological Activity of Fluorinated Nucleosides 187

C - 3 ′ - α - ﬂ uorinated product 63 in 47% yield without any formation of the C - 2 ′ - α - ﬂ uori-

nated product. In the case of ﬂ uorination with NfF, however, we found that elimination

predominated ( 63 : 64 = 1 : 3.5) (see Scheme 7.22 ).

Encouraged by these results, we further investigated the ﬂ uorination of ditrityl pro-

tected compound 65 using several ﬂ uorinating reagents (see Scheme 7.23 ). Although the

reaction with DAST gave a complex mixture, the desired C - 3 ′ - α - product 66 was obtained

in 63% yield with NfF/NEt

3

, along with the elimination product. Next, we optimized the

reaction conditions. When we used diisopropylethylamine (DIPEA) as the base, elimina-

tion was completely suppressed, albeit the yield was not improved. The best yield (91%)

was achieved when we used an excess amount of NfF and DIPEA.

Scheme 7.22

Scheme 7.23

188 Fluorine in Medicinal Chemistry and Chemical Biology

The ﬂ uorination product 66 was then treated with acetic acid followed by reductive

desulfurization with Raney nickel in aqueous NaOH to give deﬂ uorination product ddG,

but not FddG ( 2 ). Accordingly, we tried the desulfurization of compound 66 in various

solvent systems prior to deprotection with the acid. After several unsuccessful attempts,

we obtained the desired Tr

2

- FddG 67 in 61% isolated yield when we carried out Raney -

nickel reduction in toluene. This method is advantageous because ﬂ uorination can be

achieved using the scalable reagent NfF.

In this section, synthetic approaches to FddG ( 2 ) with particular focus on industrially

applicable ﬂ uorination methods are described. At the beginning of this study, these

approaches which used a nucleoside as a starting material required SF

4

reagents such as

DAST and morpholinosulfur triﬂ uoride (MOST) for ﬂ uorination because other agents gave

mainly elimination products. However, SF

4

- type reagents are not desirable for industrial -

scale synthesis because of their poor availability and inherent toxicity. To overcome these

problems, we developed a new nucleoside ﬂ uorination method that involved the participa-

tion of neighboring groups. With this methodology, we achieved the ﬂ uorination of a

guanosine derivative at the C - 3 ′ position in good yield using readily available NfF. This

would provide a useful stereoselective method for introducing a ﬂ uorine atom into the

sugar moiety of nucleosides.

7.4 Biological Activity of Fluorinated Nucleosides and Correlations with

Their Conformations

7.4.1 Sugar Ring Conformation of 2 ′ - Deoxy - 2 ′ - a - ﬂ uoronucleosides

7.4.1.1 Properties of Modiﬁ ed RNA Containing 2 ′ - Deoxy - 2 ′ - α - ﬂ uoronucleosides

In 1968, four years after the ﬁ rst synthesis of 2 ′ - deoxy - 2 ′ - α - ﬂ uorouridine ( 4 ), Fox and

co - workers reported that 4 adopts the 3 ′ - endo conformation (N - form) more readily than

the 2 ′ - endo conformation (S - form) [87] . In the 1970s, some studies examined the relation-

ships between the conformations of 2 ′ - deoxy - 2 ′ - α - substituted nucleosides and the electro-

negativity of their 2 ′ - substituents, and revealed that an increase in electronegativity led to

a high proportion of the 3 ′ - endo conformation. According to these studies, the proportion

of the 3 ′ - endo conformer of 4 is approximately 85% [88] . With regard to 2 ′ - substituted

purine nucleosides [89] , Uesugi and co - workers also reported that 2 ′ - deoxy - 2 ′ - α - ﬂ uoro-

adenosine ( 10b ) favors the 3 ′ - endo conformation, and this trend remained unchanged even

when 10b was contained in dinucleoside monophosphate [90] . Although ribonucleoside

generally favors the 3 ′ - endo conformation, 2 ′ - deoxy - 2 ′ - α - ﬂ uoro analogues increase this

tendency more than ribonucleosides. However, despite the difference in sugar puckering,

the torsion angles of the C - 4 ′ – C - 5 ′ bond and the C - 5 ′ – O - 5 ′ bond in the 2 ′ - deoxy - 2 ′ - α -

ﬂ uoro analogues are analogous to those of ribonucleosides. Thus, a nucleic acid that con-

tains the 2 ′ - deoxy - 2 ′ - α - ﬂ uoronucleoside forms a structure similar to RNA, in which the

proportion of the 3 ′ - endo conformation is higher than that in RNA.

This property naturally inﬂ uences their biological activities. For example, it has been

reported that poly(2 ′ - deoxy - 2 ′ - α - ﬂ uoroadenylic acid) ( 69a ) is as good a template as

poly(adenylic acid) ( 68a ) for some reverse transcriptases and DNA polymerase [91]

Synthesis and Biological Activity of Fluorinated Nucleosides 189

(Figure 7.4 ). Likewise, poly(2 ′ - deoxy - 2 ′ - α - ﬂ uoroinosinic acid) ( 69b ) and poly(2 ′ - deoxy -

2 ′ - α - ﬂ uorocytidylic acid) are effective templates for reverse transcriptases [92] . Notably,

69a also functions as mRNA in protein - synthesizing systems in vitro , in which [

14

C]lysine

is incorporated into polypeptides [93] . Moreover, modiﬁ ed mRNA that contains 2 ′ - deoxy -

2 ′ - α - ﬂ uoroadenosine ( 10b ) can give rise to the corresponding protein (luciferase). Interest-

ingly, modiﬁ ed RNA that contains 2 ′ - deoxy - 2 ′ - α - ﬂ uorouridine ( 4 ) does not act as mRNA

[94] . A similar trend has been observed in a study on the induction of interferon by double -

helical RNA (poly I · poly C). The complex of poly(2 ′ - deoxy - 2 ′ - α - ﬂ uoroinosinic acid)

( 69b ) · poly C shows higher interferon - inducing activity than that of poly I · poly C, while

the complex of poly I · poly(2 ′ - deoxy - 2 ′ - α - ﬂ uorocytidylic acid) is not an effective inter-

feron inducer [95] .

7.4.1.2 Properties of 2 ′ - Deoxy - 2 ′ - α - ﬂ uoronucleosides

Although the relationship between conformation and biological activity is not well docu-

mented at the nucleoside level, several 2 ′ - deoxy - 2 ′ - α - ﬂ uoronucleosides are known to have

biological activity, such as antiviral activity. Tuttle and co - workers reported that several

2 ′ - deoxy - 2 ′ - α - ﬂ uoropurine nucleosides exhibited antiviral potency against inﬂ uenza A and

B viruses. The 2 - amino group of the purine moiety is critical [96a] for this activity, and

the antiviral activity is much better than those of amantadine and ribavirin [96b] . Notably,

2 ′ - deoxy - 2 ′ - α - ﬂ uoro - 2 ′ - C - methylcytidine shows increased inhibitory activity in the hepa-

titis C virus (HCV) replicon assay compared to 2 ′ - C - methylcytidine, and low cellular

toxicity [97] . Inﬂ uenza virus and HCV are classiﬁ ed as RNA viruses, which are a major

target of current chemotherapy. However, the development of effective drugs against these

virus infections is still slow; further investigation of 2 ′ - deoxy - 2 ′ - α - ﬂ uoronucleosides is

expected to accelerate the development of such drugs.

Another interesting biological activity of 2 ′ - deoxy - 2 ′ - α - ﬂ uoropuromycin has been

observed. Unlike other nucleoside analogues, puromycin inhibits protein biosynthesis

without phosphorylation of the 5 ′ - hydroxyl group. As mentioned above (Section 7.2.2.3.1 ),

2 ′ - deoxy - α - 2 ′ - ﬂ uoropuromycin ( 20b ) showed antitumor and antibacterial activity

Figure 7.4 Structures of polynucleotides and their analogues.

190 Fluorine in Medicinal Chemistry and Chemical Biology

comparable to that of puromycin. Since 2 ′ - deoxypuromycin, which favors the 2 ′ - endo

conformation, showed no biological activity, the 3 ′ - endo conformation is thought to be

essential for its activity.

In general, the 3 ′ - endo conformation of ﬂ uoronucleoside is essential for antiviral

activity against RNA viruses although the anti - HIV activity is an exception (the details of

anti - HIV activity are addressed in the next section).

7.4.2 Sugar Ring Conformations of F dd A and F dd G and

Their Anti - HIV Activities

Mu and co - workers reported that the introduction of a ﬂ uoro group to the C - 2 ′ - α position

of 2 ′ ,3 ′ - dideoxyadenosine 5 ′ - triphosphate (ddATP) led to the 3 ′ - endo conformation like a

nucleoside congener, while introduction to its β position led to the 2 ′ - endo conformation

[98] . In contrast, the 2 ′ - endo conformation was predominant when the ﬂ uoro group was

introduced to the C - 3 ′ - α position of 2 ′ ,3 ′ - dideoxynucleosides [99] . Further conformational

analysis of alovudine (3 ′ - deoxy - 3 ′ - ﬂ uorothymidine, FLT) (see Figure 7.3 ), a potent anti -

HIV agent, has revealed that approximately 90% of FLT is ﬁ xed to the 2 ′ - endo conforma-

tion in aqueous solution [100] . Another conformational analysis of four monoﬂ uorinated

analogues of 2 ′ ,3 ′ - dideoxyuridine (i.e., 2 ′ - α - F, 2 ′ - β - F, 3 ′ - α - F, and 3 ′ - β - F analogues, see

Figure 7.5 ) also revealed that the 2 ′ - up and 3 ′ - down analogues favor the 2 ′ - endo confor-

mation [101] . This preference can be explained by a gauche effect, in which a more elec-

tronegative substituent favors an axial orientation [15] .

We now discuss the relationship between these conformations and anti - HIV activity.

In 1989, Roey and co - workers reported the correlation between the sugar ring conforma-

Figure 7.5 Sugar - puckering of four monoﬂ uorinated analogues of 2 ′ ,3 ′ - dideoxyuridine.

Synthesis and Biological Activity of Fluorinated Nucleosides 191

tion and the anti - HIV activity of some nucleoside analogues. They discovered that the 2 ′ -

endo conformation is preferable for anti - HIV activity [102] . In the 2 ′ - endo conformation,

the C - 5 ′ moiety takes an axial orientation, which directs its 5 ′ - hydroxyl group to an advan-

tageous position for the kinase - mediated phosphorylation process, or to a favorable posi-

tion for its afﬁ nity with reverse transcriptase (RT). Mu and co - workers reported a molecular

dynamics simulation of ternary complexes of an HIV - 1 - RT, a double - strand DNA, and

2 ′ ,3 ′ - dideoxy - 2 ′ - ﬂ uoroadenosine 5 ′ - triphosphate (FddATP), and discussed the activity of

FddATPs (2 ′ - α - or 2 ′ - β - forms) as inhibitors [98] . Based on the preference of the RT to

bind incoming dNTP (or ddNTP), a 3 ′ - endo conformer (i.e., α FddATP) is believed to ﬁ t

the polymerase site better than β FddATP. Interestingly, however, their study has revealed

that Tyr115 of the RT, which appears to function as a steric gate against the incoming

dNTP, prevents the effective binding of α FddATP, while the 2 ′ - endo conformer, β FddATP,

can pass the gate without hindrance to the RT. Consequently, the 2 ′ - endo conformer,

β FddATP, shows stronger anti - HIV activity, although this conformation shows a worse ﬁ t

to the polymerase site of HIV - RT.

As mentioned above, nucleoside analogues have to clear many hurdles to exhibit

biological activity. For example, those hurdles include phosphorylation by kinase, further

conversion to triphosphate, penetration to the active site of the target enzyme through a

steric gate, and strong afﬁ nity to the active site of the enzyme. Several dideoxynucleosides

like ddI and ddC, which have been approved as anti - HIV agents, are ﬂ exible enough to

clear all of these hurdles and show good anti - HIV activity. However, the introduction of

a ﬂ uoro group to the sugar moiety of nucleoside brings about rigid 2 ′ - endo or 3 ′ - endo

conformation, and such a ﬁ xed conformation makes it difﬁ cult to clear all of these hurdles

in some cases. If these hurdles can be overcome, the many advantages of ﬂ uoronucleoside,

such as chemical and pharmacological stability, could lead to stronger biological

activity.

7.5 Conclusion

Since the discovery of nucleocidin, a large number of ﬂ uorinated nucleosides have been

synthesized and have contributed to the development of biologically active agents. The

practical use of gemcitabine as an anticancer agent and also the upcoming use of clevudine

as an anti - HBV agent reﬂ ect this development. Early in this chapter, we described the

syntheses and biological activities of 2 ′ - deoxy - 2 ′ - α - ﬂ uoronucleosides and their oligomers.

Such fundamental studies led to the use of ﬂ uorinated nucleosides in other ﬁ elds, such as

antisense and ribozymes, due to the chemical and biological stability of ﬂ uorinated nucleo-

sides. Next, we described the synthesis of a potent antiviral agent, FddA, with special

focus on synthetic issues (e.g., the difﬁ culty of β - side - selective ﬂ uorination) and its

process - scale synthesis. The possible process - scale synthesis of FddG was also described.

The relationships between the sugar ring conformations and the biological activities of

several ﬂ uorinated nucleosides were also discussed. We hope that this chapter provides a

better understanding of the usefulness of ﬂ uorinated nucleosides as well as valuable refer-

ences for their syntheses.

192 Fluorine in Medicinal Chemistry and Chemical Biology

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Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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