The Synthesis of an Antiviral Fluorinated Purine Nucleoside: 3'-Î±

Chapter 22

The Synthesis of an Antiviral Fluorinated Purine Nucleoside: 3'-α-Fluoro-2',3'-dideoxyguanosine Downloaded by NORTH CAROLINA STATE UNIV on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch022

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KunisukeIzawa ,Takayoshi Torii , Tomoyuki Onishi , and Tokumi Maruyama 2

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2

AminoScience Laboratories, Ajinomoto Company, Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Japan 210-8681 Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido 1314-1, Sanuki-city, Kagawa, Japan 769-2193

In this review, the synthesis of FddG, a potential HIV reverse transcriptase inhibitor is described focusing on regio- and stereoselective fluorination at the C3'α-position of the nucleoside. These results, which include a synthetic strategy employing retentive fluorination, may provide a new approach towards a variety of C3'α -substituted nucleosides.

Introduction Acquired immunodeficiency syndrome (AIDS) and the viral infectious diseases, which are represented in hepatocellular carcinoma by hepatitis Β and C viruses, have become serious medical problems worldwide. Human immunodeficiency virus (HIV), the pathogenic virus that causes AIDS, belongs to the retrovirus. This type of virus utilizes a reverse transcriptase (RT) for synthesizing the proviral D N A from the R N A of H I V genome to enable © 2007 American Chemical Society

In Current Fluoroorganic Chemistry; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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Downloaded by NORTH CAROLINA STATE UNIV on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch022

364 sustained infection of HIV Thus, the R T has borne important function for the multiplication of the HIV, therefore, it has become the target enzyme to develop the novel anti-HIV drugs. A s a result of computational structure activity relationship studies, many nucleoside derivatives appeared in development candidacy. In the course of these researches, a variety of nucleosides possessing a fluorine atom in the sugar moiety were synthesized, and their activities were duly evaluated. A fluorine atom is similar to a hydrogen atom in size but possesses very different electronic properties which not only reinforce activity but also improve bioavailability; in addition, the presence of a fluorine atom may bring about increased metabolic stability. The substitution of a fluorine atom at the C 3 ' α - or C2'β-position of a nucleoside was shown in a number of cases to confer significant anti-HIV activity. Conversely, those compounds with the opposite configuration exhibited lower activity (1). A typical example of the former is Lodenosine (FddA, 1) (2), and of the latter Alovudine (FLT, 2) (3). Recently, FddG 3 which has the same sugar moiety as F L T 2 (Figure 1) was taken into clinical development having attracted much attention for both its antiH I V activity (4) and its anti-HBV activity (5). A s regards the synthesis of FddG 3, the development of an industrial-scale process is somewhat problematic due to the peculiar physical properties of guanine base and no suitable manufacturing method has been reported. In this chapter, we review the recent research on the synthesis of FddG 3 including our own latest results.

H O - ^ Lodenosine FddA 1

^ Alovudine FLT 2

FddG 3

Figure 7. The nucleosides derivatives bearing fluorine in the sugar moiety

Results and Discussion Synthesis of F d d G from fluorinated sugars A convenient synthetic approach to FddG 3 is to couple the fluorinated sugar with the purine base. There have been many reports of the preparation of 3a-fluoro-2,3-dideoxyribose derivatives from natural monosaccharides such as D-xylose 4 (6) and 2-deoxy-D-ribose 9 (7), since the fluorinated sugars are key intermediates for F L T 2. The first synthesis of such fluorinated sugars was reported by Fleet et al. in 1987 for the preparation of F L T 2 (6a). The key fluorination step was performed via triflate formation followed by a fluorination


365 reaction with tetrabutylammonium fluoride to give the fluorinated sugar 8 (Scheme 1).

H

~OH

i)HCI/MeOH i') neutralization

OH 4

iii)acetone/H* 72% (3 steps)

0

»)Bu SnH

O M e

^ C^

^

0

^

0 0

A

90%

O

M

''

TBDPSO^VbHT' \ 0 7

M

e

0C{sS)SMe

6 ^V ° y -yO M e H-O ' ^/V

i)Tf i) Tf0/pyridine 0/pyrjdine

e

0

V

5 v

ii) TsOH/MeOH iii) TBDPSCI imidazole 55% (3 steps)

CS , Mel NaH 2

C^Voy'

A

^ v ^JO^ O

3


n 0

v

22

O M e

ii) TBAF/THF A R 9 / / 0 4 6 % ( 2

u C

H O

e l a n e X S l e p S )

p

\_7 o

Scheme 1

A more efficient method was reported by Saischek et al. in 1991 (Scheme 2) (7a). They also used the same fluorination conditions as those reported by Fleet et al., although the yield was slightly improved probably because of the changed protecting group. i) HCl/MeOH |50 1) 70 98% yield 70 17area%(70 71 >50.1) 70 90 area% (70 71 =41 1) 70 91% yield (70.71 >50.1)

3

2

2

2

2

2

2

U


375


The fluorination product 70 was then treated with acetic acid followed by reductive desulfurization with Raney N i in aq. NaOH affording ddG 72 but not FddG 3 (Scheme 17).

Scheme Accordingly, we tried to achieve the desulfurization of compound 70 in various solvent systems prior to deprotection with the acid. The results are listed in Table 3. The reaction of 70 with Raney N i in EtOH gave a small amount of the desired Tr -FddG 73 along with Tr -ddG 74 as a major product in a ratio of 73:74 = 1:4 (Run 1). B y elevating the reaction temperature using 1-BuOH, the ratio of 73:74 was improved slightly to 1:3 (Run 2). To our delight, when we used toluene as a solvent, the preferential formation of Tr -FddG 73 vs. Tr -ddG 74 was observed. Eventually, we discovered that the desulfurization of compound 70 with Raney N i in toluene without any additives gave the best ratio of 73:74 in 6:1 (Run 5); the desired product 73 was isolated in 61% yield after column chromatography. 2

2

2

2

Table 3. Desulfurization of ditritylated compound 70

70

73

run

solvent

additive (eq)

temp

1 2 3

EtOH 1-BuOH toluene 1-BuOH toluene

NEt (4) NEt (4) NEt (4) none none

80 °C 100 °c 90 °C 100 °c 90 °C

4

5

3

3

3

74

results 73:74= 1:4 73:74= 1.3 73:74* 1.7:1 73.74= 1:1.5

73 61% yield, 73:74 = 6:1

The Tr -FddG 73 thus obtained was deprotected under acidic conditions to give FddG 3 in 69% yield (Scheme 18). This synthetic method using retentive fluorination at the C3'-position has the advantage of providing FddG 3 in high yields with a safer fluorination agent, NfF (30). However, there is a drawback for industrial scale synthesis in the need to perform desulfurization using an excess amount of Raney N i . 2



376

Conclusion This review has examined the synthetic methods for FddG 3 focusing in particular on fluorination methods. Initial approaches using a nucleoside as the starting material required S F reagents such as D A S T or M O S T for the fluorination since other agents afforded mainly elimination products. However, S F reagents are not desirable for industrial scale synthesis due to their poor availability and inherent toxicity. In order to overcome this problem, we developed a new nucleoside fluorination method utilizing neighboring participation. Applying this methodology, we succeeded in carrying out the fluorination of a guanosine derivative at the C3'-position in good yield using readily available NfF. This may provide a novel stereoselective method for introducing a fluorine atom into die sugar moiety of nucleosides. 4

4

References 1. 2.

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The Synthesis of an Antiviral Fluorinated Purine Nucleoside: 3'-Î±

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