Tetrahedron 64 (2008) 85858603

Contents lists available at ScienceDirect

Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Tetrahedron report number 845

Recent advances in the synthesis of purine derivatives and their precursors

Michel Legraverend
UMR176 CNRS, Institut Curie, Bat. 110 Centre Universitaire, 91405 Orsay, France

a r t i c l e i n f o
Article history: Received 19 May 2008 Available online 3 June 2008 Keywords: Purine libraries Purine chemistry ATP analogues Enzyme inhibitors Receptor antagonists

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8586 Functionalisation at position 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8586 2.1. Functionalisation of the purine ring from guanosine, via a 6-arylsulfonate intermediate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8586 2.2. Preparation of C-6-arylpurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8587 2.3. Synthesis of 6-amidopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8587 2.4. Substitution reactions of 6-chloropurine and 2-amino-6-chloropurine with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8588 Functionalisation at position 9: preparation of 9-substituted purine derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8589 3.1. Regioselective and stereoselective coupling of 6-(substituted-imidazol-1-yl)purines with 1-chloro-20 -deoxyribose . . . . . . . . . . . . . . . . . . . . . . . . . . 8589 3.2. Michael addition of adenine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8590 3.3. Arylation at N-9 of 7-deazapurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8590 3.4. Arylation at N-9 of purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8590 3.5. Mitsunobu alkylation at N-9 position with either primary or secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 8591 3.6. Use of an aminoalkane and pyrimidine precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8591 Functionalisation at N-1, N-3, N-7 and C-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8592 4.1. Preparation of xanthine derivatives from 6-aminouracils (Traube synthesis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8592 4.2. Synthesis of purines from an imidazole precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8592 4.3. Solid-phase synthesis of xanthine derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8592 4.4. Synthesis of N-1,N-7-disubstituted purines from 6-chloropurine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8595 Functionalisation at position 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8595 5.1. Pyrimidine precursors of 2,6,8,9-tetrasubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8595 5.2. Synthesis of 2,6,8,9-tetrasubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8596 5.3. Synthesis of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) from pyrimidine precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8597 Functionalisation at position 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8598 6.1. Synthesis of 8,9-disubstituted adenines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8598 6.2. Synthesis of 2,8,9-trisubstituted adenines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8598 6.2.1. Synthesis of 2,8,9-trisubstituted adenine inhibitors of HSP90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8598 6.2.2. 8-Aryl-9-methyladenine derivatives from a 4,6-dichloropyrimidine precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8599

3.

4.

5.

6.

Abbreviations: ATP, adenosine 50 -triphosphate; GTP, guanosine 50 -triphosphate; GDP, guanosine 50 -diphosphate; cAMP, cyclic adenosine 30 ,50 -monophosphate; cGMP, cyclic guanosine 30 ,50 -monophosphate; AcCoA, acetyl-coenzyme A; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; FAD, avin adenine dinucleotide; PAPS, 30 -phosphoadenosine 50 -phosphosulfate; SAM, 50 -S-adenosyl methionine. E-mail address: michel.legraverend@curie.u-psud.fr 0040-4020/$ see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.05.115

8586

M. Legraverend / Tetrahedron 64 (2008) 85858603

7.

6.3. Synthesis of 6,7,8-trisubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8599 6.4. Preparation of 6,8-disubstituted purine analogues: thiazolopyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8600 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8600 References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8601 Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8603

1. Introduction The purine ring is the most ubiquitous nitrogen-containing heterocycle in nature,1 since, besides the numerous purine derivatives found in various marine organisms and plants, it is the core structure of adenine and guanine in nucleic acids (RNA and DNA). In addition, purines are involved in many metabolic processes as cofactors associated with a great number of enzymes and receptors, notably ATP, GTP, GDP, cAMP, cGMP, AcCoA, NAD, NADP, FAD, PAPS and SAM,1,2 which play key roles at different phases of the cell cycle, in cell signalling and other fundamental biological processes.3 It should be noted that all of these associated proteins contain a purine recognition pocket and, consequently, purine derivatives have long been developed to selectively inhibit or antagonise each of these enzymes and receptors. Indeed, a great variety of di-, tri- or tetrasubstituted purines described in the literature have been found to be potent inhibitors of chaperone HSP90, protein kinases (MAP, Src and Cdk), sulfotransferases, phosphodiesterases and microtubule assembly, inducers of interferon and dedifferentiation and antagonists of adenosine receptors and corticotropin-releasing hormone receptors.2 This wide range of biological activities displayed by purines is conferred by a judicious choice of the nature of the substituents that can be combined on the N-1, C-2, N-3, C-6, N-7, C-8 and N-9 centres (Fig. 1).
6 1N 2 7 8

Following a previous article, which highlights the interest in purines as inhibitors and modulators of key biological targets,2 the goal of the present article is to review recent advances in the synthesis of purine derivatives, with particular emphasis on methods that can lead to purine libraries.

2. Functionalisation at position 6 6-Aminopurines are traditionally obtained in four steps from a nucleoside precursor in a process, which requires protection of the sugar moiety followed by halide formation, often under harsh conditions. Interestingly, Wan and co-workers5 have recently described the synthesis of several 6-aminopurine derivatives 2 in one step and high yield from unprotected inosine 1 (XOH) (Scheme 1), by BOP-mediated amination. Polycyclic aromatic hydrocarbons (PAH) are potent mutagens and carcinogens that are challenging synthetic targets. This method also allowed the synthesis of PAH derivative 3 from 20 -deoxyinosine 1 (XH) as well as the rare DNA constituent 4 in almost quantitative yield. Under these conditions, several 6-substituted purines 2ah (Table 1, entries 18) were prepared from unprotected inosine in high yield from various aryl- or benzylamines. Using similar reaction conditions, the acetyl-protected inosine 5 led to the corresponding 6-substituted-9-(2,3,5-tri-O-acetyl-b-Dribofuranosyl)-purines 6ag (Scheme 2, Table 2, entries 17).

N N
3

N9 H

Figure 1. Purine (imidazo[4,5-d]pyrimidine) ring.

2.1. Functionalisation of the purine ring from guanosine, via a 6-arylsulfonate intermediate The use of a 6-arylsulfonate for CC bond formation with boronic acids at room temperature on the purine ring was reported for the rst time in 2005.6 This palladium-catalysed cross-coupling reaction of nucleoside arylsulfonates and arylboronic acids required the use of a ligand and could be generalised to various boronic acids (Scheme 3). The starting compound, 6-arylsulfonyl-30 ,50 -bis-O-(tert-butyldimethylsilyl)-20 -deoxyguanosine 7, was synthesised from 20 deoxyguanosine in high yield, in the presence of Et3N and DMAP, with 2,4,6-trimethylphenylsulfonyl chloride.
R N N 98% X

With such an easy access to so much structural diversity, the purine core has become a privileged structure in medicinal chemistry,4 and an important scaffold in the preparation of combinatorial libraries. In general, two strategies are applied for the preparation of purine libraries. In the rst procedure, a preformed purine ring loaded with various reactive functionalities is directly modied, which allows good regiocontrol at C-2, C-6, C-8 and N-9. Alternatively, substituted pyrimidine or imidazole precursors are functionalised, generating the second heterocycle of the purine core in the process with better regiocontrol at N-1, N-3, N-7 and N-9.

O N O HO HO X 1 X = OH, H 3: R = X=H NH2 4: R = X=H

Scheme 1.

HN NH BOP (1.5 equiv) DIPEA (2.0 equiv) R-NH2 (1.2-5.0 equiv) DMF/EtOH (65-99%) HO HO N O N

2: R = alkyl, aryl (PAH adduct)

(rare DNA constituent)

M. Legraverend / Tetrahedron 64 (2008) 85858603 Table 1 Amination of sugar-unprotected inosine and 20 -deoxyinosine Entry 1 2 3 X OH H OH Amine BnNH2 BnNH2 Methoda A A B Product 2a 2b 2c Yield (%) 99 99 91

8587

Of the nucleoside arylsulfonates evaluated, the O-6-(2,4,6-trimethylphenyl)sulfonate 7 proved to be optimal in cross-coupling reactions with tetrahydropyran (THP) as the best solvent, to form 8. 2.2. Preparation of C-6-arylpurines It has been proposed that DNA containing C-6-arylpurines could exhibit unusual properties,7 prompting a number of studies on the introduction of substituted aryl moieties at the C-6 position of the purine ring in recent years. For example, Lakshman and co-workers have synthesised a wide variety of C-6-arylpurine 20 -deoxyribosides 10ag via the Pd-mediated SuzukiMiyaura cross-coupling of arylboronic acids with C-6 halonucleosides 9 (Scheme 4 and Table 3). For several C-6 arylations, the chloronucleoside gave higher coupling yields than the bromo analogue (see Table 3). With arylboronic acids containing electron-withdrawing groups performing less well, several ligands were tested, but the system Pd(OAc)2/ K3PO4/2-(dicyclohexylphosphino)biphenyl was found to be superior.7 Hocek and co-workers have reported8 that the regioselectivity of the SuzukiMiyaura cross-coupling of 2,6-dihalopurines (11 and 14) with 1 equiv of phenylboronic acid is dependent on the halogen at position 2. Thus, 9-benzyl-2,6-dichloropurine 11 gave 12, the product of cross-coupling at position 6, whereas the corresponding iodopurine 14 gave the 2-arylpurine derivative 15. In the presence of 3 equiv of phenylboronic acid, both halogenopurines led to 9benzyl-2,6-diphenylpurine 13 in high yield (Scheme 5). The scope of this reaction was extended to substituted phenyland heteroarylboronic acids.9,10 A high yield (70%) of 2-chloro-6-(3pyridyl)purine 17d was obtained from 2,6-dichloropurine 16 with 1 equiv of 3-pyridylboronic acid in an aqueous phase (H2O/MeCN 2:1). It is interesting to note that no protection at N-9 was necessary (Scheme 6 and Table 4),9 although the regioselectivities and yields at position 6 (17ad) were inferior to those under the previously described conditions (toluene, K2CO3, Pd(PPh3)4, 100  C, 820 h; Scheme 5) as the unwanted 2,6-disubstituted products 18a,b were also observed. Various 6-aryl-, 6-heteroaryl-, 6-phenylethynyl- or 6-styrylpurines 20ae have also been prepared by Stille couplings on the parent halopurine 19a,b, and were found to be antimycobacterial agents (Scheme 7, and Table 5).11 2.3. Synthesis of 6-amidopurines Olomoucine, roscovitine and purvalanol A and B are well-known representatives of the 2,6-diaminopurine class of molecules that exhibit a great variety of biological activities against CDKs and other enzymes and receptors.2 Large libraries of 2,6,9-trisubstituted purines bearing an amino substituent at positions 2 and 6 have been synthesised.1220 These derivatives are easily obtained from various 2,6-dihalogenopurines, the halogen at position 6 (Cl or Br) being more reactive than that at position 2 (F, Cl, Br or I) under SNAr conditions.
X Ligand:

NH2

OH

NH2

2d

74

NH2
5 OH B 2e 81

O NH2
6 OH B 2f 85

Ph

O NH2
B 2g 65

OH

OH

NH2

2h

72

a A: BOP (1.2 equiv), DIPEA (1.5 equiv), RNH2 (1.2 equiv), rt; B: BOP (1.5 equiv), DIPEA (2 equiv), RNH2 (5 equiv), rt, overnight, then 60 or 80  C.

O N O AcO AcO N 5 OAc N NH BOP (1.2 equiv) DIPEA (1.5 equiv) R-NH2 DMF, rt
Scheme 2.

HN N O AcO N N

R N

AcO

6a-g OAc

Table 2 Amination of sugar-protected inosine Entry 1 2 3 4 5 Amine Bn-NH2 Reaction conditions rt, <1 h rt, overnight rt, overnight rt, overnight rt, overnight rt, overnight then 80  C, 10 h Product (%) 6a 6b 6c 6d 6e Yield (%) 98 99 99 87 70

NH2 NH2 NH O NH NH2

6f

78

NH2
7 rt, 48 h 6g 74

O O S O N O RO RO N N N NH2

X B(OH)2 Ligand-Pd THP or PhMe rt, or 45 C RO RO N O N N N

NH2

PCy2

7 : R = TBDMS
Scheme 3.

8588

M. Legraverend / Tetrahedron 64 (2008) 85858603

R X N O RO RO R = TBDMS 9
Scheme 4.

N N

1.5 equiv arylboronic acid 2 equiv K3PO4 10 mol% Pd(OAc)2 15 mol% Ligand anhyd dioxane RO RO

N O N N

Ligand: PCy2

10a-g

Table 3 Synthesis of C-6 aryl 20 -deoxynebularine derivatives Arylboronic acid Phenylboronic acid 4-Methoxyphenylboronic acid 3-Methoxyphenylboronic acid 2-Ethoxyphenyboronic acid 3-Nitrophenylboronic acid 4-Acetylphenylboronic acid 3-Thiopheneboronic acid
a b

Time (h) 1a 1.5a 1a 19.5a 1.5a 8.5a 6a

Product 10a 10b 10c 10d 10e 10f 10g

Yield (%) 91 69 73 62 59 49 58

Arylboronic acid Phenylboronic acid 4-Methoxyphenylboronic acid 3-Nitrophenylboronic acid 4-Acetylphenylboronic acid 3-Thiopheneboronic acid

Time (h) 1.5b 1.5b 1.5b 1.5b 8b

Product 10a 10b 10e 10f 10g

Yield (%) 91 69 73 62 59

XBr. XCl.

Cl N Cl N N N PhB(OH)2 (1 equiv) 77% Cl N

Ph N N N

11 84 % Conditions: PhMe, K2CO3, Pd(PPh3)4 Ar, 100 C, 8-20 h PhB(OH)2 (3 equiv)

12 Ph N Ph PhB(OH)2 (3 equiv) 88 % Cl N N N

On the contrary, 6-amido-2-aminopurines are not so easily obtained and this perhaps explains why the biological activities of such derivatives have not been explored to date. Recently, the regioselective syntheses of 6-amidopurine derivatives 22 and 24 from 2,6-dihalogenopurines 21 and 23, respectively, have appeared, which give convenient access to this type of derivative (Scheme 8).21 Furthermore, the halogen at position 2 can then be substituted by amines under SNAr conditions from uoropurine 22 or Pd(0)mediated coupling from the corresponding iodo derivative 24. A further Pd(0)-catalysed cross-coupling at position 2 in 24 is also possible with boronic acids or alkynes. 2.4. Substitution reactions of 6-chloropurine and 2-amino-6chloropurine with nucleophiles

13 Cl

N I N

N N PhB(OH)2 (1 equiv) 81% Ph

N N

N N

14
Scheme 5.

15

Substitution reactions of 6-halogenopurines with nucleophiles, particularly amines, have been widely exploited in medicinal chemistry, for example, in the synthesis of ATP analogues.22 A library of 6-O-alkylguanine derivatives has been synthesised as cyclin-dependent kinase 1 and 2 inhibitors.23,24 Recently, a rapid, high-yielding nucleophilic displacement reaction of 6-chloropurine 25 and 2-amino-6-chloropurine 26 with various nucleophiles under microwave irradiation has been described (Scheme 9 and

X (N) Cl N Cl N N N H C6H4B(OH)2 or 3-pyrB(OH)2 (1 equiv) Pd(OAc)2, Cs2CO3, (3-NaO3SC6H4)3P Ar microwave irradiation Cl (N)

N N

N N H

+ (N) X

N N

N N H

16

17a-d

18a-b

X= H, 4-MeO, 3-NO2
Scheme 6.

M. Legraverend / Tetrahedron 64 (2008) 85858603 Table 4 The SuzukiMiyaura reactions of 2,6-dichloro-9H-purine Boronic acid Phenyl 4-Methoxyphenyl 3-Nitrophenyl 3-Pyridyl Equiv 1 1 1 1 Product 17a 18a 17b 18b 17c 17d Yield (%) 55 5 57 6 26 70 Table 6 Reaction of 2-amino-6-chloropurine with nucleophiles Nucleophile Solvent Molar proportion of nucleophile 10 20 30 10 10 10 10 3 3 3 3 4 2.2 3 2 Temperature ( C) Time (min) R (27)

8589

Yield (%)

NH2Bn NH2(CH2)3Me CyNH2 PhNH2

Cl N R N N N R'-SnBu3 (1.5 equiv) (Ph3P)2Pd(Cl)2 DMF R N

R' N N N

PhNH2 Morpholine Piperidine MeONa EtONa EtONa BnOH PhONa MeSNa MeSNa PhSNa

19a: R = H 19b: R = NH2

20a: R = H; R' = Ph-C 20b: R = NH2; R' = Ph-C 20c: R = NH2; R' = (E)-PhCH 20d: R = NH2; R' = Ph 20e: R = H; R' = 2-Furyl
Scheme 7.

No solvent No solvent No solvent No solvent No solvent No solvent No solvent NMP DMSO NMP DMSO DMSO DMF NMP DMF

110 80 130 130 130 90 90 100 100 100 100 150 90 90 80

15 15 1 5 5 1 1 1 2 3 1 10 1 1 1

NHBn NH(CH2)3Me NHCy NHPh NHPh NMorpholyl Piperidyl OMe OEt OEt OBn OPh SMe SMe SPh

93 84 94 96 48 99 93 99 83 98 74 96 91 99 99

Table 5 Pd-catalysed coupling between purines 19a,b and organotin reagents Starting material 19a 19b 19b 19b 19a Product 20a 20b 20c 20d 20e Temperature ( C) 75 80 100 110 95 Time (h) 2.5 21 21 24 17 Yield (%) 77 64 77 30 93

O Cl N F N 21 RCONH2, 3 equiv NaH, 3 equiv, DMF 0 C to rt, 2-4 h N 23

Scheme 8.

R N N RCONH2, 1 equiv Pd2(dba)3/ Xantphos F Cs2CO3, dioxane, 100 C 22 O R N I 24 N

NH N N N

R = Ph 85% R = 4-Cl-Ph 78 % R = 4-OMe-Ph 69% R = 2-OH-Ph 74% R = i-Bu 70%

Table 6).25 This method is particularly suitable for the rapid construction of libraries of purines with a high diversity at position 6. In a few minutes, 6-substituted purines 27 were obtained from 26 and primary amines, including anilines, and secondary amines, as well as O- and S-nucleophiles, including MeONa, EtONa, PhONa, MeSNa and PhSNa. In 2007, Liu and Robins26 reported a complete study of SNAr reactions between 6-uoro-, 6-chloro-, 6-bromo-, 6-iodo- and 6alkylsufonylpurine nucleosides and nitrogen, oxygen and sulfur nucleophiles. In several cases, 6-halogenopurines do not follow the classical order of reactivity for SNAr reactions of 1-halogeno-2,4dinitrobenzenes (F>Cl>Br>I); the reactivity at C-6 in purines clearly depends on the leaving group and the nucleophile. For example, the relative ease of displacement with a weakly basic arylamine (aniline) was inverted (I>Br>Cl>>F), as compared to benzylamine (F>Br>Cl>I) (Table 7).
Table 7 Orders of leaving group reactivities with various 6-substituted purines Nucleophile BuNH2 MeOH/DBU i-PentSH/DBU PhNH2 PhNH2/TFA Reactivity F>RSO2>Br>Cl>I RSO2>F>BrzCl>I RSO2>F>BrzI>Cl I>Br>RSO2>Cl>F F>RSO2>I>Br>Cl

Cl N I N N

NH N N N

R = Ph R = 4-Cl-Ph R = i-Bu

50% 56 % 35%

3. Functionalisation at position 9: preparation of 9substituted purine derivatives 3.1. Regioselective and stereoselective coupling of 6(substituted-imidazol-1-yl)purines with 1-chloro-20 deoxyribose

Cl N R
N

R N nucleophile, solvent N H 26 microwave irradiation H2N N 27 N H N N

25: R = H 26: R = NH2

Scheme 9.

Alkylation of purines usually results in the formation of regioisomeric mixtures of N-7- and N-9-alkylpurines. The desired N-9 compound is normally the major product, but the formation of signicant amounts of the N-7 isomer, as well as other alkylation products, is often observed.27 Glycosylation of purines suffers from a similar lack of regioselectivity with the additional problem that complex diastereomeric mixtures may be encountered.

8590

M. Legraverend / Tetrahedron 64 (2008) 85858603

This traditional problem in purine chemistry was recently solved by Robins and co-workers.2729 Unsubstituted heteroaryl rings appended at C-6 of purines adopt essentially coplanar ring alignments, and it was reasoned that the proton above the N-7 atom would prevent any N-7 alkylation. Indeed, the N-9 regiospecic glycosylation of purine acceptors with furanosyl and pyranosyl sugar donors was improved by the presence of an imidazole substituent at position 6 of the purine ring (28). Such purines undergo regiospecic N-9 glycosylation, but the stereoselectivity of glycosylation (a or b) was still dependent on the solvent used for the glycosylation reaction. Such derivatives (28) were readily prepared, improving the solubility and solvation of the purine in mixed solvents. Glycosylation of the 6-sodium salts of (imidazol-1yl)purines 28 with a protected chlorosugar proceeded with high regioselectivity (100%) and stereoselectivity (98%) in high yield (>90%) to afford exclusively the b anomer-N-9 regioisomers 29 (Scheme 10).29 Ammonolysis of the imidazolium salts 30, generated in situ from 29 with BnCl and NaI, gave high yields of the adenine derivative, Cladribine 31, a clinical anticancer drug.

nucleophilic character. Similarly, coupling of 6-chloropurine (25) with benzyl acrylate in DMF, in the presence of base (DIEA) at room temperature, gave the 9-substituted product in 74% yield.31 Furthermore, methyl, ethyl, or tert-butylacrylate also react regioselectively with 6-chloropurine under microwave irradiation in water to give the 9-substituted products in good yield.32 These authors noted that, again, no protection was necessary if amino or hydroxy groups were present in the molecule, and that the purine was exclusively alkylated at N-9.32 3.3. Arylation at N-9 of 7-deazapurines LamChan33 or Buchwald34 coupling conditions can be applied to perform N-arylation of the N-7 atom of pyrrolo[2,3-d]pyrimidines such as 35 to form 36 (Scheme 12). The LamChan protocol was applicable for the introduction of meta- and para-substituted aryl rings, but it could not be extended to ortho-substituted aryl rings or heterocyclic systems. In these cases, the transformation was carried out using the Buchwald procedure. The pyridine/ Cu(OAc)2 combination was found to be optimal for the LamChan reaction, while the use of Cs2CO3/N,N-dimethylcyclohexane-1,2diamine at 140  C in DMF gave superior results for the Buchwald procedure.35
(a) pyridine/Cu(OAc)2, ArB(OH)2 4 MS, 3 d for aryl introduction N 35 N H (b) CuI, Cs2CO3/N,N-dimethylcyclohexane-1,2-diamine, 140 C, DMF, 24 h for heteroaryl introduction
Scheme 12.

I N R N Cl N 28 N N N H 1) NaH/MeCN 2) chlorosugar Cl R N N O TolO R = Pr, iPr, Bu, Pent... TolO 29 TolO TolO 30 N N N N BnI/MeCN 60 C, 1.5 h Cl R N N O N N N N

N Cl

N Cl N 36 N Ar(Het)

NH3/MeOH 60 C, 11 h

3.4. Arylation at N-9 of purines

NH2 N Cl cladribine: 31 HO HO
Scheme 10.

N N O N

In 2001, Ding and co-workers36 described one of the rst N-9 arylations of purines such as 16 via boronic acid/cupric acetate/NEt3 in dichloromethane to form 37 (Scheme 13 and Table 8). Bakkestuen and Gundersen later described37 a regioselective N9 arylation of purines 38 using arylboronic acids 39 in the presence of Cu(II) and an organic base. Trials revealed phenanthroline to give
R Cl B(OH)2 N N 16 N H Cu(OAc)2 (anhyd.) 4 MS Et3N, DCM Cl N N 37 Cl N N R

3.2. Michael addition of adenine Highly efcient Michael addition reactions of adenine 32 to a,bunsaturated esters 33 under microwave irradiation to form 34a d have been reported (Scheme 11),30 where it was unnecessary to protect the exocyclic amino group, due to its relatively weak
NH2 N N N + N H 32 CO2R3 R1 R2 DABCO/TBAB microwave irradiation 200-300 W 8-12 min N N Cl

Scheme 13.

NH2 N N R1 34a-d 34 a b c d
Scheme 11.

R2 CO2R3 R1 H H H Me R2 H H Me H R3 Et n-Bu Et Et

33

M. Legraverend / Tetrahedron 64 (2008) 85858603 Table 8 N-9 Arylation of purine N-9 Aryl substituent Yield (%) 45 N-9 Aryl substituent Yield (%) 47

8591

Me

Me O
43 44

involves fewer steps and gives higher overall yields. All of the reported approaches, however, do not work efciently with electron-rich purines, such as guanine, due to side reactions. The triphenylphosphine-diethyl (or -diisopropyl) azodicarboxylate Mitsunobu inversion procedure has become very useful to synthesise nucleoside analogues.3944 Thus analogues 42 and 44 have been synthesised from 6-chloropurine 25 and alcohols 41 and 43, respectively (Schemes 15 and 16).
Cl Cl N N N 25 BtDPS
Scheme 15.

O O Me

N N

signicantly higher yields of 40 than triethylamine or pyridine (Scheme 14 and Table 9). Under these conditions, 2-amino-6-chloropurine 26 did not react, due to solubility problems. N-9 Arylation was, however, possible with various boronic acids in comparable conditions
Y Y N X N 38 N N H +R
2

O + O O OH 41

N H

1) PPh3, DEAD THF, 0 C 2) -78 C, purine, c-C5H10

O O 42 O tBDPS

(78%)

R1

N X B(OH)2 4 MS, phenanthroline, DCM, 4 d Cu(OAc)2 (anhyd.) N

N N Cl N N N MMTr O N Boc
Scheme 16.

39
Scheme 14.

40

R1

R2

MMTr 25 +

O
N

OH 43

PPh3, DEAD THF, rt

Boc

44

Table 9 Cu-mediated reaction between purines 38 and arylboronic acids 39 X H H H H H Cl Cl NH2 H H H H Y Cl Cl Cl Cl Cl Cl Cl Cl NH2 SCH3 SH/SPh 2-Thienyl R1 H H H H Cl H H H H H H H R2 H CH3 OCH3 Cl H H CH3 H H H H H Yield (%) 71 68 52 41 73 52 48 42 No reaction 76 81 68

(Cu(OAc)2/pyridine/molecular sieves/CH2Cl2) and with good yields (4181%) on condition that the reaction was carried out on the bisBoc-amino 6-chloropurine derivative.38 At present, these arylations have been achieved with phenyland substituted phenylboronic acids (Table 9). Other conditions may be needed to generalise this reaction with heteroarylboronic acids. The use of Cs2CO3/N,N-dimethylcyclohexane-1,2-diamine/ Het-X at 140  C in DMF was, however, recently found to be the optimum conditions to introduce heterocyclic systems on the pyrrole nitrogen of various pyrrolo[2,3-d]pyrimidines (7deazapurines).35 It is noteworthy that this copper(II)-mediated N-9 arylation methodology greatly enhances the structural diversity of possible purine libraries, since other methods, such as anionic alkylation with an alkyl halide, Mitsunobu alkylation and various glycosylation reactions, do not allow regioselective N-9 arylation. 3.5. Mitsunobu alkylation at N-9 position with either primary or secondary alcohols Nucleoside analogues are generally prepared either by direct coupling of a base with a carbon substrate or by construction of purines and pyrimidines from aminoalkanes. The rst route usually

This alkylation reaction tolerates virtually any alcohol without additional acidic hydrogens (pKa<1012).12 The large number of commercially available alcohols offers a considerable diversity in libraries of N-9 substituted purine derivatives.45 Coupling of unprotected guanine with alcohols under Mitsunobu conditions has, however, been reported to be impossible, probably due to a solubility problem with THF, the best solvent for the Mitsunobu reaction.46,47 Although successful coupling of various alcohols with 2-amino6-chloropurine was reported by Toyota and co-workers in 1993,46 it was only recently that a general method for highly N-9 regioselective and high-yield coupling of a series of alcohols with a protected guanine (45) to form 46aj was reported (Scheme 17 and Table 10).47 This method was applied to various 2- or 6(di)chloropurines.
O Ph N Ph Ac N H O N N 45
Scheme 17.

O N
N H

+ R-OH

1) DIAD, PPh3, THF, 70 C, twice

HN N 46

N N R

2) 1:1 NH3-H2O/MeOH, 60 C 2 h H N 2

This method is compatible with a very large range of substrates and allows stereochemical control of the couplings, as shown by the isolation of a single diastereoisomer when a diastereoisomeric alcohol was employed.47 3.6. Use of an aminoalkane and pyrimidine precursors Condensation of guanidine 47 and ethyl aminomalonate 48 under basic conditions led to 2,5-diamino-4,6-dihydroxypyrimidine

8592 Table 10 Reaction substrate scope in the guaninealcohol coupling Alcohol Product

M. Legraverend / Tetrahedron 64 (2008) 85858603

4. Functionalisation at N-1, N-3, N-7 and C-8

Yield (%) 86 85 83 85 76

TBSO

4.1. Preparation of xanthine derivatives from 6-aminouracils (Traube synthesis) Xanthines constitute an important class of pharmacologically active compounds, which are commonly used for their effects as mild stimulants, bronchodilators, phosphodiesterase inhibitors, CFTR chloride-channel activators and adenosine receptor antagonists.50 The syntheses of xanthines from 6-aminouracils, such as 52, generally involve multistep reactions and require tedious chromatographic separations, which limit the synthesis of a large number of compounds. In addition, the Traube synthesis is generally incompatible with the introduction of complex N-substituents,51 although interesting xanthine derivatives have been prepared from 5-bromo-6-aminouracil 53 (Scheme 19), 5,6-diaminouracil such as 56 (Scheme 20),52,53 and N-1(or N-3) monosubstituted-5,6-diaminouracil (Scheme 19).54 In the present example, the cyclisation step (54af to 55af) was carried out under microwave irradiation (Scheme 19). Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)xanthine derivatives such as 59, 61a,b and CVT-5440 have been synthesised55,56 as potent and selective A2B adenosine receptor antagonists or inverse agonists56 (Scheme 20). These targets were synthesised in a similar fashion from 56 by coupling the corresponding carboxylic acids 57, 60 and 4-benzyloxybenzoic acid in the presence of a coupling agent (EDCI, EDAC). The ring closure of the intermediate pyrimidines (e.g., 58) was effected by treatment with aqueous NaOH to afford 59, 61a or 62, the CVT-5440 precursor. CVT-5440 (Scheme 20) is a high-afnity A2B adenosine receptor antagonist for the potential treatment of asthma.57 4.2. Synthesis of purines from an imidazole precursor An alternative approach to the synthesis of xanthines from aminouracils is to use an imidazole starting material. A solutionphase synthesis of a xanthine substituted at the N-1 and N-7 positions was achieved from benzyl alcohol 63 as a substitute for Wang resin (Scheme 21).50 The N-substituted glycine benzyl ester 65 was obtained by reacting 63 with bromoacetic acid to give 64, which in turn, could be treated with butylamine in THF to provide 65. Treatment of 65 with ethoxymethylene cyanamide gave intermediate 66, which upon reaction with a strong base underwent imidazole ring formation to afford 67. Imidazole 67 was treated with an isocyanate to provide 68 in 90% yield before subsequent ring closure with NaOEt to give the 1,7-disubstituted xanthine 69 in 90% yield. The new synthetic procedure summarised in Scheme 21 allowed the preparation on solid support of di-, tri-, or tetrasubstituted xanthines 75 (Scheme 22).50 4.3. Solid-phase synthesis of xanthine derivatives The versatility of this chemistry was illustrated by the preparation of a library of 22 di-, tri- or tetrasubstituted xanthines

OH OH OH OH

46a 46b 46c 46d 46e

OH OH OH

46f

81

46g

72

OH
46h 78

OH TBSO

46i

74

OH

46j

84

49, which is a precursor of 2-amino-6-chloropurines 51, via the 2,5diamino-4,6-dichloropyrimidine 5048,49 (Scheme 18) bearing an N-9 substituent arising from substitution of one chlorine atom in 50 by a primary amine.16,19,48

O H2N C NH2 47 Cl POCl3 H2N N N 50 NH2 1) R-NH2 Cl 2) ethyl orthoformate H2N N N NH + O NH2 O O 48 EtONa, EtOH H N H2N 49 Cl

O NH2 N OH

N N R

51 R = i-Pr, Me, c-C5H9, c-C6H11, Bn

Scheme 18.

The synthesis of pyrimidine 49 was performed on a 37-g scale in 65% yield, while the subsequent chlorination was achieved in a POCl3/benzyltriethylammonium chloride/PCl5/MeCN mixture in only 32% yield.48 An improvement of this chlorination was reported in 200049 using the Vilsmeier reagent, which gave the bis[(dimethylamino)methylene]amino derivative of 50. This derivative had to be carefully hydrolysed in acidic conditions to give 50 in 42% yield from 49.
RNH2, microwave Br irradiation NH2 120 C 10 min

O HN O N 52 Br2, NaHCO3 NH2 MeOH

O

O HN N 53

O HN O N 54 a-f

R NH NH2

O EtOC(O)SK MW, 120 C 10 min HN O N 55 a-f N

R SH N

a: R = nBu, b: R = Bn, c: R = PhCH2CH2, d: R = p-F-PhCH2CH2, e: R = o-PyCH2, f: R = m-PyCH2

Scheme 19.

M. Legraverend / Tetrahedron 64 (2008) 85858603

8593

O N O HO O N N N

H N O NH2

N N 2 N NaOH, MeOH reflux, 80 % O N

H N N

N N

57 EDCI, MeOH, rt 92% 1) O HO N N O

58

59

O OEt 60 , EDAC, MeOH 2) NaOH, 70 C O N

O N O 56 N NH2 NH2

O H N N N N 61a: R = OH amine, DMF HOBt, EDAC 61b: R =HN O O O R

1) 4-benzyloxybenzoic acid, EDCI, MeOH 2) NaOH 2 N, MeOH, 70 C N O

O H N N N 62 O Ph O N

H N O N R CVT-5440 O Me

R=

N N O

Scheme 20.

O OH 63 HOCCH2Br, DDC DMAP, DMF O NC-N=CHOEt THF 66 NaOEt THF/MeOH O N H O O

O Br BuNH2, THF O 65 O tBuOK, tBuOH N CN DMF 67 O Hex N Bu N N 69 O H2N Bu C6H13NCO N o-xylene N

H N

Bu

64

Bu N

O O HN Hex N H O

Bu N N 68

Scheme 21.

OH Wang resin R2 NC-N=COEt DBU, THF

O HOCCH2Br, DDC DMAP, DMF O O 72 R1 R2 N N CN O R3 O N N R4

O O 70 O tBuOK, tBuOH DMF R1 N N R2 75 73 O H2N R1 N N R3NCO R2 o-xylene Br R1NH2, THF O

H N

R1

71 O O 74 HN O R1 N N R2

1) NaOEt THF/MeOH 2) R4X, DIEA, THF

R3 N H

Scheme 22.

8594 Table 11 Library of substituted xanthines

M. Legraverend / Tetrahedron 64 (2008) 85858603

O Hex O N N H 75a 35%

Bu N N O

O N N H

Bu N N Ph O N

Bu N Bn O N

Bu N

O Hex N O N H

Bn N N

N H

N H

75b 35%

75c 34%

75d 29%

75e 25%

O Ph N O N H

Bn N N

Bn N O

Bn N N O

Bn N Ph O N

Bn N Ph O N

Bn N

N H

N H

N 75i 20%

75f 30%

75g 23%

75h 27%

75j 19% O O N O N Bn N N O N N O Bn N N O N N Bn N N O 75m 23% N N Bn 75n 24% 75o 23% O Ph O Ph O N N Bn 75p 20% O N O N Ph O N 75v 6% N Bn N N O N H N O N N Ph N O O N O N N Bn 75s 14% O N N 75t 14% O N N N N O Bn N N Ph O N N O Bn N N

75k 20%

75l 19%

75q 16% O N N Ph

N N H 75r 15%

N N H 75u 7%

OH R H2N N OH N CH2 Ph CH(NH)NH2.HCl 2-MeOCH2CH2OH reflux N N N OH N CH2 Ph 78 CH3I, K2CO3, DMF, rt O NOE: nuclear overhauser effect NOE H 79
Scheme 23. Scheme 25.

O 83 1) RNCO, NEt3, PhH, 100 C 2) NaOMe, MeOH, reflux, 73% R O N N H 84 R = Et, i-Pr N Me N

77: R = CONH2 76: R = CN

N N

N OH N CH2 Ph

(75av) (Table 11). The solid-phase synthesis (7075, Scheme 22) was adapted from preliminary solution-phase studies (Scheme 21). The overall yields obtained were 1435%, indicating an average yield of 75% for each step of the solid-phase reaction, for all but the most encumbered analogues (75u and 75v). Imidazole precursors such as 7658 allow the synthesis of purines bearing substituents at N-1, C-8 and N-9 (7779), as outlined in Schemes 2325.

EtO

O C

CN

EtO

O C

CN MeC(OEt)3 100 C NH
2

EtO

O C N

CN OEt Me

BnNH2 EtOH, 80 C

EtO

O C

N Me N

H2N 83

80

81
Scheme 24.

82

M. Legraverend / Tetrahedron 64 (2008) 85858603

8595

O Et O H2N

DMB N N 85

O O S O

O N N H

DMB R3-X N N K2CO3, DMF

O O S O 87

O N N R3

DMB N N

86

KOtBu DMB = 2,4-dimethoxybenzyl THF, 0 C O 90% TFA CH2Cl2 R1 O N N R3 O R1-X K2CO3, DMF HN O N R3

O R1 O N N R3

H N N 90

DMB N N 89 O

DMB N N 88

90

R7-X K2CO3, DMF

R1 O

N N R3

R7 R1 = Me, All, Bn R3 = Me, Bn, EtOH N N 91 R7 = Me, Et

Scheme 26.

5-Aminoimidazole derivatives such as 83 can be elaborated in a few steps from 80 and ethyl 2-aminocyanoacetate 81 via 82, as shown in Scheme 24.59 Aminoimidazole 83 was treated with various isocyanates (RNCO), setting the stage for cyclisation step in methanol/MeONa under reux to afford 1,8,9-trisubstituted xanthines 84 (Scheme 25).59,60 Recently, an elegant synthesis from aminoimidazole 85 of a key precursor (86) of functionalised xanthines was reported51 that does not need to use isocyanates to introduce the N-1 substituents (Scheme 26). This method, which allows maximum exibility for modication at N-1 (88/89), N-3 (86/87) and N7 (90/91) is based on the selective removal of each N-protecting group under mild conditions. This allows efcient access to a range of disubstituted xanthines with the less common 1,7- and 3,7-substitution patterns, as well as 1,3,7-trisubstituted derivatives (91) (Scheme 26), from a common precursor 86. N-3 Protection can be achieved, if required, with allylmethyl chloride in the presence of K2CO3, and cleaved under neutral conditions by Pd(0) catalysis.

4.4. Synthesis of N-1,N-7-disubstituted purines from 6-chloropurine N-1,N-7-Disubstituted purines 97ao (Table 12) can be synthesised in ve steps from 6-chloropurine 25 and 92 via an initial Michael addition. Subsequent acid-catalysed hydrolysis of 93 afforded 94 that was N-1-alkylated with butyl iodide to give 95. Quaternisation of 95 occurred on heating with further BuI to afford 96, which gave 97, the N-9 deprotected product, in the presence of ammonia (Scheme 27).31 This methodology, developed on solid-phase, has permitted the synthesis of a library of 15N-1,N-7-disubstituted purines in 1327% overall yield (average yield of 70% for each step) (Table 12). 5. Functionalisation at position 2 5.1. Pyrimidine precursors of 2,6,8,9-tetrasubstituted purines Pyrimidines are versatile substrates for the synthesis of variously substituted purines. Pyrimidine synthesis from amidines

Table 12 Library of N-1,N-7-disubstituted purines

O Bu N N 97a 18%

Bu N N

O Bu N N N N Bu N

O N

Ph Hept N

O N

O Hept N

Bu N

97b 17% O Hept N N 97f 18% O N N 97k 13% Bu N N Bn N N

N N 97c 15% O Bn N N N N Bu Bn

N N 97d 20% O N N

N N 97e19% O N N 97i 18% Bu N N N N 97j 13% O N N Bn

97g 14% O N N 97l 27% Bu N N

N N 97h 16% O N N 97m 20% N N Bn

O N N

Bu N N

O N N N

Bn

97n 15%

97o 16%

8596

M. Legraverend / Tetrahedron 64 (2008) 85858603

Cl O Ph O 92 O Bu BuI, DBU DMF, rt 95 O N N N N O O R NH3/MeOH N N R' N N 97a: R = R' = Bu

Scheme 27.

O N 85% HCOOH HN N O Ph O Bu BuI, DBU N N 96 O O 94 O Bu N N Ph N N O Ph

25 DIEA, DMF

N N 93

Ph DMF, 70 C

O NH2 C R2 NH 98 R2 = H, Me + EtO EtO R O EtONa, EtOH R2 N

OH H N OH 1) HNO3 2) POCl3 R2 N

Cl NO2 N Cl

99 a: R = H 99 b: R = NO2

100 : R2 = H 101 : R2 = Me
Scheme 28.

102 : R2 = H 103 : R2 = Me

constitutes a very efcient strategy to prepare 2-substituted purines, due to the great variety of commercially available alkyl, aryl or heterocyclic amidines (Scheme 28),61,62 which provide the rst point of structural diversity.61,63 For example, amidines 98 were condensed with diethyl malonate (99a) in the presence of sodium ethoxide to obtain the 4,6-dihydroxypyrimidines 100 and 101. Controlled nitration with fuming nitric acid and chlorination with phosphorus oxychloride afforded the corresponding dichloropyrimidines (102 and 103) in good yields.62 Replacement of diethyl malonate by ethyl cyanoacetate 80 in an alkaline medium provides a 6-aminopyrimidinone 104 (Scheme 29), another interesting purine precursor.6467
O H2N S C + O 80
Scheme 29.

99b

thiourea, EtONa EtOH

O HN HS N 105
Scheme 30.

Cl NO2 OH S N N 106 NO2 Cl

H N HS

N N 104

H NH2

NH2 thiourea

Diethyl nitromalonate 99b has not been widely used to synthesise 5-nitropyrimidines, since, as shown above, good yields for the nitration of dioxopyrimidines 102 or 103 are obtained. In the case of the 2-thiopyrimidine derivative 105, however, Harnden and Hurst have observed that the use of commercial diethyl nitromalonate might be a better strategy than the nitration of 2methylthiopyrimidine-4,6-diol.68 The 5-nitropyrimidine-2-thiol (105) was obtained in 41% yield, the low yield being the result of the effect of the 5-nitro group on the hydrolytic stability of the 2-mercapto substituent (Scheme 30). A methylation of 105 gave the 2-methylthio derivative in 64% yield, which was chlorinated to give 106 in good yield. 5.2. Synthesis of 2,6,8,9-tetrasubstituted purines A synthesis of tetrasubstituted purines has been reported from 4,6-dichloro-2-methyl-5-nitropyrimidine (103), itself prepared

according to a literature procedure.69,70 The second point of diversity is introduced by the substitution of one chlorine atom of the 5-aminopyrimidine 107 by various amines (see Section 5.1 and Scheme 28 for the rst point of diversity).71 Incorporation of an alkylthio group at the 6-position in 103 or 108 led to 110 or 109, respectively (Scheme 31). Cyclisation with aldehydes in the presence of FeCl3 afforded 111, which was oxidised to the corresponding sulfone 112 for displacement by various amines to give the third point of diversity (113) (Scheme 32). The fourth point of diversity at position C-8 can be introduced with aldehydes (Scheme 32). The 2-methylthiopyrimidine 106 (Scheme 30) constitutes an interesting starting material towards libraries of 2,6,8,9-tetrasubstituted purines with complete regiospecicity at every step, including a wide variety of substituents at the 9 position.72,73 This liquid-phase methodology (Schemes 31 and 32) was validated by the synthesis of a 216-member 2,6,8,9-tetrasusbstituted purine library (113) (Scheme 32),74 and was applied recently on solid support75 (114119) to build a library of 24 purines (120) (Scheme 33). Substitution of the methyl sulfone at position 2 can be achieved easily on the pyrimidines 117, which leads to 2-amino-substituted pyrimidines 118. On the contrary, it should be noted that substitution by amine nucleophiles of 2-methyl- or 2-phenylsulfonylpurines is considered to be difcult.73,7577 Functionalisations at position 2 in purines are otherwise carried out from 2-halogenopurines, since 2halogens (F, Cl, Br, I) are generally less reactive than the 6-halogen in SNAr. Whiteld and co-workers noted in 2003 that SNAr displacement reactions of 6-O-alkyl-2-uoropurine with various weak

M. Legraverend / Tetrahedron 64 (2008) 85858603

8597

reduction first approach Cl N N 103 NO2 Fe/HCl Cl N N 107 Cl NH2 Cl n-BuNH2 n-BuOH, Et3N 100 C Cl N N 108 Fe/NH4Cl S R2NH2 then BnSH, rt N N 110
Scheme 31.

NH2 NH R2

BnSH, Et3N n-BuOH, 100 C S N N 109 Ph NH2 NH R2

substitution first approach Ph NO2 NH R2

103

R2 = n-Bu, i-Bu, Cy 2-furyl-CH2, Bn, Ph

S 109 R3-CHO FeCl3/SiO2 N N 111

Ph N N R2 R3 mCPBA CH2Cl2

O O S N N

Ph N N R2 R3 R4-NH2 (excess)

HN N N

R4 N N R2 R3

112
Scheme 32.

113

R1NH2 Na(OAc)3BH O DCE, rt

NR1 H 114

106, DIEA THF, 1 h, rt N

R1

R2-NH2 DIEA THF, 1 h, rt NO2 N S

NR1 NO2 N 116 NH R2

Oxone NaHCO3 24 h, rt

(ArgoGel-MB)

Cl 115

N N O S O

R1 NO2 R3-NH2 1 h, rt CrCl2 HN R3 N

R1 R4-C(OMe)3 + NH2 H , 80 C NH R2 HN R3 N

N R1 N N N R2 119
Scheme 33.

HN R1 9:1 TFA/H2O rt, 3 h R4 HN R3 N N N N R2 R4

N 117

NH R2

N 118

120

nucleophiles (anilines) were dramatically accelerated in the presence of triuoroacetic acid and 2,2,2-triuoroethanol as solvent.78 5.3. Synthesis of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) from pyrimidine precursors 7-Deazapurines (pyrrolo[2,3-d]pyrimidines)79 are among the most intensively studied purine analogues and display various biological activities. A number of synthetic strategies are available including their preparation from various pyrimidine precursors.80,81 Compounds 124128 (Scheme 34) were synthesised as potential thymidylate synthase inhibitors, from the key intermediate, 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine 123,82,83 (itself prepared from diaminopyrimidin-4-one 121 and chloroacetone 122) to which various arylthiols were conveniently

attached at the 5-position via a modication of an oxidative thiolation procedure reported by Gangjee and co-workers (Scheme 34).79,82 Similarly, 7-deazapurines may be obtained from pyrimidines bearing adjacent amino and vinyl functionalities, e.g., 131. The different reactivities of the three halogens of the pyrimidine 129 allow a regioselective amination to give 130, followed by a regioselective Stille coupling to yield the intermediates 131. A thermal cyclisation step in acetic acid affords the desired pyrrolo[2,3-d]pyrimidines 132 (Scheme 35).35 Pyrrolo[2,3-d]pyrimidines have also been prepared from 5-allyl2-amino-4,6-dichloropyrimidine 133, itself obtained from guanidine and ethyl allylmalonate in two steps.84 An ozonolysis of 133 leads to the aldehyde 134, which is protected as the diethylacetal derivative 135. A monosubstitution by a primary amine gives 136, which is cyclised to the 7-deazapurines 137 in dilute aqueous hydrochloric acid (Scheme 36).84

8598

M. Legraverend / Tetrahedron 64 (2008) 85858603

O HN H2N N 121 Cl + NH2 O Me 122 NaOAc/H2O 100 C HN H2N

O Me N 123 N H I2, EtOH/H2O (2/1) HN

100-110 C; arylthiol H N 2

Me N H 124: R = 3',4'-diF N 125: R = 3',5'-diF 126: R = 3',5'-diCF3 127: R = 3',5'-diNO2 128: R = 3',5'-diCl

Scheme 34.

N Cl N 129

Br

RNH2

N N 130

Br R N H

Bu3SnCH:CHOEt Pd(PPh3)2, PhMe, 110 C, 24 h Cl

N N NH R 131 R = Me, Bn

OEt

Cl THF, rt, 12 h Cl

N AcOH, 120 C, 2 h Cl N 132

Scheme 35.

N R

Cl N H2N N 133 OH O C CH2 NH R CH2 Cl O3, -78 C MeOH-AcOEt H2N N

Cl

O CH2 EtOH, H+ H2N N

Cl

OH O C CH2

N 134

Cl

N 135

Cl

Cl RNH2, BuOH NEt3, 100 C, 2 d H N 2 N N 136

Cl HCl-H2O, rt H2N N N 137 HO HO OH HO HO OH N R

HO R= HO OH

Scheme 36.

6. Functionalisation at position 8 6.1. Synthesis of 8,9-disubstituted adenines The highly potent water-soluble protein chaperone HSP90 inhibitor 138 (Rt-BuCH2) (Fig. 2) is an 8,9-disubstituted adenine, which induced inhibition of tumour growth.85 It is synthesised in three steps from adenine by alkylation at position 9 followed by bromination at position 8 with Br2 in a mixture of THF, AcOH and H2O. Exchange of the bromo atom of 139 for a sulfur and substitution of the thionoadenine 140 (Scheme 37) by the phenyldiazo derivative 141 gave intermediates 142.
NH2 N N 138 N S N (CH2)n NHR
Figure 2.

The alcohol function of 143 is then revealed to create the mesyl leaving group required for subsequent amination. Further HSP90 inhibitors 146 and 149 can be synthesised according to two related strategies starting from di- or triaminopyrimidines 144 or 147 (Schemes 38 and 39). In the rst sequence, the butyl substituent of 146 is introduced prior to the cyclisation of 145 and before amination at C-6 with NH3 (Scheme 38). Alternatively, the butyl substituent of 149 can be introduced at the last step from the 4,5,6-triaminopyrimidine precursor 147 (Scheme 39),85 via cyclisation of the amido intermediate 148. 6.2. Synthesis of 2,8,9-trisubstituted adenines 6.2.1. Synthesis of 2,8,9-trisubstituted adenine inhibitors of HSP90 Commercially available 2,4,5,6-tetraaminopyrimidine 150 (Scheme 40) and 2-uoroadenine 152 (Scheme 40) have been featured in strategies towards the preparation of libraries of functionalised 2-uorinated purines, from which very potent 8-arylsulfanyl-adenine inhibitors of HSP90 were synthesised.86 Interestingly, the uorine atom at C-2 increased the solubility and

M. Legraverend / Tetrahedron 64 (2008) 85858603

8599

O NH2 N N N thiourea, n-BuOH Br reflux, 3 h (88%) N (CH2)3 OAc 139 140 N N NH2 H N S N (CH2)3 OAc 141 N2

I BF4 NH2 N N N N S (CH2)3 OR 142: R = Ac 143: R = H 1) mesylation 2) amination 138 I O

DMSO, rt, 24 h (51%)

Scheme 37.

Cl N N NH2 NH 2,5-(MeO)2C6H3CH2CO2H N TsCl, Et3N, DCE 40 C, 16 h (71%)

Cl

H N NH O

NH2 O NH3, MeOH 120 C, 3 d (80%) O N N N O N

O 146

144

145
Scheme 38.

NH2 N N NH2 NH2 147 3-MeOC6H4CH2CO2H.HCl NMP, 40-50 C, (98%) N

NH2

H N NH2 O

1) MeONa n-BuOH, reflux 2 h, (75%) 2) BuI, Cs2CO3 DMF, rt, 16 h (54%)

NH2 N N 149 N N

148
Scheme 39.

NH2 N H2N N 150 NH2 NH2 CS2, NaHCO3 H2O/EtOH, reflux H2N N

NH2 N SH N 151 F N H N N NH2 N S N R 154 R' O O O

NH2 N F N 152 N

1) ROTs, Cs2CO3, DMF 80 C, 50% F

NH2 N N 153 N Br N R

N 2) NBS, DMF, rt, 80% H

R: 2-iprOCH2CH2, Bu, pent-4-ynyl R': H, Cl

Scheme 40.

potency of the resulting inhibitors. Cyclisation of 150 in CS2 gave the purinethiol 151 before reaction with aryl iodides and alkylation at N-9 afforded the 8-arylsulfanyl-adenines 154. Transformation of the C-2-amino group to uorine in 151 with HF/pyridine in the presence of sodium nitrite86 gave the 2-uoroadenines 154. Similarly, the target 2-uoroadenines 154 were synthesised from 2uoroadenine 152 after alkylation at N-9 with tosylates, bromination at C-8 with N-bromosuccinimide giving 153 and thioarylation at C-8 in DMF/K2CO3. 6.2.2. 8-Aryl-9-methyladenine derivatives from a 4,6dichloropyrimidine precursor Treatment of N-1-(4,6-dichloro-5-nitropyrimidin-2-yl)acetamide 155 with an aqueous solution of methylamine neutralised with acetic acid gave the monomethylamino derivative in good

yield before nitro reduction with Raney nickel afforded the diamino derivative 156. The Schiff base 157, obtained by condensation of 156 with an aldehyde, was directly converted by oxidative ring closure87 into 2-amino-8-aryl-6-chloropurine 158, which was further functionalised to 159 (Scheme 41).88 Considerable diversity can thus be introduced at C-8, N-9 and C-2 with aldehydes, amines and alkynes, respectively. 6.3. Synthesis of 6,7,8-trisubstituted purines N-7-Substituted purines can be synthesised by direct alkylation of 6-chloropurine 25, but, in this case, N-7- and N-9-substituted purines are obtained as a mixture of regioisomers (see Section 3.1). Liu and co-workers have recently reported an efcient and regiospecic strategy to prepare N-7-substituted purines (Scheme 42).89

8600

M. Legraverend / Tetrahedron 64 (2008) 85858603

Cl N AcHN N NO2 Cl 1) 40% MeNH2, AcOH/THF 2) H2, Raney Ni/MeOH AcHN N

Cl NH2 N 156 Cl 1) FeCl3/EtOH 2) HCl/H2O-THF H2N N N N Ar N Me 158 R' 159 N N NH2 N NH Me ArCHO AcOH/MeOH AcHN N

Cl N N 157 NH Me Ar

155

Ar N Me

Ar: Ph, 2-furyl, 2-thienyl, 2-pyridyl, 2-FPh, 3-FPh, 4-FPh, 3-ClPh, 4-ClPh, 3-CNPh... R': c-C4H10(OH), c-C5H8(OH), c-C7H12(OH)
Scheme 41.

This method is based on the mono-amination of pyrimidines 161 with ethanolic ammonia in a sealed tube at 120  C, followed by displacement of the second chloro group with an excess of thiophenol in reuxing n-butanol, leading to the intermediates 163. Cyclisation in the presence of a carboxylic acid or an aldehyde gave 7,8-disubstituted purines 164. The strong electron-donating effect of the newly introduced amino group in pyrimidines 162 prevents a second amination.
Cl N N 160 NH2 R -X 1 Cl NaH N N 161 SAr R2COOH or R2CHO N N 164
Scheme 42.

by the reaction of a purine precursor, 4-chloro-5,6-diaminopyrimidine (166), with isothiocyanates or by the reaction of 5-amino4,6-dichloropyrimidine 160 with isothiocyanates (Scheme 43 and Table 13).90
Table 13 Reaction of 4,6-dichloro-5-aminopyrimidine with aryl isothiocyanates Entry 1 2 3 4 5 6 7 Isothiocyanate 168 169 170 171 172 173 174 R1 Ph 2,6-Me2Ph p-MePh p-MeOPh p-CF3Ph p-NO2Ph 3-Pyridyl Product 175 176 177 178 179 180 181 Yield (%) 92 90 93 95 82 50 80

Cl NHR1 NH 3 Cl N

Cl NHR1 PhSH N N 162 R3 R1 N N R2 1) mCPBA 2) R3R4NH N N 165 N R4 R1 N7 N9 R2 NH2

SPh NHR1 N 163 NH2

A 40-membered library of 6,7,8-trisubstituted purines (165) was constructed, demonstrating the potential utility of this regiospecic strategy. 6.4. Preparation of 6,8-disubstituted purine analogues: thiazolopyrimidines Thiazolopyrimidines are widely used bioisosteres of the purine base (Scheme 43) and this heterocycle can be obtained in one step
Ar H2N 160 Ar n-BuOH N N 166 Cl N C S R1 Cs2CO3 (2 eq) N N N S R1 NH NH NH2 Cl Ph

These compounds (175181) are interesting 6,8-disubstituted purine analogues that can be obtained in one or two steps from a readily available pyrimidine precursor (160). The thiazolopyrimidines 175181 can be aminated at the last step under microwave irradiation to give the disubstituted thiazolopyrimidine derivatives 182. 7. Conclusions The purine motif is a privileged substructure, which is recognised by an enormous number of proteins.91 This biological relevance and the occurrence of the purine heterocycle in nature make it an attractive target for chemical modication. Being one of the most studied heterocycles in medicinal chemistry, a wide range of
Ar N N 167 R2 R2 NH2 N NH N R1 NH NH N S Ph NH

N C S DBU, DMF

Et3N, 80 C (80%)

48 h (20%)

168-174 MeCN, 50 C, 16 h Ar = 3,4,5-(MeO)3Ph-

175-181

S N acid or base microwave irradiation, 182 150 C R1: see table 13 R2: 3,4,5-(MeO)3PhCH2-, Me-(CH2)3-, t-Bu-, Ph-, p-MeOPh, m-ClPh-, p-NO2Ph-

Scheme 43.

M. Legraverend / Tetrahedron 64 (2008) 85858603

8601

chemical reactions can now be applied, opening up the possibility of building large libraries of new molecules bearing a great diversity of functions in seven directions around its small core. Recent advances in purine chemistry have been illustrated in this review, either by new synthetic routes or by improvements of known reactions, which widen the scope, and allow better regioselectivity with a higher yield. This article highlights the potential for combinatorial chemistry on the purine ring; for example, with only two non-identical substituents and seven possible points of attachment, as many as 42 different regioisomeric disubstituted purines can be envisaged. Thus, while much of the purine chemical space remains to be explored, the recent advances in purine chemistry should lead to more potent and specic inhibitors of known biological targets and pave the way to new inhibitors or antagonists of targets that have yet to be described. In conclusion, purines offer an exceptional scaffold for the synthesis of relevant tools in biology through a combination of the high level of regio-functionalisation and the diversity of the chemistries that are possible with this heterocycle. References and notes
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Rosemeyer, H. Chem. Biodivers. 2004, 1, 361401. Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 39874006. Schmidt, A. P.; Lara, D. R.; Souza, D. O. Pharmacol. Ther. 2007, 116, 401416. Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med. Chem. 2006, 49, 45684573. Wan, Z.-K.; Binnun, E.; Wilson, D. P.; Lee, J. Org. Lett. 2005, 7, 58775880. Lakshman, M. K.; Gunda, P.; Pradhan, P. J. Org. Chem. 2005, 70, 1032910335. Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.; Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123, 77797787. Havelkova, M.; Dvorak, D.; Hocek, M. Synthesis 2001, 17041710. Capek, P.; Vrabel, M.; Hasnk, Z.; Pohl, R.; Hocek, M. Synthesis 2006, 35153526. Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 58695873. Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.; Nolsoe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 12071210. Chang, Y. T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Chem. Biol. 1999, 6, 361375. Chapman, E.; Best, M. D.; Hanson, S. R.; Wong, C.-H. Angew. Chem., Int. Ed. 2004, 43, 35263548. Krystof, V.; Lenobel, R.; Havlicek, L.; Kuzma, M.; Strnad, M. Bioorg. Med. Chem. Lett. 2002, 12, 32833286. Moravec, J.; Krystof, V.; Hanus, J.; Havlicek, L.; Moravcova, D.; Fuksova, K.; Kuzma, M.; Lenobel, R.; Otyepka, M.; Strnad, M. Bioorg. Med. Chem. Lett. 2003, 13, 29932996. Legraverend, M.; Ludwig, O.; Leclerc, S.; Meijer, L. J. Heterocycl. Chem. 2001, 38, 299303. Legraverend, M.; Tunnah, P.; Noble, M.; Ducrot, P.; Ludwig, O.; Grierson, D. S.; Leost, M.; Meijer, L.; Endicott, J. J. Med. Chem. 2000, 43, 12821292. Chang, Y.-T.; Choi, G.; Bae, Y.-S.; Burdett, M.; Moon, H.-S.; Lee, J. W.; Gray, N. S.; Schultz, P. G.; Meijer, L.; Chung, S.-K.; Choi, K. Y.; Suh, P.-G.; Ryu, S. H. ChemBioChem 2002, 897901. Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L.; Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999, 7, 12811293. Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J. W. J. Org. Chem. 1997, 62, 201203. Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 70267029. Elphick, L. M.; Lee, S. E.; Gouverneur, V.; Mann, D. J. ACS Chem. Biol. 2007, 2, 299314. Gibson, A. E.; Arris, C. E.; Bentley, J.; Boyle, F. T.; Curtin, N. J.; Davies, T. G.; Endicott, J. A.; Golding, B. T.; Grant, S.; Grifn, R. J.; Jewsbury, P.; Johnson, L. N.; Veronique Mesguiche, V.; Newell, D. R.; Noble, M. E. M.; Julie, A.; Tucker, J. A.; Whiteld, H. J. J. Med. Chem. 2002, 45, 33813393. Hardcastle, I. R.; Ian, R.; Arris, C. E.; Bentley, J.; Boyle, F. T.; Chen, Y.; Curtin, N. J.; Endicott, J. A.; Gibson, A. E.; Golding, B. T.; Grifn, R. J.; Jewsbury, P.; Menyerol, J.; Mesguiche, V.; Newell, D. R.; Noble, M. E. M.; Pratt, D. J.; Wang, L.-Z.; Whiteld, H. J. J. Med. Chem. 2004, 47, 37103722. Huang, L.-K.; Cherng, Y.-C.; Cheng, Y.-R.; Jang, J.-P.; Chao, Y.-L.; Cherng, Y.-J. Tetrahedron 2007, 63, 53235327. Liu, J.; Robins, M. J. J. Am. Chem. Soc. 2007, 129, 59625968. Zhong, M.; Robins, M. J. J. Org. Chem. 2006, 71, 89018906. Zhong, M.; Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem. 2006, 71, 4216 4221. Zhong, M.; Nowak, I.; Robins, M. J. J. Org. Chem. 2006, 71, 77737779. Khala-Nezhad, A.; Zarea, A.; Soltani Rad, M. N.; Mokhtari, B.; Parhami, A. Synthesis 2005, 419424. Fu, H.; Lam, Y. J. Comb. Chem. 2005, 7, 734738. Qu, G.-R.; Zhang, Z.-G.; Geng, M.-W.; Xia, R.; Zhao, L.; Guo, H.-M. Synlett 2007, 07210724. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674676.

16. 17. 18.

19. 20. 21. 22. 23.

24.

25. 26. 27. 28. 29. 30. 31. 32. 33.

34. Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 41204121. 35. Moriarty, K. J.; Koblish, H. K.; Garrabrant, T.; Maisuria, J.; Khalil, E.; Ali, F.; Petrounia, I. P.; Crysler, C. S.; Maroney, A. C.; Johnson, D. L.; Galemmo, J.; Robert, A. Bioorg. Med. Chem. Lett. 2006, 16, 57785783. 36. Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G. Tetrahedron Lett. 2001, 42, 8751 8755. 37. Bakkestuen, A. K.; Gundersen, L.-L. Tetrahedron Lett. 2003, 44, 33593362. 38. Jacobsen, M. F.; Knudsen, M. M.; Gothelf, K. V. J. Org. Chem. 2006, 71, 91839190. 39. Jenny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron Lett. 1991, 32, 70297032. 40. Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 27872797. 41. Wachtmeister, J.; Classohn, B.; Samuelsson, B. Tetrahedron 1995, 51, 20292038. 42. Wang, P.; Schinazi, R.; Chu, C. K. Bioorg. Med. Chem. Lett. 1998, 8, 15851588. 43. Jacobson, K. A.; Ji, X.-D.; Li, A.-H.; Melman, N.; Siddiqui, M. A.; Shin, K.-J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem. 2000, 43, 21962203. 44. Nandanan, E.; Jang, S.-Y.; Moro, S.; Kim, H. O.; Siddiqui, M. A.; Russ, P.; Marquez, V. E.; Busson, R.; Herdewijn, P.; Harden, T. K.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2000, 43, 829842. 45. Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997, 38, 11611164. 46. Toyota, A.; Katagiri, N.; Kaneko, C. Heterocycles 1993, 36, 16251630. 47. Lu, W.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. J. Org. Chem. 2007, 72, 50125015. 48. Legraverend, M.; Boumchita, H.; Bisagni, E. Synthesis 1990, 587589. 49. Daluge, S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A. Nucleosides Nucleotides Nucleic Acids 2000, 19, 297327. 50. He, R.; Ching, S. M.; Lam, Y. J. Comb. Chem. 2006, 8, 923928. 51. Allwood, M. B.; Cannan, B.; van Aalten, D. M. F.; Eggleston, I. M. Tetrahedron 2007, 63, 1229412302. 52. Zhang, L.; Zhang, Y. J. Tetrahedron Lett. 2006, 47, 775778. 53. van den Berg, D.; Zoellner, K. R.; Ogunrombi, M. O.; Malan, S. F.; Terre0 Blanche, G.; Castagnoli, N., Jr.; Bergh, J. J.; Petzer, J. P. Bioorg. Med. Chem. 2007, 15, 3692 3702. 54. Kalla, R. V.; Elzein, E.; Perry, T.; Li, X.; Gimbel, A.; Yang, M.; Zeng, D.; Zablocki, J. Bioorg. Med. Chem. Lett. 2008, 18, 13971401. 55. Elzein, E.; Kalla, R.; Li, X.; Perry, T.; Parkhill, E.; Palle, V.; Varkhedkar, V.; Gimbel, A.; Zeng, D.; Lustig, D. Bioorg. Med. Chem. Lett. 2006, 16, 302306. 56. Varani, K.; Gessi, S.; Merighi, S.; Vincenzi, F.; Cattabriga, E.; Benini, A.; Klotz, K.-N.; Baraldi, P. G.; Tabrizi, M. A.; Lennan, S. M. Biochem. Pharmacol. 2005, 70, 16011612. 57. Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhedkar, V.; Xiao, D.; Piscopio, A.; Maa, T.; Gimbel, A.; Hao, J. Bioorg. Med. Chem. Lett. 2005, 15, 609612. 58. Kazaoka, K.; Sajiki, H.; Hirota, K. Chem. Pharm. Bull. 2003, 51, 608611. 59. Ahn, H.-S.; Bercovici, A.; Boykow, G.; Bronnenkant, A.; Chackalamannil, S.; Chow, J.; Cleven, R.; Cook, J.; Czarniecki, M.; Domalski, C.; Fawzi, A.; Green, M.; Gundes, A.; Ho, G.; Laudicina, M.; Lindo, N.; Ma, K.; Manna, M.; McKittrick, B.; Mirzai, B.; Nechuta, T.; Neustadt, B.; Puchalski, C.; Pula, K.; Silverman, L.; Smith, E.; Stamford, A.; Tedesco, R. P.; Tsai, H.; Tulshian, D. B.; Vaccaro, H.; Watkins, R. W.; Weng, X.; Witkowski, J. T.; Xia, Y.; Zhang, H. J. Med. Chem. 1997, 40, 21962210. 60. Boyle, C. D.; Xu, R.; Asberom, T.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Guzik, H.; Hu, Y.; Hu, Z.; Lankin, C. M.; Pissarnitski, D. A.; Stamford, A. W.; Wang, Y.; Skell, J.; Kurowski, S.; Vemulapalli, S.; Palamanda, J.; Chintala, M.; Wu, P.; Myers, J.; Wang, P. Bioorg. Med. Chem. Lett. 2005, 15, 23652369. 61. Brown, D. J.; Mason, S. F. The Pyrimidines. In The Chemistry of Heterocyclic Compounds; Sons, J. W., Ed.; Interscience: New York, NY, London, 1962; pp 3181. 62. Baindur, N.; Chadha, N.; Player, M. R. J. Comb. Chem. 2003, 5, 653659. 63. Kenner, G. W.; Lythgoe, B.; Todd, A. R.; Topham, A. J. Chem. Soc. 1943, 388390. 64. Taddei, D.; Slawin, A. M. Z.; Woollins, J. D. Eur. J. Org. Chem. 2005, 939947. 65. Marchetti, F.; Sayle, K. L.; Bentley, J.; Clegg, W.; Curtin, N. J.; Endicott, J. A.; Golding, B. T.; Grifn, R. J.; Haggerty, K.; Harrington, R. W.; Mesguiche, V.; Newell, D. R.; Noble, M. E. M.; Parsons, R. J.; Pratt, D. J.; Wang, L. Z.; Hardcastle, I. R. Org. Biomol. Chem. 2007, 5, 15771585. 66. Gibson, C. L.; La Rosa, S.; Suckling, C. J. Org. Biomol. Chem. 2003, 1, 19091918. 67. Sayle, K. L.; Bentley, J.; Boyle, F. T.; Calvert, A. H.; Cheng, Y.; Curtin, N. J.; Endicott, J. A.; Golding, B. T.; Hardcastle, I. R.; Jewsbury, P. Bioorg. Med. Chem. Lett. 2003, 13, 30793082. 68. Harnden, M. R.; Hurst, D. Aust. J. Chem. 1990, 42, 5562. 69. Albert, A.; Brown, D. J.; Wood, H. C. S. J. Chem. Soc. 1954, 38323839. 70. Brown, D. J.; Jacobsen, N. W. J. Chem. Soc., Perkin Trans. 1 1965, 37703778. 71. Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X. J. Comb. Chem. 2005, 7, 474482. 72. Hammarstrom, L. G. J.; Meyer, M. E.; Smith, D. B.; Talamas, F. X. Tetrahedron Lett. 2003, 44, 83618363. 73. Hammarstrom, L. G. J.; Smith, D. B.; Talamas, F. X.; Labadie, S. S.; Krauss, N. E. Tetrahedron Lett. 2002, 43, 80718073. 74. Liu, J.; Dang, Q.; Wei, Z.; Zhang, H.; Bai, X. J. Comb. Chem. 2005, 7, 627636. 75. Hammarstrom, L. G. J.; Smith, D. B.; Talamas, F. X. Tetrahedron Lett. 2007, 48, 28232827. 76. Trivedi, B. K.; Bruns, R. F. J. Med. Chem. 1989, 32, 16671673. 77. Ding, S.; Gray, N. S.; Ding, Q.; Wu, X.; Schultz, P. G. J. Comb. Chem. 2002, 4, 183 186. 78. Whiteld, H. J.; Grifn, R. J.; Hardcastle, I. R.; Henderson, A.; Meneyrol, J.; Mesguiche, V.; Sayle, K. L.; Golding, B. T. Chem. Commun. 2003, 28022803. 79. Gangjee, A.; Jain, H. D.; Kisliuk, R. L. Bioorg. Med. Chem. Lett. 2005, 15, 2225 2230. 80. Arnold, L. D.; Calderwood, D. J.; Dixon, R. W.; Johnston, D. N.; Kamens, J. S.; Munschauer, R.; Rafferty, P.; Ratnofsky, S. E. Bioorg. Med. Chem. Lett. 2000, 10, 21672170.

8602

M. Legraverend / Tetrahedron 64 (2008) 85858603 86. Llauger, L.; He, H.; Kim, J.; Aguirre, J.; Rosen, N.; Peters, U.; Davies, P.; Chiosis, G. J. Med. Chem. 2005, 48, 28922905. 87. Muller, C. E.; Shi, D.; Manning, J.; Malcolm; Daly, J. W. J. Med. Chem. 1993, 36, 33413349. 88. Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.; Matsukura, M.; Kabasawa, Y.; Niijima, J.; Kotake, Y.; Watanabe, N.; Kawata, T.; Inoue, T.; Horizoe, T.; Yasuda, N.; Minami, H.; Nagata, K.; Murakami, M.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S. J. Med. Chem. 2001, 44, 170179. 89. Liu, J.; Dang, Q.; Wei, Z.; Shi, F.; Bai, X. J. Comb. Chem. 2006, 8, 410416. 90. Liu, J.; Patch, R. J.; Schubert, C.; Player, M. R. J. Org. Chem. 2005, 70, 1019410197. 91. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893930.

81. Chien, T.-C.; Meade, E. A.; Hinkley, J. M.; Townsend, L. B. Org. Lett. 2004, 6, 28572859. 82. Gangjee, A.; Mavandadi, F.; Kisliuk, R. L.; McGuire, J. J.; Queener, S. F. J. Med. Chem. 1996, 39, 45634568. 83. Gangjee, A.; Yang, J.; McGuireb, J. J.; Kisliuk, R. L. Bioorg. Med. Chem. 2006, 14, 85908598. 84. Legraverend, M.; Ngongo-Tekam, R. M.; Bisagni, E.; Zerial, A. J. Med. Chem. 1985, 28, 14771480. 85. Biamonte, M. A.; Shi, J.; Hong, K.; Hurst, D. C.; Zhang, L.; Fan, J.; Busch, D. J.; Karjian, P. L.; Maldonado, A. A.; Sensintaffar, J. L.; Yang, Y.-C.; Kamal, A.; Lough, R. E.; Lundgren, K.; Burrows, F. J.; Timony, G. A.; Boehm, M. F.; Kasibhatla, S. R. J. Med. Chem. 2006, 49, 817828.

M. Legraverend / Tetrahedron 64 (2008) 85858603

8603

Biographical sketch

Michel Legraverend was born in Saint-Pair-sur-Mer, Normandy, France. After receiving a rst degree (DEUG) in Chemistry and Biology at the University of Caen, he completed further studies (Maitrise and DEA) in Chemistry and Molecular Biology at the University of Paris-sud in Orsay. He carried out graduate studies at the CNRS, ICSN at Gif sur Yvette under the supervision of Prof. E. Lederer. He joined the laboratory of Medicinal Chemistry and Biology, Applied Pharmacology Section of Dr. David Johns, with Dr. Robert I. Glazer, from 1977 to 1979, at the National Cancer Institute, NIH, Bethesda, MD. He joined the laboratory of Chemical Pharmacology of Dr. Emile Bisagni at the Institut Curie, Orsay, France, where he completed his doctoral studies (University of Paris XI, Orsay) and obtained a researcher position at INSERM, France. He worked then under the directorship of Dr. David S. Grierson (19982006) and presently with Dr. M.-P. Teulade-Fichou. His current research interest includes the search of new methods for the synthesis of polysubstituted purines, as inhibitors of various targets involved in the cell cycle and cell signalling.