Synthesis of the enantiomer of nelarabine

Article abstract of DOI:10.1016/j.tetlet.2005.03.039

A synthesis of the enantiomer of nelarabine is described. Subtle changes in the protecting group strategy allow for an efficient inversion of the C-2′ stereocentre.

Full text of DOI:10.1016/j.tetlet.2005.03.039

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2961–2964
Synthesis of the enantiomer of nelarabine
Karim Herbal,* John Kitteringham, Martyn Voyle and Andrew J. Whitehead
Synthetic Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 20 January 2005; revised 1 March 2005; accepted 8 March 2005
Available online 22 March 2005
Abstract—A synthesis of the enantiomer of nelarabine is described. Subtle changes in the protecting group strategy allow for an
efficient inversion of the C-20 stereocentre.
Ó 2005 Elsevier Ltd. All rights reserved.
The nucleoside nelarabine 1 is a novel water soluble pro-
drug of arabinosylguanine 2, which is currently being
developed for the treatment of acute lymphoblastic
leukaemia.1,2
unsuitable and therefore an alternative procedure was
pursued.
One preferred method for the construction of nucleoside
derivatives is via the use of the Vorbruggen reaction.4 In
¨
this case, however, a Vorbruggen reaction on 1,2,3,5-
6 would lead
¨
tetra-O-acetyl-L-arabinose derivative
O
N
OCH3
OCH3
predominantly to the undesired a-anomer 7 of the
protected nucleoside derivative and not the desired
b-substituted nucleoside5 (Scheme 2).
N
N
N
N
N
N
HN
HO
N
N
H2N
H2N
N
O
H2N
N
O
O
Our preferred strategy was to invert the C-20 stereocen-
tre of a nucleoside, which in turn would be prepared via
a Vorbruggen reaction between a suitably functionalised
¨
OH
OH
OH
HO
HO
OH
OH
OH
L-ribose derivative and a purine as depicted in Scheme 3.
1
2
3
Hence, commercially available L-ribose 8 was acetylated
to give the 1,2,3,5-tetra-O-acetyl-L-ribofuranoside 9
according to the method reported by Guthrie and
The synthesis of nelarabine is depicted in Scheme 1.3
The key step in the synthesis is an enzyme catalysed
trans-glycosylation reaction between 2-amino-6-meth-
oxy-9H-purine 4 and 1-b-D-arabinosyl uracil 5 using a
combination of purine nucleoside phosphorylase and
uridine phosphorylase.3 This enzymatic process is to-
tally regio- and stereoselective as none of the alpha ano-
mer or the N-7 regioisomer are observed. Furthermore,
this transformation is totally stereospecific as the 1-b-L-
arabinosyl uracil does not react.
Smith.6 Vorbruggen reaction of 9 and 2-amino-6-meth-
¨
oxy-9H-purine 4 under standard conditions predomi-
nantly gave the N-7 adduct.7 However, replacing
2-amino-6-methoxy-9H-purine 4 with 2-amino-6-chlo-
ropurine 10 gave exclusively the desired N-9 adduct
11.8 Tandem chloride displacement and deprotection
of the ester functionalities was carried out using excess
sodium methoxide in methanol and this afforded the
desired nucleoside 12 (Scheme 4).9
To support the development program of nelarabine, the
enantiomer 3 was required. Clearly the enzymatic
approach used in the synthesis of nelarabine was
Selective protection of the C-30 and C-50 alcohol func-
tionalities was achieved using di-tert-butyldichlorosilane
to give the silyl ether10 13, which was reacted with triflic
anhydride to give the desired triflate 14. Surprisingly,
attempts to invert the C-20 stereocentre with a range
of nucleophiles proved unsuccessful as the C-20 triflate
did not react (Scheme 5).
Keywords: Nelarabine; Enantiomer; Nucleosides; Vorbruggen.
¨
*
Corresponding author. Tel.: +44 14 38 76 8122; fax: +44 14 38 76
4869; e-mail: karim.9.herbal@gsk.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.039

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K. Herbal et al. / Tetrahedron Letters 46 (2005) 2961–2964
Cl
OCH3
N
N
N
(i)
N
OCH3
N
H
H2N
N
N
H
H2N
N
N
N
4
N
O
N
O
N
(iv)
O
H2N
N
O
N
HN
O
HN
OH
HO
O
(ii)
O
(iii)
O
N
OH
OH
OH
OH
O
O
OH
HO
HO
OH
5
HO
Scheme 1. Reagents and conditions: (i) NaOMe, MeOH; (ii) (EtO)2CO, NaHCO3; (iii) NaOH (aq); (iv) purine nucleoside phosphorylase, uridine
phosphorylase, K2HPO4, KH2PO4.
R
N
R
N
O
N
O
OAc
N
Vorbrüggen reaction
AcO
AcO
N
N
+
R'
N
H
AcO
OAc
N
AcO
OAc
R'
6
7
Scheme 2.
OMe
OMe
N
N
N
inversion of C-2' and
deprotection
N
O
O
N
N
N
HO
N
PO
NH2
NH2
HO
OH
PO
OH
selective protection of
C-3' and C-5' hydroxy
OMe
N
O
Vorbrüggen reaction
HO
O
OH
protection
OP
HO
PO
N
O
N
HO
OH
N
PO
OP
NH2
L-ribose
HO
OH
Scheme 3.
O
O
O
OMe
OH
OAc
(iii)
(i), (ii)
AcO
HO
AcO
AcO
OAc
HO
OH
AcO
OAc
8
X
9
N
N
(iv)
N
H
NH2
X=OMe 4
X=Cl 10
N
X
OMe
N
N
N
(v)
N
O
O
N
N
AcO
N
HO
N
NH2
NH2
AcO
OAc
11
HO
OH
12
Scheme 4. Reagents and conditions: (i) MeOH, HCl; (ii) Ac2O, pyridine; (iii) AcOH, Ac2O, H2SO4; (iv) BSA, TMSOTf, MeCN, 75 °C; X = Cl, N-9
adduct 90%; X = OMe, N-7:N-9 1:1, 90%; (v) X = Cl, NaOMe, MeOH, N-7 adduct 60%; X = OMe, Na2CO3, MeOH–H2O, N-9 adduct 97%.

K. Herbal et al. / Tetrahedron Letters 46 (2005) 2961–2964
2963
OMe
N
OMe
N
N
N
O
O
N
N
(i)
O
tBu2Si
N
HO
N
NH2
NH2
O
OH
13
HO
OH
12
(ii)
OMe
N
OMe
N
N
N
O
N
nucleophile
X
O
tBu2Si
N
O
NH2
N
O
N
O
OTf
NH2
tBu2Si
14
O
Nu
t
Scheme 5. Reagents and conditions: (i) Bu2SiCl2, AgNO3, Et3N, DMF, 92%; (ii) Tf2O, DMAP, pyridine, DCM, 80%.
OMe
N
OMe
N
N
O
N
(i)
N
O
N
O
NH2
N
Si
HO
N
O
OH
15
NH2
O
Si
HO
OH
12
(ii)
OMe
N
N
OMe
N
N
O
N
(iii)
O
O
Si
N
(iv-v)
N
NH2
3
O
Si
N
NH2
O
OTf
O
Si
O
OAc
17
O
Si
16
Scheme 6. Reagents and conditions: (i) TIBDSCl2, pyridine, 98%; (ii) Tf2O, DMAP, pyridine, DCM, 82%; (iii) Bu4NOAc, toluene, 83%;
(iv) Na2CO3, MeOH, 97%; (v) TBAF, AcOH, THF, 51%.
Protection of the C-30 and C-50 functionalities of 12 by
reaction with 1,3-dichloro-1,1,3,3-tetraisopropyldisilox-
ane (TIPDSCl2), however, gave the disilyloxyl ether11
15, which was reacted with triflic anhydride under stan-
dard conditions to gave the C-20 triflate 16. Exposure of
the triflate 16 to tetrabutylammonium acetate in toluene
led to complete inversion of the C-20 stereocentre and
the desired acetate 17 was isolated in 83% yield. Quanti-
tative removal of the acetate protecting group with
catalytic sodium carbonate in methanol and water,
followed by desilylation of the 1,3-diol moiety with
TBAF afforded the desired enantiomer 3 of nelarabine
(Scheme 6).
In conclusion, an efficient synthesis of the enantiomer of
nelarabine is reported whereby subtle changes in the
protecting group strategy allowed for a highly effective
inversion of the C-20 stereocentre.
References and notes
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