1132
Scheme 1. Reagents and conditions: (i) ((CH3)2CHCO)2O, DMAP, DMF, rt, 4 h, 2a: 80%; (ii) CH3CH2C(OCH3)3, TFA, DMF,
rt, 2 h, then, H2O, overnight, 2b: 87%; (iii) ((CH3)2CHCO)2O, DMAP, pyridine, reflux, 1 h, 2c: 99%; (iv) 8 M NaOMe, MeOH,
rt, 16 min, 2d: 79%
Triisobutyl derivatization of ganciclovir 2c was successfully carried out with isobutyric anhydride in
refluxing pyridine using DMAP as a catalyst (Scheme 1). During the synthesis of acyclovir prodrugs,
the use of strong base (8 M NaOCH3/CH3OH) resulted in a selective O-deacylation in the presence of
N2-acyl as reported previously.9 The same protocol when applied to compound 2c produced mono-N2-
isobutyrate amide of ganciclovir 2d in 79% yield.
To avoid potential difficulty in selective hydrolysis of O-acyl groups, preparation of mono-N2-pivalate
amide of ganciclovir 5 was accomplished in a three-step procedure (Scheme 2). This preparation required
the protection of both primary hydroxyl functions, which was reported by direct silylation of ganciclovir
in DMF with tert-butyldimethyl silyl chloride (TBDMSCl) in the presence of imidazole.2 However,
our investigation revealed that TBDMS groups were unstable at reflux in pivalic anhydride. The more
acidic stable silyl protecting group, tert-butyldiphenylsilyl, was satisfactory. Treatment of the bis-O-tert-
butyldiphenylsilyl derivative 3 with trimethyl acetic anhydride in pyridine, followed by removal of the
silyl protecting group with tetrabutylammonium fluoride (TBAF) in DMF, gave the desired mono-N2-
pivaloyl derivative 5 in 52% yield.
Scheme 2. Reagents and conditions: (i) TBDPSCl, imidazole, DMF, rt, 24 h, 3: 91%; (ii) trimethylacetic anhydride, DMAP,
pyridine, reflux, 1 h, 4; (iii) TBAF, THF, DMF, 1 h, 5: 52% for two steps
Synthesis of di-N2,O-diisobutyl ganciclovir derivative 9 required selective protection of one of two
primary hydroxyl functions in ganciclovir (Scheme 3). This was achieved by treating mono-O-propionate
ester 2b in DMF with TBDPSCl in the presence of imidazole, followed by removal of the propionate
ester with strong base (8 M NaOCH3/CH3OH). The resulting mono-O-tert-butyldimethylsilyl derivative
7 was then treated with isobutyric anhydride in refluxing pyridine in the presence of DMAP to give
fully protected product 8. Removal of the TBDPS silyl group with TBAF provided the desired di-N2,O-
diisobutyl ganciclovir derivative 9 in 62% yield.
Two di-O-amino acid esters (12a and 12b) were prepared in two steps according to the same method
as for preparation of acyclovir amino acid derivatives (Scheme 4).10,11 A solution of ganciclovir in DMF
was treated with the N-carbobenzyloxy-protected amino acid (10a and 10b) using the coupling agent
DCC and DMAP as a catalyst. The resulting N-protected ester derivatives (11a and 11b) were purified