Total syntheses of novel dideoxynucleoside analogues using chiral amino acids

Article abstract of DOI:10.1016/S0040-4039(00)01004-2

N-Tritylated L- and D-methionine and L-glutamic acid were used to obtain novel chiral iso-dideoxynucleoside analogues incorporating a tetrahydrofuranyl or a tetrahyropyranyl ring as the pseudosugar part, and at positions 2 and 3 of the ring an hydroxyethyl group and thymine or adenine, respectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01004-2

Tetrahedron Letters 41 (2000) 6191±6194
Total syntheses of novel dideoxynucleoside analogues using
chiral amino acids
George Balayiannis,a George Karigiannis,a Panayiotis Gatos,a
Dionissios Papaioannoua,* and Erik De Clercqb
aDepartment of Chemistry, University of Patras, GR-265 00 Patras, Greece
bRega Institute, Katholieke Universiteit Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium
Received 22 May 2000; accepted 14 June 2000
Abstract
N-Tritylated l- and d-methionine and l-glutamic acid were used to obtain novel chiral iso-dideoxy-
nucleoside analogues incorporating a tetrahydrofuranyl or a tetrahyropyranyl ring as the pseudosugar
part, and at positions 2 and 3 of the ring an hydroxyethyl group and thymine or adenine, respectively.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids and derivatives; amino alcohols; dideoxynucleosides; protecting groups.
20,30-Dideoxynucleosides (ddN), such as AZT (1) and ddC (2) and iso-dideoxynucleosides (iso-
ddN) analogues like iso-ddA (3) are potent anti-HIV agents which act by inhibiting the enzyme
reverse transcriptase.1 In addition to the lack of an HO-group in position 30, other important
structural features for their biological activity appear to be the distance between the nucleobase
(B) and the HO-group at C-50 and the presence of the lone electron pairs on the O atom of the
ring,2 whereas analogues like 3 are characterized by increased hydrolytic stability.3 We now wish
to report the total syntheses of the novel iso-ddN analogues 4±10 (Fig. 1), incorporating these
structural characteristics, and using amino acids (AAs) as chiral templates. Retrosynthetically,
Figure 1. Structures of the new dideoxynucleoside analogues synthesized
* Corresponding author. E-mail: d.a.papaioannou@chemistry.upatras.gr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01004-2

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the amino alcohols (AAls) 17, 20 and 27 or O-benzylated derivatives (ABes) like 18, 19, 21 and 28
(Schemes 1 and 2) were envisaged as key-intermediates. These compounds may be obtained from
the lactones 11, 15 and 23 which in turn may be readily prepared from the commercially available
chiral AAs l- or d-methionine (Met) or l-glutamic acid (Glu), respectively.
Scheme 1. Synthesis of tetrahydrofuranyl AAls and ABes from l- and d-Met. Reagents: (i) (a) Me3SiCl; (b) Trt-Cl/
Et3N; (c) MeOH; (ii) MeI; (iii) NaOH/H2O; (iv) DCC; (v) DIBAH; (vi) Ph3PˆCHCO2Me; (vii) TBAF; (viii)
i
.
.
crystallization; (ix) LiAlH4; (x) TsOH H2O/ PrOH; (xi) Bn-Br/NaH; (xii) BH3 THF; (xiii) MMPI; (xiv) NH4OH or
HCl/MeOH; (xv) H2/Pd-C
Scheme 2. Synthesis of tetrahydropyranyl AAls and ABes from l-Glu. Reagents: (i) MeOH/SOCl2; (ii) (a) Me3SiCl;
(b) Trt-Cl/Et3N; (c) MeOH; (iii) LiAlH4; (iv) DCC; (v) DIBAH; (vi) Ph3PˆCHCO2Me; (vii) TBAF; (viii) NaOH/H2O;
(ix) DCC/HOBt; (x) FCC; (xi) TFA:CH2Cl2 (1:2); (xii) HCl/MeOH; (xiii) Trt-Cl/Et3N; (xiv) Bn-Br/NaH; (xv)
i
.
TsOH H2O/ PrOH
Indeed, we have already reported that l-Met can be readily converted, via the N-tritylated
l-homoserine lactone (11, Scheme 1) into a 1:3 mixture of the cis-(12) and trans-(13) esters which,
in small scale experiments, can be separated by ¯ash column chromatography (FCC).4 For larger

6193
scales, however, we have now developed an alternative separation methodology, which involves
crystallization from Et2O of the ester 12 directly from the reaction mixture. On the other hand,
saponi®cation of the remaining mixture and crystallization, also from Et2O, provided the
corresponding pure acid 14. Additional quantities of ester 12 may be obtained through reester-
i®cation with MeOH, using the Mitsunobu reaction, and crystallization. In this way, from 200
mmol of lactone 11, 14.1 g (81%) of the ester 12 and 31.4 g (61%) of acid 14 were recovered from
the mixture of the diastereomeric esters. Similarly, from 60 mmol of d-Met we recovered 55% of
the cis-ester 16 from the mixture of the diastereomeric esters produced from lactone 15. From the
ester 12, the AAl 17 was obtained in 92% yield, through LiAlH4-mediated reduction, followed by
i
detritylation with 4-toluenesulphonic acid hydrate (TsOH.H2O) in re¯uxing PrOH. When, prior
to detritylation, O-benzylation with benzyl (Bn) bromide in the presence of NaH was performed,
the preparation of the ABes 18 (from ester 16) and 19 in 75±80% yields was secured. On the other
hand, the AAl 20 and the corresponding ABe 21 were prepared in 95 and 70% yields,
respectively, from the trans-acid 14 through BH3-mediated reduction, followed by detritylation or
O-benzylation, also followed by detritylation.
The preparation of the cis-AAl 27 and the trans-ABe 28, incorporating a tetrahydropyranyl
ring, followed similar synthetic pathways as the ones described above. Thus, the AA l-Glu was
initially converted to the selectively protected derivative 22 (Scheme 2), which was then sequen-
tially subjected to a regioselective reduction with LiAlH4,5 and N,N0-dicyclohexylcarbodiimide
(DCC)-mediated ring-closure to provide the N-tritylated l-hydroxynorvaline lactone (23) in 45%
overall yield. This lactone, upon reduction with diisobutylaluminium hydride (DIBAH), followed
by Wittig reaction with the phosphorane Ph3PˆCHCO2Me gave the hydroxyalkene 24 in 79%
yield. Tetrabutylammonium ¯uoride (TBAF)-mediated ring-closure gave an inseparable mixture
of the expected diastereomeric cis- and trans-esters in almost equimolar quantities. For the
purpose of their separation, the obtained mixture was saponi®ed and treated with DCC in the
presence of 1-hydroxybenzotriazole (HOBt), whereby a mixture of the expected cis-(25) and the
unexpected trans-(26) lactams was obtained in 58% yield. However, these lactams could be
readily separated by FCC and thus pure 25 and 26 were obtained in the ratio 25:26=3.2:3.8.6
From these lactams, the AAl 27 and the ABe 28 were obtained in 35 and 44% overall yields,
respectively, through a sequence of steps involving detritylation with tri¯uoroactetic acid
(TFA):CH2Cl2 (1:2), ring-opening with HCl in anhydrous MeOH, routine N-tritylation with
triphenylmethyl (trityl, Trt) chloride in the presence of Et3N, LiAlH4-mediated reduction and
®nally detritylation or O-benzylation, followed by detritylation.
For the construction of the adenine7,8 and thymine9 rings on AAls or ABes, literature
methodologies were employed. Thus, treatment of the AAl 17 with 5-amino-4,6-dichloro-
pyrimidine (ADCP) in re¯uxing BuOH,7 in the presence of Et3N, for 36 h, provided the expected
pyrimidine derivative, which upon sequential treatment with CH(OEt)3 in the presence of conc.
HCl, gave the corresponding chloropurine 29 (Scheme 3). On the other hand, the ABes 19 and 21
were treated with 4,6-dichloro-5-nitropyrimidine (DCNP)8 in CH2Cl2/DMF for 1 h at room
temperature (rt) to provide the corresponding pyrimidine derivatives which upon sequential
hydrogenation in the presence of Raney±Ni and CH(OEt)3-mediated ring-closure gave the
chloropurines 30 and 31, respectively.6 From chloropurines 29±31, the ®nal products 4 and 7 were
obtained through ammonolysis, followed by catalytic hydrogenolysis, where appropriate, in 78±
93% overall yields. Ammonolyses were routinely performed, in an autoclave at 80ꢀC, with
methanolic solutions of chloropurines saturated with gaseous NH3. Best results were obtained
with AAls in combination with the reagent ADCP.

6194
Scheme 3. Construction of nucleobase rings from AAls and ABes. Reagents: (i) ADCP; (ii) DCNP; (iii) Raney±Ni; (iv)
CH(OEt)3/HCl; (v) NH3/MeOH; (vi) H2/Pd-C; (vii) MMPI; (viii) NH4OH or HCl/EtOH
The thymine ring of the iso-ddN analogues 5, 6 and 8±10 was constructed upon reacting the
appropriate AAls 17, 20 and 27 or the ABes 18 and 28 (Scheme 3) with the freshly prepared acyl
isocyanate MeOCHˆC(Me)C(ˆO)NCO (MMPI)9 in the presence of Et3N in anhydrous CH2Cl2,
initially at 0ꢀC and then rt for 30 min, followed by treatment with a catalytic quantity of conc.
HCl in re¯uxing EtOH for 2 h and ®nally catalytic hydrogenolysis, where appropriate. The ®nal
products were obtained in 45±76% yields. Best results were obtained when ABes were used in the
reaction with MMPI. Biological tests, to determine the e€ect of the nucleobase, the relative
stereochemistry of the nucleobase and the hydroxyethyl side-chain, the absolute stereochemistry
and the size of the pseudosugar ring on the potential anti-HIV activity of the iso-ddN analogues
4±10, are currently in progress.
Acknowledgements
The General Secretariat for Research and Technology of the Greek Ministry for Development
is gratefully acknowledged for the ®nancial support of this research project.
References
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