Synthesis of 2'-O-substituted ribonucleosides.

Article abstract of DOI:10.1081/NCN-120022724

An efficient synthesis of 2'-O-substituted ribonucleosides, including 2'-O-TBDMS and 2'-O-TOM protected as well as 2'-O-Me and 2'-O-allyl derivatives is presented. Di-t-butylsilylene group was employed for simultaneous protection of 3'- and 5'- hydroxyl functions of nucleoside on the first step. Subsequent silylation or alkylation of free 2'-OH followed by introduction of suitable protection on the base moiety and removal of cyclic silyl protection gave target compounds in a high yield.

Full text of DOI:10.1081/NCN-120022724

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Synthesis of 2′-O-Substituted Ribonucleosides
V. Serebryany a b & L. Beigelman a
a Ribozyme Pharmaceuticals Inc. , Boulder, Colorado, USA
b Ribozyme Pharmaceuticals Inc. , 2950 Wilderness Place, Boulder, CO, 80301, USA
Published online: 31 Aug 2006.
To cite this article: V. Serebryany & L. Beigelman (2003) Synthesis of 2′-O-Substituted Ribonucleosides, Nucleosides,
Nucleotides and Nucleic Acids, 22:5-8, 1007-1009, DOI: 10.1081/NCN-120022724
To link to this article: http://dx.doi.org/10.1081/NCN-120022724
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1007–1009, 2003
Synthesis of 20-O-Substituted Ribonucleosides
*
V. Serebryany and L. Beigelman
Ribozyme Pharmaceuticals Inc., Boulder, Colorado, USA
ABSTRACT
An efficient synthesis of 20-O-substituted ribonucleosides, including 20-O-TBDMS
and 20-O-TOM protected as well as 20-O-Me and 20-O-allyl derivatives is pre-
sented. Di-t-butylsilylene group was employed for simultaneous protection of
30- and 50- hydroxyl functions of nucleoside on the first step. Subsequent silylation
or alkylation of free 20-OH followed by introduction of suitable protection on the
base moiety and removal of cyclic silyl protection gave target compounds in a
high yield.
Increasing demand for synthetic RNA-based therapeutics has stimulated a
search for efficient routes toward 20-O-protected or other 20-O-substituted ribo-
nucleosides. However, large-scale preparation of such compounds is usually com-
plicated due to the necessity of the separation of 20- and 30-isomers by
chromatography. This complication could be overcome if suitable protecting group
for simultaneous protection of 30- and 50-hydroxyl groups of starting nucleosides is
employed. It has been shown that di-tert-butylsilylene protection[1,2] of 50- and 30-
hydroxyls can be orthogonal to TBDMS protecting group.[3] We were interested if
this synthetic methodology could be applied for the preparative synthesis of 20-O-
substituted nucleosides.
*Correspondence: V. Serebryany, Ribozyme Pharmaceuticals Inc., 2950 Wilderness Place,
Boulder, CO 80301, USA; Fax: þ1 303 449 8829; E-mail: serebru@rpi.com.
1007
DOI: 10.1081/NCN-120022724
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1008
Serebryany and Beigelman
Scheme 1. Reagents & Conditions: i) t-Bu2Si(OTf)2, Im, DMF, 0ꢀC; ii) t-BuMe2SiCl, Im,
DMF, 60ꢀC, 80–87% (two steps); iii) 4a: iBu-Cl, Py-CH2Cl2, then MeNH2, 96%; 4b: Bz-Cl,
Py, then morpholine, 77%; 4c: Ac2O, Py, 76% from 1c; iv) HF-Py, CH2Cl2, 0ꢀC, 90–95%;
v) DMT-Cl, Py, 0ꢀC, 90%.
20-O-TBDMS-50-O-DMT-protected nucleosides 6a–d were obtained according
to the Sch. 1.[4] Starting nucleosides 1–d were reacted with t-Bu2Si(OTf)2 as
described[3] to afford 30,50-O-protected intermediates 2a–d. Without isolation from
the reaction mixture, compounds 2a–c were silylated to produce derivatives 3a–d
as crystalline solids in 80–87% yield. Acylation of base amino functions gave fully
protected crystalline compounds 4a–c. Subsequently, di-tert-butylsilylene protection
was removed using HF-Py in dichloromethane to obtain diols 5a–d, which were trea-
ted with DMT-Cl in pyridine to give 6a–d, no significant 20 ! 30-silyl migration was
observed. Overall yield of target compounds 6a–d from the starting nucleosides 1a–d
is 60–66%. All key intermediates, as well as the final compounds 6a and 6c are crys-
talline thus eliminating chromatographic purification steps. In the synthesis of 6b,d
only final chromatography step is necessary. A similar sequence of reactions was
used for the preparation of 20-O-TOM nucleosides[5] (Sch. 2). 50,30-O-Silylated
nucleosides 2a–c were reacted with TOM-Cl in the presence of DBU, resulting in
protected derivatives 7a–c. Subsequent acylation of base amino functions in 7a–c
provided fully protected intermediates 8a–c. We found that the treatment of com-
pounds 8a–c with HF-Py in CH2Cl2 at 0ꢀC leads to completely selective removal
of 50,30-protection, leaving TOM group intact. Unfortunately, in the case of uridine,
only products of base alkylation were detected in the reaction with TOM-Cl=DBU.
Scheme 2. Reagents & Conditions: i) TOM-Cl, DBU, THF, 0ꢀC, 70–75%; ii) 8a: iBu-Cl, Py,
then MeNH2, 80%; 8b: Bz-Cl, Py, then morpholine, 77%; 8c: Ac2O, Py, 75%; iii) HF-Py,
CH2Cl2, 0ꢀC, 95%, iv) Me2SO4 or allyl iodide, NaH, DMF, ꢁ20ꢀC, 65%.

Synthesis of 20-O-Substituted Ribonucleosides
1009
Analogous approach was also used for the synthesis of 20-O-Me and 20-O-allyl
adenosine. Treatment of 2b with dimethyl sulfate or allyl iodide in the presence of
NaH provided 20-alkylated adenosines 10a,b in 60–65% yield. Subsequent benzoyla-
tion followed by removal of 50,30-protection resulted in the target adenosine deriva-
tives 12a,b. It is important to note, that synthesis of 20-O-Me adenosine 12a does not
require any chromatography purification – all intermediates (2b, 10a, 11a) as well as
the final compound 12a were isolated by crystallization.
In summary, an efficient methodology for the preparation of 20-O-TBDMS, 20-O-
TOM protected as well as 20-O-alkyl nucleosides using di-t-butylsilylene protection
for 50,30-hydroxyl groups has been developed.
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1. Trost, B.M.; Caldwell, C.G. Tetrahedron Lett. 1981, 22, 4999–5002.
2. Corey, E.J.; Hopkins, P.B. Tetrahedron Lett. 1982, 23, 4871–4874.
3. Furusawa, K.; Ueno, K.; Katsura, T. Chem. Lett. 1990, 97–100.
4. Serebryany, V.; Beigelman, L. Tetrahedron Lett. 2002, 43, 1983–1985.
5. Wu, X.; Pitsch, S. Nucleic Acids Res. 1998, 26, 4315–4323.