2) HSiCl3SiH Cl

LiSiH Si H

Cl2

CH2Cl2

SiCl Si Cl

1

Cl1) Mg

TETRAISOPROPYLDISILANE-1,2-DIYL – A NEW BIFUNCTIONAL

PROTECTING GROUP IN NUCLEOSIDE CHEMISTRY

Sylwia Musiał1, Grzegorz Hreczycho2, Hieronim Maciejewski2, Marcin K. Chmielewski1 and Wojciech T. Markiewicz1*

1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, PL-61704 Poznań, Poland

2Department of Organometallic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, PL-60780 Poznań, Poland

* correspondence to: markwt@ibch.poznan.pl

1,2-Dichloro-1,1,2,2-tetraisopropyldisilane (1) was obtained in high yield starting with

trichlorosilane and appropriate Grignard reagent. Then homocoupling in the presence of

lithium giving dihydrodisilane, which in the chlorination reaction gave silylating reagent.

The development and introduction into organic synthesis of tetraisopropyldisiloxane-1,3-

diyl [1] and other bifunctional silyl protecting groups [2-5] substantially simplified and shortened

many reaction procedures in nucleic acids chemistry and related fields.

Functionalization of ribonucleosides is still an exciting synthetic problem as there is a

great interest in chemical synthesis of RNA and its analogues as well as in new nucleoside

analogues.

Besides a wide scope of applications of tetraisopropyldisiloxane-1,3-diyl (TIPDSi) group

there were numerous efforts to find its analogues that would be more stable under basic

conditions or easier accessible and cheaper. The carba analogue of the disiloxane protection

TIPDSi was described and patented [5].

We decided to explore a reactivity of disilane analogues of tetraisopropyldisiloxane-1,3-

diyl protection towards ribonucleosides.

A new bifunctional protecting group can be introduced into ribonucleosides in a one-step

procedure to protect simultaneously either 2’,3’- or 3’,5’-OH functions selectively.

Initial working hypothesis is based on the electronegativity of atoms attached to silicon

atom. By comparing the difference in electronegativity between the atoms forming protecting

groups, we found that the more electropositive silicon atom is, the more energy is needed to

break the Si-Cl bond, thus decreasing the reactivity of protecting reagent.

In summary, we have developed the first bifunctional silyl protective group which can be

introduced into ribonucleosides in a one-step procedure to protect simultaneously either 2’,3’-

or 3’,5’- hydroxyl functions selectively.

Tetraisopropyldisilane-1,2-diyl group is compatible with wide range of reaction conditions

used in organic synthesis. Its properties including selective removal with fluorides are similar

to known silyl protecting groups, yet further increase a scope of their synthetic applications.

Results covered by patent protection within Project co-financed by the European Regional

Development Fund within Operational programme Innovative Economy

Si SiCl

C

C

Si SiCl

C

C

C Si SiCl

C

C

O>>

Si Si

0

Si C

0.65

Si O

1.54

H2’

H2’

H5

H1’

H5’

H3’ H4’ H5”

H5

H1’

H3’ H5’ H4’ H5”

B

O

OO

O

Si

SiC O

H3C

B

O

OHO

O

Si

Si

H3’ H5

H1’

H4’

H5’,H5”

H5 H1’ H2’ H3’

H4’ H5’ H5”

H2’

B

O

OO

O

Si Si

C

O

H3C

B

O

OO

HO

Si Si

+

SiCl Si Cl

1

imidazole,

Et3N, THF,

r.t., 2h

Si SiN N

4

N N

B

O

OHOH

HO

2

B

O

OO

HO

Si Si

3

B

O

OHO

O

Si

Si

5

B = nucleobases; a) pyridine, r.t., 1 h, 95% yield; b) pyridine, THF, r.t., 1.5 h, 90% yield

+

b

a

1. Markiewicz, W.T., Wiewiórowski, M., Nucleic Acids Symp. Ser., 1978, 185-190; Markiewicz,

W.T., J. Chem. Research (S), 1979, 24-25.

2. Ryu, S., Murai et al., J. Org. Chem., 1978, 43, 780-782; Corey, E.J., Hopkins, P.,B. et al., J.

Am. Chem. Soc., 1979, 101, 7131-7134.

3. Markiewicz, W.T., Nowakowska, B., Adrych, K., Tetrahedron Lett., 1988, 29, 1561-1564.

4. Markiewicz, W.T., Adrych, K., Nucleosides and Nucleotides, 1988, 7, 671-674.

5. Chow, S., Wen, K., Sanghvi, Y.S. et al., Nucleosides, Nucleotides and Nucleic Acids, 2003,

22, 583-587.

6. Markiewicz, W.T., Musiał, S., Hreczycho, G., Maciejewski, H., Chmielewski, M.K., Patent

Application PL399003, 2012.