Selective cleavage of O-(dimethoxytrityl) protecting group with sodium periodate

Article abstract of DOI:10.1135/cccc20020502

Sodium periodate in aqueous organic solvents selectively removes, under mild reaction conditions, the O-(dimethoxytrityl) protecting group. Selectivity of the cleavage was studied using the nucleoside derivatives protected by various types of groups commonly used in nucleoside and nucleotide chemistry.

Full text of DOI:10.1135/cccc20020502

5
02
Rejman et al.:
SELECTIVE CLEAVAGE OF O-(DIMETHOXYTRITYL) PROTECTING
GROUP WITH SODIUM PERIODATE
1
2
3
4
Dominik REJMAN , Šárka KRÁLÍKOVÁ , Zdeněk TOČÍK , Radek LIBOSKA
5
,
and Ivan ROSENBERG *
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: rejman@uochb.cas.cz,
2
3
4
5
kralik@uochb.cas.cz, tocik@uochb.cas.cz, liboska@uochb.cas.cz, ivan@uochb.cas.cz
Received February 12, 2002
Accepted March 20, 2002
Sodium periodate in aqueous organ ic solven ts selectively rem oves, un der m ild reaction con -
dition s, th e O-(dim eth oxytrityl) protectin g group. Selectivity of th e cleavage was studied us-
in g th e n ucleoside derivatives protected by various types of groups com m on ly used in
n ucleoside an d n ucleotide ch em istry.
Keyw ord s: Dim eth oxytrityl; Periodate an ion s; Oxidation s; Solven t effects; Catalysis; Lewis
acids; Nucleosides; Deprotection ; Protective fun ction s.
Th ere is a n um ber of variation s on th e oxidative cleavage of alkoxy-
activated arom atic protectin g groups. Th us, ceric am m on ium n itrate h as
1
been used to deprotect bis(4-m eth oxyph en yl)m eth yl an d 4-m eth oxy-
2
,3
ph en yl groups wh ereas potassium persulfate h as been em ployed for th e
4
cleavage of 2,4-dim eth oxyben zyl group . As to silyl groups, th eir stability
5
un der various oxidative con dition s was reviewed ; tert-butyl(diph en yl)silyl
(
TBDPS) group was stable un der treatm en t with RuO /NaIO wh ereas a sin -
2 4
6
gle n ote m en tion s NaIO with out RuO to cleave trieth ylsiloxy group. Th e
use of KO /DMSO/18-crown -6 in th e cleavage of TBDMS an d TBDPS eth ers
an d th e cleavage of O-TBDMS group by N-brom osuccin im ide were also re-
ported.
4
2
7
2
8
We report h ere th e cleavage of O-(dim eth oxytrityl) group usin g n eutral
9
sodium periodate. Durin g th e oxidation of th ioeth er bon d in 2-N-(2-m eth yl-
propan oyl)-5′-O-(dim eth oxytrityl)-6-O-{2-[(4-n itroph en yl)sulfan yl]eth yl}-2′-
deoxyguan osin e (7) to sulfoxide derivative with sodium periodate (NaIO4)
in aqueous m eth an ol, we h ave observed a quan titative cleavage of
O-(dim eth oxytrityl) lin kage (O-DMTr) (Sch em e 1). NaIO h as been exten -
4
0
1
sively used in sugar ch em istry to cleave especially diols but we foun d n o
referen ce in th e literature on its use with th e dim eth oxytrityl substituen t.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20020502

Selective Cleavage of O-(Dimethoxytrityl) Protecting Group
503
To learn m ore about it, we subjected various dim eth oxytrityl derivatives of
n ucleosides to th e treatm en t with sodium periodate in aqueous water-
m iscible solven ts. Th e results of th is study are sum m arized in Table I. Un -
der con dition s specified in Table I, th e O- an d N-(dim eth oxytrityl) groups
in com poun ds 1–11, 20 an d also TBDMS groups in com poun ds 19 an d 20
were quan titatively cleaved off. Th e O-(m eth oxytrityl) group exh ibited a
OCH3
OCH3
NaIO4
O R
OH
+
HO R
H2O/acetone
OCH3
-10
OCH3
1
R = nucleoside residue
SCHEME 1
m uch h igh er stability (com poun ds 12, 13) th an th e O-DMTr group wh ich
suggests a possibility, in particular cases, to discrim in ate between th ese
types of groups. In con trast, a sm all exten t of th e cleavage of trityl (15, 16),
isopropyliden e (19), TBDPS (12, 13, 17, 18) an d ben zyl (6) protectin g
groups was observed on ly at elevated tem peratures. Also th e tetra-
h ydropyran yl group at th e secon dary h ydroxy group in com poun d 23 was
reason ably stable at room tem perature but it was cleaved off com pletely at
5
0 °C. Fin ally, th e 3′,5′-tetraisopropyldisiloxan yl group in uridin e deriva-
tive 22 was cleaved selectively at th e 5′-en d of th e protected n ucleoside so
th at th e 3′-h ydroxy group rem ain ed protected by (di)siloxan yl m oiety.
Th ese fin din gs could be of practical im portan ce in partial selective
deprotection of n ucleoside derivatives. In our laboratory we successfully
utilized th e described NaIO cleavage in th e purin e 2′-deoxyn ucleoside se-
4
ries to avoid depurin ation s occurin g un der acidic con dition s. We also suc-
ceeded in an IO -driven detritylation of th ym in e n ucleoside 8 wh ich
4
proceeded with out an y an om erization th at was oth erwise en coun tered
1
1
wh en detritylation was perform ed in 80% aqueous acetic acid
.
Our attem pts to gath er m ore facts to un derstan d possible m ech an ism of
th e cleavage with NaIO provided th e followin g im portan t fin din gs (as per-
4
form ed with com poun d 1). Th e rate of cleavage of (dim eth oxytrityl)oxy
bon d rises both with con cen tration of NaIO4 in th e reaction m ixture an d
with polarity of th e solven t. Alth ough aqueous m eth an ol an d eth an ol seem
to be better solven ts for th e cleavage th an aqueous aceton e or dioxan e,
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

5
04
Rejman et al.:
careful an alysis of 0.5 M solution s of NaIO in 70% aqueous aceton e, 70%
4
aqueous eth an ol (or m eth an ol), an d water, after stan din g at room tem pera-
ture for 36 h , revealed th e presen ce of substan tial am oun ts of NaIO3 in
aqueous aceton e (10 m ole %) an d aqueous eth an ol (50 m ole %); n o NaIO3
was foun d in water. Obviously, th e organ ic solven t itself or its trace im puri-
ties caused, actin g in a catalytic m an n er, a con siderable reduction of NaIO4
to NaIO . In addition , we h ave foun d th at th e cleavage of m eth yl
3
[
4-N-ben zoyl-2′-deoxy-5′-O-(dim eth oxytrityl)cytidin -3′-O-yl]m eth ylph os-
ph on ate (9) with 20 equiv. of NaIO (12 h at room tem perature) in aqueous
4
solution free from organic solvents provided 7 equiv. of NaIO (clearly a non-
3
stoichiom etric am ount). On the other hand, treatm ent of NaIO (20 equiv.)
4
with 2′-deoxyth ym idin e in water for 16 h left both NaIO an d n ucleoside
4
un ch an ged; n o NaIO was form ed. It can be con cluded th at th e presen ce of
3
a n on -stoich iom etric am oun t of NaIO3 form ed in th e cleavage of th e
O-DMTr lin kage in water free from organ ic solven t m ust be caused by cata-
lytic redox reaction s between dim eth oxytrityl-con tain in g species an d
NaIO . Th is “catalysis” h ypoth esis seem s to be supported by th e fin din gs
4
th at n o oth er DMTr-con tain in g species except DMTr-OH were foun d in th e
reaction m ixture after th e cleavage.
Furth erm ore, we h ave foun d th at pH value of th e reaction m ixture re-
m ain s sligh tly acidic (pH 4.7 in water) durin g th e reaction but th e pH value
per se affects th e DMTr group stability on ly a little. Th us, th e cleavage of th e
O-DMTr bon d in com poun d 1 perform ed in aqueous eth an ol wen t to com -
pletion in 10 h with NaIO4 (10 equiv.) but n ot in 0.25 M form ic acid (10
equiv. relative to th e DMTr derivative) wh ere on ly ca 5% of th e startin g
com poun d was cleaved after th e sam e tim e. In addition , th e presen ce of
various organ ic an d in organ ic bases (see Table I, n ote c) com pletely pre-
ven ts th e cleavage.
To clarify m ore th e n ature of th e cleavage, we perform ed experim en ts in
a two-ph ase system com posed of a saturated aqueous solution of NaIO an d
4
an eth yl acetate or dich lorom eth an e solution of 5′-O-DMTr-T 1, both in th e
+
−
absen ce an d in th e presen ce of Bu N HSO as th e ph ase-tran sfer catalyst
4
4
(
PTC). A sm all exten t of detritylation , n ot exceedin g 10% after 16 h for
both solven t system s, was foun d with out PTC wh ile th e addition of PTC in -
creased th e cleavage to 60–70% after 20 h . We also in vestigated th e cleav-
age un der exclusion of water. It was foun d th at th e presen ce of water is
strictly required for th e cleavage reaction ; n o cleavage of th e O-DMTr bon d
was observed in absolute eth an ol, dich lorom eth an e or ben zen e with out or
with 18-crown -6 used as an NaIO solubilizer.
4
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Selective Cleavage of O-(Dimethoxytrityl) Protecting Group
505
Last but n ot least, we h ave foun d th at a direct sun ligh t does n ot in flu-
en ce th e rate of th e cleavage, an d n o free iodin e is released durin g th e
cleavage.
Sin ce th ere were reason s for th e ration alization th at th e cleavage of th e
O-DMTr lin kage proceeded in an oxidative m an n er, we perform ed addi-
tion al experim en ts with th e use of oth er types of oxidation agen ts. Th us,
n eith er h ydrogen peroxide, lead tetraacetate n or sodium perch lorate caused
th e cleavage of th e (dim eth oxytrityl)oxy bon d in com poun d 1. On th e
oth er h an d, potassium persulfate worked as efficien tly as NaIO itself in th e
4
cleavage reaction with com poun d 1 (14 h at room tem perature), but its
acidity is m uch h igh er th an th e acidity of NaIO . On th e basis of all th ese
4
observation s, a fun dam en tal question em erges: Is th e cleavage of O-DMTr
lin kage a sim ple NaIO -m ediated h ydrolytic reaction or a redox reaction as-
4
sociated with th e reduction of NaIO to NaIO ?
4
3
Alth ough th e form ation of NaIO in th e cleavage of th e O-DMTr lin kage
3
could support an oxidative (probably n on -radical) m ech an ism of th e cleav-
age reaction , th e experim en t perform ed with com poun d 9 in water stron gly
suggests th at th e form ation of a n on -stoich iom etric am oun t (excess) of
NaIO is caused by th e dim eth oxytrityl-con tain in g species servin g as a cata-
3
lyst for th e NaIO4 reduction . Th is fact seem s to be un am biguously con -
firm ed by th e experim en t with 2′-deoxyth ym idin e an d NaIO4 in water
wh ere n o NaIO was form ed. We can con clude th at NaIO reduction could
3
4
be a side reaction th at n eed n ot n ecessarily be con n ected with th e cleavage
of th e O-DMTr lin kage.
Wh at could be th en th e m ost likely m ech an ism of th e cleavage? It is
−
kn own th at periodate ion IO4 coordin ates in aqueous solution s two m ole-
–
12
cules of water to form th e h ypervalen t iodin e species H IO 6 (ref. ). Th is
4
ion ic com poun d could be a relatively stron g Lewis acid (workin g in water)
respon sible for th e cleavage of th e eth er an d acetal (ketal) lin kages. Th is as-
sum ption seem s to be stron gly supported by th e fin din g th at n o cleavage
occurred un der strictly an h ydrous con dition s. Alth ough th e aqueous solu-
–
tion of NaIO is sligh tly acidic (pH 4.7), th e acidity of th e H IO ion s does
4
4
6
n ot seem to be a sin gle factor sufficien t to cleave th e O-DMTr lin kage as
proved in th e experim en t in wh ich th e pH per se affected th e cleavage on ly
–
a little. Th ese fin din gs suggest th at H IO ion h as to be coordin ated to th e
4
6
electron -rich oxygen atom of th e cleaved lin kage eith er via replacem en t of
–
on e m olecule of water in th e H IO ion for th e oxygen atom with h igh est
4
6
electron den sity, or via form ation of h ydrogen bon d to th e sam e oxygen
–
atom . In both cases th e coordin ation of th e H IO 6 ion (probably a rate-
4
lim itin g factor) would h ave a destabilizin g effect on th e C–O lin kage result-
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

5
06
Rejman et al.:
TABLE I
Stability of th e selected protected n ucleosides in th e presen ce of NaIO4
Cleavage, %
Com poun d
0.05–0.1 M solution in MeOH–water 7 : 3)
NaIO
equiv.
Tim e
h
4
(
2
0 °C
50 °C
2
′-Deoxy-5′-O-DMTr-th ym idin e
(1)
0.25
1
3
20
0.25
3
16
16
16
6/16
16
16
0
0
0
5
95
–
0
–
a
(
(
(
(
(
1)
1)
1)
1)
1)
a
a
5
a
a
95 /100
0
b
c
0
a
2
′-Deoxy-3′-O-DMTr-th ym idin e
(2)
2)
3
10
16
16
50
100
–
–
a
(
a
2
2
4
3
2
′-Deoxy-5′-O-DMTr-6-N-(1-dim eth ylam in oeth yliden e)aden osin e
′-Deoxy-5′-O-DMTr-2-N-(2-m eth ylpropan oyl)guan osin e
-N-Ben zoyl-2′-deoxy-5′-O-DMTr-cytidin e
(3)
(4)
(5)
(6)
(7)
20
20
20
13
2
8
8
100
–
–
–
–
–
a
100
a
a
6/16
48
80 /100
a
′-O-Ben zyl-2′-deoxy-5′-O-DMTr-th ym idin e
100
a
′-Deoxy-5′-O-DMTr-2-N-(2-m eth ylpropan oyl)-6-O-{2-[(4-n itrofen yl)-
16
100
sylfan yl]eth yl}guan osin e
a
1
-(2-Deoxy-5-O-DMTr-β-D-threo-pen tofuran osyl)th ym in e
(8)
(9)
6
16
8
100
–
–
a
Meth yl(4-N-ben zoyl-2′-deoxy-5′-O-DMTr-cytidin e-3′-O-yl)m eth yl-
ph osph on ate
20
100
d
a
2
6
3
5
-(2-{-[(Dim eth oxytrityl)oxy]eth oxy}eth oxy)eth an ol
-[Meth oxy(trityl)am in o]h exan ol
(10)
(11)
(12)
(13)
3
3
16
16
16
16
100
–
–
–
–
e
100
f
e
′-O-[tert-Butyl(diph en yl)silyl]-2′-deoxy-5′-O-(m eth oxytrityl)th ym idin e
20
20
20
e
′-O-[tert-Butyl(diph en yl)silyl]-2′-deoxy-3′-O-(m eth oxytrityl)-
5
f
th ym idin e
f
1
,3-di-O-Tritylglycerol
(14)
4
20
16
16
0
0
0
–
(
14)
2
1
3
5
5
′-Deoxy-5′-O-tritylth ym idin e
(15)
(16)
(17)
(18)
(19)
2
20
20
20
16
20
20
20
0
0
0
g
-(3-Azido-2,3-dideoxy-5-O-trityl-β-D-erythro-pen tofuran osyl)th ym in e
′-O-[tert-Butyl(diph en yl)silyl]-2′-deoxyth ym idin e
′-O-[tert-Butyl(diph en yl)silyl]-2′-deoxyth ym idin e
′-O-[tert-Butyl(dim eth yl)silyl]-2′,3′-O-isopropyliden euridin e
10
0
–
0
10h
–
30h
2
12
16
16
h
h
(
19)
50
100
a
3
3
′-O-[tert-Butyl(dim eth yl)silyl]-2′-deoxy-5′-O-DMTr-th ym idin e
(20)
(21)
20
17
20/72
120
100 /50h
–
–
a
′-O-[tert-Butyl(diph en yl)silyl]-2′-deoxy-5′-O-DMTr-2-N-(2-m eth yl-
70
i
propan oyl)guan osin e
j
j
j
3
′,5′-O-(Tetraisopropyldisiloxan -1,3-diyl)uridin e
(22)
4
12
16
16
10
–
30
100
(
22)
k
k
4
-N-Ben zoyl-1-(2,3-di-O-tetrah ydropyran -2-yl-β-D-arabin ofuran osyl)-
(23)
(23)
2
20
16
16
0
5
10
90
k
cytosin e
a
Dim eth oxytrityl)oxy bon d cleavage; b in th e presen ce of AIBN; c in th e presen ce of
(
trieth ylam in e, sodium h ydrogen carbon ate, trieth ylam m on ium h ydrogen carbon ate,
d
e
4
-m eth oxypyridin e-1-oxide or 2,6-lutidin e; 0.025 M solution in water; (m eth oxytrityl)oxy
f
g
h
bon d cleavage; 0.05–0.1 M solution in aceton e–water 7 : 3; trityl cleavage; tert-butyl-
i
j
(
dim eth yl)silyloxy bon d cleavage;
furth er details in Experim en tal;
(tetraisopropyl-
k
disiloxan -1,3-diyl)oxy bon d cleavage (on ly at th e 5′-en d); (tetrah ydropyran -2-yl)oxy bon d
cleavage. Note: th e exten t of th e cleavage was determ in ed by RP HPLC or estim ated from
TLC; th e products were com pared with auth en tic sam ples.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Selective Cleavage of O-(Dimethoxytrityl) Protecting Group
507
in g in its im m ediate h ydrolysis. As it can be seen from th e Table I, th e m ore
polarized is th e C–O lin kage th e faster is its cleavage.
In our opin ion , th e gath ered kn owledge seem s to favor th e NaIO -m edi-
4
ated m ech an ism of th e O-DMTr lin kage h ydrolysis; a detailed study to sup-
port th e suggested course is un der way. Still, at th is poin t we h ave th e
reason to believe th at th e described cleavage reaction can be of practical
im portan ce in th e n ucleoside an d n ucleotide ch em istry an d in oth er areas
as an altern ative to classic acid h ydrolysis if a problem is en coun tered. Th e
fin din gs in cluded in Table I suggest th at th e use of NaIO4 en larges th e
n um ber of available selective deprotectin g reaction s.
EXPERIMENTAL
Th e protected n ucleosides 1–8, 10–23 an d th e ph osph on ate derivative 9 (see Table I) as well
as all products of th e cleavage (for com parative study) were prepared earlier in our labora-
tory. Sodium periodate (purum ) purch ased from Lach em a Brn o, Czech Republic was used in
all experim en ts.
Typical Preparative Procedures
In th e followin g preparative experim en ts we used an aqueous aceton e as th e solven t in stead
of aqueous eth an ol (or m eth an ol) because of m uch better solubility of startin g protected n u-
cleosides.
3
′-O-[tert-Butyl(diphenyl)silyl]-2′-deoxy-2-N-(2-methylpropanoyl)guanosine13. Powdered NaIO4
(
74 g, 346 m m ol) was added in five un equal portion s (32 g, 16 g, 2 × 10 g, 6 g; each after
1
5
6 h ) to th e vigorously stirred solution of 2′-deoxy-3′-O-[tert-butyl(diph en yl)silyl]-
′-O-(dim eth oxytrityl)-2-N-(2-m eth ylpropan oyl)guan osin e (21) (17.6 g, 20 m m ol) in 70%
1
3
aqueous aceton e (800 m l). Th e suspen sion was filtered, th e filtration cake wash ed with ace-
ton e, an d th e com bin ed filtrates were evaporated to dryn ess. Th e residue was dissolved in
aceton e, an d th e turbid solution filtered th rough Celite to rem ove traces of in organ ic salts.
Ch rom atograph y on silica gel in 5% eth an ol in ch loroform afforded 9.52 g (85%) of
3
′-O-[tert-butyl(diph en yl)silyl]-2-N-(2-m eth ylpropan oyl)guan osin e an d 1.7 g (10%) of th e
startin g m aterial.
′-O- Benzyl-2′-deoxythymidine14. 3′-O- Ben zyl-2′-deoxy-5′-O-(dim eth oxytrityl)th ym idin e14
332 m g, 0.5 m m ol) in 70% aqueous aceton e (10 m l) was treated for 48 h with NaIO4 (1.39 g,
.5 m m ol) added in two portion s (1.07 g an d 0.32 g with in a period of 16 h ). TLC in 10%
eth an ol–ch loroform revealed com plete detritylation . Th e workup as described above afforded
3
(
6
1
30 m g (78%) of 3′-O-ben zyl-2′-deoxyth ym idin e.
This work was supported by the Grant Agency of Ministry of Health (grant No. NL5441-3) and by
the Grant Agency of the Academy of Sciences of the Czech Republic (grant No. A4055902). The au-
thors are indebted to Dr M. Masojídková (this Institute) for measurements and interpretation of the
NMR spectra and to Dr J. Plešek of the Institute of Inorganic Chemistry (Řež near Prague) for valuable
discussion.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

5
08
Rejman et al.:
REFERENCES
1
. Ito Y., Kobayashi Y., Kawabata T., Takase M., Terashima S.: Tetrahedron 1989, 45, 5767.
2
. Manhas M. S., Hedge V. R., Wagle D. R., Bose A. K.: J. Chem. Soc., Perkin Trans. 1 1985,
2
045.
3
4
. Greenlee M. L., Di Nino F. P., Salzmann T.: Heterocycles 1989, 28, 195.
. Fetter J., Lampert K., Kajtár-Peredy M., Simig G.: J. Chem. Soc., Perkin Trans. 1 1988,
1
135.
5
6
7
8
9
. Muzart J.: Synthesis 1993, 11.
. Smith A. B., Richmond R. E.: J. Am. Chem. Soc. 1983, 105, 575.
. Torisawa Y., Shibasaki M., Ikegami S.: Chem. Pharm. Bull. 1983, 31, 2607.
. Batten R. J., Dixon A. J., Taylor R. J. K.: Synthesis 1980, 234.
. Mag M., Muth J., Jahn K., Peyman A., Kretzschmar G., Engels J. W., Uhlmann E.: Bioorg.
Med. Chem. 1997, 12, 2213.
1
0. Guthrie R. D. in: Methods in Carbohydrate Chemistry (R. L. Whistler and M. L. Wolfrom,
Eds), Vol. I, p. 432. Academic Press, New York 1962.
1
1
1. Rejman D.: Unpublished results.
2. Remy H.: Lehrbuch der anorganischen Chemie, Band I. Geest und Portig K.-G., Leipzig
1
957.
3. Perbost M., Hoshiko T., Morvan F., Swayze E., Griffey R. H., Sanghvi Y. S.: J. Org. Chem.
995, 60, 5150.
4. Griffin B. E., Todd A. R.: J. Chem. Soc. 1958, 1389.
1
1
1
Collect. Czech. Chem. Commun. (Vol. 67) (2002)