O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU): A new reagent for the cleavage of tetrahydropyranyl, silyl and 4,4'- dimethoxytrityl ethers

Article abstract of DOI:10.1055/s-1999-2724

A new reagent for the cleavage of tetrahydropyranyl, silyl and 4,4'- dimethoxytrityl ethers is described.

Full text of DOI:10.1055/s-1999-2724

LETTER
709
O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium Tetrafluoroborate
(TBTU): A New Reagent for the Cleavage of Tetrahydropyranyl, Silyl and
4,4’-Dimethoxytrityl Ethers
Kanda S. Ramasamy*, Devron Averett
Research Division, ICN Pharmaceuticals, Inc., 3300 Hyland Avenue, Costa Mesa, CA 92626, USA
Received 25 March 1999
The deprotection was found to be very selective for the
THP ether in the presence of TBDMS ether. As expected,
reaction of the substrate (entry 2) with TBTU cleaved the
THP group without affecting the benzyl protecting group.
Next, we examined the removal of THP group in a steri-
cally hindered environment. Treatment of substrate (entry
3) with TBTU gave the desired product in 93% yield.
Moreover, when THP is secondary and TBDMS ether is
primary (entry 4), the THP group was removed in 0.5 h se-
lectively. The same trend was noticed in the case of en-
tries 5 and 6. Most remarkably, the THP group was
removed in the presence of isopropylidene functionality
(entries 5 and 6). We have also observed the selective re-
moval of TBDMS ethers in the presence of tert-butyl-
diphenylsilyl (TBDPS) ethers. TBTU cleaved TBDMS
ether selectively in less than 2.5 h (entries 7 & 8). In con-
trast, the TBDPS group took more than 12 h to remove
(data not shown). These results indicate that TBTU can
readily differentiate not only THP over TBDMS but also
TBDMS over TBDPS derivatives.
Abstract: A new reagent for the cleavage of tetrahydropyranyl, si-
lyl and 4,4’-dimethoxytrityl ethers is described.
Key words: Cleavage, THP, DMT, TBTU
The utility of various protecting groups1 for the protection
of hydroxyl function has been enhanced by the availabili-
ty of diverse methods for their introduction and removal.
Among these, tetrahydropyranyl and tert-butyldimethyl-
silyl groups have been exploited widely in organic synthe-
sis and nucleoside synthetic chemistry. On the other hand,
the 4,4’-dimethoxytrityl (DMT) protecting group has
been used extensively for the protection of 5’-hydroxyl
groups of nucleoside units during oligonucleotide synthe-
sis. Moreover, the facile selective removal of tetrahydro-
pyranyl (THP) and tert-butyldimethylsilyl (TBDMS)
ethers render them attractive in complex carbohydrate
synthesis.
A host of reagents are known for the removal of THP2-13
and TBDMS10,14-24 protecting groups. In contrast to THP
and TBDMS ethers, DMT ethers are removed only with a
handful of reagents.25-28 We report here a new reagent, O-
(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tet-
rafluoroborate (TBTU) which efficiently removes THP,
TBDMS and DMT ethers.
During the cleavage of THP ethers, we noticed that TBTU
is an effective reagent for the deprotection of DMT ethers
too. Thus, when the substrate (Table 2; entry 1) was treat-
ed with 1 equivalent of TBTU, the DMT group was re-
moved to give 3’-O-tert-butyldimethylsilyl-2’-deoxy-b-
D-erythro-pentofuranosylthymine in 93% yield. To illus-
trate the utility of TBTU for the deprotection of DMT
group, we prepared different substrates having primary
and secondary DMT groups and studied their cleavage
(see Table 2). In all cases the deprotection reaction went
to completion quickly and the products were obtained in
high yields. From Table 2 it is clear that DMT groups are
cleaved selectively in the presence of TBDMS, isopropyl-
idene and benzyl ethers. Remarkably, even if the DMT
ether is secondary and the TBDMS is primary, we did get
selectivity (Table 2; entry 2). Furthermore, the DMT
group is more readily cleaved than isopropylidene groups
(entry 6). However, if the reaction time of entry 5 (Table
2) is extended beyond 0.25 h, the isopropylidene groups
are also cleaved.
TBTU is a coupling reagent that was developed by Knorr
et al29 in 1989. This reagent has been used in peptide cou-
pling reactions with minimum racemization. However,
when we used this reagent in a coupling reaction where
THP ether was present, we discovered that the THP group
was removed quantitatively. This led us to investigate the
possibility of utilizing TBTU as an effective reagent for
the cleavage of THP ethers. To verify our finding, we re-
acted the readily available 1-O-tetrahydropyranyl-2-(Na-
tert-butyloxycarbonyl)amino-3-O-(tert-butyldimethylsil-
yl)-propane-1,3-diol (entry 1) with 1 equivalent of TBTU
in CH3CN/water mixture. After 12 h of stirring at room
temperature, complete removal of THP ether was ob-
served in 90% yield. When the same reaction was tried at
75 °C, the THP group cleaved selectively in 0.25 h. How-
ever, heating of the same reaction mixture for 3 h removed
not only the THP group but also the TBDMS ether in 75%
yield. To test the versatility of the reagent, we synthesized
various THP ethers having TBDMS, Bn, Bz, Boc and iso-
propylidene protecting groups, and studied their cleavage
with TBTU. The results are summarized in Table 1.
All the deprotection reactions were found to proceed
smoothly in an acetonitrile-water mixture. In contrast,
when the reaction was examined in neat acetonitrile, the
reactions were sluggish, only producing 50% of the de-
sired cleavage product even under reflux for 16 h. Prelim-
inary investigation suggests that acetonitrile/water (7:3) is
the best choice for deprotection reactions with TBTU. In
Synlett 1999, No. 6, 709–712 ISSN 0936-5214 © Thieme Stuttgart · New York

710
K. S. Ramasamy, D. Averett
LETTER
Table 1 Deprotection of THP and TBDMS Ethers with TBTU
other solvents like THF, CH3OH and CH2Cl2, the depro- acid and boric acid.30 The production of HF and boric acid
tection does not work well.
may be responsible for the deprotection of THP, TBDMS
and DMT ethers. In addition, the cleavage of tert-
butyldimethylsilyl ethers can be rationalized by the
We believe that the mechanism of this selective hydroly-
sis involves the generation of H3O+in the reaction medi-
-
donation of fluoride ion from BF4 to silicon, directly pro-
-
um. BF4 that is present in TBTU acts as a source of
-
-
ducing silyl fluoride and OBF3 . The OBF3 species are
further hydrolyzed with water resulting in the formation
of the desired alcohol.
fluoride ion and Lewis acid (i.e., BF3). The BF3 on contact
with water decomposes further producing hydrofluoric
Synlett 1999, No. 6, 709–712 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Reagent for the Cleavage of Tetrahydropyranyl, Silyl and 4,4’-Dimethoxytrityl Ethers
711
Table 2 Deprotection of 4,4’-Dimethoxytrityl Ethers with TBTU
In conclusion, we have shown that TBTU is useful for the was washed with brine, dried and evaporated. The crude
deprotection of tetrahydropyranyl, silyl ethers, and 4,4’- material was crystallized in a suitable solvent or purified
dimethoxytrityl groups. This reagent allows the removal by flash chromatography to give the pure product. The
of THP ether in the presence of TBDMS group as well as product that obtained was identical with an authentic sam-
the selective cleavage of DMT functionality over TBDMS ple by tlc, 1H NMR and C, H, N analysis.
ether. This selectivity is of use in a variety of synthetic
schemes.
References and Notes
General Procedure for Deprotection reactions: To a
stirred solution of the substrate (0.15 mmol) in aceto-
nitrile/water (7:3; 10 ml) was added O-(benzotriazol-1-
yl)-N,N,N’,N’-tetramethyluronium
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
(2) Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J.
tetra-fluoroborate
J. Org. Chem. 1979, 44, 1438.
(TBTU; 50 mg, 0.15 mmol). The reaction mixture was
placed in a preheated oil bath at 75 °C and stirred at that
temperature. The reaction was monitored by tlc. After the
reaction was complete, the reaction mixture was immedi-
ately cooled, quenched with 5% sodium bicarbonate solu-
tion (5 ml) and evaporated to dryness. The residue was
extracted with suitable solvent, and the organic extract
(3) Johnson, R. D.; Marston, C. R.; Krieger, P. E.; Goe, G. L.
Synthesis 1988, 393.
(4) Otera, J.; Nozaki, H. Tetrahedron Lett. 1986, 27, 5743.
(5) Wagner, A.; Heitz, M.-P.; Mioskowski, C. J. Chem. Soc.,
Chem. Commun. 1989, 1619.
(6) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
1977, 42, 3772.
(7) Gigg, J.; Gigg, R. J. Chem. Soc. C, 1967, 431.
Synlett 1999, No. 6, 709–712 ISSN 0936-5214 © Thieme Stuttgart · New York

712
K. S. Ramasamy, D. Averett
LETTER
(8) Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100,
1942.
(9) Morizawa, Y.; Mori, I.; Hiyama, T.; Nozaki, H. Synthesis
1981, 899.
(10) DattaGupta, A.; Singh, R.; Singh, V. K. Synlett 1996, 69.
(11) Raina, S.; Singh, V. K. Synth. Commun. 1995, 25, 2395.
(12) Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439.
(13) Ogawa, Y.; Shibasaki, M. Tetrahedron Lett. 1984, 25, 663.
(14) Wetter, H.; Oertle, K. Tetrahedron Lett. 1985, 26, 5515.
(15) Metcalf, B. W.; Burkhart, J. P.; Jund, K. Tetrahedron Lett.
1980, 21, 35.
(22) Cormier, J. F. Tetrahedron Lett. 1991, 32, 187.
(23) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30,
19.
(24) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153;
Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918.
(25) Hosaka, H.; Suzuki, Y.; Sato, H.; Gug-Kim, S.; Takaku, H.
Nucleic Acids Res. 1991, 19, 2935.
(26) Caruthers, M. H. J. Chem. Ed. 1989, 66, 577 and references
cited therein.
(27) Ravikumar, V. T.; Krotz, A. H.; Cole, D. L. Tetrahedron Lett.
1995, 36, 6587.
(16) Corey, E. J.; Yi, K. Y. Tetrahedron Lett. 1992, 33, 2289.
(17) Pilcher, A. S.; Hill, D. K.; Shimsock, S. J.; Waltermire, R. E.;
DeShong, P. J. Org. Chem. 1992, 57, 2492.
(28) Leonard, N. J.; Neelima, Tetrahedron Lett. 1995, 36, 7833.
(29) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1929-1930.
(18) Dahlhoff, W. V.; Taba, K. M. Synthesis 1986, 561.
(19) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Perkin
Trans. 1, 1992, 2997.
(30) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267-
277.
(20) Corey, E. J.; Jones, G. B. J. Org. Chem. 1992, 57, 1028.
(21) Newton, R. F.; Reynolds, D. P. Tetrahedron Lett. 1979, 20,
3981.
Article Identifier:
1437-2096,E;1999,0,06,0709,0712,ftx,en;S06498ST.pdf
Synlett 1999, No. 6, 709–712 ISSN 0936-5214 © Thieme Stuttgart · New York