Mild and adaptable silver triflate-assisted method for trityl protection of alcohols in solution with solid-phase loading applications

Article abstract of DOI:10.1021/ol0614018

Trityl ethers were prepared in solution in a matter of minutes by treating trityl chloride with silver triflate in the presence of alcohols. Yields were comparable or better than known literature methods. The method was compatible with the base-labile Fmo

Full text of DOI:10.1021/ol0614018

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3915-3918
Mild and Adaptable Silver
Triflate-Assisted Method for Trityl
Protection of Alcohols in Solution with
Solid-Phase Loading Applications
Joseph T. Lundquist, IV,* Andrew D. Satterfield, and Jeffrey C. Pelletier
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road,
CollegeVille, PennsylVania 19426
lundquj@wyeth.com
Received June 8, 2006
ABSTRACT
Trityl ethers were prepared in solution in a matter of minutes by treating trityl chloride with silver triflate in the presence of alcohols. Yields
were comparable or better than known literature methods. The method was compatible with the base-labile Fmoc protecting group of amino
alcohols and adapted for trityl protection of halo-containing alcohols. These base- and nucleophile-sensitive intermediates were anchored on
trityl resin and further functionalized, displaying the utility of this approach for future combinatorial applications.
The masking of hydroxyl functionalities early in a synthetic
route is often necessary to successfully perform subsequent
multistep synthetic manipulations.1 The ability to easily
install the desired protecting group, followed by facile
removal at the end of synthesis, is paramount in the design
of any synthesis. The conditions to peform these operations
should ideally be compatible with other functional groups
in the molecule and display orthogonal reactivity patterns
with other protective groups.
The triphenylmethyl (trityl) functionality represents an
attractive alcohol protecting group since it is readily removed
under mildly acidic conditions2 (1% TFA in dichloro-
methane) to regenerate the alcohol. Furthermore, the ad-
ditional chromophore in the trityl group, along with increased
lipophilicity can aid in intermediate purification. The trityl
protecting group can be employed orthogonally with blocking
groups that can be removed with stronger acidic conditions
or basic conditions.2 Given these advantages, the formation
of trityl ethers is not always straightforward, with some
procedures requiring extensive preparation of reagents.3
Additionally, some methods require harsh or basic reaction
conditions and/or lengthy reaction times.4
Our initial focus was aimed at the development of a rapid
and mild solution-phase protocol for trityl ether formation.
This milder method, facilitated by utilizing silver triflate
(AgOTf), was compared with conventional methods with use
of simple alcohol substrates and alcohols which are poten-
tially unstable to the conventional conditions. The results
were used to tailor solid-phase applications. The advantages
of this approach on the solid phase, with base-labile
protecting groups or with reactive electrophilic functional-
ities, are highlighted with two applications detailed in this
paper.
(1) For a review of hydroxyl protection and deprotection, see: (a)
Jarowicki, K.; Kocienski, P. Contemp. Org. Chem. 1996, 3, 397-431. (b)
Greene, T. W.; Wutts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; Wiley and Sons: New York, 1999. (c) Robertson, J.; Stafford, P.
M. Selective Hydroxyl Protection and Deprotection. In Carbohydrates;
Osborn, H. M. I., Ed.; Elsevier Science: Oxford, England, 2003; pp 9-68.
(2) Rothman, D. M.; Vazquez, M. E.; Vogel, E. M.; Imperiali, B. J.
Org. Chem. 2003, 68, 6795-6798.
(3) (a) Hanessian, S.; Staub, A. P. A. Tetrahedron Lett. 1973, 14, 3555-
3558. (b) Murata, S.; Noyori, R. Tetrahedron Lett. 1981, 22, 2107-2108.
(4) (a) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20,
95-98. (b) Hernandez, O.; Chaudhary, S. K.; Cox, R. H.; Porter, J.
Tetrahedron Lett. 1981, 22, 1491-1494. (c) Colin-Messager, S.; Girard,
J.-P.; Rossi, J.-C. Tetrahedron Lett. 1992, 33, 2689-2692.
10.1021/ol0614018 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/12/2006

Two established methods for trityl protection of alcohols
are displayed in Scheme 1.4a Method 1 uses pyridine as the
Scheme 2. Silver Triflate-Assisted Trityl Protection of
Alcoholsa
Scheme 1. Established Methods for Trityl Ether Formation
a Procedure: trityl chloride (1.0-1.1 mmol) was added to alcohol
(R-OH) (1 mmol), AgOTf (1.1-1.2 mmol), and 2,6-di-tert-
butylpyridine (1.5 mmol) in CH2Cl2 (2 mL) at 0 °C. After 1 h the
reaction was filtered and purified (see the Supporting Information
for details).
solvent, with heating. Method 2, also performed under basic
conditions, requires a longer reaction time, but occurs at
ambient temperature. Formation of the reactive pyridinium
intermediates is the rate determining step in the formation
of trityl ethers with these methods. We realized that the basic
conditions used in these methods may preclude the use of
alcohols containing base-labile or electrophilic functionalities
and sought to develop a milder protocol.
The rationale for an alternative method of trityl protection
was derived from a general method for alcohol alkylation.
The literature method5 for etherification of alcohols with
primary alkyl halides in the presence of AgOTf is displayed
in eq 1. Reported yields were between 39% and 96% for
primary halides. In addition, the reaction was also applied
to the secondary halide, isopropyl iodide, for which a yield
of 25% was reported.
taken after 5 min, indicating rapid ether formation. The
methods for trityl ether formation detailed in Schemes 1 and
2 were employed with a variety of alcohols and are compared
in Table 1.
Yields of trityl ethers 1-4, which were prepared with
simple alcohols and AgOTf (Method 3), were generally
comparable to or better than the literature procedures
(Methods 1 and 2) with the advantage of a shorter reaction
time and milder conditions. For the secondary alcohol used
to prepare 1, 2 equiv of alcohol provided a slightly better
yield with Method 3. Attempts with several tertiary alcohols
failed to provide useful results for all three methods probably
due to steric hindrance.
For the halo-containing ethers, 5-9, Method 3 was
modified in some cases. With more reactive halides (for
ethers 5, 7, 8,8 and 99) the halo alcohol was added 5 min
after trityl cation formation, leading to better yields. This
improvement can be attributed to preventing competition for
AgOTf by the halide on the alcohol substrate, since AgOTf
is consumed rapidly by trityl chloride. For solubility purposes
the yield for 8 was improved significantly by using 1-methyl-
2-pyrrolidinone (NMP) as the solvent. Addition of the halo
alcohol 5 min post cation formation for ethers 5 and 8
improved the yield from the 20% range to the 60% range;
similarly the yield for 7 was improved from 0% to 67%.
Overall for 5-9, Method 3 was superior to Methods 1 and
2, and provided products in 63% to 73% yield.
The base-labile 9-fluorenylmethoxycarbonyl (Fmoc) amine
protecting group is widely used in orthogonal solid-phase
peptide syntheses. This group is readily cleaved by a variety
of inorganic and organic bases.10 To determine if an
orthogonal trityl/Fmoc strategy could be suitably developed,
trityl protection of two Fmoc-protected amino alcohols (for
ethers 10 and 11) was attempted with use of the basic
It was envisioned that treatment of trityl chloride with
AgOTf could easily generate the more stable trityl cation in
the presence of alcohols to facilitate the SN1 reaction to form
the desired trityl ethers under milder conditions.6,7 When trityl
chloride and an alcohol were treated with AgOTf (Scheme
2) a bright red to yellow color was initially observed, which
indicated formation of the trityl cation. Usually, the color
disappeared within 5 min indicating that the cation had been
quenched and formation of the trityl ether was complete.
When the reactions were run for 1 h, no difference in the
crude LC/MS traces were observed when compared to those
(5) Burk, R. M.; Gac, T. S.; Roof, M. B. Tetrahedron Lett. 1994, 35,
8111-8112.
(6) 4,4′-Dimethoxytrityl triflate (DMTOTf) has been used in excess with
pyridine to protect hydroxyl groups of monomers with the DMT functional-
ity in the preparation of oligonucleotide analogues. For examples, see: (a)
Egger, A.; Leumann, C. J. Synlett 1999, S1, 913-916. (b) Ahn, D.-R.; Egger,
A.; Lehmann, C.; Pitsch, S.; Leumann, C. J. Chem. Eur. J. 2002, 8, 5312-
5322. (c) Renneberg, D.; Leumann, C. J. J. Am. Chem. Soc. 2002, 124,
5993-6002.
(7) Trityl triflate (TrOTf) has been used as a hydride ion acceptor to
generate the 1-adamantyl cation intermediate leading to 1-adamantyl
derivatives: Bochkov, A. F.; Kalganov, B. E. IzV. Akad. Nauk SSSR, Ser.
Khim. 1987, 11, 2560-2563.
(8) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.;
Waltermire, R. E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. J. Org. Chem.
1996, 61, 444-450.
(9) (a) Stumpp, M. C.; Schmidt, R. R. Tetrahedron 1986, 42, 5941-
5948. (b) Krakowiak, K. E.; Bradshaw, J. S.; Huszthy, P. Tetrahedron Lett.
1994, 35, 2853-2856.
(10) For a review of the use of Fmoc protection in peptide synthesis,
see: Atherton, E.; Sheppard, R. C. The Fluorenylmethoxycarbonyl Amino
Protecting Group. In The Peptides; Udenfriend, S., Meienhofer, J., Eds.;
Academic Press: Orlando, FL, 1987; Vol. 9, pp 1-38.
3916
Org. Lett., Vol. 8, No. 18, 2006

ambient temperature for 2 to 5 days.12 The favorable results
obtained in solution prompted adaptation of our milder
AgOTf method to the solid phase (Scheme 3). With use of
Table 1. Comparison of Trityl Ether Formation Methods with
Selected Alcohols
Scheme 3. Silver Triflate-Assisted Trityl Resin Loading
commercially available trityl chloride resin, ether formation
can be driven quickly to completion by using excess alcohol
equivalents to provide 10S and 11S. Upon completion, excess
alcohol and reagents were easily removed by washing the
resin. Additionally, 2-bromoethanol was successfully loaded
onto the trityl resin, providing 9S by addition of the alcohol
after the trityl cation was preformed.
The preparation of amino alcohols from halo-containing
alcohols can prove difficult with solution-phase methodology.
Some concerns include over-alkylation of the amine and the
need for a protection of the hydroxyl functionality with a
group that can be easily removed and separated from the
polar crude product. The following solid-phase approach on
trityl resin addresses both issues (Scheme 4). The alkylating
agent 9S is separated on the resin by pseudoinfinite dilution,
a Method 1 as detailed in Scheme 1. b Method 2 as detailed in Scheme
1. c Method 3 as detailed in Scheme 2. d 2 equiv of alcohol used. e Alcohol
added 5 min after reaction of AgOTf with TrCl. f NMP used as a solvent
instead of CH2Cl2. N.D. ) not determined.
Scheme 4. Solid-Phase Synthesis of a Secondary Amino
Alcohol
conditions of the standard methods and compared to the
milder conditions of Method 3. For ether 10, the yields were
slightly better with Method 3 when compared with Method
1. For ether 11 the improvement in yield for Method 3 (60%,
using NMP as solvent for solubility of alcohol) was even
more dramatic in comparison to Method 1 (1.6%). Overall,
the good yields for Method 3 led to the realization that a
solid-phase orthogonal trityl resin/Fmoc protection strategy
could potentially be developed.
Common methods for solid-phase trityl ether formation
with trityl chloride resin use either excess pyridine in
combination with heating11 or pyridine as the solvent at
(11) For a review of the use of trityl resins, see: NoVabiochem Catalog,
Reagents for Peptide and High-Throughput Synthesis; Novabiochem: San
Diego, CA, 2004; pp 2.16-2.20.
Org. Lett., Vol. 8, No. 18, 2006
3917

preventing excessive alkylation of the secondary amine
product 12S, which forms upon treatment with phenethyl-
amine. In this case, after washing away excess amine, the
crude product 1213 was easily isolated after cleavage from
the trityl resin in good yield and purity.
for the replacement of a C-terminal carboxyl group with an
alcohol can be explored by incorporating this modification
at the beginning of the synthesis.
In conclusion, a mild method for trityl ether formation
(Method 3) was developed in solution and gave equal or
better yields than standard trityl protection methods for
alcohols (Methods 1 and 2). The rate for the SN1 reaction
was improved by using AgOTf to generate the stable trityl
cation, decreasing the reaction time to minutes rather than
hours. The method was adapted for use with reactive halo
alcohols by preforming the trityl cation and was also
compatible with the base-labile Fmoc protecting group. The
use of AgOTf was successful when dichloromethane or NMP
was employed as the solvent to accommodate alcohols with
different solubility properties. In addition, this method can
easily be applied in any chemistry lab, since all of the
necessary reagents are available from commercial suppliers.
The method was also adapted to anchor alcohols on solid
support by forming the trityl ether linkage. The scope of this
approach was expanded by taking advantage of a solid-phase
strategy to prepare the amino alcohol (12) and tripeptides
containing C-terminal alcohol functionalities (13 and 14).
These relatively simple examples display the ease of this
approach and offer promise for future parallel and combi-
natorial applications.
Another useful solid-phase application is displayed in
Scheme 5. With 10S and 11S as starting points, two
Scheme 5. Synthesis of Tripeptides Containing a C-Terminal
Alcohol Functionality
tripeptides containing C-terminal alcohols (13 and 14) were
synthesized by using a standard Fmoc peptide solid-phase
synthesis protocol.14 Reactions were monitored with the
Kaiser test15 and the products were isolated in respectable
yields following resin cleavage. These examples display the
ease with which the structure-activity relationship (SAR)
Acknowledgment. A.D.S. thanks the Wyeth Research
Summer Intern Program for support. We thank the Chemical
Technologies group at Wyeth for analysis of compounds.
Supporting Information Available: Full experimental
details for 1-11, as well as experimental details for solid-
phase trityl resin loading and preparation of 12-14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Fre´chet, J. M. J.; Haque, K. E. Tetrahedron Lett. 1975, 16, 3055-
3056. (b) Chen, C.; Ahlberg Randall, L. A.; Miller, R. B.; Jones, A. D.;
Kurth, M. J. J. Am. Chem. Soc. 1994, 116, 2661-2662.
(13) Chan, D. C. M.; Laughton, C. A.; Queener, S. F.; Stevens, M. F.
G. J. Med. Chem. 2001, 44, 2555-2564.
(14) (a) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37, 3404-
3409. (b) Wang, S. S. J. Am. Chem. Soc. 1973, 95, 1328-1333. (c)
Meienhofer, J.; Waki, M.; Heimer, E. P.; Lambros, T. J.; Makkofske, R.;
Chang, C. C. Int. J. Peptide Protein Res. 1979, 13, 35-42.
OL0614018
(15) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 595-598.
3918
Org. Lett., Vol. 8, No. 18, 2006