4,4-Dimethoxytrityl chloride

[40615-36-9]  · C21H19ClO2  · (MW 338.83)

(reagent used for the protection of hydroxyl, amino, and sulfhydryl groups1)

Alternate Name: DMTr-Cl, 4,4-dimethoxytriphenylmethyl chloride or di-p-anisylphenylmethyl chloride.

Physical Data: mp 119-123 °C.

Solubility: readily soluble in most organic solvents, mainly used in methylene chloride, THF, and pyridine.

Form Supplied in: pink powder; widely available.

Handling, Storage, and Precautions: Use in a well-ventilated hood with chemical safety goggles and rubber gloves. Do not breathe dust. Avoid prolonged or repeated exposure. Wash thoroughly after handling. It is an irritant. Keep tightly closed and refrigerate. Incompatible with strong oxidizing agents as well as strong bases. Toxic decomposition product is hydrogen chloride gas.

Selective Protection of Alcohols in Carbohydrate Chemistry

In the search for protecting groups of alcohols for the use in the synthesis of polynucleotides, Khorana and co-workers2 first prepared the 5-O-dimethoxytrityl (DMTr) ethers of uridine and adenosine derivatives.2a These ethers proved to be labile enough to be removed with acid treatment without causing depurination that had been a problem with standard trityl ethers. Since the introduction by Khorana, the DMTr ether has been a standard protecting group in oligonucleotide synthesis for over 40 years and continues to be used in standard protocols today. For instance, Khorana and co-workers produced 5-O-di-p-anisyldiphenylmethyl-uridine from uridine using 4,4-dimethoxytrityl chloride in pyridine in 78% yield (1).2a The DMTr group is removed in 15 min in 80% acetic acid at 27 °C. By comparison, trityl ethers require 48 h for complete deprotection under these conditions, whereas the monomethoxytrityl (MMTr) group requires approximately 2 h for deprotection under these conditions.

The DMTr group has allowed for the large scale synthesis of oligonucleotides by the modified triester method. It is usually the first protecting group introduced to the base pair. The large scale preparation of 5-O-dimethoxytritylthymidine is described in a review of the modified triester method by Narang et al.3 Three other useful intermediates for phosphoramidite synthesis are the amidines derived from deoxyadenosine, deoxyguanosine, and deoxycytidine developed by Caruthers. To prepare for phosphoramidite coupling, the primary hydroxyl group of 2-N-(1-(dimethylamino)ethylidene)-2-deoxyguanosine was treated with DMTr-Cl in pyridine to afford an 81% yield of the DMTr ether (2).4

This protecting group has also been utilized with the corresponding ribose sugars. For instance, N-6-dimethylaminomethy-lene-adenosine has been treated with DMTr-Cl in a mixture of DMF and pyridine to afford the DMTr ether in high yield (3).5

More recently, it has been shown that the amine containing nucleosides can be tritylated in the presence of the free amine. The 5-O-selective dimethoxytritylation of 2-deoxyguanosine was conducted using three different methods—either by the use of DMTr-Cl in the presence of a mixture of imidazolium mesylate and diisopropylethylamine, a mixture of imidazole and diisopropylethylammonium mesylate or a 1:1:1 mixture of imidazole, diisopropylamine, and methanesulfonic acid in DMF at room temperature (4).6

The DMTr group is compatible with the disulfide linkage and has been used in the synthesis of a C-5-modified deoxyuridine for the preparation of an n-butyl-DNA disulfide conjugate. The requisite phosphoramidite was prepared by a two-step sequence of protection of the 5-alcohol as the dimethoxytrityl ether and functionalization of the 3-hydroxyl as the phosphoramidite (5).7

Thionucleic acids have been prepared for use in oligonucleotide synthesis, thus the dimethoxytrityl ethers containing sulfur heterocycles are readily prepared.8,9 The DMTr ether of S-(2-cyanoe-thyl)-4-thio-2-deoxyuridine was synthesized in high yield under standard conditions (6).9

An interesting recent report on process method for the capture and reuse of the 4,4-dimethoxytriphenymethyl group during manufacturing of oligonucleotides was disclosed.10

Simple sugar derivatives are easily monotritylated at the primary hydroxyl. For instance, allyl b-D-galactopyranoside was treated with DMTr-Cl in pyridine at room temperature to give the DMTr ether in 82% yield (7).11

Selective Protection of Cyclic Alcohols

During the synthesis of (-)-shikimate-3-phosphate the secondary alcohol at C-3 of methyl shikimate was selectively protected through the use of an O-stannylene acetal (8).12

Selective Protection of Primary Alcohols

In simple acyclic systems, primary hydroxyl groups can be selectively protected over secondary alcohols. For instance, (R)-3-allyloxy-propane-1,2-diol was converted to its DMTr ether in good yield under standard conditions (9).13

For the partial synthesis of the antifeedant (-)-specionin, the primary hydroxyl group (a (-)-catalpol derivative) was selectively protected as its DMTr ether (10).14

The DMTr group can be used to protect a primary hydroxyl group in the presence of a carboxylic acid. Thus, 10-hydroxy-decanoic acid was converted to its DMTr ether under standard conditions in 69% yield.15 Additionally, the primary hydroxyl of a glycine pyrimidinyl derivative was protected as its DMTr ether in the presence of a carboxylic acid using DMTr-Cl, triethylamine as base, and DMF and methylene chloride as solvent (11).16

Protection of Nitrogen-Containing Functional Groups

In nucleoside chemistry, protection of a primary amino group in a 5-amino-2,5-dideoxyadenosine derivative was used for the synthesis of oligonucleotides with modified primary structure (12).17

An imidazole nitrogen can be protected with a DMTr. 1H-imidazole-4-acetic acid ethyl ester was treated with DMTr-Cl and triethylamine in methylene chloride to give the DMTr derivative in good yield (13).18

One of the urea nitrogens of a biotin derivative has been converted into its DMTr derivative to allow for incorporation of the biotin moiety into oligonucleotides via the phosphoramidite method.19

Protection of Sulfhydryl Groups

A primary sulfhydryl group of a uridine derivative was protected as its DMTr thioether, by treatment with DMTr-Cl and triethylamine and then selective removal of the DMTr group from oxygen was carried out with 80% aqueous acetic acid (rt, 10 min) (14).20 The DMTr group can selectively be cleaved from the thiol by treatment with silver nitrate.

Related Reagents.

4-Methoxytrityl chloride; trityl chloride.

1. Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis; Wiley: New York, 1999; p 105.
2. (a) Smith M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G., J. Am. Chem. Soc. 1962, 84, 430. (b) Khorana, H. G., Pure Appl. Chem. 1968, 17, 349. (c) For a review of the use of various trityl groups in nucleotide synthesis, see Beaucage, S. L.; Iyer, R. P., Tetrahedron 1992, 48, 2223.
3. Narang, S. A.; Brousseau, R.; Hsiung, H. M.; Michniewicz, J. J., In Methods in Enzymology; Dennis, M. G.; Dennis, E. A., Eds.; Academic: New York, 1980; Vol. 62, p. 610.
4. (a) Mcbride, L. J.; Kierzek, R.; Beaucage, S.; Caruthers, M. H., J. Am. Chem. Soc. 1986, 108, 2040. (b) Jones, R. A.; Kung, P. P., Tetrahedron Lett. 1992, 33, 5869.
5. Xi, C.; Zhang, J. D.; Zhang, L. H., Synthesis 1989, 5, 383.
6. Kataoka, M.; Hayakawa, Y., J. Org. Chem. 1999, 64, 6087.
7. Goodwin, J. T.; Glick, G. D., Tetrahedron Lett. 1993, 34, 5549.
8. (a) Clivio, P.; Fourrey, J. L., J. Org. Chem. 1994, 59, 7273. (b) Clivio, P.; Fourrey, J. L.; Gasche, J.; Favre, A., Tetrahedron Lett. 1992, 33, 69.
9. Coleman, R. S.; Kesicki, E. A., J. Am. Chem. Soc. 1994, 116, 11636.
10. Guo, Z.; Pfundheller, H. M.; Sanghvi, Y. S., Org. Proc. Res. & Develop. 1998, 2, 415.
11. Nakahara, Y.; Ogawa, T., Carbohydr. Res. 1989, 194, 95.
12. Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisnes, P.; Zedde, C., J. Org. Chem. 1992, 57, 5798.
13. Toepfer, A.; Kretzchmar, G.; Bartnik, E., Tetrahedron Lett. 1995, 36, 9161.
14. Van der Eycken, E.; Janssens, A.; Vandewale, M., Tetrahedron Lett. 1987, 28, 3519.
15. Truffert, J. C.; Asseline, U.; Brack, A.; Thuong, N. T., Tetrahedron Lett. 1996, 52, 3005.
16. Breipohl, G.; Will, D. W.; Peyman, A.; Uhlmann, E., Tetrahedron 1997, 53, 14671.
17. Hennningeld, K. A.; Arslan, T.; Hecht, S. M., J. Am. Chem. Soc. 1996, 118, 11701.
18. Bashkin, J. K.; Gard, J. K.; Modak, A. S., J. Org. Chem. 1990, 55, 5125.
19. Pon, R. T., Tetrahedron Lett. 1991, 32, 1715.
20. Huang, Z.; Benner, S. A., Synlett 1993, 1, 83.

David J. Madar

Abbott Laboratories, Abbott Park, Illinois

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.