4-Methoxytrityl chloride

[14470-28-1]  · C20H17ClO  · (MW 308.81)

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

Alternate Name: MMTr-Cl, monomethoxytrityl chloride, p-ani-sylchlorodiphenylmethane.

Physical Data: mp 122-124  °C.

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

Form Supplied in: yellow to orange powder; widely available

Handling, Storage, and Precautions: use in a fume hood, with chemical safety goggles and rubber gloves. Do not breathe dust. Avoid prolonged or repeated exposure. Wash thoroughly after handling. 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 a search for protecting groups of alcohols for the use in the synthesis of polynucleotides, Khorana2 first prepared the 5-O-monomethoxytrityl (5-O-MMTr) ethers of uridine and adenosine derivatives.2a These ethers proved to be labile enough to be removed with acid treatment without causing depurination which had been a problem with standard trityl ethers.2c Since the introduction by Khorana almost 40 years go, the MMTr ether (and to a greater extent the dimethoxytrityl ether) has been a standard protecting group in oligonucleotide synthesis and continues to be used in standard protocols today.2 For instance, Khorana et. al. produced 5-O-mono-p-methoxytritylthymidine from thymidine using 4-methoxytritylchloride in pyridine in 82% yield (1).3 The MMTr group is removed in 1.5 h in 80% acetic acid at 27 °C. The MMTr group is removed 24 times faster under these conditions than a trityl ether, and eight times slower than the dimethoxytrityl group.2

As another example of selective protection, the primary hydroxyl group of 2,3-O-isopropylidene-b-D-ribofruanose was protected as its MMTr ether in high yield under similar conditions (2).4

The primary hydroxyl groups of glucitol, mannitol, and galactitol were selectively protected as their MMTr ethers in high yield for use in the synthesis of some conduritol derivatives (3).5

For the synthesis of some inhibitors of the D-fructose transporter GLUT5, the selective protection of the primary hydroxyl group of methyl a-D-fructofuranose was utilized (4).6

In the synthesis of some interesting 4-purinylpyrrolidine nucleosides, the selective protection of an N-Boc-D-prolinol derivative gave a key intermediate (5).7

During the synthesis of D-altritol nucleoside building blocks for oligonucleotide synthesis the D-altro-hexitol was tritylated in DMF with silver nitrate as a catalyst (6).8

Selective Protection of Hydroxyl Groups in Acyclic Systems

The primary hydroxyl of the diol in 7 was selectively protected over the secondary allylic alcohol in good yield.9

For the synthesis of an abasic linker for the use in some DNA-peptide chimeras, the MMTr ether of a glycine derivative was prepared (8).10

Protection of the Amino Group

The MMTr group has been used in a few cases as an amino protecting group. MMTr-protected amines react with acid chlorides and chloroformates above -40 °C in the presence of base, but only react with activated esters, carbonates, and alkylating agents under vigorous conditions. The amine group on the side chain of lysine was protected as its MMTr derivative by a two step procedure starting from Fmoc-lysine (9).11 Silylation of the amino acid derivative with TMS-Cl, followed by treatment of the transiently bis-silyalted compound with MMTr-Cl gave the MMTr amine in 91% yield. The MMTr-protected lysine was then incorporated into a doxorubicin analog.11

Protection of the primary amine of 3-aminopropanol allowed for the hydroxyl group to be coupled to a proline derivative in an EDC coupling (10).12

MMTr amines have been utilized in the synthesis of oligonucleotides. The amino unit of an adenosine derivative was protected as its MMTr amine and then incorporated into a short DNA strand to probe the structure of the topoisomerase I-DNA binary complex (11).13

The MMTr amine was used for the synthesis of the azirdine portion of the antitumor antibiotic azinomycin. A serine derivative was treated with MMTr chloride and triethylamine at -10 °C in methylene chloride, followed by tosylation and cyclization by heating in the presence of triethylamine (12).14 This MMTr-protected aziridine proved to be remarkably stable in a variety of conditions.

The MMTr group has been used successfully as a protecting on an imidazole nitrogen. The imidazole ring of 4-imidazoleacetic acid was protected as a MMTr ether under standard conditions (13).15 When compared to the trityl group and dimethoxytrityl group, the MMTr group proved to be the protecting group of choice for the imidazole during oligonucleotide synthesis using the phosphoramidite approach.

Related Reagents.

Trityl chloride; 4,4-dimethoxytrityl chloride.

1. Greene, T. W.; Wuts, P. G. M., Protecting Groups in Organic Synthesis, Wiley: New York, 1999, 105-106.
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 protecting groups in nucleotide synthesis, see: Beaucage, S. L.; Iyer, R. P., Tetrahedron 1992, 48, 2223.
3. Schaller, H.; Weimann, G.; Lerch, B.; Khorana, H.G., J. Am. Chem. Soc. 1963, 85, 3821.
4. Mandal, S. B.; Achari, B., Synth. Commun. 1993, 23, 1239.
5. Ackermann, L.; El Tom, D.; Furstner, A., Tetrahedron 2000, 56, 2195.
6. Tatibouet, A.; Yang, J.; Morin, C.; Holman, G. D., Bio. Med. Chem. Lett. 2000, 8, 1825.
7. Vince, R.; Peterson, M. L., J. Med. Chem. 1991, 34, 2787.
8. Allart, B.; Busson, R.; Rozenski, J.; Aerschot, A. V.; Herdewijn, P., Tetrahedron 1999, 55, 6527.
9. Hassan, H. A. M.; Abdel, M. M., Synth. Commun. 2000, 30, 201.
10. Greiner, B.; Breipohl, G.; Uhlmann, E., Helv. Chim. Acta 1999, 82, 2151.
11. Dubowchik, G. M.; Radia, S., Tetrahedron Lett. 1997, 38, 5257.
12. Dubowchik, G. M.; Ditta, J. L.; Herbst, J. J.; Bollini, S.; Vinitsky, A., Bio. Med. Chem. Lett. 2000, 10, 559.
13. Henningfeld, K. A.; Arslan, T.; Hecht, S. M., J. Am. Chem. Soc. 1996, 118, 11701.
14. Moran, E. J.; Tellew, J. E.; Zhao, Z.; Armstrong, R. W., J. Org. Chem. 1993, 58, 7848.
15. Polushin, N. N.; Chen, B.-C.; Anderson, L. W.; Cohen, J. S., J. Org. Chem. 1993, 58, 4606.

David J. Madar

Abbott Laboratories, Abbott Park, Illinois, USA

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