Organic Chemistry Portal
Organic Chemistry Highlights

Monday, June 12, 2006
Douglass Taber
University of Delaware

Protection of N- and O-Functional Groups

The DDQ cleavage of a benzyl ether is a classic transformation, yet it has not always been reliable. Kazunobu Toshima of Keio University has recently (Tetrahedron Lett. 2005, 46, 7307. DOI: 10.1016/j.tetlet.2005.08.132) found that the efficiency of the deprotection, e.g. conversion of 1 to 2, is substantially improved if the reaction is exposed to long wavelength UV. With acid sensitive substrates, yields are improved by the inclusion of insoluble BaCO3. The previously observed variability in this deprotection may be due to differences in ambient laboratory lighting.

One way to avoid the difficulties of benzyl deprotection has been to use the more easily oxidized p-methoxybenzyl (PMB) group. Gregory B. Dudley of Florida State University has developed (Tetrahedron Lett. 2005, 46, 3283. DOI: 10.1016/j.tetlet.2005.03.110) a group that is orthogonal to p-methoxy benzyl, based on a p-siletanyl group (PSB). Mild conditions convert 3 to the p-hydroxybenzyl ether, which is removed very quickly with FeCl3. In competition experiments, deprotection of PMB could be carried out in the presence of PSB, and the deprotection of PSB could be carried out in the presence of PMB.

Protection of 1,2- and 1,3-diols is also important. Chien-Tien Chen of National Taiwan Normal University and Chung-Cheng Lin of the Academia Sinica, Taipei have found (Org. Lett. 2005, 7, 3343. DOI: 10.1021/ol051178z) that arylidene protection can be effected by direct condensation of an aromatic aldehyde with the diol (e.g. 5) in the presence of catalytic vanadyl triflate. This observation will make arylidene protection, especially with less common aryl groups, more readily available.

Fernando Sartillo-Piscil of the Universidad Autónoma de Puebla, Mexico, has uncovered (J. Org. Chem. 2005, 70, 7107. DOI: 10.1021/jo050753+) a new protocol for the selective deprotection of 1,2-diols. Exposure of 7 to allyltrimethyl silane in the presence of BF3.Et2O yields the monoadduct 8. After phosphorylation, the alcohol protecting group is readily removed by exposure to BF3.Et2O, to deliver 9.

Ester hydrolysis can present difficulties if there are sensitive functional groups elsewhere in the molecule. Uwe T. Bornscheuer of Greifswald University and George Kokotos of the University of Athens have found (J. Org. Chem. 2005, 70, 3737, DOI: 10.1021/jo050114z; 8730, DOI: 10.1021/jo051004v.) that some readily-available enzymes can remove t-butyl, methyl and benzyl esters, in the presence of amine protecting groups such as Boc, Z, and Fmoc.

There is a widespread perception that the N-tosyl group is difficult to remove. In fact, it is often easily removed reductively. In the course of a synthesis of the Dendrobatid alkaloid 205B (14), Amos B. Smith III of the University of Pennsylvania demonstrated (Org. Lett. 2005, 7, 3247. DOI: 10.1021/ol0510264) that the N-tosyl group could be reductively removed under conditions that did not affect two other organosulfur functional groups, mesylate and dithiane.

The 4-methoxyphenyl N-protecting group has often resisted efficient oxidative removal (J. Org. Chem. 2005, 70, 10592. DOI: 10.1021/jo051867o). Marc L. Snapper and Amir H. Hoveyda of Boston College have now shown (Org. Lett. 2005, 7, 2711. DOI: 10.1021/ol050910r) that the alternative 2-methoxyphenyl N-protecting group can be removed cleanly by exposure to iodosobenzene diacetate.

D. F. Taber, Org. Chem. Highlights 2006, June 12.