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Monday, June 10, 2013
Tristan H. Lambert
Columbia University

Functional Group Protection

Martin D. Burke at the University of Illinois at Urbana-Champaign reported (Nature Chem. 2012, 4, 996. ) that the amphotericin B derivative 1 could be site-selectively acylated at the C15, C4’, or C2’ hydroxyls by electronic tuning of the acylating agent (e.g. 2 leading to 3). Another impressive example of selective protection was disclosed (Nature Chem. 2012, 4, 789. ) by Andreas Herrmann at the Zernike Institute for Advanced Materials, who found that RNA aptamers such as 5 selectively bind to Neomycin 4, leaving only one of the amino groups exposed for acylation to selectively furnish, for example, 7.

A convenient new benzylating reagent called TriBOT (9) was introduced (Org. Lett. 2012, 14, 5026. ) by Munetaka Kunishima at Kanazawa University and shown to be useful for the benzylation of alcohols such as 8. Subhash P. Chavan at the National Chemical Laboratory in India reported (Tetrahedron Lett. 2012, 53, 4683. ) a very practical method for PMB protection of alcohols including 11 using simply p-anisyl alcohol and Amberlyst-15.

For PMB deprotection, Aurélien Blanc and Patrick Pale at the University of Strasbourg reported (J. Org. Chem. 2012, 77, 9227. ) that catalytic AgSbF6 and trimethoxybenzene (14) is a mild and effective method, even in the context of potentially sensitive substrates such as 13. The deprotection of tosylated amines is a classic problem in synthesis. Now Katsuhiko Tomooka at Kyushu University has developed (J. Am. Chem. Soc. 2012, 134, 19358. ) a unique strategy involving nucleophilic attack at nitrogen by phosphide anion, a process which readily lends itself to the conversion of substrates such as 16 to (for example) carbamate 17.

Propylphosphonic anhydride (T3P) was found (Tetrahedron Lett. 2012, 14, 5030. ) by John Kallikat Augustine and Pujari Vijaykumar at Syngene International Ltd. in India to catalyze the acetalization of aldehydes such as 18 under essentially neutral conditions. Interestingly, acetalization of aldehydes and ketones, including 20, under basic conditions using N-hydroxybenzenesulfonimide was reported (Synlett 2012, 23, 2773. ) by Alfred Hassner at Bar-Ilan University in Israel. In terms of acetal deprotection, Hiromichi Fujioka at Osaka University found (Heterocycles 2012, 86, 455. ) that the combination of TBSOTf and 2,2’-bipyridyl selectively cleaves methylene acetals in the presence of acetonides, as in the conversion of 22 to 23. The use of lithium tetramethylpiperidide (LTMP) to deprotect 1,3-dioxolanes such as 24 was reported (Tetrahedron Lett. 2012, 14, 6972. ) by Bo Liu at Sichuan University and the Shanghai Institute of Organic Chemistry.

An intriguing example of catalyst-controlled chemoselectivity in the acylation of diol 26 at the more sterically hindered secondary hydroxyl using DMAP-type catalyst 27 was reported (Chem. Commun. 2012, 48, 6981. ) by Takeo Kawabata at Kyoto University. Finally, the trimethoxyphenylthio protecting group was developed (Org. Lett. 2012, 14, 5468. ) by Fernando Albericio at the University of Barcelona as an easy to remove replacement for the t-butylthio group in solid phase peptide synthesis.

T. H. Lambert, Org. Chem. Highlights 2013, June 10.