Chem. Rev. 2009, 109, 2455–2504 2455 Amino Acid-Protecting Groups Albert Isidro-Llobet,† Mercedes A´ lvarez,*,†,‡,§ and Fernando Albericio*,†,‡,| Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain; CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain; Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain; and Department of Organic Chemistry, University of Barcelona, Martı´ i Franque´s 1, 08028 Barcelona, Spain Received April 28, 2008 Contents 6.3.1. Protecting Groups Removed by Acid 2476 (Table 14) 1. Introduction 2456 6.3.2. Other Protecting Groups (Table 15) 2477 2. R-Amino 2457 7. Asparagine (Asn) and Glutamine (Gln) 2478 2.1. General 2457 7.1. General 2478 2.2. Introduction of the Protecting Groups 2457 7.2. Introduction of the Protecting Groups 2479 2.3. Removal 2457 7.3. Removal 2479 2.3.1. Protecting Groups Removed by Acid 2457 7.3.1. Protecting Groups Removed by Acid 2479 (Table 1) (Table 16) 2.3.2. Protecting Groups Removed by Base 2459 8. Arginine (Arg) 2480 (Table 2) 8.1. General 2480 2.3.3. Other Protecting Groups (Table 3) 2460 8.2. Introduction of the Protecting Groups 2480 3. Lysine (Lys), Ornithine (Orn), Diaminopropionic 2463 8.3. Removal 2480 Acid (Dap), and Diaminobutyric Acid (Dab) 8.3.1. Protecting Groups Removed by Acid 2480 3.1. General 2463 (Table 17) 3.2. Introduction of the Protecting Groups 2466 8.3.2. Protecting Groups Removed by Base 2481 3.3. Removal 2467 (Table 18) 3.3.1. Protecting Groups Removed by Acid 2467 8.3.3. Other Protecting Groups (Table 19) 2481 (Table 5) 9. Cysteine (Cys) 2481 3.3.2. Protecting Groups Removed by Base 2467 9.1. General 2481 (Table 6) 9.2. Introduction of the Protecting Groups 2481 3.3.3. Other Protecting Groups (Table 7) 2467 9.3. Removal 2483 4. R-Carboxylic Acid 2467 9.3.1. Protecting Groups Removed by Acid 2484 4.1. General 2467 (Table 20) 4.2. Introduction of the Protecting Groups 2468 9.3.2. Protecting Groups Removed by Base 2484 4.3. Removal 2468 (Table 21) 4.3.1. Protecting Groups Removed by Acid 2468 9.3.3. Other Protecting Groups (Table 22) 2484 (Table 8) 10. Methionine (Met) 2488 4.3.2. Protecting Groups Removed by Base 2469 10.1. General 2488 (Table 9) 10.2. Introduction of the Protecting Groups 2488 4.3.3. Other Protecting Groups (Table 10) 2470 10.3. Removal: Sulfoxide Reduction 2488 5. Aspartic (Asp) and Glutamic (Glu) Acids 2473 11. Histidine (His) 2489 Downloaded via UNIV OF GDANSK on November 19, 2019 at 12:26:11 (UTC). 5.1. General 2473 11.1. General 2489 5.2. Introduction of the Protecting Groups 2473 11.2. Introduction of the Protecting Groups 2489 5.3. Removal 2473 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 11.3. Removal 2489 5.3.1. Protecting Groups Removed by Acid 2473 (Table 11) 11.3.1. Protecting Groups Removed by Acid 2489 (Table 23) 5.3.2. Protecting Groups Removed by Base 2474 (Table 12) 11.3.2. Protecting Group Removed by Base 2491 (Table 24) 5.3.3. Other Protecting Groups (Table 13) 2474 11.3.3. Other Protecting Groups (Table 25) 2491 6. Amide Backbone 2476 12. Serine (Ser), Threonine (Thr), and Hydroxyproline 2492 6.1. General 2476 (Hyp) 6.2. Introduction of the Protecting Groups 2476 12.1. General 2492 6.3. Removal 2476 12.2. Introduction of the Protecting Groups 2493 12.3. Removal 2493 * To whom correspondence should be addressed. Fax: 34 93 403 71 26. 12.3.1. Protecting Groups Removed by Acid 2493 E-mail: [email protected]; [email protected]; † Institute for Research in Biomedicine. (Table 26) ‡ CIBER-BBN. 12.3.2. Other Protecting Groups (Table 27) 2493 § Laboratory of Organic Chemistry, Faculty of Pharmacy, University of 13. Tyrosine (Tyr) 2493 Barcelona. | Department of Organic Chemistry, University of Barcelona. 13.1. General 2493 10.1021/cr800323s CCC: $71.50 2009 American Chemical Society Published on Web 04/13/2009 2456 Chemical Reviews, 2009, Vol. 109, No. 6 Isidro-Llobet et al. 13.2. Introduction of the Protecting Groups 2495 13.3. Removal 2495 13.3.1. Protecting Groups Removed by Acid 2495 (Table 28) 13.3.2. Other Protecting Groups (Table 29) 2495 14. Tryptophan (Trp) 2497 14.1. General 2497 14.2. Introduction of the Protecting Groups 2497 14.3. Removal 2497 14.3.1. Protecting Groups Removed by Acid 2497 (Table 30) 14.3.2. Protecting Groups Removed by Base 2497 14.3.3. Other Protecting Groups (Table 31) 2497 15. Abbreviations 2497 16. Acknowledgments 2498 Albert Isidro-Llobet was born in El Prat de Llobregat (Spain) in 1981. He studied Chemistry at the University of Barcelona (Spain) and obtained 17. References 2498 his Ph.D. in 2008 at the Barcelona Science Park (University of Barcelona) under the supervision of Professors Fernando Albericio and Mercedes 1. Introduction A´lvarez. His Ph.D. work involved the development of new protecting groups for the synthesis of complex peptides. In October 2008, he moved to Dr. Synthetic organic chemistry is based on the concourse of David R. Spring’s group at the University of Cambridge (U.K.) where he reagents and catalysts to achieve the clean formation of new is currently a postdoctoral fellow working in Diversity Oriented Synthesis bonds, and appropriate protecting groups are required to of small molecules as antibiotics. His research interests include the prevent the formation of undesired bonds and side reactions.1,2 development of new methodologies for solid- and solution-phase peptide Thus, a promising synthetic strategy can be jeopardized if synthesis and the research for new bioactive compounds. the corresponding protecting groups are not properly chosen. Emil Fischer was possibly the first to recognize the need to temporally mask a functional group to allow regioselective bond formation in the synthesis of carbohydrates.3 However, the first “modern” protecting group was the benzylozycar- bonyl (Z) developed by Bergmann and Zervas.4 Z fits with Mercedes A´ lvarez received her Ph.D. in Chemistry from the University of Barcelona under the supervision of Prof. Ricardo Granados. She has a permanent position in the University of Barcelona as Associate Professor in the Faculty of Pharmacy. In 1990, she spent a sabbatical year in The Manchester University working with Prof. John A. Joule. After that period, she started a long collaboration between Manchester and Barcelona Universities for developing new procedures for the synthesis of marine Professor Fernando Albericio was born in Barcelona, Spain, in 1953. He natural products with polyheterocyclic structure and biological activities. received his Ph.D. in Chemistry at the University of Barcelona, in 1981. In 2002, she was invited to joint with the group led by Prof. Fernando Following postdoctoral work at Tufts University (Boston), at the Universite´ Albericio and to move her research group to the Science Parc of d’Aix-Marseille (France), and at the University of Minnesota (1981-1984), Barcelona. Currently, she holds a double appointment as Professor at he returned to Barcelona as Associate Professor. During the 1992- 1994 the University of Barcelona and Researcher at the Barcelona Biomedical period, he was Director of Peptide Research with Milligen/Biosearch in Research Institute in the Barcelona Science Park. Her major research Boston. He rejoined the University of Barcelona, where he was promoted interests cover synthesis of natural products, heterocyclic chemistry, to professor in 1995. Nowadays, he is holding various appointments: combinatorial chemistry, and solid-phase methodology, as well as synthesis General Director of the Barcelona Science Park, Professor at the University of small molecules with therapeutic activities. of Barcelona, and Group Leader at the Institute for Research in Biomedi- cine. Professor Albericio’s major research interests cover practically all the main characteristics associated with a protecting group: aspects of peptide synthesis and combinatorial chemistry methodologies, as well as synthesis of peptides and small molecules with therapeutic (i) it is easily introduced into the functional group; (ii) it is activities. He has published over 500 papers, several review articles, and stable to a broad range of reaction conditions; and (iii) it is 22 patents, and he is coauthor of 3 books. He is editor of several scientific safely removed at the end of the synthetic process or when journals and acts in the editorial board of several others. In addition, the functional group requires manipulation. Another corner- professor Albericio is deeply involved in the development of the third stone in this field was when Barany et al.5,6 described the mission of the University, the transference of knowledge and technology orthogonality to society. He has founded several biotech companies and is acting in concept of , in the sense that the two or more the board of directors of several foundations and companies. Furthermore, protecting groups belong to independent classes and are he is consultant for several companies in the chemical and pharmaceutical removed by distinct mechanisms. The groups can be re- areas. moved,therefore,in any order and in the presence of the rest. Amino Acid-Protecting Groups Chemical Reviews, 2009, Vol. 109, No. 6 2457 Orthogonal protection schemes are usually milder because selective deprotection is governed by alternative cleavage mechanisms rather than by reaction rates. Since the pio- neernig work of Bergmann and Zervas, the development of new protecting groups has been deeply tied to peptide chemistry. Protection is totally mandatory for the construction of these polyfunctional molecules, which contain up to eight distinct functional groups in addition to indole and imidazole rings, which should also be protected.