Backbone Amide Linker (BAL) Strategy for Solid-Phase Synthesis of C-Terminal-Modified and Cyclic Peptides1,2,3
详细信息 查看全文
- 作者：Knud J. Jensen ; Jordi Alsina ; Michael F. Songster ; Josef Vá ; gner ; Fernando Albericio ; and George Barany
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：June 10, 1998
- 年：1998
- 卷：120
- 期：22
- 页码：5441 - 5452
- 全文大小：288K
- 年卷期：v.120,no.22(June 10, 1998)
- ISSN：1520-5126
文摘
Peptide targets for synthesis are often desired withC-terminal end groups other than the more usualacid and amide functionalities. Relatively few routes exist forsynthesis of C-terminal-modified peptides-includingcyclic peptides-by either solution or solid-phase methods, and knownroutes are often limited in terms ofease and generality. We describe here a novel BackboneAmide Linker (BAL) approach, whereby thegrowingpeptide is anchored through a backbone nitrogen, thus allowingconsiderable flexibility in management of thetermini. Initial efforts on BAL have adapted the chemistry of thetris(alkoxy)benzylamide system exploitedpreviously with PAL anchors. Aldehyde precursors to PAL, e.g.5-(4-formyl-3,5-dimethoxyphenoxy)valericacid, were reductively coupled to the 
-amine of the prospectiveC-terminal amino acid, which was blockedas a tert-butyl, allyl, or methyl ester, or to theappropriately protected C-terminal-modified amino acidderivative.These reductive aminations were carried out either in solution oron the solid phase, and occurred withoutracemization. The secondary amine intermediates resulting fromsolution amination were converted to the9-fluorenylmethoxycarbonyl (Fmoc)-protected preformed handlederivatives, which were then attached to poly(ethylene glycol)-polystyrene (PEG-PS) graft orcopoly(styrene-1% divinylbenzene) (PS) supports andusedto assemble peptides by standard Fmoc solid-phase chemistry.Alternatively, BAL anchors formed by on-resin reductive amination were applied directly. Conditions wereoptimized to achieve near-quantitative acylationat the difficult step to introduce the penultimate residue, and a sidereaction involving diketopiperazine formationunder some circumstances was prevented by a modified protocol forN-protection of the second residue/introduction of the third residue. Examples are provided for thesyntheses in high yields and purities ofrepresentative peptide acids, alcohols, N,N-dialkylamides,aldehydes, esters, and head-to-tail cyclic peptides.These methodologies avoid postsynthetic solution-phasetransformations and are ripe for further extension.
-amine of the prospectiveC-terminal amino acid, which was blockedas a tert-butyl, allyl, or methyl ester, or to theappropriately protected C-terminal-modified amino acidderivative.These reductive aminations were carried out either in solution oron the solid phase, and occurred withoutracemization. The secondary amine intermediates resulting fromsolution amination were converted to the9-fluorenylmethoxycarbonyl (Fmoc)-protected preformed handlederivatives, which were then attached to poly(ethylene glycol)-polystyrene (PEG-PS) graft orcopoly(styrene-1% divinylbenzene) (PS) supports andusedto assemble peptides by standard Fmoc solid-phase chemistry.Alternatively, BAL anchors formed by on-resin reductive amination were applied directly. Conditions wereoptimized to achieve near-quantitative acylationat the difficult step to introduce the penultimate residue, and a sidereaction involving diketopiperazine formationunder some circumstances was prevented by a modified protocol forN-protection of the second residue/introduction of the third residue. Examples are provided for thesyntheses in high yields and purities ofrepresentative peptide acids, alcohols, N,N-dialkylamides,aldehydes, esters, and head-to-tail cyclic peptides.These methodologies avoid postsynthetic solution-phasetransformations and are ripe for further extension.