Transcription of ORTHOGONALITY OF PROTECTING GROUPS - …
1 ORTHOGONALITYOF PROTECTINGGROUPSO rthogonality2 ORTHOGONALITY OF PROTECTING GROUPSThe term orthogonal was coined by Barany and Merrifield in 1977 to designate classes of PROTECTING GROUPS which are re-moved by differing chemical mechanisms. Therefore they can be removed in any order and in the presence of the other classes. Orthogonal protection schemes allow milder overall reaction con-ditions as well as the synthesis of partially protected peptides (G. Barany and Merrifield). The combination Fmoc/tBu is truly orthogonal whereas, under the conditions of Boc-SPPS, Boc/Bzl is not, as both PROTECTING GROUPS are cleaved by acids. As Boc can be selectively removed in the presence of Z/Bzl, the combination has been termed quasi-orthogonal.
2 UNUSUAL amino ACIDSIn addition to our comprehensive choice of derivatives of all stereo-isomers of the 20 canonical amino acids we offer an extensive range of unusual amino acids, which can serve as building blocks for the synthesis of peptide analogs and for use in structure-activity relationship (SAR) studies. Furthermore, these compounds are valuable chiral educts for organic ProtectionFmoc/tBu probably is the most popular or-thogonal combination of PROTECTING to the definition of this term by Barany and Merrifield [1], this combination is truly orthogonal, Fmoc can be removed selectively in the presence of tBu and the latter is split off under conditions leaving the amino - PROTECTING group intact. On the other hand, the pairs Boc/OPp or Fmoc/ivDde are merely quasi-orthogonal because both GROUPS are acid -labile or cleaved by bases, respectively.
3 OPp can be removed selectively in the presence of Boc/tBu by weak acid , and Fmoc by piperidine/DMF with preservation of ivDde protection, whereas the order of deprotection cannot be reverted. Modified peptides may be sensitive towards both bases and acids, so it should be kept in mind that Aloc/OAll and Z/Bzl may be removed under neutral , when conceiving the synthesis of more complex or modified peptides ( side-chain cyclized peptides), the tactics of synthesis, the choice of side-chain 3protecting GROUPS and type of resin, has to be considered on-resin modification Aloc/OAll, Dde and ivDde/Dmab, Mtt and Mmt/OPp may be selectively cleaved from peptides bound to Wang resin. Aloc can be removed on-resin in the presence of Mmt and vice versa during Fmoc-SPPS.
4 The combination of orthogonal PROTECTING GROUPS allows the synthesis of very complex peptides, impres-sive examples have been published by Hirschmann et al. [2] or Royo et al. [3]. Orthogonal protection schemes can also be devised for Boc-SPPS, Boc/Fm, Boc/allyl. An additional dimension of orthogo-nality, the hydrogenolysis of benzyl-derived PROTECTING GROUPS , is available in solution-phase peptide synthesis. This deblocking method is only rarely used in SPPS. Enzy-matically cleavable PROTECTING GROUPS as phenylacetyl have also been employed for peptide modifications, mostly in aqueous risk of aspartimide formation has to be kept in mind when considering a postsyn-thetic modification of the -carboxy moiety of Asp. This notorious side reaction is facili-tated by unhindered -carboxy protectinggroups such as OBzl, OAll or ODmab.
5 The selectively cleavable OPp is nearly as effec-tive as OtBu in suppressing base-catalyzed aspartimide formation [4].The sterically demanding OMpe group has been developed as an even more efficient tool for preventing this side reaction, but it can t be removed selectively under the conditions of standard Fmoc-SPPS [5].Even though Glu tends far less than Asp to base-catalyzed cyclization, unhindered -carboxyl protective GROUPS as allyl pro-mote the side reaction. Cysteine requires special consideration when conceiving a synthetic strategy based on multidimensional orthogonal protection, please see our brochure Cysteine Deriva-tives for more [1] and Am. Chem. Soc. 99, 7363 (1977)[2] R. Hirschmann et 54, 7179 (1998).[3] et al.
6 Tetrahedron Lett. 43, 2029 (2002)[4] Lauer et Peptide Sci. 1, 197 (1994)M. Mergler et Pept. Sci. 9, 36, (2003)M. Mergler et Pept. Sci. 9, 518 (2003).[5] A. Karlstr m and n, Tetrahedron Lett. 37, 4243 (1996) ORTHOGONALITY Dimension Examples for feasible combinations of PROTECTING groups2ndFmoc/tBu3rdFmoc/tBu/allyl3rdFmo c/tBu/Mmt13rdFmoc/tBu/Dde14thFmoc/tBu/Mm t/allyl4thFmoc/tBu/allyl/Dde5thFmoc/tBu/ allyl/Dde/Mmt5thFmoc/tBu/allyl/Dde/Bzl1, 25thFmoc/tBu/Mmt/allyl/Dde6thFmoc/tBu/Mm t/allyl/Dde/Bzl1partly quasi-orthogonal 2 Bzl: hydrogenolytic cleavageOrthogonality4 Protection TypetBu and OthersDifferentAllylDde and AnalogsBzl, Analogs and OthersFunctionalityTypical Cleavage Conditions95% aq TFA/Scavengers1% TFA/DCMPd(PPh3)4/PhSiH32% N2H4 H2O/DMF Catalytic Hydrogenation COOHFmoc-Asp(OtBu)-OH , ,*,xFmoc-Asp(OMpe)-OH*Fmoc-Asp(OtBu)-OPf p*Fmoc-Asp(OtBu)-OSuFmoc-Asp-OtBu*Fmoc-N -Me-Asp(OtBu)-OHB-1065B-3560B-1110B-1075 B-1735B-2195 Fmoc-Asp(2-phenylisopropyl ester)-OH*Fmoc-Asp-ODmb*B-2475B-2175 Fmoc-Asp(OAll)-OHFmoc-Asp-OAllB-2325B-27 15 Fmoc-Asp(ODmab)-OHB-3240 Fmoc-Asp(OBzl)-OH*Fmoc-Asp(OBzl)-OPfpFmo c-Asp-OBzlB-1060B-1760B-2780 COOHFmoc-Glu(OtBu)-OH H2O , ,*,xFmoc-Glu(OtBu)-OPfp*Fmoc-Glu(OtBu)-O SuFmoc-Glu(OSu)-OtBuFmoc-N-Me-Glu(OtBu)
7 -OHB-1315B-1130B-1325B-2310B-2395 Fmoc-Glu(2-phenylisopropyl ester)-OHB-2500 Fmoc-Glu(OAll)-OH*Fmoc-Glu-OAllB-3255B-2 720 Fmoc-Glu(ODmab)-OHFmoc-Glu-ODmabB-3010B- 3005 Fmoc-Glu(OBzl)-OH*B-1310 OHFmoc-Ser(tBu)-OH , ,*,xFmoc-Ser(tBu)-OPfpFmoc-Ser(tBu)-ODhb tFmoc-N-Me-Ser(tBu)-OHFmoc-Ser(BSi)-OH*F moc-Ser(PO(OBzl)OH)-OH*B-1235B-1180B-164 0B-3400B-1225B-3455 Fmoc-Ser(Trt)-OHB-2550 Fmoc-Ser(Bzl)-OH*B-1200 OHFmoc-Thr(tBu)-OH , ,*,xFmoc-Thr(tBu)-OPfpFmoc-Thr(tBu)-ODhb tFmoc-allo-Thr(tBu)-OH* Fmoc-N-Me-Thr(tBu)-OH Fmoc-Thr(PO(OBzl)OH)-OH*B-1245B-1185B-16 35B-1815B-3420B-3460 Fmoc-Thr(Trt)-OHB-2545 Fmoc-Thr(Bzl)-OH* B-1210 OHFmoc-Tyr(tBu)-OH , ,*,xFmoc-Tyr(tBu)-OPfpFmoc-Tyr(PO3(MDPSE )2)-OH Fmoc-Tyr(PO3Me2)-OHFmoc-Tyr(PO(OBzl)OH)- OH* Fmoc-Tyr(malonyl-di-OtBu)-OHFmoc-Tyr(SO3 )-OH sodium saltFmoc-Tyr(SO (ONeopentyl))-OHB-1255B-1195B-2910B-1990 B-3565B-2825B-2765B-4230 Fmoc-Tyr(Bzl)-OH Fmoc-Tyr(2-bromo-Z)-OHFmoc-Tyr(2,6-dichl oro-Bzl)-OH B-1215B-2795B-1280NH2 Fmoc-Orn(Boc)-OH ,* Fmoc-Orn(Boc)-OPfp Boc-Orn(Fmoc)-OH* B-1090B-2155A-3325 Fmoc-Orn(Aloc)-OH* B-2890 Fmoc-Orn(Dde)-OHFmoc-Orn(ivDde)-OHB-3185 B-4470Z-Orn(Fmoc)-OH* C-3325NH2 Fmoc-Lys(Boc)-OH , ,*,x Fmoc-Lys(Boc)-OPfpBoc-Lys(Fmoc)-OH* Fmoc-Lys(Boc)(Me)-OHFmoc-Lys(Boc)(isopro pyl)-OH Fmoc-Lys(retro-Abz-Boc)-OHFmoc-Lys(N-Me- Abz-Boc)-OH Fmoc-N-Me-Lys(Boc)-OHB-1080B-1155A-1610B -3575B-2455B-3180B-2515B-3685 Fmoc-Lys(Adpoc)-OHFmoc-Lys(Mtt)-OH , ,*,xFmoc-Lys(4-methoxytrityl)-OHFmoc-Lys (4-methoxytrityl)
8 -OPfpB-2520B-2535B-3215B-4470 Fmoc-Lys(Aloc)-OH* B-2240 Fmoc-Lys(Dde)-OH Fmoc-Lys(ivDde)-OHFmoc-Lys(Nde)-OH Dde-Lys(Fmoc)-OHB-3015B-3515B-3380E-3385 Fmoc-Lys(Z)-OH* Fmoc-Lys(2-chloro-Z)-OHZ-Lys(Fmoc)-OH* B-1270B-2790C-4125 also available linked to SASRIN resin also available linked to Wang resin x H-derivative linked to 2-Chlorotrityl-resin also available * D-enantiomer also available Fmoc is not stable under these cleavage conditions. Dde and analogs may be cleaved selectively in the presence of the other PROTECTING GROUPS listed here Fmoc may not be fully stable in some cases towards hydrogenation5 Protection TypetBu and OthersDifferentAllylDde and AnalogsBzl, Analogs and OthersFunctionalityTypical Cleavage Conditions95% aq TFA/Scavengers1% TFA/DCMPd(PPh3)4/PhSiH32% N2H4 H2O/DMF Catalytic Hydrogenation COOHFmoc-Asp(OtBu)-OH , ,*,xFmoc-Asp(OMpe)-OH*Fmoc-Asp(OtBu)-OPf p*Fmoc-Asp(OtBu)-OSuFmoc-Asp-OtBu*Fmoc-N -Me-Asp(OtBu)-OHB-1065B-3560B-1110B-1075 B-1735B-2195 Fmoc-Asp(2-phenylisopropyl ester)-OH*Fmoc-Asp-ODmb*B-2475B-2175 Fmoc-Asp(OAll)-OHFmoc-Asp-OAllB-2325B-27 15 Fmoc-Asp(ODmab)-OHB-3240 Fmoc-Asp(OBzl)-OH*Fmoc-Asp(OBzl)
9 -OPfpFmoc-Asp-OBzlB-1060B-1760B-2780 COOHFmoc-Glu(OtBu)-OH H2O , ,*,xFmoc-Glu(OtBu)-OPfp*Fmoc-Glu(OtBu)-O SuFmoc-Glu(OSu)-OtBuFmoc-N-Me-Glu(OtBu)- OHB-1315B-1130B-1325B-2310B-2395 Fmoc-Glu(2-phenylisopropyl ester)-OHB-2500 Fmoc-Glu(OAll)-OH*Fmoc-Glu-OAllB-3255B-2 720 Fmoc-Glu(ODmab)-OHFmoc-Glu-ODmabB-3010B- 3005 Fmoc-Glu(OBzl)-OH*B-1310 OHFmoc-Ser(tBu)-OH , ,*,xFmoc-Ser(tBu)-OPfpFmoc-Ser(tBu)-ODhb tFmoc-N-Me-Ser(tBu)-OHFmoc-Ser(BSi)-OH*F moc-Ser(PO(OBzl)OH)-OH*B-1235B-1180B-164 0B-3400B-1225B-3455 Fmoc-Ser(Trt)-OHB-2550 Fmoc-Ser(Bzl)-OH*B-1200 OHFmoc-Thr(tBu)-OH , ,*,xFmoc-Thr(tBu)-OPfpFmoc-Thr(tBu)-ODhb tFmoc-allo-Thr(tBu)-OH* Fmoc-N-Me-Thr(tBu)-OH Fmoc-Thr(PO(OBzl)OH)-OH*B-1245B-1185B-16 35B-1815B-3420B-3460 Fmoc-Thr(Trt)-OHB-2545 Fmoc-Thr(Bzl)-OH* B-1210 OHFmoc-Tyr(tBu)-OH , ,*,xFmoc-Tyr(tBu)-OPfpFmoc-Tyr(PO3(MDPSE )2)-OH Fmoc-Tyr(PO3Me2)-OHFmoc-Tyr(PO(OBzl)OH)- OH* Fmoc-Tyr(malonyl-di-OtBu)-OHFmoc-Tyr(SO3 )-OH sodium saltFmoc-Tyr(SO (ONeopentyl))-OHB-1255B-1195B-2910B-1990 B-3565B-2825B-2765B-4230 Fmoc-Tyr(Bzl)-OH Fmoc-Tyr(2-bromo-Z)-OHFmoc-Tyr(2,6-dichl oro-Bzl)-OH B-1215B-2795B-1280NH2 Fmoc-Orn(Boc)-OH ,* Fmoc-Orn(Boc)-OPfp Boc-Orn(Fmoc)-OH* B-1090B-2155A-3325 Fmoc-Orn(Aloc)-OH* B-2890 Fmoc-Orn(Dde)-OHFmoc-Orn(ivDde)-OHB-3185 B-4470Z-Orn(Fmoc)-OH* C-3325NH2 Fmoc-Lys(Boc)-OH , ,*,x Fmoc-Lys(Boc)-OPfpBoc-Lys(Fmoc)-OH* Fmoc-Lys(Boc)(Me)-OHFmoc-Lys(Boc)(isopro pyl)-OH Fmoc-Lys(retro-Abz-Boc)-OHFmoc-Lys(N-Me- Abz-Boc)-OH Fmoc-N-Me-Lys(Boc)
10 -OHB-1080B-1155A-1610B-3575B-2455B-3180B -2515B-3685 Fmoc-Lys(Adpoc)-OHFmoc-Lys(Mtt)-OH , ,*,xFmoc-Lys(4-methoxytrityl)-OHFmoc-Lys (4-methoxytrityl)-OPfpB-2520B-2535B-3215 B-4470 Fmoc-Lys(Aloc)-OH* B-2240 Fmoc-Lys(Dde)-OH Fmoc-Lys(ivDde)-OHFmoc-Lys(Nde)-OH Dde-Lys(Fmoc)-OHB-3015B-3515B-3380E-3385 Fmoc-Lys(Z)-OH* Fmoc-Lys(2-chloro-Z)-OHZ-Lys(Fmoc)-OH* B-1270B-2790C-4125 also available linked to SASRIN resin also available linked to Wang resin x H-derivative linked to 2-Chlorotrityl-resin also available * D-enantiomer also available Fmoc is not stable under these cleavage conditions. Dde and analogs may be cleaved selectively in the presence of the other PROTECTING GROUPS listed here Fmoc may not be fully stable in some cases towards hydrogenationOrthogonality6 Additional Orthogonally Protected Fmoc amino acid Derivatives offered by BachemAad -Aminoadipic AcidFmoc-Aad(OtBu)-OHB-2440 Gla -Carboxy-glutamic AcidFmoc- -carboxy-Glu(OtBu)2-OH*B-1265 Dap , -Diaminopropionic AcidFmoc-Dap(Adpoc)-OH Fmoc-Dap(Aloc)-OH Fmoc-Dap(Boc)-OH* Fmoc-Dap(ivDde)-OHBoc-Dap(Fmoc)-OH*Z-Dap (Fmoc)-OH* B-2865B-2845B-2380B-3885A-3580C-4200 Dab , -Diaminobutyric AcidFmoc-Dab(Adpoc)-OH Fmoc-Dab(Aloc)-OH Fmoc-Dab(Boc)-OH* Fmoc-Dab(ivDde)-OHFmoc-Dab(Z)-OH Boc-Dab(Fmoc)
