TY - JOUR
T1 - Preparation and Application of the 5-(4-(9-Fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)-valeric Acid (PAL) Handle for the Solid-Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions
AU - Fernando, Albericio
AU - Kneib-Cordonier, Nancy
AU - Gera, Lajos
AU - Barany, George
AU - Biancalana, Sara
AU - Masada, R. Irene
AU - Hudson, Derek
PY - 1990
Y1 - 1990
N2 - The acid-labile 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) handle 1 is described for the solid-phase synthesis of C-terminal peptide amides. The pure para isomer of 1 was prepared by each of two efficient five-step routes, in overall yields from 52% to 74%. The handle 1 was coupled onto a variety of amino group-containing supports to provide a general starting point for stepwise assembly of peptide chains according to a wide range of chemistries. In particular, protocols based on the base-labile Na-9-fluorenylmethyloxycarbonyl (Fmoc) group worked well with PAL handle 1. For small model peptides, final cleavage of tert-butyl side-chain protecting groups and of the anchoring linkage proceeded smoothly in trifluoroacetic acid-dichloromethane-dimethyl sulfide (14:5:1) (reagent A) at 25 °C for 2 h. For cleavage of complex peptides that contain several sensitive side-chain functionalities, or that include arginine residues blocked with the 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr) or 2,2,5,7,8-pentamethylchroman-6-ylsulfonyl (Pmc) groups, a mixture of trifluoroacetic acid-thioanisole-l,2-ethanedithiol-anisole (90:5:3:2) (reagent R), applied for 2–8 h at 25 °C, was preferred. A side reaction involving alkylation at tryptophan was elucidated, and conditions were developed to minimize its occurrence. The methodology was demonstrated by syntheses of over a hundred peptides, among which acyl carrier protein (65–74) amide (natural and retro sequences), luteinizing hormone-releasing hormone, adipokinetic hormone, PHI porcine fragment (18–27), and human gastrin-I are highlighted in this report. In comparative studies, the yields and purities of peptide amides prepared with PAL were shown to be equivalent or superior to those found for products prepared by alternative procedures from the recent literature.
AB - The acid-labile 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) handle 1 is described for the solid-phase synthesis of C-terminal peptide amides. The pure para isomer of 1 was prepared by each of two efficient five-step routes, in overall yields from 52% to 74%. The handle 1 was coupled onto a variety of amino group-containing supports to provide a general starting point for stepwise assembly of peptide chains according to a wide range of chemistries. In particular, protocols based on the base-labile Na-9-fluorenylmethyloxycarbonyl (Fmoc) group worked well with PAL handle 1. For small model peptides, final cleavage of tert-butyl side-chain protecting groups and of the anchoring linkage proceeded smoothly in trifluoroacetic acid-dichloromethane-dimethyl sulfide (14:5:1) (reagent A) at 25 °C for 2 h. For cleavage of complex peptides that contain several sensitive side-chain functionalities, or that include arginine residues blocked with the 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr) or 2,2,5,7,8-pentamethylchroman-6-ylsulfonyl (Pmc) groups, a mixture of trifluoroacetic acid-thioanisole-l,2-ethanedithiol-anisole (90:5:3:2) (reagent R), applied for 2–8 h at 25 °C, was preferred. A side reaction involving alkylation at tryptophan was elucidated, and conditions were developed to minimize its occurrence. The methodology was demonstrated by syntheses of over a hundred peptides, among which acyl carrier protein (65–74) amide (natural and retro sequences), luteinizing hormone-releasing hormone, adipokinetic hormone, PHI porcine fragment (18–27), and human gastrin-I are highlighted in this report. In comparative studies, the yields and purities of peptide amides prepared with PAL were shown to be equivalent or superior to those found for products prepared by alternative procedures from the recent literature.
UR - http://www.scopus.com/inward/record.url?scp=0025032015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025032015&partnerID=8YFLogxK
U2 - 10.1021/jo00299a011
DO - 10.1021/jo00299a011
M3 - Article
AN - SCOPUS:0025032015
SN - 0022-3263
VL - 55
SP - 3730
EP - 3743
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 12
ER -