Application of tetralinymines of carboxamide protecting groups in peptide synthesis

Abstract

A study was carried out to convert 1-tetralone and some of its derivatives to the amines by Leuckart reaction. In this reaction, the ketones (1) 1-cetralone, (2) 5-methoxy-1 -tetra1 one, (3) 6-methoxy-l-tetralone, (4) 7-methoxy-1-tetralone and (5) 5,7-dimethyl-l-tetralone were converted to the formyl derivatives. These formamides namely, (la) 1,2,3,4-tetrahydro-l-naphthvl, (2a) 5-methoxy- -1, 2,3,4-tetrahydro-1-naphthy1, (3a) 6-methoxy- - 1,2,3,4-tetrahydro-1-naphthy1, (4a) 7-methoxy-1,2,3, 4-tetrahydro-l-naphthyl and (5a) 5,7-dimethy1- - 1,2,3,4-tetrahvdro-l-n3phthyl formamides were then hydrolyzed to their corresponding amines:- (lb) 1-aminotetralin , (2b) 1-amino-5-methoxytetra1in, (3b) 1-amino-G-methoxytetralin, (4) l-.omino-7- -methoxytetralin, and (5b) l-amino-5,7-dimethyltetral This was carried out by both acidic (concentrated hydrochloric acid) and basic (1C% aqueous NaOH) conditions. The former gave yields ranging from 0% to 75%, while the latter gave yields ranging from 90% to 97%. Acid hydrolysis of 3a and 4a gave black-gummy compounds and no amines were obtained. This showed that hydrolysis of formyl derivatives under basic conditions gave better results and is recommended. (vi) Suitability of these 1-tetralinyl groups as potential carboxamide protecting -for asparagine and glutamine side chain amide groups were investigated. The amines lb,2b,3b,4b and 5b were used as precursors to prepare the carboxamide protected derivatives namely, (6) Boc-Gln(1,2,3, 4-tetrahydro- -l-naphthyl)-a-OBzl, (7 ) Boc-Asn(1,2,3,4-tetrahydro- « -1-naphthyl)-B-OBzl, ( 8 ) Boc-Gln(5-methoxy- -1,2,3,4-tetrahydro-l-napnthyl)-a-OBzl, (9 ) Boc-Asn- (5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-B-OBzl, tl Q) Boc-Gln(6-methoxy-l,2,3, 4-tetrahyd ro-l-napthy1)- -a-OBzl, (11) Boc-Asn (6-methoxy-1,2,3, 4-tet rahydro- -1-naphthyl)-a-0Bzl, ( 12) Boc-G1n(7-methoxy-1,2,3,4- -tetrahydro-l-naphthyl)-a-OBzl, ( 13 ) Boc-Asn- -(7-methoxy-l,2,3,4-tetrahydro-l-naphthyl)-a-0Bzl, (14 ) Boc-Gln(5,7-dimethyl-l,2, 3,4-tetrahydro-l- -naphthyl)-a-0Bzl,(15) Boc-Asn(5,7-dimethyl-l,2,3,4- -tetrahydro-l-naphthyl)-g-OBzl. The N,N'-dicyc- -lohexylcarbodiimide/N-hydroxysuccinimide (DCC-HONSU) coupling methoO gave yields ranging from 40% to 86%. These carboxamide protected derivatives were subjected to cleavage studies in TFA-Ch^C^-anisole (50:46:2- v/v) . The protecting groups in glutamine derivatives (6, 6,10,12. and 14) were removed within 24hr. In the carboxamide protected derivatives of asparagine (7 , 9,11,13 andl5), the protecting groups in 9 and 11 were found too labile to be used during (vii) peptide synthesis. The protecting groups in 7 , 13 and 15 were stable in the above deprotecting reagent upto 24hr. These derivatives (7 , 13 and 15)were therefore subjected to cleavage studies in boron trifluoride complex with acetic acid (BTFA). This completely removed the protecting . groups. The group in 7 was cleaved completely after 4hr, in 13 after 3hr and in 15 after 3hr. This showed that the groups 1,2,3,4-tetrahydro-1-naphthyl,7-methoxy- -1,2,3,4-tetrahydro-l-naphthy1 and 5,7-dimethyl- -1,2,3,4-tetrahydro-l-naphthyl were found to be potential carboxamide protecting groups due to their stability in TFA-CH2Cl2-anisole (50:48:2 v/v) and their easy cleavage by BTFA. The carboxamide protected derivatives whose protecting groups were found promising (7.,13 and 15Jwere used in the synthesis to the dipeptides Boc-Phe-Asn(1,2,3,4-tetrahydro-1-naphthyl)-g-OBzl, Boc-Phe-Asn(7-methoxy-1,2,3,4-tetrahydro-1-naphthyl)- -a-OBzl and Boc-Phe-Asn(5,7-dimethy1-1,2,3,4- -tetrahydro-l-naphthyl)-g-OBzl. The carboxamide protecting groups in these dipeptides also behaved in the same way as in 7,13 and 15. These dipeptides were used in .synthesis to the tripeptides, Boc-Ile-Phe-Asn- (1,2,3,4-tetrahydro-1-naphthyl)-6-OBzl, Boc-I1e-Phe-Asn- (7-met hoxy-1, 2, 3, 4-tetrahydro-l-naphthyl) -ct^CBzl and Boc-I1e-Phe-Asn(5,7-dimethyl-1,2,3,4-tetrahydro-1-naphthyl )- B-OBzl .