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Novel Heterospirocyclic 3‐Amino‐2 H ‐azirines as Synthons for Heterocyclic α‐Amino Acids
Author(s) -
Strässler Christoph,
Linden Anthony,
Heimgartner Heinz
Publication year - 1997
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19970800515
Subject(s) - chemistry , azirine , lithium diisopropylamide , tripeptide , synthon , dipeptide , stereochemistry , amino acid , thioamide , amide , intramolecular force , piperidine , hydrolysis , medicinal chemistry , ring (chemistry) , organic chemistry , deprotonation , ion , biochemistry
The heterospirocyclic N ‐methyl‐ N ‐phenyl‐2 H ‐azirin‐3‐amines (3‐( N ‐methyl‐ N ‐phenylamino)‐2 H ‐azirines) 1a ‐ d with a tetrahydro‐2 H ‐thiopyran, tetrahydro‐2 H ‐thiopyran, and a N ‐protected piperidine ring, respectively, were synthesized from the corresponding heterocyclic 4‐carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCI), and sodium azide ( Scheme 4 ). The reaction of these aminoazirines with thiobenzoic acid in CH 2 Cl 2 at room temperature gave the thiocarbamoyl‐substituted benzamides 13a ‐ d in high yield. The azirines 1a‐d were used as synthons for heterocyclic α‐amino acids in the preparation of tripeptides of the type Z‐Aib‐Xaa‐Aib‐N(Ph)Me ( 18 ) by following the protocol of the ‘azirine/oxazolone method’: treatment of Z‐Aib with 1 to give the dipeptide amide 15 , followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2‐dimethyl‐2 H ‐azirin‐3‐amine 17 gave 18 , again in high yield ( Scheme 5 ). With some selected examples of 18 , the selective deprotection of the amino and the carboxy group, respectively, was demonstrated ( Scheme 6 ). The solid‐state conformations of the protected tripeptides 18a ‐ d , as well as that of the corresponding carbocyclic analogue 18e , were determined by X‐ray crystallography ( Figs. 1‐3 and Tables 1‐3 ). All five tripeptides adopt a β‐turn conformation of type III or III′. The solvent dependence of the chemical shifts of the NH resonances ( Fig. 6 ) suggests that there is an intramolecular H‐bond between H‐N(4) and O(11) in all cases, which is an indication that a relatively rigid β‐turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H‐bond in the crystalline state ( Fig. 7 ); O(11) is involved in an intermolecular H‐bond with the OH group of the carboxy function.