Synthesis and analysis of a macrocyclic triproline-derived template containing a local conformational constraint

doi:10.1016/0040-4039(95)00706-I

Tetrahedron Letters

Volume 36, Issue 23, 5 June 1995, Pages 4019-4022

https://doi.org/10.1016/0040-4039(95)00706-I Get rights and content

Abstract

A convergent synthesis of 3 is reported. By ¹H NMR COSY and ROESY techniques 3 in solution is assigned the ctt d ecl conformation shown in 3b.

A convergent synthesis of 3 is reported and the ctt conformation 3b is assigned by COSY and ROESY NMR techniques.

References (6)

D.S. Kemp et al.
J. Org. Chem.
(1991)
D.S. Kemp et al.
Nature
(1991)
D.S. Kemp et al.
Tetrahedron Lett.
(1995)

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Synthesis and analysis of a macrocyclic triproline-derived template containing a local conformational constraint

Abstract

J. Org. Chem.

Nature

Tetrahedron Lett.