The ‘Azirine/Oxazolone Approach’ to the Synthesis of Aib‐Pro Endothiopeptides |
| |
Authors: | Artur Budzowski Anthony Linden Heinz Heimgartner |
| |
Institution: | 1. Organisch‐Chemisches Institut der Universit?t Zürich, Winterthurerstrasse 190, CH‐8057 Zürich, (phone: +41446354282;2. fax: +41446356812);3. Present address: Department of Organic Chemistry, Jagiellonian University, ul. Ingardena 3, PL‐30‐060 Krakow, Poland.;4. Postdoctoral stay at the University of Zürich (02.2003–08.2004). |
| |
Abstract: | The reaction of methyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate ( 2a ) with thiobenzoic acid at room temperature gave the endothiopeptide Bz‐AibΨCS]‐Pro‐OMe ( 7 ) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)‐protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z‐Pro‐AibΨCS]‐Pro‐OMe ( 12 ). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H2S. A second reaction with 2a led to the endodithiotetrapeptide 9 , but extensive epimerization at Pro2 was observed. Similarly, saponification of 12 and coupling with either 2a or H‐Phe‐OMe and 2‐(1H‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium tetrafluoroborate/1‐hydroxy‐1H‐benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer BzΨCS]‐Aib‐Pro‐AibΨCS]‐N(Me)Ph ( 21 ) was achieved via isomerization of 7 to BzΨCS]‐Aib‐Pro‐OMe ( 16 ), transformation into the corresponding thioacid, and reaction with N,2,2‐trimethyl‐N‐phenyl‐2H‐azirin‐3‐amine ( 1a ). The structures of 12 and 21 were established by X‐ray crystallography. |
| |
Keywords: | Endothiopeptides Peptides ‘ Azirine/oxazolone method’ α ‐Amino isobutyric acid (Aib) 2H‐Azirin‐3‐amines X‐Ray crystallography |
|
|