Possible Reason for the Unusual Regioselectivity in Nucleophilic Ring Opening of Trisubstituted Aziridines under Mildly Basic Conditions

Abstract

2,2,3-Trisubstituted aziridines are known to undergo ring opening at the more substituted carbon under mildly basic conditions. However, the reason for the formation of the more sterically encumbered product has never been examined. Several trisubstituted aziridines, with different substitution patterns at the C-2 and C-3 carbons, were synthesized to change the electronics of the aziridine ring system. These changes had no effect on the regioselectivity of the ring-opening reaction. Using the B3LYP/6-31G* DFT basis set it was determined that the transition state for opening at the more substituted carbon proceeds at a lower energy than the transition state at the less substituted carbon.

Total synthesis of the reported structure of ceanothine Dviaa novel macrocyclization strategy

“…Next, rapid removal of the silyl protecting group furnished linear precursor 2 , which was suitably positioned for the key macrocyclization step. Gratifyingly, our methodology 22 in regio- and stereoselective ring opening of a trisubstituted aziridine translated well into the present intramolecular system despite concerns of creating a strained para -cyclophane ( Scheme 2 ). To the best of our knowledge, this is the first effective macrocyclization of a 14-membered cyclopeptide precursor with the chemically sensitive Z -enamide intact.…”

“…Starting from commercially available N -Boc- d -serine, known precursor 6 was prepared in five steps ( Scheme 2 ). 22b , 25 Pinnick oxidation 22 , 23d to the corresponding acid 5 , followed by EDCI-mediated coupling with free amine of l -leucineamide afforded the amino alcohol 7 in good yield. Mitsunobu cyclization 22 , 23a , b , d furnished the desired trisubstituted aziridine ( 3 ), and its structure was secured by X-ray crystallographic analysis.…”

“…22b , 25 Pinnick oxidation 22 , 23d to the corresponding acid 5 , followed by EDCI-mediated coupling with free amine of l -leucineamide afforded the amino alcohol 7 in good yield. Mitsunobu cyclization 22 , 23a , b , d furnished the desired trisubstituted aziridine ( 3 ), and its structure was secured by X-ray crystallographic analysis. Treatment of the TBDPS protected commercially available 4-hydroxybenzaldehyde with the Stork–Zhao reagent 16 , 24 gave the corresponding Z -vinyl iodide 4 as the major product (see ESI † ).…”

“…Previous research efforts in our group led to the development of a new methodology to generate such motifs via stereocontrolled regioselective ring opening of a trisubstituted aziridine by a variety of phenol nucleophiles. 22 This intermolecular reaction was successfully implemented on the syntheses of natural products and analogues containing chiral tertiary alkyl-aryl ethers. 23 Ceanothine D presented an excellent opportunity to further highlight the utility and versatility of this robust methodology, utilizing an intramolecular variant of the reaction, which addresses two major synthetic challenges associated with the molecule: the formation of the chiral tertiary alkyl-aryl ether fragment and macrocyclization in a single transformation.…”

Synthesis of Methyl l-Kijanosides by Regio- and Stereoselective Ring Opening of 2-Oxazolidinone-Fused Aziridines

“…45−47 The calculation study indicated that the presence of an alkynyl group stabilizes the transition state and lowers the activation energy needed for this pathway. 48 We speculated that the beneficial effect of an alkynyl group in aziridine ring opening could also be implanted by the 2-oxazolidinone-moiety of 4, as the ring strain is relieved when the ring opening occurs at the tertiary carbon. Indeed, ring-opening reactions of mono-and disubstituted, 2-oxazolidinone-fused aziridines have been studied 49,50 and nicely applied.…”