Sulfur Ylide Promoted Synthesis of N‐Protected Aziridines: A Combined Experimental and Computational Approach

Abstract

A range of N-protected aziridines [N-Tosyl (N-Ts), N-2-trimethylsilylethanesulfonamide (N-SES), N-tert-butoxycarbonylamido (N-Boc), and N-o-nitrobenzenesulfonamide (oNs)] were prepared in moderate to good yield and with high enantiomeric excess of both isomers starting from N-protected imines, using a sulfonium salt derived from Eliel's oxathiane. The diastereoselectivities of the reactions are influenced by the imine N-protecting group, the imine substituent, and the sulfide structure. An unusual cis selectivity was observed in the formation of N-tosyl-2-phenyl-3-tert-butylaziridine and N-o-trimethylsilylethanesulfonamide-2-phenyl-3-tert-butylaziridine, which was explained by using computational models. The analysis suggests that betaine formation in the case of N-tosyl-tert-butylaldimine aziridination using oxathiane benzyl sulfonium ylide 1' is reversible and that the selectivity is determined at the rotation step, which is unusual for semistabilized ylide aziridination. We have shown herein that the steric bulk of an imine substituent, in combination with a sterically demanding sulfonium ylide, can also affect the reversibility of the reaction. This is the first example of this sort involving aziridinations using semistabilized ylides.

Practical and Highly Selective Sulfur Ylide-Mediated Asymmetric Epoxidations and Aziridinations Using a Cheap and Readily Available Chiral Sulfide: Extensive Studies To Map Out Scope, Limitations, and Rationalization of Diastereo- and Enantioselectivities

“…The imine derived from pivaldehyde ( t -BuCHNTs) also worked (entry 8) and gave the aziridine with high trans selectivity and again perfect er. Interestingly, Hameršak obtained the cis -aziridine exclusively with this imine using the benzyl sulfonium ylide derived from Eliel’s oxathiane 7 , opposite to what we observed with isothiocineole 2 . It should be noted that pivaldehyde itself could not be employed in epoxidations because it was too unreactive and led to competing elimination of the sulfonium salt, indicating the higher reactivity of the N -Ts imines relative to aldehydes.…”

“…It is difficult to explain why the unsaturated imine derived from cinnamaldehyde gave such high diastereoselectivity (Table , entry 5). The stark contrast between the high trans selectivity obtained with pivaldehyde-derived imine ( t -BuCHNTs) compared to the high cis selectivity obtained by Hameršak is not something we can rationalize either at the present time.…”

Recent Advances in the Stereoselective Synthesis of Aziridines

“…(Scheme 89). 133,134 Huang and co-workers used a chiral sulfonium ylide generated in situ from the C 2 -symmetric sulfide 224 and benzyl bromide in the presence of potassium carbonate, for the aziridination of aromatic N-Ts imines. By performing the reactions in acetonitrile and in the presence of tetrabutylammonium iodide (TBAI), as phase-transfer catalyst, the desired chiral trans-configured aziridines 225 were obtained in good yields and excellent enantioselectivities (Scheme 90).…”

Recent Developments in Asymmetric Aziridination

“…[17] Indeed, various N-Ts, N-SES, N-Boc, and N-o-Ns protected chiral aziridines were achieved in moderate to good yields (31-88%) and remarkable enantiomeric excesses for both cis-and trans-diastereomers of up to > 99% ee. [17] Indeed, various N-Ts, N-SES, N-Boc, and N-o-Ns protected chiral aziridines were achieved in moderate to good yields (31-88%) and remarkable enantiomeric excesses for both cis-and trans-diastereomers of up to > 99% ee.…”

“…In 2010, Hamersak et al. reported the synthesis of a range of chiral variously N ‐protected aziridines based on the reaction of aldimines with a chiral Eliel’s oxathiane‐derived benzylsulfonium salt, as depicted in Scheme 17. Indeed, various N ‐Ts, N ‐SES, N ‐Boc, and N ‐ o‐ Ns protected chiral aziridines were achieved in moderate to good yields (31–88%) and remarkable enantiomeric excesses for both cis‐ and trans‐ diastereomers of up to >99% ee .…”