Synthesis of tryptophans by Lewis acid promoted ring-opening of aziridine-2-carboxylates: optimization of protecting group and Lewis acid

Synthesis of β-substituted tryptamines by regioselective ring opening of aziridines

“…14–17 Carbamates, such as benzyl (Cbz) and tert -butyl (Boc), can be removed under very mild conditions, but are less common as aziridine protecting groups since rearrangement byproducts are possible. 18–21 The 4-nitrobenzyl carbamate (PNZ) had been sparingly used as an aziridine activating group until recently. 22–31 The PNZ group is more activating than Cbz and more resistant to cleavage under acidic conditions.…”

“…34,35 An initial report of indoles adding to aziridinium ions 36 was followed by methods for opening carbamate-protected aziridines. 37,38 Extensive effort has been made to control the final tryptamine structure in high yield, 21,39–41 where unsymmetrical aziridines, such as 1 , can open at either backbone carbon (Scheme 1). For carbamate-protected aziridines with a C2 ester substituent (R 1 ), addition of indole to the least hindered carbon produces the α-substituted tryptamine ( 2 ).…”

“…Yields of 2 have steadily improved as new Lewis acid catalysts are developed and side reactions are minimized. 21 The synthesis of a β-substituted tryptamine ( 3 ) from a mono-substituted aziridine has only been reported in low yields for carbamate-protected aziridines; 21,42 however, limited examples with alternative nitrogen protecting groups are known. 33,43 This report details our discovery that PNZ-protected, alkyl substituted aziridines ( 4 ) undergo selective ring opening by C2 attack with indoles to produce β-substituted tryptamines ( 5 ).…”

Selective Cleavage of Carbamate Protecting Groups from Aziridines with Otera's Catalyst

“…During the course of our studies on aziridine ring-opening reactions [3] we were surprised to find that treatment of Cbzprotected aziridine-2-carboxylate methyl ester 3a with benzyl alcohol in the presence of Otera's catalyst not only resulted in transesterification to the benzyl ester, but also the cleavage of the Cbz group, generating aziridine 4. Benzyl carbonate was isolated as a by-product, confirming that benzyl alcohol attacks the carbamate carbonyl group, displacing the aziridine.…”

Highly Enantioselective Ring‐Opening Reactions of Aziridines with Indole and Its Application in the Building of C3‐Halogenated Pyrroloindolines

“…[7a] Given these well-developed methods in this context, we found that there is still no successful example in asymmetric ring-opening reactions of aziridines with indoles that could provide an easy access to indolethylamine scaffolds and that could be further transformed to chiral pyrroloindoline architectures. [8] To date, there are several examples of Lewis acid promoted ring-opening reactions of aziridines with indoles; [9] however, the catalytic asymmetric version of this approach has not been realized. We postulated that the blankness of literature reports on this enantioselective transformation was related to the difficulty in controlling the enantiotopic center with an effective chiral catalyst.…”