Functionalization of nucleophiles with chiral azetines

Functionalization of nucleophiles with chiral azetines

Our research group investigates catalytic asymmetric cycloaddition of enoldiazo compounds – a methodology that opens doors to a library of structurally different carbo- and heterocyclic compounds.1 We developed broad applications of [3+3]- and [3+2]-cycloaddition reactions using 1,3-dipoles and activated alkenes, but the construction of a four-membered ring via [3+1]-cycloaddition required a previously undemonstrated reaction of a metallo-enolcarbene (from enoldiazo compounds) with a carbene or ylide. Our report on highly enantioselective copper(I) catalyzed [3+1]-cycloaddition of enoldiazo acetates with a-acyl sulfur ylides, which provided easy access to donor-acceptor cyclobutenes, demonstrated the feasibility of the process.2 Inspired by these results we focused on the development of a [3+1]-cycloaddition that would allow the introduction of a heteroatom to the four-membered ring, and with optimization we discovered that donor-acceptor azetines (donor = silyloxy group, acceptor = carboxylate group) could be formed in up to 95% isolated yield and 99% enantioselectivity (Fig. 1) and that these azetines could be conveniently converted to all-cis substituted azetidines.3

Fig. 1 Generation of 3-azetidinones using catalytic [3+1]-cycloaddition of silyl-protected enoldiazoacetates with imido-sulfur ylides

We envisioned that removal of the silyl group from the 2-azetine product would form 3-azetidinones that would be susceptible to retro-Claisen ring opening4 because of the high ring strain in the four-membered ring. However, our initial attempt to remove the silyl group using TBAF under standard conditions resulted in a facile ring opening reaction with a mixture of products, and all attempts to modify conditions to form the 3-azetidinone failed. The cleavage reaction demonstrated the innate instability of the 3-azetidinone-2-carboxylate as well as the potential for nucleophilic ring opening of the donor-acceptor azetine. We envisioned this process as a general methodology for nucleophile induced retro-Claisen reactions and, because the reactant 2-azetine could be formed with high enantioselectivity, the ring opened product would retain the same optical purity. Mechanistic studies revealed that the product was formed in near quantitative yields only if two equivalents of the nucleophile were used at room temperature - one equivalent of the nucleophile for silyl group removal and the other for nucleophilic ring opening. This retro-Claisen reaction, aided by strain release, provides a methodology for the attachment of chiral units to a variety of amines and alcohols, and tolerates a broad scope of nucleophiles, including naturally occurring amines, alcohols, amino acids, and other nitrogen-based nucleophiles (Fig. 2).

Fig. 2 Structural diversity of amino acid derivatives obtained from chiral donor-acceptor azetines via nucleophilic ring opening

Recent studies have shown that these reactions can be performed in aqueous media with the use of only one equivalent of nucleophile. In addition, the mild reaction conditions, high enantiocontrol, and broad scope demonstrated in this work portray a process that is expected to have wide applications. Future efforts in our group will be directed toward expanding the applicable nucleophiles and methods for further functionalization, as well as applying the retro-Claisen methodology to other strained products of catalytic asymmetric [3+1]-cycloaddition.

Interested about more details on this strain-release methodology and scope of the ring opening reaction?

The full article can be found here


1. Cheng, Q.-Q., Deng, Y., Lankelma, M. & Doyle, M. P. “Cycloaddition reactions of enoldiazo compounds” Chem. Soc. Rev. 46, 5425-5443 (2017).

2. Deng, Y., Massey, L. A., Zavalij, P. & Doyle, M. P. Catalytic asymmetric [3+1]-cycloaddition reaction of ylides with electrophilic metallo-enolcarbene intermediates. Angew. Chem. Int. Ed. 56, 7479–7483 (2017).

3. Marichev, K. O. et al. Synthesis of chiral tetrasubstituted azetidines from donor-acceptor azetines via asymmetric copper(I)-catalyzed imido-ylide [3+1]-cycloaddition with metallo-enolcarbenes. Angew. Chem. Int. Ed. 58, 16188–16192 (2019).

4. Jukic, M., Sterk, D. & Casar, Z. Recent advances in the retro-Claisen reaction and its synthetic applications. Curr. Org. Synth. 9, 488−512 (2012).