Enantioselective Ammonium Ylide Mediated One‐Pot Synthesis of Highly Substituted γ‐Butyrolactones

Abstract

An ammonium ylide mediated access towards trans‐β,γ‐disubstituted, all‐trans‐α,β,γ‐trisubstituted, and α,α,β,γ‐tetrasubstituted γ‐butyrolactones bearing a broad variety of functionalities was developed. Starting from widely accessible benzylidene Meldrum's acid derivatives and α‐bromo carbonyl compounds, γ‐butyrolactones were obtained in yields between 32–99% with up to excellent diastereoselectivities (>95:5) via a DABCO‐mediated [2+1] annulation. Utilization of enantiomerically pure cinchona alkaloid derivatives enables the first asymmetric ammonium ylide mediated method to provide (3R, 4R)‐β,γ‐disubstituted and (2R, 3R, 4R)‐α,β,γ‐trisubstituted γ‐butyrolactones in moderate to good yields with up to very good enantiomeric ratios (97:3). The scalability of the transformation was proven while determining the absolute configuration.

Synthesis of 1,3‐oxazepine derivatives via tandem reaction of 5‐benzylidine Meldrum's acids with TosMIC in presence of potassium carbonate

“…Synthesis steps via 5-benzylidine Meldrum's acid derivatives were designed to synthesize this compound. 5-Benzylidine Meldrum's acid derivatives are among the most important substrates used by researchers in organic synthesis in recent years [18,19]. Knowing ketene chemistry from my previous studies [20][21][22], the Meldrum's acid derivatives decompose to ketene, releasing CO 2 and acetone [23].…”

“…Knowing ketene chemistry from my previous studies [20][21][22], the Meldrum's acid derivatives decompose to ketene, releasing CO 2 and acetone [23]. Therefore, Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (12) and aldehyde derivatives (13) were first reacted in acetonitrile in presence of piperidine to give 5-benzylidine Meldrum's acid derivatives (14) at the end of 3 h at 82 C [19]. Then, to a mixture of 5-benzylidine derivatives ( 14) in acetonitrile, p-toluenesulfonylmethyl isocyanide (TosMIC) (15) and base were added and the reaction was continued for 18 h at 82 C and this step is a Michael reaction.…”

“…The proposed mechanism for the synthesis of the 1,3-oxazepine compounds (16) resulting from this tandem reaction is summarized in Scheme 4. The reaction of Meldrum's acid (12) with an aldehyde (13) in the presence of piperidine gives the 5-benzylidine Meldrum's acid (14) [19]. It continues with the 1,4-conjugate addition of tosylmethylisocyanide anion, (17) which occurs when the acidic proton of tosylmethylisocyanide ( 15) is abstracted with the K 2 CO 3 anion to the Michael acceptor 5-benzylidine Meldrum's acid (14) [24].…”