Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

Abstract

A nucleophilic retro-Claisen ring-opening of donor–acceptor cyclobutenes, formed with high stereocontrol by [3 + 1]-cycloaddition of TIPS-protected enoldiazoacetates with α-acyl sulfur ylides, has been developed. Removal of the TIPS group to form the isolable β-keto ester precedes the strain-induced ring-opening. Various amines, alcohols, thiols, and amino acid derivatives are effective nucleophiles, and their products are formed in very high yields via stoichiometric reactions. The chirality of the reactant donor–acceptor cyclobutenes is fully retained in the ring-opening reactions. The 3-acylglutaric acid products are converted to various valuable structures, including amido-diols, γ-aminobutyric acid (GABA) derivatives, and heterocycles.

Strain‐Induced Nucleophilic Ring Opening of Donor–Acceptor Cyclopropenes for Synthesis of Monosubstituted Succinic Acid Derivatives

“…Therefore, according to our calculations, the loss of enantiocontrol for DACP ring opening originates from cyclopropene formation, and the ratio of R and S configurations is retained after DACP ring opening. In addition, calculations of transition states TSFG‐1 w and TSGH‐2 w revealed that one or two molecules of water assist the ring opening step compared to water free conditions, [26] which is consistent with our previous experimental studies on retro ‐Claisen reaction rates [13, 14] …”

“…Our previous studies on ring opening of donor–acceptor azetines [13] indicated that the reaction was sluggish with methanol and primary alcohols, occurred only at elevated temperatures, and did not occur with secondary or tertiary alcohols. The ring opening of silyl‐protected donor–acceptor cyclobutenes with methanol (but not with primary, secondary or tertiary alcohols) occurred at room temperature in the presence of DMAP (2 equiv) [14] . We now report that use of only 15 mol % of DMAP as a catalyst allows the ring opening of more reactive DACP 2 or 5 to occur with primary and even secondary (but not tertiary) alcohols at room temperature in good yields.…”

“…The ring opening of silyl-protected donor-acceptor cyclobutenes with methanol (but not with primary,s econdary or tertiary alcohols) occurred at room temperature in the presence of DMAP (2 equiv). [14] We now report that use of only 15 mol %o fD MAPa sacatalyst allows the ring openingo fm ore reactive DACP 2 or 5 to occur with primary and even secondary (but not tertiary)a lcohols at room temperature in good yields.…”

“…In addition, calculations of transition states TSFG-1 w and TSGH-2 w revealed that one or two molecules of water assist the ring openings tep compared to water free conditions, [26] which is consistentw ith our previous experimental studies on retro-Claisen reactionrates. [13,14] Application in the synthesis of natural products…”

“…To the best of our knowledge,t he only example of nucleophilic ring opening of aD ACP occurred in acidic methanol (Scheme1a) and was reported as ap roof of the DACP structure, [11] but this transformation has remained undeveloped. Our research group recently reported av ariation of the retro-Claisenr eaction [12] for uncatalyzed nucleophilic ring opening of four-membered ring b-ketoesters [13,14] (Scheme 1b). Intrigued by these resultsw ew ere interestedi nf urthere xplorationo f small ring systems in this strain-induced reactionb ut, although cyclobutanone derivatives are known to be relativelys table, cyclopropanones often decompose instantly at room temperature.…”