Chiral donor–acceptor azetines as powerful reactants for synthesis of amino acid derivatives

Abstract

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon–oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor–acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.

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

“…Consistent with our previous report, [13] DACPs that contain an ester group undergo ring openingw ith aqueous solutions of strong nucleophilest or esulti np roducts of nucleophilic substitution at an ester group, and at least two equivalents of as trongn ucleophile is required to complete the reaction. [24] DACP 2a upon treatment with excess (2.5 equiv) hydrazine hydrate, a5 0% aqueouss olution of hydroxylamine, and a3 4% aqueous solution of ammonia formed the corresponding dihydrazide 9 (88 %y ield), dihydroxamic acid 10 (82 %y ield), and diamide 11 (92 %y ield) that are highlys oluble in water but not in organics olvents (Scheme 3).…”

“…To obtain access to monosubstituted succinic mixed diesters and amidoesters we optimized DACP formation—ring opening of 4‐substituted enoldiazo‐acetates 1 a and 1 b and ‐acetamide 4 b with primary and secondary alcohols (Table 5). 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] .…”

“…[9] Our previousi nvestigationsr evealed optimal conditions for the retro-Claisen ring opening of donor-acceptor azetines that involved the use of only one equivalent of an ucleophile and one equivalent of water in tetrahydrofuran. [13] In this work, initial optimizationf or the one-pot generation of DACP 2a was started from triisopropylsilyl-protected 4-ethyl-substituted enoldiazoacetate 1a [18] in dichloromethane at room temperature for 30 minutes.T he subsequenti ns itu reaction of 2a with benzylamine in THF was performed after the evaporation of dichloromethane (Table 1). Excellent yields of ring openeda mide-ester product 3a (up to 92 %) were obtained with 1mol %o fd irhodium(II) tetraacetate [Rh 2 (OAc) 4 ], dirhodium(II) tetraoctanoate [Rh 2 (oct) 4 ], or bis[rhodium(a,a,a',a',-tetramethyl-1,3-benzenedipropionic acid)] Rh 2 (esp) 2 (entries 1-3).…”

“…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.…”