C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Abstract

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral β,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

Use of a (β‐Amidoallyl)boronate as a Nucleophilic Reagent in Catalytic Enantioselective Addition to Isatins

“…The newly formed product was identified as 3‐amidoallylated 2‐oxindole 3a (10 % yield after purification; Table , Entry 1) by comparison with an authentic sample To compensate for the low reactivity of 1 , it was thus highly desired to explore the possibility of synergistic enhancement of the nucleophilic character by adding an appropriate chemical species as an effective promoter. As a first choice, we employed a catalytic amount of anhydrous ZnCl 2 (10 mol‐%) for the same transformation . Under these conditions, the reaction proceeded with a markedly improved yield (71 %) of 3a , which demonstrated that this metal salt possessed high catalytic activity to increase the overall reaction efficiency to a practical level (Table , Entry 2).…”

Organocatalytic Enantioselective Synthesis of Tetrasubstituted α‐Amino Allenoates by Dearomative γ‐Addition of 2,3‐Disubstituted Indoles to β,γ‐Alkynyl‐α‐imino Esters

“…For instance, Shimizu and co‐workers reported an umpolung N‐addition to β,γ‐alkynyl α‐imino esters followed by nucleophilic α‐ or γ‐acylation for the synthesis of α‐quaternary alkynyl amino esters and allenoates (Scheme , path a) . Meanwhile, Ishihara and co‐workers developed a regio‐ and diastereoselective C‐alkyl addition to chiral β,γ‐alkynyl α‐imino esters using a Grignard reagent (RMgX) derived zinc(II)ate to construct optically active α‐quaternary alkynyl amino acid derivatives (Scheme , path b) . More recently, the same group accomplished an enantioselective aza‐Friedel–Crafts reaction of 2‐methoxyfuran with β,γ‐alkynyl‐α‐imino esters through the use of a chiral Brønsted acid catalyst, albeit with only one successful example .…”

Synthesis of α‐Ethynyl Glycines

“…[35] The enantioselectivity of this reaction was similar for both alkyl-and phenyl-substituted alkynes 21. Singh's group investigated the use of several PyBOX 23 analogues in the three-component reaction of ethyl glyoxylate (48), p-anisidine (49), and terminal alkynes 21.…”

“…Stefani et al reported the Yb(OTf ) 3 -catalyzed three-component reaction of alkynyltrifluoroborate salts 28 with ethyl glyoxylate (48), and either aniline 49 or 50 to give protected alkynyl amino acids 22 and 51, respectively (Scheme 12). [37] Both alkyland aryl-substituted alkynyltrifluoroborates were suitable components in the reaction.…”

“…[48] It was proposed that the Lewis acidic [MgX] + ion activates the carbon atom of the imino group by N-and O-chelation of the (E) isomer (complex N, Scheme 21) to promote attack by the . These conditions were also successfully used in the case of the less reactive iPrMgCl Grignard reagent.…”