Catalytic in Situ Generation of Zn(II)-Alkynilides under Mild Conditions:  A Novel CN Addition Process Utilizing Terminal Acetylenes

Frantz, Doug E.; Fässler, Roger; Carreira, Erick M.

doi:10.1021/ja993074n

Cited by 233 publications

(87 citation statements)

References 16 publications

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“…14 In 1999, our group reported a distinct method for the formation of zinc alkynylides under very mild and operationally simple conditions using Zn(OTf) 2 and an amine base at room temperature. 15,16 The alkynylides obtained under these conditions react in situ with a variety of electrophiles such as nitrones, aldehydes, ketones, and N-acylimminium ions. 4, 17 The addition of such alkynylides to aldehydes can be performed in an asymmetric fashion in the presence of inexpensive N-methylephedrine.…”

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confidence: 99%

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Fujimori¹,

Knöpfel²,

Zarotti³

et al. 2007

Bulletin of the Chemical Society of Japan

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In this account, new methods for the catalytic and stereoselective conjugate addition of terminal alkynes are described. Our laboratories have disclosed asymmetric addition reactions to aldehydes and imines using a combination of a zinc or copper salt and a terminal alkyne. Under these conditions, terminal alkyne is transformed in situ into an alkynyl metal species. Recently, it was found that these in situ generated alkynyl metal species can undergo conjugate additions to alkylidene malonate-type acceptors. In the zinc(II) triflate-catalyzed system, a highly diastereoselective conjugate addition has been realized using a chiral oxazepene acceptor. Subsequently, alternative conjugate addition protocols have been developed which employ a terminal alkyne, substoichiometric amounts of copper and a highly eletrophilic Meldrum's acid derived acceptor. This reaction can be made enantioselective using a novel atropisomeric P,Nligand (PINAP). With this ligand, excellent enantioselectivities can be achieved for the conjugate addition of aromatic alkynes to various Meldrum's acid derived acceptors.

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confidence: 99%

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Fujimori¹,

Knöpfel²,

Zarotti³

et al. 2007

Bulletin of the Chemical Society of Japan

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“…We then switched our efforts to other transition metals, such as Zn(II), Cu(I)͞(II), Ir(I), and Sc(III) ( Table 1), some of which have been reported to lead the formation of metal alkynilides (33)(34)(35)(36)(37)(38)(39)(40)(41). In the investigation of 4-phenyl-1-butyne 2a addition to ␣-imino ester 1, none of the target was essentially detected in the presence of IrCl⅐2COD, Zn(OTf) 2 , ZnCl 2 , and Sc(OTf) 3 (entry 1).…”

Section: Resultsmentioning

confidence: 99%

Catalytic asymmetric alkynylation of α-imino ester: A versatile approach to optically active unnatural α-amino acid derivatives

Chan

2005

Proc. Natl. Acad. Sci. U.S.A.

105

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The catalytic asymmetric introduction of alkynyl functionality to ␣-amino acid derivatives was realized by the direct addition of terminal alkynes to ␣-imino ester in the presence of chiral Cu(I) complex under mild reaction conditions. Owing to the rich chemistry to which alkyne can be subjected, the present system provides a remarkably versatile tool for the construction of optically active ␣-amino acid derivatives. Good yields and enantiomeric excess values were achieved with an array of terminal alkynes and challenging, biologically active, unnatural ␣-amino acid derivatives could be conveniently obtained. asymmetric catalysis Optically active nonproteinogenic ␣-amino acids are of exceptional and rapidly increasing popularity as important tools in protein engineering and peptide-based drug discovery due mainly to their implementation into nonscissile peptide mimics and peptide isosteres (1-7). Hence, intense research has been focused on the preparation of enantiomerically enriched unnatural ␣-amino acids, and, so far, several approaches, such as bioresolution routes (8-10) and the rhodium-or rutheniumcatalyzed asymmetric hydrogenation of dehydroamino acids derivatives (11-13), have shown much promise. Nevertheless, there is still a great demand for more efficient and, especially, technically feasible methods for convenient construction of various types of rational designed unnatural amino acid derivatives. In this regard, enantioselective nucleophilic addition to ␣-imino esters represents one of the most direct strategies (14), because a new chiral center and a new COC bond can be built in a single operation and an appropriately designed side chain can be introduced in the meantime. Previous work in this field mainly focused on the catalytic asymmetric alkylation of ␣-imino esters, in which enol silane (15-18), allyl-metal compounds (19,20), trimethylsilyl nitronate (21), ketone (22), and nitroalkane (23) have been used as nucleophiles.Recently, we reported the successful alkynylation of ␣-imino ester by demonstrating the feasibility of direct addition of terminal alkynes to ␣-imino ester 1 in the presence of Ag(I) salts under mild reaction conditions (Scheme 1) (24). In this process, a new bond between an sp 3 carbon and an sp carbon is formed.Capitalizing on this method, we envisioned an attractive route to optically active ␣-amino acid derivatives via the direct asymmetric alkynylation of ␣-imino ester. The following considerations are particularly noteworthy:1. The HC'C moiety is an excellent two-carbon medium for the delivery of biologically interesting units into the ␥-position of ␣-amino acids, because it could be easily hydrogenated to saturated status after completing the nucleophile role. In contrast, owing to the rich chemistry to which alkyne can be subjected, the presence of a C'C bond in the desired targets offers a unique and highly valuable opportunity for further synthetic elaboration on the ␤,␥-positions of ␣-amino acids. For example, semireduction of the products could directly afford vinyl...

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“…[22] Zinc acetylides have been shown to be even more reactive then their Cu counterparts when treated with nitrones, according to previous investigations by Carreira. [23] Zinc triflate has also been used in some special cases such as the addition of cyclopropylacetylene to reactive cyclic trifluoromethylated N-acylimines. [24] Because ketimines are less reactive than aldimines, there is a need to increase the nucleophilicity of the attacking alkyne nucleophile.…”

Section: Introductionmentioning

confidence: 99%

Zinc(II)‐Catalyzed Synthesis of Propargylamines by Coupling Aldimines and Ketimines with Alkynes

et al. 2018

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Catalytic in Situ Generation of Zn(II)-Alkynilides under Mild Conditions: A Novel CN Addition Process Utilizing Terminal Acetylenes

Cited by 233 publications

References 16 publications

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Catalytic asymmetric alkynylation of α-imino ester: A versatile approach to optically active unnatural α-amino acid derivatives

Zinc(II)‐Catalyzed Synthesis of Propargylamines by Coupling Aldimines and Ketimines with Alkynes

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