Catalytic Asymmetric Addition of Dialkylzinc Reagents to α-Aldiminoesters

Abstract

The first catalytic, enantioselective addition of organozinc reagents to α-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.Optically active natural and nonnatural amino acids are versatile building blocks for a range of biologically important molecules. 1 Enantioselective addition to α-iminoesters as a route to the synthesis of important chiral amino acids has been achieved 2 via the iminoene reaction, 3 Friedel Crafts reaction, 4 enol ether addition 5 and enolisable ketone 6 and aldehyde 7 addition.In comparison, the enantioselective addition of unstabilized anions to α-iminoesters which provides entry to key congeners of α-amino acids has not been reported. While related diastereomeric processes have been forthcoming, 8 the enantioselective processes have proven more difficult. To date only enantioselective additions of stoichiometric allyl zinc reagents have appeared. 9 On the other hand, the corresponding aldimine additions have met with greater success. 10 α-Iminoesters are significantly more challenging due to their higher reactivity and the presence of a bicoordinate metal binding site ( Figure 1); both factors lead to substantial racemic background processes.We have previously reported the enantioselective addition of Et 2 Zn to α-ketoesters using salen-derived independent Lewis acid/Lewis base bifunctional catalysts. 11 In these systems, the electrophile coordinates to the Lewis acid, while the electronically decoupled Lewis base activates the nucleophile. These independent moieties facilitate enantioselective addition (Figure 2). Here we report the first enantioselective addition of organozinc reagents to α-iminoesters using these bifunctional catalysts. Our initial experiments showed that the addition of Et 2 Zn to α-ketiminoesters (Figure 3, R ≠ H) proceeded with poor regioselectivity, yielding 1,2-addition, 1,4-addition and reduction. A survey of prior work revealed similar regioselectivity problems. Mg, Al and Cu mediated alkylations have resulted in 1,4-additions, whereas Zn mediated additions lead to mainly 1,2-additions ( Figure 3). 12Upon screening aldiminoester substrates (Figure 3, R = H) against metal adducts of bifunctional salens 1-4, we found that PMP (para-methoxyphenyl) protected aldiminoester 6 gave only 1,2-addition (eq 1) and was chosen for further exploration. Pure 6 can be synthesized on a large scale by condensation of ethylglyoxylate and para-methoxyaniline and subsequent distillation. 13Importantly, treating 6 with Et 2 Zn at −40°C in the absence of catalyst led to the formation of significant racemic addition product within 2 h. Thus, these substrates are much more challenging than most aldehydes (no background reaction) ...

Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

“…25 Moberg performed the enantioselective cyanation of aldehydes to produce optically active cyanohydrin esters in high yield and ee, employing a catalytic system derived from a dimeric Ti IV -salen complex and triethylamine. 26 Kozlowski has used a novel titaniumsalen complex containing a remote nucleophile to catalyze dialkylzinc additions to various substrates, including α-ketoesters 27 and α-iminoesters, 28 with high yield and moderate enantioselectivity. The Lewis acid complex activates the electrophile, and the nucleophile enhances the reactivity of dialkylzinc (Figure 6).…”

Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

“…More attractively, the transformation of α-imino esters can provide an easy access to various natural and unnatural α-amino acid esters [6–10]. Up to now, a series of nucleophilic substrates have been reported to react with α-imino esters, such as enamine [11–14], carbamate ammonium ylide [15], 1,3-dipolar cycle [16], boronic acid [17], acetylide [18], proparygylic anion [19] and ketene silyl acetal [20].…”

Alkylation of Aryl N‐(2‐Pyridylsulfonyl)aldimines with Organozinc Halides: Conciliation of Reactivity and Chemoselectivity

“…Initial attempts to isolate a copper complex of aldimine 1 f failed as a result of its high propensity to undergo hydrolysis. However, the treatment of the more stable ketimine 38 with 1 equivalent of [Cu(CH 3 CN) 4 ]PF 6 [22] in CH 2 Cl 2 at room temperature produced an instantaneous color change from colorless to deep red, accompanied by nearly quantitative formation of complex 42, which was isolated as an air-stable red solid. X-ray diffraction analysis of suitable crystals [23] revealed a distorted trigonal-pyramidal N,N,N,Ntetracoordinated copper complex [24] in which the Cu I atom coordinates to two molecules of 38 through the imino and pyridyl nitrogen atoms (Figure 1).…”

“…[1] Consequently, a number of synthetically useful addition reactions for the formation of carbon-carbon bonds have been developed with organolithium, [2] Grignard, [3] dialkyl zinc, [4] alkenyl zirconium, [5] aryl tin, [6] aryl titanium, [7] and aryl boron [8] reagents as nucleophiles, including some very efficient catalytic enantioselective procedures. [9] Despite this great progress, limitations in the scope of this reaction remain, especially with regard to functional-group compatibility.…”

“…Organozinc reagents show an optimal compromise in terms of reactivity and wide functional-group tolerance, but only a limited number of simple dialkyl zinc reagents (typically dimethylzinc or diethylzinc) have been used for the alkylation of imines. [4] Owing to their straightforward preparation [11] and commercial availability, alkyl zinc halides offer a unique opportunity to satisfy the need for a general method for the alkylation of imines that combines high reactivity and wide functional-group tolerance. Although an increasing number of methodologies benefit from the unique reactivity/selectivity profile of RZnX reagents, [12] alkyl zinc halides have been scarcely used as nucleophiles in 1,2-addition reactions to imines, [13] probably as a result of the poor electrophilicity of the imine group.…”