Ketenes asymmetric protonation

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

Silyl enol ethers, known as chemically stable and easy handled enolates, can be protonated by a strong Bronsted acid. Our group demonstrated that a Lewis acid-assisted Bronsted acid (LBA 17), generated from optically pure binaphthol and tin tetrachloride, was a chiral proton source of choice for asymmetric protonation of silyl enol ethers possessing an aromatic group at the a-position [33, 34]. Binaphthol itself is not a strong Bronsted acid, however, LBA 17 can proto-nate less reactive silyl enol ethers since the acidity of the phenolic protons of 17 is enhanced by complexation with tin tetrachloride. The catalytic asymmetric protonation of silyl enol ethers was accomplished for the first time by LBA 18. Treatment of ketene bis(trimethylsilyl)acetal 60 with 0.08 equiv of LBA 18 and a stoichiometric amount of 2,6-dimethylphenol as an achiral proton source afforded (S)-2-phenylpropanoic acid (61) with 94% ee (Scheme 10) [35]. LBA 19 derived from binaphthol monoisopropyl ether has been successfully applied to the enantioselective protonation of meso 1,2-enediol bis(trimethylsilyl) ethers under stoichiometric conditions [36]. 

Asymmetric protonations of prochiral ketenes, metal enolates or enamines are performed with chiral alcohols, amines or amine salts [552], Recently, good enantiomeric excesses ( 80%) have been obtained in ketene protonations with the following a-hydroxyesters methyl (R)- or ([Pg.88]

Irradiation using 0.8 MeV proton irradiation or far-UV photolysis at 10—20K of polar and apolar ices rich in CO2, containing acetylene or methane with analysis by IR, gave evidence for ketene formation, which was proposed to occur by free radical processes. Reagents labeled with and were used in most of the experiments, since the normal ketene asymmetric stretch is nearly coincident with the solid CO fundamental vibration near 2136 cm . A major route for ketene formation from acetylene was assigned to reaction with oxygen atoms (Eqn (4.15)). Acetamide (CH3CONH2) has an abundance in space comparable to that... 

In pioneering studies by Pracejus, C9 O-acetylquinine 19 was observed to catalyze the addition of methanol to phenyl methyl ketene (Scheme 6.23). Nucleophilic attack of the nitrogen atom of the quinuclidine was rate determining and was followed by an asymmetric protonation step [7]. 

The latter mode of activation, in which a charged tetraaminophosphonium salt acts as a Bronsted acid, was realized by the same research group in 2009. Enanti-oselective aza-Michael reaction of 2,4-dimethoxyaniline with nitroalkenes afforded the conjugate addition products in excellent yields and high enantiomeric excesses (Scheme 10.70) [173, 174]. Similarly, chiral diaminooxaphosphonium salts have been used as Br0nsted acids in the asymmetric protonation reactions of ketene disilyl acetals [175]. 

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

To the best of our knowledge, no synthesis of natural products or bioactive products involving the asymmetric protonation of ketenes was reported so far in the literature. However, because of the importance of this method, we disclose the most relevant methodologies and the mechanistic considerations of the enantioselective protonation of ketenes. 

During the last 15 years, in the course of the development of nucleophilic planar chiral A-heterocycles as orga-nocatalyst, Fu and co-workers published a succession of papers dealing with the asymmetric protonation of ketene (Scheme 31.22). Indeed, by use of various protic nucleophiles such as alcohols, phenols, amines, enolysable aldehydes, or hydrazoic acid, they developed straightforward accesses to enantioenrichied esters,amides, " and amines. " ... 

SCHEME 31.22. Fu and co-workers developments in asymmetric protonation of ketene. 

Uraguchi D, Kinoshita N, Ooi T. Catalytic asymmetric protonation of a-amino acid-derived ketene disilyl acetals using P-spiro diaminodioxaphosphonium barfates as chiral proton. J. Am. Chem. Soc. 2010 132 12240-12242. 

For the first asymmetric protonation of ketene see Pracejus H. Organische Katalysatoren, LXI1) asymmetrische synthe-sen mit Ketene I alkaloid-katalysierte asymmetrische synthe-sen von a-phenyl-propionsameestern. Justus Liebigs Atm. Chem. 1960 634 9-22. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

Under optimized reaction conditions this two step synthesis for asymmetric preparation of /1-lactams is performed as follows. First, the organocatalyst 46 is added as a shuttle base to a solution of the acid chloride, 47, and the proton sponge , 49, at low temperature. Within a few minutes the soluble ketene and the hydrochloride salt, 49 HC1, as a white precipitate, are formed. Subsequently, the imino ester 44 is added to this solution at —78 °C, which results in the asymmetric formation of the /Mactam. Thus, the alkaloid 46 acts both as a dehydrohalogena-tion agent and as an organocatalyst for subsequent lactam formation [49, 52]. 

Pioneering work by Pracejus et al. in the 1960s, using alkaloids as catalysts, afforded quite remarkable 76% ee in the addition of methanol to phenylmethyl-ketene [26-29]. In 1999 Fu et al. reported that of various planar-chiral ferrocene derivatives tried, the azaferrocene 35 performed best in the asymmetric addition of methanol to several prochiral ketenes [30, 31]. In the presence of 10 mol% catalyst 35 (and 12 mol% 2,6-di-tert-butylpyridinium triflate as proton-transfer agent), up to 80% ee was achieved (Scheme 13.16). 

For catalytic asymmetric aldol-type reactions, the transformation of the methylene compounds to a silyl enolate or a silyl ketene acetal was at one time necessary. Recently, the aldol reaction of aldehydes with non-modified ketones was realized by use of the lanthanum-Li3-trisf(/ )-bi-naphthoxidej catalyst 22 [18]. According to the proposed catalytic cycle, after abstraction of an a-proton from the ketone, the reaction between the lithium-enolate complex and the aldehyde... 

The 1/BQ system alone or with Lewis acid additives was also employed for asymmetric catalysis in the synthesis of /3-amino acids235. During an elaboration of the tandem catalytic asymmetric chlorination/esterification process, Lectka and coworkers found that proton sponge 1 competes with ketenes in the reaction with halogenating agents, such... 

The pioneering studies in this field are done by Pracejus and coworkers in a series of papers published in the 1960s in which they studied the asymmetric addition/protonation of alcohols to ketenes [8]. They carried out a number of experiments to demonstrate the catalytic role of a tertiary amine on the nucleophilic... 

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

The first catalytic asymmetric Staudinger reaction to be described used chiral tertiary amines 14 and 15 derived from the Cinchona alkaloids as the nucleophile to activate the ketene via zwitterion formation. The ketene was conveniently generated in situ from the acid chloride. Because the HCl generated in the elimination would consume the chiral tertiary amine catalyst, a nonnucleophilic strong base (e.g.. Proton Sponge) was included to remove the HCl formed. Yields of -lactams were on the order of 60% in 99% ee. 

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