Aldehydes direct catalytic asymmetric aldol

Y. M. A Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Direct Catalytic Asymmetric Aldol Reactions of Aldehydes and Unmodified Ketones, Angew. Chem. Int. Ed EngL 1997, 36,1871-1873. 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

Bpgevig A, Kumaragurubaran N, Jprgensen KA (2002a) Direct catalytic asymmetric aldol reactions of aldehydes. Chem Commun (Camb) Mar 21 620-621... 

Yamada YM, YoshikawaN, SasaiH, Shibasaki M (1997) Direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones. Angew Chem Int Ed Engl 36 1871-1873... 

We speculated that it might be possible to develop a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones by employing heterobimetallic catalysts. Our initial concerns were dominated by the possibility that our heterobimetallic asymmetric catalysts would be ineffective at promoting aldol reactions because... 

This newly developed heteropolymetallic catalyst system was applied to a variety of direct catalytic asymmetric aldol reactions, giving aldol products 48-64 in modest to good ee, as shown in Table 16. It is worthy of note that even 62 can be produced from hexanal 54 in 55% yield and 42% ee without the formation of the corresponding self-aldol product (-50 °C). This result can be imderstood by considering that aldehyde enolates are not usually generated by the catalyst at low temperatme, an assumption which was confirmed by several experimental results. It is also worthy of note that the direct catalytic asymmetric aldol reaction between 46 and cyclopenta-none 55 also proceeded smoothly to afford 64 in 95% yield synlanti = 93 7, syn = 76% ee, anti = 88% ee). 

Although the development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis [35—37], in all of these reactions pre-conversion of the ketone moiety to a more reactive species such as an enol silyl ether, enol methyl ether, or ketene silyl acetal has been an unavoidable necessity. However, quite recently Shibasaki et al. reported that a direct catalytic asymmetric aldol reaction, which is known in enzyme chemistry, is also possible in the presence of heterobimetallic lanthanoid catalysts [38]. Using fR)-LLB (20 mol%), which shows both Lewis acidity and Bron-sted basicity similar to the corresponding aldolases, the desired optically active aldol adducts were obtained with up to 94% ee. A variety of aldehydes and unmodified ketones can be used as starting materials (Scheme 11). 

A direct catalytic asymmetric aldol reaction using aldehydes and unmodified ketones is promoted by an anhydrous lanthanide, LnLi3-tris-(/f)-binaphthoxide. Combination of this catalyst with potassium hydroxide and water yields a more active heteropolymetallic catalyst. The scope and limitations of this reaction have been explored, and ketone deprotonation is the rate-determining step. 

A direct catalytic asymmetric aldol reaction (30-93% ee) using aldehydes and unmodified ketones has been described for the first time. Deprotonation of the ketones by the heteropolymetallic asymmetric catalyst (a lanthanum lithium binaph-thol) is rate limiting, there being no dependence on the concentration of aldehyde. 

At the time these relatively modest results represented the state-of-the-art in direct catalytic asymmetric aldolizations with a-unbranched aldehyde acceptors. Neither Shibasaki s nor Trost s bimetallic catalysts, the only alternative catalysts available, gave superior results. Moreover, even non-asymmetric amine-catalyzed cross aldolizations with a-unbranched acceptors are still unknown. That the practicality of the process can compensate for the modest yield and enantioselectivity was illustrated by a straightforward synthesis of the natural pheromone (S)-ipsenol (139) from aldol 136d, featuring a high-yielding Stille coupling (Scheme 4.27). 

In 1999, Shibasaki et al. reported on the direct catalytic asymmetric aldol reaction (Scheme 8.36), which was not necessary to preconvert the ketone moiety into the more reactive species such as an enolate ion and enol ether." The addition of bulky aldehyde 248 into the mixture of ethyl methyl ketone 249 and LaLi3tris(/ -binaphthoxide) [(/ )-LLB)] afforded aldol adduct 250 in excellent stereoselectivity. However, this reaction required a large amount of ketones (50 equiv), and catalyst (20 mol%) were required. They improved the conditions to reduce the amount of ketone (5 equiv) and catalyst (8 equiv) by using the hetero-polymetallic asymmetric catalyst (Scheme 8.37). The addition of the catalytic amount of potassium bis(trimethylsilyl) amide (KHMDS) and H2O was found to be effective to the catalysis. Adduct 253 was converted into ester 254 by the... 

Iwata et al. also established the direct catalytic asymmetric aldol reaction of thioamides (Scheme 8.39)." Treatment of an aldehyde and thioamide 259 in the presence of the catalyst containing [Cu(MeCN)4]BF4, (7 ,/ )-Ph-BPE, and lithium phenoxide 260 gave (3-hydroxythioamide 261 in good yield with high stereoselectivity. Thioamide features the direct transformation into aldehyde by using a Schwarz reagent (Scheme 8.40)." They converted aldol adduct 261 into (3-siloxyal-dehyde 262, which was further submitted to the direct stereoselective aldol reaction. Both diastereomers 263 and 264 were obtained in good yield. This protocol is effective to synthesize sequential 1,3-polyols. 

SCHEME 8J9. Conversion of thioamide into aldehyde and the further direct catalytic asymmetric aldol reaction. 

Class II aldolase mimics (Scheme 10.4) were the first small-molecule catalysts that were reported for the direct intermolecular aldol reaction. These catalysts are characterized as bimetallic complexes that contain both Lewis acidic and Brpnsted basic sites. Shibasaki et al. first reported on the use of such a catalyst in the aldol reaction in 1997, demonstrating its potential with the reaction of various acetophenones 52 and aldehydes 53 (Scheme 10.13). Aldols 55 were obtained in good yields and enantioselectivities. A similar approach was used in the direct catalytic asymmetric aldol-Tishchenko reaction.Nevertheless, for the moment, this method does not provide access to true polypropionate fragments. ... 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Benito Alcaide, Pedro Almendros The Direct Catalytic Asymmetric Cross-Aldol Reaction of Aldehydes, Angew. Chem. 115(8), 884-886 (2003), Angew. Chem. Int. Ed. 42(8), 858-860 (2003)... 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Shibasaki and co-workers have reported the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic multifunctional catalysts. Later, Trost and co-workers reported the direct... 

Since oxazolidines and oxazolidinones are fiindamental structural classes in organic chemistry (chiral auxiliaries) and in medicinal chemistry (e.g., Linezolid) and since they mask P-hydroxy-a-amino acids, which are widespread in various biologically active compounds and in natural products, the enantioselective synthesis of oxazolidinones is a challenging topic. Indeed, a new method for the direct synthesis of chiral 4-carboxyl oxazolidinones 168 by the catalytic asymmetric aldol reaction of isocyanato-malonate diesters 166 with aldehydes 167 in the presence of a thiourea catalyst (TUC) was developed. Since the resulting chiral 4-carboxy oxazolidinones are the equivalent of P-hydroxy-a-amino acids, this procedure... 

Chiral amines can react with so-called Mannich donors such as ketones or aldehydes. The resulting chiral enamines wiU then attack a Mannich acceptor, usually a prochiral aldimine, thereby introducing one or two chiral centers in the Mannich product. This usually is a P-aminoaldehyde or P-aminoketone, optionally substituted at the a-position. Inspired by their work on proline-catalyzed asymmetric aldol reactions [1], the List group envisioned that the related Mannich reactions might also be carried out with a catalytic amount of an enantiomerically pure chiral amine. This led in 2000 to the first direct catalytic asymmetric organocatalyzed Mannich reaction, catalyzed by L-proline (1, Scheme 5.1) [2],... 

The direct application of unmodified aldehydes in catalytic Michael additions can be severely hindered due to the presence of undesirable intermolecular self-aldol reactions (Hagiwara, Komatsubara et al. 2001 Hagiwara, Okabe et al. 2001). Barbas and co-workers achieved the first direct catalytic asymmetric Michael reaction between unmodified aldehydes and nitroolefins. The usage of an (S)-2-(morphohnomethyl) pyrrolidine catalyst in 20 % furnished the Michael addition products in 72 % enantioselectivity, 12 1 diastereoselectivity and 78 % yield (Betancort and Barbas 2001 Betancort, Sakthivel et aL 2004 Mosse, Andrey et al. 2006). The utilization of the ionic hquid tagged catalysts 25 and 26 in the Michael reactions of frans- -nitrostyrenes to aldehydes resulted in high yields but... 

Kanda and Fukuyama applied the catalytic asymmetric aldol reaction to the total synthesis of leinamycin, an antitumor agent (Scheme 8.26). Aldehyde 162 was submitted to the reaction with enol ether 163 under the conditions of Kobayashi to afford anti aldol adduct 164 in high yield. After protection of the 3-alcohol, thioester was converted directly into aldehyde 165 by treatment with Et3SiH in the presence of the Pd catalyst. The resulting aldehyde was transformed into vinyliodide by the Takai procedure. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

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