Aldol-type reactions directed

The use of an anionic reagent for addition at carbonyl carbon rather than a fully esterified form of a trivalent phosphorus acid obviates a troublesome aspect of the Abramov reaction. Specifically no dealkylation step is required. Mechanistic investigations257 258 indicate that the reaction proceeds much as a simple "aldol"-type reaction in which the anionic phosphorus site adds directly to the carbonyl center. While the initial efforts concerned with the "Pudovik reaction"259 were directed toward the use of sodium salts of the simple dialkyl phosphites, as shown in Equation 3.17,260 266 with a, 5-unsaturated carbonyl systems (vide infra) competition between sites for addition can occur. Addition at the carbonyl carbon site is the kinetically favored route.267-270... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Aldol-type reactions comprise one of the most important classes of synthetic reactions. Although direct enantioselective condensation of aldehydes and unmodified ketones is not easy (280), it is highly desirable. A partly successful example is given in Scheme 115 (281). 

Scheme 8C.25. Tandem and two-directional aldol-type reaction.

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],... 

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Some other directing groups which involve the sp2 nitrogen can also function as a directing group in place of the pyridine ring. The reaction of aromatic imines with CO and ethylene in the presence of Ru3(CO)12 did not stop at the carbonylation step, but rather indenone derivatives were the final products and were formed via an intramolecular aldol-type reaction of the expected carbonylation products in situ (Eq. 27) [44]. The treatment of the reaction mixture with silica gel selectively afforded indenones in good yields. 

Having developed an efficient catalytic asymmetric nitroaldol reaction, we next applied our attention to a direct catalytic asymmetric aldol reaction. The aldol reaction is generally regarded as one of the most powerful carbon-carbon bond-forming reactions. The development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis. In all these catalytic asymmetric aldol-type reactions, however, preconversion of the ketone moiety to a more reactive speeies such as an enol silyl ether, enol methyl ether or ketene silyl... 

Direct aldol-type reaction of oxindoles with trifluoropyruvate... 

The original methods for directed aldol and aldol-type reactions of aldehydes and acetals with silyl enolates required a stoichiometric amount of a Lewis acid such as TiCh, Bl i-OI y, or SnCl.j [18]. Later studies have introduced many Lewis acids which accelerate these processes with a catalytic quantity (vide infra). In addition, it has been found that fluoride ion sources also work as effective catalysts of the aldol reaction [19]. In the last decade, much attention has been paid for the development of diastereo- and enantioselective aldol reactions [20, 21], aqueous aldol reactions using water-stable Lewis acids [22], and novel types of silyl enolate with unique reactivity. 

They applied the intermediary oxocarbenium to a direct aldol type reaction of azlactones [78] via their oxazole tautomer and obtained the corresponding products with excellent enantio and diastereoselectivities (Scheme 3.35) [79]. The method enables efficient access to biologically and pharmaceutically intriguing p hydroxy a amino acid derivatives having a quaternary stereogenic center at the a carbon atom. 

In Section 9.4.A, it was noted that there were problems with aldol-type reactions, especially with the directed aldol condensation. In particular, aldehydes with an a-hydrogen have great difficulty adding to ketones due to their propensity for self-condensation. The ability to use kinetic control conditions in enolate reactions of ketones and aldehydes often solves this problem. There are also several alternative approaches that involve the use of carbanions derived from imines and hydrazones and these can be very useful. l... 

Cinchona based catalysts, e.g., 30 (Scheme 8), also have been used by Shibata, Tom, and coworkers to direct enantioselective Aldol-type reactions of 3-substituted... 

Sc(OTf)3 is effective in the aldol-type reaction of silyl enolates with aldehydes in aqueous media (H2O-THF) without any significant decomposition of the water-sensitive silyl enolates. Thus, aldehydes available in aqueous-solution such as formaldehyde and chloroacetaldehyde can be directly used to afford the corresponding aldol adduct in high yield (eq 3). ... 

A direct catalytic asymmetric aldol-type reaction of 3-substituted-2-oxindoles with glyoxal derivatives was catalyzed by a similar chiral )V,A -dioxide-Sc(OTf)3 complex (eq 33). The complex efficiently catalyzed the aldol reaction affording the 3-(a-hydroxy-/3-carbonyl) oxindoles with vicinal quaternary-tertiary stereocenters, in up to 93% yield, 99 1 dr, and >99% ee under mild conditions. 

Efficient access to biologically and pharmaceutically interesting hydroxy-oc-amino acids derivatives (145) having a quaternary stereogenic center at the a-carbon atom, through the direct aldol-type reaction of azalactone (144) with an oxocarbenium ion obtained via protonation of vinyl ethers (143), by a chiral phosphoric acid catalyst (127) in a highly enantio- and diastereoselective manner, have been developed by Terada and co-workers (Scheme 38). ... 

Dialkylzincs promote direct aldol-type reaction of ethyl diazoacetate with trilluoro-methyl ketones to give highly functionalized products, R-C(0H)(CF3)-C(=N2)-C02Et, in good to excellent yield. Preliminary screening of chiral catalysts gives some good ccs. ... 

Aspartate 4-semialdehyde, seen, for example, in Scheme 12.13, which provided a pathway for the biosynthesis of the essential amino acid methionine (Met, M) and in Scheme 12.14, which holds a representation of the biosynthesis of threonine (Thr, T), is also a place to begin to describe a pathway to lysine (Lys, K). As shown in Scheme 12.19, aspartate 4-semialdehyde undergoes an aldol-type reaction with pyruvate (CHsCOCO ") in the presence of dihydropicoUnate synthase (EC 4.2.1.52) to produce a series of intermediates that, it is presumed, lead to (5)-23-dihydropyridine-2,6-dicarboxylate. Then, dihydrodipicolinate reductase (EC 1.3.1.26) working with NADPH produces the tetrahydropyridine, (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate.This heterocycle, in the presence of glutamate (Glu, E) and water, is capable of transamination directly to 2-oxoglutarate and (2S, 6S)-2,3-diaminopimelate in the presence of LL-diaminopimelate aminotransferase (EC 2.6.1.83), while the latter, in the presence of the pyridoxal dependent racemase... 

The influence of the presence of carbohydrate solutes had been previously briefly explored by Lubineau and Scherrmann in the case of the Mukaiyama aldol-type reaction of silylenol ethers with aldehydes, which had been found to be accelerated with effects on the syn-anti selectivity similar to what is observed under high pressure. Favoring the syn aldol product was clearly consistent with its smaller transition state volume as compared to the anti one. When this reaction was studied in the presence of carbohydrate solutes, a moderate yield increase was observed, in the same ty -directed selectivity. This effect was however ascribed to slower competitive hydrolysis of the silylenol ether, probably related to a limitation of water activity in the medium, responsible for this undesired side reaction. ... 

Terada, M. Tanaka, H. Sorimachi, K. Enantioselective Direct Aldol-Type Reaction of Azlactone via Protonation of Vinyl Ethers by a Chiral Bronsted Acid Catalyst. /. Am. Chem. Soc. 2009,131,3430-3431. 

Aldol-type Reactions. In 1993, Kobayashi et al. first introduced Sc(OTf)3 as an effective catalyst in aldol reactions of silyl enol ethers with aldehydes in aqueous media. Since then, other rare earth metal triflates [RE(OTf)3] have been shown to be useful for the aldol reaction, including Y(OTf)3. In general, Y(OTf)3 is less active than Sc(OTf)3 for the aldol reaction. However, good yields of the direct aldol reaction can be obtained at room temperature when stoichiometric amounts of Y(OTf)3 and a tertiary amine are used (eq 1). ... 

Over the past 12 years or so, significant progresses of the "direct" aldol reaction have been achieved. In particular, the aldol-type reactions of pyruvic acid and its derivatives are useful for the synthesis of isotetronic acid derivatives. In 2000, Jorgensen et al. [23] reported the first example of asymmetric homoaldol reaction of ethyl pyruvate 26a in this work, chiral (R)-f-Bu-bis(l,3-oxazolin-2 -yl)methane (BOX)-Cu(OTf)2 catalyst was used (Scheme 11). Organocata-lytic version of similar reactions has been investigated. For instance, Dondoni et al. examined catalyst efficiency of several prolin-based organocatalysts for homoaldol reaction of 26a and foxmd that a combination of (S)-l-(2-pyrro-lidinylmethyl)pyrrolidine 29 and trifluoroacetic acid is effective [24]. 

The potential of 9 as a chiral Lewis base catalyst was further demonstrated by application to the aldol reaction of trichlorosilyl enol ethers of ketones with aldehydes, which proceeded with high diastereo- and enantioselectivity [32], The observed stereospecificity suggested the intervention of a six-membered cyclic transition state (Scheme 7.17). Notably, enoHzation of cyclohexanone derivatives and aliphatic aldehydes appeared feasible by SiCLt with the assistance of amine base and 9, leading to the estabhshment of a new protocol for direct aldol-type reactions between ketones and aldehydes or two aldehydes (Scheme 7.18) [33]. 

The direct aldol-type reaction of azlactone 106 with an oxocarbenium ion via a protonation of vinyl ethers (107) by the chiral phosphoric acid 95a as a catalyst provides (l-alkoxy-a-amino acid derivatives (108) bearing a quaternary stereogenic center with high diastereo- and enantioselectivity (Scheme 28.9). The ion pairs 109... 

C-H 0 Hydrogen bonding model Scheme 28.9 Direct aldol-type reactions of aziactone. 

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