Aldol synthesis

Enantiomerically Pure Aldols Synthesized by Antibody Catalyzed Kinetic Resolution. 

CHART 3.12. iyw-Aldols synthesized from unprotected dihydroxyacetone (55). 

CHART 3.22. Aldols synthesized via a Br0nsted acid-catalyzed aldol reaction. 

Aldol Reactions.—The trend towards the use of enolates of metals other than the alkali metals (e.g. Mg, B, or Al) has led to a range of regio- and stereo-selective aldol syntheses. 

The same group also reports an alternative method of generating the intermediate ( )-vinyloxyboranes from diazo-ketones and trialkylboranes. Isomerization of (E) - to (Z) -intermediates can be effected simply, and both isomers are again used in stereoselective aldol syntheses. Interestingly, hydrolysis of the intermediates leads directly to ketones, and hence constitutes a synthesis of ketones from carboxylic acid derivatives (Scheme 77). Evans etal. have reported similar results from the use of boron enolates in the stereochemical control of aldol reactions. ... 

Lithium enolates are useful for crossed aldol syntheses. 

Table 5. Aldol Synthesis from Chlorodifluoromethyl Ketones [9]...

A radical approach to asymmetric aldol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a nitroalkene, has been reported, as shown in Eq. 4.93.113 The radical precursor is prepared from the corresponding carboxylic add by the Barton reaction,114 which has been used for synthesis of new (3-lactams.115... 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

In the direction of aldol synthesis, DHAP enters FucA as the first substrate and coordinates to zinc by both hydroxyl and carbonyl oxygens in an extended con-... 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

Unlike the Dakin-West and Henry nitro-aldol methods previously mentioned, the reaction of aldehydes with organometallics has only been used for the synthesis of peptidyl trifluoromethyl ketones. This method, along with the Henry nitro-aldol synthesis, eliminates the use of the toxic reagents required for the Dakin-West synthesis and starts with readily... 

A similar chiral bis(oxazoline)/Cu(II) catalyst is useful for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and glyoxylates [63] (Eq. 8A.39). Other bis(oxa-zoline)/M(OTf)2 (M = Sn, Mg) complexes are not effective. This method provides new routes to asymmetric aldol synthesis upon hydrolysis of the resulting adducts. 

Several interesting synthetic applications of hydroformylation are known. As one example, hydroformylation of enol ethers to afford -hydroxy aldehydes can be extended to catalytic aldol synthesis. The Rh-catalysed hydroformylation of the cyclic enol ether 42 affords the protected. vy -3,5-dihydroxyaldchydc 43 without forming the anti product 44. The regioselectivity of attack on the terminal carbon is also very high [28],... 

Three-component aldol synthesis.1 This rhodium carbonyl can promote aldol coupling of enol silyl ethers with aldehydes or ketones. It can also effect coupling of an enone, an aldehyde, and a trialkylsilane to provide a silyl aldol. In the case of an enolizable aldehyde, yields are improved by addition of a phosphine ligand such as... 

Although typical equilibrium constants for formation of a tertiary aldol prohibit direct forward aldol synthesis (0.002 M 1 for the aldol reaction of acetone with acetophenone) (Guthrie and Wang, 1992), the retro-aldol reaction is greatly favored (a 1 mM solution of the resulting tertiary aldol is converted almost completely to acetone and acetophenone at equilibrium) (List et al., 1999). 

In a different strategy (Scheme 46), albeit specialized, the tandem cycloaddition-aldol synthesis of triazolo[l,5-a]pyridines (249) from the azidotriazoles (247) proceeds with the intermediacy of the... 

Highly ry//-selective aldol synthesis from cr-iodo ketones is promoted under aqueous conditions by a distannane system, (BujSnb, Bu2SnF2, and HMPA. Aqueous solutions of acetaldehyde or formaldehyde provide /3-hydroxy ketones.272 The ate complex Li+[//-Bu2Snl ( generated from Lil and -Bu2SnI2 leads to the highest class of syn-diastereoselectivity in the Reformatsky-type reaction (Equation (106)).273... 

Enantioselective aldol synthesis. The dioxolones formed from (S)- or (R)-l and aromatic aldehydes undergo a diastereoselective condensation with enol silyl ethers. Optically active aldols are obtained by removal of the chiral auxiliary by oxidative decarboxylation with PbfOAcfj. A typical example using the dioxolone (2) formed from (R)-1 and benzaldehyde is shown in equation (I). However, only moderate diastereoselectivity... 

Diels-Alder reaction Aldol synthesis Ene reaction... 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

Stereospecific aldol synthesis of / -hydroxy acids derived from R) + )-t-butyl-p tolysulfinyl acetate has been reported [25 Eq. (18)]. The t-BuMgBr was crucial to the enolate generation without racemization. Magnesium diisopropylamide was used in preparation of the acetate precursor. 

Each of the growth steps can materialize by several specific mechanisms which have not been resolved in detail. We shall give examples of plausible mechanisms for the three dominant processes Bg, Uq and ig Q to account for the dependence of the product composition on the H2/CO ratio and on the basicity of the alkali hydroxide promoter. The Bg attack dominates at low H2/CO ratios and in the presence of CsOH, indicating that aldol synthesis of aldehyde precursors or products of alcohol dehydrogenation is involved. As shown below, only primary or secondary but not tertiary B-carbon is attacked by the Bg process, a feature characteristic of aldol condensation. 

Inl989, Yamamoto introduced the chiral (acyloxy)borane (CAB) complex for catalytic asymmetric Diels-Alder reactions [18], which has been utilized as a magic hand catalysis for the aldol synthesis and for the Sakurai-Hosomi reaction so far [19,20]. In contrast to R=H of 17, which is both air and moisture sensitive, the B-alkylated catalyst, R=Ph or alkyl, is stable and can be stored in closed containers at room temperature. This catalyst is easily prepared from phenyl- or alkylboric acid and 16 simple mixing of a 1 1 molar ratio of the ester 16 and phe-... 

Enantioselective aldol reactions. Enders et ul. have reported a regiospecific and enantioselective aldol synthesis. The method involves conversion of a methyl ketone into the chiral hydrazone 2, a-metalation, reaction with a carbonyl compound, and silylation to form a doubly protected ketol 3. The chiral ketols 4 are obtained by oxidative hydrolysis with H2O2 (30%) at pH 7 or by sensitized photooxidation in THF followed by reduction with dimethyl sulfide. Optical yields are 30-60%. The absolute configuration of the ketols is not known at present. 

Aldol synthesis. A new synthesis of 3-hydroxy ketones and esters involves regiospecific conversion of an a-bromo ketone or ester into an aluminum enolate by a coupled reaction with diethylaluminum chloride and zinc activated with copper(I) bromide in THF at —20°. This enolate adds to carbonyl compounds to give, after work-up, j3-hydroxy ketones (equation I). 

Aldolases are a group of C—C bond forming enzymes with widespread applications. The stereoselective aldol addition reaction catalyzed by aldolases represents an attractive alternative to conventional chiral organic chemistry methods for chemical and pharmaceutical industries. Aldolases are classified according to both their proposed catalytic mechanism and the structure of the donor substrate, their sources and microbial production processes being presented in this chapter. To design appropriate bioreactors for aldol synthesis, the characteristics of aldolase biocatalysts obtained after purification procedures in free and immobilized form are discussed. 

A Directed Aldol Synthesis Using a Lithium Enoiate... 

Outline a directed aldol synthesis of the following compound. 

PRACTICE PROBLEM 19.15 Starting with ketones and aldehydes of your choice, outline a directed aldol synthesis of... 

A MECHANISM FOR THE REACTION ] A Directed Aldol Synthesis Using a Lithium Enolate 875... 

In 2005 Yamamoto et al. reported the first example of asymmetric Bronsted acid-catalysed nitroso-aldol synthesis in particular 1-naphthyl-TADDOL 2a was particularly efficient in promoting the addition of achiral enamines 22 to nitrosobenzene with high regio- and enantioselectivities (Scheme 24.8). ... 

Since the Wittig synthesis is a longer one that begins with a more complex starting material, the simpler aldol synthesis is likely to be the preferred route in this case. 

The inefficient equilibrium constant of the NeuA reaction usually requires an excess of pyravate (5) to drive the product formation. Such comphcations may be circumvented altogether by coupling the aldol synthesis (e.g., 4 -I- 5 o-1) to a thermodynamically favored process, for example, by combination with a practically irreversible formation of sialoconjugates via nucleotide activation and sialyltransfer (Scheme 17.19). This principle has been utihzed early on for the one-pot preparation of complex sialylated oligosaccharides [71], even including in situ cofactor... 

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