Acid Aldol, with thioester

BBN trifluoromethanesulphonate is a useful reagent for allowing directed aldol condensations between aldehydes and ketones.(EtSjaB reacts with carboxylic acids to give thioesters, RCOSEt, whilst trialkoxyboranes may be converted into alkenes (Bp3,OEt2) or alkyl halides (HCl-ZnCl2). ... 

Grignard reagents such as 66a have been successfully added to a,p-iuisaturated thioesters 67 in the presence of the Cu/JOSIPHOS catalyst (Scheme 11.26) with high enantioselectivity. The diastereoselectivity for the second aldol process was controlled by the bulkiness of the substituent of the enolate at the y-position. This methodology has served for the synthesis of phaseolinic acid, a paraconic acid derivative with... 

A similar aldol reaction is encountered in the Krebs cycle in the reaction of acetyl-CoA and oxaloacetic acid (see Section 15.3). This yields citric acid, and is catalysed by the enzyme citrate synthase. This intermediate provides the alternative terminology for the Krebs cycle, namely the citric acid cycle. The aldol reaction is easily rationalized, with acetyl-CoA providing an enolate anion nucleophile that adds to the carbonyl of oxaloacetic acid. We shall see later that esters and thioesters can also be converted into enolate anions (see Section 10.7). 

The Krebs cycle intermediate that reacts with acetyl-CoA is oxaloacetate, and this reacts via an aldol reaction, giving citryl-CoA. However, the enzyme citrate synthase also carries out hydrolysis of the thioester linkage, so that the product is citrate hence the terminology citric acid cycle . The hydrolysis of the thioester is actually responsible for disturbing the eqnilibrinm and driving the reaction to completion. 

Polycarboxylic acid synthases. Several enzymes, including citrate synthase, the key enzyme which catalyzes the first step of the citric acid cycle, promote condensations of acetyl-CoA with ketones (Eq. 13-38). An a-oxo acid is most often the second substrate, and a thioester intermediate (Eq. 13-38) undergoes hydrolysis to release coenzyme A.199 Because the substrate acetyl-CoA is a thioester, the reaction is often described as a Claisen condensation. The same enzyme that catalyzes the condensation of acetyl-CoA with a ketone also catalyzes the second step, the hydrolysis of the CoA thioester. These polycarboxylic acid synthases are important in biosynthesis. They carry out the initial steps in a general chain elongation process (Fig. 17-18). While one function of the thioester group in acetyl-CoA is to activate the methyl hydrogens toward the aldol condensation, the subsequent hydrolysis of the thioester linkage provides for overall irreversibility and "drives" the synthetic reaction. 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

Optically active 1,2-diol units are often observed in nature as carbohydrates, macrolides or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol units with high enantioselectivities. However, there still remain some problems, for example, preparation of the optically active anti-1,2-diols and so on. The asymmetric aldol reaction of an enol silyl ether derived from a-benzyloxy thioester with aldehydes was developed in order to introduce two hydroxyl groups simultaneously with stereoselective carbon-carbon bond formation by using the chiral tin(II) Lewis acid. For example, various optically active anti-a,p-dihydroxy thioester derivatives are obtained in good yields with excellent diastereo-... 

Copper Lewis acids have found many applications in the last decade in a variety of organic transformations and more notably in enantioselective reactions. In particular, Cu(OTf)2 and Cu(SbFg)2 in conjunction with chiral bisoxazolines are the chiral Lewis acids of choice for cycloadditions, aldol reactions, ene reactions, and other selective transformations. Moderately Lewis acidic copper salts are also reagents for transesterifications, dehydrations, and hydrolysis. The thiophilic nature of copper makes them ideal for selective deprotection of thio acetals and thioesters and offer practical advantages over mercury salts. 

Fats and carbohydrates are metabolized down to carbon dioxide via an acetyl unit, CH3C=0, which is attached to a coenzyme, HSCoA, as a thioester called acetyl CoA. Acetyl CoA enters the citric acid cycle and eventually is converted to two molecules of carbon dioxide. The first step in the citric acid cycle is the aldol of acetyl CoA with oxaloacetate (Fig. 8.6). What is so elegant about this aldol is that the acidic and basic groups within the enzyme s active site provide a route that avoids any strongly acidic or basic intermediates. The enzyme accomplishes an aldol reaction at neutral pH, without an acidic protonated carbonyl or basic enolate intermediate via push-pull catalysis (Section 7.4.3). 

The synthesis of the E-ring 476 started with aldehyde 473, prepared via boron-mediated aldol reaction. FeUdn-selective Lewis acid-catalyzed aldol reaction of 473 with thioketene acetal afforded a-alcohol 474 (dr = 94 6). Fukuyama reduction of thioester to aldehyde followed by hemiacetalization and TBS protection furnished the E-ring 475, which was converted into phenylsulfone 476 in standard fashion. 

Carbon-carbon bond formation is a reaction of fundamental importance to the cellular metabolism of all living systems and includes alkylation reactions involving one and five carbon fragments as well as carboxylation reactions. In addition, a very common method of generating carbon-carbon bonds in biology includes the reactions of enolates and their equivalents (such as enamines) with aldehydes, ketones, keto acids, and esters. Reactions in which the enolate derives from an acyl thioester are Claisen condensations, whereas the remainder are classified as aldol reactions. 

Thiomethyl-PS 6b, prepared from Merrifield s resin la by reaction with thioacetate followed by reduction, can be acylated to give thioesters [263]. The resin-bound thioesters have been converted to silyl enol ethers, which were shown to form aldol products that could be released from the resin by three methods [264], Thus, reduction with lithium borohydride or diisobutylaluminum hydride (DIBAL) gave diols and aldehydes, respectively alternatively, base hydrolysis afforded carboxylic acids. Resin 6b thereby extends the range of functional groups available compared with cleavage of related molecules from an ester anchor. 

A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(II) carboxylic thioester enolates with imines has been reported (Scheme 90) the method was used to synthesize an intermediate of the carbapenem antibiotic... 

Titanium complexes are often encountered in Lewis acid-catalysed reactions. This is certainly true for catalysed aldol reactions. Mikami and Matsukawa demonstrated that titanium/BINOL complexes e.g. complex (7.20) afforded high yield and enantioselectivity in the aldol reactions of thioester ketene silylacetals with a variety of aldehydes. In contrast to some of the aldol reactions described above, the stereochemistry of the adducts is dependant on the geometry of the enol ether. Thus, reaction of the (B)-enol ether (7.21) with aldehyde (7.22) yields the sy -aldol adduct (7.23) predominantly while the (Z)-e.no ether (7.24) results in isolation of the anti-adduct (7.25) as the major product. The authors invoke a closed silatropic ene transition state (structure (7.26) for syn-transition state), substantiated by suitable crossover experiments, to explain the diastereoselectivities... 

The isomeric 2-deoxy-2-C-methyl-pentonic acids (34) have been prepared by Lewis acid-catalysed aldol condensation of the thioester silyl ketene acetal (35) with 2,3-di-O-benzyl-D-glyceraldehyde either epimer can be obtained as the major product depending on the precise experimental procedure adopted. 

Malonic acid half thioesters, H02C-CH(R )-C0-SR (R =H/Me), undergo an enantioselective decarboxylative aldol reaction with aldehydes, using a chiral catalyst bearing a hydrogen-bond donor and acceptor. In situ ESI-MS evidence supports a complex between the conjugate base of the substrate and the conjugate acid of the... 

In the first reaction of the citric acid cycle, acetyl-CoA reacts with oxaloacetate to form citrate. The mechanism for the reaction shows that an aspartate side chain of the enzyme removes a proton from the a-carbon of acetyl-CoA, creating an enolate ion. This enolate ion adds to the keto carbonyl carbon of oxaloacetate and the carbonyl oxygen picks up a proton from a histidine side chain. This is similar to an aldol addition where the a-carbanion (enolate ion) of one molecule is the nucleophile and the carbonyl carbon of another is the electrophile (Section 18.10). The intermediate (a thioester) that results is hydrolyzed to citrate in a nucleophilic addition-elimination reaction (Section 16.9). 

Enantioselective Aldol Additions. The reagent undergoes Lewis acid-catalyzed Mukaiyama-type additions to aldehydes to give -hydroxy thioesters with good yields and remarkable enan-tioselectivity (eq l). Slow addition of the aldehyde (3-20 h) is necessary for high enantioselectivity. ... 

This interesting and promising result prompted us to examine the use of Sc(OTf)3 as a Lewis-acid catalyst in the aldol reactions of silyl enolates with carbonyl compounds. Several examples of the Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were examined. Silyl enolates derived from ketones, thioesters and esters reacted smoothly with aldehydes in the presence of 5mol% of Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in the aldol-type... 

Many aldehydes react with the (E) silicon enolate [63] derived from propionic acid thioester 79, to give syn aldol adducts in high yield and with perfect stereochemical control, by combined use of tin(II) trifiate, chiral diamine 80, and dibutyltin acetate (Eq. (41)) [64-66]... 

Mevalonic acid itself is a product of acetate metabolism. Three molecules of acetate coenzyme A, produced by the citric acid cycle, are used to form mevalonic acid (Scheme 5.1). Two molecules undergo a Claisen condensation via acetyl-CoA-acetyltransferase enzyme [EC 2.3.1.9] to produce acetoacetyl-CoA, and a third is incorporated in a stereospecific aldol addition to the formation of p-hydroxy-p-methylglutaryl-CoA (HMG-CoA) by the aid of HMG-CoA synthase [EC 2.3.3.10]. The first Claisen reaction was found to involve formation of Cys-89 acetyl-5-enzyme reaction intermediate [9]. Then, Cys-378 residue on the active site of the enzyme activates a second molecule of acetyl-CoA to initiate the condensation reaction (Fig. 5.4) [11]. Similarly, in HMG-CoA synthases (S. aureus HMG-CoA synthase), Cysl 11/129 are the crucial residues of covalent attach to acetyl-CoA to produce acetyl-enzyme thioester with the subsequent loss of coenzyme A (Fig. 5.4). Glu79/95 residues are responsible for the enolization of acetyl-enzyme intermediate in order to react with acetoacetyl-CoA, which is bound to His233/264 residues [12]. 

In the first step, acetate (as a coenzyme A thioester) plus malonate gives acetoacetate, just as for the fatty acids. The next step is a different kind of reaction. Another acetate unit (as malonate) is added via an aldol condensation, using a HMG-CoA synthase enzyme, to give 3-hydroxy-P-methylglutaryl coenzyme A (HMG-CoA). This is reduced by NADPH with a HMG-CoA reductase to mevalonic acid (MVA) in the ratedetermining step for the whole sequence of reactions that builds up the... 

---