Aldol reaction stereospecific

Scheme 2.6 Late generation synthesis of desoxy epothilone B and epothilone B. The key steps in this total synthesis are a stereospecific aldol reaction, B-alkyl Suzuki coupling, and stereoselective Noyori reaction.

Fig. 24 (a, b) Chemo-enzymatic process for synthesis of tetrahydroxylated pyrrolizidines 1-epi-alexine, australine and 3-epi-australine utilising dihydroxyacetone phosphate (DHAP), stereospecific aldol reaction catalysed by fructose-1.6-diphosphate aldolase (FDPA) and acid phosphatase (Pase) [149]... 

Scheme 5.65. p-di ketone chemical trap hapten. Stereospecific aldol reaction catalyzed by the elicited catalytic antibodies Ab38C2 and Ab33F12. 

Figure 8.5 The stereospecific aldol reaction goes via the least hindered chair transition state.

The first total synthesis of trihydroxydecipiadiene (45), a member of the structurally unique decipiene diterpenes, has been reported. A route involving cycloaddition of dichloroketen and reductive dehalogenation led to (42) which was found to undergo a stereospecific aldol reaction to give (43) under carefully controlled conditions. As expected, catalytic hydrogen was stereospecific giving the desired isomer (44), which in turn was converted to (45) in several steps. 

The aldol reaction has been known for over a century. Though largely attributed to Wilrtz, the first aldol reaction was reported several years earlier by Borodin.81 813 Stimulated by the observation that (Z)- and (A)-enolates react stereospecifically to provide syn- and //////-aldol addition products, several catalytic systems for aldol addition... 

An interesting problem in stereoisomerism is found in the aldol reactions of the achiral aldehydes which are obtained by ozonolysis of the homoallylic alcohols 174. After stereospecific conversion by the FruA [230], the products can be readily induced to form an intramolecular glycoside 175 by acidic (R=OH) or alkaline treatment (R=C1), under which conditions the two equatorial ring hydroxyl groups completely direct the stereogenic acetal formation [234]. The corresponding RhuA catalyzed reactions deliver the enantiomeric... 

The six-member ed transition state for the reaction of an allylic borane or boron ate is very reminiscent of the cyclic transition state for the aldol reaction you met in Chapter 34. In this case the only change is to replace the oxygen of the enolate with a carbon to make the allyl nucleophile. The transition state for the aldol reaction was a chair and the reaction was stereospecific so that the geometry of the enolate determined the stereochemistry of the product aldol. The same is true in these reactions. -Crotyl boranes (or boronates) give anti homoallylic alcohols and Z-crotyl boranes (or boronates)... 

The use of enzymes for the aldol reaction complements traditional chemical approaches. In the early twentieth century a class of enzymes was recognized that catalyzes, by an aldol condensation, the reversible formation of hexoses from their three carbon components.3 The lyases that catalyze the aldol reaction, are referred to as aldolases. More than 30 aldolases have been characterized to date. These aldolases are capable of stereospecifically catalyzing the reversible addition of a ketone or aldehyde donor to an aldehyde acceptor. Two distinct mechanistic classes of aldolases have been identified (Scheme 5.1).4... 

The Aldol reaction is one of the most powerful methods for creating the C-C bond. Typical conditions involve the formation of an enolate, usually with a stoichiometric equivalent of base. Stereoinduction is nsnally accomplished with chiral enolates, aldehydes, or auxiliaries.Nature, however, is much more efficient, having created enzymes that both catalyze the aldol reaction and produce stereospecific product. These enzymes, called aldolases, are of two types. The type II aldolases make use of a zinc enolate. Of interest for this section are the type I aldolases, which make use of enamine intermediates. Sketched in Scheme 6.6 is... 

The enzymatic aldol reaction represents a useful method for the synthesis of various sugars and sugar-like structures. More than 20 different aldolases have been isolated (see Table 13.1 for examples) and several of these have been cloned and overexpressed. They catalyze the stereospecific aldol condensation of an aldehyde with a ketone donor. Two types of aldolases are known. Type I aldolases, found primarily in animals and higher plants, do not require any cofactor. The x-ray structure of rabbit muscle aldolase (RAMA) indicates that Lys-229 is responsible for Schiff-base formation with dihydroxyacetone phosphate (DHAP) (Scheme 13.7a). Type II aldolases, found primarily in micro-organisms, use Zn as a cofactor, which acts as a Lewis acid enhancing the electrophilicity of the ketone (Scheme 13.7b). In both cases, the aldolases accept a variety of natural (Table 13.1) and non-natural acceptor substrates (Scheme 13.8). 

SCHEME 13.9 Stereospecific FDPaldolase-catalyzed aldol reaction of DHAP + G3P FDP. 

In the next example, the chiral ketone happens to be optically pure but it is still an example of relative stereocontrol. We shall see more of relative stereocontrol with optically pure materials in Chapter 30. We saw in the Diels-Alder reaction that different features of reactivity are responsible for different aspects of resulting stereochemistry — geometry of starting materials, stereospecificity of reaction and endo selectivity all have their part to play. Ketone 177 is reacted with a boron chloride to give boron enolate 178. Significantly, this is a trans enolate which means we can expect an anti relationship from the aldol reaction which we do indeed see 179. 

One normally expects antibodies to have a low tolerance to substrate modifications, however an ongoing feature of these aldolase antibodies is their wide scope. They accept a remarkable range of aldol donors and acceptors and perform crossed-, intramolecular- and retro-variants of this reaction, with high yields, rates, and stereospecificities [81,82,83]. Substrate modification experiments have revealed that when acetone is the aldol donor in a ketone-aldehyde crossed aldol reaction, stereoinduction is linked to attack of the sz-face of a prochiral aldehyde with typically >95% ee and when hydroxyacetone is the donor substrate, attack occurs preferentially at the re-face of the aldehyde leading to a diastereomeric a,P-dihydroxy ketones with the two stereogenic centers having an a-syn configuration. This reaction leads to stereospecificities of typically 70 to >99% ee. 

An intramolecular counterpart of the photochemical step used in the formation of (6) has been successfully applied to the synthesis of 12-epi-lycopodine (14). Photolysis of (10) yielded the intermediate (11) which was converted into the diketone (12). The latter compound gave the aldol product (13) which, in four steps, produced 12-epi-lycopodine (14). An amazing simplification of the overall route resulted when it was found that the diketolactam corresponding to the ketal (15) underwent a stereospecific Michael reaction to give (13) directly in 30% yield. 

Addition of lithium enolate (56) to trifluorocrotonate (55) proceeded smoothly in almost quantitative yields with excellent stereoselectivity. The intramolecular chelation in 57 retards the retro-aldol reaction. On the other hand, nonfluorinated crotonate (59) provided 60 in a poor yield because of the faster retro-aldol reaction [26]. The stereochemistry of the chelated intermediate (57) was proven by trapping 57 as its ketenesilylacetal (61). Pd-catalyzed Ireland-Claisen rearrangement of 61 proceeded stereospecifically to give a single stereoisomer (62), suggesting a rigid control of the three consecutive stereocenters (Scheme 3.12) [27]. 

Trimethylsilyl enol ethers react rapidly with boryl triflate reagents (Scheme 26). Subsequent aldol reaction occurs with apparent stereospecificity provided that the by-product trimethylsilyl triflate is... 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

A nice example of the foregoing stratagem is seen in equation (17) enone (6) undergoes copper(I)-catalyzed reaction with vinylmagnesium bromide from its less-hindered face to give an enolate that reacts with formaldehyde from the opposite face to provide decalone (7), an intermediate in the synthesis of insect antifeedants. Yoshida and coworkers have used this method for the stereospecific generation of tetrasubstituted thioamide enolates, which undergo remarkably stereoselective aldol reactions (equation 18). ° The stereochemistry of this process is discussed in Section 1.6.3.6. 

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