Natural synthons

If we attempt the disconnection of one of the other bonds, two possibilities are available because the two fragments are different. We can use either ad1 -fa3 strategy or an a1 + d3 strategy. In each case w have one natural synthon and one with umpolung. 

The 1,2- and 1,4-relationships require one synthon of unnatural polarity, such as (6). (7), or (8), in combination with a natural synthon from Table 18.1, and these relationships follow in Chapters 23 and 25. The 1,6-relationship is left until last (Chapter 27) as it requires a new logic—that of reconnection instead of disconnection. 

A better strategy is to change the 1,4-reIationship in (9) into a 1,3-relationship (11) by removing the CH2 group so that natural synthon (12) can be used. 

Unsaturated ester (8) is made by dehydration of alcohol <9). The next disconnection should be of bond (a) in (9) but this needs the unnatural synthon <10). A better strategy is to change the 1,4-relationship in (9) into a 1,3-relationship (11) by removing the CHa group so that natural synthon (12) can be used. 

For skeletal bond-forming reactions in the Lewis-acid realm, the reactive electrophile, an a-synthon, is frequently not used in a stoichiometric fashion, but is generated in substoichiometric amounts in situ in the presence of the donor partner. This can be achieved via in situ umpolung from a d -synthon to an a -synthon, which appears to be a rather roundabout way to reach a natural synthon. The in situ technique, though, has an advantage, because the presence of the less readily oxidized donor partner suppresses any undesired homocoupling (cf. Scheme 2.16) in the oxidation of the starting d -synthon (Scheme 2.21). 

Bond formation between two functionalities in a 7,i-relationship can be readily achieved using natural synthons. Hence, this is the standard way to accomphsh this task (Scheme 2.48). 

Aside from the standard use of natural synthons and the routes via double umpolung, there is the possibility of enlisting 1,3-dipolar cycloadditions to form 7,5-difunctionalized molecular skeletons. Typical examples include the addition of nitrones, silyl nitronates [94], or nitrile oxides to alkenes. The initial products of the latter cycloaddition are isoxazolines, which may be refunctionalized in various ways (Scheme 2.52). When this generates sensitive functionalities, refunctionalization may be postponed until later in the synthesis sequence [95]. 

A disconnection at bond C in Scheme 2.65 favors the polarity pattern with natural synthons (Scheme 13.11). 

Groups. The acidic surface groups that result from surface oxidation of carbon black are natural synthons for the attachment of fimctionality. Generally, chemistry is done through either phenolic or carboxylic acid groups on the surface. Some... 

SCHEME 1.9 (a) Biosynthetic pathway of wUd-type metabolites (b) precursor-directed biosynthesis the modified synthon B replaces the natural synthon B (c) biosynthetic pathway blocked by a mutation (the enzyme E4 is not functional) (d) mutasynthesis a mutasynthon B is introduced to replace B and is incorporated in the biosynthesis, leading to a mutated natural product. 

PLE catalyzes the hydrolysis of a wide range of meso-diesters (Table 2). This reaction is interesting from both theoretical and practical standpoints. Indeed, the analysis of a large range of kinetic data provided sufficient information to create a detailed active site model of PLE (31). From a practical standpoint, selective hydrolysis of y j (9-cyclo-I,2-dicarboxylates leads to chiral synthons that are valuable intermediates for the synthesis of a variety of natural products. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

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