Subject synthons

A saturated alkyl group does not exhibit functionality. It is not a d -synthon, because the functional groups, e.g. halide or metal ions, are lost in the course of the reaction. It functions as an alkyl synthon. Alkenyl anions (R. West, 1961) on the other hand, constitute d -synthons, because the C = C group remains in the product and may be subject to further synthetic operations. 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

Chrzanowska and Rozwadowska (60) performed a total synthesis of ( )-43, using amine 49 and the thioacetal of methoxycarbonylpiperonal (26) as substrates (Scheme 13). These two synthons were joined together under the influence of LDA, and the resulting addition product 50 was subjected to reductive desulfurization with Raney nickel to give racemic peshawarine (43). 

This landmark discovery paved the way for the development of transition metal-catalyzed hydroboration. The conversion of an alkene into an organoborane intermediate has made this a valuable synthetic technique, particularly since the development of enantioselective variants.9,10 They serve as synthons for numerous functional groups11 and are often subjected to a consecutive carbon-oxygen, carbon-carbon, boron-carbon, boron-chlorine, or carbon-nitrogen24 bond-forming reaction (Scheme 3). 

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. 

Some subsequent discussion on compound 3 followed our original paper on this subject (N. Masciocchi, M. Bergamo, A. Sironi, Comments on the elusive crystal structure of 4-iodo-4 -nitrobiphenyl Chem. Comm, 1998,1347-1348 J. Hulliger, P. J. Langley, On intrinsic and extrinsic defect-forming mechanisms determining the disordered structure of 4-iodo-4 -nitrobi-phenyl Chem Comm, 1998, 2557-2558), but these papers, which describe the effects of small amounts of 4,4 -dinitrobiphenyl impurity in 3, only reinforce the idea of structures based on N02—I synthons. 

The identification of the set of interactions that constitute a synthon is, in the end, subjective. In the limit, any possible combination of interactions may be defined as a supramolecular synthon but then there is the risk that the term will be degraded or fall into disuse much like its molecular sibling. Interactions or groups of interactions that are needlessly identified as supramolecular synthons, but are unable subsequently to sustain a predictive role in crystal engineering, will... 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

The oxidation of sulfides to sulfones has been the subject of extensive studies, since sulfones are useful synthons for the construction of various chemically and biologically significant moleculesJ Recently, a new catalytic system has been developed by exchanging potassium osmate onto chloride-saturated layered double hydroxides (Figure 9.1), which we have shown to be an efficient catalyst for the direct oxidation of sulfides to sulfones, using molecular oxygen as the stoichiometric oxidant and with delivery of two oxygen atoms simultaneously to the sulfide, reminiscent of olefin dihydroxylation reactions. 

A beautiful extension of this reaction has recently been communicated by Nozaki, Oshima, and Utimo-to.184 These workers simply admixed f-butyl iodide (3 equiv.), benzaldehyde (1 equiv.), methyl vinyl ketone (1 equiv.) and triethylborane (1 equiv.) in benzene (Scheme 60). After 5 min at 25 C, the reaction was subjected to standard extractive work-up and the crude product was purified by chromatography to give (54) in 63% yield. If methanol is substituted for benzaldehyde, the protonated product (55) is isolated in 79% yield. Although enones are equivalents of synthon (56), such a direct coupling of radical and ionic reactions had not been achieved previously. 

Among the numerous classes of heterocyclic cations that are now actively studied, pyrylium salts are distinguished by the extraordinary variety of their transformations, making them good synthons and widely applicable. An exhaustive review on this subject has been published by an international group of chemists dealing with pyrylium chemistry [82AHC(Suppl.)]. 

Treatment of 6-(2-bromoethyl)-2,2 -bipyridine with lithiophosphine afforded the corresponding 2-diphenylphosphinoethyl derivative, which when subjected to [Ru(CO)2Cl2] in methanol at 25 °C to gave the 2 1 metallo-synthon possessing tram phosphane ligands addition of Cu(I) generated the 36-membered metallocycle 28 [95CC2033]. 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

To cover the reductive behavior of all types of heterocycles bearing more than one heteroatom within the confines of one brief chapter is impossible, thus the content of this chapter has been edited to reflect those topics and systems in which there is most interest. Many polycyclic and less common heterocyclic molecules are not included. Similarly the weighting of the subject matter is not uniform, and greater emphasis is placed on those areas where the reduction of heterocycles gives access to useful synthons or provides templates which exert stereochemical control in target-orientated syntheses. 

Since R-48 is also an important versatile synthon for prostaglandin synthesis, there has been interest in devising asymmetric methods for its preparation. Japanese workers 7 subjected a 1 1 mixture of cis and trans 44 to esterases from baker s yeast and were able to obtain the optically active (R,R)-45, (R,R)-46 and (S)-predominant 47. Thus a simultaneous kinetic resolution of the dlacetate (44) and asymmetric synthesis of the monoacetate (46) were effected by this hydrolysis. These were converted to prostaglandin synthons.6 ... 

---