Synthon isomeric

The subsynthons S (X) are generated by fixed rules and cannot therefore be modified. We turn our effort to devising an additional tool for modifying the valence states of atoms outside X in the synthon S(A) such that the formed new synthons isomeric to S(A) are classified as SPS. This approach is called stabilization. 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

Note When such synthons are unsymmetric, they can give rise to isomeric products on condensation with unsymmetric substrates. 

Direct oxidation of A9-THC at position C-11 involves mainly an isomerization to A8-THC another opportimity in the synthesis of A9-THC-metabolites is the pretreatment of terpenoid synthons by introduction of protective groups, e.g., 1,3-dithiane (6.1 in Fig. 6) followed by the condensation with olivetol (6.2) [76]. The formed product is a protected derivate... 

A one-pot three-step conversion of aryl fluorides to phenols based on a consecutive nucleophilic aromatic substitution/isomerization/hydrolysis sequence has been reported by Levin and Du (Scheme 6.126) [256], The authors discovered that 2-butyn-l-ol can function as a hydroxyl synthon through consecutive SNAr displacement, in situ isomerization to the allenyl ether, and subsequent hydrolysis, to afford phenols rapidly and in good yields. In most cases, excesses of 2-butyn-l-ol (1-2 equivalents) and potassium tert-butoxidc (2-4 equivalents) were required in order to achieve optimum yields. 

The growing interest in enantioselective isomerization of meso oxiranes to allylic alcohols arises from the ready availabihty of starting materials and the synthetic value of the homochiral products. First apphed to simple meso cycloalkene oxides, this methodology has been successfully exteuded to fuuctioualized meso oxiranes, and even to the kinetic resolution of racemic oxiranes, demonstrating its potential in accessing highly advanced synthons. 

As discussed in Sect. 3.4, the synthon 20 was prepared from the dibromo-heptonolactone, which in turn was obtained from the cheap commercially available D-g(ycero-D-gM/o-heptono-l,4-lactone (Table 1). The other isomeric dibro-moheptonolactones shown in Table 1, which were prepared from the heptonates, obtained from chain extension of o-mannose and o-galactose, respectively, were also converted into unsaturated bromodeoxyheptonolactones. Finally, we obtained 2-0-acetyl-7-bromo-3,7-dideoxy-D-x7(o-hept-2-enono-l,4-lactone and the corresponding D-/yxo-isomer by the Kiliani extension of o-gulose. These substrates were all cyclized to cyclopentane lactones, stereoisomers of 65 [98]. 

Table I illustrates this synthesis in schematic form. The first column lists all functions A and B of the 1,3-dicarbonyl compounds or their equivalents that are used to introduce certain substituents R and R" into positions 5 and 7 e.g., unsubstituted TP is formed by malondialdehyde, the 5,7-dione by diethyl malonate, and the 5,7-diamine by malonitrile. Unsymmetrical C3-synthons with different A and B moieties may form two isomeric TPs in which R and R" interchange their positions. The direction of attack depends on both synthon structure and reaction conditions.

Because of their high reactivity, these complex salts react rapidly and regiospecifically, at low temperature, with a number of carbon and heteroatomic nucleophiles, including thiols, amines, and alcohols. Finally, exposure of the double bond takes place under particularly mild conditions so that isomerization of the (3,Y-unsaturated carbonyl system may be avoided. The present scope of reactions with these vinyl cation synthons is summarized in [able I. 

Regioselective isomerization of these p-methylenaldehydes in Et2NH produce the compound (E Z 97/3). These synthons were synthesized by formylation of ionones and concomitant acetalysation of the sodium salts of the hydroxymethylenic compounds. Wittig reaction and acidic hydrolysis of the p-methyleneacetals produced the p-methylenealdehydes. 

Few pyran-3-ones are known but 6-acetoxy-2,6-dihydropyran-3-one (590) dimerizes at room temperature in the presence of a base to give the diketone (591) on heating this at 140 °C, it isomerizes to dimer (592). This has a pair of each functional group but, as it is possible to react one of these selectively, the compound is valuable as a synthon (80JOC3361). 

A key compound for levoglucosan chemistry is 1,6-anhydro-2,4-di-<3-tosyl-/ -D-gl ucopyranose (36)176 which, after treatment with sodium ethoxide, affords a valuable starting compound, l,6 3,4-dianhydro-2-O-tosyl-jS-D-galactopyranose, as a single product (see Section IV. 1). Another example illustrating synthetic versatility of the ditosylate 36 is its oxidation to 3-keto derivative 37124.210.211 followed by reductive detosylation to afford the useful chiral synthon, l,6-anhydro-2,4-dideoxy-/i-D-g/ycero-hcxopyranos-3-ulose (38).210,212 Keto derivative 37 is readily isomerized by the action of pyridine into compounds of the D-arabino, D-xylo, and D-lyxo configurations.210... 

Supramolecular isomerism Supramolecular isomerism has been defined by Zaworotko64 as the existence of more than one type of network superstructure for the same molecular building blocks, and hence he adds that it is therefore related to structural isomerism at the molecular level. In cases where the molecular building blocks are capable of forming more than one type of supramolecular synthon then supramolecular isomerism is identical to polymorphism. Zaworotko defines another kind of supramolecular isomerism, however, in which the same building blocks exhibit different network architectures or superstructures. We will see examples of this phenomenon in chapter 9, particularly regarding interpenetrated networks. 

Usually, the a-pyranic addition products (3) cannot be isolated because they isomerize immediately in a thermally allowed electrocyclic process affording acyclic dienones (4), which in many cases react further. Therefore, pyrylium salts 2A react with most nucleophiles as if they had the electronic structure 2B, and thus the pyrylium cation behaves as a useful synthon, namely the last vinylog in the series of acyl halides (Cj synthon) - p-halovinyl ketones (C3 synthon) - pyrylium (C5 synthon) [50, 51],... 

A nickel catalyst containing Me-DuPhos has been shown to be effective in the enantioselective isomerization of 4,7-dihydro-l,3-dioxepins 72.71 Diastereoselective oxidation of the resulting 4,5-dihydro-l,3-dioxepins 73 allowed access to a range of C-4 chiral synthons (Scheme 13.26). 

Two large-scale syntheses were reported by Quaedflieg et al. at Tibotec.31 Chiral synthon 20, obtained from ascorbic acid, was converted to a,p-unsaturated ester 21 in 92% yield and E/Z ratio was > 95 5. Michael addition of nitromethane to 21 was carried out with DBU as base to provide 22 in 80% yield and a syn/anti ratio of 5.7 1. A Nef reaction then converted 22 to a mixture of lactone 23 (major, 56%) (a/p = 3.8 1) and ester 24 (minor). The a-23 was obtained via recrystallization in isopropanol (37%), with high enantiomeric purity (> 99%). Isomerization of P-23 followed by recrystallization in isopropyl alcohol gave an additional 9% yield of a-23. It is interesting that most of 24 remained in the aqueous layer. Lithium borohydride reduction of a-23 followed by acid-catalyzed cyclization resulted in (-)-ll. 

In several synthetic studies, cyclopropane derivatives were used as synthones or building elements for ring enlargement steps, e.g. reaction of enamines with cyclopropenone [65], synthesis of 2,3-dihydro-l,4-diazepine by thermal isomerization of 1,2-diamino-cyclopropanes [32] [66], and preparation of 3-amino-fulvenes from methylencyclopropenes with alkynamines [67]. 

Supramolecular isomerism also lies at the heart of gaining a better understanding of supramolecular synthons and, by inference, how they develop and occur in other solid phases and even solution. The Cambridge Structural Database remains a very powerful tool in this context but it must be remembered that even such a large database will not necessarily be reflective of the full range of compounds that will be isolated and characterized in future years. 

The notion of isomerism for synthons was defined in [18,21,16], in the present communication we shall study the synthons that are constructed over the same vertex set A. Therefore, they are automatically isomeric. The set of all synthons (nonisomorphic) constructed over the set A is called the family of isomeric synthons, and is denoted by 3F A). The synthons from a family will be advantageously classified in our forthcoming considerations as stable, unstable, and forbidden. This will be done by making use of the concept of valence states of vertices. 

The reaction distance [16,18,21,25] between two isomeric synthons Si (A) and S2(A) will be used as a proper tool for the construction of reaction graphs [29]. The reaction graph obtained corresponds to the minimal number of the so-called elementary chemical transformations, the number of which determines the reaction distance between the synthons SjfA) and S2(A). 

For a fixed family 3 (A) of isomeric synthons we construct the so-called graph of reaction distances [18, 21, 16, 25] denoted by RD(A). The vertex set of this graph is formally identical with the family A) without forbidden synthons, its two distinct vertices v and v, assigned to the synthons S(d) and S (/l), are connected by an edge [u, v ] if such an elementary transformation i = a, p exists so that the synthon S(/l) is transformed into the synthon i.e. 

The above outlined method can serve as an almost exact approach for the evaluation of reaction distance between two isomeric synthons S(A) and S (A). Its almost exactness follows from the fact that there can be no previously prescribed mapping of vertices and than the reaction graph is not unique. There can be constructed corresponding reaction graphs for every mapping and the reaction distance should be obtained as a minimum of minimal coverings of those reaction graphs. 

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