In cyclic substrates

The presence of an amine or amide group in cyclic substrates greatly fiicilitates the hydroxylation by Beauveria sulfurescens. Numerous mono-, di- and tri-cyclic amides and saturated nitrogen heterocycles have been stuped and a rational basis for the position at vriiich the hydroxy group is inttoduced into the substrate molecule has been put forward however, yet more work is required to define all the factors controlling the selectivi of hydroxylation. Neverdieless useful regio-, stereo- and in some cases... 

The use of osmium tetroxide for the conversion of an alkene to a 1,2-diol is a well-established reaction [19-22]. The formation of an intermediate cyclic ester accounts for the cis-stereochemistry [21, 23-32] as reaction occurs on the least hindered face of the alkene [21, 30, 33-38]. This steric effect is amplified in cyclic substrates [39, 40]. The reaction conditions have to be carefully controlled to avoid oxidative cleavage of the diol product [28]. 

The control of stereoselectivity in acyclic substrates is more difficult than in cyclic substrates. As discussed previously, palladium can serve as a template to provide rigidity in an acyclic system thus favoring higher stereoselectivity. Palladium(0)-mediated substitution of the chiral nonracemic ally acetate depicted below yields only racemic material68, n-o-n Rearrangement of the intermediate 7t-allyl complex involving the unsubstituted allyl terminus is probably faster than nucleophilic attack. 

The rearrangement of the optically active oxy-Cope substrates 9 and 10 to (S)-ll with 28% cc and (7 )-l 1 with 18%ee, respectively, indicates that the equatorial/axial preference of the alkoxide in acyclic systems is not as significant as in cyclic substrates. The low selectivity might be explained by the fact that the preference for the equatorial position of the alkoxide group is compensated, in part, by a positive stereoelectronic contribution to the lowest unoccupied orbital of the molecule 1 30,995. 

It has even been suggested that the ester 4 is formed directly from the zwit-terion 2 In our opinion this does not seem very likely. We will discuss successively the second step of this mechanism in juxtacyclict linear series, as well as in cyclic series. In linear substrates the transformation of 1 via the cyclopropanone intermediate 3, or via the zwitterion 2, will depend on the base strength and the solvation. In cyclic substrates, structural features will have to be considered in addition. 

Further examples indicating the retention mechanism in cyclic substrates are provided by the reactions of substrates 93 and 94 that lead to the respective products 95 and 96. 

The classic method for controlling stereochemistry is to perform reactions on cyclic substrates. A rather lengthy but nonetheless efficient example in the prostaglandin field uses bicyclic structures for this purpose. Bisacetic acid derivative S is available in five steps from Diels-Alder reaction of trans-piperylene and maleic anhydride followed by side-chain homologation. Bromolactonization locks the molecule as bicyclic intermediate Esterification, reductive dehalogen-... 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

Such effects are observed inter alia when a metal is electrochemically deposited on a foreign substrate (e.g. Pb on graphite), a process which requires an additional nucleation overpotential. Thus, in cyclic voltammetry metal is deposited during the reverse scan on an identical metallic surface at thermodynamically favourable potentials, i.e. at positive values relative to the nucleation overpotential. This generates the typical trace-crossing in the current-voltage curve. Hence, Pletcher et al. also view the trace-crossing as proof of the start of the nucleation process of the polymer film, especially as it appears only in experiments with freshly polished electrodes. But this is about as far as we can go with cyclic voltammetry alone. It must be complemented by other techniques the potential step methods and optical spectroscopy have proved suitable. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

In anti addition to a cyclic substrate, the initial attack by the electrophile is also from the less-hindered face. However, many (though not all) electrophilic additions to norbomene and similar strained bicycloalkenes are syn additions." In these cases attack is always from the exo side, for example," ... 

In addition to the cyclic substrates described above, several open-chain compounds are known to undergo heterolytic cleavage of a carbon-carbon tr bond. 

Owing to flexibility in the substrate, the TycATE was also used to synthesize a variety of novel cyclic structures. Inclusion of a propargylated amino acid into the linear substrate allowed the synthesis of over 247 macrocyclic glycopeptides, where azido-sugars were coupled onto the cyclized alkyne via copper-catalyzed 1,3-dipolar cycloaddition [44] (Figure 13.12). 

Ketone p-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

PHENAP 65 was prepared and resolved98 in a similar manner to QUINAP 60 and tested in asymmetric rhodium-catalyzed hydroboration-oxidations." Impressive enantioselectivities were obtained and the sterically demanding cyclic substrates were hydroborated with 64-84% ee. Compared to the corresponding results obtained with diphosphine ligands, it is clear that QUINAP 60, and structural relatives 61-64 and PHENAP 65, give superior results in the asymmetric rhodium-catalyzed hydroboration of several vinylarenes, and are essentially the only practical solution for / -substituted alkenes.100 The reasons for this are not well understood, but thought to be due to the particular... 

The reaction also tolerated the thiol group on the cyclic substrate butylthio-cyclooctene 37 was ring-opened in the presence of an excess of ethene to give a good yield of the diene 38 (Eq. 30). 

Use of a symmetrical acyclic alkene limits the possible metathesis products to the desired diene (for example 45) and products formed from polymerisation of the cyclic substrate. Competing ROMP was suppressed in these reactions by using dilute conditions and a tenfold excess of hex-3-ene. By adding the cyclic substrate slowly to a solution of the catalyst and ris-hex-3-ene (which was significantly more reactive than the trans isomer), less than two equivalents of the acyclic alkene were used without causing a significant drop in the cross-metathesis yield. 

Good levels of regioselectivity were observed, however, when analogous cyclic substrates containing a hydroxy (51) or methyl substituent (52) projecting from the exo-face of the cyclobutene were used. Formation of exclusively tram double bonds in the major regioisomers was also observed with these substrates (Eq. 37) (Table 4). 

In these reactions, the major diastereomer is formed by the addition of hydrogen syn to the hydroxyl group in the substrate. The cationic iridium catalyst [Ir(PCy3)(py)(nbd)]+ is very effective in hydroxy-directive hydrogenation of cyclic alcohols to afford high diastereoselectivity, even in the case of bishomoallyl alcohols (Table 21.4, entries 10-13) [5, 34, 35]. An intermediary dihydride species is not observed in the case of rhodium complexes, but iridium dihydride species are observed and the interaction of the hydroxyl unit of an unsaturated alcohol with iridium is detected spectrometrically through the presence of diastereotopic hydrides using NMR spectroscopy [21]. 

Other functional groups which have a heteroatom rather than a hydroxyl group capable of directing the hydrogenation include alkoxyl, alkoxycarbonyl, carboxylate, amide, carbamate, and sulfoxide. The alkoxy unit efficiently coordinates to cationic iridium or rhodium complexes, and high diastereoselectivity is induced in the reactions of cyclic substrates (Table 21.3, entries 11-13) [25, 28]. An acetal affords much lower selectivity than the corresponding unsaturated ketone (Table 21.3, entries 14 and 15) [25]. 

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