Barton procedure

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

Although the Barton procedure is usually successful with hindered carbonyls, failures or low yields have been noted. For example, ketone (10) was recovered unaltered, a result attributed to the extremely hindered environment of the carbonyl (lO was also unaffected by NaBHa and failed to give a semicarba-zone or 2,4-dinitrophenylhydrazone). Likewise, Barton conditions failed to remove the highly hindered ketone in a triterpenoid (partial structure 11). ... 

After deprotection of the methoxymethyl (MOM) ether under acidic conditions, alcohol 319 was deoxygenated through the Barton procedure to obtain the natural alkaloid (—)-pyrinodemin A (Scheme 72) <20030L2611>. 

The di-O-tosylates (prepared by action of tosyl chloride in pyridine) are reduced with zinc (Nal/Zn route e Tipson-Cohen reaction) [13]. Cyclic ortho-esters (prepared by reaction of the diol with ethyl orthoformate) are transformed into olefins by simple heating in the presence of acids (Eastwood reaction, route b) [14]. Cyclic thiocarbonates (obtained by reaction of a diol with thiophosgene or (V,(V -thiocarbonyl-di-imidazole) are reduced to olefin with trimethyl phosphite (Corey-Winter method, route c) [15]. Finally, reduction of vicinal di-xanthates with tri- -butyltin hydride according to the Barton procedure [16] affords olefins via a reductive elimination process route a). The Corey-Winter, Garegg, and Tipson-Cohen methods are most commonly applied for deoxygenation of sugar diols. 

The Ireland s)mthetic intermediate 176 was deoxygenated by the Barton procedure to provide 194 (O Scheme 22). Stepwise deprotection and protection of hydroxy groups in 194 afforded 195. De-O-tritylation and Swem oxidation of 195 gave the C10-C15 segment 192. As shown in Scheme 22, this aldehyde was transformed into the C10-C20 segment 197. 

There is one report of the hydroxymethylene bridge being deoxygenated using the Barton procedure, leading to the C-analog of lactose 130 [71] (O Scheme 26). 

An alternative approach to the stereocontrolled synthesis of ulosonic acids was based on nucleophilic acylation of 2,3 5,6-di-O-isopropylidene-D-mannose 173 with a glyoxylate carboanion [116] derived from the mercaptal glyoxylate (Scheme 37). As a result the corresponding thio-octulosonates 174 and 175 were formed in 76% yield. Both compounds were converted to 176 using NIS (or NBS) and then MeONa. Applying Barton procedure [117] 176 was deoxygenated at C-3 to afford KDO derivative 124. 

Removal of the C-2 substituent was accomplished by Chen and his colleagues, who prepared the xanthate 3.4.16 from the corresponding 2-debenzoylbaccatin III and then deoxygenated it by the Barton procedure. Side chain attachment gave 2-debenzoyloxytaxol 3.4.17 with 100-fold reduced cytotoxicity to the HCT116 cell line (722). 

Figure 10.23 Alternative halo-decarboxylation following the Barton procedure...

Another elegant procedure is that devised by Barton for the introduction of a 17a-hydroxyl group into a 20-ketopregnane. As is so often the case, the method arose as a matter of commercial necessity, since the more traditional procedures were not completely successful with the substrates being used in a particular technical synthesis. The original sequence is as follows ... 

On using Barton-oxidation procedures cyclohexane is oxidized by 1949, in the presence of FeCb and the Fe "-picolinate complex, to give cyclohexanone and cyclohexanol [166] whereas with FeCl2 1-chlorocyclohexane is the mayor product, with cyclohexanone and a small amount of cyclohexanol [167] (Scheme 12.47). 

The success of dibekacin prompted worldwide attention to the removal of selected OH groups in aminoglycoside antibiotics susceptible to modification by resistant bacteria, and the chemical deoxygenation procedure of D. H. R. Barton was found particularly useful. 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

IChemE acknowledges that there is no standard procedure for evaluating chemical reaction hazards (Barton and Rogers, 1997 p. 120). The CSB survey further highlights the variety of approaches to reactive hazard evaluation companies rely to varying degrees on quantitative and qualitative evaluation methods. 

Both IChemE (Barton and Rogers, 1997 p. 137) and HSE (2000 p. 42) briefly address operator training in systems that involve reactive hazards. None of the guidelines, however, address the transfer and communication of this information to technical personnel. There is little guidance on integrating reactive hazard information into operating procedures, training, and communication practices. 

Caution Barton esters are light sensitive therefore all procedures should be carried out in the absence of light. 

The reduction of thiocarbonyl derivatives by EtsSiH can be described as a chain process under forced conditions (Reaction 4.50) [89,90]. Indeed, in Reaction (4.51) for example, the reduction of phenyl thiocarbonate in EtsSiD as the solvent needed 1 equiv of dibenzoyl peroxide as initiator at 110 °C, and afforded the desired product in 91 % yield, where the deuterium incorporation was only 48% [90]. Nevertheless, there are some interesting applications for these less reactive silanes in radical chain reactions. For example, this method was used as an efficient deoxygenation step (Reaction 4.52) in the synthesis of 4,4-difluoroglutamine [91]. 1,2-Diols can also be transformed into olefins using the Barton-McCombie methodology. Reaction (4.53) shows the olefination procedure of a bis-xanthate using EtsSiH [89]. 

Another stereospecific synthesis of2-deoxy-DL-en/tfiro-pentose was based10 on cis-l-(tetrahydropyran-2-yloxy)-2-penten-5-ol (156) as the substrate. cts-Hydroxylation of 156, followed by oxidation of the unprotected, primary hydroxyl group to an aldehyde group according to Barton s procedure, yielded the desired sugar 2 in low yield. 

More recently, radical additions to fluoroethenes have attracted attention. Eguchi et al. [125] applied the Barton decarboxylation procedure to add a range of alkyl radicals to l,l-dichloro-2,2-difluoroethene. Addition was regioselective and the terminal carbon could be hydrolysed to a carboxyl group with silver(I) mediation (Eq. 39). The fluoroalkene is effectively an equivalent for either difluoroacetyl anion or cation synthons, because the adding radical can be approached from either polarity manifold. 

This procedure Illustrates a simple, general method for the rieoxygenation of secondary hydroxyl groups. It is particularly useful for reducing hindered alcohols. The method was first described hy Barton and McCombie who have reviewed a number of other examples. ... 

Scheme 44 summarizes an addition reaction by the Barton method. Thiohydroxamate esters (32) are readily prepared and isolated, but, more typically, they are generated in situ. Experimental procedures have been described in detail148151 and often entail the slow addition of an acid chloride to a refluxing chlorobenzene solution of the readily available sodium salt (31), dimethylaminopyridine (DMAP, to catalyze the esterification), and excess alkene. The products are usually isolated by standard aqueous work-up and chromatographic purification. 

Loss of a carbon atom from the precursor need not always result. Barton and Crich have introduced a related procedure based on the chemistry of mixed oxalates, an example of which is provided in Scheme 49.159 Double decarboxylation is involved in the decomposition of oxalate precursors, such as (39). Unfortunately, there are indications that this method may to be limited to tertiary alcohols one secondary alcohol derived mixed oxylate did not fragment completely to the alkyl radical. 

In 1983, Barton et al. described a new procedure for the oxidation of saturated hydrocarbons [1] by the use of metallic iron, adamantane, hydrogen sulfide or sodium sulfide, pyridine, acetic acid and a small amount of water. The reactions were run under air and afforded adamant-l-ol together with a mixture of adamant-2-ol and adamantanone. The substrate scope could be extended to other hydrocarbons. However, all of them led to product mixtures of the corresponding alcohol(s) and ketone (Scheme 3.1). 

---