Thiocarbonates deoxygenation

Nitro-aldols, which are readily available (see Henry reaction Section 3.1), are converted into olefins via conversion of the hydroxyl group to the corresponding phenyl thiocarbonate ester and treatment with tin radical.158 The yield was not reported. Because the radical deoxygenation via thiocarbonate (Barton reaction) proceeds in good yield, the elimination of Eq. 7.115 might be good choice for olefin synthesis.159... 

A fused OZT was obtained in the course of the reduction of vicinal azido-thiocarbonates via formation of the intermediate amine, which attacks the thiocarbonyl group (Scheme 37). The condensation reaction proved faster than the deoxygenation process for the synthesis of 2 -amino-2, 3 -dideoxyuridine50 or methyl 3-amino-4,6-0-benzylidene-3-deoxy-2-0-phenoxythiocarbonyl-a-L-talopyranoside.51... 

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]. 

The alcohol derivatives that have been successfully deoxygenated include thiocarbonates and xanthates.134 Peroxides can also be used as initiators.135 Dialkyl phosphites can also be used as hydrogen donors.136 (see Entry 4, Scheme 5.7)... 

Because vicinal dibromides are usually made by bromination of alkenes, their utility for synthesis is limited, except for temporary masking of a double bond. Much more frequently, it is desirable to convert a diol to an alkene. Several useful procedures have been developed. The reductive deoxygenation of diols via thiocarbonates was developed by Corey and co-workers.210 Triethyl phosphite is useful for many cases, but the more reactive reductant l,3-dimethyl-2-phenyl-l,3,2-diazaphosphohdine can be used when milder conditions are required.211 The reaction presumably occurs by initial P—S bonding... 

The A ring is closed by a Ti-mediated reductive coupling (step H-5). The C(ll)-C(12) double bond is introduced from the diol by deoxygenation of the thiocarbonate [step I-... 

Barton-McCombie deoxygenation is not always stereoselective the diastereo-meric ratios strongly depends on the nature of the protecting groups and of the ester moiety. However, in 2-C-trifluoromethyl-2-deoxyfuranose, the a compound is the major product of the reaction, due to steric hindrance of this a side. In 3-C-trifluoromethyl-3-deoxyfuranose, deoxygenation by tributyltin hydride yields only the a product, if it is performed with oxalate instead of thiocarbonate. Another possibility to obtain this selectivity is to perform the reaction with 1,2,5,6-di-O-isopropylidene-a-D-glucofuranose (Figure 6.34). ... 

Cyclic thiocarbonates offer another class of substrates for radical deoxygenation (Scheme 3.9b). In particular, thiocarbonates formed from a diol derived from a primary and secondary hydroxyl are of particular interest, since they can be deoxygenated regioselectively with tributyltin hydride and AIBN.53 In these cases, the secondary position is deoxygenated owing to the higher stability of secondary over primary radicals. As expected, radical reduction of thiocarbonates derived from two secondary hydroxyls leads to a mixture of deoxygenated isomers.52b 53... 

Radical deoxygenation of alcohols is important, and the reduction of xanthates prepared from alcohols, with Bu3SnH in the presence of AIBN is called the Barton-McCombie reaction (eq. 2.13) [37-51]. The driving force for the reaction is the formation of a strong C=0 bond from the C=S bond, approximately 10 kcal/mol stronger. This reaction can be used for various types of substrates such as nucleosides and sugars. Though methyl xanthates, prepared from alcohols with carbon disulfide and methyl iodide under basic conditions are very frequently used, other thiocarbonates, as shown in eq. 2.14, can also be employed. 

Deoxygenative reduction can be carried out at room temperature with Et3B as an initiator [19,20]. However, this reaction is limited to thiocarbonates derived from sec- and tert-alcohols, since the C-0 bond cleavage of thiocarbonates derived from pr/m-alcohols does not occur easily at room temperature. 

There are a number of reactions of C02 with metal complexes in which prior coordination is likely. For example, the anion W(CO)5OH reacts with C02, COS, or CS2 to give the corresponding bicarbonate or thiocarbonate complexes.104 With complexes of oxophilic metals like Ti or Zr, deoxygenation to CO may occur while in others disproportionation to give CO and C03 occurs an example of the latter reaction is... 

Monodeoxygenation of 1,2- and 1,3-diols was achieved via their cyclic thiocarbonates, prepared from the diol and A/,A/ -thiocarbonyldiimidazole, by reaction with BusSnH-AIBN followed by alkaline hydrolysis (presumably, F would also be effective for the cleavage step). Equation (14) shows this process applied to synthesis of a derivative (73) of 5-deoxyglucose. Exclusive secondary deoxygenation is expected on the basis of radical stability in contrast, the derivative (72) was readily converted by an ionic process to an intermediate suitable for 6-deoxygenadon, since treatment with KI gave (74) quantitatively. 

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. 

Xanthates and also thiocarbonates are useful for deoxygenation of an alcohol moiety. " The reaction, called the Barton-McCombie deoxygenation, involves treatment of the derived xanthate or thiocarbonate with n-BugSnH in the presence of an initiator such as AIBN, as shown below. 

Deoxygenation of alcohols. Thiocarbonate derivatives of alcohols are con veniently reduced to alkanes by potassium and 18-crown-6 in /-butylamine. 

L-Threonate 289 obtained from 3 was converted to thiocarbonate 290, which, on deoxygenation with BujSnH/AlBN, gave dihydroxybutanoate 291 (Scheme 59). Treatment of 291 with aqueous H2SO4 in tetrahydrofuran gave lactone 293, while reduction of 291 with Li AIH4 gave butanetriol 292 (88S226). 

Eliminations. Thionocarbonates derived from 1,2-diols are transformed into iodo thiocarbonates with RI, which decompose into alkenes on treatment with RLi. The three-step process represents a reductive deoxygenation. 

Careful studies by Chen revealed that deoxygenation of baccatin derivatives at C-2 can be accompanied by free-radical rearrangement reactions. As examples the cyclic 1,2-thiocarbonate 3.4.20 gave both a simple A-nor product 3.4.21 and the more complex rearrangement product 3.4.22 (124). Deoxygenation of the 10-acetoxy analog of 3.4.20 only gave A-nor product. 

The epoxide 4.2.1.2 proved resistant to nucleophilic attack, but the diol 4.2.1.1 could be converted into a number of new analogs. These included simple analogs such as various C-6 acyl derivatives 4.2.1.4 (167) but also various derivatives produced by deoxygenation at C-7. Thus diol 4.2.1.1 could be protected as its 2 -(triethylsilyl)ether, converted to its cyclic 6,7-a-thiocarbonate, and deoxygenated to the 7-deoxyanalog 4.2.I.5. Analog 4.2.1.5 can be oxidized to the ketone 4.2.1.6, which can then be reduced to the /5-alcohol 4.2.1.7 (176). Both compounds 4.2.1.5 and 4.2.1.7 were as active as taxol in a tubulin-assembly assay, but were 4 and 10 times less potent than taxol in a cytotoxicity assay with the HCT-116 human colon tumor cell line (176). 

The A ring is closed by a Ti-mediated reductive coupling (step H-5). The C(11)-C(12) double bond is introduced from the diol by deoxygenation of the thiocarbonate [step I-(1,2)]. The final sequence for conversion of the product from steps 1-1-8 to baccatin III begins with a copper-mediated allylic oxidation and also involves an allylic rearrangement of the halide. The exocyclic double bond was then used to introduce the final oxygens needed to perform the oxetane ring closure. 

The preparation of the CD building block was continued as follows. After reductive opening of the epoxide 91 with sodium cyanoborohydride, the resulting diol was converted into the bis-acetyl ester 92. Selective hydrolysis of the less sterically hindered ester was followed by conversion of the unprotected alcohol into the thiocarbonate. After deoxygenation via a Barton-McCombie reaction, the ensuing product 93 is set up for deprotection and oxidation to a key chiral CD intermediate for vitamin D synthesis. 

Additionally, the reduction process of Barton and McCombie has been developed into a useful technology. The Barton-McCombie procedure (Scheme 8.22) involves the conversion of an alcohol to a thiocarbonate (or dithiocarbonate) derivative (usually in two steps) and the reaction of the latter with tributyltin hydride and azobisisobutyronitrile (AIBN) (bis(l-cyano-l-methylethyl)diazine, [(CH3)2C(CN)N=NC(CN)C(CH3)2]). As shown in Scheme 8.22, decomposition of AIBN produces a radical, which, in turn, abstracts hydrogen from tributyltin hydride, generating the tributyltin radical. The reaction of the latter with sulfur and the subsequent decomposition of that intermediate produces a deoxygenated. 

A new mild reaction for the deoxygenation of secondary alcohols has been applied successfully to sugars the reaction, which is radical in character, involves the reduction of a thiobenzoate with tributylstannane (see Scheme 25). Other references to the use of thioesters and the photochemical transformation of dithiobis(thioformates) into thiols are reported in Chapter II, the reaction of cyclic thiocarbonates with methyl iodide to give tu-iodo-iS-methyl thiocarbonates... 

New methods have been reported for the deoxygenation of carbohydrate derivatives. One such procedure reported by Barton s group has been noted in Chapter 6 (see Scheme 25). This group has also shown that ring-opening reactions of diol thiocarbonates can be usefully applied to the synthesis of 6-deoxy-sugars (Scheme 75) 374 Thus, the diol thiocarbonate (201) was transformed into the iodo-thio-... 

Product distribution is highly dependant on the substitution pattern on the radical center of 11. For cyclic thiocarbonate 15 containing primary and secondary centers, fragmentation gives the more stable 2° radical intermediate, thus generating 16 as the sole product. For cyclic carbonate 17 with two secondary centers, a mixture of two regiomeric deoxygenated products 18 and 19 is obtained. ... 

Robins later introduced the (phenoxy)thiocarbonate 24 as a more reactive derivative for deoxygenation of secondary centers. Subsequently, Barton and Jaszberenyi showed that introduction of electron-withdrawing groups on the phenyl ring increased the speed of the desired fragmentation. In particular, use of the 2,4,6-trichlorophenoxy (25) or perfluorophenoxy (26) derivatives allowed reduction to proceed within 15 minutes in an AIBN/BusSnH system at 110 °C. In addition to the simpler procedure for preparation of these thionocarbonate derivatives and their deoxygenation, the formation of side products for the latter step was minimized. 

---