Dithioesters reduction

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

Scheme 11. Bis(oxepane) synthesis using a photochemical dithioester cyclization and a reductive hydroxy ketone cyclization.

The conversion of dithioesters into aldehydes is also easily realized through reduction to a mixed dithioacetal by tributyltin hydride [264]. 

The reduction of the dithioester group to a thiomethyl group has been achieved by sodium borohydride in acetonitrile at reflux [156, 157], offering an easy synthesis of thiomethyl phosphonates. Milder conditions or use of BMS provided the hemithioacetals. 

Dithioesters can be reduced in anhydrous acetonitrileor in methanol,the best results being obtained with dimethyl sulfate as alkylating agent. The most convenient procedure involves a simple electrolysis cell with a lead cathode and methanol as solvent. Eight substrates (68 X = SMe) were tested, with R equal to phenyl, chloro- and methoxy-substituted phenyls, and f-butyl. Unlike the corresponding reductions of thioamides, the reactions were not entirely clean and gave substantial amounts of side products such as (70). The product dithioacetals (69 X = SMe, R = Me) were formed in yields of 40-60%. On two of the substrates, better yields (ca. 70%) could be obtained in anhydrous acetonitrile, but a more sophisticated apparatus was required. One enolizable substrate (71) was tested, but the yield was only 30%. ... 

Dithioesters (54b) undergo the Clemmensen reduction with desulfuration, so that the thiono group is converted into the methylene group (Scheme 36). 

Ketones with useful heteroatomic functional groups containing nitrogen 199 2121, oxygen[163, 213 2171, phosphorus12181 and sulfur11 4, 18+1 219-2271 have been reduced by biocatalysts. For example, an intermediate in the synthesis of p-lactam antibiotics was obtained by microbial reduction of a P-keto ester as shown in Fig. 5-39(a)(1991, while yeast reduction of a p-keto dithioester afforded an easily separable mixture of p-hydroxy-dithioesters, the major component of which was converted enantiose-lectively into a sex attractant of the pine saw-fly as shown in Fig. 15-39(b)12191. 

If the corresponding thio- and dithioesters are used, highly selective reductions by baker s yeast are achieved143. 

Alternatively, Whittaker et al. utilized the reversible oxidation/reduction of a thiol-terminated linear polymer as a homocoupling reaction to access macrocycles that could be reversibly cyclized and cleaved (Scheme 12.5) [29]. The linear precursors were prepared using reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene from a bifunctional initiator (16). The desired polystyrene with thiol end groups could be isolated in near-quantitative yields by aminolysis of the polymer with terminal dithioester groups (17). The linear dithiols... 

The PEO-based macroinitiator (PDI = 1.05 1.10) LMI-7 can then be used to polymerize a variety of vinyl monomers, such as St, to give amphiphilic block copolymers of type LMB-8, which have accurately controlled molecular weight and very low polydispersity, 1.05-1.10 (Scheme 3.16) [84]. Compared to typical small molecule initiators, generally it is found that using a macroinitiator gives extremely low polydispersities because diffusion and reactivity of the macroinitiator are decreased, leading to the reduction in radical terminations and a more controlled polymerization. This phenomenon is also observed for the RAFT process. For example, the acid functional dithioester LMI-9 can be... 

Transient Species.— Treatment of carbonyl compounds with hydrogen sulphide under pressure in the presence of molybdenum sulphide leads to reduction, and involves the formation of thioketonic intermediates. Aliphatic thioketones and a )8-unsaturated thioketone (27) are proposed as intermediates in the reaction of Grignard reagents with various dithioesters. A mechanistic... 

---