Regioselectivity epoxide reduction

Being aware of the very high oxophiUcity of boron reagents, one is not surprised to find these also at work in regioselective epoxide reduction [28]. 

Give an explanation of the regioselectivity obtained in the epoxide reduction of step k. 

Give reasons for the regioselectivity observed in the epoxide reduction step u. 

Regioselectivity of C—C double bond formation can also be achieved in the reductiv or oxidative elimination of two functional groups from adjacent carbon atoms. Well estab llshed methods in synthesis include the reductive cleavage of cyclic thionocarbonates derivec from glycols (E.J. Corey, 1968 C W. Hartmann, 1972), the reduction of epoxides with Zn/Nal or of dihalides with metals, organometallic compounds, or Nal/acetone (seep.lS6f), and the oxidative decarboxylation of 1,2-dicarboxylic acids (C.A. Grob, 1958 S. Masamune, 1966 R.A. Sheldon, 1972) or their r-butyl peresters (E.N. Cain, 1969). 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

Reagents of choice for reduction of epoxides to alcohols are hydrides and complex hydrides. A general rule of regioselectivity is that the nucleophilic complex hydrides such as lithium aluminum hydride approach the oxide from the less hindered side [511, 653], thus giving more substituted alcohols. In contrast, hydrides of electrophilic nature such as alanes (prepared in situ from lithium aluminum hydride and aluminum halides) [653, 654, 655] or boranes, especially in the presence of boron trifluoride, open the ring in the opposite direction and give predominantly less substituted alcohols [656, 657,658]. As far as stereoselectivity is concerned, lithium aluminum hydride yields trans products [511] whereas electrophilic hydrides predominantly cis products... 

The third method makes use of the one-flask procedure, which is advantageous from the preparative point of view. However, opening of certain stereoisomeric epoxides (263) with selenophenol suffers from low regioselectivity, resulting in a low yield of the final product. The other disadvantage is the basic reaction-medium occasioned by the method used for the generation of selenophenol, namely reduction of diphenyl diselenide with sodium borohydride in solution in anhydrous alcohol (see Ref. 356) some epoxides are sensitive to basic media. However, David (see Ref. 356) did not observe side reactions in his syntheses of 256. 

Cyclic enol ethers such as 8 are also easily epoxidized. R. Daniel Little of the University of California, Santa Barbara has found (J. Org. Chem. 2005, 70, 5249) that such an epoxide is reduced with Tifffl) regioselectively to the radical, that adds with remarkable diastereocontrol to enones such as 7 to give the adduct 9. Reductive cyclization converted 9 to the tricyclic ether 10. The C-Br bond of 10 was stable both to the Et,SiH conditions, and to the free radical removal of the xanthate derived from the alcohol. 

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