Carbinols stereoselective synthesis with

Raddeanamine (360) is an unusual spirobenzylisoquinoline alkaloid having a tertiary methyl group in five-membered ring. Methylation of the corresponding ketone gave the methyl carbinol with the reverse stereochemistry, namely, the methyl carbinol 361 was obtained from the reaction of the ketone 294 with methyllithium (Scheme 64). Stereoselective synthesis of ( )-raddeanamine was accomplished by an intramolecular oxyfunctionalization via the 8-methyl-8,14-cycloberbine 364 (175). 

Julia and co-workers (87, 88) have developed a novel synthesis of homoallyl-ic bromides by rearrangement of cyclopropyl carbinols on treatment with hydrobromic acid. For instance, the secondary cyclopropyl carbinols 301 have been converted into trans-bromo olefins 302 with 90-95% stereoselectivity. 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

Stereoselective synthesis of oxathiane tertiary carbinols (8, 508-509). This reagent is now preferred over the isomeric 4,6,6-trimcthyl-l,3-oxathiane (8, 508-509) for a two-step, highly stereoselective synthesis of oxathiane tertiary carbinols (3, equation I), which can be cleaved to enantiomerically pure tertiary a-hydroxy aldehydes. The first step, acylation with retention of configuration, gives the more stable equatorial adduct 2... 

Synthesis of P-Keto Sulfoxides. Optically active p-keto sulfoxides are very useful building blocks (eq 4) because they can be stereoselectively reduced to afford either diastereomer of the corresponding p-hydroxy sulfoxide under appropriate conditions (Diisobutylaluminum Hydride or Zinc ChloridefDlBALf and thus give access to a wide variety of compounds chiral carbinols by desulfurization with Raney Nickel or LithiumJethyhmme ini the case of allylic alcohols epoxides via cyclization of the derived sulfonium salt butenolides by alkylation of the hydroxy sulfoxide 1,2-diols via a Pummerer rearrangement followed by reduction of the intermediate. ... 

Surprisingly, the introduction of the pyridine ring not only influences the velocity of the enzymatic transformations, but also induces promising stereochemical effects (Table 1). For instance, at 40% conversion (R)-phenylethanol is obtained from the pyridyl acetate 25 with 73 % ee, whereas the value for the corresponding phenylacetate is only 28%. Also, the secondary alcohol liberated from the ester 26 displays 98% ee at 40% conversion, whereas the respective phenylacetate leads to 1-phenylpropanol with 94% ee but at a conversion rate of 12% only [19,20]. These results demonstrate that the stereoselecting properties of penicillin acylase may be enhanced by appropriate engineering of the substrate. This is of particular interest since this enzyme has already been used for the kinetic resolution of various chiral alcohols [21-24], e.g. furyl alkyl carbinols [24], which are valuable precursors for the de novo synthesis, with moderate to high ee values, of carbohydrates. 

Johnson3 wished to apply this rearrangement in one step of a stereoselective synthesis of (ran.v-trisubstituted double bonds but encountered some undesired isomerization due to the strongly acidic conditions. Anhydrous zinc bromide in ether was then found more satisfactory. Thus the carbinol (1) was treated with phosphorus tribromide in the presence of collidine to give a mixture of bromides (2) and (3). 

MAD and MAT have played a crucial role in the stereoselective synthesis of hitherto inaccessible equatorial carbinols from cyclohexanones and primary allyl Grignard reagents or methyllithium [44). In the reaction of cyclohexanone derivatives with tert-butylmagnesium chloride, reduction takes precedence over alkylation in the presence of MAD (Scheme 6.37) [45). 

Phenyl trifluoromethyl ketone has been used as a standard for comparing stereoselectivities in Meerwein-Ponndorf-type reductions with chiral alkoxyalu-minium and magnesium halides derived from monoterpenoid alcohols, and (24) is one of the few to show high selectivity (77% enantiomer excess). The alkylative addition of butyl-lithium to aldehydes in chiral media has been studied as part of a general programme to develop auxiliaries, based on tartaric acid, for asymmetric synthesis. Optical yields of up to 40% in the butyl carbinol products are obtained at low temperature in solutions containing chiral 1,2-dihetero-ethane derivatives such as (25), which are believed to complex the alkyl-lithium as in (26). 

In 1982, Solladi reported a highly efficient, asymmetric synthesis of both enantiomers of methyl carbinols based on the stereoselective reduction of an enantiomerically pure P-ketosulfoxide [1], Prior to this work, only low to moderate levels of enantiomeric purity had been observed by Cinquini [2] and Johnson [3] in similar studies. The P-ketosulfoxides used in Solladie s study were prepared by condensation of the a-sulfinyl carbanion of (J )-methyl p-tolyl sulfoxide with esters (Scheme 4.1). 

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