Chiral tertiary alcohols

Dosa and Fu reported the first catalytic enantioselective phenyl transfer reaction to ketones (equation 25)100. In the presence of 1.5 equivalents of MeOH, the chiral tertiary alcohol was produced in good yield and with high enantioselectivity. Walsh and workers recently reported the Ti(OE -i Vchiral dihydroxybis(sulfonamide) catalyst 34 system, whereby enones have been converted to enantioenriched allyl alcohols101. 

Interestingly, this substitution reaction can be applied to the stereoselective assembly of chiral quaternary centers and has been extended to the preparation of chiral tertiary alcohols via a stereoselective Baeyer-Villiger rearrangement, and chiral tertiary amines via a stereoselective Curtius rearrangement (Scheme 15)130>130a... 

The chiral tertiary alcohol (/ )-3-methyl-3-hexanol reacts with HBr by an SnI pathway. HBr protonates the hydroxyl group, which dissociates to yield a planar, achiral carbocation. Reaction with the nucleophilic bromide anion can occur from either side of the carbocation to produce ( )3-bromo-3-methylhexane. 

This reaction was extended to a synthesis of a chiral tertiary alcohol in 72% ee from the corresponding chiral ketal. 

Compared to the well-developed organozinc addition to aldehydes, the related addition to ketones has been far less studied. However, the first catalytic addition of diaUcylzinc to ketones has been achieved few years ago using camphorsulfonamide alcohols ligands and Ti(0-(-Pr)4 salt (equation 66). In the same year, it was also discovered that 15 mol % of (-l-)-DAIB catalyze the diphenylzinc addition to ketones to generate chiral (see Chiral) tertiary alcohols with up to 91% e.e. (equation 67). 

Cyclopropylcarbinols are prepared from dicyclopropylzinc, and t)ie use of mixed diorganozincs such as MejSiCHjZnEt for the addition has also been explored. Chiral tertiary alcohols are obtained from organozinc addition to ketones in the presence of functionalized isobomeols. (15,2/f)-2-(A -piperidinyl)-l-phenylpropane-l-thiol acetate is a ligand prepared from (+)-norephedrine ° and it catalyzes asymmetric addition of diethylzinc to aldehydes very effectively. 

Another slightly different approach to diastereoselective radical cyclizations uses group transfer methodology in order to access chiral tertiary alcohol moieties commonly found in natural products (Eq. (13.35)) f47J. The reaction occurs anti to the bulky r-butyl group, resulting in the formation of the major product 112. 

Asymmetric Synthesis of Chiral Tertiary Alcohols in High Enantiomeric Excess... 

The synthesis of chiral tertiary alcohols by addition of Grignard reagents to glycosulose derivatives has been reviewed. The reaction of 1,2 5,6-di-O-iso-propylidene-Q -D-nZ>o-hexos-3-ulose (2) with Grignard reagents affords better yields of the c//o-adduct (3) when conducted at —30 C in the presence of anhydrous magnesium bromide. ... 

Aromatic a-keto esters (38) have been also used as electrophilic partner in this transformation. Thus, catalyst mt-60c (15 mol%) combined with acetic acid (150 mol%) allowed the reaction between acetone (3a, 27.3 equiv.) and several a-keto esters affording the corresponding chiral tertiary alcohols (70) in good results. When other ketones such as cyclohexanone, 3-pentanone or 2-butanone were used, the products were obtained albeit in low yields [132]. 

Most reports in the field of organocatalytic, direct, asymmetric aldol reactions involve aldehydes as acceptors. Reactions where ketones act as electrophiles have been less explored, though they may provide efficient access to chiral tertiary alcohols. 

Fig. 3 Examples of marketed drugs and biologically active compounds bearing chiral tertiary alcohols...

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