Diphenylprolinol synthesis

The methods reported for the preparation of the oxazaborolidine include the reaction of diphenylprolinol with methylboronic acid 1) in toluene at 23°C for 1.5 hr with 4 A molecular sieves present and 2) in toluene at reflux for 3 hr using a Dean-Stark trap, bolh followed by evaporation of solvent and molecular distillation (0.1 mm, 170°C).5( An alternate method involved heating a toluene solution of 2-naphthylprolinol and methylboronic acid at reflux for 10 hr using a Soxhlet extractor containing 4 A molecular sieves.5 These methods afforded erratic results. The submitters therefore developed an alternate synthesis. 

Hayashi and co-workers took advantage of the organocatalyzed reaction for the stereoselective synthesis of the cyclohexane structure. Diphenylprolinol silyl ether ent-6a proved to be effective for the domino Michael reaction/Horne-Wardsworth-Emmons reaction. They synthesized (-)-oseltamivir by three one-pot operations, with a total yield of 57% (Scheme 10.4) [38]. 

The (S)-diphenylprolinol-derived oxazabotohdine with an ethanediolated boron atom is a new catalyst for the as3fmmetric reduction of ketones with BH3 SMe2- 1,3-Cyclo-alkanediones undergo CBS-reduction to provide (3if)-hydroxycycloalkanones. Based on this method a very short synthesis of chiral estrone methyl ether is completed. ... 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

L-Prohne catalyzes the direct hydroxymethylation of aldehydes and ketones, though with low yields [116]. Higher yields and enantioselectivities are generated by a,a-diphenylprolinol trimethylsilyl ether [117]. The desired a-substituted P-hydroxymethylated products are not stable and have to be converted to more readily isolable derivatives. This method should be the first choice for synthesis of a-hydroxymethylated aldehydes since it is suitable for large scales (75.8 g of aldol). 

Nitroethanol was recently employed as C/O bis-nucleophile by Hayashi and coworkers [38] for the synthesis of optically active functionalized tetrahydropyrans by reaction with enals using diphenylprolinol silyl ether as the organocatalyst (Scheme 16.18). The diastereoselectivity of the Michael/acetalization sequence was improved by isomerization to the thermodynamically more stable trans isomers upon basic treatment. 

The scope of organocatalyzed cycloaddition reactions was also extended to different syntheses of pyrrolidine derivatives. In this direction, Cdrdova and coworkers explored the combination of diphenylprolinol 76 and simple oxime cocatalyst 77 to promote the synthesis of functionalized proline derivatives bearing four contiguous stereocenters where one is an all-carbon quaternary one (Scheme 2.21) [47]. The success of the transformation relies on a cooperative combination of iminium and H bond activation to afford chemo- and stereoselective [3 + 2] cycloaddition under kinetic control. The reaction proceeds... 

Another example to illustrate the synthesis of proline derivatives 78 was published by Vicario and coworkers in 2013 [48]. Starting from aromatic aldehydes, diethyl malonate, and a,p-unsaturated aldehydes upon catalysis of unprotected diphenylprolinol, the synthesis of polysubstituted pyrrolidines was achieved in a one-pot condensation and [3+2] cycloaddition reaction in aqueous medium. 

Likewise, the application of a similar protocol to unsaturated pyrazolones 149 allowed Rios and coworkers to accomplish the synthesis of several spiropyrazolones 150 bearing four chiral centers (Scheme 2.44) [74]. The proposed Michael/ Michael/aldol reaction resulted to be quite efificient in terms of both yields (up to 65%) and stereoselectivity (dr up to >25 1, ee up to >99%) when the (S)-a,a-diphenylprolinol 70 was employed as catalyst together with benzoic acid as additive. 

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