Prolinol reaction

Recently, Pal et al. found that (.S )-prolinol could facilitate the coupling reaction of terminal alkynes with 3-iodoflavone under palladium-copper catalysis in aqueous DMF to give 3-alkynyl substituted flavones of potential biological interest (Eq. 4.17). The coupling of iodobenzene with terminal alkynes at room temperature in water without any cosolvent was completed within 30 minutes, affording the desired product in good yield.36... 

Pal et al. explored an efficient Pd/C-catalyzed reaction of 2-iodophenols with terminal alkynes in water without the use of any organic cosolvents in the presence of PPh3, Cul, and prolinol to give the expected benzofuran products (Eqs. 4.42, 4.43).78 The hydroxyl group was well tolerated during reactions. When used as a base, prolinol afforded better yields of products than triethylamine, a common organic base, possibly due to its better miscibility with water. 

Synthesis of 1,3,2 oxazaphospholidines 128a-c derived from (S)-prolinol 127 was based either on the thermal aminoalcoholysis of the latter with prochiral alkyl(aryl) phosphonousdiamides 51a-c or its condensation reaction with /-butylphosphonous dichloride carried out in the presence of triethylamine (Scheme 37) [68], The diastereomeric excesses of the prepared derivatives ranged from 80 to 95%. 

An exploration of structural modifications on the activity of prolinol catalysts has been published <06T12264>. More electron-rich aromatic rings on the prolinol scaffold improve the activity in the epoxidation of a, 3-enones. The reaction of 10 with an enone and f-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. 

In this reaction, prolinol serves as a chiral auxiliary, but it cannot be easily... 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Tetrahydropyrrolo[l,4]oxazine 74, obtained by photoinduced electron-transfer (PET) oxidative activation of substituted prolinol, undergoes nucleophilic substitution of the OH at position C-3 with allyltrimethylsilane in the presence of TiCU (Scheme 8). The reaction was highly stereoselective and produced, after hydrolysis of the resultant amide 75, optically active a-hydroxy acid 76 together with the auxiliary (.S )-prolinol that can be effectively recycled <1998TL7153>. 

The reaction of prolinol with 3-bromo-5-ethyl-2-isopropylthiophene-l,1-dioxide... 

Borane reduction catalyzed by chiral oxazaborolidines (CBS reduction, CBS = Corey, Bakshi, and Shibata) exhibits excellent enantio- and chemoselectiv-ity for a wide variety of ketonic substrates (Figure 1.27). This reaction was originally developed as a stoichiometric system consisting of diphenylvalinol and borane, ° but was later extended to a useful catalytic method. Because of the high efficiency of this reaction, many chiral oxazaborolidines have been synthesized from p-amino alcohols.Among them the prolinol-derived oxazaboro-lidine is one of the most widely used catalysts. ... 

Prolinol derived catalyst 30 has also been used in the [3+2] cycloaddition of nitrones with a,P-unsaturated aldehydes (Scheme 10) [69]. Importantly, the reactions proceed at room temperature in just 24 h, showing excellent levels of cata-lystactivity, withuniformly high endo exo ratios (11.5 1-99 1) andenantioselectivity... 

The alkylated pyrrolo[l,2-c]oxazolone 5, obtained from the reaction with 3-bromocyclohexene, can be converted to the trans-prolinol derivative 6 by treatment with lithium aluminum hydride in tetrahydrofuran at reflux temperature, then further reduced with palladium on charcoal to provide the cyclohexane derivative 7. 

The combined Birch reduction alkylation of chiral, enantiomerically pure aroyl amides of 2-pyrrolidinemethanol (prolinol) or 2-pyrrolidinecarboxylic acid (proline) gives chiral, non-racemic, 1,1-disubstituted 2,5-cyclohexadienes 1 or 2-cyclohexenes 2, respectively, in high diastereomeric ratios. These reactions are useful for the preparation of valuable chiral synthetic intermediates 3 25 29-31-36. 

Then it was alkylated with iodide (168) in the presence of HMPA. Finally the reaction was quenched to produce (169) in 46% yield with 96.6% diastereomeric purity. The amide (169) was hydrolyzed to produce (R)-(170) with 93% e.e. In the same manner, by alkylating (R)-prolinol propionamide with (168), the amide (169 ) was obtained. Acid hydrolysis of (169 ) produced (S)-( 170) with 92% e.e. 

Some diastereoselectivity was also observed in the reaction of (S)-prolinol with the dichloride (257) leading to the chiral organophosphorus compounds (258). 

Attempts to use the lithium enolates of the prolinol amides in the aldol condensation were unrewarding, for these reactions proved stereorandom. On protecting the hydroxyl... 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

The synthesis of 1 starts with the reaction of dichloro(dimethylamino)borane with the Grignard reagent from 2,5-dibromohexane, and includes a resolution with (S)-prolinol. 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

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